2 Comments

7 PAIN OR SWELLING OF JOINTS

7 PAIN OR SWELLING OF JOINTS
Harrison’s Manual of Medicine

7

PAIN OR SWELLING OF JOINTS

Goals for the Initial Assessment of a Musculoskeletal Complaint
Historic Features
Physical Examination
Laboratory Investigations
Diagnostic Imaging
Special Considerations in the Elderly Patient
Bibliography

Musculoskeletal complaints are extremely common in outpatient medical practice and are among the leading causes of disability and absenteeism from work. Pain in the joints must be evaluated in a uniform, thorough, and logical fashion to ensure the best chance of accurate diagnosis and to plan appropriate follow- up testing and therapy. Joint pain and swelling may be manifestations of disorders affecting primarily the musculoskeletal system or may reflect systemic disease.
Goals for the Initial Assessment of a Musculoskeletal Complaint (See Fig. 7-1)

FIGURE 7-1. Algorithm for the diagnosis of musculoskeletal complaints. An approach to formulating a differential diagnosis (shown in italics). (ESR, erythrocyte sedimentation rate; CRP, C-reactive protein, DIP, distal interphalangeal; CMC, carpometacarpal; PIP, proximal interphalangeal; MCP, metacarpophalangeal; MTP, metatarsophalangeal; PMR, polymyalgia rheumatica; SLE, systemic lupus erythematosus; JA, juvenile arthritis.)

1.
Articular versus nonarticular. Is the pain located in a joint or in a periarticular structure such as soft tissue or muscle?

2.
Inflammatory versus noninflammatory. Inflammatory disease is suggested by local signs of inflammation (erythema, warmth, swelling), systemic features (morning stiffness, fatigue, fever, weight loss), or laboratory evidence of inflammation (thrombocytosis, elevated ESR or C-reactive protein).

3.
Acute (6 weeks or less) versus chronic.

4.
Localized versus systemic.
Historic Features

Age, sex, race, and family history.

Duration of symptoms: acute versus chronic.

Number and distribution of involved structures: monarticular (one joint), oligoarticular (2–3 joints), polyarticular (>3 joints); symmetry.

Other articular features: morning stiffness, effect of movement, features that improve/worsen Sx, migratory pain, Sx intermittent/continuous.

Extraarticular Sx: e.g., fever, rash, weight loss, visual change, dyspnea, diarrhea, dysuria, numbness, weakness.

Recent events: e.g., trauma, drug administration, travel, other illnesses.
Physical Examination
Complete examination is essential: particular attention to skin, mucous membranes, nails (may reveal characteristic pitting in psoriasis), eyes. Careful and thorough examination of involved and uninvolved joints and periarticular structures; this should proceed in an organized fashion from head to foot or from extremities inward toward axial skeleton; special attention should be paid to identifying the presence or absence of:

Warmth and/or erythema

Swelling

Synovial thickening

Subluxation, dislocation, joint deformity

Joint instability

Limitations to active and passive range of motion

Crepitus

Periarticular changes

Muscular changes including weakness, atrophy
Laboratory Investigations
Additional evaluation usually indicated for monarticular, traumatic, inflammatory, or chronic conditions or for conditions accompanied by neurologic changes or systemic manifestations.

For all evaluations: include CBC, ESR, or C-reactive protein.

Should be performed where there are suggestive clinical features: rheumatoid factor, ANA, ANCA, antistreptolysin O titer, Lyme antibodies.

Where systemic disease is present or suspected: renal/hepatic function tests, UA.

Uric acid—useful only when gout diagnosed and therapy contemplated.

CPK, aldolase—consider with muscle pain, weakness.

Synovial fluid aspiration and analysis: always indicated for acute monarthritis or when infectious or crystal-induced arthropathy is suspected. Should be examined for (1) appearance, viscosity; (2) cell count and differential (suspect septic joint if WBC count > 50,000/µL); (3) crystals using polarizing microscope; (4) Gram’s stain, cultures (Fig. 7-2).

FIGURE 7-2. Algorithmic approach to the use and interpretation of synovial fluid aspiration and analysis.

Diagnostic Imaging
Plain radiographs should be considered for

Trauma

Suspected chronic infection

Progressive disability

Monarticular involvement

Baseline assessment of a chronic process

When therapeutic alterations are considered
Additional imaging procedures, including ultrasound, radionuclide scintigraphy, CT, and MRI, may be helpful in selected clinical settings.
Special Considerations in the Elderly Patient
The evaluation of joint and musculoskeletal disorders in the elderly pt presents a special challenge given the frequently insidious onset and chronicity of disease in this age group, the confounding effect of other medical conditions, and the increased variability of many diagnostic tests in the geriatric population. Although virtually all musculoskeletal conditions may afflict the elderly, certain disorders are especially frequent. Special attention should be paid to identifying the potential rheumatic consequences of intercurrent medical conditions and therapies when evaluating the geriatric pt with musculoskeletal complaints.
Bibliography

For a more detailed discussion, see Cush JJ, Lipsky PE: Approach to Articular and Musculoskeletal Disorders, Chap. 320, p. 1994, in HPIM-15.

Leave a comment

Biosynthesis, and ,Cytoplasmic Trafficking, Membranes, Vesicles, and, Intracellular Transport

11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
11. Biosynthesis and Cytoplasmic
Trafficking:
Membranes, Vesicles and Intracellular Transport
I.  Transport Vesicles
A.  Assembly of Coats, Budding and Formation of Vesicles
Adaptors and receptors
Involvement of phosphatides
B.  Targeting of Proteins and Vesicles; SNAREs
C.  Fusion
NSF
SNAPs
D.  The GTPases
E.  ER and Golgi Transport
ER to Golgi Transport
Transport from Golgi Stacks
II.  Recognition of Targets
A.  Cell Polarity
Maintenance of polarity
Components of tight junctions
B.  Targeting of Plasma Membrane Proteins
C.  Targeting in Secretion and Transcytosis
D.  Transport of the Vesicles
E.  Recycling of the Plasma Membrane
F.  Formation of Lysosomes and Storage Vesicles
Lysosomes
Secretory storage granules
G.  Synaptic Vesicles
http://www.albany.edu/~abio304/text/chapter_11.html (1 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
Suggested Readings
References
Web Resources
Back to List of Chapters
Understanding the intricate details of the interactions between membranes and membrane bound
compartments is a challenging task. Electronmicroscopy using immunological methods together
with genetic approaches and molecular studies of reconstituted systems are beginning to provide the
needed framework of information. This chapter focuses on some of these processes.
I. TRANSPORT VESICLES
As we saw in Chapter 10, most intracellular transport is thought to be mediated by small vesicles,
although an alternative mechanism for the transfer from the VTCs to the cis-Golgi (see Chapter 10,
Section III) is likely and, in addition, transport between Golgi stacks may involve alternative
mechanisms (see Chapter 10, Section IIIC). The transport can occur in either direction: from the ER
to the periphery of the cell or in the opposite direction. The transport processes are discussed in
relation to endocytosis in Chapter 9, in relation to the motility of cell components in Chapter 23 and
the discussion of neuronal transport can be found in that Chapter and in Chapter 24.
Chapter 9 discussed the involvement of clathrin in the formation of endocytotic vesicles. Some other
transport vesicles are also clathrin-coated. They carry proteins originating from the trans-Golgi
system (see Brodsky, 1988). They include transport vesicles destined to the lysosomes (e.g., Schulze-Lohoff et al., 1985) containing acid hydrolases and mannose-6-phosphate receptors, and those
destined to storage vesicles containing densely packed secretory products (see Section II F, below).
Vesicles coated with proteins other than clathrin (non-clathrin coated) represent another set of
transport vesicles. These are involved in the translocations within the Golgi stack, between the ER
and the Golgi, from the TGN in the constitutive secretory pathway and in retrograde transport (e.g.,
from Golgi to ER)
The present conventional view maintains that non-clathrin coated vesicles are involved in the
transport between ER and Golgi and between Golgi stacks. The transport from the ER to the cis-Golgi is carried out by COPII vesicles (see Barlowe, 1998). In contrast, retrograde transport from
Golgi to ER takes place in coatomer protein (COPI) coated vesicles (Cosson and Letourneur, 1997;
Gaynor et al., 1998) for proteins either with KKXX, KKXX-like (see below) or the KDEL amino
acid motif (see Chapter 10) but not by glycosylated Golgi enzymes or Shiga toxin (Girod et al.,
1999). Forward and retrograde transport between Golgi stacks is also thought to be mediated by
COPI (Orci et al., 1997). In this latter case, electron microscope immunocytochemistry shows that
both anterograde-cargo and retrograde-cargo are present in separate COPI-coated vesicles budding
from all stacks of the Golgi. Packaging of anterograde and retrograde cargo into separate vesicles
can also be demonstrated in vitro even when budding is driven by highly purified coatomer and a
recombinant, small GTPase, ARF.
http://www.albany.edu/~abio304/text/chapter_11.html (2 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
All in all, at this time four different coat proteins are clearly defined, including two clathrin proteins
and COPI and COPII (listed in Table 1, Rothman and Wieland, 1996). In Table 1, the two different
clathrin coats are shown to function in conjunction with different adaptor molecules (see below). All
these coats are associated with GTP-binding proteins (or GTPases) (see below). Their origin and
initial destination are listed in the fourth column. Besides the four coat proteins listed in the Table,
more coat proteins have been demonstrated and others are likely to be revealed by further studies. A
lace-like coat has been described in the TGN (Ladinsky et al., 1994; Narula et al., 1995), a neuronal
variant of COPI has been found (Newman et al., 1995) and another is thought to be associated with
endosomal vesicle traffic (Whitney et al., 1995). A distinct coating for vesicles involved in
endosome-to-Golgi retrograde transport of sorting receptors is operative in yeast (Seaman et al.,
1998). The vesicles are slightly larger than the COPI vesicles. In Saccharomyces cerevisiae, a novel
vesicle 30-40 nm in diameter transferring fructose-1,6-bisphosphatase to the vacuole for
degradation, has been described (Huang and Chiang, 1997) . There is growing evidence for other
coat proteins similar to clathrin. A gene (HC22) has been identified with the potential of coding for
a protein similar to the clathrin heavy chain. mRNA corresponding to HC22 is expressed
predominantly in skeletal muscle and alternative transcripts of H22 are expressed in a tissue specific
fashion (see Brodsky, 1997).
Table 1. Coat proteins or vesicle shuttles (from Rothman and Wieland 1996, reproduced by
permission)
Type of coated
vesicle
Subunits of coat  GTPase  Origin-destination
AP-1 clathrin Clathrin, AP1
adaptor
ARF  TGN-prelysosomes
AP-2 clathrin Clathrin, AP2
adaptor
ARF?  Plasma membrane-endosomes
COPI Coatomer (COPI
proteins)
ARF  ER-Golgi;
bidirectional within
Golgi; Golgi-ER
COPII COPII proteins SAR  ER-Golgi
It is now recognized that the process of targeting and interaction between components occurs in
many steps starting from the translocation of vesicles to their target and ending with their fusion to
their target. The translocation of the vesicles (see Section IID and Chapter 24, section on
cytoplasmic dynein and kinesin) has not been elucidated in detail. Upon arrival processes involved
in membrane recognition (tethering) leaves the two sets of membranes at some distance from each
http://www.albany.edu/~abio304/text/chapter_11.html (3 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
other. The binding of SNAREs (docking) leaves the membranes in close proximity and is followed
by fusion. One kind of SNARE, SNAREv,resides on the surface of the vesicle being transported and
SNAREt resides on its membrane target (see Section C). Tethering is thought to be the primary step
in determining specificity. Rab GTP-binding proteins have been implicated as well (see Pfeffer,
1999; Novick and Zerial, 1997; Zerial and McBride, 2001). However, a variety of proteins and
protein complexes have been found to play essential roles in targeting and to be specific for
individual steps. Before fusion, priming events must take place (Klenchin and Martin, 2000) and a
fusion trigger, most frequently Ca2+, is needed (e.g., Heidelberger et al., 1994; Peters and Mayer,
1998; Beckers and Bach, 1989; Colombo et al., 1997). The priming includes ATP-dependent steps,
such as the NSF-mediated priming of SNARE protein complexes, the ATP-dependent synthesis of
phosphoinositides, and protein kinase-mediated protein phosphorylation. The protein munc 13 is
also involved in the priming.
The intracellular transport of proteins in vesicles raises a number of issues: (a) how the appropriate
proteins are selected in the formation of specific vesicles, (b) the nature of the mechanism of
budding, (c) how the vesicles are targeted unidirectionally and in an orderly fashion, and (d) the
mechanism of fusion of the targeted vesicles. Unfortunately, only partial answers are known.
The first issue, (a), was discussed in Chapter 10. The formation of vesicles (Section A), their
targeting (Section B) and fusion to their target membranes (Section C) and the special role of the
GTPases (Section D) will be discussed first, followed by an examination of some of the details of
the various pathway segments (Section E).
A. Assembly of Coats, Budding and Formation of Vesicles
This and the following sections will be referring to several components: NSF, SNAP and SNARE.
As in many other cases in this book, these acronyms stand for certain appellations that are only of
historical importance.  NSF stands for N-ethyl maleimide sensitive factor, SNAP for soluble NSF-attachment protein and SNARE  for SNAP receptors. The acronysms will be used  in the text that
follows.
The process of vesicle formation and their delivery to a target are summarized in the diagram of Fig.
1 which will serve as the basis of this discussion. This representation reflects the bare bones, so-called SNARE hypothesis. As discussed below some of the present evidence indicates that SNAREs
are responsible for docking and act downstream from tethering. The assembly described in Fig. 1A
typified for COPI vesicles, occurs stepwise with (i) the binding of the small GTP-GTPase first (see
Section E) (in this case ARF; open spheres: GDP-GTPase; closed spheres: GTP-GTPase) where
GDP has been replaced by GTP (i-ii), followed by activation by GTP and formation of coated bud
by recruitment from the cytoplasmic pool. The pinching off of the vesicle requires acyl-CoA binding
(not shown, Ostermann, et al., 1993) and the GTPase, dynamin (not shown, e.g., Takei et al., 1995;
Hinshaw and Schmid, 1995). Dynamin is thought to assemble around the neck of endocytotic
invagination and participates in pinching off the vesicles (see below and Chapter 9). Subsequently,
the hydrolysis of GTP induces the detachment of the GTP-binding protein, now bound to GDP
(Melançon et al., 1987; Orci et al., 1989) (iii-iv). Finally, dissociation of the coat follows (v) . The
http://www.albany.edu/~abio304/text/chapter_11.html (4 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
steps diagrammed in Fig. 1B and C are discussed in more detail below. Basically, the uncoated
vesicles bind to the target protein on the target membrane (part B of the diagram). The binding is
mediated by the v-SNARE and its cognate, t-SNARE, in the target membrane (see Section C). The
fusion (part C of the diagram) requires ATP, GTP, AcylCoA, the NEM-sensitive-factor (NSF),
SNAPs and other factors. NSF catalyzes the hydrolysis of ATP which disrupts the SNARE complex
(see Section C), and initiates fusion.
This model is supported by experimental observations: (a) the presence of coated vesicles coincides
with biochemically defined transport (Orci et al., 1986); (b) coated vesicles containing cargo
proteins, in this case G-VSV-protein, transfer from donor to acceptor stacks of the Golgi and can be
trapped at this stage by the presence of GTPγS (Orci et al., 1989); (c) after a GTPγS block is
reversed the vesicles disappear; (d) budding requires fatty acylCoA; (e) addition of NEM (or AlF4-,
which acts as a phosphate analog) causes a buildup of uncoated 75 nm vesicles at the Golgi complex
in intact cells; and (f) the accumulation of uncoated vesicles produced by NEM is reversed by the
addition of a soluble cytoplasmic factor (NSF) (Malhotra et al., 1988).

Fig. 1 Model of the vesicle shuttle (see text) (A) Vesicle budding. (B) Targeting of vesicles. (C)
Fusion. Reproduced with permission from Rothman, J.E. and Wieland, F.T. (1996) Protein sorting
by transport vesicles, Science 272:227-234, copyright &copy1996, American Association for the
Advancement of Science.
http://www.albany.edu/~abio304/text/chapter_11.html (5 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
As implied by Fig. 1A, several features in the assembly of coated vesicles are common to all three
systems that have been studied. They all first require the recruitment of small GTP-GTPases. Later
binding of coat proteins induces a deformation of the membrane to form a bud. Transmembrane
proteins of the donor membranes recruit the proteins that will form the coat (see Fig. 12A of Chapter
10). In addition, they can function in the selection of cargo. However, there are significant
differences. The assembly of COPI-coated vesicles recruits a pre-assembled coat present as a
soluble complex ( e.g., Zhao et al., 1997, 1999), whereas COPII proceeds stepwise. The recruitment
of clathrin is also nucleotide dependent and requires ARF1. However, unlike COPI vesicles, in
clathrin vesicle assembly, ARF1 only recruits AP-1 (an adaptor protein, see below) (e.g. Zhu et al,
1998) followed by formation of the coat. In addition, clathrin disassembly in neurons requires the
heat shock protein Hsc70 together with the cofactor auxilin and proceeds with the hydrolysis of
ATP. In other cells cyclin G-associated protein kinase (GAK) acts similarly to auxilin. The
disassembly of the clathrin coat (e.g., Ungewickell et al., 1995; Umeda et al., 2000) differs from the
dissociation of the other two coats.
The ability of clathrin to self assemble into polyhedral cages (Woodward and Roth, 1978) has
suggested that budding occurs by a stepwise assembly of coat structure from subunits in the
cytoplasm. In this model, each addition progressively deforms the membrane to eventually form the
bud and then a detached vesicle (see Le Borgne and Hoflack, 1998).
However, the process is best understood for the cases of budding from the ER (Barlowe et al., 1994)
and the Golgi cisternae that do not involve clathrin. As already mentioned, the budding process is
regulated by GTP-binding proteins (see Table 1, Fig. 1A), which initiate the process (Donaldson et
al., 1992; Helms and Rothman, 1992). Then the coat proteins can begin to be assembled. In contrast,
the hydrolysis of the bound GTP to form bound GDP, initiates the release of the coat (Tanigawa et
al., 1993). An enzyme in the donor compartment catalyzes the exchange of GTP for GDP (Barlowe
and Shekman, 1993).
The components of the COPII coat needed for vesicle assembly can be shown by genetic approaches
in yeast. In addition, ER membranes can be used in an in vitro assay after extraction of peripheral
proteins. The stripped membranes produce vesicles by budding after the addition of cytosol extracts
and GTP. The active ingredients of the cytosol extracts correspond to a 700 kDa complex of
Sec31p/Sec13p, a 400 kDa complex of Sec23p/Sec24p and the small GTPase, Sarp1 (Barlowe and
Sheckman, 1993). Sar1p-GDP is normally in the cytoplasm. It is recruited to the ER membrane by
Sec12p, an integral membrane protein of the ER. Sec12p also functions as a guanine exchange
factor (GEF) (Barlowe and Sheckman, 1993), thereby facilitating the exchage of GTP for GDP. In
contrast, the disassembly, required for fusion, involves GTP hydrolysis activated by Sec23p (see
Kaiser and Ferro-Novick, 1998).
Another protein of 240 kDa, Sec16p, is tightly bound to the ER and acts as a scaffold for the
assembly. Sec23p, Sec24p, Sec31p and Sed4p (a homolog of Sec12p) are bound to different sites in
the Sec16p molecule (e.g., Shaywitz et al., 1997).
The minimum system to function in the formation of COPII vesicles and buds has also been
http://www.albany.edu/~abio304/text/chapter_11.html (6 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
determined by reconstituting purified proteins in entirely synthetic liposomes (Matsuoka et al.,
1998). By adding 5’guanylyl imidodiphosphate (GMP-PNP), a non-hydrolyzable analog of GTP,
Sec12p (which functions as a nucleotide exchange protein) is not required. After Sar1p-GMP-PNP
is bound to the membrane, the Sec23p/Sec24p and Sec31p/Sec13p complexes are sequentially
attached in that order. The process differs somewhat from the native process suggesting that other
factors (e.g., the presence of cargo) may facilitate the process. Apparently a minimum of 10% acidic
phospholipids is required (Matsuoka et al., 1998).
Sorting of integral membrane proteins is thought to require binding of the cytoplasmic domain of
the protein to the Sec23p-Sec24p complex (Aridor, et al., 1998). Sorting of soluble proteins requires
transmembrane receptors. These receptors would require at least one transmembrane domain, a
lumenal domain that can bind to the cargo and a cytoplasmic exposed domain that would bind to
coat subunits. One of these is the KDEL receptor that binds to a carboxy-terminal KDEL peptide
and retrieves the proteins that have escaped from the ER (Lewis and Pelham, 1992). Two proteins of
the p24 family are receptors that have been found in COPII-coated vesicles (Schimoller et al., 1995)
and are needed for the secretion of certain proteins. Their cytoplasmic domain contains a diphenyl
and a dibasic motif at the carboxy terminals.
In order to fuse to their target the vesicles must contain v-SNAREs (see Section B). vSNAREs have
been demonstrated in COPI and COPII coats. Two ER to Golgi v-SNAREs, Bet1p and Bos1p,
interact specifically with Sar1p, Sec23p, and Sec24p in a guanine nucleotide-dependent fashion
(Springer and Sheckman, 1998).
The assembly of COPI-coated vesicles proceeds as follows. First the GTPase ARF1 (ADP-ribosylation factor 1) binds to the membrane. This requires binding to its GEF. ARF1 is
myristoylated. The myristoyl moiety is exposed when the GTPase binds GTP, allowing ARF1 to
bind to lipids. The hydrolysis of GTP leads to the retraction of the meristoyl-moiety into a pocket of
the ARF1 molecule, so that the GTPase is no longer able to attach to lipids. The assembly of the
coat takes place by recruitment of a preassembled coat via its β and γ-COP subunits, resulting into a
deformation of the membrane to form the bud (Zhao et al., 1997; 1999).
Adaptors and receptors
The assembly of coated vesicles probably involves many more interactions than those considered so
far. The adaptor molecules AP-1 (present in the clathrin coated vesicles that originated from the
TGN) and AP-2 (from the clathrin coated vesicles originating during endocytosis) appear to have a
key role in the processes involved in vesicle formation. Their structure and function have been
recently reviewed (Traub, 1997; Robinson, 1997). In addition to AP-1 and AP-2, a third adaptor
protein has been identified, AP-3 (Dell’Angelica et al., 1997). AP-3 is likely to function in transport
to the lysosomes (in yeast the vacuole). Deletion of any of the subunits, leads to mistargeting of
some of the vacuolar proteins but not others (Cowles et al., 1997; Stepp et al., 1997; Vowels and
Payne, 1998). Similarly, in mammalian cells, antisense oligonucleotides for the AP-3 gene (see
Chapter 1) also send lysosomal glycoproteins to the cell surface without affecting AP-1 mediated
transport, such as that of the mannose 6-phosphate receptors (Le Borgne et al., 1998). An additional
http://www.albany.edu/~abio304/text/chapter_11.html (7 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
function is suggested by the observation that in vitro synaptic vesicle can be formed from
endosomes in the presence of AP-3 (Faundez et al., 1998).
AP-1, AP-2 and AP3 are heterotetramers [two large δ subunits of 160 kDa, and two β3A (120 kDa)
subunits associated with µ3 (47 kDa) and σ3 (22 kDa)].The β-subunits of these adaptors promote
clathrin-cage formation (e.g., Gallusser and Kirchhausen, 1993). AP-1 and -2 also bind in vitro to
the cytoplasmic domains of membrane receptors (e.g., Pearse, 1988, Glickman et al., 1989) and
clathrin (e.g., Ahle and Ungewickell, 1989; Shih et al., 1995; Traub et al., 1995, Schröder and
Ungewickell, 1995). In addition, they bind the tyrosine or di-leucine sorting motifs (Heilker et al.,
1996) important for endocytosis and lysosomal targeting (see Sandoval and Bakke, 1994). The µ-1
and µ-2 subunits of AP-1 and AP-2, bind to the tyrosine endocytotic motif (Ohno et al., 1995). The
adaptors are therefore responsible for the selectivity of the vesicle as well as their assembly.
The receptor molecules, such as the mannose 6-phosphate receptors (MPRs) sorted out in the TGN,
were found to be needed for the recruitment of AP-1 to the clathrin vesicles in an in vitro system (Le
Borgne et al., 1996). The amount of AP-1 recruited by clathrin coated vesicles of the TGN was
found to depend on the presence of the MPRs and the integrity of their cytoplasmic domains (Le
Borgne and Hoflack, 1997).
Many homologues of adaptor subunits AP-1, AP-2 and AP-3 have been found. In one case, clathrin
coated vesicles associated with endosomes have been shown to have neither AP-1 nor AP-2,
suggesting the presence of another adaptor complex (see Stoorvogel et al., 1996). Some of the
adaptors function independently of clathrin (e.g., Stepp et al., 1995; Simpson et al., 1996). These
adaptors could function in conjunction with clathrin-like molecules or other unknown coat proteins,
possibly interacting with COPI.
In summary, adaptors, receptors and clathrin appear to act in concert to produce coated vesicles.
The subunits of COPI, coatomer, (β, δ and ζ-COP) have some sequence homology with the β, µ and
σ-adaptor subunits of AP-1 and AP-2. Interestingly, the B subcomplex of COPI binds the di-lysine
motif (e.g., Fiedler et al., 1996). Therefore, in contrast to clathrin, coatomer subunits have a role
similar to the adaptor molecules. Coatomer coat subunits have been shown to interact with KKXX
motif (Letourneur et al., 1994) needed for retrieval to the ER. Therefore they do function as
receptors for retrograde transport.
The interaction of coatomer with a domain of the peptide p23 (a p24 protein thought to act as a
receptor for cargo) has been studied in vitro (Reinhard et al., 1999). The binding of the two kinds of
protein results in a conformational change and polymerization of the complex in vitro with a
stoichiometry of 1:4, COPI:peptide. This conformation is also seen on the surface of isolated COPI
vesicles. These results suggest a mechanism by which the induced conformational change of
coatomer accompanying its polymerization is responsible for the formation of the bud on the Golgi
membrane during biogenesis of a COPI vesicle. In vitro experiments using liposomes reveal the
formation of coatomer vesicles requires ARF, GTP and the cytoplasmic tails of the p24 proteins
receptors, or cargo proteins with the KKXX retrieval signal (Bremser et al., 1999).
http://www.albany.edu/~abio304/text/chapter_11.html (8 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
Knowledge of the possible role of adaptor-like molecules in COPII is still lacking. However, COPII-coated vesicles are selective, in some cases, as shown by the fact that they concentrate proteins
exported from the ER (Balch et al., 1994; Bednarek et al., 1995). We saw that only the COPII
proteins are required for vesicle formation (see above) (Matsuoka et al, 1998). However,
phosphatidylinositol 4-phosphate or phosphatidylinositol 4,5-bisphosphate are needed to bind them
to liposomes and the GTP-bound form of Sar1p is needed to recruit the proteins to either liposomes
or the ER membranes.
Heteromeric complexes of proteins of the p24 family are found in both COPI and COPII vesicles as
well as ER and Golgi membranes (e.g., Füllekrug et al., 1999; Marzioch et al., 1999) suggesting that
p24 cycles between ER and Golgi as would be expected for receptor proteins. In mammals the p24
proteins are thought to be involved in exit from the ER (Lavoie et al., 1999). In yeast there are eight
genes encoding these family members. Mutations of several of these genes exhibit selective protein
transport defects or secretion of the ER lumenal protein Kar2p (e.g., Marzioch et al., 1999). For
example, deletion of one p24 gene slows down the transport of Gas1p from ER to Golgi (e.g.,
Marzioch et al., 1999). Gas1p is a GPI-anchored protein.
Mutations of the genes coding for p24 proteins do not inhibit anterograde passage from the ER
completely and the export of some of the proteins from the ER do not require p24-proteins at all.
This suggests that only some proteins require this receptor or any receptor at the ER exit step. In
agreement with this notion, many secreted proteins have been shown not to be concentrated in
COPII-coated vesicles (Martínez-Menárguez et al., 1999). The incomplete inhibition by some of the
mutants that seem to be involved in the p24 system may be explained by the occurrence of bulk flow
which would be of significance in the absence of receptors. However, in some cases, the role of p24-proteins is clearly that of receptors. The Emp24 complex is needed for for packing Gas1p into
vesicles of the ER (Muñiz et al., 2000). In agreement with the notion that Emp23 acts a receptor,
Gap1p was shown to become chemically cross-linked to two of the Emp24 proteins in experiments
using cross-linking reagents.
Cargo proteins have been found to have a role in the assembly of coat proteins (see Springer et al.,
1999; Bremser et al., 1999). In addition, in view of the central role of the GTPases in coat assembly,
it would seem likely that the GTPases have a role in regulating cargo recognition. A special role of
GTPases is suggested by experiments using a cell-free system. During COPI vesicle formation,
competing sorting signals were shown to act through a GTPase switch thereby providing specificity
for the process (Goldberg, 2000). The signal sequence of hp24a (a p24 protein, supposedly a
receptor) inhibits coatomer-dependent GTP hydrolysis. In contrast, the di-lysine retrieval signal (see
above) that binds the same coatomer site has no effect on the GTPase. The results suggest that the
activity of the GTPase can select or discard a cargo protein.
Involvement of phosphatides
Several phospholipid modifying enzymes are involved in the formation of vesicles from buds (e.g.,
endophilin, synaptojanin and phospholipase D). Endophilin is an acyltransferase that binds to the
small GTPase, dynamin (see below), and transfers fatty-acyl from arachidonic and palmitic acid to
http://www.albany.edu/~abio304/text/chapter_11.html (9 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
lysophosphatidic acid to produce phosphatidic acid (Schmidt et al., 1999). This reaction may induce
negative membrane curvature by converting an inverted-cone-shaped lipid into a cone-shaped lipid
in the cytoplasmic layer of the bilayer. Phospholipase D produces phosphatidic acid from
phospholipids, possibly affecting membrane curvature (Zimmerberg, 2000). Synaptojanin is a
polyphosphoinositide phosphatase. See also Chapter 4 for a discussion of membrane curvature.
Although their role is not well understood, the phosphoinositides (PIs) have been shown to be part
of the machinery responsible for the formation of vesicles, for example, in the the TGN, the plasma
membrane and the endosomes (see Martin, 1997; De Camilli, 1996; Ohashi et al., 1995). The
phosphoinositides are thought to be part of the discrete membrane sites (see Chapter 4) required for
the recruitment of cytoplasmic proteins needed for vesicle formation and budding.
An involvement of the lipid system is shown by the dependence of secretion on phosphatitylinositol
transfer proteins (PITPs). PITPs are enzymes reponsible for the transfer of phospholipids between
membrane structures or serum lipoproteins (see Wirtz et al., 1991). These enzymes have a distinct
preference for phosphatidylinositol over phosphatidylcholine. The β isoform, present in the Golgi
system, has a high transfer activity in relation to sphingomyelin (see deVries et al., 1995). In yeast,
mutations in the SEC14 gene which codes for a PITP, block post-Golgi secretory traffic (e.g.,
Bankaitis et al., 1990). In agreement with these results, experiments carried out on a cell free system
from a neuroendocrine cell line (Ohashi et al., 1995) found that the α and β isoforms of PITPs
stimulate formation of vesicles from the TGN.
Phosphatidylinositol kinases (PIKs) which phosphorylate PIs have also been implicated. In yeast,
the Vps15 protein kinase and the Vps34 PI-3-kinase have been shown to function as a membrane-associated complex which facilitates the delivery of proteins to the yeast vacuole (e.g., Stack and
Emr, 1994) which has a similar function than lysosomes in a mammal. Subsequent work has
indicated that polyphosphoinosides phosphorylated at the 4′ and 5′ or alternatively the 3′ positions of
the inositol ring determine the location of events involved in membrane traffic. It is now generally
recognized that phosphorylation-dephosphorylation of the polar heads of phosphoinositides in
specific locations coincides with the recruitment or the activation of proteins essential for vesicular
transport (see De Camilli et al., 1996).
The compartmentation of PPIs is probably the result of synthesis at specific locations. The targeting
of PI 4-kinase would permit a segregated synthesis. PI 4-kinase catalyzes the phosphorylation of
phosphatidylinositol to form PI 4-phosphate. PI 4-kinases have been found in plasma membranes
and intracellular organelles including Golgi, lysosomes, ER, nuclear envelope, coated vesicles,
exocytotic vesicles and secretory granules (see De Camilli et al., 1996; Carpenter and Cantley,
1996). The immunoreactivity for this PI 4-kinase molecule was found mostly in close association
with the membranes of the Golgi vesicles and vacuoles (Nakagawa et al., 1996).
The association between PI-kinases and membranes occurs despite the absence of transmembrane
sectors. However, these proteins could bind directly to lipids or indirectly by anchoring to integral
proteins. Some of the mammalian kinases have a pleckstrin-homology (PH) domain (Nakagawa et
al., 1996) that would allow them to interact with lipids. Alternatively, the kinase could be anchored
http://www.albany.edu/~abio304/text/chapter_11.html (10 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
by binding to membrane receptors, as is the case of PI 4-kinase that links to transmembrane proteins
and integrins (Berditchevski et al., 1997). A mammalian adaptor protein p150 (homolog of the yeast
VPS15) that recruits the PI 3-kinase to the Golgi membrane, has been identified (Panaretou et al.,
1997). Recombinant p150, PI 3-kinase and PITP form a complex also present in the cytoplasm of
human cells.
Not surprisingly, a polyphosphoinositide phosphatase (synatpojanin 1) has been found to be
involved in presynaptic endocytotic vesicle recycling in neurons. Synaptojanin 1 was found at high
levels at nerve terminals (McPherson et al., 1996), which are involved in the exocytosis of synaptic
vesicles. Synaptojanin 1-deficient mice exhibit neurological defects and die shortly after birth,
phosphatidylinositol 4,5-biphosphate (PIP2) levels are increased and clathrin-coated vesicles
accumulate at the nerve endings (Cremona et al., 1999)
Undoubtedly, the binding of phosphoinositides to coat components has a role in trafficking. They
bind AP-2 (e.g., Gaidarov et al., 1996), AP-3 (AP180) (e.g., Hao et al., 1997) and COPI coatomer
(e.g., Chaudhary et al., 1998), dynamin, synaptojanin (Cremona et al., 1999) and in addition
arrestins (Gaidarov et al., 1999). Dynamin is involved in vesicle formation (see Chapter 9).
Arrestins are involved in the inhibition of Gs proteins (e.g., see Chapter 7) and also act as clathrin
adaptors (see Goodman et al., 1996). Mutants of arrestin3 expressed in cells in culture fail to
participate in β2-adrenergic receptor internalization and fail to be recruited to the coated pits
although they are recruited to the plasma membrane (Gudrov et al., 1999). Similarly, mutation of the
α subunit of the AP-2 adaptor protein at high expression levels results in failure to localize at
clathrin coated pits (Gaidarov and Keen, 1999).
In addition to their separate roles in vesicle formation and secretion, the phosphoinositide system
and the GTP-binding proteins are functionally and intimately linked. ARF activates phospholipase
D (PLD) (Brown et al., 1993). PLD catalyzes the conversion of phosphatidyl choline to phosphatidic
acid. The latter activates PI-4 kinase to produce PIP2 (see Martin, 1997; DeCamilli et al., 1996)
which has been shown to be involved in vesicle formation (Tüscher et al., 1997). In addition, ARF
has a direct effect in increasing the level of PIP2 (Godi et al., 1998) and PI-4 kinase-β and, by
recruitment, another unidentified kinase in the Golgi (Godi et al., 1999). This increases the synthesis
of PI-4-phosphate and PI2 levels independently of PLD activation. The PI-4 kinase is required to
maintain the integrity of the Golgi. Mutants that lack the kinase exhibit a disorganized Golgi (Godi
et al., 1999).
Other effects of ARF on the Golgi and vesicle pathway are less clearly understood. The actin
binding proteins ankyrin and spectrin, are at the cytoplasmic surface of the Golgi (see Beck et al.,
1998; De Matteis et al., 1998). ARF recruits a specific spectrin to Golgi membranes (Godi et al.,
1998) in a mechanism involving the PIP2 binding domain of spectrin [the pleckstrin-homology (PH)
domain]. Spectrin is needed for maintaining the structural integrity of the Golgi. Agents that block
the binding of spectrin inhibit the transport of vesicular stomatitis virus G protein from the ER to the
medial compartment of the Golgi complex.
http://www.albany.edu/~abio304/text/chapter_11.html (11 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
B. Targeting of Proteins and Vesicles; SNAREs
As we saw in Chapter 10, the sorting signals of cargo proteins are responsible for the targeting of
proteins. Similarly, retention signals are likely to be required for retention by the appropriate
compartment. The sorting signal is recognized directly or indirectly by the proteins that form the
vesicle coat to insure packaging of the cargo protein in the corresponding vesicle. Once assembled,
specific tethering and docking of the transport vesicle are needed to deliver the vesicle to the
acceptor compartment. At the target site, the docking depends on the complementary SNAREs.
SNAREs are integral proteins of intracellular membranes with a large domain on the cytoplasmic
phase. SNAREs present in a transport vesicle (v-SNARE; e.g. synaptobrevin in neurons) (Söllner et
al., 1993a) are recognized by another similar protein on the surface of the target compartment (t-SNARE; e.g. syntaxin in neurons) (Rothman, 1994; Søgaard et al., 1994) (see Fig. 1B). The two
usually correspond to R-and Q-SNAREs respectively (i.e., named after the glutamine and arginine
residues of the their cytoplasmic domains) (see Jahn and Südhof, 1999).The specific interaction is
apparently mediated by the extended cytoplasmic domain of the two different kinds of SNAREs
(Chapman et al., 1994). The role of SNAREs has been delineated most completely for the shuttles
between the ER and the Golgi (see Rothman; 1994, Paek et al., 1997) and from the Golgi to the
plasma membrane (Brennwald et al, 1994). A SNARE protein that functions within the Golgi
system has been isolated from mammalian cells in culture (Hay et al., 1997; Nagahama et al., 1997).
This protein of 28 kDa is associated with Golgi membranes. The transport from the ER to the trans-Golgi and TGN is blocked by the cytoplasmic domain of this protein or an antibody to it. These
agents are thought to block transport between the medial-Golgi and the trans-Golgi and TGN (Hay
et al., 1997). A yeast v-SNARE protein has been implicated in retrograde transport to the cis-Golgi
(Lupashin et al., 1997) and probably the anterograde transport from late Golgi and a prevacuolar
compartment (von Mollard, et al., 1997).
The two kinds of SNARES, v-SNARES and t-SNARES, must be capable of binding each other
specifically. Complementary pairs have been identified in yeast for the ER-Golgi step (Lian and
Ferro-Novick, 1993; Søgaard et al., 1994) and the Golgi-plasma membrane step (Aalto et al., 1993;
Propopov et al., 1993; Brennwald et al., 1994). In addition, SNARE-pairs have been identified in
regulated exocytosis of neuronal synapses (see Südhof, 1995). A study of Nichols et al. (1997) has
shown, in yeast vacuoles, the need for t-SNARE in one membrane and v-SNARE in another for
fusion to occur. In a more systematic approach, McNew et al. (2000) tested all of the potential v-SNAREs encoded in the yeast genome to examine whether they can partner t-SNAREs of the Golgi,
the vacuole and the plasma membrane. Vesicle and target SNAREs were reconstituted into two
separate sets of liposomes and tested for fusion (see Weber et al., 1998). In these experiments, the
phospholipids in the vesicles reconstiuted with v-SNAREs were labeled with a mixture of probes
whose fluorescence is quenched. When fusion to the vesicles containing t-SNAREs occurs, the
fluorescent probes are diluted and become fluorescent as the quenching decreases. The SNARE
proteins reconstituted in liposomes were found to function as predicted by the SNARE hypothesis
by exhibiting the appropriate specificity. However, other factors seem to play an important role as
well (see below). These are proteins involved in the localization of vesicles, such as tethering
factors, or those involved in the activation of the SNARE complexes (see Waters et al., 1999;
http://www.albany.edu/~abio304/text/chapter_11.html (12 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
Mellman and Warren, 2000).
The assembled v-SNARE/t-SNARE complex consists of a bundle of four helices (Parlati et al.,
2000; Fukuda et al., 2000). For the transition between ER and Golgi, one SNARE contains three of
the helices (t-SNARE) and the other one (v-SNARE). Fusion does not take place with any other
combination. For t-SNAREs on the plasma membrane, the protein syntaxin, supplies one helix and a
SNAP-25 protein contributes the other two. The assembly of SNARE complexes involves Rab (see
Rothman, 1994; Søgaard et al., 1994) and Sec1. Rab proteins are GTP-binding proteins (Simons and
Zerial, 1993, see below). Sec1 proteins (Aalto et al., 1992) bind specifically to t-SNARE subunits
(Pevner et al., 1994).
The need for separate and complementary v-SNAREs and t-SNARES, one in the cargo carrying
vesicle and the other in the target membrane, explains many of the available data. However, in
COPII vesicles the situation is more complex. The vesicles originating from the ER must first
cluster to form VTCs (see Chapter 10). The large vesicles of the VTC are then targeted to the cis-Golgi with which they fuse. Consistent with this view, yeast vesicles can be isolated in clusters
(Lian and Ferro-Novick, 1993). In addition, the t-SNARE syntaxin 5 is present in the vesicles, as we
might expect if they fuse and not in the Golgi membranes (Rowe et al., 1998) and is essential for the
assembly of vesicular-tubular-preGolgi intermediates as well as for the delivery of the cargo to
Golgi.
We saw that the SNARE hypothesis postulates that the specificity of membrane fusion events
resides on the SNARE receptors, SNAREv and SNAREt joining with each other. A good deal of
data just reviewed supports this view (e.g., see Weber et al., 1998). However, recent studies suggest
that the process is more complex. It has been argued that the specificity of targeting may not depend
on SNAREs (e.g., Kaiser and Ferro-Novick, 1998). t-SNAREs are not localized at specific sites of
the target membrane (e.g., Garcia et al., 1995) and v-SNARE can bind to more than one t-SNARE
(von Mollard, et al., 1997; Holthuis et al., 1998). In some cases the system may be able to bypass
SNAREs entirely. The disruption of SNAREs [e.g., caused by microinjection of the cytoplasmic
domain of synaptobrevin (Hunt et al., 1994) or cell mutants lacking synaptobrevin or syntaxin
(Broadie et al., 1995)] does not prevent vesicle docking. A v-SNARE can reside in both anterograde
and retrograde-directed vesicles and a single v-SNARE can bind to several t-SNARES and a single t-SNARE can bind to several different v-SNAREs (see Götte and Fischer von Mollard, 1998; Pfeffer
et al., 1999). In the case of the ER-to-Golgi transport, another entity, the 800 kDa complex of 8
subunits, the transport protein particle (TRAPP) may account for the specificity. TRAPP, located in
the cis-Golgi, has a role in targeting and fusion (Sacher et al., 1998) and may have a role in
providing specificity since it is unique to this step, whereas all SNARE molecules are very similar.
As reviewed above, t-SNAREs and v-SNAREs present in separate vesicles interact. However, other
components are active in this process (Ungermann et al., 1998; Peters and Mayer, 1998). The small
GTP-binding protein Ypt7p holds together the vacuoles in a reversible reaction (Ungermann et al.,
1998). This stage requires the presence of various factors (see next section) but not SNAREs. A
similar SNARE independent attachment was first described in the attachment of the ER vesicles to
the Golgi (Cao et al., 1998a).
http://www.albany.edu/~abio304/text/chapter_11.html (13 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
In Saccharomyces cerevisiae, Vam7 (a t-SNARE) is targeted to vacuoles in a manner dependent on
the presence of phosphatidylinositol 3-phosphate in the vacuolar membrane. This interaction
involves the phox homology (PX) domain of Vam7 (Cheever et al., 2001). The PX domain is an 80-125 amino acid residue region of proteins involved in binding phosphoinositides (Kanai et al.,
2001).
C. Fusion
The machinery responsible for fusion is composed of three distinct proteins (Söllner et al., 1993):
NSF (Sec18p in yeast), SNAP (Sec17p in yeast) family members, and the SNAREs. Once
assembled, the complex forms a 20S particle (where 20S refers to the sedimentation coefficient).
Models of the structures of the proteins in the complex derived from crystallography give us some
understanding of the assembly of the 20S fusion particle (May et al. 1999; Yu et al., 1999; Rice and
Brunger, 1999). These studies provide us with a detailed view of the very similar structures seen
with the EM of the 20S particles (Hohl et al., 1998). The SNARE complex is rod shaped (2.5 x 15
nm). SNAP binds laterally, whereas NSF binds to one end of the complex to form a particle 22 nm
in length.
The association of SNAP and NSF with SNARE to form the 20S particle is sequential. The v-SNARE-t-SNARE complex binds 3 to 6 SNAP proteins and subsequently NSF (Söllner et al.,
1993b; Hayashi et al, 1995). The release of SNAP, which requires NSF, is accomplished before
vesicle docking (Mayer et al., 1996). Subsequently, v-SNARE from t-SNARE dissociate (Söllner et
al., 1993) and the fusion takes place. The SNAP and NSF proteins are common to most, if not all,
different transport steps. It might be expected the SNAREs are specialized since their interaction
determines the final fate of the cargo (Fig. 1B) (see Ferro-Novick and Jahn, 1994). However, this
was found not to be the case. In vitro testing showed very promiscuous binding of SNAREs derived
from different sources (Yang et al., 1999).
The SNAP proteins (Clary et al., 1990) and an ATPase, the NSF (Block et al., 1988; Malhotra et al,
1988; Wilson et al, 1989) assemble after docking. The v-SNARE-t-SNARE complex binds 3 to 6
SNAP proteins and subsequently NSF (Söllner et al., 1993b; Hayashi et al, 1995). The hydrolysis of
ATP dissociates v-SNARE from t-SNARE and releases the SNAP molecules (Söllner et al.,
1993).The fusion process is still not well understood.
In one of the current models of fusion, SNAREs have a role in bringing the two bilayers together in
a zipper like process (see Chen and Scheller, 2001). When the two bilayers become fused a pore
opens and then pore expands producing one continuous bilayer. At least in exocytosis, freeze
fracture EM (Chandler and Heuser, 1980) and patch clamping ( Breckenridge and Almers, 1987)
confirm the formation of a pore. Present thinking suggests that the pore is in the lipid components
with protein scaffolding, possibly SNAREs (see Monck and Fernandez, 1994, 1996;Lee and Lentz,
1997)
In mammals, the fusion of early endosomal vesicles and more mature endosomal vesicles requires
http://www.albany.edu/~abio304/text/chapter_11.html (14 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
the early endosome-associated protein (EEA1) and Rabaptin-5. EEA1 binds to phosphatidylinositol
3-phosphate in the endosomal membrane through its FYVE domain (e.g., Simonsen et al., 1998)
NSF
NSF was discovered in isolated systems. In low concentrations, the sulfhydryl alkylating agent
NEM, inactivated the acceptor membrane fraction of the intra-Golgi transport system so that it
would no longer be able to fuse to the incoming vesicles (Glick and Rothman, 1987). Untreated
peripheral proteins of the Golgi membranes restored function. A 76 kDa polypeptide, forming a
homotetramer in its native form, NSF, was found to be responsible for the activity (Block et al.,
1988). EM examination of the Golgi membranes of blocked cells (Diaz et al., 1989) indicated an
accumulation of uncoated intermediate transport vesicles associated with membranes. This
observation suggested that NSF acts as part of the complex needed to fuse the vesicle membrane
with the acceptor membrane. NSF was subsequently found to be needed for the in vitro fusion of
vesicles involved in the transport from ER to Golgi and for the fusion of endocytotic vesicles.
NSF shows 48% sequence identity to Sec18p of yeast. Furthermore, Sec18p can replace NSF in the
mammalian cell free system. NSF is a hydrophilic molecule not likely to interact with hydrophobic
domains such as the hydrocarbon leaflets of the bilayer membrane. However, it has two ATP-binding domains and displays ATPase activity, which determines its attachment to the membrane. In
addition to NSF, five other proteins have been found to be necessary in vesicle mediated transport.
Many others might also be required. The in vivo requirement for Sec18p was demonstrated using a
temperature sensitive mutant (Graham and Emr, 1991). The proteins of the cells were labelled by
exposure for a short period to radioactive amino acids at the permissive temperature (20oC),
followed by a chase at the nonpermissive temperature (37oC). The fate of two proteins, F and CPY,
was examined. These two were selected because the proteins undergo stepwise modifications in the
Golgi complex that can be easily recognized using SDS gel electrophoresis and
immunoprecipitation. In the case of the wild type cells, the F precursor proteins were rapidly chased
to the mature form of the protein (mF). In contrast, in the mutant cells the inactivation of the sec18
protein left the F protein in all intermediate compartments. These results indicate that each
sequential step must occur in a separate compartment, as we saw for other systems, and Sec18p is
involved in each step.
NSF is a member of the ATPases responsible for varied cellular activities, the AAA (ATPases
associated with a variety of cellular activities) superfamily (see Patel and Latterich, 1998;
Confalonieri and Duguet, 1995, see Frölich on the Web) which also includes proteasomal
components (see also Chapter 15). Some members of this family perform chaperone tasks (i.e.,
folding tasks) (see Chapter 15), others are associated with assembly, remodeling and disassembly.
They act in a variety of cellular functions (see Neuwald et al., 1999), including cell-cycle regulation,
protein degradation, organelle biogenesis and vesicle-mediated protein transport, and the initiation
of transcription. The AAA motif corresponds to a 230-amino-acid domain that contains Walker ATP-binding homology sequences and imparts ATPase activity.
NSF is involved in eukaryotic fusion events which also require SNAREs. The SNAREs are
associated at their cytoplasmic domains forming stable complexes (Hay and Scheller, 1997; Weber
http://www.albany.edu/~abio304/text/chapter_11.html (15 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
et al., 1998). SNAREs (v and t) constitute the minimum requirement for fusion of membranes for
one round of fusion. NSF and SNAPs being required for separation of the two SNAREs to allow for
the next round of fusions (see Weber et al., 1998). This activity depends on ATP hydrolysis. The
dissociation events require the soluble NSF attachment proteins (SNAPs) to bind to SNAREs
providing a binding site for NSF (Whiteheart et al., 1992; Wilson et al., 1992). The binding to
SNARE and SNAP increases the ATPase activity of NSF and at the same time the complex is
disassembled (Morgan et al., 1994, Barnard et al., 1997). NSF is made up of three domains: the
amino-terminal domain which is capable of interacting with SNAPs and SNAREs, and two similar
ATPase domains (D1 and D2). D1 is thought to be involved in remodeling the 20S particle; D2 is
thought to be responsible for the formation of NSF-hexamers (Neuwald, 1999). The complex is
thought to function similarly to chaperones in driving the remodeling of effector molecules using the
free energy generated by the hydrolysis of ATP (see Patel and Latterich, 1998; Neuwald, 1999)
SNAPs
SNAPs constitute a family of soluble proteins required for NSF to bind to Golgi membranes
(Weidman et al., 1989, Clary et al., 1990). α, β and γ SNAPs are 35, 36 and 39 kDa in molecular
weight, respectively. α-SNAP has also been shown to be required in vivo. In yeast, α-SNAP is
encoded by the SEC17 gene. In the absence of this protein, vesicles are accumulated (Kaiser and
Shekman, 1990). SNAPs bind to specific sites on the membranes the SNAREs) and this binding is
required for interaction with NSF. The binding site can be identified by crosslinking with
crosslinking reagents (Whiteheart et al., 1992). These show that α-SNAP attaches to a 30-40 kDa
protein. The various SNAPs bind at different sites of a receptor complex.
D. The GTPases
The GTP-binding proteins or GTPases discussed above (also referred to as G-proteins, not to be
confused with the VSV-G glycoproteins) have been shown to have a key role in intracellular
transport. Mutations in the genes known to code for GTP-binding proteins block several steps in
secretion. Furthermore, in mammalian cells, the Rab or Ras proteins which correspond to GTPases
are localized in specific membranes associated with the secretory pathway and intracellular transport
is blocked by treatments that inhibit small GTP-binding proteins.
There are seven major groups of GTPases. They share domains needed for guanine binding and
GTP hydrolysis. These domains are so similar that the three-dimensional crystal structure of the
proteins are superimposable. They diverge significantly in amino acid sequences in other regions of
the molecules. Presumably, these are the regions which determine functional specificity.
The role of heterotrimeric GTP-binding proteins in signal transduction was discussed in Chapter 7.
In this complex, the α-subunit of 40-50 kDa binds to the guanidine nucleotide. There are also two
additional subunits (β and γ of 35-36 and 8 kDa respectively). The present section will discuss both
the heterotrimeric and the lower molecular weight GTPases in relation to intracellular trafficking.
In contrast to the heterotrimeric GTPase, those of the Ras superfamily (also called Rab when
http://www.albany.edu/~abio304/text/chapter_11.html (16 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
derived from cDNA libraries from rat brain) are monomers (Sar1, ARF, Rab/YPT, Rac/CDC42 and
Rho families) 20 to 30 kDa in molecular weight. Those of the dynamin family are 60-80 kDa. With
the exception of ARF, all form complexes with cytoplasmic or membrane proteins which may have
a function similar to the β and γ subunits of the trimeric GTPase. Fatty acid residues are added
posttranscriptionally to several GTPases. In some cases, these have been shown to permit direct
interaction with membranes (Rossi et al., 1991). Rab, Rho, Rac and the γ-subunit of the
heterotrimeric GTP-binding protein have one or two prenyl moieties at the carboxyl terminal or at
cysteine residues. Members of the ARF and Gα family are myristylated at an amino-terminal
glycine residue. Palmitylation of cysteine residues may occur in the amino or carboxyl terminal of
Ras and G.
GTPases were originally shown to have a role in all the steps of intracellular transport through the
effects of guanosine-5-O-thiotriphosphate (GTPγS) and AlF4-. GTPγS, a non-hydrolyzable analog of
GTP blocks all GTPases. It inhibits almost all of the steps in the transport.
The heterotrimeric GTPase appears to function as an inhibitor of transport. Two specific α-subunits
are associated with the Golgi. Overexpression (by transfection, see Chapter 1) of one of these Gαs
leads to slowing of the transport of proteoglycan through the Golgi (Stow et al., 1991). Conversely,
inhibition of Gα speeds up transport. A similar role is suspected for ER to Golgi transport at the
budding stage (Schwaninger et al., 1992).
The well-defined morphology of the mammalian system provides a clear picture of the role of the
small GTP-binding proteins. A minimum of 12 mammalian rab genes have been isolated from
cDNA libraries using probes recognizing ras sequences. The proteins of six rab genes (rab1 to
rab6) have been shown to bind and hydrolyze GTP. Immunofluorescence,
immunoeletronmicroscopy and the immunological reactions after cell fractionation have provided
information on the localization of these proteins, as summarized in Table 2 (Rothman and Orci,
1992). This association of each Rab protein with a specific structure in the intracellular transport
pathway suggests that each GTP protein acts at a different step. However, direct evidence has been
provided by genetic approaches in yeast. These findings were extended to other systems using
cDNA technology and in vitro reconstitution systems. Numerous additional rab110,111 and ARF65
genes have been cloned and sequenced but the proteins have not yet been localized. In most cases,
there is a substantial pool of soluble GTPases in addition to the membrane-bound forms.
The transport of VSV G-protein was followed in vitro by measuring the incorporation of [3H]-N-acetylglucosamine (GlcNAc) from donor membranes (from a cell line lacking GlcNAc-transferase)
to acceptor membranes isolated from wild type cells (containing GlcNAc transferase) (Balch et al.,
1984a,b). The use of synthetic polypeptides representing partial amino acid sequences of specific
GTPases, or the use of antibodies to the individual GTPases, identified the individual steps in which
they are involved. A polypeptide will block the action of a GTPase when it competes with it, for
example, for a receptor site. Similarly, a specific antibody can block individual steps by depleting
the cells of the Rab-protein.
Table 2 Partial list of GTPases and their location.
http://www.albany.edu/~abio304/text/chapter_11.html (17 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
Small GTP-binding
protein
Location(s) when
membrane bound
Rab family rab1Ap/rab1Bp/ypt
rab2p
rab3Ap
rab4p
rab5p
rab6p
rab7b
sec4p
ER and Golgi
GCN
Neurosecretory vesicles
Early endosomes, plasma
membrane
Early endosomes, plasma
membrane
Golgi stack
Late endosomes
Post-Golgi vesicles, plasma
membrane
ARF family ARF1p
SAR1p
Golgi stack
ER
Reproduced with permission from Nature (1992) Rothman, J.E. and Orci, L. 355:409-415.
Research efforts are now directed toward understanding how the small GTP-binding proteins
interact with specific membranes. This is likely to require the identification and study of multiple
binding proteins in the various membranes.
A summary of some of the functions of GTPases is presented in Table 3. In this table, an important
function of the GTPase is listed in the first column, however, some of them have multiple functions.
The GTPase responsible is listed in the second column and the evidence available is listed in the
third.
The precise mechanism of the action of small GTPases is not known. However, their properties
provide hints that they can function as switches, initiating or terminating biological processes. We
have seen this kind of role in the docking of ribosomes and nascent polypeptide chains in the ER.
http://www.albany.edu/~abio304/text/chapter_11.html (18 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
The GTPases change in conformation in response to the phosphorylative state of the bound
nucleotide. The active conformation occurs when the bound GDP exchanges with GTP. Hydrolysis
of the GTP returns the protein to its inactive conformation. The reactions of the GTPases require the
presence of other proteins. Two proteins regulate the conformational changes. The exchange of GDP
for GTP is facilitated by the guanine nucleotide dissociation proteins (GEPs) and inhibited by
guanine nucleotide dissociation inhibitors (GDIs). In addition, the GTPase activity of the Ras
superfamily is slow in the absence of GTPase activating proteins (GAPs).
Table 3 Role of GTPases in Intracellular Transport
FUNCTION  GTPase  EVIDENCE
vesicle budding from ER  Sar 1  overcoming mutant block
(1)
location in ER, trnaslational
elements and Golgi (2)
formation of COP vesicles
from Golgi
ARF (ADP ribosylation
factor)
in vitro assay (3)
endocytotic role dynamins accumulation of coated pits
in defective mutants (4)
transport from ER and cis to
trans Golgi
Rab1 in vitro assay (5)
early endosome fjunction Rab2, 5 and 7 Rab domains target to
endosomes (6)
TGN vesicle budding  Rab6 antibodies to Rab6 block
TGN budding (7)
exocytosis: synaptic vesicle Rab3A required for transfer from
vesicle to cell surface (8)
exocytosis: mast cells   discharge of granules when
Rab delivered into cells (9)
Ref. (1) Nakano, A. and Maramatsu, M. (1969), J. Cell Biol. 109:2677-2691.
(2) Kuge, O., Dascher, C., Orid, L., Amherdt, M., Plutner, H., Ravazzola, M., Tanigawa, G.
Rothman, J.E. and Balch, W.E. (1994) J. Cell Biol.. 125:51-65
http://www.albany.edu/~abio304/text/chapter_11.html (19 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
(3) Orci, L., Palmer, D.J.,, Perrelet, A., Amerdt, M.., Palmer, D.J. and Rothman, J.E.. Nature
362:648-652; 364:732-734.
(4) Kosaka, T. and Ikeda, L. (1983) J. Neurobiol.. 14:207-225.
(5) Plutner, H., Cox, A.D., Pind, S., Khosravi-Far, R., Bourne, J.R. et al., (1991) J. Cell Biol. 115:31-43.
(6) Chavier, P., Gorvel, J.P., Steizer, E., Simons, K., Greenberg, J. and Zerila, M. (1991) Nature
353:769-772.
(7) Jones, S.M., Crosby, J.R., Salamero, J. and Howell, K.E. (1993) J. Cell Biol . 122:775-788.
(8) Matteoli, M., Takel, K., Cameron. R., Hurbult, P., Johnston, P.A. et al. (1991) J. Cell Biol .
115:625-633.
(9) Oberhauser, A.F., Monck, J.R., Balch, W.E. and Fernandez, J.M.. (1992) Nature 360:270- 273.
Dynamins (see McNiven et al., 2000) constitute a family of large (100-kDa) GTPases that seem to
fulfill several roles in membrane trafficking in eukaryotic organisms. Different dynamin isoforms
are present in different tissues and even in the same tissue. At least 25 different mRNAs are
produced by the 3 dynamin genes by alternative splicing ( Cao et al., 1998b).
Dynamins have been shown to play important roles in endocytosis and vesicle formation (see
Chapter 9 and above). Dynamin is needed for clathrin-mediated endocytosis (e.g., Herskovits et al.,
1993; van der Bliek, 1993) and the formation of vesicles from caveolae (see Chapter 9) (Henley et
al, 1998; Oh et al., 1998). Inhibition of dynein function, inhibits the scission of caveolae both in
vivo and in vitro. Dynamin has also been implicated in other kinds of endocytosis (see Sandvig and
van Deurs, 1996), including the intake of fluid in cultured mammalian cells (Henley et al., 1999)
and phagocytosis in macrophages (Gold et al., 1999).
Dynamins have a role in vesicle formation in steps of the endocytotic pathway other than vesicle
formation from the plasma membrane. In HeLa cells, the expression of a mutant of dynamin does
not affect clathrin-independent endocytosis. However, the pathway from endosomes to Golgi is
blocked (Llorente et al., 1998). Similarly, disruption of a dynamin-family proteins in Dictyostelium
discoideum has a very broad effect (including a defective fluid-phase uptake) (Wienke et al., 1999).
In addition, dynamin was found to colocalize with vacuolin, a marker of a postlysosomal
compartment. In mammalian cells, confocal imaging (see Chapter 1) showed that dynamin is
associated not only with the plasma membrane but also the trans-Golgi network, and a perinuclear
cluster of structures containing cation-independent mannose 6-phosphate receptor. Electron
microscopy showed that the structures correspond to late endosomes with a localization of dynamin
preferentially in tubulo-vesicular processes of these endosomes (Nicoziani et al., 2000). In other
studies, dynamin was found associated with the TGN (Henley et al., 1996; Maier et al., 1996). GFP-dynamin chimeras (see Chapter 1) expressed in cultured rat hepatocytes appeared in the clathrin
coated vesicles at the cell surface and the TGN (Jones et al., 1998). An in vitro system produced
dynamin in clathrin coated and non-clathrin coated vesicles. Cells expressing a mutant of dynamin
were found to accumulate GFP-protein chimeras in the TGN (Kreizer et al., 2000). In
Saccharomyces cerevisiae, a dynamin, dnm1p, has been shown to be involved in transport to the
vacuole from the TGN (Gammie et al., 1995).
http://www.albany.edu/~abio304/text/chapter_11.html (20 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
The dynamins are capable of interacting with several components. Their pleckstrin homology (PH)
domain allows them to bind to phosphoinositides and their proline-rich domain (PRD) allows to
bind to the SH3-domains of variety of effector molecules. A coiled-coil region (CC domain) f
dynamins is a GTPase effector domain (Sever et al., 1999).
In vivo, dynamin interacts with other proteins that may alter the geometry of lipid structures to
produce vesicles. An interaction with endophilin 1 (Schmidt et al., 1999) (that transfers arachidonate
to lysophosphatidic acid) has been demonstrated. This reaction is likely to favor the formation of
highly curved lipid structures. There is at least one example of this mechanism: BARS (Weigert et
al, 1999) (that acylates lysophosphatidic acid) was shown to induce the formation of vesicles in
Golgi membranes of rat brain. However, in this case the system seems to operate independently of
dynamin.
Several studies have indicated the dynamin is associated with actin or actin-binding or actin-depolymerizing proteins, suggesting a role of these interactions in the formation of vesicles (e.g.,
Witke et al., 1998; Qualmann et al., 1999)
E. ER and Golgi Transport
ER to Golgi Transport
Present information indicates that COPII vesicles mediate the transfer of cargo from the ER to the
Golgi. However, the process may be more complex. We saw that larger vesicular components,
formed by vesicle clustering, carry cargo to the cis-Golgi (see Chapter 10, Section III). Therefore,
the vesicular tubular clusters (VTC) and not the COPII vesicles are targeted to the cis-Golgi.
Consistent with this view, the t-SNARE, syntaxin 5, is present in the vesicles as well as in the cis-Golgi (Rowe et al., 1998) and is essential for the assembly of VTCs. What this suggests is that the
VTCs are formed by an aggregation of these vesicles. Unfortunately, since retrograde transport also
takes place, it is difficult to consider this argument decisive.
The role of COPII in anterograde transport from the ER is well established. However, much of the
present evidence also supports a role of COPI for anterograde transport between ER and Golgi and
between Golgi stacks (Chapter 10, Section 3C; see also Kreis et al., 1995). However, studies with
yeast COPI mutants demonstrate ER to Golgi transport in COPI-impaired cells for some proteins but
a complete block for others (Gaynor and Emr, 1997). In contrast, the remaining ER to Golgi
transport required COPII.
A possible explanation for the complex role of COPI in anterograde transport from the ER, might
rest on a sequential role of the two coat complexes. In in vitro experiments using isolated ER
fragments, showed that vesicles released by the ER-derived system were COPII coated and
contained VSV-G protein and p58. p58 is an endogenous recycling protein. However, preparations
from ARF1 mutants that prevent COPI recruitment blocked subsequent movement to the isolated
Golgi membranes (Rowe et al., 1996). These observations suggest that COPII drives the export from
the ER and then COPI replaces COPII in the vesicles.
http://www.albany.edu/~abio304/text/chapter_11.html (21 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
In yeast, the transfer of cargo from the ER to the cis-Golgi involves the transport protein particle
(TRAPP), a 1100 kDa complex (Sacher et al., 1998). TRAPP mediates vesicle docking and fusion.
Proteins analogous to the subunits of TRAPP have been found in mammalian species (see Guo et
al., 2000). Subunits of TRAPP have been found in early Golgi membranes, in X-100 insoluble
membrane components suggesting a presence in rafts.The protein p115 (also known as TAP) is
needed for the transport from the VTC to the cis-Golgi (Nelson et al., 1998). It plays a more general
role in intra-Golgi transport (see next section). In yeast, two other factors have been implicated in
ER-to-Golgi transfer of cargo. Uso1p acts before SNAREs and is required for tethering (Cao et al.,
1998). Sec34p and Sec35p also function in tethering (VanRheenen et al., 1998).
Transport from the Golgi stacks
Isolated Golgi stacks incubated with cytosol and ATP generate 75 nm vesicles from the cisternae
(Balch et al., 1984a) (now recognized as COPI-coated vesicles). They correspond to transport
vesicles because they can be shown to contain transported proteins (in these experiments the G-protein of vesicular stomatatis virus, VSV). The transport between cisternae, also mediated by
vesicles, can be followed biochemically through the progression in the glycosylation of proteins.
Like other transfers studied so far in vitro, these also require cytosol and ATP (e.g., Braell et al.,
1984a).
The 75 nm vesicles can be either coated or uncoated (Orci et al., 1986). The relationship between
these two kinds of vesicles is revealed by the effect of two inhibitors. GTPγS, a non-hydrolyzable
analog of GTP, produces an accumulation of buds and coated vesicles (Melançon et al., 1987). GTP
hydrolysis is needed for the fusion of vesicles onto their target compartment and GTPγS blocks this
process. N-ethylmaleimide (NEM) block, on the other hand, produces an accumulation of uncoated
vesicles (Melançon et al., 1987). As discussed later, NEM blocks the docking of vesicles to the
target membrane (see below). Simultaneous treatment with GTPγS and NEM produces an
accumulation of coated vesicles (Orci et al., 1989); therefore, the coated vesicles are the precursors
of the uncoated vesicles. Both kinds of vesicles should accumulate if the two were produced
independently. Alternatively, if the uncoated vesicles were the precursor, only the uncoated vesicles
would accumulate.
The accumulation of vesicles derived from the Golgi stacks in a cell free system in the presence of
GTPγS, permitted the isolation and direct biochemical study of the COPI (coatomer) coated vesicles
(Malhotra et al., 1989; Serafini and Rothman et al., 1992).
The COPI coatomer is composed of seven proteins (α, β, β’, γ, ε and ζ) ranging in molecular weight
between 60 and 160 kDa. β-COP has been localized with immunofluorescence and immunoelectron
microscopy in the CGN and TGN and has also been found in soluble cytoplasmic complexes
(Duden et al., 1991b, Waters et al., 1991). Presumably, the cytosolic β-COP is the source of this
subunit of the vesicle’s coat.
Members of the p24 protein family bind to COPI coatomeres and may have a role in the recruitment
http://www.albany.edu/~abio304/text/chapter_11.html (22 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
of COPI to the Golgi membranes (Dominguez et al., 1998). p24 and p23 are cargo receptors found
in both COPI and COPII coated vesicles. In COPI coated vesicles, they are present in stoichiometric
amounts relative to coatomer and the GTPase, ARF. The cytoplasmic domains of these proteins bind
to coatomer (e.g., Sohn et al., 1996) and are needed for cycling in the early secretory pathway (e.g.,
Nickel et al., 1997). COPI coatomer vesicles also bind to KKXX (di-lysine motif) and KXKXX
containing proteins. The KDEL receptor that binds to proteins containing the KDEL motif is also
transported in these vesicles. The γ subunit recognized the lysine motifs (Harter et al., 1996). These
motifs are retrieval signals (see Table 2, Chapter 10) in line with the role of COPI coated vesicles in
retrograde transport.
COPI is required for intra-Golgi retrograde transport in vitro (see Lin et al., 1999). COPI vesicles or
transport intermediates can be isolated or produced in vitro and have a high level of Golgi-resident
enzymes (Lanoix et al., 1999; Love et al., 1998) and KDEL receptors (Sönnichsen et al., 1996)
suggesting that they are recycling intermediates.
Although there is evidence for the involvement of COPI in anterograde transport (see previous
section), the evidence for a role of COPI in retrograde transport is less ambiguous. Subunit of the
coatomer bind directly to proteins with the di-lysine retrieval motif (Cosson and Letourneur, 1994).
Furthermore, mutation in some of these subunits prevents recovery to the ER of proteins with the di-lysine retrieval motif (Cosson et al., 1996). In view of these findings, some investigators are
postulating that the role of COPI in anterograde transport is indirect, recycling components needed
for COPII transport by retrograde transport. However, results of several experiments continue to
support a direct role of COPI in both anterograde and retrograde transport. Immunocytochemistry
with the electron microscope using colloidal gold and antibodies (to COPI subunits, KDEL
receptors and proinsulin) have demonstrated that both anterograde transport of proinsulin and VSV
G protein and retrograde transport of a KDEL receptor occur in COPI vesicles. These vesicles
constitute two distinct populations that together account for at least 80% of the vesicles present. The
COPI vesicles bud from every level of Golgi cisternae. Similar results were obtained in in vitro
experiments (Orci et al., 1997).
In addition to a retrograde pathway which involves COPI coat proteins, a transport pathway from
Golgi to ER has been found which functions independently from COPI coat proteins (see Storrie et
al., 2000). This pathway returns Golgi resident proteins (as well as protein toxins) to the ER and
may have a primary role in the recycling of lipids. Microinjection of antibodies to coatomer, block
recycling of KDEL receptor and a lectin-like molecule, ERGIC-53, from Golgi to ER. Proteins
containing sequences recognized by the KDEL receptor are also inhibited (Girod et al., 1999). In
contrast, microinjection of anti-COPI antibodies or an Arf-1 mutant (Arf is required for COPI-coated vesicle assembly) does not interfere with the transport to the ER of Golgi-resident
glycosylation enzymes or Shiga toxin/Shiga-like toxin-1. However, overexpression of a Rab6 (a
small GTPase, see discussion below) mutant blocks retrieval of Golgi-resident glycosylation
enzymes and Shiga toxin/Shiga-like toxin-1. However, it has no effect on KDEL receptor, KDEL
containing proteins or ERGIC-53. These observations indicate that there are two pathways for the
retrieval of proteins from the Golgi to the ER.
The protein p115 (TAP), which has a role in the transport from the VTC to the cis-Golgi (see
http://www.albany.edu/~abio304/text/chapter_11.html (23 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
previous section) is required for intra-Golgi transport (Waters et al., 1992) and is likely to function
in tethering several steps. It has been implicated in the binding to the plasma membrane during
transcytosis (Barroso et al., 1995).
II. RECOGNITION OF TARGETS
A. Cell Polarity
In an organized tissue, many cells have regions of the cytoplasm and the cell surface that differ in
composition and function. They are said to be polar. This polarity can be preserved when the cells
are cultured on a solid medium. Epithelial and endothelial cells form sheets in which they are held
together by junctional complexes which prevent exchange between the two domains and prevent
exchanges between compartments. A diagrammatic representation of polar cells in Fig. 2 shows
apical and basolateral surfaces. The adherens junction is responsible for adhesion between the cells.
In vertebrates the tight junction and in other animals the septate junction, prevent the exchanges.
Vertebrate epithelial and endothelial cells, are held together by the tight junctions at contact points,
the desmosomes which serve as anchoring points for intermediate filaments. In the polarized cell,
the apical and the basolateral surfaces have distinct lipid and protein domains (Simons and Fuller,
1985). This distinct composition could not be maintained unless the two were prevented from
exchanging materials and the various components were specifically targeted when newly
synthesized.
Essentially, tight junctions play a dual role as barriers and fences (see Chapter 4) (e.g., see
Gumbiner, 1993; Anderson and Van Itallie, 1995). The barrier function refers to the tight seal that
prevents diffusional exchanges between separate compartments The fence function refers to the
prevention of exchanges between the basolateral and apical domains of the plasma membrane to
maintain specialized functions, such as unidirectional secretion or active transport across the sheets.
In addition to their structural role, cell junctions can also provide signals that initiate cascades
involved in cell growth and differentiation (e.g., see Clark and Brugge, 1995; Takahashi et al.,
(1998); Reichert et al., 2000). For example, note that components of the signaling systems are
present at junctions (see below). In some cases, the role of the cell junction component may more
direct, for example, the adherens junction protein β-catenin (see below) is translocated into the
nucleus and binds to a transcription factor (see Nusse, 1997; Eger et al., 2000). Similarly, the
junctional component CASK (see Hata et al., 1996) is translocated into the nucleus (Hsueh et al.,
2000) and is required for EGF receptor localization and signalling in the nematode Caenorhabditis
elegans. CASK is membrane-associated guanylate kinase that is bound to the adhesion protein,
syndecan, at epithelial cell junctions (Cohen et al., 1998). In the nucleus, a complex of CASK and
Tbr-1 binds to a specific DNA sequence. Tbr-1 is a T-box transcription factor that is involved in
forebrain development. The complex of the CASK and Tbr-1 activates several genes containing the
T-box. T-box gene family have a binding domain, the T-domain which is important for
development.
http://www.albany.edu/~abio304/text/chapter_11.html (24 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
The structure and formation of tight junctions as well as the factor that underlie the formation and
maintenance of distinct membrane domains have been explored.
Maintenance of polarity
Some progess has been made in the study of the maintenance of polarity in Drosophila epithelium.
Proteins which localize to one of three surfaces and suspected to have a role in organizing the
corresponding domain have been called epithelial cell surface organizers (ECSOs) (see Tepass,
1997). These include cadherins (see below) that localize laterally (see Drubin and Nelson, 1996),
Crumbs proteins of Drosophila that localize to the apical surface in (e.g., Wodarz et al., 1995) and
β1, α integrins (see Chapter 6) located in the basal surface of kidney epithelium (Sorokin et al.,
1990) and Madin-Derby canine kidney (MDCK) cells (e.g., Schoenenberger et al., 1994). ECSOs
are thought to be recruited and retained to their domain by external signals such as homophilic
adhesion in the case of cadherin. The interaction of ECSDOs with cytoplasmic factors permit
interactions with the cytoskeletal system.
In Drosophila, the mutation in four genes (stardust, sdt, bazooka, baz, crumbs, crb, and discs lost,
dlt) has been shown to be lethal by eliminating polarity in epithelial cells (see Tepass, 1997). CRB
and DE-cadherin are considered key regulators of polarity. CRB is an integral membrane protein
with a single transmembrane domain. It contains thirty EGF-like (for other examples see Chapter 6,
Fig. 10 and 11) and four laminin AG domain-like repeats in its extracellular segment and a short
cytoplasmic tail of thirty seven amino acids. CRBs is expressed apically in ectodermally derived
epithelia. Interestingly the mRNA for CRBs is found in the apical cytoplasm ( Tepass et al., 1990),
suggesting that it is the mRNA and not the protein which is targeted to this region. Several examples
of proteins targeted via their mRNA are known (see Chapter 10). Overexpression of CRB expands
the apical plasma membrane and reduces the basolateral domain. In contrast, BAZ and DLT are
cytoplasmic proteins with protein-protein interacting domains such as the PDZ domain. At least in
vitro, one of the PDZ domains of DLT binds to the cytoplasmic domains of CRB ( Bhat et al., 1999,
Klebes and Knust, 2000) and the laterally localized Neurexin IV (NRXIV). Interference with DLT
(mutations or introduction of double-stranded RNA) lead to mistargeted CRB and NRX IV and
disruption of epithelial polarity. The apical distribution of DLT depends on the presence of CRB.
These and other observations suggest that CRB and DLT together with other proteins define the
localization of the zonula adherens ( Klebes and Knust, 2000) and independently the loss of cell
polarity (Grawe et al., 1996). An additional protein, Scribble was found to be necessary to maintain
the polarization of cells (Bilder and Perrimon, 2000), as development proceeds in Drosophila
embryogenesis. Scribble is localized to the epithelial septate junction. Without Scribble, adherens
proteins no longer assemble in the apical-basolateral region interface and apical proteins are no
longer localized at the apical region. Scribble, a protein of 195 kDa (calculated from the cDNA),
was found to contain many protein-protein binding domains and is likely to correspond to a scaffold
needed for other proteins to assemble.. The carboxy-end has four PDZ domains (the initials of the
first three proteins that were discovered with the motif). The amino-end contains sixteen leucine-rich repeats. Similar repeats are known to bind RhoA and Rac-GTPases, known to be associated
with polarity and junctions (Jou and Nelson, 1998; see Kaibuchi et al., 1999). Many PDZ proteins,
including Scribble localize at septate junctions, although others localize elsewhere. The actual
molecular role of Scribble is still unknown. It may have a a role in targeting or it might even be part
http://www.albany.edu/~abio304/text/chapter_11.html (25 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
of the fence that prevents exchanges between the two regions.
Components of tight junctions
EM studies of thin sections (Farquhar and Palade, 1963) revealed discrete sites at which tight
junctions produced close contacts between cells (“kissing points”). Freeze-fracture EM showed
anastomosing strands in the cytoplasmic leaflet of the plasma membrane with complementary
grooves in the external face of the bilayer (see Staehelin, 1974).

Fig. 2. Arrangement of epithelial cells forming a sheet.
Occludin, a 60 kDa integral protein was identified in tight junction strands (Furuse et al., 1993;
Ando-Akatsuka et al., 1996). The cloning of the corresponding cDNA (see Chapter 1) and
hydrophobicity plots (see Chapter 4) showed that occludin had four possible transmembrane
domains and three cytoplasmic domains including the amino- and carboxy-terminals (see Ando-Akatsuka et al., 1996). Occludin is involved in forming barriers and fences. The barrier function is
shown, for example, by the increase electrical resistance across the epithelium when chicken
occludin is overexpressed in under conditions in which they formed tight junctions (McCarthy et al.,
1996). Expression of the carboxy-terminally truncated occludin, rather than wild-type occludin
(Balda et al., 1996), was found to render MDCK cells incapable of maintaining a fluorescent lipid in
a specifically labeled cell surface domain, indicating that occludin is also involved in providing an
apical/basolateral intramembrane diffusion barrier.
More recently, claudin-1 and claudin-2, two 23 kDa integral membrane proteins, were found in tight
junctions of chick liver or transfected MDCK cells (Furuse et al., 1998a). Hydrophobicity analysis
(see Chapter 4) indicated four possible transmembrane domains and cDNA analysis showed no
sequence similarity to occludin. Immunofluorescence and immunoelectron microscopy (see Chapter
1) revealed that both claudins were present in the tight junction strands. When introduced in
fibroblasts lacking tight junctions, these proteins induced the formation of a network of strands and
http://www.albany.edu/~abio304/text/chapter_11.html (26 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
grooves at contact sites (Furuse et al., 1998b). The strands more closely resemble those in native
tight junctions, suggesting that the occludins are major components of the junctions. Extensive
studies indicate that the claudin family contains many members, as many as fifteen have been found
in data-base searches of cDNA (Morita et al., 1999a,b,c; Tsukita and Furuse, 1999).
Certain claudins appear to be associated with specific tissues. Claudin-5 and -6 have been found in
tight-junctional strands of endothelial, but not of epithelial cells (Morita et al., 1999b). Clostridium
perfringes enterotoxin, which binds specifically to claudin-3 and -4, were shown to disrupt tight
junction strands in transfected L fibroblast cells and MDCK cells (Sonoda et al., 1999) implicating
their presence in those junctions. The possibility of other molecular components forming tight
junctions cannot be excluded at this time (see Tsukita and Faruse, 1999)
Aside from the proteins forming tight junctions, there must be some structural basis for establishing
polarity. In addition to targeting sequences and corresponding receptors there must be an assembly
that includes cytoskeletal elements and permits the transfer of cargo to specific locations. The
generation of polarity is of fundamental importance in the physiology of a variety of cells. A general
model of the development of cell polarity has been presented (Drubin and Nelson, 1996). In this
model, clues at the surface lead to localized assemblies of submembrane elements, including the
cytoskeleton responsible for the organization of a pathway along an axis of polarity.
In the case of epithelial cells, the position of adhesion receptor proteins is determined by adhesion to
other cells or the extracellular matrix (ECM) (for cell-cell adhesion, E-cadherin; for adhesion to the
ECM, the integrins) (see also Fig. 7C, Chapter 4). This interaction generates localized assembly of
cytoskeletal elements. Integrins are bound by α-actinin and talin which recruit actin and actin-associated proteins. In turn, these serve as a scaffold for the assembly of signaling components, such
as adhesion kinase and components of the Ras pathway (such as SOS and Grb2 and GTP-binding
proteins), and may even lead to regulating gene expression as already discussed. Similarly, cadherin
recruits cytoplasmic proteins such as β-catenin, plakiglobin and P120. The binding of these proteins
to α-catenin (that has some homology with vinculin) may connect the complex to actin. Cadherin-catenin complexes recruit kinases (Src and Yes) and protein-tyrosine phosphatase, components
associated with signaling (see Chapter 7). GTP-binding proteins and Ras may associate with the
complex. In addition, the region that remains free, the apical region, also seems to respond and
assemble a distinct actin network cross-linked with villin, fimbrin and myosin I. Talin, α-actinin and
vinculin are involved in the formation of fibers containing actin at focal contacts (see Chapter 23).
Catenin, vinculin, α-actinin and plakoglobin have a similar mission but are part of an actin
containing belt connecting epithelial cells and are attached to cadherins. Fimbrin and villin are actin
bundling proteins (villin is present only in microvilli) (see Chapter 24). Talin, α-actinin and vinculin
are involved in the formation of fibers containing actin at focal contacts.
The events accompanying cell adhesion also redistribute the microtubules with consequences on the
targeting of secretory products. Depletion of kinesin disrupts the basolateral delivery, and depletion
of kinesin and dynein disrupts apical delivery (Lafont et al., 1994). Kinesin and dynein are motor
molecules that move along microtubules (see Chapter 24). The difference between the microtubules
transport to the two faces suggest that the organization of the microtubules is distinct in the two
http://www.albany.edu/~abio304/text/chapter_11.html (27 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
systems.
The determination of specific targeting of secretory vesicles is clearly closely dependent on these
events. In yeast, this is shown by mutations of the genes coding for sec6/sec8 which lead to the
accumulation of secretory vesicles in the bud of a daughter cell (Novick et al., 1990; TerBush,
1996). The proteins are found only at the tip of the bud, hence they determine polarity.
The sec6/sec8 complex, also known as exocyst, has been implicated in exocytosis and is specifically
located at sites of vesicle fusion. In yeast, the complex contains seven subunits of 70 to 155 kDa,
whereas in the rat, the complex has eight components ranging from 71 to 110 kDa (see Hsu et al.,
1996, 1998). In rat brain, sec6 and sec8 are two components of a 17S complex of 743 kDa
homologous to the yeast Sec6/8/15 complex of 834 kDa, which is required for exocytosis. The rat
brain complex associated with the plasma membrane has been implicated in exocytosis by its
immunoprecipitation with syntaxin, a plasma membrane protein critical for neurotransmission (see
above and Chapter 22).
In the rat brain, the complex is present at sites of neurosecretion such as the hippocampal synapses
(Hsu et al., 1996) and is essential for survival. Mice with a mutation in Sec8 die early during
embryogenesis at the primitive streak stage (Friedrich et al., 1997). In the MDCK cell line, the
complex is required for calcium dependent cell adhesion (Grindstaff et al., 1998). When the cells are
rendered permeable by streptolysin, Sec8 antibodies inhibit delivery of LDL receptor to the basal-lateral membrane, but not the delivery of the receptor for the nerve growth factor p75NTR to the
apical membrane. These findings suggest that the complex is needed to recruit vesicles to specific
domains. Similar conclusions were reached in neuronal tissues where the sec6/8 complex seems to
specify sites for targeting vesicles at domains of neurite outgrowth and potential active zones during
synaptogenesis (Hazuka et al., 1999).
B. Targeting of Plasma Membrane Proteins
Viral coat proteins with different plasma membrane targets share the transport pathway through the
Golgi system (Rindler et al., 1984), as shown by immunological EM methods using colloidal gold
markers of different sizes in doubly infected cells. What routes do these glycoproteins follow after
leaving the TGN? Are they targeted directly to their surface of residence or do they make a stopover
at the other surface?
The proteins are sorted out in the TGN (Rodriguez-Boulan and Nelson, 1989). Whether the delivery
is direct or indirect can be determined by growing the cells in sheets so that either the apical or
basolateral surface is separately accessible to antibodies or proteases. A block in the transport would
implicate a stopover in the alternative surface. The answers are not simple. Some of the
glycoproteins are sorted out in the TGN so that they are targeted directly to either the apical or the
basolateral surface. The delivery of the G-protein of VSV to the basolateral surface (Pfeiffer et al.,
1985) and of the hemagglutinin of influenza virus to the apical surface is direct (Matlin et al., 1983;
Matlin and Simons, 1984). However, other patterns are possible. In rat hepatocytes, all membrane
proteins appear to be delivered to the basolateral surface and eventually, the proteins destined to the
http://www.albany.edu/~abio304/text/chapter_11.html (28 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
apical surface are then rerouted to their final destination (Bartles et al., 1987; Schell et al., 1992). In
other cells, such as a polarized intestinal epithelium cell line (Caco-2), apical proteins can either
proceed directly to the apical surface or arrive first to the basolateral surface (e.g., Matter et al.,
1990a, Le Bevic et al., 1990).
How are the membrane proteins targeted? The targeting need not differ in principle from other
targeting processes. The transported protein may have a targeting domain. Targeting could also have
an entirely different mechanism, possibly involving the lipid components of the membrane and acyl
chains attached to the targeted protein. As discussed below, there is evidence in some cases, for a
targeting mechanism involving glycosphingolipids. The sorting machinery (such as the TGN) must
recognize the signal. In addition, the protein must then be targeted to the appropriate membrane site,
possibly by the presence of another targeting domain. A separate but related problem is the
preservation of the makeup of the target membrane itself.
Originally, most investigators assumed that plasma membrane proteins were targeted by a signal to
the apical surface, a basolateral targeting occurring by default. However, sorting signals have been
demonstrated in the cytoplasmic domain of proteins destined to the basolateral surface (Hunzinker et
al., 1991, Casanova et al., 1991, Mostov et al, 1992). One set of signals appears to be contained in
the Tyr-containing signals for endocytosis via clathrin-coated pits (Mostov et al., 1992). Mutations
of the cytoplasmic tail block basolateral targeting and the proteins are delivered to the apical
surface. Internalization signals, required for endocytosis, can substitute for basolateral signals
(Collawn et al., 1991). It has been suggested that the signal consists of the presence of a reverse β-turn in the protein. Some signals are distinct from the endocytotic signal (e.g., Hunziker et al., 1991,
Aroeti et al., 1993) and, in some cases, mutation of the cytoplasmic Tyr that blocks endocytosis has
no effect on basolateral sorting (Hunziker et al., 1991).
A short amino acid sequence (approximately 14 residues) serves as a signal for basolateral
localization of some proteins (Yokode et al., 1992; Mostov et al., 1992). When expressed in livers of
transgenic mice, the LDL receptor containing this sequence is targeted to the basolateral surface.
Mutant receptors lacking the sequence are delivered to the apical side. The probable sequence of a
cytoplasmic domain is Arg Asn X Asp XX Ser/Thr XX Ser, perhaps recognized by an adaptor
molecule of the Golgi.
In polarized MDCK cells the transferrin receptor (TR) is localized in the basolateral surface. After
binding transferrin, ligand and receptor are taken up in coated pits by endocytosis and then returned
to the basolateral surface. TR, whether synthesized de novo or recycled from vesicles, depends on
its cytoplasmic tail for targeting. The targeting signal for both pathways is contained in residues 19
to 41. However, within this region the targeting sequence for the biosynthetic pathway is distinct
from that for the endocytotic pathway (Odorizzi and Trowbridge, 1997)
A variety of observations suggest more complexity than that presented in this discussion. For
example, integrins and laminin have been shown to be transported from the TGN to the basolateral
surface in separate vesicles (Boll et al., 1991), demonstrating the possibility that more than one
pathway may be responsible for the same localization.
http://www.albany.edu/~abio304/text/chapter_11.html (29 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
The glycosyl phosphatidylinositol (GPI) anchor of certain proteins (see Chapter 4) could serve as an
apical signal (see Simons and Ikonen, 1997) by clustering with glycosphingolipids, forming “rafts”
that may correspond, at least in part, to caveolin containing elements (see Chapter 4 and Chapter 9).
After the separation of lipid-linked proteins in the Golgi, vesicle budding could segregate them from
other components. A role of GPI in apical targeting has been demonstrated in Madin-Darby canine
kidney (MDCK) cells and intestinal cells by attaching a GPI anchor to proteins not originally
destined to the apical surface (e.g., see Soole et al., 1985; Brown et al., 1989; Lisanti et al., 1989).
Conversely, replacement of the GPI anchor of placental alkaline phosphatase with the
transmembrane and cytoplasmic domains of VSV G, switched its targeting from the apical to the
basolateral surface (Brown et al., 1989).
The recognition of GPI-anchored proteins could occur in an early step of the cis-Golgi (see Brown
and Rose, 1992) because these proteins were found associated with the glycosphingolipid
microdomains at stages requiring cis-Golgi reactions.
Although many observations are compatible with the raft -GPI model, other significant factors are
likely to come into play. Fisher rat thyroid cells (FRT) (Zurzolo et al., 1993) and MDCK
Concanavalin A-resistant cells (MDCK-ConAr) (Zurzolo et al., 1994) behave differently from other
polarized epithelial cell lines. FRT cells target glycosphingolipids and six out of nine detectable
endogenous GPI-anchored proteins to the basolateral surface. In contrast, two other GPI-anchored
proteins are apical and one is present at either surface. Transfection (see Chapter 1) of several model
GPI proteins, previously shown to be apically targeted in MDCK cells, also led to unexpected
results. The GPI anchored form of Decay accelerating factor (DAF) was targeted to the basolateral
domain. Similarly, the Herpes simplex gD-1 protein attached to GPI in the form of fusion protein,
gD1-DAF, was targeted basolaterally, where gD1-DAF was delivered directly from the Golgi
apparatus to the basolateral surface.
Similar discrepancies are exhibited by MDCK-ConAr cells. In most polarized epithelial cell lines
(e.g., MDCK), both gD1-DAF and glucosylceramide (GlcCer) are sorted to the apical membrane. In
contrast, in MDCK-ConAr cells, gD1-DAF was sorted to both surfaces, but GlcCer was still
targeted to the apical surface (Zurzolo et al., 1994). In both MDCK and MDCK-ConAr cells, gD1-DAF became associated with TX-100-insoluble GSL clusters during transport to the cell surface. In
the FRT cell line gD1-DAF and GlcCer were both targeted basolaterally. Although gD1-DAF and
glucosyl ceramide distributed to the basolateral surface, gDI-DAF did not associate with membrane
clusters. Among several possible alternatives, this surprising finding could be explained by the
presence of a small subset of specialized clusters available for basolateral targeting.
In addition, in some cases, the role of the GPI anchor is in doubt. In MDCK cells, Thy-1 (a
glycoprotein of 25 kDa and unkownn function present in mouse thymocytes, T-cells and neurons)
anchored to GPI was delivered apically. However, a truncated form of Thy-1, lacking 22 out of 31
hydrophobic amino acids at the carboxy-terminal, still resulted in apical secretion of Thy-1 despite
the fact that the GPI anchor was not attached (Powell et al., 1991). It would therefore seem that Thy-1 contains apical targeting information in its protein sector, as well as in the GPI anchor.
GPI anchors are synthesized in the ER and added to primary translation products while they are
http://www.albany.edu/~abio304/text/chapter_11.html (30 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
being translocated across the ER membrane (see Thomas et al, 1990). In the plasma membrane, the
GPI anchors are attached to the external leaflet of the plasma membrane. The motif in the protein
directing attachment to the GPI resides in the amino acid sequence. The signal at the carboxy-end of
the proteins differ with the protein (see Medof et al., 1996). Characteristically, GPI anchored
proteins lack charged amino acids at the carboxy-end of the protein. An additional signal, 15 to 30
amino acids upstream of the terminal hydrophobic stretch of the protein, is needed for GPI
anchoring (see Medof et al., 1996).
In at least some cases, targeting may be a function of the lipid composition of the membrane. The
outer leaflet of the apical membrane of the epithelial Madine-Darby canine kidney (MDCK) cells
contains mainly glycosphingolipids held together by H-bonds. These lipids exclude glycerol-based
phospholipids (Thompson and Tillack, 1985). Similarly, glycosphingolipid clusters are present in
other membranes (see Chapter 4, Section VI).
Signals other than GPIs have also been found (e.g. see Weimbs et al., 1997). Saturated acylated
proteins (e.g., Src family kinases) appear to be targeted to detergent resistant membrane domains
which are thought to correspond to rafts (see Chapter 4). In contrast prenylated proteins (e.g., Ras)
are usually not found in these domains (Melkonian et al., 1999). This is likely to be the consequence
of the ordered environment of lipid rafts or caveolae (see Brown and London, 1998) which is more
likely to favor the incorporation of acyl chains. These chains tend to be present in an extended
configuration, whereas the prenyl moieties are branched and bulky. Studies in intact cells confirm
these observations (Zacharias et al., 2002). This study used FRET (see Chapter 1) a technique which
allows the study the interaction between two chromatophores separated by 10 nm or less and
therefore the proximity of the protein pairs. GFP variant pairs (donor-acceptor) were used. They
were combined to peptides with consensus sequences for either acylation or prenylation or with
caveolin, a protein components of rafts. The fluorescent GFP variants had to be modified to prevent
their dimerization. Again, the acyl proteins but not the prenylated proteins were found in rafts.
Furthermore, in contrast to the acylated proteins, the prenylated proteins were found insensitive to
cholesterol depletion.
The finding of the location of proteins in microdomains or caveolae is significant in relation to
regulatory cascades. The lipid microdomains contain signaling kinases so that when receptors are
bound to their ligand they move to these microdomains initiating a signaling cascade (see Pierce,
2002).
N-glycans of secretory (Scheiffele et al., 1995) or in N- and O-glycans of membrane proteins act as
apical signals (Yeaman et al., 1997; Gut et al., 1998). The hypothesis that N-linked carbohydrates
are responsible for apical targeting was tested with three membrane proteins (Gut et al., 1998). Two
are normally not glycosylated and another is a glycoprotein. In all three cases, N-linked
carbohydrates were clearly able to mediate apical targeting. However, the presence of cytoplasmic
basolateral targeting motifs remained basolateral even when attached to N-linked sugars. To
compare the role of GPI and N-glycans, GPI was attached to the rat growth hormone (rGH) which is
normally secreted in non-polarized manner (Benting et al., 1999). This modification did not lead to
an apical delivery. However, the addition of N-glycans to the GPI-anchored rGH did target mostly
to the apical surface. A transmembrane form of rGH accumulated intracellularly unless attached to
http://www.albany.edu/~abio304/text/chapter_11.html (31 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
N-glycans that delivered them to the apical surface. The N-or O-linked oligosaccharide could
possibly attach to lectins present in the rafts (such as VIP36) (see Fiedler and Simons, 1995).
As with other transport systems, it has been possible to partially reconstitute the basolateral targeting
system (Gravotta et al., 1990). The fusion of the vesicles to the surface requires energy and
cytoplasmic extracts. A GTP-binding protein is presumed to be involved because the fusion is
inhibited by GTPγS. As already discussed, GTP-binding proteins of the Rab family are thought to be
involved in fusion of vesicles in the intracellular transport system. There are some indications that
Rab8 is localized in the basolateral transport vesicles in MDCK cells.
Once incorporated into one of the cell membrane faces, the diffusibility of the proteins in the plane
of the membrane appears to be constrained by binding to the cortical cytoskeleton (Vega-Salas,
1987). Na+-K+, ATPase, the Na+-channel, and the anion exchange protein bind to ankyrin/fodrin
complexes (see Nelson and Hammerton, 1989).
The probable interactions involved in establishing and maintaining cell polarity are summarized in
Fig. 3 (Nelson, 1992).
C. Targeting in Secretion and Transcytosis
Secretion may also require targeting to a specific cell surface. This may be a consequence of the
common mechanism accounting for plasma membrane transport and secretion. Although some cells
release secretory products around their perimeter, many polar cells release them only in specific
regions of the membranes. Thus, the same kind of targeting has to be considered in secretion. In
MDCK cells, endogenous constitutively secreted proteins are released in the apical domain (Kondor-Koch et al., 1985; Gottlieb et al., 1986), whereas exogenous proteins (produced after transfection)
release at both the apical and basolateral cell surfaces.
http://www.albany.edu/~abio304/text/chapter_11.html (32 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport

Fig. 3 Mammalian polarized epithelial cell organization of protein trafficking pathways. Protein
sorting and transport between the trans Golgi network (TGN) and different cell surface domains are
regulated. In the TGN, proteins can be sorted by signal-mediated or bulk flow pathways into
different vesicles. Signal-mediated sorting of proteins to the apical plasma membrane (Ap-PM) is
regulated by glycosphingolipid patching, whereas signal-mediated sorting of protein to the
basolateral plasma membrane (BL-PM) is regulated by protein clustering of adaptor proteins; other
signal-mediated pathways may also exist. Docking with targeting patches in each membrane is
regulated by domain-specific GTPase cycles (Ap-GTPase, apical membrane GTPase; BL-GTPase,
basal-lateral membrane GTPase) (from Nelson 1992). Reproduced by permission.
Most cells carry out receptor-mediated endocytosis (Chapter 9), in which the ligand is generally
degraded in the lysosomes and the receptor is either degraded or recycled to the surface. However,
in transcytosis, which is ubiquitous in epithelial cells, the endosomes transfer receptor and ligand to
the surface of opposite polarity, so that the material traverses the cell.
The transcytosis of polymeric immunoglobulin (poly-Ig) is probably the best understood of the
various known cases. Poly-Ig is produced by plasma cells and transported through epithelial cells by
transcytosis. In this process, the epithelial cell adds a polypeptide, the secretory component (SC) or
secretory piece, part of the receptor molecule, to the poly-Ig. The poly-Ig receptor is originally
incorporated in the basolateral surface, where it binds poly-Ig. After transcytosis, the endocytotic
vesicle discharges its contents at the apical surface by exocytosis and the receptor is cleaved. So far,
only one signal has been identified in transcytosis, the phosphorylation of a Ser in the cytoplasmic
domain of the receptor (Casanova et al., 1990).
http://www.albany.edu/~abio304/text/chapter_11.html (33 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
Despite the flow of membranes from one pole of the cell to the other in transcytosis, the two surface
domains remain distinct. This is illustrated by VSV G-protein, which is normally in the basolateral
surface of the infected MDCK cells. When artificially inserted into the apical surface by fusing it to
viral coats at low pH, the VSV-G protein is taken up by endocytosis and delivered to the basolateral
surface (Matlin et al., 1983). Therefore, it would seem possible that portions of the membranes
involved in transcytosis can be recycled to their original location by a process akin to transcytosis in
reverse.
D. Transport of the Vesicles
What is responsible for the movement of vesicles? The information presently available suggests a
varied pattern (see Bloom and Goldstein, 1998).
The diffusion coefficient of granules in cells is approximately 2.5 x 10-10 cm2/s (Felder and Kam,
1994). It has been calculated that a vesicle 160 nm in diameter can diffuse for a distance of 10 µm in
10 minutes (Bloom and Goldstein, 1998). Therefore, no special mechanism is required in small cells
for a variety of vesicular transport events. For a neuron, the distances from cell body to periphery,
however, is prohibitive (the vesicles may have to travel 1 m or more from the cell body to the
neuron terminal) and microtubular transport is essential.
Normally, the transport from the compartments intermediate between ER and Golgi (ICs) to the
Golgi, occurs on microtubules (Presley et al., 1997; Scales et al., 1997) as shown by direct
observation using conjugates of VSV-G glycoprotein and green fluorescent protein (see Chapter 1,
Chapter 10, Section III). However, in some cases, the absence of MTs does not preclude secretion at
close to normal rates (e.g., van de Moortele et al., 1993). Apparently, in these cases, the Golgi
cisternae segment in ministacks. These ministacks distribute throughout the cytoplasm (Rogalski
and Singer, 1984) adjacent to IC sites and the ER (Cole et al., 1996). Presumably in these cases the
transport can proceed efficiently by diffusion.
These considerations and other presently available information suggest that in anterograde transport
microtubules have no role in transport from ER to IC or in intra-Golgi transport. However, they are
needed for transport from IC to Golgi or from TGN to the cell surface (see Lippincott-Schwartz,
1998).
In the retrograde pathway, microtubules are also involved in many steps. Golgi to ER transport is
driven by kinesin (Lippincott-Schwartz et al., 1995), a microtubular motor, and microtubules are
involved in the transport of endosomes and lysosomes toward the centrosome, as shown by direct
observation and the use of microtubular inhibitors (Matteoni and Kreis, 1987).
In polarized epithelial cells, microtubules seem to be involved in the movement of vesicles to the
apical surface (Nelson, 1991, 1992). Depolymerization of microtubules interferes with trafficking
between TGN and the apical membrane (e.g., Rindler et al.,1987; Van Zeijl and Matlin, 1990) and
decreases transcytosis from the basolateral to the apical surface (e.g., Matter et al., 1990b, Breitfeld
et al., 1990). The presence of colchicine, vinblastine or nocodazole (all drugs which interfere with
http://www.albany.edu/~abio304/text/chapter_11.html (34 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
the microtubules) redirects the vesicles from the apical to the basolateral surface. In contrast, the
basolateral traffic is not affected. However, in budding yeast, microtubules do not have a role in
polarized secretion (e.g., Huffaker et al., 1988; Jacobs et al., 1988). In contrast, in these cells, actin
(e.g., see Novick and Botstein, 1985) has been found to be involved in conjunction with Myo2p, a
myosin V (see Chapter 24) (e.g., Santos and Snyder, 1997; Catlett and Weisman, 1998; Schott et al.,
2000).
The experiments carried out with mammalian cells indicate a primary role of microtubules in apical
vesicular transport. The presence of myosin I in Golgi derived vesicles (Fath and Burgess, 1993) and
in apical membranes (Mooseker and Coleman, 1989) also suggests a role of the actomyosin system
in at least some of the processes of intracellular transport. Myosin I is found in vesicles in intestinal
brush border cells where they are linked to actin filaments (Drenckhahn and Dermietzel, 1988).
Similarly, myosin I was localized by immunoblotting and immunolabel negative staining of the
isolated vesicles during the assembly of these cells (Fath and Burgess, 1993). This protein was
found at the outer surface of Golgi associated vesicles during the assembly of these cells. The
vesicles contained galactosyl transferase, a trans-Golgi enzyme, as well as alkaline phosphatase, an
apical membrane targeted enzyme. The vesicles were also shown to bundle actin, suggesting that the
actomyosin system functions in the peripheral translocation of vesicles. The results suggest an
involvement of both microtubules and the actomyosin system, the latter perhaps only in the final
step of the delivery in the apical pathway. However, the details are still not clear.
How are the vesicles connected to the transporting systems? Present evidence implicates dynactin.
Dynactin is a 1.2 MDa complex of ten peptides (and includes actin) that is required for cytoplasmic
dynein motility and in vitro vesicle movement (Schroer and Sheetz, 1991).
Electron microscopy of this complex shows an actin-like filament, 37 nm long, with laterally
projecting sidearms (Schafer et al., 1994). A model of dynactin is shown in Fig. 4 (Schroer et al.,
1996). The filamentous part of the molecule is made up of the actin related protein (Arp1) and
probably one molecule of actin. The interaction between dynactin and the MT-dynein system
probably involves the sidearms that contain a microtubule binding site (Waterman-Storer et al.,
1995) and also bind dynein (Collins and Vallee, 1989). The most likely role of the Arp1 portion of
the complex is to provide a connection to the cargo vesicle.
Many myosins of the myosin I family bind directly to phospholipid. Myosin I isoforms associate
with specific membranes (Baines et al., 1995). It is entirely possible then that dynactin binding to
the vesicles is mediated by myosin, although other possibilities are also likely (e.g., ponticulin or an
annexin, see Schroer et al., 1996).
http://www.albany.edu/~abio304/text/chapter_11.html (35 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport

Fig. 4 Current model of dynactin structure. The localization of Arp1, actin-capping protein, p62 and
p150Glued/P135Glued are based on ultrastructural analysis of antibody decorated molecules. The
location of actin, p50, p24 and p27 is uncertain. Because of their similar properties, actin is likely to
be in the Arp1 filament. The overexpression of p50 causes p150Glued to dissociate suggesting the
location in the diagram. From Schroer et al., 1996, reproduced by permission.
E. Recycling of the Plasma Membrane
The process of exocytosis adds a considerable amount of material to the plasma membrane. Much of
this material is recycled through endocytosis. Because of this continuous recycling, the turnover
time of the membranes of granules is relatively long compared to that of ordinary cytoplasmic
proteins (Meldolesi, 1974).
The availability of antibodies to membrane proteins of the luminal side of the secretory vesicle
membrane has permitted following the fate of the secretory vesicles in the regulated secretion of
catecholamine granules (Patzak and Winkler, 1986). Glycoprotein III (gpIII) is exposed to its
fluorescently labelled antibody at exocytosis. The protein appears in coated pits and vesicles in the
first 5 min after exocytosis. Then it passes through the smooth ER and reappears in the trans Golgi
network and in dense-core secretory granules within 30 to 45 min. The protein was never found in
the cisternal lumen, indicating that the membrane itself is being recycled. Similar results were found
for the transferrin receptors (Woods et al. 1986). Their presence was demonstrated in several Golgi
cisternae; therefore, recycling must involve some of the same steps followed by the transport of
newly synthesized protein.
These observations imply that some steps in the recycling process must involve transport in the
opposite direction from that discussed in most of this chapter, that is retrograde transport.
Retrograde transport is beginning to be studied by taking advantage of the effect of the antibiotic
Brefeldin A (Tan et al., 1992). Brefeldin, a macrocyclic lactone synthesized by fungi, prevents the
assembly of nonclathrin coated vesicles and blocks the transport from ER to Golgi (e.g., Klausner et
al., 1992). The retrograde transport, however, is not inhibited, redistributing material such as
enzymes from the Golgi back to the ER. This transport is also blocked by GTPγS, suggesting that
http://www.albany.edu/~abio304/text/chapter_11.html (36 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
GTP-binding proteins are involved in both forward and backward transport.
F. Formation of Lysosomes and Secretory Storage Vesicles
Lysosomes
The study of the transport system in the formation of lysosomes received great impetus from the
recognition of at least 30 human lysosomal storage disorders. I-cell disease, a deficiency in
lysosomal enzymes, results from a failure in the recognition marker needed for targeting. Study of I-cell mutants has permitted the identification of the recognition marker, the mannose-6-phosphate
(M6P) residue, and the M6P receptor, MPR (Sahagian et al., 1981). The receptor spans the
membrane and 10 kDa of its carboxy-terminal protrudes into the cytosol (Sahagian and Steer, 1985).
Two distinct but related MPRs are known (see Kornfeld, 1992). One is a type I (amino group
external to the cell) transmembrane glycoprotein of 275 kDa which does not require divalent
cations. The other receptor is also a type I glycoprotein of 46 kDa. The bovine and murine forms of
the latter, but not the human or porcine forms, require divalent cations for optimal binding.
M6PRs bind to lysosomal hydrolases while they are transported from the trans-Golgi to the
lysosomes. In turn, targeting signals in the M6PRs are needed to arrive at their final destination. The
Golgi-localized γ-ear containing, ARF-binding (GGAs) adaptors have been found to bind to the
lysosomal targeting signals of the cation-independent M6PRs, the acidic cluster-dileucine motif of
their cytoplasmic tails. The GGAs, already implicated in protein trafficking between the Golgi and
the endosomes, have all the properties expected for an adaptor mediating the binding of the
receptors to the components needed for transport. They contain a Vps27p/Hrs/STAM (VHS)
domain, binding sites for clathrin, a GTP-ARF binding domain and a domain that binds to proteins
involved in coat assembly such as γ-synergin. The VHS domain of 153 residues is present in various
proteins involved in endocytic trafficking (Lohi and Lehto, 1998). The M6PRs bind to the VHS
domain of the GGAs. The GGAs were found to be present in the TGN, tubules and vesicles which
bud from the TGN and the cell surface as expected from its presumed function (Zhu et al., 2001;
Puertollano et al., 2001).
Lysosomal enzyme precursors are transported through the common pathway, as indicated by
immunocytochemical experiments (Geutze et al., 1984). However, processing continues on arrival
in the cis-Golgi (Fig. 5, Kornfeld, 1987), where lysosomal hydrolases are recognized by GlcNAc-phosphotransferase, which adds GlcNAc-phosphate to α-1,2-mannose residues of the hydrolases.
The phosphotransferase probably recognizes a signal patch, because recognition is very sensitive to
conformation changes. After this modification, M6P residues are exposed by removal of the N-acetylglucosamine and are recognized by MPR. The interaction between receptors and M6P residues
is responsible for the lysosomal enzyme segregation (see von Figura and Hasilik, 1986; Kornfeld,
1987). The two can be detected together in buds and coated vesicles in the TGN, which eventually
form lysosomes (Geutze et al., 1985, Griffiths et al., 1985).
In addition to the processing of the oligosaccharides, lysosomal enzymes are proteolytically cleaved
to their mature form (Gieselman et al., 1983).
http://www.albany.edu/~abio304/text/chapter_11.html (37 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport

