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Chapter 6 – Chemotherapy for Head and Neck Cancer

Chapter 6 – Chemotherapy for Head and Neck Cancer

William H. Liggett Jr.
Arlene A. Forastiere
The otolaryngologist frequently cares for patients with head and neck cancer who will receive chemotherapy as part of their treatment ( Table 6–1 ). These patients usually have metastatic or locally advanced disease that is not amenable to curative therapy with surgery or radiation. Many have previously undergone surgery and radiotherapy. Chemotherapy also is indicated for those with advanced carcinomas of the larynx as part of primary curative treatment when voice preservation is desired. Chemotherapy also may be used in experimental protocols as primary therapy or combined with radiotherapy (chemoradiation) for patients with a high risk of relapse. The majority of the malignancies encountered are squamous carcinomas, with salivary gland cancers the next most common histology. Melanomas and sarcomas also are seen in the head and neck, although they are much rarer.
To evaluate the appropriate use of chemotherapy for these patients, the surgeon should be familiar with the following: (1) the principles of clinical trials, (2) the proper doses and expected toxic reactions of specific chemotherapeutic agents, (3) the basic principles of combination chemotherapy and combined modality programs, and (4) the standard use and experimental approaches of chemotherapy for head and neck squamous cancers and salivary gland tumors.

The efficacy of chemotherapy or combined modality programs is investigated through clinical trials.[190] To evaluate the use of a particular treatment, clinicians establish at the onset the parameters to be evaluated: object response rate, survival, disease-free survival or duration of response, and toxicity. The parameters of interest for a specific trial design are defined before the initiation of study and analyzed at the completion of the study. The primary endpoint depends on the nature of the clinical trial or phase of testing.
The evaluation of chemotherapeutic agents occurs in three steps or phases. The goals of phase I trials are to determine the toxic effects associated with a new drug and to establish the highest dose of the drug that can be safely administered. Patients with different tumor types refractory to conventional chemotherapy are enrolled. The purpose of phase II trials is to determine if a drug or drug combination tested in patients with the same tumor type has enough activity to warrant further testing in a comparative trial. The primary endpoint is response rate. Phase III trials are randomized comparisons of two or more treatment options, often comparing a standard treatment to a new or more complex therapy. Response rate, disease-free survival, or response duration and survival are primary endpoints. The determination of sample size, patient entry criteria, and the follow-up evaluation and monitoring of patients are critical for a valid interpretation of a phase III trial.[161]
Standard definitions exist for the various endpoints in clinical trials that allow objective reporting of results. Definitions of response are complete, partial, minor, stable, and progressive disease ( Box 6–1 ). The most meaningful response in terms of prolongation of survival is the attainment of a complete response in which no tumor is detectable after a thorough examination. By convention, a partial response indicates that the disease has regressed by at least 50% as determined by serial bidimensional measurements and that

TABLE 6-1 — Chemotherapeutic agents with activity in head and neck cancers
DNA cross-linker
Neutropenia, nausea, cystitis
DNA cross-linker
Myelosuppression, cystitis, confusion, alopecia
Binds dihydrofolate reductase
Mucositis, myelosuppression
Inhibits thymidylate synthetase
Mucositis, myelosuppression, diarrhea
Scission of DNA
Pulmonary fibrosis, rash, mucositis
DNA intercalator
Cardiotoxicity, mucositis, myelosuppression, alopecia
Vinca Alkaloids
Mitotic arrest
Neurotoxicity, myelosuppression, alopecia
Mitotic arrest
Neurotoxicity, myelosuppression, alopecia
DNA intercalator
Nephrotoxicity, vomiting, ototoxicity, neuropathy
DNA intercalator
Microtubule stabilizer
Myelosuppression, neuropathy
Microtubule stabilizer
Edema, neutropenia, neuropathy

Box 6-1. Criteria for response
Complete response
Complete disappearance of all evidence of tumor for at least 4 weeks.
Partial response
Disease regression by at least 50% of the sum of the product of the perpendicular diameters of all measurable tumor for at least 4 weeks. No simultaneous increase in the size of any lesion or appearance of new lesions may occur.
Minor response
Regression by less than 50% of the sum of the products of the perpendicular diameters of all measurable lesions.
Stable disease
No appreciable change in dimensions of all evaluable lesions.
Progressive disease
Increase in the size of any detectable lesions by at least 25% or the appearance of new lesions.

no new lesions have appeared elsewhere for a period of at least 4 weeks. The response rate represents the number of complete and partial responders. Minor response or stable disease usually is of little value.
Once a study is completed, there are several ways to compute response rate. In calculating the fraction of responders,the numerator should always be the number of patients who qualify in a particular response category, but the denominator often varies from study to study. Some investigators compute response rate using all patients entered into a study, whereas others evaluate response rates after eliminating early death or patients failing to receive a specific number of cycles of treatment. The latter method of computing a response rate results in a much larger value than the former.
Survival usually is calculated from date of study entry until date of death. Disease-free survival is calculated from study entry until disease progression or from achievement of complete response until disease progression. Duration of response is calculated from response date until date of disease progression. Toxicity should be strictly defined for every study before initiation. The National Cancer Institute has developed a comprehensive set of standardized drug-induced toxicity criteria. Using a 0 to 4 grading scale, toxicity to each organ system can be objectively assessed. All toxic reactions should be reported in detail in the final results.
In planning a clinical trial, particularly a phase III trial, having comparable patients in each group is critical. This requirement often is accomplished by randomization with stratification for important prognostic variables. Prognostic variables are those factors known to influence response, regardless of treatment. One of the more well-known, important prognostic variables is the Karnofsky Performance Status. In 1948, a 0 to 100 performance scale was devised by


Box 6-2. Performance status*

ECOG, SWOG, Zubrid Scales
0 Fully active, able to carry on all predisease performance without restriction

1 Restricted in physical strenuous activity but ambulatory and able to do work of a light or sedentary nature, e.g., light housework, office work

2 Ambulatory and capable of all selfcare but unable to do any work activities; up and about more than 50% of waking hours

3 Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours

4 Completely disabled. Cannot do any selfcare; totally confined to bed or chair

5 Dead
Karnofsky Scale
100 Normal, no complaints, no evidence of disease

90 Able to carry on normal activity; minor signs or symptoms

80 Normal activity with effort; some signs or symptoms of disease

70 Cares for self; unable to do normal activity or active work

60 Requires occasional assistance, but is able to care for most needs

50 Requires considerable assistance and frequent medical care

40 Disabled, requires special care and assistance

30 Severely disabled, hospitalization indicated; death not imminent

20 Very sick, hospitalization and active support treatment necessary

10 Moribund, fatal process, progressing rapidly

0 Dead
* ECOG—Eastern Cooperative Oncology Group; SWOG—Southwestern Oncology Group

David Karnofsky to describe a patient’s functional ability. This scale is used today interchangeably with a 0 to 5 point scale ( Box 6–2 ) adapted by several cooperative groups. Performance status is an established prognostic variable that directly correlates with response to chemotherapy. Those patients with a performance status greater than 2 or less than 50% are poor candidates for phase II and III clinical trials and are poor candidates for chemotherapy with palliative intent. These patients usually have a large tumor burden, are malnourished, and have a very short survival time regardless of treatment. By definition, they are nonambulatory for more than 50% of their waking hours and require special care and assistance. If a trial is randomized but not stratified for performance status, a large number of patients with poor Karnofsky Performance Status could be randomized to one of the treatment groups and make it appear less efficacious than a second, when it actually may be equal or better. Important prognostic variables should be defined at the onset of a study and analyzed in the results.
It is important in designing and drawing conclusions from trials to note whether the trial is prospectively randomized with concurrent controls or is a clinical trial with historical controls. Proponents of the randomized trial believe that one is more certain of equality between the two groups by a concurrent randomization process.[190] This will reduce the bias of selecting controls from a historical pool and also will reduce the problem of improvements in management or changes in treating physicians with time.
Overview of current concepts
Before 1970, chemotherapy had a limited role in the management of squamous cell cancer of the head and neck in community practice and at academic centers. In part, this was because of the paucity of available drugs with documented antitumor activity for this disease. The only drug with clearly established activity, used worldwide, was the folic acid analog methotrexate. Many other drugs had been tested, although the assessment criteria used to define response were not uniform. Hence, the reported response rates were unreliable, representing an accumulation of observations of any degree of tumor regression. In contrast, during the past two decades, a rigid system has been applied to the testing of potentially useful drugs. There now are clearly defined parameters for the objective evaluation of response and survival time and statistical guidelines for the design of clinical research trials to establish efficacy or to show improvement compared with standard therapies.
The serendipitous identification of the metal compound cisdiamine-dichloroplatinum (II) (cisplatinum) as a potential anticancer agent by Rosenberg [173] in 1968 spurred clinical research efforts to test new agents and combination chemotherapy regimens for the palliation of patients with locally recurrent and metastatic head and neck cancer. Several highly effective chemotherapy regimens were identified and then incorporated into a combined modality approach to treating the newly diagnosed patient. The goal was to improve survival time. It became clear that chemotherapy administered before definitive surgery or radiotherapy could result in rapid regression of tumor in the majority of patients without increasing the morbidity of subsequent surgery or radiation. Further, a proportion of the responding patients would have no evidence of tumor in the resected specimen. This increased the possibility of altering the standard surgical approach at some sites to preserve organ function. In addition to investigative trials using chemotherapy before definitive local therapy, traditional adjuvant chemotherapy administered after surgical resection and chemotherapy used

as a radiosensitizer concomitant with radiotherapy have been under active investigation.
Prognostic factors
Many chemotherapy trials have been analyzed to determine factors that would predict response to chemotherapy and prolonged survival time. Because squamous cell cancer of the head and neck is a heterogeneous disease, each factor should be evaluated in the context of multiple primary sites. Most single-institution trials have only modest numbers of patients and therefore lack the statistical confidence to draw firm conclusions. For patients with recurrent disease, poor prognostic factors are a low performance status, poor nutrition, a large tumor burden, and extensive previous radiotherapy and surgery.[13] In these circumstances, any response to chemotherapy is likely to be marginal and brief without impact on overall survival time. However, it seems clear that survival time may be prolonged in patients who achieve a complete response to chemotherapy. These patients in general have a good performance status; they are not malnourished and have not received previous chemotherapy for recurrent disease.
For the newly diagnosed patient treated with induction chemotherapy, the most consistent prognostic factor for overall response and complete response is T and N stage. There is a significant correlation between tumor size and response, with lower response rates observed in T4 and N3 stage disease in particular.[38] [70] [103] The importance of primary site as a prognostic factor for response to chemotherapy is unclear. One investigator, in an analysis of 208 patients, reported that cancers within the oral cavity and nasopharynx were significantly associated with high response rates.[105] Nasopharynx cancer was found significant in two other trials.[6] [70] The pattern of failure for patients with nasopharyngeal carcinoma also is different from that of other sites with metastatic sites assuming a larger proportion. Besides nasopharyngeal carcinoma, most trials have failed to demonstrate differences by site, which may be because of inadequate patient numbers and ineffective chemotherapy regimens.
Because of the importance of performance status as a predictor of outcome for the recurrent disease patient, induction chemotherapy trials have excluded patients with poor performance status (<50% on the Karnofsky scale). Within the range of 50% to 100%, no differences have been observed. Tumor differentiation does not appear to be a predictive factor in studies that have used cisplatin-based combination chemotherapy regimens. It is well established that overall survival time correlates with performance status, T and N stage, primary site,[5] [70] [103] and extracapsular extension of tumor.[119] [192] The survival time of patients with cancers of the nasopharynx and larynx is longer than those with oral cavity and hypopharyngeal primary cancers after other factors are corrected for in multivariate analyses of patients receiving induction chemotherapy.
The application of biologic factors, such as DNA content,[68] immunologic status, and circulating immune complexes,[185] to predict response and survival outcome is under investigation. Evidence exists that DNA ploidy and DNA content can predict for survival and disease-free survival times.[212] [239] Molecular markers (such as p53 and p16) that act as predictors for response and survival time also are under investigation.[22] [23]
Systemic management of recurrent head and neck cancer is a major concern because 30% to 50% of patients diagnosed this year will die with recurrent local and regional disease within 5 years. Distant metastases will be present clinically in 20% to 40% of patients, but occult disease determined at autopsy may be present in up to 60%.[128] The primary goal of conventional chemotherapy used for palliation should be to prolong survival time. Patients with locally advanced or disseminated recurrent squamous cell carcinomas of the head and neck have a median survival time of 6 months, and 20% survive 1 year. Chemotherapy has not yet altered these statistics, although it has been useful in palliation. One often hears that pain relief can be achieved with chemotherapy, but this should not constitute the sole reason for treatment. Small amounts of tumor regression may be associated with a transient diminution of pain, although the aggressive use of a variety of available oral analgesics (tablet and elixir preparations) is a much more rational approach to pain management.
Single agents
The response rate (complete and partial) of recurrent or metastatic squamous cell cancer to commonly used agents is provided in Table 6–2 . In general, about one third of patients respond. The majority are partial responses, with less than 5% of patients achieving a complete response. Response duration is brief, on the order of 2 to 4 months, and the median survival time is 6 months.
Methotrexate is a folic acid analog that is S-phase specific. Its mechanism of action involves binding to the enzyme dihydrofolate reductase, which blocks the reduction of dihydrofolate to tetrahydrofolic acid. Tetrahydrofolic acid is necessary for the synthesis of thymidylic acid and purine synthesis. This then interrupts the synthesis of DNA, RNA, and protein. The cytostatic effects of methotrexate can be circumvented by the administration of reduced folates, such as leucovorin, which can be converted to the tetrahydrofolate coenzyme required for purine biosynthesis. The therapeutic index of methotrexate can be increased if leucovorin is administered at intervals after methotrexate is given. This results from a selective rescue of nonmalignant cells and forms the basis for the use of high doses of methotrexate followed by leucovorin to ameliorate methotrexate toxicity to healthy cells. Cancer cells may lack transport sites for leucovorin

TABLE 6-2 — Activity of single agent chemotherapy
Dosing schedule
Response/rate (%)
40–50 mg/m2 weekly
80–120 mg/m2 every 3–4 weeks
400 mg/m2 every 4 weeks
135–200 mg/m2 every 3–4 weeks
75 mg/m2 every 3 weeks
1.5–2.5 g/m2 every 4 weeks
15 mg/m2 twice weekly
500 mg/m2 weekly
and are subject to the lethal effects of methotrexate. Mechanisms for resistance to methotrexate include selection of cells with decreased transport of methotrexate into cells and increased dihydrofolate reductase activity.
Methotrexate can be administered by intramuscular injection or subcutaneous, intravenous, or oral routes. Weekly or biweekly administration is the preferred schedule. A conventional dose of intravenous methotrexate is 40 to 60 mg/m2 weekly. When higher doses of methotrexate are used, they may be in the moderate-dose range (250 to 500 mg/m2 , intravenous) or the high-dose range (5 to 10 g/m2 ). These are both followed by leucovorin rescue, usually beginning at 24 hours and continuing until the plasma methotrexate level is less than 10-8 mol/l. At this dose range, the toxicity for patients with normal renal function usually is limited to mild stomatitis and myelosuppression. More severe, life-threatening reactions consisting of confluent mucositis, pancytopenia, liver function abnormalities, and an exfoliative maculopapular rash occur rarely and require intensive medical support. Renal dysfunction may occur with high-dose methotrexate administration because of precipitation of the drug, especially in an acid urine. Hydration and alkalinization of the urine before and after methotrexate administration can reduce the risk.
Methotrexate is the most widely used drug for management of squamous cancers of the head and neck and is the standard to which new agents or combinations often are compared. Therapy with this drug is relatively nontoxic, inexpensive, and convenient. Response rates to conventional doses vary between 8% and 50%, averaging 30%.[17] Weekly treatment, if tolerable, is superior to twice monthly or monthly treatments. Levitt and others[134] have shown in vitro that when moderate- to-high doses of methotrexate are used with leucovorin rescue, an enhanced therapeutic index results from the high intracellular levels of drug associated with selective rescue of healthy tissue. The initial results of pilot trials of moderate- or high-dose methotrexate suggested improvement in response rates for those with head and neck cancers. However, there is no evidence of improved responses to the higher dose of drug, as much as 5000 mg, from prospective randomized trials comparing conventional with moderate- or high-dose methotrexate with or without leucovorin rescue.[223] [238]
Cisplatin is an inorganic metal coordination complex with major antitumor activity in a number of diseases. The drug behaves as a bifunctional alkylating agent binding to DNA to cause interstrand and intrastrand cross-linking. Cisplatin also binds to nuclear and cytoplasmic proteins. Resistance is believed to develop through increased metabolic inactivation. Cisplatin is administered by the intravenous route and requires aggressive hydration and diuresis to prevent renal tubular damage. A dose of 80 to 120 mg/m2 every 3 or 4 weeks is the usual dose given by intravenous infusion with mannitol diuresis[102] or by 24-hour infusion. [114] The drug is not schedule-dependent, although it has been shown that 5-day continuous infusion increases exposure to the active platinum species when compared with bolus dosing.[81]
The major toxic reaction is renal dysfunction, manifested by an increase in serum creatinine levels or a decrease in creatinine clearance. The peak serum creatinine level occurs at 1 or 2 weeks and returns to baseline by 3 or 4 weeks. An increase in serum creatinine level to 2 mg/dl has been noted in up to 20% of patients in several series. This drug should not be used in patients with a creatinine clearance below 40 ml/min. Nausea and vomiting are almost universal. Ototoxicity can occur, usually in the 4000 to 8000 Hz range. It tends to be dose-related and cumulative and may be permanent. Hematologic toxicity, including neutropenia and thrombocytopenia, is mild, with a nadir at 2 weeks. Anemia is common and appears to be a result of bone marrow suppression; rarely patients manifest an acute hemolytic anemia. Hypomagnesemia can occur in part because of renal wasting. A peripheral neuropathy—predominantly sensory—occurs and is related to cumulative cisplatin dosage. Ototoxicity and peripheral neuropathy are common toxicities when the cumulative cisplatin dose approaches or exceeds 600 mg/m2 . These toxicities preclude long-term management with cisplatin in chemotherapy responders and dose intensification. This led to a search for analogs with similar efficacy but a different spectrum of toxicity.
Cisplatin has the same response rate as methotrexate, approximately 30%, with some reported complete responses and a duration of response of approximately 4 months.[114] [236] Two controlled trials comparing methotrexate with cisplatin found no difference in response rate or survival time between the two but only different toxicities.[94] [107] Advantages of cisplatin over methotrexate are its relatively rapid response rate and the fact that it needs to be given only once every 3 or 4 weeks, although methotrexate is more convenient because it can be given on an outpatient basis, whereas the higher doses of cisplatin require hospitalization. Cisplatin has been studied at different doses to determine if a dose–response effect exists. In a comparison of 60 mg/m2 and 120 mg/m2 , Veronesi and others[218] found no difference in response rates.

Forastiere and others [78] conducted a pilot trial evaluating 200 mg/m2 and observed a 73% response rate or double that expected with conventional dosing. Although this suggested benefit from the higher dose, ototoxicity and neurotoxicity occurred frequently and limited treatment duration.
More than one dozen derivatives of cisplatin have been evaluated for clinical development. Of these, carboplatin (cis-diamine-cyclobutane dicarboxylato-platinum II) was the first to become widely available. Carboplatin appears to have a mechanism of action similar to the parent compound, but it has a different toxicity profile. The dose-limiting toxicity is myelosuppression, primarily leukopenia and thrombocytopenia, which should be considered when carboplatin is combined with other myelosuppressing agents. Renal toxicity, ototoxicity, and neurotoxicity are rare, and the emetogenic potential of carboplatin is less. The drug can be administered in the outpatient setting without the need for hydration. Based on pharmacokinetic parameters, an intravenous dose of 400 mg/m2 is considered the equivalent in potency to 100 mg/m2 of cisplatin and can be safely administered to patients with creatinine clearance of 60 mg/ml or more. For patients with poor renal function, carboplatin dose should be calculated using the Calvert[30] or Egorin[64] formulae, which account for delayed renal excretion leading to increased drug exposure.
Carboplatin has a 24% response rate in phase II trials in patients with recurrent squamous cell cancer of the head and neck. It does not appear to be as active as cisplatin; one comparative trial in patients with untreated disease has documented an inferior outcome for carboplatin.[10] Thus, carboplatin should be reserved for patients who are not candidates for cisplatin therapy because of renal impairment or preexisting peripheral neuropathy. Carboplatin can be administered in the outpatient setting and requires no prehydration. The major toxicity caused by carboplatin is myelosuppression, which limits the total dose that can be given and the frequency of drug administration. The availability of colony-stimulating factors that can lessen the degree and duration of myelosuppression may provide a new avenue for clinical investigations with this agent.
The taxanes are a new class of compounds that include paclitaxel (taxol) and docetaxel (taxotere). These drugs act by stabilizing microtubules by binding to the ß-subunit of tubulin, thereby inhibiting microtubule depolymerization, which results in a cell cycle arrest at G2 . Preclinical studies showed that the taxanes were active against a variety of solid tumors and that prolonged infusions were more effective.[86] [95] [168] [220] Trials of head and neck cancer patients have shown response rates of approximately 30% to 40%.[33] [63] [77] [80] [208]
Paclitaxel has been dosed at 135 to 250 mg/m2 given over 3 or 24 hours, and docetaxel has been given at 60 to 100 mg/m2 by bolus injection every 3 weeks. The major toxicity is neutropenia particularly with high doses, and infection is the chief concern. Growth factors such as GM-CSF and G-CSF often are used to shorten the neutropenic nadir duration and hopefully lessen the risk of infection.[174] Given this risk, only patients with good performance status should be treated with high doses (200 to 250 mg/m2 ). Patients with poor performance status should receive lower doses, starting at 135 mg/m2 , and escalate the dose, depending on individual toxicity. Paclitaxel has been given over several schedules, and the optimal dosing schedule is being investigated. Docetaxel is a semisynthetic agent and may be more effective than paclitaxel. In two small phase II studies, response rates of 32% and 50% were observed.[34] [63]
Ifosfamide is structurally related to cyclophosphamide (to be discussed) and has a similar mechanism of action, leading to DNA interstrand and intrastand cross-linking that disrupts DNA replication. It is activated by hepatic p-450 mixed-function oxidase, and its metabolites are excreted in the urine. Ifosfamide in total doses of 7 to 10 g/m2 usually is administered as a 5-day continuous infusion or over 3 to 5 days in equally divided doses. The drug is repeated at 3 or 4 week intervals. Sodium mercaptoethane sulfonate (MESNA) is a thiol compound that should be administered concomitantly with ifosfamide to limit urothelial toxicity. The total daily dose of MESNA should equal the daily dose of ifosfamide. It may be administered as a continuous infusion or in five divided doses given every 4 hours starting 30 minutes before ifosfamide is administered each day. Patients need to be well hydrated before drug administration. The major dose-limiting toxicity is hemorrhagic cystitis, although with the use of MESNA, myelosuppression, nausea, vomiting, and hyponatremia are more frequent toxicities. Central nervous system toxicities, which include cerebellar dysfunction, seizures, confusion, and lethargy, occur in up to 30% of patients treated with doses of 8 to 10 g/m2 over 5 days. Early phase II results with this drug are promising with reported response rates ranging from 6% to 43% with a median of 26%.*
Bleomycin (Blenoxane) is an antineoplastic antibiotic that binds to DNA and produces DNA strand breaks by generating oxygen free-radicals. The conventional dose of bleomycin is 10 to 20 units/m2 once or twice weekly given intramuscularly or intravenously. It also may be given by a continuous 24-hour infusion over 5 or 7 days at a dose of 10 units/m2 each 24 hours. The major disposition of bleomycin is via the kidneys. It is important that the dose of bleomycin be reduced if the level of serum creatinine is abnormal.

* Refs. [27] [35] [111] [125] [145] [219] .

A 50% dose reduction is recommended for a creatinine clearance of 15 to 30 ml/min, and a 75% reduction is recommended if the creatinine clearance is below 15 ml/min. Approximately half of the patients receiving this drug will develop fever or chills during the first 24 hours, which can be reduced with the use of antipyretics. A rare complication is an anaphylactic reaction. It has been recommended that a dose of 1 unit be given several hours before the first dose of bleomycin. Alopecia can occur, particularly with the higher dosage of drug. Skin toxicity, including erythema, thickening, and hyperpigmentation, is common. Patients may develop stomatitis, which necessitates discontinuing a prolonged infusion.
Pulmonary toxicity is potentially one of the most serious complications of bleomycin administration. Patients may develop pneumonitis, a dry cough, and rales. Pulmonary function tests most commonly show a decreased carbon monoxide diffusion capacity. Pulmonary fibrosis with associated hypoxia and restrictive lung disease can result. Bleomycin pulmonary toxicity is more common in elderly patients, in patients who have had previous lung irradiation, and in patients who have had a total dose higher than 200 units. Patients should be closely monitored with serial tests of diffusion capacity when the cumulative dose exceeds 150 units. Giving the drug by continuous infusion may lessen pulmonary toxicity.[230]
Bleomycin has undergone testing using an intermittent bolus dosing schedule with response rates of 18%. A pharmacokinetic advantage may be achieved by continuous infusion because both agents have a short plasma half-life. Bleomycin is most frequently used combined with other agents.
5-Fluorouracil (5-FU) is a fluorinated pyrimidine similar to uracil. 5-FU competes for the enzyme thymidylate synthetase by displacing uracil, which in turn inhibits the formation of thymidine, an essential factor in DNA synthesis. The conventional intravenous dose of 5-FU is 10 to 15 mg/kg weekly. An alternate method of delivery is a loading dose of 400 to 500 mg/m2 daily for 5 days, followed by a weekly intravenous dose of 400 to 500 mg/m2 . It is recommended that no more than 800 mg be given as a single bolus. The therapeutic index of 5-FU may be enhanced by giving it by continuous infusion, which allows delivery of up to 1 g/m2 /day for 5 days repeated every 3 or 4 weeks, without enhanced toxicity. Continuous infusion of 5-FU has been studied primarily in patients with adenocarcinomas of the gastrointestinal tract. However, the results of one randomized trial in head and neck cancer patients comparing bolus and continuous infusion of 5-FU showed improved response rates with continuous infusion.[124] 5-FU toxic reactions include myelosuppression with neutropenia and thrombocytopenia occurring at 1 or 2 weeks. Nausea, vomiting, and diarrhea may occur, and stomatitis is common with higher doses. Patients may develop alopecia, hyperpigmentation, or a maculopapular rash. 5-FU is most commonly used in combination with other drugs. In patients with head and neck carcinomas, treatment with 5-FU can produce response rates of 15%, thus it usually is used in combination with other agents, particularly cisplatin.[8] [162]
Other Single Agents with Activity in Head and Neck Cancer
Several other chemotherapeutic agents were reported to have response rates in excess of 15% for patients with recurrent disease. They include adriamycin, cyclophosphamide, hydroxyurea, and vinblastine.[9] Several of these are only marginally effective as single agents for recurrent disease, although when used in combinations or in patients with no previous treatment, they may be more efficacious. These agents will be discussed.
Cyclophosphamide is activated in the liver by microsomal enzymes. Its major mechanism of action is cross-linking DNA strands, preventing further division. Cyclophosphamide can be given orally or intravenously. When given intravenously, it usually is given as a single dose of 500 to 1500 mg/m2 repeated every 3 or 4 weeks. It can be given daily at 60 to 120 mg/m2 but should be adjusted according to blood count results. It is important to hydrate patients well before and after giving cyclophosphamide. Drugs that stimulate liver enzymes, such as barbiturates, should be avoided, or the cyclophosphamide dose should be modified. After an intravenous dose, bone marrow suppression, predominantly neutropenia, can occur in 1 or 2 weeks, with a recovery at 2 or 3 weeks. Many patients have some degree of nausea and vomiting. Alopecia and ridging of the nails can occur. Azoospermia and cessation of menses, often with permanent infertility, can occur with most alkylating agents.
Acute hemorrhagic cystitis occurs most commonly in patients who are poorly hydrated. It is recommended that patients drink at least 2 quarts of fluid per day while taking cyclophosphamide. Toxicity may occur as microscopic hematuria or gross bleeding. This can eventually result in a fibrotic bladder, and a few cases of bladder carcinoma have been described in patients who have received cyclophosphamide.
Adriamycin (doxorubicin) is an anthracycline derivative that intercalates between nucleotide pairs in DNA to interfere with nuclei acid synthesis. This drug is given intravenously, usually at doses of 60 to 90 mg/m2 every 3 weeks. Alternate schedules that are associated with much lower risk of cardiac toxicity include doses of 20 to 30 mg/m2 daily for 3 days repeated every 3 weeks, low doses given weekly, or prolonged infusions.[16] The urine may be red for 1 or 2 days after adriamycin treatment.
If adriamycin infiltrates subcutaneous tissue, it can cause

severe necrosis of skin and subcutaneous tissue. The drug causes alopecia, which can be decreased by using scalp hypothermia. Stomatitis, nausea, vomiting, and diarrhea are common. Adriamycin, like actinomycin D, can cause radiation recall in patients who have had previous radiotherapy. The drug also can cause neutropenia and thrombocytopenia with a nadir at 1 or 2 weeks and a return to normal values by 3 weeks.[18]
The most dose-limiting toxic effect of adriamycin is cardiac toxicity, which manifests as a cardiomyopathy,[228] leading to congestive heart failure in approximately 10% of patients who receive a cumulative dose greater than 550 mg/m2 . Other predisposing factors include age, previous cardiac irradiation, other cardiotoxic chemotherapeutic agents, and a previous history of heart disease. Many methods of observing patients have been used, including endomyocardial biopsy. Radionuclide ejection fraction is a relatively easy and accurate way to determine the amount of damage to the heart from adriamycin.
Vinca alkaloids
Vinblastine and vincristine are vinca alkaloids and act by disrupting microtubular spindle formation, causing mitotic arrest. Vinblastine (Velban) can be given weekly at 5 mg/m2 , or it may be given by continuous infusion over several days. The major toxic reactions are myelosuppression, alopecia, and myalgias. Vincristine (Oncovin) usually is given at 1.0 to 1.5 mg/m2 once or twice monthly. It is recommended for adults that a single dose not exceed 2 mg. The drug is neurotoxic, which is most commonly manifested as a sensory motor peripheral neuropathy or hoarseness that will progress if the drug is not discontinued. Most patients will experience constipation, and they should take stool softeners with the drug. Vincristine causes alopecia, but it has almost no myelosuppressive effects.
Hydroxyurea (Hydrea) inhibits ribonucleotide reductase, interfering with the conversion of ribonucleotide to deoxyribonucleotide and causing inhibition of DNA synthesis. The drug is given orally, usually in an intermittent regimen of 80 mg/kg every third day. The major toxic responses are neutropenia and thrombocytopenia, so that the dose should be reduced or delayed if the leukocyte count decreases to less than 25,000/mm3 or the platelet count decreases to less than 1,000,000/mm3 . The nadir occurs approximately 10 days after starting the drug. Nausea and diarrhea are common. Stomatitis can occur, particularly if there is concurrent irradiation. Patients also may develop a maculopapular rash.
New single agents
Many new drugs are being investigated for their activity in patients with head and neck cancer in phase I and II studies. Topotecan is a topoisomerase I inhibitor that had activity in one small phase II study.[170] Response rates of 25% were observed and have led to further evaluation by two large cooperative groups—the Southwestern Oncology Group (SWOG) and the Eastern Cooperative Oncology Group (ECOG). Results of these trials are pending.
Gemcitabine is a pyrimidine antimetabolite that may have antitumor activity in patients with head and neck carcinomas. This agent is converted to an active triphosphate metabolite, which is then incorporated into DNA and terminates transcription. Early phase II results have demonstrated only modest activity with response rates of 18%.[34]
Vinorelbine is a semisynthetic vinca alkaloid with dramatically less neurotoxicity than other agents of its class. Early studies have demonstrated response rates of 22%.[90] [207] Finally, analogs of methotrexate have been evaluated for response in small series. Trimetrexate, edatrexate, and piritrexim are active in squamous cell carcinomas of the head and neck but offer no advantage over methotrexate.[53] [169] [178] [213] [226]
In an effort to improve response rates and hopefully survival time, combination chemotherapy was developed. Many combination chemotherapy regimens have been evaluated in phase II trials in a few patients with recurrent head and neck cancer. Often, the results indicate a high response rate that suggests improvement over that expected from single agent methotrexate or cisplatin. However, the median duration of response ranges from 2 to 6 months, and no one has yet documented improved survival time over single-agent chemotherapy. Many of the regimens are complex, often with additional toxic effects.
Only through large comparative trials with patients randomized and stratified for prognostic variables can it be determined if therapeutic benefit exists with combination chemotherapy. The results of 12 trials comparing combination chemotherapy to single-agent cisplatin or methotrexate are shown in Table 6–3 (Table Not Available) . Some of the studies had small numbers of patients and lacked balance between treatment groups for prognostic factors such as performance status and extent of previous treatment. However, four large multiinstitutional trials that were well designed with respect to prognostic factors showed a significant difference in response rates between the combination treatment and the single-agent control arm.[40] [76] [83] [116] [222]
The ECOG compared an outpatient regimen of cisplatin, bleomycin, and methotrexate to weekly methotrexate.[222] The response to single agent therapy with methotrexate was 35%, and to the combination 48%, a significant improvement (P= 0.04). However, toxicity was greater for the combination with no difference in survival time.
The SWOG reported a comparison of cisplatin and 5-FU and carboplatin and 5-FU to weekly methotrexate.[76] [83] The response rates for the three arms were 32%, 21%, and 10%, respectively. There was a significant difference comparing

TABLE 6-3 — Randomized trials of chemotherapy for recurrent head and neck cancer
(Not Available)
Reprinted with permission from Tumors of the nasal cavity and paranasal sinuses, nasopharynx, oral cavity, and oropharynx. In Schantz SP, Harrison LB, Forastive AA: Cancer—principles and practice of oncology, ed 5, Philadelphia, 1997, Lippincott-Raven.
the cisplatin combination with methotrexate (P < 0.001); the difference between the response to the carboplatin combination and the response to methotrexate approached statistical significance (P= 0.05). The cisplatin and 5-FU arm was associated with significantly more toxicity than methotrexate; carboplatin and 5-FU were intermediate in toxicity. Despite these findings, the median survival times were not different, varying between 4.7 and 6.6 months.
The third study to show a difference in response rates compared the combination of cisplatin and 5-FU with each drug used alone.[116] The response rate to the combination was 40% compared with 18% for cisplatin and 15% for continuous infusion 5-FU (P < 0.01). Although the median survival times were not different, an analysis of patients surviving longer than 9 months showed a 40% survival rate for the combination treatment group compared with 27% and 24% for the single-drug treatments (P < 0.05).
The latter two trials also are of interest in the similar response rates observed for cisplatin and 5-FU, which were administered using the same dose and schedule in both studies. Cisplatin and 5-FU is a commonly used drug regimen for the treatment of patients with head and neck cancer for palliation and in combined modality programs. Response rates to this combination reported from small phase II trials in patients with recurrent disease range from 11% to 79%.[214] The results of these two large multiinstitutional trials have served to establish a response rate of 32% that can be expected from the cisplatin and 5-FU combination in patients with recurrent head and neck cancer.
Clavel and others[40] also observed significant differences between combination chemotherapy and single agents. They found significant differences in response rate for two cisplatin-containing combinations compared with single agent methotrexate, 34%, 31%, and 15%, respectively. These data corroborate the work of Vogl, Jacobs, and Forastiere.
Two comparative trials listed in Table 6–3 (Table Not Available) showed significant differences in median survival time.[31] [155] Morton and others[155] compared the combination of cisplatin and bleomycin to each single agent and to a no-treatment control arm. The response rate to each of the three chemotherapy arms was low, although the two cisplatin arms had median survival times of 4.0 and 4.2 months, which was improved over a 2.1-month survival time for the no treatment arm. In the four-arm trial reported by Campbell and others,[31] survival time was significantly longer for single-agent cisplatin compared with methotrexate, and there was no advantage for the combination treatments. Both of these trials had small numbers of patients and were unevenly balanced for prognostic factors, which serves to decrease the reliability of the statistical interpretation. Thus, from these randomized trials, it appears that higher response rates can be achieved with some combination chemotherapy regimens. Toxicity is more severe, and overall survival time as measured by median survival time is not improved. However, one study did find that a significantly greater proportion of patients treated with cisplatin and 5-FU lived longer than 9 months when compared with those receiving single-agent therapy. The patients who are more likely to be in the subset showing improvement have a better performance status.
As for other sites, the most effective combinations for treating those with nasopharyngeal carcinoma are cisplatin-based regimens. Higher complete and partial response rates than those from other sites have been reported in several phase II trials. * A few long-term disease-free survivors have been seen with cisplatin-based combinations.[21] [39] [73] French

* Refs. [21] [39] [45] [52] [73] [90] .

investigators have formed a collaborative group to study nasopharyngeal cancer. They have reported a series of studies evaluating cisplatin combination chemotherapy. Their regimen of cisplatin, bleomycin, and 5-FU resulted in a 20% complete response rate and an 86% overall response rate. Four patients with metastatic disease were long-term disease-free survivors for 52 to 58 months.[21] [48] [143] In their series, 131 patients with metastatic nasopharyngeal carcinoma were treated between 1985 and 1991. Ten percent of this group were long-term disease-free survivors. Thus, this disease entity shows a unique chemosensitivity even in patients with either bone or visual metastasis.[73] Browman and Cronin[25] summarized all of the available data regarding combination therapy by use of a metaanalysis. They analyzed all randomized trials published between 1990 and 1992 and concluded that cisplatin was the most effective single agent. Further, they found that the combination cisplatin and 5-FU was more efficacious than any single agent or other reported combinations. The combination of cisplatin and 5-FU is the gold standard to which all new combinations should be compared. Response rates achieved with this combination are approximately 32%, and the complete response rate ranges from 5% to 15%. Given these low response rates, one of the goals of clinical trials is to find new single agents and new combinations that may be more effective. Patients with locally advanced or metastatic disease should be considered for trials in an effort to improve on these statistics. Patients who have undergone previous surgery and radiation with good performance status and no previous chemotherapy are the best candidates to test new treatment protocols.
Although surgery and radiotherapy cure a high percentage of patients with early-stage squamous cell carcinoma of the head and neck, conventional treatment will not cure the majority of those with advanced disease. Because treatment for recurrent disease with chemotherapy is far from satisfactory, much effort has been directed toward improvements in the primary treatment program by using combined modality therapy. To this end, three general approaches have been undertaken: (1) induction also known as neoadjuvant therapy where chemotherapy is given before surgery or radiation; (2) chemoradiation where chemotherapy is given simultaneous with radiation to enhance its effect; and (3) adjuvant therapy where chemotherapy is given after surgery or radiation in an effort to decrease metastatic disease burden.
Induction chemotherapy
Theoretically, treating with chemotherapy before surgery or radiation has several advantages. Neoadjuvant chemotherapy allows for the delivery of drugs to the best possible host in terms of medical condition, which leads to increased compliance and better tolerance of therapy. Chemotherapy when given first can reduce tumor burden and downstage patients, resulting in the preservation of organ function by obviating the need for surgery. Further, induction therapy can reduce metastatic seeds and eliminate problems with poor vascularity that often occur after surgery or radiation, thus reducing a potential pharmacologic sanctuary.
One of the first uses of induction chemotherapy involved methotrexate with leucovorin rescue given twice before surgery.[204] It was reported that 77% of patients had some tumor shrinkage, although by strict criteria of tumor response (greater than 50% in all sites), the response rate was only 20%. Although it could not be concluded that the result was better than with surgery alone, no increased incidence of postoperative complications occurred. Many other studies followed using single agent methotrexate and bleomycin. The complete response rate was approximately 5% in these studies.
With the introduction of cisplatin into clinical trials in the mid-1970s, combination therapy consisted of cisplatin followed by a 5- to 7-day continuous infusion of bleomycin. Early series[108] [165] reported overall response rates of 71% to 76% with a 20% complete response rate. Other investigators added vinblastine, vincristine, or methotrexate to the two-drug combination with similar results.[9] An alternate and probably more effective regimen tested in the 1980s at Wayne State University is cisplatin (100 mg/m2 ) followed by a 5-day infusion of 5-FU (1 g/m2 per day by continuous infusion).[172] In phase II trials, this regimen was associated with as high as a 93% overall response rate and a 54% complete response rate when three cycles were administered. Although the toxicity from cisplatin is the same, 5-FU appears to be better tolerated than bleomycin, without the associated allergic phenomena or lung toxicity.
Ensley and others[66] [67] from Wayne State University have reported a high complete response rate using five or six courses of cisplatin and 5-FU alternating with methotrexate, leucovorin, and 5-FU. In one study, the complete response rate was 65% in 31 patients completing the protocol, although toxicity was formidable, and approximately one third of patients withdrew from the study early. Despite the potential for improvement in response rate, the feasibility of this approach has yet to be demonstrated.
Investigators at the Dana Farber Cancer Center[61] and at the University of Chicago[225] have used leucovorin to biochemically modulate the cytotoxic effects of 5-FU. Leucovorin results in an increase in intracellular-reduced folate levels and inhibition of thymidylate synthase.[152] Dreyfuss and others[61] administered cisplatin, 5-FU, and high-dose leucovorin (500 mg/m2 ), all by continuous infusion, over 6 days to 35 patients with local regionally advanced head and neck cancer. The overall response rate was 80%, and 66% had a complete response by clinical assessment. A pathologic complete response was documented in 14 of 19 patients (74%). Moderate-to-severe mucositis occurred in the majority of patients, although with dosage adjustment, the regimen was tolerable and acceptable to patients. Vokes and others[225]

treated 31 patients with similar disease with a less intensive cisplatin, 5-FU, and leucovorin regimen. Leucovorin was administered orally in a dose of 100 mg every 4 hours during the 5-day infusion of 5-FU. After two courses, the overall response rate in 29 evaluable patients was 90%, and the complete response rate was 30%.
Since the early 1980s, the many uncontrolled trials of induction chemotherapy before surgery or radiotherapy have shown that this approach is feasible for those with locally advanced disease and does not add to the morbidity of subsequent definitive local treatment.[130] [196] With the cisplatin plus 5-FU regimen, response can be expected in 80% to 90% of patients with, on average, a 40% complete response rate. Approximately two thirds of complete responses by clinical examination will be confirmed pathologically. Response to induction chemotherapy correlates with response to subsequent radiotherapy.[69] [92] [110] Thus patients who are resistant to cisplatin-based induction chemotherapy have a high likelihood of not responding to radiotherapy. Large randomized trials that consider all the important prognostic variables and have long-term follow-up periods are necessary to draw conclusions regarding disease-free survival and overall survival benefit.[82] The results of 17 randomized controlled trials of induction chemotherapy before surgery or radiotherapy or both have been published.
Three of the most important trials are listed in Table 6–4 (Table Not Available) , The Head and Neck Contracts program,[103] the SWOG trial,[180] and the Veterans Affairs Laryngeal Cancer Study Group trial,[221] were large multiinstitutional randomized studies. The patients had advanced resectable head and neck cancer, and the treatment arms were well balanced to T, N stage, and primary site. The Head and Neck Contracts program randomized patients to one of three treatments: (1) surgery followed by radiation, (2) induction chemotherapy with one cycle of cisplatin plus bleomycin followed by surgery and radiation, or (3) induction chemotherapy, surgery, radiation, and maintenance chemotherapy with cisplatin for 6 months. The 5-year survival rates were 35%, 37%, and 45%, respectively, for the three regimens; the differences were not significant. However, the time to development of distant metastases and the frequency of distant metastases as a site of first recurrence were significantly less in patients in the maintenance chemotherapy arm compared with the other two groups. On subgroup analysis, there was a significant difference in disease-free survival time for patients receiving maintenance chemotherapy for oral cavity primary tumors and for N1 or N2 disease.[117] In retrospect, it is not surprising that this trial did not show any improvement in overall survival time because only one cycle of cisplatin and bleomycin was administered before surgery, resulting in a low response rate of 37%.
The SWOG[180] randomized patients to receive either three cycles of cisplatin, bleomycin, methotrexate, and vincristine before surgery and radiotherapy or standard treatment with surgery and radiotherapy. The median survival time was 30 months for patients in the standard treatment arm compared with 18 months for the induction chemotherapy arm. The distant metastatic rate was 49% with standard treatment and 28% with induction chemotherapy. Although differences in survival time and pattern of recurrence are striking, statistical significance was not reached. This trial fell short of its accrual goals and had a high rate of noncompliance, with only 56% of patients randomized to induction chemotherapy completing the treatment per protocol.
The most encouraging data to emerge from induction chemotherapy trials are in the area of organ preservation (see the section on organ preservation). The Veterans Affairs Laryngeal Cancer Study Group[221] completed a randomized trial in patients with resectable stage III and IV squamous cell cancer of the larynx. Patients were randomized to receive standard therapy with total laryngectomy and postoperative radiotherapy or to receive a maximum of three cycles of cisplatin and 5-FU chemotherapy followed by radiotherapy. Surgery was reserved to salvage patients with persistent or recurrent disease. If patients did not have at least a partial response at the primary site after two cycles of chemotherapy, they underwent immediate surgery. The complete and partial response rate after two cycles of chemotherapy was 85%, and after three cycles was 98%. The pathologically confirmed complete response rate at the primary site was 64%. At a median follow-up period of 33 months, there was no significant difference in survival time. However, the patterns of relapse differed: recurrence at the primary site was 2% with surgery versus 12% with chemotherapy (P= 0.0005); regional node recurrence rates were similar (P= 0.305); distant metastases were 17% with surgery versus 11% with chemotherapy (P = 0.016); rate of second primary malignancies was 6% with surgery versus 2% with chemotherapy (P = 0.029). After 3 years of follow-up, 66% of surviving patients in the induction chemotherapy treatment group had a preserved, functional larynx. Similar results were reported by the EORTC comparing cisplatin and 5-FU induction chemotherapy followed by radiotherapy to laryngopharyngectomy and radiation in patients with locally advanced cancer of the hypopharynx. No survival time differences were observed, and 28% of patients were alive with a functional larynx. The larynx preservation rate was 42% at 3 years, considering only deaths from local disease as failure.[133]
None of the listed trials in Table 6–4 (Table Not Available) has demonstrated a survival benefit from induction chemotherapy. Two trials showed an improvement in survival time for chemotherapy-treated patients after subset analysis. Paccagnella and others[156] [157] in a large Italian study observed an improvement in local control, metastatic rate, and survival time for inoperable patients. In a follow-up study to the Head and Neck Contracts Program, Jacobs and others reported an improvement in survival time for the subgroup with oral cavity primaries and limited nodal disease. In terms of patterns of