Fig. 5 Schematic pathway of lysosomal enzyme targeting to lysosomes. Lysosomal enzymes and
secretory proteins are synthesized in the rough endoplasmic reticulum (RER) and glycosylated by
the transfer of a performed oligosaccharide from dolichol-P-P-oligosaccharide (DOL). In the RER,
the signal peptides (hatching) are excised. The proteins are translocated to the Golgi, where the
oligosaccharides of secretory proteins are processedto complex-type units and the oligosaccharides
of lysosomal enzymes are phosphorylated. Most of the lysosomal enzymes bind to mannose6-phosphate receptors (MPRs) ( ) and are translocated to an acidified prelysosomal
compartment where the ligand dissociates. The receptors recycle back to the Golgi or to the cell
surface, and the enzymes are packaged into lysosomes where cleavage of their propieces is
completed ( ). The Pi may also be cleaved from the mannose residues. A small number of the
lysosomal enzymes fail to bind to the receptors and are secreted along with secretory proteins (
). These enzymes may bind to surface MPRs in coated pits ( ) and be internalized into
the prelysosomal compartment. ( ) N-Acetylglucosamine; ( ) mannose; ( ) glucose; ( )
galactose; ( ) sialic acid. Reprinted with permission from S. Kornfield, Federation of American
Societies for Experimental Biology Journal, Vol.1, No.6: 463, 1987.
The MPRs are recycled. Before the primary lysosomes are formed, the MPRs are sent back to the
trans Golgi. Recovery of receptor probably follows its dissociation from the ligands brought about
by lowering the pH, as in the case of endocytotic vesicles discussed in Chapter 9. Although most
lysosomal enzymes remain segregated in vesicles, a small portion of the lysosomal enzymes are
secreted and are thought to be recovered by endocytotic uptake after binding MPRs present at the
surface (Willingham et al., 1981).
http://www.albany.edu/~abio304/text/chapter_11.html (38 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
Secretory storage granules
Regulated secretion differs from constitutive secretion in the need to store the secreted products in
the secretory vesicles until a physiological signal permits their discharge. Therefore, they must be
separated from the other products destined to the cell surface. This separation occurs in the trans-Golgi, but the selection mechanism is still unknown. The process can be very selective. However, it
also allows for packaging very different proteins in the same vesicle.
The possibility that a receptor is involved in targeting storage secretory products is also supported
by the observation that the precursor of insulin, proinsulin, is bound to Golgi membranes (Munro
and Pelham, 1986), indicating the likelihood that a receptor is present.
G. Synaptic Vesicles
Presynaptic cells discharge neurotransmitters by exocytosis of their synaptic vesicles. Postsynaptic
membrane receptors bind the neurotransmitters. These receptors are channels that open more
frequently after binding the neurotransmitters. The increased conductance of the membrane initiates
the depolarization that can culminate in an action potential (see Chapter 22). The presynaptic
neurotransmitter vesicles are continuously discharged and continuously reformed. Most of the
recycling involves the recovery of synaptic vesicles by endocytosis and their reloading with
neurotransmitter (See Chapter 22). However, there is also a turnover of the synaptic vesicles
themselves; their components are degraded and resynthesized in the cell body. Eventually, the newly
formed vesicles must be targeted to the nerve terminals through axonal transport. The integral
proteins follow the usual path from RER to TGN. These proteins obviously can be found at synaptic
sites, but also (with few exceptions) throughout the Golgi system.
All indications are that the forward or anterograde transport of newly synthesized synaptic vesicle
components is microtubular and is powered by the motor protein of the kinesin family (Chapter 24).
Kinesin is implicated by its association with vesicles (e.g., Morin et al., 1993) and by its
accumulation when the axonal flow is blocked by ligation (Hirokawa et al., 1991). The vesicles and
the kinesin (indentified by immunocytochemistry) accumulate on the cell body side of the ligature.
Evidence from genetic studies also implicates a kinesin-like molecule. The unc-104 gene codes for a
kinesin-like motor, thought to be neuron specific in the nematode Caenorhabditis elegans. This
protein has a kinesin-like motor domain at the amino terminal, but otherwise it has little homology
to other kinesins. Mutant alleles of this gene block the accumulation of synaptic vesicles in axons
(Hall and Hedgecock, 1991). The movement of other vesicles is not affected, suggesting a unique
targeting role for the protein coded by the unc-104 gene.
The study of the biogenesis of synaptic vesicle proteins can be carried out most readily in
neuroendocrine cells and neurons in culture. PC12 cells, derived from pheochromocytoma of the rat
adrenal medulla, have characteristics of both neural and endocrine cells. They synthesize, store and
release the neurotransmitter acetylcholine (Greene and Rein, 1977) and have both regulated and
constitutive secretory pathways. In these cells, regulated secretion involves large dense-core
granules related to chromaffin granules. Small electron-translucent vesicles are also present and are
thought to be related to cholinergic synaptic vesicles. Dense granules were purified and shown to
http://www.albany.edu/~abio304/text/chapter_11.html (39 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
contain the regulated secretory protein secretogranin II. The synaptic protein synaptophysin was
used as a marker for the smaller vesicles (Cutler and Cramer, 1990). Synaptophysin is a major
integral protein of synaptic vesicle membranes. Pulse-chase experiments using immunoprecipitation,
demonstrated that synaptophysin is associated with the smaller vesicles and does not occupy the
dense granules at any time. These findings indicate two separately regulated secretion routes. In
another study, synaptophysin was also traced by pulse-chase (Régnier-Vigouroux et al., 1991). It
was found to follow a route involving the trans Golgi network (TGN). The protein was found to
reach the cell surface from the TGN with a half time of 10 min and was found to cycle between cell
surface and vesicles. The endosomal fraction was identified by exposing the terminals to
peroxidases and tracing this enzyme. Peroxidase is taken up by endocytosis and represents the
material dissolved in the external medium.
The molecular mechanism by which the synaptic vesicle proteins are sorted out is not clear. A
common sequence motif that could be recognized by receptors used in targeting has not been found
in examining the various proteins of the secretory vesicles, and signals involving secondary or
tertiary folding are suspected. A role of specific complexes of synaptic proteins in targeting is also
possible because multimeric complexes can be recovered from synaptic vesicles after detergent
treatment (Bennett et al., 1992).
SUGGESTED READING
Bloom, G.S. and Goldstein, L.S.B. (1998) Cruising along microtubule highways: how membranes
move through the secretory pathway, J. Cell Biol. 140:1277-1280. (MedLine)
Kirchhausen, T. (2000) Clathrin, Annu. Rev. Biochem. 69:699-727. (MedLine)
Lippincott-Schwartz, J. (1998) Cytoskeletal proteins and Golgi dynamics, Curr. Opin. Cell Biol.
10:52-59.
McNiven, M.A., Cao, I., Pitts, K.R. and Yoon, I. (2000) The dynamin family of mechanoenzymes:
pinching in new places, Trends Biochem Sci 25:115-120.(MedLine)
Mellman, I. and Warren, G. (2000) The road taken: past and future foundations of membrane traffic,
Cell 100:99-112. (MedLine)
Morgan, A. (1995) Exocytosis, Essays in Biochemistry 30:77-95.
Nelson, W. J. (1992) Regulation of cell surface polarity from bacteria to mammals, Science 258:948-955. (MedLine)
Robinson, M.S. (1997) Coats and vesicle budding, Trends in Cell Biol. 7:99-102.
Schekman, R. and Orci, L. (1996) Coat proteins and vesicle budding, Science 271:1526-1533.
(MedLine)
http://www.albany.edu/~abio304/text/chapter_11.html (40 of 41) [3/5/2003 7:56:56 PM]
11. Biosynthesis and Cytoplasmic Trafficking: Membranes, Vesicles and Intracellular Transport
Simons, K. and Ikonen, E. (1997) Functional rafts in cell membranes, Nature 387:569-572.
(MedLine)
Springer, S., Spang, A. and Schekman, R. (1999) A primer on vesicle budding, Cell 97:145-148.
(MedLine)
Weimbs, T., Low, S.H., Chapin, S.J. and Mostov, K.E. (1997) Apical targeting in polarized
epithelial cells: there’s more afloat than rafts, Trends in Cell Biol. 7:393-399.
Wieland, F. and Harter, C. (1999) Mechanisms of vesicle formation: insights from the COP system,
Curr. Opin. Cell Biol. 11:440-446. (MedLine)
WEB RESOURCES
Kirchhausen, T. and Bruce, A. Clathrin-coat formation in time and space: modelling.

http://www.hms.harvard.edu/news/clathrin

REFERENCES
Search the textbook
http://www.albany.edu/~abio304/text/chapter_11.html (41 of 41) [3/5/2003 7:56:56 PM]
Chapter 11: References
Back to Chapter 11
REFERENCES
Aalto, M.K., Keränen, S. and Ronne, H. (1992) A family of proteins involved in intracellular transport,
Cell 68:181-182. (Medline)
Aalto, M.K., Ronnel, H. and Carragheenin, S. (1993) Yeast syntaxis Sso1p and Ssop2 belong to a family
of related membrane proteins that function in vesicular transport, EMBO J. 12:4095-4104. (Medline)
Ahle, S. and Ungewickell, E. (1989) Identification of clathrin binding subunit in the HA-2 adaptor protein
complex, J. Biol. Chem. 264:20089-20093. (Medline)
Anderson, J.M. and Van Itallie, C.M. (1995) Tight junctions and the molecular basis for regulation of
paracellular permeability, Am. J. Physiol. 269:G467-475. (Medline)
Ando-Akatsuka, Y., Saitou, M., Hirase, T., Kishi, M., Sakakibara, A., Itoh, M., Yonemura, S., Furuse, M.
and Tsukita, S. (1996) Interspecies diversity of the occludin sequence: cDNA cloning of human, mouse,
dog, and rat-kangaroo homologues, J. Cell Biol. 133:43-47. (Medline)
Aridor, M., Weissman, J., Bannykh, S., Nuoffer, C. and Balch, W.E. (1998) Cargo selection by the COPII
budding machinery during export from the ER, J. Cell Biol. 141:61-70. (MedLine)
Aroeti, B., Kosen, P.A., Kuntz, I.D., Cohen F.E. and Mostov, K.E. (1993) Mutational and secondary
structural analysis of the basolateral sorting signal of the polymeric immunoglobulin receptor, J. Cell.
Biol. 123:1149-1160. (Medline)
Baines, I.C., Corigliano-Murphy, A. and Korn, E.D. (1995) Quantification and localization of
phosphorylated myosin I isoforms in Acanthamoeba castellanii, J. Cell Biol. 130:591-603. (Medline)
Bhat, M.A., Izaddoost, S., Lu, Y., Cho, K.O., Choi, K.W. and Bellen, H.J. (1999) Discs Lost, a novel
multi-PDZ domain protein, establishes and maintains epithelial polarity, Cell 96:833-845. (MedLine)
Balch, W. E., Dunphy, W. G., Braell, W. A. and Rothman, J. E. (1984a) Reconstitution of the transport of
protein between successive compartments of the Golgi measured by the coupled incorporation of N-acetylglucosamine, Cell 39:405-416. (Medline)
http://www.albany.edu/~abio304/ref/ref11.html (1 of 32) [3/5/2003 7:57:08 PM]
Chapter 11: References
Balch, W. E., Glick, B. S. and Rothman, J. E. (1984b) Sequential intermediates in the pathway of
intercompartmental transport in a cell free system, Cell 39:525-536. (Medline)
Balch, W. E., Wagner, R. R. and Keller, D. S. (1987) Reconstitution of transport vesicular stomatitis virus
G protein from the endoplasmic reticulum to the Golgi complex using a cell free system, J. Cell Biol.
104:749-760. (Medline)
Balch, W.E., McCaffery, J.M., Pluttner, H. and Farquhar, M.G. (1994) Vesicular stomatitis virus
glycoprotein is sorted and concentrated during export from the endoplasmic reticulum, Cell 76:841-852.
(Medline)
Balda, M.S., Whitney, J.A., Flores, C., Gonzalez, S., Cereijido, M. and Matter, K. (1996) Functional
dissociation of paracellular permeability and transepithelial electrical resistance and disruption of the
apical-basolateral intramembrane diffusion barrier by expression of a mutant tight junction membrane
protein, J. Cell Biol. 134:1031-1049. (Medline)
Bankaitis, V.A., Aitken, J.R., Cleves, A.E. and Dowhan, W. (1990) An essential role for a phospholipid
transfer protein in yeast Golgi function, Nature 347:561-562. (Medline)
Bannykh, S.I. and Balch, E.E. (1997) Membrane dynamics at the endoplasmic reticulum-Golgi interface,
J. Cell Biol.138:1-4. (Medline)
Barlowe, C. (1998) COPII and selective export from the endoplasmic reticulum, Biochim. Biophys. Acta
1404:67-76. (MedLine)
Barlowe, C. and Shekman, R. (1993) SEC12 encodes a guanine-nucleotide-exchange factor essential for
transport vesicle budding from the ER, Nature 365:347-349. (Medline)
Barlowe, C., Orci, L., Yeung, T., Hosobuchi, M., Ravazzola, M. Amherdt, M. and Shekman, P. (1994)
COPII: a membrane coat formed by SEC proteins that drive vesicle budding from the endoplasmic
reticulum, Cell 77: 895-907. (Medline)
Barnard, R.J., Morgan, A. and Burgoyne, R.D. (1997) Stimulation of NSF ATPase activity by α-SNAP is
required for SNARE complex disassembly and exocytosis, J. Cell Biol. 139:875-883. (Medline)
Barroso, M., Nelson, D.S. and Sztul, E.(1995) Transcytosis-associated protein (TAP)/p115 is a general
fusion factor required for binding of vesicles to acceptor membranes, Proc. Natl. Acad. Sci. USA 92:527-531. (MedLine)
Bartles, J. R., Feracci, H. M., Stieger, B. and Hubbard, A. L. (1987) Biogenesis of the rat hepatocyte
http://www.albany.edu/~abio304/ref/ref11.html (2 of 32) [3/5/2003 7:57:08 PM]
Chapter 11: References
plasma membrane in vivo: comparison of the pathways taken by apical and basolateral proteins using
subcellular fractionation. J. Cell Biol. 105:1241-1251. (Medline)
Beck, K.A. and Nelson, W.J. (1998) A spectrin membrane skeleton of the Golgi complex, Biochim.
Biophys. Acta. 1404:153-160. (Medline)
Beckers, C.J. and Balch, W.E. (1989) Calcium and GTP: essential components in vesicular trafficking
between the endoplasmic reticulum and Golgi apparatus, J. Cell Biol. 108:1245-1256. (MedLine)
Bednarek, S.Y., Ravazzola, M., Hosobuchi, M., Amherdt, M., Perrelet, A., Shekman, R. and Orci, L.
(1995) COPI and CopII-coated vesicles bud directly from the endoplasmic reticulum in yeast, Cell
83:1183-1196. (Medline)
Bennett, M.K., Calakos, N., Kreiner, T. and Scheller, R.H. (1992) Synaptic vesicle membrane proteins
interact to form a multimeric complex, J. Cell Biol. 116:761-775. (Medline)
Benting, J.H., Rietveld, A.G. and Simons, K. (1999) N-Glycans mediate the apical sorting of a GPI-anchored, raft-associated protein in Madin-Darby canine kidney cells, J. Cell Biol. 146:313-320.
(Medline)
Berditchevski, F., Tolias, K.F., Wong, K., Carpenter, C.L. and Hemler, M.E. (1997) A novel link between
integrins, transmembrane-4 superfamily proteins (CD63 and CD81), and phosphatidylinositol 4-kinase, J.
Biol. Chem. 272:2595-2598. (Medline)
Bilder, D. and Perriman, N. (2000) Localization of apical epithelial determinants by the basolateral PDZ
protein Scribble, Nature 403:676-680. (Medline)
Block, M.R., Glick, B.S., Wilcox, C.A., Wieland, F.T. and Rothman, J.E. (1988) Purification of an N-ethylmaleimide-sensitive protein catalyzing vesicular transport, Proc. Natl. Acad. Sci. USA 85:7852-7856.
(Medline)
Bloom, G.S. and Goldstein, L.S.B. (1998) Cruising along microtubule highways: how membranes move
through the secretory pathway, J. Cell Biol. 140:1277-1280. (Medline)
Boll, W., Partin, J.S.,Katz, A.I., Caplan, M.J.. and Jamieson, J.D. (1991) Distinct pathways for basolateral
targeting of embrane and secretory proteins in polarized epithelial cells, Proc. Natl. Acad. Sci. USA
88:8592-8596. (Medline)
Braell, W. A., Balch, W. E., Dobbertin, D. C. and Rothman, J. E. (1984a) The glycoprotein that is
transported between successive compartments of the Golgi in a cell free system resides in stacks of
cisternae, Cell 39:511-524. (Medline)
http://www.albany.edu/~abio304/ref/ref11.html (3 of 32) [3/5/2003 7:57:08 PM]
Chapter 11: References
Breckenridge, L.J. and Almers, W. (1987) Currents through the fusion pore that forms during exocytosis
of a secretory vesicle, Nature 328:814-817. (MedLine)
Breitfeld, P.P., McKinnon, W.C. and Mostov, K.E. (1990) Effect of nocodazole on vesicular traffic to the
apical and basolateral surfaces of polarized MDCK cells, J. Cell Biol. 111:2365-2373. (Medline)
Bremser, M., Nickel, W., Schweikert, M., Ravazzola, M., Amherdt, M., Hughes, C.A., Sollner, T.H.,
Rothman, J.E. and Wieland, F.T. (1999) Coupling of coat assembly and vesicle budding to packaging of
putative cargo receptors, Cell 96:495-506. (MedLine)
Broadie, K., Prokop, A., Bellen, H.J., O’Kane, C.J., Schulze, K.L. and Sweeney, S.T. (1995) Syntaxin and
synaptobrevin function downstream of vesicle docking in Drosophila, Neuron 1 5:663-673. (MedLine)
Brodsky, F.M. (1988) Living with clathrin: its role in intracellular membrane traffic, Science 242:1396-1402. (Medline)
Brodsky, F.M. (1997) New fashions in vesicle coats, Trends in Cell Biol. 7:175-179.
Brown, D.A. and Rose, J.K. (1992) Sorting of GPI-anchored proteins to the glycolipid-enriched
membrane subdomains during transport to the apical cell surface, Cell 68:533-544. (Medline)
Brown, D.A. and London, E. (1998) Structure and origin of ordered lipid domains in biological
membranes, J. Membr. Biol. 164:103-114. (MedLine)
Brown, D.A., Crise, B., and Rose, J.K. (1989) Mechanism of membrane anchoring affects polarized
expression of two proteins in MDCK cells, Science 245:1499-1501. (Medline)
Brown, H.A., Gutowski, S., Moomaw, C.R., Slaughter, C. and Sternweis, P.C. (1993) ADP-ribosylation
factor, a small GTP-dependent regulatory protein, stimulates phospholipase D activity, Cell 75:1137-1144. (Medline)
Cao, X., Ballew, N., and Barlowe, C. (1998a) Initial docking of ER-derived vesicles requires Uso1p and
Ypt1p but is independent of SNARE proteins, EMBO J. 17:2156-2165. (Medline)
Cao, H., Garcia, F. and McNiven, M.A (1998b) Differential distribution of dynamin isoforms in
mammalian cells, Mol. Biol. Cell 9:2595-2609. (MedLine)
Carpenter, C.L. and Cantley, L.C. (1996) Phosphoinositide kinases, Curr. Opin. Cell Biol. 8:153-158.
(Medline)
http://www.albany.edu/~abio304/ref/ref11.html (4 of 32) [3/5/2003 7:57:08 PM]
Chapter 11: References
Casanova, J.E., Breitfeld, P.P., Ross, S.A., and Mostov, K.E. (1990) Phosphorylation of a polymeric
immunoglobulin receptor required for efficient transcytosis, Science 248:742-745. (Medline)
Casanova, J.E., Apodaka, G. and Mostov, K.E. (1991) An autonomous signal for basolateral sorting in the
cytoplasmic domain of the polymeric immunoglobulin receptor, Cell 66:65-75. (Medline)
Catlett, N.L and Weisman, L.S. (1998) The terminal tail region of a yeast myosin-V mediates its
attachment to vacuole membranes and sites of polarized growth, Proc. Natl. Acad. Sci. USA 95:14799-14804.
Chandler, D.E. and Heuser, J.E. (1980) Arrest of membrane fusion events in mast cells by quick-freezing,
J. Cell Biol. 86:666-674. (MedLine)
Chapman, E.R., Au, S., Barton, N. and Jahn, R. (1994) SNAP-25, a t-SNARE which binds to syntaxin
and synaptobrevin via domains that may form coiled coils, J. Biol. Chem. 269:27427-27432. (Medline)
Chaudhary, A., Gu, Q.M., Thum, O., Profit, A.A., Qi, Y., Jeyakumar, L., Fleischer, S. and Prestwich,
G.D. (1998) Specific interaction of Golgi coatomer protein α-COP with phosphatidylinositol 3,4,5-trisphosphate, J. Biol. Chem. 273:8344-8350. (Medline)
Cheever, M.L., Sato, T.K., de Beer, T., Kutateladze, T.G., Emr, S.D. and Overduin, M. (2001) Phox
domain interaction with PtdIns(3)P targets the Vam7 t-SNARE to vacuole membranes, Nature Cell Biol.
3:613-618. (MedLine)
Chen, Y.A. and Scheller, R.H. (2001) SNARE-mediated membrane fusion, Nature Rev. Mol. Cell Biol.
2:98-106. (MedLine)
Clark, E.A. and Brugge, J.S. (1995) Integrins and signal transduction pathways: the road taken, Science
268:233-239. (MedLine)
Clary, D.O., Griff, I.C., Rothman, J.E. (1990) SNAPs, a family of NSF attachment proteins involved in
intracellular membrane fusion in animals and yeast, Cell 61:709-721. (Medline)
Cohen, A.R., Woods, D.F., Marfatia, S.M., Walther, Z., Chishti, A.H., Anderson, J.M. and Wood, D.F.
(1998) Human CASK/LIN-2 binds syndecan-2 and protein 4.1 and localizes to the basolateral membrane
of epithelial cells, J. Cell Biol. 142:129-138. (MedLine)
Cole, N.B., Sciaky, N., Marotta, A., Song, J. and Lippincott-Schwartz, J. (1996) Golgi dispersal during
microtubule disruption: regeneration of Golgi stacks at peripheral endoplasmic reticulum exit sites, Mol.
Biol. Cell. 7: 631-650. (Medline)
http://www.albany.edu/~abio304/ref/ref11.html (5 of 32) [3/5/2003 7:57:08 PM]
Chapter 11: References
Collawn, J.F., Kuhn, L.A., Liu, L.-F. C., Tainer, J.A. and Trowbridge, I.S. (1991) Transplanted LDL and
mannose-6-phosphate receptor internalization signals promote high-efficiency endocytosis of transferrin
receptor, EMBO J. 10:3247-3254. (Medline)
Collins, C.A. and Vallee, R.B. (1989)Preparation of microtubules from rat liver and testis: cytoplasmic
dynein is a major microtubule associated protein, Cell Motility and Cytosk. 14:491-500. (Medline)
Colombo, M.I., Beron, W. and Stahl, P.D. (1997) Calmodulin regulates endosome fusion, J. Biol. Chem.
272:7707-7712. (MedLine)
Confalonieri, F. and Duguet, M. (1995) A 200-amino acid ATPase module in search of a basic function,
BioEssays 17:639-650. (Medline)
Cosson, P. and Letourneur, F. (1994) Coatomer interaction with di-lysine endoplasmic reticulum retention
motifs, Science 263:1629-1631. (MedLine)
Cosson, P. and Letourneur, F. (1997) Coatomer (COPI)-coated vesicles: role in intracellular transport and
protein sorting, Curr. Opin. Cell Biol. 9:484-487. (MedLine)
Cosson, P., Demolliere, C., Henneke, S., Duden, R. and Letourneur, F. (1996)δ and ζ-COP, two coatomer
subunits homologous to clathrin-associated proteins are involved in ER retrieval, EMBO J. 15:1792-1798.
(Medline)
Cowles, C.R., Odorizzi, G., Payne, G.S., Emr, S.D. (1997) The AP-3 adaptor complex is essential for
cargo-selective transport to the yeast vacuole, Cell 91:109-118. (Medline)
Cremona, O., Di Paolo, G., Wenk, M.R., Luthi, A., Kim, W.T., Takei, K., Daniell, L., Nemoto, Y.,
Shears, S.B., Flavell, R.A., McCormick, D.A. and De Camilli, P (1999) Essential role of phosphoinositide
metabolism in synaptic vesicle recycling, Cell 99:179-188. (MedLine
Cutler, D.F. and Cramer, L.P. (1990) Sorting during transport to the surface of PC12 cells: divergence of
synaptic vesicle and secretory granule proteins, J. Cell Biol. 110:721-730. (Medline)
De Camilli, P., Emr, S.D., McPherson, P.S. and Novick, P. (1996) Phosphoinositides as regulators in
membrane traffic, Science 271:1533-1539. (Medline)
Dell’Angelica, E.C., Ohno, H., Ooi, C.E., Rabinovich, E., Roche, K.W. and Bonifacino J.S. (1997) AP-3:
an adaptor-like protein complex with ubiquitous expression, EMBO J. 16:917-928. (Medline)
De Matteis, M.A. and Morrow, J.S. (1998) The role of ankyrin and spectrin in membrane transport and
http://www.albany.edu/~abio304/ref/ref11.html (6 of 32) [3/5/2003 7:57:08 PM]
Chapter 11: References
domain formation, Curr. Opin. Cell Biol. 10:542-549. (Medline)
de Vries, K.J., Heinrichs, A.A., Cunningham, E., Brunink, F., Westerman, J., Somerharju, P.J., Cockcroft,
S., Wirtz, K.W. and Snoek, G.T. (1995) An isoform of the phosphatidylinositol-transfer protein transfers
sphingomyelin and is associated with the Golgi system, Biochem. J. 310:643-649. (Medline)
Diaz, R., Mayorga, L.S., , Weidman, P.J., Rothman, J.E. and Stahl, P.D.(1989) Vesicle fusion following
receptor-mediated endocytosis requires a protein active in Golgi transport, Nature 339:398-400.
(Medline)
Dominguez, M., Dejgaard, K., Fullekrug, J., Dahan, S., Fazel, A., Paccaud, J.P., Thomas, D.Y., Bergeron,
J.J. and Nilsson, T. (1998) gp25L/emp24/p24 protein family members of the cis-Golgi network bind both
COP I and II coatomer, J. Cell Biol. 140:751-765. (MedLine)
Donaldson, J.G., Finazzi, D. and Klausner, R.D. (1992) Brefeldin A inhibits Golgi-membrane catalyzed
exchange of guanine nucleotide into ARF protein, Nature 360:350-352. (Medline)
Drenckhahn, D. and Dermietzel. R. (1988) Organization of the actin filament cytoskeleton in the intestinal
brush border: a quantitative and qualitative immunoelectron microscope study, J. Cell Biol. 107:1037-1048. (Medline)
Drubin, D.G. and Nelson, W.J. (1996) Origins of cell polarity, Cell 84:335-344. (MedLine)
Duden, R., Allan, V. and Kreis, T. (1991a) Involvement of p-COP in membrane traffic through the Golgi
complex, Trends Cell Biol. 1:14-19.
Duden, R., Griffiths, G., Frank, R., Argos, P. and Kreis, T. E. (1991b) p-COP, a 110 kd protein associated
with non-clathrin-coated vesicles and Golgi complex, shows homology to ξβ-adaptin, Cell 64:649-665.
(Medline)
Eger, A., Stockinger, A., Schaffhauser, B., Beug, H. and Foisner, R. (2000) Epithelial mesenchymal
transition by c-Fos estrogen receptor activation involves nuclear translocation of β-catenin and
upregulation of β-catenin/lymphoid enhancer binding factor-1 transcriptional activity, J. Cell Biol.
148:173-188. (MedLine)
Farquhar, M.G. and Palade, G.E. (1963) Junctional complexes in various epithelia, J. Cell Biol. 17: 375-412.
Ferro-Novick, S. and Jahn, R. (1994) Vesicle fusion from yeast to man, Nature 370:191-193. (Medline)
http://www.albany.edu/~abio304/ref/ref11.html (7 of 32) [3/5/2003 7:57:08 PM]
Chapter 11: References
Fiedler, K. and Simons, K. (1995) The role of N-glycans in the secretory pathway, Cell 81:309-312.
(Medline)
Frölich K.U. http://yeamob.pci.chemie.uni-tuebingen. de/AAA/Tree.html
Fukuda, R., McNew, J.A., Weber, T., Parlati, F., Engel, T., Nickel, W., Rothman, J.E. and Söllner, T.H.
(2000) Functional architecture of an intracellular membrane t-SNARE, Nature 407:198-202. (MedLine)
Füllekrug, J., Suganuma, T., Tang, B.L., Hong, W., Storrie, B. and Nilsson, T. (1999) Localization and
recycling of gp27 (hp24gamma3): complex formation with other p24 family members, Mol. Biol. Cell
10:1939-1955. (MedLine)
Furuse, M., Hirase, T., Itoh, M., Nagafuchi, A., Yonemura, S., Tsukita, S. and Tsukita, S. (1993)
Occludin: a novel integral membrane protein localizing at tight junctions, J. Cell Biol. 123:1777-1788.
(Medline)
Furuse, M., Fujita, K., Hiiragi, T., Fujimoto, K. and Tsukita, S.(1998a) Claudin-1 and -2: novel integral
membrane proteins localizing at tight junctions with no sequence similarity to occludin, J. Cell Biol.
141:1539-1550. (Medline)
Furuse, M., Sasaki, H., Fujimoto, K. and Tsukita, S. (1998b) A single gene product, claudin-1 or -2,
reconstitutes tight junction strands and recruits occludin in fibroblasts, J. Cell Biol. 143:391-401.
(Medline)
Faundez, V., Horng, J.T. and Kelly, R.B. (1998) A function for the AP3 coat complex in synaptic vesicle
formation from endosomes, Cell 93:423-432. (Medline)
Fath, K.R. and Burgess, D.R. (1993) Golgi derived vesicles from developing epithelial cells bind actin
filaments and possess myosin-I as a cytoplasmically oriented peripheral membrane protein, J. Cell Biol.
120:117-27. (Medline)
Felder, S. and Kam, Z. (1994) Human neutrophil motility: time-dependent three-dimensional shape and
granule diffusion, Cell. Motil. Cytoskel. 28: 285-302. (Medline)
Fiedler, K., Veit, M., Stamens, M.A. and Rothman, J.E. (1996) Bimodal interaction of coatamer with p24
family of putative cargo receptors, Science 273:1396-1399. (Medline)
Friedrich, G.A., Hildebrand, J.D. and Soriano, P. (1997) The secretory protein Sec8 is required for
paraxial mesoderm formation in the mouse, Dev. Biol. 192:364-374. (Medline)
http://www.albany.edu/~abio304/ref/ref11.html (8 of 32) [3/5/2003 7:57:08 PM]
Chapter 11: References
Gaidarov, I. and Keen, J.H. (1999) Phosphoinositide-AP-2 interactions required for targeting to plasma
membrane clathrin-coated pits, J. Cell Biol. 146:755-764. (Medline)
Gaidarov, I., Chen, Q., Falck, J.R., Reddy, K.K. and Keen, J.H. (1996) A functional phosphatidylinositol
3,4,5-trisphosphate/phosphoinositide binding domain in the clathrin adaptor AP-2 α subunit. Implications
for the endocytic pathway, J. Biol. Chem. 271:20922-20929. (Medline)
Gaidarov, I., Krupnick, J.G., Falck, J.R., Benovic, J.L. and Keen, J.H. (1999) Arrestin function in G
protein-coupled receptor endocytosis requires phosphoinositide binding, EMBO J. 18:871-881. (Medline)
Gallusser, A. and Kirchhausen (1993) The 1 and 2 subunits of the AP complexes are the clathrin coat
assembly components, EMBO J. 12:5237-5244. (Medline)
Gammie, A.E., Kurihara, L.J., Vallee, R.B. and Rose, M.D. (1995) DNM1, a dynamin-related gene,
participates in endosomal trafficking in yeast, J. Cell Biol. 130:553-566. (Medline)
Gaynor, E. C. and Emr, S.D. (1997) COPI-independent anterograde transport: cargo-selective ER to Golgi
protein transport in yeast COPI mutants, J. Cell Biol. 136:789-802. (Medline)
Gaynor, E.C., Graham, T.R., Emr, S.D. (1998) COPI in ER/Golgi and intra-Golgi transport: do yeast
COPI mutants point the way? Biochim. Biophys. Acta 1404:33-51. (MedLine)
Geutze, H. J., Slot, J. W., Strous, J. A. M., Hasilik, A. and von Figura, K. (1984) The ultrastructural
localization of the mannose 6-phosphate receptor in rat liver, J. Cell Biol. 98:2047-2054. (Medline)
Geutze, H. J., Slot, J. W., Strous, J. G., Hasilik, A. and von Figura, K. (1985) Possible pathway for
lysosomal enzyme delivery. J. Cell Biol. 101:2253-2263. (Medline)
Gieselman, V., Pohlmann, R., Hasilik, A. and van Figura, K. (1983) Biosynthesis and transport of
cathepsin D in cultured human fibroblasts, J. Cell Biol. 97:1-5. (Medline)
Girod, A., Storrie, B., Simpson, J.C., Johannes, L., Goud, B., Roberts, L.M., Lord, J.M., Nilsson, T. and
Pepperkok, R. (1999) Evidence for a COP-I-independent transport route from the Golgi complex to the
endoplasmic reticulum, Nature Cell Biol. 1:423-430. (MedLine)
Glick, B.S. and Rothman J.E. (1987) Possible role for fatty acyl-coenzyme A in intracellular protein
transport, Nature 326:309-312. (Medline)
Glickman, J.N., Conibear, E., and Pearse, B.M.F. (1989) Specificity of binding of clathrin adaptors to
signals on the mannose 6-phosphate / insulin-like growth factor II receptor, EMBO J. 4:1041-1047.
http://www.albany.edu/~abio304/ref/ref11.html (9 of 32) [3/5/2003 7:57:08 PM]
Chapter 11: References
(Medline)
Godi, A., Santone, I., Pertile, P., Devarajan, P., Stabach, P.R., Morrow, J.S., Di Tullio, G., Polishchuk, R.,
Petrucci, T.C., Luini, A.and De Matteis, M.A. (1998) ADP ribosylation factor regulates spectrin binding
to the Golgi complex, Proc. Natl. Acad. Sci. USA 95:8607-8612. (Medline)
Godi, A., Pertile, P., Meyers, R., Marra, P., Di Tullio, G., Iurisci,C., Luini, A., Corda, D. and De Matteis,
G. (1999) ARF mediates recrutiment of PtdIns-4-OH kinase-β and stimulates synthesis of PtdIns(4,5)P2
on the Golgi complex Nature Cell Biol. 1:280-287. (Medline)
Gold, E.S., Underhill, D.M., Morrissette, N.S., Guo, J., McNiven, M.A. and Aderem, A. (1999) Dynamin
2 is required for phagocytosis in macrophages, J. Exp. Med. 190:1849-1856. (MedLine)
Goldberg, J. (2000) Decoding of sorting signals by coatamer through GTPase switch in COPI coat
complex, Cell 100:671-679. (Medline)
Goodman, O.B., Jr., Krupnick, J.G., Santini, F., Gurevich, V.V., Penn, R.B., Gagnon, A.W., Keen, J.H.
and Benovic, J.L. (1996) β-arrestin acts as a clathrin adaptor in endocytosis of the β2-adrenergic receptor,
Nature 383:447-450. (Medline)
Götte, M. and Fischer von Mollard, G. (1998) A new beat for the SNARE drum, Trends Cell Biol. 8:215-218. (MedLine)
Gottlieb, T. A., Beaudry, G., Rizzolo, L., Colman, A., Rindler, M., Adesnik, M. and Sabatini, D. D.
(1986) Secretion of endogenous and exogenous proteins from polarized MDCK cell monolayers, Proc.
Natl. Acad. Sci. USA. 83:2100-2104. (Medline)
Graham, T.R. and Emr, S. (1991) Compartmental organization of Golgi-specific modification and
vacuolar protein sorting events defined in yeast sec18 (NSF) mutant, J. Cell Biol. 114:207-218. (Medline)
Gravotta, D., Adesnik, M. and Sabatini, D.D. (1990) Transport of influenza HA from the trans-Golgi
network to the apical surface of MDCK cells permeabilized in their basolateral plasma membranes:
energy dependence and involvement of GTP-binding proteins, J. Cell Biol. 111:2893-2908. (Medline)
Grawe, F., Wodarz, A., Lee, B., Knust, E. and Skaer, H. (1996) The Drosophila genes crumbs and
stardust are involved in the biogenesis of adherens junctions, Development 122:951-959. (MedLine)
Greene, L.A. and Rein, G. (1977) Synthesis, storage and release of acetylcholine by a noradrenergic
phaeochromocytoma cell line, Nature 268:349-351. (Medline)
http://www.albany.edu/~abio304/ref/ref11.html (10 of 32) [3/5/2003 7:57:08 PM]
Chapter 11: References
Griffiths, G., Pfeiffer, S., Simon, K. and Matlin, K. (1985) Exit of newly synthesized membrane proteins
from the trans cisternae of the Golgi complex to the plasma membrane, J. Cell Biol. 101:949-964.
(Medline)
Grindstaff, K.K., Yeaman, C., Anandasabapathy, N., Hsu, S.C., Rodriguez-Boulan, E., Scheller, R.H. and
Nelson, W.J. (1998) Sec6/8 complex is recruited to cell-cell contacts and specifies transport vesicle
delivery to the basal-lateral membrane in epithelial cells, Cell 93:731-740. (Medline)
Gumbiner, B.M. (1993) Breaking through the tight junction barrier, J. Cell Biol. 123:1631-1633.
(Medline)
Guo, W., Roth, D., Walch-Solimena, C. and Novick, P. (1999) The exocyst is an effector for Sec4p,
targeting secretory vesicles to sites of exocytosis, EMBO J.18:1071-1080. (MedLine)
Guo, W., Sacher, M., Barrowman, J., Ferro-Novick, S. and Novick, P. (2000) Protein complexes in
transport vesicle targeting, Trends Cell Biol. 10:251-255. (MedLine)
Gut, A., Kappeler, F., Hyka, N., Balda, M.S., Hauri, H.P. and Matter, K. (1998) Carbohydrate-mediated
Golgi to cell surface transport and apical targeting of membrane proteins, EMBO J. 17:1919-1929.
(Medline)
Hall, D.H.and Hedgecock, E.M. (1991) Kinesin related gene unc-104 is required for axonal transport of
synaptic vesicles, Cell 65:837-847. (Medline)
Hao, W., Tan, Z., Prasad, K., Reddy, K.K., Chen, J., Prestwich, G.D., Falck, J.R., Shears, S.B. and Lafer,
E.M. (1997) Regulation of AP-3 function by inositides. Identification of phosphatidylinositol 3,4,5-trisphosphate as a potent ligand, J. Biol. Chem. 272:6393-6398. (Medline)
Harter, C., Pavel, J., Coccia, F., Draken, E., Wegehingel, S., Tschochner, H. and Wieland, F. (1996)
Nonclathrin coat protein γ, a subunit of coatomer, binds to the cytoplasmic dilysine motif of membrane
proteins of the early secretory pathway, Proc. Natl. Acad. Sci. USA 93:1902-1906. (MedLine)
Hata, Y., Butz, S. and Sudhof, T.C. (1996) CASK: a novel dlg/PSD95 homolog with an N-terminal
calmodulin-dependent protein kinase domain identified by interaction with neurexins, J. Neurosci.
16:2488-2494. (MedLine)
Hay, J.C. and Scheller, R.H. (1997) SNAREs and NSF in targeted membrane fusion, Curr. Opin. Cell
Biol.9:505-512. (Medline)
Hayashi, T., Yamasaki, S., Nauenburg, S., Binz, T. and Niemann, H.(1995) Disassembly of the
reconstituted synaptic vesicle membrane fusion complex in vitro, EMBO J. 14:2317-2325. (Medline)
http://www.albany.edu/~abio304/ref/ref11.html (11 of 32) [3/5/2003 7:57:08 PM]
Chapter 11: References
Hazuka, C.D., Foletti, D.L., Hsu, S.C., Kee, Y., Hopf, F.W., and Scheller, R.H. (1999) The sec6/8
complex is located at neurite outgrowth and axonal synapse-assembly domains, J. Neurosci. 19:1324-1334. (Medline)
Heidelberger, R., Heinemann, C., Neher, E. and Matthews, G. (1994) Calcium dependence of the rate of
exocytosis in a synaptic terminal, Nature 371:513-515. (MedLine)
Heilker, R., Manning-Krieg, U., Zuber, J.-F., and Spiess, M. (1996) In vitro binding of clathrin adaptors
to sorting signals correlates with endocytosis and basolateral sorting, EMBO J. 15:2893-2899. (Medline)
Helms, J.B. and Rothman, J.E. (1992) Inhibition by brefeldin A of a Golgi enzyme that catalyzes
exchange of guanine nucleotide bound to ARF, Nature 360:352-354. (Medline)
Henley, J.R. and McNiven, M.A. (1996) Association of a dynamin-like protein with the Golgi apparatus
in mammalian cells, J. Cell Biol 133:761-775. (MedLine)
Henley, J.R., Krueger, E.W., Oswald, B.J. and McNiven, M.A. (1998) Dynamin-mediated internalization
of caveolae, J. Cell Biol. 141:85-99. (MedLine)
Henley, J.R., Cao, H. and McNiven, M.A. (1999) Participation of dynamin in the biogenesis of
cytoplasmic vesicles, FASEB J. 13, Suppl 2:S243-S247. (MedLine)
Herskovits, J.S., Burgess, C.C., Obar, R.A., Vallee, R.B. (1993) Effects of mutant rat dynamin on
endocytosis, J. Cell Biol. 122:565-578. (Medline)
Hinshaw, J. E. and Schmid, S.L. Dynamin self-assembles into rings suggeting a mechanism for coated
vesicle budding, (1995) Nature374:190-192. (Medline)
Hirokawa, N., Sato-Yoshitake, R., Kobayashi, N., Pfister, K.K., Bloom, G.S. and Brady, S.T. (1991)
Kinesin associates with anterogradely transported membranous organelles in vivo, J. Cell Biol. 114:295-302. (Medline)
Hohl, T.M., Parlati, F., Wimmer, C., Rothman, J.E., Söllner, T.H. and Engelhardt, H. (1998) Arrangement
of subunits in 20 S particles consisting of NSF, SNAPs, and SNARE complexes, Mol Cell 2:539-548.
(Medline)
Hope, H.R. and Pike, L.J. (1996) Phosphoinositides and phosphoinositide-utilizing enzymes in detergent-insoluble lipid domains, Mol. Biol. Cell 7:843-881. (Medline)
http://www.albany.edu/~abio304/ref/ref11.html (12 of 32) [3/5/2003 7:57:08 PM]
Chapter 11: References
Hsu, S.C., Ting, A.E., Hazuka, C.D., Davanger, S., Kenny, J.W., Kee, Y. and Scheller, R.H. (1996) The
mammalian brain rsec6/8 complex, Neuron 17:1209-1219. (Medline)
Hsu, S.C., Hazuka, C.D., Roth, R., Foletti, D.L., Heuser, J. and Scheller, R.H. (1998) Subunit
composition, protein interactions, and structures of the mammalian brain sec6/8 complex and septin
filaments, Neuron 20:1111-1122. (Medline)
Hsueh, Y.P., Wang, T.F., Yang, F.C. and Sheng, M. (2000) Nuclear translocation and transcription
regulation by the membrane-associated guanylate kinase CASK/LIN-2, Nature 404:298-302. (MedLine)
Huang, P.-H. and Chiang, H.-L. (1997) Identification of novel vesicles in the cytosol to vacuole protein
degradation pathway, J. Cell Biol. 136:803-810. (Medline)
Huffaker, T.C., Thomas, J.H. and Botstein, D. (1988) Diverse effects of β-tubulin mutations on
microtubule formation and function, J. Cell Biol. 106:1997-2010. (MedLine)
Hunt, J.M., Bommert, K., Charlton, M.P., Kistner, A., Habermann, E., Augustine, G.J. and Betz, H.
(1994) A post-docking role for synaptobrevin in synaptic vesicle fusion, Neuron 12:1269-1279.
(MedLine)
Hunziker, W., Harter, C., Matter, K. and Mellman, I. (1991) Basolateral sorting in MDCK cells requires a
distinct cytoplasmic domain determinant, Cell 66:907-920. (Medline)
Jacobs, C.W., Adams, A.E., Szaniszlo, P.J. and Pringle, J.R. (1988) Functions of microtubules in the
Saccharomyces cerevisiae cell cycle, J. Cell Biol. 1071409-1426. (MedLine)
Jahn, R. and Südhof, T.C. (1999) Membrane fusion and exocytosis, Annu. Rev. Biochem. 68:863-911.
(MedLine)
Jones, S.M., Howell, K.E., Henley, J.R., Cao, H. and McNiven, M.A. (1998) Role of dynamin in the
formation of transport vesicles from the trans-Golgi network, Science 279:573-577. (MedLine)
Jou, T.S. and Nelson, W.J. (1998) Effects of regulated expression of mutant RhoA and Rac1 small
GTPases on the development of epithelial (MDCK) cell polarity, J. Cell Biol. 142:85-100. (Medline)
Kaibuchi, K., Kuroda, S., Fukata, M. and Nakagawa, M. (1999) Regulation of cadherin-mediated cell-cell
adhesion by the Rho family GTPases, Curr. Opin. Cell Biol. 11:591-596. (Medline)
Kaiser, C.A. and Shekman, R.(1990) Distinct sets of SEC genes govern transport vesicle formation and
junction early in the secretory pathway, Cell 61:723-733. (Medline)
http://www.albany.edu/~abio304/ref/ref11.html (13 of 32) [3/5/2003 7:57:08 PM]
Chapter 11: References
Kanai,F., Liu, H., Field, S. J., Akbary, H., Matsuo, T., Brown, G. E.,Cantley, L.C. and Yaffe, M.B. (2001)
The PX domains of p47phox and p40phox bind to lipid products of PI(3)K, Nature Cell Biol. 3:675-678 .
(MedLine)
Klausner, R.D., Donaldson, J.G. and Lippincott-Schwartz, J. (1992) Brefeldin A: insights into the control
of membrane traffic and organelle structure, J. Cell Biol. 116:1071-1080. (Medline)
Klebes, A. and Knust, E. (2000) A conserved motif in Crumbs is required for E-cadherin localisation and
zonula adherens formation in Drosophila, Curr. Biol. 10:76-85. (MedLine)
Klenchin, V.A. and Martin, T.F. (2000) Priming in exocytosis: attaining fusion-competence after vesicle
docking, Biochimie 82:399-407. (MedLine)
Kondor-Koch, C., Bravo, R., Fuller, S. D., Cutler, D. and Garoff, H. (1985) Exocytotic pathways exist to
both apical and basolateral cell surface of the polarized epithelial cell MDCK, Cell 43:297-306. (Medline)
Kornfeld, S. (1987) Trafficking of lysosomal enzymes, FASEB J. 1:462-468. (Medline)
Kornfeld, S. (1992) Structure and function of the mannose 6-phosphate/insulinlike growth factor II
receptors, Annu. Rev. Biochem. 61:307-330. (MedLine)
Kreis, T.E., Lowe, M. and Pepperkok, R. (1995) COPs regulating membrane traffic, Ann. Rev. Cell Biol.
11:677-706. (Medline)
Kreitzer, G., Marmorstein, A., Okamoto, P., Vallee, R. and Rodriguez-Boulan, E. Kinesin and dynamin
are required for post-Golgi transport of a plasma-membrane protein, Nature Cell Biol. 2:125-127.
(MedLine)
Ladinsky, M.S, Kremer, J.R, Furcinitti, P. S., McIntosh, J.R. and Howell, K.E. (1994), HVEM
tomography of the trans-Golgi network: structural insights and identification of a lace-like vesicle coat, J.
Cell Biol. 127:29-38. (Medline)
Lafont, F., Burkhardt, J.K. and Simons, K. (1994) Involvement of microtubule motors in basolateral and
apical transport in kidney cells, Nature 372:801-803. (Medline)
Lanoix, J., Ouwendijk, J., Lin, C.C., Stark, A., Love, H.D., Ostermann, J. and Nilsson T. (1999) GTP
hydrolysis by arf-1 mediates sorting and concentration of Golgi resident enzymes into functional COP I
vesicles, EMBO J. 18:4935-4948. (MedLine)
Lavoie, C., Paiement, J., Dominguez, M., Roy, L., Dahan, S., Gushue, J.N. and Bergeron, J.J. (1999)
http://www.albany.edu/~abio304/ref/ref11.html (14 of 32) [3/5/2003 7:57:08 PM]
Chapter 11: References
Roles for alpha(2)p24 and COPI in endoplasmic reticulum cargo exit site formation, J. Cell Biol.146:285-299. (MedLine)
Le Bevic, A., Quaroni, A., Nichols, B. and Rodriguez-Boulan, E. (1990) Biogenetic pathways of plasma
membrane proteins in Caco-2, a human intestinal epithelial cell line, J. Cell Biol. 111:1351-1361.
(Medline)
Le Borgne, R., Griffiths, G. and Hoflack, B. (1996) Mannose 6-phosphate receptors and ADP-ribosylation
factors cooperate for high affinity interaction of the AP-1 Golgi assembly with membranes, J. Biol. Chem.
271:2162-2170. (Medline)
Le Borgne, R. and Hoflack, B. (1997) Mannose 6-phosphate receptors regulated the formation of clathrin-coated vesicles in the TGN, J. Cell Biol. 137:335-345. (Medline)
Le Borgne, R. and Hoflack, B. (1998) Mechanisms of protein sorting and coat assembly: insights from
clathrin coated vesicle pathway, Curr. Opin. Cell Biol. 10:499-503. (Medline)
Le Borgne, R., Alconada, A., Bauer, U. and Hoflack, B. (1998) The mammalian AP-3 adaptor-like
complex mediates the intracellular transport of lysosomal membrane glycoproteins, J. Biol. Chem.
273:29451-29461. (Medline)
Lee, J. and Lentz, B.R. (1997) Evolution of lipidic structures during model membrane fusion and the
relation of this process to cell membrane fusion, Biochemistry 36:6251-6259. (MedLine)
Letourneur, F., Gaynor, E.C., Hennecke, S., Démollière, C., Duden, R., Emr, S.D., Riezman, H. and
Cosson, P. (1994) Coatamer is essential for retrieval of dilysine-tagged proteins to the endoplasmic
reticulum, Cell 79:1199-1207. (Medline)
Lewis, M.J. and Pelham, H.R. (1992) Ligand-induced redistribution of a human KDEL receptor from the
Golgi complex to the endoplasmic reticulum, Cell 68:353-364. (MedLine)
Lin, C.-C., Love, H.D., Gushue, J.N., Bergeron, J.J. and Ostermann, J. (1999) ER/Golgi intermediates
acquire Golgi enzymes by brefeldin A-sensitive retrograde transport in vitro, J. Cell Biol. 147:1457-1472.
(MedLine)
Lippincott-Schwartz, J. (1998) Cytoskeletal proteins and Golgi dynamics, Curr. Opin. Cell Biol.10:52-59.
(MedLine)
Lippincott-Schwartz, J., Cole, N.B., Marotta, A., Conrad, P.A and Bloom, G.S. (1995) Kinesin is the
motor for microtubule-mediated Golgi-to-ER membrane traffic, J. Cell. Biol. 128: 293-306. (Medline)
http://www.albany.edu/~abio304/ref/ref11.html (15 of 32) [3/5/2003 7:57:08 PM]
Chapter 11: References
Lisanti, M.P., Caras, I.W., Davitz, M.A. and Rodriguez-Boulan, E. (1989) A glycophospholipid
membrane anchor acts as an apical targeting signal in polarized epithelial cells, J. Cell Biol. 109:2145-2156. (Medline)
Llorente, A., Rapak, A., Schmid, S.L., van Deurs, B. and Sandvig, K. (1998) Expression of mutant
dynamin inhibits toxicity and transport of endocytosed ricin to the Golgi apparatus, J. Cell Biol. 140:553-563. (MedLine)
Lohi, O., and Lehto, V.-P. (1998) VHS domain marks a group of proteins involved in endocytosis and
vesicular trafficking, FEBS Lett. 440: 255-257. (MedLine)
Love, H.D., Lin, C.C., Short, C.S. and Ostermann, J. (1998) Isolation of functional Golgi-derived vesicles
with a possible role in retrograde transport, J. Cell Biol. 140:541-551. (Medline)
Maier, O., Knoblich, M. and Westermann, P. (1996) Dynamin II binds to the trans-Golgi network,
Biochem. Biophys. Res. Commun. 223:229-233. (MedLine)
Malhotra V., Orci, L., Glick, B.S.. Block, M.R. and Rothman, J.E. (1988) Role of an N-ethylmaleimide-sensitive transport component in promoting fusion of transport vesicles with cisternae of the Golgi stack,
Cell 54:221-227. (Medline)
Malhotra, V., Serafini, T., Orci, L., Shepherd, J.G. and Rothman, J.E. (1989) Purification of a novel class
of coated vesicles mediating the biosynthetic protein transport through the Golgi stacks, Cell 58:329-336.
(Medline)
Martin, T.F. (1997) Phosphoinositides as spatial regulators of membrane traffic, Curr. Opin. Neurobiol.
7:331-338. (Medline)
Martínez-Menárguez, J.A., Geuze, H.J., Slot, J.W. and Klumperman, J. (1999) Vesicular tubular clusters
between the ER and Golgi mediate concentration of soluble secretory proteins by exclusion from COPI-coated vesicles, Cell 98:81-89. (MedLine)
Marzioch, M., Henthorn, D.C., Herrmann, J.M., Wilson, R., Thomas, D.Y., Bergeron, J.J. and Solari, R.C.
and Rowley, A. (1999) Erp1p and Erp2p, partners for Emp24p and Erv25p in a yeast p24 complex, Mol.
Biol. Cell 10:1923-1938. (MedLine)
Matlin, K. and Simons, K. (1984) Sorting of a plasma membrane glycoprotein occurs before it reaches the
cell surface in cultured epithelial cells, J. Cell Biol. 99:2131-2139. (Medline)
Matlin, K., Bainton, D. F., Pesonen, M., Louvard, D., Genty, N. and Simons, K. (1983) Transepithelial
transport of viral membrane glycoprotein implanted into the apical plasma membrane of Madin-Darby
http://www.albany.edu/~abio304/ref/ref11.html (16 of 32) [3/5/2003 7:57:08 PM]
Chapter 11: References
canine kidney cells. I. Morphological evidence, J. Cell Biol. 97:627-637. (Medline)
Matsuoka, K., Orci, L., Amherdt, M., Bednarek, S.Y., Hamamoto, S., Schekman, R. and Yeung, T. (1998)
COPII-coated vesicle formation reconstituted with purified coat proteins and chemically defined
liposomes, Cell 93:263-275. (MedLine)
Matteoni, R. and Kreis, T.E. (1987) Translocation and clustering of endosomes and lysosomes depends on
microtubules, J. Cell. Biol. 105:1253-1265 (Medline)
Matter, K., Brauchbar, M. and Hauri, H.-P. (1990a) Sorting of endogenous plasma membrane proteins
occurs from two sites in cultured human intestinal epithelial cells (Caco-2), Cell 60:429-437. (Medline)
Matter, K., Bucher, K. and Hauri, H.-P.(1990b) Microtubule perturbation retards both the direct and the
indirect pathway but does not affect sorting of plasma membrane proteins in intestinal cells (Caco-2)
EMBO J. 9:3163-3170. (Medline)
May, A.P., Misura, K.M.S., Whiteheart, S.W. and Weiss, W.I. (1999) Crystal structure of the amino-terminal domain of N-ethylmaleimide-sensitive fusion protein, Nature Cell Biol. 1:175-182. (Medline)
Mayer, A., Wickner, W. and Haas, A. (1996) Sec18p (NSF)-driven release of Sec17p (α-SNAP) can
precede docking and fusion of yeast vacuoles, Cell 85:83-94. (Medline)
McCarthy, K.M., Skare, I.B., Stankewich, M.C., Furuse, M., Tsukita, S., Rogers, R.A., Lynch, R.D. and
Schneeberger, E.E. (1996) Occludin is a functional component of the tight junction, J. Cell Sci. 109:2287-2298. (Medline)
McNew, J.A., Parlati, F., Fukuda, R., Johnston, R.J., Paz, K., Paumet, F., Söllner, T.H. and Rothman, J.E.
(2000) Compartmental specificity of cellular membrane fusion encoded in SNARE proteins, Nature
407:153-159. (MedLine)
McNiven, M.A., Cao, I., Pitts, K.R. and Yoon, I. (2000) The dynamin family of mechanoenzymes:
pinching in new places, Trends Biochem Sci 25:115-120. MedLine
McPherson, P.S., Garcia, E.P., Slepnev, V.I., David, C., Zhang, X., Grabs, D., Sossin, W.S., Bauerfeind,
R., Nemoto, Y. and De Camilli, P. (1996) A presynaptic inositol-5-phosphatase, Nature 379:353-357.
(Medline)
Medof, M.E., Nagarajan, S. and Tykocinski, M.L. (1996) Cell-surface engineering with GPI-anchored
proteins, FASEB J. 10:574-586. (Medline)
http://www.albany.edu/~abio304/ref/ref11.html (17 of 32) [3/5/2003 7:57:08 PM]
Chapter 11: References
Melançon, P., Glick, B.S., Malhotra, V., Weidman, P.J., Serafini, T., Gleason, M.L., Orci, L. and
Rothman, J.E. (1987) Involvement of GTP-binding “G” proteins in transport through the Golgi stack, Cell
51:1053-1062. (Medline)
Meldolesi, J. (1974) Dynamics of cytoplasmic membranes in guinea pig pancreatic acinar cells. I.
Synthesis and turnover of membrane proteins, J. Cell Biol. 61:1-13.
Melkonian, K.A., Ostermeyer, A.G., Chen, J.Z., Roth, M.G. and Brown, D.A. (1999) Role of lipid
modifications in targeting proteins to detergent-resistant membrane rafts. Many raft proteins are acylated,
while few are prenylated, J. Biol. Chem. 274:3910-3917. (MedLine)
Mellman, I. and Warren, G. (2000) The road taken: past and future foundations of membrane traffic, Cell
100:99-112. (MedLine)
Monck, J.R. and Fernandez, J.M. (1994) The exocytotic fusion pore and neurotransmitter release, Neuron
12:707-716. (MedLine)
Monck, J.R. and Fernandez, J.M. (1996) The fusion pore and mechanisms of biological membrane fusion,
Curr. Opin. Cell Biol. 8:524-533. (MedLine)
Mooseker, M.S. and Coleman, T.R. (1989) The 110-kD protein-calmodulin complex of the intestinal
microvillus (brush border myosin I) is a mechanoenzyme, J. Cell Biol. 108:2395-2400. (Medline)
Morgan, A., Dimaline, R. and Burgoyne, R.D. (1994) The ATPase activity of N-ethylmaleimide-sensitive
fusion protein (NSF) is regulated by soluble NSF attachment proteins, J. Biol. Chem. 269:29347-29350.
(Medline)
Morin, P.J., Johnson, R.J. and Fine, R.E. (1993) Kinesin is rapidly transported in the optic nerve as a
membrane associated protein, Biochim. Biophys. Acta 1146:275-281. (Medline)
Morita, K., Furuse, M., Fujimoto, K. and Tsukita, S. (1999a) Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands, Proc. Natl. Acad. Sci. USA 96:511-516. (Medline)
Morita, K., Sasaki, H., Furuse, M. and Tsukita, S. (1999b) Endothelial claudin. claudin-5/TMVCF
constitutes tight junction strands in endothelial cells, J. Cell Biol. 147:185-194. (Medline)
Morita, K., Sasaki, H., Fujimoto, K., Furuse, M. and Tsukita, S. (1999c) Claudin-11/OSP-based tight
junctions of myelin sheaths in brain and Sertoli cells in testis, J. Cell Biol. 145:579-588. (Medline)
Mostov, K., Apodaca, G., Aroeti, B. and Okamoto, C. (1992) Plasma membrane protein sorting in
http://www.albany.edu/~abio304/ref/ref11.html (18 of 32) [3/5/2003 7:57:08 PM]
Chapter 11: References
polarized epithelial cells, J. Cell Biol. 116:577-583. (Medline)
Muñiz, M., Nuoffer. C., Hauri, H.P. and Riezman, H. (2000) The Emp24 complex recruits a specific
cargo molecule into endoplasmic reticulum-derived vesicles, J. Cell Biol. 148:925-930. (MedLine)
Munro, S. and Pelham, H. R. B. (1986) An H5P70-like protein in the ER: identity with the 78 kd glucose-regulated protein and immunoglobulin heavy chain binding protein, Cell 46:291-300. (Medline)
Nakagawa, T., Goto, K. and Kondo, H. (1996) Cloning, expression, and localization of 230-kDa
phosphatidylinositol 4-kinase, J. Biol. Chem. 271:12088-12094. (Medline)
Narula, N. and Snow, J.C.(1995) Distinct coat vesicles labeled for p200 bud from trans-Golgi neet work
membranes, Proc. Natl. Acad. Sci. USA 92:2874-2878. (Medline)
Nelson, W.J. (1991) Cytoskeleton functions in membrane traffic in polarized cells, Seminars in Cell Biol.
2:375-385. (Medline)
Nelson, W. J. (1992) Regulation of cell surface polarity from bacteria to mammals, Science 258:948-955.
(Medline)
Nelson, W. J. and Hammerton, R. W. (1989) A membrane-cytoskeleton complex containing Na+, K+
ATPase, ankyrin and fodrin in Madin-Darby canine kidney (MDCK) cells: implications from the
biogenesis of epithelial cell polarity. J. Cell Biol. 108:893-902. (Medline)
Nelson, D.S., Alvarez, C., Gao, Y.S., Garcia-Mata, R., Fialkowski, E. and Sztul, E. (1998) The membrane
transport factor TAP/p115 cycles between the Golgi and earlier secretory compartments and contains
distinct domains required for its localization and function, J. Cell Biol. 143:319-331. (MedLine)
Neuwald, A.F. (1999) The hexamerization domain of N-ethylmaleimide-sensitive factor: structural clues
to chaperone function, Structure Fold. Des. 7:R19-23. (Medline)
Neuwald, A.F., Aravind, L., Spouge, J.L. and Koonin, E.V. (1999) AAA+: A class of chaperone-like
ATPases associated with the assembly, operation, and disassembly of protein complexes, Genome Res.
9:27-43. (Medline)
Newman, L.S., McKeever, M.O., Okano, H.J. and Darnell, R.B. (1995) β-NAP, a cerebellar degeneration
antigen, is a neuron-specific vescile coat protein, Cell 82:773-783. (Medline)
Nichols, B.J., Ungermann, C., Pehham, H.R.B., Wickner, W.T. and Haas, A. (1997) Homotypic vacuolar
fusion mediated by t- and v-SNAREs, Nature 386:199-902. (Medline)
http://www.albany.edu/~abio304/ref/ref11.html (19 of 32) [3/5/2003 7:57:08 PM]
Chapter 11: References
Nickel, W., Sohn, K., Bunning, C. and Wieland, F.T. (1997) p23, a major COPI-vesicle membrane
protein, constitutively cycles through the early secretory pathway, Proc. Natl. Acad. Sci. USA 94:11393-11398. (MedLine)
Nicoziani, P., Vilhardt, F., Llorente, A., Hilout, L., Courtoy, P.J., Sandvig, K. and van Deurs, B. (2000)
Role for dynamin in late endosome dynamics and trafficking of the cation-independent Mol. Biol. Cell
11:481-495. (MedLine)
Novick, P. and Zerial, M. (1997) The diversity of Rab proteins in vesicle transport, Curr. Opin. Cell Biol.
9:496-504. (MedLine)
Novick, P., Field, C. and Schekman, R. (1980) Identification of 23 complementation groups required for
post-translational events in the yeast secretory pathway, Cell 21:205-215. (Medline)
Novick, P. and Botstein, D. (1985) Phenotypic analysis of temperature-sensitive yeast actin mutants, Cell
40:405-416. (MedLine)
Nusse, R. (1997) A versatile transcriptional effector of Wingless signaling, Cell 89:321-323. (MedLine)
Odorizzi, G. and Trowbridge, I.S. (1997) Structural requirements for basolateral sorting of human
transferrin receptor in biosynthetic and endocytotic pathways in Madin-Darby canine kidney cells, J. Cell
Biol. 137:1255-1264. (Medline)
Oh, P., McIntosh, D.P. and Schnitzer, J.E. (1998) Dynamin at the neck of caveolae mediates their budding
to form transport vesicles by GTP-driven fission from the plasma membrane of endothelium, J. Cell Biol.
141:101-114. (MedLine)
Ohashi, M., Jan de Vries, K., Frank, R., Snoek, G., Bankaitis, V., Wirtz, K. and Huttner, W.B. (1995) A
role for phosphatidylinositol transfer protein in secretory vesicle formation, Nature 377:544-547.
(Medline)
Ohno, H., Stewart, J.,m Fournier, M.C., Bosshart, H., Rhee, I., Miyatake, S., Saito, T., Gallusser, A.,
Kichhausen, T. Banifacion, J.S. (1995) Interactions of tyrosine-based sorting signals with clathrin-associated proteins, Science 269:1872-1875. (Medline)
Orci, L., Glick, B. S. and Rothman, J. E. (1986) A new type of coated vesicular carrier that appears not to
contain clathrin: its possible role in protein transport within the Golgi stacks, Cell 46:171-184. (Medline)
Orci, L., Malhotra, V., Amherdt, M., Serafini, T. and Rothman, J.E. (1989) Dissection of a single round of
vesicular transport: sequential intermediates for cisternal movement in Golgi stack, Cell 56:357-368.
http://www.albany.edu/~abio304/ref/ref11.html (20 of 32) [3/5/2003 7:57:08 PM]
Chapter 11: References
(MedLine)
Orci, L., Stamnes, M., Ravazzola, M., Amherdt, M., Perrelet, A., Söllner, T.H. and Rothman, J.E. (1997)
Bidirectional transport by distinct populations of COPI-vesicles, Cell 90:335-349. (Medline)
Ostermann, J., Orci, L., Tani, K. Amherdt. M., Ravazzola, M., Elazar, Z. and Rothman, J.E. (1993)
Stepwise assembly of functionally active transport vesicles, Cell 75: 1015-1025. (MedLine)
Panaretou, C., Domin, J., Cockcroft, S. and Waterfield, M.D. (1997) Characterization of p150, an adaptor
protein for the human phosphatidylinositol (PtdIns) 3-kinase. Substrate presentation by
phosphatidylinositol transfer protein to the p150.Ptdins 3-kinase complex, J. Biol. Chem. 272:2477-2485.
(Medline)
Parlati, F., McNew, J.A., Fukuda, R., Miller, R., Sollner, T.H. and Rothman, J.E. (2000) Topological
restriction of SNARE-dependent membrane fusion, Nature 407:194-198. (MedLine)
Patel, S. and Latterich, M. (1998) The AAA team: related ATPases with diverse functions, Trends Cell
Biol. 8:65-71. (Medline)
Patzak, A. and Winkler, H. (1986) Exocytotic exposure and recycling of membrane antigens of
chromaffin granules: ultrastructural evaluation after immunolabeling, J. Cell Biol. 102:510-515.
(Medline)
Pearse, B.M. (1988) Receptors compete for adaptors found in plasma membrane coated pits, EMBO J.
11:3331-3336. (Medline)
Pelham, H.R.B. (1999) SNAREs and the secretory pathway-lessons from yeast, Exp. Cell Res. 247:1-8.
(MedLine)
Pelham, H.R.B. (2001) SNAREs and the specificity of membrane fusion, Trends Cell Biol. 99-101.
Peter, F., Plutner, H., Zhu, H., Kreis, T.E. and Balch, W.E. (1993) β-COP is essential for transport of
protein from the endoplasmic reticulum to the Golgi in vitro, J. Cell Biol. 122:1155-1167. (Medline)
Peters, C. and Mayer, A (1998) Ca2+/calmodulin signals the completion of docking and triggers a late
step of vacuole fusion, Nature 396:575-580. (MedLine)
Pevner, J., Hsu, S.-C. and Scheller, R.H. (1994) n-Sec1: a neural-specific syntaxin-binding protein, Proc.
Natl. Acad. Sci. USA 91:1445-1449. (Medline)
http://www.albany.edu/~abio304/ref/ref11.html (21 of 32) [3/5/2003 7:57:08 PM]
Chapter 11: References
Pfeffer, S.R. (1999) Transport-vesicle targeting: tethers before SNAREs, Nature Cell Biol. 1:E17-22.
(MedLine)
Pfeiffer, S., Fuller, S. D. and Simons, K. (1985) Intracellular sorting and basolateral appearance of the G
protein of vesicular stomatitis virus in Madin-Darby canine kidney cells. J. Cell Biol. 101:470-476.
(Medline)
Pierce, S.K. (2002) Lipid rafts and B-cell activation, Nature Rev. Immunol. 2:96-105. (MedLine)
Pike, L.J. and Casey, L. (1996) Localization and turnover of phosphatidylinositol 4,5-bisphosphate in
caveolin-enriched membrane domains, J. Biol. Chem. 271:26453-26456. (Medline)
Powell, S.K., Lisanti, M.P. and Rodriguez-Boulan, E.J. (1991) Thy-1 expresses two signals for apical
localization in epithelial cells, Am. J. Physiol. Cell Physiol. 29:C715-720. (Medline)
Presley, J.F, Cole, N.B., Schroer, T.A., Hirschberg K., Zaal K.J., Lippincott-Schwartz J. (1997) ER-to-Golgi transport visualized in living cells, Nature 389:81-85. (Medline)
Propopov, V., Govindan, B., Novick, P., and Gerst, J.E. (1993) Homologs of the syaptobrevin/VAMP
family of synaptic vesicle proteins function on the late secretory pathway of S. cerevisiae, Cell 74:855-861. (Medline)
Puertollano, R., Aguilar, R.C., Gorshkova, I., Crouch, R.J and Bonifacino, J.S. Sorting of mannose 6-phosphate receptors mediated by the GGAs, Science 292:1712-1716. (MedLine)
Qualmann, B., Roos, J., DiGregorio, P.J. and Kelly, R.B. (1999) Syndapin I, a synaptic dynamin-binding
protein that associates with the neural Wiskott-Aldrich syndrome protein, Mol. Biol. Cell 10:501-513.
(MedLine)
Régnier-Vigouroux,A., Tooze, S.A., and Huttner, W.B.(1991) Newly synthesized synaptophysin is
transported to synaptic-like microvesicles via constitutive secretory vesicles and the plasma membrane,
EMBO J. 10:3589-35601. (Medline)
Reichert M, Muller T, Hunziker W (2000) The PDZ domains of zonula occludens-1 induce an epithelial
to mesenchymal transition of madin-darby canine kidney I cells. Evidence for a role of β-catenin/tcf/lef
signaling, J. Biol. Chem. 275:9492-9500. (MedLine)
Reinhard, C., Harter, C., Bremser, M., Br gger, B., Sohn, K., Helms, J.B. and Wieland, F. (1999)
Receptor-induced polymerization of coatomer, Proc. Natl. Acad. Sci. USA 96:1224-1228. (Medline)
http://www.albany.edu/~abio304/ref/ref11.html (22 of 32) [3/5/2003 7:57:08 PM]
Chapter 11: References
Rice, L.M. and Brunger, A.T. (1999) Crystal structure of the vesicular transport protein Sec17:
implications for SNAP function in SNARE complex disassembly, Mol. Cell. 4:85-95. (Medline)
Rindler, M. J.. Ivanov, I. E., Plesken, H., Rodriguez-Boulan, E. and Sabatini, D. D. (1984) Viral
glycoproteins destined for apical or basolateral plasma membrane domains traverse the Golgi apparatus
during the intracellular transport in doubly infected Madine-Darby canine kidney cells (MDCK), J. Cell
Biol. 98:1304-1319. (Medline)
Rindler, M.J., Ivanov, I.E. and Sabatini, D.D. (1987) Microtubule -acting drugs lead to the non-polarized
delivery of influenza hemagglutinin to the cell surface of polarized Madin-Darby canine idney cells, J.
Cell Biol. 104:231-241. (Medline)
Robinson, M.S. (1997) Coats and vesicle budding, Trends in Cell Biol. 7:99-102
Rodriguez-Boulan, E. and Nelson, W.J. (1989) Morphogenesis of the polarized epithelial cell phenotype,
Science 245:718-724. (Medline)
Rogalski, A.A. and Singer, S.J. (1984) Associations of elements of the Golgi apparatus with microtubules,
J. Cell. Biol. 99: 1092-1100 (Medline)
Rossi, G., Jiang, Y., Newman, A. and Ferro-Novick (1991) Dependence of Ypt1 and Sec 4 membrane
attachement on Bet2, Nature 351:158-161. (Medline)
Rothman, J.E. (1994) Mechanisms of intracellular protein transport (1994) Nature 372:55-62. (Medline)
Rothman, J. E. and Orci, L. (1992) Molecular dissection of the secretory pathway Nature 355:409-415.
(Medline)
Rothman, J.E. and Wieland, F.T. (1996) Protein sorting by transport vesicles, Science 272:227-234.
(Medline)
Rowe, T., Aridor, M., McCaffery, J.M., Plutner, H. and Nuoffer, C. and Balch, W.E. (1996) COPII
vesicles derived from mammalian endoplasmic reticulum microsomes recruit COPI, J. Cell Biol. 135:895-911. (Medline)
Sacher, M., Jiang, Y., Barrowman, J., Scarpa, A., Burston ,J., Zhang, L., Schieltz, D., Yates, J.R. 3rd,
Abeliovich, H. and Ferro-Novick, S. (1998) TRAPP, a highly conserved novel complex on the cis-Golgi
that mediates vesicle docking and fusion, EMBO J. 17:2494-2503. (Medline)
Sahagian, G. G. and Steer, C. J. (1985) Transmembrane orientation of a mannose-6-phosphate receptor in
http://www.albany.edu/~abio304/ref/ref11.html (23 of 32) [3/5/2003 7:57:09 PM]
Chapter 11: References
isolated clathrin coated vesicles, J. Biol. Chem. 260:9838-9842. (Medline)
Sahagian, G. G., Distler, J. and Jourdian, G. W. (1981) Characterization of a membrane-associated
receptor from bovine liver that binds phosphomannosyl residues of bovine testicular -galactosidase, Proc.
Natl. Acad. Sci. USA. 78:4289-4293. (Medline)
Salama, N.R., Yeung, T. and Shekman, R.W. (1993) The sec 13p complex and reconstitution of vesicle
budding from ER with purified cytosolic proteins, EMBO J. 12:4073-4082. (Medline)
Sandoval , I.V. and Bakke, O. (1994) Targeting of membrane proteins to endosomes and lysosomes,
Trends in Cell Biol. 4:292-297.
Sandvig, K. and van Deurs, B. (1996) Endocytosis, intracellular transport, and cytotoxic action of Shiga
toxin and ricin, Physiol. Rev. 76:949-966. (MedLine)
Santos, B. and Snyder, M. (1997) Targeting of chitin synthase 3 to polarized growth sites in yeast requires
Chs5p and Myo2p, J. Cell Biol. 136:95-110. (MedLine)
Scales, S.J., Pepperkok, R. and Kreis, T.E. (1997) Visualization of ER-to-Golgi transport in living cells
reveals a sequential mode of action for COPII and COPI, Cell 90:1137-1148. (Medline)
Schimmoller, F., Singer-Kruger, B., Schroder, S., Kruger, U., Barlowe, C. and Riezman, H. (1995) The
absence of Emp24p, a component of ER-derived COPII-coated vesicles, causes a defect in transport of
selected proteins to the Golgi, EMBO J. 14:1329-1339. (MedLine)
Schoenenberger, C.A., Zuk, A., Zinkl, G.M., Kendall, D. and Matlin, K.S. (1994) Integrin expression and
localization in normal MDCK cells and transformed MDCK cells lacking apical polarity, J. Cell Sci.
107:527-541. (MedLine)
Schafer, D.A., Gill, S.R., Cooper, J.A., Heuser, J.E. and Schroer, T.A. (1994) Ultrastructural analysis of
the dynactin complex: an actin-related protein is a component of a filament that resembles F-actin, J. Cell
Biol.126:403-412. (Medline)
Scheiffele, P., Peranen, J. and Simons, K. (1995) N-glycans as apical sorting signals in epithelial cells,
Nature 378:96-98. (Medline)
Schell, M.J., Maurice, M., Stieger, B. and Hubbard. A.L. (1992) 5′ nucleotidase is sorted to the apical
domain of hepatocytes via an indirect route, J. Cell Biol., 119:1173-1182. (Medline)
Schmidt, A., Wolde, M., Thiele, C., Fest, W., Kratzin, H., Podtelejnikov, A.V., Witke, W., Huttner, W.B.
and Soling, H.D. (1999) Endophilin I mediates synaptic vesicle formation by transfer of arachidonate to
http://www.albany.edu/~abio304/ref/ref11.html (24 of 32) [3/5/2003 7:57:09 PM]
Chapter 11: References
lysophosphatidic acid, Nature 401:133-141. (MedLine)
Schott, D., Ho, J., Pruyne, D. and, Bretscher, A. (1999) The COOH-terminal domain of Myo2p, a yeast
myosin V, has a direct role in secretory vesicle targeting, J. Cell Biol. 147:791-808. (MedLine)
Schröder, S. and Ungewickell, E. (1991) Subunit interaction and function of clathrin-coated vesicle
adaptors for the Golgi and the plasma membrane, J. Biol. Chem. 266:7910-7918. (Medline)
Schroer, T.A. and Sheetz, M.P. (1991) Two activators of microtubule-based vesicle transport, J. Cell Biol.
115:1309-1318. (Medline)
Schroer, T.A., Bingham, J.B. and Gill S.R. (1996) Actin-related protein 1 and cytoplasmic dynein based
motility-what’s the connection, Trends Cell Biol. 6:212-215.
Schulze-Lohoff. E., Hasilik, A. and von Figura, K. (1985) Cathepsin D precursors in clathrin coated
organelles from human fibroblasts, J. Cell Biol. 101:824-829. (Medline)
Schwaninger, R., Plutner, H., Bokoch, G.M. and Balch, W.E. (1992) Multiple GTP-binding proteins
regulate vesicular transport from the ER to Golgi membranes, J. Cell Biol. 119:1077-1096. (Medline)
Seaman, M.N., McCaffery, J.M., Emr, S.D. (1998) A membrane coat complex essential for endosome-to-Golgi retrograde transport in yeast, J. Cell. Biol. 142:665-681. (Medline)
Serafini, T. and Rothman, J.E. (1992) Purification of Golgi cisternae-derived non-clathrin-coated vesicles,
Methods Enzymol. 219:286-299. (MedLine)
Sever, S., Muhlberg, A.B. and Schmid, S.L.(1999) Impairment of dynamin’s GAP domain stimulates
receptor-mediated endocytosis, Nature 398:481-486. (MedLine)
Shaywitz, D.A., Espenshade, P.J., Gimeno, R.E. anf Kaiser, C.A. (1997) COPII subunit interactions in the
assembly of the vesicle coat, J. Biol. Chem. 272:25413-25416. (Medline)
Shih, W., Galluser, A. and Kirchhausen, T. (1995) A clathrin binding site in the hinge of the β2 chain of
mammalian AP-2 complexes, J. Biol. Chem. 270:31083-31090. (Medline)
Simons, K. and Fuller, S. D. (1985) Cell surface polarity in epithelium, Annu. Rev. Cell Biol. 1:243-288.
(Medline)
Simons, K. and Ikonen, E. (1997) Functional rafts in cell membranes, Nature 387:569-572. (Medline)
http://www.albany.edu/~abio304/ref/ref11.html (25 of 32) [3/5/2003 7:57:09 PM]
Chapter 11: References
Simons, K. and Zerial, M. (1993) Rab proteins and the road map for intracellular transport, Neuron
11:789-799. (Medline)
Simonsen, A., Lippe, R., Christoforidis, S., Gaullier, J.M., Brech, A., Callaghan, J., Toh, B.H., Murphy,
C., Zerial, M. and Stenmark, H. (1998) EEA1 links PI(3)K function to Rab5 regulation of endosome
fusion, Nature 394:494-498. (MedLine)
Simpson, F., Bright, N.A., West, M.A., Newman, L.S., Darnell, R.B. and Robinson, M.S. (1996) A novel
adaptor-related protein complex, J. Cell Biol. 133:749-760. (Medline)
Sohn, K., Orci, L., Ravazzola, M., Amherdt, M., Bremser, M., Lottspeich, F., Fiedler, K., Helms, J.B. and
Wieland, F.T. (1996) A major transmembrane protein of Golgi-derived COPI-coated vesicles involved in
coatomer binding, J. Cell Biol. 135:1239-1348. (MedLine)
Sönnichsen, B., Watson, R., Clausen, H., Misteli, T. and Warren, G. (1996) Sorting by COP I-coated
vesicles under interphase and mitotic conditions, J. Cell Biol. 134:1411-1425. (MedLine)
Soole, K.L., Jepson, M.A., Hazlewood, G.P., Gilbert, H.J., and Hirst, B.H. (1985) Epithelial sorting of a
glycosylphosphatidylinositol-anchored bacterial protein expressed in polarized renal MDCK and
intestinal Caco-2 cells, J. Cell Sci. 108:369-377. (Medline)
Sorokin, L., Sonnenberg, A., Aumailley, M., Timpl, R. and Ekblom, P. (1990) Recognition of the laminin
E8 cell-binding site by an integrin possessing the α6 subunit is essential for epithelial polarization in
developing kidney tubules, J. Cell Biol. 111:1265-1273. (MedLine)
Søgaard, M., Tani, K., Ye, R.R., Geromanos, S., Tempst, P., Kirchhausen, T. Rothman, J.E. and Söllner,
T. (1994) A rab protein is required for the assembly of SNARE complexes in the docking of transport
vesicles, Cell 78:937-948. (Medline)
Söllner, T., Whiteheart, S.W., Brunner, M., Erdjument-Bromage, H., Geromanos, S. Tempst, P. and
Rothman, J.E. (1993a) SNAP receptors implicated in vesicle targeting and fusion, Nature 362:318-324.
(Medline)
Söllner,T., Bennett, M.K., Whiteheart, S.W., Scheller, R.H. and Rothman, J.E. (1993b) A protein
assembly-disassembly pathway in vitro that may correspond to sequential steps of synaptic vesicle
docking, activation and fusion. Cell 75:409-418. (Medline)
Sonoda, N., Furuse, M., Sasaki, H., Yonemura, S., Katahira, J., Horiguchi, Y. and Tsukita, S. (1999)
Clostridium perfringens enterotoxin fragment removes specific claudins from tight junction strands.
Evidence for direct involvement of claudins in tight junction barrier, J. Cell Biol. 147:195-204. (Medline)
http://www.albany.edu/~abio304/ref/ref11.html (26 of 32) [3/5/2003 7:57:09 PM]
Chapter 11: References
Springer, S. and Schekman, R. (1998) Nucleation of COPII vesicular coat complex by endoplasmic
reticulum to Golgi vesicle SNAREs, Science 281:698-700. (MedLine)
Springer, S., Spang, A. and Schekman, R. (1999) A primer on vesicle budding, Cell 97:145-148.
(MedLine)
Stack, J.H. and Emr, S.D. (1994) Vps34p required for yeast vacuolar protein sorting is a multiple
specificity kinase that exhibits both protein kinase and phosphatidylinositol-specific PI 3-kinase activities,
J. Biol. Chem. 269:31552-31562. (Medline)
Staehelin, L.A. (1974) Structure and function of intercellular junctions, Int. Rev. Cytol. 39:191-283.
(Medline)
Stepp, J.D., Pellicena-Palle, A., Hamilton, S., Kirchhausen, T. and Lemmon, S. K. (1995) A late Golgi
sorting function for Saccharomyces cerevisiae Apm1p, but not Apm2p, a second yeast clathrin AP
medium chain-related protein, Mol. Biol. Cell 6:41-58. (Medline)
Stepp, J.D., Huang, K. and Lemmon, S.K. (1997)The yeast adaptor protein complex, AP-3, is essential for
the efficient delivery of alkaline phosphatase by the alternate pathway to the vacuole, J. Cell Biol.
139:1761-1774. (Medline)
Stone, S., Sacher, M., Mao, Y., Carr, C., Lyons, P., Quinn, A.M. and Ferro-Novick, S. (1997) Bet1p
activates the v-SNARE Bos1p, Mol. Biol. Cell 8:1175-1181 (Medline)
Stoorvogel, W., Oorschot, V. and Geutze, H.J. (1996) A novel class of clathrin-coated vesicles budding
from endosomes, J. Cell Biol. 132:21-33. (Medline)
Storrie, B., Pepperkok, R. and Nilsson, T. (2000) Breaking the COPI monopoly on Golgi recycling,
Trends Cell Biol. 10:385-390. (MedLine)
Stow, J.L. de Almeida, J.B., Narula, N., Holzman, E.J., Ercolani, L. and Ausiello, D.A. (1991) A
heterotrimeric G protein G1-3, on Golgi membranes regulates the secretion of a heparan sulfate
proteoglycan in LLC-PK1 epithelial cells, J. Cell Biol. 114:1113-11124. (Medline)
Takahashi, K., Matsuo, T., Katsube, T., Ueda, R. and Yamamoto, D. (1998) Direct binding between two
PDZ domain proteins Canoe and ZO-1 and their roles in regulation of the jun N-terminal kinase pathway
in Drosophila morphogenesis, Mech. Dev. 78:97-111. (MedLine)
Takei, K., McPherson, P.S., Schmid, S.L. and De Camilli, P. (1995) Tubular membrane invaginations
coated by dynamin rings are induced by GTP-S in nerve terminals, Nature 374:186. (Medline)
http://www.albany.edu/~abio304/ref/ref11.html (27 of 32) [3/5/2003 7:57:09 PM]
Chapter 11: References
Tan, A., Bolscher, J., Feltkamp, C. and Ploegh, H. (1992), Retrograde transport from the Golgi region to
the endoplasmic reticulum is sensitive to GTPγS, J. Cell Biol. 116, 1357-1367. (Medline)
Tanigawa, G., Orci, L., Amherdt, M., Ravazzola, M., Helms, J.B. and Rothman, J.E. (1993) Hydrolysis of
bound GTP by ARF protein triggers uncoating of Golgi-derived COP-coated vesicles, J. Cell Biol.
123:1365-1371. (Medline)
Tepass, U. (1997) Epithelial differentiation in Drosophila, BioEssays 19:673-682. (MedLine)
Tepass, U., Theres, C. and Knust, E. (1990) crumbs encodes an EGF-like protein expressed on apical
membranes of Drosophila epithelial cells and required for organization of epithelia, Cell 61:787-799.
(MedLine)
TerBush, D.R., Maurice, T., Roth, D. and Novick, P. (1996) The Exocyst is a multiprotein complex
required for exocytosis in Saccharomyces cerevisiae, EMBO J. 15:6483-6494. (Medline)
Thomas, J.R., Dwek, R.A. and Rademacher, T.W. (1990) Structure, biosynthesis and function of
glycosylphosphatidylinositols, Biochemistry 29:5413-5422. (Medline)
Thompson, T.E. and Tillack, T.W. (1985) Organization of glycosphingolipids in bilayers and plasma
membranes of mammalian cells, Ann. Rev. Biophys. Biophys. Chem. 14:361-386. (Medline)
Traub, L.M. (1997) Clathrin-associated adaptor proteins-putting it all together, Trends in Cell Biol. 7:43-46.
Traub, L.M., Kornfeld, S. and Ungewickell, E. (1995) Different domains of the AP-1 adaptor complex are
required for Golgi membrane binding and clathrin recruitment, J.Biol. Chem. 270:4933-4942. (Medline)
Tsukita, S. and Furuse, M. (1999) Occludin and claudins in tight-junction strands: leading or supporting
players? Trends Cell Biol. 9:268-273. (Medline)
Umeda, A., Meyerholz, A. and Ungewickell, E. (2000) Identification of the universal cofactor (auxilin 2)
in clathrin coat dissociation, Eur. J. Cell Biol. 79:336-342. (MedLine)
Ungewickell, E., Ungewickell, H., Holstein, S.E., Lindner, R., Prasad, K., Barouch, W., Martin, B.,
Greene, L.E. and Eisenberg E. (1995) Role of auxilin in uncoating clathrin-coated vesicles, Nature
378:632-635. (MedLine)
van de Moortele, S., Picart, R., Tixier-Vital, A., and Tougard, C. (1993) Nocodazole and taxol affect
subcellular compartments but not secretory activity of GH3B6 prolactin cells, Eur. J. Cell Biol. 60:217-http://www.albany.edu/~abio304/ref/ref11.html (28 of 32) [3/5/2003 7:57:09 PM]
Chapter 11: References
227. (Medline)
van der Bliek, A.M., Redelmeier, T.E., Damke, H., Tisdale, E.J., Meyerowitz, E.M. and Schmid, S.L.
(1993) Mutations in human dynamin block an intermediate stage in coated vesicle formation, J. Cell Biol.
122:553-563. (MedLine)
VanRheenen, S.M., Cao, X., Sapperstein, S.K., Chiang, E.C., Lupashin, V.V., Barlowe, C. and Waters,
M.G. (1999) Sec34p, a protein required for vesicle tethering to the yeast Golgi apparatus, is in a complex
with Sec35p, J. Cell Biol. 147:729-742. (MedLine)
Van Zeijl, M.J.A.H. and Matlin, K.S (1990) Microtubule perturbation inhibits intracellular transport of an
apical membrane glycoprotein in a substrate dependent manner in polarized Madin-Darby canine kidney
cells, Cell Reg. 1:921-936. (Medline)
Vega-Salas, D.E., Salas, P.J.I., Gundersen, D. and Rodriguez-Boulan, E. (1987) Formation of the apical
pole of the epithelial (Madin-Darby canine kidney) cells:polarity of an apical protein is independent of
tight junctions while segregation of a basolateral marker requires cell-cell interactions, J. Cell Biol.
104:905-916.
von Figura. K. and Hasilik, A. (1986) Lysosomal enzymes and their receptors. Annu. Rev. Biochem.
55:167-193. (Medline)
von Mollard, F.G.and Stevens, T.H. (1999) The Saccharomyces cerevisiae v-SNARE Vti1p is required
for multiple membrane transport pathways to the vacuole, Mol. Biol. Cell. 10:1719-1732. (MedLine)
von Mollard, G.F., Nothwehr, S.F. and Stevens, T.H. (1997) The yeast v-SNARE Vti1p mediates two
vesicle transport pathways through interactions with the t-SNAREs Sed5p and Pep12p, J. Cell Biol.
137:1511-1524. (MedLine)
Vowels, J.J. and Payne, G.S. (1998) A dileucine-like sorting signal directs transport into an AP-3-dependent, clathrin-independent pathway to the yeast vacuole, EMBO J. 17:2482-2493. (Medline)
Waterman-Storer, C.M., Karki, S. and Holzbauer, E.L.F. (1995) The p150Glued component of the dynactin
complex binds to both microtubules and the actin related protein centractin (Arp1) Proc. Natl. Acad. Sci.
USA 92:1634-1638. (Medline)
Waters, M.G. and Pfeffer, S.R. (1999) Membrane tethering in intracellular transport, Curr. Opin. Cell
Biol. 11:453-459. (MedLine)
Waters, M. G., Serafini, T. and Rothman. J. E. (1991) ‘Coatamer': a cytosolic protein complex containing
subunits of non-clathrin-coated Golgi transport vesicles, Nature 349:248-251. (Medline)
http://www.albany.edu/~abio304/ref/ref11.html (29 of 32) [3/5/2003 7:57:09 PM]
Chapter 11: References
Waters, M.G., Clary, D.O. and Rothman, J.E. (1992) A novel 115-kD peripheral membrane protein is
required for intercisternal transport in the Golgi stack, J. Cell Biol. 118:1015-1026. (MedLine).
Weber, T., Zemelman, B.V., McNew, J.A., Westermann, B., Gmachl, M., Parlati, F., Söllner, T.H. and
Rothman, J.E. (1998) SNAREpins: minimal machinery for membrane fusion, Cell 92:759-972. (MedLine)
Weidman, P.J., Melançon, P., Block, M.R. and Rothman, J.E. (1989) Binding of an N-ethylmaleimide-sensitive fusion protein to Golgi membranes requires both soluble protein(s) and an integral membrane
receptor, J. Cell Biol. 108:1589-1596. (Medline)
Weigert, R., Silletta, M.G., Spano, S., Turacchio, G., Cericola, C., Colanzi, A., Senatore, S., Mancini, R.,
Polishchuk, E.V., Salmona, M., Facchiano, F., Burger, K.N., Mironov, A., Luini, A. and Corda, D. (1999)
CtBP/BARS induces fission of Golgi membranes by acylating lysophosphatidic acid, Nature 402:429-433. (MedLine)
Weimbs, T., Low, S.H., Chapin, S.J. and Mostov, K.E. (1997a) Apical targeting in polarized epithelial
cells: there’s more afloat than rafts, Trends in Cell Biol. 7:393-399.
Weimbs, T., Low, S.H., Chapin, S.J., Mostov, K.E., Bucher, P. and Hofmann K.(1997b) A conserved
domain is present in different families of vesicular fusion proteins: a new superfamily, Proc. Natl. Acad.
Sci. USA 94:3046-3051. (MedLine)
Whiteheart, S.W., Brunner, M., Wilson, D.W., Wiedmann, M. and Rothman, J.E. (1992) Soluble N-ethylmaleimide-sensitive fusion attachment proteins (SNAPs) bind to a multi-SNAP receptor complex in
Golgi membranes, J. Biol. Chem. 267:1239-12243.
Whitney, J.A., Gomez, M., Sheff, D., Kresi, T.E. and Mellman, I. (1995) Cytoplasmic coat proteins
involved in endosome function, Cell 83:703-713. (Medline)
Wickner, W. and Haas, A. (2000) Yeast homotypic vacuole fusion: a window on organelle trafficking
mechanisms, Annu. Rev. Biochem. 69:247-275. (MedLine)
Wienke, D.C., Knetsch, M.L., Neuhaus, E.M., Reedy, M.C. and Manstein, D.J. (1999) Disruption of a
dynamin homologue affects endocytosis, organelle morphology, and cytokinesis in Dictyostelium
discoideum Mol. Biol. Cell 10:225-243. (MedLine)
Willingham, M. C., Pastan, I. H., Sahagian, G. G., Jourdian, G. W. and Neufeld, E. F. (1981)
Morphologic study of the internalization of a lysosomal enzyme by mannose-6-phosphate receptor in
cultured Chinese hamster ovary cells, Proc. Natl. Acad. Sci. USA 78:6967-6971. (Medline)
http://www.albany.edu/~abio304/ref/ref11.html (30 of 32) [3/5/2003 7:57:09 PM]
Chapter 11: References
Wilson, D.W., Wilcox, C.A., Flynn, G.C., Chen, E., Kuang, W.-J., Henzel, W.J., Block, M.R., Ulrich, A.
and Rothman, J.E. (1989) A fusion protein required for vesciel-mediated transport in both mammalian
cells and yeast, Nature 339:355-359. (Medline)
Wilson, D.W., Whiteheart, S.W., Wiedmann, M., Brunner, M. and Rothman, J.E. (1992) A multisubunit
particle implicated in membrane fusion, J. Cell Biol. 117:531-538. (Medline)
Wirtz, K.W. (1991) Phospholipid transfer proteins, Annu. Rev. Biochem. 60:73-99. (Medline)
Witke, W., Podtelejnikov, A.V., Di Nardo, A., Sutherland, J.D., Gurniak, C.B., Dotti, C. and Mann, M.
(1998) In mouse brain profilin I and profilin II associate with regulators of the endocytic pathway and
actin assembly, EMBO J. 17:967-976. (MedLine)
Wodarz, A., Hinz, U., Engelbert, M. and Knust, E. (1995) Expression of crumbs confers apical character
on plasma membrane domains of ectodermal epithelia of Drosophila, Cell 82:67-76. (MedLine)
Woods, J.W., Doriaux, M. and Falquhar, M.G. (1986) Transferrin receptors recycle to the cis and middle
as well as trans Golgi cisternae in Ig-secreting myeloma cells, J. Cell Biol. 103, 277-286. (Medline)
Woodward, M.P. and Roth, T.F. (1978) Coated vesicles: characterization, selective dissociation, and
reassembly, Proc. Natl. Acad. Sci. USA 75:4394-4398. (Medline)
Yang, B., Gonzalez, L. Jr., Prekeris, R., Steegmaier, M., Advani, R.J. and Scheller, R.H. (1999) SNARE
interactions are not selective. Implications for membrane fusion specificity, J. Biol. Chem. 274:5649-5653. (Medline)
Yeaman, C., Le Gall, A.H., Baldwin, A.N., Monlauzeur, L., Le Bivic, A. and Rodriguez-Boulan, E.
(1997) The O-glycosylated stalk domain is required for apical sorting of neurotrophin receptors in
polarized MDCK cells, J. Cell Biol. 139:929-940. (Medline)
Yokode, M., Pathak, R.K., Hammer, R.E., Brown, M.S.. Goldstein, J.L. and Anderson, R.G.W. (1992)
Cytoplasmic sequence required for basolateral targeting of LDL receptor in liver of transgenic mice, J.
Cell Biol. 117:39-46. (Medline)
Yu, R.C., Hanson, P.I., Jahn, R. and Brunger, A.T. (1998) Structure of the ATP-dependent
oligomerization domain of N-ethylmaleimide sensitive factor complexed with ATP, Nature Struct. Biol.
5:803-8011. (Medline)
Yu, R.C., Jahn, R. and Brunger, A.T. (1999) NSF N-terminal domain crystal structure: models of NSF
function, Mol. Cell 4:97-107. (Medline)
http://www.albany.edu/~abio304/ref/ref11.html (31 of 32) [3/5/2003 7:57:09 PM]
Chapter 11: References
Zacharias, D.A., Violin, J.D., Newton, A.C. and Tsien, R.Y. (2002) Partitioning of lipid-modified
monomeric GFPs into membrane microdomains of live cells, Science 296:913-916. 9MedLine)
Zerial, M. and McBride, H. (2001) Rab proteins as membrane organizers, Nature Rev. Mol. Cell Biol.
2:107-117. (MedLine)
Zhao, L., Helms, J.B., Brugger, B., Harter, C., Martoglio, B., Graf, R., Brunner, J. and Wieland, F.T.
(1997) Direct and GTP-dependent interaction of ADP ribosylation factor 1 with coatomer subunit β, Proc.
Natl. Acad. Sci. USA 94:418-423. (MedLine)
Zhao, L., Helms, J.B., Brunner, J. and Wieland, F.T. (1999) GTP-dependent binding of ADP-ribosylation
factor to coatomer in close proximity to the binding site for dilysine retrieval motifs and p23, J. Biol.
Chem. 274:14198-14203. (MedLine)
Zhu, Y., Traub, L.M. and Kornfeld, S. (1998) ADP-ribosylation factor 1 transiently activates high-affinity
adaptor protein complex AP-1 binding sites on Golgi membranes, Mol. Biol. Cell 9:1323-1337.
(MedLine)
Zhu, Y., Doray, B., Poussu, A., Lehto, V.P. and Kornfeld, S. (2001) Binding of GGA2 to the lysosomal
enzyme sorting motif of the mannose 6-phosphate receptor, Science 292:1716-1718. (MedLine)
Zimmerberg, J. (2000) Are the curves in the right places? Traffic 1:366-368.
Zurzolo, C., Lisantu, M.P., Caras, I.W., Nitsch, L. and Rodriguez-Boulan, E. (1993)
Glycosylphosphatidylinositol-anchored proteins are preferentially targeted to the basolateral surface in
Fischer rat thyroid epithelial cells, J. Cell. Biol. 121:1031-1039. (Medline)
Zurzolo, C., van’t Hof, W., van Meer, G. and Rodriguez-Boulan, E. (1994) VIP21/caveolin,
glycosphingolipid clusters and the sorting of glycosylphosphatidylinositol-anchored proteins in epithelial
cells, EMBO J. 13:42-53. (Medline)
http://www.albany.edu/~abio304/ref/ref11.html (32 of 32) [3/5/2003 7:57:09 PM]

Leave a comment

Transport of Ions: Mechanisms and Models

21. Transport of Ions: Mechanisms and Models
21. Transport of Ions:
Mechanisms and Models
I.  Coupling Between ATP Hydrolysis and Transport
II.  Synthesis of ATP by Transport ATPases
III.  Models of Ion Transport and Structure
Suggested Reading
References
Back to List of Chapters
Examining simple models and possible alternatives sometimes can provide insights into biological
processes. This approach has proved very useful in sorting out the data on ion transport and their possible
interpretation, and it provides the perspective of this chapter.
Section I examines data obtained in a study of Na+, K+-ATPase and, for discussion, uses the model
represented in Fig. 1 based on the experiments presented in Chapter 20. This model undoubtedly will
require extensive modification and elaboration, but it is a useful summary. Very similar data are
available from studies of the Ca2+-ATPase and a similar model could also be drawn for the transport of
Ca2+. Section II examines some of the characteristics of the phosphorylation of ADP by inorganic
phosphate, catalyzed by transport ATPases in the absence of ionic gradients. These phenomena may
reveal some new features of the ATPases and perhaps have some bearing on our understanding of the
synthesis of ATP by the ATP synthase of mitochondria, chloroplasts and bacteria. Section III
concentrates on possible molecular mechanisms of ion transport and discusses the information gained
from knowledge of the amino acid sequences and the reconstruction of the structure of the Ca2+-ATPase.
I. COUPLING BETWEEN ATP HYDROLYSIS AND TRANSPORT
The evidence reviewed in Chapter 20 unmistakably demonstrates that the active efflux of Na+ and the
influx of K+ are coupled to the hydrolysis of ATP. As suggested in step 1 of Fig. 1, the coupling between
the translocation of the ions and the hydrolysis of ATP may result from the required phosphorylation of
the transporter molecule. The incubation of membrane preparations with ATP labeled with [32P] in its
terminal position, labels the membranes. The phosphate, and not the whole ATP molecule, is
incorporated since [14C]ATP does not label the membranes. Table 1 (Post et al., 1965) summarizes the
incorporation of [32P] into kidney plasma membranes as a function of the cation present in the medium.
When Na+ is present, the incorporation is highest, 97 pmoles/mg protein, compared to the incorporation
in its absence (between 14 and 29 pmoles). Even in the presence of Na+, the incorporation may not seem
http://www.albany.edu/~abio304/text/21part1.html (1 of 8) [3/5/2003 8:24:03 PM]
21. Transport of Ions: Mechanisms and Models
very large. This is because the Na+,K+-ATPase is a minor component of the cell membrane (see below).
Much higher values can be obtained for membrane fragments containing the Ca2+-ATPase, which
represents a very large proportion of the total protein of the sarcoplasmic reticulum. Actually, in both
cases the amount of [32P] incorporated corresponds to one per ATPase molecule. In step 1 of the model
of Fig. 1, the phosphorylation of X produces Y~P. Different letters, X and Y, are used to denote the two
forms because they have very different properties. Y is able to bind Na+ (step 2) and transfer it to the
external membrane interface (step 3), from which it is released (step 4). X-P is generated from Y~P (step
5) and it binds K+ (step 6), transfers it to the internal membrane interface (step 7), and releases it to the
cell’s interior (step 8) with hydrolysis of X-P.
Fig. 1 Early model of the functioning of the Na+,K+-ATPase. The step corresponds to the following: step
1, the phosphorylation of the ATPase indicated as Y; step 2, the binding of Na+ to Y~P; step 3, the
movement of the binding group from the cytoplasmic side of the membrane to the outside; step 4, the
release of Na+; step 5, the hydrolysis of Y~P to form a different form of Y, X; step 6, the binding of K+;
step 7, its displacement to the cytoplasmic side of the membrane; and step 8, its release into the
cytoplasm.
Table 1 Effect of Monovalent Cations on Labeling of Kidney Membranes After Incubation with
Mg2+ and [32P]ATP
Addition Labelling
(pmol 32P/mg protein)
None 26
Li+ 20
http://www.albany.edu/~abio304/text/21part1.html (2 of 8) [3/5/2003 8:24:03 PM]
21. Transport of Ions: Mechanisms and Models
Na+ 97
K+ 16
NH4+ 14
Rb+ 18
Cs+ 14
Tris+ 19
Reproduced with permission from R.L. Post et al., J. Biol. Chem. 240:1437-1445. Copyright ©1965 The American Society
for Biochemistry and Molecular Biology.
This scheme suggests that the formation of Y~P requires the presence of Na+, as shown by the results in
Table 1. Other univalent cations cannot substitute. Fig. 2 shows the dependence of the phosphorylation
expressed as % of the maximum (ordinate) on the concentration of Na+ (abscissa). The phosphorylation
is related to transport, as shown by the inhibition of a large portion of the Na+-dependent
phosphorylation by ouabain (Post et al., 1965) which blocks the transport of Na+ and K+. In Chapter 20
we saw that ouabain is an inhibitor of the Na+,K+-ATPase. The scheme also predicts that K+ would favor
the hydrolysis of Y~P, as shown by the experiment represented in Fig. 3 (Post et al., 1965). In this
experiment the membranes were first labeled with radioactive [32P]ATP. Then after the addition of
unlabelled ATP, they were incubated in the presence of K+. Although the [32P] is released even in the
absence of K+, the release is sharply accelerated when K+ is present. The rates of phosphorylation and
dephosphorylation are comparable to those of the ATPase activity (e.g., Kyte, 1974) which, in turn,
correspond very closely to the moles of ions being transported, as shown in Table 6 of Chapter 20.
The nature of the phosphorylated ATPase has also been examined in relation to its sensitivity to ADP.
The increased hydrolysis favored by K+ also appears in the results of the experiment of Fig. 4 (curve 1),
carried out with the same protocol as in Fig. 3, but with the addition of K+ or ATP after a 5 min
incubation (Post et al., 1965). In this experiment, K+ decreases the radioactivity as expected (curve 1),
whereas the addition of ADP (curve 2) has no effect, suggesting that the phosphorylated ATPase is no
longer in a high-energy form. In its high energy form, the phosphorylation of the enzyme would be
reversible.
The results are different when the ATPase has first been treated with N-ethylmaleimide (NEM), which
http://www.albany.edu/~abio304/text/21part1.html (3 of 8) [3/5/2003 8:24:03 PM]
21. Transport of Ions: Mechanisms and Models
reacts with sulfhydryl groups. Treatment of the ATPase with NEM, blocks the ATPase activity but not
the phosphorylation. As shown in Fig. 5 (Post et al., 1965), the NEM-treated ATPase is not sensitive to
K+ but is sensitive to ADP. These results suggest that the ATPase may be present in two distinct forms: a
form with a high and another with a low phosphate group transfer potential, the latter corresponding to a
K+-sensitive form. NEM blocks the conversion of the high energy form to the low-energy form. This
scheme is consistent with the following reactions:
Nai+ + E1 + ATP ↔ E1~P.Na+ (1)
E1~P.Na+↔ E2-P + Nao+ (2)
E2-P + Ko+ ↔ E2-P.K+ (3)
E2-P.K+↔ E2 + K+i + Pi (4)
where E represents the transporter molecule. The subscripts are used to distinguish the various molecular
configurations of the enzyme; E1 and E2 correspond to the Y and X of Fig. 1, respectively.
Fig. 2 Effect of ouabain on the sensitivity of the [32P]-labeled intermediate to the concentration of sodium
ion. The concentration of ouabain was 2.5 x 10-4 M, and that of Mg-ATP was 0.1 mM. Incubation was for
12 s at 23C. The results are the average of two experiments. Reproduced with permission from R. L. Post,
et al., Journal of Biological Chemistry, 240:1437-1445. Copyright ©1965 The American Society for
Biochemistry and Molecular Biology.
http://www.albany.edu/~abio304/text/21part1.html (4 of 8) [3/5/2003 8:24:03 PM]
21. Transport of Ions: Mechanisms and Models
Fig. 3 Influence of K+ on the rate of breakdown of the [32P]-labeled intermediate. Kidney membranes
were stirred with 0.04 mM Mg-ATP labeled with [32P] for 2 min at 8.5C in the presence of 16 mM Na+ in
a volume of 1.0 ml. ( ) K+ absent; ( ) K+ present at 0.04 mM. Then 0.1 ml of 20 mM unlabeled (Tris)
ATP was added to reduce the specific activity of the labeled ATP to 2% of its initial value. After the time
intervals on the horizontal axis the reaction was stopped with acid. The solid line indicates exponential
disappearance with a time constant of 21 s. The dashed line is similar, with a time constant of 4 s.
Reproduced with permission from R. L. Post, et al., Journal of Biological Chemistry, 240:1437-1445.
Copyright ©1965 The American Society for Biochemistry and Molecular Biology.
The estimates of size of the molecule, together with estimates of the turnover number of the transport
ATPase [i.e., moles of product x (moles of enzyme x minutes)-1], permit a number of interesting
approximations. The turnover number was calculated to be about 12,000, based on the phosphate
hydrolyzed. 1 mmol of Pi per hour is hydrolyzed from the ATP by 1 liter of cells. If we assume that there
are 1.1 x 1013 cells per liter, there must be 1.3 x 10-22 moles of enzyme per cell. Multiplied by
Avogadro’s number (the number of molecules in one mole) this value corresponds to about 80 transporter
molecules per cell. Assuming that the volume of each transporter molecule is 3.2 x 10-19 cm3, the total
volume of transporter per cell is 80 X (3.2 x 10-19) = 2.6 x 10-17 cm3. The red blood cell surface area is
about 1.55 X l0-6 cm2 and its thickness is approximately 5 nm, therefore, the volume of the membrane is
about 0.78 x 10-12 cm3. Thus, the transport ATPase occupies about 0.0003% of the membrane volume,
an extremely tiny portion of the cell membrane. In the red cell ghost, the Na+,K+-ATPase has been found
by a cytochemical electron microscopic method (Charnock et al., 1972) to be distributed evenly over the
membrane surface. However, other membranes are quite different. The Ca2+-ATPase is the major protein
http://www.albany.edu/~abio304/text/21part1.html (5 of 8) [3/5/2003 8:24:03 PM]
21. Transport of Ions: Mechanisms and Models
present in the sarcoplasmic reticulum. In addition, the distribution may not be even, the Na+, K+-ATPase
of polar cells such as epithelial cells, is present only on one surface, the apical surface.
Fig. 4 Sensitivity of the phosphorylated intermediate of the native enzyme to ADP and K+. The ATPase
was labeled with [32P]ATP. At zero time the radioactivity of the ATP was chased using a 100-fold excess
of unlabeled ATP. From Post et al. (1969). Reproduced from The Journal of General Physiology, by
copyright © permission of the Rockefeller University Press.
http://www.albany.edu/~abio304/text/21part1.html (6 of 8) [3/5/2003 8:24:03 PM]
21. Transport of Ions: Mechanisms and Models
Fig. 5 Sensitivity of the phosphorylated intermediate of the Na+,K+-ATPase to ADP and K+ after
treatment with N-ethylmaleimide. From Post et al. Reproduced from The Journal of General Physiology,
by copyright permission ©1969 of the Rockefeller University Press.
II. SYNTHESIS OF ATP BY TRANSPORT ATPases
As we saw in Chapter 10, when ion pumps are run in reverse, ATP can be synthesized from ADP and Pi.
These findings have certain implications related to the model of Fig. 1. ATP can be synthesized only if
the phosphorylated form of Y(Y~P) is a high-energy form (high phosphate group transfer potential); i.e.,
the G for its hydrolysis is sufficiently low to support the synthesis of ATP from ADP. However, as
described above, the evidence indicates that the usual phosphorylated form of the ATPase is hydrolyzed
with the addition of K+, but not ADP. As already noted, a possible explanation is that there are two
phosphorylated forms of the transporter molecule: a high-energy form involved in the transport of Na+
and a low-energy form that interacts with K+ (X-P). Furthermore, since X-P is a low-energy form, it
should be possible to phosphorylate the molecule with Pi in the absence of Na+, and this was found to be
the case (Post et al., 1965; Schoot et al., 1977; Sen et al., 1969). In the formulation of Fig. 1, Y~P would
then be the precursor of X-P. The Na+,K+-ATPase is present in two forms, E1 and E2, which differ in
conformation, as shown by a variety of techniques means such as exposure of regions of the molecule at
the membrane surface to tryptic digestion (see below). The Y~P and X-P would then correspond,
respectively, to the phosphorylated forms of E1 and E2 (Jorgensen and Petersen, 1979). Digestion of the
http://www.albany.edu/~abio304/text/21part1.html (7 of 8) [3/5/2003 8:24:03 PM]
21. Transport of Ions: Mechanisms and Models
enzyme phosphorylated with either ATP or Pi, produces identical electrophoretic patterns (Bontig et al.,
1979; Siegel et al., 1969).
However, it is not necessary to have an ion gradient to synthesize ATP in the case of either the Na+,K+-ATPase (Post et al., 1974) or the Ca2+-ATPase (Knowles and Racker, 1975). The in vitro synthesis is
carried out in two steps. First, the ATPase is phosphorylated; we saw that this can be done in the case of
the Na+,K+-ATPase by incubation with Pi. Then ATP is synthesized when ADP is added in the presence
of a high concentration of Na+. Obviously, this proceeds only for a single turnover.
The sequence of events perhaps can be understood best by examining the reactions in some detail. If K+
is ignored, the reactions would be as shown in Eqs. (5) to (7):
E2 + Pi↔ E2-P (5)
E2-P + Na+ ↔ E1P.Na+ (6)
E1P.Na+ + ADP ↔ E1 + ATP + Na+ (7)
These reactions represent the reverse of the normal sequence of active transport. The passage from Eq.
(5) to Eq. (7) would be highly improbable unless the Na+ concentration was raised sufficiently, which is
predictable from the law of mass action. However, as discussed more fully in Section III, the
phosphorylation of the ATPase by ATP, presumably reaction (7) run from right to left, decreases the
binding constant of the cation — and the effect is reversible. When the binding of one component (e.g.,
the phosphorylation) to a protein capable of undergoing conformational change affects the binding of
another (e.g., the cation), the inverse will be true. The nature of the enzyme-phosphate bond will thereby
be affected by the binding of the cation (Weber, 1972, Weber, 1974). Presumably, the binding of Na+
would then convert the low-energy bond into a high-energy bond.
The possibility of obtaining ATP from the reverse of ion transport can be explained by the considerations
discussed in this section. The high Na+ present on the outside of the cell will permit the formation of the
high-energy phosphate [reaction of Eq. (6)]. The phosphorylation of ADP removes the phosphate and the
enzyme can be used again for another cycle of phosphorylation.
Go to Part 2
REFERENCES
Search the textbook
http://www.albany.edu/~abio304/text/21part1.html (8 of 8) [3/5/2003 8:24:03 PM]
21. Transport of Ions: Mechanisms and Models
Back to Part 1
III. MODELS OF ION TRANSPORT AND STRUCTURE
The simplest model for transport of an ion would include the following steps: (1) binding of the ion by
specific binding groups on the transporter molecule at the loading site; (2) movement of the complex
from one interface to the other; and, (3) release of the ion at the discharge site of the membrane. This
model ignores a membrane potential to avoid complications unnecessary for our present discussion. The
Ca2+ pump of the sarcoplasmic reticulum imports 2 Ca2+ and exports 1 H+per ATP hydrolyzed; the
Na+/K+ pump exports from the cell 3 Na+ and simultaneously imports 2 K+ per ATP hydrolyzed.
The model would carry out the net transport of the ion. Active transport, i.e., transport against an
electrochemical gradient, could take place in this same model when two other conditions are met: (1) the
affinity of the binding group changes from high at the loading interface to low at the discharge interface
and (2) the free energy of the sequence of reactions decreases. In a transport ATPase the energy is
provided by the coupled hydrolysis of ATP.
Models capable of carrying active transport can be constructed without postulating a change in binding
constants. However, all transport systems known have been shown to have this feature (see Table 2). For
simplicity, in the present discussion we assume that the transport of all ions occurs by the same basic
process. This approach is not unreasonable because, as we saw in Chapter 20, there is considerable
evidence that the transport functions are analogous for the Na+,K+-ATPase, Ca2+-ATPase, the H+,K+-ATPase and the H+-ATPase of plants and Neurospora. Furthermore, the properties of these molecules
are very similar.
A mechanism of active transport, involving the phosphorylation of the transporter and changes in binding
constants, is supported by a variety of observations. The experiments discussed here (Ikemoto, 1976)
were carried out with a stop-flow apparatus (Fig. 6), which delivers reactants and enzyme (from syringes
shown at A) into the same chamber (B) with very rapid mixing in relation to the time course of the
reaction. Then the flow is stopped, also very rapidly. The light absorption of the contents of the chamber
can be recorded (E). An oscillosope (D) is required to record very rapid reactions. These experiments
used a purified preparation of Ca2+-ATPase from the sarcoplasmic reticulum and the Ca2+ indicator
Arsenazo III, which changes color when it binds Ca2+. The record of Fig. 7 represents the light
absorption with time. The two sets of panels differ in the time scale: set I shows fast changes (intervals
correspond to 50 ms) and set II shows slower changes (intervals represent 5 s). The downward
deflections reflect increases in the concentration of Ca2+. The concentration of ATP added is shown at
the left in the records. In the control (IA and IA), no ATP was added and no Ca2+ was released. The Ca2+
http://www.albany.edu/~abio304/text/21part2.html (1 of 16) [3/5/2003 8:24:10 PM]
21. Transport of Ions: Mechanisms and Models
released increases with the concentration of ATP added (compare B and D) until the system appears
saturated (compare D and E), as would be expected because the amount of ATPase is finite. As shown by
the longer time scale in set II, the release is temporary; eventually the Ca2+ is bound again, presumably
when all the ATP is hydrolyzed. The results show that the ATPase binds Ca2+ and that activation by ATP
reversibly decreases the binding. Fig. 8 shows the level of phosphorylation of the enzyme (determined
after rapid filtration, curve 1) compared to the Ca2+ release (curve 2) calculated from Fig. 7. The two
panels represent identical results plotted on two different time scales. The changes in phosphorylation of
the ATPase precede the release of the Ca2+, suggesting that phosphorylation is responsible for the change
in binding constants. These results indicate the Ca2+ is bound more tightly (larger binding constant)
before activation. Similar data are available for other transport systems, such as Na+,K+-ATPase (Masui
and Homareda, 1982; Yamaguchi and Tonomura, 1980). The binding constants on the two sides of the
membrane for different transport systems are shown in Table 2 (Tanford, 1983).

Fig. 6 Stop-flow apparatus.
http://www.albany.edu/~abio304/text/21part2.html (2 of 16) [3/5/2003 8:24:10 PM]
21. Transport of Ions: Mechanisms and Models

Fig. 7 ATPase-coupled changes in Ca2+ binding to purified Ca2+-ATPase of the sarcoplasmic reticulum.
From Ikemoto (1976), with permission.
The transport process seems to involve precise stoichiometry. As mentioned, 2 Ca2+ are transported per
ATP hydrolyzed. Furthermore, 2 Ca2+ are bound per phosphorylated transporter molecule (Inesi et al.,
1980). In the case of active transport, the affinity of the binding groups of the transporter for the ligand,
decreases when the transporter molecule is phosphorylated and this lower affinity should represent the
state of the transporter on the side with the higher concentration at steady state. A model of active
transport involving ion binding sites and shuttling of ions across the plasma membrane is consistent with
the data.
However, these considerations do not resolve how the binding sites can move from one interface to the
other without a major movement of the transporter. Integral proteins have distinct domains corresponding
to the two different membrane surfaces. It follows that the transporter molecule does not flip or rotate.
Furthermore, the Na+,K+-ATPase continues to function even when anchored at one interface with an
antibody (Kyte, 1974). These difficulties could be resolved by proposing that the binding sites do not
traverse the whole membrane thickness, but rather move over much shorter distances. This would be
possible if the binding sites were inside a channel traversing the membrane.
http://www.albany.edu/~abio304/text/21part2.html (3 of 16) [3/5/2003 8:24:10 PM]
21. Transport of Ions: Mechanisms and Models

Fig. 8 Relationship between Ca2+ release and rebinding and the formation and decay of the
phosphorylated intermediate. ( ) Ca2+ release; ( ) P in enzyme. Reproduced with permission from N.
Ikemoto, Journal of Biological Chemistry, 251:7275-7277. Copyright &copy1976 The American Society
of Biological Chemistry and Molecular Biology.
http://www.albany.edu/~abio304/text/21part2.html (4 of 16) [3/5/2003 8:24:10 PM]
21. Transport of Ions: Mechanisms and Models
Table 2 Binding Constants for Transported Ions
Binding constant, Keq(M-1)
Protein  Ion  Uptake side  Discharge side
SR Ca2+ pump Ca2+  107-108  300
Na+ pump Na+  4 X 103  <20
Chloroplast FoF1 H+  >108  <106
Na+/ Ca2+ exchange Ca2+  2 x 105-106  400
Tanford (1983), reproduced with permission from the Annual Review of Biochemistry Vol. 52, copyright &copy1983 by
Annual Reviews Inc.
There are, in fact, many indications that the transporters can act as channels, at least when reconstituted
in artificial membrane systems. Addition of purified Ca2+-ATPase to a bilayer (in this case a bilayer
made of oxidized cholesterol) changes its conductivity (Shamoo and MacLennan, 1975). Under some
conditions, the Na+, K+-ATPase incorporated into planar bilayers of phospholipid shows electrical
conductance transitions typical of channels (Last et al., 1983). The anion transporter (Giebel and Passow,
1960) also behaves like a channel. In this case, the selectivity of the transport system appears to depend
on the size of the molecule, suggesting a channel 0.8 to 0.9 nm in diameter. The channel behavior is
related to the transport process of the native systems and not some irrelevant coincidence. This is shown
by the sensitivity of the channel behavior to inhibitors of transport. HgCl2 inhibits both the Ca2+-ATPase
activity and the Ca2+ conductivity in parallel. Ouabain and vanadate, both inhibitors of the Na+/K+
transport, inhibit the Na+, K+-ATPase channel behavior.
Evidence of conformational rearrangements comes from many kinds of experiments. The sensitivity of
the transporter molecule to proteolytic digestion differs at different stages of transport (e.g., see Chapter
4). Gresalfi and Wallace (1984) have examined the circular dichroism (CD) spectra of purified and
membrane-attached Na+,K+-ATPase in its E1 and E2 forms, obtained by introducing either Na+ or K+.
The spectra for the peptide backbone (190-240 nm) were consistent with extensive conformational
differences between E1 and E2. The changes appear to be reversible when the ion composition is altered.
Phosphorylation of the ATPase is accompanied by fluorescence changes of its tryptophan residues
(Nakamura et al., 1994), indicating a conformational change.
http://www.albany.edu/~abio304/text/21part2.html (5 of 16) [3/5/2003 8:24:10 PM]
21. Transport of Ions: Mechanisms and Models
The involvement in transport of rearrangements within the ATPase is also shown by x-ray diffraction
studies of packed membranes from the sarcoplasmic reticulum containing Ca2+-ATPase (Blasie et al.,
1985). A significant portion of the ATPase juts into the cytoplasmic phase, as also shown by three-dimensional reconstruction of negatively stained crystals in sarcoplasmic reticulum membranes (see
below). Activation of the ATPase produces a conformational change with a displacement of the structure
into the bilayer. Both the binding of Ca2+ (DeLong and Blasie, 1993; Cheong et al., 1996) and the
phosphorylation of the enzyme (Blasie et al., 1985, Pascolini et al., 1988) were found to change the
conformation of the enzyme as seen using X-ray diffraction. The experiments correlating specific steps
in the transport used flash photolysis of caged ATP, a compound which releases ATP in response to a
flash of light, assuring rapid and synchronous activation.
Important details have been provided by other studies, some of them more recent. Ten transmembrane
helices (M1 to M10, shown by the numbers in Fig. 9) have been proposed based on the amino acid
sequence (MacLennan et al., 1985) and confirmed by high resolution EM (8-Å, Zhang et al., 1998). The
functional portions of the cytosolic domains of the head region of the molecule are distinct. The P
domain is involved in the phosphorylation, the N domain contains the nucleotide binding site and the A
or actuator domain (also called the transducer domain) is thought to have a special role in the
transduction (see Toyoshima et al., 2000; Toyoshima and Nomura, 2002). These are represented in the
diagram of Fig. 9 and discussed below. Fig. 9 was drawn from models derived from X-ray diffraction
data (Toyoshima et al., 2000).
The more recent crystallographic study (Toyoshima and Nomura, 2002) with a resolution of 3.1 Å has
provided data on the Ca2+-ATPase in its E2-state (with no Ca2+, but protonated with 2 H+).The
conformation of E2 was found to differ from that of E1 (with 2 bound Ca2+) as follows. In E1 the three
domains (P, N and A domains) are widely separated. In E2 they form a compact structure as shown in
Fig. 9. In addition, six out of the ten transmembrane segments also undergo conformational changes
when assuming the E2 conformation. These changes might be required for the release of the Ca2+ into the
SR lumen by opening a channel for the passage of Ca2+ and the permitting the counter-transport of 2 H+
to cytoplasm in exchange for 1 Ca2+ per 1 ATP hydrolyzed .(see fig. 2 of Green and MacLennan, 2002)
as indicated in the model of Fig. 16 below.
The structure deduced for the Ca2+-ATPase allowed the construction of an atomic homology model of
the H+-ATPase of Neurospora by comparing it to an 8 Å map of the Neurospora proton pump derived
from electron microscopy (Kühlbrandt et al., 2002). The model, shows the probable path of the proton
through the membrane and indicates that the nucleotide-binding domain rotates by approximately 70o to
deliver ATP to the phosphorylation site of the ATPase. This model differs somewhat from that proposed
for the Ca2+-ATPase.
http://www.albany.edu/~abio304/text/21part2.html (6 of 16) [3/5/2003 8:24:10 PM]
21. Transport of Ions: Mechanisms and Models
align=”center”>
Fig. 9 Schematic representations of the Ca2+-ATPase in the Ca2+-binding configuration, based on the
reconstruction of Toyoshima et al. (2000). The red P in the P-domain represents the phosphorylated site.
The yellow oval represent the site of nucleotide binding in the N-domain. The ten helices traversing the
membrane are represented by cylinders and the two red dots represent the bound Ca2+.
In summary, it appears that the transport of ions proceeds by binding the ions to specific sites. These sites
are probably present in a channel of the transporter that traverses the membrane. The translocation is
associated with some movement of the binding sites, so that the sites are exposed first to one, and then to
the other side of the membrane and major rearrangments of the large cytoplasmic domains of the
transporter.
How can this information be put together in a single model? The presence of a conventional channel
would only allow passive flow in the direction of the gradient and could not carry out transport against an
electrochemical gradient. For this reason, the models generally considered propose alternating access
(see Fig. 10), in which a small conformational change (in this case a rotation) exposes the binding sites
first to the water phase on one side of the membrane, and then to the water phase on the other side
(Tanford, 1983). The channel would remain closed at all times, but would alternate using two different
http://www.albany.edu/~abio304/text/21part2.html (7 of 16) [3/5/2003 8:24:10 PM]
21. Transport of Ions: Mechanisms and Models
“gates”, comparable to the gates in a lock connecting two bodies of water of different heights. The
movement of the binding groups could increase the distance between them, as represented in the diagram
and, therefore, could also account for the change in the affinity for the transported ion. During the
working cycle of the alternating access pump, when both “gates” are closed, the ion is unavailable for
exchange. The ion in the transporter molecule is said to be occluded. Occlusion suggests the presence of
an intermediate position of the binding sites, apart from their location at either the uptake or the
discharge site (see Glynn and Karlish, 1990). An alternating access model of the Ca2+-ATPase is shown
in Fig.16.

Fig. 10 Representation of the alternate-access model of transport. The structures represent polypeptide
chains traversing the phospholipid bilayer of the plasma membrane. The circles indicate the binding sites
of the transported ion. The closeness of the binding groups on the left accounts for the high-affinity
binding, the separation on the right for the decrease in affinity. The slight rotation of the polypeptides
accounts for the access of the binding sites from either the uptake site (left) or the discharge site (right).
Mutational studies have identified amino acids critical for transport (see MacLennan et al., 1997). Site-specific mutagenesis substitutes amino acids at defined locations in the molecule and delineates the
functional role of amino acids or amino acid clusters in the transport. In some of these experiments,
mutant DNA was incorporated into COS cells, a transformed simian cell line, using a vector and then
assayed for function (see MacLennan, 1990). These studies have identified amino acids critical for
transport (see MacLennan et al., 1997). Negatively charged residues in M4, M5, M6 and M8 are thought
to constitute high affinity Ca2+-binding site (Clarke et al., 1989). The two Ca2+-binding sites are formed
by the juxtaposition of acidic and oxygen containing amino acids next to each other in the middle of the
four transmembrane helices (Clarke et al., 1989; see Andersen, 1995 and MacLennan et al., 1997) as
represented in Fig. 15. Small changes in the position of the helices forming this cluster would disrupt
these binding sites. The study of (Toyoshima et al., 2000) suggests the pathway lined by oxygen atoms,
allowing for the in-and-out passage of Ca2+ and shows the disruption of structure of the M4 and M6
helices to provide a Ca2+-binding cavity. In addition, they identified mutation-sensitive carbonyl groups
in the M4 helix.
http://www.albany.edu/~abio304/text/21part2.html (8 of 16) [3/5/2003 8:24:10 PM]
21. Transport of Ions: Mechanisms and Models
The properties common to at least some of the transport systems are summarized in Table 3. Some of
these examples correspond to active transport, others do not. For all transport systems, the transporter
binds the transported substrate. Furthermore, the transporters have been shown to undergo a
conformational change. Channel behavior has been shown, at least under some conditions, for some of
the transporters.
Table 3 Summary of the Properties of Some Transport Systemsa
Ion or Solute Active
Transport
Binding
demonstrated
Channel
Properties
Conformational
change of
transporter
Anion
Exchanger
No  Yesb  Yesc  Yesd
Na+, K+
(ATPase)
Yese  Yes
(Table 2)
Yesf  Yesg
Ca2+
(ATPase)
Yes  Yes
(Table 2)
Yesh  Yesi
H+
(ATP synthase)
Yes  Yes
(Table 2)
Yesj  Yes
(see Chapter 17)
Na+-glucose
(cotransporter)
Yes  —  —  Yesk
Na+-amino acid
(cotransporter)
Yes  —  —  Yesl
a Yes indicates that the phenomenon has been observed for the solute or the transporter b Falke et al. (1984b); c Giebel and
http://www.albany.edu/~abio304/text/21part2.html (9 of 16) [3/5/2003 8:24:10 PM]
21. Transport of Ions: Mechanisms and Models
Passow (1960); d Falke et al (1984b);e Yamaguchi and Tonomura (1980);f Last et al. (1983); gJorgensen (1975); Karlish
and Yates (1978); Koepsell (1972) h Shamoo and MacLennan (1975) i Imamura et al. (1984); j Tanford (1983); k Peerce
and Wright (1984);l Wright and Peerce, 1984.
Many years of collected evidence support the alternate access model represented in Fig. 10. This model,
adapted to reflect the various experimental findings for the Ca2+-ATPase, is shown in Fig. 11. In this
figure, 2 Ca2+ are shown to be bound sequentially. One of these is not readily accessible from either side
of the ATPase-channel (occlusion). ATP phosphorylates the ATPase so that the two Ca2+ are released
sequentially. In this figure the stripes indicate the Ca2+ which is bound to the ATPase first (reaction 1-2)
and the dotted circles represent the second Ca2+ bound in reaction 3. As shown, the first Ca2+ is not
readily available from the outside or from inside the vesicle. It will equilibrate slowly with Ca2+ in the
medium. However, phosphorylation of the enzyme (reaction 4) allows the sequential discharge of Ca2+
to the inside of the vesicles: the first Ca2+ to be bound is released into the vesicles first (reaction 5); the
second Ca2+ to be bound is released second (reaction 7) and corresponds to the Ca2+ which is readily
exchangeable with 40[Ca2+] before phosphorylation.
An alternate access model for the Ca2+-ATPase highlighting the structural aspects is shown in Fig. 16
(Inesi, 1987).

Fig. 11 Diagram representing the sequential mechanism of calcium binding and translocation upon ATP
hydrolysis by SR ATPase. From Inesi, 1987. Reproduced by permission. Copyright &copy1987 The
American Society for Biochemistry and Molecular Biology.
Inesi (1987) explored details of the Ca2+-ATPase mediated transport of the SR with a pulse chase
technique. In one experiment, SR vesicles containing Ca2+-ATPase were first equilibrated with the
radioactive isotope [45Ca]2+. This incubation was then followed by a chase with nonradioactive [40Ca]2+.
The time course of the release of the labelled Ca2+ at low temperature is shown in Fig. 12 (Inesi, 1987).
http://www.albany.edu/~abio304/text/21part2.html (10 of 16) [3/5/2003 8:24:10 PM]
21. Transport of Ions: Mechanisms and Models
In this figure, bound radioactive Ca2+ in the ordinate is shown as a function of the time after addition of
the nonradioactive Ca2+. The total initial binding corresponds to 2 Ca2+ per enzyme molecule. A rapid
initial release, over in about 0.2 s, is followed by a much slower one, which cannot be seen with the time
scale used. The vastly different rates of release are in agreement with the sequential model of Fig. 11.
The faster release corresponds to the Ca2+ which is bound second and readily accessible from the outside
medium.
La3+ displaces all bound Ca2+, so that in the presence of ATP, any Ca2+ not displaced by La3+ represents
Ca2+ which has been occluded or transported into the vesicle. The relationship between translocation and
binding was examined in an experiment whose results are represented in Fig. 13. The experimental
design is shown diagrammatically on the left side of the figure. Curve A represents results obtained
without a chase. [45Ca]2+ was first bound to the ATPase of the vesicles and ATP added subsequently.
La3+ was added at the various times indicated in the abscissa. The Ca2+ translocated into the vesicle is
first very rapid, corresponding to the translocation of Ca2+ initially bound to the ATPase. This is
followed by a slower transport that represents the Ca2+ subsequently transported into the vesicle. When
ATP is added simultaneously to a chase with [40Ca]2+, the amount transported (curve B) corresponds
exactly to that bound (2 Ca2+/enzyme); no additional translocation of the radioactive Ca2+ can take place
because of the chase. As indicated by Fig. 12, a chase of 0.2 s with [40Ca]2+ removes the molecule of
Ca2+ that was bound second by the ATPase. The transport of the remaining Ca2+ ion (the first to be taken
up) can, therefore, be followed by introducing ATP after a 0.2 s chase with the non-radioactive Ca2+
(curve C). After the 0.2 seconds chase, only half of the radioactive Ca2+ was transported into the vesicle
(curve C). This indicates that the Ca2+ which occupies the position closer to the outside, is transported
first into the vesicle, as predicted from a sequential model of Fig. 11.

http://www.albany.edu/~abio304/text/21part2.html (11 of 16) [3/5/2003 8:24:10 PM]
21. Transport of Ions: Mechanisms and Models
Fig. 12 Isotopic exchanges of bound Ca2+. From Inesi, 1987. Reproduced by permission. Copyright
&copy1987 The American Society for Biochemistry and Molecular Biology.

Fig. 13 Quench-flow measurements of ATP-dependent calcium uptake. From Inesi, 1987. Reproduced by
permission. Copyright &copy1987 The American Society for Biochemistry and Molecular Biology.
The Ca2+ uptake of the initial burst (Fig. 13A) may include Ca2+ that is not exchangeable and is trapped
in the ATPase, i.e. occluded. A different experimental design can differentiate between bound Ca2+ and
occluded Ca2+. When ADP is added in the presence of a Ca2+-chelator [ethylene glycol-bis-(β-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA)], the phosphorylation of the transporter is reversed.
ADP is phosphorylated and the occluded Ca2+ is released into the medium. Only one single cycle of the
enzyme is possible because there is no Pi present. In contrast, the Ca2+ transported into the vesicles
would be retained (and would not be released by La3+). The results of this experiment are shown in Fig.
14, which shows the radioactive Ca2+ uptake in the ordinate. The time shown in the abscissa represents
the time of addition of ADP + EGTA which is then followed by the addition of La2+. In curve A, the
preparation is preincubated in [45Ca]2+. Then [40Ca]2+ and ATP are added simultaneously. In this case,
the Ca2+ uptake after the ADP+EGTA addition represents the transported Ca2+ (amount taken up +
amount occluded). At the earlier times of addition of ADP + EGTA, 4 to 5 nanomoles of Ca2+ are taken
up per mg, compared to 9 to 10 without the ADP + EGTA treatment (Fig. 14A). Therefore,
approximately half of the original Ca2+ taken up is in the occluded form. When ATP is added after the
0.2 s of [40Ca]2+ chase (which removes the more external Ca2+) (Fig. 14B), half of the Ca2+ uptake has
already become ADP + EGTA insensitive. This shows that the insensitive Ca2+ (released into the
vesicles) is the one that was bound first (see Fig. 11). These results elaborate and support the alternating-site model and indicate a sequential release of the Ca2+.
http://www.albany.edu/~abio304/text/21part2.html (12 of 16) [3/5/2003 8:24:10 PM]
21. Transport of Ions: Mechanisms and Models
Much the same information is available for the Na+, K+-ATPase from entirely different experiments. As
we have seen, 3 Na+ and 2 K+ bind to separate sites of the protein. First they become occluded (i.e.,
trapped inside the transporter) and then are released to the other side (see Post et al., 1972; Beaugé and
Glynn, 1979). In the absence of K+, Na+ is still translocated (Garrahan and Glynn, 1967) and the
translocation is electrogenic (Fendler et al., 1985; Nakao and Gadsby, 1986). The electrical signal during
the ion pumping corresponds to the movement of the ions across the channel that traverses the membrane
(e.g., Hilgemann, 1994) and is associated with charge movements. The rate of these electrogenic
reactions is dependent on the membrane potential, so that enzymes conformations can be shifted. High
speed voltage jumps can be used to initiate this redistribution. Three phases are apparent (Holmgren et
al., 2000), reflecting the de-occlusion of the three ions. The results indicate that three are released one at
a time, in order.

Fig. 14 ADP reversal of ATP-induced calcium translocation. From Inesi, 1987, reproduced by permission.
Analyses of the phosphorylating reactions were also carried out. Either ATP or Pi can phosphorylate the
enzyme. The ATP phosphorylation depends on high affinity Ca2+ binding. In contrast, the
phosphorylation by Pi is blocked by Ca2+.
The Ca2+ occlusion was studied on detergent solubilized SR vesicles in the presence of CrATP. CrATP
allows occlusion without the hydrolysis of ATP and it also stabilizes the Ca2+-enzyme complex. A
HPLC-molecular sieve procedure was used (see Chapter 1) to separate the proteins from free Ca2+.
Mutations at the sites thought to bind Ca2+, prevented occlusion (Vilsen and Andersen, 1992, Andersen
and Vilsen, 1994).
http://www.albany.edu/~abio304/text/21part2.html (13 of 16) [3/5/2003 8:24:10 PM]
21. Transport of Ions: Mechanisms and Models

Summary of amino acid substitution introduced into the predicted Ca2+-binding domain. Glu309, Glu771,
Asn796, Thr799, Asp800, and Glu908 are thought to be in the transmembrane segments M4, M5, M6 and
M8 respectively. From Clarke et al., 1990b. Reproduced by permission.
As already discussed, there is considerable evidence that the ATPase pumps require a channel-like
structural arrangement. Modeling of the four helices thought to be involved in Ca2+ binding and which
are amphiphilic, show that polar and charged residues are predominantly in one face of each helix with
the hydrophobic residues in the opposite face. The hydrophilic components could therefore form
hydrophilic clusters in the internal surfaces, thereby forming a channel. The hydrophobic residues, on the
other hand, could interact with the bilayers providing the transmembrane arrangement.
Present information (e.g., Inesi et al., 1992; Toyoshima et al. 2000) indicates that the Ca2+-binding
domain and the catalytic domain are separated by 50 Å. This spatial arrangement would require that any
interaction would be indirect, via a conformational change. We have seen that conformational changes
have been demonstrated (see Fig. 9). A possible mechanism for the transport of Ca2+ involving the
http://www.albany.edu/~abio304/text/21part2.html (14 of 16) [3/5/2003 8:24:10 PM]
21. Transport of Ions: Mechanisms and Models
transmembrane helices is indicated in Fig. 16 (MacLennan, 1990). The shift from E1 to the E2 form
accompanying phosphorylation, would shift the negatively charged binding groups from the outer to the
inner interface. Furthermore, the conformational shift would disrupt the arrangement of the high affinity
binding groups to produce low affinity binding sites.

Fig. 16 Model illustrating the possible mechanism of Ca2+ transport by the Ca2+-ATPase. In the E1
configuration, high affinity Ca2+-binding sites are accessible to the cytoplasmic Ca2+. ATP hydrolysis
induces the E2 configuration, in which the access of the binding groups from the cytoplasmic side is
blocked and their configuration of the binding groups is disrupted. The disruption results in a low affinity
binding. From MacLennan, 1990, reproduced by permission.
SUGGESTED READING
Inesi, G., Zhang, Z., Sagara, Y. and Kirtley, M.E. (1994) Intracellular signaling through long-range
linked functions in Ca2+ ATPase, Biophys. Chem. 50:129-138. (Medline)
MacLennan, D.H., Rice, W.J. and Green, N.M. (1997) The mechanism of Ca2+ transport by
sarco(endo)plasmic reticulum Ca2+-ATPases, J. Biol. Chem. 272:28815-28818. (MedLine)
Stein, W.D. and Lieb, W.R. (1986) Transport and Diffusion Across Cell Membranes, Chapter 6, pp. 475-http://www.albany.edu/~abio304/text/21part2.html (15 of 16) [3/5/2003 8:24:10 PM]
21. Transport of Ions: Mechanisms and Models
612. Academic Press, New York.
Tanford, C. (1984) The sarcoplasmic reticulum calcium pump. Localization of free energy transfer to
discrete steps of the reaction cycle, FEBS Lett. 166:1-7. (Medline)
General Reviews
Inesi, G.(1994) Teaching active transport at the turn of the twenty first century: recent discoveries and
conceptual changes, Biophys. J. 66:554-560. http://www.biosci.umn.edu/biophys/OLTB/BJ/Inesi.pdf
Adobe Acrobat from http://www.adobe.com is required for reading pdf files.
Lauger, P. (1984) Channels and multiple conformational states: interrelations with carriers and pumps,
Curr. Top. Membr. Transport 21:309-326.
REFERENCES
Search the textbook
http://www.albany.edu/~abio304/text/21part2.html (16 of 16) [3/5/2003 8:24:10 PM]
Chapter 21: References
Back to Chapter 21
REFERENCES
Andersen, J.P. and Vilsen, B. (1994) Amino acids Asn796 and Thr799 of Ca2+-ATPase of sarcoplasmic
reticulum bind Ca2+ at different sites, J. Biol. Chem. 269:15931-15936. (MedLine)
Beaugé, L.A. and Glynn, I.M. (1979) Occlusion of K ions in the unphosphorylated sodium pump, Nature
280:510-512. (Medline)
Blasie, J. K., Herbette, L. G., Pascolini, D., Skita, V., Pierce, D. H. and Scarpa, A. (1985) Time resolved
x-ray diffraction of sarcoplasmic reticulum membrane during active transport, Biophys. J. 48:9-l8.
(Medline)
Bontig, S. I., Schuurmans Stekhoven, F. M. A. H., Swarts, H. G.P. and dePont, J. J. H. H. M. (1979) The
low-energy phosphorylated intermediate of Na+,K+-ATPase. In Na,K-ATPase, Structure and Kinetics
(Skou, J. C., and Nφrby, J. G., eds.), pp. 317-330. Academic Press, New York.
Charnock, J. S., Trebilcock, H. A. and Casley-Smith; J. R. (1972) Demonstration of transport adenosine
triphosphatase in the plasma membranes of erythrocyte ghosts by quantitative electron microscopy, J.
Histochem. Cytochem. 20:1069-1080. (Medline)
Cheong, G.W., Young, H.S., Ogawa, H., Toyoshima, C. and Stokes, D.L. (1996) Lamellar stacking in
three-dimensional crystals of Ca(2+)-ATPase from sarcoplasmic reticulum, Biophys. J. 70:1689-1699.
(MedLine)
Clarke, D.M., Maruyama, K., Loo, T.W., Leberer, E., Inesi, G. and MacLennan, D.H. (1989) Functional
consequences of glutamate, aspartate, glutamine and aspargine mutations in the stalk section of the Ca2+-ATPase of sarcoplasmic reticulum, J. Biol. Chem. 264:11246-11251. (Medline)
Clarke, D.M., Loo, T.W. and MacLennnan, D. (1990a) The epitope for monoclonal antibody A20 (amino
acids 870-890) is located in the luminal surface of the Ca2+-ATPase of sarcoplasmic reticulum, J. Biol.
Chem. 265:17405-17408. (Medline)
Clarke, D.M., Loo, T.W. and MacLennnan, D. (1990b) Functional consequences of alterations to amino
acids located in the nucleotide binding domain of the Ca2+-ATPase, of sarcoplasmic reticulum, J. Biol.
Chem. 265:6262-6267. (Medline)
http://www.albany.edu/~abio304/ref/ref21.html (1 of 5) [3/5/2003 8:24:14 PM]
Chapter 21: References
DeLong, L.J. and Blasie, J.K. (1993) Effect of Ca2+ binding on the profile structure of the sarcoplasmic
reticulum membrane using time-resolved x-ray diffraction, Biophys. J. 64:1750-1759. (Medline)
Fendler, K., Grell, E., Haubs, M. and Bamberg, E. (1985) Pump currents generated by the purified
Na+K+-ATPase from kidney on black lipid membranes, EMBO J. 4:3079-3085. (Medline)
Garrahan, P.J. and Glynn, I.M. (1967) The behaviour of the sodium pump in red cells in the absence of
external potassium, J. Physiol. (London) 192:159-174. (MedLine)
Giebel, O. and Passow, H. (1960) Die permeabilität der eythrocytemembran für organische anionen,
Pfluegers Arch. 271:378-388.
Glynn, I. M. and Karlish, S. J. D. (1990) Occluded cations in active transport, Annu. Rev. Biochem.
59:171-205. (Medline)
Green, N.M. and MacLennan, D.H. (2002) Calcium callisthenics, Nature 418:598-599.
Gresalfi, T.J. and Wallace, B.A. (1984) Secondary structural composition of the Na/K-ATPase E1 and
E2 conformers, J. Biol. Chem. 259:2622-2628. (MedLine)
Hilgemann, D.W. (1994) Channel-like function of the Na,K pump probed at microsecond resolution in
giant membrane patches, Science 263:1429-1432. (Medline)
Holmgren, M., Wagg, J., Bezanilla, F., Rakowski, R.E., De Weer, P. and Gadsby, D.C. (2000) Three
distinct and sequential steps in the release of sodium ions by the Na+/K+-ATPase, Nature 403:898-901.
(Medline)
Ikemoto, N. (1976) Behavior of Ca2+ transport sites linked with the phosphorylation reaction of ATPase
purified from the sarcoplasmic reticulum, J. Biol. Chem. 251:7275-7277. (Medline)
Inesi, G. (1987) Sequential mechanism of calcium binding and translocation in sarcoplasmic reticulum
adenosine triphosphatase, J. Biol. Chem. 262:16338-16342. (Medline)
Inesi, G., Kurzmack, M., Coan, C. and Lewis, E. (1980) Cooperative calcium binding and ATPase
activation in sarcoplasmic reticulum vesicles, J. Biol. Chem. 255:3025-3031. (Medline)
Inesi, G., Lewis, D., Nikic, D. and Kirtely, M.E. (1992) Long range intramolecular linked functions in
calcium transport ATPase, in Advances in Enzymology. Meister, A., ed.. Wiley and Sons, New York, pp.
185-215. (Medline)
http://www.albany.edu/~abio304/ref/ref21.html (2 of 5) [3/5/2003 8:24:14 PM]
Chapter 21: References
Inesi, G., Zhang, Z., Sagara, Y. and Kirtley (1994) Intracellular signaling through long-range linked
functions in Ca2+ ATPase, Biophys. Chem. 50:129-138. (Medline)
Jorgensen P. L., and Petersen, J. (1979) Protein conformations of the phosphorylated intermediates of
purified Na+,K+-ATPase studied with tryptic digestion and intrinsic fluorescence as tools. In
Na+,K+ATPase Structure and Kinetics (Skou, J. C., and Nφrby, J. G., eds.), pp. 143-155. Academic
Press, New York.
Knowles, A. F. and Racker, R. (1975) Formation of adenosine triphosphate from Pi and adenosine
triphosphate by purified Ca2+-adenosine triphosphatase, J. Biol. Chem. 250:1949-1951. (Medline)
Kühlbrandt, W., Zeelen, J. and Dietrich, J. (2002) Structure, mechanism, and regulation of the
Neurospora plasma membrane H+-ATPase, Science 297:1692-1696. (MedLine)
Kyte, J. (1971) Purification of the sodium- and potassium-dependent adenosine triphosphatase from
canine renal medulla, J. Biol. Chem. 246:4157-4165. (Medline)
Kyte, J. (1974) The reactions of sodium and potassium ion activated adenosine triphosphatase with
specific antibodies, J. Biol. Chem. 249:3652-3660. (Medline)
Kyte, J. (1981) Molecular considerations relevant to the mechanism of active transport, Nature 292:201-204. (Medline)
Last, T. A., Gantzer, M. L. and Tyler, C. D. (1983) Ion-gated channel induced in planar bilayers by
incorporation of (Na+,K+)-ATPase, J. Biol. Chem. 258:2399-2404. (Medline)
MacLennan, D. H. (1990) Molecular tools to elucidate problems in excitation-contraction coupling,
Biophys. J. 58:1355-1365. (Medline)
MacLennan, D.H., Brandl, C.J., Korczak, B. and Green, N.M. (1985) Amino-acid sequence of a Ca2+ +
Mg2+-dependent ATPase from rabbit muscle sarcoplasmic reticulum, deduced from its complementary
DNA sequence, Nature 316:696-700. (MedLine)
MacLennan, D.H., Rice, W.J. and Green, N.M. (1997) The mechanism of Ca2+ transport by
sarco(endo)plasmic reticulum Ca2+-ATPases, J. Biol. Chem. 272:28815-28818. (MedLine)
Masui, H. and Homareda, H. J. (1982) Interaction of sodium and potassium ions with Na+,K+-ATPase. I.
Ouabain-sensitive alternative binding of three Na+ or two K+ to the enzyme, J. Biochem. 92:193-217.
http://www.albany.edu/~abio304/ref/ref21.html (3 of 5) [3/5/2003 8:24:14 PM]
Chapter 21: References
Nakamura, S., Suzuki, H. and Kanazawa, T. (1994) The ATP- induced change in tryptophan
fluorescence reflects a conformational change upon formation of ADP-sensitive phosphoenzyme in the
sarcoplasmic reticulum Ca2+-ATPase, J. Biol. Chem. 269:16015-16019. (Medline)
Nakao, M. and Gadsby, D.C. (1986) Voltage dependence of Na translocation by the Na/K pump, Nature
323:628-630. (Medline)
Pascolini, D., Herbett, L.G., Skita, V., Asturias, F., Scarpa, A. and Blasie, J.K. (1988) Changes in the
sarcoplasmic reticulum membrane profile induced by enzyme phosphorylation to the E1P at 16 resolution
via time-resolved X-ray diffraction, J. Biophys. 54:679-688. (Medline)
Peerce, B.E. and Wright, E.M. (1984) Sodium-induced conformational changes in the glucose transporter
of intestinal brush borders, J. Biol. Chem. 259:14105-14112. (Medline)
Post, R.L., Hegyvary, C. and Kume, S. (1972) Activation by adenosine triphosphate in the
phosphorylation kinetics of sodium and potassium ion transport adenosine triphosphatase, J. Biol. Chem.
247:6530-6540. (Medline)
Post, R. L., Sen, A. K. and Rosenthal, A. S. (1965) A phosphorylated intermediate in adenosine
triphosphate-dependent sodium and potassium transport across kidney membranes, J. Biol. Chem.
240:1437-1445.
Post, R. L., Kume, S., Tobin, T., Orgutt, R., and Shu, A. K. (1969) Flexibility of an active center in
sodium plus potassium adenosine triphosphatase, J. Gen. Phys. 54:306s-326s.
Post, R. L., Taniguchi, K. and Toda, G. (1974) Synthesis of adenosine triphosphate by Na+,K+-ATPase,
Ann. N.Y. Acad. Sci. 242:80-91. (Medline)
Schoot, B. M., Schoots, A. F. M., dePont, J. J. H. H. M., Schuurmans Stekhoven, F. M. A. H., and
Bonting, S. L. (1977) Studies on (Na+-K+) activated ATPase. XVI. Effects of N-ethylmaleimide on
overall and partial reactions, Biochim. Biophys. Acta 483:181-192. (Medline)
Sen, A., Tobin, T. and Post, R. L. (1969) A cycle for ouabain inhibition of sodium- and potassium-dependent adenosine triphosphatase, J. Biol. Chem. 244:6596-6604. (Medline)
Shamoo, A. and MacLennan, D. H. (1975) Separate effects of mercurial compounds on the ionophoric
and hydrolytic functions of the (Ca2+ Mg2+)-ATPase of sarcoplasmic reticulum, J. Membr. Biol. 25:65-74. (Medline)
Siegel, G. J., Koval, G. J. and Albers, R. W. (1969) Sodium- potassium-activated adenosine
http://www.albany.edu/~abio304/ref/ref21.html (4 of 5) [3/5/2003 8:24:14 PM]
Chapter 21: References
triphosphatase, J. Biol. Chem. 244:3264-3269. (Medline)
Tanford, C. (1983) Mechanism of free energy: coupling in active transport, Annu. Rev. Biochem. 52:379-409. (Medline)
Tokoshima, M., Sasabe, H. and Stokes, D.L. (1993) Three-dimensional cryo-electron microscopy of the
calcium ion pump in the sarcoplasmic reticulum membrane, Nature 362:469-471.
Toyoshima, C., Nakasako, M., Nomura,H. and Ogawa, H. (2000) Crystal structure of the calcium pump
of sarcoplasmic reticulum at 2.6 Å resolution, Nature 405:647-655. (MedLine)
Toyoshima C. AND Nomura, H. (2002) Structural changes in the calcium pump accompanying the
dissociation of calcium, Nature 418:605-611. (MedLine)
Vilsen, B. and Andersen, J.P. (1992) CrATP-induced Ca2+ occlusion in mutants of the Ca2+-ATPase of
the sarcoplasmic reticulum, J. Biol. Chem. 267:25739-25743. (Medline)
Weber, G. (1972) Ligand binding and internal equilibria in proteins, Biochemistry 11:864-878. (Medline)
Weber, G. (1974) Addition of chemical and osmotic energies by ligand protein interactions, Ann. N.Y.
Acad. Sci. 227:486-496. (Medline)
Wright, E.M. and Peerce, B.E. (1984) Identification and conformational changes of the intestinal proline
carrier, J. Biol. Chem. 259:14993-14996. (Medline)
Yamaguchi, M. and Tonomura, Y. (1980) Binding of monovalen cations to Na+,K+-dependent ATPase
purified from porcine kidney, J. Biochem. 88:1365-1375. (Medline)
Yu, X., Carroll, S., Rigaud, J.L., and Inesi, G. (1993) H+ countertransport and electrogenicity of the
sarcoplasmic reticulum Ca2+ pump in reconstituted proteoliposomes, Biophys. J. 64:1232-1242.
(MedLine)
Zhang, P., Toyoshima, C., Yonekura, K., Green, N.M., and Stokes, D.L. (1998) Structure of the calcium
pump from sarcoplasmic reticulum at 8-Å resolution, Nature 392:835-839. (MedLine)
http://www.albany.edu/~abio304/ref/ref21.html (5 of 5) [3/5/2003 8:24:14 PM]

5 Comments

The Gist of Emergency Medicine

The Gist of Emergency Medicine
Michael O. Hebb MD,CCFP(EM),DABEM
Woodlawn Medical Clinic 110 Woodlawn Road Dartmouth, Nova Scotia Canada B2W 2S8
Copyright 1998
[Please Note] [TOC]

Table of Contents

Preface

The Mnemonic & Preamble

The Management Guide

The Short Form of the Management Guide

Significant Reminders

CPR -Electrolytes -Acid Base

Cardiac Arrythmias & ACLS Drugs (1st of 2 sections)

Septic Shock.

Central Nervous System (1st of 2 sections)

Pediatrics (1st of 2 sections)

Cardiology (2nd of 2 sections)

Chest

Gastrointestinal & Genitourinary Systems

Obstetrics & Gynecology.

Pediatrics (2nd of 2 sections)

Endocrinology & Hematology

Central Nervous System (2nd of 2 sections)