TABLE 6-4 — Randomized trials of neoadjuvant chemotherapy before surgery or radiotherapy
(Not Available)
Reprinted with permission from Tumors of the nasal cavity and parnasal sinuses, nasopharynx, oral cavity, and oropharynx. In Schantz SP, Harrison LB, Forastive AA: Cancer—principles and practice of oncology, ed 5, Philadelphia, 1997, Lippincott-Raven.
failure, five trials showed a decrease in the rate of distant metastasis.[116] [133] [157] [180]
These trials have helped to clarify many issues. First the overall response rates range from 60% to 90% with complete response rates of 20% to 50%. Survival time is improved in patients with a complete response compared with nonresponders, and pathologic complete response can be seen in 30% to 70%. Second, response to chemotherapy predicts for response to radiotherapy. Patients who fail to respond to chemotherapy do not respond to radiation. Third, neoadjuvant chemotherapy does not increase either surgical or radiotherapy complication rates. Fourth, the most critical prognostic factors for response are TN stage and type of chemotherapy. Biologic behavior appears to differ per site. Fifth, although no benefit in overall survival time has yet been shown, a significant reduction in the rate of distant metastases has been observed. Finally, organ preservation and improved quality of life can result with induction chemotherapy. For patients with advanced laryngeal cancer who would require a total laryngectomy, the available data indicate that laryngeal function can be preserved in two thirds without jeopardizing survival time.
Neoadjuvant chemotherapy has been used to manage advanced nasopharyngeal carcinoma similarly to other sites. To date, two randomized prospective trials have been conducted. The International Nasopharyngeal Study Group[113] randomized 339 patients to receive three cycles of bleomycin, epirubicin, and cisplatin chemotherapy followed by radiotherapy to radiotherapy alone in high risk for relapse patients (i.e., N2 , N3 disease). At a median follow-up period of 49 months, there was a significant difference in disease-free survival time, 42% versus 29% at 4 years, P = 0.006, in favor of the chemotherapy arm. No difference in overall survival time was observed, 50% versus 42%, although median survival time was superior for the chemotherapy and radiation arm compared with radiation alone, 50 and 37 months, respectively.
In the second study, Chan and others[36] randomized 82

patients to receive either radiotherapy alone or two cycles of cisplatin and 5-FU followed by radiotherapy. These patients had tumors 4 cm or large or N3 nodal disease. The overall response rate to chemotherapy was 81%, and this increased to 100% after radiation versus 95% for radiation alone. However, at a median follow-up period of 28.5 months, 2-year survival and disease-free survival time were not significantly altered by the addition of chemotherapy. This lack of difference may be accounted for partly by the less intensive nature of the chemotherapy with the 5-FU being given at 1000 cy/m2 /day over 3 days.
Concurrent radiotherapy and chemotherapy
Concurrent radiotherapy and chemotherapy have been used primarily in patients with unresectable disease to improve local and regional control. The major drugs with efficacy for this tumor type and in vitro evidence of radiation enhancement capability have been tested as single agents since the 1960s. The theoretic rationale and mechanism for the interaction between cytotoxic drugs and radiation that results in additive or synergistic enhancement have been reviewed in detail.[87] [194] [202] This biologic phenomenon rests on several mechanisms. These include (1) inhibition of DNA repair, (2) redistribution of cells in sensitive phases of the cell cycle, and (3) promoting oxygenation of anoxic tissues. The net effect is to improve cellular cytotoxicity.[225] Most of the single agents used to treat patients with head and neck cancer have been combined with radiation.
Nearly all reported trials of concomitant chemotherapy and radiotherapy have noted enhanced acute radiation-induced toxicity, primarily mucosal, which often has resulted in dose reductions and lengthy interruptions in radiation without evidence of survival benefit. Thus, in combining these two treatment modalities, it is essential that toxicity not preclude the use of chemotherapy and radiation in the optimal dose and schedule.
Single agents and radiotherapy
For an outline of randomized trials of simultaneous single agent chemotherapy with radiotherapy versus radiotherapy, see Table 6–5 (Table Not Available) .
Methotrexate plus radiotherapy.
Methotrexate can produce an S-phase block of the cell cycle, resulting in accumulation of cells in the G1 phase and causing increased radiosensitivity. [14] In one early study, 96 patients with inoperable disease were randomized to receive radiotherapy alone or radiation preceded by intravenous methotrexate. [126] The complete response rate was the same in both groups, as was the 3-year survival rate. However, the incidence of mucositis increased in those patients who received chemotherapy. A second large study of patients with stage III and IV squamous cell carcinoma, similar to the previous study, again showed no difference in the 3-year survival rate, although the rate of distant metastases was only 19% in patients who received chemotherapy plus radiation compared with 33% of patients who received radiotherapy alone.[142] The Radiation Therapy Oncology Group (RTOG) randomized 712 patients to radiotherapy alone or radiation plus pretreatment methotrexate.[74] No difference occurred in survival time between the treatment groups, and more patients failed to complete irradiation in the combined therapy group. In a randomized study published by Condit and others,[42] there was no improvement in survival time in the combined group. In another study, Gupta[96] observed an improvement in survival time and better control of the primary tumor. This was especially true for those with oropharyngeal tumors. Thus three randomized series with adequate patient numbers showed negative results, and a fourth study showed improved survival time.
Hydroxyurea plus radiotherapy.
Hydroxyurea kills cells in the S-phase and synchronizes cells into the more radiosensitive G1 phase. Despite good theoretic activity, three randomized trials have shown no advantage of hydroxyurea in addition to radiotherapy. In one series, 12 patients with advanced cancer were randomized to radiation alone or with hydroxyurea (80 mg/kg biweekly).[195] The complete response rate at the primary site was 40% in both groups, but survival time was inferior in the combination group. In addition, distant metastases developed in 23% of patients receiving combined treatment as compared with 8% receiving irradiation alone. Another study of 40 patients comparing radiotherapy alone or with hydroxyurea (80 mg/kg three times per week) showed no difference in complete response rate or survival times, but it did show a 40% incidence of mucositis in the combined group.[167]
Bleomycin plus radiotherapy.
Bleomycin and irradiation have been studied in vitro, and the enhanced effects are believed to be caused by interference with cellular repair after irradiation. Nine randomized trials have compared radiotherapy alone with radiation plus bleomycin. The first series included 227 patients with advanced oropharyngeal carcinomas.[29] Bleomycin was given at 15 mg twice weekly for 5 weeks. No difference in response rate or survival time was noted, and bleomycin was not well tolerated, causing a significant amount of mucositis. The results were unchanged in a recent update of this trial.[71] Similar results were reported by Vermund and others.[217] In contrast, a third large series,[184] from India, included patients with advanced buccal mucosa cancers and compared radiotherapy given alone with radiation plus bleomycin (10 to 15 mg three times per week for 6 weeks). The complete response rate in the radiotherapy group was 21% compared with 77% in the combined therapy group.
An improvement in disease-free survival time, local and regional control, and complete response rate, but not overall survival time, was reported by Fu and others.[88] In this Northern California Oncology Group trial, patients received either radiotherapy alone or radiation with bleomycin (5 mg twice weekly) followed by 16 weeks of maintenance bleomycin and methotrexate. The complete response rates were 45%

TABLE 6-5 — Randomized trials of simultaneous single agent chemotherapy with radiotherapy versus radiotherapy
(Not Available)
Reprinted with permission from Tumors of the nasal cavity and paranasal sinuses, nasopharynx, oral cavity, and oropharynx. In Schantz SP, Harrison LB, Forastive AA: Cancer—principles and practice of oncology, ed 5, Philadelphia, 1997, Lippincott-Raven.
with radiotherapy alone and 67% for the combined treatment (P = 0.056). The 2-year local and regional control rate was significantly improved with the addition of bleomycin, 26% versus 64% (P= 0.001). The incidence of distant metastases as a site of failure was similar in both treatment groups, indicating that the bleomycin and methotrexate maintenance regimen was ineffective in controlling micrometastatic disease. In this trial, in contrast to the others reported, the dose of bleomycin used with radiotherapy was well tolerated. A significant reduction in radiation dose or treatment delays did not occur as a result of enhancement of acute radiation toxicity.
Nine randomized trials of bleomycin and radiation have been completed. Only three of these showed a response benefit.[88] [121] [183]
5-Fluorouracil plus radiotherapy.
Several early trials indicated that 5-FU was an active radiosensitizer for patients with head and neck cancer. Three randomized trials have been published. Lo and others[140] randomized 134 patients with advanced head and neck cancer to radiotherapy with or without 5-FU (10 mg/kg per day for 3 days, 5 mg/kg per day for 4 days, 5 mg/m2 three times per week). The 5-year survival rate for radiation alone was 14%, and for combined treatment, it was 32%. This improvement in survival time occurred for patients with primary lesions in the tongue or tonsil only. In another study, Shigematsu[188] used intraarterial 5-FU with radiotherapy to treat patients with maxillary sinus carcinoma and observed an improvement in disease-free survival time. Browman[26] randomized patients to infusional 5-FU and radiation to radiation alone and observed a higher complete response rate but no change in survival time.
Mitomycin and radiotherapy.
Mitomycin is an antibiotic that during hypoxic conditions is enzymatically reduced to form an active alkylating species.[175] It is selectively toxic to hypoxic cells. Therefore, because hypoxic cells within tumors have reduced sensitivity to the effects of radiation, it has been hypothesized that combined treatment could improve the therapeutic ratio.[171] This concept was tested by Weissberg and others[231] in a randomized trial by treating 120 patients with advanced head and neck cancer with radiotherapy alone or with radiation with mitomycin (15 mg/m2 ). Disease-free survival time at 5 years was 49% for the radiotherapy alone patients and 75% for those treated with mitomycin (P< 0.07). Local and regional control rates were significantly improved with administration of mitomycin, 55% versus 75% (P< 0.01). There was no difference in the incidence of distant metastases or overall survival time between treatment groups.
Cisplatin and radiotherapy.
The exact echanism of interaction between cisplatin and radiation is not known. Hypoxic and aerobic cell sensitization and the inhibition of cellular repair processes for sublethally damaged cells contribute to the effects observed in in vitro systems.[56] In a phase II trial, the RTOG administered cisplatin (100 mg/m2 ) every 3 weeks to 124 patients with locally advanced, unresectable head and neck cancer.[6] Sixty percent of patients completed the combined treatment per protocol, and 69% of

all patients achieved a complete response. Separate analysis of the disease-free and overall survival times for those with nasopharynx and nonnasopharynx primary sites with more than 5 years of follow-up have been published.[7] [144] A comparison to RTOG patients treated with radiotherapy alone suggested improvement in survival time for the combined treatment.
Wheeler and others[233] piloted high-dose cisplatin (200 mg/m2 ) every 4 weeks with concurrent radiotherapy in 18 patients with unresectable disease and observed complete responses in 94%. The median survival time was 23 months with 56% and 41% alive and disease-free at 1 and 2 years, respectively. A high rate of distant relapse was observed. Only one randomized trial has been conducted to evaluate concomitant cisplatin and radiotherapy.[101] Through the Head and Neck Intergroup mechanism, 371 patients with unresectable local regional squamous cell head and neck cancer were randomized to receive radiotherapy alone or radiation plus weekly low-dose cisplatin, 20 mg/m2 .
There was a significant difference in overall response rate (complete and partial), 59% for those receiving radiation alone and 73% for those receiving the combined treatment (P = 0.007). However, there was no significant difference in complete response or survival time. The lack of survival benefit may be because of the low total dose of cisplatin received, only 120 to 140 mg/m2 over the 6 to 8 weeks of radiation treatment.
Concomitant chemotherapy and radiotherapy have been useful for the treatment of patients with nasopharyngeal carcinoma. A small group of patients were treated with cisplatin and radiotherapy by Al-Sarraf and others.[7] Local control and survival time were improved in comparison to historical controls. A head and neck intergroup trial closed in November 1995 showed promising results for the combined approach in this disease.[11] In this study, patients received either radiotherapy alone or cisplatin (100 mg/m2 days 1, 22, and 43) during radiotherapy followed by adjuvant chemotherapy with cisplatin and 5-FU (three cycles). Analysis of 138 randomized patients revealed significant differences in 2-year survival time (80% versus 55%) and progression-free survival time (52 months versus 13 months) favoring the chemotherapy group. This exciting result has now changed the standard of care for those with nasopharyngeal carcinoma in the United States. Patients with stage III or IV disease should be treated with concomitant chemoradiotherapy followed by adjuvant chemotherapy.
Randomized trials of single agents and radiotherapy have shown improved survival time with methotrexate, bleomycin, and 5-FU.[140] [184] Improved disease-free survival but not overall survival time has been shown in two other trials with use of bleomycin and mitomycin.[88] [231] Because mucosal toxicity is enhanced with these regimens and because overall survival time, although improved, remains poor, none of these regimens has become a standard therapy. The exciting results of the intergroup trial using concurrent cisplatin in patients with locally advanced nasopharyngeal cancer cannot be generalized to other sites but will form a basis for further investigation.
The favorable results from concurrent cisplatin and radiotherapy followed by adjuvant chemotherapy establish this as a standard management approach for locally advanced nasopharyngeal cancer in the United States.
Multiple agents and radiotherapy
Combining several drugs with radiation will enhance acute toxicity, which may be severe. Therefore, investigators have piloted trials designed with split-course radiation to allow for healthy tissue recovery. Most of these studies are limited to patients with stage III and IV locally advanced unresectable squamous cell cancer and have improved survival time as the primary goal. These regimens alternate chemotherapy and radiotherapy or use split-course radiotherapy to maximize tumor cell kill and minimize tissue toxicity. For those with head and neck cancer, protracted radiation results in decreased local control rates because of accelerated repopulation of cancer cells that survive the initial insult.[12] [158] Thus, alternating two non–cross-resistant agents may potentially eliminate not only tumor cell repopulation but primary drug resistance.
Early phase I and II studies have used infusional 5-FU as originally reported by Byfield and others,[28] adding cisplatin[1] [205] or hydroxyurea[224] with concurrent split-course single daily fraction radiation. Alternatively, cisplatin and fluorouracil with leucovorin modulation have been combined with split-course accelerated radiotherapy.[232] Several studies with long follow-up periods reported promising survival and response data but also severe toxicity.[3] [98] [205] [227] [232]
Mature data were reported by Taylor and others[205] using cisplatin plus continuous infusion 5-FU and radiotherapy and alternating 1 week of treatment with 1 week of rest. The median survival time for 53 patients with a median follow-up period in excess of 4 years was 37 months. The complete response rate was 55%. The total dose received of radiation and 5-FU but not cisplatin correlated with outcome. Local control was poorest in stage IV patients with N3 disease.
Although these pilot trials all report encouraging data for improved survival time, randomized trials that use radiotherapy alone as the control are needed before these approaches can be recommended outside the research setting. Data from six randomized trials are shown in Table 6–6 (Table Not Available) . The South-East Cooperative Oncology Group (SECOG)[193] compared alternating with sequential chemotherapy and radiotherapy. The chemotherapy selected was vincristine, bleomycin, and methotrexate with a further randomization to inclusion of 5-FU or not. Survival rates were lower than observed in a previous pilot trial, and a significant improvement in disease-free survival time was observed on subset analysis for larynx primaries managed with the alternating schedule. The alternating regimen was associated with a higher frequency of severe mucosal reactions.

TABLE 6-6 — Randomized trials of concomitant or alternating combination chemotherapy and radiation
(Not Available)
Reprinted with permission from Tumors of the nasal cavity and paranasal sinuses, nasopharynx, oral cavity, and oropharynx. In Schantz SP, Harrison LB, Forastive AA: Cancer—principles and practice of oncology, ed 5, Philadelphia, 1997, Lippincott-Raven.
Merlano and others[149] published the final report of a randomized comparison of alternating and sequential chemotherapy (vinblastine, bleomycin, methotrexate) and radiotherapy followed by surgical salvage if feasible. Four courses of chemotherapy were alternated with three courses of radiotherapy (20 Gy each). All patients had unresectable stage III or IV squamous cell cancer. The complete response rate before and after surgical intervention and the overall survival time at 4 years were significantly superior for patients receiving concomitant treatment. Severe mucosal toxicity was observed in 30.5% of patients in the alternating regimen compared with only 6% of those receiving chemotherapy before radiotherapy. The results of a follow-up trial reported by Merlano and others[149] [150] showed a significant difference in relapse-free and overall survival time for patients treated with alternating cisplatin plus 5-FU and radiotherapy compared with radiotherapy alone. All patients had unresectable locally advanced squamous cell cancer of the head and neck.
In a small randomized trial, Adelstein and others[2] compared simultaneous cisplatin plus 5-FU and radiotherapy to sequential treatment. Patients with stage II, III, or IV, either resectable and unresectable disease, were eligible. In the simultaneous treatment, patients were evaluated for surgery after chemotherapy and 30 Gy. Complete responders and those with unresectable disease continued treatment with chemotherapy and radiotherapy. In the sequential treatment, surgical evaluation occurred after three cycles of chemotherapy and before radiotherapy. The results with follow-up period ranging 9 to 41 months showed a significant difference in disease free-survival but not overall survival time. At this point in follow-up, 18 of 48 patients were complete responders and had not required surgery.
Finally, Taylor,[206] similarly to Adelstein and others, [3] compared cisplatin plus 5-FU and concomitant radiotherapy with sequential treatment. They found a significant improvement in local and regional control on subset analysis for patients with T3–T4 N0 and T1–T2 N2 diseases receiving concomitant treatment.
The results of these trials indicate that improved disease-free and overall survival times are possible for patients with locally advanced squamous cell head and neck cancer using alternating or concomitant chemotherapy and radiotherapy. Well-designed clinical trials are needed to determine optimal chemotherapy and radiotherapy schedules. Randomized trials are currently in progress to help clarify these issues.
Adjuvant chemotherapy
Adjuvant chemotherapy after primary surgery has been shown to be effective in patients with breast cancer and osteogenic sarcoma. To date, three randomized trials have been designed to address this question in those with head and neck cancer. Adjuvant chemotherapy has several potential advantages over neoadjuvant treatment. With adjuvant treatment, surgery is not delayed, and a patient with resectable disease can undergo surgery sooner. Secondly, neoadjuvant therapy can blur the margins of disease, making the degree of surgical resection less obvious. Finally, neoadjuvant therapy, if successful, can lead to symptom abatement, resulting in patient refusal of surgery afterward.
Through the Head and Neck Intergroup mechanism, a large multiinstitutional trial was conducted to test whether

the addition of chemotherapy to surgery and radiotherapy prolonged survival time or altered the pattern of recurrence.[132] Patients with stage III or IV squamous cell carcinoma of the oral cavity, oropharynx, or larynx and those with stage II, III, or IV of the hypopharynx who had negative pathologic margins of resection were eligible.
Randomization was to immediate postoperative radiotherapy or to three cycles of cisplatin plus 5-FU chemotherapy followed by radiotherapy. A preliminary analysis of the 503 patients randomized has shown no significant difference in disease-free survival time, overall survival time, and local and regional control. However, there was a significantly lower rate of distant metastases as a site of failure (P = 0.016) at any time for patients treated with adjuvant chemotherapy. Perhaps more important was the finding that a high-risk subset of patients (those with extracapsular extension, carcinoma in situ, or close surgical margins) appears to benefit from adjuvant chemotherapy with increased survival time and local control that approached statistical confidence when compared with those receiving radiation alone.
Two trials testing induction chemotherapy added maintenance chemotherapy to one treatment group and observed differences in outcome. The Head and Neck Contracts Program[103] trial of one course of cisplatin and bleomycin induction chemotherapy before surgery and radiation included 6 months of maintenance chemotherapy in one of the three treatment arms. There was a significant decrease in the distant metastatic rate observed for those patients. Ervin and others[70] randomized patients showing a response to cisplatin, bleomycin, and methotrexate induction chemotherapy to receive three additional cycles or observation after definitive surgery and radiotherapy. The 3-year disease-free survival time for patients receiving maintenance chemotherapy was 88% compared with 57% for the controls (P= 0.03). In a phase II pilot, Johnson and others[119] treated 42 patients with extracapsular spread of tumor in cervical lymph node metastases with 6 months of methotrexate and 5-FU after resection and radiotherapy. The 2-year disease-free survival rate was 66%, which was improved from an expected control rate of 38% based on historical experience.
Considered together, the results of these five trials indicate that adjuvant chemotherapy can affect micrometastatic disease and decrease the rate of distant recurrence. The data also suggest that disease-free survival time may be improved. The major impediment to successfully conducting adjuvant or maintenance chemotherapy trials in patients with head and neck cancer is patient noncompliance. The morbidity of the primary treatment, combined with the medical and social situations of this group of patients, makes classical adjuvant chemotherapy unacceptable or not feasible in many patients. In addition, there appears to be no role for adjuvant chemotherapy in low-risk patients, although high-risk patients may benefit.
Many squamous cell cancers of the head and neck are diagnosed at a late stage. Stage III and IV tumors often necessitate extensive or radical surgery that can alter function. Problems with radical surgery include loss of speech, loss of swallowing function, or disfigurement without a concomitant improvement in survival time. Therefore, preservation of function has become one of the major challenges of the 1990s. A role for combined modality treatment in preserving organ function already has been noted for laryngeal preservation as in the V.A. larynx study. In this study, neoadjuvant chemotherapy followed by radiotherapy was more successful in preserving voice function compared with surgery without a loss in survival time.
Neoadjuvant chemotherapy has been used to preserve organ function for patients with hypopharyngeal, laryngeal, and oropharyngeal cancers. Several nonrandomized studies have been completed using cisplatin-based chemotherapy. In these studies, patients were required to have achieved either a partial or complete response to go on to conventional radiotherapy. Nonresponders then went on to radical surgery. In these pilot studies, there were no survival differences between the surgical groups and the groups that avoided surgery, suggesting that quality of life may be improved without worsening survival. *
In addition to the V.A. larynx study,[221] one other large randomized study has been completed. This study[133] was done in Europe by the European Organization for Research and Treatment of Cancer (EORTC) beginning in 1990 and compared a larynx-preserving therapy (induction chemotherapy plus radiation) with conventional surgery plus postoperative radiation. The design of the EORTC study was similar to the V.A. larynx study, as patients were randomized to either treatment, and patients receiving induction chemotherapy received cisplatin plus 5-FU. After two cycles of chemotherapy, only responders (i.e., partial or complete responders) received a third cycle. Patients achieving a complete response then received definitive radiotherapy. Nonresponding patients or those with partial response underwent conventional surgery followed by postoperative radiation.
As in the V.A. study, the overall survival data were not different between the two arms, and the median duration of survival time was longer for the chemotherapy arm. Local failures occurred more commonly in the chemotherapy arm, but the distant metastatic rate was lower. In both studies, a large number of patients were enrolled, and of the surviving patients, a significant percentage were able to retain their larynx. These exciting results are changing the standard of care for patients with advanced laryngeal cancer and suggest that this approach may be feasible for other sites. Patients with stage III or IV laryngeal or hypopharyngeal carcinomas should now be given the option of organ preservation therapy (chemotherapy and radiotherapy). Further, patients with advanced

* Refs. [51] [54] [91] [122] [129] [131] [160] [164] [189] .

carcinomas of the oropharynx and oral cavity should be enrolled in organ-preservation trials to assess the effectiveness of this therapy versus standard care.
Poor response to chemotherapy after surgery or radiotherapy may be caused by impaired drug delivery into the region. Intraarterial chemotherapy has been used in attempts to overcome this for almost three decades. The rationale for intraarterial therapy is based on the steep dose–response curve exhibited by most cytotoxic drugs.[84] Maximum cell kill occurs when the tumor exposure to a high concentration of drug is optimized. Drug toxicity also follows a steep curve. Therefore, regional drug delivery has the potential to increase tumor drug exposure and reduce systemic exposure that affects critical healthy tissues.[37] [41] The principal determinant of a drug’s therapeutic advantage is the ratio of total body clearance to the regional exchange rate.
Several factors should be considered in choosing a drug for intraarterial delivery: (1) drug concentration, not time of exposure, is the major factor in cell killing; (2) the drug should be deactivated in the systemic circulation; (3) there should be a high tissue extraction; and (4) a drug should not require activation in the liver.
Intraarterial cisplatin has been shown to be effective and relatively nontoxic in patients with several solid tumors. Pharmocakinetic studies have shown a regional increase in plasma and tissue platinum concentrations in the infused area. Several studies indicate significant palliation in patients with head and neck squamous cancers in whom irradiation and surgery failed to eradicate the tumor. A response rate of 87% using intraarterial 5-FU, methotrexate, and bleomycin was reported by Donegan and Harris.[59] Tumor regression lasted up to 13 months. Intraarterial methotrexate and bleomycin have been used before irradiation for patients with advanced head and neck cancer, with a 28% partial response rate.[240] Intraarterial cisplatin given before surgery or radiation has produced responses in the 70% to 80% range.[93] [154]
One of the major drawbacks of intraarterial therapy is catheter-related complications: air and plaque emboli, sepsis, and patient immobility during chemotherapy administration. These problems have been overcome by the introduction of an implantable infusion pump.[15] This system has been used successfully in treating patients with recurrent head and neck cancer with continuous infusion of dichloromethotrexate and fluorodoxyuridine.[79] [234]
One primary site for which intraarterial chemotherapy has been more extensively studied is paranasal sinus cancer. Japanese investigators have favored cannulation of the superficial temporal artery and infusion of 5-FU integrated with surgery and radiotherapy.[176] [187] More recently, investigators in the United States have evaluated superselective arterial catheterization and short-term intraarterial chemotherapy to debulk locally advanced resectable and unresectable paranasal sinus carcinoma. This approach minimizes potential toxic effects to adjacent healthy tissues. Dimery[58] reported evaluating intraarterial cisplatin and bleomycin by this technique combined with intravenous 5-FU. A complete response rate of 23% was achieved in those receiving the chemotherapy alone. After surgery or radiotherapy, 63% of patients were disease-free, and 61% were spared orbital exenteration.
Although intraarterial therapy has several theoretic advantages over systemic chemotherapy, it has not been established as a superior approach. Most series contain small numbers of selected patients. This therapy should not be viewed as a standard of care by the community, but further investigation appears warranted.
Cancers of the salivary gland represent approximately 3% of all neoplasms in the head and neck region. The majority originate in the parotid gland. Despite optimal treatment with surgery and postoperative radiotherapy, patients with advanced salivary gland cancers have a poor prognosis, with survival times ranging from 0% to 32% at 10 years. Survival time varies with histology, with 10-year survival rates of 96% reported for low-grade mucoepidermoid carcinoma and 29% reported for adenoid cystic carcinoma.[85] Probability of recurrence also varies with site. Local or distal recurrence occurs in up to 66% of patients with cancers of major salivary glands and in up to 92% of patients with cancers of the minor salivary glands.[43] Reasons for recurrence include failure of local control and spread of disease to distant sites, particularly the lung.
Chemotherapy in the management of salivary gland cancers has been used mainly for the treatment of patients with recurrent disease. Because of the relatively small number of patients, trials often contain few patients with a variety of histologic findings. Many reports document single cases, leaving uncertainty as to the number of patients who may have been treated. Suen and Johns[200] showed that response to chemotherapy varies with histologic findings. They also found that response varies with site recurrence, with local and regional disease having a higher response rate than distal disease. In addition, patients without previous radiotherapy had a better response to chemotherapy. Drawing conclusions from most series is difficult because they usually include a group of patients treated for many years with a variety of combinations and single agents. In addition, some cancers with distal spread, such as adenoid cystic carcinoma, can grow at such a slow rate that responses and impact on survival time are difficult to interpret.
Suen and Johns[200] reported large series of patients treated at their institutions and at others in an attempt to define the best single agents or combinations of drugs for salivary gland cancers of specific histologic categories. For those with adenoid cystic carcinoma, the best single agents are cisplatin, 5-FU, and doxorubicin ( Table 6–7 ). Cisplatin has been reported

TABLE 6-7 — Combination chemotherapy for salivary gland cancer
Number of patients
Response (CR and PR) (%)
Adenoid cystic carcinoma
Posner, 1982[163]
Adriamycin + cyclophosphamide
Dreyfuss, 1987[62]
Cisplatin + adriamycin + cyclophosphamide
Venook, 1987[215]
Cisplatin + adriamycin + 5-FU
Triozzi, 1987[211]
Cyclophosphamide + vincristine + 5-FU
Creagan, 1988[47]
4 cisplatin-based regimens
Alberts, 1981[4]
Cisplatin + adriamycin + cyclophosphamide
Dreyfuss, 1987[62]

Creagan, 1988[47]
4 cisplatin-based regimens
Venook, 1987[215]
Cisplatin + adriamycin + 5-FU
Mucoepidermoid carcinoma
Posner, 1982[163]
Cisplatin + bleomycin + methotrexate
Venook, 1987[215]
Cisplatin + adriamycin + 5-FU
Creagan, 1988[47]
4 cisplatin-based regimens
CR—Complete response; PR—Partial response.
to have a complete response rate of 29% and an overall response rate of 64% in 14 treated patients.[179] [200] Complete responses lasted from 7 to 18 months. 5-FU has been reported to have a partial response rate of 46% in 13 patients.[120] [203] Adriamycin was noted to have a response rate of 13% in seven patients.[166] [216] Methotrexate, vincristine, and cyclophosphamide appear to have little activity for adenoid cystic carcinoma. The combination of adriamycin and cyclophosphamide has been used in five patients with a 40% partial response rate.[163] Because of poor prognosis of patients with advanced disease and the activity of cisplatin, Sessions and others[181] treated four patients with intraarterial cisplatin before further therapy. All patients had some tumor shrinkage, but only two had a partial response. There was minimal toxicity.
Very few studies of single-agent chemotherapy for mucoepidermoid carcinoma exist. Several of the studies were done before the widespread use of cisplatin, and data on its use as a single agent for the management of this carcinoma are not available. Methotrexate has been used in four patients, with one achieving a complete response and one having a partial response. Posner and others[163] used two different combinations for recurrent mucoepidermoid carcinoma. Two of three patients responded to a combination of cisplatin, bleomycin, and methotrexate. Three patients failed to respond to a combination of cyclophosphamide and adriamycin. Further studies need to be done to determine the most active agents for mucoepidermoid carcinoma.
Only scattered reports of the use of chemotherapy for the other salivary gland cancers exist. The combination of adriamycin, cisplatin, and cyclophosphamide achieved one complete response and two partial responses in three treated patients with adenocarcinoma.[4] The small numbers of patients in each series preclude firm conclusions regarding the true level of antitumor activity of these drugs. However, the data provide an indication of which drugs are reasonable to choose for single-agent or combination chemotherapy. Creagan and others[47] reported the results of cisplatin-based chemotherapy in 34 patients with locally recurrent or metastatic cancers originating from the salivary gland or contiguous structures (see Table 6–7 ). Most patients received cyclophosphamide or mitomycin, plus adriamycin and cisplatin combination chemotherapy. A 38% response rate was observed, listing a median of 7 months. The median survival time was 18 months for responders to chemotherapy and 15 months for nonresponders. Thus, response to treatment did not appear to confer a survival advantage. Dreyfuss and others[62] also evaluated cyclophosphamide, adriamycin, and cisplatin in a series of 13 patients (nine with adenoid cystic carcinoma and four with adenocarcinoma), observing responses in 46% (three complete and three partial responses).
In another combination chemotherapy trial, Venook and others[215] treated 17 patients with advanced or recurrent salivary cancer with cisplatin, adriamycin, and 5-FU. Thirty-five percent of patients responded to chemotherapy. In this small series, response rate was not influenced by the extent of previous treatment.
In conclusion, cisplatin, adriamycin, and 5-FU or cyclophosphamide appear to be the most active agents and combinations for those with adenoid cystic carcinoma and adenocarcinoma. The most active agents for the other cancers have not been defined. Whether combination chemotherapy can improve survival time in patients with recurrent disease is not clear. In some patients with recurrent disease, particularly adenoid cystic carcinoma, the pace of disease can be so slow that patients often do not need to be treated with chemotherapy for a prolonged period. This slow growth rate in some patients may be one of the factors accounting for the poor response to chemotherapy. New agents need to be

evaluated in adequate numbers of patients to determine activity with statistical confidence. One such trial is in progress in the ECOG. The taxane derivative paclitaxel (Taxol) is being studied in cohorts of patients with adenoid cystic, mucoepidermoid, and adenocarcinoma of the salivary gland origin in this multicenter trial. Studies of adjuvant chemotherapy in the disease have not been undertaken because of the small numbers of patients and relatively ineffective chemotherapy. Clearly, collaborative efforts by many investigators will be necessary before conclusions can be drawn concerning the use of chemotherapy for salivary gland cancers.
Chemoprevention is defined as the administration of pharmacologic agents to inhibit the events occurring during the multistep process of carcinogenesis or the reversal of a premalignant condition. The biology of carcinogenesis leading to upper aerodigestive tract malignancies is not well understood. Tumor formation is believed to be a multistep process involving biochemical and molecular changes that result in dysregulated differentiation and proliferation.[75] Chromosomal alterations and mutations of specific oncogenes are associated with epithelial cancers.[99] [237] Investigators studying various genomic, proliferation, and differentiation biomarkers have found alterations in specific markers (keratin, involucrin, transglutaminase) during the process of abnormal squamous differentiation. These biomarkers may be useful as intermediate end points in future chemoprevention trials.[136] Our understanding of the biology of carcinogenesis for head and neck cancer and other aerodigestive tract tumors is expected to rapidly expand in the next decade.
Chemoprevention is particularly relevant to patients who are curatively treated for an early stage head and neck squamous cell cancer. It is recognized that second primary malignancies develop at a constant rate of 3% to 4% per year in these patients.[44] [135] The explanation for this risk is based on the concept of field cancerization first formulated in the 1950s.[191] [199] Repeated exposure of the entire epithelial surface to carcinogens, such as tobacco and alcohol, can lead to the development of multiple sites of premalignant and malignant change. The ability of retinoids and carotenoids to affect epithelial growth and differentiation is supported by in vitro, animal, and epidemiologic studies.[20] Although the exact mechanism by which retinoids inhibit carcinogenesis is not known, retinoids have been shown to modify genomic expression at the level of messenger RNA synthesis and to regulate transcription of specific genes.[141] [229] Clinically, retinoids and carotenoids have been used to prevent malignant transformation of dysplastic leukoplakia lesions. Most recently, retinoids have been studied in the prevention of second primary cancers. Retinoids are the synthetic and natural analogs of vitamin A. ß-carotene is the major source of vitamin A in the diet.
The major limitation in the use of retinoids is the associated toxicity. Acute toxicity includes dryness of conjunctival and oral mucous membranes, cheilitis, skin desquamation, hypertriglyceridemia, bone tenderness, arthralgias, and myalgias. Chronic toxicities include hepatotoxicity and bone remodeling.[104] These compounds are teratogenic, causing multiple malformations. Because of these toxicities, a number of retinoids have been synthesized. Four used clinically are vitamin A or retinol; ß-all-transretinoic acid or retinoid; 13-cis retinoic acid or isotretinoin; and an aromatic ethyl ester derivative, etretinate.[104] In contrast to the retinoids, the major toxicity of the carotenoids is yellowing of the skin. Other compounds that may have use in chemoprevention based mainly on in vitro and animal data are a-tocopherol (vitamin E), selenium, and N-acetyl cysteine. The latter compound is a precursor of intracellular glutathione that enhances its antioxidant activity as a free radical scavenger. N-acetyl cysteine is nontoxic and currently under investigation in Europe for the prevention of second malignancies in patients with a previous head and neck or lung carcinoma.[24] [104]
Studies with retinoids and carotenoids in patients with leukoplakia are listed in Table 6–8 . Stich and others [197] [198] reported two trials conducted in India and the Philippines in betel nut chewers. In one placebo-controlled trial, ßcarotene was compared with ß-carotene plus vitamin A. Complete response was observed in 3% of the placebo patients, in 15% of ß-carotene–treated patients, and in 28% of those taking the combination. These patients demonstrated significant suppression of micronuclei expression and index of DNA damage on serial cytologic examinations. In a subsequent study, patients were randomized to placebo or twice the dose of vitamin A (200,000 IU/week) received in the first trial. A 57% complete response rate was observed with total suppression of the development of new leukoplakic lesions. In the placebo group, the complete response rate was 3%, and there was a 21% rate of new lesion formation.[198] In a small pilot study, Garewal and others[89] observed a 71% complete and partial response rate in 24 patients treated with ß-carotene. There was no significant toxicity. The preliminary results of a fourth study[209] showed only a 27% response rate, although the dose of ß-carotene was higher. Other investigators reported complete and partial response rates ranging from 60% to 100% with 13-cis retinoic acid.[127] [182]
These results led Hong and others[106] to conduct a randomized placebo-controlled trial of 13-cis retinoic acid (1 or 2 mg/kg/day) in oral leukoplakia with dysplastic change. All patients were assessed with pretreatment and posttreatment biopsies. Patients were treated for 3 months and observed for 6 months. There was a highly significant difference in response rate, 67% versus 10%, comparing the treated with the placebo group. Histologic reversal of dysplastic change was documented in 54%. Unfortunately, after stopping treatment, the relapse rate was high within 2 or 3 months, and the regimen was associated with considerable toxicity. In a follow-up trial,[137] 56 patients received 13-cis

TABLE 6-8 — Results of randomized chemoprevention trials in the head and neck
Number of patients
Intervention and dose
Oral premalignancy
Hong and others, 1986[106]
Isotretinoin (2 mg/kg/d)
Lippman and others, 1993[138]
Isotretinoin (0.5 mg/kg/d)
Stich and others, 1988[198]
Vitamin A (200,000 IU/wk)
Han and others, 1990[97]
Retinamide (40 mg/d)
Costa and others, 1994[46]
Fenretinide (200 mg/d)
Previous cancer
Hong and others, 1990[109]
Isotretinoin (50 to 100 mg/m2 /d)
Bolla and others, 1994[19]
Etretinate (50 mg/d; 25 mg/d)
Reprinted with permission from Lippman and others: Strategies for chemoprevention study of premalignancy and second primary tumors in the head and neck, Curr Opin Oncol 7:234, 1995.
retinoic acid (1.5 mg/kg/day) for 3 months, followed by randomization to low-dose 13-cis retinoic acid (0.5 mg/kg/day) or ß-carotene maintenance therapy. cis-Retinoic acid proved superior in maintaining remissions and had an acceptable level of toxicity in this low dosage.
Most recently, Hong and others[109] reported the results of using 13-cis retinoic acid to prevent second primary malignancies in patients with squamous cell cancer of the head and neck rendered disease-free with surgery and radiotherapy. This placebo-controlled chemoprevention trial randomized 103 patients to receive high-dose 13-cis retinoic acid (50 to 100 mg/m2 /day) or placebo for 1 year. At a median follow-up period of 32 months, second primary tumors had developed in 4% of those receiving retinoic acid compared with 24% of the placebo group (P= 0.005). The results of this trial have led to the initiation of two multiinstitutional confirmatory trials in the United States; two chemoprevention trials are in progress in Europe.[24] In the United States, the North Central Cancer Treatment Group and ECOG are randomizing patients with stage I and II squamous cancers of the head and neck rendered disease-free with surgery or radiotherapy to placebo or low-dose 13-cis retinoic acid (0.15 mg/kg/day) for 2 years. Patients should be randomized within 35 days of definitive local therapy. The MD Anderson Cancer Center and Radiation Therapy Oncology Group are conducting a placebo-controlled trial for the same patient group testing a higher dose of cis-retinoic acid, 30 mg/day, for the first year with dose reduction, if toxicity occurs, in years 2 and 3. Patients may enter the study if disease-free between 16 weeks and 3 years after their primary treatment.
These trials along with those ongoing in Europe should establish the benefits and risks of these particular retinoids in the prevention of second cancers in these patients. Etretinate and isotretinoin (13-cis retinoic acid) are commercially available for other indications. Their use in patients with oral premalignant lesions or in patients with curatively treated early-stage head and neck cancer is not recommended outside an investigational research trial. These agents are associated with considerable toxicity; moreover, the minimal effective dose and duration of treatment are not known. Less toxic retinoids or combinations of retinoids and carotenoids may prove to be more effective, but this can only be determined through carefully designed clinical and laboratory investigations.
Tumors of various histologic types occur in the head and neck. Excluding the thyroid, approximately 80% are squamous cell carcinomas. Data evaluating the impact of chemotherapy on survival time, particularly for combined modality treatments, are limited to this common histologic type where patient numbers are available for randomized comparative trials. Phase I, II, and III studies in patients with locally recurrent or metastatic disease have shown that chemotherapy can produce response rates of 30% to 40%, and combination chemotherapy is more effective than single agents. These response rates, however, have a brief duration and thus, in general, have not prolonged survival time. Thus, chemotherapy for these patients is palliative. An exception to this is for patients with tumors of the nasopharynx in whom higher response rates and a small proportion of long-term disease-free survivors are observed. Prognostic factors have been identified that should be used by the physician to select patients most likely to benefit from palliative treatment.
In the newly diagnosed patient with locally advanced disease, high response rates have been achieved with induction chemotherapy. Improved curability, however, has not been shown. A more important role for chemotherapy may be to preserve organ function at selected sites. Two large multicenter randomized trials were successfully conducted to preserve laryngeal function. A proportion of patients with resected

Figure 6-1 Management of late-stage squamous cell carcinomas of the head and neck.
disease at high risk for recurrence treated with chemotherapy in the adjuvant setting may achieve improvement in survival time. This needs to be confirmed, and multicenter trials are in progress. Chemotherapy concurrent with radiotherapy has improved local control and survival time in selected series. The increase in toxicity associated with these regimens should be carefully considered when selecting patients for this combined treatment. Chemotherapy for those with parotid cancers has been studied only for recurrent disease. Response rates are low, and impact on survival time has not been demonstrated.
Figure 6–1 shows an algorithm for management of late stage (locally advanced) squamous cell carcinomas of the head and neck. Patients with earlier stage disease (i.e., stage I or II) should receive conventional therapy with either surgery or radiotherapy or both. Patients with stage III or IV disease can be divided into those with resectable or unresectable disease. Those with unresectable disease should be treated with either radiotherapy or entered into a combined chemoradiation treatment program. Those with stage III disease may benefit the most from combination treatment as part of a clinical trial. Patients with metastatic disease should receive chemotherapy with palliative intent if they exhibit good performance status.
Patients with resectable disease can be further divided by site. Those with primary oral cavity or oropharynx tumors would be best served by surgery followed by radiation, whereas patients with larynx or hypopharyngeal tumors can receive conventional therapy or be offered neoadjuvant chemotherapy followed by radiation in an organ preservation approach.
Chemoprevention will continue to be an important area of research in the coming decade. One randomized trial has shown a decreased rate of second primary tumors in patients with curatively treated upper aerodigestive tract primary tumors. Confirmatory trials are in progress in the United States and Europe.
The management of head and neck cancer has become multidisciplinary. The identification of effective chemotherapeutic agents and their integration into the initial curative therapy of head and neck cancer has the potential to improve survival time and preserve organ function. Through well-designed and executed clinical trials, coupled with basic research of the biology of upper aerodigestive tract tumors, further advances in the management a

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Chapter 5 – Current Concepts in Antibiotic Therapy

Chapter 5 – Current Concepts in Antibiotic Therapy

Emily J. Erbelding
Anne M. Rompalo
With the availability of an increasing array of antibiotic agents, the approach to antimicrobial therapy is becoming complex. Increasing cost pressures in this era of managed medical care and new patterns of antibiotic resistance among clinical isolates make this area a challenging one for the continuing education of any practitioner. This chapter will discuss the principles of antibiotic selection and summarize the general features of the more common antibiotics that may be useful in the treatment of head and neck infections.

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Chapter 4 – Biophysiology and Clinical Considerations in Radiotherapy

Chapter 4 – Biophysiology and Clinical Considerations in Radiotherapy

George E. Laramore

The use of ionizing radiation in medicine dates back almost to the very date of its discovery. In 1895, Wilhelm Roentgen discovered x-rays, and 3 years later, Pierre and Marie Curie announced that they had isolated radium from pitchblende. The first documented radiation biology experiment was performed inadvertently at about this time when Antoine Becquerel developed a “burn” on his chest from carrying a vial of radium salt in his vest pocket. It soon became apparent that this newly discovered entity—radiation—had the ability to affect profound biologic change. The public embraced this new agent, and it was touted as a cure for almost every ailment known to humans. The results of these early clinical trials are not well documented, but it is probably safe to assume that most were not very successful. However, the first “cure” of a malignant neoplasm achieved with ionizing radiation was reported in 1899.[10]
During the early 1900s, most clinical radiotherapy was done by surgeons who used it as another form of cautery. Radiation was used in large doses to produce a “tissue slough” and the adverse side effects associated with its early use still color the attitudes many physicians have toward radiotherapy. Used properly, ionizing radiation produces selective modifications of cells through subtle changes introduced into deoxyribonucleic acid (DNA) and other cellular elements. Special training is required to understand these effects and how to best use them in clinical settings. From this need, radiation oncology has emerged as a separate medical specialty.
The capabilities of the radiation oncologist have increased in keeping with advancing technology. Initially, only low-energy x-rays were available, and these were capable of treating only superficial tumors, without causing severe side effects to the intervening healthy tissues. High-energy linear accelerators were then developed for research purposes and soon were used to produce “megavoltage” x-rays for medical use in a few large centers, although the “megavoltage” era in radiotherapy really began with the use of ?-ray beams from 60 Co sources. Now compact linear accelerators are used routinely in radiotherapy departments. Similarly, research into nuclear physics made it possible to produce many artificial radioisotopes that have had application in medicine; the field is no longer restricted to 226 Ra as it was in the past. Also, specialized, high-dose rate brachytherapy devices have been developed, which reduce the duration of the implant and simplify the radiation protection problem. Investigations in new areas such as particle beam radiotherapy, radiation protecting agents, hypoxic cell sensitizers, chemotherapy–radiotherapy combination treatments, and hyperthermia are taking place today and have the potential for changing the field of radiotherapy as much in the future as it has been changed in the past.
The purpose of this chapter is to provide the clinician with an overview of the basic principles of physics and biophysiology that underlie modern radiotherapy. Limitations of space necessitate the presentation of the overall picture only, rather than a detailed chronologic account of the development

of the field. Topics will be covered in a manner that assumes no previous expertise on the part of the reader. The references cited will be representative and illustrative in nature rather than comprehensive.

Conventional types of radiation
Radiotherapy is performed most commonly using high-energy photons or “quanta” of electromagnetic radiation. The electromagnetic spectrum is a continuum with radiowaves 10 to 1000 m in length lying at one end and energetic cosmic rays 10-12 cm in length lying at the other end. The ?-rays produced from a 60 Co source are about 1.3 million electron volts (MeV) in energy, which corresponds to a wavelength of 10-10 cm. Energies of 3 to 5 electron volts (eV) are needed to break chemical bonds, and this typically requires photons shorter than 10-4 cm. Microwaves used for heating purposes are less energetic than this and act by exciting bending and rotational modes in molecules (e.g., H2 O).
High-energy photons used in radiotherapy initially interact in matter (i.e., tissue) to produce high-energy electrons by one of three principal processes: photoelectric effect, Compton scattering, or pair production. In the photoelectric effect, a photon excites a tightly bound, inner-shell electron and is completely annihilated. This process scales like Z3 /E3 per gram of material, where Z is the “effective” nuclear charge of the material, and E is the photon energy. This process is most important for photon energies in the range of 10 to 50 kiloelectron volts (keV), which is the range typically used in diagnostic radiology. The higher effective “Z” of bone relative to soft tissue causes it to show up well on diagnostic films.
The Compton effect is most important in the 500 keV to 10 MeV range of photon energies used in therapy. It scales like Z0 per gram of material and decreases in a complex way with increasing energy. Physically, a photon can be thought of as transferring a part of its energy to a loosely bound outer electron and emerging at a lower energy and longer wavelength. Within this energy range, all tissues absorb photons at about the same rate on a gram-for-gram basis. This is important for therapeutic purposes, such as when managing soft-tissue tumors adjacent to bone. On films exposed with megavoltage x-rays, the distinction between bone and soft tissue is lost.
Pair production refers to a high-energy photon being annihilated in the strong electromagnetic field of an atomic nucleus and producing an electron–positron pair. The threshold energy for this process is 1.02 MeV. It scales like Z per gram of material and increases with increasing photon energy. For a 10 MeV photon, this accounts for about 28% of the total absorption cross-section in tissue. Other processes also can take place at higher photon energies.
Once one of these primary processes has occurred, a high-energy electron is produced, which creates secondary ionization events as it travels through tissue. Typically, about 34 eV of energy is lost for each ion pair that is produced. The resulting ionization clusters are relatively isolated on a scale of typical cellular distances. Most of the events involve water molecules in the cell cytoplasm, and their reaction products initiate complex sequences of chemical reactions that generally involve free radicals. The biologic properties of different megavoltage photon beams are equivalent per unit of energy deposited.
Radiation doses are specified in terms of the energy deposited in a unit quantity of material. In the past, the conventional dose unit was the rad, which was equivalent to 100 ergs being deposited per gram of material. More recently, an international commission[58] has agreed that radiation doses should be specified in terms of gray (Gy), which corresponds to 1 joule being deposited per kilogram of material. The older literature will have radiation doses specified in terms of rad, whereas the newer literature will have the doses specified in terms of Gy. Doses in this chapter will be specified in terms of the latter unit. Numerically, doses in rad can be converted to equivalent doses in Gy by dividing by 100 (i.e., 100 rad = 1 Gy).
Typical depth–dose curves for photon beams used in the therapy of head and neck cancers are shown in the upper panel of Figure 4–1 . The plots are for the dose along the central axis for a 10 cm × 10 cm field size. The energy of the beam is specified by the energy to which the incident electron beam is accelerated before impacting the target and actually producing the x-rays. The x-ray beam is a continuum with the maximum energy equal to that of the electron beam. To express that a range of x-ray energies is produced, the term MV is used rather than MeV. Appropriate filtering elements also are used to “harden” and “shape” the beam, but for most practical purposes, at a given source-axis distance (SAD), the beams from given energy linear accelerators are essentially equivalent. The three curves have the same general shape but vary somewhat in specific details. Note that they do not start out at their maximum value, but rather there is a build-up region, which occurs because the initial, high-energy electrons produced by the photon beam are directed primarily in the forward direction. The number of these electrons increases with depth until a distance equal to the average electronic path length is reached. The deposited dose is low at the surface and then increases to a maximum, after which it decreases with depth because of attenuation of the radiation field. The distance of the dose maximum from the surface is referred to as Dmax. It varies from 1.2 cm for the 4 MV (80 cm SAD) beam, to 1.3 cm for the 6 MV (100 cm-SAD) beam, and to 3 cm for the 15 MV (100 cm SAD) beam. The skin and subcutaneous tissues are spared within this build-up region, enabling the delivery of


Figure 4-1 Typical depth–dose curves for megavoltage photon and electron beams commonly used in the therapy of head and neck cancers. The upper panel shows curves for 10 cm × 10 cm fields for a 4-MV (80-cm SAD) linear accelerator (dashed line), a 6-MV (100-cm SAD) linear accelerator (solid line), and a 15-MV (100-cm SAD) linear accelerator (dotted line). The lower panel shows depth–dose curves for 10 cm × 10 cm fields for 6-MeV (dashed line), 12-MeV (solid line), and 20-MeV (dotted line) electron energies.
a higher dose of radiation to a deeper tumor. Higher energy photon beams can be used with even greater values of Dmax, but these have increased usefulness for the more deeply seated tumors of the thorax, abdomen, or pelvis.
Alternatively, the high-energy electron beam produced by the linear accelerator can be used directly in patient treatments. Typical depth–dose curves for various electron energies are shown in the lower panel of Figure 4–1 . Note that these beams typically penetrate a given distance and then fall off rapidly. There is a slight amount of skin sparing for the 6 MeV beam but not for the others. These beams are useful for treating skin cancers, tumors of the buccal mucosa, or even superficial tumors of the oral cavity, provided that appropriate applicator cones are used.[55] Optimal treatment of a given lesion may require some combination of electron and photon beams,[50] and this in turn requires the services of a comprehensive radiation treatment facility. Megavoltage electron beams have the same biologic properties as megavoltage photon beams for an equivalent dose of absorbed radiation.

Figure 4-2 The upper panel shows a typical depth–dose curve for a neutron beam used in therapy. It is for a 10 cm × 10 cm field size and was generated from a 50-MeV p ? Be reaction at 150 cm SAD. The lower panel shows the pure Bragg curve (solid line) for a neon ion beam of energy 425 MeV/amu and the resulting curve (dotted line) when a 4-cm spiral ridge filter (SRF) is used to broaden the beam for therapy. The data in the lower panel are from the BEVALAC facility at the Donner Laboratories.
Particle radiation
In the strictest sense, the electron beams used in conventional radiotherapy facilities are a type of “particle” radiation, but this section will be devoted to the heavier charged particles (e.g., protons, a-particles, heavy ions, p-mesons, and fast neutrons) used experimentally at a small number of radiotherapy centers throughout the world. These particles are of special interest because of their different radiobiologic properties or their better depth–dose characteristics, which allow for higher tumor doses without causing a commensurate increase in the dose to the surrounding healthy tissues.
The particle for which there has been the greatest amount of clinical work to date is the fast neutron. A depth–dose curve for a beam from the cyclotron facility at the University of Washington is shown in the upper panel of Figure 4–2 . Note that this is similar in general appearance to the photon beam curves in Figure 4–1 . Fast neutrons are of clinical interest because of their radiobiologic properties, which occur because of the much greater amount of energy they deposit when they go through tissue. Neutrons are neutral particles

and interact with the atomic nuclei, producing “heavy” charged particles such as protons, a-particles, or nuclear fragments that in turn create a dense chain of ionization events as they go through tissue. The distribution of these secondary particles depends on the energy spectrum of the neutron beam, and hence the biologic properties of the beam strongly depend on its energy spectrum. Neutrons used in therapy generally are produced by accelerating charged particles, such as protons or deuterons, and impacting them on a beryllium target. To a first approximation, the beam can be specified by indicating the charged particle that is accelerated, the energy of the particle when it impacts the target, and the distance between the target and the treatment axis (SAD). The curve in Figure 4–2 , for example, is for a 10 cm × 10 cm field for a beam produced by accelerating a stream of protons to 50 MeV and impacting them on a beryllium target of a thickness that absorbs about 50% of the beam energy. It has approximately the same penetration characteristics as the photon beam from a 6 MV linear accelerator. Most often, cyclotrons are used to accelerate the charged particle beams, but special linear accelerators can be used.
Neutrons also are produced using deuterium–tritium (DT) generating tubes that yield a quasimonoenergetic beam of 14 or 15 MeV neutrons. Although the cost of systems using the DT reaction is lower than cyclotron-based systems, their lower neutron output makes them less suitable for therapy. Although once popular, such DT systems now are used for clinical purposes only in a few centers in Europe. Neutrons in the energy range most commonly used in therapy deposit most of their energy via a “knock-on” reaction, whereby a hydrogen nucleus is impacted, producing a recoil proton. This process is more efficient in tissues that contain a greater quantity of hydrogen, such as adiopose or nerve tissue, and is less efficient in bone. Compared with muscle, the absorption can vary by ± 10%.[7] Typically, the recoil fragments produced by therapy neutron beams deposit 50 to 100 times more energy than the electrons created by megavoltage photon beams. The energy deposited by a radiation beam is characterized by its linear energy transfer (LET) spectrum. The primary high-energy electrons produced by megavoltage photons have LETs in the range of 0.2 to 2 keV per micron traversed, whereas the recoil protons produced by fast neutrons have LETs in the range of 20 to 100 keV per micron. It is this difference in LETs that results in the special radiobiologic properties discussed in the next section.
There also is considerable interest in using the charged particle beams directly for therapeutic purposes, which generally requires beams of much higher energy than those used to produce neutrons. The lighter particles, such as protons and a-particles, are of interest because of their extremely favorable depth–dose characteristics. The radiobiologic properties of these beams are similar to those of conventional photon or electron beams. In the United States, proton beam radiotherapy is carried out at the Massachusetts General Hospital using a Harvard University cyclotron and at a dedicated clinical facility at Loma Linda, California. Heavy charged particles combine the favorable depth–dose properties of the proton and a-particle beams with the favorable biologic properties of the neutron beams. Energies are on the order of several hundred MeV per nucleon rather than the few MeV per nucleon for the recoil fragments produced by neutrons. These highly energetic particles do not deposit much energy in tissue until they reach the end of their path, where they are moving slowly. Hence, they do not produce much radiation damage in the intervening tissues.
The lower panel of Figure 4–2 shows a “pure” Bragg peak for a neon beam (solid line) and for its spread form (dotted line). These data are from the BEVALAC facility at the Donner Laboratories in Berkeley, California. Note the high ratio of the energy deposited at the peak compared with that deposited at shallower depths for the unspread beam. The Bragg peak itself is narrow, and so it must either be “scanned” across a tumor while its penetration depth is being varied, or it must be spread out by passing it through appropriate filters. The dotted curve shows the result after the beam is passed through a 4 cm spiral ridge filter (SRF). Note that this lowers the peak-to-plateau ratio of energy deposition, and at the same time, it broadens the trailing edge of the peak. Clearly, both are undesirable for therapeutic purposes, although the dose of radiation deposited along the initial portion of the path is still lower than that deposited across the spread peak, which represents an advantage over the other types of radiation discussed thus far in this chapter. The broadening of the trailing edge of the peak occurs because of fragmentation of the neon nuclei in the filter, and this does not occur with protons or a-particles. Thus, the spread peaks for the latter two particles have somewhat better localization than the curve shown here. A more sophisticated approach is to use true three-dimensional scanning, which changes the particle energy as the beam is swept across the target. Currently, heavy ion radiotherapy is available only at the Heavy Ion Medical Accelerator (HIMAC) facility in Chiba, Japan.
Another type of charged particle that has been used in radiotherapy is the p-meson. The p-meson is a subatomic particle produced by accelerating protons to energies of 400 to 800 MeV and then impacting them into an appropriate target. Magnetic fields are then used to focus the resulting p-mesons into a beam that can be used for therapy. The p-meson is much lighter than the other charged particles discussed in this section, being only 273 times the mass of the electron (the proton, for example, is 1836 times the mass of the electron). Like the other charged particles, it does not lose much energy until it is near the end of its path, resulting in a “Bragg-peak” type of energy deposition curve. When it stops, an atomic nucleus “captures” it and then explodes into massive charged fragments that deposit considerable energy in a very localized region. Neutrons also are produced in this process, and they deposit their energy throughout a somewhat greater volume. The biologic properties of a p-meson

beam are complex because of the large number of processes involved, but in a crude sense, they can be thought of as behaving like a mixture of low-LET and high-LET radiation.
Cell killing by radiation
Within the cell, there are certain key “targets” that must be affected by the radiation before the cell is killed. The nuclear DNA is probably the most critical target, but other elements, such as the nuclear membrane and mitochondria, also may be important. When any form of radiation interacts with the cell material, there is some probability that one or more of the key target areas will be directly affected. This is the “direct” mechanism of action. Conversely, the radiation interaction may be with some other element such as a molecule in the cell’s cytoplasm, and the loss of this molecule may not be critical to the cell’s continued function. The reaction products may be capable of damaging the critical targets, provided that they can diffuse to them and interact before being converted to nontoxic elements by other chemical interactions (for the OH radical produced by the interaction of radiation with H2 O in the cell, the diffusion distance is about 2 nm). This is the “indirect” mechanism of action. All forms of radiation interact by both mechanisms, but because of the smaller amount of energy deposited by low-LET radiation, it primarily interacts through the “indirect” mechanism. High-LET radiation kills a significant fraction of cells via the “direct” mechanism. Comparing the biologic effects of low- and high-LET radiation provides a way of studying the results of these two processes.
Perhaps the simplest biologic experiment imaginable is simply to irradiate a colony of cells with different amounts of a given type of radiation and see how many are alive and able to reproduce afterward. This is done by plating the cells out on a new growth medium and counting the resulting colonies. This assays for a reproductive viability that is the quantity of paramount importance in tumor control. The radiation is given in a single dose, and the cells are plated out immediately.
A plot of the surviving fraction of cells as a function of the radiation dose is shown in Figure 4–3 (Figure Not Available) . By convention, the surviving cell fraction is plotted on a logarithmic scale, and the radiation dose is plotted on a linear scale. This curve is representative of most mammalian cells. Consider the solid curve, which represents the survival data. Note that there are two distinct regions to the curve. There is an initial region for low radiation doses, where the slope of the curve is shallow. In this region, small incremental changes in the amount of radiation are not very effective at increasing the number of cells that are killed. This is called the shoulder region, and its width is characterized by the parameter Dq. It is the distance along the dose axis at a surviving fraction of unity between the abscissa and the point where the extrapolated linear portion of the curve is intersected. It is a measure of the ability of the cells to repair small amounts of radiation damage.
At higher doses of radiation, the curve becomes a straight line on a semilog plot. Its slope is characterized by Do, which is the incremental dose change required to reduce the surviving cell fraction to 1/e of its value. The steeper the slope in this region, the smaller is the value of Do and the more radiosensitive is the cell line. When extrapolated back to a zero radiation dose, it intersects the abscissa at a value N. A curve of this type can be modeled using the equation

where S is the surviving fraction, D is the radiation dose, and N and Do are as indicated in the figure. In target theory, N can be thought of as the number of distinct targets in the cell that should receive one radiation “hit” before the cell is inactivated. Other parameters also can be introduced into the analysis by requiring more than one radiation “hit” to
Figure 4-3 (Figure Not Available) A representative cell survival curve (solid line) for mammalian cells exposed to single doses of radiation. The surviving cell fraction is plotted on a logarithmic scale, and the radiation dose is plotted on a linear scale. Dq characterizes the width of the shoulder region, which in target theory also may be characterized by the extrapolation number, N. Do characterizes the slope of the “straight line” portion of the curve. The dotted line shows the extrapolation of the linear portion of the curve back to the abscissa. The dashed line shows the regeneration of the cell survival curve if, after giving a certain amount of radiation, 6 to 8 hours are allowed to pass before additional radiation is given. (Redrawn from Hall EJ: Radiobiology for the radiologist, Philadelphia, 1994, JB Lippincott.)

inactivate a given target, but such refinements are beyond the scope of this overview. Radiobiologic data also can be analyzed using a linear–quadratic model of the form

where a and ß are simply parameters used to fit the curve over some restricted dose range.[35] Large ß:a ratios correspond to curves with large shoulder regions. There is one final point to note from Figure 4–3 (Figure Not Available) . If 5 Gy are given, resulting in a 10% cell survival, and then 6 to 8 hours pass before giving additional radiation, the shoulder region of the survival curve is regenerated as shown by the dashed curve. During the waiting period, the cells have recovered most of their original ability to recover from small doses of radiation. This is called sublethal damage repair.
The basic features of the cell survival curves can be qualitatively understood in terms of DNA repair processes as outlined in Figure 4–4 . The complementary strands of the helix are represented by the parallel straight lines, and the base pairings between the strands are represented by the open circles and dots that link the lines. In the upper panel, a photon schematically interacts with one strand of the DNA, which could either be via the direct or the indirect mechanism, with the particular nature of the damage event being irrelevant to the present discussion. What is important is that only one strand of the DNA is affected. Most cells contain repair enzymes that can excise the damaged portion and then, using the information on the complementary strand, can resynthesize the damaged portion. This is what is taking place in the shoulder region of the cell survival curve. If small amounts of radiation are given, there is a likelihood that many cells will experience only one damage event that can be repaired in this manner, although when larger amounts of radiation are given, a situation as shown in the lower panel occurs. Now many of the cells experience multiple damage events, and there is increased probability that some cells will have damage to both strands of the DNA. When the cell attempts to repair the radiation damage, a portion of both strands is excised, and a portion of the genetic information is lost. If this information loss occurs in a “silent” region of the DNA, the cell continues to live. If the information loss occurs in a key area of the genome, then the cell ultimately dies. This is the situation that occurs in the straight portion of the cell survival curve.
Relative biologic effectiveness and oxygen enhancement ratio
High-LET radiation deposits so much energy as it goes through the cell that radiation damage events are clustered closely in space and time, which means that if one strand of the DNA is damaged, there is a high probability that the other strand also will be damaged. Thus, the situation as shown in the lower panel of Figure 4–4 occurs, with an increasing portion of the radiation damage being irreparable. As the LET of the radiation is increased, expect to see the shoulder of the cell survival curve decrease (i.e., Dq ? 0) and the slope of the straight portion of the curve become steeper (i.e., Do ? 0). This effect is shown in Figure 4–5 , which shows survival curves for human kidney cells exposed to 250 kVp x-rays, 15 MeV neutrons from a DT generator, and 4 MeV a-particles. The LET of the radiation increases as indicated, and the curves change as expected.
Because the shapes of the cell survival curves shown in

Figure 4-4 Schematic illustration of the interaction of radiation with cellular deoxyribonucleic acid (DNA). In the upper portion, the radiation interacts with one strand of the DNA, and using the appropriate repair enzymes, the cell can excise the damaged portion and resynthesize the affected region using the genetic information on the complementary strand. In the lower portion, the radiation interacts with both strands of the DNA. When the cell attempts to repair the radiation damage, genetic information is lost.


Figure 4-5 Survival curves for cultured human cells exposed to radiation having different linear energy transfers (LETs). The triangles indicate data for 250 kVp x-rays, the open circles indicate data for 15 MeV neutrons from a DT reaction, and the closed circles indicate data for 4 MeV a-particles. Note that with increasing LET, the shoulder on the curve decreases, and the slope of the straight portion increases. (Redrawn from Hall EJ: Radiobiology for the radiologist, Philadelphia, 1994, JB Lippincott; original data from Broerse JJ, Bardensen GW, van Kersen GR: Int J Radiat Biol 13:559, 1967.)
Figure 4–5 differ according to the type of radiation used, it is difficult to define biologically equivalent doses for therapeutic purposes. Consider the neutron and the x-ray curves, for example. If one chooses as an endpoint the amount of radiation required to kill 99% of the cells, this requires about 9.3 Gy of x-rays but only about 4.2 Gy of neutrons. Hence on a physical dose basis, the neutrons are more effective, and a relative biologic effectiveness (RBE) of 9.3/4.2 = 2.2 can be defined. If one chooses as an endpoint the amount of radiation required to kill 50% of the cells, then the respective doses are 2.8 Gy of x-rays and 1.1 Gy of neutrons for an RBE of 2.5. This situation illustrates a general phenomenon: because of the increased shoulder on the cell survival curves for low-LET radiation, the RBE for neutrons and other high-LET radiation increases with lower dose increments. The change is greatest for cell lines that have the largest shoulders on the low-LET curves (e.g., gut, nerve tissue) and is smallest for cell lines having small shoulders (e.g., bone marrow, germ cells).[30] In the early days of neutron radiotherapy, workers did not appreciate the dependence of the RBE on dose size and tissue type, which led to a high incidence of treatment-related complications. These effects now are being considered, and the incidence of complications is much lower.
Previously in this chapter, it was noted that low-LET radiation primarily killed cells through the “indirect” mechanism, which involved the radiation interacting with molecules in the cell cytoplasm. The sequence of chemical reactions that can take place is complex, but at some point, a free radical generally is involved. A free radical is a chemical species that contains an unpaired electron and is highly reactive. Oxygen acts to stabilize the free radicals, thus allowing them to diffuse to the DNA or other target regions where they react chemically to produce damage. An obvious question is how great an oxygen concentration is required. Experiments have been performed on many species of bacteria, yeasts, and mammalian cells; the overall conclusions are summarized in Figure 4–6 , which shows the relative radiosensitivity as a function of the oxygen concentration in Torr (1 Torr = 1 mm Hg). Note that the radiosensitivity does not change much until the oxygen concentration decreases below about 20 Torr, and then it decreases fairly rapidly. At essentially 0 Torr, the cells are 2.5 to 3.0 times less radiosensitive than they are on the flat portion of the curve. Healthy tissues of the body are at oxygen concentrations between that of arterial and venous blood—between 40 to 100 Torr—and so are on the radiosensitive portion of the curve. However, large tumors tend to outgrow their blood supply and develop regions of necrosis surrounded by cells in a very hypoxic state. These tumor cells lie on the radioresistant portion of the curve, and this is thought to be one reason why large tumors are not as well controlled by radiotherapy as small ones.
One way of avoiding this problem is to use a mode of radiotherapy that is not as dependent on the presence of oxygen for cell killing. One possibility is to use high-LET radiation, for which the “direct” mechanism of cell killing is more important. Figure 4–7 shows cell survival curves for human kidney cells irradiated in well-oxygenated (open circles) and hypoxic (closed circles) conditions. If a 90% cell kill is chosen as the endpoint, then for 250 kVp x-rays,it takes 2.5 times as much radiation to kill hypoxic cells as it does when they are well oxygenated. The oxygen enhancement ratio (OER) is 2.5. As the LET of the radiation increases—going to 15 MeV neutrons from a DT reaction and then to 4 MeV a-particles, and finally to 2.5 MeV a-particles—the OER decreases to 1. This shows the effect of the increasing importance of the “direct” mechanism as the LET of the radiation increases. In general, the OER decreases with increasing LET until a value of 1 is reached, for a LET of about 150 keV/micron.
Cell cycle effects
Cycling mammalian cells proliferate by undergoing mitotic divisions. To define terms, take mitosis or M phase as a starting point. After this comes a “resting” phase, G1 , before the cell starts undergoing DNA synthesis. After DNA synthesis (S), there is another “resting” phase, G2 , before the cell again enters mitosis. Although it is well recognized that many chemotherapeutic agents act at specific points along the cell cycle, it is not commonly appreciated that cells vary in their degree of radiosensitivity according to their position in the cell cycle. Synchronously dividing cell populations are needed in experiments that measure this effect.


Figure 4-6 Plot of relative radiosensitivity of cells as a function of the oxygen concentration in Torr. Well-oxygenated cells are 2.5 to 3.0 times more sensitive than their hypoxic counterparts. Oxygen concentrations for room air and 100% O2 at 1 atmosphere of pressure are indicated by the arrows. This curve is schematic and is not meant to represent any particular cell line.
One way of producing such a cell population is to exploit the fact that at the time of mitosis, many cells growing in monolayers attached to the surface of culture containers will take on a spherical shape and become loosely attached to the vessel wall. If the container is subjected to a gentle shaking motion, these cells will become detached and float to the surface of the growth medium where they can be collected. These cells can then be inoculated into a fresh growth medium, wherein they will grow in synchrony through several cell cycles. Radiobiologic experiments can be performed on these cells at different times after “shake-off,” and they can be caught at different points along the cycle.
The result of radiosensitivity measurements for typical mammalian cells is shown in Figure 4–8 . Relative radioresistance is shown along the abscissa as a function of position along the cell cycle. The position of the cells along the cycle is shown at the top of the figure. The cells are radiosensitive early in the M phase but become more resistant toward the end of this phase. They are resistant in the early G1 phase but then become more sensitive in the late G1 and early S phases. They then become sensitive again in the late G2 and M phases. Cell lines vary in the time they require to go through the cycle, but this is mostly caused by different lengths of the G1 phase. The exact mechanisms underlying this change in radiosensitivity are not clear, but it is interesting to note that at the beginning of mitosis, the DNA in the chromosomes aggregates into a discrete state, whereas in the late S phase, the DNA content of the cell has doubled. These points in the cycle correspond, respectively, to the points of maximum and minimum radiosensitivity. Other variations in radiosensitivity may correlate with different amounts of sulfhydryl compounds in the cell. Sulfhydryl compounds act as free radical scavengers and so act to protect the cell from the “indirect” effects of radiation.
Figure 4–9 shows specific cell survival curves for Chinese hamster ovary cells at different points along the cell cycle.[22] [23] [42] The open symbols are for cells exposed to ?-rays from a 60 Co source, and the closed symbols are for cells exposed to a fast neutron beam. Note that for each form of radiation there is the same type of variation along the cell cycle, but the degree of variation is about a factor of 4 less for the neutron beam. OERs are about the same for different points along the cycle, so this represents an effect apart from this.
Many tumor systems contain an appreciable fraction of cells in a noncycling or Go phase. Radiation damage to cells in this phase cannot be monitored until the cells are recruited back into the cycle and until it can be seen whether they produce viable progeny. Noncycling cells can be produced in the laboratory by allowing them to grow in a medium until some key nutrient is exhausted. Cell proliferation then stops, and if the cells are kept in this suboptimal medium, the number of cells remains constant. Such cells are said to be in the plateau phase of growth[29] and are mostly in the Go phase. These cells can be irradiated and then can either be immediately inoculated into fresh growth medium or can be incubated for a period in the suboptimal medium before the inoculation takes place. Once they are placed in the fresh growth medium, they return to their normal cycling mode, although the cell survival curve varies depending on whether they have been incubated for a time before being placed in the fresh medium.
This effect is shown in Figure 4–10 . The circular data points indicate cells treated with 60 Co radiation, and for a


Figure 4-7 Cell survival curves for human kidney cells irradiated during hypoxic and well-oxygenated conditions for radiation beams having different LET values. The open circles represent the well-oxygenated cells, and the closed circles represent the hypoxic cells. A, 250 kVp x-rays; B, 15 MeV neutrons from a DT generator; C, 4 MeV a-particles; and D, 2.5 MeV a-particles. Values of the oxygen enhancement ratio (OER) are indicated in the respective panels. The OER decreases as the LET increases. (Redrawn from Hall EJ: Radiobiology for the radiologist, Philadelphia, 1994, JB Lippincott; original data from Broerse JJ, Bardensen GW, van Kersen GR: Int J Radiat Biol 13:559, 1967.)

Figure 4-8 Schematic illustration of the variation in the radiosensitivity of mammalian cells with their position along the cell cycle. The abscissa shows relative radioresistance as a function of time after “shake-off.” The relative position along the cell cycle is indicated along the top of the curve. The curve is schematic and not meant to represent any particular cell line.

Figure 4-9 Cell survival curves for synchronously dividing Chinese hamster ovary cells at different points along the cell cycle. The open symbols indicate cells irradiated with 60 Co ?-rays, and the closed symbols indicate cells irradiated with a 50 MeV D?Be neutron beam from the TAMVEC facility. The circles represent cells in late S and early G2 ; the squares represent cells in late G1 ; and the triangles represent cells in mitosis. (From Gass RL and others: Radiat Res 76:283, 1977 and 1978.)

Figure 4-10 Potentially lethal damage repair for Chinese hamster ovary cells irradiated in the plateau phase. The circular data points correspond to cells irradiated with 60 Co photons, and the square data points correspond to cells irradiated with a 50 MeV D?Be neutron beam from the TAMVEC facility. The open symbols indicate cells plated out immediately, and the closed symbols represent cells plated out after an 8-hour delay. Surviving cell fraction is plotted along the abscissa as a function of the radiation dose. (From Gass RL and others: Radiat Res 76:283, 1977 and 1978.)

given dose of radiation, there are more surviving cells after an 8-hour delay than if the cells immediately started cycling. This effect is called potentially lethal damage repair because the effect of the radiation damage depends on what happens to the cell after the irradiation. The dose is only “potentially” but not necessarily lethal to the cell because the cell can repair itself before reentering the mitotic cycle where it is expressed. The square data points are for cells irradiated with 50 MeV D?Be neutrons. For high-LET radiation, potentially lethal damage cannot be repaired (or can be repaired only to a limited extent), a fact that may be important in certain clinical settings.
Dose–response curves for tumor control and normal tissue damage are sigmoidal in shape. Whether radiation can safely control a given tumor depends on the relative positions of these two curves. Dose–response curves for a “radiosensitive” tumor are shown in Figure 4–11 . Here, giving a therapeutic dose of radiation results in a 95% probability of tumor control and only a 5% probability of normal tissue complication. There is a large gap between the two curves—that is, there is a wide “therapeutic window.” This should be contrasted with the situation shown in Figure 4–12 for a “radio-resistant” tumor. In this situation, a dose of radiation that would result in a 95% probability of tumor control would result in an unacceptably high probability of normal tissue damage. Giving doses that are within the limits of normal tissue tolerance would yield only a low likelihood of tumor control, and the separation between the two curves is narrow. Clearly, the concept of a therapeutic window depends on the radiobiologic properties of the tumor and the healthy tissue in the irradiated volume.
In general, local control of tumors can be improved by better dose localization, which means moving higher on the tumor-response curve without moving higher on the normal

Figure 4-11 Dose–response curves for tumor control (solid line) and for healthy tissue damage (dashed line) for a “radiosensitive” tumor. This corresponds to a wide “therapeutic window,” in that doses that yield a high probability of tumor control have a low probability of causing healthy tissue damage.

Figure 4-12 Dose–response curves for tumor control (solid line) and for healthy tissue damage (dashed line) for a “radioresistant” tumor. This corresponds to a narrow “therapeutic window,” in that doses that yield a high probability of tumor control have a high probability of causing healthy tissue damage.

tissue complication curve, or by exploiting some intrinsic difference in the properties of the tumor and normal tissues, which effectively widens the gap between the two curves. Three-dimensional treatment planning and delivery, brachytherapy, intraoperative radiotherapy, and the use of charged particle radiation are examples of the former approach; the use of high-LET radiation, altered fractionation schedules, radiosensitization agents, and radioprotective agents are examples of the latter.
Fractionated radiotherapy
The intent of clinical radiotherapy is to sterilize tumors and at the same time to avoid untoward damage to the healthy tissues in the treatment volume. To accomplish this goal, fractionated schemes of delivering radiotherapy have evolved over time. The tumor and the healthy tissue consist of heterogeneous populations in regard to the position of the cells in the cycle. In addition, the tumor may have an appreciable fraction of its cells in a hypoxic state. Figure 4–13 shows what happens when such a mixture of cells is irradiated with equal-dose fractions of magnitude D. The

Figure 4-13 Illustration of the effects of fractionated radiotherapy on a heterogeneous cell population. Surviving cell fraction is plotted along the abscissa as a function of the radiation dose. The dose is given in increments, D¯, with the time interval between successive doses being long enough to allow for sublethal damage repair. The initial dose increment kills a greater fraction of well-oxygenated cells than it does their hypoxic counterparts. It also preferentially kills those cells in the radiosensitive phases of the cell cycle. The solid curve indicates when the remaining cells reoxygenate and redistribute along the cell cycle before the next radiation dose is given. The dashed curve indicates when there is no reoxygenation or redistribution, and successive radiation doses are delivered to a more radioresistant cell population. The figure is schematic and is not meant to represent any particular cell line.
first dose increment preferentially kills the cells that are well oxygenated and are in radiosensitive portions of the cell cycle. If several hours pass before delivering the next dose increment, during this period, there is repair of sublethal damage. With the killing of a substantial number of cells, there is less competition for the available oxygen, hence some of the formerly hypoxic cells can reoxygenate. Also, some of the cells can proceed along the cell cycle and thus be in a more radiosensitive phase when the next dose of radiation is delivered. Assuming that both effects occur, the result is the solid curve shown in Figure 4–13 . If there is no reoxygenation or redistribution throughout the cell cycle, then the result is the dotted curve, which shows less cell kill because the remaining cells are in a radioresistant state. These are not the only effects: there is continued cell division and regrowth during the time interval between radiation fractions. These tumor repopulation kinetics have not been considered in Figure 4–13 . To maximize the cell kill, it is important that the size of the dose fractions be greater than Dq —the width of the shoulder region of the single fraction cell survival curve.
These effects are known as the four Rs of radiotherapy: (1) repair (of sublethal damage), (2) redistribution (across the cell cycle), (3) repopulation, and (4) reoxygenation. Fractionated radiotherapy has evolved to exploit the differences in these effects between tumors and healthy tissues. With few exceptions, radiotherapy works not because tumors are intrinsically more radiosensitive than normal tissue (i.e., a smaller value of Do , but because normal tissues are better at repair and repopulation.
Time–dose considerations are important in estimating the effect of a given total radiation dose. If the dose were given in a single fraction, then the healthy tissues would experience more cell killing than if it were given in a fractionated manner. This difference occurs because single fractions allow no opportunity for sublethal damage repair. In general, smaller total radiation doses given over shorter total treatment times produce the same normal tissue effects as larger total radiation doses given over longer time intervals. The classic measurements that illustrate this point are the isoeffect measurements on skin that were made by Strandquist.[49] He showed that the isoeffect lines for various degrees of skin damage and for curing skin cancer were straight when plotted on a log-log scale of total dose versus time. Moreover, the lines appeared to have the same slope (i.e., were parallel). The required dose to produce a given effect was proportional to time to the 0.33 power. Ellis[17] extended this concept to clinical radiotherapy by allocating a portion of the exponent 0.33 to the overall treatment time, T, and a portion to the number of fractions, N. He defined the nominal standard dose (NSD) by

where Dt is the total radiation dose. The exponents in this expression are for skin and no doubt vary for other tissues.

The linear–quadratic model discussed previously in this chapter provides another way of comparing the biologic effectiveness of different radiation schedules. Assuming that there are “n” separated doses of radiation of magnitude, “D,” the cumulative biologic effect of the treatments can be given by

where Dt is the total dose of radiation. Dividing through by a the following is obtained

where E/a is the biologically effective dose. For purposes of comparing radiation schedules, a/ß = 3 can be used for late-responding tissues, and a/ß = 10 can be used for early-responding tissues (i.e., acute effects). It is also possible to modify this expression to crudely account for tumor proliferation during the radiation course.[30]
Altered fractionation schedules
The highly fractionated radiotherapy schemes used today are the result of many years of clinical experience, but radiobiologic considerations may provide guidance for their future improvement. For example, acute radiation side effects such as mucositis and pharyngeal edema are caused by changes in tissues that are composed of rapidly proliferating cells. Late effects, such as subcutaneous fibrosis, vascular damage, radiation necrosis, and spinal cord injury, are caused by changes in tissues composed of more slowly proliferating cells. Radiobiologic measurements indicate that for low-LET radiation, the tissues experiencing late effects are characterized by cell survival curves having large shoulders.[57] It is the late effects that ultimately limit the total dose that can be delivered in the treatment of head and neck cancer. Hence, a logical approach would be to give smaller radiation treatment fractions so as not to exceed the shoulder on the “late effects” tissue curves and then give a higher total dose, which, it is hoped, would result in greater tumor control. This would effectively widen the therapeutic window. Note that the assumption is implicitly made that the tumor will behave like the rapidly proliferating healthy tissues and thus will not have a large shoulder on its cell survival curve. To avoid too great a prolongation of the overall treatment time and hence allowing tumor repopulation kinetics to dominate, multiple daily fractions should be given. A sufficient time interval (generally =6 hours) should elapse between the multiple daily treatments to allow for adequate repair of sublethal and potentially lethal damage in the healthy tissues.
Hyperfractionation refers to giving multiple daily doses of radiation of such a size that the overall treatment time is about the same as for conventionally fractionated course of once-a-day radiotherapy. Several randomized clinical trials recently have been completed using the hyperfractionation approach. The European Organization for Radiation Therapy in Cancer (EORTC) reported on a trial comparing a “standard” radiation schedule of 2 Gy-fractions, once-a-day treatment to 70 Gy versus a hyperfractionation schedule of 1.15 Gy-fractions given twice daily to 80.5 Gy.[32] A total of 356 patients with oropharyngeal lesions were studied. At the 5-year endpoint, the local control rates were 59% versus 40% (P = 0.02) in favor of the hyperfractionation arm. There was a suggestion of improved survival for the hyperfractionation arm, but this did not achieve statistical significance (P = 0.08). There was no increase in complications on the hyperfractionation arm, which agrees with the basic radiobiologic concepts discussed in a preceding section of this chapter. In the United States, comparative, hyperfractionation studies have been conducted that indicate the potential for improved local control for more advanced head and neck tumors.[45] The Radiation Therapy Oncology Group (RTOG) has conducted a dose-searching study to determine the maximum dose that could safely be given for patients with head and neck cancers.[11] Patients were randomized to receive either 67.2, 72, 76.8, or 81.6 Gy at 1.2 Gy given twice daily. A preliminary analysis based on 479 patients suggested an improvement in local tumor control at 2 years with increasing radiation doses for the lowest three dose arms: 25% versus 37% versus 42% (P = 0.08). No survival differences were noted, and the incidence of major late complications was the same at all three dose levels. Data analysis is still pending for the 81.6 Gy arm. A phase III clinical trial comparing hyperfractionation versus conventional fractionation for head and neck cancers is currently underway.
Accelerated fractionation refers to giving multiple daily doses of such a size that the overall treatment time is shortened relative to that of conventional radiotherapy. This may have a potential advantage for overcoming repopulation effects in rapidly proliferating tumors.[51] Wang has used such a schema in the treatment of advanced head and neck tumors.[54] [56] He uses 1.6 Gy fractions twice daily, which is too high a total daily dose for patients to tolerate without a planned treatment interruption to allow for repopulation and recovery of the mucosa. No randomized trials have been conducted using this schema, but a comparison with historical controls indicates a possible benefit.
One of the more extreme accelerated schedules is the continuous hyperfractionated accelerated radiotherapy treatment (CHART) regimen.[14] This regimen consists of giving three daily radiation treatments of 1.5 Gy each to a total dose of 54 Gy without giving any weekend breaks. As might be expected, acute radiation reactions have been severe, but of more concern was the fact that there were two incidences of cervical myelitis. A comparative analysis with similar patient groups seems to show an improvement in local control, but as yet there have been no randomized studies with this regimen.
Another version of accelerated radiation that attempts to

limit the healthy tissue acute reactions is the concomitant “boost” regimen proposed by Ang and others, which delivers the accelerated portion of the radiation only during the last phase of treatment.[1] In this approach, the volume of tissue receiving the twice-daily treatments is limited to the primary target volume, and no breaks in treatment are given. There is a further theoretic advantage in that the accelerated portion of the radiation is given at a time when the proliferation rate has been increased for the tumor and the healthy tissues. The RTOG is currently carrying out a randomized trial using this approach as one arm of the study.
The altered fractionation approaches discussed previously have their rationale in the basic radiobiology of tumor and healthy tissue response. They all incorporate at least a 6-hour interval between sequential radiation treatments to allow for repair of sublethal and potentially lethal damage in the irradiated healthy tissues. Other types of “hybrid” schemes have been reported in the context of phase I trials involving small patient numbers. Although conceptually attractive, nonstandard radiation schemes have inherent toxicities and should be used with caution in nonprotocol settings. Late morbidity and efficacy data are still accumulating.
Many radioactive isotopes are used in modern radiotherapy practice. Although radium needles are still used as implants in certain head and neck tumors, the trend now is toward afterloading techniques using 192 Ir sources. These sources produce a lower-energy ?-ray, thus simplifying the radiation protection requirements associated with routine patient care. These sources are left in place for a specified time and then are removed. Alternatively, permanent implants using 198 Au and 125 I can be used. These implants deliver their total radiation dose over the effective lifetime of the radioactive material.
One obvious advantage to using implants for a portion of the planned radiotherapy is better dose localization, which results in less radiation damage to the healthy tissue surrounding the tumor. Another advantage is the relatively prolonged time over which the radiation is delivered. External beam radiation is given at the rate of 1.5 to 2.0 Gy per minute. A typical 192 Ir implant delivers its dose at the rate of 0.4 to 0.8 Gy per hour. This can be thought of as “continuous” fractionation, and it allows for healthy tissue repair and reoxygenation of the tumor throughout the time course of the implant. A typical 125 I implant delivers its dose at an even slower rate. Often high total doses in the range of 100 to 200 Gy are given, but one half of the total dose is given during the first 60-day half-life, one fourth of the total dose is given during the next 60-day half-life, and so on. The actual radiobiology of such extremely low dose rates is somewhat uncertain.
More recently, high-dose rate remote afterloading devices have been developed. These devices push a single, high-activity 192 Ir source through a set of interstitial catheters,and a computer program controls the source dwell time at various points throughout the implant. Typically, about 3.0 to 3.5 Gy is given to a distance of about 1 cm from the periphery of the catheters each treatment, and two daily treatments are given about 6 hours apart. Each treatment takes about 15 to 30 minutes, depending on the strength of the radioactive source and the complexity of the implant. There are approximate guidelines to determine how a radiation dose delivered in this manner corresponds to the more familiar doses delivered via low-dose rate implants,[5] [52] but long-term late effects data are still being accrued. Because these treatments are given in a shielded area in the radiation oncology department, no radioactive material is left in the catheters when patients return to their room, and the radiation protection problem is greatly reduced.
Intraoperative radiotherapy
During the past several decades, there has been increasing interest in Japan and in the United States in radiotherapy directly administered to the exposed tumor bed at the time of surgery. Intraoperative radiotherapy (IORT) is given as a single, large fraction using either orthovoltage x-rays or megavoltage electrons. In this approach, it is often possible to move critical structures outside the radiation fields, and the surgeon can aid in identifying the areas at highest risk for residual tumor. A few institutions have dedicated equipment in operating rooms, but the majority of facilities offering IORT transport patients from the operating room to a sterilized unit in the radiation oncology center where the radiation actually is delivered.
Because the biologic effectiveness of a single large dose of radiation is much greater than if the same amount of radiation was given in multiple increments, the total dose given intraoperatively should be reduced compared with that given in a course of fractionated radiotherapy. Most of the IORT experience is for tumors of the abdomen and pelvis, but some general guidelines can be given regarding the tolerance of certain classes of normal structures of importance in the head and neck region. Major blood vessels tolerate single doses in the range of 20 to 25 Gy, whereas damage to peripheral nerves has been noted at doses higher than 20 Gy.[36] Tumor hypoxia may be a greater problem when the radiation dose is given in a single increment because there is no time for reoxygenation to take place. High electron affinic radiation sensitizers, such as misonidazole or SR-2508, may play a role in future IORT study protocols. Similarly, tumor redistribution kinetics do not have time to operate during IORT, and thus tumor cells in radioresistant parts of the cell cycle may be preferentially spared with this technique.
IORT probably can best be used in patients in whom there is a limited number of well-defined sites at high risk for microscopic residual disease. Possible indications are (1) tumor fixation to the carotid artery or deep structures of the neck, (2) “close” margins because of the necessity to preserve vital structures, or (3) tumor extending to bony

structures such as the base of the skull, spinal column, sternum, or clavicle.
High-linear energy transfer radiation
Most clinical data on the use of high-LET radiation in the management of head and neck tumors are for fast neutrons. This will be the topic of this section.
Squamous cell carcinomas
The usefulness of fast neutron radiotherapy in the treatment of squamous cell carcinomas of the head and neck is a subject of considerable controversy. The first reported work dates back to the 1940s when Stone and others conducted a series of clinical studies using an early cyclotron at Berkeley.[48] A total of 249 patients were treated, and about half of these patients had head and neck tumors. Although many dramatic tumor responses were reported, the late complication rate was unacceptably high. Interest in fast neutron radiotherapy waned until the late 1950s when a better understanding of fast neutron radiobiology indicated that most of Stone’s patients had inadvertently received extremely high doses of radiation. Investigation of fast neutron radiotherapy then began at Hammersmith Hospital, and an early report noted dramatic tumor response again, but this time with a more acceptable complication rate.[8] Unfortunately, other trials in Europe and the United States failed to confirm this benefit.[15] [16] [24] [27] They showed no improvement in either local control at the primary site or in survival rates with neutron radiation, although they seemed to show improved local control for clinically positive neck nodes—45% versus 26%, P = 0.004.[25] [27] This fact can be qualitatively understood in terms of the basic radiation biology of these tumors. Battermann and others measured the response rates of pulmonary metastases from various tumor histologies using fast neutrons and conventional photon irradiation.[3] They found that the RBE for squamous cell tumors was about the same as for the normal tissue side effects (RBE—3.0 to 3.8), so a therapeutic gain would not necessarily be expected if some other factor such as tumor hypoxia was not a problem and if OER effects would come into play. Guichard and others[28] have demonstrated in animal models that metastatic lymph nodes often have a greater fraction of hypoxic cells than primary tumors of equal size. Measurements of oxygen partial pressure in humans show that hypoxic regions within cervical lymph node metastases constitute approximately 20% of their volume.[21] Hence, it may be that tumor hypoxia in enlarged cervical lymph nodes, and not at the primary tumor site, accounts for the clinical observations reported thus far. In an attempt to resolve this matter, the RTOG undertook yet another randomized trial to study squamous cell tumors of the head and neck. The sophisticated treatment techniques now possible with modern neutron radiotherapy facilities were used, but unfortunately no particular benefit was noted for fast neutron radiotherapy for those with squamous cell tumors.[40]
Tumors that recur after initial radiotherapeutic or after surgical treatment represent another situation wherein high-LET radiotherapy may offer some benefits over conventional radiotherapy. Such recurrences may derive from clones of cells exhibiting a resistance to conventional photon irradiation. Further, the initial treatment may have compromised the vascularity, and the recurrent tumors may have a greater degree of hypoxia than tumors treated de novo. Two nonrandomized clinical trials support this hypothesis. Fermi Laboratories reported an 85% initial response rate, a 45% complete response rate, and an ultimate local control rate of 35% in 20 patients irradiated with neutrons for squamous cell carcinoma recurrent in regions that had received previous photon irradiation.[46] A report from Hammersmith on nine similar patients showed an 89% complete remission rate and a 56% local control rate at 1 year.[18] The rate of major treatment complications was about 25%.
Salivary gland malignancies
Based on the radiobiologic data of Battermann and others, salivary gland tumors exhibit high RBEs for neutron irradiation.[3] They found an RBE of 8 for fractionated neutron radiation of acinic cell carcinoma metastatic to lung, which would indicate a large therapeutic gain factor in using neutrons to treat this tumor system. Phase II clinical trials and a randomized phase III study support this conclusion.
The randomized trial and the historical series are summarized in Table 4–1 .[26] [37] The data in this table are for patients treated for gross disease—either de novo or for tumor recurrent after surgery. Patients with microscopic residual disease after a surgical resection are not included. Although the number of patients in the randomized trial is small, the difference in the local control rates at 2 years is statistically significant (P = 0.005). The rates of complete tumor clearance in the cervical lymph nodes were six of seven (86%) for the neutron group and one of four (25%) for the photon group. There was an association between improved local control and survival rate at 2 years—62% for the neutron group versus 25% for the photon group (P = 0.1). Given the dramatic differences between the two groups of patients and historical control data that closely paralleled the trial results, it was

TABLE 4-1 — Local control rates for salivary gland tumors treated definitively with radiotherapy
Photon radiation
Historical data
Randomized trial
Neutron radiation
Historical data
Randomized trial
The appropriate references are in the papers by Laramore and Griffin and others. (Laramore GE: Int J Radiat Oncol Biol Phys 13:1421, 1987 and Griffin TW and others: Int J Radiat Oncol Biol Phys 15:1085, 1988; by permission Pergamon Press.)

thought to be unethical to continue the trial further. Ten-year data on this study recently have been published that continue to show improved local and regional control in the neutron group (56% versus 17%, P = 0.009) but no difference in survival rate.[39] The lack of correlation between improved local and regional control and survival rate was a result of distant metastases, which became of greater importance on the neutron arm because of a reduction in deaths caused by local disease. Neutron facilities now consider fast neutron radiation the treatment of choice for patients with either inoperable lesions or with gross residual disease after surgery. Salivary gland tumors constitute a diverse spectrum of histologies, and the fact that the number of patients in the randomized trial is small can certainly be criticized in this respect. Analysis of the historical series seems to indicate that all histologies of salivary gland tumors respond equally well to fast neutron treatments. There also was no apparent difference between major and minor salivary gland tumors. Given the rarity of these tumors and the current opinions of the radiotherapy community, it is unlikely that the randomized trial will be repeated, although data from larger patient series with longer follow-up times will continue to be of interest.
Charged particle radiotherapy
The use of “heavy” charged particles in radiotherapy allows the delivery of high radiation doses to tumors without causing much damage to the healthy intervening tissue. In terms of the curves in Figure 4–12 , this enables work to be done at comparatively low doses on the healthy tissue side effects curve and at high doses on the tumor-response curve. The trailing edge of the Bragg peak for protons and a-particles decreases very rapidly because there are no fragmentation effects. With such beams, it is possible to deliver very high doses to the target volume with millimeter precision. In certain patients, such as those with juxtaspinal cord tumors, some head and neck sarcomas, and cordomas of the clivus, these beams often are the only way of delivering curative doses of radiation without causing life-threatening complications. Local control rates using this approach are excellent.[2] [4] [33] These beams also are used in the treatment of ocular melanomas, wherein they allow eradication of the tumor and preservation of vision at the same time. A study is currently underway comparing this approach for ocular melanoma with 60 Co plaque therapy.
Hyperthermia and radiotherapy
Hyperthermia refers to the use of elevated temperatures in an attempt to control tumors. In killing cells with heat alone, the temperature to which the tissue is increased and the exposure time at that temperature are the critical factors. There are at least three basic mechanisms that have been proposed in heat-induced cell death: (1) altered membrane permeability, (2) microtubule breakdown, and (3) enhancement of antigen expression or antigen–antibody complexation.
A marked synergy has been shown between hyperthermia and ionizing radiation. Tissue culture experiments show that the cytotoxic effects of these two modalities are additive in the G1 phase of the cell cycle but are synergistic in late S phase. This may be a result of inhibition of DNA repair by heat shock proteins or by alterations of cellular membrane structures important in the repair process. Hyperthermia also seems to inhibit repair of potentially lethal damage in Go phase cells. A low pH renders cells more sensitive to heat, and in tumors, a low pH generally is associated with hypoxic cells. Hence, hyperthermia could potentially help to eradicate the fraction of cells most resistant to conventional photon irradiation.
The most significant impediment to a thorough study of hyperthermia is the inability to deliver and monitor thermal dosages in clinical trials. Methods of delivery include radiofrequency heating, use of microwaves, and ultrasound. In most patients, the resulting temperature profiles are highly inhomogenous, making it difficult to address fundamental issues such as the optimal sequencing of the two modalities. Although the relatively superficial tumors of the head and neck are easier to heat than more deeply seated tumors located elsewhere in the body, interest in the approach is waning because of lack of any documented clinical benefit.
Radiosensitizers and radioprotectors
Radiosensitizers are chemical agents that potentiate the effects of radiation. They should, ideally, be nontoxic in themselves. The basic idea is to increase the effect of the radiation on tumor cells but not on healthy tissue and thus “separate” the two dose–response curves. Hence, these agents should exploit some key differences between the two tissues. The halogenated pyrimidines such as 5-bromodeoxyuridine (BUdR) are preferentially incorporated into the DNA of rapidly proliferating cells in place of thymidine. After their incorporation, the cells are able to repair radiation damage to a lesser degree. The application of these agents for head and neck cancer may be limited because the oral mucosa is a rapidly cycling tissue and also is sensitized. High electron-affinic hypoxic cell sensitizers, such as misonidazole and SR-2508, preferentially sensitize hypoxic cells, which should be more common in tumors than in healthy tissue. Many studies using misonidazole have been done; the results are mixed. A review by Dische[13] showed that misonidazole was beneficial in only five of 33 clinical trials involving various tumor sites.
More recently, several randomized trials using misonidazole have been done. As noted in the preceding section on altered fractionation, the EORTC conducted a trial combining misonidazole with an altered fractionation regimen and found no improvement in either local control or survival rate compared with a course of standard fractionation radiotherapy.[53] A randomized trial was conducted in Denmark to

evaluate the effect of adding misonidazole to two different split-course radiotherapy regimens.[43] A total of 626 patients was entered into the study. There was no difference in overall local control rates with the addition of misonidazole (37% versus 34%), but a subset analysis showed a benefit for the patients with pharyngeal lesions. The preirradiation hemoglobin level also was found to be of prognostic importance. The RTOG performed a trial of 298 patients, evaluating the addition of misonidazole to a “standard” course of radiotherapy.[19] [20] There were no significant differences in either local control or survival rate, and subset analysis failed to reproduce the results of the Danish group with respect to either pharyngeal primaries or pretreatment hemoglobin levels.
A problem with the use of misonidazole as a hypoxic cell radiosensitizer relates to peripheral neuropathy, which is its principal toxicity. This limits the amount of radiosensitizer that can be used, and it may be that insufficient amounts have been used in the clinical trials reported to date. New agents, such as SR-2508 and Ro-03-8799, are more efficient radiosensitizers than misonidazole, and clinical trials using these agents may be more adequate tests of the radiosensitization concept.
Another approach to widening the therapeutic window is to shift the normal tissue-response curve to the right without changing the position of the tumor-response curve via the use of agents that selectively “protect” the healthy tissues in the radiation field. The radioprotective agent studied most extensively thus far is a thiophosphate derivative of cysteine known as WR-2721. This compound probably protects cells by neutralizing intracellular free radicals before they can interact with the key target areas. Clinical work shows that it protects the bone marrow during hemibody irradiation.[9] It is known that WR-2721 preferentially concentrates in the salivary glands, and thus it may be advantageous in reducing the xerostomia that often is a result of the radiotherapeutic treatment of head and neck cancer. New and more effective agents are being developed.
There are two basic intents to the addition of chemotherapy to the treatment regimen for those with head and neck cancer: (1) there is potentially a synergistic effect with radiotherapy by the chemotherapy altering the radiobiologic parameters “a,” “ß,” and the effective tumor doubling time, and (2) the chemotherapy may be effective at eradicating micrometastases, thus reducing the incidence of distant metastases. By far, the most data have been accumulated on the sequential addition of chemotherapy to the regimen. To date, there has been no consistent, overall improvement in local and regional control or survival rate, although there have been several large, randomized studies that have shown a reduction in the incidence of distant metastases even though the basic intent of these studies was different. The Intergroup Study 0034 investigated the effect of adding sequential chemotherapy after surgery and before radiotherapy for patients with operable tumors.[38] The Head and Neck Contracts study compared three arms—one with standard therapy consisting of surgery and postoperative radiotherapy, one with induction chemotherapy before standard therapy, and one arm with induction chemotherapy followed by standard therapy followed by maintenance chemotherapy.[31] [34] A Southwest Oncology Group study[47] investigated the use of induction chemotherapy before surgery, and the Veterans Administration laryngeal study[12] investigated using the response to induction chemotherapy as a predictor of radioresponsiveness. The Padua, Italy, study compared the effect of four cycles of neoadjuvant chemotherapy plus radiation with radiation alone for patients with inoperable tumors.[44] The common finding in all these studies was a reduction in the overall incidence of distant metastases for the patients on the chemotherapy arm (in the case of the Head and Neck Contracts study, it was only for the group on the maintenance chemotherapy arm). Because distant failure is not the main cause of death for patients with squamous cell tumors of the head and neck, there was, in general, no improvement in overall survival rate. The Padua, Italy, study was the only one of the five that also showed an improvement in local and regional control and survival rate. The data are consistent with some modest efficacy of current chemotherapeutic agents for this class of tumors.
Currently, there is more interest in using chemotherapy concomitantly with radiotherapy, which has greater potential for giving a synergistic rather than an additive effect but also is associated with increased acute toxicity. Large scale, randomized clinical trials using this approach are only now being done. An early success of this approach is Intergroup Study (IG0099) for locally advanced nasopharyngeal cancer that has been stopped early because an interim analysis showed a statistically significant advantage to the experimental arm. In the experimental arm, patients were given concomitant chemotherapy consisting of cisplatinum at 100 mg/m2 every 3 weeks along with radiotherapy followed by four cycles of consolidation chemotherapy with cisplatinum and 5-fluorouracil. In the control arm, patients were treated with standard fractionated radiotherapy. At the time of closure, median progression-free survival rate was 52 months on the experimental arm versus 13 months (P < 0.0001)on the control arm and respective absolute survival rates were “median not yet reached” versus 30 months (P = 0.0007). Nasopharyngeal cancer is unique among head and neck cancers in many respects, and the extension of this approach to other head and neck sites must await the results of other clinical trials.