ENT – Skin – Joints – Allergy

Infections

Poisoning

Environmental Injuries

Trauma

Psychiatric Disorders

References

A Request for Feedback

°Preface and Acknowledgments
Hello there! This publication originated as a one page outline in January 1987, when I began to prepare for the American Board of Emergency Medicine’s simulated patient oral examinations, and it grew from there. I finished it in its present form in April 1990, and I have made many hundreds of additions and modifications since (the book* has become my “hobby”). I still have vivid recollections of the somber, stressful atmosphere of the examination waiting room, and some candidates shaking their heads and muttering to themselves. But once you got beyond that, it was fun (in a “sick” sort of way), like other competitions.
The simulated patient oral examination experience, has made me more appreciative of the value of the observation component of real patient encounters. Also, the adventure highlighted the indispensability of other health care professionals and support staff (that you tend to take for granted).
This manual was written for oral board candidates, practicing physicians, residents, interns and medical students. It is meant to compliment standard texts and oral board courses (“practice makes perfect”). Also, it is designed to refresh and reinforce the “trouble-shooting neuronal synapses” (prn) of the emergency room physician, and as a brief reference in the ER (I find it particularly useful for “warming up,” just prior to returning to work following a vacation). I have attempted with this 1998 edition to at least “touch on everything,” and have purposely double spaced the text throughout, so that you can make your own strategically placed notes (pencil recommended). I have also tried to editorialize some “life” into the book, by drawing on my own experiences with patient encounters. However, in order to forewarn the readership, I should inform you that reading this book is much like working a shift in the ER, at times it’s easy, and sometimes it is hard work! (but still reader friendly I hope). Readers are advised to frequently pause, visualize, and reflect, while proceeding through the text.
I would like to thank my wife, Diane, for putting up with my preoccupation with emergency medicine (and Daytona Beach), and my twenty-two year-old son, publisher, and second year medical student, Adam, for his perseverance. In addition, thanks to my other “post-graduate neuroscience kids,” Andrea, Jonathan (now a first year medical student), and Matthew for their encouragement and assistance. Also, I would like to thank my four year old granddaughter, Adrienne, who, on more than one occasion during the past two years, has reminded me of the importance of listening: “You’re not listening to my words, Grampie.” As well, this publication would not have been possible without the input from the countless patients, family members, and significant others, that I have encountered during my “graveyard shifts” at the Dartmouth General Hospital’s emergency department over the past sixteen  years.
Last, but not least, I would like to thank the nursing staff at the DGH/ER for their input, their expertise, and for tolerating my idiosyncrasies.
Finally, I hope you find that reading this book is the closest thing to the everyday practice of emergency medicine that you can do, at home, in the comfort of your favorite easy chair.
A.M.O.H.
°The Mnemonic and the Preamble
– the management of real or simulated patient encounters -
Before starting the simulated patient encounter/oral examination, write the following mnemonic across the top of the notepad provided in the examination room (takes about ten seconds): AACBC – FUNM – GTAAFF – HPD (a bizarre mnemonic!)
AACBC = allergies/airway and cervical spine/cord, breathing, circulation, and finish the primary survey.
FUNM= foley, urinalysis, ng, and mast.
GTAAFF= gram stains/cultures/other investigations, tetanus prophylaxis, antibiotics, analgesics, flow sheets, and frequent vital signs.
HPD = history (finish), physical (secondary survey), and additional investigations, procedures, and therapeutic measures; diagnosis(es) and disposition.
See page 74 for the short form of the management guide (one page).
Remember, in addition to the patient, the examiner will role play or represent anyone that you want him/her to (or references, e.g. poison control centre). Try to imagine that the examiner is the various people that he/she is role playing (not easy, takes practice, had any acting experience?). (This also helps the examiner feel more like the person(s) they are role playing, making for a more “enjoyable encounter.” Remember that the examiner/patient is also under “stress.”). Take your time during the simulated patient encounter, as there is a tendency to rush. Take brief notes, and speak at a reasonable pace, as the examiner needs the time to digest and record what you have said. Listen for cues from the examiner, but don’t depend on it; some examiners, like some patients, can be rather stingy with their cues.  The examiner’s “cues” may be real, or simply distractions. They are meant to test your resolve, your flexibility, and your ability to use the cues to the patient’s benefit.
Explain to the reluctant patient/examiner the importance of the history. Explain your actions (and procedures) to the examiner/patient (e.g. the insertion of a ng tube), and determine the clinical response. Obtain informed consent prn. Ensure that all your orders have been carried out, and the results of your investigations have been returned. Be careful not to read into x-rays, EKGs, etc., what you want or expect to see. Talk to the patient (e.g. “feeling better?”), nursing staff, family, and significant others, as appropriate throughout the encounter. Do not forget to introduce yourself, and shake hands if appropriate (patient’s mental status?). During your introduction, let the patient know that you are aware of the nature of their problem, for example, “the nurses tell me that you have had a fever and a cough for a couple of days.” Treat the family, friends, and the significant others with the importance and respect they deserve, it is essential to have them “on your side” (along with the patient!).* You may be asked by the family if the patient “will be all right,” before your assessment is completed, do not brush them off with a “will be fine” answer. Keep them informed and if necessary, find a quiet, private room for them (e.g. the patient is critically ill or injured). Be user friendly and non-judgmental (not always easy). Try to anticipate and show the appropriate concern for the psychological, the sociological, and the economic needs† of the patient, the relatives, and the significant others. Refer to the patient by name (how’s your short term memory?), beware of treating the patient as, for example, a “kidney stone” (not hard to do during the oral exams or when the ER is busy). Caution against the human tendency to blame the victim (e.g. “if she had locked her car doors she wouldn’t have been mugged”). Be objective, resist the temptation of becoming the judge and the jury (e.g. injured impaired driver). Remember in the real world any emergency room patient encounter can result in a complaint being lodged against you, and the relatives and the friends (including those not present), often exert a strong influence on that decision (even a “trivial” complaint can trigger a time consuming investigation). Beware of those gray area patient discharges from the emergency department. The patient may accept your decision to send them home, but not necessarily agree with it, and not tell you unless you ask them specifically, e.g. “Do you feel well enough to go home?” “I would if I was younger and didn’t live alone” discussion. Always assume the worst case scenario until determined otherwise, not vice versa, for example, acute myocardial infarction, pulmonary embolism, ectopic pregnancy, acute appendicitis. Err on the side of consultation/observation/admission. Good interpersonal relations, along with exemplary care, and adequate, legible, medical records is your best defense in the minefields of emergency medicine (don’t forget to note the times when recording your assessments and reassessments). “Gallows humor,” if in “good taste,” and “out of the earshot” of the patients, and the public, can be useful for reducing tension during the difficult times in the emergency department. However, beware of cynicism, which is detrimental to the functioning of the emergency room (an endemic problem).
Remember the adage “when the going gets tough, the tough get going” (sometimes with a little help from caffeine).
Additional suggestions (when appropriate), regarding real patient emergency room encounters are respectively submitted as follows*:
(1) Keep the patients with non-urgent problems in the waiting room, until you are almost ready to see them. There is no surer way to unnecessarily create an irritable patient, than a prolonged wait in a confining examining cubicle. In the waiting room, they can either watch television, talk, read or “people watch.” However, keep in mind that patients with “trivial” or bizarre complaints, can sometimes be harboring serious disease, which can be missed at triage (e.g. shoulder pain / coronary artery disease). In any case, the “missed” patient may be more visible in the waiting room, than tucked away in an examining cubicle.
(2) Whenever feasible, have the relatives/significant others with the patient when you assess them (beware of the “vasovagal spectator,” e.g. when suturing lacerations). This will save you explanation time, discourage you from doing only a partial assessment when you are busy, or feeling tired and lazy, and make the patient, their relatives, and their significant others all feel that they played a part in the decision making process. This may make them more forgiving should things not go well, or an error is made. For example, if you fail to diagnose a subtle fracture after having shown the x-rays to the patient, and their relatives or significant others, they are more likely to understand why the fracture was missed (advise the patient that your “soft tissue injury only” diagnosis is provisional, and that the x-rays will be reviewed by the radiologist (r) then provide the patient with a follow-up procedure plan, as part of your management of the injury).
Remember to make it clear to the patient and their significant others, whether the diagnosis is, (a) established, e.g. fractured wrist, (b) presumptive, e.g. acute appendicitis, or (c) not yet determined, e.g. the differential diagnosis of chest pain.
Be candid with the patient and their significant others, for example, “At this point in time I don’t know what the exact diagnosis is” ? followed by a discussion of your differential diagnosis and your plan of action (patients and their significant others “love to hear what is going through your mind”).
(3) Simulate an office setting as much as possible, if appropriate. For example, have the patient sitting or lying on a stretcher, the relatives/significant others sitting in chairs, and the physician sitting on a stool using a night table as a desk (sitting is more conducive for “creative thinking,” and facilitates getting on the “right track” with the “right gut feeling”). This way everyone will be more comfortable and at about the same eye level (decreasing their likelihood of feeling intimidated). You may have to practice some “crowd control,” e.g. the significant others constantly interrupting, or rattling their car keys. When assessing a patient, take advantage of any opportunity to shut out the noise from the rest of the emergency department (e.g. close the door if there is one/let the nursing staff know where you are (r) also applies when you have gone to, for example, the cast room).
(4) During a patient encounter, always be pleasant, or at least polite, and try never to become angry* (sometimes a challenge, especially when you are not in a “good mood,” e.g. obnoxious patient with an equally obnoxious personal hygiene, e.g. “toxic socks syndrome”; however, a short burst of “controlled anger” may very occasionally be useful for patients with a behavior problem: caution!, it may backfire). Be careful not to unduly antagonize† patients (another endemic ER problem). It is self-defeating, and may occasionally precipitate violence. Make a conscious effort during patient encounters to try not to appear impatient, or in a hurry (may take some practice). Strive to maintain an informal, friendly demeanor (at times a conscious effort is required). You can make a five minute encounter seem like ten minutes to the patient, or vice versa (however the patients like to see you going at top speed while they are waiting for your “presence”.) Remember: even when the ER is chaotic, you still have to be able to patiently listen‡ to what the patient has to say (can be difficult at times: keep in mind that the history is the foundation of the diagnosis, the management, and patient rapport).
(5) Complete the chart, prescriptions, and off work slips, etc. in the patient’s presence, otherwise the patient will not appreciate the total time that you spent on them. This is a good public relations maneuver with no increase in time consumption (also increases the legal credibility of your medical records). In addition, I often go through the patient’s old chart in their presence (I tell them I am going to look through their “book” which appears to amuse them). I get the definite impression that this reassures the patient that you have a good working knowledge of their pre-existing medical problems.
Remember, at least a little smile at the end of the patient encounter goes a long way, and is not likely to be misinterpreted. You should take advantage of any appropriate opportunity to share a smile or a laugh with patients, significant others, or staff, “laughter is the best medicine”.* For example, when informing patients regarding their x-rays (e.g. cervical/lumbar spondylosis), I often start out by saying “a little rusty,” which seems to amuse the patients and their significant others (one of the few advantages of being an older physician who appears a little “weather worn” himself).
(6) At shift change, before transferring the care of a patient over to the oncoming physician, review the case to determine if you can make any decisions regarding disposition, e.g. additional investigations?/procedures?/therapeutic measures?, consultation?, continued observation?, admission?, discharge? (I usually begin preparing for my 8am exit with a 5:30am “round up”). If you are the oncoming physician accepting the care of a patient, obtain a full report and beware! Take nothing for granted, and do your own complete assessment, or sooner or later you will get “burned” (also applies to patients returning to the ER for whatever reason). Remember, taking over the care of a patient is frequently more difficult and hazardous, than if you had seen the patient from the beginning.
(7) Patients are frequently accompanied by the police (e.g. psychiatric assessment), who at times can be recruited to assist in the patient’s management (e.g. countertraction during the reduction of a shoulder dislocation). Treat the police as significant others (unless the patient objects) , this often results in a “bond” between the police and the patient, which usually works to everyone’s advantage, including the patient’s.
In addition, the police often bring assault victims to the ER to have their injuries documented and treated. Guard against the tendency to become, over time, desensitized to the plight of the victims of violence. Sit down with the patient and take a brief, but unhurried history of the assault (e.g. “tell me what happened”), and give a response if appropriate (e.g. “when I hear a story like this it makes my blood boil”). This will help you develop some individual empathy for the patient. The patient will feel better for it (out of proportion to the treatment you provide), and so will you.  Furthermore, the police frequently ask for a copy of an assault victim’s ER chart. A solution is to give the patient two copies of their ER chart, and they can then give one copy to the police if they so wish (e.g. the patient, ER visit completed, is being accompanied by the police back to the police station to give a statement, to take injury photographs etc.). Remember to record this transaction on the patient’s ER chart.
(8) When requesting a consultation, don’t ramble, and don’t waffle (attention spans may be shortened by fatigue). Make sure your “homework” is done, and decide what the patient’s needs are before placing the telephone call (have the patient’s chart in front of you and “stick to your guns” prn). For example, “I have a 51 year old man with unstable angina and documented critical three vessel disease. He needs admission to CCU.” Consultant: “See you shortly.”
If the consultation is not urgent, make that clear, e.g. 2230 hours, “This is a tomorrow patient” (consultant gives a sigh of relief on the other end of the phone). “She is a 25 year old with Crohn’s disease that I have admitted to the floor, the orders are written, could you see her in the morning?” Consultant: “Sure! Tell me more about the patient.”
Do not call the consultant unnecessarily in the middle of the night, especially when it will not make any significant difference in the patient’s immediate management. However, make the consultant aware of the timing when you call in the a.m. (helps improve early morning attitude). For example, 0700 “I have a 45 year old patient here in the department with a trimalleolar fracture. He has been here since 0300, he’s otherwise in good health, and the pre-op workup is done.” Appreciative consultant: “I’ll be right in, I’m in the OR all day.” (If I have to have surgery, I would prefer that my surgeon has had a good night’s sleep!).
The consultation process is of course frequently more challenging than depicted above (especially interhospital). Unfortunately, unprofessionalism and arrogance, on the other end of the telephone are not rare entities, and may surface with stress and fatigue.
Beware of accepting telephone advice, especially from another hospital, as it can vary from being completely suitable, to totally inappropriate. Don’t struggle with a bad telephone connection, ask them to call you back.
(9) Remember there is the “well elderly,” who tend to have typical presentations, e.g. chest pain/ischemic heart disease, and the “frail elderly,” who often have atypical presentations, e.g. confusion/urinary tract infection. The frail elderly are usually accompanied by a caregiver, and may demonstrate the “suitcase” sign (almost pathognomonic for requiring admission).
In elderly patients with dizziness and/or syncope, do not forget to check for postural hypotension, which is often due to their medication, e.g. antihypertensive.
Beware of the elderly patient who has fallen, complains of hip/back pain, and you see “nothing” on their hip/pelvis/lumbar x-rays. If the patient cannot flex their hip, or move around on the stretcher without grimacing in pain, do not be too quick to send them home. They may have a subtle fracture, and in any case may have to be admitted for pain control (consult radiology/orthopedics).
(10) Avoid prejudging the lack of seriousness of the chief complaint, because for example: (1) you know the patient from many previous visits, e.g. somatoform disorder/now acute appendicitis, (2) the triage information on the chart (or old chart), e.g. sore arm/IHD, migraine/subarachnoid hemorrhage, (3) the attitude of the nursing staff (or yourself) towards the patient, e.g. alcohol abuser, or (4) the patient has been placed in a non-urgent cubicle, e.g. abd. pain/abd. aneurysm.
(11) If a patient declines an examination or investigation (for example a pelvic or rectal exam in the presence of lower abdominal pain), make sure they understand that your assessment will be incomplete and why (they will often then change their mind). If the patient is otherwise cooperative, you have to continue as best you can. Remember there is a fine line between a patient’s refusal of care, and the physician’s abandonment of the patient.
Not infrequently, after you have assessed a patient, the nurse comes to you and says that the patient is now refusing part or all of the clinical plan, that they appeared to have previously agreed upon, e.g. analgesics, blood work, I.V.’s, admission. Beware of uttering a reflex response to the nurse, that may contain sub-optimal tone and content. If you are overheard by the patient, it is as if you said it directly to that patient, dissipating any rapport that you may have had with that patient (and perhaps other patients if they overheard).
(12) In addition to the correct diagnosis and treatment, don’t forget to make the patient feel better with symptomatic therapy, for example, inform (e.g. explain the mechanism of their renal colic), comfort and reassure, fluids, antipyretics, analgesics. Keep in mind that like drugs, health care workers have a placebo-therapeutic effect. Do not lose site of the fact that you are in the “feel better business.” Sometimes, it may be useful to ask a patient with a chronic/recurring problem “what works?” ? e.g. “a shot of toradol worked the last time.”
A specific diagnosis is not always necessary or possible, and the inappropriate aggressive pursuit of same can result in considerable patient discomfort or worse. Remember the timeless principle “first do no harm (“stay out of trouble,” avoid iatrogenic misadventures), cure sometimes and comfort always.”
Patients should not wait unnecessarily to receive adequate analgesia. For example, (1) a multiple trauma patient, or (2) denying a patient analgesia because it might interfere with making the diagnosis of acute appendicitis*. Informed consent is probably more reliable in the patient whose pain has been at least partially alleviated.
(13) While all simulated patients require at least an abbreviated complete assessment, some real patients do not, e.g. minor ankle sprain. However, the decision to do only a partial assessment must be a conscious one, and based on the patient’s past and present history and vital signs, e.g. diabetic patient who presents with a “sore finger” but is also having chest pain and tachycardia. Remember that one painful injury may “drown out” the discomfort from another less painful, but perhaps more serious injury or injuries, e.g. fractured wrist and cervical spine fracture.
(14) In the presence of chronic or terminal illness, remember to determine the patient’s and family’s expectations. Some may want only varying degrees of supportive care, while others may request that “everything be done.” When indecision/guilt prevails, your role as a facilitator of decisions may include attempting to reach a consensus by proposing an appropriate plan of management (discourage unnecessary investigations and fruitless therapeutic interventions). Remember to appropriately specify on the order sheet, e.g. “No CPR” (with other orders to suit the situation, e.g. 50% O2 prn).
In addition: do not underestimate the value of your participation in palliative care. “Stealing” even a few minutes to be with the dying stranger is time very well spent (and very much appreciated by the patient, family, and significant others).
(15) Patients may bring various specimens with them to the ER, that you may not need or wish to see, for example, a dirty diaper (yuk!). Be diplomatic (avoid making unpleasant “primate” facial expressions). “Inexplicably”, patients with urinary tract symptoms rarely bring a urine sample with them to the emergency department (and sometimes can’t provide one ? be tolerant, not annoyed). The ability to chuckle about the many little irritants encountered in the ER (which seems to become bigger when you are busy), is a useful attribute, another example, a fully conscious adult patient lying on a stretcher, in no acute distress, who keeps their eyes closed while talking to you, even after you have diplomatically requested eye contact (this drives the nurses “crazy” too). Conversely, some patients also seem to be able to “laugh off” the many little annoyances, that they may encounter during their “adventure” in the ER (patient survey?).
(16) On the rare occasion, during a psychiatric assessment, the patient discloses that he is planning a homicide, and identifies the intended victim (e.g. estranged girlfriend or wife). In addition to the proper disposition of the patient, there is a moral and medical-legal obligation (Tarasof, California; no legal precedent yet in Canada), to ensure that the contemplated victim is informed of the threat. Do not overlook a death threat because, for example, “I didn’t think he was serious” (psychiatrist’s testimony / a recent first degree murder conviction in Canada). The patient making the death threat needs to be detained, until a formal assessment for a voluntary/involuntary psychiatric admission is completed, and the police are informed of the threat, and the requirement that the intended victim be notified of the threat.
(17)
(A) Alcoholics with evidence of liver disease: try telling the patient they are on “alcoholic death row.” That seems to hold their attention while you are discussing rehabilitation with them (you may at least get them to go to the detox unit). Be on the watch for the undiagnosed, unexpected, alcohol abuser, for example, the pleasant, elderly, vodka drinker. Be liberal about adding an ethanol level to your bloodwork orders. There will be the occasional surprise.
(B)Smokers with early respiratory disease: try saying to the patient that they are on the “slippery slope to chronic ill health and premature aging,” or, “you are on the fast track to emphysema.” They then seem to listen while you discuss with them the importance of smoking cessation (a few may even quit!).
(C)Be on the lookout for drug seekers, somatization patients, and the occasional Munchausen’s syndrome (and rarely Munchausen’s by proxy (r) usually, but not always, a pediatric patient, for example, poisoning, or an infant with recurrent apnea or sepsis/needle tracks?). All three will challenge your clinical skills, your tolerance, and your stamina, (striving to be physically fit helps maintain your stamina and partially alleviates the night shift* “jet lag”). The nursing staff can sometimes “sniff these patients out,” but be careful, they can be dead wrong too.
(D)Don’t let anxious parents or significant others “rattle you.” Listen to them, acknowledge their anxiety, and proceed (sometimes simultaneously), in a warm and deliberate fashion. Otherwise, their anxiety (and yours) may escalate, e.g. a small child with a fever and you have just begun your assessment, “what’s wrong with her doctor?”.
(18) Investigations: all investigations should be of course medically indicated. However, the judicious use of “therapeutic tests” can be at times clinically efficacious (and may facilitate the patient’s “closure” of a minor medical problem). For example: (1) ankle/skull x-rays: the patient appears overly concerned about the possibility of a fracture, is only partially reassured by your assessment, and your reasons for not doing x-rays fall on “deaf ears,” e.g. “that’s what they told me the last time and my ankle turned out to be broken”; (2) EKG: the patient with benign chest wall pain who is very anxious about heart disease, e.g. “thanks for doing the cardiogram doctor, I feel much better now, better safe than sorry they say” (the nursing staff may have already done a preemptive EKG); (3) chest x-ray: the patient believes he has pneumonia or lung cancer (he may be right); (4) chemstrip/urinalysis: the patient fears they may have diabetes or “kidney infection,” and (5) CBC*: the patient feels her “blood is down.” Caution, this “thinking” tends to drift you towards excessive ordering of investigations and medications, e.g. skull and ankle† x-rays, antibiotics (the pervasive temptation of expediency and increased patient satisfaction). Remember: it may be wise not to be too quick to discount the patient’s self-diagnosis. Withhold your “famous last words” until the “verdict” is in, because the patient can be embarrassingly correct.
Be very reluctant to order any investigations on a patient with a somatization disorder, except when very clearly indicated. Their satisfaction, if any, will be short lived.
Caution: if the results of your investigations do not fit the clinical picture, reassess the situation and repeat the investigations(s) prn (e.g. error in blood work labeling?, venipuncture above an I.V. site?).
Be careful not to get in the habit of inadvertently ordering unnecessary or poorly organized investigations, as a means of delaying your decision regarding a patient’s disposition. Attempt to order all the investigations that you will require, when you initially assess the patient. If further tests become necessary, request them as soon as the need becomes apparent. The decision to admit a patient can frequently be made, and the preliminary emergency/admitting orders written, at the time of your initial assessment, before the investigations are completed, e.g. acute exacerbation of COPD (I call them rapid sequence admissions).
(19) Lawsuits (scary stuff!)  12% of the medical lawsuits in Canada arise from the patients seen initially in the emergency room. The most frequent clinical problems involved are: myocardial infarction, appendicitis, meningitis, ectopic pregnancy, intracranial hemorrhage, testicular torsion, and extremity injuries, e.g. tendon, nerve, foreign body, scaphoid fracture. Beware of returning patients (e.g. same day, same problem), patients who leave against medical advice, and violent, intoxicated, or disoriented patients (relatives of a drug or alcohol abuser, even if previously estranged, may pursue a complaint with vigor). Also ensure that: (1) the attending physician (or his designated duty doc), for every patient you admit to hospital is personally notified (and recorded on the chart, or in the ER logbook), (2) your interpretation of x-rays is on the chart for the radiologist to see, and (3) delayed EKG, x-ray, and lab reports are properly followed up (for example, I booked a follow-up gallbladder ultrasound on a patient which revealed gallstones, and a right renal carcinoma. He has since had a cholecystectomy, and a right nephrectomy, and apart from a recent coronary angioplasty is alive and well 10 years later. I recently have had two more gallstones/renal carcinoma patients).
Communication, care, and records are the key words. Always read the nurses’ notes. Beware of undue delays (especially in these days of the downsizing of Canada’s medicare), e.g. suspected subarachnoid hemorrhage/ CT scan/ angiogram/ accessible berry aneurysm/ neurosurgical intervention. In addition, do not forget to do what you tell the patient you are going to do, e.g. booking an appointment for an urgent mammogram. In addition, provide a backup plan, just in case the investigation(s) are inadvertently not booked, or the results are not communicated to the patient. For example, tell the patient to call their family doctor if they have not received an appointment time in the next day or two, and to see their physician after the investigation to obtain the results of same (and for a follow-up assessment). Tell the patient not to assume that it was subsequently decided that the investigation was not necessary, or that the findings were ok.
Take very seriously that free, informal advice that you give out to other physicians or nurses around the x-ray viewing boxes (the hub of the ER). This is especially important if you have been taken for a “quick look at the patient,” e.g. rash, lumps, erythematous area. Keep in mind that there is no good samaritan law to protect you (patients can be very observant). Take similar precautions with all patient care telephone discussions.
Remember the “relative management test,” that is to manage every patient as you would want a favorite relative of yours managed* (not always a simple task). Do not subject a patient to any risk or regimen that you would not subject yourself or your family to (might be a useful policy to promulgate in court, should you ever be a defendant in a malpractice case). Before discharging patients from the ER, ask yourself: would your decision to send this patient home be defensible, should the threat of a legal action arise? Do not send a patient home, that you still have the least amount of uncomfortable concern about, e.g. fever, chest pain (no one will fault you for holding onto these patients). Beware of unintentionally medically discriminating against certain patients (e.g. minimizing the history which may lead to inadequate management), some examples: alcohol/ drug/ nicotine/ abuse/ overdose, asocial behaviour, psychiatric disorders, the disadvantaged, the minorities, the obese, the “unattractive,” the “poor historian,” homosexuals. Remember, negative or derogatory remarks about patients, may adversely influence the care that other health care providers may give. Avoid negativism (not always easy, another endemic ER problem). Keep the following adage in mind: “If you can’t say something nice, don’t say anything at all” (at times you may have to “bite your tongue”).
One of the challenges in emergency medicine is the ability to manage properly the occasional patient, known to you, that for whatever reason, you have a distinct dislike for (the feeling may be mutual/double jeopardy!). An extra effort to focus on the patient’s problem(s), will help you push the animosities, at least temporarily, into the background. Remember, no one wins a shouting match*.
Occasionally, a patient may request to be transferred to another hospital for personal reasons (e.g. the patient or significant other has more confidence in another health care facility when the necessity for surgery arises, for example, open reduction of an ankle fracture). Avoid any confrontation, or “subtle” displays of “bad feelings” (easy to say). Arrange a safe, smooth, and timely transfer of the patient to the hospital of their choice.
Never use the words “I don’t care” in the emergency department, in any context. For example, a patient who is waiting for an ankle x-ray and threatens to leave, “It is up to you if you stay for your x-ray or not, I don’t care.” The only words the patient will remember are “I don’t care,” and if a complaint or legal action subsequently raises its ugly head, then you are “dead in the water” (you can’t help what you think, but you do have control over what you say). Poor public relations is the catalyst† for most complaints and legal actions. That is not to say, that you have to take limitless verbal abuse from “competent,” cantankerous patients. If appropriate, record on the chart, excerpts of exactly what the patient said. For example, “referred to me as a pig-faced, baldheaded, Fxxx Axxx” (perhaps they should be charged with uttering profanities in a public place).
Another catalyst of complaints/litigation is the “if only” comments made to the patient, and/or their families by subsequent health care providers (e.g. patients subsequently diagnosed with cancer or meningitis). Remember that, “it is so easy to be wise after the event, and condemn as negligence that which is a misadventure” (Denning, L.J.: Roe v. Ministry of Health {1954} 2Q.B.66 {C.A.}). Sometimes, an explanation of the natural history of the disease/injury, and management options and pitfalls (with no real or apparent “cover-up”), will help to clear up any festering misunderstandings that the patient, or significant others may have. When I am working in the ER I often remember the old adage, “people who live in glass houses should not throw stones.”
Caution: except in unusual or simplistic situations, telephone advice to the public should be limited to an appropriate invitation to come to the emergency department (telephone encountering with patients is usually the nursing/receptionist staff’s responsibility).
Warning: when the beds are in short supply, you tend to tighten your admission criteria, and as a result you have to be vigilante that you do not send a patient home, whom you would otherwise admit (e.g. atypical chest pain). In the same vein, resist the temptation to take “shortcuts” during the busier times in the ER (or you will get “burnt”).
Since becoming a full time ERP, I frequently remember my mother’s words, “stay out of trouble” (sometimes my parting words to the appropriate patient of any age which invariably ends the visit on a somewhat jovial note. Another alternative message is “try to be more careful”).
(20) Allegations of sexual impropriety (very scary stuff!) Never do a pelvic examination in the ER without a nurse in attendance (no matter how busy the department is). Ideally, a nurse should also be present during breast or rectal examinations (often not feasible). If a significant other wants to be present during an examination and the patient agrees (or vice versa), do not put up any resistance. Take extra care to be sure the patient understands why you will need to examine sensitive areas. Proper draping practices are essential. Do not unnecessarily expose those areas that you are not presently examining. If you have the “gut feeling” that a patient is a high risk (or on the basis of their past history), take full precautions (nurse present during all “encountering”). Do not use the fear of allegations as an excuse for omitting indicated examinations.
(21) Remember the medical record can be your best friend. Records don’t necessarily have to be extensive, but they need to be complete with the times of your assessments and reassessments (in addition, write down on the patient’s chart the results of your investigations, e.g. EKG, X-rays, CBC, ethanol level, also with the times prn). What may be a perfectly adequate medical record for a simple ankle sprain with no legal connotations, may be inadequate for the same injury occurring in a shopping centre, or during an assault. Keep in mind that the courts generally accept verbatim, and do not challenge your medical record, that was written in your own handwriting, during or immediately following the patient’s visit (including ethanol levels; at least that has been my experience). In court have a copy of your chart with you, and stick to it as much as possible, otherwise the lawyer for the other side may try to “trip you up,” and discredit your testimony (e.g. assault victim’s injuries, “the injuries were consistent with the patient’s description of how the injuries occurred,” e.g. punched, kicked, choked, or “the injuries were consistent with but not specific for being assaulted”).
Charting “as you go,” is particularly useful when you have several patients with various problems “on the go” (helps compensate for a fading short term memory), for example, an assortment of patients with an assortment of problems, such as fever, alcohol/drug/abuse/overdose, asthma/COPD, chest/abdominal pain, trauma, migraine, P.V. bleeding, ureteral calculus. Again, remember to start out each notation with the time.
(22) When patients ask, “why did I get this,” avoid long convoluted explanations, especially when the etiology is unclear. You may only exacerbate the patient’s confusion, rather than alleviate it. With “minor” problems, e.g. bursitis, I sometimes begin my reply to that question by saying, “probably bad luck” (or “good question!!”), which invariably elicits a laugh from the patient and significant others (in a non-derogatory fashion, I sometimes refer to the orthopod as the carpenter and the urologist as the plumber which also elicits a chuckle, see #5, above).
Nonetheless, an easily understandable, straightforward explanation is essential (but easy to overlook); it improves patient compliance, and may potentiate the effects (e.g. biliary colic analgesia), or decrease the discomfort of your diagnostic (e.g. lumbar puncture), and therapeutic interventions (“explain the pain”). The patient and significant others can be somewhat distracted, and may need the explanation repeated on one or more occasions before it “sinks in.” The patient may be more attentive during history taking or explanations, if you place a comforting hand (prn) on their shoulder or forearm.
(23) A significant portion of the patients seen in the emergency department do not have emergent/urgent problems, and would have been more appropriately attended to in a family physician’s office (or in some instances self care would have sufficed). Physicians are not the health care police, and should resist the temptation from acting as such (however a patient who I have admitted on several occasions with COPD used to good-heartedly refer to me as the warden). You should assume that every patient has a significant problem(s), until you have determined otherwise. However if the visit is inappropriate, and that does not become self-evident to the patient during your clinical assessment, you may then want to educate the patient regarding the appropriate use of the ER (you may make a contribution of consequence to the education of the public!)*.
(24)When you are working solo in the ER, the situation may arise when you have no choice but to assess and treat your family members, relatives, friends or colleagues (that has happened to me on several occasions). The Nike(r) slogan says it best, “Just do it.” The adult patient usually appreciates the uncomfortable position you find yourself in.
(25)In the ER there is not much time to develop patient rapport. Depending on the appropriateness of the situation, it may be beneficial for the “one night stand,” to let the patient know that they are not alone, e.g. “We have had several other patients in the last day or two with the stomach flu and dehydration, and they frequently required I.V. fluids for a few hours.” In addition, referring briefly to your own personal medical experience may be helpful as well, e.g. “I have also had severe pain after root canal work, I’ll give you what worked for me.”  Sometimes, the first thing the patient or significant other says to you is, “Do you remember me?” (e.g. “I was here nine months ago with a sprained ankle.”). If you do remember, great! If you don’t, you are in a no win situation. If you say yes, you are being dishonest (tempting). If you say no, they are disappointed no matter what your explanation is. I simply sidestep the issue by saying, “I fail all memory tests” (they usually laugh and we get on with the present problem).
(26)Croskerry in his article, “Pitfalls in the Emergency Room” 15 describes ten cognitive errors that frequently take place in Emergency Medicine: (1) Playing the Odds: Ruling out a diagnosis just because it is unlikely, e.g. headache/fever/bacterial meningitis.
(2) Gambler’s fallacy, for example, you have already seen four patients during the shift with unstable angina, so you tend to think that the fifth patient with chest pain can’t be unstable angina as well. Vice versa: you think all five patients with abdominal pain have viral gastroenteritis, but one has appendicitis.
(3) Sutton’s slip: you tend to stop looking once you have found “the diagnosis,” for example, pyelonephritis and bacterial meningitis.
(4) Zebra retreat (not all hoof beats are horses): you think of an unusual/serious diagnosis but you talk yourself out of it (e.g. it is 0400, your CT scanner is broken down, and the nearest one is in another hospital ten miles away).
(5) Ying-Yang out: because the patient has already been worked up “the ying-yang,” there is the tendency to begin with a defeatist attitude. Nevertheless, the diagnosis may now be evident at this point in time, or this may be an entirely new problem. Try not to let any defeatist feelings that you may have, be apparent to the patient. Patients always appreciate a sincere attempt at elucidating their problem.
(6) Vertical probability error: the most probable diagnosis is not correct, for example, the patient with flank pain, microscopic hematuria, and a past history of renal calculi, is diagnosed as having renal colic; only the less rigid “lateral thinking,” will result in the right diagnosis of a leaking abdominal aneurysm being made.
(7) Posterior probability error: the patient’s past history must be interpreted with caution, for example, a patient with many previous ER visits for migraine headaches, but now has a subarachnoid hemorrhage.
(8) Psych-out errors: there is the tendency to medically under-assess and under-treat psychiatric patients.
(9) Anchoring illusion: the tendency to favor the diagnosis considered first, e.g. appendicitis/ectopic pregnancy.
(10) Representativeness error: the patient does not represent the patient-profile associated with a disease, e.g. 32 year-old female/chest pain/ischemic heart disease.
(27) A harmonious working relationship between the nursing staff and the medical staff is an essential ingredient of patient care in the ER (an understatement). Some of the nurses’ “pet peeves” regarding ER physicians are as follows: (1) frequently irritable (unperturbable is the optimum), (2) doesn’t consider the nurses’ suggestions, (3) doesn’t keep the nurses’ informed, (4) orders tests and therapy piecemeal, (5) procrastinates (e.g. contributing to the “traffic jam” in the ER by continuing to see new non-emergent patients, while other previously assessed patients are ready and waiting for decisions to be made), (6) too many verbal orders, (7) frequently late for shifts/slow charting/misplaces charts/forgets patients/disorganized, (8) tries to avoid the difficult patients (e.g. the “weak and dizzies”), (9) illegible handwriting, and (10) spending prolonged periods on the telephone organizing “the rest of their life,” or discussing the latest hockey game in detail with the other emergency room physician or consultant (when all the stretchers are occupied and standing room only in the waiting room). I must admit I have been guilty of some of the above at one time or another.
In addition, do not discourage the nursing staff from doing what they feel is appropriate presumptive management (e.g. O2, IV’s, monitors, EKG, blood work), particularly in patients with an atypical presentation (e.g. acute myocardial infarction with minimal interscapular pain).
Assume that all patients have drug allergies, and remember to determine the presence or absence of drug allergies before giving any drugs (including topicals and aerosols). This basic maneuver can easily be overlooked in the “heat of the moment.”
If during the oral examinations, you end up down a blind alley, don’t panic, retrace your steps beginning with the vital signs (has your assessment of the patient been complete?), limit the damage, do not do anything that carries a significant risk unless clearly indicated. There is a tendency to do “stupid” things you would never do in actual practice (“I can’t believe I did that”), and omit things you routinely do in real life (dawns on you as you are walking down the hall from the examination room). Beware of the clear-cut case, patients may have more than one significant problem, e.g. fractured hip/ neck injury/ IHD/ CHF/ diabetes. Be diligent, and pay attention to detail, do a complete history and physical otherwise you may miss an important diagnosis (e.g. glaucoma, testicular torsion), or at the very least lose points. Do not forget to examine the breasts, back (log roll prn ? exit wound?), lymphatic system, Gu (ectopic pregnancy?), rectum (carcinoma?), and CNS. Remember to remove the diaper in infants and the disabled. When examining a region if the examiner says, “normal,” move on, if he/she says, “what are you looking for?” that is a clue that you will probably uncover an abnormal finding(s) in that region (or your verbal physical examination skills for that particular system are being tested in detail). The bottom line in actual or simulated patient encounters is: be complete, and do not stop looking once you have uncovered a serious illness or injury.
Some timely procedures to keep in mind are intubation, needle chest or tube thoracostomy, pericardiocentesis, cardioversion, peritoneal lavage, and culdocentesis. Some of the procedures and investigations (e.g. colonoscopic), are included in this guide to serve as reminders for possible discussion with the consultants. You may be asked by the examiner to describe how you would do a certain procedure (e.g. a chest tube insertion).
Remember, you are in charge, and unlike real life, nothing will be done during the oral examinations unless you specifically order it (e.g. “Start CPR”). The onus is on you to verbally seek clinical information from the multiple role playing examiner, give orders, diagnose and direct the management of the patient as you would a real case. In both simulated and actual situations, be pleasant, specific, assertive, decisive, but flexible, and never lose your “cool” (easier said than done, especially during a night shift when you have just been awakened from a dead sleep, and you are still in a “postictal state”). Obtain timely consults prn (e.g. surgery, radiology), and use references prn (Micromedex(r)??(r) look up infrequently used drugs and treatment, for example, you may want to call poison control {Poisindex(r)?}, to see if you are forgetting anything/new treatment guidelines?). If the examiner says a consultant or certain investigation is not available, that means he/she wants you to continue for the present without them. Do not confuse or irritate the examiner (he/she is the patient too!). Making the patient/examiner “feel better” will enhance your score. Stabilize patients as early as necessary. Ensure that all monitors are being observed by trained staff and alarms are set(prn).
All the simulated patients are either admitted, or very infrequently discharged. There is no room for prolonged observation in the hypothetical emergency department (e.g. overnight). Do not leave critical patients unattended by staff, have the nurse report to you immediately any change in the patient’s vital signs. Be cautious about sending the patient (unstable?) out of the department for investigations, e.g. x-rays (remember the timeless adage, “out of sight, out of mind”).
Follow this guide, but be flexible, the sequence and content will have to be altered to suit the situation, but at least an abbreviated complete assessment of all patients is required. Resist the temptation to do only a partial assessment.
When reading this manual (or your favorite text), visualize as much as possible. That is visualize the patients, the anatomy, the physiology, historical items, symptoms, signs, investigations, actions, procedures, diagnoses, management, and disposition. This will help you to “think of it,” when managing a real or simulated patient.
This book is meant to be read repeatedly cover to cover, and if you know it “cold”, you should find your automatism* when dealing with real or simulated patients is increased (my impression), leaving you more time to think through the more difficult problems, and to “stay in control”. In addition, if you attend an oral board course and/or practice “homemade” cases (based on real patients), with your colleagues or fellow medical students, you may also discover that your clinical / candidate performance is further enhanced (also my impression). Medical students can adapt the manual to suit the stage which they are presently at in their medical education.
°The Management Guide
(r) remember to pause, visualize and reflect, while reading through the guide.
(r) use universal precautions.
? don’t forget to wash your hands between patients (easy to overlook!).
(1)Examiner briefs you on the pre-admission condition of the patient: Radio communication with the ambulance personnel: description of the patient and the vital signs
? if the approximate age; sex, present problem(s), plus all the vital signs are not given, ask for them (level of consciousness, P, R, B/p and body temperature): ask: what does the patient look like?, and for monitor strip or interpretation prn: give orders pertaining to the BCLS, ACLS & ATLS necessary for a safe transfer depending on the personnel and equipment available. Do not order cardioversion without first knowing the mental status of the patient (? I.V. versed(r) (midazolam) or valium(r) ± demerol(r) prn plus synchronization prn). When you are directing on-site stabilization via radio, timely orders include at which point to transfer the patient to your or another facility, e.g. a trauma centre (do not forget to phone the other hospital’s emergency room physician).
AND / OR (2) Examiner briefs you on the condition of the patient on arrival at the emergency room: if the approximate age; sex, present problem(s), plus all the vital signs are not given, ask for them (level of consciousness, P, R, B/p and body temperature). Use a flexible rectal probe with an electronic thermometer prn (hypo or hyperthermia?). Know your pediatric vital signs:
Age Pulse Resp.
SB/p Approximate weights
0-2 yrs 140-120 40-25 60-90 Newborn 3.5kg ± 2-4 yrs 120-100 25-20 90-100 6 Months  7kg ± 4-16yrs  < 100 20-16 100-120 1 Year  10kg ± 5 Years  20kg ± 10 Years  35kg ±
(3) Candidate to the examiner:
(r) “What does the patient look like?”
e.g. obtunded, distressed, SOB, pale, diaphoretic, cyanotic, jaundiced, lethargic, anxious, agitated, depressed, hostile.
(r) “What does the nurses’ triage and admission notes tell me?”  e.g. history of present problem(s), allergies, meds, preexisting conditions, and the nurses’ physical assessment.
? At this point pause for a moment to digest the opening scenario, and then proceed with rapid stabilization if necessary, e.g. dyspnea, chest pain, hypotension. Alert the nursing*, x-ray, and lab staff prn. Remember to stay focused.
(4) or (5) (depending on the urgency) Introduce yourself to the patient (and/or parent(s) prn): For example, “Hello Mr. Smith, I am Dr. Jones and I will be looking after you.” Ask the patient pertinent questions regarding the present illness or injury (trauma / medical / psychiatric / assessment), for example, “What hurts?” (MVA? ask about seat belt use, shoulder or lap type? airbags?). “Tell me about this chest pain that you have been having.” “Tell me about how you are feeling,” e.g. tense?, angry?, depressed?, weak? “Do you have any other medical problems?” “Are you taking any medications?” “Are you taking your medications as directed?” “Have there been any recent changes to your medications?” “Are you allergic to any drugs or anything else?” “Is there anything else bothering you?” “Is there anything else about you I should know?” (e.g. previous hospitalizations, surgery/splenectomy?, serious illness or injury). “What is it that you fear* might be wrong with you?” (e.g. heart attack?, appendicitis?, meningitis?, “killer strep infection”?, cancer?). Inform the patient of your immediate plans, for example, physical examinations, investigations, therapeutic measures ? “Do you have any questions Mr. Smith?” “I want you to feel free to ask me or the nurses questions at any time.” Remember that with alcohol/drug abuse/overdose, the history of drug or alcohol ingestion is frequently unreliable. Beware of the patient who wants “nothing to be wrong with them,” and minimizes or omits their symptoms†.
History may also be obtained from the parents (e.g. child), other family members, significant others, EMTs, police, old charts, and the family physician. Use the telephone prn to acquire the necessary information. First aid treatment administered prior to arrival? (e.g. poisonings, frostbite).
(In cases of sexual assault, ? ACBC’s, supportive care, call the sexual assault team if your hospital has one, and protect the “chain of evidence” by ensuring an appropriate forensic examination is performed {does your ER have a prepackaged sexual assault kit?}).
(4) or (5) (depending on the urgency) Candidate to the examiner (as appropriate for this patient):  While I am doing the ABC’s, I want the nurses to give the patient O2* (50-100%), place the patient on the cardiac monitor, pulse oximeter, and automatic sphygmomanometer, obtain a monitor strip and start I.V.(s) ? one or more?, site(s)?, size?, ringers? (warm prn), rate? (pressure infusions prn), pediatric microdrip prn (except with hemorrhagic shock), pediatric bolus(es) prn ? ringers 20cc/kg ? maintenance 2cc/kg/hr. Take several tubes of venous blood for STAT: CBC-diff-sed.rate, BUN, creatinine, glucose, lytes, etc. prn (e.g. chemstrip for serum glucose?, blood cultures {aerobic, anaerobic, viral?}, x-match, coagulation studies, CPK-MB, LDH, ethanol, acetaminophen, salicylates, other serum drug levels {e.g. theophylline, dilantin(r), tegretol(r), digoxin}, amylase, sgot, alk. phos., bilirubin, mono spot, Ca, Mg, PO4, serum osmolarity). Do the arterial blood gases prn (plus a carboxyhemoglobin level?), an EKG and a urinalysis. Obtain a list of the patient’s present medications (including contraceptives, topicals, transdermal patches, inhalers, aerosols/home O2, and over the counter medications), and drug allergies (medical alert bracelet or necklace?). Undress the patient as soon as feasible.
Obtain the patient’s old charts (often invaluable). Inform me immediately of any changes in the patient’s vital signs.
The patient may have to be restrained*, searched (photo? ID?, medical information?, drugs?, weapons?), or have their clothes cut off (and/or motorcycle helmet carefully removed using the standardized technique). In addition, the patient’s premises may have to be searched by the EMTs, police, or significant others (drugs?, empty drug containers?, suicide note?, poisons? e.g. methanol?).
(6) Airway and C-Spine/Cord: Ask the conscious patient pertinent questions: e.g. any trouble breathing, speaking, or swallowing?, any neck pain?, any weakness or numbness? (recent onset?, transient neurological symptoms?) Examine the airway and the cervical spine: apnea?, kussmaul breathing?, airway already in place? (e.g. intubated?, check tube placement), airway patency?, stridor?, F.B.?, tracheal deviation?, gag reflex?, trauma?, tender cervical spine?, jugular venous distension?, subcutaneous emphysema?, unexplained hypotension?
( place the patient in a position of respiratory comfort prn, 50-100% O2 prn, pulse oximetry prn, immobilize the c-spine prn, and after the patient has been stabilized, call for a portable lateral x-ray prn (c-spine may already have been immobilized by the EMTs with a Philadelphia collar, Ked, backboard, light weight spacers, and chin/forehead/body straps/tape; patient may also require sedation, e.g. I.V. haldol(r) 5-10mg prn); suction prn (plus nostrils in infants), remove dentures prn, jaw thrust prn (relatively safe with suspected c-spine injuries), soft xylocaine lubricated nasopharyngeal airway prn (may be used in patients with or without a gag reflex; size = tip of nose to tragus of ear), oropharyngeal airway prn (contraindicated in patients with a gag reflex), prn  racemic epinephrine aerosol (0.5cc 2.25% in 4.5cc of saline/specify, with O2, not medical air), ventilate with bag and transparent mask prn, with careful in-line traction prn, thiamine 100mg I.V. prn (prevent/treat Wernicke’s syndrome), 50% dextrose 50cc I.V. prn, narcan(r)* 2mg I.V. prn ± flumazenil (benzodiazepine antagonist, careful!, consult references), 0.3mg q 1 minute prn to 2mg (restrain patient first?, either narcan(r) or flumazenil can precipitate violent behavior/acute withdrawal); orotracheal tube prn (uncuffed to 6-7 years of age (r) size of external nare or “#5 at 5 years”), nasotracheal tube prn (1 size less than an orotracheal tube), needle cricothyroidotomy/percutaneous translaryngeal ventilation prn (must be no obstruction to exhalation, use a #12-14 intracath through the cricothyroid membrane with 3cc syringe barrel and a #7 endotracheal tip, also requires manual intermittent high pressure O2 source/ 50 psi ? exhalation obstructed? ? 2nd or 3rd intracath prn); cricothyroidotomy prn (with #4 or 5 Shiley or #5 endotracheal tube), tracheostomy prn (by consultant). Open cricothyroidotomy in young children is fraught with difficulties.
Before intubating, place the patient on a cardiac monitor, suction with a rigid tonsillar suction prn, xylocaine(r) spray prn ( sedate prn ± paralyze prn, ventilate for 1-5 minutes with 100% O2 prn ( Sellick’s manoeuvre prn (? nitrogen washout ? pulmonary O2 reservoir increased), check the intubation tube cuff for air leaks (plus lubricate the tube and stylet with xylocaine jelly), and place the patient in the sniffing position unless contraindicated. After intubation, inflate the cuff, and hold the intubation tube at level of the orifice until cut and secured, ventilate with 100% O2 (hyperventilate prn), auscultate over both axillae and the stomach, suction the trachea and major bronchi prn (use a well lubricated soft suction catheter less than 1/2 the size of the lumen to be suctioned), and then pass a nasogastric tube (nasopharyngeal airway may be used as a conduit) ? an orogastric tube may be easier. Next, reduce the cuff pressure to the minimum required to eliminate air leaks, and order a chest x-ray and a ventilator. Intubate comatose patients without a gag reflex, and before removing an esophageal obturator airway (EOA). Use Sellick’s manoeuvre prn to assist intubation, and help prevent gastric distension, emesis, and subsequent aspiration.
Make use of xylocaine(r) spray and jelly prn, nasoconstrictors prn, I.V. valium(r) or versed(r) prn, I.V. atropine prn, I.V. xylocaine(r) prn, neuromuscular blockade prn, soft tissue x-rays of neck prn, indirect and direct laryngoscopic exams prn, and McGill forceps as indicated. With orotracheal intubation use a lubricated stylet, otherwise you will need perfect visualization (be careful to ensure the stylet does not protrude through the distal end of the tube). If you are having a problem passing the tube through the larynx (adequate lubricant? edema?), try a tube 0.5-2.0 sizes smaller. A small endotracheal tube will suffice, at least temporarily (and may be lifesaving!).
Rapid sequence induction and intubation When intubating the awake, fatigued patient (e.g. COPD), I have had success to date with copious xylocaine(r) spray and jelly plus I.V. valium(r) prn. If time permits, I call the anesthetist to do a rapid sequence induction and intubation* with neuromuscular blocking, etc. (know your limitations). If the patient goes to sleep for a few minutes after I have taken over their ventilation, then I know that I made the right decision!
An oropharyngeal airway may be used as a bite plate in a patient with an orotracheal tube. Patients not intubated, and without neck injuries, especially children, should be kept in the sniffing position. Use a nasotracheal tube when intubating patients with seizures, trismus, or cervical spine injuries (orotracheal intubation may be attempted in patients with possible cervical spine injuries, if strict in-line traction is employed, and the neck is kept in the neutral position. Fiberoptic assisted?). When C-7 is not visualized, repeat the lateral c-spine x-ray with the shoulders pulled down, or obtain a swimmer’s view prn (CT scan?).  Bag and mask ventilation, even without in-line traction, may be more effective using two people, one on the mask ± in-line traction, the other bagging. Patients with epiglottitis can be bagged (not always) if necessary, and taken immediately to the OR for rapid sequence induction and intubation (if you are required to immediately intubate the patient in the ER, direct a smaller than usual tube through the “eye of the cherry”). In addition to epiglottitis, prophylactic intubation may be required for head, neck, and chest injuries, multiple trauma, and burns.
In newborns, assess their tone, ventilatory effort, and heart rate. Most asphyxiated newborns will respond to 100% O2 ventilation with bag and mask, and protection against hypothermia (they need a 34-36?C environment). Use a straight Miller blade in patients less than 4 years of age. In newborns use a Miller blade size 0 to 1, and an endotracheal tube size 2.5 – 3.5. The recommended distance from the tip of the endotracheal tube to the lips, in 1, 2 or 3 kg infants is 7, 8, or 9 cm respectively. The Broselow Pediatric Resuscitation Tape(c) (AHA-PALS) displays the appropriate ACLS drug doses, fluid volume requirements, equipment selection, and basic life support techniques, all based on the length of the patient, which directly correlates with the weight. Remember that when intubating pediatric patients, the larynx is more anterior and cephalad than in adults (e.g. C2-3 level in infants versus C5-6 in adults). In addition, the smallest diameter of the airway in infants and young children, is below the cords at the cricoid ring.
Foreign bodies, e.g. a coin in the esophagus usually faces forward, and in the trachea it usually faces side on. In patients with a partial upper airway obstruction due to a foreign body, if they are ventilating adequately, do not interfere with their efforts to expel the foreign body. If ventilation is inadequate, treat as a complete obstruction ? back blows X 5 prn, abdominal or chest thrusts X 5 prn, and remove the FB if visible ? the sequence is repeated prn, and/or direct laryngoscopic exam and removal with McGill forceps as appropriate.
The pediatric I.V. doses of narcan(r) = 0.01mg/kg I.V. prn, dextrose 50%, 25% or 10% = 1-2cc kg/I.V./prn, valium(r) = 0.2mg/kg/I.V./prn. The tidal volume is 10cc/kg x 12-20/min.
Drugs that can be given endotracheally, using twice the I.V. doses are: narcan(r), atropine, isoproterenol, lidocaine, epinephrine, and diazepam (mnemonic = NAILED).  Brief pause prn: any change in the clinical status or the vital signs?: assessment: investigations and available results: timely management prn: inform, comfort, and reassure the patient prn. Beware of iatrogenic hypothermia, especially in infants and the elderly ? prophylactic heat lamp/warming blanket prn.
(7) Breathing: Ask the conscious patient pertinent questions e.g. any SOB, chest pain, or hemoptysis?  Examine the chest: inspection first, e.g. dyspnea?, audible wheeze?, labored breathing?, chest contusion?, permanent pacemaker? (patients frequently forget to tell you about their pacemaker).
? place the patient in a position of respiratory comfort prn, 50-100% O2 prn, pulse oximetry prn, needle chest prn (e.g. tension pneumothorax/ 2nd interspace midclavicular line or nipple level/ 5th interspace midaxillary line), chest tube prn (nipple level/ 5th interspace midaxillary line), aerosol ? prn (e.g. 1cc ventolin(r)*, plus 2cc atrovent(r), plus 3cc saline/ or racemic epinephrine 2.25% 0.5cc in 4.5cc saline/specify, with O2, not medical air, measure the PEFR before and after, if appropriate), prn adrenaline 0.3-0.5cc (0.01cc/kg/child) 1:1000 s.c., bag and mask with 100% O2 prn, intubate and ventilate prn, order portable chest x-ray prn (+ expiratory film?, upright or supine? ? hemothorax may be difficult to see in the supine film, may have a granular appearance), arterial blood gases etc. prn (e.g. theophylline and other drug levels prn). Use the largest chest tube (32-40 F) that you can when draining a hemothorax. Patients may have to have a chest needle or tube inserted before the chest x-ray. When intubated or bronchospasmic patients go sour, think of a tension pneumothorax (e.g. decreased or absent breath sounds unilaterally ± shock due to impaired venous return) ? immediate needle decompression with an intracath prn (e.g. #14), which is then connected to an underwater seal drainage as a temporary measure, until a chest tube is inserted.
The normal bicarbonate level is 21-26 meq/L (metabolic acidosis / normal / metabolic alkalosis) and the normal pCO2 is 35-45mmHg (respiratory alkalosis / normal / respiratory acidosis).
When ordering ventilators, specify a volume (preferred), or pressure model, percent O2, tidal volume, rate, automatic or triggered, ± peep (5-10cm H2O). For children < 10kg, use a preset pressure, or time-flow ventilator. Order chest x-rays (+ expiratory film?) after intubation, chest needle or tube, thoracocentesis, pericardiocentesis, intercostal nerve blocks, CVP, subclavian or internal jugular venipunctures, and transvenous pacing. Repeat chest x-ray in 6 hours prn.
?: for example, tension pneumothorax, hemopneumothorax, sucking chest wounds, esophageal rupture (blunt trauma?, iatrogenic?, violent emesis?, plus pneumomediastinum?, plus fever?), diaphragmatic rupture (or hernia in the newborn), massive hemoptysis, tracheal-bronchial rupture (air embolism?), sternal fracture (myocardial contusion?), flail chest (pulmonary contusion?), aspiration, ARDS, pulmonary embolism, pneumocystis carinii pneumonitis (occurs in heterosexuals too!), bronchospasm and respiratory failure. In addition to the standard therapy, consider giving MgSO4 I.V. (e.g. adults 2-4+g) for moderate-severe bronchospasm (may alleviate the need for intubation?*).
Brief pause prn: any change in the clinical status or the vital signs? assessment: investigations and available results: timely management prn: inform, comfort, and reassure the patient prn. Remember that agitation/hyperventilation may be due to anoxia or metabolic acidosis, not anxiety.† (8) Circulation: Ask the conscious patient pertinent questions: e.g. any chest pain or SOB?  Examine the cardiovascular system: Pediatric systolic pressure = 80 + 2 X years of age Radial pulse present = SB/p ? 80 Femoral pulse present = SB/p ? 70 Carotid pulse present = SB/p ? 60 Orthostatic vital signs prn (e.g. unapparent GI hemorrhage?); capillary refill?
?: CPR prn*, direct pressure for bleeding prn, 50-100% O2 prn, pulse oximetry prn, cardiac monitor and strip prn, EKG prn, trendelenburg prn, mast prn (± inflation), I.V.(s) prn ? cut downs prn, anterior tibial interossessus infusion in children prn (use a bone marrow needle if available, 1-3cms below and medial to the tibial tuberosity, use a screwing motion prn/direct away from the epiphysis; remember the external jugular vein may be easily available in infants and children; in adults use the distal tibia), crystalloids prn, e.g. ringers lactate; packed red blood cells prn ? O neg prn, type specific prn, or matched prn (in increasing order of preference, urgency dependant) ? diluted with warm saline prn (40-45°C) ± blood warmer prn, and under pressure prn; fresh frozen plasma prn, cryoprecipitate prn (safe?), platelets prn, vagal maneuvers prn, ACLS drugs prn (± ET route prn), cardioversion prn (± synchronization prn, ± I.V. versed(r) or valium(r) prn ± demerol(r) prn, or general anesthesia prn), pacing prn (transcutaneous or transvenous), pericardiocentesis prn ± 0.5-2 liter bolus of ringers prn (false negative tap?, echocardiogram?, CT scan?), heparinize prn, thrombolytic therapy prn, emergency angiography prn/angioplasty prn/CABG prn/intraaortic balloon pump prn/thoracotomy prn.
Acute myocardial infarction? ? rule out pulmonary embolism, aortic dissection, cardiac tamponade, hypovolemia, and septic shock. Repeat “normal” EKGs prn, e.g. reoccurrence of chest pain. An EKG should be performed on all distressed patients (e.g. abdominal. pain, panic attacks), who have ischemic heart disease, or who are candidates for same. Compare the present EKG with previous EKGs prn.
Transcutaneous (50-200 MA), and transvenous (2-20 MA) pacing, particularly the former, may need I.V. versed(r) or valium(r) ± demerol(r) for sedation. Pacing should be set on the demand mode, or in special circumstances overdrive.
?: for example, life threatening arrhythmias, shock (hypovolemic?, vasogenic?, cardiogenic?), acute myocardial ischemia (cocaine use?) or contusion, pulmonary edema (MI?, arrhythmia?, cardiomyopathy?, acute valvular dysfunction?, non-cardiac pulmonary edema?), pulmonary embolism (DVT?), pericarditis, pericardial tamponade (supraclavicular cyanosis?), pulmonary hypertension, hypertensive emergencies and dissecting thoracic aortic aneurysm (± neurological signs?, ± MI?), or rupturing abdominal or thoracic aortic aneurysm (including traumatic, widened mediastinum?).
Ventricular fibrillation ? defibrillate immediately with 200 joules, and repeat x 2 prn (200J, 360J), then continue ACLS (but not so fast with the defibrillator that the patient is still awake, treat the patient not the monitor, loose or detached leads?).
Electrical mechanical dissociation ? rule out tension pneumothorax, hypovolemia, pericardial tamponade, acidosis, hypoxemia, hyperkalemia, hypercalcemia, pulmonary embolism, and ruptured ventricular wall or valve.
Beware of the wide complex tachycardia, treat as a ventricular tachycardia, e.g. lidocaine and/or procainamide prn (no verapamil or digoxin), cardioversion prn (usually synchronized, 25-50J+, ± sedation/general anesthesia prn). Cardiovert unstable patients prn (e.g. ischemia, hypotension, CHF, decreased cerebral status) ? cardioversion is contraindicated in digitalis toxicity (last resort? 10-25J).  Do not hesitate to give indicated ACLS drugs prn (know doses!), for example, epinephrine (high dose?), NTG (often I.V.), lasix(r), morphine, atropine, lidocaine, procainamide, bretylium, amiodarone, dopamine ± fluid bolus(es) if appropriate; verapamil, adenosine, beta blockers. Following the administration of an ACLS drug, give a 20mL I.V. fluid bolus, and elevate the arm in order to speed the delivery to the central circulation.  For cardiac arrest not responding to standard ACLS protocols, consider giving MgSO4 2-4+g I.V. bolus.
Use ringers lactate in adequate amounts for hemorrhagic shock (several litres prn, 3:1 rule), recheck HB after 2-3 liters (after 20ml/kg bolus(es) in children ? total blood volume = 80 ± /mL/kg). Do not hesitate to give packed red blood cells prn (5-10cc/kg bolus(es) in children), with informed consent* if appropriate. Do a quick examination before, or while the mast is being applied (e.g. urethral injury?). Thomas splint(s) may have to be removed in patients with fractured femur(s) ± fractured pelvis, so that the mast may be applied. A blood pressure cuff can be used as a temporary tourniquet for brisk bleeding from an extremity, e.g. lacerated brachial artery. Caution: there are early reports that suggest that raising the systolic blood pressure above the minimum required (90-100) for adequate perfusion, may aggravate or reinitiate the bleeding in hemorrhagic shock.
Remember that any patient that requires ringers for hemorrhagic shock may require packed red cells. With severe or moderate shock, plus ongoing bleeding, the decision to give packed red cells in addition to the ringers can be made immediately (plus fresh frozen plasma prn with massive transfusions).
In patients with hemorrhagic shock who fail to respond to volume replacement, look for tension pneumothorax, hemothorax, pericardial tamponade, unrecognized blood loss (e.g. abdomen, retroperitoneum, pelvic or femoral fracture), acute gastric distension, neurogenic shock, and medical problems, e.g. MI, DKA, adrenal failure.
Traumatic Cardiac Arrest (or high risk of/have the trauma team notified immediately) ? ? ACBC’s ? tension pneumothorax?, pericardial tamponade?, hypovolemia? ? needle chest?, pericardiocentesis?, simultaneous fluid replacement ? immediate thoracotomy? ? treat cardiac tamponade prn (open decompression), direct cardiac massage (external cardiac compressions considered ineffective in traumatic cardiac arrest), control bleeding prn, aortic cross clamping prn. Blunt trauma plus cardiac arrest, ± thoracotomy ? dismal prognosis ? penetrating trauma plus cardiac arrest, plus thoracotomy ? 5-30% survival.
Brief pause prn: any change in the clinical status or the vital signs?: assessment: investigations and available results: timely management prn: inform, comfort and reassure the patient prn.
Hemorrhagic shock = at least 15% loss in the total blood volume.
Pediatric cardiac arrest is frequently secondary to respiratory arrest or shock.
(9) Patient responsiveness: Ask the conscious patient pertinent questions: e.g. any headaches, speech problems, weakness or numbness?
Mnemonic for altered states of consciousness and coma: TIPS: T:
I:
P:
S:  trauma, temp., thiamine
infection, AIDS.
psychiatric, porphyria.
space occupying lesion, stroke, intracranial hemorrhage, shock, status epilepticus (seizures may be subtle).
VOWELS: A:E:I:O:U:
alcohol, drugs, toxins.
Endocrine, liver, lytes.
Insulin, oral hypoglycemic agents, diabetes mellitus.
O2, CO2, CO, opiates.
Uremia, hypertension.
Examine the nervous system: Level of consciousness (AVPU = (1) fully awake, or (2) responds to verbal stimuli, or (3) responds to painful stimuli only, or (4) unresponsive); lateralizing signs (± aphasia?), Glasgow scale (best visual, verbal, and motor response, score 3 – 15). Rule out head and neck trauma in all patients with a decreased level of consciousness. Memory or focal deficit?, hypo/hyperglycemia?, uremia?, other metabolic encephalopathy?, prolonged postictal state? (has an underlying problem?, e.g. encephalitis?), status psychomotor seizures? (EEG?), new headache?; coma nyd? ? include gastric lavage?, and charcoal?; CT scan?, MRI?, lumbar puncture?
Increased intracranial pressure (+ reflex hypertension?) ? Avoid hypoxemia, hypercapnia, agitation, seizures, pyrexia, and cerebral edema.
? ? ACBC’s, intubate prn and hyperventilate prn with 100% O2 to a pCO2 of 25-30 prn, mannitol 20% 5-10cc/kg/I.V. prn (caution), lasix 1-2mg/kg/I.V. prn (caution), dexamethasone (decadron(r)) prn, initial dose 1mg/kg to 50mg I.V. (plus Zantac(r) 50mg I.V. for stress ulcer prophylaxis?), reverse trendelenburg position if not contraindicated. ( seizures prn (e.g. I.V. valium(r)/dilantin(r), consider giving dilantin(r) prophylactically: 15mg/kg/I.V. over 30-60 minutes), ? agitation prn (e.g. I.V. haldol(r) 5-10mg and/or ativan(r)1-2mg prn), ? pyrexia prn (e.g. Tylenol(r) supp./external/core cooling prn), and treat underlying conditions prn (e.g. meningitis, intracranial hemorrhage, head injuries).
Seizures ? ACBC’s, thiamine 100mg I.V. prn, dextrose 50% 50cc I.V. prn, valium(r)5-10mg I.V. prn (pediatric 0.2mg/kg), dilantin(r) I.V. prn (15mg/kg loading dose over 30-60 minutes).
Emergency burr hole(s) prn (e.g. epidural hemorrhage) ? ? ACBC’s, burr hole(s) 1 inch above the zygomatic arch and 1 inch in front of the ear.
Critically ill patients with bacterial meningitis should begin antibiotic treatment in less than 30 minutes, regardless of how many investigations have been completed (however, always do blood cultures before giving the first dose of antibiotics, e.g. adults/ceftriaxone 2g plus ampicillin 2g). Beware of the early bacteremic stage with fever alone, which may respond initially to symptomatic treatment (significant pyrexia? ? suppressed with a recent antipyretic?, toxic?, immunocompromised state?, focus of infection? ? septic workup? ? presumptive antibiotic therapy prn). Remember that several disorders may result in a septic appearing infant, for example, (1) bacterial/viral/mycoplasma infections (e.g. sepsis, meningitis, pneumonia, “flu”), (2) dehydration/shock (± electrolyte problems) from any cause, (3) overdoses (e.g. ASA), (4) hypoglycemia (e.g. ASA overdose, infections), (5) cardiac failure/arrhythmia (e.g. congenital heart disease, SVT), (6) shaken baby syndrome (+ other CNS trauma/bleeds), (7) anemia (e.g. aplastic, hemolytic, blood loss), (8) renal failure, (9) infantile botulism (never seen it), (10) HIV/infections (e.g. pneumocystis carinii pneumonia).
Combative patient ? hypoxic?, hypovolemic?, hypoglycemic?, infection?, head/ cervical spine injury?, alcohol?, drugs?, e.g. cocaine, PCP, anabolic steroid rage; substance withdrawal?, psychosis?, postictal?, personality disorder? ? do not under estimate a patient’s potential for violence (female patients too!). Weapons?, mental status?
? ? ACBC’s, thiamine 100mg I.V. prn, 50% dextrose 50cc I.V. prn, haldol(r) 5-10mg I.M./I.V. ± ativan(r) 1-2mg I.M./I.V. q15-60 minutes prn if appropriate, continued physical restraints prn, and ? underlying problems.
Brief pause prn: any change in the clinical status or the vital signs?: assessment: investigations and available results: timely management prn: inform, comfort, and reassure the patient prn. Beware of prematurely attributing dyspnea/weakness/parathesia to a psychogenic etiology.
(10) Finish the primary survey (an abbreviated complete physical assessment), plus ? foley catheter prn (urethra ok? ? obtain a spontaneously voided specimen first if feasible  ? micro/gross hematuria?), urinalysis, measure urine output, nasogastric (cribiform plate ok?)/orogastric tube prn (acute gastric dilation?), mast prn (if not already applied during the ABC’s), gram stains (of buffy coat?) and cultures prn (± other stains?), tetanus toxoid prn/tetanus immune globulin prn, antibiotics prn (often I.V., cultures first prn), analgesics prn (early prn, often I.V.), flow sheets prn (e.g. glasgow scale, vital signs, fluid input/output, and other assessments, investigations and therapeutic interventions). Monitor the central venous pressure (± PCWP) prn.
Other points: type and amount of ng drainage (bile only?; swallowed blood from epistaxis/hemoptysis?) ? continuous or intermittent gastric suction?, zantac(r) I.V.? (stress ulcer prophylaxis?); gross or micro hematuria? (no red cells? (r) myoglobinuria?; red cell casts?/nephritis?, on anticoagulants?, trauma or renal/bladder tumor?, UTI?, renal calculus?), minimum urine output 1cc/kg/hr for children to 50+cc/hr for adults, instill xylocaine jelly into the urethra prior to catheterizing males, obtain toxic screens on gastric aspirate and urine prn, use an infusion pump prn (e.g. dopamine), and give prophylactic low dose heparin (e.g. 5000 units s.c. q12h), if appropriate. Multiple trauma patients require the following (portable?) x-rays (± others prn): skull, cervical spine, chest, abdomen, and pelvis. CT Scan?, MRI? (e.g. shaken baby syndrome ? retinal hemorrhages?). Last meal?, keep NPO?
Be on the look out for the abuse (psychological/physical/ sexual), and neglect of children, women, the handicapped, and the elderly (discrepancies in the history and physical?).
Brief pause prn: any change in the clinical status or the vital signs?: assessment: investigations and available results: timely management prn: inform, comfort, and reassure the patient prn.
Once the patient is stabilized, don’t hesitate to take a few moments to collect your thoughts and review the case with the help of the mnemonic (see page 4). Ask yourself, “Am I missing anything?”, ” Is there something else going on?” It may be helpful to visualize the anatomy involved (e.g. abdominal pain), in order to assist you in your differential diagnosis. Beware of making premature decisions, or excessive procrastinating. Obtain appropriate, timely, consultations prn.
(11) History (finish): whenever and from whoever (patient ± significant others via the nurse prn, e.g. family, friends, EMTs, police, family physician), old charts prn if available (often invaluable/faxed from other institutions prn).
(A) Chief complaint(s) and history of present illness or injury ? new illness?, reason for seeking care at this time? (the patient may have another “agenda,” e.g. depression, substance abuse, cancer/heart-phobia). Keep in mind that the older generation frequently have memory deficits (one elderly gentleman told me that he had “craft disease,” which he described as “can’t remember a fxxxing thing.”)
(B) Functional inquiry, for example, fatigue (anemic?), fever, chills, rigors (pneumonia/pyelonephritis?), malaise, night sweats (TB?), heat or cold intolerance (hyper/hypo-thyroid?), myalgia, pain (where?, what hurts?), anorexia, polyphagia (diabetes?), weight change, insomnia (depressed?), nervousness, agitation, anger, depression, suicidal preoccupation? ? “Are you a danger to yourself or others?” (record the patient’s response on the chart) ? suicide note?, method contemplated?
Headache(s) (new? meningitis?, brain tumor?, warning leaks?), vision (detached retina?/vascular occlusion?), diplopia (myasthenia gravis?), ocular pain (iritis?, glaucoma?), hearing loss (sudden?, idiopathic?), tinnitus (acoustic neuroma?, Menière’s disease?, ASA toxicity?), dizziness (cardiac arrhythmia?), vertigo ± nausea (labyrhinitis?), nasal obstruction and discharge (purulent?, sinusitis?), epistaxis (on ASA?), mouth sores (neoplastic?), teeth, bleeding gums (bleeding disorder?), pain or swelling of face or neck (infection?, neoplasm?), sore throat(s) (recurrent tonsillitis?), odynophagia (epiglottitis?), dysphagia (ca of esophagus?), hoarseness (ca of larynx?), difficulty with breathing, snoring (sleep apnea?, pickwickian syndrome?).
Cough (smoker?, aspirated foreign body?), sputum (purulent?), hemoptysis (group A strep. infection?, cancer?), wheezing (asthma? and/or toxic exposure?), dyspnea (e.g. exertional, paroxysmal nocturnal, orthopnea, or at rest); chest pain (visceral?, somatic?, with radiation?, related to exercise?, cold?, meals?, stress?, or coitus?); palpations (PVC’s?), intermittent claudication (PVD?), pretibial edema (CHF?); breast lumps or discomfort (mammogram?), nipple discharge (ductal ca?).
Thirst (infants/ decreased diaper change/ dampness?), heartburn (IHD?/Ca?), antacid* use?, abdominal pain or discomfort (location? e.g. mid-epigastrium/Ca of pancreas?), nausea, vomiting (fever?, others also ill?, neurological symptoms/signs?, vector? e.g. seafood); hematemesis (on NSAIDs?), jaundice (hepatitis?, neoplasm?), bowel function (Ca of colon?), diarrhea, melena (on iron tabs?), hematochezia, rectal bleeding (Ca of rectum?), rectal problems, groin discomfort/hernias, (“pigging out” on fresh beets, which contains the food pigment anthrocycan, may result in simulated hematochezia/ hematuria. Blueberries can result in pseudomelena/liquid tylenol in vomitus may be reported as blood by the patient).
Dysuria/urgency/frequency (UTI?), polyuria/polydipsia (diabetes mellitus/insipidus?), nocturia (prostatic Ca?), hematuria (bladder/renal neoplasm?, UTI?), perineal lesions (STD?, cancer?), urethral discharge (STD?), testicular pain/discomfort or lumps (cancer?, torsion?, epididymitis?), L.M.P.? (BCP?), menstrual problems (e.g. secondary dysmenorrhea, endometriosis?), pregnancy (ectopic?) and menopausal problems, vaginal discharge (Ca of cervix?), dyspareunia (pelvic pathology?/endometriosis?).
Joint, back and skin problems (e.g. rash?, easy bruising?), lumps anywhere?
Problems with memory, thinking, speech, movement, gait (Guillian-Barré syndrome?), sensation; syncope? (while standing? or recumbent?, with effort/exercise?, orthostatic hypotension?, vasovagal?, posttussive or postmicturition?, obstructive cardiomyopathy?); drop attacks? (with no change in mental status/posterior circulation TIA?).
(C) Past history and current health status ? old charts (ask the examiner: “what do the old charts tell me?”) ? past and pre-existing problems ? medical, surgical (including OB & GYN), psychiatric; e.g. diabetes?, hypertension?, IHD?, hyperlipidemia?, seizures?, surgeries?, pacemaker?, artificial heart valves?, splenectomy?, previous blood transfusions?, hepatitis B+/C+?, HIV+? Past history of psychological, physical, and/or sexual abuse? (patients with a history of dysfunctional behaviour may have a higher incidence of being a victim of past or present abuse ? opening line e.g. “What was your childhood like?”).
(D) Personal history: allergies, medications including contraceptives, topicals, transdermal patches, inhalers, aerosols/home O2, and over the counter meds (e.g. NSAIDs, megavitamens), ± recent changes, ± compliance (takes less or more than the recommended dosage (r) “we all have trouble remembering to take our medications, how often do you forget?”). Inquire about substance abuse, e.g. nicotine, excessive alcohol, “drugs,” e.g. cocaine, excessive caffeine (anxiety?, hypokalemia?). Remember to ask about exposure to second hand cigarette smoke (e.g. asthmatic child/adult and/or patients with, for example, frequent sinusitis and/or chest infections). Stress the importance of a smoke free environment.
Other: recent foreign travel (e.g. malaria); occupation (e.g. coal miner), pets/animal exposure (e.g. parakeets/psittacosis), martial status (e.g. recently divorced), socially isolated?, financial or family problems?, regular adequate exercise?
Make the appropriate allowances for a patient’s cultural differences prn. Do not pass up the opportunity to briefly* counsel patients on their life-style or substance abuse, when they may be very vulnerable to your suggestions (you may even precipitate a change in their behaviour!†). I often tell patients about a friend of mine who, “out of the blue,” quit smoking (1-2 packs/day), and drinking (20-40 oz./rum/day), one Monday morning, now some twenty years ago (without AA, nicotine patches, valium(r), or even a physician visit; said he hadn’t planned to quit that day, said it was because he woke up that morning with such a bad taste in his mouth; his actual description was much more “graphic in detail”).
In addition, when appropriate, discuss accident/injury prevention with the patient, e.g. defensive driving?, seat belt use?, motorcycle/bicycle helmet use?, workplace safety/protective gear/safe work habits?
(E) Family history e.g. coronary artery disease in the relatively young (e.g. 40’s). Familial hyperlipidemia?, other familial disorders?
(12) Physical exam (secondary survey and additional investigations and procedures): Tell the examiner/patient you are going to do a complete physical examination: inspection first, e.g. what do I see when I look at etc.?
Remember that a careful physical examination (not necessarily academically detailed), and judicious investigations/consultations, may turn up something that you did not expect to find. Some examples are: glaucoma, mild Bell’s palsy, carotid artery stenosis, CNS neoplasm, subcutaneous emphysema, pericardial rub, mediastinal crunch, myocardial infarction, atypical pneumonia, pancreatitis, mild jaundice, appendicitis, pyelonephritis, incarcerated hernia (strangulated?), torsion of the testicle, ectopic pregnancy, abdominal aortic aneurysm, cancer of the skin/oral cavity/larynx/breast/lung/kidney/colon/bladder/ovary/uterus/cervix/rectum, diabetes mellitus, anemia, leukemia, renal failure, hypokalemia, hyponatremia, poisonings.
General description, vital signs and skin: awake?, alert? appears acutely or chronically ill?, toxic?, distressed?, diaphoretic?, (patient’s hand placement?, e.g. gallbladder area), SOB?, pale?, cyanosed? (peripheral or central cyanosis?, supraclavicular cyanosis/pericardial tamponade?), jaundiced?, anxious?, agitated?, tremulous?, appears hostile or angry?, looks depressed?, apparent age?, approximate height and weight?, nutrition?, hydration? rash?, erythroderma?, exfoliation?, petechiae?, purpura? (palpable?, nonpalpable?, nonblanching?, +hematuria?); wounds?, lacerations?, bites?, linear abrasions and contusions? (assault?), needle tracks?, skin lesions (undiagnosed neoplasm?, e.g. melanoma?*, refer for adequate excision/biopsy prn), decubitus ulcers?, cellulitis?, burns? ? 100% O2?, copious ringers?, prophylactic intubation?, escharotomy?, toxic combustion gases? e.g. carbon monoxide, cyanide, phosgene, (be liberal about ordering carboxyhemoglobin levels).
HEENT: inspect and palpate the scalp, the cranium, and the face; auscultate the head, the eyes and the neck prn, transillumination prn, x-rays?, CT scan?, MRI?, arteriography?  Eyes: ptosis?, pupils, visual acuity (including visual fields), eye movements, nystagmus (horizontal?, vertical?, rotary?), lids, conjunctiva, sclera, cornea (contact lens?), anterior and posterior chambers, retina (subhyaloid hemorrhage?), macula, disc, bruits, slit lamp exam prn, tonometry prn (with a weight of 5.5grams, a reading of > 4 represents a normal intraocular pressure of 20mmHg or less; glaucoma?, steamy cornea?, marble hard eye?), fluorescein staining of the cornea prn (caution: contact lenses will take up fluorescein), x-rays prn (intraocular foreign body?), eye patch prn (± antibiotic ung?), eye shield prn.
Caution: ocular procedures (e.g. removal of a corneal foreign body), may occasionally precipitate a vasovagal reaction.
Remember that vision is the vital sign of the eye.
Ears: external ear (hematoma?), TM (hemotympanum?, CSF leak? ? basilar skull fracture?), hearing.
? Beware of perichondritis, malignant otitis externa (diabetic?, immunocompromised?), acute tympanic perforation with vertigo and/or complete hearing loss, unilateral serous otitis (pharyngeal neoplasm?), mastoiditis, cholesteatoma, Menière’s disease and acoustic neuroma.
Nose: general appearance (fracture?), patency, foreign body? (e.g. toddler), septum (hematoma?), tumor?, CSF leak?, purulent discharge? (acute sinusitis?), epistaxis? (nasal cautery and/or nasal packing/Epistat(r) prn), nasal flaring in infants (respir. distress?). Note: titrate the amount of saline injected into the Epistat(r) balloons with the nasal bleeding and the patient’s discomfort. You may have to give several small injections of 1-2mL of saline, allowing the patient a “breather” in between saline injections. (I have never yet had to, or been able to, completely fill the Epistat(r) balloons. A very useful device, especially at 0400* hours!) Oral cavity: breath odor (occasionally helpful, e.g. DKA, tonsillitis), mucosa, teeth, tongue, pharyngeal tonsils/adenoids enlarged?/infected?/throat culture?, intraoral laceration from unwitnessed seizure?, undiagnosed neoplasm?
Neck: stridor? (impending complete upper airway obstruction?), voice (hoarse?, cancer?) , thyroid (scar?), movement (cervical precautions prn) and posture (nuchal rigidity?), JVP (CHF?), lymph nodes (infection?, lymphoma?, metastatic?), larynx (fracture?), trachea (midline?), carotids (bruits?), subcutaneous emphysema?, injuries?.
Chest:  Inspection ? dyspnea?, audible wheeze?, respirations (tachypnea?), use of accessory muscles, indrawing, asymmetry, grunting (infants), injuries.
Palpation – percussion ? point?/tenderness? (costochondritis?, #rib*), dullness, tactile fremitus.
Auscultation ? air entry?, rales, rhonchi, rubs (pleurisy?, pulmonary embolism?, pericardial rub?, or mediastinal crunch?), whispered pectoriloquy, (basal rales cleared by coughing?).
In addition: pulse oximetry prn, PEFR prn, arterial blood gases prn, chest x-ray prn (portable? + expiratory film?), FEV1 prn, FVC prn, thoracocentesis prn, bronchoscopic prn, ventilation and perfusion scan prn, pulmonary angiogram prn.
It may be useful not to take a smoking history until immediately after listening to the typical smokers’ chest ? “How much do you smoke?” “A pack a day.” “Maybe your chest is trying to tell you something.” ? the patient usually nods in agreement  ? discussion ? “In other words, I should stop smoking.” Keep in mind that smoking is still public enemy number two (second of course, to man’s inhumanity to man, e.g. the snipers of Sarajevo†). Is the patient being admitted? ? try a written “No Smoking” order.
Breasts: general appearance, skin (“orange peeling” sign?, retraction?), nipples
(discharge?, ductal Ca?), lumps (cancer?, mastitis-abscess?), axillary/ cervical lymphadenopathy?, aspiration of breast cyst prn, mammogram prn, biopsy prn.
Cardiovascular System: Inspection ? distended neck veins?, JVP, precordial heave.
Palpation ? apex, thrill, B/p bilateral, peripheral pulses and edema, capillary refill (< 2 seconds?).
Auscultation (r) rhythm, rate, murmurs, clicks, snaps, pericardial friction rubs (pericarditis?), and mediastinal crunch (pneumomediastinum?); bruits.
In addition: central lines prn ? CVP prn (normal = 5-10cm H2O), Swan-Ganz cathader prn (pcwp normal = 10mmHg), cardiac index prn, arterial lines prn, doppler prn, angiography prn, CT scan prn, echocardiogram prn, holter monitoring prn, stress EKG prn, cardiac cathaderization prn, angioplasty prn, bypass prn, intraaortic balloon pump prn.
Abdomen and Rectum: Inspection ? distension?, surgical scars? (splenectomy?), mass? (pulsating?), hernias?, peristaltic movements?
Auscultation ? bowel sounds (normal?, absent?, ileus?); bruits.
Percussion ? tenderness? (localized by coughing?), liver, spleen, shifting dullness? (ascites?).
Palpation ? tenderness? (flank?/renal?), peritoneal irritation? (involuntary rectus spasm?, board-like rigidity?), mass?, pulsating? abdominal aneurysm?, hernias?, liver, spleen, kidneys.
Rectal (bimanual prn)   ? fissures?, fistula?, herpes?, condyloma?, hemorrhoids?, anal sensation and sphincter tone, fecal impaction?, F.B.?, tumor?, prostate, abscess? (e.g. ischio-rectal), pelvic tenderness?, blood? (hematochezia?, melena?/occult bleeding?), rectal/stool smears/cultures (and ova/parasites) prn, pelvic fracture? (careful rectal exam).
In addition: obturator/psoas/heel tapping signs (appendicitis?, diverticulitis?, PID?), Murphy sign’s (GB disease?), pelvic exam prn, serial abdominal girth prn, abdominal series prn (need an upright chest or a left lateral decubitus x-ray following 5-10 minutes of positioning prn in order to demonstrate free air), ultrasound prn, proctoscopic prn, sigmoidoscopic prn, gastroscopic prn (endoscopic sclerotherapy/coagulation?, e.g. esophageal varices; inject site of bleeding gastric/duodenal ulcer with adrenaline?), water soluble contrast UGI and/or barium enema prn, gastric lavage prn (e.g. poisoning, UGI hemorrhage {bloody aspirate clears?}
(r) intubate first prn {e.g. tricyclic overdose with (LOC} (r) trendelenburg and left side position ? use a Ewald tube, adult size = 36 – 40, children = ± 18 – 36 F); peritoneal lavage prn and/or CT scan prn (for peritoneal lavage use ringers 20cc/kg to 1 litre ? ng, foley and abdominal series 1st, old abdominal surgical scars?); appropriate antibiotics prn, Blakemore tube prn, colonoscopic prn, nuclear scans prn, retrograde cholangiopancreatography prn, liver biopsy prn.
? for example, rupturing abdominal. aneurysm, GI hemorrhage, ectopic pregnancy, perforated viscus (including esophagus), peritonitis, acute mesenteric occlusion (disproportional pain), toxic megacolon, peptic ulcer (helicobacter pylori infection?), gastritis, esophagitis (xylocaine/antacid po?), cholecystitis (hemorrhaging hepatic adenoma?), hepatitis, pancreatitis, appendicitis (only ruled out with time and reassessments including rectal exam prn; left shift WBC’s?, ultrasound?, mesenteric adenitis?, Mettelschmerz?, Meckel’s diverticulum?); diverticulitis, inflammatory bowel disease (irritable bowel syndrome?), sigmoid volvulus (distended sigmoid extends to RUQ), or cecal volvulus (distended cecum extends to LUQ), ischemic colitis, incarcerated/strangulated? hernia, bowel obstruction, renal calculus? (complete ureteral obstruction?), UTI?, trauma (e.g. ruptured spleen, lacerated liver, retroperitoneal hemorrhage {fractured pelvis?}, pancreatic tear, bowel perforation, kidney/bladder rupture); pyloric stenosis (infant), intussusception (child ± 1 year, RUQ mass?), midgut-volvulus (child ± 1 year). Also, intrathoracic disease (e.g. pneumonia, acute inferior MI), diabetic ketoacidosis (± intraabd. pathology), sickle cell crises and others (e.g. porphyria/porphyrinuria? ± neurological manifestations?), may present with abdominal pain.
Remember that: (1) the patient may temporarily feel better when the appendix perforates, (2) abdominal pain sometimes turns out to be a result of constipation often promptly “cured” by a fleet enema (more frequent in children?), (3) any middle-aged/elderly patient with abdominal/back pain should have an abdominal aortic aneurysm ruled out (it may or may not be palpable or pulsatile, ultrasound?, CT scan?). Beware of attributing the pain of a leaking abdominal aortic aneurysm to, for example, diverticulitis/appendicitis/UTI/renal calculus, or radicular pain (abdominal aortic aneurysms may also present with weakness/syncope/intermittent or sustained hypotension with minimal or no pain, a “great imitator”), and (4) X-ray confirmation is required to demonstrate that a radiopaque foreign body (e.g. a coin) has passed into the child’s stomach. Beware of button batteries that lodge in the esophagus.
In addition, be careful to distinguish between uncomplicated and complicated gallbladder disease, for example, simple biliary colic, cholecystitis requiring antibiotics, concomitant pancreatitis, perforated gallbladder, cholangitis (life threatening).
Genitourinary System: examine the genitalia (beware of undiagnosed gynecological cancers/testicular tumors and testicular torsion); gonorrhea, chlamydia, and herpes cultures prn (plus a gram stain for gonorrhea ± other smears and cultures etc. prn ? e.g. “hanging drop”, darkfield microscopy ± VDRL, PAP smear; HIV antibodies?); urinalysis and culture prn, KUB prn, IVP prn (in head injury patients do CT scan 1st); continuous bladder irrigation (CBI) prn; urethrogram prn (suprapubic drainage of a distended bladder with a temporary intracath prn); cystogram prn, cystoscopic and a retrograde pyelogram prn, CT scan prn, arteriography prn, dialysis prn, renal biopsy prn.
Pregnancy and more Gynecology: prenatal record available? (the patient may have a copy), serum pregnancy test prn (ectopic pregnancy?), ultrasound prn (transvaginal?), culdocentesis prn, D and C prn, gynecological biopsies prn, laparoscopic prn; fetal monitoring prn (external or scalp), and monitor strip prn, fetal scalp blood gases prn, immediate obstetrical delivery prn (double setup exam in the OR?, cervical dilation?, station?) ? vaginal delivery or c-section prn. Avoid doing a vaginal or rectal exam in the ER on patients with third trimester p.v. bleeding (r) ( ABC’s, ultrasound, consult obstetrics. Rh negative? (r) WinRho SD(r) 120-300+?g prn.
On occasion, a patient may arrive at the ER, in labor, delivery imminent, who at triage complains of abdominal pain, but makes no mention of or denies pregnancy (may also present with headache/seizure/coma/hypertension/other features of preeclampsia/ eclampsia).
Beware of an ectopic pregnancy, a ruptured hemorrhaging ovarian cyst, a ruptured tubo-ovarian abscess, and vaginal tears. Remember that any female capable of becoming pregnant (including those with a history of tubal ligation*), with lower abdominal pain (especially unilateral; ± p.v. bleeding; endometriosis?), should have a serum pregnancy test done (ICON), and if positive, the diagnosis is an ectopic pregnancy until proved conclusively otherwise. In normal pregnancies the serum beta-HCG levels should double every second day.
Lymphatic/hematologic ? epitrochlear, cervical, axillary, and inguinal lymph nodes (lymphoma?); spleen; bone marrow aspiration prn, lymph node biopsy prn. Anemia? (r) acute/chronic blood loss? (e.g. ca of the colon), or decreased production (e.g. pernicious anemia), or increased destruction (e.g. hemolytic anemia). Serum iron and/or  B12 and folate levels?, coombs test?
Back, pelvis and extremities: ? Inspection and range of movement of the back, tenderness?, log roll prn (exit wound?); if an injury is suspected, restrain on a backboard until a fracture and/or neurological injury is ruled out, CT scan?, MRI?
? Pelvis ? fracture? ? hemorrhagic shock?, associated inquiries?, e.g. ruptured bladder.
? Extremities: injuries?, needle tracks?, lesions?, range of movement?, radicular pain?, varicose veins?, DVT?, peripheral vascular disease?, popliteal aneurysm?, crush injury? (compartment syndrome?), neurovascular-tendon status?, arterial injury? (pulse oximetry?).
? Joints ? overlying erythema?, deformity?, warm to touch?, effusion?, hemarthrosis? (hemophilia?), crepitus?, associated muscle atrophy?, movement. Polyarticular involvement? ? fever?, lethargy?, anorexia?, other systems involved?, e.g. skin, eyes, heart, GI, renal, lymphatic/ hematologic, CNS.
Beware of the septic joint, osteomyelitis, and osteogenic sarcoma.
? Fractures (compartment syndrome?) ? open?, gross deformity?, point tenderness?, bony crepitus?, instability? ? splint fractures and reduce dislocations with pre and post neurovascular status assessment.
(r) In addition: x-rays prn, myelogram prn, CT scan prn, MRI prn, arthrocentesis* prn/arthroscopic prn ? irrigate joint prn (septic joint?), arthrogram prn (complete rotator cuff tear? ? persistent limited movement after local lidocaine injection?), ESR/ ANA/ Rh factor prn, STD/chlamydia?, streptozyme(r)?, sickeldex(r)?, bone scans prn, venogram/ultrasound prn, doppler prn, arteriography prn.
Central Nervous System:  Mental status ? alert?, orientated?, cooperative?, mood, speech, thought, insight.
(r) infant ? playfulness?
Cranial nerves ? smell, visual acuity and fields, eye movement (nystagmus?), pupils (reactive?, use magnification prn), corneal reflexes, papilledema? (bulging fontanelle in infants?), facial sensation, facial movements (lower facial paralysis only in upper motor neuron disease), hearing, vestibular tests prn, gag reflex?
Motor ? neck, arms, trunk, legs ? involuntary movements? (tremulous?, asterixis?), wasting?, atophy? ? power, tone, coordination, gait (Romberg’s sign?, cerebellar or dorsal column ataxia?).
Reflexes ? deep tendon reflexes/plantar reflex/symmetrical?, clonus?, grasp and sucking reflexes?.
Sensory ? stimulate above and below the foramen magnum; pain and temperature (anterior cord), vibration and position (posterior cord), touch, two point discrimination, stereognosis (cortex); ipsilateral and contralateral straight leg raising, nuchal rigidity?, Kernig’s or Brudzinski’s signs.
In addition: ??Infant ? inconsolable crying or crying when picked up by the parents ? meningitis?
??Trauma ? CSF leaks? (clear fluid draining from the nose or ears?, dipstix positive for glucose?), CT scan?, MRI?
? Uncal syndrome ? ataxic respirations, ipsilateral pupillary dilation (oculomotor nerve) and contralateral hemiparesis ? epidural hemorrhage?
? Pinpoint pupils ? narcotic, clonidine or phenothiazine overdose?, cholinergics?, miotic eye gtts?, pontine hemorrhage (ocular bobbing?) or cerebellar hemorrhage?, (miosis reversed with narcan(r)? ? acute opiate withdrawal?, restrain patient first?); stat CT scan prn, refer neurosurgery prn (cerebellar hemorrhage needs immediate neurosurgical intervention).
? Pupil reactivity is retained in toxic/infectious/metabolic coma.
? Drop attacks (no LOC) ? posterior circulation TIA?
? Sacral sparing (incomplete cord lesion).
? Spinal shock ? hypotension, priapism.
? Locked-in syndrome (destruction of ventral pontine tracts).
(r) Beware of bizarre neurological symptoms ± physical findings, e.g. warning CNS bleeds, brain tumors, TIA, multiple sclerosis (r) CT Scan?, MRI?, LP?, referral?
? X-rays ? special views?, e.g. flexion and extension views of the cervical spine (with a physician present; unstable ligamentous disruption?).  ? Lumbar puncture prn (with seizures, a decreased mental status, papilledema or focal signs do a CT scan first before deciding to proceed) ? repeat the L.P. in 6 hours?, L.P. contraindicated in bleeding disorders (DIC in progress?). If the possibility of bacterial meningitis crosses your mind then, unless contraindicated, you should go ahead and do a lumbar puncture (do blood cultures first and then I.V. antibiotics before or after the L.P., depending on the patient’s clinical status, err on the side of giving antibiotics, for example, adults/ceftriaxone 2g plus ampicillin 2g).
? Fundi ? spontaneous venous pulsations in the recumbent position ? no increase in intracranial pressure.
? Emergency myelogram prn (e.g. acute spinal cord compression from metastasis or central disk protrusion or abscess; focal back pain?, level?, urinary incontinence or retention?, CT scan?, MRI? (the “gold standard”), I.V. decadron(r)?, I.V. antibiotics?, radiation?, emergency surgery?).
? Emergency EEG prn (seizure arrest in status epilepticus real or apparent?; status psychomotor seizures?).
? Intracranial pressure monitoring prn, normal = 5-15mmHg.
(r) Third cranial nerve palsy (r) dilated pupil, eye deviated downwards and laterally (5 o’clock).
(r) Sixth cranial nerve palsy (r) eye deviated downwards and medially (7 o’clock).
(r) Sustained upwards/downwards gaze (r) brainstem/cerebral damage.
? Dermatomes, some examples: C6 – thumb (biceps reflex).
T10 – umbilicus.
L3 – anterior knee (knee reflex).
L5 – great toe.
S1 – lateral foot (ankle reflex).
? Nerve conduction studies prn.
(r) early pain control may significantly reduce the number of analgesics required later (neuroplasticity).
(13) Conclusion:
A) Review the diagnosis(es) and treatment with the consultant(s), the patient, the family, and the family doctor, e.g. “Please call the cardiologist.” Beware of consultant inertia. Ask the patient and the family if they have any questions, and give a realistic prognosis. For example (excerpt), “All heart attacks are serious.” “He is stable right now.” “I cannot give you any guarantee, but I expect him to do OK.” “The cardiologist will be able to tell you more over the next few days.” (Displaying the “cross your fingers” sign {(“so far, so good”}, may be at times an appropriate adjunct to relaying your “gut feelings” to the patient/family, e.g. epistaxis, threatened abortion).
(B) Disposition*
1) Admit ? to where? ? for example, to a standard bed†, a monitored step-down bed, the ICU, the burn unit, the alcohol and drug detoxification unit, or the psychiatric floor (involuntary admission?). The patient may be first sent directly to, for example, the operating room, the hyperbaric chamber, or the dialysis unit. Ideally, the attending physician should see the patient and write the admitting orders in the emergency department. However, for low risk patients, the practice of the ER physician writing the admission orders and the attending physician reassessing the patient “upstairs” at a later time, is both acceptable and realistic. The emergency room physician is responsible for the patient, until the patient is seen by the attending physician.
The mnemonic “Diet” (Diet, Investigations / consults, Exercise/activity and Treatment) is useful for writing observation/admission orders. Does the patient have any advance medical directives? e.g. end stage COPD/no intubation.
Remember: do not let a patient talk you into discharging them, when admission is clearly indicated. However, circumstances may necessitate some flexibility.
2) Transfer (via land, air, sea, to for example a trauma center) with adequate immobilization of the entire patient; the ambulance requires police assistance with traffic?; the simulated patient in a board examination is unlikely to be transferred. Air Transport: the volume of gas increases with a decrease in the barometric pressure (r) adjust prn, e.g. ET cuff; vent prn, e.g. ng or rectal tube.
Remember: (1) to ensure that continued active management of the patient occurs during transit, (2) to make mutually satisfactory arrangements for the patient transfer with the receiving hospital, (3) to phone an update on the patient’s condition upon the patient’s departure, or while in transit, (4) to provide nurse/physician escorts prn, and (5) to send copies of the medical, nursing and pertinent old charts, x-rays, Ekg’s, and lab reports with the patient. Expedite the patient transfer prn, beware of undue delays.
3) Observation in the emergency room* ? prolonged observation of the simulated oral examination patient is unlikely. When actual patients are being kept for overnight observation, it may be necessary to give the relatives or significant others “permission” to go home (relieve the guilt).
4) Discharge* ? instructions† , prescriptions, and time off work slips‡ (the patient needs to be accompanied home by a supportive relative or significant other?) ? follow-up ? family doctor, social services (requires home support?, needs immediate placement in a women’s/children’s shelter?); public health and other reporting (e.g. child and elder abuse ? usually admitted; motor vehicle registry for review of driver’s license, e.g. alcoholism). Transportation home? ? present fitness to drive a motor vehicle? (e.g. alcohol, drugs ± iatrogenic?, head injury) ? also applies to patients who leave against medical advice. Remember to invite the patient to return if necessary.
5) Patient wishes to leave against medical advice ? Is the patient competent to refuse treatment?, e.g. drugs, alcohol, psychosis, mentally handicapped, head injury ? document your substantiating findings, e.g. mental status ? have the patient sign the refusal of treatment form if possible. Do not let an incompetent patient with a significant problem leave the ER§ (easier said than done). Remember to give the patient an invitation to return anytime, and a “welcome back” if they do return (“He’s back!!!” (r) sometimes a test of your cordiality). In addition, you should attempt to provide optimal outpatient management, e.g. antibiotics for pneumonitis. For the board oral examination purposes, the simulated patient will stay if the importance is explained to them.
6) Patient expires (all simulated patients survive) ? try to have the family prewarned, even if only for a few moments beforehand ? grief counseling, coroner’s case?, autopsy?, organ donations? Avoid “breaking the news” over the telephone, if at all possible, without being untruthful.
During grief counseling, try to accomplish the following (as appropriate):
(1) Relieve the family and significant others of any blame.
(2) Review the diagnosis and treatment, and stress that everything that should have been done, was in fact done.
(3) Clear up any misconceptions or misunderstandings (sometimes not possible). For example, a patient with lung cancer who has just expired as a result of a sudden, massive hemoptysis (r) angry wife “his doctor said he would live for one or two years” (r) fact and fate related discussion.
(4) Advise the relatives and significant others not to hold their feelings back,* and avoid the “stiff upper lip.”
(5) Advise delaying any important decisions (e.g. selling the family home), for a considerable time (e.g. 6-12+ months).
(6) Give the relatives the opportunity to view the body of the deceased if they so wish (after the resuscitation room has been “cleaned up”).
(7) Refer the “victims” to their family physician for follow-up, and to support groups prn, for example, the parents of a SIDS patient. Remember that the grief reaction doesn’t always resolve itself, and may result in long term sequelae, e.g. depression, divorce, alcohol abuse.
In addition, stress the importance of not interfering with the grief reaction with sedatives. However, it may be comforting for them to have a few tablets on hand just in case they feel they really need them. If so, give placebo amounts (e.g. ativan(r) 1mg tabs 5), so as not to interfere significantly with the grief reaction. Remind the family, friends, and significant others that they, not medications, will provide the most important comfort to each other.
Remember the grief reaction can include anger. If the family becomes angry and hostile, stay calm, and try not to take it personal.
Other “victims”, for example, an operator of a motor vehicle which has just hit and killed a pedestrian, may also need early psychological intervention. As well, the ER staff after a prolonged unsuccessful resuscitation attempt may need “debriefing” (e.g. a pediatric drowning).
Last but not least: when patients are leaving your care (admitted, discharged, transferred, shift change), don’t forget to say goodbye (and good luck!).
Please note: most of the simulated patients will require admission. Following the case the examiner will usually ask you a few straight forward questions (know your pathophysiology and therapeutics).
°The Short form of the Management Guide
(1) The initial description of the patient, and the vital signs as supplied by the examiner (are the vital signs complete? (r) level of consciousness, P, R, B/p, and body temperature).
(2) Ask: “What does the patient look like?” (and for any missing vital signs).
? “What does the nurses’ triage and admission notes tell me?”
(3 or 4) Order the initial stabilization by the nurses, and/or the EMTs, e.g. CPR, O2, monitor, pulse oximetry, I.V.(s) etc., e.g. bloodwork, drug allergies?, present meds?, old charts?, restrain prn, search prn, undress. Have the patient’s premises searched prn, by the EMTs/police/significant others (suicide note?, drugs?, poisons?).
(3 or 4) Introduce yourself to the patient, and take an initial history.
? use universal precautions, and don’t forget to wash your hands between patients (easy to overlook!).
(5) Airway/cervical spine/cord: thiamine prn, dextrose prn, narcan(r) prn(± flumazenil?).
(6) Breathing.
(7) Circulation, and finish the primary survey (an abbreviated complete assessment).
(8) Foley catheter drainage prn (urethra ok?).
(9) Urinalysis prn.
(10) Nasogastric tube prn (cribiform plate ok?).
(11) Mast prn (usually applied during the ABC’s).
(12) Gram stains and cultures prn, ± other stains prn.
(13) Tetanus toxoid prn, and tetanus immune globulin prn.
(14) Antibiotics prn (often I.V., cultures first prn).
(15) Analgesics prn (early prn, often I.V.).
(16) Flow sheets prn ? assessments, investigations, and therapeutic measures.
(17) Frequent vital signs, and patient reassurance prn.
(18) Finish the history (present, past, personal, family).
(19) Physical exam (secondary survey), and additional investigations, procedures, and therapeutic measures.
(20) Diagnosis(es), treatment, and the disposition of the patient (e.g. ICU).
Significant Reminders
? These are numbered, indexed, and loosely arranged by organ systems or specialty, and are not necessarily related to the preceding or subsequent significant reminder. This makes it necessary for the reader to “change gears” frequently, much like when working in the ER, where patients present in an unpredictable pattern.
(r) “Listen up” (including me): remember to pause, visualize, and reflect, while reading through the significant reminders.
°I. CPR – Electolytes – Acid Base
(1) Basic Life Support
(A) The “Chain of Survival”  (r) early access, early CPR, early defibrillation, and early ACLS.
(B) CPR:
(1) Establish unresponsiveness.
(2) Obtain assistance (help!); activate the EMS.
(3) Properly position the patient.
(4) Open the airway.
(5) Establish breathlessness.
(6) Ventilate the patient (airway obstructed?, Heimlich manoeuvre?).
(7) Establish the presence or absence of a pulse (carotid).
(8) Precordial thump?
(r) perform closed-chest compressions prn: depth, 0.5 to 1 inch (infant), 1 to 1.5 inches (child), or 1.5 to 2 inches (adult), times 80-100+/minute.
Compressions/Ventilation ratios = 15:2 or 5:1 for one or two rescuers, respectively, for adults. 5:1 for both situations in infants and children. Compression rates = 80-100 for children and adults, 100+ for infants.
(2) Cardiac arrest/Ventricular tachycardia Remember that not all cardiac arrhythmias/arrests are due to coronary artery disease. Specific management in addition to CPR is required. For example, consider the following as appropriate (see index prn): 1. Drug overdoses, e.g. tricyclics (bicarb prn), digoxin (bicarb prn, MgSO4 prn, dilantin(r) prn, digibind(r) prn), calcium blockers (calcium gluconate prn, glucagon prn), beta blockers (glucagon prn).
2. Smoke inhalation/carbon monoxide and/or cyanide poisoning?/from burning synthetic furniture materials? ? 100% O2/sodium thiosulfate 25% 1mL/kg to 50mL prn/converts cyanide to nontoxic thiocyanate/early presumptive therapy? Hyperbaric O2 chamber prn.
3. Hypothermia (core rewarming prn, bretylium prn).
4. Tension pneumothorax/cardiac tamponade (needle decompression prn).
5. Others, e.g. shock (ringers prn), anoxia (ventilate prn), acidosis (bicarb prn), hyperkalemia (bicarb prn), pulmonary embolism (100% O2, heparin, thrombolytics?, surgery?), trauma (thoracotomy?).
(A) Ventricular fibrillation or pulseless ventricular tachycardia ( Precordial thump?, BCLS, ACLS, defibrillate immediately with 200J, and repeat X 2 prn (200J, 360J), then prn*. Epinephrine prn, lidocaine prn, consider bicarbonate, bretylium prn, procainamide prn, amiodarone prn, consider MgSO4.
* hypothermic cardiac arrest?, see also #(2), p.200.
(B) Ventricular tachycardia with a pulse ? Precordial thump?, BCLS, ACLS, lidocaine prn, procainamide prn, consider bretylium, cardioversion prn (usually synchronized, 50+J ± sedation prn; cardiovert unstable patients prn, e.g. ischemic chest pain, CHF, hypotension, decreased cerebral status).
Accelerated idioventricular rhythm (slow ventricular tachycardia) usually requires no treatment.  (r) Beware of iatrogenic ventricular tachycardia secondary to, for example, quinidine (hyperkalemia?), or type 1C antiarrhythmics, e.g. rythmol(r). See also #(12), p.91.
(C) Asystolic cardiac arrest ? precordial thump?, BCLS, ACLS, epinephrine prn, atropine prn, if in doubt defibrillate prn (fine ventricular fibrillation?), consider bicarbonate, consider immediate transcutaneous pacing. Hypothermic cardiac arrest?, see also #(2), p.200.
(D) Electromechanical dissociation (EMD) ? also referred to as pulseless electrical activity (PEA).
? BCLS, ACLS, epinephrine prn, rule out correctable conditions, e.g. tension pneumothorax (needle chest prn), pericardial tamponade (pericardiocentesis prn), hypovolemia (ringers prn), hypothermia (core warming prn); consider bicarbonate, consider transcutaneous pacing.
(3) Racemic epinephrine aerosol ? 0.5ml 2.25% in 4.5ml saline (e.g. acute laryngeal edema, croup, epiglottitis, bronchospasm). Beware of cardiac arrhythmias, and rebound stridor.
(r) I am starting to use a little more racemic epinephrine aerosols, versus ventolin(r) aerosols, for bronchospasm, especially when it is severe, and I am thinking that I may have to intubate this patient, or when it is part of an allergic complex, e.g. urticaria, angioedema, anaphylaxis. Nevertheless, for bronchospasm, I still use ventolin(r) aerosols the vast majority of the time (an exceptionally safe drug).
(4) Venous cutdowns: Proximal saphenous vein ? 5cm below the junction of the medial third of the inguinal ligament.
Femoral vein ? just medial to the femoral artery.  Distal saphenous vein ? just anterior to the medial malleolus.  Basilic vein ? 2fb above and medial to the olecranon.
(5) Central Venous Pressure ? zero reference point at 1-3cm. anterior to the midaxillary line at the 4th intercostal junction. Normal CVP = 5-10cm H2O. Do not use the cephalic vein for central lines, because of the high failure rate of insertion due to its tortuous course.
(6) pH pH decreased by 0.10 ? bicarb decreased 5meq, or pCO2 increased 10mmHg (r) K+ increased 0.5meq ? O2 availability increased 10% ? ionized calcium increased 0.10meq, and vice versa for pH increase of 0.10.
(7) Anion gap (r)(r) Na – (Cl + CO2 content) = 12 (normal) (8) Metabolic Acidosis  (A) Anion gap metabolic acidosis (an acute process) ? mnemonic mudsleep = methanol, uremia, diabetic ketoacidosis, salicylates, lactic acid, ethanol, ethylene glycol, paraldehyde, and cyanide. In addition, carbon monoxide, iron, or isoniazid poisoning, and any situation that results in hypotension, seizures, or cellular dysfunction.
(B) Non-anion gap metabolic acidosis (a more chronic process) ? e.g. diarrhea?, cholestyramine?, hyperalimentation?, renal insufficiency?, pyelonephritis?, diamox(r)?, obstructive uropathy?, renal tubular acidosis?
(9) MAST ? tamponades bleeding, increased initial venous return, increased perivascular resistance, selective perfusion of the upper body, and stabilization of fractures. Pulmonary edema is an absolute contraindication, and beware of compartment syndromes with inflation times greater than two hours. Deflate MAST very cautiously! (little by little, abdomen first; in the OR?).
(10) Sodium bicarbonate  ??1meq/kg over 15-30 minutes to avoid paradoxical cerebral acidosis (may have to be given as a bolus in desperate situations, e.g. cardiac arrest, critical hyperkalemia with bizarre looking Ekg complexes).
??repeat arterial blood gases prn.
Children ??dilute with equal amounts of sterile water.
(11) Metabolic alkalosis ? most commonly a result of excessive diuresis, or loss of gastric secretions, or massive transfusions. Chloride responsive alkalosis (urine Cl < 20meq/L), or chloride resistant alkalosis (may need large quantities of KCl).
? chloride deficit = 20% x wt.(kg) x (100 – serum chloride) ? give 1/2 of the chloride deficit over 8-12hrs ? give as NaCl/KCl (75:25), and with severe metabolic alkalosis add 0.1 N HCl (NaCl/KCl/HCl ? 50:25:25). See also #(17)(A), p. 82.
(12) Chronic respiratory acidosis (r) relatively normal pH.
? lower pCO2 by 5mmHg/hr.
(13) THIRTEEN Dead space normal = 2ml/kg.
Tidal volume normal = 10ml/kg.
Minute volume normal = 5-6 L/minute (100ml/kg).
Right to left shunting = lung perfused but not ventilated.
(14) Fluids and electrolytes (r) correct in this order : ? (1) shock/significant dehydration (e.g. boluses of ringers), (2) pH, (3) K+, (4) Ca and Mg, and (5) NaCl. Dehydration/pH/lytes may only be partially corrected initially, with complete correction over time in conjunction with the treatment of the underlying condition, e.g. diabetic ketoacidosis. See also #(17)(A), p.82.
? Remember to consider adverse drug reactions/interactions/toxicity, e.g. diuretics (( NaCl, ( K+), theophylline (( K+), digoxin (( K+), ACE inhibitors (( K+), SSRIs (( NaCl/SIADH).
(15) Daily water loss (approximate) ? urine = 1-1.5 liters, skin = 300mL, and lungs = 700 mL.
Severe thirst denotes a water loss of > 3% total body water.
(16) Osmolarity (r) 2 x Na + glucose/mmol/L + Bun/mmol/L = 275-295 mosm/L.
Osmolar gap normal ? 10 (actual minus calculated).
(17) Sodium (A) Hyponatremia ? dilution, loss (urine Na < 20meq/L), or SIADH (Ca of the lung?, taking a SSRI?) ? ABC’s, fluid restriction prn, 0.9-3% saline prn, lasix prn.
? too rapid a correction of serum sodium may result in cerebral edema, and permanent neurological damage. Remember the “idiogenic osmole” factor.
? initial correction prn of 6-8meq in the serum sodium over 3-4 hours, followed by a correction of ? 12meq/day. Remember that I.V. potassium also contributes to the osmolar load.
? 3% saline is reserved for severe symptomatic hyponatremia (e.g. seizures, 4mL/kg, caution!).
(B) Hypernatremia ? decreased water intake (e.g. coma), increased water loss (e.g. diarrhea, diabetes insipidus), increased sodium intake (e.g. I.V. sodium bicarbonate), or decreased sodium loss (e.g. renal disease).
? ABC’s, bolus ringers prn, 0.45% saline prn, ? diabetes insipidus prn, ? other electrolyte problems, e.g. hypokalemia.
? same correction precautions as for hyponatremia.
(18) Hypokalemia ? urine loss, for example, diuretics, diabetic ketoacidosis, alcohol abuse, theophylline toxicity, renal tubular acidosis, cushing’s disease, licorice toxicity; GI loss, for example, vomiting, diarrhea, villous adenoma.
? serum NaCl also decreased?
? ABC’s, adults 10-40mEq KCl/I.V./hr prn, and treat the underlying etiology (see above).
? 40meq KCl raises serum potassium by approximately 1 mEq.
? I frequently give a “bolus” of potassium po in addition to the intravenous route, e.g. micro-K, 4 capsules.
(19) Hyperkalemia  ? tall peaked T waves (in extreme cases may resemble the QRS).
? renal failure? ± diabetic ketoacidosis?, ACE inhibitors?, digitalis toxicity?, addison’s disease?, myoglobinuria?
Emergency ? (may be required before the electrolyte levels are available/ T wave changes).
??ABC’s ? Sodium bicarbonate 50-100meq I.V. over 15-30 minutes prn (if the patient is critical a bolus may be required). Children ? 1meq/kg.
??Calcium gluconate 10% 10-20ml I.V. in D5W over 15-30 minutes prn (not with digitalis toxicity). Children ? 0.2mL/kg.
??20 units insulin in 100ml of 50% dextrose I.V. over 1 hour prn. Children, ?: 1mL/kg 50% dextrose followed by regular insulin 0.1 unit/kg/I.V. (with renal failure/diabetic ketoacidosis, give a bolus of I.V. insulin {10 units adults, 0.1 units/kg children}, followed by an insulin drip, and of course no dextrose. See also Diabetic ketoacidosis (#(2), p. 149).
??Kayexalate and sorbitol, 15g of each qid po prn (adult dose).
??Kayexalate and sorbitol, 50g of each in 150ml H2O enema prn. Children, 1 g/kg of both in 50-150mL H2O enema prn.
??Lasix, 1mg/kg I.V. prn (adult/child dose).
??Dialysis prn.
(20) Hypocalcemia ? ABC’s, calcium gluconate 10% 1-10ml prn slowly I.V. (pediatric = 0.2ml/kg), and treat the underlying cause, e.g. pancreatitis.
Hypercalcemia ? ABC’s, saline boluses prn, K+ prn, MgSO4 prn, lasix prn, steroids prn, etidronate disodium prn, plicamycin prn, calcitonin prn, dialysis prn, and treat the underlying cause, e.g. bone metastasis, multiple myeloma, sarcoidosis, hyperthyroidism, hyperparathyroidism.
(21) Hypomagnesemia (r) for example, alcoholics, diabetics, diuretic therapy ? ABC’s, MgSO4 2-4+g I.V. prn over 30-60 minutes, or IM prn.
Hypermagnesemia, e.g. iatrogenic; ? ABC’s, I.V. fluids, calcium gluconate 10% 1-10ml prn slowly I.V., lasix prn, dialysis prn.
(22) Hypophosphatemia (r) for example, diabetic ketoacidosis ? ABC’s, KH2PO4, K2HPO4, and calcium prn.
Hyperphosphatemia  (r) ? ABC’s, regular insulin and 50% dextrose, aluminum hydroxide antacid, plus see the following.
(r) with renal failure (r) ? dialysis (r) without renal failure, ? saline, diamox(r) 500mg q6h I.V., calcium prn.
°II. Cardiac Arrhythmias & ACLS Drugs
(1st of 2 sections) (r) See also #(1) and #(2), pp.75-77, and Cardiology (second of two sections), p. 113.
(1) Cardiac rhythm ? PR interval = 0.12 – 0.20 seconds.
? QRS = 0.06 – 0.10 seconds.
? QT = 0.33 – 0.42 seconds.
(2) Bradycardias ? ABC’s, 100% O2 prn, atropine prn, dopamine prn, epinephrine prn (infants), isoproterenol prn, transcutaneous pacing prn, transvenous pacing prn, permanent pacing prn.
(3) Atrial flutter ? ABC’s, 100% O2 prn, synchronized cardioversion prn (25-50+J with sedation/general anesthesia prn), or I.V. digoxin or verapamil prn ? neither drug with WPW.
(4) Atrial fibrillation (r) myocardial ischemia?, hypokalemia?, mitral stenosis?, thyrotoxicosis?, alcohol abuse?
? ABC’s, 100% O2 prn, synchronized cardioversion prn (100-200 joules with sedation/general anesthesia prn) ? only in recent onset AF, or patients anticoagulated for 6 weeks.
??? I.V. digoxin or verapamil prn ? neither drug with WPW.
??AF with regular ventricular response ? digitalis toxicity?
? Untreated AF with slow ventricular response ? sick sinus syndrome?
??Inadequately digitalized AF patients may have a controlled ventricular response only at rest due to the vagal effects of digitalis.
??Atrial fibrillation of recent onset ? alternate therapy (personal communication with a cardiologist) ? stable patient, ? sotalol, if beta blockers contraindicated, ? rythmol(r) ? if not converted after 2-3 days ? ? synchronized cardioversion with sedation/general anesthesia prn; unstable patient, ? procainamide I.V. ? synchronized cardioversion prn with sedation/general anesthesia prn. Caution, both sotalol and rythmol(r) may be proarrhythmic. See #(13)(D), p.91, and #(16)(C), p.93.
(5) SVT (Supraventricular Tachycardia)
(A) SVT with digitalis toxicity ? ABC’s, 100% O2 prn, correct hypokalemia prn, I.V. lidocaine prn, MgSO4 1g I.V. prn, digitalis fab antibody fragments, no cardioversion. Hyperkalemia? ? ? fab fragments plus standard hyperkalemic therapy, except no calcium (see #(19), p.83).
(B) SVT without digitalis toxicity ? ABC’s, 100% O2 prn, increase vagal tone, verapamil 5mg I.V. (or adenosine 6mg I.V., repeat with 12mg prn), repeat verapamil prn, 5mg in 5-10 minutes (give calcium gluconate 10% 1-10ml slowly I.V. for significant verapamil induced hypotension prn), cardiovert unstable patients prn (synchronized, 25-50+J with sedation/general anesthesia prn). I have had a good experience with using verapamil, and it is still my drug of choice for uncomplicated SVT. If verapamil doesn’t work, use adenosine and vice versa. See also #(11), p.90, #(18), p.93, #(19), p.93.
(C) SVT with acute myocardial ischemia/infarction ? ABC’s, 100% O2, vagal manoeuvres, adenosine 6mg I.V. prn ? 12mg X 2 I.V. prn q 2minutes ? synchronized cardioversion prn, with sedation/general anesthesia prn. Adenosine is a better choice than verapamil in the unstable patient.
(6) SIX
(A) Torsade de pointes ? ABC’s, 100% O2, isoproterenol I.V. drip, and/or MgSO4 1-2g slowly I.V. ? 1-2g/hr prn, overdrive pacing prn, discontinue causative drug, e.g. quinidine, rythmol(r), hismanol(r), seldane(r). Children and young adults can also develop torsade de pointes as a result of an inherited long Q-T syndrome. Diagnosis, referral, and treatment with, for example, a beta blocker, following a warning syncope or seizure may prevent a future sudden death.
(B) Wide complex tachycardias ? as a ventricular tachycardia ? ? ABC’s, 100% O2, I.V. lidocaine, and/or I.V. procainamide, cardiovert unstable patients prn (usually synchronized, 25-50+J with sedation/general anesthesia prn). No verapamil or digoxin.
(7) Aberrant conduction Aberrant conduction (r) you may see a P(wave, a varying BBB, and a decreased ventricular rate with carotid massage, versus PVC’s ? fusion beats, a full postectopic pause, a constant coupling interval, and a QRS > 0.14
(8) Mobitz I (Wenckeback) ? nodal and transient (usually a narrow QRS complex).
? ? ABC’s, atropine 0.5 mg I.V. prn.
(A) Mobitz II  ? infranodal structural damage, which may progress to complete heart block (usually a wide QRS complex) (r) ? ABC’s, 100% O2 prn, presumptive/pacing prn.
(B) Complete heart block ? narrow QRS @ ± 50/minute ? nodal and usually transient ? ABC’s, 100% O2 prn, atropine prn, presumptive/pacing prn (transcutaneous pacing usually requires sedation).
? wide complex @ ? 40/minute ? permanent infranodal structural damage ? ABC’s, 100% O2, isoproterenol prn ? transcutaneous ? transvenous ? permanent pacing ? avoid isoproterenol with MI if possible.
(9) Electromechanical dissociation (EMD)  ? also known as pulseless electrical activity (PEA).
? rule out a tension pneumothorax, cardiac tamponade, hypovolemia, acidosis, hypoxemia, hyperkalemia, hypercalcemia, pulmonary embolism, and a ruptured ventricular wall or valve. For the management of EMD, see #(2)(D), p.77.
(10) Sick sinus syndrome ? intermittent brady and tachy arrhythmias ? holter monitoring prn.
? ABC’s, 100% O2 prn, ACLS drugs prn, and pacing prn.
(11) Preexcitation syndromes Bypass tracts (some examples) 1. Atrium to ventricle (WPW) ? short PR interval, plus a delta wave.
2. Atrium to bundle of His (LGL syndrome) ? short PR interval, no delta wave.
3. Bundle of His to ventricle (Mahaim fibres) ? normal PR interval, plus a delta wave.
Wolff-Parkinson-White syndrome (WPW)  may mimic a MI on the EKG ? the bypass tract may be hidden.
(r) WPW with wide complex tachycardia ± atrial fib or flutter ? treat like a ventricular tachycardia.
(r) ? ABC’s, 100% O2, lidocaine prn, procainamide prn, cardiovert unstable patients prn (usually synchronized 25-100+J with sedation/general anesthesia prn). No digoxin or verapamil.
(r) WPW with reentrant SVT ? narrow complex ? ? ABC’s, 100% O2 prn, procainamide prn, adenosine prn, synchronized cardioversion prn (25-50+J with sedation/general anesthesia prn). No digoxin or verapamil.
(12) Antiarrhythmics Class IA quinidine procainamide disopryamide Class II propranolol metoprolol acebutolol IB lidocaine phenytoin mexitil(r) III bretylium amiodarone sotalol IC rythmol(r) IV verapamil cardizem(r)
V Unclassified: adenosine digoxin
(13) THIRTEEN  (A) Procainamide 100mg q5 minutes slowly I.V. until converted, or hypotension, or increased QRS or QT, or 1g given ? drip 2-6 mg/min/prn. See also #(2), p.138.
(B) Lidocaine ? 1-2mg/kg bolus ? repeat prn to total 3mg/kg ? 2-4 mg/min drip. Children 1mg/kg bolus ? 1mg/kg/hr.
(C) Dilantin(r) ? 15mg/kg I.V. over 30-60 minutes (loading dose), for digitalis toxicity with ventricular tachyarrhythmias and ectopics. See also #(10)(A), p.189.
(D) Rythmol(r) (propafenone) ? type 1C antiarrhythmic, ? initial dose 150mg q8h po. See also #(4), p.86.
(r) caution, may be proarrhythmic.
(14) FOURTEEN (A) Inderal(r) (r) the original beta blocker.
? 0.5-1mg I.V. prn to a total of 5+mg (e.g. adjunct ? in acute MI), or children 0.01 – 0.1mg/kg/I.V., to a maximum 0.5-1mg dose.
(B) Metoprolol (r) beta1 blocker (r) indications (r) angina, hypertension, and adjunctive ( for acute MI.
(r) ( 5mg I.V. prn (r) ( 50mg bid po (initial dose).
(C) Acebutolol (r) beta1 blocker (r) indications (r) angina, hypertension.
(r) ( 100mg bid po (initial dose).
(15) Labetalol (r)?I.V. for the emergency treatment of severe hypertension.
? alpha and beta blocker ? 20mg I.V., then 40 mg I.V. q10 min prn, to a total dose of 300mg prn.
(r) Oral dose = 100-400mg bid.
(16)  SIXTEEN (A) Bretylium (r) indicated for resistant ventricular tachycardia and fibrillation, e.g. hypothermic cardiac arrest.
? 5-10 mg/kg I.V. q15 min prn to 30mg/kg ? drip 1-2mg/min prn.
(B) Amiodarone ? for refractory ventricular fibrillation, consider giving amiodarone 150-600mg I.V. over 5-15 minutes.
(C) Sotalol ? beta blocker and type III antiarrhythmic, ? initial dose 80 mg bid po. See also #(4), p.86.
(r) caution, may be proarrhythmic (antidote glucagon I.V.?).
(17) MgSO4 ? consider giving 2-4+g I.V. bolus for cardiac arrest not responding to standard ACLS protocols (for other uses of MgSO4, see the index).
(18) Verapamil ? for uncomplicated SVT 5mg I.V., repeat 5mg prn in 5-10 minutes, children 0.1 mg/kg. Do not use verapamil in children less than 2 years of age, or patients with wide complex tachycardia, WPW with atrial fib/flutter or SVT, LGL syndrome, CHF, or sinus or AV node disease. If necessary, give the antidote calcium gluconate 10% 1-10ml I.V. (adult dose, child = 0.1-0.2 mL/kg), over five minutes should significant hypotension occur.
(19) Adenosine ? for SVT ? 1/2 life is about 10 seconds ? may get transient bradycardia, AV block, bronchoconstriction, or facial flushing ? ? 6mg I.V. ? 12mg X 2 I.V. prn q 2 minutes (pediatric 0.1mg/kg (r) 0.2mg/kg prn). Useful for SVT ± acute myocardial ischemia/infarction. A better choice than verapamil in the unstable patient. The drug of choice for patients under 2 years of age. Adenosine may also be used for narrow complex SVT associated with WPW.
(20) Epinephrine ? alpha and beta1,2 agonist  ? contraindicated in hydrocarbon poisoning.
? 5-10 mL 1:10,000 I.V. prn (child = 0.1ml/kg) ? consider the empiric use of high-dose epinephrine (adult 5-15mg, child 0.1-0.2+mg/kg) during cardiopulmonary resuscitation.
? if ineffective during CPR, consider giving a 50meq (1meq/kg) bolus of sodium bicarbonate before repeating the epinephrine (and/or an initial presumptive bolus prn). Epinephrine’s effectiveness is decreased in an acidotic environment.
? ? 0.3 cc 1:1000 s.c. prn (child 0.01ml/kg to 0.3cc), e.g. for severe urticaria.
(21) Atropine ? parasympatholytic, ? 0.5mg I.V. prn. (pediatric 0.02mg/kg/dose, minimum 0.1mg).
? having the patient cough is parasympatholytic, and may alleviate the need for atropine.
(r) atropine is ineffective in heart transplant patients with bradycardia (denervated heart).
(22) Cardioversion (r) ± synchronization prn, ± I.V. versed or valium(r) prn, ± I.V. demerol(r) prn (r) ± consultation anesthesia/general anesthetic prn, if time permits.
??contraindicated in digitalis toxicity (last resort? 10-25J) ??cardiovert unstable patients prn, e.g. decreased level of consciousness, ischemic chest pain/MI, SOB/CHF, hypotension.
??atrial fibrillation 100+J ??ventricular fibrillation 200+J (defibrillate immediately, repeat 200J, 360J prn).
??atrial flutter 25-50+J ??SVT 25-50+J ??ventricular tachycardia 25-50+J (r) See also #(7), p.109.
(23) Norepinephrine (r) the sympathetic nerve transmitter substance ? alpha and beta1 agonist.
? ? 4 mg/500cc D5W at 30cc hr ? increase prn.
? antidote, alpha blocker phentolamine 5 mg I.V. prn, or mix with 10 mL saline for local infiltration for local vasoconstriction prn (as a result of interstitial leaking of norepinephrine).
(24) Alpha stimulation = vasoconstriction beta1 = tachycardia and inotropic.
beta2 = vasodilation and bronchodilation.
(25) Dopamine (adults, children) ? 2-5 ?g/kg/min ? vasodilation ? 5-15 ?g/kg/min ? beta stimulation ? 15-30+ ?g/kg/min ? alpha stimulation (26) Isoproterenol ? beta1,2 stimulator ? 2mg/500ml D5W at 30-60 cc/hr for bradycardia ? give 2.5mg sublingual tablet prn while preparing the I.V. ? avoid isoproterenol with acute myocardial ischemia/infarction if possible.
(r) pediatric 0.1(g/kg/min/I.V., and increase q5-10min prn.
(27) Digoxin ? 0.5mg I.V., then 0.25mg q1h I.V. prn, to total of 1 mg (adult digitalizing dose, obtain a serum digoxin level prn). Initial pediatric digitalizing dose = 5-20(g/kg/I.V. (consult references).
(28) Calcium gluconate 10% ? ? hypocalcemia, hyperkalemia (not with digitalis toxicity), hypermagnesemia, cardiac arrest with renal failure, overdose or hypotension with calcium blockers, hydrofluoric acid poisoning, black widow spider bites/venomous caterpillar stings with pain, and venomous snake bites with seizures.
? ? 1-10mL slowly I.V. prn (pediatric = 0.1-0.2mL/kg to 5mL).
(29) Sodium nitroprusside ? veno and arteriodilator ? ( 0.5-1?g/kg/min, and increase prn.
(30) Nitroglycerin ? venodilator (all doses), coronary artery dilator (all doses), and arteriodilator (high doses).
? ? NTG 0.3mg sublingual tablet (or spray) prn (tabs deteriorated?/ok if sublingual burning sensation present).
? ? Nitrong(r) SR 2.6-5.2mg tid po.   ? ? NTG 2% ung 1-2 inches q3-24h prn (or dermal patch 12-14 hours/day).
? ? NTG 5-10?g/min/I.V. ? increase by 5-10?g/min every 5 minutes prn.
? For NTG induced vasovagal bradycardia/hypotension, have the patient cough several times prn (parasympatholytic), and give atropine 0.3-1.0mg I.V. prn.
? NTG is useful (especially I.V.) for (1) acute myocardial ischemia, (2) moderate hypertension associated with pulmonary edema, or unstable angina, or myocardial infarction, and (3) for pulmonary edema by decreasing preload and afterload, and counteracting the initial increase in LV filling pressures caused by I.V. lasix. NTG is contraindicated in critical aortic stenosis.
(31) Nifedipine ? 10-20mg po prn for hypertensive urgencies. A very useful drug! See also #(9)(A), p.119. Do not give nifedipine sublingually (uneven absorption, unpredictable effects on blood pressure, JAMA 1996; 276: 1328-31).
(32) Lasix ? 1mg/kg I.V. or po ± NTG (see #(30), p.97). Patient allergic to sulfas?, prior lasix? ? caution prn ? substitute ethacrynic acid prn, 50mg I.V. or po prn.
(33) Morphine ? 2.5mg-5mg I.V. prn ± gravol(r) (dimenhydrinate) 10mg I.V. prn for nausea.
(r) 0.1mg/kg in children ± gravol(r) prn.
(34) (A) Demerol(r) (meperidine)  ? 12.5-25mg I.V. prn (children 0.2-0.3mg/kg) ± gravol(r) 10mg I.V. prn. Demerol(r) is preferred over morphine by some clinicians for the pain of inferior MI’s. Both demerol(r) and morphine will result in sedation and analgesia, leading to a decrease in myocardial O2 demand. Do not underestimate the value of alleviating the pain of ischemic heart disease. Treat the pain aggressively. Remind the nursing staff prn of the benefits of pain relief (more often vice versa).
(r) Analgesia with demerol(r)/morphine may require frequent initial doses I.V., until the patient’s loading dose is reached (endogenous opioid receptor binding).
(r) when demerol(r) does not result in adequate analgesia, try morphine and vice versa.
(B) Versed (midazolam) ? an excellent sedative, e.g. cardioversion, shoulder reduction, ? 2-3mg I.V. over 2-3 minutes ? titrate with 1-2mg q 2minutes prn, to maximum of 0.07 – 0.1mg/kg.
(r) See also #(8)-(11) pp. 119-119 for additional cardiovascular drugs.
°III. Septic Shock
? immunocompromised?, e.g. splenectomy, chemotherapy, AIDS.
? various presentations: fever alone, hypothermia, oliguria, respiratory alkalosis, confusion, metabolic acidosis, hypotension. DIC?
? ABC’s, supportive care, drainage of pus prn, debridement prn, and antibiotics. Narcan(r)? Treat according to the site of origin, for example, the GI tract.
? (for example) claforan(r) 50-180mg/kg daily for children, or 4-12g daily for adults plus tobramycin 3-5mg/kg daily children/adults plus flagyl(r) 10mg/kg/q8h I.V. for children, or 500mg/q8h I.V. for adults Tobramycin or gentamycin therapy ? monitor with serum levels.
(r) See also Toxic shock syndrome, #(3)(A), p.176.
°IV. Central Nervous System
(1st of 2 sections) (r) See also Central Nervous System (second of two sections), p. 160.
(1)  Locked-in syndrome ? CVA with destruction of the ventral pontine tracts ? patient appears to be in a coma, but has vertical eye movement on command.
(2) Cheyne-stokes breathing ? bilateral cerebral hemispheric disease?  Hyperventilation ? upper brain stem damage?
Apneustic breathing ? like breath holding ? lesion about 5th cranial nerve?
Cluster breathing ? short bursts ? lesion pons?  Yawning ? posterior fossa lesion?
Vomiting, hiccuping, and coughing ? lower brain stem injury?
(3) Fundi ? spontaneous venous pulsations in the recumbent position ? no increase in the intracranial pressure.  pinpoint pupils ? narcotic, phenothiazine, or clonidine overdose?, cholinergics?, miotic eye gtts?, pontine hemorrhage? (ocular bobbing?), cerebellar hemorrhage?; (miosis reversed with narcan(r)? ? acute narcotic withdrawal?, restrain patient first?) ? CT scan prn, refer neurosurgery prn (cerebellar hemorrhage needs immediate neurosurgical intervention).
(4) If both eyes cross the midline the brain stem is intact.
“Doll’s eyes” movement present (brain stem intact) ? contraindicated in suspected cervical spine injuries.
Oculovestibular testing (no basilar skull fracture is suspected, plus the Tm’s must be intact) ? external auditory canals are sequentially irrigated with 50cc of ice water ? bilateral nystagmus (no coma, hysterical?) ? eyes deviated towards side of irrigation (brain stem intact) ? no deviation (brain stem damage?; drugs? ? reactive pupils?) ? unilateral deviation (structural damage of the brain stem? ? CT scan, refer neurosurgery).
(5) Acute cerebellar hemorrhage ? headache, alert ? vertigo, vomiting, unable to stand, truncal ataxia ? progressing to coma ± decerebrate posturing ± pinpoint pupils ± eyes deviated away from the side of the lesion.
? ABC’s, ? hypertension prn, and increased intracranial pressure prn ? immediate neurosurgical decompression (also for traumatic posterior fossa hemorrhage).
(6) Decorticate posturing ? flexion of the arms and extension of the legs ? upper midbrain lesions.
Decerebrate posturing ? extension of both arms and both legs ? central midbrain or posterior fossa lesion?
(7)
(A) Mnemonic for altered states of consciousness and coma: TIPS: T:
I:
P:
S:  trauma, temp., thiamine
infection, AIDS.
psychiatric, porphyria.
space occupying lesion, stroke, intracranial hemorrhage, shock, status epilepticus VOWELS: A:
E:
I:
O:
U: alcohol, drugs, toxins.
endocrine, liver, lytes.
insulin, oral hypoglycemic agents, diabetes mellitus.
O2, CO2, CO, opiates.
uremia, hypertension.
(B) Syncope A frequently encountered problem in the ER. Before you “pass it off” as benign, satisfy yourself that there is not something more serious going on. For example, arrhythmia/cardiomyopathy, unapparent hemorrhage/GI/ectopic pregnancy, expanding/rupturing abdominal aortic aneurysm, adverse drug reaction, hypoglycemia, subarachnoid hemorrhage, carotid sinus hypersensitivity.
(C) Vertigo Peripheral vertigo ? acute, intense, ± nausea, ± vomiting, ± diaphoresis, ± tinnitus, ± hearing loss, positional, latency 2-20 seconds, fatiguable, plus unidirectional nystagmus with ocular fixation inhibition ? benign positional vertigo?, labyrinthitis?, Menière’s disease?, cerebellopontine tumor?, acute cerebellar hemorrhage?
Central vertigo ? less intense, ± neurological signs, not fatiguable or positional, plus multidirectional nystagmus not inhibited by ocular fixation ? conditions affecting the brain stem or cerebellum, drug toxicity?
°V. Pediatrics
(1st of 2 sections) ? See also Pediatrics (second of two sections), p. 138.
(r) remember to listen carefully to what the parent(s), or other caregivers have to say (you may have to simultaneously take the history, examine, and treat the child).
? it may sometimes be helpful to reassure the parents/caregivers, by expressing to them that you are treating their infant/child/teenager, as you would one of your own (e.g. your grand-daughter).
(1) ONE
(A) Fever in children up to 24 months of age (r) DPT immunization in the past 24-48 hours?
(r) petechiae?, bacteremia?/meningitis? {DIC?}, pneumonia?, UTI?, tonsillitis/otitis?, cellulitis?, viral illness? ? has the pyrexia been suppressed with a recent antipyretic? ? playful?, inconsolability?, increased irritability when held?, focus of infection?, toxic? ? how sick does the child appear? ? have a low threshold for doing investigations (immunocompromised state?, e.g. splenectomy, chemotherapy ? full septic work-up). Purpura? ? aspirate ? gram stain and culture. Patients with sepsis/meningitis may also have a concurrent focus of infection, e.g. otitis media.
0-3months of age ? temp. ? 38.3?C ? septic work-up prn ? chest x-ray, CBC-diff-sed.rate, Bun, creatinine, glucose, lytes, urinalysis, lumbar puncture, and cultures/gram stains (e.g. nose/throat, urine, blood?gram stain of the buffy coat?, CSF), ? presumptive antibiotic therapy prn.
3-24 months of age ? temp. ? 39.4?C ? prn CBC-diff-sed.rate ? wbc 15,000+, or bands 500+, or polys 10,000+, or sed. rate > 30 ? full septic workup prn ? presumptive antibiotic therapy prn.
Sepsis/meningitis (the patient may be hypothermic) ? critically ill patients should begin antibiotic treatment within 30 minutes, regardless of how many investigations have been completed (ensure that the blood cultures are done before giving the I.V. antibiotic(s)).
Remember that several disorders may result in a septic appearing infant, for example, (1) bacterial/viral/mycoplasma infections (e.g. sepsis, meningitis, pneumonia, “flu”), (2) dehydration/shock (± electrolyte problems) from any cause, (3) overdoses (e.g. ASA), (4) hypoglycemia (e.g. ASA overdose, infections), (5) cardiac failure/arrhythmia (e.g. congenital heart disease, SVT), (6) shaken baby syndrome (or other CNS trauma/bleeds), (7) anemia (e.g. aplastic, hemolytic, blood loss), (8) renal failure, (9) infantile botulism (never seen it), (10) HIV/infections (e.g. pneumocystis carinii pneumonia).
(B) Diarrhea in children ? viral?, shigella?, salmonella?, campylobacter?, yersinia?, clostridium difficile?, giardia lambia?, staph toxin?, E. Coli?, bacillus cereus?, post viral enteritis lactose intolerance?
(r) Caution! May rapidly develop into a life threatening situation with, for example, shock, acute renal failure, DIC, ARDS (e.g. E. Coli food poisoning from undercooked hamburger meat). One symptom of E.Coli hemorrhagic colitis is severe abdominal cramps which may develop prior to the diarrhea.
? remember to note on the stool culture requisition what you are suspecting, e.g. E. Coli, bacillus cereus, clostridium difficile.
(2) ASA, Tylenol(r) (r) ? 10-15mg/kg/q4h prn.
(r) early antipyretic therapy may facilitate the assessment/observation of patients but the effects are not predictable of bacteremia.
? giving the crying child a popsicle may result in an instantaneous improvement in their mental status (and their parents, and maybe you too!).
(r) do not use ASA in patients with chickenpox or influenza, as there is an association with the development of Reye’s syndrome. There is also a preliminary report of a possible association between chickenpox, ibuprofen, and the “killer strep infection.” See also #(3), p.176.
Toradol(r) 0.5mg/kg/I.M./I.V. to 30mg (an analgesic NSAID).
Demerol(r) (meperidine) 1-2mg/kg/I.M. prn (0.2-0.3mg/kg/I.V. prn).
Morphine 0.1mg/kg/I.M./I.V. prn Codeine 0.5-1.0mg/kg/p.o. prn Fentanyl 0.5-2?g/kg/I.V. prn (r) Avoid I.M. injections of analgesics in children if possible.
Remember: all narcotics have a steep dose – response curve ? a small increase in the plasma level may result in a large increase in analgesia ? titration may be required for adequate analgesia (frequent initial I.V. doses prn until the patient’s loading dose has been reached/ endogenous opioid receptor binding). Narcotics can be combined with benzodiazepines, e.g. valium(r) 0.2mg/kg/I.V./prn, or versed 0.05mg/kg/I.V. prn. Have narcan(r) available (0.01mg/kg/I.V. prn). See also chronic pain, #(17), p.157.
(3) THREE
(A) Pediatric fluids and electrolytes Maintenance up to 10kg body weight = 100 mL/kg/day plus from 11 to 20kg = 50 mL/kg/day plus from 21 to 70kg = 20 mL/kg/day  = total maintenance requirement/day 0 Dehydration (isonatremic, hyponatremic, hypernatremic) mild = 3-5% of body wt. = 30- 50ml/kg moderate = 6-9% of body wt. = 60- 90ml/kg  severe = 10-15% of body wt = 100-150ml/kg ? ABC’s, 50-100% O2 prn, ringers 20ml/kg bolus prn for shock, repeat X 2 prn. NaHCO3 1meq/kg over 30-60 minutes (careful!) for pH ? 7.10, or serum NaHCO3 < 10, Hypo/ hyperglycemic?
? Replace the remaining fluid and lyte deficit (+ maintenance) over 1 to 2 days. Use 0.25 – 0.5NS + 5% dextrose (if not hyperglycemic), plus 20-40 mEq KCl/L (once urine output begins). Give 3 % saline prn (4mL/kg, careful!) for severe hyponatremia (e.g. with seizures), and D25W 2-4ml/kg prn for hypoglycemia. See also #(17), p. 82.
Oral rehydration ? e.g. Pedialyte(r) 120-150ml/kg/day or 2-2.5oz./lb/day maintenance, plus replace deficits. Give in small, very frequent amounts.
? if a child with, for example viral gastroenteritis, is going to be hydrated at home, emphasize to the parents that “dehydration is the enemy.”
(B) Pyloric stenosis ? 1-12 weeks of age (usually 2-6 weeks).
? ABC’s, ? dehydration, ? hypokalemia, ? metabolic alkalosis prn, NG tube, U/S prn, consult pediatric surgery.
(4)  Neonatal – Pediatric resuscitation ? Pediatric cardiac arrest is usually secondary to, for example, apnea or shock.
? Use the umbilical vein for I.V. administration in newborns.
? Use the Broselow Pediatric Resuscitation Tape(c) prn (AHA-PALS).
? B/P ? 70 systolic (child) ? poor perfusion? ? unstable?
? ? ACBC’s, 100% O2, avoid hypothermia, plus the following prn: Epinephrine 1:10,000 0.1+ml/kg q3-5min I.V. prn.
Narcan(r) 0.01mg/kg/I.V./prn.
Isoproterenol 0.1?g/kg/min/I.V. prn, and increase prn.
Ringers 20ml/kg bolus(es) prn.
Packed red blood cells 5-10ml/kg/prn.
Fresh frozen plasma 10-20ml/kg/prn.
Cryoprecipitate 0.2 bags/kg/prn (safe? see (9)(C), p. 154).
Platelets 0.2units/kg prn for platelet counts < 50,000.
Atropine 0.02mg/kg/I.V. prn, minimum dose 0.10mg, maximum 0.5mg.
Bicarbonate 1-2meq/kg/I.V. prn (careful!), Neonate: dilute 1:1 with sterile water prn ? repeat arterial blood gases prn.
Lasix 1mg/kg/I.V. prn Diazoxide 1-3mg/kg/dose/I.V./prn, to 150mg q4-24hrs.
Hydralazine 0.1mg/kg/I.V./q4-6 hrs prn.
Mannitol 20% solution 2.5-5cc (0.5-1g)/kg/I.V. slowly q4-6hrs prn.
Cardioversion/defibrillation: see #(7), p. 109.
? Newborns: beware of prematurity, asphyxia, meconium aspiration, hypothermia, diaphragmatic hernia, choanal atresia, tracheoesophageal fistula, RDS, pneumothorax, shock, and maternal drug abuse. Remember the congenital infections mnemonic TORCHS = toxoplasma, rubella, cytomegalovirus, herpes, and syphilis.
(5) Neonatal seizures ? CNS and infection workup.
1. ABC’s and bloodwork.
2. Dextrose 25% 2mL/kg/I.V./prn.
3. Calcium gluconate 10% 0.2ml/kg/I.V./prn.
4. MgSO4 50% 0.1ml/kg/I.V./prn.
5. Pyridoxine 50mg I.V. prn.
6. Valium(r) 0.2mg/kg/I.V. prn.
7. Phenobarbital 20mg/kg/I.V. prn (loading dose) ? 5mg/ kg/daily.
8. Dilantin(r) 20mg/kg/I.V. prn (loading dose) ? 5mg/ kg/daily.
(6) Meconium staining in the newborn ? Try to avoid aspiration of the meconium by suctioning the pharynx and trachea, before initiating assisted ventilation.
(7) Pediatric paddle size/Defibrillation/Cardioversion ? 4.5cm paddles for infants, 8cm paddles for children.
Defibrillation (do not do blind in children) ? ? 2 joules/kg (r) cardioversion ? ? 1/4-1/2 joules/kg ? unsuccessful defibrillation or conversion? ? ? double the dose. Cardiovert unstable patients (plus sedation prn, e.g. valium(r)0.2mg/kg/I.V., plus synchronization prn). Consult anesthesia/cardiology before cardioversion if time permits.
(8) A cough is uncommon in infants less than 6 months of age ? pertussis?, chlamydia pneumonia?, cystic fibrosis?/frequent chest infections/malabsorption/failure to thrive.
(9) NINE
(A) Stridor ? inspiratory stridor only (partial airway obstruction at the larynx or above), both inspiratory and expiratory stridor (partial tracheal obstruction), or expiratory stridor only (partial airway obstruction below the carina).
? croup?, epiglottitis?, F.B.?, bacterial tracheitis?, peritonsillar abscess?/tonsillitis/pre-existing tonsillar hypertrophy?, retropharyngeal abscess?, allergic reaction/angioedema? ? all seven may result in upper airway obstruction. Do not agitate the child, leave them in a position of respiratory comfort.
? Bag and mask with 100% O2 prn.
? Intubation? Use an ET tube 1-2mm smaller than usual prn (with adequate lubricant, e.g. xylocaine jelly). A small ET tube will suffice, at least temporarily. Consult anesthesia if time permits.
? Epiglottitis?, direct the ET tube through the “eye of the cherry.”
Aspiration of F.B. into tracheal-bronchial system?, esophagus?, unilateral wheezing? ? do bilateral decubitus expiration views prn, or an upright expiratory film if the patient can cooperate (the side with the F.B. may demonstrate air trapping).
(B) Croup (r) viral?, bacterial?, spasmodic?
? ? ABC’s, position of respiratory comfort, humidified 100% O2 prn, supportive care, ice-saline aerosol prn, racemic epinephrine aerosol prn (0.5cc 2.25% with 4.5cc of saline/100% O2), intubate prn, decadron(r) 0.25-0.6mg/kg IM/po prn, antibiotics prn, extended hospital observation prn. Admit ICU prn.