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Chapter 3 – Overview of Diagnostic Imaging of the Head and Neck

Chapter 3 – Overview of Diagnostic Imaging of the Head and Neck

Robert W. Dalley
William D. Robertson
Patrick J. Oliverio
S. James Zinreich

Diagnostic medical imaging has changed medical and surgical diagnosis in ways never imagined. Every area of clinical medicine has been affected in a profound way. Medical imaging specialists are able, through their consultations, to assist the otolaryngologist in a variety of ways, including providing primary diagnosis, confirming a clinical impression, evaluating regional anatomy, assessing response to treatment, and assisting in definitive treatment of patients.
Neuroradiologists are subspecialty trained diagnostic radiologists who specialize in the imaging of the head and neck, skull base, temporal bone, brain, and spine. They are the primary imaging consultants for otolaryngologists.
This chapter will provide an introduction and overview of modern head and neck imaging for the otolaryngologist. The various imaging modalities available will be discussed. Imaging strategies for various regions and clinical questions will be reviewed. The basic approach to the radiologist’s image acquisition and interpretation will be described so that the referring physician will gain a measure of understanding of this field. This is intended to maximize the usefulness of diagnostic imaging in the care of patients.
The scope of head and neck imaging is too broad a topic to be covered in one chapter. The authors intend to provide the clinician with an outline and brief synopsis of the field. There are definitive textbooks for each area of head and neck imaging.[14] [48] [50] [54]

Conventional radiography
Since the discovery of the x-ray, it has been used in imaging the head and neck region. The traditional projections obtained with conventional radiography that are applicable to head and neck imaging include the following.
Views of the facial bones and sinuses include the lateral view, Caldwell view, Waters view, and submentovertex (SMV or base) view. The lateral view will show the frontal, maxillary, and sphenoid sinus. It is best obtained 5° off the true lateral position to avoid superimposition of the posterior walls of the maxillary sinuses. The Caldwell view displays the frontal sinuses and posterior ethmoid air cells. It is obtained in the posteroanterior (PA) projection with 15° of caudal angulation of the x-ray beam. The Waters view can show the maxillary sinuses, anterior ethmoid air cells, and orbital floors. It is obtained in the PA projection with the neck in 33° of extension. The SMV view can show the sphenoid sinuses and the anterior and posterior walls of the frontal sinuses. It is obtained in the anteroposterior (AP) projection with the head in 90° of extension.
Views of the neck AP and lateral views of the neck exposed for soft-tissue detail are useful to evaluate the overall contour of the soft tissues of the neck. These are essentially the same projections used in the evaluation of cervical traumas, but they are not exposed for bone detail.
Cervical spine imaging The complete plain film assessment

of the cervical spine requires an AP, lateral, RAO and LAO oblique views, and an open mouth AP view of the upper cervical spine to visualize the odontoid process of the second cervical vertebral body. Specialized views such as the “swimmer’s” or Twining view or “pillar” views can be used as needed. A “swimmer’s” view is used to identify the lower cervical vertebral bodies when they cannot be seen from a routine lateral view. The “pillar” view is used to visualize the cervical articular masses en face.
Temporal bone imaging There are several accepted projections for visualizing portions of the temporal bone, including the Schuller projection, a lateral view of the mastoid obtained with 30° of cephalocaudad angulation. The Stenvers projection is an oblique projection of the petrous bone obtained with the patient’s head slightly flexed and rotated 45° toward the side opposite the one under study. The beam is angulated 14°. The transorbital projection is a frontal projection of the mastoids and petrous bones. Conventional imaging of the temporal bone has largely been replaced by computed tomography (CT) scanning.
Computed Tomography
CT was developed for clinical use in the mid-1970s by Hounsfield. CT uses a tightly collimated x-ray beam that is differentially absorbed by the various body tissues to generate highly detailed cross-sectional images. The degree of attenuation of the x-ray photons is assigned a numeric readout. These units of attenuation are known as Hounsfield units (HU) and generally range from -1000 HU to +1000 HU. Water is assigned a value of 0 HU.
To create images, CT uses complex mathematical reconstruction algorithms. Bone disease and bone trauma are best visualized with a bone detail algorithm ( Fig. 3–1 ). The raw data generated from the scan can be used in any number of ways. Images from a given reconstruction algorithm can be displayed in various ways to highlight differences in attenuation of different structures. In CT scanning, window width refers to the range of attenuation values in HU that make up the gray scale for a given image. The window level refers to the center HU value for that given window width. There are standard window width and level settings used for various types of CT scans.
Computed tomography image display
Multiple options for displaying the image (adjusting the window level and width parameters on the imaging console) and recording it permanently on radiographic film are available. Each pixel (picture element) of the CT image is given a density value. Water has been assigned a value of 0 on this scale developed by Hounsfield, fat is approximately -80 to -100 HU. Calcium and bone are in the 100 to 400 HU range, and most fluids are in the 0 to 30 HU range. The window level is simply the midpoint of the densities chosen for display. The range of densities chosen above and below the window level define the window width. A narrow window width of 80 HU and a level of +40 HU is frequently used for brain imaging because it centers the density at the common density of brain tissue and displays only those densities 40 HU greater than and 40 HU less than the window level. Thus any density greater than +80 HU will be displayed as white, and any density less than 0 will be displayed as black on the gray scale. Any intermediate density will be spread out evenly along the gray scale. For imaging of the soft tissues of the head and neck, a window level of approximately 40 to 70 HU is usually chosen, at a midpoint approximately equal to the density of muscle. The window width frequently is in the 250 to 400 HU range, thus displaying a wider range of densities including calcification, intravenous contrast, muscle, and fat to best advantage. For imaging bony structures such as paranasal sinuses and temporal bone, window levels from 0 to + 400 HU and a wide window width of 2000 to 4000 HU may be chosen. The reason for a wide bone window width is that a wide range of densities ranging from cortical bone (approximately +1000 HU) down to gas (-1000 HU) need to be displayed on the same image. However, structures of intermediate density between bone and gas occupy a narrow range on the gray scale at this window width and are poorly discriminated (appear washed-out) on these settings. The terminology commonly used to describe the previously mentioned windows includes soft-tissue windows (window width of 250 to 400 HU) and bone windows (2000 to 4000 HU).
It is important to understand that these display windows are completely independent of the mathematical imaging algorithm chosen for creation of the image. In other words, an image created by a soft-tissue algorithm can be displayed with soft tissue and bone window widths ( Fig. 3–1 A , C ). Conversely, the image may be computer reconstructed using a bone algorithm and displayed with either soft tissue or bone window width ( Fig. 3–1 B , D ). To optimize the imaging of the soft tissue lesion and the adjacent bone, a soft-tissue and a bone algorithm may be used, generating images with the appropriate soft-tissue and bone windows (see also Fig. 3–10A , C ).
Patient cooperation
Patient cooperation is necessary to obtain optimal image quality. The patient is instructed not to swallow and to stop breathing or to maintain quiet breathing during each slice acquisition to minimize motion artifact from the adjacent airway and pharyngeal structures. Occasionally, provocative maneuvers such as blowing through a small straw or using a cheek-puffing (modified Valsalva) maneuver to distend the hypopharynx or phonating to assess vocal cord movement may be necessary ( Figs. 3–2 and 3–3 ).
CT scanners have evolved over time such that the most advanced scanners now scan in a “helical” fashion, in which the scanner uses a slip-ring technique. This allows the table to move as the scan is performed, resulting in complete volumes of tissue being imaged with skipping tissue between


Figure 3-1 Comparison of various computed tomography algorithms and windows. A, Soft-tissue algorithm and, B, bone algorithm images of a laryngeal hematoma (arrowheads) using soft-tissue windows (350 HU width). The bone algorithm image has much more grainy appearance, whereas the standard algorithm gives a more pleasant smoothed image. C, Soft-tissue algorithm and, D, bone algorithm images of the skull base using bone windows (4000 HU width). Note improved sharpness of petrous apex trabeculae (arrowheads) and bony walls of mastoid and ethmoid sinus air cells (arrows).

Figure 3-2 Larynx without and with modified Valsalva maneuver. A, Axial contrast-enhanced computed tomography (CECT) performed during quiet breathing does not allow discrimination of retrocricoid carcinoma (arrow) because posterior pharyngeal wall is collapsed against mass. B, Axial CECT in the same patient (a few minutes later) obtained with modified Valsalva maneuver causes distension of now air-filled hypopharynx, permitting tumor detection (arrow).


Figure 3-3 Axial contrast-enhancing computed tomography during breath holding and while phonating. A, This axial computed tomography, obtained during breath holding, shows true vocal cords adducting and approximating eachother (arrowheads). Note superb high-contrast density in common carotid artery (asterisk) and jugular veins. B, Phonating “eeee” causes vocal cords to partially adduct into paramedian position. Note the contrast density has significantly decreased in common carotid artery (asterisk) and jugular veins in this delayed image, obtained well after contrast infusion had finished.

Figure 3-4 Contrast-enhancing computed tomography (CECT) with suboptimal contrast infusion. This axial CECT of a patient with left piriform sinus tumor was obtained with insufficient contrast infusion, resulting in poor discrimination of common carotid artery (asterisk) and jugular vein (v) from isodense adjacent metastatic lymph node (arrow). Inadequate contrast infusion also reduces likelihood of identifying focal defect in nodal metastasis.
slices. Currently CT scanners can obtain slices 1- or 1.5-mm thick. These levels of precision are of value in evaluating the temporal bone.
Contrast enhancement often is used to opacify blood vessels and to identify regions of abnormal tissue as identified by abnormal enhancement patterns ( Fig. 3–4 ). As it relates to head and neck imaging, contrast is particularly useful in CT scans of the neck and orbits. Contrast often is not needed in evaluation of the temporal bones, although it can be necessary on occasion. CT of the facial bones and paranasal sinuses usually does not require intravenous contrast.
As a brief review, the radiation exposure (dose) that a patient receives is known as the radiation absorbed dose. This radiation absorbed dose is a measure of the total radiation energy absorbed by the tissues, and it is expressed in an SI unit known as the Gray (Gy). One Gy is the amount of radiation needed to deposit the energy of 1 Joule (J) in 1 kg of tissue (1 Gy = 1 J/kg). Formerly, the unit used to express radiation absorbed dose was the rad (1 rad = amount of radiation needed to deposit the energy of 100 ergs in 1 g of tissue). The conversion of rads to Gy is: 1 Gy = 100 rad.
Radiation dose equivalent is a more useful term as it considers the “quality factor” (Q) of the radiation involved (radiation dose equivalent = radiation absorbed dose × Q). The quality factor considers the varying biologic activity of various types of ionizing radiation. For x-rays, the Q = 1. Thus, when discussing diagnostic x-rays, the radiation dose equivalent equals radiation absorbed dose. The SI unit for the radiation dose equivalent is the Sievert (Sv). The former unit was the rem. In summary, 1 Gy = 1 SV, and 1 Sv = 100 rem.
Radiation dose equivalent depends on the kVp and mAs of the exposure. For a given kVp, radiation dose equivalent varies linearly with the mAs. At 125 kVp, the radiation dose equivalent for a CT slice is approximately 1.1 to 1.2 cSv/100 mAs (1.1 to 1.2 rem/100 mAs). The actual dose will vary from machine to machine. Table 3–1 illustrates the dose can be reduced by the use of low mAs technique when possible.
In contiguous CT imaging, the dose to the region scanned is approximately equal to the per slice dose. The dose will be slightly lower if a gap is maintained between slices, and it will be slightly higher if there is overlap between slices.
The effective dose equivalent was developed as a means


TABLE 3-1 — Relative radiation dose for sinus CT (using 125 kVp)
Radiation dose equivalent
4.95–5.40 cSv (4.95–5.40 rem)
2.64–2.88 cSv (2.64–2.88 rem)
1.76–1.92 cSv (1.76–1.92 rem)
0.88–0.96 cSv (0.88–0.96 rem)
From Zinreich S: Imaging of inflammatory sinus disease, Otolaryngol Clin North Am 26:535, 1993.

TABLE 3-2 — Estimated effective dose equivalent of common examinations
Effective dose equivalent
Sinus series, four views
7.0 mrem
Chest, PA and lateral
7.2 mrem
Kidneys and upper bladder
8.7 mrem
Lumbar spine, five views
125.1 mrem
CT, brain*
112.0 mrem
CT, sinus (160 mAs)†
51.2 mrem
CT, sinus (80 mAs)†
25.6 mrem
From Zinreich S: Imaging of inflammatory sinus disease, Otolaryngol Clin North Am 26:535, 1993; and Zinreich S, Abidin M, Kennedy D: Cross-sectional imaging of the nasal cavity and paranasal sinuses, Operative Techniques Otolaryngol Head Neck Surg 1:93, 1990.

* 120 kVp, 240 mAs, 10-mm slice thickness, contiguous.
† 125 kVp, 160 mAs, 3-mm slice thickness, contiguous.
†† 125 kVp, 80 mAs, 3-mm slice thickness, contiguous.

of representing the fraction of the total stochastic risk of fatal cancers and chromosomal abnormalities resulting from the irradiation of a particular organ or tissue when the body is uniformly irradiated. A system of weighting is used to consider the individual sensitivity of the body’s major tissues and organs. A full discussion of this is beyond the scope of this introductory chapter. Suffice it to say that for a given examination, the effective dose to the patient is less than the dose (radiation dose equivalent) received by the area under examination. A list of common radiographic procedures and their effective dose equivalents is seen in Table 3–2 .
Magnetic resonance imaging
Magnetic resonance imaging (MRI) is an imaging modality that uses the response of biologic tissues to an applied and changing magnetic field to generate images. It is not possible to completely describe the principles of MRI in an introductory chapter of all head and neck imaging. A brief summary of MRI follows.
There are two types of magnets that are used to perform clinical MRIs: permanent magnets and superconducting magnets. Permanent magnets do not require continual input of energy to maintain the magnetic field. They are composed of large magnetic metallic elements set up to generate a uniform magnetic field between components. Superconducting magnets are electromagnets usually composed of niobium-titanium wire. They require input of energy to start them, but once they are up to strength, they are maintained in a superconductive state by means of an encasing system of liquid nitrogen and liquid helium shells.
The earth has a magnetic field strength of 0.5 Gauss (G). The tesla (T) is another unit of magnetic strength that is related to G by the equation 1 T = 10,000 G. Clinical MRI units usually operate at magnetic field strengths of between 0.3 and 1.5 T. Small bore research scanners of strengths of 4.0 T are in use.
There are many available MR pulse sequences available to generate images. The most common pulse sequence in MRI is the spin-echo technique.
MRI is one of the most active areas of development and research within diagnostic radiology. MRI derives signal from hydrogen protons most abundant in tissue fat and water, by placing them in a high magnetic field. This tends to align the spinning protons in the direction of the magnetic field. Radio frequency pulses are transmitted into the subject to excite the spinning protons, changing their orientation with respect to the magnetic field. As the protons realign with the magnetic field, they lose energy and give off signal, which is measured and reconstructed by the MR scanner into an image. The quality of MRI depends on a high signal-to-noise ratio, which improves image contrast and spatial resolution.[15] In general, the higher the field strength of the magnet, the higher the signal-to-noise ratio. Thus MRI scanners with field strengths of 0.5 to 2.0 T are commonly used for imaging.
Surface coils significantly improve the quality of head and neck imaging by increasing the signal-to-noise ratio. A surface coil is a receiving antenna for the radio frequency signal that is emitted from the imaging subject after the initial radio frequency stimulation. The standard head coil is usually adequate for studying head and neck disease above the angle of the mandible. A head coil allows imaging of the adjacent brain and orbits, an advantage when head and neck lesions extend intracranially. Neck coils cover a larger area from the skull base to the clavicles and come in various configurations, for example, volume neck coil, anterior neck coil, 5-inch flat coil placed over the anterior neck, and bilateral temporomandibular joint (TMJ) coil. Slice thickness on MRI is most commonly 5 mm, with 3-mm sections used for smaller regions of interest. However, a thinner slice has a smaller signal-to-noise ratio. Occasionally, 1- to 2-mm sections may be needed for small structures (e.g., facial nerve), requiring a volume acquisition technique. The number of slices is limited in MRI (as opposed to CT) by the specific sequence used, ranging from six to eight slices with a short TI inversion recovery technique up to 14 to 18 slices with a T2-weighted sequence; volume acquisition techniques will allow 60 or more thin slices.


Figure 3-5 Magnetic resonance imaging artifacts. A, Motion during axial short T1 inversion recovery sequence caused significant degradation of image with anatomic distortion and mismapping of signal intensity. B, Metallic dental braces cause artifacts distorting anterior facial structures in this T1-weighted image of a boy with juvenile angiofibroma filling nasal cavity (arrow) and nasopharynx. Anterior maxilla and portion of nose have been distorted.
Magnetic resonance imaging artifacts
Motion artifact, chemical shift artifact, dental work (amalgam, implants, braces, etc.), and eyelid mascara degrade MRIs ( Fig. 3–5 ). Motion artifact becomes more prominent with increased field strength, increased length of individual pulse sequences, and the total length of the imaging study. A typical imaging sequence may last from 2 to 8 minutes. To limit motion artifact, sequences less than 4 minutes are preferred, and the patient should be instructed not to swallow and to breath shallowly and quietly.
Chemical shift artifact arises from the differences in resonance frequencies of water and fat protons. The result is an exaggerated interface (spatial mismapping) in areas where fat abuts structures containing predominantly water protons such as the posterior globe or a mass. Chemical shift artifact may produce the appearance of a pseudocapsule around a lesion or cause obscuration of a small-diameter structure such as the optic nerve. Chemical shift artifact may be identified by a bright band on one side of the structure and a black band on the opposite side. This is usually most noticeable on T1-weighted images (T1WIs).
Metallic artifact from dental work varies in severity depending on amount and composition of the metal in the mouth, as well as the pulse sequence and field strength of the MRI scanner. Most dental amalgam causes mild distortion to the local magnetic field, resulting in a mild dropout of signal around the involved teeth. Extensive dental work, metallic implants, and braces may cause more severe distortion of the image, precluding visualization of the maxilla, mandible, and floor of the mouth. Mascara containing metallic compounds can also cause localized signal loss in the anterior orbit and globe.
Magnetic resonance imaging pulse sequences
Numerous pulse sequences are available on clinical MRI units; the details of the physics of MRI may be found in most radiology/MRI textbooks.[7] Commonly used imaging protocols include T1-weighted, spin (proton) density, T2-weighted, gadolinium-enhanced T1-weighted, fat-suppressed, and gradient echo imaging; magnetic resonance angiography is infrequently obtained ( Figs. 3–6 and 3–7 ). The abbreviations used to identify sequence parameters on hard copy film or in journal articles are repetition time (TR), echo time (TE), and inversion time (TI) and are measured in milliseconds. The following description of pulse sequences is presented to assist the clinician in identifying and understanding the commonly performed sequences and in determining their respective use in the head and neck.
T1-weighted images.
T1-weighted (short TR) sequences ( Figs. 3–6 , A and Figs. 3–7 , A ) use a short TR (500 to 700 ms) and a short TE (15 to 40 ms). T1-weighted imaging is the fundamental head and neck sequence because it provides excellent soft tissue contrast with a superior display of anatomy, a high signal-to-noise ratio, and a relatively short imaging time (2 to 5 minutes), minimizing motion artifacts. Fat is high signal intensity (bright or white) on T1WIs and provides natural contrast in the head and neck. Air, rapid blood flow, bone, and fluid-filled structures (e.g., vitreous and cerebrospinal fluid [CSF]) are low signal intensity (dark or black) on T1WIs. Muscle is low to intermediate in signal intensity on T1WIs. The inherent high contrast of fat relative to adjacent structures allows excellent delineation of the muscles, globe, blood vessels, and mass lesions that border on fat. Surrounding bone is black, except for the enclosed bone marrow (e.g., sphenoid wing, mandible, and thyroid


Figure 3-6 Common magnetic resonance imaging pulse sequences without fat suppression. A, Axial T1-weighted image (T1WI) of left glottic tumor (arrowheads), which is intermediate in signal intensity and thickens true cord. Note cerebrospinal fluid (CSF) surrounding spinal cord (arrow) is black, indicating that this is a T1WI. B, Spin density-weighted image also reveals high signal intensity (caused by increased water content) of vocal cord tumor. CSF is now isointense to spinal cord (arrow), indicating this is a spin density sequence. C, T2-weighted image demonstrates high signal intensity mass clearly demarcated against dark background of fat and muscle. D, Postgadolinium T1WI shows enhancement of cord tumor (arrowheads). CSF remains black (arrow).
cartilage), which is bright from fat within the marrow. The aerated paranasal sinuses are black, whereas retained mucous or mass lesions are of low to intermediate signal intensity. Most head and neck mass lesions will show a low-to-intermediate signal intensity on T1WIs. Fewer slices are available with a short TR compared with a long TR sequence. (To quickly identify a T1WI: fat is white, CSF and vitreous are black, and nasal mucosa is low signal.)
Spin (proton) density-weighted images.
Spin density-weighted sequences (also known as proton density, balanced, or mixed sequences) use a long TR (2000 to 4000 ms) and a short TE (20 to 40 ms). Spin density images ( Fig. 3–6 , B ) show air and bone as low signal intensity and fluid-containing structures and muscles as intermediate signal intensity, with fat remaining moderately high in signal intensity but somewhat decreased in signal from T1WI. A solid mass or fluid-filled lesion with a high protein content will demonstrate moderate-to-high signal intensity, which may improve its visibility relative to muscle but may obscure it relative to the adjacent fat. Paranasal sinus inflammation typically appears very bright on spin density images. (To quickly identify a spin density image: CSF and vitreous are intermediate in signal.)
T2-weighted images.
T2-weighted images ( Fig. 3–6 , C ) use a long TR (2000 to 4000 ms) and a long TE (50 to 90 ms) and are sometimes referred to as long TR/long TE images. Note that spin density and T2WI are acquired simultaneously from a single sequence that produces two sets of images with the same TR but different TEs; for example, spin density = 2000/30 and T2WI = 2000/80. T2WIs are most useful for highlighting pathologic lesions. T2WIs show the vitreous and CSF as high signal intensity (bright) relative to the low-to-intermediate signal intensity of head and neck fat and muscle. Fat loses signal intensity with increased T2 weighting. Most head and neck masses are higher signal intensity on a T2WI compared with their low-to-intermediate signal intensity on T1WI. The combination of the T1WI and T2WI is often useful for characterizing fluid-containing structures, solid components, and hemorrhage. Bone, rapid vascular flow, calcium, hemosiderin, and air-containing sinuses are black. Inflammatory sinus disease and normal airway mucosa appear very bright. (To quickly identify a


Figure 3-7 Magnetic resonance imaging pulse sequences with fat suppression. A, Axial T1-weighted image (T1WI) without contrast in a patient with squamous cell cancer shows poorly defined mass in left parotid gland (arrowheads). Suboptimal signal in image is the result of signal drop-off at the edge of the anterior neck surface coil. B, Axial postgadolinium T1WI with fat saturation has adequate suppression of subcutaneous fat (compared with A) and enhancement of tumor (arrowheads). Center of mass enhances less and likely is necrotic. Cerebrospinal fluid (CSF) is black (arrow), indicating a T1WI. Note marked enhancement of inferior turbinates (asterisks) compared with precontrast T1WI. C, Axial postgadolinium spin density image with fat saturation shows high signal in mass (arrowheads) with lower-intensity necrotic center (asterisk). Fat signal is suppressed and image is similar to B; CSF is isointense with spinal cord indicating use of a spin density sequence. Turbinates are very bright. D, Axial T2-weighted image with fat saturation demonstrates nearly ideal fat suppression, almost as good as short T1 inversion recovery (STIR) sequence. Necrotic or cystic center of mass (asterisk) and CSF (arrow) have become very bright. E, On this axial STIR image with excellent fat suppression, margin and center of mass are bright.

T2WI: CSF, vitreous, and nasal mucosa are white. Fat is low to intermediate in signal.)
Gadolinium enhancement.
Paramagnetic gadolinium compounds are commonly used in central nervous system (CNS) imaging for lesion enhancement. Gadolinium is used in conjunction with T1WI sequences (gadolinium shortens the T1), and with the dose used it has little effect on T2WI. The advantages of gadolinium enhancement are increased lesion conspicuity and improved delineation of the margins of a mass relative to the lower signal of muscle, bone, vessel, or globe.[9] However, gadolinium enhancement (without concomitant fat suppression) has had limited usefulness within the head and neck, as well as in the orbit, because of the large amount of fat present within these regions ( Fig. 3–6 , D ). Following gadolinium injection the signal increases within a lesion, often obscuring the lesion within the adjacent high signal intensity fat.[40] Therefore for head and neck imaging, gadolinium is optimally used with specific fat supression techniques that turn fat dark or black (see below). Gadolinium enhances normal structures including nasal and pharyngeal mucosa, lymphoid tissue in Waldeyer’s ring, extraocular muscles, and slow-flowing blood in veins, all of which may appear surprisingly bright, especially if combined with fat suppression techniques. (To quickly identify a gadolinium-enhanced T1WI: nasal mucosa is white, fat is white, and CSF and vitreous are black. Also look for Gd-DTPA or Magnevist [Berlex] printed directly on the image or on adhesive study labels.)
Fat suppression methods.
Several sequences have been developed that suppress fat signal intensity. T2WIs, short TI inversion recovery (STIR), spectral presaturation inversion recovery (SPIR), and chemical shift selective presaturation (fat saturation) are some of the more common clinically available methods of fat suppression. One advantage of fat suppression is reduction or elimination of chemical shift artifacts by removing fat signal from the image while preserving water signal. Additionally, some fat suppression techniques take advantage of gadolinium enhancement by eliminating the surrounding high intensity signal from fat while retaining the high intensity enhancement produced by gadolinium. Most pathologic lesions have increased water content, and gadolinium exerts its paramagnetic effects while in solution in blood vessels and in the increased extracellular fluid of the lesion, but gadolinium does not enhance fat.

T2WIs provide a moderate degree of fat suppression and discrimination of fat from water protons, yet enough fat signal persists to obscure some head and neck inflammatory and neoplastic lesions, especially lymph nodes. This sequence may be used before or after gadolinium and, because of the long TR used, yields the highest number of slices.

STIR ( Fig. 3–7 , E ) is superior to T2WI for suppressing fat signal. The inversion time (e.g., TI = 140 ms)is individually “tuned” for each patient to place fat at the null point of signal intensity and thus eliminates fat signal by turning it completely black. STIR images show the mucosa, vitreous, and CSF as very high signal intensity.[2] Most mass lesions in the head and neck will have similar high signal intensity on STIR and T2WI. The disadvantage of STIR is image degradation secondary to a decreased signal-to-noise ratio, an increased susceptibility to motion artifacts, and increased scan time. It is inadvisable to perform STIR after gadolinium administration because the gadolinium can result in a “paradoxical” signal loss (rather than enhancement) by shortening the T1; the longer the T1 of a structure, the brighter it becomes on STIR. STIR is often limited to six to eight slices, making full neck evaluation difficult, unless a concatenated technique is used, which increases slices acquired but requires a doubling of scan time. (To quickly identify a STIR image: fat is almost completely black; CSF, vitreous, and mucosa are white. A TI time is listed with the TR and TE times on the image.)

Chemical shift selective presaturation sequences ( Fig. 3–7 , B ) used with a spin-echo technique (Chem-Sat, General Electric) or with an inversion recovery technique (SPIR, Phillips) selectively suppress either water or fat signal, but fat saturation (suppression) is the most clinically useful technique. (Note that for the remainder of this chapter the terms fat suppression and fat saturation are used interchangeably and refer to chemical shift selective presaturation techniques.) T1-weighted fat saturation sequences take full advantage of gadolinium enhancement. A gadolinium-enhancing lesion within the head and neck retains its high signal intensity and is not obscured, because fat is suppressed to become low-to-intermediate signal intensity. Enhancing masses within the head and neck and orbit are particularly well imaged with this technique.[28] The disadvantages of fat saturation sequences are that non-gadolinium-enhancing lesions may be less well discriminated, that these sequences are more susceptible to artifacts, and that nonuniform fat suppression occurs. Also, two to three fewer slices are acquired compared with T1WI, unless the TR time is lengthened. (To quickly identify a gadolinium-enhanced T1WI with fat saturation: mucosa and small veins are white, fat is low to intermediate intensity, and CSF and vitreous are black.) Fat saturation can optimize long TR (spin density and T2WI) sequences ( Fig. 3–7 , C , D ). The advantage occurs when the spin density image is performed after gadolinium, since moderate T1-shortening effects by gadolinium occur with this sequence. Most lesions and vascular structures will show a mild degree of enhancement, with an image almost equivalent with a postgadolinium fat saturation T1WI. Fat-saturated T2WIs provide excellent fat suppression almost equivalent to STIR, optimizing the high signal from normal structures and lesions

that are high in water content contrasted against a black background of fat.
Gradient echo techniques.
Numerous new and faster gradient echo sequences are available that have a variety of applications. Gradient echo scans have a very short TR (30 to 70 ms), a very short TE (5 to 15 ms), and a flip angle of less than 90°. They have a variety of proprietary acronyms including GRASS, MPGR, and SPGR (General Electric) and FLASH and FISP (Siemens). Gradient echo sequences take advantage of the phenomenon of flow-related enhancement; that is, any rapidly flowing blood will appear extremely bright. These sequences are useful for localizing normal vessels, detecting obstruction of flow in compressed or thrombosed vessels, or showing vascular lesions that have tubular, linear, or tortuous bright signal representing regions of rapid blood flow ( Fig. 3–8 ). Gradient echo sequences may be obtained faster than conventional spin-echo techniques, although their increased susceptibility to motion artifact decreases the benefits of a short scan time. Gradient echo techniques also permit volume; that is, three-dimensional versus two-dimensional acquisition of images, allowing computer workstation reconstruction of any imaging plane at any desired thickness with increased spatial resolution.The disadvantage of gradient echo sequences is the increased magnetic susceptibility artifact from bone or air, thus limiting their role near the skull base or paranasal sinuses. (To quickly identify a gradient echo image: arteries and often veins are white; fat, CSF, vitreous, and mucosa may have variable signal intensities depending on the technique used.)

Figure 3-8 Gradient echo sequence in patient with right vagal paraganglioma. Coronal multiplanar gradient echo image demonstrates mass (arrowheads) displacing internal carotid artery (c) medially. Arterial blood flow is very high in signal intensity in medially displaced internal carotid artery, as well as within feeding vessels deep inside mass.
Magnetic resonance angiography.
Magnetic resonance angiography is a technique that takes advantage of phase or time-of-flight differences in flowing blood relative to motionless structures and selectively produces images of structures with rapid blood flow. Two- and three-dimensional images of normal vessels and vascular lesions can be generated. At present magnetic resonance angiography does not equal the spatial resolution of conventional angiography, but the technology is in rapid evolution. Early experience in the head and neck indicates magnetic resonance angiography will be useful for evaluating vascular compression and vessel patency and for characterization of vascular masses and malformations.[37]
Magnetic resonance imaging disadvantages
Several disadvantages of MRI of the head and neck bear consideration. MRI frequently requires 45 to 90 minutes of scanning time, during which time the patient must remain motionless, a process difficult for a sick patient to accomplish. Motion artifacts are more frequently encountered than with CT, although dental artifacts may be less problematic. Although no known harmful effects during pregnancy have been demonstrated, at most institutions MRI is used sparingly during the first trimester. (MRI avoids the use of ionizing radiation, and no harmful effects have been shown with its use at current field strengths.) Absolute contraindications to MRI include patients with cardiac pacemakers, cochlear implants, and ferromagnetic intracranial aneurysm clips. Those patients at risk for metallic orbital foreign bodies should be screened with plain films or CT before MRI. Generally, ocular prostheses and ossicular implants are safe. Unfortunately, MRI is also the most expensive of all the imaging modalities.
High-resolution diagnostic ultrasound uses the properties of reflected high-frequency sound waves to produce cross-sectional images, obtainable in almost any plane. The transducer, a high-frequency 5- or 10-MHz probe, scans over the skin surface of the region of interest. Fat has a moderate degree of internal echoes (echogenicity). Skeletal muscle is less echogenic than fat. A solid mass has well-defined margins and variable echogenicity but is usually less echogenic than fat. A cyst has few, if any, internal echoes, a strongly echogenic back wall, and strong through-transmission of sound behind the cyst. Both calcium and bone are strongly echogenic, thus obscuring adjacent structures by an acoustic shadow. Ultrasound has no known harmful effects and no contraindications. High-resolution ultrasound is quick and accurate; further, it is relatively inexpensive compared with CT or MRI.
Nuclear medicine
Scintigraphy has several applications in the head and neck. In salivary gland imaging technetium-99m (99m Tc)-pertechnetate imaging may be useful for assessing salivary

gland function in autoimmune and inflammatory disease of the salivary glands. If the salivary glands are obstructed, the degree of obstruction as well as the follow-up of obstruction after treatment can be assessed. In evaluating neoplasms of the salivary glands the findings of the 99m Tc-pertechnetate scan are almost pathognomonic of Warthin’s tumor and oncocytoma. Spatial resolution is approximately limited to 1.5 cm, so accurate localization of the mass within the gland is difficult. Single photon emission computed tomography (SPECT) may be useful in some cases.
Techniques of thyroid imaging and thyroid therapy are described in several textbooks.[33] [53] Many centers use I-123 to obtain a thyroid update determination, and 99m Tc-pertechnetate is used to obtain whole gland images. It is these images that determine if thyroid nodules are “hot” or “cold.” I-131 is used for therapy of hyperthyroidism and in follow-up to detect and treat residual, recurrent, and metastatic thyroid cancers.
Medullary carcinoma of the thyroid is difficult to visualize, but 99m Tc-DmSA has been used. More recently, In-111 pentetreotide has been used with some success.
Identification of parathyroid adenomas has been done for

Figure 3-9 A, Technetinum-99m (99m Tc)-pertechnetate scintigraphy in a patient with suspected parathyroid adenoma is essentially normal. B, Corresponding T1-201 scintigraphy reveals an apparent area of increased uptake adjacent to the lower pole of the right lobe. C, Subtraction of the 99m Tc-pertechnetate study from the T1-201 study confirms the presence of a parathyroid adenoma.

several years with a subtraction technique using 99m Tc-pertechnetate and Tl-201 ( Fig. 3–9 ). The basis of this test is that thallium is taken up by thyroid tissue and parathyroid tissue. 99m Tc-pertechnetate is taken up only by thyroid tissue. Therefore, the subtraction of the 99m Tc-pertechnetate image from the thallium-201 image should leave only parathyroid tissue. The sensitivity of this technique is believed to be excellent for lesions over 1 g. Sensitivity decreases with smaller lesions, and the subtraction technique can be hampered by patient motion. Lately, 99m Tc-sestamibi has been used to identify parathyroid adenomas. A single radiopharmaceutical double-phase protocol is the most recent improvement in identification of parathyroid adenomas.
CSF leaks can be detected with 111 In DTPA placed into the subarachnoid space. This technique is described and illustrated in Chapter 63 .
Three-dimensional reconstruction techniques
Image data from either CT or MRI can be processed to create three-dimensional reconstructions, but a separate computer workstation with appropriate imaging software is necessary. CT data are loaded as a stack of contiguous two-dimensional slices that defines the scanned volume. Reconstructions are created either from choosing a specific range of densities for display or by manually tracing the outline of the desired structure. Magnetic resonance data for image analysis are best acquired using a “volume acquisition” method, in which data are acquired as a complete three-dimensional block rather than as individual slices. Because volume acquisition takes longer, gradient echo techniques are usually required to reduce the imaging time. Once acquired, the data are displayed in any desired plane and, by selecting a range of signal intensities or by tracing specific structures with a cursor, three-dimensional surface models are created.
The utility of three-dimensional reconstruction is best appreciated with craniofacial reconstructions.[17] [32] Contiguous 1- to 2-mm noncontrast CT axial sections are processed on the workstation to obtain a three-dimensional model of the bone surfaces. Directly visualizing the three-dimensional relationships of the facial structures aids surgical planning. Three-dimensional models of the face and orbital structures are useful for teaching medical students, residents, and anatomy students. To date, the spatial resolution of CT is superior to MRI in the head and neck for displaying bony relationships. However, MRI provides a superior display of transcranial soft-tissue structures, such as the entire visual pathway, and has better tissue contrast resolution than CT. Thus CT and MRI will likely have complementary roles in three-dimensional image display.
Each anatomic region requires a different imaging approach to optimize the detection and characterization of the structure or lesion of interest. The following is a description of the indications for using CT, MRI, or ultrasound in specific head and neck regions, plus a general imaging approach relevant to each anatomic region in terms of imaging planes, slice thickness, contrast agents, and pulse sequences. Whenever possible CT and MRI are performed before biopsy or resection of lesions because the resulting edema may obscure the true margins of a mass.
Application of computed tomography by head and neck region
Suprahyoid neck
Suprahyoid neck CT is often performed for simultaneous evaluation of the deep extent of mucosal-based tumors and to evaluate associated metastatic disease to the cervical lymph node chains. To cover the region from the skull base down to the root of the neck, contiguous axial 3- to 5-mm sections from the bottom of the sella down to the hyoid bone, followed by 3- to 5-mm sections at 5-mm intervals from the hyoid bone down to the sternal notch (thoracic inlet), are required. Because streak artifacts from dental fillings frequently obscure the oropharynx and nasopharynx, it is usually necessary to obtain additional angled sections to assess the pharynx directly posterior to the dental work ( Fig. 3–10 ). Direct coronal 3- to 5-mm images are very useful in defining craniocaudal relationships in lesions of the oral cavity and facial bones. The use of intravenous contrast is critical for adequate performance and interpretation of this study, especially the axial sections. Optimally, contrast is continuously infused during the entire scanning sequence so that a high concentration of intravascular (both arterial and venous) contrast allows differentiation of vessels (see Figs. 3–3 and 3–4 ) from other higher density structures such as lymph nodes and muscle. Otherwise, determination of vascular invasion, compression, and discrimination of vessels from nodes and small muscle bundles can be extremely difficult. Contrast is best administered with a mechanical pump infusion (although a drip infusion technique may also be effective) giving a single dose (40 g iodine) up to a double dose (80 g iodine) of contrast. Frequently, only a soft-tissue algorithm is necessary with each slice photographed with both soft-tissue and bone windows. However, sections of the skull base and mandible may need reconstruction using a bone algorithm if a suspicion of bone erosion or destruction by tumor or inflammation exists. Direct coronal images are advantageous when assessing lesions of the tongue, floor of mouth, retromolar trigone, mandible, or skull base.
Cervical lymphadenopathy
Lymph node CT evaluation is concomitantly performed during CT investigation of most suprahyoid and infrahyoid tumors or inflammation. Axial 3- to 5-mm slices must extend from the skull base to the clavicles to encompass the many node chains that extend the length of the neck. As mentioned above, the quality of lymph node assessment depends very much on the success of achieving a high concentration of


Figure 3-10 Avoiding dental artifacts on computed tomography (CT). A, Lateral scout image without angulation of CT gantry (dotted lines represent selected axial images) in a patient with numerous metallic densities in teeth from dental work. Posterior tongue (asterisk) and soft palate lie directly posterior to metal. B, Axial contrast-enhanced computed tomography (CECT) at level of dental work is uninterpretable because of numerous streak artifacts caused by metallic fillings and crowns. C, Scout view depicting additional slices with CT gantry angled to avoid dental work. D, Angled axial CECT at the same level as B shows significant improvement in image quality of posterior tongue and oropharynx.
contrast in the arterial and venous structures of the neck; otherwise, nodes and vessels may appear remarkably similar.
Postoperative neck
Imaging the postoperative neck uses the same techniques as the suprahyoid/infrahyoid neck. Thinner sections or supplemental coronal images in the region of suspected recurrence may be required.
Salivary glands
Salivary gland CT is most frequently performed with the axial plane parallel to the infraorbitomeatal line and can be used for assessment of both the parotid and the submandibular gland. However, dental amalgam can cause significant streak artifacts that obscure the parotid or submandibular gland parenchyma. If the dental work is identified on the lateral scout view (scanogram), dental artifacts can usually be avoided if an oblique semiaxial projection is chosen with the scanner gantry angled in a negative direction (between a coronal and an axial plane), thus avoiding the teeth. This plane has the advantage of visualizing both parotid and submandibular glands in the same slice and is parallel to the posterior belly of the digastric muscle.[55] The direct coronal projection may yield additional anatomic information for

evaluating both the parotid and the submandibular glands and avoids creating dental artifacts through the parotid gland, but the dental artifacts may still compromise visualization of the submandibular duct and gland. A slice thickness of 3 to 5 mm is generally adequate for evaluating the gland parenchyma. Occasionally, supplemental 1- to 2-mm slices are required for evaluating smaller lesions.
With the current generation of high-resolution scanners, noncontrast computed tomography (NCCT) may suffice for the salivary glands. However, contrast-enhanced computed tomography (CECT) is preferable to NCCT in most cases because CECT maximizes the tissue contrast resolution between a salivary lesion and the adjacent normal gland, fat, and muscle.[10] [47] CECT is also essential for assessment of salivary tumor metastases to the lymph node chains of the neck. A normal parotid gland is a relatively fatty structure with a density intermediate between the low-density facial fat and the higher-density adjacent masseter muscle. However, the parotid gland has a wide variation in normal density and may have increased density approaching that of muscle in children and adults or in patients with chronic inflammation. The submandibular gland normally has density just slightly less than skeletal muscle and lymph nodes. In those occasional cases in which the gland parenchyma is similar to muscle in density, either MRI, CECT, or even CT sialography (CTS) may be necessary to discriminate the margins of a suspected mass from the surrounding glandular tissue.
Sialography and computed tomography sialography
Conventional sialography remains the best radiographic method for evaluating ductal anatomy in obstructive, inflammatory, and autoimmune salivary gland diseases. Supplemental CTS may be performed when routine sialography shows an unexpected mass lesion or in the infrequent situation when NCCT (or CECT) shows a dense, enlarged gland in which a mass is suspected but not clearly demarcated. CTS is unnecessary in most salivary tumor cases because of the much improved capabilities and thin sections of the high-resolution third- and fourth-generation CT scanners compared with early-generation scanners. However, MRI may be the preferred alternative method of studying dense salivary glands. CTS may be obtained at the time of intraductal injection of fat-soluble or water-soluble contrast or after a routine sialogram (the gland may be reinjected during the CT with the catheter left in place). The plane of study is the same as that used for NCCT and should be similarly angled to avoid dental filling artifacts. The use of concentrated sialographic contrast material may cause significant streak artifacts if too much contrast collects in dilated ducts, acini, or large pools, all of which can obscure smaller masses in the gland. For optimal CTS, the injection is extended into the acinar phase to maximize parenchymal opacification and thereby silhouette mass lesions within the parenchyma.[16]
Larynx and infrahyoid neck
Laryngeal and infrahyoid neck CT is most commonly requested to evaluate squamous cell carcinoma of the larynx or hypopharynx, associated cervical lymph node metastasis, trauma, and inflammation. Thus axial imaging from the angle of the mandible down to the sternal notch is required to survey the lymphatic chains and infrahyoid neck, using 3- to 5-mm contiguous sections and intravenous contrast infusion. However, the fine detail of the larynx and vocal cords requires thinner contiguous sections of 2 to 3 mm. When assessing the true vocal cords and the arytenoid cartilages, 1- to 1.5-mm contiguous sections may occasionally be necessary to get adequate spatial resolution. Sections through the vocal cords are optimally obtained parallel to the plane of the cords by angling the scanner gantry parallel to the plane of the hyoid bone or the closest adjacent cervical disk space. Because assessment of vocal cord mobility is important in staging glottic carcinoma, various provocative techniques may facilitate laryngeal imaging in those cases where the vocal cords are obscured on physical examination. Quiet breathing places the cords in a partially abducted position. By having the patient blow through a straw or do a modified Valsalva maneuver (puffing out the cheeks) the hypopharynx and supraglottic larynx can be distended, allowing better separation of the aryepiglottic folds from the hypopharynx, while simultaneously abducting the cords (see Fig. 3–3 ). The vocal cords can be assessed by phonating (“eeee”), which causes the cords to adduct and move to a paramedian position (see Fig. 3–3 ). Breath holding will also adduct the vocal cords, close the glottis, and significantly reduce motion artifacts. By scanning the larynx twice, once to adduct and a second time (sections limited to the glottis) to abduct the vocal cords, the radiologist can assess vocal cord motion and identify fixation. Intravascular contrast should be given to differentiate vascular structures from adjacent nodes and muscles and to assess tumor margins. Evaluation of laryngeal trauma may not require intravenous contrast. Bone windows are helpful for assessing cartilage fractures or tumor erosion. In a cooperative patient with a flexible neck it may be possible to obtain direct coronal images to assess the configuration of the true and false vocal cords, yielding similar information to that obtained by conventional AP tomography of the larynx.
Thyroid and parathyroid glands
Thyroid gland CT is performed in the same manner as the scanning of the larynx. The indication for performing CT arises when physical examination, ultrasound, or a nuclear medicine study suggests an unusually large or fixed mass. CT can help determine the extent of invasion and compression of adjacent structures in the larynx, hypopharynx, and mediastinum. The 3- to 5-mm sections are obtained from the hyoid bone to the top of the aortic arch to cover potential sites of ectopic thyroid and parathyroid tissue. Although the

normal thyroid is hyperdense because of its natural iodine content on NCCT, a CECT is preferred for this study. The normal thyroid enhances intensely on CECT, with most mass lesions of the thyroid enhancing less. The parathyroids are rarely imaged primarily by CT because nuclear medicine and ultrasound techniques are excellent procedures for localizing these small glands.
Paranasal sinuses
Paranasal sinus CT can be approached in several ways depending on the anticipated disease process. Plain films may be used as the initial screening device for evaluating sinusitis or facial trauma. Once a mass or inflammatory lesion is detected within the sinuses, CT is the method of choice for further evaluation. A better substitute for the plain film sinus series is a screening axial sinus NCCT ( Fig. 3–11 , A ), which gives superior information on specific sinus involvement by inflammatory processes as well as better delineation of bony sclerosis or destruction. One method is to use 5-mm thick sections obtained at 10-mm intervals (5-mm gap), which can cover the entire paranasal sinuses with six to eight slices. Using a bone algorithm and photographing using bone windows, an accurate assessment of the presence or absence of sinus disease can be made. Another advantage of using the axial plane rather than the coronal plane for screening the sinuses is the inclusion of the mastoid air cells and middle ear, which can be another source of infection in a patient with a fever of unknown origin.
When endoscopic sinus surgery is anticipated, direct coronal NCCT imaging of the sinuses is mandatory for pre-operative evaluation of the extent of sinus disease, to detect anatomic variants, and for planning the surgical approach ( Fig. 3–11 , B ). This study is done with thin sections ranging from 2 to 3 mm of thickness. Five-millimeter slice thickness is frequently suboptimal, causing volume averaging of small structures and obscuring the fine details of ostiomeatal anatomy. Coronal imaging may be performed with the neck extended in either the prone or the supine position. An advantage of the prone position is that free fluid in the maxillary sinus layers dependently in the inferior portion of the sinus. In the supine position, fluid and mucus layer superiorly at the maxillary sinus ostium and may cause confusion with inflammatory mucosal thickening. Frequently, only the bone algorithm with its edge enhancement properties is needed for evaluating the detailed anatomy of the ostiomeatal complex. Contrast-enhanced sinus CT is usually not necessary for routine sinusitis, although when severe nasal polyposis is suspected, contrast may be useful to demonstrate the characteristic “cascading” appearance of the enhancing polyps or to characterize an associated mucocele. A soft-tissue algorithm with soft-tissue windows may be useful when using CECT for intracranial complications from sinus inflammatory processes. A nasal decongestant may be used to help decrease normal but asymmetric nasal mucosa congestion (normal nasal mucosal cycle) from a mucosal-based mass.

Figure 3-11 Computed tomography in evaluation of sinusitis. A, Axial 5-mm sinus screening noncontrast computed tomography (NCCT) using bone algorithm and bone windows in a patient with chronic right maxillary sinusitis. Excellent bony detail is obtained of both maxillary sinuses (posterior wall thickening and sclerosis are present on right) and mastoids. Clear discrimination of soft-tissue opacification of right maxillary sinus (asterisk) is achieved compared with normal air-filled left maxillary sinus. Pneumatized pterygoid process (arrow) is an extension of sphenoid sinus pneumatization. B, Coronal 3-mm NCCT with bone algorithm and bone windows in same patient clearly demonstrates mucosal thickening and opacification of right maxillary and ethmoid sinuses, and left maxillary infundibulum (arrow). Sharp anatomic detail of bony architecture and the use of coronal plane are essential for preoperative planning before endoscopic sinus surgery. C, Axial 3-mm contrast-enhanced computed tomography with soft tissue algorithm and soft tissue windows exaggerates right maxillary sinus posterior wall thickness (arrows). Thickened mucosa has thin rim of enhancement along its luminal margin (arrowhead). Combination of bony sclerosis and mucosal thickening is often seen in chronic sinusitis.

The assessment of sinus tumors requires the most detailed imaging. Both axial CECT and coronal CECT with 3-mm sections are used to precisely determine the extent of sinus tumor spread into adjacent compartments including the anterior and middle cranial fossa, orbit, and parapharyngeal space. For an optimal study, both soft-tissue and bone algorithms are used, allowing differentiation of the soft tissue component as well as evaluating subtle bony destruction ( Fig. 3–11 , A , C ). The coronal plane is best for evaluating the cribriform plate. CECT is used to maximize the enhancement characteristics of the tumor and differentiate it from adjacent soft-tissue structures. In some cases it may be necessary to extend the axial sections beyond the sinuses to include the cervical lymph node chains of the neck. If this is the case, a constant infusion technique is performed, scanning from the sternal notch up to the top of the paranasal sinuses, followed by the coronal images through the paranasal sinuses. This permits the optimal concentration of intravascular contrast to be obtained in the lower neck to distinguish vessels from lymph nodes.
Facial trauma
Facial trauma CT characterizes fractures and facial soft tissue injury very well. Both axial NCCT and coronal NCCT are obtained to optimally determine the three-dimensional relationships of fracture fragments. Scanning may be performed with either 3-mm sections in both planes or, alternatively, contiguous 1.5-mm sections with coronal reformatted images when the patient cannot tolerate the coronal position because of other trauma or cervical spine instability. However, reformatted images are frequently degraded by motion artifact, and spatial resolution is usually unsatisfactory unless thin sections are used. Bone algorithm is preferred; images are photographed with bone and soft-tissue windows. Soft-tissue algorithm for assessing orbital and facial soft-tissue injury is optional and requires additional image reconstruction time. Three-dimensional reconstructions may help the surgeon plan facial restoration.
Temporal bone and skull base
In the past, evaluation of the skull base and temporal bones was principally performed using plain films and conventional tomography performed in the AP and lateral projections to assess bone destruction and mastoid or middle ear opacification. Tomograms are now rarely done or needed. The development of CT has completely eliminated the need for tomography in this region since the spatial and contrast resolution is superior; also, overlapping structures do not degrade the CT image. CT of the temporal bones requires imaging, preferably in two planes, using thin sections. Contiguous 1- to 1.5-mm sections are frequently obtained in the axial and the direct coronal planes. In some cases if the need for reformatted images is anticipated, scanning in the axial plane with a 0.5-mm overlap may optimize reformatted coronal and sagittal images. In general, intravenous contrast is not necessary for temporal bone imaging,although vascular tumors or squamous cell carcinoma invading the temporal bone may require the use of intravenous contrast plus supplemental soft-tissue algorithms to best image the extracranial and intracranial soft-tissue component of the lesion. However, bone algorithm with bone windows is used in all temporal bone imaging. CECT of other lesions of the skull base proper may require both axial and coronal 3-mm sections. Bone and soft-tissue algorithms are necessary for assessing skull base tumor spread.
Application of magnetic resonance imaging by head and neck region
Suprahyoid neck
MRI is ideally suited for imaging the suprahyoid neck (including nasopharynx, oropharynx, oral cavity, and tongue). Surface oils that improve signal detection may be used for imaging this area. The standard head coil will permit visualization of the suprahyoid neck structures caudally down to approximately the level of the inferior margin of the mandible and floor of mouth. For imaging the oral cavity, floor of mouth, submandibular space, and cervical lymph node chains, a head coil will not suffice. Either an anterior or volume neck coil is needed to visualize the entire neck from the skull base to the thoracic inlet (from dura to pleura). Several pulse sequences and imaging planes using 5-mm thick sections are required to adequately assess the deep and superficial structures of the neck. (Implicit in this discussion of MRI technique for all areas of the head and neck is the fact that a sagittal T1WI is obtained as the initial sequence in all of the authors’ studies and is used primarily as a scout view for the proper positioning in other imaging planes, as well as for anatomic information.) A precontrast axial T1WI and often a coronal T1WI are required to optimally assess fat planes in the neck. Fat provides an excellent white background from which muscle and fascial planes, bone, sinus, and vascular structures can easily be discriminated. The coronal plane is particularly useful for visualizing the relationships of the suprahyoid neck structures to the skull base and also for delineating the anatomy of the tongue and floor of mouth. A T2WI, usually obtained in the axial plane, is required to detect structures with a long T2 (e.g., water, tumors, edema, proteinaceous cysts) that appear brighter than the background muscle and fat (fat loses signal intensity with increased T2 weighting). Postgadolinium T1WIs with fat saturation (suppression) in the axial and coronal plane are frequently helpful to discriminate the enhancing margins of a lesion or to detect perineural spread of tumor. The T2WI may also be combined with fat suppression and gadolinium usage to optimize the information obtained by this more time-consuming long TR sequence.
Before the widespread use of gadolinium and fat suppression techniques, MRI was often less sensitive and less specific than CT in detecting cervical lymph node metastases.

However, improved MRI scanner technology, gadolinium enhancement, and fat suppression sequences have allowed considerable progress toward that goal. Also, the MRI detection of carotid artery invasion by extracapsular spread of tumor from nodes is often superior to CECT. Controversy still exists in defining the role of MRI in cervical lymph node imaging. Prospective studies of MRI in head and neck tumor and node staging are planned.
An anterior or volume neck coil using 5-mm thick sections with a small 1- to 2-mm interslice gap is necessary to encompass the entire lymph node chains throughout the neck from the skull base to the clavicles within the imaging field of view. The axial plane is frequently used, but the full craniocaudal extent of nodal disease is often better appreciated on coronal and sagittal views. Because the primary tumor is being scanned concomitantly, a choice between pulse sequences for characterizing both the lymph nodes and primary lesion must be made, yet with a minimum number of sequences (shortening the total scan time). Although most of the following sequences are quite sensitive for detecting adenopathy, few of them are specific in discriminating malignant metastatic nodes from reactive (inflammatory) adenopathy. The detection of cervical lymphadenopathy with MRI may be accomplished with (in decreasing order of sensitivity) a STIR sequence, a fat saturation T2WI, a fat saturation postgadolinium T1WI, a conventional T2WI, or a precontrast T1WI. Although STIR is the most sensitive sequence, it also yields the fewest slices, making full nodal evaluation problematic. However, a fat saturation T1WI can be obtained in a much shorter time than either a STIR or T2WI, and the fat saturation T1WI promises improved MRI specificity in metastatic node differentiation from inflammatory disease. The significance of a ring-enhancing node on MRI should be analogous to ring enhancement of a metastatic node seen with the current gold standard, CECT.
Salivary glands
MRI of the parotid gland can be accomplished with a standard head coil using 3- to 5-mm slices but at the risk of excluding a portion of the submandibular gland that lies at the edge of the usable field of view. A volume neck coil is the better coil for imaging both parotid and submandibular glands within the same field of view, especially if a malignancy is suspected and cervical lymph node metastases are sought lower in the neck. A smaller TMJ coil may be necessary for evaluation of perineural tumor spread along with facial nerve into the mastoid segment of the facial nerve canal. As discussed previously in assessing the suprahyoid neck (in which the salivary glands also reside) the MRI sequences that are most suited to salivary imaging include axial or coronal precontrast T1WI or both, axial and coronal fat saturation postgadolinium T1WI, axial T2WI (precontrast or postgadolinium with fat saturation), and often an axial or coronal STIR (for lymph node detection). T1WIs allow for detection of a low-intensity mass within the high-intensity background of a fatty parotid gland or for assessment of the adjacent fat planes.[10] The fat saturation postgadolinium T1WI is used for detecting the margins of a mass within a less fatty parotid or submandibular gland, for detecting extension beyond the margins of the gland, and especially for detecting perineural tumor spread along the fifth and seventh cranial nerves (best appreciated in the coronal plane). T2WIs are useful for localizing a tumor with a high water content or one with cystic or necrotic areas.[47]
Larynx and infrahyoid neck
The larynx and infrahyoid neck require either an anterior or a volume neck coil, preferably using no thicker than 3-mm sections for the larynx. The field of view should include the area from the inferior margin of the mandible to the clavicles. Although the larynx can be examined well by both axial CECT and MRI, laryngeal MRI has a higher proportion of suboptimal studies. Laryngeal MRI is more susceptible to motion artifacts than MRI of other regions of the neck because of a combination of swallowing, breathing, and vascular pulsation from the adjacent common carotid arteries. A brief training session instructing the patient how to minimize swallowing and breathing artifacts may significantly improve results if it is done immediately before scanning. Additionally, shorter pulse sequences (i.e., T1WI) are more likely to be free of swallowing artifacts. Precontrast axial and coronal T1WIs are essential to assess the paralaryngeal (paraglottic) fat planes; the coronal plane, angled parallel to the airway, is especially useful for determining transglottic tumor spread.[52] Fat saturation postgadolinium T1WIs in the axial and coronal planes are best for detecting lesion margins, invasion of adjacent cartilage, and associated malignant nodes. T2WI in the axial plane may help detect moderately increased tumor signal and improve detection of high signal cystic or necrotic neck lesions. The longer T2WI and STIR sequences are more prone to motion artifacts and are occasionally suboptimal in quality.
Thyroid and parathyroid glands
The same techniques and slice thickness as those of the larynx are used for the thyroid and parathyroid glands. The field of view may need lower centering to include the upper mediastinum and ensure complete evaluation of the inferior extent of a thyroid tumor or an ectopic parathyroid gland. Coronal and sagittal views aid understanding of the craniocaudal extent of the lesion relative to the aortic arch, great vessels, and mediastinum; this information is especially useful to the surgeon. Although MRI may detect an unsuspected thyroid or parathyroid lesion during routine neck or cervical spine imaging, MRI is less frequently used for primary evaluation of these lesions because of the cost of the study and susceptibility to motion artifacts. The normal thyroid gland will enhance mildly on both gadolinium-enhanced MRI and CECT. A solid mass in the thyroid or parathyroid is usually low intensity on T1WI and high signal on T2WI, and it may enhance with gadolinium. Cystic lesions are bright on T2WI.

Paranasal sinuses
Sinus MRI is primarily indicated for evaluating sinus tumors (and occasionally inflammatory disease such as a mucocele) and may be accomplished with a standard head coil, using 3- to 5-mm slices. The principal value of MRI over CT for sinus tumors is the ability of MRI to distinguish between tumor and obstructed sinus secretions and to predict the true extent of the tumor. A precontrast sagittal, axial, or coronal T1WI will provide a good demonstration of the sinuses, nasal cavity, cribriform plate, masticator and parapharyngeal spaces, and orbits. T1WI may differentiate hydrated from viscous sinus secretions; secretions are low signal when hydrated or fluid-like and are intermediate to high signal when viscous and desiccated. Coronal T2WIs or axial T2WIs (either pregadolinium, or postgadolinium with fat saturation) are useful for detecting inflammatory sinus secretions, which are high signal when hydrated or fluid and are low signal when viscous and desiccated. However, tumors tend to be intermediate in signal on T2WI. Because fat is not present to any significant degree in the paranasal sinuses, a STIR sequence frequently adds little over a T2WI and is unnecessary. Sagittal, coronal, or axial fat saturation T1WI is recommended to better define the sinus tumor margins when the tumor extends directly or by perineural spread beyond the sinus into the anterior cranial fossa, orbit, parapharyngeal space, or pterygopalatine fossa. The sagittal and coronal planes are very helpful for evaluating cribriform plate extension; the coronal and axial planes are best for orbital, cavernous sinus, pterygopalatine fossa, and parapharyngeal space spread.
Temporal bone
MRI has significantly improved the detection of internal auditory canal (IAC), facial nerve canal, and jugular foramen lesions. Gadolinium-enhanced MRI has eliminated the need for air-contrast CT cisternography to detect a small intracanalicular acoustic schwannoma. MRI is useful, in combination with CT, for assessing expansile or destructive lesions of the temporal bone and external auditory canal. A standard head coil is adequate for most temporal bone lesions, but a smaller 5- to 10-cm TMJ coil may be needed for evaluating the mastoid and parotid segments of the facial nerve. The small size of the temporal bone structures and their respective lesions requires high spatial resolution images, which may be accomplished by using thinner slices of 0.5 to 3 mm (preferably without an interslice gap), smaller surface coils (higher signal-to-noise ratio), volume acquisition, or T1WI (higher signal-to-noise ratio). Precontrast T1WI in the sagittal and axial planes is useful for defining anatomy and for detection of high-signal lesions such as fat, methemoglobin, and viscous or proteinaceous cysts. Postgadolinium T1WIs (without or with fat saturation) in the axial and coronal planes are essential for detecting small enhancing lesions and determining the extent of larger lesions. In fact, for routine evaluation of a suspected acoustic schwannoma only a postgadolinium axial and coronal T1WI study may be required. T2WIs are frequently unnecessary for IAC tumors but may be helpful when brainstem ischemic or demyelinating disease, meningioma, blood products, proteinaceous secretions, or a large destructive tumor is suspected or is being further evaluated after a preliminary temporal bone CT. A facial nerve lesion in the mastoid segment of the facial nerve canal is best evaluated for proximal and distal extension using a TMJ coil with sagittal and coronal pregadolinium and postgadolinium T1WIs.
Skull base
MRI may be indicated for primary lesions of the skull base or for intracranial and extracranial lesions that secondarily involve the skull base. A standard head coil using 3- to 5-mm slices images this region well. Pregadolinium sagittal, axial, and/or coronal T1WI allows for assessment of the fat planes of the suprahyoid neck and detection of high-signal intensity blood breakdown products, proteinaceous fluids, or fat within the lesion. Postgadolinium axial and coronal (occasionally sagittal) fat saturation T1WIs are excellent for determining the extent of an enhancing lesion above, below, and within the skull base. T2WI in the axial or coronal plane may be helpful for detecting a high-signal lesion. STIR images usually give similar information to T2WIs in the skull base and may not be necessary.
Ultrasound applications in the head and neck
High-resolution ultrasound evaluation of the suprahyoid neck, salivary glands, and infrahyoid neck is limited to the more superficial neck structures because of the impediment to sound transmission caused by the highly reflective facial bones, mandible, mastoid tip, and air within the oral cavity and pharynx. The ultrasound technique, using a high-frequency, 5- to 10-MHz probe and multiple imaging planes, is similar for all these regions. A small superficial lesion is best seen with a high-frequency probe, whereas a larger and deeper lesion may require a lower frequency probe. Color flow Doppler technique may help differentiate vascular structures from a cystic or solid lesion. Head and neck ultrasound is performed less frequently in North America than in Europe, perhaps because of the common availability of CT in North America and the perception of the greater accuracy of CT. Head and neck ultrasound has no role as a staging modality for skull base and sinus neoplasms.
Suprahyoid neck
Ultrasound may be used for the assessment of tumors of the floor of the mouth, anterior two thirds of the tongue, malignant adenopathy, and invasion of the carotid artery and jugular vein. The deep structures centered around the parapharyngeal space are inadequately assessed by this technique and are better investigated by CT and MRI. Ultrasound can assess tumor extent in the floor of the mouth and tongue but has limitations: The mandible obscures the pterygoid muscles; pharyngeal air hides the posterior pharyngeal wall

and epiglottis.[18] Ultrasound excels in differentiating cystic from solid masses; a cyst has few internal echoes, a strongly echogenic back wall, and strong through-transmission of sound, whereas a solid mass has many internal echoes and no additional through-transmission.
Metastatic lymphadenopathy
Ultrasound is very sensitive for detecting metastatic involvement of the lower two thirds of the internal jugular, spinal accessory, submental, and submandibular nodes. Its accuracy may exceed CT for detecting enlarged lymph nodes, but ultrasound does not reliably differentiate large reactive nodes from metastatic nodes.[24] The upper one third of the internal jugular, retropharyngeal, and tracheoesophageal groove nodes are poorly evaluated because of obscuration by bone or airway structures. Ultrasound may be the best method (possibly better than MRI or CT) for determining the presence of tumor invasion of the common or internal carotid artery and internal jugular vein by adjacent primary tumor or extracapsular spread from metastatic nodes. Invasion of the carotid artery is characterized by loss of the echogenic fascial plane between the vessel wall and the tumor.
Salivary glands
Ultrasound has indications for both inflammatory and neoplastic disease. It may detect salivary duct stones as small as 2 mm. An obstructed dilated duct may appear as a tubular cystic structure. An abscess may be detected and drained under ultrasound guidance during the acute stage of sialadenitis, a time during which sialography is contraindicated. A mass in the superficial parotid gland is easily assessed by ultrasound, but the deep lobe of the parotid gland is obscured by the mandible, styloid process, and mastoid tip. Ultrasound is also very sensitive for a mass in the submandibular gland. Although ultrasound can determine the sharpness of margins of the lesion (well-defined margins usually indicate a benign mass and infiltrative margins suggest malignancy), an aggressive neoplasm or inflammatory process extending beyond the margins of the gland is better evaluated by MRI or CECT because the deep landmarks are more easily demonstrated with MRI or CECT.
Infrahyoid neck
Ultrasound using a high-frequency transducer is usually the first imaging modality for evaluating superficially located thyroid gland and parathyroid gland masses because it is relatively inexpensive and easily performed. In the infrahyoid neck, ultrasound is not used for the larynx, retropharyngeal space, or thoracic inlet because overlying cartilage, airway structures, sternum, and clavicles cause acoustic shadows that may obscure lesions. The right, left, and pyramidal lobes may be evaluated by scanning in the axial, sagittal, and oblique planes. A thyroid mass and highly echogenic calcification are easily assessed. A parathyroid adenoma is readily evaluated if its location is cranial to the sternum. Ultrasound-guided fine needle biopsy of a thyroid or parathyroid mass is possible at the time of scanning. Large cystic and solid masses of the infrahyoid neck may be differentiated by ultrasound. Lymphoma of the neck may appear weakly echogenic, sometimes simulating a cyst.
Strategy for image interpretation and differential diagnosis
This section is included to aid the beginning surgeon or oncologist in developing a basic strategy for image interpretation. Normally, the radiologist chooses and supervises the appropriate imaging study, evaluates and interprets the images, and communicates its significance to the referring physician. However, frequent dialogue between the referring physician and the radiologist will significantly improve interpretation of the imaging study. Accurately interpreting an imaging study of the head and neck requires a systematic method of observation, a knowledge of the complex anatomy, spaces, and pathophysiology, and an understanding of imaging principles. The differential diagnosis of lesions of the head and neck requires a systematic approach as well. One such diagnostic imaging process is summarized below:

Obtain clinical data: age, sex, history, physical findings.

Survey the films for all abnormalities and summarize these findings.

Compartmentalize the lesion.

Interpret the chronicity and aggressiveness of the observations: acute or chronic, nonaggressive or aggressive, benign or malignant.

Develop a differential diagnosis. Use pathologic categories: congenital, inflammatory, tumor, trauma, vascular. Use clinical and radiographic information to narrow the choices and arrive at the most appropriate diagnosis.
By using such a strategy it is unlikely that important findings will be missed because all the images have been evaluated. This may be done by looking at all the anatomic spaces on each slice and proceeding sequentially through all the slices; alternatively each anatomic space can be evaluated on serial slices, followed by the next anatomic space, and so on. Characterizing a lesion requires specific observations: location, anatomic space of the epicenter, size, definition of margins, extent of spread in each direction, invasion of adjacent compartments, involvement of neurovascular structures, enhancement pattern, cysts, calcification, density, signal intensity, echogenicity, hemorrhage, and lymphadenopathy. Next, summarizing the findings helps to tie them together into a logical pattern. Compartmentalizing a lesion is the last step in the observational process and requires placing the epicenter or site of origin of the lesion in a specific anatomic space, although some lesions may be multicompartmental. The origin of a lesion is limited by the types of tissue that reside in each specific space. An example of such a summary would be, “A 35-year-old male has a cystic,

nonenhancing mass in the sublingual space.” A frequent cause of misdiagnosis is the failure to make all the observations first; interpretation and differential diagnosis of the lesion are the final steps.
The interpretation of the significance of a lesion uses both its radiologic and clinical features; for example, inflammatory (edema; abscess cavity; fever), nonaggressive (remodeling of bone; slow progression of symptoms), aggressive (destruction of bone; rapid progression), benign neoplastic (well-defined margins; displacement of adjacent structures; nonpainful), malignant (poorly defined margins; invasion and destruction of adjacent structures; pain and neuropathies), or cystic (low-density center with a thin rim of enhancement; fluctuant). The differential diagnosis is narrowed by further refining the interpretation, “A 35-year-old male has an asymptomatic cystic, nonenhancing mass in the sublingual space that appears chronic and nonaggressive.” With knowledge of the relevant clinical findings, the proper differential diagnosis, which is specific for each anatomic space, can then be constructed and limited to one (or at least a few) possible pathologic causes. In this example, a ranula would be the most likely consideration.
Spaces of suprahyoid neck
The traditional approach to radiographic interpretation of the head and neck region has been to follow a surgical compartmental approach: nasopharynx, oropharynx, oral cavity, pharynx, and larynx. The nasopharynx extends vertically from the skull base to the soft palate; the oropharynx encompasses the area from the soft palate/hard palate to the hyoid bone. The oral cavity is located anterior to the oropharynx. Below the hyoid bone reside the larynx anteriorly and the hypopharynx more posteriorly. With the advent of cross-sectional imaging in radiology, first with CT and later with MRI, the radiologic interpretive approach changed from a pattern based on surgical compartmental anatomy to one dependent on fascial spaces. However, a combination of the two interpretive approaches, for example, parapharyngeal space at the nasopharyngeal level (with the compartmental designation serving as a modifier) may be more helpful in precisely defining a lesion location.
The head and neck region, the anatomic territory that extends from the skull base to the thoracic inlet, is best and most conveniently divided into the suprahyoid and infrahyoid neck with the hyoid bone serving as the divisional point.[26] Figures 3–12 , 3–13 , 3–14 demonstrate normal cross-sectional CT and MRI anatomy of the suprahyoid neck. The suprahyoid neck may be divided into a series of fascial spaces based on the division and layers of the superficial and deep cervical fascia. The superficial cervical fascia surrounds the face and neck, providing a fatty layer on which the skin is able to slide. The underlying deep cervical fascia is separated into three distinct layers: superficial (investing) layer, middle (visceral) layer, and deep (prevertebral) layer. (Space limitations and the complexity of the fascial spaces do not allow for a detailed description or explanation of the deep cervical fascia.) Although not usually visualized on CT or MRI, these fascial layers divide the suprahyoid neck into distinct anatomic and surgically defined spaces:

Parapharyngeal space (PPS)

Pharyngeal mucosal space (PMS)

Parotid space (PS)

Carotid space (CS)

Masticator space (MS)

Retropharyngeal space (RPS)

Prevertebral space (PVS)

Oral cavity (OC)

Sublingual space (SLS)

Submandibular space (SMS)
Inflammatory and neoplastic disease, the major pathophysiologic processes of the head and neck territory, tend to grow and spread in the boundaries and confines of these fascial spaces.[5] Nevertheless, this approach based on the use of fascial anatomy allows delineation of specific anatomic spaces, with identification of disease-specific lesions for each of these spaces. As a consequence, a more accurate differential diagnosis and resulting final diagnosis are attained.
Parapharyngeal space
The crucial anatomic center point to understanding suprahyoid anatomy is the parapharyngeal space (PPS); this fibrofatty fascial space extends from the skull base to the level of the hyoid bone and serves as a marker space around which the remaining fascial spaces are arranged. It contains fat, portions of the third division of cranial nerve V, the internal maxillary artery, the ascending pharyngeal artery, and the pterygoid venous plexus. In the axial plane, this space has a triangular configuration and demonstrates bilateral symmetry. In the coronal plane the PPS has an hour-glass shape, thicker at the skull base and hyoid level and thinner in the midsuprahyoid neck.
The PPS is clearly defined and located on both the axial and coronal planes with both CT and MRI.[43] With the former technique, the predominant fat content serves as a low-density marker between the medial muscles of deglutition found in the pharyngeal mucosal space and the muscles of mastication, located more laterally. With MRI the PPS has a bright signal intensity on T1WI (the scanning sequence that best highlights fat and muscle tissue differences); with longer TR times and more T2 weighting this fatty space becomes less intense in signal.
Because this space is the epicenter around which the other fascial spaces are arranged, it serves as a potential marker or pivotal space. By noting the position and direction of displacement of the PPS, one can determine the epicenter


Figure 3-12 The normal computed tomography anatomy of suprahyoid neck. A, Coronal contrast-enhanced computed tomography (CECT) and, B, axial CECT demonstrate low-fat density of the parapharyngeal space (arrow). Note its central position as a marker space. The following structures can be identified: anterior belly of digastric muscle (d), genioglossus muscle (g), geniohyoid muscle (gh), lateral pterygoid muscle (lp), masseter muscle (m), medial pterygoid muscle (mp), masticator space (MS), mylohyoid muscle (asterisk), nasopharyngeal mucosal space (PMS, small arrows), parotid space (PS), ramus of mandible (r), sublingual space (SL), submandibular space (SM), soft palate (sp), and intrinsic tongue musculature (T).

Figure 3-13 The normal computed tomography anatomy of sublingual space, submandibular space, and oral cavity. A, Axial contrast-enhanced computed tomography at superior and, B, inferior tongue levels, respectively. Note the following structures: internal carotid (c), epiglottis (e), genioglossus muscle (g), jugular vein (J), lingual tonsil (l), masseter muscle (m), medial pterygoid muscle (mp), masticator space (MS), mylohyoid muscle (asterisk), pharyngeal mucosal space of oropharynx (small arrows), prevertebral space (PVS), retropharyngeal space (arrowheads), sublingual space (SL), submandibular space (SM), submandibular gland (smg), intrinsic musculature of tongue (T), and uvula of soft palate (u).


Figure 3-14 The normal magnetic resonance imaging anatomy of suprahyoid neck. A, Sagittal midline noncontrast T1-weighted image (T1WI). B, Axial noncontrast T1WI at the level of jugular foramen. C, Axial postgadolinium T1WI at the same level of B demonstrates enhancement of nasopharyngeal mucosa and jugular veins. D, Axial noncontrast T1WI at the level of C2 vertebral body and midtongue demonstrates high signal intensity of parapharyngeal space fat. The following structures are labelled: cerebellum (cb), clivus (cl), hard palate (hp), internal carotid artery (arrow), inferior turbinates (it), jugular vein (J), lateral pterygoid muscle (lp), masseter muscle (m), medulla (md), masticator space (MS), nasopharyngeal mucosal space (small arrows), pons (p), parotid gland (pg), parapharyngeal space (PPS), parotid space (PS), retropharyngeal space (arrowheads), sphenoid sinus (s), soft palate (sp), intrinsic musculature of tongue (T), temporalis muscle (tp), and retromandibular vein (v).
and fascial space origin of a suprahyoid lesion. Because the PPS contains few structures from which lesions arise, most lesions found in this space have spread here secondarily from an adjacent fascial space.[44]
The fascial spaces that are centered about the parapharyngeal space include the pharyngeal mucosal space (PMS), the carotid space (CS), the parotid space (PS), the masticator space (MS), the retropharyngeal space (RPS), and the prevertebral space (PVS). Each space has well-defined anatomic boundaries, contains major structures of importance, and gives rise to pathologic processes that are site selective for that space. For consideration of pathologic processes in each fascial space, it is convenient to use the following outline: congenital, inflammatory, neoplastic (benign and malignant), pseudolesions, and miscellaneous. This approach, using these few disease categories, elicits most of the major

lesions to be found in the head and neck, and is used in the following discussion of suprahyoid and infrahyoid lesions.
Pharyngeal mucosal space
The PMS lies medial to the PPS and anterior to the PVS. It encompasses the mucosal surfaces of the inner boundaries of the nasopharynx and oropharynx and includes lymphoid (adenoidal) tissue, minor salivary glands, portions of the constrictor muscles, and muscles of deglutition; the medial portion of the eustachian tube passes through it. These structures lie medial to or on the airway side of the buccopharyngeal fascia; this fascial structure may be seen on MRI as a band of low signal intensity. On CECT or gadolinium-enhanced MRI studies, the overlying pharyngeal mucosa enhances.
The PMS extends from the skull base to the lower margin of the cricoid cartilage, extending into the upper portion of the infrahyoid neck. It encompasses the nasopharynx, oropharynx, and portions of the hypopharynx. Lesions in this space displace the PPS laterally.
In general, caution is used when interpreting the mucosal surfaces of the pharynx, oral cavity, and larynx. The normal mucosa is high signal on T2WI and STIR and enhances on postgadolinium T1WI (and with CECT); it may be confused with a superficial mucosal-based malignancy. Likewise, a small superficial mucosal-based tumor may be indistinguishable from the adjacent normal mucosa. The direct clinical examination of the mucosal surfaces is still superior to cross-sectional CT or MR imaging in detecting superficial tumor; however, both CT and MRI excel in detecting submucosal tumor and deep invasion. Mucosal irregularity and slight asymmetry are common, especially near the fossa of Rosenmüller (the lateral pharyngeal recesses of the nasopharynx), and care is taken in ascribing abnormality. Repeat studies with a modified Valsalva maneuver to distend the airway may be helpful. Involvement of the submucosal muscles and adjacent deep structures, such as the PPS, will confirm the presence of a suspected neoplastic mucosal lesion. Lymphoid (adenoidal) tissue is often hypertrophic and prominent, especially in children and young adolescents, and may encroach on the airway. On CT lymphoid tissue is isodense to muscle; with MRI it has a similar intensity to muscle on T1WI but has a bright signal on T2WI. It lies superficial to the buccopharyngeal fascia and is relatively homogeneous.
Inflammatory lesions of the PPS include pharyngitis, abscess (especially tonsillar abscess), and postinflammatory retention cysts ( Fig. 3–15 ). Benign mixed salivary tumor is the most common benign neoplasm.
A Thornwaldt cyst is a common congenital lesion of the midline posterior nasopharyngeal mucosa and only rarely becomes secondarily infected. It is very bright on long TR sequences on MRI.
Squamous cell carcinoma (SCC), the most common tumor of the upper aerodigestive tract, originates from the PMS; the majority of lesions arise from squamous epithelium

Figure 3-15 Tonsillar abscess. Axial contrast-enhanced computed tomography demonstrates low-density left tonsillar lesion (arrowheads) with thin peripheral rim enhancement. The left tonsil is increased in size. Partially effaced left parapharyngeal space (arrow) is lateral in position.
in the region of the lateral pharyngeal recess ( Figs. 3–16 and Fig. 3–17 ). Small submucosal lesions may be missed on the clinical examination but may be detected with crosssectional imaging. Involvement of the adjacent musculofascial spaces confirms the presence of a mucosal lesion. It may become large and lead to extensive invasion and destruction of the neighboring fascial spaces or extend medially to involve the PPS. With CT, SCC demonstrates inhomogeneous lesion enhancement, commonly with extension into adjacent spaces. With MRI it is of intermediate intensity on T1WI and high intensity on T2WI and enhances after gadolinium infusion.[39] It may cause serous otitis media and mastoid cell opacification because of dysfunction of the eustachian tube from invasion or mass effect. Extension superior to the skull base is common; the foramen lacerum, foramen ovale, carotid canal, jugular foramen, and clivus may be affected. Perineural tumor spread along cranial motor nerve V is common and its presence should be diligently sought, especially if there is unilateral atrophy of the muscles of mastication innervated by the mandibular division of the fifth cranial nerve. Inferiorly, nasopharyngeal SCC may extend to involve the soft palate, tonsillar pillars, and nasal cavity. Asymptomatic cervical adenopathy with involvement of the superior internal jugular and spinal accessory lymph node chains is the presenting mode in over 50% of patients. Lymph nodes are usually considered positive when over 1.5 cm in diameter; an enhancing lymph node rim with necrotic low-density center on CECT indicates neoplastic involvement. On MRI lymph nodes have bright signal intensity on


Figure 3-16 Nasopharyngeal carcinoma. A, Axial contrast-enhanced computed tomography (CECT) demonstrates enhancing lesion (asterisk) involving pharyngeal mucosa space, retropharyngeal spaces, and prevertebral space; tumor abuts skull base. B, Axial CECT image with bone settings at the level of the skull base demonstrates lytic destructive lesion involving anteromedial left petrous bone (asterisk), medial portion of greater sphenoid wing (arrowhead), and adjacent clivus (arrow).

Figure 3-17 Squamous cell carcinoma of oropharynx. Axial contrast-enhanced computed tomography demonstrates mixed-density enhancing lesion (asterisk) in right oropharynx. The tumor has extended posterolaterally to surround carotid vessels (arrow). Enhancing lymph node (arrowhead) with low-density necrotic center is noted posterior to carotid space, lying just beneath sternocleidomastoid muscle. Enhancement of the adjacent sternocleidomastoid muscle indicates muscle invasion.
T2WI; on T1WI postgadolinium administration, lymph node enhancement may be seen.
The extensive lymphoid tissue in this space is a source for development of non-Hodgkin’s lymphoma ( Fig. 3–18 ). Both SCC and lymphoma may have extensive lymph node

Figure 3-18 Nasopharyngeal lymphoma. Axial non-contrast computed tomography demonstrates large homogeneous pharyngeal mucosal space with nasopharyngeal mass lesion, displacing prevertebral and retropharyngeal spaces posteriorly. The lesion bulges into parapharyngeal space bilaterally (arrows).
involvement; the nodes associated with SCC commonly have necrotic centers whereas those of lymphoma are usually noncavitary and homogeneous. Malignant minor salivary gland tumors also occur in this space. The above three malignant lesions are difficult to separate radiologically.

Parotid space
The PS, the home of the parotid gland and the extracranial portion of the facial nerve, lies lateral to both the PPS and the CS and posterior to the masticator space. It extends superiorly from the level of the midsquamous temporal bone to the angle of the mandible inferiorly. It contains the parotid gland, multiple lymph nodes (within and outside the parotid gland parenchyma), the facial nerve, the retromandibular vein, and branches of the external carotid artery. The parotid gland overlies the posterior portion of the masseter muscle; its deep retromandibular portion lies posterior to the mandible and lateral to the PPS and the CS. The posterior belly of the digastric muscle separates the PS from the CS.
Because of its high fat content, especially in the adult, the parotid gland parenchyma is frequently low density on CT but may vary and approach muscle density. It is high intensity on T1WI (slightly less than subcutaneous fat) and has decreased intensity on T2WI but often retains its bright T2 signal intensity relative to muscle. The retromandibular vein lies just posterior to the lateral margin of the mandibular ramus. The diagonal course of the facial nerve, paralleling a line drawn from the stylomastoid foramen to a point just lateral to the retromandibular vein, divides the parotid gland into superficial and deep portions. Although this is not a true anatomic division, it is useful for surgical planning. The facial nerve may be seen on some MRI studies. Its course must be considered and determined when removal of deep parotid lobe lesions is planned.
Lesions in the parotid space are usually surrounded by parotid gland tissue and are better defined with MRI than CT.[49] With NCCT, lesions are usually isodense to the normal gland or increased density; with MRI, lesions are muscle intensity on T1WI and usually hyperintense to normal parotid gland on T2WI.[41] When small, parotid lesions tend to be homogeneous; with increase in lesion size areas of hemorrhage, necrosis, and calcification may develop. If the lesion extends or originates from the deep portion of the gland, it displaces the PPS medially and occasionally anteriorly. Large lesions in the parotid gland proper will cause widening of the stylomandibular notch, the space between the posterior border of the mandible and the styloid process; comparison to the contralateral side will make subtle widening of this space evident.[25] Deep lobe lesions, if large, may displace the carotid artery posteriorly. Benign lesions as a general rule are usually well defined; malignant lesions have indistinct margins and may invade adjacent structures. Lesions in the PPS or CS may extend laterally into the parotid space, mimicking a parotid lesion clinically.
Congenital lesions of the PS include hemangioma, lymphangioma, and first and second branchial cleft cyst, the latter presenting as a cystic-appearing lesion with smooth walls.[27] Enhancing margins of the cyst indicate it is secondarily infected. Inflammatory disease may present as diffuse swelling or as a localized abscess; infection of the adjacent skull base is best demonstrated with CT. Infection may occur secondary to calculus disease.

Figure 3-19 Benign pleomorphic adenoma of the right parotid gland. Axial contrast-enhanced computed tomography demonstrates dumbbell-shaped tumor with enhancement of its superficial portion; its deep portion is predominantly low density. Parapharyngeal space is displaced medially (arrow). The lateral pterygoid muscle is indented and lies anteriorly (arrowhead). The lesion has displaced ramus of mandible anteriorly.
Calculi are also best demonstrated by sialography as intraluminal filling defects or by CT because of its tenfold higher sensitivity over plain films for detecting calcified calculi. Sialadenitis, autoimmune disease, and strictures are still best evaluated by conventional sialography, which best demonstrates ductal anatomy. Chronic sialadenitis will cause the affected parotid gland CT density to approach that of muscle; this appears as lower parotid gland signal on T1WI and brighter signal on T2WI than that of the contralateral parotid gland. Autoimmune diseases such as Sjögren’s syndrome demonstrate bilateral parotid enlargement. Bilateral gland enlargement by benign lymphoepithelial cysts is seen in acquired immunodeficiency syndrome.
Benign pleomorphic adenoma (benign mixed tumor), the most common benign neoplasm of the parotid gland, is well defined and demonstrates variable degrees of contrast enhancement ( Fig. 3–19 ). It is usually ovoid in configuration and may involve either the superficial or deep lobe of the parotid gland or less commonly both. Rarely, benign mixed tumors may arise from salivary rest tissue medial to the deep lobe and have a fat border on both their medial and lateral margins. Calcification is occasionally seen within the tumor. The tumor is hypointense on T1WI and hyperintense on T2WI. Both the superficial and deep lobes of the parotid gland may be involved, leading to a dumbbell configuration of the mass and associated widening of the stylomandibular notch.
Malignant lesions include mucoepidermoid carcinoma, adenoid cystic carcinoma, acinic cell carcinoma, and malignant


Figure 3-20 Acinic cell tumor of left parotid gland. A, Axial contrast-enhanced computed tomography at level of C1 and C2 demonstrates inhomogeneous irregular mass lesion involving both superficial and deep portions of the left parotid gland. Lesion displaces parapharyngeal space anteriorly and medially (arrow). Stylomandibular distance is increased. Areas of patchy enhancement are noted around periphery and throughout lesion. Lesion has displaced carotid artery posteriorly (arrowhead). B, Axial T1-weighted image demonstrates superior contrast resolution of magnetic resonance imaging. Both superficial and deep portions of lesion are well outlined. The margin of the lesion can be separated from lateral pterygoid muscle (p), which is displaced anteriorly and laterally. PPS (arrowheads), indicated by its high-intensity fat, is displaced medially. The flow void marks the site of left carotid artery (arrow). C, Axial spin density magnetic resonance imaging image at the level of the skull base demonstrates well-defined lesion of increased signal intensity. Involvement of both superficial and deep lobes is well delineated.
mixed tumor ( Fig. 3–20 ). High-grade malignant lesions have infiltrative borders. MRI is superior to CT for showing lesion margins and extent. Because of the abundant lymph node tissue within the parotid gland, lymph node involvement may be seen with non-Hodgkin’s lymphoma, and metastatic involvement may be seen with SCC and malignant melanoma. Basal cell carcinoma of the adjacent ear and cheek may metastasize to the parotid lymph nodes.
Carotid space
The CS, the space of vessels, nerves, and lymph nodes, lies posterior to the PPS, lateral to the retropharyngeal space, anterolateral to the prevertebral spaces, and medial to the PS and styloid process. The posterior belly of the digastric muscle separates the CS from the parotid space. The CS is formed from portions of all three layers of the deep cervical fascia. The CS extends from the temporal bone and base of the skull superiorly to the mediastinum inferiorly.[19] It contains the common carotid artery, its major divisions, the internal and external carotid artery, the jugular vein, cranial nerves IX to XII, sympathetic plexus, and lymph nodes. The jugular vein lies lateral and posterior to the carotid artery; the vagus nerve lies in the posterior groove between the two vessels. Cranial nerves IX, XI, and XII migrate to the anteromedial portion of the CS lower in the neck. Lesions of the CS displace the PPS anteriorly and, if large, may remodel the styloid process, displacing it anterolaterally.
Infection of the CS occurs most commonly secondary to spread of infection from adjacent fascial spaces. Reactive inflammatory lymph nodes, which are characteristically homogeneous and less than 1 cm in size, may be seen in any portion along the carotid space and be seen with such varied infectious processes as sinusitis, infectious mononucleosis, and tuberculosis. Suppurative lymph nodes may have low-density centers and may not be distinguished from malignant lymph nodes; clusters or groups of lymph nodes lumped into large masses are not uncommon. Cellulitis causes a loss of normal soft-tissue planes; abscesses are characterized by focal fluid collections with enhancing margins.
On CECT, normal blood vessels demonstrate contrast enhancement; with dynamic CECT a wash-in phase (early visualization of contrast) may be demonstrated within normal vessels and within the feeding or draining vessels of a mass, which further indicates the vascular etiology of a lesion. On MRI, blood vessels appear as circular or linear areas of flow void, because of flow of fast-moving blood. Turbulent or slow flow may lead to areas of mixed signal intensity. Vessel ectasia, dissection, aneurysm, pseudoaneurysm, and thrombosis may be diagnosed readily with either cross-sectional imaging technique. Assessment of adjacent sectional images will demonstrate a tubular configuration to the lesion. An ectatic carotid artery or an asymmetrically enlarged jugular vein may present clinically as a lateral neck mass but is readily discernible radiologically. The right jugular vein is usually larger than the left and at times may be several times larger than the left, reflecting its greater venous drainage


Figure 3-21 Left carotid space and retropharyngeal space ganglioneuroma. Axial contrast-enhanced computed tomography at the level of midtongue demonstrates a C- or sausage-shaped, well-defined, low-density lesion in anteromedial portion of left carotid space. The lesion partially encases the left carotid artery (asterisk) and displaces it posterolaterally. It extends medially into the left retropharyngeal space (arrow). Parapharyngeal space has been displaced laterally. Pharyngeal mucosal space (arrowheads) lies anterior to lesion.
from the brain. Thrombosis, either arterial or venous in nature, appears as a linear or tubular intraluminal filling defect with or without associated mass effect on CECT because the vasa vasorum of the vessel wall enhances in a ring-like fashion.[1] Subacute thrombosis or vessel wall hemorrhage secondary to dissection or trauma will yield a bright signal on T1WI because of the T1 shortening effects of paramagnetic methemoglobin, a blood breakdown product.
Most mass lesions originating in the CS are of neoplastic origin. Most neurogenic tumors are schwannomas ( Fig. 3–21 ). A schwannoma arises from Schwann cells that form the covering of nerves and most commonly originate from the vagus nerve and less commonly from the sympathetic plexus. A neurofibroma contains mixed neural and Schwann cell elements and arises from the peripheral nerves. Neurofibromas are rare and when present usually are multiple and part of neurofibromatosis, type two. Both tumors are well defined with CT with either tumor having a low-density component because of fat infiltration. On CECT neurofibromas demonstrate variable degrees of enhancement; on MRI they have a similar appearance. On both CT and MRI most neural tumors have similar density and intensity characteristics to salivary gland tumors and often may not be differentiated. Neural tumors may have dense enhancement and simulate paragangliomas. On angiography, neuromas characteristically are hypovascular in contrast to paragangliomas, which are hypervascular. Neurogenic lesions arise posterior to the internal carotid artery and thus cause anterior displacement of the latter.
Paragangliomas, lesions developing from neural crest cell derivatives, may arise in the jugular foramen (glomus jugulare), along the course of the vagus nerve (glomus vagale), or at the carotid bifurcation (carotid body tumor) ( Figs. 3–22 and Fig. 3–23 ). Paragangliomas are multiple in up to 5% of patients. The lesion is ovoid with smooth margins. Because of its marked hypervascularity, it is densely enhancing on CT; angiography reveals a very vascular tumor with dense capillary staining. At the skull base, it erodes the jugular spine and causes permeative bone erosion of the jugular foramen in contradistinction to a schwannoma, which causes a smooth expansion with intact cortical margins. A jugular foramen paraganglioma may extend into the temporal bone or infiltrate through the skull base, presenting as a posterior fossa mass. In the midneck a paraganglioma causes characteristic displacement of the carotid artery anteriorly and the jugular vein posterolaterally. At the carotid bifurcation a lesion causes splaying of the internal and external carotid arteries. On MRI it is recognized by its hypervascularity characterized by multiple areas of signal void and flow-related enhancement from enlarged feeding and draining vessels.[35]
Lymph node involvement in the CS may be seen most commonly with metastases from SCC or as part of a general involvement by non-Hodgkin’s lymphoma. Lymph node involvement may be the initial manifestation of squamous cell carcinoma. Extracapsular spread of disease may occur; complete encasement of the carotid artery (carotid fixation) may indicate inoperability. However, the carotid artery may be sacrificed at operation if the patient successfully tolerates a carotid balloon occlusion test. Metastatic lymph nodes are characteristically inhomogeneous, especially after contrast enhancement.
Masticator space
The MS, the space of the muscles of mastication and the posterior portion of the mandibular ramus, lies anterior to the PS and is separated from the muscles of deglutition in the pharyngeal mucosal space by the PPS.[11] It contains the masseter, temporalis, and medial and lateral pterygoid muscles, motor branch of the third division of cranial nerve V, inferior alveolar nerve (sensory second division of cranial nerve V), internal maxillary artery and its branches, pterygoid venous plexus, and the ramus and posterior body of the mandible. It includes the temporal fossa (suprazygomatic MS) superiorly, encompasses the zygomatic arch, and extends inferiorly to include the infratemporal fossa and structures on both sides of the mandible. A mass in the MS displaces the PPS posteriorly and medially.
Infection (cellulitis, abscess, osteomyelitis) may involve the mandible or the muscles of mastication; extension through the skull base or involvement of the suprazygomatic masticator space may occur and should be ruled out ( Fig. 3–24 ).


Figure 3-22 Glomus vagale (paraganglioma) of right carotid space. A, Axial T1-weighted image (T1WI) at the level of C2 demonstrates mixed-density, predominantly low-density lesion involving posterior aspect of left carotid space. The lesion displaces the posterior belly of digastric muscle laterally (white arrow) and internal and external carotid arteries anteriorly (black arrows). Parapharyngeal fat is displaced medially (arrowhead). The lesion bulges into medial aspect of airway. The small areas of punctate low intensity noted along the margin and in the anterior portion of the lesion represent tumor vessel flow voids. B, Axial T1WI at the same level postgadolinium injection demonstrates dense patchy enhancement of lesion. Again noted are multiple punctate vascular flow voids within the lesion and around periphery. Carotid vessels (arrows) are noted overlying anterior lesion margin.

Figure 3-23 Glomus vagale of left carotid space. A, Axial contrast-enhanced computed tomography at the level of midtongue demonstrates relatively homogeneous, well-defined enhancing lesion in the left carotid space. Carotid vessels lie on anteromedial margin of lesion (arrowhead). Parapharyngeal space is displaced medially (arrow). The lesion lies deep to sternocleidomastoid muscle (asterisk). B, Anteroposterior digital subtraction angiogram demonstrates densely vascular staining tumor displacing internal carotid artery medially (arrows). Vascularity and dense tumor stain indicate the lesion is paraganglioma.


Figure 3-24 Left masticator space abscess. Axial contrast-enhanced computed tomography at the level of superior alveolar ridge demonstrates low-density lesion (asterisk) in medial aspect of left masticator space, involving left lateral pterygoid muscle. The abscess is surrounded by a rim of irregular enhancement. Edema has infiltrated and obscured parapharyngeal space. Left masseter muscle (arrow) is thickened and edema is present in soft tissue planes, lateral to masseter muscle and in buccal space anteriorly. Note the accessory parotid gland overlying right masseter muscle (arrowhead).
Abscesses commonly arise from an odontogenic focus or from poor dentition. The bone changes of osteomyelitis are best demonstrated with CT.
Benign lesions include hemangioma and lymphangioma ( Fig. 3–25 ). Nasopharyngeal angiofibroma, a tumor of young adolescent males, arises in the pterygopalatine fossa and commonly extends into the masticator space ( Fig. 3–26 ). Primary bone neoplasms may arise from the mandible; chondrosarcoma and osteosarcoma present with chondroid calcification and new bone formation, respectively. The bone lesion is characteristically muscle intense on T1WI and hyperintense with T2WI; postgadolinium T1WI demonstrates extensive enhancement. An infiltrating mass with mandibular destruction may be indistinguishable from metastatic disease. Non-Hodgkin’s lymphoma may present with bone involvement, with a soft tissue mass, or as a lymph node mass.SCC presents as an infiltrating mass and occurs secondary to extension from a neighboring fascial space ( Fig. 3–27 ). Perineural spread of tumor is common in the MS; the fifth nerve should be assessed for thickening and enhancement along its course as it passes from the brainstem to the cavernous sinus, through the foramen ovale, and eventually below the skull base as it passes inferiorly to innervate the individual muscles of mastication ( Fig. 3–28 ). The foramen ovale may be increased in size and tumor may be found within the cavernous sinus. Tumor involvement of the inferior alveolar nerve may cause erosion, irregular enlargement, or destruction of the inferior alveolar canal of the mandible.[3]

Figure 3-25 Lymphangioma of left masticator space. A, Axial T1-weighted image at the level of the base of the tongue and tonsillar region of oropharynx demonstrates inhomogeneous low-density soft tissue mass involving left lateral pterygoid muscle (asterisk). It displaces parapharyngeal space medially and anteriorly (arrow). The mass extends to the anterior medial wall of the left oropharynx (arrowhead). B, Axial spin density image with fat suppression demonstrates a lesion with bright signal intensity. The lesion margins are now better defined; the lesion can now be separated from the lateral pterygoid muscle. The lesion abuts anteromedial wall of oropharynx. Anteriorly, the lesion extends into buccal space (arrow), anterior to cortical margin of mandible.