? rebound stridor following a racemic epinephrine aerosol usually occurs within 2 hours (if at all).
(r) some clinicians are using pulmicort(r) aerosols (budesonide) 0.5-2mg, instead of, or in addition to, decadron(r).
(C) Epiglottitis  (r) the child is sitting in the “sniffing position” (r) toxic, fever, muffled voice, dysphagia/drooling, ± cyanosis.  (r) ? ABC’s, position of respiratory comfort, humidified 100% O2, racemic epinephrine aerosol prn (0.5cc 2.25% with 4.5cc saline/100% O2), portable x-ray?, bag and mask with 100% O2 prn, intubate in the OR prn, and claforan(r) 100mg/kg/I.V./day. The patient may require immediate intubation in the ER. The presence of pharyngitis does not rule out epiglottitis. Bacterial tracheitis presents and is managed similarly to epiglottitis.
Epiglottitis prophylaxis: ? rifampin  ? adults 600mg of rifampin bid X 4 days   ? 1 month to 12 years of age, 10mg/kg bid X 4 days  ? less than 1 month, 5mg/kg bid X 4 days (D) Retropharyngeal or peritonsillar abscess ? tonsillitis/pre-existing tonsillar hypertrophy?
? ABC’s, position of respiratory comfort, humidified 100% O2 prn, intubate prn, penicillin G 100,000 units/kg/day/I.V., incision and drainage in the OR prn.
(10) TEN
(A) Post-Group A beta-hemolytic streptococcal infection glomerulonephritis ? renal failure, hypertension, and congestive heart failure.
? ABC’s, supportive care, antibiotics prn, refer nephrology.
(B) Hemolytic-uremic syndrome (r) usually follows an episode of gastroenteritis or respiratory infection.
(r) may result from eating undercooked hamburger meat contaminated with E. Coli.
(r) nephropathy, hemolytic anemia, and thrombocytopenia.
(r) seizures, hypertension, petechiae, acute renal failure.
( ABC’s and supportive care (e.g. ( seizures, hypertension, hyperkalemia/renal failure, anemia, thrombocytopenia), consult pediatrics, admit ICU prn.
(C) Henoch-Schönlein Purpura (r) acute vasculitis of small vessels with frequent multisystem involvement.
? etiology unknown, but believed to result from immune complex reactions to various antigenic stimuli.
(r) pathognomonic skin lesions (r) erythematous progressing to purpuric, predominately on the buttocks and lower extremities (feet and ankles in adults).
(r) GI, renal, pulmonary, CNS, and arthritic manifestations.
( ABC’s, supportive care, corticosteroids prn, consult pediatrics.
°VI. Cardiology
(2nd of 2 sections) (r) See also Cardiac Arrhythmias and ACLS Drugs (first of two sections), p. 86.
(1) ONE
(A) Unstable Angina ? ABC’s, 100% O2 prn, NTG prn (often titrated I.V./avoid hypotension), I.V. morphine/demerol(r) prn, aggressive pain control prn, atropine prn, heparinize prn, beta blockers prn (e.g. acebutolol 100mg bid po), Ca blockers prn, ASA prn, angioplasty/CABG prn, admit CCU.
(B) Acute Myocardial Infarction ? ABC’s, 100% O2 prn, NTG prn (often titrated I.V./avoid hypotension), I.V. morphine/demerol(r) prn, aggressive pain control prn, atropine prn, lidocaine prn, beta blockers prn (e.g. metoprolol 5mg I.V. prn), lasix prn, dopamine prn, heparinize prn, thrombolytics prn (as early as possible; “time is muscle”), ASA prn, angioplasty prn (cardiogenic shock?), CABG prn, admit CCU.
Beta blockers are especially useful in an acute MI (if not contraindicated), for the management of reflex tachycardia, systolic hypertension, continuing or recurrent ischemic chest pain, and tachyarrhythmias, e.g. atrial fibrillation.
MgSO4 I.V. bolus, followed by an I.V. drip is presently being investigated as an adjunctive treatment for acute ischemic heart disease.
? Cocaine induced coronary artery spasm?
(C) Thrombolytic therapy for acute myocardial infarction ? May use I.V. NTG as well.
1) Consult drug protocols (regimens may vary). Review the contraindications, e.g. head/CNS lesion/surgery, recent major surgery (< 2 weeks), active internal bleeding, bleeding disorder, previous hemorrhagic stroke, pregnancy, aortic dissection.
2) Tissue plasminogen activator (tPA) ? not antigenic, rapid onset, and there is no generalized fibrinolytic state.
? activase(r) 15mg bolus I.V. over 2 minutes, then 50mg over 30 minutes, then 35mg over the next hour. Give heparin, 5000 units I.V. bolus, then 1000 ± units/hr/I.V. at the start of  the activase(r) infusion, and continue for 72 hours. ASA 325mg/day.
3) streptokinase (streptase(r)) ? approximately one sixth the cost of tPA, but unlike tPA, streptokinase can only be used on one single occasion on the same patient.
? 1.5 million units of the streptokinase I.V. over 1 hour, heparin 5000 units I.V. bolus on completion of the streptokinase infusion, then 1000 ± units/hr/I.V. X 72 hours. ASA 325mg/day.
4) tPA versus streptokinase  Consult your cardiologist for the most recent recommendations. tPA is becoming the drug of choice, but streptokinase is equally effective in certain situations (e.g. uncomplicated acute inferior MI). The cost saving with using streptokinase makes it an attractive alternative to tPA, when used appropriately.
5) Some centers regard angioplasty/CABG, rather that thrombolytic therapy, as the treatment of choice for acute myocardial ischemia/infarction in suitable candidates.  (D) Acute myocardial infarction with left ventricular failure ? requires invasive monitoring.
systolic B/p > 100 ??nitroprusside (correct arrhythmias)  75-100 ? dopamine, angioplasty?
< 75 ??high dose dopamine plus noradrenaline?, angioplasty?
? Cardiogenic Shock without CHF ? trial of ringers 100cc bolus(es) prn ? improvement in vital signs?
(2) Acute Myocardial Ischemia with PVC’s ? Inherent bradycardia with escape PVC’s. ? atropine 0.5-1mg I.V. prn (having the patient cough is parasympatholytic and may alleviate the need for atropine).
? normal inherent rate with new? PVC’s. ? lidocaine prn 50-100mg I.V. bolus, then 1-4mg/minute I.V. drip.
? careful! vice versa can be disastrous.
(3) THREE (A) Congestive heart failure with acute pulmonary edema (r) precipitating problem?, recurring episodes?
(r) tachy/bradyarrhythmia?, hypertension?, hypotension?, acute myocardial ischemia/ infarction?, mitral stenosis?, hyperdynamic state?, hypertrophic cardiomyopathy?
? ABC’s, 100% O2, patient sitting upright with legs dependent prn, NTG prn if not hypotensive (S.L.?I.V.?), lasix prn, morphine/demerol prn, dopamine prn, correct dysrhythmias prn, ventolin(r) aerosols prn/aminophylline prn (cardiac asthma?), phlebotomy prn (anuric?), intubate prn/consult anesthesia prn (if time permits), admit CCU. Beware of (1) right ventricular infarction, (2) pulmonary embolism, (3) acute valvular dysfunction, and (4) ventricular septal rupture. No diuretics for (1) or (2) as there is no pulmonary edema.
? some clinicians are using capoten(r) 12.5mg S.L. prn to decrease afterload.
(r) occasionally acute pulmonary edema has a non-cardiac etiology, e.g. inhaled toxins (e.g. smoke, phosgene), fat embolism, ARDS (e.g. near drowning, delayed immersion syndrome, sepsis, poisonings, e.g. ASA, narcotics, carbon monoxide). See #(4), p.124.
(r) beware of the rote treatment of acute pulmonary edema, nevertheless, the majority of patients will respond satisfactorily to 100% O2, NTG, morphine, and lasix.
(B) Chronic congestive heart failure ? ABC’s, diuretic (e.g. lasix, spironolactone), vasodilator (e.g. capoten(r)), low salt diet.
(4) FOUR (A) Pericarditis ? infectious (e.g. viral), non-infectious (e.g. uremia), or idiopathic.
? retrosternal, pleuritic chest pain ( pericardial friction rub.
? wide spread ST elevations (upward concavity) with no reciprocal depressions (caution: do not confuse with acute myocardial infarction).
? ? ABC’s, treat complications (e.g. pericardial tamponade, arrhythmias), and underlying disease (e.g. uremia, neoplasm); NSAIDs prn, steroids prn, antibiotics prn, admit step-down/CCU prn.
(B) Pericardial tamponade (r) cyanosis from the neck up?
(r) impaired venous return and cardiac filling (r) tachycardia, hypotension (may be orthostatic only), muffled heart sounds, ± distended neck veins, ± paradoxical pulse, ± clear lung fields.
? etiology?, e.g. trauma?, dissecting aneurysm? (± MI?, ± neurological signs?), iatrogenic? (e.g. CPR, on anticoagulants?), metastatic pericardial disease?, Dressler’s syndrome?, infection?, sarcoid?, AIDS?, dialysis patient?, undiagnosed uremia?
? ACBC’s, large bolus ringers prn (0.5-2 litres), dopamine prn, echocardiogram and/or CT scan if appropriate prn, immediate? pericardiocentesis prn, ? underlying cause and refer.
(5) Alveolar – arterial gradient (r) 140 – (pO2 + pCO2) ? 15 normal ? pulmonary embolism? ? ventilation and perfusion scan? ? pulmonary angiogram?
(6) Pulmonary Embolism (r) Deep vein thrombosis (DVT)?  ? ABC’s, 100% O2 prn, bolus(es) ringers prn, dopamine prn, heparin 5000 units I.V. bolus, then 1000 ± units/hr/I.V., and adjust the heparin drip so that the PTT is 1.5-2 times the control. Initiate presumptive heparin therapy if indicated, e.g. strong suspicion/delayed availability of the ventilation and perfusion scan. Massive embolism? ? thrombolytic therapy?, surgery? (also refer to vascular surgery if heparin is contraindicated).
Heparin antidote ? I.V. protamine sulfate ? 1mg will neutralize 100 units of heparin (consult references).
Remember: the diagnosis of pulmonary embolism is missed 2/3 of the time. The four most common symptoms and signs are: dyspnea, pleuritic pain, tachypnea, and rales (r) pulse oximetry?, chest x-ray?, blood gases? ? ventilation and perfusion scan? ? pulmonary angiogram?
Warfarin ? for long term anticoagulation, ? 2-10mg/daily ? PT maintained at 1.3-2 times the control.
(7) Seven
(A) Malignant hypertension/accelerated hypertensive crises ( ABC’s, 100% O2 prn, lower the diastolic blood pressure to the 100 range, and treat other problems prn, for example, acute encephalopathy (seizures?), CHF, acute myocardial ischemia, intracranial hemorrhage, aortic dissection, renal failure.
? MAOI hypertensive crises?, drug intoxication? e.g. amphetamines?, cocaine?
? Admit to the ICU prn.
? See also #(8)-(11), pp.119-120, #(15), p. 92, #(29), p.96. (various antihypertensive drugs).
(B) Hypertension/preeclampsia/eclampsia ? ABC’s ??valium(r) 5-10mg I.V. prn for seizures (or threatened).
??hydralazine 5-10mg I.V. prn for hypertension.
??MgSO4 4 grams I.V. with 250ml D5W over 10-30 minutes ? 1-2g/hr prn ? monitor level of consciousness, respirations, B/p, reflexes, urine output, and magnesium levels prn.
? 10% calcium gluconate is the antidote for MgSO4, ? 1-10ml slowly I.V. prn.
? treat other problems prn, e.g. acute renal failure, CHF, intracranial hemorrhage.
??evacuation of the uterus as soon as it is feasible.
(8) Trimethaphan ? ganglionic blocker ? secondary drug for aortic dissection with hypertension.
? ? 500mg/500 D5W at 1-4cc/minute.
(9) NINE
(A) Nifedipine ? vasodilator, first line drug for moderate/severe hypertension, ? 10-20mg po prn. A safe, very effective drug (I have never seen nifedipine induced hypotension, despite my frequent use of this agent). The antidote is 10% calcium gluconate, 1-10ml slowly I.V.
(B) Diazoxide  ? direct arteriolar dilator, ? 50mg I.V. prn q5-10 minutes (1-3mg/kg in children).
(10) Clonidine ? central (and peripheral) alpha2 adrenergic agonist ? decreased catecholamines/blood pressure ? if abrupt withdrawal of clonidine occurs ? rebound hypertension ? ? clonidine 0.2mg po, then 0.1mg q 1 hour prn, or labetalol I.V., or phentolamine followed by inderal(r) I.V. See also #(8), p.188.
(11) ELEVEN
(A) Captopril (capoten(r)) ? angiotension converter enzyme (ACE) inhibitor ? ? 25±mg bid-tid ? may get hyperkalemia with ACE inhibitors. For urgent hypertension ? ? 25mg SL/po initially, then prn.
(B) Vasotec(r) (enalapril)  (r) ACE inhibitor (r) ( 5-40mg p.o. daily.
(r) for urgent hypertension, ( 1.25mg I.V. (consult references).
? ACE inhibitors can cause life threatening angioedema (initially or after prolonged use). See #(7), p.174.
(12) TWELVE (A) Rupturing abdominal aortic aneurysm (r) pale, diaphoretic, abdominal/back pain.
? ABC’s (try to maintain a systolic pressure in the region of 90-100) ? immediate referral for surgical intervention. See caution, p.46.
(r) any middle-aged/elderly patient with abdominal/back pain, should have an abdominal aorta aneurysm ruled out. Beware of attributing the pain to diverticulitis/appendicitis/ UTI/ureteral calculus, or radicular pain. In addition, an abdominal aortic aneurysm may present with a history of weakness and/or syncope, and episodic or sustained hypotension, with minimal or no pain. The aneurysm may or may not be palpable (ultrasound?, CT scan?). Abdominal aneurysms are one of the great imitators in medicine (has even simulated renal colic with microscopic hematuria, and has been discovered during an “emergency appendectomy”).
Popliteal or femoral aneurysms ? may rupture (rare), thrombose, result in distal emboli, or compress local structures, e.g. popliteal vein.
? ? ABC’s, 100% O2 prn, immediate vascular surgery consultation.
(B) Acute peripheral arterial occlusion ? thrombus, embolus, or trauma ? ? ABC’s, 100% O2 prn, doppler prn, angiography prn, heparin prn, thrombolytics prn, surgery prn. An immediate referral to a vascular surgeon is crucial.
(C) Intra-arterial injection of drugs e.g. drug abuser.
? vasospasm, e.g. hand ? ? ABC’s, pulse oximetry, 100% O2 prn, heparin prn, vasodilators prn (e.g. nifedipine?, phentolamine?), sympathetic nerve block prn, HBO2?, immediate referral to vascular/plastic surgery.
(D) Massive iliofemoral venous thrombosis ? ( ABC’s, 100% O2 prn, heparin prn, thrombolytics prn, surgery prn.
? urgent surgical consultation.
(E) Dissecting thoracic aortic aneurysm ? chest and/or back pain ? shock?, CVA?, MI?, aortic insufficiency?, pericardial tamponade?, hemothorax?, widened mediastinum? ? CT scan prn, aortogram prn.
? ABC’s, 100% O2 prn, ? hypertension prn (e.g. labetalol), ? shock prn (pericardiocentesis?) ? immediate cardiovascular surgery referral.
°VII. Chest
(1) Pneumonias  ? the patient may or may not have pyrexia, or purulent sputum.
(r) beware of the pneumonia where GI symptoms predominate (legionella?).
? be on the lookout for the less frequent, or unusual pneumonia, e.g. TB, Q fever, coccidioidomycosis (obtain a history regarding living and working conditions, and recent travel).
? ABC’s, position of respiratory comfort, 50-100% O2 prn, ventolin(r) aerosols prn, hydrate prn, antipyretics/analgesics prn, antibiotics prn, and see the following: (1) Atypical pneumonias  ? Mycoplasma (bullous myringitis?, cold agglutinins?) ? e.g. erythromycin( .5-1g q6h I.V. ? po ? Legionella ? e.g. erythromycin† .5-1g q6h I.V. ? po (legionella requires total of 3 weeks of antibiotic therapy).
? Chlamydia ? e.g. erythromycin† .5-1g q6h I.V. ? po ? Viral, for example, influenza A: ? amantadine
(2) Typical pneumonia ± ?60 years of age, ± alcoholism, ± COPD, ± nursing home acquired. ? e.g. mandol(r) 1-2g q6-8h I.V. for strep. pneumonia, hemophilus influenza, staph. aureus, klebsiella pneumonia, and moraxella catarrhalis. Add erythromycin† if you suspect that mycoplasma/legionella/chlamydia infection may be the etiology.
(3) Rapidly progressive pneumonia.
??erythromycin 1g q6h I.V., plus rifampin 600mg od po, plus claforan(r) 2 grams q6h I.V.
(4) Aspiration pneumonia ? penicillin ? add claforan(r) if on H2 blockers.
(5) Ca of lung + postobstructive pneumonia ? penicillin, bronchoscopy.
(6) Pneumocystis carinii pneumonitis (occurs almost exclusively with AIDS) (r) occurs in heterosexuals too!
? the chest x-ray may be negative initially.
? consult references/infectious disease specialist, recommendations may have changed.
? bactrim(r) = 20mg trimethoprim/kg and 100mg sulfamethoxazole /kg/day/I.V./divided q6h (concomitant prednisone?) ? po, total of 3 weeks of therapy ? prophylactic therapy, e.g. q 4 week pentamidine aerosols. See also #(4)(F), p.179.
(7) Pneumonia in immunosuppressed patients e.g. chemotherapy, asplenic, systemic steroids, HIV+ ? if at all possible, establish an etiological diagnosis.
? e.g. claforan(r) + tobramycin + clindamycin, until culture results are known.
? See also Pneumocystis carinii pneumonitis, above.
(8) An uncomplicated community acquired pneumonia may be treated with erythromycin, but this does not cover hemophilus influenza. Azithromycin may be used for mild to moderate infections (covers H. influenza), ( 500mg po stat then 250mg/day for days 2-5.
(9) Nursing home acquired pneumonia, if not requiring I.V. antibiotics may be given cipro(r) (ciprofloxacin*) 250-750mg bid po, plus penicillin po. Substitute a macrolide for penicillin prn (e.g. Biaxin(r)).
(2) Lateral decubitus films (r) may reveal small pleural effusions, and underlying disease in larger effusions.
Thoracocentesis ? remove up to 1500cc ± biopsy ? studies ? rbc’s, wbc’s, cytology, cultures, stains, specific gravity, protein, glucose.
(3) Uncomplicated TB ? isoniazid 300mg (+ pyridoxine?), and rifampin 600mg od, plus pyrazinamide (15mg/kg/day), or in pregnancy, substitute ethambutol (15mg/kg/day) for pyrazinamide. Is the patient HIV positive?
(4) ARDS (Adult respiratory distress syndrome)  ? ABC’s, invasive hemodynamic monitoring prn, peep prn, diuretics prn, vasodilators prn, I.V. fluids prn, and ? precipitating cause, e.g. sepsis. Admit ICU.
(5) Asthma (r) smoker?, exposed to second hand smoke?
(r) previous severe asthmatic attacks?/intubations?/admissions to ICU?
? beware of air hunger, the quiet chest (air entry?), paradoxical respirations, use of accessory muscles, and pulsus paradoxis. Decreased level of consciousness?, respiratory fatigue?, severe respiratory acidosis?, fever?
Severe asthma ? PEFR ? 80, FEV1 ? 1, pO2 ? 60, pCO2 ? 45 Moderate asthma ? PEFR = 80-200, FEV1 = 1-1.5 (r) ( ABC’s, see also #(7)(A), p.142.
(r) measure the PEFR before and after aerosol treatments (specify, with O2, not medical air), for example, ? ventolin(r) 0.5-1cc + atrovent(r) 1-2cc + saline 3cc ? the initial aerosol ? may be followed prn by, 0.33cc ventolin(r) in 3-4cc saline q20 minutes X 1-6 doses. It may be useful to give saline aerosols between ventolin(r) aerosols for “pulmonary hydration” (may facilitate the expectoration of thick mucus plugs).
? pulmicort(r) may also be added to the initial ventolin(r)/atrovent aerosol, then as indicated.
(r) racemic epinephrine aerosol is also useful for moderate-severe bronchospasm, ( 0.5cc 2.25% in 4.5cc saline/100% O2. See also #(3), p.78.
Aminophylline I.V. ? give a loading dose prn ? 3-6mg/kg with 50cc D5W over 30 minutes ? maintenance 0.2-0.8mg/kg/hr ? do theophylline levels before and after prn; combining theophylline and erythromycin is contraindicated ? may result in toxic levels of theophylline. Theophylline† is not as popular as it once was, but I still use it frequently.
Solu-cortef(r) ? 3-5mg/kg q6h I.V., or solu-medrol(r) ? 1-2mg/kg q6h I.V.
(r) caution: stay well within the recommended doses, plus use the minimal dose and time required (recent out of court settlement {Canadian Medical Protective Association}, the patient developed bilateral avascular necrosis of the hips, following solu-medrol(r) therapy for an exacerbation of Crohn’s disease; informed consent recommended).
Prednisone ( 40mg daily x 5-10 days (instead of, or following a course of I.V. steroids).
Antibiotics ? if there is evidence of secondary infection, e.g. purulent sputum, pyrexia, sinusitis,‡ pneumonitis.
MgSO4 ? In addition to the standard treatment regimen, consider giving I.V. MgSO4 prn (e.g. adults 2-4+g) for moderate-severe bronchospasm (may alleviate the need for intubation?). See footnote, p. 142.
Asthma in pregnancy ? ventolin(r), theophylline, steroids, and certain antibiotics are ok (e.g. amoxil(r), erythromycin) ? avoid epinephrine in early pregnancy.
Anxiety?/hyperventilation? and/or subclinical bronchospasm? ? pulse oximetry, measure PEFR ? improvement with ventolin(r) aerosol?; pulmonary embolism?, ASA overdose?, metabolic acidosis?
COPD (chronic obstructive pulmonary disease) ? measure FEV1 and FVC.  (r) purulent sputum?, pneumonitis?, secondary infection with moraxella catarrhalis?
(r) ( ABC’s, 28%-100% O2 (caution), ventolin(r) aerosols prn, theophylline prn, steroids prn, antibiotics prn, monitor with clinical assessments and pulse oximetry/arterial blood gases. In addition, hydrate prn, keep in a position of respiratory comfort, MgSO4? (may alleviate the need for intubation?), admit ICU prn.
(r) insist that smokers, not smoke, at least not during their hospital stay (notation on the order sheet?/easy to write the order, but may not be so easy to implement).
°VIII. Gastrointestinal & Genitourinary Systems
(1) ONE
(A) Vasopressin ? 20 units in 200ml saline, over 40-80 minutes, for bleeding esophageal varices (not with ischemic heart or cerebral vascular disease), and/or sclerotherapy?.
(B) Esophageal perforation (e.g. trauma/iatrogenic?, Boerhaaves syndrome) ? ( ABC’s, 100% O2 prn, supportive care, and give antibiotics, for example, cefoxitin (mefoxin(r)) 3g or 40mg/kg I.V. (children), and clindamycin 600mg or 10mg/kg I.V. (children), for the inevitable mediastinitis while awaiting emergency surgery.
(C) Esophageal F.B. e.g. bolus of meat ? try glucagon 1mg I.V. ? repeat 2mg I.V. in 20 minutes prn ? refer prn (endoscopic intervention prn). Some clinicians are having the patients with esophageal f.b. (food) drink small amounts of soda pop e.g. cola. The gas may dilate the esophagus enough for the food to pass.
? Button batteries lodged in the esophagus need to be removed emergently.
(D) Peptic Ulcer ? Helicobacter pylori infection confirmed by gastroscopy/biopsy.
? ? (7 day regimen) Losec(r) 20mg bid, Biaxin(r) 500mg bid, and Flagyl(r) 500mg bid.
(2) TWO
(A) Toxic megacolon (r) complication of ulcerative colitis.
? air filled colon > 6cm, “thumb printing”.
? ABC’s, supportive care, I.V. ampicillin, clindamycin, and steroids. Immediate referral.
(B) Pseudomembranous enterocolitis ? usually follows a course of antibiotics, e.g. UTI.
? clostridium difficile infection.
? abdominal cramps and diarrhea, ( fever.
? ABC’s, supportive care, flagyl(r), or vancomycin, or bacitracin.
(3) Viral Hepatitis AntiHAv = hepatitis A antibody ? no subsequent carrier state, or chronic liver disease.
HBsAg = hepatitis B surface antigen ? persists in carriers.
AntiHBc = hepatitis B core antibody.
Hepatitis non A non B non C, D, E ? chronic hepatitis and carrier state ? no reliable screening method.
Hepatitis ? routine investigations = HBsAg, Igm AntiHBc, Igm AntiHAv, PT, PTT, sgot, and bilirubin. Also antibodies and RNA for the HC, HD, and HE viruses.
HB vaccine ? injection of HBsAg ? repeat at 1 and 6 months.
(r) a hepatitis A vaccine has recently become available. It can be given concurrently with the hepatitis B vaccine (same schedule), but at another site. The second injection can be given at two weeks, if rapid protection is required.
Immune globulin ? 0.02-0.06ml/kg for prevention of hepatitis A and non A/non B/non C?, D?, E?
HB immune globulin ? 0.06ml/kg for prevention of hepatitis B ? AIDS/Hepatitis ? cytomegalovirus?, toxoplasmosis?
? Drugs? (e.g. oral contraceptives), or other hepatotoxins (e.g. alcohol, mushrooms, untreated or unsuccessfully treated Tylenol(r) overdose occurring a few days before).
? referral to a hepatologist required?
(4) FOUR
(A) Portosystemic encephalopathy  ? ABC’s, supportive care, treat the precipitating cause (bleeding esophageal varices?), cleanse the gut (cathartics, enemas, neomycin, lactulose); flumazenil?
? spontaneous bacterial peritonitis?
? Caution: hemorrhoids may be the result of chronic liver disease/portal hypertension (undiagnosed?). Before incising hemorrhoids in the ER, satisfy yourself that the patient does not have, or is not a candidate for, portal hypertension.
(B) Acute pancreatitis (r) gallbladder disease?, alcohol abuse?, hyperlipidemia?, drugs?, trauma?, following an ERCP?
(r) with serum calcium less than 7mg/100ml ? poor prognosis.
(r) ( ABC’s, supportive care, analgesics prn, Zantac(r) I.V., ng tube prn, ultrasound prn, admit ICU prn.
(r) hemorrhagic pancreatitis?
(r) pancreatic pseudocyst?
(C) Infectious diarrhea ( ABC’s, supportive care, I.V. ringers, or po balanced electrolyte fluids prn. If empiric antibiotics are required, give ciprofloxacin 500mg bid po or 200-400mg q8h I.V. (covers for shigella, salmonella campylobacter, or E. Coli), plus metronidazole 250-750mg q8h po or I.V., if C. difficile, giardia, or amebiasis is suspected. AIDS/diarrhea ? consult references.
(5) Renal Failure (r) acute?, chronic?, acute on chronic?
? prerenal (e.g. shock), renal (e.g. nephritis, acute tubular necrosis) or postrenal (e.g. bladder outlet obstruction).
? oliguric renal failure (< 500 mL/urine/day), or nonoliguric (> 500 mL/day).
? ABC’s, balance the electrolytes (e.g. K+, NaCl), treat the underlying cause, diuretics may convert an oliguric to a non-oliguric failure, limit the fluids to 500ml plus the urine output, limit the protein, adequate nutrition (tube feeding or hyperalimentation prn), dopamine 1-3?g/kg/min prn, dialysis prn, renal biopsy prn.
(6) SIX
(A) Beware of post urinary retention diuresis, testicular torsion (doppler?), and testicular tumors (tumors ? painless ± hydrocele ? ultrasound and refer) ? blue-black dot sign = torsion of appendix testis; epididymitis/orchitis?, incarcerated hernia?
(B) Testicular torsion ? abrupt onset in mostly boys and young men ? may present with abdominal pain and vomiting ? the testicle is rotated internally (right clockwise, left counterclockwise).  ? distorsion attempt? ? rotate the testicle externally (prehn’s sign?, inject lidocaine at external inguinal ring?) ? immediate referral if the distorsion attempt is unsuccessful.
(C) Paraphimosis ? reduction attempt, dorsal slit prn, circumcision prn.
(D) Acute pyelonephritis ? ABC’s, supportive care, ampicillin or cephalosporin, treat any underlying problems, e.g. ureteral stone, diabetes mellitus.
(E) Renal colic analgesia ? e.g. morphine/demerol(r) I.V./I.M. Some clinicians are using toradol(r) (ketorolac) 30mg I.V./I.M. as a first line treatment. Toradol(r) frequently results in adequate analgesia, or may decrease the total amount of the narcotic required to control the renal colic (my impression).
? Remember that in addition to renal calculi, renal colic may be caused by blood clots from a bleeding renal carcinoma (a clue may be gross hematuria occurring hours before the renal colic). If an IVP reveals a renal carcinoma, obtain a chest xray, and look for pulmonary metastasis ? refer urology, CT scan.
°IX. Obstetrics & Gynecology
(1) Life threatening gynecological emergencies (r) ectopic pregnancy, ruptured hemorrhaging ovarian cyst, ruptured tubo-ovarian abscess, and trauma (e.g. vaginal tear with hypovolemic shock).
(2) Dysfunctional uterine bleeding (r) ectopic pregnancy?, endometritis?, endometriosis?
? ABC’s, ringers prn, CBC, X match, coagulation profile, serum beta-HCG pregnancy test, IUD?, ultrasound prn, culdocentesis prn, laparoscopic prn, conjugated estrogen (premarin(r)) 25mg I.V. prn over 10-15 minutes, repeat in 2-6 hrs prn, progesterone 100mg I.M. prn, ovral(r) prn, D and C prn ? pathology report? Do not omit a pregnancy test in women who have had a tubal ligation.
(3) Incomplete abortion (septic?) ? ABC’s, ringers prn, CBC, X match prn, coagulation profile, antibiotics prn, syntocin 80 units in 1 L ringers, 100cc wide open prn, then 100cc/hr prn ? D and C prn. Rh negative? ? WinRho SD(r) (120-300+µg) prn. Postpartum hemorrhage ? ? as above plus fundal massage prn (bimanual prn), and search for delivery trauma.
? Remember, abortion can be a very emotionally traumatic event, for both the patient and her partner, and can result in the eventual breakup of their relationship. They may or may not appear upset. Explain abortion’s inevitable nature and possible ramifications. Advise then not to hold back their grief.
(4) Chronic hypertension in pregnancy ?: for example, methyldopa, beta blockers, hydralazine.
(5) Asymptomatic bacteriuria in pregnancy (r) ?, for example, ampicillin, erythromycin.
(6) Preeclampsia with liver involvement (acute fatty liver) ? ABC’s ? urgent delivery, see #(7)(B), p. 118.
(7) Cholecystitis, pyelonephritis, and appendicitis (r) can be confused with one another, particularly in the third trimester.
(8) Third trimester bleeding (r) placenta previa?, abruptio placenta?
? ABC’s, fetal heart monitor prn ? ultrasound and referral ? prn examination in the OR with a double setup (do not perform a pelvic or rectal exam in the ER).
(9) Premature breech in labor ? ABC’s, fetal heart monitor ? refer ? c/section if the premature labor has not been arrested. See #(10), p.134.
(10) Early premature labor ? ABC’s, fetal heart monitor, bed rest, bolus 1+ liters of ringers, MgSO4 4g in 500cc of ringers I.V. over 10-30 minutes, and/or terbutaline 0.25mg s.c. ? refer.
(11) Premature rupture of membranes?  ? leaking vaginal fluid? ? nitrazine litmus paper ? alkaline?, avoid doing a pelvic exam in the ER ? refer.  (12) Questran(r) (r) ( 10-12g/po/daily for cholestatic jaundice of pregnancy.
(13) Heparin (r) ok for use in pregnancy ? oral anticoagulants are contraindicated.
(14) FOURTEEN
(A) Emergency delivery ? ABC’s, monitor the fetal heart ? fetal bradycardia? (prolapsed cord?, nuchal cord?) ? ? 100% O2, the patient lying on her left side, bolus(es) ringers, and for tetanic contractions give MgSO4 4 grams in 500cc ringers I.V. over 10-30 minutes, and/or terbutaline 0.25mg s.c. ? refer prn, if time permits. Postpartum ? remember to keep the newborn warm. Beware of the patient arriving at the ER, in labor, delivery imminent, who at triage makes no mention of, or denies, pregnancy (soon to be grandparents are also unaware). I have seen four such patients in the past ten years, fortunately turning out to be a happy event for everyone involved (the element of surprise is very effective).
(B) Third trimester blunt abdominal trauma ? abruptio placenta?, ruptured uterus?
? ? ACBC’s, 100% O2 prn, the patient lying on her left side prn (cervical spine ok?), fetal heart monitoring prn, ultrasound prn, consult obstetrics prn, extended observation prn, DIC?
(C) Third trimester cardiac arrest ? if salvage of a live infant is possible, perform a classical cesarean section after ( 4 minutes of unsuccessful BCLS/ACLS, while continuing resuscitation efforts.
? a desperate situation with minimal time to obtain the services of an obstetrician. You may have to “go it alone.”
(15) Pid ± perihepatitis (IUD?) ? ABC’s, supportive care, analgesics prn, amoxil(r) 3g + probenecid 1g po, plus vibramycin(r) 100mg bid po X 2 weeks, or gentamycin and clindamycin I.V. See also #(A), p.178.
(16) Sixteen
(A) Candida smear  ? add 2gtts of 10% potassium hydroxide ? ? nystatin prn (or for example, miconazole or fluconazole).
Clue cells = bacteria adhered to epithelial cells ? gardnerella vaginitis ? ? flagyl(r) 2g po, or flagyl(r) vaginal cream in pregnancy (caution in the first trimester).
Trichomonas ? flagyl(r) 2g po, or in pregnancy flagyl(r) vaginal cream (caution in the first trimester).
Chlamydia ? vibramycin(r) 100mg bid po X 7-10 days (erythromycin in pregnancy).
? chlamydia infection may present as an acute arthritis. See #(4)(B), p.179.
Acyclovir§ 5-10+mg/kg/q8h I.V., or 200-400-800mg q4-8-12h po (consult references) ? for herpes simplex, herpes zoster, or chickenpox, particularly in immunosuppressed patients (acyclovir safe in pregnancy??). Herpes simplex encephalitis requires early presumptive I.V. acyclovir (consult references). Caution: intravenous acyclovir may cause reversible renal toxicity.
Pregnancy prophylaxis ? ? e.g. ovral(r) tabs II stat, and repeat in 12 hrs. Give with gravol(r) (dimenhydrinate) prn for nausea, pregnancy test 1st prn (serum ICON?). Follow-up pregnancy test in 3-4 weeks prn (offer therapeutic abortion prn because of an increased teratogenic risk).
(B) Diclectin(r) (doxylamine 10mg/pyridoxine 10mg) (r) is approved in Canada for the treatment of the nausea and vomiting of pregnancy, ( tabs II h.s., plus tab I a.m. prn, and tab I p.m. prn.
°X. Pediatrics
(2nd of 2 sections) ? See also Pediatrics (first of two sections), p. 103.
(1) Near miss SIDS  ? seizure?, sepsis?, pertussis?, child abuse?
(r) ( ABC’s, 100% O2 prn, supportive care, refer for immediate pediatric assessment.
(r) it is now recommended that babies sleep on their back, or their side.
(2) Pediatric heart disease Common presentations: cyanosis, murmurs, abnormal pulses, hypertension, syncope, CHF, (infants/dyspnea with feeding?), cardiogenic shock, and tachyrhythmia.
? Patients with congenital heart disease, and a right to left shunt, may tolerate blood loss poorly, and may require an early transfusion of packed red cells. In addition, be careful with I.V. therapy ? air bubbles ? across right to left shunt ? systemic air embolism.
(r) the B/p cuff should cover 2/3 to 3/4 of the infants’ upper arm, or forearm.
1. Tetralogy of Fallot with a hypercyanotic spell ? ABC’s, 100% O2, knee-chest position, I.V. morphine 0.1-0.2mg/kg/I.V. prn, bolus(es) ringers prn, hypoglycemia?, acidosis?, emergent cardiology consult.
2. Cardioversion (r) consult anesthesia/cardiology if time permits. See also #(7), p.109.
3. SVT (narrow complex) (r) ? ABC’s, 100% O2 prn, vagal manoeuvres prn, < 2 years of age ( digoxin prn, 5-20(g/kg/I.V./initial digitalizing dose; > 2 years of age, verapamil prn, 0.075-0.15mg/kg I.V.; cardioversion 0.25-1 joules/kg prn (usually synchronized, ± sedation/general anesthesia prn, e.g. valium(r) 0.2mg/kg I.V. prn). Adenosine 0.1mg/kg/I.V. may be used instead of digoxin or verapamil, and has become the drug of choice for patients under 2 years of age. WPW? ? verapamil and digoxin are both contraindicated. See #(19), p.93.
4. Atrial fibrillation or flutter ? ABC’s, 100% O2 prn, digoxin prn, 5-20(g/kg/I.V./initial digitalizing dose (no digoxin with WPW), procainamide 2mg/kg I.V. prn, up to 10-15mg/kg prn (careful; see #(13)(A), p.91), cardiovert prn (usually synchronized, ± sedation/general anesthesia prn).
5. Wide complex tachycardia (including ventricular tachycardia) ? ABC’s, 100% O2 prn, lidocaine 1mg/kg/I.V. prn, procainamide prn (see above ( atrial fib/flutter), cardiovert prn (usually synchronized, ± sedation/general anesthesia prn). No digoxin or verapamil.
6. Ventricular fibrillation and bradyarrhythmias (r) ? similar to adults using pediatric doses, see also #(2)4, (C), (D) (p. 76), #(2)(p. 86), # (4) (p.107), #(7) (p.109).
? pediatric cardiac arrest is frequently secondary to, for example, respiratory dysfunction or shock.
7. Congestive heart failure ? congenital heart disease?, dilated cardiomyopathy?
? ABC’s, 100% O2 prn, morphine 0.1mg/kg I.V. prn, lasix 1mg I.V. prn, dopamine prn, digitalize prn.
8. Hypertrophic cardiomyopathy ? dyspnea, chest pain, syncope, ± physical findings.
? may result in sudden death.
? ABC’s, 100% O2 prn, EKG, echocardiogram, beta or calcium blockers prn, refer.
9. Kawasaki Disease ? vasculitis (coronaries?), conjunctivitis, lymphadenitis, erythema of lips, tongue, hands and feet.
? ABC’s, EKG, echocardiogram, gamma globulin, ASA, refer.
(3) Pneumonias ? cough (may be minimal), ± fever, ± tachypnea, ( rales/rhonchi/bronchospasm.
? bacterial?, mycoplasma?, chlamydia?, viral?, cystic fibrosis/sweat test?
? ? ABC’s, position of respiratory comfort, 100% O2 prn, ventolin(r) aerosols prn, hydrate prn, antibiotics prn, refer prn.
(4) Gonorrhea in children = sexual abuse.
? amoxil(r) 50mg/kg, plus probenecid 25mg/kg to one gram, and child protection.
(5) Antibiotics
Amoxil 40+mg/kg/day
Erythromycin 50+mg/kg/day
Clarithromycin 15mg/kg/day Keflex(r) 50+mg/kg/day
Keflin(r) 50+mg/kg/day
Cloxacillin 50+mg/kg/day
(6) Sepsis and meningitis in children (r) See also #(1) p.103, #(5)(A) p.180.
? begin antibiotic treatment < 30 minutes, or as soon as feasible.
? ABC’s, 100% O2 prn, supportive care, antibiotics, dexamethasone? (decreased incidence of permanent hearing loss with meningitis?)**. Hypoglycemia?, septic shock?, DIC?, seizures? increased intracranial pressure?
? infants may present with fever, irritability, lethargy, and poor feeding (fever may be absent).  (r) beware of herpes simplex encephalitis. See #(5)(B), p.182.
Antibiotic regimen #1: < 7 days of age gentamycin 5mg/kg/day/q12h/I.V. and ampicillin 100mg/kg/day/q12h/I.V.
> 7 days < 1 month gentamycin 7.5mg/kg/day/q4h/I.V. and ampicillin 200mg/kg/day/q4h/I.V.
> 1 month ampicillin 300mg/kg/day/q4h/I.V. and chloramplenical 100mg/kg/day/q4h/I.V.
or Antibiotic regimen #2: claforan(r) (cefotaxime) 80-200mg/kg/day/I.V. (q12-8-6-4h), plus in the 1st  three months of life ampicillin 100mg/kg/day/I.V.
Meningitis prophylaxis ? rifampin ? adults 600mg bid X 2 days.
? 1 month to 12 years of age, 10mg/kg/bid X 2 days.
? < 1 month, 5mg/kg/bid X 2 days.
(7) SEVEN
(A) Asthma (r) ± secondary infection ? bronchospasm(± cough, ± audible wheezing), bronchoedema, and increased mucus production ? hypoxemia, respiratory acidosis, and metabolic acidosis ? may progress to respiratory/cardiac arrest.
? ABC’s, position of respiratory comfort, humidified 50-100% O2 prn, ventolin(r) ( atrovent(r) aerosols prn/racemic epinephrine aerosols prn, MgSO4?†† (may alleviate the need for intubation?), steroids prn, theophylline prn, hydrate prn, antibiotics prn. Monitor with clinical assessments, PEFR, pulse oximetry, and arterial blood gases. Extended stay in the ER?, admit ICU? See also #(8)-(10) pp. 143-144, #(5) p. 124, footnote p. 126, #(2)(E) p. 171.
(r) rule out other less common causes of wheezing, for example, bronchiolitis, foreign body, cystic fibrosis, CHF (r) stridor not wheezing?; asthma trigger?, e.g. allergy, infection, smoker/second hand smoke‡‡; previous severe asthmatic episodes/admissions to ICU?
(B) Bronchiolitis (respiratory syncytial virus) ? may progress to apnea.
? RSV rapid slide test/culture ? ABC’s, position of respiratory comfort, humidified 50-100% O2 prn, ventolin(r) aerosols prn, and other bronchodilators prn (See also #(8)-(10), pp. 143-144), hydrate prn, ribavirin aerosols.
(8) Aminophylline ? 5-7mg/kg/I.V. loading dose prn ? maintenance 0.6-1.2/kg/hr/I.V.
? before and after theophylline levels prn ? theophylline 5mg/kg/qid/po (r) some pediatricians use aminophylline only in the seriously ill.
(9) Corticosteroids (r) See also #(5), p.124 Solu-medrol(r) ? 1-2mg/kg/I.V./q 6h prn Solu-cortef(r) ( 3-5mg/kg/I.V./q 6h prn Decadron(r) ? 0.25-0.6mg/kg/I.V./I.M. q 6h prn Prednisone ? 1-2mg/kg/po/OD X 3-5 days (short course for asthma) (r) patients who develop chickenpox within three weeks of receiving steroids, may require intravenous acyclovir.
(10) TEN
(A) Adrenaline 1:1000 ( 0.01ml/kg to maximum of 0.3cc s.c.
(B) Aerosols ? measure the PEFR before and after each aerosol treatment (if feasible).
(r) with O2 when available, rather than medical air, be specific.
? e.g. ventolin(r) 0.03cc/kg to 0.5-1.0cc + atrovent(r) 0.5-1.0cc (5-12yrs) + saline 3cc ? the initial aerosol treatment may be followed prn by ventolin(r), 0.01cc/kg in 3cc saline q 20 minutes X 6 doses.
(r) ( e.g. racemic epinephrine 0.5cc 2.25% in 4.5cc saline.
(C) Antibiotics (r) have no role in asthma except when bacterial infection is documented (e.g. sinusitis, pneumonitis), or strongly suspected (e.g. toxic appearing patient).
(11) Reye’s syndrome ? liver and brain dysfunction ? elevated blood ammonia, hypoglycemia, no jaundice, cerebral edema ? the liver biopsy is diagnostic.
? ? ABC’s, supportive care, immediate referral.
(12) Mannitol 20% ? for emergency ( of increased intracranial pressure/cerebral edema.
(r) ? 5-10cc (1-2g)/kg/I.V. over 30-60 minutes (caution).
? See also #(1), p.215.
(13) Infantile spasms ? ( ABC’s, supportive care, urgent pediatric neurology consult (the EEG will be abnormal).
(14) FOURTEEN
(A) Seizures in children (r) See also #(5), p.108 ? focal component?, secondary cause? (e.g. febrile?, meningitis?, trauma?, child abuse/shaken baby syndrome?, hypoglycemia?/chemstrip, alcohol?, overdose/drugs?, inadequate anticonvulsant therapy/compliance?, intracranial hemorrhage?, brain tumor or abscess?). Aspiration of stomach contents?, and/or head/neck injury? from seizure/fall. Do not confuse decerebrate posturing with seizures.
Status epilepticus ? the distinct possibility of permanent neurological damage if the seizures are not terminated within 30-60 minutes (subtle seizure activity?).
? fever, leukocytosis, (CPK, metabolic acidosis (bicarb prn).
1. ? ACBC’s, 100% O2 ? blood work ? chemstrip, anticonvulsant levels, etc., hypo/ hypernatremia?, hypocalcemia?, hypomagnesemia?, hyperkalemia?, myoglobinuria?
2. Dextrose 10-25% 2ml/kg/I.V. prn. (thiamine prn, pyridoxine prn).
? seizures increase the brain’s requirements for glucose.
3. Valium(r) 1mg/year of age to 10mg, or 0.2mg/kg/I.V. (rectal route prn 0.5mg/kg) 4. Dilantin(r) 15mg/kg/I.V. (loading dose) over 30-60 minutes (with cardiac monitoring).
5. Repeat valium(r) prn to a total dose of 2.6mg/kg/I.V.
6. Add phenobarb 15mg/kg/I.V. prn (loading dose).
7. Add lidocaine 2mg/kg/I.V. prn ? 1mg/kg/hr drip.
8. General anesthetic prn.
9. EEG? ? seizure arrest real or apparent? (continuous EEG monitoring prn).
10. CT scan?, MRI?, LP? (after the seizures are terminated).
(B) Febrile seizures ? ABC’s, 100% O2 prn, dextrose I.V. prn, valium(r) I.V. or per rectum prn, tylenol(r) rectal suppositories prn, cooling prn (no rubbing alcohol); rule out, for example, hypoglycemia, sepsis/meningitis, trauma, alcohol poisoning, drug overdose, e.g. salicylates.
(15) Fifteen Campylobacter
(r) ? erythromycin 50mg/kg/day/po Yersinia
??? bactrim(r): 3mg trimethoprim + 15mg sulfamethoxazole/ kg/bid/po Clostridium difficile
(r) ? flagyl(r) 25mg/kg/day/po
(A) Child abuse (r) psychological, physical, sexual, and neglect ? Discrepancies in history/physical?, atypical injuries and locations?, e.g. cigarette burns, buttock contusions; multisystem injuries?, e.g. CNS, skin, bone, abdomen; evidence of neglect and poor supervision?, e.g. failure to thrive, alcoholic or drug abusing parents; evidence of sexual abuse, e.g. gonorrhea (HIV status?).
? shaken baby syndrome ? coma/seizures, ± retinal hemorrhages, ± new or healing rib/extremity fractures, ± other injuries.
(r) Munchausen’s by proxy, e.g. apnea spells, sepsis, poisoning.
? bruises ? red-blue (1 day old) ? green (5 days) ? yellow (7 days) ? brown (10 days) ? remember that mongolian spots or folk remedies may simulate bruises.
? coagulation studies?, skeletal survey?, CT scan?, MRI?
? parent/caretaker volunteers that they were abused as a child?
? ACBC’s, supportive care, rule out legitimate injuries/illness, e.g. accidental burns, leukemia; treat other problems, e.g. injuries, STD (sexually transmitted disease); pregnancy test/prophylaxis prn (ovral(r) prn), colposcopy/forensic examination prn (photos prn), child protection, appropriate reporting, counseling, admit prn.
(r) postscript (r) society continues to pay an ever increasing price (e.g. violence, substance abuse, family discord, and other dysfunctional behaviours), for the inappropriate care, neglect, and abuse of its children (my impression).
(16) Seventeen (r) beware of entrapment/tourniquet injuries of the penis and digits in infants (e.g. hair, clothing material).
°XI. Endocrinology & Hematology
(1) Unexplained? hypoglycemia  ? Pancreatic or other tumors?, drugs?, e.g. alcohol; endocrine disorder?, e.g. myxedema; surreptitious administration of insulin or oral hypoglycemic agents?
? seizures?, coma?, confusion or bizarre behaviour?
? do a serum glucose, a serum insulin, insulin antibodies, and c-peptide levels prn.
? ABC’s, I.V. dextrose prn ? 5, 10, 25, or 50% prn, glucagon 1-5mg I.V. prn, Solu-cortef(r) 250mg I.V. prn, and diazoxide 300mg I.V. prn over 30minutes. Treat other problems, e.g. hypothyroidism. Alcoholics require thiamine 100mg I.M./I.V.
? hypoglycemia may simulate a CVA, especially in the elderly (including focal deficits).
(r) ketotic hypoglycemia can occur in children 1-5 ( years of age.
Oral hypoglycemic agents ? beware of prolonged hypoglycemic effect (hours, days).
(2) Diabetic ketoacidosis (DKA) (r) undiagnosed diabetic?
? hyperglycemia, dehydration, electrolyte loss, and metabolic acidosis.
? kussmaul breathing?, vomiting?, coma?, shock?, other problems?, e.g. pneumonitis, trauma. Preexisting medical problems?, e.g. chronic renal failure plus DKA may result in life threatening hyperkalemia.
? ? ABC’s, I.V. fluids/lytes (K+ prn, bicarbonate prn, NaCl prn {saline, ringers}, phosphate?, Mg?, Ca?), low dose I.V. insulin drip, and ? precipitating cause, e.g. UTI, MI, trauma. Use a flow sheet (assessments, investigations {e.g. blood gases, lytes, glucose}, and therapeutic measures).
(r) Admit ICU prn (r) the patient may require invasive monitoring, e.g. history of CHF.
? Give boluses of normal saline/ringers for dehydration/shock (20mL/kg in children).
? Add 40meq KCl/liter to 0.5-N saline once urine output begins (if not hyperkalemic), or before if the T waves are flat (serum K+ pending) or the serum K+ is low.  (r) Beware of an initial hyperkalemia, e.g. concomitant acute or chronic renal failure (peaked T waves and wide QRS) ? emergency ? prn (r) sodium bicarbonate 1meq/kg/I.V. prn, calcium gluconate 10% 5-10mL I.V. prn (0.2mL/kg in children), bolus regular insulin 10 units I.V. (0.1 unit/kg in children), and bolus normal saline 1-2liters (20mL/kg in children).
? give sodium bicarbonate 1-2meq/kg I.V. prn for pH < 7.1 (over (-2 hours, no I.V. push except if the patient is critical: caution ? be on the alert for hypokalemia, hypomagnesemia, and paradoxical cerebral acidosis/edema).
? replace 1/2 of the fluid (+ maintenance), and electrolyte deficits over the 1st 8-12 hours (after the initial saline boluses prn). The total deficits may be Na 9 mEq/kg, K+ 2-6 mEq/kg, and fluids 100mL/kg. The patient may also require MgSO4, calcium, or phosphate. See also #(17)-(22), pp. 82-85.
Regular insulin (low dose I.V. drip)   ? children ??0.1unit/kg/hr/I.V.
adults ??5-10units/hr/I.V.
? also give an initial I.V. bolus of insulin equal to a one hour’s dose.
When serum glucose is reduced to 250mg (14mmol/L), add dextrose to I.V., and continue I.V. insulin until acidosis clears, then give insulin/sliding scale s.c. (as follows).
SLIDING SCALE REGULAR INSULIN qid s.c.
serum glucose     insulin (dose may vary) 5 – 10 mmol/L (90 – 180mg/100mL) ( 2-4 units s.c.
10 – 15 mmol/L (180 – 270mg/100mL) ? 4- 6 units s.c.
15 – 20 mmol/L (270 – 360mg/100mL) ? 6- 8 units s.c.  20+ mmol/L (360+mg/100mL) ? 8-10 units s.c.
(3) Alcoholic ketoacidosis ? hyperventilation, dehydration, electrolyte loss, metabolic acidosis.
? ACBC’s, thiamine, 50% dextrose prn, D5ringers, bicarb?, phosphate?, and treat other problems, e.g. pancreatitis, alcohol ( other drug withdrawal.
(4) Lactic acidosis ? hyperventilation, weakness, otherwise unexplained high anion gap (e.g. salicylates), lactic acid ? 7mmol/L. Methanol poisoning?
? ABC’s, I.V. fluids, bicarb prn to pH 7.2+ (careful: paradoxical CSF acidosis, hyperosmolality); hemodialysis prn, and ? underlying cause, e.g. sepsis, near drowning.
(5) Nonketotic hyperosmolar coma (r) underlying heart or renal failure?
? weakness, dehydration, confusion to coma.
? ABC’s, I.V. fluids/lytes (substantial loss), low dose I.V. insulin drip, and ? precipitating cause, e.g. CVA, pneumonitis. See also #(2), p.149.
(6) Thyroid storm ? signs of thyrotoxicosis, plus fever, dehydration, and cardiovascular, CNS, and GI dysfunction (beware of apathetic hyperthyroidism in the elderly).
? initial blood work (e.g. T3, T4, free thyroxin, cortisol).
? ABC’s, supportive care, I.V. fluids/lytes, 50% dextrose prn, multivitamins prn, cooling/Tylenol(r) prn (no ASA), treat the precipitating cause (e.g. pyelonephritis), and specific treatment, as follows, (: 1. Propylthiouracil (inhibits thyroid hormone synthesis, and T4 ? T3 conversion) ? 900-1200mg po stat ? 300mg q6h prn ? then 300-600mg/day X 3-6 weeks.
2. Iodine solution (blocks hormone release) ? start 2 hours after the propylthiouracil has been given ? 30 gtts po/day X 10-14 days.
3. Inderal(r) (beta blockade) 1mg I.V. prn, to total of 10mg ? 20-120mg q6h po (blocks thyroxin’s peripheral effects, and T4 to T3 conversion).
4. Solu-cortef(r) 250mg q6h I.V. for “stress”, also blocks thyroxin release, and peripheral T4 to T3 conversion.
5. Plasmapheresis prn, dialysis prn, RAI (later prn).
? patient requires admission to ICU.
(7) Myxedema coma  ? manifestations of hypothyroidism, plus CNS, respiratory, cardiovascular, and metabolic dysfunction. The elderly may have an atypical presentation.
? do routine bloodwork, EKG, chest x-ray, plus T4, T3, TSH, and cortisol levels.
? you may have to initiate specific ( before laboratory confirmation.
? ? ABC’s and supportive care, 50-100% O2 prn, 50% dextrose prn, ringers prn, Solu-cortef(r) 100-500mg q4-6h I.V., thyroxin 500?g I.V. (after the initial dose of Solu-cortef(r)), then 100?g I.V. daily. Treat any other problems (e.g. hypothermia, hyponatremia), or precipitating cause, for example, pneumonitis, UTI. Caution with underlying heart disease, ( of hypothyroidism may precipitate CHF/angina/MI. ICU admission is required.
(8) Adrenal crises ? abrupt cessation of prednisone therapy?
? sepsis?/anticoagulant therapy?/adrenal hemorrhage?
? lethargy, fever, shock, nausea, vomiting.
(r) the diagnosis of subacute adrenal failure is often missed, or delayed.
? order routine bloodwork, plus ACTH and cortisol levels (also do ACTH testing if appropriate).
? ? ABC’s, D5saline boluses prn, bicarb prn for hyperkalemia, Solu-cortef(r) 500mg I.V. (initial dose), dopamine prn, and treat any precipitating cause that may have converted a chronic adrenal insufficiency into an acute crises, e.g. pneumonitis, trauma.
(9) Nine (A) Platelets (r) ABO matching is not required (r) 10 packs of platelets will raise the platelet count by approximately 40-50,000, children ? 0.2 packs/kg body wt.
? platelet count greater than 50,000 is OK; less than 20,000 is critical, e.g. substantial risk of CNS hemorrhage.
? follow with frequent platelet counts prn. See #(11), p.154.
(B) Fresh frozen plasma ? ABO matching is required: contains all the clotting factors (1 unit/cc).
(C) Cryoprecipitate ? no ABO matching is required: contains factor 8, fibrinogen (5-10units/cc), and Von Willebrand’s factor. Normal fibrinogen levels = 200-400 mg/dl. Caution: can your blood agency assure the safety of their cryoprecipitate? (e.g. HIV, HB, HC).
(10) Hypoprothrombinemia (r) e.g. excessive warfarin therapy (r) ? vitamin K 2.5-25mg po/s.c./I.M. ? repeat prn. Caution: I.V. vitamin K has reportedly resulted in anaphylactoid like reactions, and death.
(11) ELEVEN
(A) Idiopathic? thrombocytopenia purpura ? acute?, chronic?; DIC?, drugs? (e.g. antibiotics), infection? (e.g. infectious mono), alcohol? (resolves with abstinence?), AIDS?, neoplasm?, collagen disease?, transfusion reaction?, idiopathic?
? ? ABC’s, platelets prn, immune globulin prn, steroids prn, ? any underlying cause.
? platelets (10 packs/adults) may have to be given before and after the initial dose of the immune globulin (400-1000mg/kg/I.V.). Frequent platelet counts prn. See #(9), p.153.
(B) Thrombotic thrombocytopenic purpura ? thrombocytopenia, hemolytic anemia, red cell fragmentation; systemic, neurological, and renal manifestations.
? ABC’s, plasmapheresis, platelets prn, prbc’s prn.
? early intense plasmapheresis can be crucial for patient survival.
(C) DIC (Disseminated Intravascular Coagulation)  (r) may have an acute or subacute presentation (r) DIC screen: platelet count, PT, PTT, fibrinogen, fibrin degradation products.
? ABC’s, treat the precipitating cause (e.g. sepsis, trauma, shock, burns, heat stroke, head injury, transfusion reaction, cancer, obstetrical problems), I.V. heparin prn, PRBC’s prn, FFP or cryoprecipitate prn, and platelets prn. Fibrinogen should be kept above 150mg/dL (15 bags of cryoprecipitate ? approximate increase of 100mg/dL in the fibrinogen level), and the platelet count kept above 50,000 (10 packs platelets (r) an increase of 40-50,000 in the platelet count/children 0.2 packs/kg body wt). Caution: See also Cryoprecipitate, #(9)(C), p. 154.
(12) Hemophilia ? ABC’s, local pressure ± local thrombin prn, desmopressin (DDAVP) 0.3?g/kg I.V. prn (for hemophilia A, or type I von Willebrand’s disease, consult references), factor VIII/IX concentrate prn, cryoprecipitate 18-45units/kg q8-12h prn, up to 80 units/kg prn with intracranial bleeding, or serious trauma, (circulatory factor VIII/IX inhibitors present?).
? Fresh frozen plasma (FFP) may be used, but may result in volume overload.
? give prophylactic factor VIII/IX concentrate prn with head injury or major trauma.
? also ice packs, ace bandages, splinting, analgesics (I.V. narcotics?), and steroids prn.
? hemophilia occurs in males only, von Willebrand’s disease occurs in both sexes.
? Caution: See also Cryoprecipitate, #(9)(C), p. 154.
(13) THIRTEEN
(A) Autoimmune hemolytic anemia (r) etiology, for example, drugs, collagen diseases, infectious mono, mycoplasma infection, mushroom poisoning.
? ABC’s, prednisone/solu-cortef(r) prn, PRBC’s prn, treat the underlying problems, e.g. discontinue causative drugs.
(B) Sickle cell crises ? thrombotic, hemolytic, aplastic, or splenic sequestration crises; sepsis, and acute chest syndrome.
? ABC’s, 50-100% O2 prn, analgesics prn (I.V. narcotics?), I.V. fluids prn, PRBC’s prn (partial exchange transfusion?), and folic acid (5-20+mg daily). Treat infection (salmonella septic arthritis?), and metabolic acidosis if present. Beware of drug addiction and drug seeking behaviour. Autosplenectomy?
(C) Acute leukemia ? ABC’s, supportive care: beware of infection, thrombocytopenia, and DIC. Refer immediately.
(D) Infectious mononucleosis (r) beware of upper airway obstruction, encephalitis, hepatitis, thrombocytopenia, and splenic enlargement (may rupture from minor trauma).  ? ABC’s, supportive care, analgesics/antipyretics prn, prednisone prn, platelets prn. Avoid contact sports with splenomegaly. Concomitant strep. infection?
? infectious mononucleosis often simulates bacterial tonsillitis.
(14) Massive blood transfusions ? watch for a decrease in the coagulation factors (give FFP & platelets prn), ARDS (use micropore filters), hypothermia (warm transfusion products), and hypocalcemia (give calcium gluconate 10% 1-10ml slowly I.V. prn).
(15) Transfusion reactions ? febrile reactions (use washed, leucocyte poor, PRBC’s), allergic reactions (e.g. urticaria, anaphylaxis), delayed reactions (e.g. serum sickness, hepatitis B), or hemolytic reactions. Hemolytic reactions are the most life threatening, and may result in, for example, anaphylaxis, shock, DIC, renal failure. Using washed PRBC’s prevents most allergic reactions.
(16) Sepsis in immunosuppressed patients ? triple antibiotic therapy ? e.g. claforan(r) (cefotaxime) + tobramycin + clindamycin ? See also Septic Shock, p. 99.
(17) Emergency complications of malignancy ? for example, upper airway obstruction, pericardial tamponade, thrombocytopenia and hemorrhage, adrenal insufficiency and shock, acute tumor lysis syndrome, superior vena cava syndrome, acute spinal cord compression, CNS problems (e.g. seizures), hypercalcemia, SIADH, hyperviscosity syndrome, granulocytopenia, immunosuppression, infection, opportunistic infection, and sepsis.
? inadequate pain control is a frequent urgent/emergent problem of malignancy (call your palliative care consultant prn).
Remember that patients with moderate/severe chronic pain§§ may appear exhausted and depressed, rather than anxious. Trust the patient’s assessment of the severity of their pain (e.g. zero to ten = none to the most severe). Like migraine sufferers, patients with chronic pain syndrome or cancer pain may need parental analgesics for “breakthrough pain.”
Examples of the drugs and treatment modalities used (in combination prn) for chronic cancer pain (e.g. bone and/or neuropathic pain, and/or visceral pain) are: (1) morphine ? regular dosing, plus prn for breakthrough pain, no fixed upper limit dosage, addiction rare with cancer pain, (2) codeine, (3) NSAIDs, (4) acetaminophen, (5) amitriptyline, (6) carbamazepine, (7) dexamethasone, (8) antiemetics (e.g. prochlorperazine, metoclopramide, dimenhydrinate), (9) radiotherapy, (10) chemotherapy, and (11) nerve blocks. NSAIDs are useful for bone pain; tricyclic antidepressants, corticosteroids, and anticonvulsants are useful for neuropathic pain.
(r) In addition to morphine and codeine, other useful narcotics are: hydromorphone, oxycodone, fentanyl (may be given transdermally), and demerol(r) (short term only). Do not forget to put the patient on a regimen of a stool softener and a bowel stimulant. Except for the initial relief of pain (e.g. morphine 10mg plus gravol(r) 50mg plus toradol(r) 30mg I.M.), try to avoid giving analgesics via the intramuscular route for chronic cancer pain.
°XII. Central Nervous System
(2nd of 2 sections) (r) See also Central Nervous System (first of two sections), p. 100.
(1) Headache ? new headache?, acute and recurrent?, chronic?, progressive?, level of consciousness?, nausea/vomiting? (glaucoma?), pyrexia?, meningeal irritation?, focal signs?, photophobia?
(r) beware of headaches in young children (neoplasm?) ? pain in front of the external auditory meatus = fifth cranial nerve, and above the tentorium.
? pain behind the external auditory meatus = 9, 10, and 11th cranial nerves, and below the tentorium.
Severe migraine*** (rebound analgesic-induced headache?) ? first satisfy yourself that this is not an intracranial hemorrhage/neoplasm, e.g. “Are you sure this is your migraine?” “Yes, I am positive.” ? continue your complete assessment.
? try I.V. stemetil(r) (compazine, prochlorperazine) 10-20mg, or nozinan(r) (methotrimeprazine) 10-25mg, in 500-1000cc ringers over 30minutes, followed by 500-1000cc ringers wide open††† ? prn benadryl(r) 50mg I.V./I.M. for agitation, or dystonic reactions, or prevention of same.
This stemetil(r)( regimen may also be useful for viral gastroenteritis (some patients say it’s “like magic”). Stemetil(r) (10-20mg) and nozinan(r) (25-50mg) may also be given I.M.
Another alternative analgesic for severe migraine, or other causes of severe pain (e.g. renal or biliary colic), is the NSAID ketorolac (toradol(r)) 30mg I.M./I.V. (caution: allergic reactions; GI hemorrhage ? elderly). The response to parenteral toradol(r) can vary from remarkable pain relief, to absolutely no pain alleviation (but decreases the amount of narcotic required?). It is non-sedating, and is particularly useful in unaccompanied patients, who if discharged, may wish to drive themselves home.
? Other examples of non-narcotic ? of migraine are: ASA, Tylenol(r), NSAIDs, gravol(r), ergotamine (DHE), sumatriptan‡‡‡, 100% O2, nifedipine, I.V. fluids, maxeran(r), 1mL intranasal 4% xylocaine (cluster migraine), chlorpromazine, phenergan(r), dexamethasone ? narcotic required?, e.g. demerol(r) I.M. plus gravol(r) or stemetil(r) or nozinan(r) I.M. Beware of contributing to narcotic addiction and drug seeking behaviour. Always complete your assessment of the patient, before confronting them with their drug seeking behaviour (at times, it is very difficult to resist an initial confrontation).
Some emergency departments are attempting to all but eliminate the use of narcotics for the treatment of migraine headaches. I agree that the use of narcotics should be discouraged, but I can see no sense in switching the patient who gets the occasional injection of demerol(r) (which works, that’s why they ask specifically for it), to another medication. If you offer only non-narcotics to this distressed patient, they may feel that they were coerced§§§ into accepting another medication, and should any adverse reaction occur, they may think, “lawyer.” On the other hand, don’t be an “easy mark” for a narcotic or benzodiazepine prescription (or injection). The most I give “to go” is 5 tablets from the ER drug cupboard (no prescription), and refer them to their own physician for reassessment (some patients make a living off selling their prescribed narcotics/sedatives). In addition, unless contraindicated, prescribe NSAIDs (e.g. ibuprofen 400mg qid prn X 3-5days), to take in combination with the narcotic (prn) or tylenol(r) (prn). This is general analgesic advice not limited to migraines.
(Stemetil(r) is one of my favourite drugs. I have used “barrels of the stuff” I.V. mixed with ringers, and the only adverse reaction I have encountered to date is agitation, which has been quickly terminated with benadryl(r) 50mg intravenously. I find Stemetil useful for migraines, migraine-like headaches but not yet diagnosed as such, and the “flu” with nausea, vomiting, diarrhea, abdominal pain, and headache. I have also used it for “abdominal. pain nyd,” as a symptomatic treatment, while the patient is waiting for the investigations to be completed. On occasion, after the stemetil(r)/ringers infusion has been completed, the abdominal tenderness has been localized, making the diagnosis evident, e.g. acute appendicitis, gallbladder disease. Caution: the agitation from I.V. stemetil(r)/ringers, can be, on rare occasions, severe. For example, one patient, approximately five minutes after telling myself that she felt fine, ripped out her I.V., and without being seen by the nursing staff, “took off down the street,” and in a near panic state called her mother from a pay phone. The patient, accompanied by her mother, returned to the ER, and fortunately we were able to “smooth it over” (her migraine was gone).
Trigeminal neuralgia ? analgesics prn, tegretol(r) prn, dilantin(r) prn (initially I.V. prn), refer prn ? do not give erythromycin to patients on tegretol(r) ? toxic levels of tegretol(r). Also beware of tegretol(r) induced neutropenia.
Meningitis ? See #(5), p.180.
Subarachnoid Hemorrhage “worst headache I have ever had”  (unique headache, but not always severe) ? sudden onset?, on anticoagulants?, hemophiliac?
(r) Mental status may be depressed, or fluctuate due to intracranial vasospasm; ± nuchal rigidity, ± focal signs. Beware of warning leaks with bizarre, transient symptoms, e.g. pressure in one ear plus headache. CT scan negative? ? lumbar puncture prn.
? ABC’s, manage increased intracranial pressure prn ? intubate prn and hyperventilate with 100% O2 to a pCO2 of 25-30 prn, 50% dextrose 50cc or 1cc/kg I.V. prn, mannitol 20% 5-10cc/kg/I.V. prn, lasix 1-2mg/kg/I.V. prn, dexamethasone (decadron(r)) prn, initial dose 1mg/kg to 50mg I.V., (plus Zantac(r) 50mg I.V. for stress ulcer prophylaxis?); valium(r) and/or dilantin(r) I.V. prn for seizures or prevention of same ? immediate neurosurgical referral.  Space occupying lesion ? headache is constant, progressive, prolonged, and nonthrobbing ± focal signs ± focal seizures ? CT scan, or MRI and refer (e.g. brain abscess?, astrocytoma?, Ca of the lung with cerebral metastasis?).
Traumatic headache (See #(1), p.215) ? epidural?, acute or chronic subdural?
Temporal arteritis (age 50+?) ? headache, systemic symptoms, tender temporal artery, decreased ipsilateral visual acuity, sed. rate 50+ ? ? (on clinical impression), steroids e.g. prednisone 50mg OD; NSAIDs, analgesics, ? biopsy (semi-urgent) ? blindness, CVA, or seizures may result if the patient does not receive timely steroids.
Post LP headache ? beware: tension and/or migraine headache?, meningitis?, subarachnoid hemorrhage? ? manage appropriately.
? ? ABC’s, bedrest, I.V. fluids prn, analgesics/antinauseants prn, blood patch prn.
? I have found that the stemetil(r) drip (10mg in 500cc ringers), works.
Acute cerebellar hemorrhage ? headache, alert ? vertigo, vomiting, unable to stand, truncal ataxia ? progressing to coma, ± decerebrate posturing, ± pinpoint pupils, ± eyes deviated away from the side of the lesion.
(r) ? ABC’s, ? hypertension prn, and increased intracranial pressure prn ? the patient requires immediate neurosurgical decompression (also for traumatic posterior fossa hemorrhage).
Occipital neuralgia ? fingertip tenderness over the occipital nerve(s) ? may have a dramatic relief of the pain with the injection of the tender site(s) with, for example, 3-5cc 2% xylocaine plus 1cc of depo-medrol(r) (don’t forget to tell them it hurts!) ? similar results with local injections of xylocaine/depo-medrol(r) may also be achieved with, for example, an acutely painful tendonitis/bursitis of the shoulder, elbow, or knee. (The xylocaine/depo-medrol(r) injection being directed at the point of maximum tenderness; one of the “medical magic tricks” performed in the ER).
(2) Stroke syndromes (r) plus head/neck injury from fall?, hypoglycemia?, diabetes?, hypertension?, carotid artery disease?
TIA (resolves in < 24hrs), and RIND (resolves in 1-28 days).
? ? ABC’s, ASA prn, ticlid(r) (ticlopidine) prn, anticoagulants?, refer prn.
CVA (r) Thrombotic stroke (history of TIA?), and Embolic stroke (carotid artery disease?, carotid bruits?, atrial fibrillation?) ? ? ABC’s, supportive care, CT scan prn, MRI prn, lumbar puncture prn, anticoagulants prn (cardiac emboli?), refer prn. Thrombolytic therapy (tPA, not streptokinase) is now being utilized for thrombotic stroke (less than 3 hours old, no contraindications present, CT scan ok, e.g. no hemorrhage).
(r) Hemorrhagic stroke: e.g. subarachnoid, intracerebral, and cerebellar hemorrhages (see also #(1), p.160-165). ( ABC’s, supportive care (for example, management of seizures, increased ICP, hypertension), CT scan, and immediate neurosurgical consultation.
(r) Hypertensive hemorrhagic stroke ? reduce the diastolic blood pressure to the 100 range. (r) see also #(7)(A), p. 118.
? the eyes are deviated towards an inactive cortex lesion (e.g. CVA), and away from an active cortex lesion (e.g. seizure), or an infratentorial lesion.
(3) Seizures in adults ? focal component?, secondary cause? (e.g. meningitis?, trauma?, hypoglycemia? {chemstrip?}, alcohol?, overdose/drugs?, inadequate anticonvulsant therapy/compliance?, intracranial hemorrhage?, brain tumor or abscess?). Aspiration?, and/or head/neck injury? from seizure/fall, posterior shoulder dislocation?. Do not confuse decerebrate posturing with seizures.
Status epilepticus ? the distinct possibility of permanent neurological damage, if the seizures are not terminated within 30-60 minutes (subtle seizure activity?).
(r) pyrexia, leukocytosis, (CPK, metabolic acidosis (bicarb prn).
? ACBC’s, 100% O2 ? bloodwork (+ chemstrip)? anticonvulsant levels etc., hypo/ hypernatremia?, hypocalcemia?, hypomagnesemia, hyperkalemia?, myoglobinuria?
? Thiamine 100mg I.V. prn (pyridoxine prn, see #(17)(B), p.194) (r) Dextrose 50% 50cc I.V. prn (seizures increase the brain’s requirements for glucose).
? Diazepam 5-10mg I.V. prn. (rectal route prn, e.g. 20mg) ? Dilantin(r) 1g or 15mg/kg I.V. prn over 30-60 minutes (loading dose ? monitor ? watch for hypotension, bradycardia, or conduction defects).
? Phenobarbital 15mg/kg/I.V./prn (loading dose).
? Lidocaine 2-3mg/kg/I.V./prn, then 2-4mg/min.
? Lorazepam 2-4mg I.V. prn (diazepam alternate).
? Sodium valproate 600mg qid prn, via an ng tube.
? May use a diazepam drip, 100mg in 500cc D5W at 40cc(8mg)/hr (with patient intubated).
? General anesthetic prn.
? EEG ? seizure arrest real, or apparent? (continuous EEG monitoring prn).
(r) CT Scan?, MRI?, LP? (after the seizures are terminated) (
4) FOUR
(A) Guillian – Barré syndrome ? acute ascending peripheral neuropathy ? maximal paralysis within hours to one week ? may present with vague lower extremity weakness/parathesias, and decrease/loss of knee/ankle reflexes.
? ABC’s, supportive care, refer, plasmapheresis.
(B) Tick paralysis ? the presentation is similar to Guillian – Barré syndrome.  ? ABC’s, supportive care, remove tick.
(C) Bell’s palsy ? solitary, unilateral facial nerve paralysis (including forehead)  ? supportive care, prednisone (e.g. 50mg od x 1 week), protect eye prn, refer prn. Rule out other etiologies, e.g. otitis-mastoiditis, stroke, multiple sclerosis, trauma, parotid tumor.
(5) Acute myopathies ? reflexes and sensation are OK, elevated CPK?, hypo/hyperkalemia?, myoglobinuria?.
( ABC’s, supportive care, consult references, refer.
(6) SIX
(A) Myasthenia gravis (r) neuromuscular junction dysfunction.
? tensilon(r) test: 2mg I.V. ? repeat 4mg X 2 prn ? have atropine ready.
Myasthenic crises ? inadequate dose of medication, too much medication, refractory to meds, or infection/stress/trauma.
? ABC’s, atropine prn, Solu-cortef(r) prn, withhold meds prn until the tensilon(r) test is positive, and treat the precipitating cause, e.g. UTI.
? unlike myasthenia gravis and botulism, with the Lambert-Eaton syndrome, the hand grip strength increases with repetition, the so-called upwards staircase phenomenon (may occur with Ca of the lung).
(B) Botulism  (r) multiple victims?
? food borne, wound, and infantile.
? neuromuscular junction dysfunction.
? toxin/organism in food, wound, or stool.
? descending paralysis, negative tensilon(r) test.
? EMG demonstrates the downward “staircase” phenomenon.
? ? ABC’s, gastric lavage/charcoal/sorbitol prn, supportive care, ventilatory support prn, parenteral nutrition prn, antitoxin prn, wound excision prn, antibiotics prn (not aminoglyosides).
°XIII. ENT – Skin – Joints – Allergy
(1) ONE
(A) Alkali ocular burns  ? require prolonged irrigation prn (hours, days), for liquefaction necrosis. Wood ashes are alkaline, and can result in permanent ocular damage (a pediatric case recently described in the CMAJ).
(r) ocular alkali burns are also associated with automobile air-bag activation (CMAJ, Oct1/95;153/7).
(B) Corneal ulcers ? herpes zoster?, herpes simplex?
? herplex gtts prn, refer.
(C) Acute central retinal artery occlusion (r) sudden, unilateral, painless loss of vision, and a very pale retina (r) ? (<30-60minutes) needle decompression (by consultant), ocular massage, bolus heparin I.V. (5-10,000 units), tPA?
(D) Acute central retinal vein occlusion (r) monocular decrease in vision (r) engorged veins and retinal hemorrhages (r) refer immediately.
(E) Acute angle closure glaucoma ? headache, nausea, vomiting, severe eye pain, red eye, steamy cornea, mid-dilated and non-reactive pupil, and of course, increased intraocular pressure (marble hard eye?, tonometry). The patient may present with a headache ( nausea, vomiting, and not complain of a painful eye.
( ABC’s, supportive care, plus the following: (r) pilocarpine 2% gtts q30 minutes.
(r) diamox(r) 500mg I.V.
(r) mannitol 20% 500cc I.V.
(r) immediate ophthalmology referral for surgical intervention.
(F) Beware ? of chlamydial conjunctivitis (erythromycin/tetracycline/ung + po), hyphemas (? intraocular pressure?), subtle retinal detachment, intraocular foreign bodies (e.g. hammering metal against metal), iridocyclitis, optic neuritis (multiple sclerosis?), periorbital/orbital cellulitis, and blowout or depressed fractures (fracture? ? subconjunctival hemorrhage with no lateral and/or medial white sclera?, check eye movements ? diplopia?; infraorbital hypothesia?, subcutaneous or orbital emphysema?, CT scan required?). Caution: do not use topical ophthalmic steroids (refer; topical steroids can result in corneal perforation), and do not give topical ophthalmic anesthetics for home use (well, maybe a “few” drops to go, e.g. abrasion of cornea, welding flash burn/may prevent a premature return visit).
(2) TWO
(A) Facial fractures  (r) for example, Lefort I, II, or III; orbit, zygoma, mandible ? upper airway obstruction?, CSF leaks?
(r) ( ACBC’s, 100% O2 prn, refer.
? nasal fracture ? always check for septal hematomas.
(B) Epiglottitis (r) is also a disease of adults. See #(9)(C), p.110.
In addition, beware of pharyngeal abscesses, tonsillitis/pre-existing tonsillar hypertrophy, and Ludwig’s angina. See also #(9), p.109.
(C) Sudden idiopathic nerve deafness ? prednisone 50mg od, refer.
(D) Acoustic neuroma ? gradual/sudden, unilateral hearing loss/tinnitus, vertigo/dizziness, veering gait, unilateral facial paralysis ? signs of increased intracranial pressure. ( ABC’s, MRI/neurosurgical intervention.
(E) Acute otitis media (bacterial) ? decongestants prn, analgesics prn, antibiotics, and follow-up. For acute sinusitis use a similar regime plus topical/systemic decongestants X 2-3days. See also footnote (*), p. 126.
? be on the alert for the complications of otitis/sinusitis, e.g. mastoiditis, meningitis, brain abscess, orbital cellulitis, cavernous sinus syndrome, sepsis.
? prophylaxis for recurrent otitis media, ? zithromax(r) 10mg/kg/weekly.
(3) THREE
(A) Only avulsed permanent teeth can be reimplanted.
(B) Dental infections with visible facial edema ? ? penicillin and flagyl(r), or clindamycin alone.
? give initial dose(s) I.V., depending on the severity.
(C) Post-dental extraction pain (“dry socket”) ? try sprinkling clindamycin on the site (from an open capsule), followed by moist packing. Dental consult prn.
(4) Erythema multiforme ? may progress to Steven-Johnson syndrome (erythema multiforme major).
? ABC’s, treat the underlying cause, discontinue possible causative drugs, steroids prn, antibiotics prn, biopsy prn, to burn centre prn (Steven-Johnson syndrome). See also Urticaria, #(7)(C), p. 175.
(5) FIVE
(A) Toxic epidermal necrolysis (r) children usually less than 6 years ? more superficial ? due to staph toxin (r) adults ? deeper usually due to a drug ? biopsy?
? ABC’s, discontinue possible causative drugs, antibiotics prn, treat as 2nd degree burns, to burn center prn (application of a temporary skin substitute?).
(B) Poison ivy ? ABC’s, prednisone 50-60mg OD tapered over 2-3 weeks, Burow’s solution compresses prn.
(C) Pityriasis Rosea ? ABC’s, symptomatic treatment, prednisone prn.
(6) Joints ? Caution: an acute inflammatory monoarthritis is infection until proven otherwise, (overlying cellulitis?). The presence of crystals, or a negative gram stain, does not exclude a septic joint. Err on the side of I.V. antibiotics with staph coverage (plus an orthopedic consult).
(r) quick joint assessment ? hand grip, scratch back, cross legs, knees, ankles & gait.
Preparation for joint aspiration (concomitant blood cultures prn plus CBC and uric acid?) (r) surgical soap ? 2% iodine ? 99% alcohol ? sterile drape.
Synovial fluid ? mnemonic CAPS C = cells, cultures, crystals A = appearance (cloudy?, bloody?) P = protein S = sugar, gram and other stains Urate crystals are needle shaped, calcium pyrophosphate (pseudo-gout) are rhomboid shaped.
Acute gout ? NSAIDs, e.g. indocid(r) 50mg or naprosyn(r) 500mg tid po X 3 days, and other analgesics prn.
? other ( options ? intra-articular or po steroids, colchicine.
? uric acid may not be elevated during an acute gout attack. Do not initiate allopurinol during an acute episode of gout.
Beware of acute low back pain with urinary incontinence ( neurological findings.
? contralateral leg pain with straight leg raising?
? central disk protrusion?, primary/secondary neoplasm?, abscess?, hematoma?
? presumptive decadron(r) prn, 1mg/kg/I.V. to 50mg, and/or antibiotics prn.
? emergency myelogram/CT myelogram/MRI/immediate surgery prn.
? spinal cord compression may also occur in the cervical or thoracic spine. The pain may be minimal or absent.
? Polymyalagia rheumatica ? predominantly shoulder/hip pain ? age/sed rate 50+ ? may get dramatic relief with prednisone 10-15mg/day.
(7) Allergy and associated disorders (r) several mechanisms, e.g. IgE dependent, IgG immune complex, direct histamine release, prostaglandin inhibition.
(A) Anaphylaxis  ? upper airway obstruction, and/or bronchospasm, and/or shock.
? ABC’s, 100% O2, epinephrine I.V.(shock?)/s.c. prn, racemic epinephrine or ventolin(r) aerosols prn, mast prn, ringers 2-4+L prn, benadryl(r) I.V./I.M. prn, Solu-cortef(r) I.V. prn, atropine I.V. prn, aminophylline I.V. prn, dopamine I.V. prn, norepinephrine I.V. prn, extended observation prn, admit prn. Arrange a referral for possible future desensitization?
? ACE inhibitors (e.g. captopril) can cause angioedema which may not respond to adrenaline etc., and may require aggressive airway management.
(B) Hereditary angioedema ? ? ABC’s, epinephrine prn, Solu-cortef(r) prn, Clq esterase inhibitor concentrate I.V. for deficiency of same (or fresh frozen plasma).
(C) Urticaria ? ?: adrenaline prn, 1:1000 0.3cc s.c. (non-sedating), and/or tagamet(r) 300mg  I.M. (non-sedating), and/or benadryl(r) 50mg  I.M. (sedating), or po benadryl(r)/tagamet(r) for mild episodes ? steroids? See also Erythema multiforme, #(4), p. 172.
(D) Sulfite allergy patients (r) require first dose monitoring when given a sulfite-free status drug, because trace amounts may have been present in the raw materials.
(E) Epipen(r) (r) allergy therapy auto-injector (epinephrine 1:1000) (r) ( for patients with severe allergic reactions to insect bites/stings, food, drugs, and other allergens. Also indicated for severe asthma, and idiopathic or exercise induced anaphylaxis. Patients must carry it with them at all times.
°XIV. Infections
? Immunocompromised?, e.g. splenectomy, chemotherapy, AIDS.
(1) Tetanus ? ABC’s, supportive care, I.V. diazepam prn, I.V. pancuronium prn, continuous lumbar epidural anesthesia prn, 3000-10,000 units tetanus immune globulin I.M., pen G 4-8+m units/day/I.V., tetanus toxoid, surgical debridement, quiet room, admit ICU prn.
(2) Gas gangrene ? ABC’s, supportive care, pen G 10-30m units/day/I.V., plus cefoxitin (mefoxin(r)) 100mg/kg/day/I.V., plus gentamycin 4mg/kg/day/I.V., debridement, HBO2 (100%) at 3 atm X 90min X 3 over 24 hours, tetanus prophylaxis, admit ICU prn.
(3) THREE (A) Toxic shock syndrome ? See also Septic Shock, p.99.
? ABC’s, supportive care, cultures (staph. aureus toxin), cephalosporin, dopamine prn. DIC?, ARDS?, emergent infectious disease consultation, admit ICU.
? consider giving immune globulin, e.g. 400-1000mg/kg/I.V. daily.**** (r) rifampin po for the carrier state Group A beta-hemolytic streptococcal infection can result in a bacteremia, and a toxic shock like syndrome (Jim Henson’s disease), which may be accompanied by severe local tissue destruction (a frighteningly rapid life-threatening infection). Severe pain is frequent in both disorders. The treatment is similar plus debridement prn. Obtain an immediate surgical consultation if a necrotizing lesion†††† is present, e.g. lower leg. As with toxic shock syndrome, consider giving immune globulin in addition to antibiotics.
(r) There is a preliminary report of a possible association between chickenpox, ibuprofen, and this severe form of streptococcal infection.
(r) If you are unsure of the bacterial etiology, giving the serious ill patient an initial dose of claforan(r) 2g I.V., plus tobramycin 2mg/kg/I.V., plus clindamycin 600mg I.V., following the ABC’s and blood/other cultures, would be a reasonable thing to do. Critically ill patients should start antibiotic treatment within 30 minutes, regardless of how many investigations have been completed.
? beware of the patient with cellulitis and disproportional pain.
(B) Bacterial endocarditis ? acute or subacute (r) rarely fungal ? fever, murmur?, emboli?
? congenital heart disease?, abnormal valves?, prosthetic valves?, I.V. drug abuse?
? echocardiogram?, cultures (e.g. blood, Janeway lesions?).
? ? ABC’s, supportive care, antibiotics, refer emergently.
(C) Malaria  ? beware of resistant strains of P. falciparum ? ? ABC’s, supportive care, quinidine plus doxycycline, exchange transfusions?, refer.
? the patient may require admission to the ICU.
(4) FOUR
(A) Gonorrhea ? disseminated?, for example, pustular skin lesions, septic arthritis.
(r) cultures, smears, e.g. cervical, urethral, rectal, pharyngeal, blood, pustular skin lesions.
Outpatients ? ? (uncomplicated, localized) amoxil(r) 3 grams po + probenecid 1 gram po, or Rocephin(r) (ceftriaxone) 250mg I.M. (or Ig I.V.? to avoid a particularly painful Rocephin(r) I.M. injection)? both regimens are followed by vibramycin(r) 100mg bid po X 10 days. Allergic to penicillin? ? spectinomycin 2g I.M. plus vibramycin(r) 100mg bid po X 10 days, or erythromycin alone 500mg qid po X 10 days (erythromycin is safe during pregnancy).
Inpatients ? ? ABC’s, supportive care, analgesics prn, and I.V. antibiotics e.g. Rocephin(r) I.V., plus vibramycin(r) I.V. or po, or gentamycin and clindamycin I.V. Both regimens are followed by vibramycin(r) or clindamycin p.o.  ? follow up for gonorrhea, chlamydia, herpes, syphilis, and AIDS.
(B) Lymphogranuloma venereum ? chlamydia (lymphadenitis, pid, ( perihepatitis, ( conjunctivitis, ± joint involvement).
? ABC’s, supportive care, analgesics prn, incision and drainage prn, vibramycin(r) 100mg bid po X 2weeks (or initially I.V.), or erythromycin 0.5-1g q6h I.V., or gentamycin and clindamycin I.V., followed by clindamycin or vibramycin(r) po.
(C) Chancroid ? hem. ducreyi ? painful genital ulcers.
? erythromycin 500mg qid po X 10 days (or bactrim(r)).
(D) Granuloma inguinale ? painless genital ulcers.
? tetracycline 500mg qid po X 10days (or vibramycin(r) 100mg bid po, or erythromycin 500mg qid po X 15 days).
(E) Syphilis ? benzathine penicillin 2.4m I.M., or tetracycline 500mg qid po X 15days.
(F) AIDS (Acquired immune deficiency syndrome)  (r) spread via contaminated body fluids or blood products (r) occurs in heterosexuals too!
? T4 count: >500 (r) monitoring, health promotion, appropriate vaccines, e.g. influenza; 500-300 (r) mild immune dysfunction (AZT?); 300-200 (r) moderate dysfunction (PCP prophylaxis?); 200-100 (r) moderate-severe dysfunction; <100 (r) severe dysfunction, (watch closely for infections and malignancies).
??Bacterial, viral, fungal, and protozoal infections, and malignancies.
??life threatening problems ? pneumonitis (PCP?), CNS (e.g. infection, tumor, seizures?), sepsis, dehydration, and thrombocytopenia.
??Fever, ± weight loss, ± diarrhea ? frequent causes ? PCP, MAI, TB, CMV, hepatitis B, herpes, and lymphomas.
??PCP ( ABC’s, supportive care, 100% O2 prn, ventolin(r) aerosols, steroids?, bactrim(r) I.V. ? po ? alternate ?, pentamidine 4mg/kg/day.
??prophylactic therapy for PCP with bactrim(r) po, or pentamidine aerosols, or dapsone po.
? fluconazole (Diflucan(r)), I.V. or po, is indicated for localized or extensive/systemic candidiasis, or cryptococcal meningitis (also useful for prophylaxis, consult references).
Assessment ? history/physical, septic workup including syphilis, toxoplasma, coccidioides; aerobic, anaerobic, fungal, and viral cultures, plus stools for ova and parasites.
HIV prophylaxis (e.g. needle stick injuries, sexual assault), ( AZT 200mg/5 times/day, plus zalcitabine 0.75mg tid for a period of four weeks. If possible, start treatment within two hours of exposure. Consult references, recommendations may change.
(5) Five
(A) Bacterial meningitis in adults  (r) acute or subacute ? critically ill patients ? start antibiotic treatment within 30 minutes, regardless of how many investigations have been completed. Beware of the early bacteremic stage with fever alone, which may respond initially to symptomatic treatment (significant pyrexia? ? has been suppressed with a recent antipyretic?, toxic?, preexisting immunocompromised state?, focus of infection? ? septic workup? ? presumptive antibiotic therapy prn). Patients with sepsis/meningitis may also have a concurrent focus of infection, e.g. UTI.
? Patients with seizures, a decreased level of consciousness, papilledema, or focal signs, require a CT scan before deciding whether to proceed with the lumbar puncture ? L.P. contraindicated in bleeding disorders (DIC present?).
? The elderly may present with fever and delirium only.
Lumbar puncture ? cloudy CSF ? start antibiotics immediately (after blood cultures).
? xanthochromic = bleeding > 6hrs old ? CSF pressure, normal = 150 ± 33mmH2O ? take 4 tubes of CSF (total of 10-15ml) (r) protein, normal = 38 ± 10mg dl; concomitant CSF/serum glucose ratio, normal = 0.6; cell count, normal = 0-5monos/cc; stains and cultures (plus concomitant blood cultures).
? counter-current immunoelectrophoresis (CIE) is capable of identifying strep. pneumonia, Hem. Influenza, or meningococci in the CSF.
Bacterial meningitis ? ABC’s, 100% O2, supportive care, valium(r)/dilantin(r) prn (seizures?), dexamethasone I.V. prior to the antibiotic?, claforan(r) (cefotaxime ? caution with penicillin allergy) ? 2g q4h I.V., or 80-200mg/kg/day; septic shock?, DIC?, ARDS?, brain abscess? immediate infectious disease consultation, admit ICU.
(r) add ampicillin (2g q6h I.V.) if listeria monocytogenes is suspected, or tobramycin (3-5mg/kg/day/I.V.) for pseudomonas aeruginosa.
(r) give acyclovir I.V. concurrently, if your differential diagnosis includes herpes simplex encephalitis (see below).
? Caution: immunosuppressed/compromised? (AIDS?), CSF shunt?, head trauma/CSF leak?, post-op neurosurgery?, severe penicillin allergy? ? consult references/infectious disease specialist regarding the choice of antibiotics (with a minimum of delay in the initiation of treatment).
(B) Herpes simplex encephalitis (r) ( ABC’s, supportive care, early presumptive acyclovir I.V. (5-10+mg/kg q8h in ringers infused over 1 hour), consult references.
°XV. Poisoning
(1) Poisoning ? call poison control prn (Poisindex(r) ?).
Toxic syndromes ? for example, anticholinergic, anticholinesterase, cholinergic, extrapyramidal, hemoglobinopathies, metal fume fever, narcotic/sedative, sympathomimetic, and withdrawal.
Decontamination ? gastric lavage prn, and/or charcoal (activated 1g/kg), ± cathartic prn (e.g. premixed activated charcoal 25g/sorbitol 90g per container), repeat gastric lavage, and/or charcoal ± sorbitol prn; decontaminate skin prn, (e.g. organophosphates, hydrofluoric acid; protect rescuers), and eyes prn (e.g. irrigate with normal saline). Other methods of decontamination include whole bowel irrigation prn (e.g. heavy metals, sustained release preparations ? e.g. colyte(r) by ng tube), hemodialysis prn (e.g. salicylates), charcoal hemoperfusion prn (e.g. theophylline), and gastrotomy prn (e.g. iron tablets).
(r) Patients with a decreased level of consciousness may need to be intubated before the gastric lavage (however the gastric tube may promptly wake them up!).
? Some clinicians advocate charcoal before and after gastric lavage (other recommendations include charcoal ( sorbitol q4h, or continuous gastric charcoal infusion at 12g/hr/adults)..
??Specific antidotes (e.g. atropine, narcan(r)) may have to be given before decontamination.
(r) Beware of drug concretions (plain x-rays?, Ba swallow?), e.g. iron, ASA, theophylline SR.
? Syrup of ipecac is a home remedy only.
? Street drugs have frequently been adulterated.
? Poisonings may be via the intravenous route, e.g. heroin; needle tracks?
? Multiple drug ingestions are frequent, and the history is often unreliable. A minimum drug screen for acetaminophen, salicylates, and ethanol is required (tricyclics? barbiturates?). Increased anion gap and/or osmolar gap?, metabolic acidosis? Beware of sustained release preparations (radiopaque?), e.g. theophylline, and patients that are already taking MAO inhibitors (hypertensive crises?).
(r) patients have been known to continue their overdosing in the ER. Search prn (r) make sure that no drugs are available to them, e.g. pockets, purse.
? Adopt a non-judgmental caring attitude when dealing with alcohol and drug abusers, and overdose patients (not always easy). Beware of additional problems, e.g. hypoglycemia, diabetes, pneumonia, hypothermia, pregnancy, concomitant trauma, e.g. subdural hematoma. Remember to obtain a psychiatric consult prn in overdose patients.
The majority of drug overdose patients have an uneventful several hour long stay in the ER, and can then be discharged to their family physician’s care. If the patient also has alcohol “on board,” hydration with 1-2 liters of ringers over 1-2 hours, then 125-250cc/hr, often expedites their recovery (my impression). Conversely, there are patients who require early, aggressive, “life support,” and if they recover, psychiatric intervention (assuming they intentionally overdosed).
(r) See also #(23)-(30), pp. 210- 212.
(2) Tricyclic overdose ? CNS depression, seizures, anticholinergic, and cardiotoxic.
? ABC’s, supportive care, gastric lavage prn ? charcoal ± sorbitol q2-4h prn, bicarb 50meq I.V. prn (1meq/kg), I.V. fluids prn (e.g. ringers), norepinephrine prn, valium(r) prn, dilantin(r) prn, lidocaine prn, hemoperfusion with activated charcoal prn, extended cardiac monitoring prn, admit ICU prn.
(3) THREE
(A) Phenothiazine overdose ? CNS depression, anticholinergic, cardiotoxic, alpha blocker, extrapyramidal, and infrequently the neuroleptic malignant syndrome (see #(3)(C), below).
? Intact tablets may be visualized on plain abdominal. x-rays.
? ? ABC’s, supportive care, gastric lavage prn ? charcoal ± sorbitol q2-4h prn, benadryl(r) I.V. prn, lidocaine I.V. prn, I.V. fluids prn (e.g. ringers), norepinephrine I.V. prn, valium(r) I.V. prn, admit ICU prn.
(B) Physostigmine ? a controversial antidote for central and peripheral anticholinergic effects. Useful for unstable patients not responding to conventional therapy, ? 0.5-1mg I.V., consult references. See also #(23)(B), p.199.
(C) Neuroleptic Malignant Syndrome (r) Fever, tachypnea, tachycardia, hypertension, muscle rigidity (elevated cpk), metabolic acidosis, myoglobinuria.
( ABC’s, tylenol(r) prn, cooling prn, supportive care, dantrolene prn (skeletal muscle relaxant), bromocrystine prn (dopamine agonist), benadryl(r) prn (for rigidity), valium(r) prn, inderal(r) prn, nifedipine prn, consult references, refer, admit ICU.
? treat the pyrexia aggressively.
(D) Serotonin syndrome (r) usually as a result of an interaction between MAOIs and serotonergic agents, e.g. prozac(r). Narcotics may also be a causative factor.
(r) delirium, rigidity (elevated cpk), fever, hypertension, seizures, coma.
( ABC’s, narcan(r) prn, tylenol(r) prn, cooling prn, supportive care, chlorpromazine prn, valium(r) prn, dilantin(r) prn, rivotril prn (for myoclonus), nifedipine prn, inderal(r) prn, consult references, refer, admit ICU.
? treat the pyrexia aggressively.
(4) Lithium overdose ? CNS manifestations, e.g. ataxia, seizures.
? ABC’s, supportive care, gastric lavage prn, saline prn, bicarb prn, dialysis prn.
(5) Barbiturate overdose ? ABC’s, 100% O2 prn, gastric lavage prn ? charcoal q2-4h prn, supportive care, bicarb prn, dialysis prn.
(6) Dilantin(r) overdose (r) CNS, GI, and cardiopulmonary toxicity.
? ABC’s, cardiac monitoring, 100% O2 prn, gastric lavage prn ? charcoal q2-4h prn, atropine prn, fluid loading prn, inotropics prn, pacing prn, charcoal hemoperfusion prn, admit ICU prn.
(7) SEVEN
(A) Narcotic overdose ? ACBC’s, 100% O2 prn, thiamine prn, dextrose prn, supportive care, decontaminate prn, narcan(r) 2+mg I.V. prn (restrain patient first? ? acute withdrawal?) ? ? coexisting problems prn, e.g. cellulitis, alcoholism, trauma.
(r) titrate the narcan(r) in suspected narcotic addicts, to just adequately reverse the respiratory and CNS depression only, avoid inducing withdrawal.
Narcan(r) is also useful for acute epigastric pain secondary to codeine, morphine, and related drugs. Remember that the narcan(r) may wear off before the narcotic.
(B) Benzodiazepine overdose ? ACBC’s, 100% O2 prn, thiamine prn, dextrose prn, supportive care, decontaminate prn, flumazenil (adults) 0.3mg q 1 minute prn to 2mg (restrain patient first? ? acute withdrawal?; careful with concomitant tricyclic overdose (r) seizures?) ? ? other problems prn, e.g. injuries, hypothermia, alcohol abuse.
(8) Clonidine overdose (r) miosis is a helpful sign when the diagnosis is in question.
? ABC’s, 100% O2 prn, supportive care, gastric lavage prn ? charcoal prn ± sorbitol; narcan(r) prn; ?: respiratory depression, seizures, bradycardia, hypothermia, hypotension, hypertension prn. See also #(3) (p. 100), #(10) (p. 119).
(9) Nine
(A) Methanol poisoning  ? formic acid is the toxic metabolite.
? intoxication followed by coma, metabolic acidosis, renal failure, and blindness.
(r) early presumptive treatment with ethanol, before the acidosis develops is the optimum. A prolonged wait for the serum methanol level before commencing the ethanol therapy, may be fatal or result in serious sequelae.
? concomitant injuries?
? ACBC’s, 100% O2 prn, supportive care, gastric lavage prn ? charcoal prn, bicarb prn to a pH of 7.2+, 10% ethanol D5W 6cc/kg/I.V. bolus, then 0.6-1.6cc/kg/hr (maintain an ethanol blood level of 100mg/100mL), folic acid prn, early dialysis prn.
(B) Ethylene glycol poisoning ? toxic metabolites (glycolic and oxalic acid), and calcium oxalate precipitates.
(r) intoxication followed by coma, seizures, metabolic acidosis, renal, and cardiopulmonary failure.
(r) once the ethylene glycol has been metabolized, calcium oxalate monohydrate crystals in the urine (needle shaped), may be the only real-time means of confirmation of the diagnosis.
? concomitant trauma?
? ACBC’s, 100% O2 prn, supportive care, bicarb prn, ethanol I.V. (see methanol poisoning, above) calcium gluconate 10% I.V. prn, thiamine prn, pyridoxine prn, early dialysis prn. As with methanol poisoning, early presumptive therapy with ethanol may be crucial.
(10) TEN
(A) Digoxin toxicity (r) iatrogenic?, suicide attempt?
(r) therapeutic level 0.5 – 2.0 ng/ml ??arrhythmias, GI effects, and hyperkalemia.
? ABC’s, 100% O2 prn, gastric lavage prn ? charcoal 1g/kg (± sorbitol) ? 0.5g/kg q4h prn, plus the following as appropriate: ? specific therapy is Digoxin Fab fragments (Digibind(r)) ? one vial binds 0.6mg of digoxin ? give 10 vials I.V. initially if ingested dose is unknown ? also a formula using serum levels is available (e.g. from poison control).
? SVT, See #(5), p.87.
? Bradycardias ? atropine prn, pacing prn, Fab fragments.
??Ventricular tachyarrhythmias and ectopics ? lidocaine prn, dilantin(r) 15mg/kg (loading dose), MgSO4 2-4g I.V. prn, Fab fragments, last resort cardioversion (10-25J).
??Hyperkalemia ? Fab fragments, plus standard hyperkalemic ? except no calcium (see #(19), p.83).
??Hypomagnesemia ? MgSO4 2-4g I.V. prn.
(B) Beta blocker overdose ? bradycardias, hypotension, and CHF (± hypoglycemia).
? ABC’s, 100% O2 prn, gastric lavage prn ? charcoal prn ± sorbitol, glucagon prn, atropine prn, I.V. fluids prn, dopamine/dobutamine prn, isoproterenol prn, pacing prn, valium(r) prn (for seizures, no dilantin(r)), 50% dextrose prn, charcoal hemoperfusion/hemodialysis prn. See also #(10)(D), below.
(C) Calcium blockers overdose ? bradycardias, hypotension, and CHF ? ABC’s, 100% O2 prn, gastric lavage prn ? charcoal prn ± sorbitol, calcium gluconate prn, glucagon prn, atropine prn, I.V. fluids prn, dopamine/dobutamine prn, isoproterenol prn, pacing prn, valium(r) prn (for seizures, no dilantin(r)). See also #(10)(D), below.
(D) Glucagon ? 3-10mg I.V., then 2-5mg/hr for beta or calcium blocker overdose.
? pediatric dose = 0.02mg/kg I.V. prn.
(r) consult references.
(E) Theophylline toxicity (r) iatrogenic?, suicide attempt?
(r) therapeutic 55-100?mol/L, sustained release tablets?
(r) sympathomimetic toxicity.
? nausea, hypertension, hypotension, arrhythmias, seizures, and hypokalemia.
? ABC’s, 100% O2 prn, gastric lavage prn ? charcoal ± sorbitol/repeated prn, valium(r) prn, dilantin(r) prn, phenobarb prn, lidocaine prn, beta blockers prn, K+/lytes prn, Zantac(r) prn, whole bowel irrigation?, charcoal hemoperfusion/hemodialysis prn (serum levels > 400-500 µmol/L).
(11) Cocaine poisoning (r) sympathomimetic toxicity ± life threatening arrhythmias.
? ABC’s (coronary artery spasm?), charcoal prn, valium(r) I.V. prn, dilantin(r) prn, inderal(r) I.V. prn, labetalol I.V. prn, cardioversion prn; physical restraints prn.
(12) Alcohol withdrawal ? ACBC’s, thiamine 100mg I.M./I.V. daily (prevent/treat Wernicke’s syndrome, e.g. confusion, ataxia and ophthalmoplegia), dextrose I.V. prn, valium(r) 5-10mg I.V. prn, or 20mg q1h po prn until the patient settles,  fluids prn, lytes prn (NaCl?, K+?), multivitamins (vitamin K?), MgSO4‡‡‡‡  4g slowly I.V. or I.M. prn, phenobarbital I.V. prn, Zantac(r) I.V. prn, restraints prn, treat any other problems, e.g. sepsis, cellulitis, pneumonia, pancreatitis, GI bleeding (Mallory Weiss syndrome?), subdural hematoma, neck injuries, fractures, myoglobinuria?, hyper/hypokalemia? Refer to the alcohol and drug detoxification unit when medically fit.  (13) Ethanol poisoning (r) ± trauma?, other medical problems?
? ? ACBC’s, 100% O2 prn, thiamine 100mg I.M./I.V. prn, dextrose I.V. prn, ativan(r) prn, haldol(r) prn, physical restraints prn, dialysis prn.
? children may develop hypoglycemia (less frequent in adults).
? unless contraindicated 2-3 litres (10-20mL/kg bolus(es) prn in children), of ringers lactate ± 5% dextrose over 2-3 hours almost always has a positive therapeutic effect, most notably on the mental status (improved hydration/decrease in serum osmolarity?). My impression is that this ringers regimen frequently changes a “fxxx this and fxxx that” type of person, into a “yes sir!, no sir!, thanks everyone, sorry for acting like such an idiot” type of person.
(14) Isopropanol poisoning ? ( trauma?, ( other medical problems?
? ACBC’s, 100% O2 prn, thiamine prn, dextrose prn, ringers prn, ng suction prn, I.V. Zantac(r) prn (prone to hemorrhagic gastritis), dialysis prn. See also #(12), (13), p.191.
(15) Amphetamine overdose (r) sympathomimetic toxicity ± life threatening arrhythmias.
? ABC’s, 100% O2 prn, thiamine prn, dextrose prn, gastric lavage prn ? charcoal ± sorbitol prn, valium(r) I.V. prn, dilantin(r) I.V. prn, cooling prn, inderal(r)/metoprolol I.V. prn, lidocaine prn, nitroprusside I.V. drip prn, haldol(r) 5-10mg I.M./I.V. ± ativan(r) 1-2mg I.M./I.V. q15-60minutes prn. Physical restraints?; myoglobinuria?
(16) Phencyclidine abuse (PCP) (r) sympathomimetic and cholinergic toxicity, ± life threatening arrhythmias.
? paranoid, violent.
? ABC’s, charcoal ± sorbitol prn, valium(r) I.V. prn, cooling prn, antihypertensives prn, ( arrhythmias prn, haldol(r) 5-10mg I.M./I.V. ± ativan(r) 1-2mg I.M./I.V. q15-60minutes prn. Physical restraints?; myoglobinuria?
(17) SEVENTEEN
(A) Salicylate poisoning (r) oil of wintergreen§§§§?,  enteric coated?/ sustained release tablets?
? Resp. alkalosis, metabolic acidosis, gastritis; CNS, CVS, pulmonary, and liver toxicity.
? aggressive management, as there appears to be a critical CNS concentration.
? use the nomogram for acute overdoses only (need a minimum of 2-3 serum levels).
? may have normal salicylate levels with chronic salicylate toxicity (lethargy, dehydration, metabolic acidosis).
? (acute overdose) ABC’s, gastric lavage prn ? charcoal ± sorbitol repeated prn, I.V. fluids/lytes prn (hypokalemia?), 50% dextrose I.V. prn, bicarb I.V. prn (careful, give slowly) to a urine pH of 7.5, lasix prn, Zantac(r) 50mg I.V. q6-8h prn, vitamin K 10mg I.M. prn, valium(r) prn, early? hemodialysis prn, admit ICU prn.
? Pediatric patients ? D5 0.33NS, plus 25 mEq NaHCO3/L, plus 20-40meq KCl/L (once urine output begins, if not hyperkalemic) at 5-15 mL/kg/hr ? additional NaHCO3 1-2meq/kg prn (careful). Hypoglycemia?
? salicylates are ionized in an alkaline medium, and ionized salicylates not taken up by the tissues, or reabsorbed in the kidneys.
? maintain an alkaline urine output of 3-6+cc/kg/hr.
(B) Isoniazid Poisoning ? seizures, coma, metabolic acidosis.
? ? ABC’s, decontaminate prn, supportive care, valium(r) prn, bicarb prn, pyridoxine 5g I.V. q15minutes prn (gram for gram of isoniazid) for seizures, or coma; charcoal hemoperfusion?
(C) Camphorated oil poisoning (r) used predominantly as a chest rub for “colds.”
(r) if ingested, can result in seizures and respiratory depression.
(r) as little as 5mL can be fatal in a child.
(r) may also be absorbed via inhalation, or intact skin.
( ABC’s, 100% O2 prn, intubate prn, supportive care, valium(r) I.V. prn, dilantin(r) I.V. prn (15mg/kg loading dose), phenobarb I.V. prn (15mg/kg/loading dose). See also #(14), p.145, #(3), p.165.
(18) Acetaminophen overdose ?  GI, liver, and renal toxicity.
? use the nomogram for acute overdoses only (need a minimum of 2-3 serum levels).
(r) mucomyst(r) (acetylcysteine) is the antidote.
? ABC’s, supportive care, gastric lavage prn, alternate po mucomyst(r) and charcoal q2h prn, daily liver and renal studies.
Mucomyst(r) 140mg/kg/po, then 70mg/kg/po q4h X 17 doses, or I.V. 20% mucomyst(r), (useful in patients with protracted vomiting, plus no charcoal/mucomyst(r) conflict, plus a shorter treatment time of 20 versus 68 hours).
Initial I.V. dose ? 0.825ml of 20% mucomyst(r)/kg in 500cc D5W, over 1 hour.
2nd dose  ? 0.275ml/kg in 500cc D5W, over 4 hours.
3rd dose ? 0.55ml/kg in 1000cc D5W, over 16 hours.
(r) mucomyst(r) is worth trying even 2-3 days post toxic overdose.
(r) nausea may require that the rate of the initial I.V. infusion of the mucomyst(r) be decreased. Give antiemetics prn.
(19) NINETEEN
(A) Iron poisoning ? GI bleeding, shock, metabolic acidosis, coagulopathy, and multiple organ dysfunction.
? ABC’s and supportive care (for example, ringers prn, bicarb prn, blood products prn, 50% dextrose prn), gastric lavage prn, whole bowel irrigation prn (x-rays will demonstrate the iron tablets), deferoxamine mesylate 15mg/kg/hr/I.V. prn to 6 grams/day (until the urine is no longer pink = no free plasma iron) ? give the deferoxamine on clinical impression, before the serum iron level is back (maintain an adequate urine output) (r) continue the deferoxamine if the patient is put on charcoal hemoperfusion/dialysis; gastrotomy prn.
(B) Heavy metal poisoning ? consult references, e.g. lead, arsenic, mercury.
? All interfere with enzyme activity by attaching to the sulfhydryl groups, resulting in neurological, cardiovascular, gastrointestinal, hematological, and renal manifestations ± others.
? Diagnosis ? e.g. bluish gingival and long bone lead lines, metallic flecks on abdominal. x-rays, basophilic stippling of RBC’s, elevated blood lead levels, elevated 24 hour urine arsenic or mercury levels. Arsenic poisoning may result from naturally occurring contaminated well water.
? ? ABC’s ? treat, for example, seizures, arrhythmias, hypotension, renal failure ? decontaminate prn, e.g. gastric lavage prn, charcoal prn, whole bowel irrigation prn, chelation therapy prn (for example, BAL, CaNa2 – EDTA, D-penicillamine, 2,3-DMSA), dialysis prn. Prevent reoccurrence. Evaluate family, significant others, and coworkers prn.  (20) Tar and asphalt burns ? ACBC’s, cool with H2O prn, use neosporin(r)/polysporin(r) ung to dislodge from skin, burn care.
(21) TWENTY-ONE
(A) Hydrocarbon poisoning (r) epinephrine contraindicated.
(r) remember to decontaminate the skin prn.
(1) Liquid petroleum distillates, e.g. kerosene ? gastric lavage only if it contains a toxic substance, e.g. pesticide; look for chemical pneumonitis (delayed 24hrs?).
( ABC’s, 100% O2 prn, and supportive care.
(2) Gases, e.g. propane ? asphyxia, intoxication, arrhythmias.
( ABC’s, 100% O2 prn, and supportive care. Hyperbaric O2?
(3) Solvents, e.g. benzene, epoxy ? chemical pneumonitis, seizures, systemic toxicity, aplastic anemia.
( ABC’s, 100% O2 prn, valium(r) prn, lavage prn, charcoal prn, and supportive care.
(4) Halogenated hydrocarbons, e.g. methyl chloroform, carbon tetrachloride (r) CNS toxicity, hepatitis, nephritis.
? ABC’s, lavage prn, charcoal prn, and supportive care.
(B) Irritant gases e.g. chlorine, phosgene.
(r) upper airway obstruction, lower airway injury, chemical pneumonitis, and pulmonary edema.
? ABC’s, 100% O2 prn, racemic epinephrine/ventolin(r) aerosols prn, and supportive care. Admit ICU prn.
(22) Caustic ingestions (r) for example, lye ? liquefaction necrosis; acids (r) coagulation necrosis.
? upper airway obstruction?
? ABC’s, 100% O2 prn, I.V. Zantac(r), esophageal perforation? ? presumptive antibiotic therapy prn (e.g. mefoxin(r) 3g or 40mg/kg I.V., and clindamycin 600mg or 10mg/kg I.V.) ? refer immediately (e.g. endoscopic exam?). Steroids?? Remember that patients with esophageal burns may not have oral lesions. Button batteries lodged in the esophagus need to be removed emergently.
(23) TWENTY THREE
(A) Organophosphate and carbamate poisoning  ? inhibition of acetylcholinesterase.
? decrease in serum cholinesterase (20-50% of normal level = mild toxicity, 10-20%= moderate toxicity, less than 10%= severe toxicity).
? ports of entry (e.g. insecticides) are predominately skin, lungs, and GI.
(r) muscarinic effects (parasympathomimetic), nicotine effects (motor), and CNS effects (e.g. seizures, coma, cardiopulmonary depression).
? mnemonic: DUMBELS: diarrhea, urination, miosis, bradycardia, bronchorrhea, bronchospasm, excitation, lacrimation, salivation.
? ABC’s, support ventilation prn, 100% O2 prn, ventolin(r) aerosols prn,  atropine I.V. prn (atropinization), decontamination of patient (wear gloves and protective clothing prn), I.V. pralidoxime chloride prn.
(r) large doses of atropine may be required (antimuscarinic only).
? give pralidoxime chloride on clinical impression.
? 1-2g, or 20-50mg/kg, over 30min ? repeat in 2 hours prn (serum cholinesterase level?), then q12h prn.
(r) pralidoxime is antimuscarinic, antinicotinic, and counters the CNS cholinergic effects.
? ? seizures with valium(r) prn; arrhythmias with ACLS drugs prn, pacing prn, cardioversion prn. Antihypertensives prn, hyperglycemia?
(B) Anticholinergic poisoning (r) e.g. benadryl(r), dimenhydrinate, mushrooms.
(r) anxious, dilated pupils.
(r) they babble back when you speak to them.
(r) they pick with their fingers, at you, the bed sheets, the air, or whatever is available.
(r) tachycardia, hypertension, arrhythmias, seizures, coma.
( ACBC’s, supportive care, lavage/charcoal/sorbitol prn, ringers prn, bicarb prn, physostigmine prn (for example, ( of SVT, hypertension, or seizures, careful!, consult references), lidocaine prn, dilantin(r) prn, valium(r) prn, refer prn, admit ICU prn. Do not use physostigmine with tricyclic antidepressant overdose.
? concomitant trauma?
°XVI. Environmental Injuries
(1) Frostbite  ? ABC’s, active external rewarming, ? like burns; tetanus prophylaxis prn, narcotics prn, antibiotics prn, ASA prn, delay surgery, rhabdomyolysis?, hyperbaric O2?
(r) only rewarm if there is no chance of refreezing during transport.
(2) Hypothermia 32 – 35?C ? excitation stage (inappropriate behavior, e.g. hiding from rescuers, combativeness) < 32?C ? adynamic stage < 30?C ? shivering stops ? careful handling, ACBC’s, warm 100% O2, reverse trendelenburg prn, cardiac cathader/rectal probe temperature monitoring prn, active core rewarming prn, warm saline boluses prn (40-45?), thiamine prn, dextrose prn, lidocaine prn, bretylium prn, narcan(r) prn, flumazenil prn, Solu-cortef(r)/decadron(r)? prn, tagamet(r) prn, tetanus prophylaxis prn, associated trauma or disease?, alcohol or drug abuse?, myxedema coma?, continue CPR until body temperature is 30-34?C (“no one is dead until warm and dead”). Watch for complications, for example, ventricular fibrillation, increased intracranial pressure, renal failure, sepsis, GI bleeding, hyperkalemia, pancreatitis, DVT, ARDS, DIC. Admit ICU prn.
(r) defibrillation ineffective with core temperatures < 30?C, only one attempt at a time, consider lidocaine, consider bretylium.
? mild hypothermia may require external warming only.
? examples of active core rewarming are: warm (40-45?C) ? O2, I.V. fluids, gastric or rectal lavage, peritoneal dialysis, extracorporeal rewarming. See also #(17) p.207, #(2) p. 76, #(16)(A) p. 92.
(3) Heat cramps, heat syncope ? ? ABC’s, rest in cool environment, hydrate prn with I.V. NS, or electrolyte drinks. Rule out heat stroke.
Heat exhaustion ? headache, nausea, weakness, dehydration, pyrexia ? ? ABC’s, rest in cool environment, hydrate with 1-2 liters D5saline (20mL/kg bolus(es) in children), rule out heat stroke.
(4) Heat stroke ? life threatening, multiple organ dysfunction.
? may present with seizures, coma, or bizarre behavior.
? ABC’s, 100% O2 prn, supportive care, I.V. valium(r) prn, active external and core cooling (reduce body temperature to 39?C). Arrhythmia?, myoglobinuria?, hypoglycemia?, hyperkalemia?, DIC? Rule out other causes, e.g. thyroid storm. Admit ICU.
(5) Rabies ? rare in rodents.
? skunks, bats, raccoons, cows, dogs, foxes, and cats are the frequent carriers.
? ABC’s, wound care, tetanus prophylaxis prn, antibiotics prn, and the following: ? post exposure prophylaxis ? irrigate the wound with 70% alcohol ? rabies immune globulin 20 units/kg, 1/2 in the wound, 1/2 in the buttocks ? human diploid cell vaccine 1mL @ 0, 3, 7, 14, and 28 days, then do serum antibody titers ? repeat 1mL prn ? if possible, observe the animal for 2 weeks, and do a postmortem if the animal dies.
(6) Hymenoptera stings ? local, toxic, anaphylactic, and delayed serum sickness reactions.
(r) ( ABC’s, 100% O2 prn, ( allergic/anaphylactic reactions (see #(7)(A),(C),(E), pp.174-175), local treatment/remove stinger.
(7) Pus caterpillar sting ? ? ABC’s, supportive care ? remove the stingers with cellophane tape ? 10% calcium gluconate, 1-10ml slowly I.V. prn for pain.
(8) Tick-borne disease Rocky mountain spotted fever (Rickettsia Rickettsii) ? systemic symptoms ? rash begins on second to fifth day on wrists, ankles, and feet, and spreads centrally (may become purpuric).
( ABC’s, 100% O2 prn, supportive care, antibiotics, e.g. tetracycline, doxycycline, or chloramplenical po or I.V. prn (skin biopsy and immunofluorescent antibody staining?). DIC?
Lyme disease ? tick borne spirochete.  ? Stage I: 7± days after tick bite ? erythema chronicum migrans ± systemic symptoms.
? Stage II: 4+ weeks ? neurological manifestations (± focal signs), ± A-V block, ± other multisystem manifestations, e.g. hepatitis.
± Stage III: 4+ weeks ? arthritis, ± neurological signs.
Diagnosis? search for tick ? specific antibody titer (stages II, III).
? ABC’s, an antibiotic for 10-30 days, e.g. tetracycline, vibramycin(r) (first choice for non-CNS lyme disease), erythromycin, amoxil(r), PenV, or I.V. ceftriaxone (for CNS involvement).
Tick paralysis ? ascending, flaccid paralysis.
? ABC’s, supportive care, remove tick.
(9) Black widow spider bites ? history of a bite may be absent ? CNS excitement, muscle spasms, pain, paresthesias, hypertension, vomiting.
(r) complications, e.g. seizures, shock, ascending paralysis, coma, respiratory arrest.
? ABC’s, supportive care, analgesics prn, corticosteroids prn, tetanus prophylaxis prn, valium(r) prn, 10% calcium gluconate, 1-10cc slowly I.V. prn for pain, antivenim prn.
(10) Brown recluse spider bites ? local lesion, ± systemic manifestations, ± complications, e.g. seizures, shock, hemolysis, DIC.
? ABC’s, supportive care, analgesics prn, corticosteroids prn, valium(r) prn, dapsone 25-50mg qid X 1 week  (G6PD screen prn), antibiotics prn, local wound care, tetanus prophylaxis prn, and hyperbaric O2 prn. Admit ICU prn.
(11) Reptile bites ? pit viper or coral snakes?
? envenomation?, paresthesias?
? hemopathic, neurotoxic, and systemic effects.
? ABC’s, 10% calcium gluconate, 1-10cc slowly I.V. for seizures (plus valium(r) prn), bolus(es) of ringers prn, multiple doses of antivenim prn (consult references), blood products prn, tetanus prophylaxis prn, antibiotics prn, local lidocaine ± epinephrine (if not contraindicated) prn, analgesics prn (no ASA), steroids prn, keep part dependent prn, and repeated measurement of circumference of involved extremity prn, remove jewelry prn, surgery prn (compartment syndrome?), admit ICU prn, DIC?, myoglobinuria?
(12) Arizona scorpion sting ? cholinergic ? opiates are contraindicated.
? ABC’s, atropine prn, antivenim prn, benadryl(r) prn, wound care, tetanus prophylaxis prn, admit ICU prn. See also #(23)(A), p.198.
(13) THIRTEEN
(A) Marine misadventures ? for example, near drowning, divers’ problems, trauma, foreign body, envenomation, infection.
? ACBC’s, primary, secondary, or tertiary wound closure prn, tetanus prophylaxis prn, cephalosporins prn, hyperbaric O2 prn, admit ICU prn. See #(2), p.200, #(17), p.207.
Spine puncture wounds ? ACBC’s, supportive care, lidocaine prn, demerol(r) prn, antivenim prn if available, and local hot water ? prn (45-50?C X 7-90 minutes); debride and explore prn, tetanus prophylaxis prn, antibiotics prn (e.g. Bactrim(r)), admit ICU prn.
Coelenterate stings ? ABC’s, supportive care, and local vinegar.
Sponge poisoning ? ABC’s, supportive care, and local vinegar.
(B) Stingray ? envenomation and local trauma, ± near drowning.
? severe pain, bleeding, ± multisystemic manifestations.
? ? ACBC’s, supportive care, local hot water ? prn (45-50?C X 1/2 – 1hr), local or regional lidocaine block prn, debridement prn, tetanus prophylaxis prn, antibiotics prn (e.g. Cipro(r)), steroids prn, admit ICU prn.
(C) Portuguese Man of War ? envenomation, ± near drowning.
? pain, bullae, ± multisystemic manifestations.
? ? ACBC’s, supportive care, irrigate wound with saline ? vinegar, shave off nemacysts, local and systemic steroids prn, tetanus prophylaxis prn, admit ICU prn.
(D) Sea Urchin ? envenomation, ± near drowning.
? pain, ± multisystemic manifestations.
? ? ACBC’s, supportive care, local hot water ? prn (45-50?C X 1/2 – 1hr), lidocaine prn, debride and explore prn, tetanus prophylaxis prn, antibiotics prn, steroids prn, admit ICU prn.
(14) High altitude illness Acute mountain sickness ? bedrest, 100% O2, diamox(r), descent prn, HBO2?
High altitude pulmonary edema (HAPE) ? bedrest, 100% O2, descent, HBO2?
High altitude cerebral edema (HACE) ? bedrest, 100% O2, descent, HBO2?
High altitude retinopathy ? bedrest, 100% O2, descent, HBO2?
(15) Dysbarism Barotrauma of descent ? squeeze ? barotitis media ? rupture of TM? ? rupture of round or oval window? ? perilymph fistula? ? refer ENT.
Barotrauma of ascent ? Alternobaric vertigo.
? Pulmonary over pressure syndrome (POPS) ? mediastinal or subcutaneous emphysema?, pneumothorax?, air embolism?
? Air embolism (dramatic symptoms in < 10minutes) ? e.g. CNS and/or cardiovascular manifestations.
? Nitrogen narcosis.
(r) Decompression sickness ? nitrogen bubbles ? “the bends” (joints, skin), “the chokes” (pulmonary arterial system), CNS manifestations (e.g. coma); shock.
(r) ? ACBC’s, 100% O2, extreme trendelenburg prn, I.V. fluids prn, analgesics prn, immediate recompression prn, and ? other problems, e.g. injuries, DIC.
(16) Blast injuries ? TM rupture?
? ? as multiple trauma ? ACBC’s, treat specific injuries, hyperbaric O2 prn (HBO2).
(17) Near drowning ? ACBC’s, 100% O2, ventolin(r) aerosols prn, reverse trendelenburg prn, supportive care, hyperbaric O2?, antibiotics?, decadron(r)?, admit ICU prn; immersion in warm or cold water?, hypothermia?, associated injuries? (e.g. head and/or cervical spine/cord), alcohol and/or drug abuse?, suicide or homicide attempt?, MI?, CVA?, hypoglycemia?, seizure?, child abuse?, see also #(2), p.200, #(13), p.204, #(15), p.206,  #(18), p.207.
? “No one is dead until warm and dead.” (30-34?C) ? A successful resuscitation may be followed by a delayed multiple system failure (e.g. ARDS, DIC, increased intracranial pressure, lactic acidosis). See also #(4), p.124, #(11)(C), p.155, #9, p. 47, #(4), p.151.
(18) Delayed immersion syndrome ? delayed pulmonary edema? (usually symptoms < 4 hours).
(r) ( as ARDS. See also #(17), p.207, #(4), p.124.
(19) Burns ? Remember the smoke threats: (1) heat (e.g. upper airway obstruction), (2) asphyxiants (e.g. CO, cyanide), and (3) airway and pulmonary irritants, (e.g. carbon ± toxic chemicals, phosgene ? upper airway obstruction, bronchospasm, pulmonary edema).
? occurred in closed or open space?, toxic combustion gases?
(r) first degree burns (erythema, pain), second degree burns (erythema, pain, blistering), or third degree burns (pale, leather-like, painless, absent sensation).
? Rule of 9’s for adult body surface estimate:  head and arms 9 X 3 = 27 %  trunk 18 X 2 = 36 %  legs 18 X 2 = 36 %  genitalia            =  1%    100% ? children (child abuse?, e.g. scalds) ? head and neck 15-20%, arms 10% X 2, trunk 20% X 2, legs 10-15% X 2. Consult burn estimate charts prn.
? palmar surface of patient’s hand equals approximately 1% of total body surface.
? beware of burns of face, eyes, ears, hands, feet, and perineum.
? ? ACBC’s, 100% O2 prn, pulse oximetry/ABG’s prn, inhalation injury? (serial chest x-rays prn), upper airway edema?, early prophylactic intubation prn (early laryngoscopic/bronchoscopy?), racemic epinephrine/ventolin(r) aerosols prn, CO poisoning?, cyanide poisoning? (? presumptive sodium thiosulfate 25% 1mL/kg/I.V.), hypovolemic shock?, lactic acidosis?, emergency escharotomy prn (neck, chest, extremities), Xmatch prn, ringers prn (children 20mL/kg bolus(es) prn), blood products prn, ? other trauma plus new and preexisting medical problems prn (alcohol or drug abuse?), analgesics prn (e.g. I.V. morphine), antibiotics prn (I.V. prn), ng/foley prn, tetanus prophylaxis prn, flow sheet prn, local burn care/appropriate dressings prn, remove watch and jewelry prn, clean dry sheet prn, I.V./po tagamet(r) prn (stress ulcer prophylaxis), to burn centre prn. Patients may develop a delayed chest infection or sepsis (upper airway obstruction and pulmonary edema may also have a delayed onset).
? I.V. ringers 4ml X kg X % burn/day ? 1/2 in the first 8 hours after the burn, the rest in the next 16 hours ? maintain an adequate urine output (1cc/kg/hr for children to 50+cc hr for adults; myoglobulinuria?). This is in addition to bolus(es) of ringers for hypovolemic shock (follow the electrolytes). Inadequate fluid resuscitation can also result in acute renal failure, which may be fatal.
(r) See also #(20), (21), (22), pp. 209-210.
(20) Chemical burns ? ABC’s ? irrigate with large volume of water, consult references for specific antidotes, e.g. hydrofluoric acid burn ? topical and s.c. 10% calcium gluconate prn.
(r) See also #(19), (21), (22), pp.207-210.
(21) Electrical injuries ? AC/DC current?
? immediate threats: cardiac and/or respiratory arrest.
? may have progressive intravascular thrombosis, and/or rhabdomyolysis, ± renal failure, ± other injuries (e.g. cervical spine), ± myoglobinuria, ± hyperkalemia, ± hypovolemic shock/acidosis, ± entrance/exit wounds.
? ACBC’s, 100% O2 prn, supportive care, saline boluses prn, ± dopamine prn, escharotomy/ fasciotomies prn, extended cardiac monitoring prn, tetanus prophylaxis prn, to burn centre prn. See also #(19), (20), (22), pp.207- 210, and #(18), p.222
(22) Lightning injuries ? ? as multiple trauma ? secondary cardiac arrest due to prolonged respiratory arrest; electrical injuries, blast injuries, burns, CNS damage ? ? ACBC’s, 100% O2 prn, tetanus prophylaxis prn, plus specific (, to burn centre prn.
(r) See also #(19)-(21), pp.207-209.
(23) Acute exposure to toxic agents ? ACBC’s, 100% O2 prn, protect rescuers, decontamination, consult references, specific (.
(24) TWENTY-FOUR
(A) Cyanide poisoning ? ABC’s, 100% O2, amyl nitrite inhalation, 3% sodium nitrite 0.2mL/kg to 10mL, sodium thiosulfate 25% 50ml (1mL/kg) I.V. (converts cyanide to nontoxic thiocyanate), vitamin B12a?, charcoal prn, HBO2 prn.
(B) Hydrogen sulfide gas poisoning ? cellular asphyxiant similar to cyanide.
? ABC’s, 100% O2, 3% sodium nitrite, 0.2mL/kg to 10ml, HBO2 prn.
(25) Methemoglobinemia (r) exposure to, for example, nitrates, nitrites, sulfas, mushrooms.
? ABC’s, 100% O2, remove causative agent, 1% methylene blue prn 0.1cc/kg/I.V. ? repeat in 1hr prn then q4-6h prn, exchange transfusions prn, HBO2 prn.
(26) Sulfhemoglobinemia (r) exposure to, for example, phenacetin, acetanilid.
? irreversible ? ? ABC’s, 100% O2, remove causative agent, exchange transfusions prn, HBO2 prn.
(27) TWENTY-SEVEN
(A) Phenol poisoning (r) absorbed through the skin (r) multisystem toxicity.
? ABC’s, copious H2O irrigation, wash with glycerol, repeat H2O irrigation.
(B) Phosphorus burns ? ABC’s, copious H2O irrigation, debridement.
(28) Carbon Monoxide poisoning (r) other victims? (e.g. co-workers, family members), flu-like symptoms?
? treat on clinical grounds while obtaining a carboxyhemoglobin level (have a low threshold for doing COHB levels. Smoker?).
? contamination of the cellular cytochrome systems may continue after the COHB has returned to a low level ? do not hesitate to contact your local hyperbaric consultant prn.
? ACBC’s, 100% O2, COHB level, HBO2 prn. Myoglobulinuria?
? remember that the family with the “flu” may have CO poisoning (e.g. malfunctioning gas/oil heater/furnace ? “the CO flu” that can result in death or permanent neurological impairment).
(29) Radiation Injuries ? Nausea and vomiting in less than 2 hours indicates an exposure of 400+ rem.
? Lymphocyte count at 48 hours: > 1200  = good prognosis 300-1200 = fair prognosis < 300  = poor prognosis.
? Potassium Iodine (begin in less than one hour if possible) < 1 year 65mg daily/po x 2 weeks > 1 year 130mg daily/po x 2 weeks.
? ? ACBC’s, protect rescuers, decontamination, protective isolation prn, CBC/platelet count q6h prn, supportive care, appropriate consultations prn.
(30) THIRTY
(A) Mushroom poisoning ? nausea and vomiting beginning > 6hrs after ingestion may indicate a potentially lethal group ? identify the mushroom(s) if possible (multiple type ingestion?) ? pictorial reference?, mycologist?, multiple victims?
Group I ? liver and/or renal impairment (amatoxin).
? ABC’s, supportive care, decontamination, I.V. fluids prn, pen G I.V. prn, dialysis prn. Liver transplantation?
Group II ? anticholinergic intoxication ? ABC’s, decontamination, supportive care, physostigmine? See also #(23)(B), p.199.
Group III ? methemoglobinemia, or hemolytic anemia, or isoniazid like poisoning.
? ABC’s, decontamination, 1% methylene blue, 0.1ml/kg I.V. prn, or PRBC’s prn, or pyridoxine 1-5g I.V. prn as indicated. See also #(25), p.210, #(13)(A), p.156, #(17)(B), p.194.
Group IV ? cholinergic ? ABC’s, atropine prn (antimuscarinic only), decontamination, supportive care. See also #(23)(A), p.198.
Group V ? antabuse(r) like reaction ? ABC’s, decontamination, supportive care.
Group VI ? dysphoric state ? ABC’s, decontamination, supportive care, valium(r) prn. Cortinarius mushrooms may be mistaken for “magic” mushrooms, and if ingested can result in acute renal failure. The clue is that the patient does not experience the “magic” with cortinarius mushrooms. Caution: the patient may not volunteer, or may deny, the ingestion of mushrooms.  Group VII ? GI effects only, onset < 2hrs ? ABC’s, decontamination, I.V. fluids prn, supportive care, pyridoxine I.V.?
(B) Poisonous plants ? pictorial references?, botanist?
? toxins, for example, calcium oxalate, cyanide, digitalis, anticholinergics, nicotine and like, GI toxins.
? ? ABC’s, decontaminate, supportive care, specific ?.
(C) Illness associated with seafood (r) multiple victims?
1. Infections * Bacterial e.g. cholera, salmonella, shigella, staph, bacillus cereus, E. Coli, botulism.
* Viral e.g. hepatitis A, norwalk.
* Parasitic e.g. fluke, tapeworm.
( ABC’s, supportive care, consult references prn, specific ( prn, e.g. antibiotics, antitoxins; admit ICU prn.
(r) the above also applies to non-seafood food poisoning, for example, salads/staph. aureus, poultry/salmonella, hamburger/bacillus cereus/E. Coli (may develop hemorrhagic colitis/hemolytic-uremic syndrome, See #(10)(B), p.111).
2. Intoxications, for example, paralytic shellfish poisoning, diarrhetic shellfish poisoning, scombroid fish poisoning (histamine poisoning), ciguatera (multisystem manifestations). Beware of a fulminating sensorimotor polyneuropathy.
? ABC’s, intubate and ventilate prn, supportive care, gastric lavage/charcoal/sorbitol prn, consult references prn, specific ( prn, e.g. antivenim; admit ICU prn.
(D) Traveler’s diarrhea ? cipro(r) 500mg bid or bactrim tabs II bid; ( peptobismal.
°XVII. Trauma
(1) Trauma ? ( ACBC’s, supportive care, treat the specific injuries, and any preexisting medical conditions, e.g. diabetes mellitus. Is the patient on anticoagulants? Obtain an ethanol level prn. Be on the lookout for child abuse.
? injuries are the result of a suicide attempt?, e.g. motor vehicle accident (r) or the MVA was a result of: alcohol and/or drug abuse?, MI?, CVA?, seizure?, narcolepsy?, hypoglycemia?
Head injury (+ neck injury?) ? mild = Glasgow scale 13-15, moderate = 9-12, severe = 3-8; loss of consciousness?, combative?, memory or focal deficit?, rectal exam? (anal sensation and sphincter tone?).
? Head injury can result in upper airway obstruction but rarely shock (e.g. an infant with an arterial bleed from a scalp laceration). If shock is present, look for another etiology (e.g. fractured pelvis).
? All significant head injuries require CT scanning or MRI ? e.g. epidural hemorrhage? (may require stat burr holes before scanning), subdural hemorrhage?, subarachnoid hemorrhage?, intracerebral hematoma?, cerebral contusion or laceration?, depressed skull fracture?, basilar fracture? (blood behind TM?, CSF leak?), penetrating injury? (do not attempt to remove the F.B. in the ER, e.g. arrow).
? Avoid hypoxemia, hypercapnia, agitation, seizures, pyrexia, and cerebral edema.
? ? ACBC’s, 100% O2 prn, pulse oximetry prn, thiamine prn, dextrose prn, narcan(r) prn, flumazenil prn, maintain a systolic pressure > 80 (boluses of ringers prn ? maintenance rate once stabilized), arterial blood gases prn, intubate prn, and hyperventilate prn with 100% O2 to a pCO2 25-30, mannitol prn 20% 5-10cc/kg/I.V. (caution), decadron(r) prn/initial dose 1mg/kg/to 50mg I.V. (plus Zantac(r) 50mg I.V. q8h for stress ulcer prophylaxis); seizures? (or prophylaxis) ? I.V. valium(r) 5-10mg prn and/or I.V. dilantin(r) 15mg/kg/loading dose/prn, neuromuscular blockade prn; hyperglycemia?, fibrinogen < 250? ? FFP/cryoprecipitate prn*****; ? pyrexia; antibiotics prn, analgesics prn, head elevated 30?, immediate neurosurgical consultation prn. Haldol(r) 5-10mg I.V. prn is useful for uncontrollable agitation (concomitant cervical spine injury?).
(2) Spine/cord injuries (r) often an anxiety producing diagnostic problem.
? the patient may have a multiple level injury.
? ? ACBC’s ? avoid excessive traction or movement ? ? all suspected spinal fractures as unstable until proven otherwise (immobilize) ? x-rays negative? ? CT scan prn, MRI prn (soft tissue injury?), refer prn.
If spinal injuries with neurological deficit are less than eight hours old, consider giving bolus of solu-medrol(r) (methylprednisolone) 30mg/kg/I.V. followed by 5.4mg/kg/hr/I.V. for 23 hours (plus Zantac(r) I.V. for stress ulcer prophylaxis).
Spinal shock ? flaccid paralysis ? reflexes return with spastic paresis.
Spinal neurogenic shock  ? autonomic dysfunction with loss of sympathetic tone ? hypotension, bradycardia, priapism. ? ? ACBC’s, supportive care, ringers prn, dopamine prn, consult urology prn.
Sacral sparing ? incomplete lesion ? partial recovery possible.
Prevertebral space at C3, C4 ? normal =< 5mm.
Anterior cord syndrome ? loss of motor function, and pain and temperature sensation.
Central cord syndrome ? motor weakness more pronounced in the hands and arms, as compared to the legs. Patient may complain of severe pain in both arms.
(r) solu-medrol(r) I.V.? See Spine/cord injuries above.
Brown-Sequard syndrome ? motor and vibration  ? deficit ipsilateral ? pain and temperature ? deficit contralateral Remember:
1. When you are assessing the cervical spine/cord think of the mnemonic ABC’s ? Alignment, (e.g. the four spinal lines), Bones, Cartilage (children), and Soft tissues (cord, ligaments, disks, vessels/bleeding).
2. Cord injuries can occur without a fracture or dislocation (e.g. spinal epidural hemorrhage ? requires immediate neurosurgical intervention; central cord syndrome, distraction injuries, shaken baby syndrome).
3. “Physiological subluxation” can occur under 16 years of age.
4. Blankets may be required to cover the spinal board (torso portion), to compensate for the increased flexion of the cervical spine, caused by the relatively larger head in children.
5. Children tend to have upper cervical spine injuries, versus lower cervical spine injuries in adults. Pediatric cervical spines are more adult like after 8 years of age.
6. Patients with possible cervical spine/cord injuries, and transient symptoms plus negative x-rays, need continued immobilization/investigations (e.g. MRI)/admission.
7. Jefferson fracture (C1), Hangman’s fracture (C2), and odontoid fractures are not uncommon (careful, an overlying upper incisor can simulate an odontoid fracture).
8. The depth of the prevertebral space in children at C3 = < 2/3 the C3 vertebral body.
9. Torticollis versus rotary subluxation: ? Rotary subluxation has sternomastoid spasm with the chin pointing ipsilaterally.
? Torticollis has cervical spinal muscle spasm with the chin pointing contralaterally.
10. Finally, if you feel uncomfortable about “clearing” a cervical spine/cord injury, refer the patient to neurosurgery, and don’t let the consultant talk you out of it.
(3) Neck injuries ? for example, airway obstruction (expanding hematoma?), cervical spine and/or cord, arteries, veins, air embolism, A-V fistulas, brachial plexus, and other nerves (fracture 1st, 2nd ribs?), larynx, pharynx, esophagus.
? ACBC’s, endoscopy prn, plain and contrast x-rays prn, angiography prn, CT scan prn, MRI prn, neck exploration prn (do not remove penetrating foreign bodies in the ER).
(4) Thoracic trauma ? ACBC’s ? minute ventilation should be 1.5-2 X normal. CT scan?
? Clamp the chest tube, and take the patient directly to the OR, if the bleeding continues through the chest tube, and the vital signs remain or become poor.
(5) Sucking chest wounds ? requires that an occlusive dressing be placed over the wound, and a chest tube be placed at a separate site.
(6) Massive subcutaneous emphysema ? chest tube?, bronchoscopy?, linear skin incisions?
(7) Fracture 1st or 2nd ribs or sternum  ? pericardial tamponade?, myocardial contusion?, pulmonary contusion?, bronchial tears?, major vascular injury (e.g. traumatic rupture of the aorta?/mediastinal widening?).
(8) Flail chest ? pulmonary contusion? ? ( ACBC’s, 100% O2, intubate prn, peep?
(9) Myocardial contusion ? EKG and CPK-MB may be normal.
? ( ACBC’s, 100% O2, supportive care/treat similar to acute myocardial infarction (may develop arrhythmias, usually within 24 hours). See #(7), p.219.
(10) Systemic air embolism ? can occur with chest injuries plus positive pressure ventilation.
? ACBC’s, thoracotomy, HBO2 prn.
(11) Intrabronchial bleeding ? ACBC’s, suction prn, bronchoscopy prn, double lumen endotracheal tube prn, surgery prn.
(12) Pneumomediastinum ? injuries to? trachea?, major bronchi?, pharynx?, esophagus? ? mediastinitis?
(13) Diaphragmatic rupture ? bowel in chest?, pleural effusion?, blurring of diaphragm?
? ACBC’s, CT scan?, chest tube and peritoneal lavage prn ? lavage fluid through chest tube? ? surgery.
(14) Pericardial tamponade (r) cyanosis from the neck up?
(r) impaired venous return and cardiac filling (r) tachycardia, hypotension, (may be orthostatic only), muffled heart sounds, ± distended neck veins, ± paradoxical pulse, ± clear lung fields.
? ACBC’s, large  bolus of ringers prn (0.5-2liters), echocardiogram and/or CT scan if appropriate prn, immediate? pericardiocentesis prn ? leave intracath in for repeated aspiration prn, subxiphoid pericardial window prn, thoracotomy prn.
(15) Thoracic duct injury ? ? ACBC’s, chest tube ? surgery prn.
(16) Abdominal trauma (r) alcohol and/or drug abuse?, concomitant head or neck injury?, preexisting disease?, CT scan?, angiography?
? ? ACBC’s, supportive care, surgery prn.
Problems ? missed injuries, retroperitoneal injuries/hemorrhage, concomitant chest/abdominal injuries, pelvic injuries, hypothermia, and coagulopathy. Beware of the lap seatbelt contusion with no other apparent injuries ? may have an intra-abdominal injury (e.g. small bowel perforation) ? observe for 12-14 hours prn. Lap belts may also be associated with back injuries.
Instilling 10-20cc of I.V.P. contrast solution via a catheter into an abdominal stab wound, followed by an x-ray, may be a useful procedure to determine whether or not the abdominal cavity has been violated (if the abdominal series failed to demonstrate any free air).  Diagnostic peritoneal lavage (DPL) (r) ng, foley, and abdominal series first (CT scan?) (r) 10cc blood = positive test ? if negative (or positive but you want to determine if the lavage fluid drains through the chest tube), instill ringers 20ml/kg to 1 litre ? aspirate ? positive if > 500 wbc’s, or > 100,000 rbc’s, or > 200 amylase, or bile, bacteria, feces, or vegetable matter present. DPL is usually not required if laparotomy is inevitable, e.g. free air in abdomen.
(17) Bullets ? greater than 2500 ft/sec = high velocity, and may cause damage to the surrounding area outside the bullet tunnel (e.g. femoral artery) ? low velocity ? 2500ft/sec, and can be treated like a stab wound. Shotgun blasts from < 7ft cause a large single entry tunnel injury.
(18) Trauma to the GU tract ? hematuria? (*myoglobinuria? ? positive dipstick for blood but no RBC’s seen on microscopic exam ? specific testing for myoglobin).
? ACBC’s, IVP prn, urethrogram prn, cystogram prn, consult urology prn, CT Scan?, angiography?
Urethrogram ? instill 10cc of 50/50 contrast solution/water soluble lubricant ? traction on the penis ? oblique x-ray of penis and pelvis.
Cystogram ? 500ml of the contrast solution ? children 5ml/kg ? raise the contrast solution to 2 feet above the bladder ? take an A-P film with the bladder full ? take a film with the bladder empty ? wash out the bladder with saline, and take another film.
IVP (intravenous pyelogram) ? 100ml of the contrast solution, or for children 2ml/kg, and take 5,10, and 20 minute films.
*Myoglobinuria ? ACBC’s, I.V. fluids, hyperkalemia?, bicarb prn, high urine output, lasix prn, mannitol prn, dialysis prn. Alkalination of the urine increases the solubility of myoglobulin.
Testicular contusion or rupture?
? ultrasound, refer prn, surgery prn.
(19) Fractures and dislocations ? Pathological fracture?, open fracture?, neurovascular injury?, e.g. radial nerve, popliteal artery.
? Watch for a lunate dislocation (volar), perilunate dislocation (dorsal), ± fracture and/or dislocation of the scaphoid, isolated scaphoid fracture, fractures of the middle phalanges or metacarpals with rotation, fracture of the proximal phalanges, and volar plate injuries (refer all of the above to a hand surgeon).
(r) fractures and dislocations may require early adequate analgesia (e.g. narcotics I.V.).
(r) Early reduction/splinting/casting of fractures/dislocations will decrease, or alleviate the need for further analgesia (the “best analgesic”). Beware of compartment syndromes, e.g. fractured tibia.
? Check casts in 24-48 hours, or before prn.
? Beware of a posterior shoulder dislocation (epilepsy, ethanol, electricity).
? Check the axillary nerve, before and after reducing an anterior shoulder dislocation.
? Knee dislocation ? injury to the popliteal artery?
? Traumatic hemarthrosis of the knee ? think crucriates /menisci/ collateral ligaments/ fracture (fat globules?).
? Wrist fractures are frequently ? with an external fixator.  ? Injury of the long thoracic nerve? ? serratus anterior paralysis ? winging of the scapula (interesting but I have never seen it).
(20) Hand injuries and infections ? normal stance? (position of rest) ? position of function?
? Flexor profundus tendon ? stabilize the mcp and pip joints, then flex the tip.
? Flexor sublimis tendon ? extend and stabilize all but the testing finger.
? Ulnar nerve ? abduct the extended index finger.
? Median nerve ? abduct the thumb.
? Radial nerve ? extend the fingers with the wrist extended.
? All nerve lacerations, most tendon lacerations, and serious hand infections (diabetic?) need referral to a hand surgeon. Beware of the high pressure injection injury, burns, frostbite, foreign bodies, boutonniere deformity, acute carpal tunnel syndrome, and electrical and crush injuries.
(21) Pelvic fractures ? ACBC’s, unstable fracture? ? give ringers and PRBC’s promptly prn.
Associated problems ? hemorrhage, other injuries ? for example, intra-abdominal, urinary tract, gynecologic, diaphragm, nerve root ? also infection and thrombophlebitis.
(22) Children (r) orthopedic injuries (r) child abuse?
? separation of the distal femoral, or proximal tibial epiphysis ? circumferential tenderness ? refer (Osgood-Schlatter’s disease?, chrondomalacia patellae?).
? slipped capital epiphysis of the hip (may present with knee pain) ? refer (Legg-Calvé-Perthes?). Beware of the supracondylar fracture of the elbow, and growth plate injuries (both may have subtle x-ray findings).
? (on the lighter side), after reducing a “pulled elbow” (a “medical magic trick”), gently restrain the “good arm,” and see if the child will reach for a popsicle with the “bad arm” (giving a child a treat, seems to make them {and their parents}, think that you are not such a “bad guy” after all).
(23) Watch for compartment syndromes (r) of the arms, legs, and feet, secondary to fractures and soft tissue injuries, (disproportionate pain with rest and passive stretching). Beware of crush injuries. Split all tight, painful casts.
(r) compartment syndromes need immediate surgical intervention.
(24) Calcaneal fractures ? look for associated knee, hip, pelvis, and back injuries.
(25) Watch for rupture of the ankle syndesmosis ? patient may have heard a “pop” ? pain with bilateral compression of the malleoli, and with dorsiflexion ? serious long term effects ? refer. Beware of ankle dislocations ? reduce immediately to prevent skin necrosis.
(26) Pediatric hemorrhagic shock  ? hypotension is a late sign ? give packed red blood cells (10mL/kg), if the patient requires greater than 20-40ml/kg of ringer’s lactate.
(27) Wounds (r) including animal bites.
? ? ACBC’s, local or regional anesthetic (e.g. infraorbital, ulnar, and tibial nerve blocks) ? irrigate-debride-irrigate, primary or delayed repair, drainage prn, tetanus prophylaxis prn, antibiotics prn (initial dose(s) parenteral?), appropriate dressings prn, rabies prophylaxis prn, and ? other problems. Beware of penetrating joint injuries, e.g. knee.
? Antibiotics (e.g. cephalosporins) for impact wounds, or wounds greater than 3-6 hours old, or wounds contaminated with pus, feces, saliva, dirt, or vaginal secretions ? also patients with valvular heart disease, orthopedic prostheses, wounds involving lymphedematous areas, or immunosuppression (e.g. chemotherapy, splenectomy).
? Skin sutures out in less than eight days, or the patient may develop needle puncture scars.
°XVIII. Psychiatric Disorders
(r) ± medical problems?, ± drug overdose?, ± alcohol/drug abuse? ? all psychiatric patients require “medical clearance.”
? Patients with delirium have vivid hallucinations, whereas chronic psychotics can be somewhat indifferent to their hallucinations. Disorientation in psychiatric disorders tends to be more person than time, vice versa in metabolic disorders.
? Depressed/suicidal patients may also be homicidal. Depression is under-diagnosed, particularly in the elderly. Fatigue may be the chief complaint.
? ACBC’s, supportive care, ? other problems, for example, multiple drug overdose, poorly controlled diabetes; psychiatric consult/voluntary/involuntary admission prn†††††.
? Schizophrenic patients ? dangerous to themselves or others?
? ACBC’s, supportive care, antipsychotics prn, injuries?, other medical problems?, psychiatric consult/voluntary/involuntary admission prn.
? Paranoid patients ? high risk for violence if unstable; weapons?, alcohol/drug abuse?
? ACBC’s, supportive care, physical/chemical restraints prn (e.g. haldol(r) 5-10mg ± ativan(r) 1-2mg I.M./I.V. prn), psychiatric consult/voluntary/ involuntary admission prn.
? Manic patients are a high risk for violence, especially if you “cross them”. If they tend to make you laugh with them, schizophrenia is unlikely.
? ACBC’s, supportive care, haldol(r)/ativan(r) prn, psychiatric consult/voluntary/involuntary admission prn.
(r) Lethal catatonia syndrome * acutely psychotic * refuses all food/fluids.
* fever, tachycardia, acrocyanosis, mutism, rigidity, stupor (r) coma.
* caution: the patient may suddenly become violent.
( ABC’s, supportive care, haldol(r) prn, refer, ECT prn, admit ICU prn.
? Beware of contributing physical symptoms/signs to hysteria. For example, dyspnea/pulmonary embolism; hyperventilation/anxiety/salicylate poisoning; parathesias/multiple sclerosis.
Conversion disorders are typically characterized by a lack of concern by the patient, do not follow the normal neuroanatomical relationships, are free of injury, and there is no incontinence.  ? Psychogenic Fugue ? self-limited ??rule out organic causes of amnesia, e.g. alcoholic blackouts.
? Dementia ? reversible? (e.g. drugs, metabolic, subdural hematoma, depression).
? Alcohol withdrawal Autonomic hyperactivity ? 6-8 hours Hallucinations ?  24 hours Seizures ? 1-2 days Global confusion ? 3-5 days ? Haldol(r) 5-10mg I.M./I.V. ± ativan(r) 1-2mg I.M./I.V. q15-60minutes prn ? useful for combative patients ? Acute dystonias ? benadryl(r) 1mg/kg to 50mg I.V./I.M.
? Akathisia ? cogentin(r) 2-4mg I.V./I.M.
? Alpha adrenergic blockage, e.g. from an overdose of chlorpromazine.
? ABC’s, ringers ± norepinephrine.
? Xanax(r) 0.25-0.5mg bid-tid prn; Buspar(r) 5-15mg bid-tid prn.
? Ativan(r) (lorazepam) po, SL, IM, or I.V. 1-2mg prn.
? SSRIs (selective serotonin re-uptake inhibitors), e.g. Prozac(r) ? beware of adverse behavioral changes, increased suicidal risk, and adverse interaction with tricyclics, tegretol(r), haldol(r), and MAOIs. In addition, there are reports of SIADH (inappropriate secretion of antidiuretic hormone)/hyponatremia associated with the use of SSRIs. CMAJ Sept. 1, 1996; 155(5), p.519-527.
? MAOIs ? foods containing tyramine; demerol(r), and a multitude of other drugs (e.g. cold preps) are contraindicated ? hypertensive crises ? stop MAOI ? mild crises ? ? chlorpromazine 25-50mg IM prn ? severe crises ? ? phentolamine 5mg I.V. prn, plus see #(7)(A), p.118, #(3)(D), p.186.
? Lithium therapy may result in hypothyroidism.
? Hypothyroidism may present as a depression.
°References
1. Advanced Cardiac Life Support Textbook. American Heart Association
2. Advanced Trauma Life Support Manual. American College of Surgeons
3. Emergency Medicine – A Comprehensive Study Guide. American College of Emergency Physicians
4. Patient Examination and History Taking. H.J.R. Wrightman MO; Collier MacMillan Canada LTD
5. Compendium of Pharmaceuticals and Specialties; Canadian Pharmaceutical Association
6. Essentials of Emergency Medicine. Rosen, Barkin and Sternbach; Mosby-Year Book.
7. Current Emergency Diagnosis and Treatment. Lange Medical Books.
8. Emergency Pediatrics. Barkin, Rosen; Mosby-Year Book.
9. Pediatric Advanced Life Support Textbook. American Heart Association, American Academy of Pediatrics.
10. APLS: The Pediatric Emergency Medicine Course. American Academy of Pediatrics, American College of Emergency Physicians.
11. The Pain Manual, S. Lawrence Librach, MD, FCFP; Canadian Cancer Society.
12. “Toxidromes,” (unpublished) Dr. P.G. Croskerry, director, Dartmouth General Hospital Emergency Department, 325 Pleasant St., Dartmouth, Nova Scotia, Canada, B2Y 4G8.
13. “Shiftwork – adaptation strategies,” Dr. P.G. Croskerry, presented at the Annual Meeting of the Canadian Association of Emergency Physicians, Halifax, Nova Scotia, Canada. May, 1997.
14. “Diagnostic Strategies and Decision Making in Emergency Medicine,” Dr. P.G. Croskerry, presented at the ACEP National Meeting, Washington D.C., September, 1995.
15. “Avoiding Pitfalls in the Emergency Room,” Dr. P.G. Croskerry, The Canadian Journal of CME. April, 1996.
16. Emergency Medicine – House Officer Series. Pousada, Osborn and Levy; Williams and Wilkins.
17. Pediatric Emergency Medicine – A Comprehensive Study Guide. American College of Emergency Physicians. 1996.
18. “Emergency Pain Management: A Canadian Association of Emergency Physicians (CAEP) Consensus document.” The Journal of Emergency Medicine. 1994. 12:6, pp.885-866.
°A Request for Feedback
Candid comments, and suggestions for future editions will be gratefully received. I hope you have enjoyed this brief “guided tour” through Emergency Medicine.
°Index
(Deleted in this Palm version to save space.)
°Footnotes
* I passed the ABEM orals using this book (in 1992, when the book was only 74 pages long!).
* Family, friends, and the significant others, can often be excellent, and sometimes invaluable allies, e.g. the uncooperative alcoholic patient with pneumonia.
† I feel compelled to say that universal health care insurance raises a society’s minimum level of dignity (my impression). I hope Canada’s medicare system survives.
* I hope that these suggestions do not inadvertently offend anyone. The book was written primarily for my own use and I read it cover to cover periodically to “freshen up” (however, I must admit each book sale gives me a “shot in the arm”).
* If you lose your “cool” and are rude to a patient or their significant other, it may come back to haunt you (for example, a legal action, or a time consuming investigation of a complaint and its resolution, or you have to encounter with the patient or the significant other that you were rude to, at a subsequent ER visit). Maintaining your professionalism in the face of incivility can be challenging, but to do otherwise will sabotage the patient encounter. Remember the adage, “whatever goes around, comes around.”
† Agitated patients/relatives/significant others may have to be “talked down” to prevent a further escalation in their disruptive behavior (maintaining a pleasant demeanor will often counteract their irritability and vice versa). Do not take undue risks, summon security/police sooner than later. See also “Combative patient,” p. 17.
‡ Occasionally, you may get the impression that the patient does not think that you are taking their complaints seriously (they may be right). A clue is that the patient keeps repeating their complaints over and over again. If you are getting these “vibes,” refocus, and reassure the patient that you are indeed taking their complaints seriously.
* Remember the Nissan(r) automobile ad: “Life is a journey, enjoy the ride.”
* Safety of Early Pain Relief for Acute Abdominal Pain, BMJ 1992; 305:554-6. Conversely, the patient with moderate abdominal pain is usually quite willing to postpone analgesia, when the surgeon will be visiting them within the hour, e.g. “I want the surgeon to see you just as you are now.”
* Working a busy 12 hour night shift in the ER is much like running a marathon. At times, it can be almost effortless, but you frequently “hit the wall” at about 4am. If you can steal even a few minutes to “nod off,” this will facilitate you to “run through the wall.” See also reference #13, “Shiftwork – adaptation strategies”  p. 17.
* Occasionally a patient gets impatient waiting for their blood work results, and wants to go home. Encourage them to stay, as there will be the occasional surprise (e.g. new diabetic, K+ 2.7).
† Implementation of the Ottawa Ankle Rules. JAMA 1994; 271:827-832.
* It may sometimes be appropriate and useful, to reassure the patient/significant others by relating to them, that you are managing their illness/injury in the same manner, that you would want a member of your own family with the same problem managed (ask yourself, “am I?”).
* Patients who have “acted up” during a previous visit, may exhibit signs of relief when you don’t appear to remember them (“a fresh start”).
† Some “average physicians” have the ability to generate zero patient complaints in the ER, not even a trivial one. One older, quiet, but pleasant, family physician, who had a large private practice and worked part time in our department did not generate a patient complaint in 17 years. Perhaps these physicians’ practice behaviour should be studied in detail.
* Nevertheless, the proportion of “elective patient visits” in the ER population appears to be decreasing (in my humble opinion). I now regard the straightforward, “non-urgent, clinical problem” as a refreshing break from the more complex patient encounters. Resist giving these “elective patients” the impression that you have an “attitude problem” (may take a conscious public relations effort on your part, especially when the ER is busy/long patient waiting times/staff and patient fatigue). Minimizing their problem is not appreciated by the patient (e.g. “It’s only the flu, there’s nothing we can do,” instead of providing the patient with some symptomatic treatment). The adage, “If you are too nice to them, they’ll be back,” promotes sub-optimal care. See “Lawsuits (scary stuff!)” above.
* For example, taking less time for you to determine the gist of a patient’s problem. Beware of the adage, “often in error, never in doubt.”
* For example, in a calm voice with a resolute tone, “this patient needs an I.V., real soon,” followed by specific stabilization orders (the nurse may already have begun presumptive management/O2, monitors, I.V., EKG, bloodwork).
* Remember that specifically addressing any such “fears” is a “must do.”
† Conversely, there are the patients who inherently dramatize their symptoms.
* I have yet to see a case of significant respiratory depression in the ER from the use of oxygen in COPD patients.
* If you find it necessary to restrain, or threaten to restrain a patient, make a note on the chart. For example, “the patient has been consuming ethanol, and at present (e.g. 0300 hours) is incompetent, and a danger to himself and others” (also remember to obtain an alcohol level, and record it on the chart).
* Titrate the narcan(r)/flumazenil in suspected addicts to just adequately reverse the respiratory and CNS depression only, avoid inducing withdrawal.
* Recently, I witnessed an anesthetist easily intubate a tiring patient with CHF/pulmonary edema, using 10mg valium(r) I.V. followed by 40mg succinylcholine I.V.
* pediatric dose of ventolin(r) = 0.03cc/kg to 0.5-1.0cc
* I have avoided a difficult intubation on more than one occasion using I.V. MgSO4, and an another occasion using five sequential 1mL I.V. doses of epinephrine 1:10,000 plus I.V. MgSO4.
† Anxiety is more often secondary, that is the result of the present problem, e.g. chest pain, rather than the cause of the present symptoms, e.g. psychogenic hyperventilation.
* Remember that not all cardiac arrhythmias/arrests are due to coronary artery disease. See Cardiac arrest/Ventricular tachycardia, #(2), p.17.
* My usual opening line to patients who require PRBC’s is, “looks like you are going to need some of that red stuff.” Patients seem to be very aware of the pros and cons of blood transfusions.
* Ask the patient if they carry a pack of antacid tablets with them most of the time.
* Sometimes a brief discussion, or comment, is all that it takes to make a positive, permanent, alteration in a patient’s lifestyle. It is worth the effort. You may at least facilitate some harm reduction (e.g. decreased alcohol consumption). But remember, lecturing just doesn’t work!
† It may also be appropriate to have a pointed discussion with the patient regarding their multiple, behaviour-related ER visits (after the patient has settled down/sobered up, e.g. visits are always alcohol/drug related with loud, demanding, disruptive behaviour).
* The ABC’s of a melanoma (r) asymmetrical configuration, irregular border, varying degrees of pigmentation in the same lesion, recent changes in a “mole.”
* Once the epistaxis has been arrested with the Epistat(r), the patient can then be admitted, and have a daytime ENT consultation (resulting in a very grateful otolaryngologist!).
* Alcoholics may have rib fractures (new and old), and not remember any injury taking place.
† In harm’s way: Peter Vaughan, MD: CMAJ 1997; 156:855-6.
* I recently attended a patient who had an ectopic pregnancy ten months following a cesarean section/tubal ligation. The patient presented with sudden, severe, generalized lower abdominal pain and nausea (menses was six weeks previously). The lower abdominal and pelvic tenderness was also generalized, and there was no bleeding from the cervical canal (the serum pregnancy test was positive).
* Do not insert the needle through an area of overlying erythema (cellulitis?).
* Do not be too quick to discount the patient’s opinion regarding observation/ admission/ discharge. It is my impression that their judgment has a “good batting average.” Remember to make a note on the patient’s chart, e.g. “patient declined observation and elected to go home. The pertinent risks were discussed. Advised to return prn.” An exception to the above is a patient that refuses observation/ admission because they do not wish to be separated from their alcohol/ nicotine (patients are reluctant to admit to this).
† Our hospital now has home care for up to twenty selected low risk patients (e.g. COPD). The nursing staff consists of former ER and ICU nurses who were looking for new challenges.
* Even after overnight observation of a patient that is now completely asymptomatic, e.g. “flu/abdominal. pain,” remember to advise the patient to return if there is a significant recurrence of their symptoms, e.g. RLQ pain (should the patient subsequently develop acute appendicitis then they will not forever think you missed the diagnosis). Avoid “famous last words”, e.g., “this is not your appendix.”
* When discharging patients who will/may have pain at home, do not forget to give them a few analgesics tablets “to go”, e.g. tabs 5 of Tylenol(r) with codeine, or Demerol(r) 50mg (if appropriate). Even if it turns out that the patient does not need the tablets, they may find it reassuring to have them on hand (also applies to anxiety/ativan(r) tabs 5). If the patient requires additional medication, they can see their own physician (follow up may be indicated in any case). Again, be on the look out for drug seekers, or a past history of drug abuse.
† Discharge instruction sheets (e.g. head injury, fever, casts, sutures) must be explained to the patient.
‡ Reinforce the “work ethic” whenever the opportunity avails itself, for example, to the patient who wants to take as little time as possible off work, “I like your attitude.”
§ Some jurisdictions have a “hospital act” which allows the police to detain an incompetent patient for assessment/observation.
* Remember, there is nothing wrong with letting your feelings show, and making physical contact with the grieving survivors. I often make a small monetary donation to the hospital in memory of the patient, and I frequently receive back a very appreciative note from the family. It has always bothered me that before the family leaves the ER, they may see you back to work as if nothing has happened. The donation, I hope, demonstrates to the family that their relative’s death did not go “unnoticed” by the ER staff.
( Biaxin(r) (clarithromycin) 250-500mg bid po may be used for mild to moderate infections (better tolerated than erythromycin). Another alternative is doxycycline I.V. or po.
* ciprofloxacin may also be given I.V. and has a wide range of indications (consult references). Note: ciprofloxacin, clarithromycin and azithromycin are expensive antibiotics.
† Reported to result in bronchodilation, decreased respiratory muscle fatigue, and respiratory stimulation in COPD patients. Can Med Assoc J 1992; 147:420-8.
‡ Concomitant occult/overt sinusitis may aggravate asthma. The treatment of an accompanying sinusitis may alleviate the asthma symptoms, and decrease the need for systemic steriods. Sinusitis: Supplement to CMAJ 1997; 156(6). The first line antibiotic for sinusitis is amoxil(r) or bactrim. Second line antibiotics include, clavulin(r), biaxin(r), azithromycin, and cephalosporins. See also #(2)(E), p. 17.
§ Famvir(r) is a new alternative to acyclovir, 500mg tid for seven days, reduce to bid/od with decreased renal function. Valtrex(r) 500mg bid for five days is another new choice.
** I.V. dexamethasone beginning just prior to the antibiotics is now recommended by some clinicians (0.6mg/kg/day).
†† Intravenous magnesium therapy for moderate to severe pediatric asthma: J Pediatr 1996; 129:809-14. The study dose of MgSO4 was 25mg/kg (maximum 2g).
‡‡ I tell parents that a local pediatric chest specialist says, “No smoking in the house, no smoking in the car.”
§§ The denial of chronic pain. Editorial by Dr. Robert Teasell. Pain Research and Management. Vol 2, no. 2, summer 1997.
*** Some migraine sufferers complain that they are made to feel like “criminals” in the E.R. (especially if they ask for Demerol). I must admit that I have eyed some “legitimate” patients suspiciously.
††† A similar regimen using haldol(r) 5mg and normal saline has recently been described.
‡‡‡ Ergotamine and sumatriptan are both contraindicated in patients with coronary artery disease, or Prinzmetal’s angina.
§§§ Bioethics for clinicians: 4 Voluntariness. Can Med Assoc J Oct. 15, 1996; 155(8), p. 1083-1086.
**** Case report Clinical Infectious Diseases (Dec. 21, 1995). A multi-centre prospective trial is now in progress.
†††† Necrotizing fasciitis/cellulitis that does not receive surgical intervention is universally fatal, e.g. Fournier’s gangrene.
‡‡‡‡ the value of the routine use of MgSO4 in alcoholic withdrawal is now being questioned (in any case, send off a blood sample for a magnesium level before giving same).
§§§§ one teaspoon (5mL) of oil of wintergreen (methyl salicylate), contains the equivalent amount of salicylate found in twenty-one 325mg ASA tablets (6825mg).
***** See Cryoprecipitate, #(9)(C), p. 17.
††††† Certifying patients for involuntary psychiatric admission is an unpleasant task. If you make it clear to the patient (if appropriate), that their only choices are voluntary, or involuntary admission, the patient will often opt for the voluntary route. In addition, if you tell the patient that you have no choice, but “to do what you have to do,” for their safety (and maybe others), they seem less likely to hold a grudge (my impression).