Figure 3-26 Nasopharyngeal angiofibroma. A, Axial noncontrast computed tomography (NCCT) demonstrates homogeneous soft tissue mass enlarging right nasal aperture; a large component of the tumor projects posteriorly into the nasopharynx and oropharynx. B, Coronal NCCT also demonstrates complete opacification and expansion of right nasal aperture by soft tissue mass; the tumor extends into and widens right infraorbital fissure (arrow). The tumor (asterisk), having destroyed right floor, is present in sphenoid sinus. C and D, Lateral subtraction angiograms (early arterial and capillary phase) demonstrate vascular mass in nasopharynx and nasal aperture. Internal maxillary artery (arrow) gives rise to leash of tumor vessels; dense tumor stain is noted in capillary phase.
Pseudotumors may mislead the unwary. An accessory parotid gland overlying the anterior border of the masseter muscle or asymmetric enlargement of the parotid gland may simulate tumor. In both situations the parotid gland variant retains MRI signal characteristics identical to the normal parotid gland. Hypertrophy of the masseter muscle may occur secondary to teeth grinding, mimic a mass lesion, or be bilateral. If the fifth cranial nerve is injured or invaded by tumor resulting in denervation of the muscles, ipsilateral atrophy of the muscles of mastication and fat infiltration ensue; the normal contralateral muscle group may be incorrectly considered enlarged and misinterpreted as tumor involvement.
Retropharyngeal space
The RPS, a potential space between the middle and deep layers of the deep cervical fascia, lies posterior to the pharyngeal mucosal space, anterior to the PVS, and medial to the carotid space. It extends from the skull base superiorly to the T3 level of the upper mediastinum inferiorly.[13] Its importance derives from its potential to serve as a passageway for infection to spread among the head, neck, and mediastinum. Its contents are fat and lymph nodes, the principal nodes being the nodes of Rouvier (the classical lateral retropharyngeal nodes) and the medial retropharyngeal nodes. This nodal group is commonly involved in children, and up to 1


Figure 3-27 Squamous cell carcinoma (SCC) of mandibular ramus. Axial contrast-enhanced computed tomography at the level of C2 demonstrates large soft tissue tumor destroying the central portion and medial margin of the left mandibular ramus with extension of soft tissue tumor into masseter and lateral pterygoid muscles. Parapharyngeal space has been displaced medially (arrow). Thin rim of circular enhancement is noted posteriorly and laterally (arrowheads).
cm in size is considered normal; but a node over 5 mm is viewed with suspicion in an adult.
A mass lesion in the RPS will displace the PPS anterolaterally. Infection, either pharyngitis or tonsillitis, may give RPS lymph node involvement. Diffuse cellulitis or abscess may occur, the latter usually secondary to infection of the pharyngeal mucosal space or prevertebral space. Infection or mass in the lateral alar portion of the infrahyoid RPS may have a “bow-tie” appearance on axial imaging ( Fig. 3–29 ). SCC may invade the RPS directly or may present solely with lymph node involvement; the pattern is one of inhomogeneous enhancement, commonly with necrotic low-density centers. With non-Hodgkin’s lymphoma, lymph nodes are homogeneous and multiple, commonly involving more than one of the fascial spaces.
Prevertebral space
The PVS, also defined by the deep layers of the deep cervical fascia, is divided into anterior and posterior compartments. The former encompasses the anterior cervical vertebral bodies, extending from one transverse process to another; the posterior compartment surrounds the posterior spinal elements. The PVS contains the prevertebral, scalene, and paraspinal muscles, the brachial plexus, the phrenic nerve, the vertebral body, and the vertebral artery and vein. Similar to the anatomy of the RPS, the PVS extends from the skull base superiorly to the mediastinum inferiorly.
The PVS lies directly posterior to the RPS and posteromedial to the carotid space. An anterior compartment PVS mass causes thickening of the prevertebral muscles and displaces the prevertebral muscles and the PPS anteriorly. A mass in the posterior compartment of the PVS displaces the paraspinous musculature and the posterior cervical space fat laterally, away from the posterior elements of the spine. Infection and malignant disease, the common disease processes of the PVS, usually involve the vertebral body.
Infection, including tuberculosis and bacterial pathogens, characteristically involves the vertebral body as well as the adjacent intervertebral disk space. Benign processes, although much less common, include chordoma, osteochondroma, aneurysmal bone cyst, giant cell tumor, and plexiform neurofibroma. Malignant disease processes include metastatic disease, leukemia, lymphoma, and direct invasion by SCC. Vertebral body destruction with associated soft tissue mass may be seen; the spinal canal and dural sac may be compromised.
Oral cavity
The oral cavity, the space of the anterior two thirds of the tongue and the floor of the mouth, lies below the hard palate, medial to the superior and inferior alveolar ridge and teeth, anterior to the oropharynx, and superior to the mylohyoid muscle, the muscle stretching between the inferomedial margins of the mandible. The oral cavity is separated from the oropharynx posteriorly by the circumvallate papillae, tonsillar pillars, and soft palate. The oral cavity includes the oral tongue (the anterior two thirds of the tongue), whereas the oropharynx contains the base of the tongue (the posterior one third of the tongue), the soft palate, the tonsils, and the posterior pharyngeal wall.
The oral cavity can be divided into two major spaces, the sublingual space (SLS) and the submandibular space (SMS). The mylohyoid muscle, which constitutes the floor of the mouth, is the boundary marker between these two spaces. Other areas of the oral cavity include the floor of the mouth, oral tongue, hard palate, buccal mucosa, upper alveolar ridge, lower alveolar ridge, retromolar trigone, and lip; assessment of these regions is also needed.
Most masses in the oral cavity and oropharynx are amenable to direct clinical assessment; mucosal lesions are readily visualized. The purpose of sectional imaging is to evaluate the degree of submucosal involvement. The majority of neoplasms of the oral cavity are readily detected on clinical examination; SCC accounts for approximately 90% of oral cavity and oropharyngeal neoplasms ( Figs. 3–30 , 3–31 , 3–32 ). Cross-sectional imaging has an important role to play in estimation of tumor size, identification of tumor invasion, and assessment of nodal metastasis.
Congenital lesions include lingual thyroid and cystic lesions (epidermoid, dermoid, and teratoid cysts). Most infections of the oral cavity are dental in origin. Dental infections anterior to the second molar tend to involve the sublingual space and lie superior to the mylohyoid muscle; infections of the posterior molars usually involve the SMS and lie inferior to the mylohyoid muscle. Knowledge of which space is involved is crucial to plan adequate surgical drainage.


Figure 3-28 Adenoid cystic carcinoma of masticator space invading left skull base. A, T1-weighted image (T1WI) magnetic resonance imaging demonstrates low-density, well-defined lesion (asterisk) abutting the lateral border of the clivus and destroying the medial apex of the left petrous temporal bone (arrow). Lateral cortical margin of clivus has been eroded (arrowhead). B, Axial postgadolinium fat-suppressed T1WI demonstrates diffuse patchy enhancement of the left middle fossa lesion (asterisk). On this sequence, normal high signal intensity of fat has been suppressed. C, Coronal postgadolinium fat-suppressed spin density image demonstrates enhancing tumor (arrowhead) below the skull base with extension through the foramen ovale into the left middle fossa (arrow). D, Coronal spin density with fat suppression postgadolinium infusion demonstrates enhancing tumor in expanded vidian canal (arrow) and pterygoid fossa (arrowheads).
Sublingual space
The SLS is located in the anterior tongue, lateral to the intrinsic muscles of the tongue (genioglossus and geniohyoid) and superior and medial to the mylohyoid muscle. Anteriorly, it extends to the genu of the mandible, and posteriorly, it connects freely with the SMS at the posterior margin of the mylohyoid muscle. It contains the anterior portion of the hyoglossus muscle, the lingual nerve (sensory division of cranial nerve V), the chorda tympani branch of cranial nerve VII, the lingual artery and vein, the deep portion of the submandibular glands and ducts, and the sublingual glands and ducts.
Congenital lesions of the sublingual space include epidermoid, dermoid, lymphangioma, and hemangioma. Lingual thyroid tissue will result if there is failure of normal descent of developing thyroid tissue from the base of the tongue into the lower neck. On CT the lingual thyroid is midline in the posterior portion of the tongue and demonstrates dense contrast enhancement; nuclear medicine thyroid scans demonstrate functioning thyroid tissue.
Cellulitis and abscess may occur secondary to dental or mandibular infections or arise as a consequence of calculus disease of either the submandibular or sublingual glands. Abscess is characterized by central areas of low density with or without boundary enhancement ( Fig. 3–33 ). As with parotid


Figure 3-29 Retropharyngeal space (RPS) edema and abscess. A, Axial contrast-enhanced computed tomography (CECT) at the level of the superior margin of hyoid bone demonstrates nasogastric tube (asterisk) in the posterior wall of the oropharyngeal airway and mild thickening of the lateral wall of the larynx. RPS is normal (arrowhead). Two lymph nodes (arrows) with rim enhancement lie anterior to the left submandibular gland. B, Repeat axial CECT at the same level 6 months later demonstrates a well-defined “bow-tie” appearance of edema in RPS (arrowheads).

Figure 3-30 Right base of tongue and tonsillar abscess. Axial contrast-enhanced computed tomography of suprahyoid neck demonstrates inhomogeneous mixed low-density enhancing mass (arrowheads) in the base of the tongue and in the right tonsillar region. Low-density area of lesion indicates pus within the abscess.
gland calculi, CT readily identifies calcified stones and demonstrates bone destruction and sequestra of mandibular osteomyelitis. Ranula, a postinflammatory retention cyst of the sublingual gland, presents as a cystic low-density lesion. As it enlarges, it extends posteriorly and inferiorly into the submandibular space, where it is referred to as a “diving ranula” ( Fig. 3–34 ).
SCC, the most common malignancy of the SLS, may spread from the oropharynx, oral cavity, alveolar ridge, or anterior portion of the tongue. A mass with irregular areas of enhancement, ulceration, central necrosis, and lymph node involvement is characteristic; normal fat planes may be obscured. Tumor spread across the midline of the tongue, along the lingual or mandibular nerve, or invasion of the cortex or medulla of the mandible is an important finding that alters treatment planning.
Submandibular space
The SMS lies inferior and lateral to the SLS; it is located inferior to the mylohyoid bone and superior to the hyoid bone. It contains the anterior belly of the digastric muscle, fat, submandibular and submental lymph nodes, the superficial portion of the submandibular gland, the inferior portion of the hypoglossal nerve, and the facial artery and vein.
Congenital lesions are not uncommon and include second branchial cleft cyst, thyroglossal duct cyst, and cystic hygroma (lymphangioma). Branchial cleft cyst occurs most commonly at the angle of the mandible, posterior to the submandibular gland, anterior to the sternocleidomastoid muscle, and anterolateral to the carotid space ( Fig. 3–35 ). It


Figure 3-31 Squamous cell carcinoma of the base of tongue and the floor of the mouth. A, Axial contrast-enhanced computed tomography (CECT) at the level of midtongue demonstrates homogeneous lesion (asterisk), isodense relative to the muscles of mastication, involving lateral and posterior margins of the left side of tongue, left lateral pterygoid muscle, and tonsillar region of oropharynx. B, Coronal CECT demonstrates homogeneous mass involving lateral portion of tongue, extending from the floor of mouth inferiorly to the tonsillar region superiorly (asterisk). Midline septum (arrow) of tongue is displaced laterally. Necrotic lymph node (arrowhead) lies inferior to tongue.

Figure 3-32 Non-Hodgkin’s lymphoma of the base of tongue and the floor of the mouth. A, Axial contrast-enhanced computed tomography (CECT) at the midlevel of the tongue demonstrates enlargement of the right side of tongue by homogeneous mass lesion (asterisk), isodense to normal tongue musculature; submandibular space (arrow), located more laterally, is also involved. B, Coronal CECT demonstrates homogeneous involvement of the right inferior lateral base of tongue (asterisk), mylohyoid muscle (arrowhead), and floor of mouth. Lesion lies above anterior belly of digastric muscle (arrow). Homogeneous nature of lesion favors lymphoma.


Figure 3-33 Submandibular abscess and cellulitis. Axial contrast-enhanced computed tomography demonstrates mixed low-density and enhancing lesion (asterisk) involving right submandibular space (SMS). Abscess displaces midline structures of tongue to the left. Edema extends laterally from SMS into overlying soft tissues; fat is of increased density because of infiltration by edema.

Figure 3-34 Ranula of left lingual and submandibular space. Axial contrast-enhanced computed tomography at the level of body of mandible demonstrates large, low-density lesion with well-defined margins involving both sublingual and submandibular space. Lesion displaces midline tongue structures (arrow) to the right. Submandibular gland is displaced posteriorly and laterally (asterisk).

Figure 3-35 Infected branchial cleft cyst. Axial contrast-enhanced computed tomography at midlevel of tongue and base of the mandible demonstrates well-defined, low-density lesion in lateral portion of submandibular space lying anterior to the right sternocleidomastoid. A thin rim of peripheral enhancement is noted anteriorly and medially; the lateral wall demonstrates thick enhancement (arrow). Location favors the second branchial cleft cyst. Enhancement of the cyst wall indicates that it is infected.
may have an associated fistula or sinus tract. Thyroglossal duct cysts are midline in location and are found anywhere from the tongue base to the midportion of the thyroid gland. Cystic hygroma, a malformation of lymphatic channels, is a multilocular fluid density lesion that may involve both the SLS and SMS in the adult.
Ranula, a retention cyst of the sublingual gland, commonly extends into and may predominantly involve the SMS; it is unilocular in configuration. Its tail of origin should be carefully searched for in the SLS because this will aid in establishing its origin and diagnosis.
Benign tumors include benign mixed cell tumor, lipoma, dermoid, and epidermoid. Most malignant disease represents secondary submandibular and submental nodal involvement, commonly from SCC of the oral cavity and face. Multiple enlarged lymph node involvement may be seen with non-Hodgkin’s lymphoma.
Spaces of infrahyoid neck
The infrahyoid neck extends superiorly to the hyoid bone and inferiorly to the clavicles and contains the following spaces:

Infrahyoid RPS

Infrahyoid PVS

Anterior and posterior (lateral) cervical spaces

Hypopharyngeal mucosal space (PMS)

Visceral space and larynx



Figure 3-36 Normal axial contrast-enhanced computed tomography (CECT) anatomy of infrahyoid neck. CECT obtained at, A, hyoid bone; B, false vocal cord; C, true vocal cord; and D, thyroid gland levels. (Streaky densities in superficial fat of right neck area in A and B from prior radiation of right parotid mass.) Note the following structures: arytenoid cartilage (a), anterior cervical space (AC), aryepiglottic fold (ae), anterior scalene muscle (asm), brachial plexus (b), carotid artery (c), cricoid cartilage (cc), epiglottis (e), esophagus (es), hyoid bone (h), jugular vein (J), posterior cervical space (PC), preepiglottic fat (pe), paralaryngeal fat (pl), prevertebral space (PVS), pharyngeal mucosal space (small arrows), platysma muscle (large arrow), retropharyngeal space (arrowheads), strap muscle (s), superficial cervical space (SC), sternocleidomastoid muscle (scm), submandibular gland (smg), thyroid cartilage (tc), thyroid gland (tg), trachea (tr), and true vocal cord (tvc).
Normal cross-sectional anatomy of the infrahyoid neck is presented in Figs. 3–36 , 3–37 , 3–38 . The PPS ends at the hyoid bone and does not continue into the infrahyoid neck. The mucosal, carotid, retropharyngeal, prevertebral, and posterior cervical spaces are all continuous superiorly with the suprahyoid neck and extend inferiorly to the thoracic inlet.[45] These spaces are discussed in more detail under the suprahyoid neck section, except for the posterior cervical space, which is described below. Lesions may secondarily invade the structures of the infrahyoid neck from the cranial margin (submandibular, parapharyngeal, carotid, retropharyngeal, and oropharyngeal mucosal spaces), posterior margin (prevertebral space and vertebrae), and inferior margin (mediastinum and chest wall).
Infrahyoid retropharyngeal space
The infrahyoid RPS, a potential space containing a thin layer of fat and no lymph nodes, is bounded by the middle layer of deep cervical fascia anteriorly, the alar fascia of the carotid sheath laterally, and the deep layer of deep cervical


Figure 3-37 Normal axial magnetic resonance anatomy of infrahyoid neck. Noncontrast T1-weighted images obtained at, A, hyoid bone; B, false vocal cord; C, true vocal cord; and D, thyroid gland levels. The following structures are labelled: arytenoid cartilage (a), anterior cervical space (AC), aryepiglottic fold (ae), anterior scalene muscle (asm), branchial plexus (b), carotid artery (c), cricoid cartilage (cc), epiglottis (e), esophagus (es), jugular vein (J), posterior cervical space (PC), preepiglottic fat (pe), paralaryngeal fat (pl), prevertebral space (PVS), pharyngeal mucosal space (small arrows), platysma muscle (arrowheads), retropharyngeal space (large arrow), strap muscle (s), superficial cervical space (SC), sternocleidomastoid muscle (scm), thyroid cartilage (tc), thyroid gland (tg), trachea (tr), and true vocal cord (tvc).
fascia posteriorly.[12] Unlike the suprahyoid RPS, which contains both fat and lymph nodes, the infrahyoid RPS only contains fat. On CT and MRI the normal infrahyoid RPS is an inconsistently demonstrated fat stripe overlying the anterior margin of the longus colli muscles, nestled between the two carotid sheaths.
The infrahyoid RPS may be involved by processes arising from tissues within this space, but more commonly it is affected by external invasion from the adjacent spaces. Lesions within this space have a characteristic “bow-tie” configuration and lie anterior to the longus colli muscles ( Fig. 3–39 ).Lipomas and lymphangiomas are two low-density congenital lesions arising primarily in or secondarily extending into the infrahyoid RPS. Inflammation of this space may arise from pharyngeal mucosal laceration, discitis, or osteomyelitis from the PVS or from infections tracking in through the posterior cervical space. Gas in this space suggests laceration of the pharynx, larynx, or trachea, pneumomediastinum, or the presence of gas-forming organisms ( Fig. 3–40 ). Edema from inflammation in an adjacent space may track into the RPS and occasionally mimic a true fluid collection or abscess. Neoplasms arising in the hypopharyngeal MS, CS,


Figure 3-38 Normal sagittal and coronal magnetic resonance of infrahyoid neck. A, Sagittal T1-weighted image (T1WI) and, B, coronal T1WI obtained through the larynx. Note the following structures: cricoid cartilage (cc), epiglottis (e), false vocal cord (asterisk), pharyngeal mucosal space (small arrows), preepiglottic fat (pe), paralaryngeal fat (pl), retropharyngeal space (arrowheads), strap muscle (s), superficial cervical space (SC), submandibular gland (smg), trachea (tr), and true vocal cord (tvc).

Figure 3-39 Infrahyoid retropharyngeal space and visceral space abscess. A, An axial contrast-enhanced computed tomography at level of false vocal cords demonstrates low-density abscess in retropharyngeal space (arrowheads) creating a “bow-tie” configuration. The abscess extends laterally to the left posterior cervical space and anteriorly into the visceral and anterior cervical spaces. B, Communication between retropharyngeal space and mediastinum is well demonstrated by cephalad extension of this mediastinal abscess (asterisk) posterior to the trachea.


Figure 3-40 Axial non-contrast computed tomography of subcutaneous emphysema highlighting cervical spaces. Gas from a pneumonomediastinum has dissected into anterior cervical space (AC),posterior cervical space (PC), and retropharyngeal space (arrowheads). Note the “bow-tie” pattern of retropharyngeal space. Other labelled structures include hyoid bone (h), sternocleidomastoid muscle (scm), and prevertebral space (PVS).
posterior thyroid gland, and larynx may involve the RPS. Extracapsular spread of internal jugular and spinal accessory metastatic nodes, as well as recurrent visceral space neoplasms, occasionally may invade the RPS. One common pseudomass that indents into this space is a tortuous common or internal carotid artery, usually seen in the middle-aged and elderly populations.
Infrahyoid prevertebral space
The infrahyoid PVS continues superiorly into the suprahyoid PVS and inferiorly to the mediastinum. This space is susceptible to the same pathologic processes as the suprahyoid component, which include inflammatory and infectious processes (arthritis, discitis, osteomyelitis), as well as neoplasms arising in the spinal canal, brachial plexus, paraspinous musculature, or vertebral bodies ( Fig. 3–41 ).
Anterior and posterior cervical (lateral cervical) spaces
The posterior cervical (lateral cervical) space corresponds to the posterior triangle and is a fibrofatty layer containing the internal jugular, spinal accessory, and transverse cervical lymph node chains, as well as the spinal accessory and phrenic nerves. The posterior cervical space is limited by the sternocleidomastoid muscle and investing layer of deep cervical fascia anterolaterally, the carotid sheath anteriorly, and the prevertebral fascia posteromedially. It extends superiorly from the mastoid process and skull base down to the first rib and clavicles inferiorly.[36] Thus a small portion of the posterior cervical space extends into the suprahyoid neck, with the majority occupying the infrahyoid neck.
A transspatial lesion (lymphangioma, plexiform neurofibroma, lipoma, hemangioma) may invade two or more anatomic compartments, without respect for fascial boundaries.[56] Congenital lesions of the posterior cervical space include a second branchial cleft cyst, which tends to lie along the anterior margin of the sternocleidomastoid muscle, and a lymphangioma or cystic hygroma ( Fig. 3–42 ). Both lesions are CSF density on CT, low intensity on T1WI, high intensity on T2WI, and may ring-enhance if secondarily infected. Inflammation may enter this space from cutaneous lesions or from abscessed lymph nodes. Benign neoplasms include neurogenic tumors (plexiform neurofibroma, schwannoma), a lipoma, or a hemangioma. Malignant neoplasms in the posterior cervical space are most commonly metastatic to the spinal accessory or internal jugular lymph nodes, with SCC representing the largest group of both primary and secondary tumors involving this space. Less commonly, sarcomas such as liposarcoma, leiomyosarcoma, or malignant fibrous histiocytoma arise here. Normal structures such as the scalene muscles, poorly opacified vessels on CT, and high-signal, flow-related enhancement in vessels on MRI may be misinterpreted as a pseudomass. Denervation atrophy of the sternocleidomastoid muscle or other neck muscles may occasionally cause an incorrect interpretation of the contralateral (normal-sized) muscles as representing masses.
Hypopharyngeal mucosal space
The hypopharyngeal mucosal space forms the walls of the hypopharynx and includes the continuation of the pharyngeal mucosal space below the hyoid bone posteriorly, the piriform sinuses laterally, the aryepiglottic folds and epiglottis anteriorly, and the cricopharyngeus muscle inferiorly. The hypopharyngeal mucosal space, piriform sinuses, and aryepiglottic folds are frequently challenging to evaluate on CECT and MRI because they are relatively thin membranous spaces that are normally collapsed together when the pharynx is relaxed. A modified Valsalva maneuver is usually required to distend the hypopharynx enough to obtain adequate imaging (see Fig. 3–2 ).
As with the suprahyoid pharyngeal mucosal space, caution must be exercised in assigning abnormality to this space since redundancy of the mucosa and incomplete distension may mimic tumor. Foreign bodies, inflammation, and SCC are the most common lesions in this space. Inflammation may cause ulceration or swelling of the mucosa, with gas or a ring-enhancing fluid collection suggesting the diagnosis; reactive lymph nodes are common. The best indicator of hypopharyngeal malignancy is a bulky mass with invasion and destruction of submucosal and deep structures including the retropharyngeal space, aryepiglottic folds, cricoid cartilage and larynx, as well as associated necrotic lymph nodes ( Fig. 3–43 ).
Visceral space and larynx
The visceral space, corresponding to the muscular triangle, is confined by the middle layer of deep cervical fascia with the anterior fascial layer splitting around the thyroid


Figure 3-41 Prevertebral space (PVS) lesions. A, Axial contrast-enhanced computed tomography (CECT) of prevertebral abscess extending anteriorly from C5-6 discitis. Anterolateral margins of abscess (arrowheads) displace pharyngeal mucosa and posterior cervical spaces anteriorly. A small amount of gas is present in the abscess on the left. B, Axial CECT of bilateral plexiform neurofibromas (N) arising from brachial plexus in PVS shows anterior displacement of fat in the posterior cervical spaces (arrowheads).

Figure 3-42 Posterior cervical space lymphangioma. Contrast-enhanced computed tomography reveals homogeneous, bright, low-density mass with sharp margins displacing posterior cervical space fat (arrow) posterolaterally and internal jugular vein (arrowhead) anteriorly.
gland. The visceral space contains the larynx, trachea, hypopharynx, esophagus, parathyroid glands, thyroid gland, recurrent laryngeal nerve, and tracheoesophageal lymph nodes.[4] The superior margin is the hyoid bone, and the inferior border is the mediastinum. The skeleton of the larynx includes the thyroid, cricoid, arytenoid, cuneiform, and corniculate cartilages. These cartilages may reveal a variable degree of calcification or ossification; these findings progress with age. Ligaments from the stylohyoid and stylothyroid muscles frequently calcify. Knowledge of the normal patterns of calcification is helpful for distinguishing opaque foreign bodies, such as chicken bones, from normal structures on plain films or CT.
The hyoid bone supports the laryngeal skeleton and is occasionally fractured in blunt trauma or destroyed by neoplasms. Fractures of the laryngeal skeleton appear on CT as linear lucencies, often with displacement or distortion of the cartilage. A fracture is best appreciated (on bone windows) in well-ossified cartilage, but its identification is more challenging in noncalcified cartilage requiring the use of


Figure 3-43 Piriform sinus squamous cell carcinomas. Axial contrast-enhanced computed tomography shows mildly enhancing mass in the right piriform sinus (asterisk) displacing aryepiglottic fold anteromedially. Focal defects in the internal jugular and spinal accessory nodes (arrowheads) indicate metastatic tumor spread; calcification is noted in the internal jugular node.

Figure 3-44 Laryngeal trauma. Axial non-contrast computed tomography at the level of cricothyroid articulation shows laterally displaced cricoid ring (arrowheads) fracture and subglottic hematoma obstructing the airway.
a narrower window width and careful scrutiny of cartilage configuration. Laryngeal trauma may result in hematomas of the aryepiglottic folds, false cords, true cords, or subglottis and may potentially compromise the airway ( Fig. 3–44 ). Adjacent subcutaneous emphysema may result from trauma to the laryngopharyngeal mucosa, from a penetrating injury to the neck, or from upward dissection from the chest wall or mediastinum.
Laryngoceles are formed by increased intraglottic pressure (e.g., horn players, glass blowers) or from obstruction of the laryngeal ventricle and its distal appendix by inflammatory or neoplastic lesions ( Fig. 3–45 ). An internal laryngocele tracks superiorly within the paralaryngeal (paraglottic) fat, is air- or ffluid-filled (obstructed laryngocele), and causes variable compromise of the supraglottic larynx. A mixed (external) laryngocele extends further superolaterally, piercing the thyrohyoid membrane, and may present as a neck mass. A mucocele (mucous retention cyst) of the supraglottic laryngeal mucosa may be indistinguishable from an obstructed internal laryngocele. Inflammation of the supraglottic larynx may lead to epiglottitis, thickening the epiglottis and aryepiglottic folds, and compromising the airway ( Fig. 3–46 ).
Apart from routine evaluation of adenopathy from suprahyoid neck and sinus tumors, laryngeal and hypopharyngeal SCC is the most common indication for imaging the infrahyoid neck. Because both CECT and MRI are relatively insensitive to superficial mucosal-based lesions, knowledge of the physical examination findings and specific locations of concern is mandatory to facilitate lesion localization and characterization. Findings that help identify SCC of the superficial mucosa of the larynx or pharynx are a mass, mucosal irregularity or asymmetry, and ulceration. Fat planes in the laryngopharynx are critical for determining the extent of deep invasion or inflammation. The fat in the preepiglottic space, epiglottis, and aryepiglottic folds and paralaryngeal fat of the supraglottic larynx are major landmarks that are easily identified on axial CT and MRI. Coronal T1WIs are particularly useful for evaluating the configuration of the airway and for determining the craniocaudal margins of a supraglottic, glottic, infraglottic, or transglottic lesion because the vertically oriented paralaryngeal fat plane terminates inferiorly at the true vocal cords (thyroarytenoid muscle). A lesion becomes transglottic when the fat interface between the thyroarytenoid muscle (true vocal cord) and the paralaryngeal fat (false vocal cord) is eliminated, indicating the tumor has crossed the laryngeal ventricle ( Fig. 3–47 , A ). The anterior commissure should be less than 1-mm thick; greater thickness in this area represents tumor spread from the anterior margin of one cord to another. A diagnosis of vocal cord fixation may be made when the involved cord remains paramedian during quiet breathing or with a modified Valsalva maneuver ( Fig. 3–47 , B ).
Cartilage invasion or destruction by aggressive infections or tumors is an important part of staging and is often difficult to predict on CECT or MRI when the cartilage is incompletely calcified. If the cartilage has ossified, CECT and MRI are relatively sensitive for detecting cartilage erosion. MRI using a combination of T1WI, T2WI, and postgadolinium fat saturation T1WI may be more sensitive than CECT to invasion of the central layer of the thyroid cartilage, especially if the cartilage has ossified and the central fatty marrow has been locally replaced by invading tumor. The best indicator of cartilage invasion is the presence of tumor on the external margin of the cartilage in the strap muscles ( Fig. 3–48 ).
Thyroid gland.
The thyroid gland lies within the anterior leaves of the middle layer of deep cervical fascia (within the visceral space) anterior and lateral to the thyroid, cricoid, and upper tracheal cartilages. It consists of the lateral thyroid lobes, isthmus, and pyramidal lobe. Normal iodine content of the thyroid gland makes it higher density than


Figure 3-45 Laryngocele. A, Axial contrast-enhanced computed tomography (CECT) at the level of thyrohyoid membrane demonstrates air-filled internal laryngocele (L) displacing preepiglottic fat and aryepiglottic fold. Note that it is separated from piriform sinus by aryepiglottic fold. B, Axial CECT at the true cord level reveals the cause of laryngocele—an obstructing transglottic carcinoma (m).

Figure 3-46 Epiglottitis. Lateral plain film of the neck demonstrates swollen epiglottis (arrowheads) and aryepiglottic folds. The lower portion of stylohyoid ligament (arrow) has ossified bilaterally.
muscle on NCCT. The gland is normally homogeneous with enhancement on both CECT and MRI, but internal inhomogeneity from calcification, goiter, colloid cyst, or a solid mass is occasionally encountered on routine neck imaging. When physical examination, ultrasound, or thyroid scintigraphy raises the suspicion of a thyroid carcinoma or thyroid lymphoma, CECT or MRI may be used for further characterization, especially if it is a low thoracic inlet thyroid or parathyroid mass.
Absence of the thyroid gland at the level of the thyroid cartilage should redirect attention to the tongue for an ectopic lingual thyroid gland ( Fig. 3–49 ). A thyroglossal duct cyst is a remnant of the embryonic thyroglossal duct and may occur anywhere along its migratory path from the foramen cecum in the tongue to the pyramidal lobe, although most occur just inferior to the hyoid bone ( Fig. 3–50 ). Inflammatory thyroiditis may enlarge the thyroid gland. Benign enlargement may also result from colloid cysts and goiters. Thyroid calcification is nonspecific and occurs in goiters as well as in benign thyroid adenomas. Primary malignancies of the thyroid include papillary, follicular, mixed, and anaplastic carcinomas, as well as non-Hodgkin’s lymphoma, all of which may have a similar imaging appearance ( Fig. 3–51 ). Indistinct margins of a thyroid mass, infiltration of adjacent tissues, and necrotic lymph nodes are all indications of thyroid malignancy. Metastasis to the thyroid gland more commonly arises from extracapsular spread of SCC in adjacent nodes than from hematogenous deposits.
Parathyroid glands.
The parathyroid glands are usually four to six in number and underlie the posterior surface of the thyroid gland. Because they are quite small, normal parathyroid glands are frequently not visualized on routine neck imaging. An ectopic parathyroid gland may occur in the mediastinum ( Fig. 3–52 ). A parathyroid adenoma is usually a discrete mass lying deep to the thyroid lobes. Occasionally, an adenoma may be detected on routine CT or MRI as a nodular, enhancing mass that may be differentiated from lymph nodes by its location posterior to the thyroid gland.
Lymph node anatomy and classification
The nodes of the superficial triangles of the neck are organized by major lymphatic chains. The traditional classification of lymph nodes of the head and neck includes 10 groups: lateral cervical, anterior cervical, submandibular, submental, sublingual, parotid, facial, mastoid, and occipital. The lateral cervical chains are further subdivided into the deep and superficial chains. The deep lateral cervical chain includes the internal jugular, spinal accessory, and transverse cervical (supraclavicular) nodes; the superficial lateral cervical chain consists of the external jugular nodes. The anterior


Figure 3-47 Transglottic laryngeal squamous cell carcinoma with vocal cord fixation. A, True vocal cords are adducted on axial contrast-enhanced computed tomography (CECT) obtained during breath holding, with tumor extending anteriorly and superiorly from the left true cord into adjacent paralaryngeal fat (arrow) and posteriorly into cricoarytenoid joint (arrowheads). Anterior corner of calcified left arytenoid cartilage (asterisk) has been eroded by the tumor. B, Repeat axial CECT, performed during quiet breathing, reveals fixation of the left true cord in midline; right cord is partially abducted.

Figure 3-48 Transglottic squamous cell carcinoma with cartilage invasion. Axial CECT at the true vocal cord level shows enhancing mass (m) originating in the left vocal cord, crossing anterior commissure, and invading anterior third of the right cord. The tumor has invaded through anterior thyroid cartilage and displaces thyroid strap muscles anteriorly (arrowheads).
cervical (juxtavisceral) group contains the prelaryngeal (Delphian), pretracheal, prethyroid, and lateral tracheal (tracheoesophageal or paratracheal) nodes.[46] The cervical lymph node chains are found throughout several of the spaces of the neck:

Posterior cervical space: spinal accessory, transverse cervical, and internal jugular (posterior to the internal jugular vein) nodes

Carotid space: internal jugular nodes (anterior to the internal jugular vein posterior margin)

Submandibular space: submandibular and submental nodes

Parotid space: parotid nodes

Suprahyoid retropharyngeal space: medial and lateral retropharyngeal nodes

Visceral space: prelaryngeal, prethyroid, pretracheal, and tracheoesophageal nodes

Subcutaneous tissues of the scalp and face: occipital, mastoid, and facial nodes
A condensation of this nomenclature into seven groups with Roman numerals (levels I to VII) has been proposed and is a useful shorthand for node documentation and statistical analysis. Because this latter classification is not standard at all institutions, to prevent confusion its use should be agreed to by the head and neck surgeons, radiation therapists, oncologists, and radiologists. Level I combines the submandibular and submental lymph nodes. Levels II to IV divide the internal jugular chain roughly into thirds, using landmarks that are easily recognizable on cross-sectional imaging. Level II is the jugular-digastric group of internal jugular nodes from the skull base down to the hyoid bone (approximately the level of the common carotid bifurcation). Level III is the supraomohyoid internal jugular chain from the hyoid bone to the cricoid cartilage (approximately the level of the omohyoid muscle). Level IV includes the infraomohyoid internal jugular nodes from the cricoid to the clavicles. Level V combines the spinal accessory and transverse cervical (supraclavicular)


Figure 3-49 Lingual thyroid gland. A, Densely enhancing mass of ectopic thyroid tissue (T) bulges posteriorly from tongue at level of the foramen cecum on axial contrast-enhanced computed tomography. B, CECT at upper tracheal level reveals thyroid gland is absent from its normal location. Note pseudotumor of thrombosed internal jugular vein (J) mimicking ring-enhancing node metastasis.

Figure 3-50 Thyroglossal duct cyst. Low-density thyroglossal duct cyst (c) elevates thyroid strap muscles (asterisk) and laterally displaces sternocleidomastoid muscle in this axial contrast-enhanced computed tomography.
nodes from the skull base to the clavicles. Separation of internal jugular nodes from the spinal accessory nodes on cross-sectional imaging may be difficult, especially in the suprahyoid neck, because these two chains converge at the skull base. A somewhat arbitrary distinction between these chains is made using the posterior margin of the internal jugular vein as the dividing line on axial imaging; any nodes anterior to this line are defined as internal jugular nodes, and those posterior to this margin are called spinal accessory nodes. Level VI contains the prethyroid nodes. Level VII

Figure 3-51 Thyroid follicular carcinoma. Axial contrast-enhanced computed tomography just below cricoid shows large mass with nodular calcification (asterisk) displacing trachea to the right and distorting the airway; posteriorly it has invaded retropharyngeal space (arrow).
consists of the tracheoesophageal nodes. The retropharyngeal nodes are not included in this classification and are mentioned separately.
Lymph nodes: normal and pathologic
CECT remains the gold standard for detecting and classifying cervical lymphadenopathy as benign or malignant. The important considerations in radiographic lymph node detection and characterization are location, size, number, clustering,


Figure 3-52 Parathyroid adenoma. Retrotracheal ectopic parathyroid adenoma (arrowhead) looks similar to adjacent normal esophagus (arrow) on axial T1-weighted image.
enhancement pattern, calcification, sharpness of margins, and invasion or displacement of adjacent structures. First the nodes must be detected and localized to a specific nodal chain or level using one of the conventions for labeling node regions discussed previously. Node involvement is described as unilateral or bilateral and in terms of the specific level(s) or chain(s) affected.
Inflammatory (reactive) lymph nodes on CECT tend to be less than 10 mm (rarely larger than 20 mm), have central hilar or mild homogeneous enhancement, and have well-defined margins ( Fig. 3–53 ). Node margins should remain sharp in reactive adenopathy, except in cases with large abscessed nodes that elicit an inflammatory reaction in the adjacent fat, obscuring the node margins ( Fig. 3–54 ). Calcification is a common finding in previously infected or healed nodes and frequently occurs in tuberculosis or bacterial infections. Multiple nodes may be present, but they tend not to cluster. On MRI these reactive nodes are enlarged and have well-defined margins on all sequences. They are muscle intensity on T1WI, enhance moderately and homogeneously on postgadolinium fat-suppressed T1WI, and are bright on T2WI and STIR.
The correlation of lymph node size with sensitivity and specificity in predicting malignant metastasis has been performed for different neck regions in patients with head and neck carcinoma, allowing more appropriate size criteria for distinguishing normal from abnormal lymph nodes.[46] Although CT can readily detect lymph node enlargement, it has also proven capable of accurately diagnosing metastases in “normal size” nodes from head and neck primary SCC.The upper range of normal for cervical lymph node size is between 5 and 10 mm, with the jugular digastric node ranging up to 15 mm. The exceptions are the submandibular and submental nodes, which are usually abnormal if larger than 5 mm, and the retropharyngeal nodes when greater than 10 mm in children or greater than 5 mm in adults. Generally, cervical nodes larger than 10 to 15 mm are potentially malignant and nodes smaller than this are considered reactive or inflammatory. Nodes larger than 20 mm are frequently malignant because the average size of a clinically positive metastatic node is 21 mm by physical examination and 20 mm by CT. Clinically occult neck disease occurs in 15% to 40% of patients with head and neck SCC; clinically occult nodes average 12 mm ( Fig. 3–55 ). Studies comparing clinical and CT staging of nodal metastases have shown that physical examination of the neck has an accuracy of 70% to 82% compared with 87% to 93% for CT. In patients with no nodal disease on examination, CT is likely to upstage an N0 neck to N1 in 20% to 46% and upstage clinical staging of the neck between 5% and 67% overall. CT may downstage the clinical neck examination in 3% to 36% of cases.[8] [31]
The enhancement pattern on CT is very helpful, but not infallible, in distinguishing inflammatory nodes from metastatic nodes. Node detection is improved by performing CECT with a constant infusion technique. The presence of a focal defect (central low density) or peripheral enhancement is characteristic of malignancy even in normal-sized nodes less than 15 mm. A focal defect in an enlarged node is a strong indication of a necrotic node metastasis, although tuberculosis or an abscessed node may mimic this appearance. Central dense or linear enhancement of the hilum of an enlarged node without ring enhancement is usually a distinguishing sign of a reactive node. Nodes larger than 20 to 40 mm without central necrosis often indicate lymphoma or sarcoidosis ( Fig. 3–56 ). Treated lymphomatous nodes may have dystrophic calcification, and rarely, calcium matrix-forming tumors (osteosarcoma, chondrosarcoma) may have radiodense metastases. When margins of an enlarged node with central necrosis are indistinct, extracapsular penetration of the tumor through the node capsule has likely occurred ( Fig. 3–57 ). This sign may decrease the 5-year survival by 50%. The number of nodes involved is important; multiple nodes suggest a more widespread inflammatory or neoplastic process. Clustering of multiple nodes, sometimes into a seemingly single, complex mass, suggests malignancy and may be palpable as a single large mass. Round rather than bean-shaped nodes, clusters of nodes, and indistinct margins suggest malignancy but are less specific than size greater than 15 mm, ring enhancement, or focal defect.
MRI of malignant adenopathy has both advantages and limitations compared with CECT. Malignant nodes appear as muscle intensity on T1WI, may show ring enhancement on postgadolinium fat-suppressed T1WI, are very bright on STIR, and are usually bright on T2WI (although necrosis may give both high and low signal on long TR sequences) ( Fig. 3–58 ). Fat-suppressed long TR sequences will diminish background fat signal, further improving detection. The STIR image is superior to CECT in sensitivity for any enlarged lymph node but is nonspecific for metastases. MRI


Figure 3-53 Normal lymph node anatomy. A, In this 8-year-old child, normal lateral retropharyngeal nodes (arrows) lie medial to internal carotid arteries (c) and demonstrate moderately high signal on T2-weighted images. High-signal adenoidal tissue is commonly prominent at this age. B, Multiple mildly enlarged nodes (asterisks) are present in submandibular, anterior jugular, internal jugular, and spinal accessory lymphatic chains on this contrast-enhanced computed tomography. Note eccentric fatty hilum (arrows) in two nodes, a potential pitfall in diagnosis of focal defect in metastatic node.

Figure 3-54 Reactive and inflammatory lymph nodes on contrast-enhanced computed tomography (CECT) and magnetic resonance imaging. A, Axial CECT of hyperplastic nodes in a patient with acquired immunodeficiency syndrome-related complex displays multiple submental nodes (arrowheads) and enlarged internal jugular node with central hilar enhancement (arrow). B, Small, normal, or reactive lymph nodes (arrows) enhance on this fat saturation postgadolinium T1-weighted image. C, Axial CECT of tuberculous nodal mass (scrofula) with peripheral enhancement and invasion of sternocleidomastoid muscle (arrowhead) is difficult to distinguish from the cluster of metastatic nodes.


Figure 3-55 Metastatic node on contrast-enhanced computed tomography (CECT). Axial CECT in a patient with left piriform sinus squamous cell carcinoma (m) and “normal-sized” 9-mm node (arrow) with focal defect (ring enhancement with “necrotic” center) diagnostic of metastasis.

Figure 3-56 Node involvement by non-Hodgkin’s lymphoma. Axial contrast-enhanced computed tomography shows very large, homogeneous spinal accessory node (asterisk) invading both skin and prevertebral space paraspinous musculature. The absence of central necrosis or focal defects in a mass this large is suggestive but not diagnostic of lymphoma.
and CECT rely on the same criteria of size, clustering, margin sharpness, and shape for characterization of abnormal nodes. The specificity of ring enhancement on CECT is the main advantage of CT for diagnosis of metastases. The same finding of ring enhancement on postgadolinium fat-suppressed T1WI likely represents focal tumor or central necrosis as well. Otherwise, the other MRI sequences described above are nonspecific. MRI may better demonstrate invasion of adjacent structures, especially muscles, than does CECT.

Figure 3-57 Extracapsular spread in multiple nodes in a patient with tonsillar squamous cell carcinoma (SCC). Left submandibular and spinal accessory node metastases (arrows) have typical ring enhancement and central low density on axial contrast-enhanced computed tomography. The large cluster of metastatic nodes (asterisk) in left internal jugular chain shows central low-density focal defects. Note poorly defined infiltrative margins of this mass of nodes characteristic of extracapsular tumor spread; tumor is invading sternocleidomastoid muscle (arrowheads) posterolaterally and prevertebral space medially. About 40% of the left internal carotid artery (c) circumference is surrounded by tumor, which may still allow surgical preservation of the carotid artery.
With extracapsular spread, adjacent fat, bone, cartilage, and muscle are commonly compressed or invaded. Secondary invasion of adjacent structures and anatomic spaces by aggressive lymph node lesions may develop in the carotid sheath structures, skull base, PVS and vertebrae, and mandible. The superficial nodes may invade adjacent muscle and skin. Internal jugular and spinal accessory nodes may invade the carotid, parapharyngeal fat, prevertebral, and infrahyoid visceral spaces. Parotid nodes may violate the surrounding parotid parenchyma, skin, masticator space, and parapharyngeal space. Suprahyoid retropharyngeal nodes may extend laterally into the CS, posteriorly into the PVS, anteriorly into the mucosal space, and superiorly into the skull base. The tracheoesophageal nodes may involve the common carotid artery and the internal jugular vein in the CS, the recurrent laryngeal nerve, the visceral space structures of the larynx and thyroid, and the mediastinum.
Invasion of the carotid artery carries a poor prognosis with local recurrence rate of 46% and a distant metastatic rate of 56% to 68%. For patients with tumor involving the carotid artery, the 5-year survival rate decreases to 7%, and the mean survival decreases to less than 1 year. Prolonged survival is possible if the involved carotid artery is resected.


Figure 3-58 Metastatic nodes and focal defects on magnetic resonance imaging. A, Axial T2-weighted image at soft palate level depicts high-signal intensity right tonsillar squamous cell carcinoma (SCC) (asterisk). A 10-mm metastatic lateral retropharyngeal node of Rouvier with a high-signal intensity central defect (arrow) lies medial to internal carotid artery (c). B, Left jugular digastric node (arrowheads) with low-signal intensity focal defect (arrow) on gadolinium-enhanced T1-weighted image is analogous to focal defect seen with metastases on contrast-enhanced computed tomography. C, Axial short T1 inversion recovery (STIR) image achieves excellent fat suppression of subcutaneous fat (f). Metastatic neuroblastoma is demonstrated in bright internal jugular and spinal accessory nodes (arrows). Note bright appearance of normal tonsillar and parotid gland tissues on STIR.
Detection of carotid artery invasion by MRI may be more accurate than ultrasound. The best imaging modality among CECT, MRI, or ultrasound for evaluating carotid fixation remains controversial.[30] Surprisingly, criteria for carotid invasion are not well established in the literature. CT and MRI criteria, based on the work of Picus in aortic invasion by esophageal carcinoma, include effacement of the fascial plane surrounding greater than 25% of the vessel circumference.[38] More recent criteria suggest a very high likelihood of fixation exists if tumor involves three fourths or more of the circumference of the carotid and if nodal extracapsular penetration has occurred (see Fig. 3–57 ). Ultrasonography is a potentially valuable adjunctive technique capable of demonstrating invasion of the common and internal carotid artery, as well as the internal jugular vein.
Nose and paranasal sinuses
The sinonasal region can be divided into three major regions: the sinuses, the ostiomeatal complex, and the nasal cavity. The paranasal sinuses are mucosal-lined, air-filled cavities that are named after the bones of the face in which they develop. This mucosa is prone to both inflammatory and neoplastic disease. The frontal, maxillary, ethmoid, and sphenoid sinuses all drain through ostia into the nasal cavity. The frontal, maxillary, anterior ethmoid, and middle ethmoid sinuses drain into the semilunar hiatus under the middle turbinate. This area represents the ostiomeatal complex or unit; a small lesion here can cause obstruction to multiple sinus ostia. The posterior ethmoids and sphenoid sinus drain under the superior turbinate or sphenoethmoidal recess. The nasal cavity extends from the nares anteriorly to the choana posteriorly and from the hard palate inferiorly to the cribriform plate superiorly. The midline nasal septum, lateral turbinates, and maxillary and ethmoid sinuses form the walls.
The compartments adjacent to the sinuses that are at risk for invasion by aggressive inflammatory or neoplastic processes include the anterior cranial fossa, orbits, cavernous sinus (from the sphenoid sinus), MS, pterygopalatine (pterygomaxillary) fossa, oral cavity, and anterior soft tissues of the face. These compartments are carefully viewed for dural or brain invasion, optic nerve and extraocular muscle compromise, perineural spread into the skull base, or direct extension into the deep compartments of the suprahyoid neck and oral structures. Involvement of any one of these secondary compartments can significantly alter treatment planning and surgical approach.
Paranasal sinuses
Congenital and developmental anomalies of the sinonasal cavities are sought on all CT examinations. Common anatomic variants include pneumatization or paradoxical curvature of the turbinates, deviated septum, sinus hypoplasia, and Haller air cells ( Fig. 3–59 ). Sinus underdevelopment may range from aplasia to hypoplasia. Pneumatization implies sinus development has occurred; aeration indicates that the pneumatized portion of the sinus is air-filled. Mucosal thickening or opacification signifies the pneumatized section is


Figure 3-59 Normal ostiomeatal complex. Coronal non-contrast computed tomography demonstrates ostiomeatal complex to the best advantage. Normal mucociliary drainage is from maxillary sinus up through infundibulum (i) and maxillary sinus ostium into middle meatus (m). Ethmoid bulla (e) and uncinate process (u) form lateral and medial walls of infundibulum, respectively. Normal anatomic variant of a Haller air cell (H) underlying orbit causes mild narrowing of the left infundibulum; smaller Haller cell is present on the right. Note mildly asymmetric mucosa of turbinates (t), which is part of normal nasal cycle.
filled with soft-tissue inflammation or fluid. Either hypoplasia or the reactive new bone formation (chronic inflammation) may cause thickening and sclerosis of the sinus walls.
In general, evaluation of the paranasal sinuses involves assessment of two components: (1) the sinus contents (including the mucosa) and (2) the bony walls. Normal sinus mucosa is very thin and not seen on CT or MRI, and the bone is normally thin and delicate in the posterior maxillary, ethmoid, and sphenoid sinuses. CT or MRI readily reveals the presence of a normally aerated sinus, mucosal thickening (chronic sinusitis, retention cysts, or polyps), an air-fluid level (acute sinusitis, intubation, and trauma), or complete opacification (mucocele, trauma, and acute or chronic sinusitis) ( Fig. 3–60 ). The normally delicate posterolateral maxillary sinus wall is a much better indicator of bony sclerosis than the anterior wall; the normally thick anterior wall of the maxillary (and frontal) sinus may range from 1 to 3 mm (see Fig. 3–11 A , C ). Beginning observers frequently forget to assess the bone for important clues such as thickening and sclerosis (chronic sinusitis or hypoplasia), fractures, remodeling (slowly expanding mucocele or neoplasm), or destruction (malignancy or aggressive infection such as mucormycosis).
Deciding which portion of the opacified sinus, sinuses, or nasal cavity contains tumor and which contains obstructed mucous secretions is clinically important with a sinus or

Figure 3-60 Acute and chronic sinusitis. Postgadolinium fat saturation T1-weighted image demonstrates air-fluid level (arrow) in right maxillary sinus and is diagnostic of acute sinusitis (superimposed on chronic sinusitis). Left maxillary sinus is filled with low-intensity secretions and has a peripheral ring of enhancing inflamed mucosa (arrowheads) typical of chronic sinusitis. Mastoid air cells and left middle ear cavity (asterisk), which normally appear black, are filled with enhancing inflammatory tissue.
nasal tumor. The question is more problematic with NCCT or CECT because tumor and sinus secretions are frequently similar in density, and both the tumor and the mucosa may enhance; however, MRI is usually much more informative ( Fig. 3–61 ). Evaluation of this problem requires a knowledge of signal intensity patterns of tumor versus mucus. Sinonasal tumors tend to be low-to-intermediate signal intensity on T1WI and intermediate signal intensity on T2WI, although minor salivary tumors and adenoid cystic carcinoma may be of high signal intensity.[42] The highly cellular aggressive neoplasms tend to have a lower water content and are less bright on T2WI. Tumors enhance moderately and, more or less, uniformly with gadolinium. Sinus secretions are complex in their patterns. Hydrated, nonviscous mucus is low intensity on T1WI and high intensity on T2WI. Desiccated, viscous mucus tends to be high intensity on T1WI and low-to-intermediate intensity on T2WI. Extremely desiccated mucus may lack signal intensity on T1WI or T2WI, simulating bone or air. Both an obstructed sinus and an expansile mucocele frequently have two or more layers of mucus in a concentric ring pattern with the most desiccated, viscous secretions located centrally. The peripheral mucosa of an obstructed sinus enhances in chronic sinusitis or with a pyomucocele but does not enhance with a simple mucocele. The presence of tumor versus obstructed secretion is best solved by comparing the respective change in signal intensity of


Figure 3-61 Comparison of computed tomography and magnetic resonance imaging for separating sinonasal small cell tumor from sphenoid pyomucocele. A, Axial contrast-enhanced computed tomography shows a mildly enhancing mass (asterisk) in the left posterior nasal cavity and ethmoids, which appears to extend into the sphenoid sinus. Sphenoid sinus contents actually represent two different viscosities of mucus, with higher density mucus anteriorly (arrowhead) correlating with most desiccated or viscous mucus. B, Axial noncontrast T1-weighted image demonstrates intermediate-signal nasal tumor. Anterior, high-signal, viscous mucus (arrowhead) in the sphenoid sinus is clearly discriminated from nasal tumor anteriorly and from low-signal hydrated mucus (arrow) posteriorly. C, On axial noncontrast T2-weighted image, nasal tumor signal is intermediate, similar to the brain. Anterior viscous mucus (arrowhead) in sphenoid sinus has reversed signal to become low intensity, whereas hydrated mucus (arrow) posteriorly has now become very bright.
each component on the T1WI, T2WI, and postgadolinium T1WI and is rarely answered by a single sequence; a minimum of a T1WI and a T2WI is required.
Ostiomeatal complex
The ostiomeatal complex has become an area of active radiologic and pathophysiologic investigation with the development of endoscopic sinus surgery for inflammatory sinus disease. Coronal thin section NCCT is the best means of demonstrating the anatomy of this area (see Fig. 3–59 ). Pertinent observations include (1) the individual’s sinonasal anatomy and the presence of any anatomic variants (hypoplastic maxillary sinus, concha bullosa, agger nasi air cells, Haller air cells, deviated septum, deviated uncinate process, prominent ethmoid bulla, paradoxical curvature of the middle turbinate), (2) the location of obstructed air cells, (3) the extent of the chronic or acute sinus disease and whether this pattern is consistent with obstruction of the ostiomeatal complex, and (4) the presence of any prior surgical alterations (Caldwell-Luc, internal or external ethmoidectomy, uncinatectomy, etc.). Ostiomeatal complex obstruction may result from anatomic compression, mucosal inflammation, polyps, benign neoplasms, and SCCA. Mucoceles, indicated by sinus expansion and low-density mucus on CECT or by concentric rings of variably desiccated mucus in an expanded sinus on MRI, are a complication of chronic sinus obstruction ( Fig. 3–62 ). A mucocele only shows peripheral enhancement when it is infected and is then called a pyomucocele.
Nasal cavity
The nasal cavity is occasionally the site of symptomatic disease. Anatomic variants include choanal atresia, concha bullosa, paradoxical curvature of the middle turbinate, wide nasal cavity from a hypoplastic maxillary sinus, and septal deviation. The nasal mucosa of the turbinates may be asymmetric in thickness because of the normal nasal cycle or the presence of polyps or inflammation. Obstruction of the ostiomeatal complex and other sinuses may occur with benign


Figure 3-62 Simple mucocele on magnetic resonance imaging. A, Frontal mucocele on axial T1-weighted image expands right frontal sinus and has very high-signal central viscous or desiccated component (arrowheads) and lower-intensity peripheral concentric ring of less viscous mucus (arrow). B, Axial T2-weighted image reversal of signal intensities in concentric rings, with peripheral hydrated mucus (arrow) becoming bright and central viscous mucus (arrowheads) losing signal.

Figure 3-63 Invasive small cell carcinoma of cribriform plate and orbits. A, Coronal contrast-enhanced computed tomography shows mass centered in posterior ethmoid sinuses with bone destruction of cribriform plate (arrow) and medial orbits to better advantage than magnetic resonance imaging. The tumor has invaded both orbits and maxillary sinuses (arrowheads). B, Anterior cranial fossa extension (arrow) through the cribriform plate and orbital invasion (arrowheads) are well seen on coronal fat saturation postgadolinium T1-weighted image. C, Sagittal fat saturation postgadolinium T1WI depicts anterior-posterior dimension of tumor and extension of enhancing tumor (arrow) through low-intensity cribriform plate and planum sphenoidale (arrowheads).
(antrochoanal polyp, neural tumors, inverting papilloma) or malignant (SCC, adenocarcinoma, adenoid cystic carcinoma) tumors ( Fig. 3–63 ). If a nasal mass is present, the extent of the mass within the nasal cavity, adjacent sinuses, or orbits or involvement of the cribriform plate may be determined by coronal CECT or sagittal and coronal MRI because this may affect the surgical approach and postoperative therapy.
Facial trauma
Facial trauma is briefly included here because of the intimate relationship of the facial bones and sinuses. Thin-section axial and direct coronal NCCT is the ideal method for determining the full extent of facial trauma. One strategy for evaluating the extent of sinus trauma is to visually trace each bony outline on consecutive slices in both imaging planes, looking


Figure 3-64 Medial and lateral orbital blowout fractures. A, Coronal noncontrast computed tomography (NCCT) with soft-tissue windows shows orbital blowout fracture with displacement of floor (arrow), distortion of inferior rectus, and herniation of orbital fat through orbital floor defect. Both intraconal hemorrhage and high-density maxillary sinus hemorrhagic air-fluid level are well demonstrated on these windows. Medial orbital blowout fracture (arrowhead) is suspected as well. B, Axial NCCT using bone windows shows opacified left anterior ethmoid air cells that help direct the observer to the displaced medial orbital fracture (arrowheads).

Figure 3-65 Facial fractures. A, Bilateral Le Fort type II fractures of maxillary sinus anterior and posterior walls (arrows) and pterygoid plates (arrowheads) appear as discontinuities or lucencies of the bone on this 3-mm axial noncontrast computed tomography (NCCT). Indirect signs of facial fracture are opacified maxillary sinuses, gas (g) in right buccal fat pad, and premalar facial swelling. B, Coronal NCCT clearly demonstrates bilateral pterygoid plate fractures (arrowheads).
for fractures, normal fissures and canals, and displacements. However, the quickest way to locate sinus fractures is to search for indirect signs of fracture ( Fig. 3–64 ): an air-fluid level, complete opacification of a sinus with blood, and the presence of gas outside the sinus (pneumocephalus, subcutaneous emphysema, infratemporal fossa, or orbital gas). Identification of the fractures allows determination of fracture classification: nasal, orbital blowout, trimalar or tripod, Le Fort (I, II, III, and complex), or nasoethmoid complex fracture ( Fig. 3–65 ). Assessment is made of the extent of soft-tissue trauma, particularly the orbital soft tissues of the lens, globe, extraocular muscles, and optic nerve. Displaced orbital floor fractures may entrap fat or the extraocular muscles and result in enophthalmos or dysfunction of ocular motility.
Skull base
Anatomically, the skull base can be divided into the anterior, middle, and posterior fossae. The lesser and greater wings of the sphenoid bone divide the anterior fossa from the middle fossa while the petrous pyramid and mastoid portions of the temporal bone divide the middle and posterior fossae. The parietal and occipital lobes of the brain do not directly contact the skull base.
The skull base is formed from five bones: frontal, ethmoid,

temporal, sphenoid, and occipital; the frontal and temporal bones are paired. Each of these bones can be subdivided into component bones; for example, the occipital bone has basioccipital, condylar, and squamosal portions. The skull base has its longest diameter in the AP plane, extending from the region of the crista galli to the posterior margin of the foramen magnum posteriorly. It is the thinnest in its superior-inferior direction, ranging between 3 and 5 mm in most areas with the exception of the much thicker petrous temporal bone.
With CT the skull base may be imaged using the axial or the coronal plane (only a modified coronal plane is possible because of limited gantry tilt). The coronal plane is excellent for delineating the superior inferior extent of a lesion. CT gives excellent visualization of bone detail, especially when bone algorithm techniques are used. In addition to the axial plane, MRI allows imaging both in a true coronal plane and in the sagittal plane, the latter especially useful for the study of midline lesions (e.g., chordoma). MRI also yields improved lesion contrast and conspicuity and more accurate delineation of lesion extent.
Using an anatomic approach skull base lesions may be classified as anterior, middle, or posterior fossa and a unique differential then developed for the medial and lateral portions of each fossa. Lesions may also be categorized as primary, those arising within the skull base itself and secondary, those extending down from the cranial cavity above (endocranial lesions) or growing up from below (exocranial lesions). Endocranial masses are extracerebral and intracerebral lesions, whereas the exocranial lesions are secondary to extension superiorly from a disease process of the orbit, suprahyoid head and neck, cervical spine, and prevertebral muscles.
The skull base contains multiple foramina that allow the exit of cranial nerves and inflow and outflow of arteries and veins. These foramina also provide an access route for disease processes to spread from the cranial cavity to the infracalvarial structures and vice versa.[5] MRI performed after gadolinium infusion and with the use of fat suppression techniques allows sensitive detection of perineural spread, most readily seen with involvement of the fifth and seventh cranial nerves.[29]
Skull base fractures are readily detected with CT using thin slice sections and re-formation techniques. Sinus air-fluid levels, sinus opacification, and clouding of the temporal bones may herald the presence of a fracture. Similarly, sinus opacification and fracture location may indicate the site of a CSF leak.
Inflammatory skull base lesions are now less common. Osteitis is seen as sclerosis of bone margins. Osteomyelitis usually involves all three skull tables and is characterized by irregular serpiginous lytic areas, occasionally with areas of bone sequestration present.
The osseous changes of neoplastic disease may be erosive, infiltrative, expansive, lytic, sclerotic, or of mixed density. Primary skull neoplastic lesions are uncommon; benign conditions include osteoma, chondroma, giant cell tumor,cholesterol granuloma, and aneurysmal bone cyst ( Fig. 3–66 ). Osteosarcoma, chondrosarcoma, fibrosarcoma, and rarely Ewing’s sarcoma and lymphoma are examples of malignant lesions. Metastatic lesions are more common than primary skull base lesions and frequently have an associated soft-tissue component ( Fig. 3–67 ). Osteoblastic metastases are most commonly caused by carcinoma of the prostate or breast; sclerotic changes may be seen occasionally in lymphoma ( Fig. 3–68 ). Lytic lesions are more common than osteoblastic findings and are usually secondary to carcinoma of the lung, breast, kidney, or colon.
Intracerebral neoplastic processes may have associated osseous changes. Cerebral gliomas rarely cause local bone erosion or expansion; however, optic gliomas may cause expansion of the optic canal. Neuromas (nerve sheath tumors) may cause smooth expansion of skull base foramina: internal auditory canal (cranial nerve VIII), jugular foramen (cranial nerves IX, X, and XI), hypoglossal canal (cranial nerve XII), and lateral wall clivus and foramen rotundum (cranial nerve V). Paragangliomas cause irregular erosive changes in the skull base foramina ( Fig. 3–69 ). A meningioma is often heralded by hyperostosis (bone sclerosis), especially common with a lesion of the middle fossa involving either the greater or lesser sphenoid wing. Chordoma, a tumor of notochordal remnants, typically causes destruction of the clivus (basisphenoid and basiocciput), typically with associated soft-tissue mass and calcification.[34] [51] Erosion of the sella floor and sella expansion are characteristic of pituitary adenomas.
Temporal bone
Determination of temporal bone abnormality requires assessment of the external ear, middle ear, mastoid air cells, petrous apex, inner ear, IAC, facial nerve canal, and vascular compartment (jugular foramen and carotid canal). The adjacent compartments into which an aggressive temporal bone lesion can spread, or from which a lesion can invade the temporal bone include cerebellopontine angle (meningioma, acoustic schwannoma), middle cranial fossa (geniculate schwannoma, cholesteatoma), jugular foramen (schwannoma, paraganglioma, glomus tumor), skull base and clivus (chordoma), carotid space (aneurysm, schwannoma), parotid space (adenoid cystic carcinoma), and soft tissues of the external ear and scalp (SCC).
For the external ear and external auditory canal (EAC) the search for abnormality may be accomplished with either high-resolution CT or MRI. Abnormal development (external ear hypoplasia, fibrous or bony EAC atresia), soft tissue opacification (cerumen, EAC cholesteatoma, SCC), bone erosion (EAC cholesteatoma, mucormycosis, squamous cell carcinoma), bone formation (exostoses), or scutum erosion (par flaccida cholesteatoma) can easily be detected and their extent defined by CT. MRI may add additional information on soft-tissue involvement below the skull base or on infiltration of the auricle and scalp.
The middle ear is best evaluated with high-resolution CT. Ossicular chain anomalies (fusion, dislocation, prosthesis,


Figure 3-66 Cholesterol granuloma. A, and B, Axial and coronal contrast-enhanced computed tomography (CECT) images demonstrate expansile lesion of the right petrous apex and greater wing of sphenoid. Lesion is homogeneously low density in nature. Displaced right internal carotid artery (arrows) lies in the lateral aspect of the lesion. C, Axial CECT bone algorithm image using bone windows demonstrates truncation of anteromedial portion of the right petrous temporal bone (arrow) and adjacent posterolateral portion of the sphenoid bone. The lesion bulges into the right sphenoid sinus. D and E, Coronal T1-weighted image and T2-weighted image demonstrate lesion that is high intensity on both sequences, consistent with methemoglobin. Right internal carotid artery is noted in midlateral portion of lesion (arrow). The lesion extends above and below skull base and invaginates into sphenoid sinus.
stapedial foot-plate sclerosis), air-fluid level (trauma, acute otitis media), soft-tissue opacification (acute or chronic otitis media, cholesteatoma, trauma, chronic endotracheal or nasogastric intubation), and tympanic membrane thickening (otitis media) may all be characterized ( Fig. 3–70 ). The radiographic approach to the mastoid air cells and petrous apex is similar to that of the paranasal sinuses and consists of the evaluation of the mastoid and petrous apex soft-tissue contents and the bony walls. Assessment is made of development or pneumatization of these regions (pneumatization or opacification by soft tissue), the bony septae and walls (hypoplasia or sclerosis from chronic otomastoiditis), the margins of the mastoid or petrous apex (expanded by a primary or secondary cholesteatoma [ Fig. 3–71 ] or a cholesterol granuloma), bone destruction (SCC, malignant fibrous histiocytoma, glomus tumor). MRI may complement CT for assessment of larger petrous apex or mastoid masses. A normal unpneumatized, fatty (marrow-filled) petrous apex is high signal on T1WI and low signal on T2WI, but a cholesterol granuloma is high signal on T1WI and T2WI from the methemoglobin (see Fig. 3–66 ). Mucus in an air cell is low intensity on T1WI, is very high intensity on T2WI, and enhances mildly with gadolinium. A primary cholesteatoma is similar to CSF in intensity, appearing low intensity on T1WI


Figure 3-67 Skull base metastasis from adenocarcinoma of the breast. Axial noncontrast computed tomography demonstrates metastatic tumor infiltrating and destroying majority of middle fossa; clivus (arrow) and anteromedial left temporal bone (arrowhead) are especially affected.
and moderately high signal on T2WI, and does not enhance with gadolinium. Postoperative findings encountered on CT and MRI include metallic ossicular prostheses, cochlear implants, and various types of mastoidectomies.
The inner ear structures are best assessed by high-resolution CT with attention to anatomic variants and bone density. A saccular vestibule is one of the more common congenital anomalies. A cochlea with less than 2½ to 2¾ turns represents a Mondini malformation ( Fig. 3–72 ). The basal turn of the cochlea and round window may be identified on both axial and coronal CT images. The horizontal (lateral) semicircular canal cortex may be eroded by a cholesteatoma. The oval window and foot plate of the stapes are thickened in stapedial otosclerosis, and the ring of the otic capsule is demineralized in labyrinthine otosclerosis (otospongiosis). The entire petrous bone may be abnormally low density with dysplasias such as osteogenesis imperfecta or sclerotic in osteopetrosis and Paget’s disease. Inflammatory or neoplastic lesions may involve the cochlea and vestibule without obvious bony changes on CT; however, MRI with gadolinium-enhanced T1WI may show an enhancing lesion.
The IAC and facial nerve canals are best evaluated by high-resolution CT for bony detail and by gadolinium-enhanced MRI for the soft-tissue abnormality. On CT the findings might include widening (acoustic schwannoma, surgery) or narrowing (bone dysplasia, hyperostosis from a meningioma) of the IAC. The facial nerve canal may be traced along its entire course in both axial and coronal planes for areas of erosion (facial neuroma, paraganglioma, hemangioma) or abnormal position (anterior location of mastoid segment with EAC atresia). Gadolinium-enhanced MRI is the modality of choice for evaluating the seventh and eighth cranial nerves within the IAC and temporal bone (schwannomas of the facial nerve, of the vestibular nerve, or within the cochlea) or for demonstrating seventh cranial nerve inflammation (Bell’s palsy) ( Figs. 3–73 and 3–74 ). Note that the facial nerves may normally enhance mildly and usually symmetrically within the facial nerve canal; asymmetric enhancement is more likely to be abnormal.

Figure 3-68 Metastatic prostate carcinoma to left orbit. A, Axial contrast-enhanced computed tomography (CECT) demonstrates sclerotic metastasis of posterolateral margin of left orbit (asterisk). Small soft tissue component (arrow) lies deep to hyperostosis, displacing the lateral rectus muscle medially. B, Coronal CECT with bone settings demonstrates marked sclerotic reaction of superior lateral portion of the left orbit; intraorbital volume is decreased.


Figure 3-69 Glomus tumor (paraganglioma) of the right petrous temporal bone. Axial contrast-enhanced computed tomography with bone windows demonstrates infiltrative destructive lesion of the middle and superior portions of the right petrous temporal bone (arrow). Poorly defined margin of lesion is characteristic of glomus tumor. Soft-tissue mass (arrowheads) is noted in the right cerebellopontine angle cistern and in the inferior portion of the right middle ear cavity (asterisk). Previous right mastoidectomy has been performed.

Figure 3-70 Transverse petrous fracture with ossicular dislocation. High-resolution 1.5-mm noncontrast computed tomography using bone algorithm and bone windows shows a transverse petrous fracture (arrowheads) extending through mastoid bone and semicircular canals. Ossicular dislocation of the head of malleus from its articulation with fractured body of incus (arrow) is seen; middle ear opacification also confirms presence of temporal bone trauma.

Figure 3-71 Pars flaccida cholesteatoma. Middle ear cholesteatoma (c) expands mastoid antrum and epitympanic recess on axial noncontrast computed tomography. The absence of incus and soft tissue abutting the head of malleus (arrow) confirm ossicular erosion.

Figure 3-72 Mondini malformation. Saccular combined vestibule and cochlea (arrowhead) reveal a severe form of Mondini malformation on axial noncontrast computed tomography.
A preoperative CECT or MRI is extremely helpful for interpreting the postoperative neck, skull base, or face for sites of concern and potential tumor recurrence. Likewise, a baseline CECT or MRI 3 to 6 months after surgery and radiation further improves the ability of imaging to detect posttreatment tumor recurrence. The posterior cervical space is the most frequently altered neck space, and part or all of its contents may be resected for staging and treatment of

head and neck carcinoma; note is made of missing structures.[20] A radical neck dissection ( Fig. 3–75 , A ) removes the sternocleidomastoid muscle, internal jugular vein, regional lymph nodes, and most of the fibrofatty tissue that comprises this space. Modified radical, functional, and supraomohyoid neck dissections remove less.
The oral cavity and face also are affected by surgery. Facial trauma is frequently treated by internal fixation with metallic screws and plates. Internal fixation also is performed

Figure 3-73 Acoustic schwannoma. Axial fat saturation postgadolinium T1-weighted image demonstrates brightly enhancing right cerebellopontine angle mass with intracanalicular (characteristic of acoustic schwannoma) and extracanalicular components. Note the acute angle that the mass makes with petrous ridge (arrow).
as part of composite reactions where the mandible is split or when the mandible is partially resected for invasion by tumor. Metal wires, screws, and plates may cause artifacts obscuring sites of posttraumatic CSF leak or potential tumor recurrence. Sinus and palate tumors may require resection of the maxilla, palate, orbital walls and soft tissue, and cribriform plate. The fat, muscle, or bone contained in free flaps, myocutaneous flaps, and osteocutaneous flaps placed in the surgical cavity further complicates image interpretation ( Fig. 3–75 , B ). Laryngeal surgery may remove part or all of the laryngeal skeleton, often with placement of a tracheostomy. The remaining soft tissues of the collapsed visceral space are difficult to accurately evaluate.
Radiotherapy frequently causes an edematous pattern,characterized on CT by a streaky increase in density of the subcutaneous, parapharyngeal, and posterior cervical space fat planes ( Fig. 3–76 , A ); on MRI it may have increased signal on T2WI. The mucosal space of the pharynx and larynx may also develop swelling and edema, appearing as diffuse mucosal thickening and enhancement on CECT, while MRI may show high signal on long TR sequences and on gadolinium-enhanced T1WI ( Fig. 3–76 , B ). Postradiation edema, particularly of the larynx and pharynx, may mimic recurrent neoplasm for as long as 6 months to 7 years after radiotherapy.[21] Finally, treated lymph nodes may decrease in size or totally disappear, leaving a “dirty fat” appearance.
Recurrent tumor spread often produces strands or nodules of soft-tissue density within or replacing the normal fat

Figure 3-74 Magnetic resonance imaging (MRI) of internal auditory canal (IAC) and facial nerve. A, Axial postgadolinium T1-weighted image shows broad-based brightly enhancing meningioma overlying IAC. Note its obtuse angle (arrow) with petrous ridge and dural “tail” extending posteriorly (arrowhead), which are characteristic of meningioma. B, In the same patient as in A, postoperative labyrinthitis has developed on this follow-up axial postgadolinium T1-weighted images. Abnormal enhancement of vestibule, semicircular canals (straight arrow), and cochlea (curved arrow) are new findings (which can only be observed by gadolinium-enhanced MRI).


Figure 3-75 Postoperative appearance of neck. A, Axial T1-weighted image demonstrates prior left neck dissection (arrow) with removal of sternocleidomastoid muscle (s) and posterior cervical space fat. B, Patient with osteocutaneous flap, with thick fat (f) on deep and external margins of mandibular graft (g), has developed deep recurrent tumor (asterisk) around carotid sheath.

Figure 3-76 Radiation changes in neck. A, Axial contrast-enhanced computed tomography (CECT) demonstrates streaky densities in fat throughout superficial cervical and anterior cervical spaces (arrows) and thickening of platysma muscle (arrowhead). B, Different patient who had radiation therapy for glottic carcinoma has developed thickening of epiglottis and aryepiglottic folds (a) on axial CECT. This finding may persist for many months after therapy.
planes. However, CECT has difficulty detecting small (<1 cm) or mucosal-based tumors and reliably differentiating between recurrent carcinoma and fibrosis or edema. A new bulky, ring-enhancing mass, local tissue invasion, or further bone destruction is a strong sign of recurrent tumor. MRI is reportedly capable of distinguishing tumor from radiation-induced fibrosis in some cases. Posttreatment fibrosis or scarring is similar to or lower than muscle in signal on all sequences (particularly on T2WI), is usually linear, is not mass-like, and may enhance mildly in a linear fashion. MRI is superior to CT (particularly NCCT) in discrimination of recurrent tumor from muscle and vascular structures. In the posttreatment neck, gadolinium-enhanced MRI may have the potential to identify tumor recurrence and allow separation of tumor from fibrosis because recurrent tumor may ring-enhance, a pattern not seen with scar.

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Chapter 2 – The Preoperative Evaluation

Chapter 2 – The Preoperative Evaluation

James Blaugrund
Dario Kunar

Preoperative evaluation of surgical patients is, in its broadest sense, an extension of the diagnostic process. The surgeon should strive to determine the extent of disease; prove the necessity of surgery or clearly demonstrate its benefit to the patient; optimize the choice of surgical procedure; and minimize the risk to the patient by defining concomitant health problems and instituting appropriate therapy or precautionary measures. Integral to each of these goals is an appreciation of the ideal set forth in the Hippocratic Oath—Above all else, do no harm. It is the surgeon’s responsibility to ensure that an appropriate patient assessment has been completed prior to entering the surgical suite. Surgical complications can often be avoided by recognizing the physiologic limitations of the patient preoperatively. Documentation of findings, decision making, and discussion between surgeon and patient regarding surgical risks and benefits have become medicolegal imperatives.

The patient presenting with an otolaryngologic disease process that requires surgical management must be evaluated by both general and specialty-specific criteria. As with the initial patient evaluation, preoperative assessment relies heavily on a careful history and physical examination. Special attention should be given to the patient’s past medical and surgical history. A thorough review of systems helps to identify the conditions and risk factors that may complicate the perioperative course. Information should be elicited regarding the cardiovascular, pulmonary, renal, gastrointestinal, endocrine, hematologic, neurologic, immune, musculoskeletal, integumentary, and psychiatric systems. Additional testing, prophylactic measures, and behavioral modification prior to surgery can then be implemented to maximize the surgical outcome. In addition, the patient’s prior anesthetic record provides invaluable insight into issues such as airway management and overall tolerance of general, regional, local, or neuroleptic anesthesia. A social history can often be extremely beneficial as well, providing a means of anticipating postoperative needs and circumventing some prolonged admissions. Any significant issues should be raised with the departmental or hospital social worker, preferably prior to surgery. Lastly, it is important to elicit a detailed list of current medications and allergies.
In uncomplicated cases, the history and physical examination are followed by routine screening tests. Blood is drawn for a complete blood count (CBC), serum electrolytes, blood urea nitrogen (BUN), creatinine, glucose, and a clotting profile to rule out a wide range of possible occult abnormalities. In patients over 40 years of age or in those with pertinent past medical histories, chest radiography and electrocardiography (ECG) are performed. Additionally, women of childbearing age should undergo pregnancy testing.
When the need arises, consultation with appropriate specialties should be sought quickly. The consultant should be clearly informed about the nature of the proposed procedure and should be asked to comment specifically on the relative safety of performing the procedure with respect to concomitant disease processes. In cases complicated by many medical problems or in those in which the establishment of a safe airway is an issue, the authors advise close consultation with the anesthesia team to avoid undue delay, cancellation of the procedure, or an undesirable outcome.
Increasingly, the primary care physician conducts the preoperative evaluation. This phenomenon has become particularly prevalent in the managed care environment. Although a good internist can often facilitate the preoperative process,

it is imperative to have copies of all laboratory results, radiographs, and pertinent tests available for review prior to surgery. Additional studies should be ordered by the surgeon as deemed necessary.
Although a detailed discussion of the legal ramifications of informed consent is beyond the scope of this chapter, the ethical ideal deserves consideration. A thorough and candid explanation of the procedure, its risks, and the probable outcomes has become an integral part of the preoperative process. More and more patients now come to their physician prepared to ask in-depth questions and expecting to receive detailed answers. The relationship that develops between the surgeon and patient at this time often does more to prevent litigation in the unfortunate circumstance of maloccurrence than any legal document detailing the “risks and benefits.”
The surgeon must guard against anaphylactic reactions in all patients. The crux of this process is to have the patient identify any untoward reactions to medications, foods, or other materials. In most instances, many of the drug “reactions” quoted by patients do not represent true allergic phenomena. Instead, they are simply medicinal side effects. Nonetheless, these reactions require thorough documentation and avoidance in the perioperative period.
Anaphylaxis is triggered by antigen-specific immunoglobulin E (IgE) antibody crosslinking at the mast cell surface. Subsequent mast cell degranulation releases potent inflammatory agents, vasoactive substances, and proteases, all of which mediate the shock reaction. The patient may develop urticaria, profound hypotension, tachycardia, bronchoconstriction, and airway-compromising edema of the mucosal surfaces of the upper aerodigestive tract. Even in intubated patients, rapid oxygen desaturation is often a prominent feature. As the reaction progresses, cardiac arrest can ensue despite maximal resuscitative efforts. Given the potential morbidity and mortality of anaphylactic reactions, the otolaryngologist must identify all allergens in the preoperative phase.
The incidence of serious adverse reactions to penicillin is about 1%. It is widely believed that there is a 10% to 15% chance that patients who manifest these reactions also react adversely to cephalosporins. The authors frequently administer intravenous cephalosporins intraoperatively, and the safety of their use in patients allergic to penicillin often comes into question. Based on empiric observations at the authors’ institution, it is believed that unless these patients have had a history of significant atopy or penicillin-induced urticaria, mucosal edema, or anaphylaxis, they can be given cephalosporins with relative impunity. Anaphylactic reactions to cephalosporins in true penicillin-allergic patients are probably less than 2%. Moreover, cephalosporins cause their own independent hypersensitivity reactions; the notion of cross-reactivity with penicillin on skin testing seems to stem from data obtained in the 1970s, in which contamination of cephalosporins with penicillin was subsequently proven. Finally, if a serious penicillin allergy is evident, alternative antibiotics such as clindamycin may be substituted for the cephalosporins.
Mucosal absorption of latex protein allergens from the surgeon’s gloves can rapidly incite anaphylactic shock in patients who are highly sensitive to latex. In fact, the authors have recently witnessed this dramatic reaction in the operating room. In preparation for surgery, a healthy, young patient was intubated, arterial and central venous catheters were placed, and a Foley catheter was inserted. All procedures were performed by physicians and technicians wearing standard latex gloves. Shortly thereafter, the patient became profoundly hypotensive and hypoxic. Resuscitation was initiated and, after ruling out all other likely etiologies, the diagnosis of latex allergy was entertained. The patient was subsequently managed with latex-free products and, fortunately, survived a near catastrophe. The patient later recalled developing orofacial edema when he inflated balloons, and that rubber gloves would cause pruritus of his hands. Subsequent serum testing confirmed his latex allergy. It should be noted that about 7% to 10% of healthcare workers regularly exposed to latex and 28% to 67% of children with spina bifida demonstrate positive skin tests to latex proteins. Preoperatively, if a patient gives a history suspicious for latex allergy, it should be investigated prior to surgery; if the allergy is documented, perioperative precautions to avoid latex exposure must be instituted at all costs.
Similarly, patients with allergic or adverse reactions to soybean or eggs may react to propofol, a ubiquitous induction agent. Protamine and intravenous contrast agents can potentially provoke hypersensitivity responses in patients with known shellfish or other fish allergies. Although rare, some patients may have allergic reactions to ester types of local anesthetics such as cocaine, procaine, and tetracaine.
Finally, if the suspicion of allergy or adverse reaction exists, the best course of action is to avoid use of the potential offending agent altogether during surgery. If this is not feasible for some reason, then the surgeon and anesthesiologist should plan on premedicating the patient with systemic steroids, histamine antagonists, and even bronchodilators and should be prepared to deal with the potential worst-case scenario of anaphylactic shock.
Cardiovascular complications are the most common cause of perioperative mortality. Specifically, there is an almost 50% mortality rate associated with perioperative myocardial infarction. Meticulous review of the cardiovascular system is of utmost importance in determining a patient’s surgical candidacy, especially for those who will require

a general anesthetic. Risk factors for a perioperative cardiovascular complication include jugular venous distention, third heart sounds, recent myocardial infarction (MI) (within 6 months), nonsinus heart rhythm, frequent premature ventricular contractions (>5 per minute), over 70 years of age, valvular aortic stenosis, previous vascular or thoracic surgery, and poor overall medical status. Emergency surgery poses an additional risk for cardiovascular complications. In the head and neck oncology patient population, the high incidence of tobacco and alcohol abuse leads to a relatively high incidence of coronary artery disease, cardiomyopathy, and peripheral vascular disease.
The otolaryngologist should obtain a history of previous MIs, angina, angioplasty or bypass surgery, congestive heart failure (CHF) or dyspnea on exertion, hypertension, general exercise tolerance, paroxysmal nocturnal dyspnea, claudication, stroke or transient ischemic attack (TIA), syncope, palpitations or other arrhythmias, as well as known anatomic or auscultative cardiac anomalies. The presence or suspicion of coronary artery disease, heart failure, untreated hypertension, or significant peripheral vascular disease should prompt a specific anesthesiology or cardiology consultation before surgery. This evaluation would include an assessment of the electrocardiogram as well as possible exercise or chemical stress testing, echocardiography, and cardiac catheterization as indicated. The result of this consultation should determine the surgical and anesthetic risk and should optimize the patient’s preoperative cardiovascular status. Furthermore, specific intraoperative and postoperative physiologic (e.g., invasive monitors) and pharmacologic precautionary measures should be delineated, as should the level of postoperative observation.
In general, patients are maintained on their antihypertensive, antianginal, and antiarrhythmic regimens up to the time of surgery. Certain medications such as diuretics and digoxin may be withheld at the discretion of the anesthesiologist or cardiologist. Preoperatively, serum electrolytes and antiarrhythmic levels should be checked and adjusted as necessary. Coagulation studies (prothrombin time [PT]/partial thromboplastin time [PTT]) and platelet quantification are routinely obtained in patients with the above-mentioned risk factors because significant bleeding can lead to major perioperative cardiovascular complications. A relatively current chest radiograph is considered essential in this high-risk group.
Preoperatively, the otolaryngologist must be aware of the types of procedures that may have specific cardiovascular ramifications. For instance, the intravascular volume loading that occurs during and after free flap surgery, through use of agents such as dextran and Hespan (Hetastarch, Dupont Pharma, Wilmington, Delaware), can have a significant impact on patients with a history of congestive heart failure, poor ventricular function, or atrial fibrillation. Furthermore, the fall in hematocrit often seen with the use of these agents can potentially induce coronary ischemia. Patients with prosthetic valves and those with a history of rheumatic fever, endocarditis, congenital heart defects, mitral valve prolapse with regurgitation, or hypertrophic cardiomyopathy should receive prophylactic antibiotics at the time of surgery. Such prophylaxis is especially important during procedures performed on the oral cavity and upper aerodigestive tract as well as dealing with surgical drainage of head and neck infections, in which the risk of hematogenous bacterial seeding is high. For low-risk procedures, intravenous ampicillin, 2 g given 30 minutes prior to surgery followed by 1 g 6 hours later, is sufficient prophylaxis. In high-risk procedures, intravenous gentamicin, 1.5 mg/kg, and intravenous ampicillin, 2 g, are administered 30 minutes before surgery, followed by the same doses of each 8 hours later. Patients with pacemakers or implanted defibrillators and those with mitral valve prolapse without regurgitation do not require endocarditis prophylaxis.
Airway, carotid, and vagus nerve manipulation can induce bradycardia and hypotension. Agents such as lidocaine, epinephrine, and cocaine, which are frequently used in sinonasal surgery, can trigger undesirable cardiovascular events. Injury to the cervical sympathetic chain may precipitate postural hypotension postoperatively. Finally, the surgeon must also be cognizant of the fact that a unipolar electrocautery device can reprogram a pacemaker during surgery.
Postoperative pulmonary complications are considered the second most common cause of perioperative mortality. This is not surprising when considering the effects of general anesthesia and surgery on pulmonary performance. Atelectasis and ventilation/perfusion mismatch occur secondary to a number of factors, including the use of anesthetic agents and positive pressure ventilation as well as supine positioning. Anesthetic agents, barbiturates, and opioids tend to diminish the ventilatory response to hypercarbia and hypoxia. Endotracheal intubation bypasses the warming and humidifying effects of the upper airway, leading to impaired ciliary function, thickened secretions, and subsequent decreased resistance to infection. Furthermore, postoperative pain substantially affects a patient’s ability to cough, especially following thoracic or abdominal procedures (e.g., chest myocutaneous flap, gastric pull up, percutaneous endoscopic gastrostomy (PEG), rectus free-flap, iliac crest bone graft). Because of their attenuated respiratory reserve, patients with chronic pulmonary disease are much more likely to suffer postoperative pulmonary complications than are healthy patients. For instance, heavy smokers have a threefold increase in the risk of postoperative pulmonary complications when compared with nonsmokers. Hence it is imperative to identify these patients during the preoperative evaluation.
Specifically, a positive history of asthma, chronic obstructive pulmonary disease (COPD), emphysema, tobacco abuse, pneumonia, pulmonary edema, pulmonary fibrosis, or adult respiratory distress syndrome (ARDS) requires

heightened attention prior to surgery. The prior treatment of these lung problems, including the number of hospitalizations and emergency room visits; the use of medications like steroids, antibiotics, and bronchodilators; and the need for intubation or chronic oxygen therapy should be addressed. The otolaryngologist should obtain an estimate of the patient’s dyspnea, exercise limitation, cough, hemoptysis, and sputum production. Factors that exacerbate chronic lung disease must be identified. Once again, it is of paramount importance to investigate the tolerance of previous anesthetics in this high-risk group. Coexisting cardiac and renal disease such as CHF and chronic renal failure also impact heavily on pulmonary function. Pulmonary hypertension and cor pulmonale secondary to obstructive sleep apnea, cystic fibrosis, muscular dystrophy, emphysema, or kyphoscoliosis further complicate anesthetic management. Congenital diseases affecting the lungs such as cystic fibrosis and Kartagener’s syndrome (rare) present the challenge of perioperative clearance of secretions.
On physical examination, the clinician should be attuned to the patient’s body habitus and general appearance. Obesity, kyphoscoliosis, and pregnancy can all predispose to poor ventilation, atelectasis, and hypoxemia. Cachectic patients are more likely to develop postoperative pneumonia. It should be noted that clubbing and cyanosis, although suggestive, are not reliable indicators of chronic pulmonary disease. The patient’s respiratory rate is determined, and the presence of accessory muscle use, nasal flaring, diaphoresis, or stridor should be documented. Auscultation that reveals wheezing, rhonchi, diminished breath sounds, crackles,rales, and altered inspiratory:expiratory time ratios should raise the suspicion of pulmonary compromise.
In patients with pulmonary disease, preoperative posteroanterior and lateral chest radiography is mandatory, because findings will often direct modification of the anesthetic technique used during surgery. Arterial blood gas (ABG) testing on room air is also indicated. Patients with an arterial oxygen tension less than 60 mm Hg or an arterial carbon dioxide tension greater than 50 mm Hg are more likely to have postoperative pulmonary complications. Serial ABG determinations can also assess the overall efficacy of preoperative medical and respiratory therapy. As with chest radiography, preoperative ABG levels also provide a baseline for postoperative comparison. Preoperative pulmonary function tests such as spirometry and flow-volume loops are quite helpful. A quantitative measure of ventilatory function can also be used to assess the efficacy of both preoperative and surgical interventions. Spirometry can be used to differentiate restrictive from obstructive lung disease as well as to predict perioperative morbidity from pulmonary complications. Generally, a forced expiratory volume in 1 second: forced vital capacity ratio of less than 75% is considered abnormal, whereas a ratio of less than 50% carries a significant risk of perioperative pulmonary complications. Preoperative flow-volume loops can distinguish among fixed (e.g., goiter), variable extrathoracic (e.g., unilateral vocal cord paralysis), and variable intrathoracic (e.g., tracheal mass) airway obstructions.
The preoperative management of otolaryngology patients with significant pulmonary disease is vital and should follow the recommendations of a pulmonologist. Smokers are advised to cease smoking for at least a week prior to surgery. Known airway irritants and triggers of bronchospasm should be avoided as much as possible. The patient should be well hydrated and should breathe warm, humidified air or oxygen. Chest physiotherapy aimed at increasing lung volumes and clearing secretions is instituted. This includes coughing and deep breathing exercises, incentive spirometry, and chest percussion with postural drainage. It is not advisable to operate on a patient with an acute exacerbation of pulmonary disease or with an acute pulmonary infection. Acute infections should be cleared with antibiotics and chest physiotherapy prior to elective surgery. Prophylactic antibiotics in noninfected patients are not recommended for fear of selecting out resistant organisms. Finally, the medical regimen, including the use of inhaled ß-adrenergic agonists, cromolyn, and steroids (inhaled or systemic), must be optimized. Serum levels of theophylline, if used, should be therapeutic.
The preoperative identification and evaluation of renal problems is also imperative. Any significant electrolyte abnormalities uncovered during the routine screening of healthy patients should be corrected preoperatively, and surgery should be delayed if additional medical evaluation is warranted. Preexisting renal disease is a major risk factor for the development of acute tubular necrosis both during and after surgery. Renal failure, whether acute or chronic, influences the types, dosages, and intervals of perioperative drugs and anesthetics. An oliguric or anuric condition requires judicious fluid management, especially in patients with cardiorespiratory compromise. Furthermore, chronic renal failure (CRF) is often associated with anemia, platelet dysfunction, and coagulopathy. Electrolyte abnormalities, particularly hyperkalemia, can lead to arrhythmias, especially in the setting of the chronic metabolic acidosis that often accompanies CRF. Hypertension and accelerated atherosclerosis resulting from CRF are risk factors for developing myocardial ischemia intraoperatively. Blunted sympathetic responses may predispose to hypotensive episodes during administration of anesthesia. The otolaryngologist must also be wary of the potential for injury to demineralized bones during patient positioning. An impaired immune system can contribute to poor wound healing and postoperative infection. Finally, because patients with CRF have often received blood transfusions, they are at increased risk of carrying blood-borne pathogens such as hepatitis B and C.
The possible causes of renal disease, including hypertension, diabetes, nephrolithiasis, glomerulonephritis, polycystic disease, lupus, polyarteritis nodosa, Goodpasture’s or

Wegener’s syndromes, trauma, or previous surgical or anesthetic insults, should be elicited. The symptoms of polyuria, polydipsia, fatigue, dyspnea, dysuria, hematuria, oliguria or anuria, and peripheral edema are recorded, as is a complete listing of all medications taken by the patient.
In dialyzed patients, it is important to document the dialysis schedule. A nephrologist should assist with the preoperative evaluation and should optimize the patient’s fluid status and electrolytes prior to surgery. A nephrologist should also be available to help manage these issues postoperatively, especially when major head and neck, skull-base, or neurotologic surgery, which may require large volumes of fluids or blood transfusions intraoperatively, is planned.
Preoperative testing on patients with significant renal disease routinely includes ECG, chest radiography, electrolytes and chemistry panel, CBC, PT/PTT, platelet counts, and bleeding times. In addition to a nephrologic consultation, patients with significant renal disease should also receive a preoperative anesthesiology consultation, and, if indicated, further evaluation by a cardiologist.
A history of benign prostatic hypertrophy or prostate cancer, with or without surgery, may predict a difficult urinary tract catheterization intraoperatively. Finally, elective surgery should not be performed on patients with acute genitourinary tract infections because the potential for urosepsis can be increased by the transient immunosuppression associated with general anesthesia.
Preoperative evaluation of patients with suspected or clinically evident liver failure should begin with a history eliciting the details of hepatotoxic drug therapy, jaundice, blood transfusion, upper gastrointestinal bleeding, and previous surgery and anesthesia. The physical should include examination for hepatomegaly, splenomegaly, ascites, jaundice, asterixis, and encephalopathy. The list of blood tests is fairly extensive and includes hematocrit, platelet count, bilirubin, electrolytes, creatinine, BUN, serum protein, PT/PTT, serum aminotransferases, alkaline phosphatase, and lactate dehydrogenase. A viral hepatitis screen can be obtained as well. Of note, patients with moderate to severe chronic alcoholic hepatitis may present with relatively normal-appearing liver function tests and coagulation parameters; these patients are at risk for perioperative liver failure. In the last few years, at least four patients under the authors’ care ultimately succumbed to complications of liver failure following surgery.
Cirrhosis and portal hypertension have wide-ranging systemic manifestations. Arterial vasodilation and collateralization leads to decreased peripheral vascular resistance and an increased cardiac output. This hyperdynamic state can occur even in the face of alcoholic cardiomyopathy. The responsiveness of the cardiovascular system to sympathetic discharge and administration of catechols is also reduced, likely secondary to increased serum glucagon levels. Cardiac output can be reduced by the use of propranolol, which has been advocated by some as a treatment for esophageal varices. By decreasing cardiac output, flow through the portal system and the esophageal variceal collaterals is diminished. Additionally, there is likely a selective splanchnic vasoconstriction. Once initiated, ß-blockade cannot be stopped easily because of a significant rebound effect.
Renal sequelae vary with the severity of liver disease from mild sodium retention to acute failure associated with the hepatorenal syndrome. Diuretics given to decrease ascites can often lead to intravascular hypovolemia, azotemia, hyponatremia, and encephalopathy. Fluid management in the perioperative period should be followed closely and dialysis instituted as needed for acute renal failure.
From a hematologic standpoint, patients with cirrhosis often have an increased 2,3-diphosphoglycerate level in their erythrocytes causing a shift to the right of the oxyhemoglobin dissociation curve. Clinically, this results in a lower oxygen saturation. This situation is further compounded by the frequent finding of anemia. Additionally, significant thrombocytopenia and coagulopathy may be encountered. The preoperative use of appropriate blood products can lead to short-term correction of hematologic abnormalities, but the prognosis in these patients remains poor.
Encephalopathy stems from insufficient hepatic elimination of nitrogenous compounds. Although measurements of BUN and serum ammonia levels are useful, they do not always correlate with the degree of encephalopathy. Treatment includes hemostasis, antibiotics, meticulous fluid management, low-protein diet, and lactulose.
Symptoms of hyperthyroidism include weight loss, diarrhea, skeletal muscle weakness, warm, moist skin, heat intolerance, and nervousness. Laboratory test results may demonstrate hypercalcemia, thrombocytopenia, and mild anemia. Elderly patients also can present with heart failure, atrial fibrillation, or other dysrhythmias. The term thyroid storm refers to a life-threatening exacerbation of hyperthyroidism that results in severe tachycardia and hypertension.
Treatment of hyperthyroidism attempts to establish a euthyroid state and to ameliorate systemic symptoms. Propylthiouracil inhibits both thyroid hormone synthesis and the peripheral conversion of T4 to T3. Complete clinical response may take up to 8 weeks, during which the dosage may need to be tailored to prevent hypothyroidism. Potassium iodide (Lugol’s solution), which works by inhibiting iodide organification, can be added to the medical regimen. In patients with sympathetic hyperactivity, ß-blockers have been used effectively. Propranolol has the added benefit of decreasing T4-to-T3 conversion. It should not be used in patients with CHF secondary to poor left ventricular function or bronchospasm because it will exacerbate both of these conditions. Ideally, medical therapy should prepare a mildly

thyrotoxic patient for surgery within 7 to 14 days. If the need for emergency surgery arises, intravenous propranolol or esmolol can be administered and titrated to keep the heart rate below 90 bpm. Other medications that can be used include reserpine and guanethidine, which deplete catechol stores, and glucocorticoids, which decrease both thyroid hormone secretion and T4-to-T3 conversion. Radioactive iodine also can be used effectively to obliterate thyroid function but should not be given to women of childbearing years.
The symptoms of hypothyroidism result from inadequate circulating levels of T4 and T3 and include lethargy, cognitive impairment, and cold intolerance. Clinical findings may include bradycardia, hypotension, hypothermia, hypoventilation, and hyponatremia. There is no evidence to suggest that patients with mild to moderate hypothyroidism are at increased risk for anesthetic complications, but all elective surgery patients should be treated with thyroid hormone replacement prior to surgery. Severe hypothyroidism resulting in myxedema coma is a medical emergency and is associated with a high mortality rate. Intravenous infusion of T3 or T4 and glucocorticoids should be combined with ventilatory support and temperature control as needed.
The prevalence of primary hyperparathyroidism increases with age. Sixty percent to 70% of patients with primary hyperparathyroidism present initially with nephrolithiasis secondary to hypercalcemia, and 90% are found to have benign parathyroid adenomas. Hyperparathyroidism secondary to hyperplasia occurs in association with medullary thyroid cancer and pheochromocytoma in multiple endocrine neoplasia (MEN) type IIA and, more rarely, with malignancy. In humoral hypercalcemia of malignancy, nonendocrine tumors have been demonstrated to secrete a parathyroid hormone-like protein. Secondary hyperparathyroidism usually results from chronic renal disease. The hypocalcemia and hyperphosphatemia associated with this condition lead to increased parathyroid hormone production and, over time, to parathyroid hyperplasia. Tertiary hyperparathyroidism occurs when the CRF is rapidly corrected as in renal transplantation.
In addition to nephrolithiasis, signs and symptoms of hypercalcemia include polyuria, polydipsia, skeletal muscle weakness, epigastric discomfort, peptic ulceration, and constipation. Radiographs may show significant bone resorption in 10% to 15% of patients. Depression, confusion, and psychosis also may be associated with marked elevations in serum calcium levels.
Immediate treatment of hypercalcemia usually combines sodium diuresis with a loop diuretic and rehydration with normal saline as needed. This becomes urgent once the serum calcium levels rise above 15 g/dl. Several medications can be used to decrease serum calcium levels. Etidronate inhibits abnormal bone resorption. The cytotoxic agent mithramycin inhibits parathyroid hormone-induced osteocytoclastic activity but is associated with significant side effects, and calcitonin works transiently again by direct inhibition of osteoclast activity. Hemodialysis can also be used in the appropriate patient population.
The most common cause of hypoparathyroidism is iatrogenic. Thyroid and parathyroid surgery occasionally results in the inadvertant removal of all parathyroid tissue. Ablation of parathyroid tissue can also occur after major head and neck surgery and postoperative radiation therapy. Symptoms include tetany, perioral and digital paresthesias, muscle spasm, and seizures. Chvostek’s sign (facial nerve hyperactivity elicited by tapping over the common trunk of the nerve as it passes through the parotid gland) and Trousseau’s sign (finger and wrist spasm after inflation of a blood pressure cuff for several minutes) are clinically important indicators of latent hypercalcemia. Treatment is with calcium supplementation and vitamin D analogs.
Adrenal gland hyperactivity can result from a pituitary adenoma, a corticotropin hormone (ACTH)-producing nonendocrine tumor, or a primary adrenal neoplasm. Symptoms include truncal obesity, proximal muscle wasting, “moon” facies, and changes in behavior that vary from emotional lability to frank psychosis. Diagnosis is made through the dexamethasone suppression test, and treatment is adrenalectomy or hypophysectomy. It is important to regulate blood pressure and serum glucose levels and to normalize intravascular volume and electrolytes. Primary aldosteronism (Conn’s syndrome) results in increased renal tubular exchange of sodium for potassium and hydrogen ions. This leads to hypokalemia, skeletal muscle weakness, fatigue, and acidosis. The aldosterone antagonist spironolactone should be used if the patient requires diuresis.
Idiopathic primary adrenal insufficiency (Addison’s disease) results in both glucocorticoid and mineralocorticoid deficiencies. Symptoms include asthenia, weight loss, anorexia, abdominal pain, nausea, vomiting, diarrhea, constipation, hypotension, and hyperpigmentation. Hyperpigmentation is caused by overproduction of ACTH and ß-lipotropin, which leads to melanocyte proliferation. Measurement of plasma cortisol levels 30 and 60 minutes after intravenous administration of ACTH, 250 mg, aids in diagnosis. Patients with primary adrenal insufficiency demonstrate no response. Glucocorticoid replacement is required on a twice-daily basis and should be increased with stress. Mineralocorticoid therapy can be given once daily. Of note, patients treated for more than 3 weeks with exogenous glucocorticoids for any medical condition should be assumed to have suppression of their adrenal–pituitary axis and should be treated with stress-dose steroids perioperatively.
Pheochromocytoma is a tumor of the adrenal medulla that secretes both epinephrine and norepinephrine. Five percent of these tumors are inherited in an autosomal dominant fashion as part of a multiple endocrine neoplasia syndrome.