2 Comments

6 FEVER, HYPERTHERMIA, CHILLS, AND RASH

6 FEVER, HYPERTHERMIA, CHILLS, AND RASH
Harrison’s Manual of Medicine

6

FEVER, HYPERTHERMIA, CHILLS, AND RASH

Fever and Hyperthermia
Fever of Unknown Origin (FUO)
Bibliography

Fever and Hyperthermia
Fever is an abnormal elevation of body temperature due to a change in the hypothalamic thermoregulatory center. Although “normal” temperature is said to be 37°C, the maximal normal temperature ranges from 37.2°C (98.9°F) at 6 A.M. to 37.7°C (99.9°F) at 4 P.M. Rectal temperatures are generally 0.4°C (0.7°F) higher than oral readings. Fever is caused by a resetting of the hypothalamic “set point” by prostaglandins (especially PGE2), a process mediated by cytokines. Fever may result from infection, immune phenomena, vascular inflammation or thrombosis, infarction or trauma, granulomatous diseases (e.g., sarcoid), inflammatory bowel disease, neoplasms (especially Hodgkin’s disease, lymphoma, leukemia, renal cell carcinoma, and hepatoma), or acute metabolic disorders (e.g., thyroid crisis, Addisonian crisis).
Hyperthermia is an uncontrolled increase in body temperature that exceeds the body’s ability to lose heat without an elevation of the hypothalamic set point. Hyperthermia without fever may result from failure to dissipate body heat adequately (e.g., in a hot environment) or from drugs (e.g., neuroleptic malignant syndrome caused by phenothiazines and other neuroleptics, malignant hyperthermia caused by inhalation anesthetics or succinylcholine in genetically susceptible individuals).
CLINICAL MANIFESTATIONS   In addition to an elevated body temperature, patients with fever may develop generalized symptoms such as myalgias, arthralgias, anorexia, and somnolence. Chills—a sensation of cold— occur with most fevers. Rigors—profound chills—are associated with piloerection, chattering of the teeth, and severe shivering. Sweats accompany the activation of heat-loss mechanisms. Alterations in mental status, including delirium and convulsions, are most common among the very young, the very old, and the debilitated. Rash may occur with fever and may indicate a localized skin eruption or a systemic disease. The distinctive appearance of an eruption in association with a clinical syndrome may facilitate prompt diagnosis and treatment.
DIAGNOSIS   Few signs and symptoms in medicine suggest as many diagnostic possibilities as fever; thus a careful clinical evaluation is necessary. A detailed history must be obtained, including present illness and medical, social, travel, and family history. A meticulous physical exam must be performed and repeated on a regular basis. When rash accompanies fever, special attention should be given to the onset, configuration, arrangement, and distribution of the lesions. (For a more detailed description of systemic illnesses with fever and rash, see Table 18-1 in HPIM-15.) The lab workup must be individualized in light of the clinical circumstances. It should always include a CBC with differential and examination of any abnormal fluid collection (joint, pleural fluid). Other tests to consider include ESR determination, UA, LFTs, and cultures of blood, urine, sputum, or stool. Radiologic tests may include plain radiography, MRI and CT scanning (for detection of abscesses), and radionuclide scanning (esp. tagged WBC scanning). If no diagnosis can be made on the basis of less invasive tests, tissue must be obtained for biopsy, particularly from any abnormal organ; bone marrow biopsy may be useful, esp. for pts with anemia.
Fever of Unknown Origin (FUO)
Classic FUO is diagnosed when fever of >38.3°C (101°F) develops on several occasions over the course of >3 weeks and when 1 week of study in the hospital or three outpatient visits fail to result in a diagnosis. Most cases of FUO are due to infection, neoplasm, or collagen-vascular disease. Other causes include drugs, granulomatous diseases, inflammatory bowel disease, pulmonary embolism, factitious fever, erythema multiforme, familial Mediterranean fever, Behçet’s syndrome, and Fabry’s disease. FUO prolonged beyond 6 months is much less commonly due to infection and more often due to unusual or undetermined causes. When no cause can be identified, the prognosis is usually favorable. Treatment for classic FUO consists of continued observation and examination with avoidance of empirical therapy. Other specialized categories of FUO have been established for certain populations of pts (Table 6-1), with variations in diagnosis and treatment.

Table 6-1 Categories of FUOa

TREATMENT
The first decision to make is whether an elevation in body temperature reflects fever or hyperthermia. The objectives in treating fever are to reduce the elevated hypothalamic set point and to facilitate heat loss. There is no evidence that fever itself facilitates recovery from infection. Low-grade or mild fevers do not necessarily require treatment except in pregnant women, children with febrile seizures, or pts with impaired cardiac, pulmonary, or cerebral function. High fever (>41°C) should be managed with antipyretics and with physical cooling with a cooling blanket or sponge bath. Acetaminophen (0.65 g) given every 3 h around the clock (rather than intermittently, which aggravates symptoms of sweats and chills) is effective for the management of most fever and is preferred because it does not (1) mask signs of inflammation that might indicate a cause of the fever, (2) impair platelet function, or (3) cause Reye’s syndrome in children. NSAIDs and aspirin have anti-inflammatory as well as antipyretic effects. NSAIDs may be particularly useful in the management of fever due to malignancy.
By definition, hyperthermia does not respond to attempts to reset the already-normal hypothalamic set point (e.g., with acetaminophen) but does respond to physical cooling with measures such as sponging, fans, cooling blankets, and even ice baths. These measures should be instituted immediately in hyperthermia, and IV fluids should be administered. If insufficient cooling is achieved with these methods, gastric or peritoneal lavage with iced saline can be initiated; in extreme circumstances, hemodialysis or cardiopulmonary bypass with cooling of the blood can be undertaken. Malignant hyperthermia, neuroleptic malignant syndrome, drug-induced hyperthermia, and perhaps hyperthermia due to thyrotoxicosis respond to dantrolene (1–2.5 mg/kg IV q6h). Procainamide should be administered to pts with malignant hyperthermia because of the high risk of ventricular fibrillation in this syndrome.

Bibliography

For a more detailed discussion, see Dinarello CA, Gelfand JA: Fever and Hyperthermia, Chap. 17, p. 91; Kaye ET, Kaye KM: Fever and Rash, Chap. 18, p. 95; and Gelfand JA: Fever of Unknown Origin, Chap. 125, p. 804, in HPIM-15.

3 Comments

A Guide to Contraceptive Choices

Protecting Against
Unintended Pregnancy:
A Guide to
Contraceptive Choices

Barrier Methods
Vaginal Spermicides
Hormonal Methods
Intrauterine Devices
Traditional Methods
Surgical Sterilization
Preventing HIV/Other STDs
PalmaServ

by Tamar Nordenberg

I am 20 and have never gone to see a doctor about birth control. My boyfriend and I have been going together for a couple of years and have been using condoms. So far, everything is fine. Are condoms alone safe enough, or is something else safe besides the Pill? I do not want to go on the Pill.
–Letter to the Kinsey Institute for Research in Sex, Gender, and Reproduction

This young woman is not alone in her uncertainty about contraceptive options. A 1995 report by the National Academy of Sciences’ Institute of Medicine, The Best Intentions: Unintended Pregnancy and the Well-being of Children and Families, attributed the high rate of unintended pregnancies in the United States, in part, to Americans’ lack of knowledge about contraception. About 6 of every 10 pregnancies in the United States are unplanned, according to the report.

Being informed about the pros and cons of various contraceptives is important not only for preventing unintended pregnancies but also for reducing the risk of illness or death from sexually transmitted diseases (STDs), including AIDS.

The Food and Drug Administration has approved a number of birth control methods, ranging from over-the-counter male and female condoms and vaginal spermicides to doctor-prescribed birth control pills, diaphragms, intrauterine devices (IUDs), injected hormones, and hormonal implants. Other contraceptive options include fertility awareness and voluntary surgical sterilization.

“On the whole, the contraceptive choices that Americans have are very safe and effective,” says Dennis Barbour, president of the Association of Reproductive Health Professionals, “but a method that is very good for one woman may be lousy for another.”

The choice of birth control depends on factors such as a person’s health, frequency of sexual activity, number of partners, and desire to have children in the future. Effectiveness rates, based on statistical estimates, are another key consideration. FDA has developed a more consumer-friendly effectiveness table, which the agency will encourage all contraceptives marketers to add to their products’ labeling. A copy of the table can be obtained by sending a request to FDA’s Office of Women’s Health, 5600 Fishers Lane (HF-8), Room 15-61, Rockville, MD 20857.

Barrier Methods

Male Condom.

The male condom is a sheath placed over the erect penis before penetration, preventing pregnancy by blocking the passage of sperm.

A condom can be used only once. Some have spermicide added, usually nonoxynol-9 in the United States, to kill sperm. Spermicide has not been scientifically shown to provide additional contraceptive protection over the condom alone. Because they act as a mechanical barrier, condoms prevent direct vaginal contact with semen, infectious genital secretions, and genital lesions and discharges.

Most condoms are made from latex rubber, while a small percentage are made from lamb intestines (sometimes called “lambskin” condoms). Condoms made from polyurethane have been marketed in the United States since 1994.

Except for abstinence, latex condoms are the most effective method for reducing the risk of infection from the viruses that cause AIDS, other HIV-related illnesses, and other STDs.

Some condoms are prelubricated. These lubricants don’t provide more birth control or STD protection. Non-oil-based lubricants, such as water or K-Y jelly, can be used with latex or lambskin condoms, but oil-based lubricants, such as petroleum jelly (Vaseline), lotions, or massage or baby oil, should not be used because they can weaken the material.

Female condom.

The Reality Female Condom, approved by FDA in April 1993, consists of a lubricated polyurethane sheath shaped similarly to the male condom. The closed end, which has a flexible ring, is inserted into the vagina, while the open end remains outside, partially covering the labia.

The female condom, like the male condom, is available without a prescription and is intended for one-time use. It should not be used together with a male condom because they may not both stay in place.

Diaphragm.

Available by prescription only and sized by a health professional to achieve a proper fit, the diaphragm has a dual mechanism to prevent pregnancy. A dome-shaped rubber disk with a flexible rim covers the cervix so sperm can’t reach the uterus, while a spermicide applied to the diaphragm before insertion kills sperm.

The diaphragm protects for six hours. For intercourse after the six-hour period, or for repeated intercourse within this period, fresh spermicide should be placed in the vagina with the diaphragm still in place. The diaphragm should be left in place for at least six hours after the last intercourse but not for longer than a total of 24 hours because of the risk of toxic shock syndrome (TSS), a rare but potentially fatal infection. Symptoms of TSS include sudden fever, stomach upset, sunburn-like rash, and a drop in blood pressure.

Cervical cap.

The cap is a soft rubber cup with a round rim, sized by a health professional to fit snugly around the cervix. It is available by prescription only and, like the diaphragm, is used with spermicide.

It protects for 48 hours and for multiple acts of intercourse within this time. Wearing it for more than 48 hours is not recommended because of the risk, though low, of TSS. Also, with prolonged use of two or more days, the cap may cause an unpleasant vaginal odor or discharge in some women.

Sponge.

The vaginal contraceptive sponge has not been available since the sole manufacturer, Whitehall Laboratories of Madison, N.J., voluntarily stopped selling it in 1995. It remains an approved product and could be marketed again.

The sponge, a donut-shaped polyurethane device containing the spermicide nonoxynol-9, is inserted into the vagina to cover the cervix. A woven polyester loop is designed to ease removal.

The sponge protects for up to 24 hours and for multiple acts of intercourse within this time. It should be left in place for at least six hours after intercourse but should be removed no more than 30 hours after insertion because of the risk, though low, of TSS.

Vaginal Spermicides Alone

Vaginal spermicides are available in foam, cream, jelly, film, suppository, or tablet forms. All types contain a sperm-killing chemical.

Studies have not produced definitive data on the efficacy of spermicides alone, but according to the authors of Contraceptive Technology, a leading resource for contraceptive information, the failure rate for typical users may be 21 percent per year.

Package instructions must be carefully followed because some spermicide products require the couple to wait 10 minutes or more after inserting the spermicide before having sex. One dose of spermicide is usually effective for one hour. For repeated intercourse, additional spermicide must be applied. And after intercourse, the spermicide has to remain in place for at least six to eight hours to ensure that all sperm are killed. The woman should not douche or rinse the vagina during this time.

Hormonal Methods

Combined oral contraceptives.

Typically called “the pill,” combined oral contraceptives have been on the market for more than 35 years and are the most popular form of reversible birth control in the United States. This form of birth control suppresses ovulation (the monthly release of an egg from the ovaries) by the combined actions of the hormones estrogen and progestin.

If a woman remembers to take the pill every day as directed, she has an extremely low chance of becoming pregnant in a year. But the pill’s effectiveness may be reduced if the woman is taking some medications, such as certain antibiotics.

Besides preventing pregnancy, the pill offers additional benefits. As stated in the labeling, the pill can make periods more regular. It also has a protective effect against pelvic inflammatory disease, an infection of the fallopian tubes or uterus that is a major cause of infertility in women, and against ovarian and endometrial cancers.

The decision whether to take the pill should be made in consultation with a health professional. Birth control pills are safe for most women–safer even than delivering a baby–but they carry some risks.

Current low-dose pills have fewer risks associated with them than earlier versions. But women who smoke–especially those over 35–and women with certain medical conditions, such as a history of blood clots or breast or endometrial cancer, may be advised against taking the pill. The pill may contribute to cardiovascular disease, including high blood pressure, blood clots, and blockage of the arteries.

One of the biggest questions has been whether the pill increases the risk of breast cancer in past and current pill users. An international study published in the September 1996 journal Contraception concluded that women’s risk of breast cancer 10 years after going off birth control pills was no higher than that of women who had never used the pill. During pill use and for the first 10 years after stopping the pill, women’s risk of breast cancer was only slightly higher in pill users than non-pill users.

Side effects of the pill, which often subside after a few months’ use, include nausea, headache, breast tenderness, weight gain, irregular bleeding, and depression.

Doctors sometimes prescribe higher doses of combined oral contraceptives for use as “morning after” pills to be taken within 72 hours of unprotected intercourse to prevent the possibly fertilized egg from reaching the uterus. On June 28, 1996, FDA’s Advisory Committee for Reproductive Health Drugs concluded that certain oral contraceptives are safe and effective for this use. At press time in January, no drug firm had submitted an application to FDA to label its pills for this use, and the agency had not yet acted on the committee’s recommendation.

Minipills.

Although taken daily like combined oral contraceptives, minipills contain only the hormone progestin and no estrogen. They work by reducing and thickening cervical mucus to prevent sperm from reaching the egg. They also keep the uterine lining from thickening, which prevents a fertilized egg from implanting in the uterus. These pills are slightly less effective than combined oral contraceptives.

Minipills can decrease menstrual bleeding and cramps, as well as the risk of endometrial and ovarian cancer and pelvic inflammatory disease. Because they contain no estrogen, minipills don’t present the risk of blood clots associated with estrogen in combined pills. They are a good option for women who can’t take estrogen because they are breast-feeding or because estrogen-containing products cause them to have severe headaches or high blood pressure.

Side effects of minipills include menstrual cycle changes, weight gain, and breast tenderness.

Injectable progestins.

Depo-Provera, approved by FDA in 1992, is injected by a health professional into the buttocks or arm muscle every three months. Depo-Provera prevents pregnancy in three ways: It inhibits ovulation, changes the cervical mucus to help prevent sperm from reaching the egg, and changes the uterine lining to prevent the fertilized egg from implanting in the uterus. The progestin injection is extremely effective in preventing pregnancy, in large part because it requires little effort for the woman to comply: She simply has to get an injection by a doctor once every three months.

The benefits are similar to those of the minipill and another progestin-only contraceptive, Norplant. Side effects are also similar and can include irregular or missed periods, weight gain, and breast tenderness.

Implantable progestins.

Norplant, approved by FDA in 1990, and the newer Norplant 2, approved in 1996, are the third type of progestin-only contraceptive. Made up of matchstick-sized rubber rods, this contraceptive is surgically implanted under the skin of the upper arm, where it steadily releases the contraceptive steroid levonorgestrel.

The six-rod Norplant provides protection for up to five years (or until it is removed), while the two-rod Norplant 2 protects for up to three years. Norplant failures are rare, but are higher with increased body weight.

Some women may experience inflammation or infection at the site of the implant. Other side effects include menstrual cycle changes, weight gain, and breast tenderness.

Intrauterine Devices

An IUD is a T-shaped device inserted into the uterus by a health-care professional. Two types of IUDs are available in the United States: the Paragard CopperT 380A and the Progestasert Progesterone T. The Paragard IUD can remain in place for 10 years, while the Progestasert IUD must be replaced every year.

It’s not entirely clear how IUDs prevent pregnancy. They seem to prevent sperm and eggs from meeting by either immobilizing the sperm on their way to the fallopian tubes or changing the uterine lining so the fertilized egg cannot implant in it.

IUDs have one of the lowest failure rates of any contraceptive method. “In the population for which the IUD is appropriate–for those in a mutually monogamous, stable relationship who aren’t at a high risk of infection–the IUD is a very safe and very effective method of contraception,” says Lisa Rarick, M.D., director of FDA’s division of reproductive and urologic drug products.

The IUD’s image suffered when the Dalkon Shield IUD was taken off the market in 1975. This IUD was associated with a high incidence of pelvic infections and infertility, and some deaths. Today, serious complications from IUDs are rare, although IUD users may be at increased risk of developing pelvic inflammatory disease. Other side effects can include perforation of the uterus, abnormal bleeding, and cramps. Complications occur most often during and immediately after insertion.

Traditional Methods

Fertility awareness.

Also known as natural family planning or periodic abstinence, fertility awareness entails not having sexual intercourse on the days of a woman’s menstrual cycle when she could become pregnant or using a barrier method of birth control on those days.

Because a sperm may live in the female’s reproductive tract for up to seven days and the egg remains fertile for about 24 hours, a woman can get pregnant within a substantial window of time–from seven days before ovulation to three days after. Methods to approximate when a woman is fertile are usually based on the menstrual cycle, changes in cervical mucus, or changes in body temperature.

“Natural family planning can work,” Rarick says, “but it takes an extremely motivated couple to use the method effectively.”

Withdrawal.

In this method, also called coitus interruptus, the man withdraws his penis from the vagina before ejaculation. Fertilization is prevented because the sperm don’t enter the vagina.

Effectiveness depends on the male’s ability to withdraw before ejaculation. Also, withdrawal doesn’t provide protection from STDs, including HIV. Infectious diseases can be transmitted by direct contact with surface lesions and by pre-ejaculatory fluid.

Surgical Sterilization

Surgical sterilization is a contraceptive option intended for people who don’t want children in the future. It is considered permanent because reversal requires major surgery that is often unsuccessful.

Female sterilization.

Female sterilization blocks the fallopian tubes so the egg can’t travel to the uterus. Sterilization is done by various surgical techniques, usually under general anesthesia.

Complications from these operations are rare and can include infection, hemorrhage, and problems related to the use of general anesthesia.

Male sterilization.

This procedure, called a vasectomy, involves sealing, tying or cutting a man’s vas deferens, which otherwise would carry the sperm from the testicle to the penis.

Vasectomy involves a quick operation, usually under 30 minutes, with possible minor postsurgical complications, such as bleeding or infection.

Research continues on effective contraceptives that minimize side effects. One important research focus, according to FDA’s Rarick, is the development of birth control methods that are both spermicidal and microbicidal to prevent not only pregnancy but also transmission of HIV and other STDs.

Tamar Nordenberg is a staff writer for FDA Consumer.

Preventing HIV and Other STDs

Some people mistakenly believe that by protecting themselves against pregnancy, they are automatically protecting themselves from HIV, the virus that causes AIDS, and other sexually transmitted diseases (STDs). But the male latex condom is the only contraceptive method considered highly effective in reducing the risk of STDs.

Unlike latex condoms, lambskin condoms are not recommended for STD prevention because they are porous and may permit passage of viruses like HIV, hepatitis B and herpes. Polyurethane condoms are an alternative method of STD protection for those who are latex-sensitive.

Because it is a barrier method that works in much the same way as the male condom, the female condom may provide some protection against STDs. Both condoms should not be used together, however, because they may not both stay in place.

According to an FDA advisory committee panel that met Nov. 22, 1996, it appears, based on several published scientific studies, that some vaginal spermicides containing nonoxynol-9 may reduce the risk of gonorrhea and chlamydia transmission. However, use of nonoxynol-9 may cause tissue irritation, raising the possibility of an increased susceptibility to some STDs, including HIV.

As stated in their labeling, birth control pills, Norplant, Depo-Provera, IUDs, and lambskin condoms do not protect against STD infection. For STD protection, a male latex condom can be used in combination with non-condom methods. The relationship of the vaginal barrier methods–the diaphragm, cap and sponge–to STD prevention is not yet clear.

–T.N.

Publication No. (FDA)number

This article originally appeared in the April 1997 FDA Consumer.
This version is a reprint of the original article and contains revisions made in June 1997.

Brought to you by
PalmaServ

Documents for the
Palm Computing®
connected organizers.

Visit us at,
http://www.coslink.net/PalmaSrv
Mobile Edition,
http://www.coslink.net/PalmaSrv/mobile.htm
PalmaServ@topmich.com

Leave a comment

What to Order When

What to Order When: Pocket Guide to Diagnostic Imaging 2nd edition (December 1999): by Ronald L. Eisenberg (Editor), Alexander R. Margulis (Editor) By Lippincott Williams & Wilkins Publishers

By OkDoKeY

What to Order When: Pocket Guide to Diagnostic Imaging

Contents
Contributing Authors
Dedication
Preface
Preface to the First Edition

Chapter 1. Chest
Charles E. Putman
Chapter 2. Cardiovascular
Martin J. Lipton and Brian Funaki
Chapter 3. Gastrointestinal
Richard M. Gore
Chapter 4. Urinary
N. Reed Dunnick
Chapter 5. Skeletal
Donald Resnick
Chapter 6. Neurologic
Burton P. Drayer
Chapter 7. Head and Neck
William Dillon
Chapter 8. Breast
Edward A. Sickles
Chapter 9. Reproductive
Hedvig Hricak
Chapter 10. Obstetrics
Peter W. Callen and Nina S. Vincoff
Appendix I (Relative costs of individual procedures)
Appendix II (Basics of some newer imaging modalities)
Contributing Authors
Peter W. Callen, M.D.
Professor of Radiology, Obstetrics, Gynecology and Reproductive Science
University of California School of Medicine
San Francisco, California
William Dillon, M.D.
Professor of Radiology, Neurology and Neurosurgery
University of California School of Medicine
San Francisco, California
Burton P. Drayer, M.D.
Chairman, Department of Radiological Sciences
Director of Magnetic Resonance Imaging
St. Joseph’s Hospital and Medical Center
Barrow Neurological Institute
Phoenix, Arizona
N. Reed Dunnick, M.D.
Professor and Chair
Department of Radiology
University of Michigan
Ann Arbor, Michigan
Ronald L. Eisenberg, M.D., J.D.
Clinical Professor of Radiology
University of California School of Medicine
San Francisco, California
University of California School of Medicine
Davis, California
Chairman of Radiology
Alameda County Medical Center
Oakland, California
Brian Funaki, M.D.
Assistant Professor of Radiology
University of Chicago
Chicago, Illinois
Richard M. Gore, M.D.
Professor of Radiology
Northwestern University Medical School
Chicago, Illinois
Chief, Section of Gastrointestinal Radiology
Evanston Hospital-McGaw Medical Center of Northwestern University
Evanston, Illinois
Hedvig Hricak, M.D.
Professor of Radiology, Urology and Radiation Oncology
Chief, Abdominal Imaging Section
University of California School of Medicine
San Francisco, California
Martin J. Lipton, M.D.
Professor and Chairman
Department of Radiology
The University of Chicago
The University of Chicago Hospitals
Chicago, Illinois
Alexander R. Margulis, M.D., D.Sc. (hon.)
Professor of Radiology
University of California School of Medicine
San Francisco, California
Charles E. Putman, M.D.
James B. Duke Professor of Radiology
Professor of Medicine
Duke University Medical Center
Executive Vice President for Administration
Duke University
Durham, North Carolina
Donald Resnick, M.D.
Professor of Radiology
University of California, San Diego
La Jolla, California
Chief, Osteoradiology Section
Veterans Administration Medical Center
San Diego, California
Edward A. Sickles, M.D.
Professor of Radiology
Chief, Breast Imaging Section
University of California School of Medicine
San Francisco, California
Nina S. Vincoff, M.D.
Resident
Department of Radiology
University of California School of Medicine
San Francisco, California
Dedication
To Zina, Avlana, and Cherina and To Hedi
Preface
The format and approach of the first edition of this handbook has met our goal of providing a user-friendly guide to the most efficient and cost-effective imaging strategies for 300 clinical problems. Since its publication, managed care has become more prevalent and cost controls on medical care more stringent. With this in mind, the second edition offers updated imaging approaches (and some additional clinical situations) that reflect the continued technological advances in diagnostic imaging. For example, conventional radiography has become increasingly digital, with PACS making retrieval of images virtually instantaneous. In ultrasound, contrast media are now available, and harmonic imaging can diminish noise. Helical and multi-detector CT have greatly improved patient throughput, and the reduction in price of nonionic contrast media has made their widespread use more feasible. Automation of reformatting has increased specificity and improved treatment planning. Single-shot sequencing has made MRI applicable in imaging the acute abdomen, while diffusion MR imaging is now available for diagnosing stroke at an early stage. Proton MR spectroscopy shows promise in the staging and treatment follow-up of prostate cancer and in evaluating brain tumors.
One further important change in the second edition is the new title, What to Order When: Pocket Guide to Diagnostic Imaging. This change recognizes that a major audience for this book consists of residents-in-training and practicing physicians in internal medicine, general practice, emergency medicine, and surgery, and others who are on the firing lines and actually order imaging studies. It is essential that these physicians have a clear understanding of the advantages and limitations of both newer and traditional imaging procedures, as well as their relative costs, so that they can make informed decisions regarding the appropriate imaging strategies for their patients.
Medical imaging is rapidly advancing, and this pocket guide is designed to update physicians on the critical decision of What to Order When. In this way, physicians can ensure that their patients have the most appropriate imaging procedures that will lead to prompt diagnosis and timely treatment.
Ronald L. Eisenberg, M.D., J.D.
Alexander R. Margulis, M.D.
Preface to the First Edition
Medical imaging has made spectacular advances in the past fifteen years, reflecting the explosive developments in computers, electronics, and television. New cross-sectional imaging modalities are now widely used for diagnosing a broad spectrum of clinical disorders. Ultrasound is the most available and least expensive of these new techniques, but it is highly operator-dependent and requires rigorous training of technologists and physicians. Computed tomography is extremely versatile and has better signal-to-noise ratios than ultrasound. However, it is more expensive, uses ionizing radiation, and often requires the use of iodinated contrast media. Magnetic resonance imaging is the most sophisticated of these cross-sectional techniques, offering the best soft-tissue contrast resolution and the ability to image directly in multiple planes with a variety of pulse sequences. However, it is the most expensive and time-consuming of these imaging modalities. Nuclear medicine procedures now provide metabolic as well as morphological information, especially when using highly sophisticated tomographic procedures (SPECT, PET). The major disadvantage of nuclear procedures is the need for the handling and disposal, the administration to patients, and in the case of PET, the very high cost of radioactive materials.
The availability of a wide variety of alternative imaging approaches comes at a time when the medical profession is facing severe financial constraints. Thus, it is essential that the practicing physician and resident-in-training have an understanding of the advantages and limitations of the newer (and the traditional) imaging procedures and a conception of their relative costs.
To meet this critical need, we have developed the Radiology Pocket Reference to recommend the most efficient and cost-effective imaging strategies for 300 clinical problems. The book is organized to reflect the two basic situations that the clinician faces when ordering an image study. The first part of each section deals with those symptoms and signs that do not permit a single working diagnosis. The second part provides coherent strategies that can be used when there is a working clinical diagnosis to be confirmed, refined, or rejected by imaging procedures. For every symptom or sign, a list of differential diagnoses is offered; for each clinical diagnosis, there is a brief outline of typical signs and symptoms as well as predisposing factors.
Our guiding principle in selecting the order of imaging examinations has been the need to combine cost effectiveness and noninvasiveness with high diagnostic accuracy. However, the reader must always take into consideration such local conditions as the availability and adequacy of equipment and the expertise of the radiologists performing the recommended studies. Therefore, we often suggest alternative approaches to be taken when modern equipment and adequate expertise are not available.
To fit the goal of a pocket-sized book that would receive frequent use, we have used a terse outline approach, choosing to include more clinical scenarios at the expense of long explanations. We intentionally did not burden the reader with detailed statistical information on sensitivity, specificity, accuracy, and positive and negative predictive values, because these figures vary greatly, are often in dispute, and are constantly changing. Similarly, we chose not to include specific references that would have made the book substantially longer without providing any additional practical information. Nevertheless, we have taken a wealth of experimental data into account in selecting those procedures that provide the highest likelihood of leading to the diagnosis.
To ensure that the information provided to the reader is up to date, each chapter has been edited by a prominent radiologist subspecializing in that area (in most instances the author of a highly regarded textbook in the field). Rather than repeat the same information throughout the book, we have included an appendix that describes the basics of each of the newer sophisticated imaging modalities as well as the relative costs of individual procedures in multiples of the basic chest radiograph.
We sincerely hope that the pocket-sized format of the book will make it readily available when it is needed most—in the many clinical situations in which there is not enough time to go to the medical library and consult larger, more encyclopedic texts. We intend to keep this reference book current by adding or deleting information as it becomes available in the literature. To meet our overall goal, we would appreciate receiving suggestions from readers concerning ways in which we could make this pocket-sized reference book even more user-friendly.
Ronald L. Eisenberg, M.D.
Alexander R. Margulis, M.D.
CHAPTER 1. CHEST
What to Order When

CHAPTER 1. CHEST

Charles E. Putman

SIGNS AND SYMPTOMS

Cough
Common Causes

Inflammatory (laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonia, lung abscess)

Mechanical (compression of airway due to neoplasm, foreign body, granulomas, bronchospasm)

Inhalation of particulate material (pneumoconioses)

Chemical (inhalation of irritant fumes, including cigarette smoke)

Thermal (inhalation of cold or very hot air)
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Preferred imaging technique to demonstrate infection, neoplasm, or diffuse pulmonary parenchymal disease

Notes: Additional imaging studies are rarely needed, except for appropriate follow-up radiographs, because the overwhelming majority of patients with clinically significant new cough will have pneumonia, bronchitis, or some other acute infectious disease of the respiratory tract.
Because a negative chest radiograph does not exclude pneumonia (or cancer), especially in immunocompromised patients, if an antibiotic-sensitive infection is suspected clinically, a sputum specimen should be obtained and the patient treated despite the unrevealing film.

Cyanosis
Presenting Signs and Symptoms

Bluish discoloration of the skin or mucous membranes (due to excess of reduced hemoglobin in the blood)
Common Causes

Impaired pulmonary function (pneumonia, pulmonary edema, chronic obstructive pulmonary disease)

Anatomic vascular shunting (congenital heart disease, pulmonary arteriovenous fistula)

Decreased oxygen in inspired air (high altitude)

Abnormal hemoglobin
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Preferred imaging technique to demonstrate underlying pulmonary or cardiac abnormality
Dyspnea
Presenting Signs and Symptoms

Shortness of breath

Difficulty breathing on exertion

Uncomfortable awareness of breathing (increased muscular effort required)
Common Causes

Physical exertion

Hypoxia (high altitude)

Restrictive lung disease (pulmonary fibrosis, chest wall deformity)

Obstructive lung disease (emphysema, asthma)

Congestive heart failure

Pulmonary embolism
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Best imaging technique for identifying an underlying pulmonary or cardiac cause, as well as any need for appropriate additional imaging studies

Note: Soft-tissue views of the neck (or fiberoptic examination) may be helpful in patients with suspected acute upper airway obstruction.

Pleurisy
Presenting Signs and Symptoms

Pain that is aggravated by breathing or coughing (may be of sudden onset, chronic, or recurring)

Rapid and shallow respiration

Limited motion of the affected side

Decreased breath sounds on the affected side

Pleural friction rub (characteristic finding that is often absent and is frequently heard only 24 to 48 hours after the onset of pain)
Common Causes

Pneumonia

Tuberculosis

Pulmonary embolism

Trauma

Neoplasm

Occult rib fracture

Congestive heart failure

Mixed connective tissue disease

Pancreatitis
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Preferred imaging technique that may demonstrate the underlying pulmonary, rib, or chest wall abnormality, as well as a confirming pleural effusion
Hemoptysis
Presenting Signs and Symptoms

Coughing up blood (resulting from bleeding from the respiratory tract)
Common Causes

Infection (pneumonia, tuberculosis, fungal infection, lung abscess)

Bronchogenic carcinoma

Bronchiectasis

Bronchitis

Pulmonary infarction (secondary to embolism)

Congestive heart failure
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Initial imaging procedure

Normal study does not exclude neoplasm or bronchiectasis as the cause of the bleeding

2.
Fiberoptic bronchoscopy

Indicated in a patient for whom there is a high clinical suspicion of malignancy and who has a relevant abnormality on the plain chest radiograph

Relatively invasive procedure with potential complications (e.g., hemorrhage, pneumothorax, hypoxemia)

3.
Computed tomography

Indicated in a patient with a normal chest radiograph in whom the clinical suspicion of malignancy is relatively low

Indicated if a neoplasm is not detected by fiberoptic bronchoscopy (which is unreliable in locating peripheral tumors demonstrable by CT)

Indicated in any patient with recurrent symptoms of bronchitis or bronchiectasis
Caveat: Despite a systematic and intensive search, the cause of hemoptysis will not be found in 30% to 40% of patients.
Stridor/Upper Airway Obstruction
Presenting Signs and Symptoms

Musical sound that is predominantly inspiratory and is loud enough to be heard without a stethoscope at some distance from the patient (heard better over the neck than over the chest)
Common Causes

Epiglottitis

Croup

Inhaled foreign body

Pharyngeal tumor

Glottic edema

Retropharyngeal abscess
Approach to Diagnostic Imaging

1.
Plain radiograph of the neck (soft-tissue technique)

Preferred imaging technique to demonstrate narrowing or luminal obstruction of the upper airway (lateral projection is often more valuable than the frontal view)

Note: Laryngoscopy or CT of the neck may be required, especially in older patients in whom malignancy is more common and infection is a less likely cause.

Wheezing
Presenting Signs and Symptoms

Wheezing or whistling noise associated with breathing (implies obstruction to the flow of air at some level in the respiratory tract)

Most commonly heard on expiration
Common Causes

Asthma

Congestive heart failure

Pneumonia

Bronchogenic tumor

Pulmonary embolus

Foreign body
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Preferred imaging study to exclude a tumor or a foreign body

DISORDERS

Abscess (Lung)
Presenting Signs and Symptoms

Cough productive of moderate-to-large amounts of purulent, often foul-smelling sputum that may be tinged with blood

Fever and sweats

Chest pain and dyspnea

Anorexia and weight loss

Leukocytosis
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Preferred initial imaging technique to demonstrate an area of consolidation that may develop into a cavity with an air–fluid level after rupture of the abscess into the bronchial tree

May permit differentiation of a peripheral lung abscess (round; formation of an acute angle with the chest wall) from an empyema (lenticular shape; formation of an obtuse angle with the chest wall)

2.
Computed tomography

Best modality for differentiating peripheral lung abscess from empyema

Note: Most lung abscesses can be treated with antibiotic therapy and postural drainage; empyemas require a drainage procedure.

3.
Fiberoptic bronchoscopy

May allow the removal of an underlying foreign body or excessive mucus and permit material to be obtained for culture
Adult Respiratory Distress Syndrome (ARDS)
Presenting Signs and Symptoms

Tachypnea, then dyspnea (24 to 48 hours after initial illness/injury)

Noncardiogenic pulmonary edema

Hypoxemia and cyanosis
Common Causes

Diffuse pulmonary infection (bacterial or viral)

Aspiration of gastric contents

Direct chest trauma

Prolonged or profound shock

Inhalation of toxins and irritants

Systemic reaction to nonpulmonary processes (e.g., gram-negative septicemia, hemorrhagic pancreatitis, fat embolism)

Massive blood transfusion

Cardiopulmonary bypass (“pump lung”)

Narcotic overdose pulmonary edema

Burns

Near-drowning
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Nonspecific diffuse bilateral opacities similar to pulmonary edema (but cardiac silhouette within normal size and no pleural effusion)

Findings may lag many hours behind functional changes and appear much less severe than the clinical degree of hypoxemia

Required during mechanical ventilation to detect evidence of barotrauma (pneumothorax, pneumomediastinum) and to evaluate tube placements (endotracheal, chest, and nasogastric tubes; Swan-Ganz catheter; central venous line)
Asbestosis
Presenting Signs and Symptoms

Insidious onset of exertional dyspnea and reduced exercise tolerance

Symptoms of airways disease (cough, sputum, wheezing) occurring primarily in heavy smokers
Common Causes

Occupational exposure
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Preferred initial imaging technique to demonstrate irregular or linear small opacities (usually most prominent in the lower zones), characteristic diffuse or localized pleural thickening (pleural plaques), and calcification of the parietal pleura

Relatively low specificity because of frequent difficulty in differentiating pleural thickening from normal intercostal muscles and extrapleural fat companion shadows of the chest wall (more likely asbestos-related if bilateral, symmetric, and along the midlateral chest wall)

2.
High-resolution computed tomography

Superior to chest radiography for detecting pleural plaques

Not recommended as a screening examination because of its high cost (good-quality chest radiographs interpreted by an informed reader have a high sensitivity and negative predictive value in the diagnosis of pleural plaques)

Valuable for eliminating false-positive diagnoses of noncalcified plaques caused by muscle or fat and for distinguishing pleural plaques from lung
Asthma
Presenting Signs and Symptoms

Episodic respiratory distress, often with tachypnea, tachycardia, and audible wheezes

Anxiety and struggling for air

Use of accessory muscles of respiration

Hyperexpansion of the lung (due to air trapping)

Prolonged expiratory phase
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Findings varying from entirely normal to hyperinflation, increased lung opacities, bronchial wall thickening, and regions of atelectasis
Caveat: Once the diagnosis of asthma is established, chest radiographs are only required during recurrent episodes when there is clinical suspicion of complications (e.g., pneumothorax, atelectasis, secondary infection).

2.
Fiberoptic bronchoscopy

Indicated in a patient who has the potential for aspiration of a foreign body or is unresponsive to medical management

3.
Computed tomography

Indicated in a patient with chronic bronchospasm when chest radiography is normal

May reveal focal opacities of increased attenuation with air trapping (mosaic perfusion). This heterogeneous pattern could reflect bronchiolitis obliterans, hypersensitivity pneumonitis, or allergic alveolitis
Atelectasis
Presenting Signs and Symptoms

Depend on the speed of the bronchial occlusion, the extent of lung affected, and the presence of infection

Note: Hypoxemia may cause decreased perfusion and produce a ventilation–perfusion (V/Q) mismatch.

Common Causes

Mucous plugs (tenacious bronchial exudate)

Endobronchial tumor

Granuloma

Foreign body

Extrinsic compression of a bronchus (enlarged lymph nodes, tumor, aneurysm)

External compression of the lung (pleural effusion, pneumothorax)

Neonatal respiratory distress syndrome (decreased or abnormal surfactant)

Infection (resorptive atelectasis)
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Preferred imaging technique to demonstrate characteristic linear streaks (plate-like atelectasis) or a segment of shrunken, airless lung

If atelectasis involves a substantial amount of the lung, the chest radiograph may show secondary elevation of the ipsilateral hemidiaphragm; shift of the trachea, heart, and mediastinum toward the affected area; and modification of the normal pulmonary vascular pattern

May show the underlying cause of atelectasis (extrinsic mass, pleural effusion, pneumothorax)

2.
Fiberoptic bronchoscopy or computed tomography

Indicated to search for a cause of obstruction if there is no other obvious source for a collapsed segment or lobe

Note: Fiberoptic bronchoscopy may be therapeutic as well as diagnostic (e.g., removal of mucous plugs, obtaining material for culture or cytology).

Bronchiectasis
Presenting Signs and Symptoms

Chronic cough with sputum production (often after severe pneumonia with incomplete clearing of symptoms)

Hemoptysis

Recurrent pneumonia

Chronic atelectasis
Common Causes

Recurrent or chronic pneumonia

Chronic aspiration

Cystic fibrosis

Allergic bronchopulmonary aspergillosis

Interstitial pulmonary fibrosis

Tuberculous scarring (upper lobes)

Intrinsic bronchial disease (stenosis, extrinsic compression, endobronchial mass)
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Abnormal in most patients, but the specific diagnosis can be suggested less than one-half the time

Demonstrates increased interstitial opacities from recurrent inflammatory or infectious responses or changes consistent with subsegmental atelectasis

Often “tram tracking” (parallel linear shadows representing the walls of cylindrically dilated bronchi) and areas of multiple thin-walled cysts, with or without air–fluid levels, which tend to be peripheral and cluster together in the distribution of a bronchovascular bundle

2.
High-resolution computed tomography

High accuracy for demonstrating characteristic multiple, dilated, thin-walled circular lucencies (on cross-section) and parallel linear opacities (bronchial walls sectioned lengthwise)

Mucoid impactions may simulate lung nodules or branching, finger-like opacities

Cystic bronchiectasis produces a “cluster of grapes” appearance

May show evidence of inhomogeneous lung attenuation (mosaic perfusion), reflecting abnormal lung ventilation and resultant reduced perfusion

Note: CT has all but eliminated the need for contrast bronchography, except for those few patients considered for curative resection who appear to have localized disease according to CT.

3.
Fiberoptic bronchoscopy
Bronchogenic Carcinoma
Presenting Signs and Symptoms

Cough (with or without hemoptysis)

Dyspnea, wheezing, pneumonia

Weight loss

History of smoking

Pleural effusion

Recurrent Horner’s syndrome

Superior vena cava syndrome

Symptoms relating to distal metastases (e.g., occult fracture, seizure)

Note: The lesion may be an asymptomatic pulmonary nodule discovered incidentally on a routine chest radiograph.

Risk Factors

Cigarette smoking

Occupational exposure (e. g., asbestos, radiation, arsenic, chromates, nickel, mustard gas)

Pulmonary scars (e.g., old inflammatory disease such as tuberculosis)
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Preferred initial imaging technique to demonstrate a solitary pulmonary nodule, atelectasis, pulmonary opacity, bronchial narrowing, hilar or mediastinal lymphadenopathy, or pleural effusion

2.
Computed tomography

Permits percutaneous fine-needle biopsy of peripheral lesions to obtain material for cytologic studies
Staging

1.
Computed tomography (chest/upper abdomen)

Definitive noninvasive study

Detects hilar and mediastinal lymphadenopathy and bronchial narrowing

May show metastases in the liver and adrenal glands

Note: MRI may be valuable for detecting vascular invasion and mediastinal spread of tumor, as well as for clarifying whether adrenal enlargement is due to metastases or a benign cause.

Bronchopleural Fistula
Presenting Signs and Symptoms

Fever, cough, dyspnea, pleurisy

Intractable pneumothorax

Large air leak in a person with a pleural drain
Common Causes

Dehiscence of bronchial stump after lobectomy or pneumonectomy

Necrotizing pulmonary infection

Carcinoma of the lung with pleural invasion
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Demonstrates a loculated intrapleural collection of air and fluid (with an air–fluid level on upright films)

Note: In bronchopleural fistula, the air–fluid level has equal dimensions in both frontal and lateral radiographs; this is in contrast to lung abscess, in which the dimension of the air–fluid level varies between frontal and lateral projections.

2.
Computed tomography

Can often distinguish a bronchopleural fistula from a peripheral lung abscess

Occasionally may demonstrate the actual fistulous communication

3.
Sinogram

Injection of contrast material into a chest tube draining the pleural space may demonstrate the site of bronchial communication
Chronic Bronchitis
Presenting Signs and Symptoms

Chronic productive cough (excessive tracheobronchial mucus secretion sufficient to cause cough with expectoration of sputum that occurs on most days for at least 3 consecutive months in at least 2 consecutive years)
Common Causes

Cigarette smoking

Occupational exposure

Air pollution and other types of bronchial irritation

Chronic pneumonia

Superimposed emphysema
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Normal examination in about one-half of patients

May demonstrate nonspecific appearance with prominence of interstitial markings and thickened bronchial walls

Note: Chronic bronchitis is a clinical and not a radiographic diagnosis. Once the diagnosis of chronic bronchitis is established, chest radiographs are only required if there is clinical suspicion of a supervening acute pneumonia or a developing malignancy.

Emphysema
Presenting Signs and Symptoms

Exertional dyspnea (gradually progressive)

Productive cough

Abnormal pulmonary function tests
Common Causes

Cigarette smoking

Occupational exposure

a1-antitrypsin deficiency

Congenital
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Lungs often appear normal in early stages of the disease

Eventually demonstrates hyperexpansion of the lungs (depressed diaphragm, generalized radiolucency of the lungs, enlarged retrosternal air space, ability to see diaphragmatic insertions on the ribs) and focal opacifications due to atelectasis or scarring

Bullous changes (especially in the apices and subpleural regions)

Marked attenuation and stretching (even virtual absence) of pulmonary vessels

Often evidence of pulmonary hypertension (enlargement of central pulmonary arteries with rapid peripheral tapering)

In a1-antitrypsin deficiency, emphysematous changes predominantly involve the lower lobes
Caveat: Once the diagnosis of emphysema is established, repeated chest radiographs are only indicated if there is clinical indication of supervening disease (e.g., infection, congestive heart failure).

2.
High-resolution computed tomography

More sensitive than conventional radiography for detecting emphysematous changes in the lungs, but rarely necessary. (The extent of clinical derangement is generally determined by pulmonary function tests.)

Of special value in detecting otherwise unsuspected blebs and bullae in select high-risk populations, such as those with suspected a1-antitrypsin deficiency or with recurrent pneumothoraces
Empyema
Presenting Signs and Symptoms

Chest pain (varies from vague discomfort to stabbing pain and is often worse with coughing or breathing)

Rapid, shallow breathing

Fever, chills, night sweats

Cough

Weight loss

Note: If an empyema develops during the course of antibiotic treatment for bacterial pneumonia, the symptoms may be mild and the condition may go unrecognized.

Common Causes

Acute pneumonia

Lung abscess

Thoracic surgery or trauma

Spread from extrapulmonary sites (osteomyelitis of spine, subphrenic abscess)

Sepsis

Tuberculosis
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Preferred initial imaging technique

May permit differentiation of empyema (lenticular shape; formation of an obtuse angle with the chest wall) from lung abscess (round; formation of an acute angle with the chest wall)

2.
Computed tomography

Best modality for differentiating empyema from peripheral lung abscess

Note: Empyema requires a drainage procedure; most lung abscesses can be treated with antibiotic therapy and postural drainage.

May show contrast enhancement of the parietal and visceral pleura, thickening of the extrapleural subcostal tissues, and increased attenuation of the extrapleural fat, which are rarely seen with transudative effusions

3.
Thoracentesis

Required to confirm suspected empyema to avoid a delay in diagnosis, which may have serious consequences

4.
Ultrasound

Can serve as a valuable guide for obtaining fluid from a loculated empyema
Hypersensitivity Lung Disease
Presenting Signs and Symptoms

Range from mild respiratory symptoms and low fever (and prompt recovery) to severe pulmonary symptoms in a life-threatening condition

Striking blood eosinophilia (20% to 40% or more)

Coexistent bronchial asthma
Common Causes

Drug-induced eosinophilic lung disease (penicillin, aminosalicylic acid, hydralazine, chlorpropamide, sulfonamides)

Hypersensitivity pneumonitis (extrinsic allergic alveolitis)

Asthmatic pulmonary eosinophilia (hypersensitivity bronchopulmonary aspergillosis)

Tropical eosinophilia (parasites such as roundworm, filaria)

Pulmonary eosinophilia (Löffler’s syndrome)
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Preferred imaging technique for detecting the broad spectrum of pulmonary abnormalities seen in these disorders

2.
Computed tomography

Infrequently required in a symptomatic patient with normal chest radiographs as a “road map” prior to biopsy and as an aid to following the response to treatment
Infectious Granulomatous Disease
Presenting Signs and Symptoms

Varies from asymptomatic exposure to fever, productive cough, and night sweats
Common Causes

Tuberculosis (especially in HIV-positive patients and in immigrants from Asia and Central America)

Histoplasmosis (central and eastern United States)

Coccidioidomycosis (southwestern United States and Mexico)

Blastomycosis (south-central and midwestern United States)

Cryptococcosis

Actinomycosis

Nocardiosis
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Preferred imaging technique to show the various patterns of opacifications within the lung (lobar consolidation, nodular opacities ranging from miliary to more discrete nodules, masses suggesting neoplasm, and diffuse disease with or without pleural effusion)

Best imaging modality for identifying potential complications (empyema, extensive atelectasis, and focal or diffuse dissemination of the primary disease)
Mediastinal Mass (Anterior)
Presenting Signs and Symptoms

Asymptomatic and incidental finding on plain chest radiograph

Myasthenia gravis (in up to 30–50% of patients with thymoma)
Common Causes

Thymoma

Teratoma

Lymphoma

Parathyroid tumor (ectopic)

Aortic aneurysm (ascending portion)

Morgagni hernia
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Detects and determines precise compartment of a mediastinal mass but otherwise does little to characterize the mass (can demonstrate erosion of the sternum in Hodgkin’s disease and gas within a Morgagni hernia)

2.
Computed tomography

Definitive imaging study for defining the origin and extent of a mass and determines its underlying characteristics

With contrast enhancement, highly accurate in differentiating among fatty, cystic, and soft-tissue masses and aneurysms

3.
Magnetic resonance imaging

Equivalent to CT in confirming the presence and location of a mediastinal mass

Less effective than CT for assessing tracheal involvement and demonstrating calcification

Superior to CT for distinguishing tumor from fibrosis and in patients in whom the use of iodinated contrast material is contraindicated
Mediastinal Mass (Middle)
Presenting Signs and Symptoms

Asymptomatic and incidental finding on plain chest radiograph

Compression of trachea or esophagus (dysphagia, stridor, cough, wheezing, or localized or diffuse chest pain–depends more on size of mass than on its identity)
Common Causes

Lymph node enlargement (metastases, lymphoma, tuberculosis, histoplasmosis, sarcoidosis, pneumoconiosis)

Aortic aneurysm

Dilated venous structures (azygos, hemiazygos, superior vena cava)

Bronchogenic carcinoma

Bronchogenic cyst

Pericardial cyst

Mediastinal hemorrhage/inflammation/lipomatosis
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Detects and determines precise compartment of a mediastinal mass but does little to characterize it

2.
Computed tomography

Definitive imaging study for determining the origin and extent of a mass and its underlying characteristics

With contrast enhancement, highly accurate in differentiating among fatty, cystic, and soft-tissue masses and aneurysms

3.
Magnetic resonance imaging

Equivalent to CT in confirming the presence and location of a mediastinal mass

Less effective than CT for assessing tracheal involvement by a mass or for demonstrating calcification

Superior to CT for distinguishing tumor from fibrosis and in patients in whom the use of iodinated contrast material is contraindicated

Able to image directly in the coronal or sagittal plane, which is an advantage in mediastinal regions that are parallel to the axial plane (sub-carinal space, aortopulmonary window) and thus suffer from partial volume averaging effects on CT
Caveat: False-positive results may occur because of the relatively low spatial resolution of MRI, which may result in an inability to distinguish between a group of normal-sized nodes and a single enlarged node.
Mediastinal Mass (Posterior)
Presenting Signs and Symptoms

Asymptomatic and incidental finding on plain chest radiograph
Common Causes

Neurogenic tumor

Vertebral lesion (trauma, infection, tumor)

Esophageal lesion (dilatation, neoplasm, diverticulum, duplication cyst)

Hiatal hernia

Lymphoma

Aortic aneurysm (descending portion)

Bochdalek hernia
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Detects and determines precise compartment of a mediastinal mass but otherwise does little to characterize the mass (can show bone erosion in neurogenic tumor or air in a hiatal or Bochdalek hernia)

2.
Barium swallow

Indicated if there is clinical suspicion of an esophageal lesion

3.
Computed tomography

Definitive imaging study for defining the origin and extent of the mass and for determining its underlying characteristics

With contrast enhancement, highly accurate in differentiating among fatty, cystic, and soft-tissue masses and aneurysms

4.
Magnetic resonance imaging

Equivalent to CT in confirming the presence and location of a mediastinal mass

Less effective than CT for showing calcification

Superior to CT for showing the spinal cord and in patients in whom the use of iodinated contrast material is contraindicated
Mediastinal Mass (Superior)
Presenting Signs and Symptoms

Asymptomatic and incidental finding on plain chest radiograph

Displacement, deviation, or compression of the trachea (upper thoracic portion)
Common Causes

Substernal thyroid

Lymph node enlargement

Parathyroid mass

Other causes of anterior, middle, or posterior mediastinal masses
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Detects a mass displacing, deviating, or compressing the trachea but otherwise does little to characterize the mass

2.
Radionuclide thyroid scan

Most accurate method for diagnosing the presence of abnormal thyroid tissue in the neck or superior mediastinum

3.
Computed tomography

Definitive imaging study for defining the origin and extent of the mass and for determining its underlying characteristics

4.
Magnetic resonance imaging

Equivalent to CT in confirming the presence and location of a mediastinal mass

Less effective than CT for assessing tracheal involvement and for demonstrating calcification

Superior to CT for distinguishing tumor from fibrosis and in patients in whom the use of iodinated contrast material is contraindicated
Metastases (Pulmonary)
Presenting Signs and Symptoms

Most are asymptomatic and only detected incidentally during staging or follow-up of patients with a known malignancy

Develop in up to one-third of patients with cancer

Only demonstrable metastatic site in about one-half of patients with metastatic spread of tumor
Common Primary Sites of Tumor

Breast

Lung

Kidney

Thyroid

Head and neck

Melanoma
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Preferred screening technique (detects almost all metastases greater than 15 mm in diameter)

May fail to detect smaller nodules (because of overlying ribs or blood vessels) and nodules in specific areas (lung apices, inferior recesses just above dome of diaphragm, subpleural region)

2.
Computed tomography

Often detects small (3–10 mm), otherwise occult metastases (especially those located peripherally and in the subpleural region)

Unfortunately, high sensitivity of CT leads to potential problem of false-positive examinations (granulomas, intrapulmonary lymph nodes, or even pulmonary vessels on end are sometimes erroneously interpreted as metastases)

Best imaging modality for following the response of metastases to chemotherapy

Note: Although resolution of nodules indicates a positive response, persistent nodular opacities representing sterilized tumor deposits may be seen after successful treatment of metastatic seminoma, choriocarcinoma, or hypernephroma.

3.
Radionuclide thyroid scan (total body)

Highly specific and more sensitive than plain chest radiographs for detecting thyroid carcinoma metastatic to the lung
Indications for CT If Plain Chest Radiograph Is Normal

1.
High propensity of tumor spread to lung (melanoma, testicular carcinoma, choriocarcinoma, head and neck tumors)
Caveat: Common primary tumors of the lung, breast, colon, prostate, and cervix have a low propensity of spread to the lungs.

2.
Presence of metastases would alter treatment (usually by cancellation of planned extensive surgery)

Radical amputation for osteosarcoma

Extensive lymph node dissection for melanoma

Lobectomy for presumed solitary metastasis or several nodules localized to one lobe

3.
Effective therapy available for metastases (osteogenic sarcoma, choriocarcinoma, nonseminomatous testicular tumors, renal cell carcinoma, certain functioning thyroid carcinomas)
Caveat: The detection of pulmonary metastases is of no clinical significance if there is no effective treatment for metastases or if there already are obvious extrathoracic metastases.
Pleural Effusion
Presenting Signs and Symptoms

Pleuritic pain

Dyspnea

Often asymptomatic and discovered as incidental finding on chest radiograph

Decreased or absent breath sounds, percussion dullness, and decreased motion of hemithorax
Common Causes

Congestive heart failure (usually bilateral but larger on the right)

Neoplasm (primary or metastatic lung cancer, lymphoma)

Pneumonia

Ascites

Pancreatitis (usually left-sided)

Tuberculosis

Pulmonary embolism (small)

Mixed connective tissue disease (lupus, rheumatoid arthritis)

Trauma (hemothorax)
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Preferred initial imaging technique that can show classic blunting or meniscus appearance at the lateral and posterior costophrenic angles, apical cap, or increased opacity of the hemithorax without obscuring of vascular markings

Large effusions may opacify an entire hemithorax and shift the mediastinum to the opposite side

Subpulmonic effusions may be detected by an unusually lateral position of the top of the diaphragmatic contour on supine films

Lateral decubitus projection (affected side down), can determine whether pleural fluid is free or loculated and estimate the amount of the effusion

2.
Computed tomography

Procedure of choice for determining the status of the underlying lung parenchyma in a patient with extensive pleural effusion (e.g., may detect lung abscess, pneumonia, or bronchogenic carcinoma that is hidden from view on plain radiograph)

Limited value in differentiating transudates from exudates or chylous effusions

3.
Ultrasound

Readily available for bedside imaging in severely ill patients in whom a lateral decubitus projection cannot be obtained

Best technique for identifying and localizing a loculated effusion as an echo-free or hypoechoic fluid collection separate from the lung and chest wall that may mimic a mass on plain radiographs

May permit demonstration of an exudate as a complex, septated pattern or a homogeneously echogenic appearance

Permits marking of the chest wall for thoracentesis (may be performed under ultrasound guidance in difficult cases)
Pneumoconioses
Presenting Signs and Symptoms

Insidious onset of decreased pulmonary function (related to occupational exposure to inorganic dusts)
Common Types

Silicosis

Asbestosis

Coal worker’s pneumoconiosis

Talcosis
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Preferred initial imaging technique that may demonstrate a broad spectrum of chronic changes in the lung parenchyma and pleura

Note: There may be poor correlation between the extent of radiographic findings and the degree of alteration in pulmonary function.

2.
Computed tomography

More sensitive than plain chest radiography for detecting subtle changes, but not usually necessary for clinical evaluation
Pneumomediastinum
Presenting Signs and Symptoms

Chest pain

May be asymptomatic
Common Causes

Spontaneous

Trauma (injury to chest wall, bronchus, trachea, lung)

Iatrogenic (surgery or instrumentation of the esophagus, trachea, bronchi, or neck; overinflation during anesthesia and respiratory therapy)

Extension of gas from the neck or abdomen

Asthma (primarily in children)

Rupture of the esophagus (e.g., Boerhaave’s syndrome)

Hyaline membrane disease (extension of pulmonary interstitial emphysema)
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Preferred imaging technique for detecting gas separating the medial margin of the pleura from the mediastinal contents or interposed between the heart and diaphragm

Can show any associated pneumoperitoneum or gas within the soft tissues of the neck

Note: The clinical concern in patients with pneumomediastinum is the possible development of a pneumothorax, which can have dire consequences in patients whose respiratory status is already compromised.

Pneumonia
Presenting Signs and Symptoms

Cough with sputum production

Fever and chills

Chest pain and dyspnea
Predisposing Factors

Viral respiratory infection

Cigarette smoking

Chronic obstructive pulmonary disease

Alcoholism

Unconsciousness

Dysphagia with regurgitation

Hospitalization or institutionalization

Surgery/trauma

Heart failure

Immunosuppressive disorders and therapy
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Preferred initial imaging technique to show the various patterns of opacifications within the lung

Best imaging modality for identifying potential complications (empyema, extensive atelectasis, and focal or diffuse dissemination of the primary infection)

Notes: The mere presence of an opacity in a patient with fever or chest pain does not necessarily indicate the presence of an infectious process. Atelectasis, neoplasm, pulmonary embolism or infarction, and atypical pulmonary edema can all mimic pneumonia both clinically and radiographically.
Pneumonia may exist in the presence of a normal radiograph (especially with atypical organisms and those pneumonias that develop in immunocompromised hosts).
Frequent radiographs after acute pneumonia should not be obtained in the normal population (unnecessary cost and radiation exposure), unless there is some clinical reason to warrant serial studies. Symptoms usually resolve, even though the radiographic opacity may be unchanged and persistent. However, in an immunocompromised patient in whom clinical manifestations may be depressed, serial chest radiographs are justified, as they may be the only means of following the results of a course of therapy.

2.
Computed tomography

May be indicated if there is incomplete clearing of an opacity or clinical suspicion of either postobstructive pneumonia distal to an endobronchial lesion or a secondary lung abscess
Pneumonia in AIDS Patients
Presenting Signs and Symptoms

Cough with sputum production

Fever and chills

Chest pain and dyspnea
Predominant Organisms

Pneumocystis carinii

Histoplasma

Cytomegalovirus

Cryptococcus

Aspergillus

Toxoplasma

Varicella
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Preferred imaging technique to show the various patterns of opacifications within the lung

Best imaging modality for identifying potential complications (empyema, extensive atelectasis, focal or diffuse dissemination of the primary infection)

Notes: The mere presence of an opacity in a patient with fever or chest pain does not necessarily indicate the presence of an infectious process. Atelectasis, neoplasm, pulmonary embolism or infarction, and atypical pulmonary edema can all mimic pneumonia both clinically and radiographically.
The radiograph may be normal, even though there is clinical evidence of pneumonia. Conversely, in immunocompromised patients, there may be extensive radiographic findings with minimal clinical manifestations. Therefore, in this population, serial chest radiographs are justified because they may be the only means of following a course of therapy (as opposed to the normal population, in which frequent radiographs after acute pneumonia should not be obtained).

Pneumothorax
Presenting Signs and Symptoms

Range from asymptomatic to sudden, sharp chest pain, severe dyspnea, shock, and life-threatening respiratory failure

Pain may be referred to corresponding shoulder, across the chest, or over the abdomen (simulating acute coronary occlusion or acute abdomen)

Markedly depressed or absent bowel sounds

Shift of mediastinum to opposite side (with large or tension pneumothorax)
Common Causes

Spontaneous (rupture of small, usually apical bleb)

Trauma (penetrating, blunt, rib fracture)

Complication of mechanical ventilation (barotrauma)

Chronic obstructive pulmonary disease

Chronic pulmonary disease (e.g., sarcoidosis, eosinophilic granuloma)

Pneumocystis carinii pneumonia

Lung abscess with bronchopleural fistula

Rupture of the esophagus

Extension from pneumomediastinum

Iatrogenic (surgery, lung or pleural biopsy, thoracentesis, central line placement)
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Preferred initial imaging technique that shows apical and lateral air without peripheral lung markings and separated from normal lung by a sharp pleural margin

May show underlying bullous or interstitial changes consistent with chronic obstructive pulmonary disease or any chronic interstitial lung disorder

Notes: Pneumothorax is best seen on an expiration film obtained with low penetration (light film).
In patients on mechanical ventilation for ARDS, a small pneumothorax on a supine film may present subtly as a loculated collection in a subpulmonic or paracardiac location and be associated with a pneumomediastinum.

Caveat: The visceral pleural line of a pneumothorax may be mimicked by skin folds (resulting from compression of redundant skin by the radiographic cassette). The key is to identify normal vascular markings that extend peripherally beyond the skin fold interface. The visceral pleural line may also be mimicked by bullae (it is necessary to detect the thin curvilinear walls that are concave rather than convex to the chest wall).

2.
Computed tomography

More sensitive than plain chest radiographs for detecting a pneumothorax, but rarely necessary

May be required to differentiate pneumothorax from bullous disease and in patients in whom an anterior pneumothorax is suspected on a supine radiograph but who cannot undergo upright or lateral decubitus films

In a patient undergoing CT for abdominal trauma, routine sections through the chest may be obtained to detect a subtle pneumothorax that might not be evident on conventional supine radiographs
Proper Tube Placement
Indication for Study

Determination of the tip of a radiopaque tube placed within the thorax
Common Types of Tubes

Endotracheal tube

Central venous pressure (CVP) catheter

Swan-Ganz catheter

Nasogastric tube
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Demonstrates whether the tip of the tube is in the proper position

Endotracheal tube: With the head in a neutral position, the tip should be 5 to 7 cm above the carina

Note: With flexion and extension of the neck, the tip of the tube will move about 2 cm caudally and cranially, respectively.

CVP catheter: Within the superior vena cava (above the level of the right atrium), preferably at the level of the carina

Note: Up to one-third of CVP catheters are incorrectly placed at the time of initial insertion.

Swan-Ganz catheter: Within the right or left main pulmonary arteries

Note: Too peripheral a position of the tip may lead to occlusion of the pulmonary artery and resulting distal pulmonary infarction.

Nasogastric tube: Stomach

Note: The tip of the tube may remain in the esophagus above the esophagogastric junction or be misplaced in the bronchial tree.

Pulmonary Edema: Cardiac versus Noncardiac (Permeability)
Types of Edema

1.
Cardiac

Low-protein transudate due to increased hydro-static pressure generated across the capillary membrane that initially accumulates in the connective tissues surrounding the blood vessels

2.
Noncardiac

Protein-rich exudate that accumulates in the extravascular space as a consequence of increased microvascular permeability. Because of the high protein osmotic pressure of the extravasated proteins, water may not flow from the extravasation toward the loose connective tissue but may flood the alveolar space.

Note: Clearance of the protein-rich exudate is slower than that of the nonproteinaceous transudate.

Approach to Diagnostic Imaging

1.
Plain chest radiograph

Can distinguish between cardiac and noncardiac (permeability) edema in about 80% of patients using the following criteria:

Cardiac
Noncardiac
Major Signs
Kerley lines
Present
Unusual
Pleural effusions
Present
Unusual
Cardiomegaly
Present
Unusual
Opacities in lung
Diffuse
Patchy and peripheral

Minor Signs
Air bronchograms
Rare
Often present
Hilar haze
Present
Infrequent
Peribronchial cuffs
Present
Unusual

Pulmonary Fibrosis
Presenting Signs and Symptoms

Often asymptomatic except for insidious onset of exertional dyspnea

Cough (if secondary bronchial infection)

Anorexia, weight loss, fatigue, weakness, vague chest pains

Cyanosis, cor pulmonale, clubbing (severe disease)
Common Causes

Idiopathic (Hamman-Rich syndrome, UIP)

Collagen vascular diseases (scleroderma, rheumatoid arthritis)

Sarcoidosis

Eosinophilic granuloma

Occupational exposure

Immunosuppressive and antineoplastic drugs (busulfan, bleomycin, methotrexate, cyclophosphamide)
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Preferred initial imaging technique to show characteristic pattern of prominent linear markings, rounded opacities, and small cystic lesions (honeycombing), as well as evidence of pulmonary hypertension and cor pulmonale
Caveat: Chest films may be normal even in the presence of significant symptoms or functional abnormalities.

2.
High-resolution computed tomography

More sensitive than plain chest radiographs for detecting pulmonary fibrosis and suggesting the correct histologic diagnosis, but not usually required in clinical practice

Note: Lung biopsy may be needed if the imaging findings and clinical course do not indicate the precise diagnosis.

Pulmonary Nodule (Solitary)
Presenting Signs and Symptoms

Asymptomatic

Incidental finding on a chest radiograph
Common Causes

Benign nonneoplastic process (granuloma, arteriovenous malformation)

Benign neoplastic process (hamartoma, bronchial adenoma)

Primary bronchogenic carcinoma

Solitary metastasis
Age Effect on Malignancy in Benign-Appearing Nodule (Small, Round, Sharply Defined)

Younger than age 30: Cancer risk is less than 1%

Ages 30 to 45: Cancer risk is about 15%

Older than age 50: Cancer risk is 50%
Radiographic Criteria for Benignity

Central dense or popcorn calcification

No growth demonstrated on serial chest films over 2 years (comparison films must be eagerly sought)
Approach to Diagnostic Imaging

1.
Chest fluoroscopy (low kVp technique)

May detect characteristic benign calcification and thus obviate any further investigation

May show that apparent nodule actually represents only a healing rib fracture or pleural changes

2.
Computed tomography

May show additional nodules not visible on plain chest radiograph (suggesting metastases)

Detects any hilar or mediastinal metastases

Permits percutaneous fine-needle aspiration biopsy of peripheral lesions as an alternative to thoracotomy for establishing a definite diagnosis (25% pneumothorax rate, although chest tube required in only 5%; false-negative rate of about 10% in patients with carcinoma)
Pulmonary Embolism
Presenting Signs and Symptoms

Nonspecific tachypnea, dyspnea, and hemoptysis
Major Risk Factors

Prolonged bed rest

Recent surgical procedure

Recent myocardial infarction or chronic congestive heart failure

Deep venous thrombosis in the veins of the pelvis or proximal lower extremities

Indwelling venous catheter
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Usually normal (may be nonspecific opacity, pleural effusion, atelectasis, or elevation of the hemidiaphragm consistent with other pulmonary or pleural processes)

Classic pleural-based, wedge-shaped opacity (Hampton’s hump) is seen in a minority of cases with pulmonary infarction

Uncommon findings of focal oligemia (Westermark’s sign) and enlargement of the ipsilateral pulmonary artery (Fleischner’s sign)

Essential for accurate interpretation of radionuclide lung scan

2.
Radionuclide ventilation–perfusion (V/Q) lung scan

Most frequently performed noninvasive imaging study for detecting clinically significant pulmonary emboli

If the perfusion study is normal, significant embolization is excluded and no further studies are needed

If segmental or larger perfusion defects are present with normal ventilation in these areas (V/Q mismatch), there is a high likelihood of pulmonary embolism
Caveat: There may be a relatively large number of indeterminate examinations in patients with chronic pulmonary disease or parenchymal abnormalities on plain chest radiograph.

3.
Contrast-enhanced computed tomography

Has replaced V/Q lung scanning in some institutions as the preferred imaging modality for detecting and excluding pulmonary emboli

Shows a pulmonary embolus as a filling defect within the pulmonary artery or as an abrupt cutoff (complete obstruction) of a pulmonary vessel

Note: Limitations of CT include a relatively high false-positive rate and difficulty in detecting lesions in the periphery of the lung.

4.
Pulmonary arteriography

Most definitive study (“gold standard”) that shows pulmonary emboli as intraarterial filling defects or abrupt cutoff (complete obstruction) of pulmonary vessels

Although invasive, it is indicated if the radionuclide scan is indeterminate or of intermediate probability and there is a clinical need for a definitive diagnosis

Indicated to confirm a high-probability radionuclide scan only if the patient is either a surgical candidate (for venous occlusion or embolectomy) or at extremely high risk for anticoagulation

Note: Doppler ultrasound or magnetic resonance angiography of the lower extremity may be employed as noninvasive procedures to search for venous clots if the diagnosis of pulmonary embolus is equivocal in a patient for whom pulmonary arteriography is contraindicated due to an allergy to iodinated contrast material.

Sarcoidosis
Presenting Signs and Symptoms

Asymptomatic (hilar and mediastinal lymphadenopathy discovered incidentally on a routine chest radiograph)

Constitutional symptoms (fever, weight loss, anorexia, fatigue)

Erythema nodosum and other skin lesions

Uveitis

Hypercalcemia/hypercalciuria

Variety of symptoms involving the cardiac, respiratory, musculoskeletal, and central nervous systems
Common Causes

Unknown
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Preferred initial imaging technique that may demonstrate characteristic bilateral hilar and right paratracheal lymphadenopathy and a diffuse reticular pulmonary infiltration that may accompany or follow the lymphadenopathy

2.
High-resolution computed tomography

More sensitive than plain chest radiographs for detecting parenchymal pulmonary changes and enlarged lymph nodes in regions that are invisible on plain radiographs

Note: Although good correlation has been shown between the CT findings and pulmonary function, clinically this imaging modality is not as important as the response to therapy and pulmonary function tests.

Trauma (Blunt Chest)
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Preferred initial imaging study that can confirm suspected clinical diagnoses (tension pneumothorax, hemothorax, pulmonary contusion)

Can diagnose or suggest other injuries that may be difficult to detect by clinical examination (mediastinal and pericardial hemorrhage, diaphragmatic rupture, and bronchial, esophageal, or pulmonary parenchymal laceration)

May be obtained during acute resuscitation efforts

2.
Computed tomography

Far more sensitive than plain chest radiograph for detecting pneumothorax, ruptured diaphragm or esophagus, pleural or pericardial hemorrhage, and pulmonary contusion and laceration

Effective in demonstrating mediastinal hemorrhage and determining the need for aortography to exclude aortic rupture in a patient who has a limited indication for aortography (based on the reported mechanism of injury) or whose plain chest radiographs are equivocal or of suboptimal quality

Note: An unequivocally normal CT scan of the mediastinum may indicate that the aorta is intact, and thus preclude the need for aortography.

3.
Aortography

Immediately required in patients with history of blunt, decelerating thoracic injury and radiologic evidence of mediastinal hemorrhage

Only imaging modality that allows complete evaluation of the thoracic aorta from the aortic root to the diaphragmatic hiatus and the brachiocephalic arteries and their branches

Note: Transesophageal echocardiography with color flow imaging may be performed to show small aortic intimal tears, some of which are not evident at aortography.

Wegener’s Granulomatosis
Presenting Signs and Symptoms

Paranasal sinus congestion and pain

Nasal mucosal ulcerations (with consequent secondary bacterial infection)

Serous or purulent otitis media with hearing loss

Cough, hemoptysis, dyspnea, pleuritis

Glomerulonephritis (renal failure is major cause of death)
Common Causes

Unknown
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Preferred initial imaging technique to demonstrate the characteristic multiple and bilateral thick-walled cavitating lung lesions (50% of patients), as well as a pattern of diffuse or nodular opacities that may simulate metastases

2.
Computed tomography

Best imaging technique for detecting mucosal and submucosal lesions in the tracheobronchial tree (seen almost exclusively in women) that produce irregular narrowing of the airway lumen
CHAPTER 2. CARDIOVASCULAR
What to Order When

CHAPTER 2. CARDIOVASCULAR

Martin J. Lipton and Brian Funaki

SIGNS AND SYMPTOMS

Angina Pectoris
Presenting Signs and Symptoms

Episodes of precordial discomfort or pressure, typically precipitated by exertion and relieved by rest or sublingual nitroglycerin
Common Cause

Atherosclerotic coronary artery disease
Risk Factors

Elevated serum cholesterol

High cholesterol intake

Tobacco smoking (primarily cigarettes)

Diabetes mellitus

Hypertension

Strong family history
Approach to Diagnostic Imaging

1.
Radionuclide myocardial perfusion scan

SPECT scanning has a specificity and sensitivity approaching 95% for detecting areas of myocardial ischemia as perfusion defects on stress testing that fill in during an examination performed with the patient at rest

Note: Perfusion defects that are stable during both stress and rest examinations usually represent areas of infarction.

2.
Coronary arteriography

Indicated when angioplasty or bypass surgery is being considered

Evaluates the extent and severity of disease (percentage of stenosis involving one, two, or three vessels)

Left ventricular angiogram can be obtained to evaluate wall motion (if not contraindicated by potential adverse effects of additional volume of contrast material on renal or ventricular function)

Note: Wall motion can also be assessed by radionuclide techniques or echocardiography.

3.
Radionuclide gated blood pool studies

To evaluate the ejection fraction because of the important relationship between ventricular function and prognosis

4.
Angioplasty

Interventional technique in which inflation of a balloon-tipped catheter at the site of a stenotic atherosclerotic lesion can rupture the intima and media and dramatically dilate the obstruction

Note: This is an alternative to bypass grafting in patients with suitable anatomic lesions (risk is comparable to surgery).

Evaluating Postsurgical Patency of Bypass Grafts

1.
Ultrafast computed tomography or magnetic resonance imaging

Accuracy of more than 90% for establishing patency of coronary artery bypass grafts
Claudication
Presenting Signs and Symptoms

Deficient blood supply to muscles during exercise (initially intermittent, may proceed to continuous pain at rest)
Common Cause

Atherosclerotic vascular disease
Approach to Diagnostic Imaging

1.
Ultrasound with color Doppler

Preferred noninvasive imaging technique to demonstrate the presence of atherosclerotic plaques and assess the degree of luminal stenosis

2.
Ankle-brachial index (ABI)

A blood pressure cuff is inflated at the ankle, and a systolic measurement (A) is taken by Doppler at the posterior tibial and dorsalis pedis arteries. An arm pressure (B) is also recorded, and the ratio (ABI) is computed:

Normal
1.0
Claudication
0.5 to 1.0
Rest pain/ulceration
<0.5

Note: Diabetics usually have an artificially elevated ABI due to calcified tibial vessels.

3.
Arteriography

Indicated if surgery or angioplasty is contemplated to more precisely define the location and extent of a lesion and assess the status of the peripheral runoff vessels

Note: Magnetic resonance angiography (MRA) is rapidly evolving and continues to improve. Currently, two-dimensional time-of-flight is the preferred method for evaluating arteries below the knee, and contrast-enhanced MRA provides excellent images of the pelvis and thighs. In the near future, contrast-enhanced MRA may become the standard for imaging the entire legs and feet.

4.
Interventional radiology (percutaneous transluminal angioplasty)

PTA, with or without stenting, is generally considered the treatment of choice for focal iliac lesions

Nearly as durable as aorto-bifemoral bypass grafting with much lower morbidity

Excellent technical success with PTA below the pelvis, but not as durable as surgical bypass procedures
Congestive Heart Failure
Common Causes

Left ventricular failure

Valvular heart disease (stenosis or regurgitation)

Pulmonary venoocclusive disease

Congenital heart disease
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Demonstrates the classic findings of indistinct vascular markings, progressive redistribution of venous blood flow to the lungs (cephalization), and Kerley B lines (edematous thickening of the interlobular septa at the periphery of the lungs)

2.
Echocardiography

Indicated to evaluate the dimensions of the left ventricle and other cardiac chambers, ejection fraction, wall-motion dysfunction, and the presence and severity of incompetence or stenosis of the heart valves

Echo and color Doppler studies can accurately detect the presence of pericardial effusion, intracardiac thrombi, and cardiac tumors
Peripheral Ischemia (Acute)
Presenting Signs and Symptoms

Sudden onset of severe pain, coldness, numbness, and pallor of a portion of an extremity

Absent pulses distal to the obstruction
Common Causes

Embolization (from the heart, a proximal atherosclerotic plaque, or an aneurysm)

Acute thrombosis on preexisting atherosclerotic disease
Approach to Diagnostic Imaging

1.
Arteriography

Demonstrates the precise site of obstruction and permits therapeutic thrombolysis of the clot
Caveat: Lytic therapy is contraindicated in patients with active bleeding; recent gastrointestinal bleeding, central nervous system surgery, or stroke; intracranial tumor; or nonviable extremity. Complications include bleeding, puncture site hematoma, pericatheter thrombus formation, and distal embolization.

DISORDERS

Heart

Cardiac Tumors
Presenting Signs and Symptoms

Protean findings of fever, elevated erythrocyte sedimentation rate, anemia, weight loss, syncope, and embolic symptoms

Left atrial lesions may mimic rheumatic valvular disease
Common Causes

Myxoma

Rhabdomyoma, lipoma, fibroma

Sarcoma

Metastases (breast, lung, lymphoma, melanoma)
Approach to Diagnostic Imaging

1.
Echocardiography (especially transesophageal)

In left atrial myxoma, confirms the presence of a filling defect that often prolapses into the left ventricle during diastole

2.
Magnetic resonance imaging

Excellent for detecting direct extension of a lesion, intracardiac metastases, and pericardial involvement in suspected malignant cardiac tumor

3.
Computed tomography

Demonstrates invasion of the heart by noncardiac tumors of the lung or mediastinum

Electron-beam CT is diagnostic of most intracardiac masses (including blood clots)
Cardiomyopathy (Restrictive)
Presenting Signs and Symptoms

Congestive heart failure

Arrhythmias

Heart block
Common Causes

Infiltrative disorders (amyloid, glycogen storage disease, mucopolysaccharidoses, hemochromatosis, sarcoidosis, tumor infiltration of the myocardium)

Endomyocardial fibrosis (highly prevalent in the tropics)
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Typically shows a normal-sized (or even small) heart with pulmonary venous congestion

2.
Echocardiography or magnetic resonance imaging

Shows normal systolic and diastolic function, myocardial hypertrophy, and often dilatation of the atria

Demonstrates a normal pericardium, thus permitting differentiation from constrictive pericarditis (in which the pericardium is thickened)

T2-weighted MR images show high signal in the myocardium in patients with amyloidosis or sarcoidosis

3.
Electron-beam computed tomography

Highly accurate in differentiating restrictive cardiomyopathy from constrictive pericarditis
Caveat: CT has limited use in patients with severe congestive heart failure, in whom contrast material is best avoided.
Cardiomyopathy (Congestive)
Presenting Signs and Symptoms

Congestive heart failure (may be right-sided or left-sided dominance or biventricular involvement)
Common Causes

Chronic diffuse myocardial ischemia (coronary artery disease)

Infection (especially coxsackievirus, Chagas disease)

Toxins or drugs (ethanol, doxorubicin, cocaine, psychotherapeutic drugs)

Granulomatous disease (sarcoidosis, giant cell myocarditis, Wegener’s granulomatosis)

Metabolic disease (endocrinopathies, lipid or glycogen storage diseases, uremia)

Nutritional deficiencies (beriberi, selenium deficiency, kwashiorkor)

Connective tissue disorders
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Demonstrates global cardiomegaly and evidence of congestive failure

Note: Detection of coronary artery calcification may be a clue to an underlying ischemic cause.

2.
Echocardiography, radionuclide scan, magnetic resonance imaging, or electron-beam computed tomography

Echocardiography shows dilated, hypokinetic cardiac chambers with reduced fractional shortening, while excluding primary valvular disease or segmental wall-motion abnormalities (seen in discrete myocardial infarcts)

Gated myocardial scintigraphy demonstrates abnormal ejection fractions and times; gallium scanning can detect acute myocarditis

MRI shows dilatation of specific cardiac chambers, abnormal ejection fractions and stroke volumes, and an abnormal texture of the myocardial tissue. If available, MRI is excellent for assessing all types of cardiomyopathy (including asymmetric septal hypertrophy, which can be difficult to define completely using echocardiography)
Cardiomyopathy (Hypertrophic)
Presenting Signs and Symptoms

Chest pain

Syncope

Palpitations

Exertional dyspnea

Congestive heart failure

Note: Sudden death occurs in about 50% of patients (overall mortality rate about 2­3% per year).

Common Causes

Familial (autosomal dominance with variable penetration)

Obstructive (subaortic or midventricular)
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Deceptively normal-looking in about 50% of patients (because hypertrophy occurs at the expense of the ventricular cavities)

May demonstrate left atrial enlargement (commonly due to mitral regurgitation)

May show right ventricular enlargement or an unusual shape of the cardiac silhouette that is not diagnostic of any specific disorder (e.g., neither a valvular lesion nor pericardial effusion)

2.
Echocardiography

Preferred noninvasive modality that permits measurement of the thickened ventricular walls and allows differentiation among the different subgroups

Often permits quantitation of the degree of obstruction of the outflow tract (an important determinant of the effectiveness of treatment)

3.
Electron-beam computed tomography

If available, permits diagnosis and quantitation of the severity of hypertrophic cardiomyopathy (allows assessment of all areas of the myocardium and is not subject to the imaging limitations of echocardiography)

May evaluate left ventricular mass and provide indices of left ventricular function, as well as exclude other cardiac and noncardiac abnormalities
Congenital Heart Disease

Presenting Signs and Symptoms

Broad spectrum of murmurs, shunts, alterations in systemic and pulmonary blood flow, and altered workloads of specific cardiac chambers

Cyanosis (in right-to-left shunts)
Risk Factors

Chromosomal defects (trisomy 13, 18, 21; Turner’s syndrome; Holt-Oram syndrome)

Maternal illness (diabetes mellitus, systemic lupus erythematosus)

Environmental exposure (e.g., thalidomide)

History of congenital heart disease in a first-degree relative
Common Types

Atrial septal defect

Ventricular septal defect

Patent ductus arteriosus

Total anomalous venous return

Persistent truncus arteriosus

Transposition

Endocardial cushion defect

Tetralogy of Fallot

Hypoplastic right heart syndrome

Coarctation of the aorta
Approach to Diagnostic Imaging
BEFORE BIRTH

1.
Prenatal ultrasound

May permit the diagnosis of some serious defects during pregnancy (thus offering the parents the option of discontinuing the pregnancy or permitting the physician and parents to make realistic plans for the labor, delivery, and care of the child)
AFTER BIRTH

1.
Plain chest radiograph

Initial imaging study for assessing the pulmonary vasculature, size of the main pulmonary artery, size and position of the aorta (especially whether it is right-sided), and size and contour of the cardiac silhouette

2.
Echocardiography

Plays a prominent role in the initial imaging evaluation of congenital heart disease

3.
Magnetic resonance imaging

Cine studies have become the primary modality for imaging most congenital heart disease because of the ability to show directly both morphologic and functional anomalies in multiple planes

Note: Electron-beam CT can provide similar information, but it currently is less available.

4.
Angiocardiography

Definitive (but invasive) study

Note: Some authors recommend angiocardiography only if surgery is contemplated.

Cor Pulmonale
Presenting Signs and Symptoms

Exertional dyspnea

Angina pectoris

Syncope
Common Causes

Chronic obstructive pulmonary disease

Pulmonary fibrosis

Acute or chronic pulmonary embolism

Primary pulmonary hypertension

Pulmonary venoocclusive disease

Extrapulmonary diseases affecting pulmonary mechanics (morbid obesity, chest wall deformities, neuromuscular disease)
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Usually shows a normal-sized heart or only mild cardiomegaly, but there may be enlargement of the right ventricle and right atrium

Note: Plain films may be relatively insensitive indicators of right ventricular enlargement because hyperinflation of the lungs and bullae may distort the position of the heart in these patients.

Characteristic prominence of the main and central pulmonary arteries with rapid tapering (pruning) so that the lung periphery appears oligemic

Note: The lungs usually will show evidence of chronic obstructive pulmonary disease or interstitial fibrosis (i.e., right ventricular failure secondary to pulmonary arterial or parenchymal disease).

2.
Echocardiography or radionuclide studies

Indicated to evaluate the degree of function of the left ventricle (as well as the degree of enlargement of the right atrium and right ventricle)
Endocarditis (Infective)
Presenting Signs and Symptoms

Insidious onset of low-grade fever, night sweats, fatigue, malaise, weight loss

New regurgitant murmur and signs of valvular insufficiency

Chills and arthralgia

Emboli may produce stroke, myocardial infarction, flank pain and hematuria, abdominal pain, or acute arterial insufficiency in an extremity

Petechial hemorrhages and Osler’s nodes
Predisposing Factors

Rheumatic heart disease

Congenital heart disease (ventricular septal defect, tetralogy of Fallot)

Prosthetic heart valve

Intravenous drug abuse

Central venous line
Approach to Diagnostic Imaging

1.
Echocardiography

Procedure of choice for demonstrating the characteristic vegetations on affected heart valves

Note: Transesophageal studies can increase the specificity and sensitivity of echocardiography from about 60% to 90% and are indicated if the diagnosis remains in question after conventional echocardiography.
Echocardiography should be repeated after 6 weeks of intravenous antibiotic therapy for infective endocarditis.

2.
Electron-beam computed tomography

Demonstrates not only the vegetations but also valvular calcification, distorted orifices, and aneurysms of the sinus of Valsalva

Complementary to echocardiography, especially in seriously ill patients who cannot lie flat (i.e., the table can be tilted)

Note: Infections of prosthetic valves can result in perivalvular or perisutural leaks that may be detected by cine MRI.

Myocardial Infarction

Presenting Signs and Symptoms

Deep substernal chest pain (described as an aching or pressure) that often radiates to the back, jaw, or left arm

Pain similar to that of angina pectoris but usually more severe, long lasting, and relieved only a little or briefly by rest or nitroglycerin

Symptoms of left ventricular failure, pulmonary edema, shock, or significant arrhythmia may dominate the clinical appearance

About 20% of acute myocardial infarctions are silent (or not recognized as an illness by the patient)

Elevation of myocardial enzymes in the serum

Caveat: In some cases, acute chest pain may suggest possible aortic dissection.
Common Cause

Atherosclerotic coronary artery disease
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Useful as a baseline for assessing pulmonary venous congestion
Direct Infarct Imaging
Caveat: The diagnosis of myocardial infarction is usually evident from the patient’s history and confirmed by electrcardiogram and enzyme studies. Infarct imaging is indicated if the clinical, laboratory, and electrocardiographic findings are equivocal; if there has been recent cardiac surgery or trauma; or if there is a suspicion of right ventricular infarction.

1.
Radionuclide imaging, electron-beam computed tomography, or magnetic resonance imaging

Can demonstrate areas of myocardial infarction and usually can determine whether they are acute or remote

Note: Echocardiography is often performed to assess the function of the right and left ventricles, as well as to detect the 10­20% incidence of cardiac-wall clots that alter clinical management.

Valvular Heart Disease
Presenting Signs and Symptoms

Murmur and clinical symptoms vary, depending on the precise valve involved and whether there is predominant stenosis or regurgitation
Common Causes

Rheumatic fever

Congenital heart disease

Infectious endocarditis
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Inexpensive imaging technique to show enlargement of the entire heart or specific chambers, valvular calcification, and any evidence of pulmonary vascular congestion

2.
Echocardiography

More precisely demonstrates any chamber enlargement or wall thickening and the precise size of the orifices of affected valves

Doppler flow studies can assess the degree of regurgitation

Note: Although not yet widely used, cine MRI shows promise for demonstrating and quantitating the regurgitation of blood across any incompetent valve (without the need for contrast material).

Pericardium

Cardiac Tamponade
Presenting Signs and Symptoms

Cardiogenic shock (low cardiac output and low systemic arterial pressure)

Tachycardia

Dyspnea and orthopnea

Usually elevated systemic venous pressure (prominent neck veins) and pulmonary venous pressure

Distant heart sounds

Pericardial rub

Pulsus paradoxus (accentuation of the normal inspiratory decline in systemic systolic blood pressure greater than 10 mm Hg)
Mechanism

Pericardial effusion under tension causing compression of the cardiac chambers and compromising diastolic filling
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Demonstrates rapid enlargement of the cardiac silhouette with relatively normal-appearing vasculature

2.
Echocardiography

Modality of choice not only to demonstrate the accumulation of a large amount of pericardial fluid but also to show septal shift, paradoxic septal motion, diastolic collapse of the right ventricle, and cyclic collapse of the atria
Constrictive Pericarditis
Presenting Signs and Symptoms

Elevation of ventricular diastolic, atrial, pulmonary, and systemic venous pressures (unlike tamponade, the ventricular venous pressure, or ejection fraction, is usually preserved)

Dyspnea and orthopnea (prolonged elevation of pulmonary venous pressure)

Hypervolemia, engorgement of neck veins, pleural effusion, hepatomegaly, ascites, peripheral edema (elevated systemic venous pressure)

Kussmaul’s sign (inspiratory swelling of neck veins), which is absent in tamponade
Common Causes

Postpericardiotomy (although the pericardium is usually partly resected after coronary artery bypass grafting)

Viral infection (especially coxsackievirus B)

Tuberculosis

Uremia

Radiation

Neoplastic involvement

Rheumatoid arthritis

Idiopathic
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Demonstrates characteristic pericardial calcification in 50% of patients (as well as pleural effusions, small atria, a flat or straightened right heart border, and dilated superior and inferior vena cava and azygos vein)

2.
Magnetic resonance imaging or computed tomography

Preferred imaging techniques to show the abnormally thick pericardium (which permits the distinction of constrictive pericarditis from restrictive cardiomyopathy)

Notes: MRI is more specific in that it can show that the pericardial thickening represents fibrosis.
Although echocardiography can show the thickened pericardial wall, the findings are not as specific as in the case of pericardial fluid.

Pericardial Effusion
Presenting Signs and Symptoms

Severity of symptoms varies greatly depending on the underlying cause, the rate at which the pericardial fluid accumulates, and the total amount present

Milder symptoms include chest pain and a friction rub; large effusions may lead to congestive heart failure and shock

Faint, distant heart sounds on auscultation
Common Causes

Idiopathic

Infection

Autoimmune (systemic lupus erythematosus, rheumatoid arthritis, scleroderma)

Dressler’s and postpericardiotomy syndromes

Neoplasm (lymphoma, lung or breast metastases)

Drug-induced (procainamide, hydralazine, phenytoin)

Uremia

Myxedema

Congestive heart failure

Trauma
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Suggests the diagnosis if there is a rapid increase in the size of the cardiac silhouette on serial chest films (especially when the lungs remain clear)

Note: A rapid increase in heart size related to congestive heart failure is generally associated with pulmonary venous congestion.

2.
Echocardiography

Procedure of choice for demonstrating as little as 50 mL of pericardial fluid (normal, 20 mL) as a posterior sonolucent collection

Note: CT is valuable for detecting loculated pericardial effusions, whereas MRI may be able to characterize the fluid as serous or hemorrhagic (because of characteristic changes in signal intensity).

Vascular

Aneurysm (Abdominal Aorta)
Presenting Signs and Symptoms

Most are asymptomatic and discovered incidentally on routine physical examination or plain abdominal radiograph

Pulsatile mass

Severe abdominal pain and hypotension (if rupture)
Common Causes

Atherosclerosis

Trauma

Arteritis syndromes

Connective tissue disorders (Marfan’s syndrome, cystic medial necrosis)

Syphilis
Approach to Diagnostic Imaging
Caveat: Any patient with a pulsatile abdominal mass and hypotension should proceed directly to surgery without any intervening imaging study.

1.
Ultrasound

Most cost-effective initial imaging technique to show dilatation of the aorta to greater than 3 cm and the presence of intraluminal clot

Serial examinations can be easily performed to follow aneurysm size in patients who are not considered surgical candidates at the time
Caveat: Ultrasound has limited ability to consistently show the proximal and distal extent of an aneurysm and its relationship to the surrounding retroperitoneal structures (required prior to elective surgical repair).

2.
Computed tomography

Indicated if there is suspicion of retroperitoneal hematoma secondary to leaking or acute rupture

More accurate than ultrasound for determining the true diameter of an aneurysm and its longitudinal extent, but more expensive and requires contrast material

Note: Helical CT with three-dimensional reformatting permits demonstration of the abdominal aorta in multiple planes, improves the visualization of the relationship of an aneurysm to the origins of the renal arteries, and ensures a constant bolus of contrast material throughout the aorta.

3.
Magnetic resonance imaging

Alternative to ultrasound or CT

Especially useful in patients with depressed renal function (because MR contrast is not nephrotoxic)

MRA may eventually supplant catheter angiography in the preoperative assessment of abdominal aortic aneurysms

4.
Aortography

Traditionally, the preoperative procedure of choice for determining the number of renal arteries and their relationship to the aneurysm, as well as the patency of the visceral, renal, external iliac, and femoral arteries (factors that may modify the surgical approach and define additional procedures required to decrease postoperative morbidity)

Because aortography outlines only the aortic lumen, it underestimates the true size of an aneurysm if its wall is lined with thrombus.

Note: The ability of newer, less invasive techniques such as CT and MRA to demonstrate the extent of an aneurysm and the patency of other vessels has substantially reduced the need for preoperative aortography, which now is rarely required for this purpose.

Caveat: There is no indication for plain lateral radiographs of the abdomen to detect calcification in the wall of an aneurysm (very low sensitivity).
Aneurysm (Peripheral)
Presenting Signs and Symptoms

Limb ischemia (due to thrombus within the aneurysm)

Signs of distal embolization

Gangrene
Common Causes

Atherosclerosis

Trauma

Mycosis

Complication of vascular surgery
Approach to Diagnostic Imaging

1.
Ultrasound with color Doppler

Preferred initial imaging procedure to detect a peripheral aneurysm (most commonly involving the popliteal artery) and assesses its size

Note: CT angiography or MRA may be employed to evaluate a suspected aneurysm.

2.
Arteriography

Usually required prior to surgery (bypass grafting and aneurysm repair) to evaluate the status of the peripheral vessels

Covered stents inserted via the femoral artery may be used instead of bypass grafting to repair aneurysms
Aneurysm (Thoracic Aorta)
Presenting Signs and Symptoms

Asymptomatic

Symptoms related to secondary compression

Stridor, wheezing (trachea and bronchi)

Dysphagia (esophagus)

Venous obstruction of the upper extremities, head, and neck (superior vena cava)

Hoarseness (recurrent laryngeal nerve)

Substernal or back pain
Common Causes

Atherosclerosis

Syphilis

Mycosis

Connective tissue disorders (Marfan’s and Ehlers-Danlos syndromes)
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Demonstrates contour abnormalities and tortuosity of the thoracic aorta, as well as calcification within its wall
Caveat: It may be difficult to distinguish a thoracic aneurysm from other mediastinal masses.

2.
Computed tomography or magnetic resonance imaging

Preferred methods for initial evaluation and follow-up

Accurately demonstrates vessel diameter, mural thrombus, calcifications, degree of luminal patency, mass effects on adjacent mediastinal structures, and evidence of leakage or rupture

CT is superior to MRI for showing calcifications within the wall of an aneurysm

MRI is superior to CT for demonstrating the relationship of an aneurysm to the arch vessels (because of its ability to directly image in the sagittal plane) and requires no contrast material

Note: Transesophageal ultrasound is increasingly being used for accurately determining the size of thoracic aortic aneurysms, especially in unstable patients, since it can be rapidly performed at the bedside.

3.
Aortography

Indicated only for preoperative planning when it is vital to know the relationship between the aneurysm and the great vessels and coronary arteries, as well as the vascular supply to the spinal cord

Note: Aortography is unreliable for assessing the size of an aneurysm, as it only visualizes the patent portion of the lumen and cannot show the extent of mural thrombus.

Aortic Dissection
Presenting Signs and Symptoms

Sudden, severe, tearing substernal chest pain with radiation to the back

Frequent migration of pain from the original site as the dissection extends along the aorta

Aortic insufficiency murmur

Absent or asymmetric major arterial pulses

Neurologic complications (stroke, paraparesis, or paraplegia from spinal cord ischemia; ischemic peripheral neuropathy from abrupt occlusion of an artery supplying a limb)
Predisposing Factors

Hypertension

Connective tissue disorders (Marfan’s and Ehlers-Danlos syndromes)

Bicuspid aortic valve

Coarctation of the aorta

Trauma

Granulomatous arteritis

Pregnancy (cause of 50% of dissections in women younger than age 40)

Previous aortic surgery or arterial catheterization
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Demonstrates mediastinal widening in up to 90% of patients and frequently a left pleural effusion

Localized bulging of the aortic contour indicates the likely site of origin of a dissection

2.
Computed tomography

Preferred initial imaging study in acutely ill patients

Shows the classic double-barrel aorta (opacification of both the true and false lumens) and intimal flap (linear filling defect within the aortic lumen)

Note: If available, transesophageal ultrasound is also an extremely sensitive screening technique for diagnosing aortic dissection.

3.
Magnetic resonance imaging

Probably the best noninvasive technique for imaging the aorta, but often difficult to obtain in severely ill patients who require life-support systems and close monitoring

Note: MRI is the procedure of choice for the detection of chronic aortic dissection.

4.
Aortography

This most definitive study is required if surgical therapy is contemplated to identify the precise origin and extent of the dissection, the severity of any aortic insufficiency, and the extent of involvement of major arterial trunks arising from the aorta (including the coronary arteries)
Peripheral Occlusive Vascular Disease
Presenting Signs and Symptoms

Intermittent claudication that progresses to pain at rest

Coolness and numbness of the affected extremity

Nonhealing ulcers

Gangrene

Diminished pulses distal to the area of narrowing
Vessels Primarily Involved

Superficial femoral artery

Aortoiliac system

Trifurcation vessels

Popliteal artery
Approach to Diagnostic Imaging

1.
Ultrasound with color Doppler

Preferred noninvasive imaging technique to demonstrate the presence of atherosclerotic plaques and assesses the degree of luminal stenosis

2.
Ankle-brachial index (ABI)

A blood pressure cuff is inflated at the ankle, and a systolic measurement (A) is taken by Doppler at the posterior tibial and dorsalis pedis arteries. An arm pressure (B) is also recorded, and the ratio (ABI) is computed.

Normal
1.0
Claudication
0.5 to 1.0
Rest pain/ulceration
<0.5

Note: Diabetics usually have an artificially elevated ABI due to calcified tibial vessels.

3.
Arteriography

Indicated if surgery or angioplasty is contemplated

More precisely defines the location and extent of a lesion and assesses the status of the peripheral runoff vessels

Note: MRA is rapidly improving and may eventually replace contrast arteriography for evaluating the peripheral vascular system.

4.
Interventional radiology (percutaneous transluminal angioplasty)

Excellent alternative to surgery for dilating localized stenotic lesions (especially in the iliac arteries where the success rate approaches 95%)

Note: The success rate in arteries of the thigh and calf is about 50­60%.

Deep Venous Thrombosis
Presenting Signs and Symptoms

Asymptomatic (one-third of patients with symptomatic pulmonary emboli but no clinical signs of DVT will nevertheless have a lower extremity venous thrombus)

Variable combination of pain, edema, warmth, skin discoloration, and prominent superficial veins over the involved area

Delayed complications of dermatitis, ulceration, and varicosities
Common Causes

Stasis (postoperative, postpartum states; chronic illness)

Pregnancy or the use of oral contraception

Obesity

Hypercoagulability (malignant tumor, blood dyscrasia)

Endothelial injury (indwelling catheter, injection of irritating substance, septic phlebitis, thromboangiitis obliterans)

Prolonged immobilization with the legs dependent while traveling (especially on prolonged airplane flights)
Approach to Diagnostic Imaging

1.
Color Doppler ultrasound

Preferred initial imaging modality (>95% accuracy) that can demonstrate lack of compressibility of the vein (indicating the presence of thrombus within it)

Visualizes intraluminal thrombus itself and characteristic alterations in spontaneous flow that occur because of obstruction of the proximal veins

2.
Venography

Traditional “gold standard” that can demonstrate the conclusive finding of a persistent filling defect within the lumen of a vein.

Other findings that are highly suggestive of DVT include abrupt termination of the contrast column within a vein, inability to opacify a major vein, and the formation of extensive collateral venous circulation

Note: See “ Pulmonary Embolism”.

Superior Vena Cava Syndrome
Presenting Signs and Symptoms

Progressive dilatation of the veins of the head and upper extremities

Edema and plethora of the face, neck, and upper torso

Cyanosis and conjunctival edema

Dizziness, syncope, headache

Respiratory distress (due to airway edema)

Note: If the obstruction occurs slowly, the formation of a compensatory collateral venous network may prevent the development of clinical symptoms.

Common Causes

Malignant neoplasm (primary bronchogenic carcinoma, lymphoma, metastases from breast carcinoma)

Mediastinal granulomatous or fibrosing disease

Long-term indwelling central venous catheter

Aortic aneurysm
Approach to Diagnostic Imaging

1.
Computed tomography or magnetic resonance imaging

Preferred noninvasive methods to show both the proximal dilatation of the superior vena cava and its branches and the underlying cause of the obstruction

2.
Venography

Allows better definition of the superior vena cava and collateral vessels

Metallic stents are generally the preferred treatment for malignant obstruction of the SVC. These can be placed via a femoral vein puncture and usually provide relief of symptoms within several hours.
Thoracic Outlet Syndrome
Presenting Signs and Symptoms

Numbness, paresthesias, pain, and sensory and motor deficits in the hand, neck, shoulder, or arm (secondary to arterial, venous, or nerve compression)

Obliteration of the radial pulse on the involved side with 90° elevation and external rotation of the arm or with simultaneous hyperextension of the neck and turning of the head toward the affected side (if the artery is involved)

Intermittent cyanosis, edema, and thrombotic symptoms (if the vein is involved)
Common Causes

Congenital anatomic anomaly (cervical rib, abnormal insertion of the anterior scalene muscle on the first rib)

Aberrant healing of rib or clavicle fracture

Neoplasm
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Imaging study of choice to demonstrate a cervical rib or a tumor in the apex of the lung

2.
Arteriography or venography

Studies performed in both the neutral position (arms at the sides) and in the position that reproduces the patient’s symptoms may demonstrate kinking or partial obstruction of the subclavian artery or vein
CHAPTER 3. GASTROINTESTINAL
What to Order When

CHAPTER 3. GASTROINTESTINAL

Richard M. Gore

SIGNS AND SYMPTOMS

Ascites

Presenting Signs and Symptoms

Small amounts may be asymptomatic

Abdominal distension and discomfort

Anorexia, nausea, and early satiety

Respiratory distress (due to reduced lung volume)

Bulging flanks, fluid wave, shifting dullness
Common Causes

Cirrhosis

Neoplasm (hepatic cancer or peritoneal carcinomatosis)

Congestive heart failure

Tuberculosis (and other infections)

Hypoalbuminemia (nephrotic syndrome, protein-losing enteropathy, malnutrition)
Approach to Diagnostic Imaging

1.
Ultrasound

Mobile, echo-free fluid regions shaped by adjacent structures

Smallest amounts (as little as 100 mL) in a supine patient appear first around the inferior tip of the right lobe of the liver, the superior right flank, the cul-de-sac of the pelvis, and the hepatorenal area (Morison’s pouch)

2.
Computed tomography

More expensive, but may demonstrate the underlying abdominal disease process (if US fails to do so)

May be able to distinguish ascites (water attenuation) from blood (higher attenuation) or chyle (lower attenuation)
Caveat: Plain abdominal radiographs are not indicated because a large amount of fluid (800 to 1000 mL) must be present to be detected and the underlying cause is infrequently shown.
Constipation
Presenting Signs and Symptoms

Decrease in frequency of stools or difficulty in defecation
Common Causes
ACUTE

Bowel obstruction or adynamic ileus
CHRONIC

Neurologic dysfunction (diabetes, spinal cord disorder, parkinsonism, idiopathic megacolon)

Scleroderma

Drugs (anticholinergic agents, opiates, aluminum-based antacids)

Hypothyroidism

Cushing’s syndrome

Hypercalcemia

Debilitating infection

Anorectal pain (fissures, hemorrhoids, abscess, proctitis)
Approach to Diagnostic Imaging

1.
Plain abdominal radiograph

Detects mechanical bowel obstruction

2.
Barium enema

For better characterization of the site and cause of narrowing or obstruction of the bowel

3.
Radiopaque marker study

A plain abdominal radiograph 5 days after ingestion of the tablets can indicate whether there is a significant delay in clearing the radiopaque material from the bowel

4.
Defecography (evacuation proctography)

Dynamic study that can demonstrate mechanical abnormalities such as rectal intussusception, anterior wall prolapse, or rectocele
Diarrhea
Presenting Signs and Symptoms

Increased volume, fluidity, or frequency of fecal discharges
Common Causes

Osmotic (lactase deficiency, polyvalent laxative abuse)

Secretory (viral or protozoal infection, bacterial toxins, castor oil, Zollinger-Ellison syndrome, prostaglandin therapy, vasoactive intestinal peptide)

Exudative (mucosal inflammation, necrosis, neoplasm)

Malabsorption (sprue, pancreatic insufficiency, bowel resection, Whipple’s disease)

Altered intestinal motility (diabetes, hyperthyroidism, magnesium-containing laxatives, irritable bowel syndrome)
Approach to Diagnostic Imaging

1.
Small bowel study

May suggest underlying causes such as sprue or scleroderma (dilated small bowel), hypoproteinemia (regularly thickened folds), Whipple’s disease (irregularly thickened folds), inflammatory bowel disease (ileitis or colitis), tuberculosis (ileocecal inflammation), intestinal fistula, or motility disorders
Caveat: Plain abdominal radiographs are not indicated.
Dysphagia
Presenting Signs and Symptoms

Difficulty initiating swallowing

Food sticking in the upper or middle esophageal region

Odynophagia (pain on swallowing)

Regurgitation

Aspiration
Common Causes

Carcinoma

Peptic or lye stricture

Achalasia

Scleroderma

Diffuse esophageal spasm

Cervical esophageal web

Lower esophageal (Schatzki’s) ring

Neuromuscular disorder
Approach to Diagnostic Imaging

1.
Barium swallow

Imaged on video fast-sequence radiographs or digitally
Caveat: Hyperosmolar water-soluble contrast should not be used because aspiration of this material causes increased fluid to enter the tracheobronchial tree and may lead to the development of pulmonary edema.
Gastrointestinal Bleeding (Chronic, Obscure Origin)
Presenting Signs and Symptoms

Anemia (iron deficiency)

Fecal occult blood/guaiac positive stools
Common Causes

Neoplasm (benign or malignant anywhere in alimentary tube)

Peptic ulcer

Gastritis

Meckel’s diverticulum

Angiodysplasia
Approach to Diagnostic Imaging

1.
Barium enema (double contrast)

If negative, proceed to

2.
Upper gastrointestinal series (biphasic)

If negative, proceed to

3.
Enterolysis (not a “small bowel follow-through”)

If negative, proceed to

4.
Arteriography (celiac, superior mesenteric artery, inferior mesenteric artery)

May detect a vascular malformation (angiodysplasia) or an occult neoplasm that is the underlying source of the bleeding

If negative (especially in young patients), consider

5.
Radionuclide scan for Meckel’s diverticulum

Isotope may collect in ectopic gastric mucosa

Note: Endoscopy and colonoscopy can also be used to detect a source of chronic gastrointestinal bleeding, depending on the availability of physicians skilled in performing these techniques.

Gastrointestinal Bleeding (Acute Lower)
Presenting Sign and Symptom

Brisk rectal bleeding without blood in gastric aspirate
Common Causes

Diverticulosis

Angiodysplasia

Ischemic colitis

Hemorrhoids (diagnosed by proctoscopy)

Polyps/carcinoma (more frequently associated with chronic bleeding)
Approach to Diagnostic Imaging

1.
Radionuclide scan

Most sensitive diagnostic study that can document active bleeding of as little as 0.05–0.1 mL/min as a focal area of increased radionuclide activity corresponding to extravasation of blood in the gastrointestinal tract

Movement of the radionuclide proximally or distally indicates active bleeding. Lack of movement suggests an angiodysplasia, arteriovenous malformation, or vascular tumor

Note: If the radionuclide scan shows no evidence of an active bleeding site, there is no indication for arteriography.

2.
Arteriography

If bleeding continues to be rapid (>0.5–1 mL/min), may show the precise bleeding site by demonstrating extravasation of contrast material into the lumen of the bowel or the tangled blood vessels of an angiodysplasia

Offers therapeutic options through transcatheter measures (embolization or vasoconstrictive agents) and may preclude the need for surgery (especially in diverticular hemorrhage)

Note: Many patients have a positive radionuclide scan and a bleeding site demonstrated surgically but a negative arteriogram.

3.
Barium enema or colonoscopy

Indicated only if bleeding is minimal or has stopped, to search for underlying colonic pathology that may represent the bleeding site

Note: Introduction of barium into the colon prevents the performance of arteriography until the barium has cleared from the region of interest.
Colonoscopy, although valuable for assessing chronic and subacute bleeding, is not the examination of choice for acute rapid bleeding because the presence of fresh blood and clots prevents an adequate view of the mucosa.

Caveat: Unstable patients with massive hemorrhage should have emergency surgery without any diagnostic studies.
Gastrointestinal Bleeding (Acute Upper)
Presenting Signs and Symptoms

Hematemesis, melena, hematochezia

Blood in nasogastric aspirate
Common Causes

Peptic ulceration (duodenum, stomach, esophagus)

Gastric mucosal lesion (superficial erosions, stress ulcers)

Esophageal varices

Neoplasm

Mallory-Weiss tear
Approach to Diagnostic Imaging

1.
Endoscopy

Procedure of choice that can permit precise visual identification of a lesion that is actively bleeding

Offers therapeutic options (electrocautery or laser cautery, mechanical clips, tissue adhesives, or injection of sclerosing agents for varices)

May be falsely negative if there is rapid bleeding, because large amounts of fresh blood and clots may obscure the underlying bleeding lesion

2.
Arteriography

Indicated for patients with rapid bleeding (0.5 to 1 mL/min, but not if massive hemorrhage) in whom endoscopy is technically difficult

Demonstrates extravasation of contrast material or an angiodysplasia

Offers therapeutic options through transcatheter measures (embolization or infusion of vasoconstrictive agents); even if hemostasis fails or is only temporary, generally allows time for vascular volume replacement to stabilize the patient before surgery

3.
Upper gastrointestinal series

If bleeding is minimal or has stopped, this readily available, safe, and relatively inexpensive procedure is a good screening study for demonstrating an ulcer, neoplasm, or varices that mayrepresent the bleeding site

Note: Introduction of barium into the gastrointestinal tract prevents the performance of endoscopy or arteriography until the barium has cleared from the region of interest.

Caveat: Patients with massive hemorrhage whose condition is unstable should have emergency surgery without any diagnostic studies.
Jaundice: Differentiation of Medical (Hepatocellular) from Surgical (Biliary Obstruction) Causes
Presenting Signs and Symptoms

Yellowing of skin and sclera

Abnormal liver enzymes

Dark urine and pale stools
Common Causes

Common duct stone

Pancreatic carcinoma

Cholangiocarcinoma

Primary hepatocellular dysfunction (alcoholism, hepatitis)
Approach to Diagnostic Imaging

1.
Ultrasound

Preferred initial imaging technique for demonstrating dilated bile ducts (indicating biliary obstruction)

May be equivocal or incomplete in obese patients or those with large amounts of intestinal gas

2.
Computed tomography

Highly accurate for showing dilated bile ducts, as well as disease in adjacent structures (liver, porta hepatis, pancreas, adrenals, retroperitoneum)

Not adversely affected by obesity or large amounts of intestinal gas

3.
Magnetic resonance cholangiopancreatography (MRCP)

Preferred diagnostic approach if ERCP is likely to be unsuccessful, as in patients with surgical bypass procedures (Billroth II anastomosis, hepatojejunostomy) or those with acute pancreatitis (increased risk of complications from ERCP)

4.
Percutaneous transhepatic cholangiography (PTHC)

Invasive procedure of choice for defining the precise site of obstruction in a dilated biliary system

Superior to ERCP for diagnostic and therapeutic maneuvers (e.g., balloon dilatation of strictures, brush biopsy, stone removal, insertion of an endoprosthesis) that involve lesions above the porta hepatis (intrahepatic)

Generally safe, but complications include sepsis, bile leakage with peritonitis, and bleeding

5.
Endoscopic retrograde cholangiopancreatography (ERCP)

Invasive procedure of choice if the bile ducts are not dilated (e.g., sclerosing cholangitis) and if the patient has abnormal bleeding parameters

Permits therapeutic procedures such as sphincterotomy, stone extraction, brush biopsy of strictures, and insertion of an endoprosthesis

Note: Local experience often dictates the choice between PTHC and ERCP.

Caveat: Although dilated bile ducts are virtually pathognomonic of extrahepatic biliary obstruction, normal bile ducts do not absolutely exclude this diagnosis because of the underlying disease process (e.g., sclerosing cholangitis) or because the obstruction may be recent or intermittent.
Nausea and Vomiting
Common Causes

Drug reaction (chemotherapeutic agents, central nervous system [CNS]-active drugs, analgesics, cardiovascular drugs, hormones, antibiotics, diuretics, antiasthmatics)

Gastrointestinal disorders

Gastric outlet obstruction (peptic ulcer disease, gastric malignancy, extrinsic compression)

Small bowel obstruction (adhesions, inflammatory bowel disease, neoplasm)

Inflammatory conditions (gastroenteritis, peptic ulcer disease, cholecystitis, pancreatitis, Crohn’s disease)

Motility disorders (gastroparesis, irritable bowel syndrome, chronic intestinal pseudoobstruction, scleroderma)

CNS disorders (stroke, neoplasm, labyrinthine disease, motion sickness, psychiatric disorders)

Metabolic conditions (pregnancy, uremia, hyperglycemia, hyperparathyroidism, metabolic acidosis, adrenal insufficiency)

Infectious disorders (hepatitis, meningitis, labyrinthitis)
Approach to Diagnostic Imaging
Caveat: Initially, a detailed history, physical examination, and laboratory workup should be performed. Appropriate imaging studies can then be ordered, based on the probable clinical diagnosis.
SUSPECTED GASTROINTESTINAL CAUSE

1.
Plain abdominal radiograph

Inexpensive initial imaging procedure for detecting a suspected gastric outlet or small bowel obstruction

2.
Computed tomography

Best study for detecting a suspected intraabdominal inflammatory process (and for further evaluation of small bowel obstruction demonstrated on plain films)

DISORDERS

Abscess

Peritonitis
Presenting Signs and Symptoms

Generalized abdominal tenderness with rigidity

Absence of bowel sounds

Fever

Vomiting
Common Causes

Perforation of a viscus

Trauma

Strangulating intestinal obstruction

Pancreatitis

Pelvic inflammatory disease

Vascular catastrophe (mesenteric thrombosis or embolus)

Ascites (spontaneous infection or peritoneosystemic shunt)
Approach to Diagnostic Imaging

1.
Plain abdominal radiograph

Upright films to demonstrate free air beneath the diaphragm, indicating perforation of a viscus

If the patient cannot stand or sit, a lateral decubitus film (using a horizontal x-ray beam) with the patient’s left side down may be used (any free air can be more easily detected over the soft-tissue-density liver on the right than when it is overlying luminal air in the stomach, small bowel, or splenic flexure on the left)

On supine films, look for the double-wall sign (air outlining both the inner and outer walls of bowel loops), as well as free air outlining the normally invisible falciform and various pelvic ligaments
Caveat: NEVER use barium in the presence of free air in the peritoneal cavity.

2.
Computed tomography

Procedure of choice for detecting loculated fluid collections, abscesses, and strangulating obstruction
Suspected Abdominal Abscess (No Localized Findings)
Presenting Signs and Symptoms

Spiking fever, chills

Leukocytosis

Indolent course in immunosuppressed patients
Common Causes

Recent surgery or trauma

Alcoholism

Parenteral drug use

Chronic illness

Steroids, chemotherapy, immunosuppressive therapy
Approach to Diagnostic Imaging

1.
Computed tomography

Preferred initial imaging procedure for detecting, characterizing, and determining the extent of an abdominal abscess

Does not have the disadvantage of the substantial delay required with radionuclide scanning

Limited value in patients with abrupt and extreme changes in density (metallic clips, residual barium) because of “streak” artifacts

2.
Radionuclide scan (indium)

Can examine the entire abdomen simultaneously and detect multiple or extraabdominal sites of infection

Indium is superior to gallium because normal accumulation of gallium in the liver, spleen, and colon can obscure an abscess; also, gallium (but not indium) can accumulate in lymphoma and other neoplasms
Caveat: There is a substantial delay before diagnostic results can be obtained (at least 18 to 24 hours after radionuclide injection).

3.
Ultrasound

Alternative to CT in very sick patients (who can suspend respiration only briefly)

Multiplicity of scanning planes may be of value in assessing the precise anatomic relationships of a lesion

Procedure of choice for children (uses no ionizing radiation)

Because the examination requires close contact between the transducer and the skin, it may be difficult to perform on postsurgical patients with recent incisions, wound dressings, drains, superficial infections, or stomas
Hepatic Abscess
Presenting Signs and Symptoms

Subacute onset of fever, chills, nausea, anorexia, weight loss

Right upper quadrant pain

Hepatomegaly (acute onset suggests multiple abscesses from systemic bacteremia or biliary tract infection)
Common Causes

Ascending cholangitis in a partially or completely obstructed biliary tract

Portal bacteremia from an intraabdominal site (e.g., appendicitis, diverticulitis)

Systemic bacteremia (organisms reach liver through the hepatic artery)

Direct extension from adjacent extrabiliary site

Trauma
Approach to Diagnostic Imaging

1.
Computed tomography

Preferred study for detecting and characterizing a hepatic abscess

2.
Ultrasound

Alternative imaging technique
Left Subphrenic Space Abscess
Presenting Signs and Symptoms

Left upper quadrant pain and tenderness

Fever

Leukocytosis

History of surgery 3 to 6 weeks before onset
Common Causes

Surgery or trauma

Peritonitis (e.g., perforated viscus)

Spread from distant abdominal abscess
Approach to Diagnostic Imaging

1.
Computed tomography

Preferred initial imaging study (negative CT scan excludes a left subphrenic abscess)

US is usually less effective because of gas in the stomach, small bowel, or colon

2.
Radionuclide scan (indium or gallium)

Indicated if CT is equivocal (not uncommon if there has been recent surgery or trauma) and if it is impossible to differentiate an infected from a sterile collection (e.g., perisplenic hematoma)
Caveat: Barium enema is contraindicated because retained barium within the bowel significantly delays the performance of more sensitive and specific studies such as CT and radionuclide scans.
Pancreas/Lesser Sac Abscess
Presenting Signs and Symptoms

Fever and abdominal pain arising 10 to 21 days after acute pancreatitis

Nausea and vomiting

Abdominal mass

Leukocytosis

Increased serum amylase
Approach to Diagnostic Imaging

1.
Computed tomography

Preferred imaging technique

US is generally ineffective because of the large amounts of intestinal gas related to the usually associated adynamic ileus
Perihepatic Abscess
Presenting Signs and Symptoms

Right upper quadrant pain and tenderness

Fever

Leukocytosis
Common Causes

Prior surgery or trauma
Approach to Diagnostic Imaging

1.
Plain abdominal radiograph

Can detect subtle perihepatic gas collections

Localized ileus of the hepatic flexure and right pleural effusion are both suggestive but not diagnostic signs, since they may merely reflect nonspecific postoperative or post-traumatic changes

2.
Computed tomography

Preferred imaging technique

3.
Ultrasound

Alternative imaging technique

4.
Radionuclide scan (indium or gallium)

Examination of the entire abdomen and pelvis is indicated if an occult abscess is still suspected clinically despite negative US and CT studies

Negative indium or gallium radionuclide scan effectively excludes an abscess
Pelvic Abscess
Presenting Signs and Symptoms

Lower abdominal pain and tenderness

Palpable mass on vaginal or rectal examination

Fever and leukocytosis
Common Causes

Acute appendicitis

Pelvic inflammatory disease

Colon diverticulitis
Approach to Diagnostic Imaging

1.
Ultrasound

Preferred imaging technique for pelvic inflammatory disease

Fluid-filled urinary bladder provides an excellent acoustic window for examining the supravesical and paravesical spaces

2.
Computed tomography

Preferred initial imaging procedure for men and for women following total abdominal hysterectomy and bilateral salpingo-oophorectomy, as well as for diagnosing perirectal abscesses

3.
Magnetic resonance imaging

Can often best define perirectal abscesses and fistulas

4.
Radionuclide scan

May be necessary to confirm the inflammatory nature of the lesion because the differential diagnosis of cystic masses is large
Caveat: Indium is the preferred radionuclide because gallium normally accumulates in the sigmoid and rectum.
Renal/Perirenal Abscess
Presenting Signs and Symptoms

Acute onset of unilateral flank or abdominal pain and tenderness

Dysuria

Fever, chills

Leukocytosis
Common Cause

Pyelonephritis (often associated with renal calculous disease, recent urologic surgery, or obstruction by malignancy)
Approach to Diagnostic Imaging

1.
Computed tomography

Preferred initial imaging technique for detecting inflammatory and infectious renal disease

May demonstrate thickening of Gerota’s fascia, a subtle change that may be the first sign of a perirenal infection

2.
Magnetic resonance imaging

Alternate imaging technique in patients who cannot receive iodinated contrast material

3.
Ultrasound

Alternative imaging technique that demonstrates a fluid-filled intrarenal or perirenal collection
Splenic Abscess
Presenting Signs and Symptoms

Subacute onset of left-sided pain (often pleuritic) in the flank, upper abdomen, or lower chest that may radiate to the left shoulder

Left upper quadrant tenderness

Splenomegaly

Fever

Leukocytosis
Common Causes

Systemic bacteremia (e.g., endocarditis, salmonellosis)

Trauma (superinfection of hematoma)

Extension from contiguous infection (e.g., subphrenic abscess)
Approach to Diagnostic Imaging

1.
Computed tomography

Preferred imaging technique

US is of less value because most of the spleen lies between the ribs and is largely hidden from the US beam

2.
Radionuclide scan (indium or gallium)

Can specifically identify an intrasplenic mass as an abscess

Mass

Abdominal Mass in a Neonate
Organ of Origin

Kidney

Gastrointestinal tract
Approach to Diagnostic Imaging

1.
Plain abdominal radiograph

To exclude obstruction of the gastrointestinal tract

2.
Ultrasound

Can detect intrinsic renal masses and hydronephrosis

If US is normal, no further imaging is required

If US detects a mass, further imaging depends on the anatomic location and sonographic characteristics of the lesion
Abdominal Mass in a Child
Organ of Origin

Kidney

Adrenal glands

Pelvic structure
Approach to Diagnostic Imaging

1.
Plain abdominal radiograph

Can detect characteristic calcification associated with neuroblastoma (and its metastases)

2.
Ultrasound

Best initial imaging modality for detecting masses in the kidney, adrenal gland, or genital organs in a child (uses no ionizing radiation)

Can detect appendiceal abscesses or hepatobiliary lesions, the most common causes of gastrointestinal masses that develop after the neonatal period

3.
Excretory urography and voiding cystourethrography

If US shows a cystic renal mass or severe hydronephrosis, these studies can evaluate kidney function, define the bladder anatomy, and confirm or exclude vesicoureteral reflux

4.
Computed tomography

Indicated if US shows a solid mass suggestive of malignancy (to better define the anatomy and any local or metastatic spread)
Diffusely Enlarged Abdomen (No Discrete Mass)
Common Causes

Ascites

Lipodystrophy

Massive peritoneal/retroperitoneal tumor
Approach to Diagnostic Imaging

1.
Computed tomography

Best modality for defining the organ of origin of any mass in the peritoneal or retroperitoneal compartments

In patients with massive ascites, can suggest the origin of the peritoneal fluid by detecting masses, metastases, loculation, and the relative distribution of fluid in the lesser and greater sacs

Adequate US examination is often prevented by gas contained within the stomach, small bowel, and colon
Epigastric Mass
Organ of Origin

Liver

Spleen

Stomach

Duodenum

Pancreas
Approach to Diagnostic Imaging

1.
Computed tomography

Directly images the liver, spleen, gastric wall, and pancreas

Adequate US examination is often prevented by gas contained within the stomach, small bowel, and colon

2.
Upper gastrointestinal series

If there is evidence of gastric outlet obstruction, can evaluate for peptic ulcer or gastric malignancy
Hypogastric Mass
Organ of Origin

Bladder

Colon

Uterus

Ovary
Approach to Diagnostic Imaging

1.
Ultrasound

Preferred initial imaging technique because most masses in this region are related to the pelvic organs

2.
Computed tomography

Indicated to better define the extent of a lesion if a solid mass is detected by US

3.
Barium enema

Indicated if the clinical examination suggests a gastrointestinal tumor as the underlying cause
Left Lower Quadrant Mass
Organ of Origin

Colon
Approach to Diagnostic Imaging

1.
Plain abdominal radiograph

Can demonstrate large bowel obstruction or fecal impaction

2.
Computed tomography

Preferred initial imaging technique for detecting and defining the origin of a palpable mass or the extent of diverticulitis

3.
Barium enema

Can detect free or walled-off perforation or eccentric narrowing of the colonic lumen related to diverticulitis (the most likely clinical diagnosis)
Caveat: If free perforation into the peritoneal cavity is suspected, water-soluble contrast must be used.
Left Upper Quadrant Mass
Organ of Origin

Spleen

Left lobe of the liver

Stomach (gastric outlet obstruction or tumor)

Splenic flexure of the colon

Pancreas

Left kidney

Left adrenal gland
Approach to Diagnostic Imaging

1.
Computed tomography

Directly images the spleen, liver, gastric wall, pancreas, left kidney, and left adrenal gland

Adequate US examination is often precluded by gas contained within the stomach, small bowel, and colon

2.
Upper gastrointestinal series

If there is evidence of gastric outlet obstruction, can evaluate for peptic ulcer or gastric malignancy
Midabdominal Mass
Organ of Origin

Superficial structures

Peritoneal structures

Retroperitoneal structures
Approach to Diagnostic Imaging

1.
Computed tomography

Directly images the organs within all three compartments

Adequate US examination is often prevented by gas contained within the stomach, small bowel, and colon

2.
Ultrasound

Initial modality of choice in an asthenic patient with a pulsating mass suggesting aortic aneurysm
Right Lower Quadrant Mass
Organ of Origin

Gastrointestinal tract

Abscess

Enlarged lymph nodes
Approach to Diagnostic Imaging

1.
Plain abdominal radiograph

Can exclude or confirm bowel obstruction, appendicolith, or fecal impaction

2.
Computed tomography

Can differentiate among such entities as inflammatory bowel disease, abscess, and enlarged lymph nodes
Right Upper Quadrant Mass
Organ of Origin

Right lobe of the liver

Gallbladder

Bile ducts

Right kidney

Right adrenal gland

Hepatic flexure of the colon

Duodenum
Approach to Diagnostic Imaging

1.
Ultrasound

High accuracy for detecting masses involving the gallbladder (acute cholecystitis, hydrops, carcinoma, Courvoisier gallbladder) and bile ducts, as well as diffuse and focal hepatic abnormalities

Good imaging test for detecting renal lesions and differentiating renal cysts from solid tumors or abscesses

2.
Computed tomography

Indicated if there is bile duct dilatation and US fails to show an obstructing mass

Indicated for confirmation and staging if US shows a solid renal mass

Best modality for detecting adrenal masses (metastases, adenoma, carcinoma)

3.
Barium enema or upper gastrointestinal series

Highest accuracy for detecting carcinoma of the hepatic flexure or the duodenum

Esophagus

Achalasia
Presenting Signs and Symptoms

Dysphagia for solids and liquids (typically in persons 20 to 40 years old)

Nocturnal regurgitation of undigested food

Aspiration (and recurrent pneumonia)
Common Causes

Primary (idiopathic)

Malignancy (primary or metastatic)

Central and peripheral neuropathy

Cerebrovascular accident

Postvagotomy syndrome

Chagas disease
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Not sensitive, but may demonstrate characteristic findings such as an absent gastric air bubble and an esophageal air–fluid level

2.
Barium swallow

Dilated esophagus with distal “beak” or “rat-tail” narrowing and an esophageal air–fluid level

Absence of the gastric air bubble

3.
Manometry

Incomplete relaxation of the lower esophageal sphincter

Absent peristalsis in the smooth-muscle portion of the esophagus
Cancer of the Esophagus
Presenting Signs and Symptoms

Progressive dysphagia (first with solids, then liquids)

Pain (substernal or in the back due to local invasion)

Rapid weight loss

Pulmonary aspiration
Risk Factors

Ethanol abuse

Smoking

Lye ingestion and esophageal stricture

Radiation exposure

Head and neck cancer

Achalasia

Barrett’s mucosa

Tylosis
Approach to Diagnostic Imaging

1.
Barium swallow

Preferred initial imaging examination that can detect superficial and early (small) tumors if the double-contrast technique is employed

Cannot identify carcinoma in situ

2.
Esophagoscopy (with biopsy and cytology)

Most sensitive and specific test
Staging

1.
Computed tomography (chest/upper abdomen)

Most effective staging procedure that can determine the potential surgical curability of an esophageal tumor in about 90% of patients

Accuracy of 97% for detecting tracheobronchial invasion and 94% for aortic and pericardial invasion

Demonstration of enlarged mediastinal or subdiaphragmatic lymph nodes is likely to represent involvement by metastatic tumor, although the absence of lymphadenopathy is an unreliable finding (since normal-sized nodes also may harbor metastases)

2.
Endoscopic ultrasound

Superior to CT for evaluating the depth of tumor infiltration within the wall of the esophagus (local invasion) and lymph node involvement

Note: US is not as effective as CT in assessing the extraesophageal spread of tumor, which relates directly to the duration of survival.

Diffuse Esophageal Spasm
Presenting Signs and Symptoms

Intermittent substernal chest pain

Dysphagia for both liquids and solids

Symptoms frequently aggravated by very hot or cold liquids
Approach to Diagnostic Imaging

1.
Barium swallow

“Corkscrew” esophagus with pseudodiverticula

2.
Manometry

Most sensitive and specific description of the spasms

High-amplitude esophageal contractions of long duration with repetitive occurrence
Esophageal Laceration (Mallory-Weiss Syndrome)
Presenting Signs and Symptoms

Repeated vomiting followed by hematemesis (especially in men older than age 50 with history of alcohol abuse)
Approach to Diagnostic Imaging

1.
Endoscopy

Required to demonstrate the superficial lacerations or fissures near the esophagogastric junction (usually not seen on radiographic contrast studies)

Note: In rare cases, an esophagram shows contrast penetration into the wall of the esophagus.

Esophageal Perforation
Presenting Signs and Symptoms

Sudden epigastric pain radiating to the shoulder blades after vomiting, retching, or even hiccups (especially after heavy drinking)

Gravely ill appearance with pallor, sweating, tachycardia, and often shock
Common Causes

Boerhaave’s syndrome

Penetrating trauma

Complication of endoscopy
Approach to Diagnostic Imaging

1.
Plain chest radiograph

Initial imaging study for detecting air dissecting within the mediastinum and soft tissues, often with pleural effusion or hydropneumothorax

2.
Barium swallow

May demonstrate extravasation through a transmural perforation
Caveat: Water-soluble contrast material must be used first (since barium cannot be cleared from the mediastinum); if the patient cannot protect the airway, use iso-osmolar, non-ionic oral contrast material; if no gross extravasation is shown, use barium (a better contrast agent) to exclude a small leak.

3.
Computed tomography

Preferred study for defining the extent of an inflammatory process in the mediastinum secondary to an esophageal perforation
Reflux Esophagitis
Presenting Signs and Symptoms

Heartburn

Dysphagia (due to stricture)

Upper gastrointestinal bleeding (due to esophageal ulceration)
Approach to Diagnostic Imaging

1.
Upper gastrointestinal series

Frequent false-negative findings with gastroesophageal reflux and subtle esophagitis

2.
Endoscopy (with mucosal biopsy)

Preferred study in a patient with active bleeding

Directly detects esophagitis and peptic strictures

May be normal in gastroesophageal reflux
Scleroderma
Presenting Signs and Symptoms

Often asymptomatic

Heartburn and dysphagia (due to reflux esophagitis secondary to incompetence of lower esophageal sphincter)
Approach to Diagnostic Imaging

1.
Barium swallow

Dilated esophagus with absent peristalsis

Widely patent distal esophagus (in the region of the lower esophageal sphincter)

Note: The distal esophagus may be narrowed in chronic disease because of secondary reflux esophagitis. Patients are at very high risk for developing Barrett’s esophagus.

2.
Manometry

Aperistalsis (due to atrophy of esophageal smooth muscle)

Incompetent lower esophageal sphincter (leading to reflux esophagitis and stricture formation)
Varices (Esophageal/Gastric)
Presenting Sign and Symptom

Upper gastrointestinal bleeding
Common Causes

Cirrhosis

Obstruction of the splenic or portal vein (e.g., carcinoma of the pancreas)

Hepatic vein obstruction
Approach to Diagnostic Imaging

1.
Endoscopy

Procedure of choice for acute bleeding

2.
Barium swallow

Can demonstrate characteristic tortuous, beaded filling defects in the distal esophagus and gastric fundus
Interventional Radiologic Alternative

1.
Transjugular intrahepatic portosystemic shunt (TIPS)

An effective and reliable means of lowering portal venous pressure (particularly in patients with acute variceal bleeding unresponsive to sclerotherapy or with chronic variceal bleeding before liver transplantation)

Useful in the treatment of ascites and the Budd-Chiari syndrome

Stomach/Duodenum

Cancer of the Stomach
Presenting Signs and Symptoms

Progressive upper abdominal discomfort

Weight loss, anorexia, nausea, vomiting

Acute or chronic upper gastrointestinal bleeding

Early satiety
Risk Factors

Dietary habits (nitrates, smoked or heavily salted foods)

Atrophic gastritis (pernicious anemia)

Billroth II gastroenterostomy

Adenomatous gastric polyps
Approach to Diagnostic Imaging

1.
Double-contrast upper gastrointestinal series

Preferred initial imaging procedure

Requires meticulous technique to detect small, early lesions

2.
Endoscopy (with biopsy and cytology)

Most sensitive and specific test (sensitivity of up to 98% if multiple biopsy specimens are taken from a suspicious lesion to decrease the risk of sampling error)

Much less accurate in detecting scirrhous lesions
Staging

1.
Computed tomography

Most effective staging procedure for demonstrating the presence and extent of extragastric spread of tumor

More accurate in detecting distant lymphadenopathy than local lymph node enlargement
Peptic Ulcer Disease
Presenting Signs and Symptoms

Burning epigastric pain (90 to 180 minutes after meals, often nocturnal, relieved by food)

Chronic, recurring course

Gastrointestinal bleeding (melena, hematemesis, hematochezia)

Gastric outlet obstruction (about 5%)

Acute abdomen (if free perforation)
Approach to Diagnostic Imaging

1.
Upper gastrointestinal series

Signs of benignity include a smooth ulcer mound with tapering edges, an edematous ulcer collar with overhanging mucosal edge, projection of the ulcer beyond the expected lumen, and thin radiating folds extending into the crater

Size, depth, number, and location of the ulcer are of no diagnostic value in differentiating benign from malignant (except for ulcers in the cardia, which are virtually always malignant)

2.
Endoscopy

May be preferable for suspected gastric ulcer, since biopsy can be performed to exclude malignancy (1% of radiographically benign-appearing ulcers prove to be malignant)

More reliable for detecting acute ulcer craters in a scarred duodenum

Fails to detect 5–10% of peptic ulcers
Caveat: Once the diagnosis of benign peptic disease has been made, recurrences should be treated symptomatically; there is no need to repeat an imaging procedure with each recurrence.
Zollinger-Ellison Syndrome
Presenting Signs and Symptoms

Refractory peptic ulcer disease (after medical therapy or surgery)

Gastric hypersecretion

Diarrhea

Substantially elevated serum gastrin
Common Cause

Gastrinoma (usually of the pancreas)
Approach to Diagnostic Imaging

1.
Computed tomography

Preferred study for detecting the underlying pancreatic tumor, which typically is small, often multiple, and intensely enhancing

2.
Upper gastrointestinal series

May show characteristic pattern of markedly thickened gastric folds and ulcers distal to the duodenal bulb (seen in about half the patients)
Pyloric Stenosis
Presenting Signs and Symptoms

Projectile, nonbilious vomiting

Typically occurs in 2- to 6-week-old males

Palpable midabdominal mass (“pyloric olive”)
Approach to Diagnostic Imaging

1.
Ultrasound

Preferred imaging technique with almost 100% sensitivity

Demonstrates characteristic “doughnut” or “target” lesion (hypoechoic wall surrounding echogenic mucosa) on transverse view and elongated pyloric channel on longitudinal scan

2.
Upper gastrointestinal series

Indicated if US is negative and vomiting persists

Small Bowel

Small Bowel Obstruction
Presenting Signs and Symptoms

Crampy abdominal pain and bloating

Nausea and vomiting

Abdominal tenderness and peritoneal signs

Abdominal distension

Increased high-pitched bowel sounds
Common Causes

Adhesions

Hernia

Tumor

Intussusception

Extrinsic mass
Approach to Diagnostic Imaging

1.
Plain abdominal radiograph

Change in caliber of air-filled bowel (dilated proximally, collapsed distally)

String-of-beads sign on upright films

2.
Computed tomography (optional)

Only required to confirm an obstruction if plain films are equivocal or if it is necessary to show the precise site of obstruction

Much more accurate than small bowel follow-through with oral contrast agent for demonstrating the underlying cause of the obstruction
Caveat: If CT scan is inconclusive and an oral contrast examination is needed to confirm an obstruction, use barium, NOT water-soluble agents, for small bowel follow-through (hyperosmolar contrast draws fluid into the bowel, diluting the opaque material and making it difficult to clearly show the site of obstruction). Before barium is given by mouth, it is necessary to exclude a large bowel obstruction (use water-soluble contrast).
Intussusception
Presenting Signs and Symptoms
CHILDREN

Colicky abdominal pain that waxes and wanes

Vomiting, diarrhea, and other gastrointestinal symptoms in greater than 90% of patients

Palpable abdominal mass in about 50% of patients

Heme-positive or “currant jelly” stools

Accounts for 80–90% of bowel obstruction in infants and children

Peak incidence at 3 to 9 months (40%); 50% of cases occur at less than 1 year and 75% at less than 2 years; only 10% occur after age 3
ADULTS

General signs and symptoms of bowel obstruction

Often chronic and relapsing (diagnosis suggested by recurrent episodes of subacute obstruction and by variability of abdominal signs)

Palpable mass may be present during the height of an attack and disappear completely when the patient is reexamined several hours later, by which time the symptoms have resolved

Combination of an abdominal mass and the passage of blood per rectum suggests the diagnosis
Common Causes
CHILDREN

Idiopathic in 95% (most commonly involves ileocolic region); mucosal edema and lymphoid hyperplasia often follow viral gastroenteritis

Lead point in 5% (may be Meckel’s diverticulum, lymphoma, duplication cyst, enterogenous cyst, inspissated meconium, Henoch-Schönlein purpura)
ADULTS

Specific cause in 80% (benign tumor in 33%, malignant tumor in 20%; also Meckel’s diverticulum, adhesions, sprue, scleroderma)

Idiopathic in 20%
Approach to Diagnostic Imaging

1.
Plain abdominal radiograph

Normal in 25%

Small bowel obstruction in 25%

Abdominal soft-tissue mass highlighted by bowel gas (crescent sign)

2.
Contrast enema

Characteristic “coiled-spring” appearance

Abrupt, beak-like narrowing of the contrast column demonstrating a central channel

Barium enema can be employed both diagnostically and therapeutically in a medically stable child. Surgical consultation is needed prior to the study in case reduction is unsuccessful or a complication occurs.

Water-soluble contrast or air can also be employed both diagnostically and therapeutically
Caveat: Reduction of an intussusception should not be attempted in adults.

3.
Ultrasound

Shows a target or doughnut appearance on transverse scans and a “pseudokidney” sign on longitudinal scans

Most useful when the clinical suspicion is low and there is reluctance to perform a barium enema, or when a child is extremely ill and surgery is contemplated
Caveat: US is not recommended in adults.

4.
Computed tomography

Used when evaluating a patient for suspected small bowel obstruction

May demonstrate a target sign, a sausage-shaped mass with alternating areas of low and high attenuation, or a reniform mass
Gastroenteritis
Presenting Signs and Symptoms

Anorexia, nausea, vomiting

Diarrhea of variable severity

Abdominal discomfort

Low-grade fever

Travel history
Common Causes

Bacterial, viral, or parasitic infection

Enterotoxins (bacterial)

Chemical toxins (mushrooms, shellfish, contaminated food)

Food allergies
Approach to Diagnostic Imaging

No imaging studies are required unless examinations of stool specimens and stool cultures are negative and symptoms persist
Meckel’s Diverticulum
Presenting Signs and Symptoms

Rectal bleeding (ulcerating gastric mucosa within a diverticulum)

Bowel obstruction
Common Cause

Omphalomesenteric duct remnant in distal small bowel within 100 cm of ileocecal valve
Approach to Diagnostic Imaging

1.
Radionuclide scan (technetium)

Focal right lower quadrant accumulation of isotope by gastric mucosa lining the diverticulum

Note: There is generally no indication for any other imaging study.

Colon

Antibiotic-Associated Colitis
Presenting Signs and Symptoms

Range from transient mild diarrhea to a severe colitis that develops during a course of antibiotic therapy or up to 6 weeks after treatment has ended
Common Causes

Toxin-producing strains of Clostridium difficile (especially after clindamycin, ampicillin, cephalosporins, or aminoglycosides)
Approach to Diagnostic Imaging

1.
Sigmoidoscopy

Directly shows characteristic pseudomembranes

2.
Computed tomography

Demonstrates mural thickening of a hypodense colon wall

Because symptoms may be misleading, may suggest the correct diagnosis before it is suspected clinically
Caveat: Although barium enema may show the extent of mucosal abnormalities, it is contraindicated in active or severe cases because of the risk of perforation.
Appendicitis
Presenting Signs and Symptoms

Sudden onset of epigastric or periumbilical pain that shifts to the right lower quadrant

Rebound tenderness

Low-grade fever

Leukocytosis
Approach to Diagnostic Imaging

1.
Plain abdominal radiograph

Low sensitivity and specificity, but may detect a calcified appendicolith (about 15%), which is strongly suggestive of impending perforation

2.
Computed tomography

“Gold standard” for the noninvasive diagnosis of appendicitis

With contrast enhancement, can make the diagnosis by identifying an abnormal appendix (dilated with a thickened, circumferentially enhancing wall) or pericecal inflammation and/or abscess associated with an appendicolith

More sensitive than US for revealing the normal appendix, a critical observation, since definitive exclusion of appendicitis requires visualization of the normal appendix in its entirety

Note: Helical CT imaging is increasingly being used as an alternative to sonography for diagnosing possible appendicitis in nonpregnant patients, in grossly obese or large body habitus patients, in patients with severe abdominal pain, and in patients in whom sonography is inconclusive.

Highly accurate for showing unrelated intraabdominal disease that may mimic appendicitis and explain the patient’s clinical presentation

Can be used to guide percutaneous abscess drainage

Detects appendicolith in about 30% of patients

3.
Ultrasound

Highly sensitive and specific without need for ionizing radiation (especially in children and women during childbearing years)

Disadvantages include high operator dependence and limitations due to obesity, large amounts of intestinal gas, and patients with retrocecal appendix or severe abdominal pain
Cancer of the Colon
Presenting Signs and Symptoms

Bright red rectal bleeding, altered bowel habits, abdominal or back pain (left-sided lesions)

Iron deficiency anemia, occult blood in the stool, weight loss (right-sided lesions)
Risk Factors

Diet (low in fiber, high in animal fat)

Personal or family history of colorectal polyps

Familial polyposis syndrome

Family history of colorectal cancer

Ulcerative colitis

Crohn’s colitis

Hypercholesterolemia
Approach to Diagnostic Imaging

1.
Double-contrast barium enema

Preferred initial imaging procedure

Requires meticulous technique to detect small, early lesions

2.
Colonoscopy/flexible sigmoidoscopy

Slightly more sensitive and specific than barium enema, but associated with considerably higher cost and complications

Blind spots behind folds or around the flexures
Staging

1.
Computed tomography

Most effective staging procedure for demonstrating the presence and extent of extracolonic spread of tumor

2.
Transrectal ultrasound

Most accurate imaging method for staging local rectal cancer (can assess the depth of invasion within the bowel wall and can suggest the presence of tumor in adjacent normal-sized lymph nodes)
Screening

Indications for screening

General population: after age 50, every 5 years by either Double-contrast barium enema Colonoscopy

Positive family history or genetic screening: after age 30, every 2 years

Familial adenomatous polyposis: yearly double-contrast barium enema from puberty to age 22 (then optional colectomy and ileocecal anastomosis)
Crohn’s Disease
Presenting Signs and Symptoms

Abdominal pain

Fever

Anorexia and weight loss

Diarrhea (often without blood)

Fatigue

Right lower quadrant mass or fullness

Anorectal fissures, fistulas, abscesses (may be acute ileitis mimicking appendicitis or obstruction)

Complications (bowel obstruction, internal fistulas, and bile salt malabsorption leading to gallstones or oxalate kidney stones)
Approach to Diagnostic Imaging

1.
Barium enema

Demonstrates involvement of the terminal ileum and variable amounts of colon and more proximal small bowel disease characterized by nodularity and thickening of folds, aphthous ulcers, narrowing and rigidity, cobblestoning, string sign, skip areas, and fistulas

2.
Small bowel examination

Required if the terminal ileum is not visualized because of an inability to reflux barium through a competent ileocecal valve

3.
Computed tomography

In addition to showing thickening of the bowel wall, best modality for demonstrating mesenteric and extraintestinal extent of disease and abscess formation
Ulcerative Colitis
Presenting Signs and Symptoms

Bloody diarrhea

Mucus in stool

Abdominal pain (ranging from mild lower abdominal cramping to severe peritoneal signs)

Fever

Complications (toxic megacolon, colon perforation, hemorrhage, increased risk of cancer)
Approach to Diagnostic Imaging

1.
Sigmoidoscopy

Direct and immediate indication of the activity of the disease process

2.
Plain abdominal radiograph

Must exclude toxic megacolon before attempting a barium enema

Distal extent of formed fecal residue gives a good indication (although not absolute) of the proximal extent of the colitis (may overestimate but does not underestimate extent of disease)

3.
Barium enema or colonoscopy

To determine the full extent of the disease and detect the development of malignancy in patients with chronic disease
Diverticulitis
Presenting Signs and Symptoms

Abdominal pain and tenderness (typically left lower quadrant)

Altered bowel habits

Fever

Leukocytosis
Approach to Diagnostic Imaging

1.
Computed tomography

Demonstrates pericolonic fluid or a gas collection (abscess), usually with nonspecific thickening of the colon wall, narrowing of the colonic lumen, and inflammatory stranding in adjacent fat

Can be used to guide percutaneous abscess drainage

2.
Barium enema

May demonstrate extravasation of contrast through a diverticular perforation or a pericolic soft-tissue mass (walled-off perforation) causing eccentric narrowing of the colon
Caveat: If free perforation into the peritoneal cavity is suspected, water-soluble contrast must be used.

Note: Plain abdominal radiographs are not needed unless there are peritoneal signs suggesting free perforation.

Diverticulosis
Presenting Signs and Symptoms

Often asymptomatic

Unexplained lower gastrointestinal bleeding

Recurrent left lower quadrant pain

Alternating constipation and diarrhea
Approach to Diagnostic Imaging

1.
Barium enema

Contrast-filled outpouchings from the colon without evidence of extravasation or mass effect
Caveat: It can be extremely difficult to exclude a polyp or carcinoma in a segment of colon that is severely involved by diverticular disease.
Fecal Incontinence
Presenting Signs and Symptoms

Involuntary passage of stool through the anus
Common Causes

Rectal prolapse

Anorectal trauma

Abnormal rectal compliance (inflammatory bowel disease, radiation proctitis, rectal ischemia)

Irritable bowel syndrome

Polyneuropathies

CNS disorders (dementia, stroke, brain tumor, multiple sclerosis, spinal cord lesion)
Approach to Diagnostic Imaging

1.
Manometry

Anal manometry is indicated to measure basal and squeeze pressures in the anal canal

Rectal balloon manometry is performed to measure rectal sensation, rectal compliance, anorectal inhibitory reflex, and anorectal contractile response

2.
Defecography

Assesses the anorectal angle, perineal descent, and puborectalis muscle function

3.
Anal endosonography

Evaluates the integrity of the sphincter

4.
Magnetic resonance imaging

Evaluates the integrity of the sphincter
Hemorrhoids
Presenting Signs and Symptoms

Bleeding (typically after defecation and noted on the toilet tissue)

Pain (if ulcerated, thrombosed, or strangulated)

Protrusion (may regress spontaneously or be reduced manually)
Approach to Diagnostic Imaging

Imaging is not indicated

Barium enema examination should only be performed if there is clinical evidence of a more serious cause of rectal bleeding (hemorrhoidal bleeding rarely leads to anemia or an acute exsanguinating hemorrhage)
Hirschsprung’s Disease
Presenting Signs and Symptoms

Constipation in the first month of life due to absence of ganglion cells in the myenteric plexus of the rectum and distal colon
Approach to Diagnostic Imaging

1.
Plain abdominal radiograph

Demonstrates distal bowel obstruction with a large amount of retained feces

Notes: There is no indication for an upper gastrointestinal series.

2.
Contrast enema

Shows precise level of colonic obstruction

Note: A normal contrast enema examination does not entirely exclude short-segment Hirschsprung’s disease of the anus. An anorectal biopsy may be needed if the index of suspicion remains high.

Irritable Bowel Syndrome
Presenting Signs and Symptoms

Symptoms triggered by stress or ingestion of foods

Pasty, ribbon-like, or pencil-thin stools

Mucus (not blood) in the stools

Onset often before age 30 (especially in women)
Common Variants

Spastic colon (chronic abdominal pain and constipation)

Alternating constipation and diarrhea

Chronic painless diarrhea
Approach to Diagnostic Imaging

1.
Barium enema

Primarily performed to exclude inflammatory bowel disease or malignancy
Large Bowel Obstruction
Presenting Signs and Symptoms

Gradually increasing constipation leading to obstipation and abdominal distension

Lower abdominal cramps unproductive of feces

Vomiting (if incompetent ileocecal valve)
Common Causes

Malignant tumor

Inflammatory stricture (e.g., diverticulitis)

Volvulus

Hernia

Extrinsic lesion
Approach to Diagnostic Imaging

1.
Plain abdominal radiograph

Change in caliber of gas-filled colon at the site of obstruction

Lateral decubitus view (right side down) can allow gas to rise into the sigmoid and rectum and differentiate between colonic ileus (rectum/ sigmoid distended) and mechanical obstruction (rectum/sigmoid remain collapsed)

2.
Barium enema

Shows site and character of the obstruction

Notes: In patients with acute obstruction, water-soluble contrast material should be used (due to the danger of barium inspissation proximal to a colonic obstruction; if there is an adynamic ileus, retained barium will remain for a prolonged period and interfere with other imaging studies).
In patients with intussusception or volvulus, a barium enema may be therapeutic as well as diagnostic.
If endoscopy is to be performed, it should precede the barium enema.

3.
Computed tomography

Especially valuable in patients without a history of surgery who have systemic signs suggesting infection, bowel infarction, or an associated palpable mass

Can demonstrate diverticulitis or appendicitis as the cause of an obstruction

Note: Some radiologists recommend CT as the initial study (instead of barium enema) as a more direct means for establishing the diagnosis of large bowel obstruction.

Liver/Biliary Tract

Biliary Obstruction
Presenting Signs and Symptoms

Yellowing of skin and sclera

Abnormal liver enzymes

Dark urine and pale, clay-colored stools
Common Causes

Common duct stone

Pancreatic carcinoma

Cholangiocarcinoma

Obstructing metastases
Approach to Diagnostic Imaging

1.
Computed tomography or ultrasound

Demonstrates bile duct dilatation indicative of obstruction

CT is highly accurate for showing disease in adjacent structures (liver, porta hepatis, pancreas, adrenals, retroperitoneum)

Neither CT nor US can reliably exclude a common duct stone (sensitivity less than 80–85%), but no further imaging tests are needed when choledocholithiasis is diagnosed by these modalities

2.
Percutaneous transhepatic cholangiography

Invasive procedure of choice for defining the precise site of obstruction in a dilated biliary system

Superior to ERCP for diagnostic and therapeutic maneuvers (e.g., balloon dilatation of strictures, brush biopsy, stone removal, insertion of an endoprosthesis) that involve lesions above the porta hepatis (intrahepatic)

3.
Endoscopic retrograde cholangiopancreatography

Invasive procedure of choice if the bile ducts are not dilated (e.g., sclerosing cholangitis) and if the patient has abnormal bleeding parameters

Permits therapeutic procedures (e.g., sphincterotomy, stone extraction, brush biopsy of strictures, and insertion of an endoprosthesis) at the time of initial diagnosis

Highly operator-dependent (unsuccessful duct cannulation in 3–9% of patients) and substantial morbidity and mortality (7% and 1%, respectively)

Limited or no opacification of ducts proximal to a severe or complete obstruction

Routine sedation required

4.
Magnetic resonance cholangiopancreatography

Preferred diagnostic approach if ERCP is unsuccessful, as in patients with surgical bypass procedures (Billroth II anastomosis, hepatojejunostomy), or those with acute pancreatitis (increased risk of complications from ERCP)
Cholecystitis (Acute)
Presenting Signs and Symptoms

Acute colicky right upper quadrant pain and tenderness

Fever

Nausea and vomiting

Mild jaundice (occasionally)

Mild leukocytosis

Mild elevation of serum bilirubin, alkaline phosphatase, and serum glutamic oxaloacetic transaminase (SGOT)
Approach to Diagnostic Imaging

1.
Ultrasound

May demonstrate gallstones, thickening of the gallbladder wall, pericholecystic fluid, and point tenderness directly over the gallbladder (sonographic Murphy’s sign)

Permits detection of abnormalities of the liver, pancreas, or kidneys that may produce a clinical appearance mimicking acute cholecystitis (only about one-third of patients with symptoms of acute cholecystitis actually have that condition)

Indicated if there is strong clinical evidence of acalculous nonobstructing acute cholecystitis in the face of a negative cholescintigram

2.
Cholescintigraphy (technetium-IDA derivatives)

Visualized gallbladder excludes acute cholecystitis (specificity 95%) by indicating patency of the cystic duct

Nonvisualized gallbladder after 4 hours strongly suggests acute cholecystitis (sensitivity 98%) if the patient is not a chronic alcoholic or undergoing total parenteral nutrition

Note: With the use of morphine augmentation, the time required to perform a radionuclide study is reduced to 1.5 hours.

3.
Magnetic resonance cholangiopancreatography

Indicated when US findings are not diagnostic

US is superior to MRCP for evaluating gallbladder wall thickness, but MRCP is better for depicting the cystic duct and obstructing calculi in the gallbladder neck
Cholecystitis (Chronic)
Presenting Signs and Symptoms

Recurrent right upper quadrant pain and biliary colic
Approach to Diagnostic Imaging

1.
Ultrasound

Preferred initial imaging technique

Demonstrates high-amplitude echo in the gallbladder lumen (reflecting from the surface of a gallstone) or in the gallbladder fossa (if the lumen is completely filled with calculi) associated with posterior acoustic shadowing

2.
Cholescintigraphy

Cholecystokinin (CCK)-enhanced study can evaluate the ejection fraction of the gallbladder, which is diminished in chronic cholecystitis
Caveat: Plain abdominal radiographs are of limited value, since only about 20% of gallstones are radiopaque.
Fatty Liver
Presenting Signs and Symptoms

Asymptomatic hepatomegaly

Possible right upper quadrant pain, tenderness, or jaundice
Common Causes

Cirrhosis

Chemicals/drugs: (e.g., alcohol, steroids, tetracyclines, carbon tetrachloride, methotrexate)

Obesity

Malnutrition

Hyperalimentation

Cystic fibrosis
Approach to Diagnostic Imaging

1.
Computed tomography

Noncontrast CT demonstrates diffuse low attenuation of the liver parenchyma (lower than that of the spleen)

Focal fatty infiltration may simulate a liver tumor (although vessels typically run their normal course through the area of involvement)

2.
Magnetic resonance imaging

May be needed to exclude a hepatic mass when focal fat deposition is seen on CT or US in a patient with a malignancy
Hemangioma of the Liver
Presenting Signs and Symptoms

Asymptomatic and discovered incidentally on US, CT, or MRI
Approach to Diagnostic Imaging

1.
Ultrasound, computed tomography, magnetic resonance imaging, or radionuclide scan

US may show a typically well-defined, hyperechoic mass

CT may demonstrate a low-attenuation mass with well-defined borders on nonenhanced scans; after contrast injection, there may be characteristic filling in of the lesion in a centripetal fashion (entire mass becomes isodense)

MRI may show marked hyperintensity of the mass on T2-weighted images with an enhancement pattern similar to that on CT

Radionuclide scan using tagged red blood cells shows prolonged activity within the lesion on delayed images (preferred imaging study if the lesion is >3 cm)

Notes: If the lesion has a characteristic appearance, it should be left alone with no further imaging studies.
If the patient has a known malignancy, abnormal liver function tests, or symptoms, more than one imaging study should be performed.

Portal Hypertension
Presenting Signs and Symptoms

Bleeding esophageal varices

Ascites and edema

Encephalopathy

Nonspecific constitutional symptoms of fatigue, lethargy, anorexia
Common Causes

Cirrhosis

Obstruction of the extrahepatic portal vein (e.g., carcinoma of the pancreas)

Hepatic vein obstruction
Approach to Diagnostic Imaging

1.
Color and duplex Doppler ultrasound

Demonstrates patency and direction of blood flow in hepatic veins, portal veins, and collateral venous channels

2.
Computed tomography

Documents presence of venous collaterals in the mesentery and retroperitoneum

Can better define the cause of extrahepatic portal vein thrombosis and any propagation into the liver

3.
Magnetic resonance angiography

Indicated if intravenous contrast material may not be given or if CT is inconclusive
Hepatocellular Carcinoma (Hepatoma)
Presenting Signs and Symptoms

Right upper quadrant pain

Tender hepatomegaly

Unexplained deterioration in a previously stable patient with cirrhosis

Weight loss

Fever (may simulate infection)

Elevated serum a-fetoprotein (in 60–90%)
Risk Factors

Chronic hepatitis B infection

Cirrhosis (especially alcohol-induced)

Hemochromatosis

Thorotrast exposure (radiographic contrast agent used from about 1940 to 1960)
Approach to Diagnostic Imaging

1.
Computed tomography

Preferred initial imaging technique for demonstrating any of the three major patterns (diffuse infiltrative, solitary massive, and multinodular)

Multiphasic helical CT scanning (including hepatic arterial phase) is needed to establish the diagnosis of this vascular tumor

2.
Ultrasound

Used in high-prevalence areas (e.g., Japan) for screening of chronic hepatitis B virus carriers

3.
Magnetic resonance imaging

May permit a specific diagnosis of hepatocellular carcinoma by demonstrating

1.
characteristic capsule of compressed liver or scar tissue,

2.
accumulation of fat within the tumor, and

3.
propensity of tumor spread into the hepatic and portal veins

Should be performed during the arterial phase following gadolinium administration
Liver Metastases
Presenting Signs and Symptoms

Usually asymptomatic

May have nonspecific weight loss, anorexia, fever, weakness

Hepatomegaly (hard and often tender)

Ascites

Jaundice
Common Primary Tumors

Gastrointestinal tract (colon, pancreas, stomach)

Lung

Breast

Lymphoma

Melanoma
Approach to Diagnostic Imaging

1.
Computed tomography

Sensitive screening technique that is preferred to MRI if there is also a need to assess possible metastases in the adrenal glands, retroperitoneum, and other abdominal organs

Permits fine-needle aspiration biopsy for cytology to provide a definitive diagnosis

2.
Magnetic resonance imaging

Sensitive technique for detecting liver metastases

Generally indicated in patients who cannot receive intravenous iodinated contrast or who are being considered for partial hepatectomy

Improved sensitivity with the use of contrast agents containing iron or manganese

3.
Ultrasound

Less sensitive than MRI or CT, but is rapid and inexpensive and reliably identifies the majority of patients with hepatic metastases
Caveat: Radionuclide scan is less sensitive than other methods for detecting liver metastases and thus is not indicated for routine screening.

Pancreas

Pancreatitis (Acute)
Presenting Signs and Symptoms

Steady, boring midepigastric pain radiating straight through to the back

Elevated serum amylase and lipase
Common Causes

Biliary tract disease (e.g., stones)

Alcoholism

Drugs

Infection (e.g., mumps)

Hyperlipidemia

ERCP

Neoplasm

Surgery or trauma
Approach to Diagnostic Imaging

1.
Computed tomography

Imaging procedure of choice for demonstrating focal or diffuse enlargement of the gland and indistinctness of its margins

Superior to US for showing extrapancreatic spread of inflammation and edema and for detecting gas within a pancreatic fluid collection (highly suggestive of abscess)

Can also be used to suggest the prognosis

2.
Ultrasound

In addition to demonstrating symmetric enlargement of a relatively sonolucent gland, may show cholelithiasis, an important underlying cause of acute pancreatitis

Frequent occurrence of adynamic ileus with excessive intestinal gas may prevent adequate visualization of the gland

Useful for follow-up of specific abnormalities (e.g., fluid collections)
Caveat: Although plain abdominal radiographs are abnormal in 50% of patients, they usually show only generalized or localized ileus that is not specific for pancreatitis.
Pancreatitis (Chronic)
Presenting Signs and Symptoms

Midepigastric pain

Weight loss, steatorrhea, and other signs and symptoms of malabsorption
Common Causes

Alcoholism

Hereditary pancreatitis

Hyperparathyroidism

Obstruction of main pancreatic duct (stricture, stones, cancer)
Approach to Diagnostic Imaging

1.
Plain abdominal radiograph

Demonstrates virtually pathognomonic pancreatic calcifications in 30–60% of patients

2.
Computed tomography or ultrasound

Shows enlargement or atrophy of the gland, dilatation of the pancreatic duct, and pseudocyst formation

CT is more accurate in demonstrating the focal superimposition of a malignant mass, and is not adversely affected by the large amounts of intestinal gas that may accompany an acute exacerbation of inflammatory disease

3.
Endoscopic retrograde cholangiopancreatography

Shows irregular dilatation of the main pancreatic duct and pruning of its branches
Cancer of the Pancreas
Presenting Signs and Symptoms

Abdominal and back pain

Weight loss and anorexia

Painless jaundice

Enlarged, palpable gallbladder (Courvoisier’s sign)
Approach to Diagnostic Imaging

1.
Computed tomography

Shows a mass with (or without) obstructive dilatation of the pancreatic or bile duct or both

Most effective modality for demonstrating lesions in the tail and for defining the extent of tumor spread (may prevent needless surgery in patients with nonresectable lesions)

2.
Ultrasound

Useful imaging test (shows abnormalities in about 75% of patients) but may fail to detect small lesions in the body and tail

3.
Endoscopic retrograde cholangiopancreatography

Most sensitive test for tumors of the pancreatic head (deformity/stricture of the bile duct)

Indicated if clinical suspicion remains high in the face of normal CT and US examinations

4.
Magnetic resonance imaging (with MRCP)

May be helpful if other tests are inconclusive
Interventional Radiologic Alternatives

1.
Percutaneous fine-needle aspiration (under CT or US guidance)

Often provides a precise histologic diagnosis

2.
Percutaneous stent placement for biliary drainage

May be performed using either ERCP or PTHC
Trauma (Blunt Abdominal)
Approach to Diagnostic Imaging

1.
Plain abdominal and chest radiographs

Neither sensitive nor specific, but inexpensive and rapidly available studies that can direct attention to specific organ injuries

SPLEEN

Fractures of lower left ribs

Elevation of left hemidiaphragm

Left pleural effusion

Displacement of gastric air bubble

Irregular splenic outline

LIVER

Fractures of right lower ribs

Displacement of hepatic flexure

Irregular/enlarged hepatic outline

RETROPERITONEUM

Loss of psoas or renal shadow

Free retroperitoneal gas

Fracture of lumbar transverse process

DIAPHRAGM

Herniation of abdominal contents into chest

Abnormal position of nasogastric tube

Elevation and loss of definition of hemidiaphragm

Nonspecific pleural effusion and atelectasis

2.
Computed tomography

Highest sensitivity and specificity for detecting injuries to the liver, spleen, kidneys, and retroperitoneum

3.
Radionuclide scan or ultrasound

Only indicated if CT examination of the liver and spleen is ambiguous because of surgical clip artifacts or motion (or if an allergy to intravenous contrast precludes an enhanced CT study)

4.
Arteriography

Only indicated if both CT and radionuclide scan are equivocal (especially valuable as both a diagnostic and therapeutic tool in patients with pelvic ring disruption who have evidence of severe bleeding)
Caveat: Although diagnostic peritoneal lavage is traditionally the generally accepted standard for the diagnosis of possible abdominal injury, it has been replaced in most centers by CT. Diagnostic peritoneal lavage can yield false-negative results in injuries to retroperitoneal structures (e.g., kidneys, pancreas, duodenum) or the diaphragm. In addition, a positive peritoneal lavage occurs in up to 25% of patients with trivial injuries who do not require laparotomy, and may occur in patients with pelvic fractures or as a result of a traumatic peritoneal tap.
CHAPTER 4. URINARY
What to Order When

CHAPTER 4. URINARY

N. Reed Dunnick

SIGNS AND SYMPTOMS

Dysuria
Common Causes

Urethritis (infection, catheters)

Cystitis (infection, radiation, chemicals, catheters, stones)

Prostatitis

Bladder tumor

Functional bladder syndrome
Approach to Diagnostic Imaging
Caveat: In most cases, the cause of dysuria is evident from clinical examination and urinalysis, and no imaging procedures are necessary.

1.
Excretory urography or voiding cystourethrography

Can demonstrate diffuse, irregular thickening of the bladder wall in inflammatory disease, as well as a lucent filling defect resulting from a bladder stone or tumor
Hematuria (Painless)
Common Causes

Neoplasm (kidney, ureter, bladder, urethra)

Glomerulonephritis

Vascular abnormality (aneurysm, malformation, arterial or venous occlusion)

Papillary necrosis

Urolithiasis
Approach to Diagnostic Imaging

1.
Computed tomography

More sensitive than US or excretory urography for detecting renal masses

If combined with an unenhanced examination, will also detect urinary tract calculi

2.
Ultrasound

Relatively efficient imaging technique for detecting neoplastic renal masses and vascular anomalies

3.
Excretory urography

Excellent for detecting stones and papillary necrosis
Caveat: Excretory urography cannot exclude bladder or urethral pathology.

4.
Cystoscopy

Required in any adult with unexplained hematuria because a normal US examination, cystogram, or excretory urogram does not exclude a bladder tumor or cystitis.
Hematuria (Painful)
Common Causes

Ureteral calculus

Trauma

Infection (especially cystitis or urethritis)
Approach to Diagnostic Imaging

1.
Computed tomography (unenhanced)

Can detect even poorly opaque stones (e.g., uric acid calculi)

Can detect dilatation of the collecting system proximal to an obstructing stone

Can detect secondary signs of ureteral obstruction such as perinephric stranding or extravasation

Presence of tissue (edematous ureter) surrounding a calcification (rim sign) can differentiate a ureteral calculus from a phlebolith or other extraurinary calcification

Stones larger than 5 mm may require endoscopic removal

Can detect extraurinary cause of abdominal pain such as cholelithiasis and appendicitis

May be used in patients in whom intravascular contrast material is contraindicated

2.
Ultrasound

Can demonstrate the presence and degree of ureteral dilatation proximal to an impacted stone

Can demonstrate a stone as an echogenic focus with acoustic shadowing in the patient with a nonopaque, completely obstructing stone causing loss of ipsilateral kidney function

Transvaginal US may be used to increase the sensitivity for detection of distal ureteral stones

Ureteral stones may be obscured by bowel gas

US may be the procedure of choice for pregnant patients

3.
Excretory urography

Provides a broad range of morphologic and functional information concerning all portions of the urinary tract

Can define the site of an impacted ureteral stone and the degree of resulting ureteral obstruction, as well as post-traumatic extravasation of contrast material from the urinary tract

Note: If there is complete ureteral obstruction, the excretory urogram may show nonvisualization of the ipsilateral kidney or a prolonged nephrogram with lack of filling of the ureter so that it may be impossible to determine the site of the impacted stone.

Renal Failure (Acute)
Presenting Signs and Symptoms

Rapid, steadily increasing azotemia, with or without oliguria
Common Causes
PRERENAL

Hypovolemia (diarrhea, vomiting, hemorrhage, overdiuresis, pancreatitis, peritonitis)

Vasodilatation (sepsis, drugs, anaphylaxis)

Cardiac (congestive heart failure, myocardial infarction, cardiac tamponade)

Renal hypoperfusion (renal artery obstruction)
RENAL

Acute tubular injury (ischemia, toxins, hemoglobinuria, myoglobinuria, radiocontrast agents)

Acute glomerulonephritis

Acute tubular nephritis (drug reaction, pyelonephritis, papillary necrosis)

Precipitation of substances within the kidney (calcium, urates, myeloma protein)

Arterial or venous obstruction

Disseminated intravascular coagulopathy with cortical necrosis
POSTRENAL

Calculi

Prostatism

Neoplasm (bladder, pelvic, retroperitoneal)

Retroperitoneal fibrosis

Urethral or bladder neck obstruction
Approach to Diagnostic Imaging

1.
Ultrasound

Imaging procedure of choice for assessing renal size, identifying renal parenchymal disease (diffuse increase in echogenicity with loss of corticomedullary differentiation), and excluding hydronephrosis (postrenal cause)

Note: In patients with acute renal failure and large (>12 cm) or normal-sized kidneys, biopsy is often required for definitive diagnosis of renal parenchymal disease; patients with small (<9 cm) kidneys usually have irreversible end-stage renal disease and do not benefit from biopsy.

If a vascular cause is suggested clinically, color Doppler studies may demonstrate patency or occlusion of the renal artery or vein. If this is unsuccessful, radionuclide renal scan or magnetic resonance imaging can show these vessels.
Caveat: Although arteriography and venography are more definitive tests for vascular occlusion, some physicians prefer not to use radiographic contrast agents in patients with acute renal failure.
Renal Failure (Chronic)
Presenting Signs and Symptoms

Irreversible loss of renal function (uremia)

Neuromuscular (peripheral neuropathy, muscle cramps, convulsions, encephalopathy)

Gastrointestinal (anorexia, nausea and vomiting, peptic ulcer, unpleasant taste in the mouth)

Cardiopulmonary (congestive heart failure, hypertension, pericarditis, pleural effusion)

Skin (uremic frost, pruritus)

Secondary hyperparathyroidism
Common Causes

Diabetic nephropathy

Hypertension

Glomerulonephritis

Polycystic kidney disease (autosomal dominant)
Approach to Diagnostic Imaging

1.
Ultrasound

Imaging procedure of choice for assessing kidney size (usually small kidneys in chronic renal failure), as well as detecting hydronephrosis secondary to obstruction (especially in patients with risk factors such as known or suspected pelvic malignancy, or bladder outlet obstruction).

DISORDERS

Kidney

Inflammatory

Renal Abscess
Presenting Signs and Symptoms

Fever, leukocytosis, and flank pain

Frequently, a history of prior antibiotic therapy with relapse on cessation
Approach to Diagnostic Imaging

1.
Computed tomography

Preferred study for demonstrating the thick-walled, low-attenuation mass within the kidney that may extend to the perirenal space (usually thickening of Gerota’s fascia and strands of increased density in the adjacent fat)

Gas within the mass is virtually pathognomonic of renal abscess
Caveat: There is no indication for excretory urography in the patient with a suspected renal abscess.

2.
Ultrasound

Alternative method for demonstrating a renal or perinephric abscess, but less sensitive than CT

3.
Interventional radiology

Percutaneous drainage using CT or US guidance is the preferred method of therapy because it provides satisfactory clinical results using local anesthesia and precludes the need for open surgical drainage.
Perinephric (Perirenal) Abscess
Presenting Signs and Symptoms

Fever, leukocytosis and flank pain (at least a 2-week history of symptoms of urinary tract infection)

Frequently a history of prior antibiotic therapy with relapse on cessation

Referred pain to the thorax, groin, thigh, or hip (indicating that the disease has spread beyond the confines of the kidney)
Common Causes
PRIMARY

Forms when an intrarenal abscess breaks through the renal capsule into the perirenal space
SECONDARY

Hematogenous spread to the perirenal space from a distant focus or direct extension from an infection in an adjacent organ (e.g., ruptured appendix or diverticulitis)
Predisposing Factors

Staghorn calculus

Diabetes mellitus

Pyonephrosis

Neurogenic bladder

Immunocompromised patient
Approach to Diagnostic Imaging

1.
Computed tomography

Preferred study for demonstrating the low-attenuation mass (usually with an enhancing wall) as well as precisely defining the boundaries of the inflammatory process by detecting any extension into the psoas muscle and true pelvis

Gas within the mass is virtually pathognomonic of renal abscess
Caveat: There is no indication for excretory urography in patients with a suspected perinephric abscess.

2.
Interventional radiology

Percutaneous drainage using CT or US guidance is the preferred method of therapy because it provides satisfactory clinical results using local anesthesia, and precludes the need for open surgical drainage.
Pyelonephritis (Acute)
Presenting Signs and Symptoms

Rapid onset of fever and chills, flank pain, nausea and vomiting

Pyuria with white blood cell casts
Common Causes

Ascending urinary tract infection (especially Escherichia coli)

Obstruction is a predisposing factor (strictures, calculi, neurogenic bladder, vesicoureteral reflux)
Approach to Diagnostic Imaging
Caveat: Uncomplicated infection requires no imaging; imaging studies are indicated only in patients who fail to respond to treatment or who are severely ill.

1.
Computed tomography

May demonstrate a complicating renal or perirenal abscess as a thick-walled fluid collection within the kidney that may extend to the perirenal space

Notes: The “pre-abscess” state of focal bacterial infection appears as a focal wedge-shaped or rounded area of decreased density.
Uncomplicated disease appears as swollen, edematous kidneys, usually with patchy areas of decreased density or a striated parenchymal nephrogram.

2.
Ultrasound

Also can demonstrate renal or perirenal abscess (but less sensitive than CT for detecting subtle changes in the renal parenchyma associated with uncomplicated pyelonephritis)

Can efficiently diagnose hydronephrosis if it is unclear whether urinary tract obstruction is a predisposing factor to the development of infection
Caveat: Excretory urography is not indicated to confirm the diagnosis of acute pyelonephritis or to detect complications of the disease.
Pyelonephritis (Chronic)
Presenting Signs and Symptoms

Progressive renal failure

History of recurrent urinary tract infections (infrequently obtained except in children with vesicoureteral reflux)

Pyuria with white blood cell casts
Common Causes

Recurrent urinary tract infections (especially when associated with obstructive uropathy)

Vesicoureteral reflux in children
Approach to Diagnostic Imaging

1.
Excretory urography

Demonstrates characteristic focal cortical scar overlying a blunted calyx

Note: Although chronic pyelonephritis is typically lobar, with normal lobes interposed between diseased ones, there may be generalized calyceal dilatation with an irregular renal margin.

2.
Ultrasound

Alternative approach that shows focal loss of renal parenchyma, increased echogenicity in the area of the scar, and extension of the central renal sinus echoes to the periphery of the kidney in the area of abnormality
Pyonephrosis
Presenting Sign and Symptom

Signs of infection in an obstructed kidney
Approach to Diagnostic Imaging

1.
Ultrasound

Preferred initial imaging modality for demonstrating the pathognomonic appearance of a dilated collecting system with layering of echogenic pus and debris

2.
Computed tomography

May be superior to US in determining the precise site and cause of an obstruction and in defining an extrarenal abscess or fluid collection
Caveat: Excretory urography is not indicated because the affected kidney functions poorly or not at all.

3.
Interventional procedure

Placement of a ureteral stent or percutaneous nephrostomy catheter to relieve the obstruction (combined with antibiotic therapy) should be performed promptly to prevent rapid destruction of the renal parenchyma that can result if the condition is not properly treated
Urinary Tract Infection (Infant)
Major Predisposing Factors

Obstruction of urinary tract (structural or functional)

Vesicoureteral reflux
Approach to Diagnostic Imaging

1.
Radionuclide or voiding cystography

Demonstrates the presence and degree of any observed vesicoureteral reflux

Note: Radionuclide cystography is the most sensitive imaging technique for showing vesicoureteral reflux and delivers a substantially lower radiation dose to the gonads. It is especially valuable when multiple follow-up studies are needed to evaluate progression of disease and response to therapy.

2.
Ultrasound

Preferred imaging study for detecting underlying anatomic abnormalities and significant renal scarring (simple, noninvasive, no ionizing radiation)

Note: A complete investigation of the urinary tract is important after an episode of urinary tract infection in an infant because of the relatively high probability of an underlying anatomic abnormality.

3.
Excretory urography

Indicated if there is an abnormality shown by cystography or US to provide superior anatomic and functional information about the upper urinary tract

Note: Disadvantages in children include ionizing radiation and the need for injection of contrast material; even with good renal function, superimposition of intestinal gas and fecal material may make it difficult to evaluate the kidneys and detect focal renal scarring.

Urinary Tract Infection (Female Child)
Approach to Diagnostic Imaging
Caveat: There is controversy as to whether female children (who constitute the overwhelming majority of those affected) should be subjected to radiographic imaging after an initial urinary tract infection (because at least 75% have no abnormality and the risk of developing reflux nephropathy in girls with normal urinary tracts at the time of their first urinary tract infection is very small). But it is generally agreed that a workup of the urinary tract is indicated for repeat or relapsing infections.

1.
Radionuclide or voiding cystography

Demonstrates the presence and degree of any observed vesicoureteral reflux

Note: Radionuclide cystography is the most sensitive imaging technique for showing vesicoureteral reflux and delivers a substantially lower radiation dose to the gonads. It is especially valuable when multiple follow-up studies are needed to evaluate progression of disease and response to therapy.

2.
Ultrasound

Preferred imaging study for detecting underlying anatomic abnormalities and significant renal scarring (simple, noninvasive, no ionizing radiation)

3.
Excretory urography

Indicated to provide superior anatomic and functional information about the upper urinary tract if there is an abnormality shown by cystography or US

Note: Disadvantages in children include ionizing radiation and the need for injection of contrast material; even with good renal function, superimposition of intestinal gas and fecal material may make it difficult to evaluate the kidneys and detect focal renal scarring.

Urinary Tract Infection (Male Child)
Major Predisposing Factors

Obstruction of urinary tract (structural or functional)

Vesicoureteral reflux
Approach to Diagnostic Imaging

1.
Radionuclide or voiding cystography

Demonstrates the presence and degree of any observed vesicoureteral reflux

Note: Radionuclide cystography is the most sensitive imaging technique for showing vesicoureteral reflux and delivers a substantially lower radiation dose to the gonads. It is especially valuable when multiple follow-up studies are needed to evaluate progression of disease and response to therapy.

2.
Ultrasound

Preferred imaging study for detecting underlying anatomic abnormalities/significant renal scarring (simple, noninvasive, no ionizing radiation)

3.
Excretory urography

Indicated to provide superior anatomic and functional information about the upper urinary tract if there is an abnormality shown by cystography or US

Note: Disadvantages in children include ionizing radiation and the need for injection of contrast material; even with good renal function, superimposition of intestinal gas and fecal material may make it difficult to evaluate the kidneys and detect focal renal scarring.

Urinary Tract Infection (Older Child/Teenager)
Approach to Diagnostic Imaging

1.
Ultrasound

A normal study indicates that there is no reflux nephropathy and that the child (by this age) is at little risk of developing intrinsic renal disease in the future

Note: This is the only study needed if the child has only lower urinary tract signs and symptoms.

Caveat: There is no indication for excretory urography in older children or teenagers with an uncomplicated upper urinary tract infection.
Upper Urinary Tract Infection (Adult)
Presenting Signs and Symptoms

Fever

Flank pain

Pyuria
Indications for Imaging

Infection requiring hospitalization

Impaired renal function

Relapsing infection

Infection in a male
Caveat: Uncomplicated infection in a woman requires no imaging (and often shows no abnormalities).
Approach to Diagnostic Imaging

1.
Excretory urography

Provides information on structure and function of urinary tract

Normal examination in a patient with acute urinary tract infection excludes pyonephrosis and other severe renal infections (although it does not eliminate the possibility of vesicoureteral reflux or a perinephric inflammatory process)

2.
Ultrasound

Preferred imaging modality for evaluating the critically ill patient with suspected upper urinary tract infection

Preferred imaging modality for evaluating patients with impaired renal function

May demonstrate even minimal dilatation of the intrarenal collecting system, renal stones, and intrarenal masses

Excellent method for delineating and guiding drainage of a perinephric abscess

3.
Computed tomography

Indicated if US or excretory urography is normal yet there is strong clinical suspicion of an infectious process involving the kidney or the perinephric space

Excellent method for delineating and guiding drainage of a perinephric abscess

Mass

Renal Mass
Presenting Signs and Symptoms

Flank pain

Hematuria

Palpable mass

Fever (suggests renal abscess)

Often discovered incidentally in an asymptomatic patient by excretory urography, US, or CT performed for unrelated abdominal pathology
Common Causes

Cyst

Neoplasm (benign or malignant)

Abscess
Major Imaging Goal

To separate benign renal cysts (the large majority of renal masses) from solid or cystic neoplasms

Note: The unequivocal imaging diagnosis of a benign cyst usually precludes the need for surgical confirmation.

Approach to Diagnostic Imaging

1.
Ultrasound

Highly accurate for demonstrating the characteristic findings of a simple cyst:

Absence of internal echoes

Strong, sharply defined distal wall with smooth, distinct margins

Enhanced through-transmission of the sound beam

Posterior acoustic enhancement

Spherical or slightly ovoid shape
Caveats: (1) Hemorrhagic or infected cysts may be indistinguishable sonographically from solid benign and malignant neoplasms and inflammatory masses; (2) US may be inadequate in obese patients.

2.
Computed tomography

More sensitive than US for detecting renal masses

Highly accurate for demonstrating the characteristic findings of a simple cyst as a nonenhancing mass of water attenuation with clearly defined margins, compared with an enhancing mass that is typical of a solid neoplasm

Note: Although generally considered the “gold standard” for evaluating renal mass lesions, CT is more expensive than screening US and requires intravenous contrast material. Therefore, in many centers, CT is indicated only when the US examination is indeterminate or technically inadequate due to obesity or overlying gas. Because CT is more sensitive than US for detecting a renal mass, it may be used in patients with a negative US examination for whom there is a strong clinical suspicion of a renal mass. It also is appropriate to proceed directly to CT if excretory urography indicates that the renal mass is complex or likely to be solid.

Caveat: Although renal masses are often first identified on a screening excretory urogram, this technique has a substantially lower sensitivity and specificity than US or CT for making the critical differentiation between a simple cyst and a solid, possibly malignant mass.
Renal Cyst
Presenting Signs and Symptoms

Asymptomatic (discovered incidentally during US or CT performed for unrelated abdominal pathology)

Occasionally, a palpable mass, flank discomfort or pain, or hematuria
Common Causes

Unknown
Approach to Diagnostic Imaging

Note: The imaging goal is to separate benign renal cysts (the large majority of renal masses) from malignant neoplasms, because the unequivocal imaging diagnosis of a benign cyst usually precludes the need for surgical confirmation.

Approach to Diagnostic Imaging

1.
Ultrasound

Highly accurate for demonstrating the characteristic findings of a simple cyst:

Absence of internal echoes

Strong, sharply defined distal wall with smooth, distinct margins

Enhanced through-transmission of the sound beam

Posterior acoustic enhancement

Spherical or slightly ovoid shape
Caveat: Hemorrhagic or infected cysts may be indistinguishable sonographically from solid benign and malignant neoplasms and inflammatory masses.

2.
Computed tomography

Indicated if the US appearance is atypical for a simple cyst (thick wall, calcification, internal debris)

Demonstrates a hemorrhagic cyst as a homogeneous mass that appears hyperdense to normal renal parenchyma on unenhanced scans and hypodense on contrast studies

Gas within a thick-walled mass strongly suggests an infected cyst

Note: CT is indicated as the next imaging procedure if excretory urography detects a renal mass that most likely is complex or likely to be solid (rather than cystic).

Cancer of the Kidney
Presenting Signs and Symptoms

Hematuria

Flank pain

Palpable mass

Fever of unknown origin

Increasingly being detected incidentally in asymptomatic patients during US or CT performed for unrelated abdominal pathology
Approach to Diagnostic Imaging

1.
Computed tomography

Contrast-enhanced CT is more sensitive than US for detecting renal masses

When combined with an unenhanced examination, CT can distinguish hemorrhagic cysts from solid tumors

2.
Ultrasound

Can demonstrate a tumor as a solid, heterogeneous, hypoechoic or mildly hyperechoic mass that may contain cystic areas representing hemorrhage or necrosis

3.
Magnetic resonance imaging

As sensitive as CT for detecting renal masses

Useful for patients with a contraindication to iodinated intravascular contrast material

Note: Excretory urography is relatively insensitive for detecting renal masses and is not recommended as a screening procedure.

Staging

1.
Computed tomography or magnetic resonance imaging

Most effective staging procedures for demonstrating the presence and extent of extrarenal spread of tumor (including invasion of the renal vein and inferior vena cava, which is still a surgically curable stage of disease if there are no distant metastases)

Note: Doppler US also can detect echogenic tumor thrombus within venous structures.

MRI may prove to be accurate in determining whether the small opacities seen in the perinephric space on CT in many patients represent patent vessels or lymphadenopathy

Chest CT should be performed for detection of pulmonary metastases prior to any potentially curative surgical procedure

2.
Radionuclide bone scan

Should be performed to detect any skeletal metastases prior to any potentially curative surgical procedure

3.
Arteriography

Presurgical embolization of a tumor may dramatically reduce its vascularity, making resection easier by diminishing blood loss
Medullary Cystic Disease
Presenting Signs and Symptoms

Polyuria (with urinary sodium wasting)

Unexplained uremia

Retarded growth and evidence of bone disease

Symptoms usually begin before age 20
Common Causes

Genetic or congenital
Approach to Diagnostic Imaging

1.
Ultrasound

May demonstrate the multiple medullary cysts within small, smooth kidneys or merely generalized increased echogenicity of the renal parenchyma (representing diffuse atrophy)

Note: Because the cysts may be few and small, they often cannot be detected by US.

Caveat: There is no longer any indication for excretory urography.
Multicystic Dysplastic Kidney
Presenting Signs and Symptoms

Palpable abdominal mass in a neonate (asymptomatic)

Usually unilateral (can be bilateral or segmental)
Common Causes

Congenital developmental defect (resulting from occlusion of the fetal ureter, usually before 8 to 10 weeks of gestation)
Approach to Diagnostic Imaging

1.
Ultrasound

Demonstrates numerous cysts of various sizes with variable amounts of intervening dysplastic renal tissue
Polycystic Kidney Disease (Adult)
Presenting Signs and Symptoms

Initially asymptomatic (may be discovered incidentally on abdominal US or CT performed for another reason)

Onset in early or middle life with symptoms related to the effects of the cysts (lumbar discomfort or pain, hematuria, infection, or colic due to nephrolithiasis)

Hypertension (50% at time of diagnosis)

Progressive renal dysfunction with uremic symptoms

Cysts may also be present in the liver (in 50%)

Aneurysms of the circle of Willis (in 15%) that may rupture to produce subarachnoid hemorrhage
Common Cause

Autosomal dominant
Approach to Diagnostic Imaging

1.
Ultrasound or computed tomography

Demonstrates progressive replacement of the renal parenchyma by multiple noncommunicating cysts of various sizes that commonly contain internal hemorrhage

Can detect associated cysts in the liver
Caveat: Although excretory urography has traditionally been used to show the large, irregular kidneys with compressed and elongated “spidery” renal pelvis and calyces, US and CT can make the correct diagnosis at a much earlier stage.
Polycystic Kidney Disease (Childhood)
Presenting Signs and Symptoms

In neonates, there is renal dysfunction with pulmonary hypoplasia (often a protuberant abdomen with huge kidneys and an enlarged liver)

In children, signs and symptoms of portal hypertension (due to progressive hepatic fibrosis) become more prominent and renal insufficiency is only mild or moderate
Common Cause

Autosomal recessive
Approach to Diagnostic Imaging

1.
Ultrasound

Prenatal studies in late pregnancy usually can permit a presumptive diagnosis

In young children, ultrasound shows characteristic bilaterally enlarged, echogenic kidneys with dilated renal tubules arranged in a radiating pattern (may be so dilated as to appear as individual structures)

In older children and adolescents, ultrasound can show cysts in the kidneys and liver, as well as secondary signs, associated with hepatic fibrosis and portal hypertension

Note: A final diagnosis may require renal and liver biopsies.

Caveat: There is no longer any indication for excretory urography.

Vascular

Atheroembolic Renal Disease
Presenting Signs and Symptoms

Sudden or gradual development of progressive renal failure (depending on amount of atheromatous material obstructing the renal arteries)

May show evidence of embolic disease elsewhere (cholesterol emboli visible on fundoscopic examination, neurologic deficits, toe gangrene, livedo reticularis)

Usually hypertension
Common Causes

Spontaneous embolization of atheromatous plaques

Embolization subsequent to vascular surgery, angioplasty, or arteriography
Approach to Diagnostic Imaging

1.
Computed tomography

Demonstrates a resulting renal infarction as a wedge-shaped area of low attenuation within an otherwise normal kidney

Note: Typically, the outer 2 to 4 mm of cortex are preserved, even if the entire renal artery is occluded, because capsular branches remain patent and enhance the outer rim of the kidney.

2.
Arteriography

Defines vascular occlusion

Thrombolytic therapy is less likely to be successful with embolic disease than with acute thrombosis
Nephrosclerosis (Malignant)
Presenting Signs and Symptoms

Severe hypertension and rapidly progressive renal failure
Common Causes

Accelerated cardiovascular disease in the course of primary hypertension (especially untreated)

May arise from secondary hypertension (due to acute glomerulonephritis, chronic renal failure, renovascular hypertension, vasculitis)
Approach to Diagnostic Imaging
Caveat: Imaging is seldom of value.

1.
Arteriography

Demonstrates increased tortuosity and more rapid tapering of intrarenal arteries

May show filling defects and loss of cortical vessels
Renal Cortical Necrosis
Presenting Signs and Symptoms

Abrupt anuria with gross hematuria and flank pain
Common Causes
NEONATES

Abruptio placentae

Bacterial sepsis
CHILDREN

Infections

Extracellular volume depletion

Shock

Hemolytic-uremic syndrome
ADULTS

Accidents of pregnancy (abruptio placentae, placenta previa, uterine hemorrhage, puerperal sepsis, amniotic fluid embolism, intrauterine death, preeclampsia)

Bacterial sepsis

Hemolytic-uremic syndrome

Hyperacute transplant rejection

Burns

Pancreatitis

Poisoning (phosphorus, arsenic)
Approach to Diagnostic Imaging

1.
Ultrasound

Initially shows enlarged kidneys (renal size progressively diminishes and may be reduced to about 50% of normal by 6 to 8 weeks)

2.
Plain abdominal radiograph

Demonstrates characteristic late (6 to 8 weeks) sign of calcification that is often linear and is most marked at the corticomedullary junction
Renal Infarction
Presenting Signs and Symptoms

Steady aching flank pain localized to the affected renal area

May be asymptomatic (if a small branch of the renal artery is occluded)

Usually, fever, nausea and vomiting, leukocytosis, proteinuria, and microscopic hematuria
Common Causes

Renal artery occlusion (embolic, thrombotic, arteritis, sickle cell disease)

Iatrogenic (after surgery, angioplasty, selective arteriography)
Approach to Diagnostic Imaging

1.
Computed tomography

Demonstrates an infarction as a wedge-shaped area of low attenuation within an otherwise normal kidney

Note: Typically, the outer 2 to 4 mm of cortex are preserved, even if the entire renal artery is occluded, because capsular branches remain patent and enhance the outer rim of the kidney.

2.
Arteriography

Defines vascular occlusion and often allows a diagnosis of vasculitis or emboli

May be useful for thrombolytic therapy if the infarction is due to acute thrombosis
Caveat: There is no indication for excretory urography because there is no renal function in the face of occlusion of the main renal artery.
Renal Vein Thrombosis
Presenting Signs and Symptoms
ACUTE (ANY AGE)

Flank pain

Fever

Hematuria, oliguria

Edema

Leukocytosis

Renal failure
SLOWLY PROGRESSIVE (ADULTS)

Gradual onset of proteinuria

Deteriorating glomerular filtration rate

Nephrotic syndrome
Common Causes
CHILDREN

Diarrhea, dehydration

Hypercoagulability
ADULTS

Membranous glomerulonephritis

Pregnancy

Oral contraceptive use

Trauma

Extrinsic compression (lymph nodes, aortic aneurysm, tumor)

Invasion by renal cell carcinoma
Approach to Diagnostic Imaging

1.
Ultrasound

Demonstrates an enlarged kidney in acute disease and an atrophic kidney in slowly progressive disease

Note: If venous collateral vessels provide adequate drainage, the kidney may be unaffected.

Doppler studies may permit the direct detection of clot within the renal veins

2.
Computed tomography

Absence of opacification of the renal vein on contrast-enhanced study

3.
Magnetic resonance imaging

Detection of an abnormally strong signal from the renal veins (normally a dark flow void), suggesting stasis of flow

Slow-flowing laminar blood (paradoxical brightness) may outline a lower-signal clot within it

4.
Venography

May demonstrate thrombus within the renal vein, or absence of venous opacification implying obstruction
Renovascular Hypertension
Clinical Indications Suggestive of a Renovascular Cause

Onset of hypertension in a previously normotensive person older than age 50

Onset of hypertension in a person younger than age 30

Women between ages 30 and 50 who have no family history of hypertension (fibromuscular hyperplasia)

Rapid acceleration or severe hypertension

Presence of an abdominal or flank bruit

Deteriorating renal function

Poor control of blood pressure with medical therapy

Severe hypertensive retinopathy
Common Causes

Renal artery stenosis

Fibromuscular dysplasia

Takayasu’s aortitis
Approach to Diagnostic Imaging

Note: Many radiographic screening tests have been used in patients with suspected renovascular hypertension; there is no consensus as to which is best. Choice may reflect local institutional bias, available equipment, physician interest or expertise, and characteristics of the patient population.

1.
Radionuclide renogram with captopril

Noninvasive screening test

2.
Doppler ultrasound

Limited by operator dependence

3.
Arteriography

“Gold standard” for detecting renal artery stenosis (the presence of renal artery stenosis in a hypertensive patient does not necessarily mean that the patient has renovascular hypertension)

Note: Arteriography is infrequently used as a screening procedure because of its highly invasive nature.

4.
Computed tomography angiography

Noninvasive technique that can detect renal artery stenosis, including fibromuscular dysplasia

5.
Magnetic resonance angiography

Noninvasive technique that can detect renal artery stenosis

Resolution insufficient to detect rare segmental stenoses in renal artery branch vessels

Does not require iodinated intravascular contrast material and is safer for use in azotemic patients

6.
Interventional radiology

Percutaneous renal angioplasty has become a widespread technique for the nonsurgical therapy of renal artery stenosis. The overall technical success rate is reported to be 80­95%, with 10­20% of stenoses recurring (most often when there has been incomplete dilatation of the lesion). Major complications occur in about 5% of patients.

Trauma

Bladder Trauma
Presenting Signs and Symptoms

Gross hematuria

Lower abdominal or suprapubic pain

Hypotension

Pelvic fracture
Approach to Diagnostic Imaging

1.
Cystography

Sensitive imaging procedure for detecting extravasation of contrast material indicating intraperitoneal or extraperitoneal (more common) rupture
Caveat: The urethra should never be catheterized if a urethral injury is suspected. Under such circumstances, the proper approach is to perform retrograde urethrography. Only if the urethra is shown to be normal should a catheter be passed into the bladder.

2.
Computed tomography

In addition to demonstrating extravasation of contrast material, CT can precisely define the site and extent of extraperitoneal perivesical hematoma

Note: CT of the abdomen and pelvis is usually performed to evaluate injury to other organs after major abdominal trauma.

Caveat: Bladder rupture may be missed on CT (or cystography) if the bladder is decompressed by a catheter or if it is incompletely filled. With current-generation CT scanners, the entire abdomen and pelvis may be imaged before contrast material reaches the bladder. Therefore, filling the bladder with dilute contrast through a Foley catheter or taking delayed images may be required to evaluate the bladder.

3.
Arteriography

Indicated in the patient with a significant pelvic hematoma who has a decreasing hematocrit and no other apparent source of blood loss

Therapeutic embolization of a bleeding vessel may preclude the need for surgery
Renal Trauma (Blunt)
Presenting Signs and Symptoms

Hematuria

Flank pain and tenderness

Hypotension or shock

Associated injuries (skeletal fracture, signs of injury to the spleen, liver, or gastrointestinal tract)
Approach to Diagnostic Imaging
GENERAL APPROACH

1.
Unstable patients should have immediate surgical exploration without waiting for imaging studies

2.
In stable patients with microscopic hematuria and no suspected associated injuries or fractures, radiographic contrast studies have a very low likelihood of detecting significant renal injury

3.
In stable patients with gross hematuria or microscopic hematuria and shock, the yield of radiographic contrast studies is sufficiently high to influence further therapy

1.
Computed tomography

Most versatile imaging technique that, in addition to demonstrating morphologic and functional abnormalities of the kidneys, can show intraperitoneal and extraperitoneal hemorrhage, free intraperitoneal gas, and injuries to the liver, spleen, pancreas, and gastrointestinal tract

Note: Unsuspected injuries to other organs are common and are more likely to be revealed by CT than any other imaging modality.

2.
Excretory urography

Simple, quick, and readily available study that can be used to promptly determine whether both kidneys are present and functioning in a patient with a negative diagnostic peritoneal lavage and little likelihood of injury to other organs

3.
Arteriography

Seldom needed as a diagnostic test, since the integrity of the renal artery can be predicted on the basis of the CT examination

May be indicated as a prelude to surgery in a patient with a nonfunctioning kidney presumed to be due to vascular occlusion
Caveat: In 90% of patients with complete arterial occlusion, renal function is irreversibly lost after 2 hours of ischemia. Therefore, the need for immediate surgery must be balanced against the time required to complete an arteriographic examination.

Embolization of a bleeding vessel may permit stabilization of the patient and preclude the need for surgery

Note: In patients in whom iodinated contrast material is contraindicated, US may be performed to evaluate renal morphology, and radionuclide scanning may be employed to assess renal perfusion and function.

Renal Trauma (Penetrating)
Presenting Signs and Symptoms

Hematuria

Flank pain and tenderness

Hypotension or shock
Approach to Diagnostic Imaging
Caveat: In up to 6% of patients, significant occult injuries to the kidney are not suggested on clinical inspection of the wound. The absence of hematuria does not exclude renal injury. Studies have shown that (1) 30% of patients with penetrating flank and back trauma without hematuria had renal pedicle injuries; and (2) 15­42% of patients with flank or back trauma manifest only microscopic hematuria.

1.
Computed tomography

Contrast-enhanced scans are the imaging procedure of choice for demonstrating renal laceration and extravasation of contrast material from the pelvicalyceal system

2.
Arteriography

Needed to demonstrate a bleeding vessel

Therapeutic embolization of an actively bleeding vessel may preclude the need for surgery
Urethral Trauma
Presenting Signs and Symptoms

Inability to urinate

Blood at the urethral meatus

Elevation of the prostate on digital rectal examination

Perineal swelling or hematoma

Pelvic fracture
Approach to Diagnostic Imaging

1.
Retrograde urethrography

Imaging procedure of choice for demonstrating extravasation of contrast material through a partial or complete urethral tear
Caveat: If urethral injury is suspected, a retrograde urethrogram should always be obtained prior to transurethral bladder catheterization. If the bladder of a patient with a urethral injury is full, suprapubic catheterization may be performed.

Other

Glomerulonephritis (Acute)
Presenting Signs and Symptoms

Sudden onset of hematuria (dark urine with red cell casts), oliguria

Edema

Hypertension

Elevated blood urea nitrogen and creatinine
Common Causes

Prior beta-hemolytic streptococcal infection

Other prior infection (bacterial, viral, parasitic)

Multisystem disease (systemic lupus erythematosus, vasculitis, Henoch-Schönlein purpura, Goodpasture’s syndrome)
Approach to Diagnostic Imaging

1.
Ultrasound

May aid in distinguishing acute disease (usually normal or slightly enlarged kidneys) from an exacerbation of chronic disease (small kidneys)
Glomerulonephritis (Chronic)
Presenting Signs and Symptoms

Insidious onset of slowly progressive impairment of renal failure associated with peripheral edema

May be discovered incidentally on urinalysis in an asymptomatic patient (proteinuria, possibly hematuria)
Common Cause

Most frequently, develops weeks or months after an episode of acute glomerulonephritis
Approach to Diagnostic Imaging

1.
Ultrasound

Demonstrates the nonspecific pattern of bilateral small kidneys (as with other causes of chronic renal failure)

Note: US can exclude obstructive hydronephrosis as the underlying cause of progressive renal failure.

Hydronephrosis
Presenting Signs and Symptoms
ACUTE

Colicky pain
CHRONIC

Asymptomatic

Recurrent attacks of dull flank pain (resulting stasis may lead to formation of calculi and secondary infection)
Common Causes
NONOBSTRUCTIVE

Vesicoureteral reflux

Primary megacalyces
OBSTRUCTIVE

Obstruction at the ureteropelvic junction (fibrous band, aberrant vessel, ureteral kinking, renal pelvis stone or tumor)

Distal obstruction (stone, tumor, benign prostatic hyperplasia, ureteral stricture, retroperitoneal fibrosis, bladder outlet obstruction); in pregnancy, transient involvement of right ureter
Approach to Diagnostic Imaging

1.
Ultrasound

Preferred initial imaging modality for detecting urinary tract dilatation

Dilatation of the renal pelvis appears as separation of the normal sinus echogenicity by anechoic urine in the collecting system

2.
Excretory urography

Early signs of obstruction include:

Prolonged and increasingly dense nephrogram

Delay in appearance of contrast in the collecting system

Dilated pelvicalyceal system and ureter down to the point of obstruction

3.
Computed tomography

Frequently permits identification of the cause of the obstruction, in addition to demonstrating dilatation of the ureter and collecting system
Medullary Sponge Kidney
Presenting Signs and Symptoms

Usually asymptomatic

Nephrocalcinosis may lead to symptomatic complications such as colic, hematuria, and infection (from urinary stasis)
Common Cause

Congenital dysplastic dilatation of the collecting tubules
Approach to Diagnostic Imaging

1.
Excretory urography

Shows characteristic striations or saccular papillary collections of contrast material (most commonly bilateral and symmetric)

Preliminary (scout) radiographs may show calcifications in the dilated tubules in the medullary pyramids

Note: US is seldom useful because the cysts are small and located deep in the medulla; it may show papillary stones as echogenic foci.

Nephrocalcinosis
Presenting Signs and Symptoms

Asymptomatic (unless complicated by hematuria, obstruction, or infection)
Common Causes

Pathologic deposition of calcium may occur in Medulla

Hyperparathyroidism

Medullary sponge kidney

Renal tubular acidosis

Milk-alkali syndrome

Hypervitaminosis D

Hypercalcemic/hypercalciuric states

Pyramids

Hyperuricemia

Infection (tuberculosis)

Sickle cell disease

Cortex

Acute cortical necrosis

Chronic glomerulonephritis
Approach to Diagnostic Imaging

1.
Plain abdominal radiograph, ultrasound, or computed tomography

Plain abdominal radiographs are the least expensive and most readily available, but US and especially CT are more sensitive for detecting subtle calcification in the renal parenchyma

Calculi appear opaque on plain radiographs, as echogenic lesions with acoustic shadowing on US, and as high-attenuation lesions on CT
Nephrolithiasis (Urinary Calculi)
Presenting Signs and Symptoms

Asymptomatic (if not causing obstruction or passing down the ureter)

Renal colic (excruciating intermittent pain, usually originating in the flank or kidney area and radiating to the groin)

Hematuria

Chills and fever

Nausea, vomiting, and abdominal distension (clinical picture of adynamic ileus)
Common Types

Calcium oxalate or calcium phosphate (80%)

Struvite (magnesium ammonium phosphate) (13%)

Uric acid (5%)

Cystine (2%)
Approach to Diagnostic Imaging

1.
Computed tomography (unenhanced)

Most sensitive method for detecting urinary tract calculi (even “radiolucent” stones are readily visible on CT)

Can detect dilatation of the collecting system or ureter proximal to an obstructing stone

Can detect rupture of the collecting system

Can detect extraurinary causes of abdominal pain

No risk of reaction to iodinated contrast material

2.
Excretory urography

Initial plain film of the abdomen can demonstrate the majority of urinary calculi (about 80% contain enough calcium to be radiopaque)

Contrast study can demonstrate lucent stones and define the precise site of obstruction and the degree of proximal ureteral dilatation

Note: Ureteral obstruction from calculi is most likely to occur at the ureteropelvic junction or the uretero-vesical junction (the narrowest points in the collecting system).

3.
Ultrasound

Demonstrates both opaque and lucent stones as echodensities with acoustic shadowing

Shows the degree of ureteral dilatation proximal to an obstruction
Caveat: US may fail to detect small stones in the renal pelvis that do not cast acoustic shadows and thus blend in with renal sinus fat.
Retroperitoneal Hemorrhage
Presenting Signs and Symptoms

Abdominal or back pain, often with symptoms of hypotension
Common Causes

Rupture of abdominal aortic aneurysm

Trauma

Coagulopathy (anticoagulant medication or intrinsic blood dyscrasia)

Hemorrhage into renal or retroperitoneal neoplasm

Pancreatitis

Iatrogenic (following groin puncture for arteriography or cardiac catheterization, a hematoma can spread from the pelvis into any of the retroperitoneal compartments)
Approach to Diagnostic Imaging

1.
Computed tomography

Procedure of choice for demonstrating a ruptured aortic aneurysm, as well as for identifying most other morphologic causes of retroperitoneal hemorrhage

Clearly shows the location, size, and extent of the hematoma

2.
Ultrasound

Best technique for evaluating the groin after femoral vein puncture

Procedure of choice for detecting arteriovenous fistulas and pseudoaneurysms

Of limited use in the retroperitoneum in obese patients

May be difficult to differentiate a hematoma from other retroperitoneal masses (tumor, abscess)

3.
Arteriography

Indicated if CT suggests a discrete source of bleeding that could be treated with embolization (pseudoaneurysm, hemorrhage arising from a neoplasm)

4.
Magnetic resonance angiography

May be an alternative for imaging major vessels noninvasively
Caveat: Unstable patients with massive hemorrhage should have emergency surgery without any diagnostic imaging studies.
Tubulointerstitial Nephritis (Acute Tubular Necrosis)
Presenting Signs and Symptoms

Reversible renal failure, with or without oliguria

Symptoms vary with underlying cause (e.g., fever, rash, and arthralgia if cause is an allergic reaction to a drug)
Common Causes

Drug-induced (amphotericin, aminoglycosides, penicillins, sulfonamides, diuretics, nonsteroidal antiinflammatory drugs, heavy metals, radiocontrast agents)

Systemic infections

Pyelonephritis

Immune disorders (transfusion reactions, transplant rejection)

Metabolic diseases (hypercalcemia, hypokalemia, hyperuricemia)

Neoplasm (lymphoma, leukemia, multiple myeloma)

Vascular (sickle cell disease, arteriolar nephrosclerosis, shock)

Crush injuries with myoglobinuria

Burns
Approach to Diagnostic Imaging

1.
Ultrasound

Demonstrates nonspecific pattern of bilateral large, smooth kidneys and excludes obstruction as a cause for oliguria or anuria
Caveat: Although excretory urography can demonstrate the prolonged bilateral nephrogram characteristic of acute tubulointerstitial nephritis, it generally is not required, and the contrast material may aggravate the process.
Tubulointerstitial Nephritis (Chronic)
Presenting Signs and Symptoms

Progressive insidious renal failure
Common Causes

Drug-induced (analgesics, especially aspirin and phenacetin)

Obstructive uropathy

Chronic pyelonephritis

Immune disorders (transplant rejection)

Metabolic diseases (nephrocalcinosis/nephrolithiasis, oxalosis, cystinosis, gout, diabetes mellitus)

Inherited multisystem disorders (polycystic disease, multicystic kidney disease, medullary sponge kidney, sickle cell disease, hereditary nephritis)

Malignancy (multiple myeloma)
Approach to Diagnostic Imaging

1.
Ultrasound

Demonstrates nonspecific pattern of bilateral small, smooth kidneys
Urinary Incontinence
Presenting Signs and Symptoms

Ranges from inability to control urine flow at all times to persistent dribbling to leakage of urine only during times of stress
Common Causes
WOMEN

Pelvic relaxation (childbearing)

Urethral diverticulum

Urethritis/cystitis
MEN

Following prostatectomy or repair of urethral stricture
BOTH

Neurogenic bladder

Medications (e.g., antipsychotics, diuretics)
Approach to Diagnostic Imaging

1.
Voiding cystourethrography

Confirms the presence of incontinence

Can be used to classify the type of incontinence and identify the phase during which it occurs (filling, straining, coughing)

Assesses the size, contour, capacity, and contractility of the bladder

2.
Ultrasound

Not used as primary imaging technique because it cannot directly visualize urine loss or identify the phase during which incontinence occurs

Can detect urethral diverticula and determine bladder wall thickness

Better for evaluating dilatation of the more proximal urinary tract and possible renal parenchymal loss

Note: Some urologists prefer performing urodynamic studies instead of or in addition to imaging procedures.

Bladder

Cancer of the Urinary Bladder
Presenting Signs and Symptoms

Hematuria, pyuria, frequency, dysuria, and burning
Predisposing Factors

Aniline dyes

Rubber and plastics manufacturing chemicals

Tobacco tars (excretory products)

Schistosomiasis

Bladder calculi (irritative effects)

Bladder exstrophy
Approach to Diagnostic Imaging

1.
Excretory urography

May detect tumors >1.5 cm as irregular filling defects, but is less sensitive than cystoscopy
Caveat: Cystoscopic biopsy is required for histologic confirmation of the diagnosis.
Staging

1.
Magnetic resonance imaging

Superior to CT for predicting the depth of bladder wall invasion (high-signal tumor disruption of the normally low-signal bladder wall on T2-weighted images)

Equal to or better than CT for showing tumor extension into the perivesical fat (low-signal tumor versus high-signal fat on T1-weighted images)

2.
Computed tomography

Alternative procedure for staging if MRI is not available (although not as good as MRI for differentiating superficial noninvasive tumors from those invading the bladder muscle)

Superior to US for defining the pelvic structures and delineating enlargement of paraaortic lymph nodes
Neurogenic Bladder
Presenting Signs and Symptoms

Partial or complete urinary retention

Incontinence

Predisposition to infection and calculus formation
Common Causes

Acute spinal cord trauma

Meningomyelocele

Diabetes mellitus

Central nervous system neoplasm (brain or spinal cord)

Cerebrovascular accident

Herniated intervertebral disc

Demyelinating process (multiple sclerosis, amyotrophic lateral sclerosis)

Poliomyelitis

Syphilis
Approach to Diagnostic Imaging

1.
Excretory urography

Demonstrates marked thickening of the bladder wall, which has an irregular contour due to muscular trabeculation

Note: Although US also can show this appearance, it does not give any indication of the degree of kidney function.

Bladder Outlet Obstruction
Presenting Signs and Symptoms

Partial or complete urinary retention

Progressive urinary frequency, urgency, and nocturia (due to incomplete emptying and rapid refilling of the bladder)

Overflow incontinence

Predisposition to infection and calculus formation
Common Causes

Benign prostatic hyperplasia

Prostatic cancer

Bladder neck obstruction (anatomic versus functional)

Acquired bladder neck stricture (traumatic, postsurgical)

Neurogenic bladder
Approach to Diagnostic Imaging

1.
Excretory urography

Preferred imaging technique for demonstrating the size of the bladder (markedly dilated or small and shrunken)

Note: Excretory urography can also provide valuable information concerning the functional status of the upper urinary tracts. Characteristic findings may suggest prostate enlargement or neurogenic bladder. It is insensitive for detecting bladder tumors.

Cystitis
Presenting Signs and Symptoms

Dysuria, frequency, urgency

Hematuria

Suprapubic pain
Common Causes

Infection (bacteria, tuberculosis, schistosomiasis)

Drug-induced (cyclophosphamide)

Radiation
Approach to Diagnostic Imaging

Notes: Radiographic assessment of women with lower urinary tract infection is usually of little value and rarely provides information that aids in clinical management.
Because cystitis in men is often associated with obstruction of the lower urinary tract, evaluation should be directed at detecting underlying prostatic or urethral pathology.

1.
Voiding cystography or excretory urography

Demonstrates a diffuse scalloped, irregular contour of the bladder wall and a small capacity bladder

Gas may be detected within the bladder wall in patients with emphysematous cystitis
Urethritis (Gonococcal)
Presenting Signs and Symptoms

Dysuria

Thick, purulent urethral discharge

Primarily affects men
Approach to Diagnostic Imaging
Caveat: Uncomplicated infections require no imaging (indicated only to detect complications of the disease).

1.
Retrograde urethrography

Preferred technique for demonstrating the location, size, length, and number of urethral strictures, as well as periurethral communications (especially when surgery is contemplated)

Note: Retrograde urethrography is also valuable in postoperative assessment, especially in detecting residual or recurrent stenoses.

Adrenal

Addison’s Disease
Presenting Signs and Symptoms

Weakness, fatigue, orthostatic hypotension (early)

Increased pigmentation

Weight loss, dehydration, hypotension (late)

Small heart size

Anorexia, nausea and vomiting, diarrhea

Decreased cold tolerance
Common Causes

Autoimmune process (idiopathic atrophy)

Granulomatous process (tuberculosis, histoplasmosis)

Neoplasm (lymphoma, metastases)

Infarction

Hemorrhage
Approach to Diagnostic Imaging

Note: Addison’s disease is a clinical diagnosis based on classic signs and symptoms and confirmed by laboratory tests.

1.
Plain abdominal radiograph

May demonstrate adrenal calcification suggesting prior tuberculosis or histoplasmosis

2.
Computed tomography

May demonstrate enlargement of the adrenal glands secondary to lymphoma or metastases

Idiopathic atrophy results in very small adrenal glands
Adrenal Virilism (Adrenogenital Syndrome)
Presenting Signs and Symptoms

Hirsutism

Male-pattern baldness

Acne

Deepening of the voice

Amenorrhea and uterine atrophy

Decreased breast size

Increased muscularity
Common Causes

Adrenal hyperplasia (infants)

Adrenal adenoma or carcinoma (adults)
Approach to Diagnostic Imaging

1.
Computed tomography

Procedure of choice for demonstrating the underlying adrenal neoplasm or hyperplasia
Primary Aldosteronism (Conn’s Syndrome)
Presenting Signs and Symptoms

Hypertension

Hypokalemia

Increased serum and urine aldosterone (radioimmunoassay)

Low plasma renin activity
Common Causes

Hyperfunctioning adrenal adenoma (80%)

Bilateral adrenal hyperplasia (20%)
Approach to Diagnostic Imaging

1.
Computed tomography

Procedure of choice for detecting the adenoma, which is usually small (<2 cm)

Note: Intravenous contrast is not needed.

Cushing’s Syndrome
Presenting Signs and Symptoms

Truncal obesity with prominent supraclavicular and dorsal cervical fat pads (“buffalo hump”)

Rounded (moon) facies

Generalized weakness and muscle wasting

Poor wound healing and easy bruising

Hypertension

Osteoporosis

Glucose intolerance

Reduced resistance to infection

Menstrual irregularities
Common Causes

Adrenal hyperplasia (70%)

Pituitary microadenoma (ACTH-secreting)

Nonpituitary ACTH-secreting tumor (usually from lung tumor)

Adrenal adenoma (20%)

Adrenal carcinoma (10%)
Approach to Diagnostic Imaging

1.
Computed tomography (abdomen)

Preferred initial imaging procedure if biochemical tests suggest an adrenal tumor

Note: Intravenous contrast is not needed.

2.
Magnetic resonance imaging (pituitary)

Procedure of choice for detecting a functioning microadenoma causing adrenal hyperplasia

3.
Plain chest radiograph

Preferred screening study for detecting an underlying ACTH-producing lung tumor
Adrenal Metastases
Presenting Signs and Symptoms

Asymptomatic
Common Primary Tumors

Carcinomas of lung, breast, and kidney

Melanoma

Lymphoma
Approach to Diagnostic Imaging

1.
Computed tomography

Procedure of choice for detecting these relatively common metastatic lesions, which are often large, irregular, and inhomogeneous and invade adjacent structures
Caveat: Small metastases tend to be homogeneous, well defined, and indistinguishable from benign adenomas. In addition, even in patients with known primary malignancy, more than 50% of small adrenal masses are benign adrenal lesions and not metastases.

Low density of a small, homogeneous adrenal mass on unenhanced CT allows a confident diagnosis of an adenoma

Analysis of the density of an adrenal mass over time (CT washout curve) may allow a confident diagnosis of an adenoma on a contrast-enhanced study

Percutaneous biopsy may still be required for high-density adrenal masses

2.
Magnetic resonance imaging

Metastases have a higher signal intensity than benign adenomas on T2-weighted sequences

Metastases show greater enhancement than benign adenomas after gadolinium injection

On chemical-shift MRI, lipid-laden adenomas have low signal intensity, while metastases have intermediate or high signal

Chemical-shift imaging is highly accurate for identifying adrenal adenomas without biopsy, although CT-guided biopsy is still required to identify the infrequent adenoma that contains little or no lipid
Pheochromocytoma
Presenting Signs and Symptoms

Hypertension (persistent or paroxysmal)

Tachycardia, diaphoresis, postural hypotension, tachypnea, flushing, cold and clammy skin

Severe headache and tremors

Elevated levels of catecholamines and their metabolites
Common Causes

Catecholamine-secreting tumor of chromaffin cells

Adrenal medulla (90%)

Extraadrenal sites (paraaortic sympathetic chain, organ of Zuckerkandl near the bifurcation of the aorta, urinary bladder)
Approach to Diagnostic Imaging

1.
Computed tomography

Preferred imaging study for detecting tumors (usually >2 cm) involving the adrenal medulla

If no adrenal mass is found and clinical suspicion remains high, scanning must be extended to include the remainder of the abdomen and pelvis (most extraadrenal pheochromocytomas lie in the lumbar sympathetic chain)
Caveat: Intravenous contrast material is unnecessary and could precipitate a hypertensive crisis.

2.
Magnetic resonance imaging

Procedure of choice (if metaiodobenzylguanidine [MIBG] scanning is not available) to search for extraadrenal pheochromocytomas not found on CT

The tumor demonstrates extremely bright signal on T2-weighted images, allowing it to stand out from surrounding structures

Note: Radionuclide scans using MIBG are highly sensitive for localizing ectopic pheochromocytomas, but this agent is not widely available.

CHAPTER 5. SKELETAL
What to Order When

CHAPTER 5. SKELETAL

Donald Resnick

SIGNS AND SYMPTOMS

Acute Monarticular Joint Pain
Common Causes

Gout

Calcium pyrophosphate deposition disease (CPPD)

Septic arthritis

Bursitis/tendinitis

Trauma

Hemarthrosis (bleeding diathesis)

Localized manifestation of inflammatory polyarthritis (Reiter’s syndrome, psoriatic arthritis)
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

Preferred study for demonstrating soft-tissue swelling and calcification, bone erosions, joint space narrowing, and any underlying fracture
Polyarticular Joint Pain
Common Causes

Rheumatoid arthritis

Ankylosing spondylitis

Reiter’s syndrome

Psoriatic arthritis

Osteoarthritis

Systemic lupus erythematosus

Hypertrophic osteoarthropathy

Polymyalgia rheumatica

Diffuse appearance of a usually monarticular condition (gout, CPPD, calcium hydroxyapatite deposition disease, bacterial arthritis)
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

Preferred study for detecting soft-tissue swelling, calcification, bone erosions, joint space narrowing, and osteophyte formation

DISORDERS

Osteoporosis
Presenting Signs and Symptoms

Often asymptomatic

Dull aching pain in the bones (particularly in the lower thoracic and lumbar area)

Tendency to develop compression fractures of the vertebrae with minimal or no trauma

Kyphosis of the thoracic spine

Fractures at other sites (hip, wrist) with less trauma than required in normal patients
Common Causes
PRIMARY

Postmenopausal/senile
SECONDARY (<5%)

Endocrine dysfunction

Drug-induced (e.g., steroids)

Prolonged immobilization

Chronic renal failure

Osteogenesis imperfecta

Leukemia
Approach to Diagnostic Imaging

1.
Plain radiograph (spine)

May detect anterior wedging of vertebral bodies (especially in the lower thoracic and upper lumbar regions) and associated ballooning of intervertebral disc spaces, characteristic of compression fractures
Caveat: Plain radiographs of the spine are otherwise of little value because abnormal radiolucency cannot be accurately diagnosed until at least 50–70% of bone substance has been lost.

2.
Measurements of bone mineral content

Various methods (quantitative CT, single- and dual-photon absorptiometry, dual-energy x-ray absorptiometry) are available to assess the quantity of bone in the spine both for initial diagnosis and for following the response to therapy

There is much debate concerning which imaging method is superior and even whether or not knowing the bone mineral content is clinically more helpful than mere knowledge of a patient’s age and sex (in itself fairly accurate for predicting bone-mass quantity)

Note: Most authors agree that knowing the axial bone mineral measurement does not help predict which patients are at risk for developing hip and vertebral body fractures.

Osteomalacia
Presenting Signs and Symptoms

Diffuse skeletal pain and bony tenderness

Bowing of long bones and loss of height of vertebral bodies (due to weight-bearing on progressively weakened bones)
Common Causes

Vitamin D deficiency (lack of sunlight, dietary deficiency, or malabsorption due to chronic pancreatic insufficiency, gastrectomy, or malabsorption syndrome)

Abnormal metabolism of vitamin D (anticonvulsant therapy, chronic liver disease)

Kidney disease (chronic renal failure, renal tubular acidosis, Fanconi’s syndrome)

Chronic administration of aluminum-containing antacids

Tumor-induced
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

May demonstrate osteopenia (particularly in the spine, pelvis, and lower extremities) with accentuation or indistinctness of secondary trabeculae, thinning of the cortices, and insufficiency fractures (lucent lines running perpendicular to the long axis of the bone)

Arthritides

Ankylosing Spondylitis
Presenting Signs and Symptoms

Recurrent back pain (often nocturnal)

Morning stiffness (usually relieved by activity)

Kyphosis (flexed posture typically eases back pain and paraspinal muscle spasm)

Chest pain and diminished chest expansion (from diffuse costovertebral involvement)

Peripheral joint pain (especially hip or shoulder)

Cauda equina syndrome

Acute iritis (anterior uveitis) in 30%

Constitutional symptoms of fever, fatigue, anorexia, weight loss, and anemia (may be severe)

Primarily affects men (3:1), especially between ages 20 and 40
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

Earliest finding is erosion and sclerosis involving the sacroiliac joints in a symmetric fashion

Characteristic abnormalities include squaring of vertebral bodies, syndesmophyte formation, and paraspinal ligamentous calcification that eventually produce the classic “bamboo spine”

2.
Computed tomography or magnetic resonance imaging

Transverse imaging occasionally allows diagnosis when routine radiographs are normal
Calcium Pyrophosphate Deposition Disease (CPPD or Pseudogout)
Presenting Signs and Symptoms

Acute attack of pain, swelling, redness, and warmth of one or more joints (especially the knee) in about 25%

Chronic progressive degenerative changes in multiple joints (at times with intermittent acute attacks)

Most patients are asymptomatic
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

May demonstrate characteristic calcification of articular cartilage and menisci (chondrocalcinosis) in the knee, triangular fibrocartilage of the wrist, and the symphysis pubis and acetabular region

May show structural joint changes that resemble osteoarthritis but occur in sites not typically involved in osteoarthritis (shoulders, wrists, and patellofemoral joints) and are more severe
Gout
Presenting Signs and Symptoms

Acute gouty arthritis is an exquisitely painful monarthritis that typically involves the metatarsophalangeal joint of the big toe (podagra) but also commonly involves the instep, ankle, knee, wrist, and elbow (may be precipitated by minor trauma, overindulgence in food or alcohol, surgery, fatigue, emotional stress, infection, or vascular occlusion)

Chronic gout is characterized by tophaceous deposits of urate crystals in joints, walls of bursae, and tendon sheaths that may lead to chronic joint symptoms, permanent erosive changes, and joint deformity

Increased serum urate concentration and hyperuricemia

Nephrolithiasis
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

In chronic or recurrent disease, may demonstrate characteristic well defined “rat-bite” erosions with sclerotic borders and overhanging edges (especially in the first metatarsophalangeal joints) with osteoporosis or soft-tissue tophaceous deposits (especially about the elbow, patella, and hand)

2.
Magnetic resonance imaging

Pattern of disease varies, but regions of persistent low signal intensity are characteristic
Neuropathic Arthropathy (Charcot Joint)
Presenting Signs and Symptoms

Rapidly progressive destructive process with effusion, subluxation, and instability of affected joints

Pain is often absent or less severe than would be expected from the degree of joint destruction

“Bag of bones” appearance of involved joint (due to repeated fractures and bony metaplasia that produce loose fragments of cartilage or bone)

Precise site of involvement depends on underlying disorder
Common Causes

Diabetes mellitus (foot)

Tabes dorsalis (knee and hip)

Syringomyelia (upper extremity, especially elbow and shoulder)

Spina bifida with meningomyelocele

Leprosy

Quadriplegia
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

May demonstrate extensive destructive changes and heterotopic new bone formation
Osteoarthritis
Presenting Signs and Symptoms

Insidious onset and gradual progression of pain that typically involves one or only a few joints, increases with exercise, and may become worse at night or with weather changes

Primary osteoarthritis typically involves weight-bearing joints (hips, knees) and frequently used joints (fingers)

Secondary osteoarthritis is due to a predisposing factor (trauma, congenital abnormality, metabolic disorder) and may be unilateral, appear at an early age, or involve joints that usually are not affected

Stiffness in the morning or after rest (usually brief)

With progressive disease, joints may appear enlarged, motion becomes limited, flexion contractures and subluxations may develop, and tenderness and crepitus may occur
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

Demonstrates the typical findings of irregular or asymmetric joint space narrowing, hypertrophic bone formation (osteophytes) at the periphery of joints, subchondral sclerosis (increased opacity), and subchondral pseudocysts (geodes)

Note: In the hands, osteoarthritis primarily involves the distal and proximal interphalangeal joints. In the wrist, the disease affects the joints at the base of the thumb. In the knee, the medial portion of the joint is more severely involved in men.

Psoriatic Arthritis
Presenting Signs and Symptoms

Joint abnormalities in about 5% of patients with skin or nail disease
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

Demonstrates characteristic proliferative erosions (usually affecting the distal and proximal interphalangeal joints of the fingers and toes), as well as possible resorption of terminal phalanges, bony ankylosis, or arthritis mutilans (aggressive, destructive form of the disease)

May be associated with spondylitis, sacroiliitis, or both (even in the absence of peripheral arthritis)
Reiter’s Syndrome
Presenting Signs and Symptoms

Urethritis

Conjunctivitis

Peripheral arthritis

Mucocutaneous lesions (small painless superficial ulcers)
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

Demonstrates asymmetric, polyarticular proliferative erosions, typically involving the lower extremities (especially the toes and the heels)

May be associated with sacroiliac involvement (leading to back pain), which may have a unilateral distribution
Rheumatoid Arthritis
Presenting Signs and Symptoms

Symmetric polyarthritis of peripheral joints (especially in the hand, wrist, and foot) with pain, tenderness, and swelling

Typically insidious and progressive joint involvement

Morning stiffness

Rheumatoid nodules (in 30–40% of patients)

Deformities (particularly flexion contractures and ulnar deviation of the fingers)

Carpal tunnel syndrome (due to synovitis of the wrist)

Serum rheumatoid factor

Primarily affects women (3:1) between ages 25 and 50
Approach to Diagnostic Imaging

1.
Plain radiograph (hands, wrists, feet)

Demonstrates the characteristic appearance of soft-tissue swelling, periarticular demineralization, joint space narrowing, and marginal erosions that symmetrically involve the wrists and hands (primarily the metacarpophalangeal and proximal interphalangeal joints)

Similar findings at the metatarsophalangeal joints of the feet

Note: The “rheumatoid variants” (psoriatic and Reiter’s arthritis) more commonly are asymmetric and may involve the distal interphalangeal joints.

Infection

Infectious Arthritis (Septic Joint)
Presenting Signs and Symptoms

Acute joint pain associated with warmth, tenderness, swelling, and effusion

Fever, chills

Leukocytosis

May be little systemic or local response in patients receiving antiinflammatory drugs
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

Neither sensitive nor specific, but may demonstrate joint effusion, joint space narrowing, and erosive changes

Note: The diagnosis of infectious arthritis requires a high index of suspicion (especially in patients with underlying chronic joint disease). Therefore, even the remote possibility that a joint might be septic demands aspiration of synovial fluid and a search for the infecting organism by Gram stain and culture (even if plain radiographs are completely normal).

2.
Radionuclide bone scan or magnetic resonance imaging

Not specific, but permit early diagnosis in a patient with a high likelihood of joint infection
Osteomyelitis (Direct Seeding or Contiguous Spread)
Presenting Signs and Symptoms

Pain and fever with tenderness and soft-tissue swelling
Common Causes

Trauma (open fracture, surgical reduction of closed fracture, penetrating trauma)

Bacterial contamination of orthopedic prosthesis during surgery

Diabetic or atherosclerotic arterial insufficiency of lower extremities (spread from cutaneous foot ulcer)

Sinus or dental infection (osteomyelitis of skull)
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

May demonstrate bony destruction with the formation of lucent areas, radiopaque sequestra (foci of devitalized bone), and involucra

An infected prosthesis may show characteristic lucent areas within the shaft of the bone adjacent to the cement about the prosthesis (may also be seen with simple loosening)

2.
Computed tomography

Indicated to detect sequestra, which usually indicate the need for surgical removal rather than antibiotics alone (as avascular sequestra will not be effectively treated with parenteral medication)
Caveat: Radionuclide bone scan is of little value because the isotope accumulates in many noninfectious conditions, such as fracture sites, uninfected nonunion of fractures, periosteal new bone, overlying cellulitis, neuropathic arthropathy, and aseptic loosening of prostheses.

3.
Magnetic resonance imaging

Sensitive (but not specific) for detecting osteomyelitis

Diagnostic difficulty occurs owing to the presence of bone marrow edema (neighborhood reaction) in cases of adjacent soft-tissue infection
Osteomyelitis (Hematogenous)
Presenting Signs and Symptoms

Pain and fever with tenderness and soft-tissue swelling

In children, most commonly involves the long bones (especially near the physeal plate at the end of the shaft)

In adults, usually affects the vertebral bodies
Common Causes

Intravenous drug abuse

Hemodialysis

Debilitating diseases
Approach to Diagnostic Imaging

1.
Radionuclide bone scan

Demonstrates increased activity early in the disease (evidence of bone destruction on plain skeletal radiographs usually does not appear for at least 1 week)
Caveat: Bone scans may take months to normalize after a bone infection becomes sterile, and thus it may be impossible to distinguish a chronic infection of bone from normal healing.

2.
Magnetic resonance imaging

Equally sensitive as or even more sensitive than bone scintigraphy for detecting hematogenous osteomyelitis, although neither technique is specific

Note: CT has a limited role in the early diagnosis of osteomyelitis.

Osteomyelitis (Vertebral)
Presenting Signs and Symptoms

Insidious onset and gradual progression of back pain unrelieved by heat, rest, or analgesics and worsened by movement

Fever typically is minimal or absent

Tenderness to palpation and percussion over affected bone

Paravertebral muscle spasm

Guarding and splinting on motion
Approach to Diagnostic Imaging

1.
Radionuclide bone scan

Demonstrates increased activity early in the disease (evidence of bone destruction on plain skeletal radiographs usually does not appear for at least 1 week)
Caveat: Increased radionuclide uptake may be impossible to distinguish from that occurring with tumors and fractures.

2.
Magnetic resonance imaging

Sensitive for demonstrating a focal abnormal signal intensity in the bone marrow, but does not accurately distinguish between infection and tumor

Can effectively reveal the full extent of soft-tissue involvement (as can CT)

Notes: Plain radiographs of the spine are not sensitive for detecting vertebral osteomyelitis. However, the findings of vertebral body destruction and rapid loss of the adjacent intervertebral disc are highly suggestive of the diagnosis of bacterial infection.

Neoplasm

Skeletal Metastases
Presenting Signs and Symptoms

Most often asymptomatic (discovered during staging procedures)

Back pain
Common Primary Tumors

Lung

Breast

Prostate

Thyroid

Kidney

Lymphoma

Melanoma
Approach to Diagnostic Imaging

1.
Radionuclide bone scan

Preferred screening technique for detecting asymptomatic skeletal metastases, which appear as focal areas of increased radionuclide uptake (hot spots)

Note: False-negative results may occur if there is uniform, symmetric uptake of radionuclide by diffuse metastases (“superscan”). The proper diagnosis should be suggested by decreased or no labeling of the kidneys (all radionuclide taken up by skeletal structures so that little or none remains to be excreted by the usual renal route).

2.
Plain skeletal radiograph

If the radionuclide scan is equivocal, plain films should be obtained to confirm that a hot spot represents a metastasis rather than one of the many benign processes that can also cause increased uptake (e.g., infection, degenerative disease, trauma)

Generally not indicated if there are multiple focal radionuclide scan abnormalities involving the axial skeleton that are virtually pathognomonic of metastases
Caveat: Never order a “skeletal survey” to screen for metastases. Plain radiographs are insensitive (40–80% of cancellous bone must be destroyed before a lesion is apparent on these films).

3.
Computed tomography or magnetic resonance imaging

Indicated to evaluate nonspecific focal abnormality on radionuclide scan or specific symptomatic areas that cannot be demonstrated or adequately characterized on plain radiographs
Caveat: Neither CT nor MRI should ever be used as the initial screening test for suspected skeletal metastases, although either may be used to further define a symptomatic region of the body in a patient with a known primary malignant tumor.
Multiple Myeloma
Presenting Signs and Symptoms

Persistent unexplained skeletal pain (especially in the back or thorax)

Pathologic fractures and vertebral collapse

Renal failure

Recurrent bacterial infections (especially pneumococcal pneumonia)

Anemia with weakness and fatigue

Hypercalcemia

Excess immunoglobulins

Bence Jones protein
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

Demonstrates either diffuse osteoporosis or multiple discrete osteolytic (“punched-out”) lesions (due to replacement by expanding plasma cell tumors or elaboration of an osteoclast-stimulating factor); these lesions are often associated with pathologic fractures or vertebral collapse

Diffuse changes may be difficult to recognize unless thinning and expansion of the cortices are appreciated

2.
Magnetic resonance imaging

Preferred imaging study for showing the characteristic diffuse marrow abnormalities (low-intensity tumor replaces normal high-intensity marrow fat on T1-weighted images)

Can demonstrate compression of the spinal cord secondary to vertebral collapse
Caveat: Radionuclide bone scan is not indicated as a screening test for multiple myeloma because the process is primarily osteolytic with little bone production (thus radionuclide scans typically are falsely normal). “Skeletal survey” is not indicated as a screening test because it is insensitive.
Osteoid Osteoma
Presenting Signs and Symptoms

Pain that classically is worse at night and relieved by small doses of aspirin

Almost always in patients younger than 30 years
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

May demonstrate the characteristic appearance of a small radiolucent zone (nidus) surrounded by a large sclerotic zone (reactive bone)

2.
Radionuclide bone scan

Indicated if plain film findings cannot distinguish osteoid osteoma from osteomyelitis

Note: Because the nidus is extremely vascular, it avidly accumulates the radionuclide, producing the typical “double-density” sign representing an area of avid radionuclide uptake (nidus) surrounded by a region of moderately increased uptake (reactive bone). This is in contrast to the central photopenic area of osteomyelitis that represents an avascular focus of purulent material.

3.
Computed tomography

Indicated to define the exact location of the nidus (if not clearly seen on plain films) prior to surgery (because removal of the nidus usually results in complete cessation of pain)
Caveat: MRI findings in osteoid osteoma include extensive marrow and soft-tissue edema resembling those of a malignant tumor or osteomyelitis.
Primary Malignant Tumors of Bone
Presenting Signs and Symptoms

Pain, soft-tissue mass
Common Types

Osteosarcoma, fibrosarcoma, chondrosarcoma, Ewing’s sarcoma
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

Preferred initial imaging study for demonstrating a lesion’s site and appearance (which combined with a patient’s age may permit a specific diagnosis)

Note: If a single lesion is detected that could represent a metastasis, a radionuclide bone scan (not a plain-film skeletal survey) is essential to detect any other clinically silent lesions.

Caveat: Although plain radiographic signs may aid in distinguishing benign from malignant lesions, none is infallible, and a biopsy may be required.

2.
Magnetic resonance imaging

Best imaging modality for determining the bony and soft-tissue extent of a lesion (required prior to surgical resection)
Caveat: The ability of MRI to distinguish benignity from malignancy is controversial, and it may be impossible to determine whether high signal radiating from involved bone in some imaging sequences represents soft-tissue edema or tumor spread.
Soft-tissue Tumor of Extremity
Presenting Signs and Symptoms

Asymptomatic (incidentally noted either by the patient or an examining physician)

Variety of clinical manifestations, depending on the site and type of lesion
Common Causes

Lipoma

Melanoma

Liposarcoma

Malignant fibrous histiocytoma
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

Neither sensitive nor specific, but usually performed initially to demonstrate the soft-tissue lesion, its effect on the underlying bone, and any associated calcification

2.
Computed tomography or magnetic resonance imaging

Most accurate imaging procedures for defining the extent of a soft-tissue mass and its relationship to adjacent structures
Caveat: Although these techniques can sometimes suggest the nature of a soft-tissue neoplasm (especially those containing fat), a biopsy is generally required to determine the precise histologic diagnosis.

3.
Ultrasound

Imaging modality of choice for determining whether a superficial soft-tissue mass thought to represent a cyst is truly fluid-filled

4.
Arteriography

May be indicated as a preoperative study to determine the vascular anatomy

May be helpful in localizing an area within the mass that will most likely yield accurate biopsy data (the most malignant sites tend to have the greatest vascularity)

Trauma

Pathologic Fracture
Presenting Signs and Symptoms

Evidence of a fracture following a trivial injury or without a history of trauma

Concomitant evidence of preexisting abnormality (angular deformity, painless swelling, or generalized bone pain)
Common Causes

Malignant neoplasms

Metastases

Benign lesions (e.g., simple bone cyst, enchondroma, giant cell tumor)

Osteoporosis
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

Preferred initial study for demonstrating that the fracture line traverses a large area of bone destruction or that adjacent or distant bones are riddled with additional lesions
Caveat: If the underlying lesion is small, the fracture itself may obscure the abnormal lytic or sclerotic area (especially if there is displacement at the fracture site).

2.
Computed tomography or magnetic resonance imaging

May be useful for detecting more subtle indications of underlying abnormal bone
Hip Fracture
Presenting Signs and Symptoms

History of fall with inability or significant difficulty in weight bearing on involved extremity

Pain and bruising in hip region
Common Causes

Trauma

Osteoporosis
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

Provides definite diagnosis of fracture in the vast majority of cases

Angled projection may be necessary to demonstrate nondisplaced fracture of the femoral neck

2.
Magnetic resonance imaging

Highly sensitive for detecting radiographically occult fracture

Indicated if there is a high clinical suspicion of fracture despite normal plain films

3.
Radionuclide bone scan

If MRI is not available, can be used to detect or exclude occult fracture in patient with a high clinical suspicion despite negative plain films

Because false-negative results may occur in a small percentage of patients (especially the elderly) during the first 72 hours after fracture, a repeat scan may be required to reliably exclude a fracture
Pelvic Fracture
Presenting Signs and Symptoms

History of major trauma to pelvis

Pain and bruising in the pelvic region

Substantial internal blood loss

Hematuria
Common Cause

Trauma
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

Provides definite diagnosis of fracture in most cases (without the need to move the patient, who may have suffered multiple injuries)

Oblique and angled views (inlet, outlet, Judet) may be required to diagnose or exclude minor fracture

Second fractures are typical
Caveat: Sacral foramina fractures may be difficult to detect.

2.
Computed tomography

Indicated if there is a high clinical suspicion of fracture despite normal plain films

Especially valuable for detecting occult sacral fractures, as well as bone fragments in the hip joint associated with an acetabular fracture

Can demonstrate hemorrhage and soft-tissue injuries that often occur in conjunction with pelvic fractures

3.
Magnetic resonance imaging

May reveal marrow edema about the fracture site (although the fracture line itself is better seen with CT)

Note: In patients with massive hemorrhage, arteriography may be required to identify the bleeding site and permit transcatheter embolization therapy. Retrograde urethrography and cystography are indicated in fractures of the anterior pelvis to exclude injury to the posterior urethra and bladder.

Scaphoid Fracture
Presenting Signs and Symptoms

Pain in the region of the anatomic snuff-box

High incidence of complications (delayed union, nonunion, avascular necrosis)
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

Preferred initial study (although it fails to detect up to 25% of nondisplaced fractures)

Delayed radiographs (after 1 to 2 weeks of immobilization) often demonstrate “initially occult” fractures because of resorption and better demarcation around the fracture line

2.
Magnetic resonance imaging

High sensitivity for detecting fractures not evident on initial plain radiographs

Enables early diagnosis and definitive treatment (decreases risk of complications)

Acute fractures have decreased signal intensity of the proximal pole of T1-weighted images and increased signal on T2-weighted and fat-suppression sequences

Avascular necrosis classically has low signal intensity on all sequences

Gadolinium-enhanced sequences may be of value in selecting patients with acute fractures who are likely to develop avascular necrosis or delayed union, as well as in assessing surgical eligibility in those with established nonunion or avascular necrosis

3.
Radionuclide bone scan

Traditionally considered the imaging modality of choice for early diagnosis of occult fractures (high sensitivity, with optimal imaging at 48 hours after injury)

Similar findings of increased uptake can be seen in disuse states, ligamentous injuries, and reflex sympathetic dystrophy

Lack of spatial resolution may necessitate further imaging studies (CT, MRI) for more precise anatomic information prior to definitive treatment

Negative bone scan virtually excludes the possibility of scaphoid or other occult fracture
Stress Fracture
Presenting Signs and Symptoms

Activity-related pain relieved by rest (typically associated with the repetition of a new or different strenuous activity)

Localized tenderness and soft-tissue swelling
Common Examples

March fracture (metatarsals in military recruits)

Lower extremity fractures in athletes, joggers, and dancers
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

May demonstrate a radiolucent line or a band of sclerosis associated with periosteal and endosteal thickening
Caveat: Plain radiographic evidence of a stress fracture may not be detectable for several weeks.

2.
Radionuclide bone scan

Sensitive for early detection of a stress fracture

May be impossible to differentiate shin splint from early stress fracture (treated differently)

Triple-phase technique should be used to maximize specificity

3.
Magnetic resonance imaging

Extremely sensitive for detecting stress injuries and may prove to be more specific than radionuclide scanning

Usually reserved for cases in which radiographic findings are indeterminate

In early stress fractures, the marrow has low signal intensity on T1-weighted images and has progressively higher intensity with increased T2-weighting

Fat-saturation techniques are especially useful, with the increased water content of the associated medullary edema or hemorrhage resulting in high signal intensity against the dark background of suppressed fat

Fracture line may not be seen
Meniscal Tear (Knee)
Presenting Signs and Symptoms

Pain and swelling

Click in movement of the joint

Knee “giving way” or locking in a single position
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Imaging procedure of choice for detecting partial and complete meniscal tears, as well as associated abnormalities of the collateral and cruciate ligaments

Note: Arthrography of the knee is not commonly performed.

Caveat: The need for both MRI and arthroscopy is controversial. Some studies have indicated that arthroscopy alone is sufficient and financially advisable, except perhaps in instances of recurrent knee pain following previous meniscal surgery or repair.
Rotator Cuff Tear
Presenting Signs and Symptoms

Pain when the arm is raised above the shoulder or adducted across the chest, but not when the arm is held down by the side

Weakness of shoulder abduction (due to underuse atrophy of the deltoid)
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging (shoulder)

Rapidly becoming the imaging procedure of choice for detecting partial and complete rotator cuff tears

Noninvasive and does not require the technical expertise required for shoulder arthrography

Note: The imaging workup is based on the needs of the orthopedic surgeon. If all that is needed is the detection of full-thickness tears of the rotator cuff (as opposed to partial-thickness tears), arthrography of the glenohumeral joint is generally sufficient.

2.
Ultrasound

Sensitive for diagnosing rotator cuff tear, but requires considerable examiner expertise
Child Abuse
Presenting Signs and Symptoms

Nonaccidental intracranial and skeletal injuries (due to direct blows or shaking)

Most commonly involves children younger than age 2

May be bruises, seizures, coma, lethargy, retinal hemorrhage, shallow respirations
Approach to Diagnostic Imaging

1.
Plain radiographs (skeletal survey)

Demonstrates multiple fractures of varying age or unusual fractures

Injuries highly specific for child abuse include metaphyseal (corner) fractures and fractures of the posterior ribs, sternum, scapula, and spinous processes

Less specific injuries include epiphyseal injuries, complex skull fractures, and fractures of the vertebral bodies, metacarpals, and metatarsals

Fractures of the clavicle and the shafts of long bones also are common

2.
Computed tomography or magnetic resonance imaging

Indicated if there is a complex skull fracture or clinical evidence of intracranial injury to detect subdural hematoma, cortical contusion, shearing injury, or subarachnoid hemorrhage

3.
Radionuclide bone scan

May be effective to survey the entire skeleton, although metaphyseal fractures may be missed

Note: There is generally no indication for any other imaging study.

Other

Avascular Necrosis
Presenting Signs and Symptoms

Pain (most commonly affecting the hip or knee, although the ankle, shoulder, and elbow also may be involved)
Common Causes

Trauma

Steroid therapy

Alcoholism

Pancreatitis

Collagen vascular diseases

Sickle cell disease and other hemoglobinopathies

Renal transplantation

Infiltrative diseases (e.g., Gaucher’s disease)

Caisson’s disease (“the bends”)

Legg-Calvé-Perthes disease
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

Not sensitive, but ideal for following the disorder from patchy sclerosis and subchondral lucency (thin line beneath the articular surface) to collapse of the articular surface, dense bony sclerosis, and joint fragmentation

2.
Magnetic resonance imaging

Most sensitive study for detecting the earliest changes of avascular necrosis when plain radiographs and radionuclide scans are normal

In the hip, may demonstrate a characteristic abnormal signal intensity area on some imaging sequences that virtually always involves the anterosuperior portion of the femoral head

3.
Radionuclide bone scan

May show abnormal uptake when plain radiographs are still normal (although not as sensitive as MRI)
Carpal Tunnel Syndrome
Presenting Signs and Symptoms

Pain, paresthesias, and sensory deficits in the distribution of the median nerve

May be weakness or atrophy in the muscles controlling abduction and apposition of the thumb

Positive Tinel’s sign (paresthesias after percussion of the median nerve in the volar aspect of the wrist)
Predisposing Factors

Occupations requiring repetitive hand and wrist motion

Gout

Calcium pyrophosphate deposition disease (CPPD)

Acromegaly

Myxedema

Pregnancy

Oral contraceptives
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Can show swelling of the median nerve at the proximal carpal tunnel, flattening of the nerve at the distal carpal tunnel, and signal abnormalities within or surrounding the median nerve

Excellent soft-tissue contrast allows demonstration of subtle soft-tissue changes and mild compression of the median nerve

Modality of choice for assessing surrounding bony structures

2.
Ultrasound

Suggested as a low-cost alternative to MRI (similar imaging criteria)

3.
Computed tomography

Can assess the fibrous roof of the carpal tunnel and analyze the structures coursing through the canal

Note: CT is of limited value because of the similar attenuation values of the contents of the carpal tunnel.

4.
Plain radiograph (wrist)

Specific radiographic projections (including the carpal tunnel view) can permit an evaluation of the osseous structures bordering the carpal tunnel
Congenital Hip Dislocation
Presenting Signs and Symptoms

Inability to completely abduct the thigh to the surface of the examining table when the hip and knee are flexed (Ortolani’s sign)

Hip click (audible or palpable “clunk”) with abduction and external rotation of the femur (as the femoral head reenters the acetabulum)

If unilateral, shortened leg with asymmetric skin creases in the thigh
Predisposing Factors

Female infants

Breech presentation

Positive family history
Approach to Diagnostic Imaging

Note: Congenital hip dislocation is a clinical diagnosis.

1.
Plain radiograph (hips)

Often not diagnostic in the neonatal period, but may be of value as a baseline study (to permit comparison with subsequent radiographic assessment as the child grows and develops)

2.
Ultrasound

Can confirm the clinical diagnosis, even in the neonatal period, with dynamic imaging (counterpart to clinical maneuvers used in physical examination)

3.
Magnetic resonance imaging

May reveal structural abnormalities not evident on routine radiographs
Myasthenia Gravis

Presenting Signs and Symptoms

Ptosis, diplopia, and muscle fatiguability after exercise

Dysarthria and dysphagia

Bulbar symptoms (alteration in voice, nasal regurgitation, choking)

Life-threatening respiratory muscle involvement (10%)

Positive edrophonium test
Common Causes

Autoimmune condition associated with thymoma in up to 30% of patients

Note: A larger percentage (up to 50%) of patients with thymoma have or will develop myasthenia gravis.

Approach to Diagnostic Imaging

1.
Plain chest radiograph

Initial imaging procedure for detecting a thymoma, which appears as a smooth or lobulated soft-tissue mass that typically arises near the origin of the great vessels at the base of the heart

2.
Computed tomography

Most sensitive technique for detecting small thymomas not evident on conventional radiographs

Preferred method for demonstrating local invasion of tumor through thymic capsule to involve pleura, lung, pericardium, chest wall, diaphragm, and great vessels (occurs in 10–15% of patients)
Caveat: Even CT may be unable to distinguish small thymic tumors from a normal or hyperplastic gland, especially in young patients with a large amount of residual thymic tissue.
Osgood-Schlatter Disease
Presenting Signs and Symptoms

Pain, swelling, and tenderness over the anterior tibial tubercle (at the patellar tendon insertion)
Common Cause

Trauma from excessive traction by the patellar tendon on its immature apophyseal insertion
Approach to Diagnostic Imaging

1.
Plain radiograph (knee)

Demonstrates soft-tissue swelling associated with fragmentation of the anterior tibial tubercle

2.
Magnetic resonance imaging

Often reveals diffuse thickening of the patellar tendon
Paget’s Disease
Presenting Signs and Symptoms

Usually asymptomatic (discovered incidentally on radiographs or routine laboratory studies)

Symptoms (typically insidious onset) may include pain, pathologic fracture of weakened bone, deformities, high-output cardiac failure, headaches, decreased hearing, and increasing skull size

Increasingly severe pain suggests fracture or sarcomatous degeneration (1% of patients)
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

Demonstrates cortical thickening and overall increased density of affected bones, which have an abnormal internal architecture and often show bowing or overgrowth

Detects pathologic fractures or microfractures (tibia, femur)

Shows areas of osteolysis in cases of sarcomatous degeneration

2.
Radionuclide bone scan

Most efficient method for screening multiple areas of the skeleton to search for multicentric lesions

Note: MRI and CT are the most accurate imaging modalities in the patient with suspected sarcomatous degeneration of Paget’s disease.

Painful Prosthesis
Presenting Signs and Symptoms

Pain in and around the affected joint

Fever, leukocytosis (if infected)
Common Causes

Loosening of prosthesis

Infection

Particle disease related to inflammatory reaction about polyethylene or cement fragments

Pathologic fracture
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

Can demonstrate excessive lucency around the prosthesis, fracture of the prosthesis or adjacent bone, or prosthesis dislocation

2.
Radionuclide bone scan

Indicated if there is a high clinical suspicion of loosening or infection despite normal plain films

Negative scan makes infection unlikely

Note: If there is clinical suspicion of infection, the joint is aspirated to obtain fluid for culture.

3.
Arthrography

Can demonstrate loosening by showing gap between prosthesis, cement, and bone when contrast material is injected under pressure

Analysis and culture of fluid obtained during procedure can diagnose or exclude infection

4.
Magnetic resonance imaging

Currently, no role in assessing the painful prosthesis containing metal, but can be used to assess synovitis related to Silastic™ implants
Reflex Sympathetic Dystrophy (Sudeck’s Atrophy)
Presenting Signs and Symptoms

Pain and tenderness (usually of a hand or foot) associated with vasomotor instability, trophic skin changes, and rapid development of osteopenia
Common Causes

Local trauma

Peripheral nerve injury

Stroke
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

May demonstrate diffuse or patchy osteopenia of the involved extremity (especially the hands or feet)

2.
Radionuclide scan

Demonstrates diffuse increased uptake in the involved area (but this is nonspecific)

May show foci of decreased radionuclide uptake in children
Slipped Capital Femoral Epiphysis
Presenting Signs and Symptoms

Insidious onset of hip stiffness that improves with rest

Limp

Hip pain (radiating down the anteromedial thigh to the knee)

In advanced cases, pain on motion of the affected hip, with limited flexion, abduction, and medial rotation

May be associated with chondrolysis and avascular necrosis with epiphyseal collapse (if blood supply is compromised)

Most commonly affects overweight teenagers (usually boys)
Approach to Diagnostic Imaging

1.
Plain radiograph (hip)

Demonstrates widening of the physeal line and/or displacement (posterior and inferior) of the femoral head
Caveat: Early diagnosis dramatically improves the outcome because treatment becomes more difficult in advanced stages.
CHAPTER 6. NEUROLOGIC
What to Order When

CHAPTER 6. NEUROLOGIC

Burton P. Drayer

SIGNS AND SYMPTOMS

Acute Altered Mental Status
Presenting Signs and Symptoms

Vigorous stimuli required to elicit a response (stupor)

Unarousable unresponsiveness (coma)
Common Causes

Trauma (diffuse cerebral edema; epidural, subdural, intraparenchymal, or subarachnoid hemorrhage)

Anoxia or ischemia (stroke, syncope)

Epilepsy (postictal state)

Exogenous toxins (alcohol, hypnotics, narcotics)

Endogenous toxins (uremia, hepatic coma, diabetic acidosis, hypoglycemia, hyponatremia)

Brain tumor, infarction, abscess, or meningitis
Approach to Diagnostic Imaging

1.
Computed tomography

Can rapidly determine whether there is extra-axial hemorrhage, mass lesion, or herniation requiring emergency surgical decompression

Caveat: Because patients with disordered consciousness due to high intracranial pressure can deteriorate rapidly, therapy should not be delayed if CT cannot be obtained promptly.

2.
Magnetic resonance imaging

Procedure of choice in subacute phase for better visualization of the temporal lobes (e.g., herpes encephalitis), brain stem (e.g., central pontine myelinolysis), white matter (e.g., gliomatosis cerebri), superior colliculi and mammillary bodies (Wernicke’s), and globus pallidus (e.g., hepatic encephalopathy)

Note: Plain skull radiographs are of no value and should not be obtained.

Amaurosis Fugax
Presenting Sign and Symptom

Ipsilateral blindness that usually resolves fully within 2 to 30 minutes (sudden onset and brief duration)
Common Causes

Plaques or atherosclerotic ulcers involving the carotid artery in the neck

Emboli arising from mural thrombi in a diseased heart
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging (brain)

Can evaluate for infarction

2.
Magnetic resonance angiography (neck and head)

Excellent screening study for excluding significant atherosclerotic narrowing, detecting vascular occlusion, and visualizing the vertebral and the anterior, middle, and posterior cerebral arteries (in addition to the carotids)

Note: The surgical criteria of 60% stenosis (Asymptomatic Carotid Artery Stenosis Trial [ACAST]) or 70% stenosis (North American Symptomatic Carotid Endarterectomy Trial [NASCET]) can be established using magnetic resonance angiography (MRA) of the neck and head. Although nonenhanced and three-dimensional time-of-flight MRA are excellent, the addition of a rapid bolus infusion of paramagnetic contrast material may improve visualization of the carotid bifurcation and definitely improves visualization of the aortic arch.

3.
Duplex, color-flow Doppler ultrasound

Accurate noninvasive screening study that combines high-resolution, real-time imaging of the carotid arteries with hemodynamic information about blood flow velocity provided by the Doppler technique

When used with MR angiography, may obviate the need for presurgical angiography

Note: Other noninvasive tests (ophthalmodyna-mometry, oculoplethysmography) are not indicated because they cannot accurately detect carotid plaques and ulcerations.

4.
Echocardiography

Indicated to detect mural thrombi in the heart if no carotid lesion has been identified that could explain the patient’s symptoms

5.
Intraarterial digital subtraction angiography

Invasive study that provides the highest-resolution images of intraluminal vascular pathology

Indicated prior to surgical intervention if US demonstrates a high-grade stenosis or ulcerated plaque in the carotid artery

6.
Computed tomography (brain)

Can evaluate for infarction, but less sensitive than magnetic resonance imaging (MRI)

7.
Computed tomography angiography

May prove more sensitive than even color duplex US, but requires the rapid infusion of iodinated contrast material
Aphasia
Presenting Signs and Symptoms

Language disorder (abnormal comprehension, inability to speak properly, incorrect usage of words)

Receptive aphasia (Wernicke’s area)

Conduction aphasia (arcuate fasciculus)

Expressive aphasia (Broca’s area)

May be associated with right hemiparesis (usually due to a cortical lesion in the left middle cerebral artery distribution) or right hemisensory deficit

Must be distinguished from dysarthria, an abnormality of motor speech articulation rather than language
Common Causes

Cerebral infarction (dominant hemisphere)

Intracerebral hematoma

Intracerebral neoplasm or abscess (slower, subacute onset)
Approach to Diagnostic Imaging

1.
Computed tomography

Rapidly identifies or excludes intracranial hemorrhage, infarction, or mass

Remains the “gold standard” for distinguishing acute intracerebral hematoma from cerebral infarction

2.
Diffusion-weighted magnetic resonance imaging

Routinely perform T1-weighted, intermediate or FLAIR, and T2-weighted pulse sequences

Highly sensitive for diagnosing acute stroke within 3 hours of symptom onset

If negative, extremely accurate in excluding acute cerebral infarction

Provides improved localization and characterization of any cerebral abnormality detected by CT (e.g., vascular malformation, complicated hemorrhagic process, mass lesion) and improved specificity for distinguishing the etiology of aphasia

3.
Magnetic resonance angiography (neck and head)

Can often detect the site of a stenosis or occlusion related to acute infarction

Caveat: Arteriography is indicated only if noninvasive studies suggest an underlying aneurysm or arteriovenous malformation and a surgical or interventional radiologic procedure is seriously being considered.
Ataxia
Presenting Signs and Symptoms

Disorder of stance and gait

Axial signs may predominate (midline cerebellar abnormality)

Appendicular (extremity) signs may predominate (hemispheric cerebellar abnormality)

May have associated tremor, nystagmus, or cranial nerve findings

Must be distinguished from gait apraxia (frontal lobe abnormality) and gait instability related to lower motor neuron disease
Common Causes

Any abnormality involving the cerebellum, cerebellar peduncles, or cerebellar pathways in the brain stem

Common diseases include

Metabolic (alcohol- and anticonvulsant-related, remote effects of carcinoma)

Neurodegenerative (familial cerebellar degeneration, including olivopontocerebellar atrophy, Friedreich’s ataxia, and Holmes’ cerebellar atrophy)

Neoplasms (commonly medulloblastoma, astrocytoma, and ependymoma in children and metastases and hemangioblastoma in adults)

Demyelinating (multiple sclerosis, acute disseminated encephalomyelitis, progressive multifocal leukoencephalopathy)

Vascular (cerebellar hematoma or infarction)

Cysts (arachnoid, epidermoid)
Approach to Diagnostic Imaging

1.
Computed tomography

Procedure of choice in an acute case without a history of trauma to exclude an acute intraparenchymal hemorrhage or mass effect on posterior fossa structures

Less sensitive than MRI for evaluating the posterior fossa because of transverse artifacts from the temporal bones and single axial-plane visualization

2.
Magnetic resonance imaging

Procedure of choice for chronic or progressive gait disturbance

Nonenhanced study is generally adequate in terms of sensitivity and provides the added benefit of delineating secondary abnormalities (e.g., basal ganglia abnormalities in olivopontocerebellar atrophy, additional lesions in metastases)

Contrast enhancement may improve specificity (e.g., enhancing peripheral nodule in cystic hemangioblastoma, detection of multiple metastases)

Caveat: Arteriography is indicated only if noninvasive studies suggest an underlying aneurysm or arteriovenous malformation and a surgical or interventional radiologic procedure is seriously being considered.
Carotid Bruit (Asymptomatic)
Presenting Signs and Symptoms

Asymptomatic

High-pitched sound heard over the region of the carotid artery bifurcation in the neck (must be distinguished from a venous hum, which is continuous, heard best with the patient sitting or standing, and eliminated by compression of the ipsilateral internal jugular vein)
Common Cause

Narrowing of the lumen of the extracranial carotid artery related to atherosclerotic cerebrovascular disease
Approach to Diagnostic Imaging

1.
Duplex, color-flow Doppler ultrasound

Accurate noninvasive screening study that combines high-resolution, real-time imaging of the carotid arteries with hemodynamic information about blood flow velocity provided by the Doppler technique (negative predictive value greater than 99%)

Should be performed in patients with cervical bruits who are scheduled to undergo major vascular surgery elsewhere (greater than 80% carotid stenosis increases the risk for transient ischemic attack or stroke during surgery)

About 20% of carotid arteries considered to be completely occluded may still have some lumen patency.

Note: Although some advocate a battery of noninvasive tests, including ophthalmodynamometry and oculoplethysmography, these generally only add unnecessary expense.

2.
Magnetic resonance imaging (brain)

Can evaluate for infarction

3.
Magnetic resonance angiography (neck and head)

Excellent screening study for excluding significant atherosclerotic narrowing, detecting vascular occlusion, and visualizing the vertebral and the anterior, middle, and posterior cerebral arteries, in addition to the carotids

Note: If a flow gap is present (greater than 60% stenosis), then Doppler US is performed for better determination of whether the lesion falls within the surgical guidelines of 60% stenosis (ACAST) or 70% stenosis (NASCET).

4.
Intraarterial digital subtraction angiography

Invasive study that provides the highest-resolution images of intraluminal vascular pathology

Indicated prior to surgical intervention if US demonstrates a high-grade stenosis of the carotid artery

5.
Computed tomography (brain)

Can evaluate for infarction, but less sensitive than MRI

6.
Computed tomography angiography

May prove more sensitive than even color duplex US, but requires the rapid infusion of iodinated contrast material
Dementia or Movement Disorder
Presenting Signs and Symptoms

Permanent or progressive decline in intellectual function (recent memory, concentration, judgment, orientation, ability to speak or read)

Parkinsonian symptoms (including bradykinesia, rigidity, tremor)
Common Causes

Alzheimer’s disease (also Pick’s disease, frontobasal degeneration)

Parkinson’s disease

Multi-infarct

Metabolic/nutritional/endocrine (including Wernicke-Korsakoff syndrome)

Brain tumor

Chronic central nervous system infection

Normal pressure hydrocephalus

AIDS encephalopathy

Repetitive trauma (e.g., boxers)

Chronic subdural hematoma

Creutzfeldt-Jakob (prion) encephalopathy
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Most sensitive for demonstrating large masses, hydrocephalus, and other treatable abnormalities, as well as ischemic white matter disease, small infarctions, and Wernicke-Korsakoff syndrome

Increased iron in the corpus striatum (T2-weighted, 1.5-T studies) suggests Parkinson’s disease that will not be responsive to drug therapy (multiple system atrophy)

Increased signal in the globus pallidus on T1-weighted imaging (manganese accumulation) is seen with hepatic failure

Hyperintense signal in the putamen on T2-weighted imaging and in the cortex on diffusion imaging suggests Creutzfeldt-Jakob encephalopathy

2.
Positron emission tomography (PET)

Can be used as an adjunct examination in patients with suspected Alzheimer’s disease because the glucose usage pattern is relatively specific

Caveat: Because brain “atrophy” increases with age in persons with normal mental status, MRI (or CT) provides no reliable indication of intellectual impairment in the elderly population.
Developmental Disorders
Presenting Signs and Symptoms

Broad spectrum of neurologic deficits
Common Types

Cephaloceles

Chiari malformations

Tuberous sclerosis

Sturge-Weber syndrome

Von Hippel-Lindau disease

Cerebellar dysplasia

Posterior fossa cystic malformations (e.g., Dandy-Walker deformity)

Neurofibromatosis

Holoprosencephaly

Migration disorders (lissencephaly, pachygyria, polymicrogyria, heterotopic gray matter, schizencephaly, abnormalities of the corpus callosum)
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Imaging procedure of choice for characterizing and defining the extent of developmental disorders of the CNS

Other advantages include multiplanar imaging and the ability to image the spinal canal, as well as the brain

2.
Computed tomography

If the patient is uncooperative and heavy sedation is contraindicated, ease of access and rapid scanning may permit performance of CT

Useful for follow-up of shunt function
Headache
Common Causes

Increased intracranial pressure (neoplasm, abscess, hemorrhage, meningeal irritation)

Vascular disturbance (migraine, hypertension, cluster headaches)

Toxins (alcoholism, uremia, lead, systemic infection)

Trauma

Extracranial site (disorders of paranasal sinuses, eye, ear, teeth, cervical spine)

Temporal arteritis (in elderly population)
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Most sensitive technique for detecting cerebral lesions responsible for headache (especially in patients who have coexistent abnormal neurologic signs)

Imaging evaluation is usually unnecessary in patients with no neurologic abnormalities and who have either continuous headaches of long duration (many months or years) or intermittent recurrent headaches.

If an aneurysm is suspected even though CT is normal, a lumbar puncture and MRA of the head can be performed
Caveat: Patients with severe acute headaches should be imaged with noncontrast head CT because of the suspicion of subarachnoid hemorrhage, acute hydrocephalus, or an enlarging intracranial mass.

Note: There is no indication for conventional skull radiographs. If disease of the paranasal sinuses is suspected, a limited coronal CT study can be performed.

Hearing Loss: Conductive
Sites of Dysfunction

Any process that impedes transmission of sound waves from the auricle to the oval window

Note: Audiometry and careful clinical examination are essential to distinguish conductive from sensorineural hearing loss.

Common Causes

Complete obstruction of external auditory canal

Congenital atresia or stenosis

Neoplasm (exostosis)

Cholesteatoma

Cerumen impaction

Disorders of tympanic membrane

Chronic inflammation

Recurrent inflammation and healing (myringosclerosis)

Perforation

Disorders of middle ear

Congenital

Inflammation and infection (effusion)

Neoplasm (glomus tympanicum tumor)

Trauma (ossicular disruption, hemotympanum)
Approach to Diagnostic Imaging

1.
Computed tomography

Thin bone algorithms demonstrate the location and extent of middle ear neoplasms (rather than tumor enhancement) to allow the diagnosis

Contrast-enhanced imaging with soft-tissue algorithms is useful to evaluate extratemporal extension of tumors

2.
Magnetic resonance imaging

Thin-section, T2-weighted images may highlight the presence and extension of inflammatory and neoplastic abnormalities
Hearing Loss: Sensorineural
Sites of Dysfunction

Neuroepithelial hair cells of cochlea (sensory loss)

Neurons of spiral ganglion and central auditory pathways (neural loss)

Note: Hearing loss may have associated vestibular symptomatology.
Audiometry and careful clinical examination are essential to distinguish conductive from sensorineural hearing loss.

Common Causes

Congenital (genetic abnormalities, intrauterine exposure to drugs, toxins, infection)

Infection (viral, mumps, syphilis, labyrinthitis ossificans)

Neoplasm (acoustic schwannoma, meningioma, meningeal carcinomatosis, metastasis, epidermoid)

Trauma (cochlear “concussion,” fracture through labyrinth or internal auditory canal)

Autoimmune (systemic lupus erythematosus, Wegener’s granulomatosis, polyarteritis nodosa, Cogan’s syndrome, sarcoidosis)

Vascular (compromise of inner ear blood supply, sickle cell disease)

Metabolic (hypothyroidism, diabetes mellitus)

Multiple sclerosis (brain stem)
Approach to Diagnostic Imaging
TEENAGER/ADULT

1.
Magnetic resonance imaging

Best modality for demonstrating small tumors, abnormal labyrinth signal intensity, leptomeningeal enhancement, and brain parenchymal disease

Routine use of thin-section axial and coronal images using T1- and T2-weighted and enhanced T1-weighted images

2.
Computed tomography

Indicated for patients with trauma or suspicion of labyrinth dysplasia

Thin-section axial and coronal images using bony algorithms
INFANT/CHILD

1.
Computed tomography

Preferred modality for showing inner ear dysplasia
Caveat: Be aware of radiation dosage.

2.
Magnetic resonance imaging

Indicated for patients with suspected brain parenchymal disease who have a normal CT scan
Hearing Loss: Mixed
Sites of Dysfunction

Combination of sensorineural and conductive hearing loss
Common Causes

Otosclerosis

Osteogenesis imperfecta

Paget’s disease

Osteopetrosis (marble-bone disease)

Engelmann’s disease (progressive diaphyseal dysplasia)

Pyle’s disease (craniometaphyseal dysplasia)
Approach to Diagnostic Imaging

1.
Computed tomography

Thin bone algorithms are employed to detect conductive component

Contrast-enhanced imaging with soft-tissue algorithms of the internal auditory canal and brain are used to identify sensorineural component

2.
Magnetic resonance imaging

Utilize 3-mm sections in the axial and coronal planes

Infusion of contrast material is helpful for defining small tumors in the internal auditory canal region and multiple schwannomas
Proptosis
Presenting Signs and Symptoms

Anterior displacement of the globe (exophthalmos)

Redness and irritation of the eye
Common Causes

Trauma

Graves’ disease (thyroid ophthalmopathy)

Orbital neoplasm

Orbital inflammatory disease
Approach to Diagnostic Imaging

1.
Computed tomography

Procedure of choice for detecting fracture, retrobulbar hematoma, radiopaque foreign body, or abnormality of the globe

Detection of calcification often assists in improving diagnostic accuracy

Provides excellent visualization of extraocular muscles, orbital apex, and orbital vasculature

2.
Magnetic resonance imaging

Indicated if CT is equivocal or if there is clinical suspicion of intracranial extension of an orbital abnormality, carotid–cavernous mass, or carotid–cavernous fistula

Caveat: MRI is contraindicated if there is evidence or strong suspicion of metallic foreign bodies in or around the orbits.
Seizure Disorder (Epilepsy)
Presenting Signs and Symptoms

Sudden brief attacks of altered consciousness, motor activity, sensory phenomena, or inappropriate behavior
Common Causes

Congenital or developmental brain defects (usual onset of seizures at an early age)

Idiopathic (typically begins between ages 2 and 18)

Acute infection (febrile convulsion in child)

Trauma

Brain tumor

Metabolic disturbance (hypoglycemia, uremia, hepatic failure, electrolyte abnormality)

Toxic agent (lead, alcohol, cocaine)

Cerebral infarction or hemorrhage

Mesial temporal sclerosis
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Most sensitive technique for detecting underlying cerebral abnormality (indicated in all adults with an unexplained first seizure)

Follow-up MRI (at 3 to 6 months) is often of value if the initial examination failed to detect a source of the seizure disorder

Note: Examination consists of a routine brain study plus high-resolution, thin-section (2–3 mm) coronal T2-weighted images.

2.
Positron emission tomography

Using F-18 deoxyglucose, this modality improves localization of the seizure focus, particularly in a patient with complex partial (temporal lobe), medically intractable seizures who has had a normal MRI scan

3.
Computed tomography

Noncontrast scan is recommended as the initial study if the patient is in the immediate postictal state, or if residual neurologic deficit is present at the time of imaging

Less sensitive than MRI

Note: In pediatric patients, contrast enhancement is generally not required because congenital anomalies, rather than tumor, are the most common structural cause of seizures.

Tinnitus
Presenting Signs and Symptoms

Perception of sound in the absence of an acoustic stimulus (ringing, buzzing, roaring, whistling, hissing) that may be intermittent, continuous, or pulsatile

Often associated with hearing loss
Common Causes

Virtually any ear disorder (obstruction, infection, cholesteatoma, neoplasm, eustachian tube obstruction, otosclerosis)

Cerebellopontine angle tumor

Drugs (salicylates, quinine, alcohol, certain antibiotics and diuretics)

Cardiovascular disease (hypertension, arteriosclerosis, aneurysm)

Trauma
Approach to Diagnostic Imaging

1.
Computed tomography (temporal bone)

Preferred study for showing morphologic abnormality of ear bones

Note: Thin (1.5 mm) sections in axial and coronal planes are required.

2.
Magnetic resonance imaging

If CT fails to detect a cause of symptoms, high-resolution, thin-section MRI is the preferred study for demonstrating small tumors (e.g., neurinoma) of the intracanalicular portion of the 8th cranial nerve as well as vascular abnormalities in the region of the cerebellopontine angle

Contrast infusion is often used, but may be unnecessary if thin-section (2–3mm), axial, and coronal T1-weighted and coronal T2-weighted fast spin-echo images are obtained
Transient Ischemic Attacks
Presenting Sign and Symptom

Focal neurologic deficit that resolves fully within 24 hours (sudden onset and brief duration)
Common Causes

Plaques or atherosclerotic ulcers involving the carotid or vertebral arteries in the neck

Emboli arising from mural thrombi in a diseased heart
Approach to Diagnostic Imaging

Note: The results of two clinical trials indicate the need to accurately detect carotid artery stenosis: (1) NASCET confirmed the value of carotid endarterectomy for stenosis (>70%) to prevent stroke and improve quality of life; (2) ACAST suggested surgery to prevent stroke for carotid stenosis (>60%).

1.
Duplex, color-flow Doppler ultrasound

Accurate noninvasive screening study that combines high-resolution, real-time imaging of the carotid arteries with hemodynamic information about blood flow velocity provided by the Doppler technique

When used with MRA, may obviate the need for presurgical arteriography

Note: Other noninvasive tests (ophthalmodyna-mometry, oculoplethysmography) are not indicated because they cannot accurately detect carotid plaques and ulcerations.

2.
Magnetic resonance angiography

Accurate noninvasive screening study for detecting not only disease of the carotid bifurcation but also narrowing of the vertebral arteries

Reconstitution sign (flow gap) confirms >60% stenosis (i.e., surgical disease).

If surgery is contemplated, brain MR imaging and angiography can complete the diagnostic workup and preclude the need for catheter arteriography

Contrast-enhanced MRA facilitates visualization of the aortic arch and the origins of the carotid and vertebral arteries

3.
Echocardiography

Indicated to detect mural thrombi in the heart if no carotid lesion has been identified that could explain the patient’s symptoms

4.
Intraarterial digital subtraction angiography

Invasive study that provides the highest-resolution images of intraluminal vascular pathology

Indicated prior to surgical intervention if US demonstrates a high-grade stenosis or ulcerated plaque in the carotid artery

5.
Computed tomography angiography

Requires infusion of iodinated contrast material

Most often utilized in the acute setting or for individuals who are too claustrophobic for an MRA examination to be performed
Vertigo
Presenting Signs and Symptoms

Impression of movement in space or of objects, loss of equilibrium, nausea, vomiting, nystagmus
Common Causes

Labyrinthine or middle ear infection or tumor

Head trauma

Toxic agent (alcohol, opiates, streptomycin)

Meniere’s disease

Cerebellopontine angle tumor (neurinoma, meningioma, metastasis, epidermoid)

Transient vertebrobasilar ischemic attacks

Motion sickness

Multiple sclerosis (focal brain stem lesion)
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Preferred study for detecting abnormalities of the posterior fossa and cerebellopontine angle (using high-resolution and thin-sections)

Contrast enhancement is helpful for detecting a small acoustic neurinoma

Note: If paramagnetic contrast material is not used, an additional thin-section, coronal T2-weighted fast spin-echo sequence should be obtained.

2.
Computed tomography

Indicated if middle ear pathology is suspected

Note: Thin-section (1.5 mm) scanning in the axial and coronal planes using a bone-highlighting algorithm is required.

Visual Loss (Unilateral Optic Nerve Impairment)
Presenting Signs and Symptoms

Purely monocular visual loss

Normal ocular examination (or only optic atrophy) of both the symptomatic and asymptomatic eye
Common Causes

Optic neuritis (e.g., in association with multiple sclerosis)

Ischemic optic neuropathy

Compressive–infiltrative optic neuropathies (optic nerve glioma, lymphoma, leukemia, sarcoidosis)

Extrinsic compression by orbital mass (meningioma, metastasis)

Orbital pseudotumor

Thyroid ophthalmopathy
Approach to Diagnostic Imaging

1.
Computed tomography

Axial 3-mm axial sections provide clear distinction of the optic nerves, extraocular muscles, and the globe, as well as calcification

Because CT is superb for detecting the presence of calcification (very useful in the differential diagnosis of orbital masses) and orbital fat provides excellent contrast, some recommend this modality as the initial and often the definitive imaging study for orbital pathology.

2.
Magnetic resonance imaging

Has the advantage of multiplanar imaging

Note: Contrast enhancement and fat suppression generally are required to detect orbital masses.

Visual Loss (Optic Chiasm Lesion)
Presenting Signs and Symptoms

Bitemporal visual-field defects (although deficit may be substantially greater in one eye than in the other)
Common Causes

Pituitary tumor

Parasellar mass (meningioma, craniopharyngioma, aneurysm)
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Preferred study for detecting a lesion compressing the optic chiasm because of its ability to image the sella and parasellar regions in the axial, coronal, and sagittal planes

Can clearly demonstrate the entire course of the optic nerves, optic chiasm, and optic radiations, as well as the cavernous sinuses and carotid arteries

Note: Paramagnetic contrast enhancement is often helpful when multiple sclerosis or sarcoidosis is suspected.

Visual Loss (Postchiasmal Visual System Dysfunction)
Presenting Signs and Symptoms

Bilateral homonymous hemianopia (visual-field defects on same side of the vertical median for each eye)

Normal visual acuity, pupillary reflexes, and ophthalmoscopy
Common Causes

Tumor (primary or metastatic)

Abscess

Infarction

Arteriovenous malformation

Hematoma
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Preferred study for evaluating the optic tracts, optic radiations, and visual cortex

Note: T1-, intermediate-, and T2-weighted axial images are usually sufficient.

DISORDERS

Infectious Processes

Brain Abscess
Presenting Signs and Symptoms

Headache

Nausea, vomiting

Papilledema

Lethargy

Seizures

Focal neurologic deficits

Fever, chills, and leukocytosis

Underlying immune deficiency
Common Causes

Direct extension of cranial infection (osteomyelitis, mastoiditis, sinusitis, subdural empyema)

Penetrating trauma

Hematogenous spread (bacterial endocarditis, intravenous drug abuse, bronchiectasis, congenital heart disease with right-to-left shunt)
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Most sensitive study for detecting the typically ring-enhancing mass lesion and associated edema and mass effect

Superior to CT for detecting multiple brain abscesses

Demonstrates decreased diffusion (increased signal on diffusion-weighted imaging)

2.
Computed tomography

Contrast-enhanced study can identify the high-attenuation capsule surrounding the hypodense necrotic center (if MRI is not available)
Central Nervous System Manifestations in AIDS
Presenting Signs and Symptoms

Spectrum of neurologic deficits depending on region and extent of involvement
Common Causes

HIV encephalitis

Cytomegalovirus

Toxoplasmosis

Cryptococcosis

Lymphoma (primary CNS)

Progressive multifocal leukoencephalopathy (PML)
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Most sensitive imaging study in symptomatic patients for demonstrating single or multiple lesions of abnormal signal intensity or diffuse changes in the deep white matter

If nonenhanced MRI is positive, contrast enhancement is helpful in differentiating abscess and lymphoma (enhancing) from HIV encephalitis and PML (nonenhancing)

Elevated choline and lipid/lactate peaks on proton spectroscopy suggest lymphoma
HIV Encephalopathy
Presenting Signs and Symptoms

Progressive encephalopathy, somnolence, slow speech, word-finding difficulty, flat affect, and diminished attention in an HIV-positive patient
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

In addition to showing central atrophy out of proportion to the patient’s age, this modality is the most sensitive for demonstrating high-signal lesions (on T2-weighted images) that are focally or diffusely distributed throughout the deep white matter

Demonstrates decreased signal intensity on T1-weighted images in the clivus and prominent lymphoid tonsillar tissue

Note: Although there is poor correlation between the extent of atrophy and the severity of dementia in AIDS, symptomatic HIV-positive patients are more than three times as likely to have abnormal MRI examinations. Routine MRI screening of neurologically asymptomatic HIV-positive patients is not cost-effective. When an abnormality is found on nonenhanced MRI, paramagnetic contrast material assists in distinguishing HIV encephalitis and PML (which do not enhance) from abscess and primary CNS lymphoma (which do enhance).

Acute Bacterial Meningitis
Presenting Signs and Symptoms

Prodromal respiratory illness, or sore throat, headache, stiff neck, fever, vomiting, seizures, impaired consciousness
Common Organisms

Meningococci, Haemophilus influenzae type b, pneumococci, gram-negative organisms
Common Causes

Extension from nearby infected structures (sinuses, mastoid air cells)

Communication of cerebrospinal fluid with exterior (penetrating trauma, myelomeningocele, spinal dermal sinus, neurosurgical procedures)
Approach to Diagnostic Imaging

Note: The most important role of imaging is to exclude a mass (abscess) prior to performance of a lumbar puncture (the primary diagnostic test).

1.
Computed tomography (head)

Contrast scans may demonstrate characteristic enhancement of the subarachnoid spaces, in addition to small ventricles and effacement of the sulci secondary to cerebral edema

May demonstrate the underlying cause for the development of meningitis (brain abscess, sinus or mastoid infection, congenital anomaly)

Note: MRI may be normal in patients with meningitis if contrast material is not used.

Caveat: Because acute bacterial meningitis (especially meningococcal) can be rapidly lethal, use of antibiotics should not be delayed pending results of diagnostic tests.
Subacute/Chronic Meningitis
Presenting Signs and Symptoms

Similar to acute bacterial meningitis (but developing over weeks rather than days)
Common Causes

Chronic infection (fungal, tuberculosis, syphilis, amebic)

Immunosuppressive therapy

AIDS

Neoplasm (leukemia, lymphoma, melanoma, carcinomas, gliomas)

Sarcoidosis

Ruptured dermoid

Lyme disease
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Contrast scans are required to demonstrate the characteristic enhancement of the subarachnoid spaces, as well as an underlying neoplasm

Can demonstrate associated brain edema, abscess, or neoplasm, as well as inflammation of the paranasal sinuses or mastoids

Superior to CT for evaluating complications of meningitis such as subdural empyema, dural venous thrombosis, infarction, and abscess

2.
Plain chest radiograph

Indicated to search for evidence of underlying tuberculosis or sarcoidosis
Subdural Empyema
Presenting Signs and Symptoms

Headache

Lethargy

Vomiting

Fever

Focal neurologic deficits

Seizures

Often rapid clinical deterioration (an emergency condition)
Common Causes

Extension from nearby infected structure (sinusitis, ear infection, osteomyelitis, brain abscess)

Penetrating trauma

Surgical drainage of a subdural hematoma

Bacteremia (especially from pulmonary infection)
Approach to Diagnostic Imaging

1.
Computed tomography or magnetic resonance imaging

Demonstrates characteristic crescentic or lentiform extra-axial fluid collection that is of low attenuation on CT and mildly hyperintense to CSF on T2-weighted MRI

Contrast studies show an intensely enhancing surrounding membrane

Note: Subdural empyema is far easier to visualize using MRI (because it can be extremely difficult on CT to detect the extracerebral collection adjacent to the skull unless wider windowing is used).

Neoplastic Processes

Acoustic Neurinoma
Presenting Signs and Symptoms

Hearing loss (sensorineural)

Tinnitus

Dizziness and unsteadiness
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Preferred study for detecting abnormalities of the cerebellopontine angle and posterior fossa

May identify small intracanalicular tumors because of their intense contrast enhancement

Note: A thin-section, multiplanar, high-resolution study is required.

2.
Computed tomography

Indicated if there is conductive hearing loss to evaluate bony abnormality in the petrous portion of the temporal bone

Note: Thin sections with bone windows are required.

Brain Tumor
Presenting Signs and Symptoms

Slowly progressive focal neurologic deficits (depending on the site of the lesion)

Nonfocal symptoms due to increased intracranial pressure

Seizures

Mental symptoms (drowsiness, lethargy, personality changes, impaired mental faculties, psychotic episodes)

Signs of herniation
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Preferred screening technique for detecting and characterizing intracranial masses (may not require contrast infusion)

Surgical planning or tumor biopsy can be performed using an MRI-compatible stereotaxic frame

Potentially improved specificity using proton spectroscopy

Note: CT is only indicated to demonstrate bone erosion (especially at the skull base) and intramass calcification (although gradient-recalled echo sequences increase the sensitivity of MRI to calcification), as well as for CT-guided biopsy.

Epidural Spinal Metastases
Presenting Signs and Symptoms

Back pain

Progressive weakness and sensory symptoms (numbness and paresthesias)

Bowel and bladder dysfunction

Corticospinal tract signs
Common Primary Neoplasms

Lung

Breast

Prostate

Melanoma

Lymphoma

Kidney

Gastrointestinal tract
Approach to Diagnostic Imaging

1.
Plain spinal radiograph

Demonstrates single or multiple, lytic or blastic lesions or compression fractures in 60–85% of patients with epidural metastases

Ineffective for detecting early metastases because about 50% of cancellous bone in the region must be destroyed before lytic lesions show on plain radiographs

2.
Magnetic resonance imaging

Most sensitive technique that can simultaneously demonstrate the bone marrow abnormalities of vertebral metastases (hypointense on T1-weighted images and hyperintense on T2-weighted scans) and epidural extension effacing and displacing the spinal cord and nerve roots

Note: Differentiation of benign from malignant causes of vertebral body fracture can be accomplished by MRI. Factors consistent with malignancy include complete (or nearly so) tumor replacement of marrow in vertebral bodies and posterior elements, multilevel involvement, and paravertebral masses.

Caveat: Contrast enhancement may obscure evidence of destructive changes in the vertebral bodies. Always perform a nonenhanced T1-weighted sagittal image sequence.
Intracerebral Metastases
Presenting Signs and Symptoms

Headache

Focal neurologic deficits

Drowsiness

Papilledema

Seizures
Common Primary Neoplasms

Lung

Breast

Melanoma

Gastrointestinal tract

Kidney

Thyroid
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Nonenhanced MRI is extremely sensitive for detecting brain metastases (predominantly located at the gray–white junction)

Contrast enhancement makes this modality even more sensitive for detecting brain metastases

Associated vasogenic edema, seen on T2-weighted images, consists of pure edema with no tumor extension

Note: Enhanced CT is limited by artifacts in the temporal lobes and posterior fossa.

Pineal Region Tumors
Presenting Signs and Symptoms

Precocious puberty (especially in boys)

Paralysis of upward gaze (Parinaud’s syndrome relating to compression of tectal plate)

Noncommunicating hydrocephalus (due to obstruction at the aqueduct of Sylvius)

Papilledema and other signs of increased intracranial pressure
Common Causes

Germinoma

Teratoma

Glioma
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Most sensitive study for detecting a neoplasm in the pineal region, but rarely specific enough to provide a histologic diagnosis (except for the heterogeneous appearance of intratumoral fat and calcium in a teratoma)

Combination of axial and sagittal images permits visualization of even small tumors. Obstruction of the aqueduct may obliterate the normal pulsatile signal void

A benign pineal cyst may measure up to 25 mm and have a signal intensity not precisely the same as that of cerebrospinal fluid. The benign nature of the lesion is confirmed by the absence of obstructive hydrocephalus and the unchanging size on serial examinations
Caveat: Enhancement may occur normally in the pineal region. This appearance should not be mistaken for tumor enhancement.

Vascular Disorders

Acute Brain Infarction (Stroke)
Presenting Signs and Symptoms

Abrupt, dramatic onset of focal neurologic deficit that does not resolve within 24 hours

Possible headache or seizure
Common Causes

Infarction (secondary to an embolism from the heart or extracranial circulation or to hemorrhage)

Narrowing of intracranial or extracranial artery (atherosclerosis, thrombus, dissection, vasculitis)

Thrombus of the cerebral venous system

Rupture of an aneurysm or arteriovenous malformation (causing subarachnoid hemorrhage or intracerebral hematoma)

Decreased perfusion pressure or increased blood viscosity with inadequate blood flow reaching the brain
Approach to Diagnostic Imaging

1.
Computed tomography

Preferred initial procedure for assessing a suspected acute stroke because it can:

Rule out hemorrhage (subarachnoid or intracerebral)

Define patterns of ischemic injury

Show areas of abnormal vascular calcification (e.g., giant aneurysm)

Exclude a mass lesion

Note: The above information is critical for the clinician faced with determining the need for lumbar puncture, vascular surgery, anticoagulation, or other therapies.

2.
Magnetic resonance imaging

The combination of nonenhanced MR imaging and angiography is more sensitive than CT for detecting infarction and ischemic edema (especially involving the brainstem), clearly delineating an occluded or stenotic artery or vein, and distinguishing hemorrhagic from ischemic infarction
Caveat: Arteriography is indicated only if noninvasive studies suggest an underlying aneurysm or AVM and a surgical or interventional radiologic procedure is seriously being considered.

3.
Diffusion-weighted magnetic resonance imaging

This most sensitive marker of acute infarction is generally positive within 2 hours of the clinical event and thus plays a critical diagnostic role

The hyperintense signal (hypointensity on ADC map) is possibly related to cytotoxic (intracellular) edema

A negative study is highly predictive for excluding an acute brain infarction and thus is valuable in directing further diagnostic and therapeutic planning
Intraparenchymal Cerebral Hemorrhage
Presenting Signs and Symptoms

Abrupt onset of headache followed by steadily increasing neurologic deficits

Loss of consciousness

Nausea, vomiting

Delirium

Focal or generalized seizures

Signs of transtentorial herniation
Common Causes

Trauma

Hypertensive hematoma (common locations: putamen-external capsule, caudate, thalamus, pons, cerebellum, cerebral hemisphere)

Congenital aneurysm or arteriovenous malformation

Amyloid angiopathy (causes polar hemorrhage)

Mycotic aneurysm

Blood dyscrasia (bleeding diathesis)

Collagen disease

Hemorrhagic infarction (arterial or venous)

Metastases (e.g., melanoma)

Glioblastoma multiforme

Cavernous malformations
Approach to Diagnostic Imaging

1.
Computed tomography

Preferred imaging technique for detecting a focal region of increased attenuation within the brain parenchyma in acute trauma, suspected aneurysm rupture (because of superior detection of subarachnoid hemorrhage and patient comfort), or hypertensive episode
Caveat: Although it is unusual, CT may at times fail to detect subarachnoid blood found at lumbar puncture.

2.
Magnetic resonance imaging

Preferred study for detecting subacute and chronic stages of intraparenchymal hemorrhage

Hemosiderin- or ferritin-laden macrophages that develop due to prior bleeding appear as hypointense foci on T2-weighted images, persist throughout the patient’s life, and are best seen on gradient echo images

MR angiography or venography may prove helpful for detecting aneurysms, arteriovenous malformations, or venous occlusions

3.
Arteriography

Remains the “gold standard” for imaging suspected aneurysms or arteriovenous malformations and also provides a therapeutic portal

Best modality for visualizing narrowing of branch vessels due to arteritis
Subarachnoid Hemorrhage
Presenting Signs and Symptoms

Sudden onset of excruciating headache

Rapid loss of consciousness

Vomiting

Severe neck stiffness (usually not present initially but occurring within 24 hours)

Progressive palsies (reflecting pressure effects on the 3rd, 4th, 5th, and 6th cranial nerves)
Common Causes

Trauma

Rupture of congenital intracranial aneurysm

Arteriovenous malformation

Mycotic aneurysm (in patients who have infective endocarditis or systemic infection or are immunocompromised)

Blood dyscrasia (bleeding diathesis)
Approach to Diagnostic Imaging

1.
Computed tomography

Preferred study for demonstrating acute subarachnoid hemorrhage

Initial noncontrast scan to detect the presence of high-attenuation blood in the subarachnoid space

Subsequent contrast-enhanced CT or MRI/MRA may detect the underlying aneurysm or vascular malformation
Caveat: Lumbar puncture to demonstrate blood in the subarachnoid space is indicated only if CT fails to make the diagnosis and shows no evidence of a mass or obstructive hydrocephalus (lest herniation occur).

2.
Arteriography

Indicated to localize and characterize the anatomy of an aneurysm or arteriovenous malformation

If there is an aneurysm, must also evaluate for vasospasm

Note: Must selectively catheterize (or, less optimally, reflux contrast material into) both carotid and both vertebral arteries.

3.
Magnetic resonance imaging

Relatively insensitive to subarachnoid hemorrhage in the acute stage

Superior to CT for demonstrating chronic blood staining of the meninges (hemosiderosis)

Role of MRA in aneurysm detection is emerging, although the “gold standard” remains selective catheter arteriography
Cerebral Aneurysm
Presenting Signs and Symptoms

Asymptomatic

Signs of intraparenchymal or subarachnoid hemorrhage (if rupture)

Compression of cranial nerves or brain parenchyma (if large)
Common Causes

Congenital (berry aneurysm)

Atherosclerosis

Mycosis

Trauma
Approach to Diagnostic Imaging

1.
Computed tomography

Detects subarachnoid hemorrhage and intracerebral hematoma in the acute setting

2.
Arteriography

If cerebral aneurysm is suggested by CT or MRI evidence of intraparenchymal or subarachnoid hemorrhage, arteriography can:

Identify the presence of any and all aneurysms

Delineate the relationship of a given aneurysm to the parent vessel and adjacent penetrating branches

Define the potential for collateral circulation to the brain

Assess for vasospasm

3.
Computed tomography or magnetic resonance imaging

Can demonstrate a patent suprasellar aneurysm as an intensely enhancing mass (CT) or as a high-velocity flow void with signal heterogeneity due to turbulence (MRI)

4.
Magnetic resonance angiography or computed tomography angiography

Demonstrates the parent artery and the size and orientation of the neck and dome of the aneurysm

Useful screening study in asymptomatic patients, as well as in those with a family history of aneurysms or a familial disorder associated with cerebral aneurysms

Note: Future technical refinements will permit detection of progressively smaller aneurysms.

Arteriovenous Malformation
Presenting Signs and Symptoms

Asymptomatic

Sudden headache and neurologic deficits (secondary to intraparenchymal or subarachnoid hemorrhage)

Focal seizures (incited by the lesion)

Progressive focal neurologic sensorimotor deficit (due to enlarging arteriovenous malformation acting as a mass or progressive ischemic lesion)

May have arterial bruit detectable on the overlying cranial vault
Common Cause

Congenital tangle of dilated blood vessels with direct flow from arterial afferents into venous efferents
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Demonstrates AVMs as tangled flow voids with prominent feeding and draining vessels

Superior to CT for demonstrating subacute and chronic hemorrhage and secondary changes (mass effect, edema), as well as ischemic changes in the adjacent brain

Optimal for detecting low-flow and angiographically occult vascular malformations (cavernous angioma, telangiectasia, venous angioma)

Note: Gradient echo MRI is the most sensitive method for detecting even small, chronic, subtle foci of blood.

2.
Arteriography

Required to precisely demonstrate the anatomic blood supply and drainage prior to any surgical or neurointerventional procedure

Can distinguish among pial, dural, and mixed types of AVMs
Lacunar Infarction
Presenting Sign and Symptom

Focal neurologic deficit that can be pinpointed to a locus less than 15 mm in diameter
Common Causes

Embolic, atherosclerotic, or thrombotic lesions in long, single, penetrating end-arterioles supplying the deep cerebral white matter, thalamus, basal ganglia-capsular region, and pons

Hypertension (common)
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Only modality that can consistently demonstrate the well-delineated round or slit-like lesions that are hypointense to brain on T1-weighted images and hyperintense to brain on intermediate and T2-weighted images

Diffusion-weighted imaging is extremely helpful in distinguishing acute from chronic lacunae

Note: Because of their small size, most true lacunar infarctions are difficult to see on CT scans.

Magnetic resonance angiography is usually negative because of the involvement of small blood vessels (arterioles), but it can detect occlusion of a parent artery (e.g., middle cerebral artery occlusion causing infarction in the distribution of the lenticulostriate perforators) when the lacunar distribution of the infarction is larger than expected

Trauma

Acute Head Trauma
Presenting Signs and Symptoms

Focal neurologic deficits (caused by intracerebral and extracerebral hematomas)

Generalized or focal cerebral edema that may lead to symptoms of herniation (through tentorium or foramen magnum)

Concussion (post-traumatic loss of consciousness)
Approach to Diagnostic Imaging

1.
Computed tomography

Preferred study for detecting skull fracture, acute intraparenchymal bleeding, and extra-axial hemorrhage (acute subdural and epidural hematoma)

The use of wider windows improves ability of CT images to delineate isodense extracerebral hematoma

Demonstrates ventricular shift and sulcal effacement, subtle findings that should raise suspicion of an isodense subdural hematoma

2.
Magnetic resonance imaging

Indicated only in those unusual cases in which CT has failed to detect an abnormality in the presence of strong clinical suspicion of intracranial hemorrhage (primarily in the posterior fossa or high on the convexity, areas in which CT may be limited because of overlying bone)

Particularly valuable in subacute and chronic phases of head trauma to define temporal and inferior frontal lobe hemorrhagic contusion and edema, as well as shear injuries (subtle hemorrhage seen as low signal on gradient echo images) at the gray–white junctions and posterior corpus callosum

Note: There is no indication for plain skull radiography in this condition. The mere detection of a skull fracture generally has little effect on subsequent medical or surgical management. In addition, skull fractures usually are easily recognizable on CT, which can also delineate any accompanying abnormality in the underlying brain.

Epidural Hematoma
Presenting Signs and Symptoms

Symptoms developing within minutes or hours after injury (often after a lucid interval of relative neurologic normalcy)

Increasing headache, deterioration of consciousness, motor dysfunction, and pupillary changes indicate an emergency situation
Common Cause

Trauma (causing arterial laceration in the epidural space)
Approach to Diagnostic Imaging

1.
Computed tomography

Preferred study for demonstrating the characteristic appearance of a collection that is hyperintense hemorrhage convex to the brain that is located in the temporal region (middle meningeal artery) and often associated with a skull fracture

Note: There is no indication for plain skull radiographs in this condition.

Acute Subdural Hematoma
Presenting Signs and Symptoms

Progressive neurologic deterioration with signs of herniation

Progressive loss of consciousness

Hemiplegia
Common Cause

Head trauma
Approach to Diagnostic Imaging

1.
Computed tomography

Preferred study for detecting the characteristically hyperintense, medially concave, lenticular extraaxial collection of blood in the subdural space
Caveat: Thin subdural hematomas may be obscured by overlying bone (especially if they are located high on the convexity). Subfrontal or subtemporal hematomas may be difficult to detect on axial views and may require coronal reformatting or direct coronal imaging.

Effacement of cortical sulci on three or more adjacent images

Hematoma may be isodense if the hematocrit is less than 30 mL/dL

2.
Magnetic resonance imaging

Not as sensitive for detecting acute bleeding, but ability of MRI to directly obtain coronal images may be of value if CT fails to demonstrate a subdural hematoma in the face of strongly suggestive clinical findings

Note: There is no indication for plain skull films in this clinical setting.

Chronic Subdural Hematoma
Presenting Signs and Symptoms

History of head trauma (2 to 4 weeks or more prior to clinical presentation) that may have been relatively trivial and forgotten

Increasing headache

Fluctuating drowsiness or confusion

Mild-to-moderate hemiparesis

Typically occurs in alcoholics and patients older than age 50
Common Cause

Head trauma
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Preferred study for detecting hemorrhages more than a few days old as hyperintense lesions on both T1- and T2-weighted sequences

Of particular value in detecting hemorrhages in the posterior fossa and high on the convexity (difficult areas for CT because of bone artifacts)

Clearly defines secondary findings (brain contusion or hematoma, axonal shear injury at the gray–white junction and posterior corpus callosum, occipital infarction secondary to prior transtentorial herniation, communicating hydrocephalus, atrophy)

Subtle axonal shear injuries may only be detected on gradient echo pulse sequences

Note: Unlike CT, where hemorrhage becomes isodense after several weeks and thus may be impossible to recognize, hemorrhage on MRI remains hypointense for the lifetime of the patient.

Blow-Out Fracture of the Orbit
Presenting Signs and Symptoms

History of trauma

Extraocular eye movement abnormality
Approach to Diagnostic Imaging

1.
Plain radiograph (Waters view)

Preferred screening study for showing bony discontinuity and the presence of a soft-tissue mass in the superior aspect of the maxillary antrum

2.
Computed tomography (axial and coronal)

Definitive studies for showing the fracture and the extent of herniation of orbital tissues through the defect into the superior aspect of the maxillary antrum

Note: If a blow-out fracture is suspected clinically, CT can be the initial imaging procedure (omitting plain radiography).

Facial Fracture
Presenting Signs and Symptoms

Facial swelling and ecchymoses
Approach to Diagnostic Imaging

1.
Plain radiograph

Preferred screening study for demonstrating facial fractures (most commonly involving the nose, zygomatic arches, lateral walls of the maxillary antra, and floors of the orbits)

2.
Computed tomography

Indicated if plain radiographs demonstrate a complex fracture that must be defined or suggest a blow-out fracture of the floor of the orbit

Note: Both axial and coronal 3-mm-section scans are usually required for full evaluation.

Temporal Bone Fracture
Presenting Signs and Symptoms

Various symptoms depending on the fracture site (hearing loss, vertigo, nystagmus, facial paralysis)

Hemorrhage behind the tympanic membrane
Common Cause

Trauma
Approach to Diagnostic Imaging

1.
Computed tomography

In addition to demonstrating the lucent fracture line (often requiring thin cuts), CT may show secondary signs of fracture such as fluid within the mastoid air cells or tympanic cavity, intracranial gas, gas within the temporomandibular joint, and disruption of the ossicular chain

Note: Always check the temporomandibular fossa for dislocation.

Cervical Spine Trauma
Approach to Diagnostic Imaging

1.
Plain skeletal radiograph

Preferred initial screening procedure that is quickly and inexpensively performed without significant disruption of other resuscitation efforts

Note: Cross-table lateral view is generally obtained first, to avoid moving a patient who might have a cervical fracture; if it appears normal, additional films (including odontoid, oblique, flexion, and extension views) may be obtained.

Caveat: It is absolutely imperative that all seven cervical vertebral bodies be seen, to avoid missing a lower cervical spine fracture obscured by the shoulders. If the entire cervical spine is not seen, the film must be repeated with the shoulders lowered.

2.
Computed tomography

Indicated if plain skeletal radiographs are equivocal, fail to adequately image portions of the spine, or show a complex fracture of the cervical spine (especially involving the foramen transversarium housing the vertebral artery, which may be compromised by cervical trauma)

May be required in a trauma victim whose plain films are negative but who has substantial neck pain or neurologic deficits

3.
Magnetic resonance imaging

Best procedure for detecting cord contusion and edema (and its sequela, myelomalacia), herniated disk, canal compromise, or epidural hematoma complicating trauma to the cervical spine

Note: In a patient with suspected nerve root avulsion, either CT myelography or MRI can confirm the diagnosis.

Endocrine Disorders

Acromegaly/Gigantism
Presenting Signs and Symptoms

Soft-tissue and bony overgrowth (increased size of hands, feet, jaw, and cranium)

Coarsening of facial features

Peripheral neuropathies

Headache

Impaired glucose tolerance
Common Cause

Pituitary adenoma (excessive secretion of growth hormone)
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Preferred study for detecting and defining the extent of the underlying pituitary tumor (superb sensitivity and multiplanar capability)

Thin-section coronal and sagittal T1-weighted images should be obtained

Paramagnetic contrast material is generally not required for initial screening

Permits clear distinction of the sphenoid sinus and the position of the carotid artery for surgical planning

If an aneurysm is suspected on MR imaging, MR angiography is obtained

Note: There is no indication for plain radiographs of the sella in this condition.

Diabetes Insipidus
Presenting Signs and Symptoms

Excretion of excessive quantities of urine (polyuria) that is very dilute but otherwise normal

Excessive thirst (polydipsia)

Dehydration and hypovolemia (develops rapidly if urinary losses are not continuously replaced)
Common Causes
PRIMARY (IDIOPATHIC)

Marked decrease in hypothalamic nuclei of neurohypophyseal system and deficient production of vasopressin (antidiuretic hormone)
SECONDARY (ACQUIRED)

Hypophysectomy

Cranial injury (especially basal skull fracture)

Suprasellar and intrasellar neoplasm (primary or metastatic)

Histiocytosis X

Granulomatous disease (tuberculosis, sarcoidosis)

Vascular lesion (aneurysm, thrombosis)

Infection (encephalitis, meningitis)
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Preferred study for demonstrating any underlying lesion of the hypothalamus, pituitary gland, or pituitary stalk (superb sensitivity, multiplanar capability)

Note: High-resolution, thin-section study is required; contrast enhancement improves sensitivity.

Galactorrhea/Amenorrhea
Presenting Signs and Symptoms
WOMEN

Galactorrhea

Menstrual disturbances

Infertility

Symptoms of estrogen deficiency (hot flashes, dyspareunia)
MEN

Loss of libido and potency

Infertility (occasional galactorrhea or gynecomastia)
Common Causes

Prolactinoma of pituitary gland

Drugs (phenothiazines, antihypertensives)

Primary hypothyroidism

Hypothalamic/pituitary stalk disease
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Preferred study for demonstrating the prolactin-secreting pituitary microadenoma (usually <1 cm) that is the underlying cause in about 50% of patients

Requires thin-section imaging in both coronal and sagittal planes

Note: There is no indication for plain films of the sella in this condition.

Hypopituitarism
Presenting Signs and Symptoms

Variable depending on which specific pituitary hormones are deficient (gonadotropins, growth hormone, thyroid-stimulating hormone, adrenocorticotropic hormone)
Common Causes
PITUITARY LESION

Tumor (adenoma, craniopharyngioma)

Infarction or ischemic necrosis

Inflammatory or infiltrative process (e.g., sarcoidosis)

Iatrogenic (irradiation or surgical removal)
HYPOTHALAMIC LESION

Tumor

Inflammation

Trauma
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Preferred study because of its superb sensitivity and ability to directly image the sella and parasellar regions in multiple planes

Note: Paramagnetic contrast enhancement is helpful in older patients with Addison’s disease and in detecting sarcoidosis. To define tiny microadenomas, imaging should begin immediately after contrast infusion to avoid obscuring a late-enhancing adenoma.
There is no indication for plain films of the sella in this condition.

Spinal Disorders

Herniated Nucleus Pulposus
Presenting Signs and Symptoms

Pain in the distribution of compressed nerve roots (may be sudden and severe or more insidious)

Pain increased by movement or Valsalva maneuver

Paresthesias or numbness in the sensory distribution of the affected roots

Reduced or absent deep tendon reflexes in the distribution of involved nerve roots

Weakness and eventual atrophy of muscles supplied by affected nerves

Positive straight leg raising test (lumbosacral region)

Urinary incontinence or retention (from loss of sphincter function in lumbosacral involvement)

Most common in the lower lumbosacral and lower cervical regions
Common Cause

Degenerative disk disease
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Most sensitive study for demonstrating bulging, protrusion, extrusion, or free fragmentation of disk material, as well as impingement on the spinal cord and individual spinal nerve roots

Can show degeneration of the disk as loss of signal on T2-weighted images (although this may be of little clinical importance)

Can distinguish among canal stenosis, degenerative facet overgrowth, herniated disk, and synovial cyst

Permits routine visualization of conus medullaris

2.
Computed tomography

Useful for detecting herniated disk and canal stenosis, but limited by single imaging plane, poor visualization of the conus without intrathecal contrast material, and poor assessment of the postoperative spine
Caveat: Plain spinal radiographs may demonstrate disk space narrowing and hypertrophic spurring. However, they do not give any indication of whether there is critical impingement on the vertebral canal or nerve roots, and are therefore of little value when MRI or CT is employed.
Myelography should be reserved for special applications, often related to surgical planning.
Sciatica
Presenting Signs and Symptoms

Pain radiating down one or both buttocks and the posterior aspect of the leg(s) to below the knee (the distribution of the sciatic nerve)
Common Causes

Peripheral nerve root compression (intervertebral disk protrusion or intraspinal tumor)

Compression within the spinal canal or intervertebral foramen (tumor, osteoarthritis, spondylolisthesis)
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Most sensitive study for demonstrating bulging, protrusion, extrusion, or free fragmentation of disk material, as well as impingement on the spinal cord, conus, and individual nerve roots

2.
Computed tomography

Still valuable for detecting herniated disk and bony foraminal or canal stenosis

Disadvantages include poor visualization of the conus, inability to distinguish herniated disk from scar in the postoperative spine, essentially single axial-plane imaging, and radiation exposure
Caveat: Plain spinal radiographs may demonstrate disk space narrowing and hypertrophic spurring. However, they do not give any indication of whether there is critical impingement on the spinal cord or nerve roots.
Myelography is not indicated in the evaluation of sciatica and generally is not required if MRI or CT has been performed.
Scoliosis
Presenting Signs and Symptoms

Structural lateral curvature of the spine that may be suspected when one shoulder appears higher than the other or if clothes do not hang straight

Fatigue in the lumbar region after prolonged sitting or standing that may be associated with muscular backaches
Common Causes

Idiopathic

Vertebral anomaly

Hydromyelia and dysraphic states
Approach to Diagnostic Imaging

1.
Plain spinal radiograph

Demonstrates the site and severity of the curvature (typically convex to the right in the thoracic area and to the left in the lumbar area so that the right shoulder is higher than the left)

2.
Magnetic resonance imaging

Indicated to exclude an intraspinal abnormality if scoliosis is severe or has an early age of onset, or if plain radiographs show a vertebral anomaly

The cervicomedullary junction should be reviewed to detect low-lying cerebellar tissue

Note: MRI is required to detect serious anomalies, such as tethered cord, that must be addressed before the spine undergoes mechanical straightening. Coverage from the cervicomedullary junction to the sacral level is generally needed (T1-weighted images are often sufficient).

Spinal Stenosis
Presenting Signs and Symptoms

Pain in buttocks, thighs, or calves on walking, running, or climbing stairs, not relieved by standing still but by flexing the back, sitting, or lying down
Common Causes

Degenerative disease (hypertrophy of facets or ligamentum flavum, disk protrusion, postoperative scarring, synovial cyst)

Paget’s disease

Achondroplasia

Trauma

Severe spondylolisthesis
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging or computed tomography

Demonstrate bony and soft-tissue changes causing compression of the thecal sac or spinal cord centrally, as well as encroachment on the nerve root in the neural foramen or lateral recess

MRI is the study of choice because of multiplanar capability and ability to better visualize the conus, while CT is superior for demonstrating bony degenerative changes
Caveat: Plain spinal radiographs may demonstrate disk space narrowing and hypertrophic spurring. However, they do not show whether there is critical impingement on the spinal cord or nerve roots. Disk space narrowing and vertebral body alignment are better defined using MRI.
Myelography is not indicated (except in some cases for presurgical planning) to evaluate disease involving the intervertebral disks or the spinal canal. Risk of epidural injection and severe discomfort are greatest in patients with spinal stenosis.
Failed Back Syndrome
Presenting Signs and Symptoms

No relief of neurologic symptoms after surgical procedure for herniated nucleus pulposus

Occurs in the lumbar region in about 10–25% of patients
Common Causes

Recurrent or residual disk

Scarring

Lateral or central canal stenosis

Adhesive arachnoiditis

Conus abnormality
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Most accurate technique for making the crucial distinction between recurrent/residual disk and scar

Scar appears hyperintense to the annulus on T2-weighted scans (recurrent disk is hypointense) and enhances homogeneously after contrast administration (chronic disk herniation may have some peripheral enhancement because of surrounding granulation tissue)
Must be analyzed carefully for canal stenosis, far-lateral herniated disc, and conus mass
Syringomyelia/Hydromyelia
Presenting Signs and Symptoms

Spasticity and weakness of the lower extremities

Sensory defect (typically beginning in the cervical region and often extending to a cape-like defect over the shoulders and back)
Common Causes

Congenital (often associated with Chiari malformation and encephalocele)

Intramedullary tumor (if there is no associated Chiari I malformation)

Trauma (post-traumatic syrinx or cystic myelomalacia)
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Demonstrates an atrophic (chronic) or enlarged spinal cord with central cystic, haustrated cavity

Commonly associated with Chiari I malformation

Upper margin of the hydromyelia cavity is at the level of the pyramidal decussation (cephalad cervical cord)

If there is no Chiari malformation or the cystic central cord lesion does not respect the pyramidal decussation boundary and extends above the cervicomedullary junction, contrast infusion is indicated to detect an underlying spinal cord neoplasm (hemangioblastoma, ependymoma, astrocytoma)
Tethered Cord (Low Conus)
Presenting Signs and Symptoms

Back pain

Dysesthesias

Neurogenic bladder

Spasticity

Congenital/developmental kyphoscoliosis
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Preferred study for showing the low-lying (below L-2–L-3 level), posteriorly tethered conus medullaris and thickened filum terminale that may terminate in a lipoma or dermoid

Note: MRI of the entire spine is generally performed to evaluate for hydrosyringomyelia and any abnormality at the cervicomedullary junction.

Transverse Myelitis (Acute)
Presenting Signs and Symptoms

Sudden onset of local back pain followed by sensory symptoms and motor weakness ascending from the feet

Urinary retention and loss of bowel control
Common Causes

Unknown (may be related to a prior viral illness, vasculitis, intravenous use of heroin or amphetamine, multiple sclerosis, AIDS myelopathy, or dural vascular malformation)
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Shows focal enlargement of the spinal cord

T2-weighted imaging demonstrates high signal throughout the region of involvement

An acute lesion shows contrast enhancement

Often assists in defining the etiology of a lesion by the distribution of hyperintense signal, best defined on axial T2-weighted images

Note: The role of MRI is more to exclude treatable conditions, such as unsuspected cord compression, than to make a specific diagnosis.

Other Disorders

Anosmia
Presenting Sign and Symptom

Loss of sense of smell
Common Causes

Head trauma (especially in young adults)

Viral infection (especially in older adults)

Chronic nasal obstruction (polyps)

Neoplasm (interfering with olfactory apparatus)

Granulomatous disease

Male hypogonadism (Kallmann’s syndrome)
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Can detect a subfrontal mass (e.g., meningioma, metastasis or direct extension from squamous cell carcinoma, esthesioneuroblastoma)

Used for planning prior to surgery or radiation therapy

2.
Computed tomography

Can detect a neoplasm or unsuspected fracture of the floor of the anterior cranial fossa

Can demonstrate polyps or other neoplastic or granulomatous processes resulting in nasal obstruction
Bell’s Palsy
Presenting Signs and Symptoms

Unilateral facial paralysis (sudden onset)

Pain behind the ear (may precede facial weakness)

Widening of palpebral fissure (prevents closure of eye)
Common Causes

Unknown (presumably swelling of the facial nerve due to immune or viral disease with resultant ischemia and compression of the nerve as it passes through its narrow canal in the temporal bone)

Trauma, Schwannoma, vascular malformation, sarcoidosis
Approach to Diagnostic Imaging

1.
Magnetic resonance imaging

Indicated to exclude a mass or demyelinating lesion within or adjacent to the facial nerve (from its brain stem origin to the parotid gland) if symptoms are recurrent, prolonged, progressive, or associated with dysfunction of other cranial nerves

Note: High-resolution axial and coronal imaging with contrast enhancement is required.

Demonstrates contrast enhancement in almost 80% of patients with clinical Bell’s palsy (most commonly in the labyrinthine segment and descending facial nerve canal) that may persist past the point of clinical improvement
Caveat: Unfortunately, the side of enhancement may not always correlate with the clinical symptoms.
Cerebrospinal Fluid Leak
Presenting Signs and Symptoms

Leakage of CSF (iden