Symptoms include hypertension (which is often episodic), headache, palpitations, tremor, and profuse sweating. Preoperative treatment begins with phenoxybenzamine, a long-acting a-blocker, or prazosin at least 10 days prior to surgery. A ß-blocker is added only after the establishment of a-blockade to avoid unopposed ß-mediated vasoconstriction. Acute hypertensive crises can be managed with nitroprusside or phentolamine.
Diabetes mellitus
Diabetes is a disorder of carbohydrate metabolism that results in a wide range of systemic manifestations. It is the most common endocrine abnormality found in surgical patients and can be characterized as either insulin-dependent (type I or juvenile onset) or non-insulin-dependent (type II). Hyperglycemia may result from a variety of etiologies that affect insulin production and function. Management techniques seek to avoid hypoglycemia and maintain high normal serum glucose levels throughout the perioperative period. These goals are often difficult to maintain, however, because infection, stress, exogenous steroids, and variations in carbohydrate intake can all cause wide fluctuations in serum glucose levels. Close monitoring is mandatory, with correction of hyperglycemia using a sliding scale for insulin dosage or continuous intravenous infusion in more severe cases. Fluid management should focus on maintaining hydration and electrolyte balance.
A history of easy bruising or excessive bleeding with prior surgery should raise suspicion of a possible hematologic diathesis. A significant number of patients will also present on anticoagulative therapy for coexisting medical conditions. It is therefore important for the surgeon to recognize and treat the diagnosis and therapy of the more common hematologic disorders, both congenital and acquired.
After a careful history, the physician should obtain laboratory studies. PT, PTT, and platelet count are included in the routine preoperative screen. PT evaluates both the extrinsic and the final common pathways. Included in the extrinsic pathway are the vitamin K-dependent factors II, VII, IX, and X, which are inhibited by warfarin. Conversely, heparin inhibits thrombin and factors IXa, Xa, and XIa, elements of the intrinsic clotting pathway. PTT measures the effectiveness of the intrinsic and final common pathways. Relative to the normal population, some patients may demonstrate significant variation in the quantitative levels of certain factors in the absence of clinically relevant clotting abnormalities. Thrombocytopenia or platelet dysfunction can also lead to derangements in coagulation. A standard CBC includes a platelet count, which should be greater than 50,000 to 70,000 before surgery. The ivy bleeding time, a clinical test of platelet function, should be between 3 and 8 minutes. Fibrin split products may also be measured to help determine the diagnosis of disseminated intravascular coagulation.
Congenital deficiencies of hemostasis affect up to 1% of the population. Fortunately, the majority of these deficiencies are clinically mild. Two of the more serious deficiencies involve factor VIII, which is a complex of two subunits, factor VIII:C and factor VIII:von Willebrand’s factor. Sex-linked recessive transmission of defects in the quantity and quality of factor VIII:C leads to hemophilia A. Because of its short half-life, perioperative management of factor VIII:C requires infusion of cryoprecipitate every 8 hours. Historically, these patients have had a high incidence of hepatitis and HIV due to the administration of pooled blood products. Improved screening of blood products and recombinant deoxyribonucleic acid (DNA) technology have markedly diminished this problem.
von Willebrand’s disease has a milder presentation than hemophilia A; bleeding tends to be mucosal rather than visceral. There are three subtypes. Types I and II represent quantitative and qualitative deficiencies, respectively, and are passed by autosomal dominant transmission. Type I also is characterized by low levels of factor VIII:C. Much rarer and transmitted as an autosomal recessive gene, type III von Willebrand’s disease presents with symptoms similar to those of hemophilia A. Because of the longer half-life of factor VIII:von Willebrand’s factor, patients with type II von Willebrand’s disease can be transfused with cryoprecipitate up to 24 hours before surgery, with repeat infusions every 24 to 48 hours. Patients with type I von Willebrand’s disease require additional transfusion just prior to surgery in order to boost factor VIII:C levels and normalize bleeding time.
Patients with hemophilia, von Willebrand’s disease, and other less common congenital hemostatic anomalies should be followed perioperatively by a hematologist. Correction of factor deficiencies should be instituted in a timely fashion, and patients should be monitored closely for any evidence of bleeding.
Warfarin, heparin, and aspirin have become commonly used medications in the medical arsenal. Conditions such as atrial fibrillation, deep vein thrombosis, pulmonary embolism, and heart valve replacement are routinely treated initially with heparin, followed by warfarin on an outpatient basis. This therapy markedly decreases the incidence of thromboembolic events and, when appropriately monitored, only slightly increases the risk of hemorrhagic complications. Aspirin is widely used both as an analgesic and as prophylaxis for coronary artery disease. Patients taking any of these medications need careful evaluation to assess the severity of the condition necessitating anticoagulation. The benefit of surgery relative to the risk of normalizing coagulation should be clearly established with both the patient and the physician prescribing the anticoagulant.
Warfarin should be stopped at least 3 days prior to surgery

depending on liver function. Patients who have been determined to be at high risk for thromboembolism should be admitted for heparinization prior to surgery. The infusion rate can then be adjusted to maintain the PTT in a therapeutic range. Discontinuation of heparin approximately 6 hours before surgery should provide adequate time for reversal of anticoagulation. In emergency situations, warfarin can be reversed with vitamin K in approximately 6 hours and more quickly with the infusion of fresh frozen plasma (FFP). Heparin can be reversed with protamine or FFP. Of note, a heparin rebound phenomenon in which anticoagulative effects are reestablished can occur up to 24 hours after the use of protamine. Anticoagulative therapy can be reinstituted soon after surgery if necessary. Most surgeons, however, prefer to wait several days unless contraindicated. It is often helpful to discuss the timing of postoperative therapy with the hematologist prior to surgery.
Aspirin, an irreversible inhibitor of platelet function, leads to prolonged bleeding time. There is no strong evidence to link aspirin therapy with excessive intraoperative bleeding. However, the theoretical risk that aspirin and other nonsteroidal antiinflammatory medications present leads most surgeons to request that their patients stop taking these medications up to 2 weeks prior to surgery to allow the platelet population to turn over.
Liver failure
Patients with liver failure can present with several hematologic abnormalities. Bleeding from esophageal varices secondary to portal hypertension can lead to anemia. Hypersplenism and alcoholic bone marrow suppression can result in serious thrombocytopenia. An elevated PT may indicate a deficiency in the vitamin K-dependent factors of the extrinsic clotting pathway as well as factors I, V, and XI, which are also produced in the liver. Lastly, as liver failure progresses, excessive fibrinolysis may occur. All of these hematologic sequelae of hepatic failure increase the risk of operative morbidity and mortality. Preoperative management should attempt to correct anemia and thrombocytopenia as indicated and replenish deficient clotting factors with FFP. Fluid management may prove to be a difficult issue.
Another less common cause of PT elevation is the intestinal sterilization syndrome in which intestinal flora, a major source of vitamin K, are eradicated by prolonged doses of antibiotics in patients unable to obtain vitamin K from other sources. Reversal occurs rapidly with vitamin K therapy.
A decrease in platelet count can occur as a result of a variety of medical conditions, including massive transfusion, liver failure, disseminated intravascular coagulation, aplastic anemia, hematologic malignancy, and idiopathic thrombocytopenic purpura. With the increasing use of chemotherapeutics for a variety of malignancies, the prevalence of iatrogenic thrombocytopenia has risen. Preoperatively, the platelet count should be greater than 50,000; at levels below 20,000, spontaneous bleeding may occur. Additionally, any indication of platelet dysfunction should be evaluated with a bleeding time. Severe azotemia secondary to renal failure may lead to platelet dysfunction (uremic platelet syndrome). Dialysis should be performed as necessary.
Correction of thrombocytopenia with platelet transfusion should preferably come from human leukocyte antigen-matched donors, particularly in patients who have received prior platelet transfusions and may be sensitized. One unit of platelets contains approximately 5.5 × 1011 platelets. One unit per 10 kg of body weight is a good initial dose. The platelets should be infused rapidly just prior to surgery.
Of the more than 300 hemaglobinopathies, sickle cell disease and thalassemia are by far the most common. Approximately 10% of blacks in the United States carry the gene for sickle cell anemia. The heterozygous state imparts no real anesthetic risk. There are significant clinical manifestations to the 1 in 400 blacks who are homozygous for hemoglobin S. The genetic mutation results in the substitution of valine for glutamic acid in the sixth position of the ß-chain of the hemoglobin molecule, leading to alterations in the shape of erythrocytes when the hemoglobin deoxygenates. The propensity for sickling directly relates to the quantity of hemoglobin S. Clinical findings include anemia and chronic hemolysis. Infarction of multiple organ systems can occur secondary to vessel occlusion. Most patients die by 30 years of age as a result of complications of their disease.
Treatment consists of preventive measures. Oxygenation and hydration help maintain tissue perfusion. Transfusion prior to surgical procedures decreases the concentration of erythrocytes carrying hemoglobin S, thereby lowering the chance of sickling.
There are multiple types of thalassemia, each caused by genetic mutations in one of the subunits of the hemoglobin molecule. Symptoms vary on the severity of the mutation. Patients with the most severe form, ß-thalassemia major, are transfusion dependent, which often leads to iron toxicity. Other thalassemias cause only mild hemolytic anemia. If transfusion dependency exists, the patient should be screened carefully for hepatic and cardiac sequelae of iron toxicity.
A solid, working familiarity with the cranial nerves is intrinsic to the specialty of otolaryngology. Numerous pathologic processes, both benign and malignant, as well as traumatic injuries have the potential for cranial nerve and intracranial involvement. In the preoperative setting, therefore, the otolaryngologist is obliged to perform a thorough neurologic examination and review of the neurologic system. A cursory search for symptoms of visual loss, diplopia, anosmia, facial pain and tics, headaches, paresthesias and hypoesthesias,

facial paralysis or paresis, dysequilibrium, hearing loss, dysphagia, hoarseness, and tongue deviation or fasciculations forms a basis of the neurologic history. A more specific review can then be tailored based on the presenting complaint and physical findings. Recognition of constellations of signs and symptoms, as seen in Horner’s syndrome, is useful in establishing a diagnosis.
Confirmation of neurologic deficits can be made using various examinations and tests such as audiometry, electronystagmography, electromyography, cine-esophagography, videostroboscopy, and fiberoptic laryngoscopy. For medicolegal reasons, it is critical to document all neurologic abnormalities. It is important to distinguish peripheral from central lesions, and computed tomography (CT) or magnetic resonance imaging (MRI) is often helpful in this regard. Frequently, neurologic consultation is sought in the setting of subtle findings or confusing or paradoxic findings and for evaluation of possible nonotolaryngologic etiologies of certain complaints such as headache and dysequilibrium. During preoperative counseling of the patient, the surgeon must be aware of the potential for nerve injury or sacrifice and must communicate the possible sequelae of these actions to the patient.
If present, a history of seizures should be outlined with respect to the type, pattern, and frequency of epilepsy as well as the current anticonvulsant medications in use and their side effects. Phenytoin therapy can lead to poor dentition and anemia, whereas treatment with carbamazepine can cause hepatic dysfunction, hyponatremia, thrombocytopenia, and leukopenia, all of which represent concerns for the surgeon and anesthesiologist. Preoperative CBC, liver function tests, and coagulation studies are thus advised. Anesthetic agents such as enflurane, propofol, and lidocaine have the potential to precipitate convulsant activity, depending on their doses. In general, antiseizure medications must be at therapeutic serum levels and should be continued up to and including the day of surgery.
Symptomatic autonomic dysfunction can contribute to intraoperative hypotension. It may be necessary to augment intravascular volume preoperatively through increasing dietary salt intake, maximizing hydration, and administering fludrocortisone.
Additional considerations must be taken into account in patients with upper motor neuron diseases, such as amyotrophic lateral sclerosis, or lower motor neuron processes affecting cranial nerve nuclei in the brainstem. In either case,the otolaryngologist may be confronted with bulbar symptoms such as dysphagia, dysphonia, and inefficient mastication. As bulbar impairment progresses, the risk of aspiration increases significantly. When respiratory muscles are affected, the patient is likely to have dyspnea, intolerance to lying flat, and an ineffective cough. Coupled with aspiration, these factors put the patient at considerable surgical risk for pulmonary complications. Hence, if surgery is necessary for these patients, preoperative evaluation should include a pulmonary workup (including chest radiography, pulmonary function tests, ABG analysis) and consultation. A video study of swallowing function may also be indicated. Finally, the patient’s neurologist should be closely involved in the decision making (i.e., whether to proceed with surgery).
Parkinsonism presents the challenges of excessive salivation and bronchial secretions, gastroesophageal reflux, obstructive and central sleep apnea, and autonomic insufficiency, all of which predispose to difficult airway and blood pressure management in the perioperative period. Dopaminergic medications should be administered up to the time of surgery in order to avoid the potentially fatal neuroleptic malignant syndrome. Medications such as phenothiazines, metoclopromide, and other antidopaminergics should be avoided. Preoperatively, the patient’s pulmonary function and autonomic stability should be investigated.
If clinically indicated, patients with multiple sclerosis should also undergo full pulmonary evaluation preoperatively, because these patients can present with poor respiratory and bulbar function. The presence of contractures can limit patient positioning on the operating table. In addition, prior to surgery, the patient must be free of infection because pyrexia can exacerbate the conduction block in demyelinated neurons.
Otolaryngologists often must manage patients with facial trauma and head injury, usually in the acute care setting. Preoperative evaluation should be guided by the ABC’s of resuscitation. Emergency situations predisposing to loss of the airway or cardiovascular collapse must be addressed immediately. Additionally, once stabilized, a thorough neurosurgical or neurologic assessment is required prior to elective fixation of injuries such as facial fractures.
Preoperative management of patients with any of the other remaining neurologic disorders is not discussed here.Evaluation in these patients should be focused primarily on airway, cardiopulmonary, and neurologic issues, as well as any other coexisting medical problems that may compromise anesthetic outcome.
Finally, for medicolegal reasons, an estimation of the mental status of all patients should be documented preoperatively.
The elderly represent the fastest growing segment of the U.S. population. Twenty-five percent to 33% of all surgeries are currently performed on individuals over 65 years of age, and this percentage is likely to increase in the next decade as the “baby boom” generation reaches retirement age. A greater likelihood of comorbid conditions exists with increasing age. In addition, physiologic reserve is often compromised. Preoperative assessment in this population should take these considerations into account and weigh the benefit of the procedure against the often increased risks in this population. Consultation with the anesthesia service facilitates planning for high-risk elderly patients.

Approximately 50% of all postoperative deaths in the elderly occur secondary to cardiovascular events. Severe cardiac disease should be treated prior to any elective procedure and should be weighed against the benefit of any more urgent procedure. If surgery is required, cardiac precautions should be instituted. Patients with physical evidence or a history of peripheral vascular disease should be evaluated for carotid artery stenosis. If a critical stenosis is identified, carotid endarterectomy should be performed to any elective procedure that requires a general anesthetic. The risk of a cerebrovascular accident should be considered when evaluating patients for more urgent procedures. In vasculopathic patients requiring free-flap reconstruction after major head and neck resection, examination of both recipient and donor vessels should be performed prior to surgery to minimize complications and assist in the appropriate choice of reconstructive options.
From a respiratory standpoint, increasing age leads to loss of lung compliance, stiffening of the chest wall, and atrophy of respiratory muscles. In many otolaryngology procedures, the risk of intraoperative or postoperative aspiration and postobstructive pulmonary edema must also be considered. Patients with borderline pulmonary function may not tolerate even mild respiratory complications. The function of all the organ systems diminishes with age, necessitating a thorough preoperative evaluation to maximize patient safety in the elderly population.
This chapter has provided a brief overview of the preoperative evaluation. Disturbances in one organ system often have repercussions for other systems, and so an interdisciplinary approach involving the otolaryngologist, anesthesiologist, internist, and specialized consultants is often warranted. The authors have chosen to emphasize the physiologic aspects of the evaluation. This is not intended to overshadow the importance of gaining insight into a patient’s psychosocial preparedness, which often requires the help of family members, social workers, psychiatrists, and support groups as well as a keen sense of intuition on the part of the surgeon. Furthermore, preoperative teaching provides a means to reinforce postoperative expectations and coping mechanisms. Finally, it must be reiterated that the responsibility of ensuring an appropriate preoperative evaluation lies with the surgeon and that the expediency of this process should be in keeping with the best interest of the patient.

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Chapter 1 – History and Physical Examination

Chapter 1 – History and Physical Examination

Marion E. Couch

It is a privilege to be a physician requested to evaluate a person and render an opinion and diagnosis. The importance of an accurate, detailed history cannot be overemphasized because it is the framework on which the otolaryngologist places all available information, building toward an accurate diagnosis and management plan. Without this, the evaluation may be incomplete and the diagnosis flawed. Unnecessary testing may ensue, and, at the minimum, a delay in management may result. In the worst scenario, a misdiagnosis may occur. Therefore, the energy expended in obtaining a complete history is always worthwhile.
In addition to the challenge of obtaining a comprehensive history, the otolaryngologist is faced with examining the complex anatomy of the head and neck region. There are many different examination techniques to learn and much specialized equipment to use. It may take years to master the fundamentals of a complete head and neck examination. Even experienced otolaryngologists are continually modifying and refining their techniques to better examine patients.
Finally, the otolaryngologist should be efficient, and often this means politely directing the questions in the interview to avoid rambling answers from the patients that may contribute little to the history. The same efficiency is helpful when examining patients. The time saved by proficient examination of regions unrelated to the patients’ problem will allow for a more careful and thorough examination of the problem area.

Many physicians will mail a detailed and directed questionnaire to their patients before their office visit. This has multiple advantages. First, it enables patients to accurately record the symptoms they are experiencing and to chronicle the history of their problems. In addition, the names of all their medications and the correct dosages and any drug allergies can be listed. Addresses and telephone numbers that are difficult to recall, such as those of their primary care or referring physician, can be listed for later use. Some patients with special communicative disorders, such as those with laryngectomies, tracheostomies, or spastic dysphonia, may appreciate the opportunity to relay information without lengthy verbal discussions. For these reasons, the otolaryngologist is better able to efficiently gather important information even before the patient has arrived in the office. This information also may allow a preliminary differential diagnosis to be formulated in certain patients.
It also is helpful to request that previous medical records pertaining to the patient’s current problem be sent to the office before the visit. The primary care physician, referring physician, patient, or a family member often can assist in obtaining these records. If previous operations have been performed, operative reports can be important sources of information. In addition, pertinent radiographic imaging is helpful to obtain for review. Reports of computed tomography (CT) or magnetic resonance imaging (MRI) scans are valuable but cannot substitute for actual review of the imaging by the otolaryngologist. For head and neck cancer patients, any pathologic slide specimens from past biopsies should be sent to the pathology department for review so that a second opinion may be rendered. This is especially true when patients are referred with an unusual pathologic diagnosis. Finally, laboratory values can provide much information and should be carefully reviewed.

The questionnaire, although valuable, is no substitute for a thoughtful and thorough interview with the patient. The chief complaint should be addressed by determining duration, intensity, location, frequency, factors that make the problem worse or better, any past therapy, and related symptoms. Whether the complaint is vertigo, pain, sinusitis, hearing loss, allergies, or a neck mass, the approach should entail asking many of the same basic questions followed by more specific ones designed to elucidate the full scope of the problem.
A discussion of the patient’s medical history not only leads to a better understanding of the patient, but it often reveals pertinent information to the otolaryngologist. For instance, a patient with an otitis externa who also is diabetic requires a higher level of concern for malignant otitis externa, and this may be reflected in the management plan. If the patient requires surgery, complete knowledge of the patient’s medical problems is necessary before the operative procedure. Easy bruising and prolonged bleeding, pulmonary disease, or coronary artery disease are obvious examples of medical issues that should be addressed before surgery. However, what about the patient with cervical spine stenosis and intermittent limb paresis? Any manipulation of the cervical spine intraoperatively could have serious ramifications. Therefore, it is essential to elicit a complete medical history because requesting the proper preoperative evaluations and consultations can only be done if this information is known.
The surgical history is equally valuable. All the past operations of the head and neck area are important to note, including surgery for past facial trauma, cosmetic facial plastic surgery, otologic surgery, and any head and neck surgery for neoplasm, although full disclosure of all past operations may be critical. For example, the choice of a free flap may depend on whether a patient has had previous abdominal surgery with incisions that would have transected the flap pedicle. If any patient goes to surgery, it is essential to know if a patient has had previous adverse reactions to anesthetic agents or had a difficult intubation.
Obviously, any known drug allergies and side effects are critical to note prominently in the medical chart. True allergies should be distinguished from side effects because an effective antibiotic may be needlessly avoided when the patient has previously experienced common side effects such as gastrointestinal discomfort, which can be safely managed. In addition, all medications and current dosages should be accurately recorded. Often, it is valuable to inquire whether the patient has been compliant with the medication regimen that was prescribed because it is important to consider the doses that the patient actually is receiving. For instance, nasal steroids should be used daily and are not as effective when used intermittently. Therefore, a poor response may be solely a result of subtherapeutic levels of the medication.
After this, it often is advantageous to assess for risk factors associated with certain disease states. Tobacco use is important to note. It is helpful to specifically ask about cigarette, cigar, and chewing tobacco consumption—either current or past use. Patients being assessed for head and neck cancer may deny tobacco use if only asked if they smoke cigarettes, although they may have extensively used cigars or chewed “snuff.” Alcohol consumption also is occasionally difficult to quantitate unless the interviewer asks direct questions regarding frequency, choice of beverage, and duration of use. Recreational drug use should be addressed, as should risk factors for communicable diseases such as the human immunodeficiency virus (HIV) and hepatitis virus. For patients being assessed for hearing loss, major risk factors such as exposure to machinery, loud music, or gunfire should be discussed. Finally, past irradiation (implants, external beam, or by mouth) and dosage (either high- or low-dose) should be ascertained. A history of accidental radiation exposure also is important to document.
The social history should not be overlooked because it may often reveal more occult risk factors for many diseases. For instance, a retired steel worker may have an extensive history of inhaling environmental toxins, whereas a World War II veteran may have noise-induced hearing loss from his or her military service. Family history often is equally revealing, and asking patients questions about their familial history of such conditions as hearing loss, congenital defects, atopy, or cancer may uncover useful information that they had not previously considered.
Finally, a review of systems is part of every comprehensive history. This review includes changes in the patient’s respiratory, neurologic, cardiac, endocrine, psychiatric, gastrointestinal, urogenital, cutaneous skin, or musculoskeletal systems. The otolaryngologist often may derive more insight into the patient’s problem by inquiring about constitutional changes such as weight loss or gain, fatigue, heat or cold intolerance, rashes, and the like ( Box 1–1 ).
It is imperative to develop an approach to the head and neck examination that allows the patient to feel comfortable while the physician performs a complete and comprehensive evaluation. Many of the techniques used by the otolaryngologist, such as fiberoptic nasopharyngolaryngoscopy, may leave a patient feeling alienated if not done correctly, with a sensitivity to the patient’s emotions. Even allowing inspection of one’s oral cavity or nares requires a certain amount of trust by the patient. Thus, it is essential to establish a rapport with a patient before proceeding with the examination. At the same time, the physician should be confident and comfortable with a standard routine examination that allows systematic examination of every patient so that nothing is forgotten or overlooked.
A word of caution is necessary. The head and neck examination should only be done with the examiner wearing gloves and, in most instances, protective eye covering. Universal precautions are mandatory in today’s practice of medicine.


Box 1-1. History
Introduce yourself



Medical records

Radiographic imaging

Laboratory values

Pathology specimens

Inquire about chief complaints




Medical history

Surgical history



Risk factors

Tobacco, alcohol

Social history

Family history

Review of systems










Therefore, routine hand-washing and wearing gloves should be incorporated into the examination ritual. This has the added benefit of showing the patient that the examiner is concerned about not transmitting any diseases, which builds trust between the patient and physician.
General appearance
Much information can be obtained by first assessing the general behavior and appearance of the patient. For instance, the patient’s affect may suggest possible depression, anxiety, or even alcoholic intoxication. Psychotic behavior in the office may be a result of many factors but may indicate profound hypothyroidism in head and neck cancer patients. Astute observation of the patient’s appearance is equally important. Tar-stained fingernails, teeth, or moustache are harbingers for heavy tobacco consumption. Even the gait of patients as they enter or leave the office may reveal information. Neurologic impairments, especially involving the cerebellum, may affect the patient’s ability to navigate into the room.
After assessing the patient’s overall appearance, the face should be analyzed for facial asymmetry by positioning the

TABLE 1-1 — AAQ-HNS facial nerve grading system
Facial movement
I. Normal
Normal facial function at all times
II. Mild dysfunction
Forehead: moderate-to-good function
Eye: complete closure
Mouth: slight asymmetry
III. Moderate dysfunction
Forehead: slight-to-moderate movement
Eye: complete closure with effort
Mouth: slightly weak with maximum effort
IV. Moderately severe dysfunction
Forehead: none
Eye: incomplete closure
Mouth: asymmetric with maximum effort
V. Severe dysfunction
Forehead: none
Eye: incomplete closure
Mouth: slight movement
VI. Total paralysis
No movement

head squarely in front of the examiner. This simple step may yield subtle but important information. For instance, in patients considering facial plastic surgery, a hemifacial microsomia may affect the final outcome, and this should be discussed before the operation. In addition, a paretic facial nerve always is a serious finding that can be detected by observing the tone of the underlying facial musculature and overlying facial skin. Facial wrinkles are more prominent when the facial nerve is functioning. Other maneuvers to assess facial nerve function include having the patient broadly smile, wrinkle the nose, and close the eyes tightly. For patients recovering from facial nerve paralysis, the AAQ-HNS Facial Nerve Grading System is a respected standard for reporting gradations of nerve function ( Table 1–1 ).
Facial skeleton
The facial skeleton then should be carefully palpated for bony deformities. This is especially true in patients with recent facial trauma. The periorbital rims may be irregular as a result of fractures involving the zygomatic arches or orbital floor. The dorsum of the nose may be displaced as a result of a comminuted nasal fracture. After evaluation of the facial skeleton, the regions overlying the paranasal sinuses may be firmly palpated or tapped for tenderness, which may be present during an episode of sinusitis.
Evaluation of the temporomandibular joint (TMJ) is convenient to perform at this point in the examination. By having the examiner place three fingers over the TMJ region, which is anterior to the external auditory canal, anteromedial dislocation (caused by the action of the lateral pterygoid muscle) or clicking of the joint can be ascertained. The patient should open and close the jaw to assist in evaluating this synovial joint.

Masses in the parotid may be benign or malignant neoplasms of the parotid, cysts, inflammatory masses, or lymph node metastasis from other areas. The tail of the parotid extends to the region lateral and inferior to the angle of the mandible. This is a common site for parotid masses to reside. The parotid–preauricular and retroauricular lymph nodes also should be systematically assessed in every patient. By facing the patient and placing both hands behind the ears before palpating the preauricular nodes, the often-neglected retroauricular nodes will not be missed.
Skin covering the face and neck should be examined, and suspicious lesions should be noted. The external auricles often receive sun exposure and are at risk for developing the skin malignancies such as basal cell and squamous cell carcinomas. The scalp should be examined for hidden skin lesions, such as melanoma, basal cell carcinoma, or squamous cell carcinoma. All moles should be inspected for irregular borders, heterogeneous color, ulcerations, and satellite lesions.
The neck, an integral part of the complete otolaryngology examination, is best approached by palpating it while visualizing the underlying structures ( Fig. 1–1 ). The midline structures such as the trachea and larynx can be easily located and then palpated for deviation or crepitus. If there is a thyroid cartilage fracture, tenderness and crepitus may be present. In thick, short necks, the “signet ring” cricoid cartilage is a good landmark to use for orientation. The hyoid bone can

Figure 1-1 Basic anatomy of the anterior neck. Visualize structures while performing neck examination.

be inspected and palpated by gently rocking it back and forth.
Thyroid gland
Traveling more inferior in the neck, the thyroid gland, which resides below the cricoid cartilage, should be examined by standing behind the patient and placing both hands on the paratracheal area near the cricoid cartilage. Having the patient swallow or drink a sip of water often helps better delineate the thyroid lobes by having the trachea rise and fall. Pressing firmly in one tracheal groove allows the contents of the other side to be more easily distinguished by gentle palpation. Nodules or cystic structures should be carefully noted and evaluated, often by fine-needle aspiration. Adjacent adenopathy also should be carefully assessed.
After this, palpation of the supraclavicular area, from the paratracheal grooves posteriorly to the sternocleidomastoid muscle to the trapezius muscle, will help detect masses or enlarged lymph nodes, which are worrisome for metastasis from sources such as the abdomen, breast, or lung. Proceeding more superiorly, the area inferior to the angle of the mandible houses the carotid arteries and often has many lymph nodes, either “shoddy” and indistinct or firm. Palpable nodes always should be noted and may need evaluation with either fine-needle aspiration or radiologic imaging when observation is not appropriate. The carotid artery, often mistaken for a prominent node, can be assessed for the presence of bruits. The entire jugulodigastric chain of lymph nodes merits careful inspection by outlining the sternocleidomastoid muscle and palpating the soft tissue anterior and posterior to it. The submandibular and submental regions are palpated by determining the outline of the glands and any masses present. It often is difficult to distinguish masses from the normal architecture of the submandibular gland, and therefore, bimanual palpation of this area using a gloved finger in the floor of the mouth is helpful.
Triangles of the neck
It is helpful to define the neck in terms of triangles when communicating the location of physical findings ( Fig. 1–2 ). The sternocleidomastoid muscle divides the neck into a posterior triangle, whose boundaries are the trapezius, clavicle, and sternocleidomastoid muscles, and an anterior triangle, which is bordered by the sternohyoid, digastric, and sternocleidomastoid muscles. These triangles are further divided into smaller triangles. The posterior triangle houses the supraclavicular and the occipital triangles. The anterior triangle then may be divided into the submandibular, carotid, and muscular triangles.
Lymph node regions
Another classification system for neck masses uses the lymph node regions, which is especially useful for head and neck surgeons when depicting the location of adenopathy ( Fig. 1–3 ). Level IA is the submental triangle, and level IB is the submandibular triangle. The upper third of the jugulodigastric chain is level II, whereas the middle and lower third represent levels III and IV, respectively. More specifically, the jugulodigastric lymph nodes from the skull base to the hyoid bone are located in level II. Level III extends from the hyoid bone to the cricoid cartilage, and level IV includes the lymph nodes located from the cricoid to the clavicle. Level V is the posterior triangle, which includes the spinal accessory and supraclavicular nodes. The prethyroid nodes are contained in level VI, whereas the tracheoesophageal nodes are in level VII. The parotid–preauricular, retroauricular, and suboccipital regions often are designated as the P, R, and S regions.
The postauricular region, which is frequently overlooked, often has many hidden physical findings. For instance, well-healed surgical incisions signify previous otologic procedures have been performed. In children, the postauricular mastoid area may harbor important clues that a mastoiditis with a subperiosteal abscess has developed. The erythema and edema may cause the entire auricle to be pushed down outward, away from the temporal bone, obliterating the postauricular sulcus. Finally, in patients with head trauma, postauricular ecchymosis, or Battle’s sign, suggests that a temporal bone fracture may have occurred.
The area anterior to the pinna, at the root of the helix, may house preauricular pits or sinuses, which may become infected. The external auricles also may reflect abnormalities or congenital malformations, including canal atresia, accessory auricles, microtia, and prominent protruding “bat ears.” The outer ears may have edema with weeping, crusting otorrhea, which may signify an infection is present. Psoriasis of the auricle or external auditory canal with its attendant flaking, dry skin, and edema is another common finding.
Careful inspection of the auricles may reveal conditions that mandate prompt management. For instance, an auricular hematoma, with a hematoma separating the perichondrium from the underlying anterior auricular cartilage, will present as a swollen auricle with distortion of the normal external anatomy. If not surgically drained, a deformed “cauliflower ear” may result. Another important diagnosis is that of carcinoma of the auricle. Because early diagnosis is important, all suspicious lesions or masses should be judiciously biopsied or cultured. A maculopapular rash on the auricle and the external auditory canal in patients with facial nerve paralysis most likely is a result of herpes zoster oticus or Ramsey-Hunt syndrome. Finally, an erythematous painful pinna may represent many entities, such as perichondritis, relapsing polychondritis, Wegener’s granulomatosis, or chronic discoid lupus erythematosus.


Figure 1-2 Triangles of the neck. The anterior triangle is divided from the posterior triangle by the sternocleidomastoid muscle.
Metabolic disorders also may have manifestations that affect the auricles. Patients with gout may have tophus on the pinna that will exude a chalky white substance if squeezed. Ochronosis is an inherited disorder of homogentisic acid that will cause the cartilage of the auricles to blacken. These examples of various diseases and syndromes illustrate the importance of examining the auricles on a routine basis.
External auditory canal
The outer third (approximately 11 mm) of the auditory canal is cartilaginous, and the adnexa of the skin contains many sebaceous and apocrine glands that produce cerumen. Hair follicles also are present. The inner two thirds (approximately 24 mm) of the canal is osseous and has only a thin layer of skin overlying the bone. Cerumen is commonly found accumulating in the canal, often obstructing it. When removing cerumen, remember two points. The canal is well supplied with sensory fibers: CN V3, the auricular branch of CN X, C3, and CN VII. Second, the canal curves in an S-shape toward the nose. To visualize the ear canal, gently grasp the pinna and elevate it upward and backward. This will open the external auditory canal opening and allow atraumatic insertion of the otoscopic speculum. Cerumen impaction may be removed with many techniques, such as careful curetting, gentle suctioning, or irrigation with warm water.
An otitis externa, or “swimmer’s ear,” is a painful condition with an edematous, often weeping external canal. If severe, the entire canal may be so edematous and inflamed that it closes, making inspection of the tympanic membrane difficult. Gently tugging on the auricle is painful for many patients. The periauricular lymph nodes may be tender and enlarged. If the patient is immunocompromised or diabetic, the canal should be carefully inspected for the presence of granulation tissue at the junction of the cartilaginous and bony junction. This may signify that a malignant otitis externa is present, which, as an osteomyelitis of the temporal bone, requires aggressive management, including prompt intravenous antibiotics.
In older patients, atrophy of the external auditory canal skin is frequently seen and may be associated with psoriasis or eczema of the canal. If patients attempt to sooth an itch


Figure 1-3 Lymph node regions of the neck.
with foreign objects such as keys, hair pins, or cotton-tipped swabs, scabs or areas of ecchymosis may be present in the posterior canal wall.
Children are most likely to inset foreign bodies into the ear canal. Although most objects will lodge lateral to the narrowest part of the canal, the isthmus, some will be found in the anterior recess by the tympanic membrane, making it especially difficult to visualize with an otoscope, so have patients turn their head to view this area. In adults, cotton plugs are commonly lodged and often are impacted against the tympanic membrane. In patients of all ages, insects may find their way into the canal. Instilling the canal with alcohol or lidocaine is effective in killing this particularly annoying foreign body. A combination of suctioning, alligator forceps, and irrigation frequently is needed to remove foreign body objects. An operating microscope allows excellent visualization and enables the physician to use both hands to manipulate the instruments needed to remove the object.
Otorrhea is commonly seen in the external auditory canal. The characteristics of the aural discharge may reveal the etiology of the otorrhea. For instance, mucoid drainage is associated with a middle ear chronic suppurative otitis media because only the middle ear has mucus glands. In these patients, a tympanic membrane perforation should be present to allow the mucoid otorrhea to escape. Foul-smelling otorrhea may be caused by chronic suppurative otitis media with a cholesteatoma. Bloody, mucopurulent otorrhea frequently is seen in patients with acute otitis media, trauma, or carcinoma of the ear. Otorrhea with a watery component may signify a cerebrospinal fluid leak or eczema of the canal. Black spores in the otorrhea may be present in a fungal otitis externa caused by Aspergillus species. Gentle suctioning is used to clean the canal and to inspect it thoroughly.
In patients with head trauma, a temporal bone fracture is important to recognize. Bloody otorrhea in conjuction with an external canal laceration or hemotympanium are very serious findings. Longitudinal fractures often involve the external canal. Because longitudinal fractures may be bilateral, careful inspection of both canals is essential.
Tympanic membrane
To view the tympanic membranes, the correct otoscope speculum size is used to allow a seal of the ear canal. With pressure from the pneumatic bulb, the tympanic membrane will move back and forth if the middle ear space is well aerated. Perforations and middle ear effusions are common causes for nonmobile tympanic membranes.
The tympanic membrane is oval, not round, and has a depressed central part called the umbo, wherein the handle of the malleus attaches to the membrane. The lateral process of the malleus is located in the superior anterior region and is seen as a prominent bony point in atelectatic membranes. Superior to this process is the pars flaccida, wherein the tympanic membrane lacks the radial and circular fibers present in the pars tensa, which is the remainder of the ear drum. This superior flaccid area is critical to examine carefully because retraction pockets may develop here, which may develop into cholesteatomas. In congenital cholesteatomas, often diagnosed in young children, the tympanic membrane is intact, and a white mass is seen in the anterior superior quadrant. Acquired cholesteatomas in adults are different in that they often are in the posterior superior quadrant and are associated with retraction pockets, chronic otitis media with purulent otorrhea, and tympanic membrane perforations.
To assess the middle ear for effusions, use the tympanic membrane as a window that allows a view of the middle ear structures ( Fig. 1–4 ). Effusions may be clear (serous), cloudy with infection present, or bloody. When the patient performs a Valsalva maneuver, actual bubbles may form in the effusion.
Hearing assessment
Tuning fork tests, usually done with a 512-Hz fork, allow one to distinguish between sensorineural and conductive hearing loss ( Table 1–2 ). They also may be used to confirm the audiogram, which may give spurious results because of poor fitting earphones or variations in equipment or personnel. Be sure to conduct all tests in a quiet room without background noise. Also, be certain that the external auditory canal is not blocked with cerumen.
The Weber test is performed by placing the vibrating tuning fork in the center of the patient’s forehead or at the


TABLE 1-2 — Tuning fork testing
Begin with 512-Hz fork, then include 256- and 1024-Hz forks
Place tuning fork in center of patient’s forehead. Ask patient if sound is louder on one side or is heard midline.
Weber “negative”
Weber right
Weber left
Patient response
“Sound is midline”
“Sound is louder on right”
“Sound is louder on left”
Bone-conducted sound equal in both ears
Unilateral right conductive hearing loss; unilateral left sensorineural hearing loss
Unilateral left conductive hearing loss; unilateral right sensorineural hearing loss
Place tuning fork lateral to ear canal, then place it firmly on mastoid process. Ask patient if sound is louder by canal or on mastoid bone.
Rinne “positive”
Rinne “negative”
Rinne “equal”
Patient response
“Sound louder when fork by canal”
“Sound louder when fork on mastoid process”
“Sound equal”
Air conduction louder than bone conduction; normal
Bone conduction louder than air conduction; conductive hearing loss
Air and bone conduction equal

Figure 1-4 The tympanic membrane.
bridge of the nose. If the patient has difficulty with these locations, the mandible or front teeth may be used, however, the patient then should tightly clench his or her teeth. The patient then is asked if the sound is louder in one ear or is heard midline. The sound waves should be transmitted equally well to both ears through the skull bone. A unilateral sensorineural hearing loss will cause the sound to lateralize to the ear with the better cochlear function. However, a unilateral conductive hearing loss will cause the Weber test to lateralize to the side with the conductive loss because the cochlea is intact bilaterally and because bone conduction causes the sound to be better heard in the ear with the conductive loss (because there is less background noise detected through air conduction). Interestingly, a midline Weber result is referred to as “negative.” “Weber right” and “Weber left” refer to the direction the sound lateralized.
To compare air conduction with bone conduction, perform the Rinne test. The 512-Hz tuning fork is placed by the ear canal and then on the mastoid process. The patient determines whether the sound is louder when the tuning fork is by the canal (air conduction) or on the mastoid bone (bone conduction). A “positive test” result is air conduction louder than bone conduction. A conductive hearing loss will make bone conduction louder than air conduction, and this is called “Rinne negative.” When the air and bone conduction are equal, it is called “Rinne equal.”
The Schwabach test compares the patient’s hearing with the examiner’s and uses multiple tuning forks such as the 256-, 512-, 1024-, and 2048-Hz forks. The stem of the vibrating tuning fork is placed on the mastoid process of the patient and then is placed on the mastoid of the physician. This is done, alternating between the two participants, until one can no longer hear the tuning fork. Of course, this test assumes that the examiner has normal hearing. If the patient hears the sound as long as the physician, the result is “Schwabach normal.” If the patient hears the sound longer than the physician, it is called “Schwabach prolonged,” and this may indicate a conductive hearing loss for the patient. If the patient hears the sound for less time, it is called “Schwabach shortened” and is consistent with sensorineural hearing loss for the patient.
Oral cavity
The boundaries of the oral cavity extend from the skin–vermillion junction of the lips, hard palate, anterior two thirds of the tongue, buccal membranes, upper and lower alveolar ridge, and retromolar trigone to the floor of the mouth. This region may be best seen by having the otolaryngologist use a well-directed headlight and a tongue depressor

in each gloved hand. The lips should be carefully inspected and may have ulcers present that may be caused by herpes simplex virus, syphilis, or carcinoma. Remember that lip squamous cell carcinoma is more common on the lower lip. The commissures may have fissuring, which is seen in angular stomatitis or cheilosis. When the fissures and cracking are present on the mid-portion of the lips, this may be cheilitis.
The occlusion of the teeth and the general condition of the alveolar ridges, including the gums and teeth, should be noted. The tongue, especially the lateral surfaces where carcinomas are most common, should be inspected for induration or ulcerative lesions. Gently grabbing the anterior tongue with a gauze sponge allows the examiner to move the anterior tongue from side to side. By having the patient lift the tongue toward the hard palate, the floor of mouth and Wharton’s ducts (associated with submandibular glands) can be viewed. Pooling of carcinogens in the saliva on the floor of the mouth has been postulated to cause this area to have a high incidence of carcinoma in the oral cavity. Be sure to palpate the floor of mouth using a bimanual approach with one gloved hand in the mouth.
The buccal membranes should be inspected for white plaques that may represent oral thrush, if easily scraped off with a tongue blade, or leukoplakia, which cannot be removed. More worrisome for a precancerous condition is erythroplakia; therefore, all red lesions and most white lesions should be judiciously biopsied for cancer or carcinoma in situ. While examining the buccal membranes, note the location of the parotid duct, or Stenson’s duct, as it opens near the second upper molar. Small yellow spots in the buccal mucosa are sebaceous glands, commonly referred to as Fordyce spots, and are not abnormal. Aphthous ulcers, or the common canker sore, are painful white ulcers that can be on any part of the mucosa but are commonly present on the buccal membrane.
The hard palate may have a bony outgrowth known as a torus palatinus. These midline bony deformities are benign and should not be biopsied, although growths that are not in the midline should be more carefully evaluated as possible cancerous lesions.
The oropharynx includes the posterior third of the tongue, anterior and posterior tonsillar pillars, the soft palate, the lateral and posterior pharyngeal wall, the soft palate, and the vallecula ( Fig. 1–5 ). It is best visualized using a headlight and two tongue depressors. A dental mirror is instrumental in viewing the vallecula and the posterior pharyngeal wall, which often are obscured. Using a gloved finger to examine the base of tongue or tonsil may reveal indurated areas that may be appropriate for biopsy for neoplasm. The patient should be aware of the possibility that gagging may ensue when this is done. In patients with especially strong gag reflexes, a fiberoptic examination may be necessary to fully assess the base of tongue, posterior pharyngeal wall, and vallecula. By carefully passing the flexible fiberoptic endoscope

Figure 1-5 The oropharynx, which includes the posterior third of the tongue, soft palate, tonsillar pillars (anterior and posterior), lateral and posterior pharyngeal wall, and vallecula.
through the anesthetized nose, the interaction of the soft palate and tongue base during swallowing also may be viewed. The uvula should be inspected because a bifid structure may signify a submucosal cleft palate is present. In addition, an inflamed large uvula may mean the uvula is traumatized during the night if the patient snores heavily. Small carcinomas or papilloma lesions also may be present, so careful palpation may be indicated.
The size of the tonsils usually is denoted as 1+, 2+, 3+, or 4+ (for “kissing tonsils” that meet in the midline). The tonsils and the base of tongue may contribute to upper airway obstruction, especially if the soft palate and uvula extend posteriorly. Therefore, the oropharyngeal aperture should be carefully assessed in each patient. Tonsillitis, caused by either bacterial or viral sources such as group A streptococcus or mononucleosis, often presents with an exudate covering the cryptic tonsils. A culture of the exudate should be taken because of the importance of diagnosing and managing a streptococcal tonsillitis. Tonsilliths are a common cause for a foreign body sensation in the back of the throat. These yellow or white concretions in the tonsillar crypts are not caused by food trapping or infection, but they often cause the patient to have halitosis and should be removed with a cotton-tipped swab.

Larynx and hypopharynx
The larynx often is subdivided into the supraglottis, glottis, and subglottis. The supraglottic area includes the epiglottis, the aryepiglottic folds, the false vocal cords, and the ventricles. The inferior floor of the ventricle, the true vocal folds, and the arytenoids comprise the glottis. The subglottis region generally is considered to begin 5 to 10 mm below the free edge of the true vocal fold and to extend to the inferior margin of the cricoid cartilage, although this is somewhat controversial ( Fig. 1–6 ).
The hypopharynx can be challenging to understand. It extends from the superior edge of the hyoid bone to the inferior aspect of the cricoid cartilage by the cricopharyngeus muscle. It connects the oropharynx with the esophagus. Three areas comprise this region: the pyriform sinuses, posterior hypopharyngeal wall, and the postcricoid area. This area, rich in lymphatics, may harbor tumors that often are detected only in an advanced stage. Thus, early detection of these relatively “silent” carcinomas is important and should not be missed.
The examiner should not only detect anatomic abnormalities but should observe how the larynx and hypopharynx are functioning to allow the patient to have adequate airway, vocalization, and swallow function. It is not enough to survey the larynx for lesions and assess the true vocal fold function. For example, the patient with a normal-appearing larynx may have decreased laryngeal sensation with resultant aspiration and may need further diagnostic and therapeutic evaluation. Therefore, important information can be obtained if the physician carefully assesses the anatomic and functional aspects of this complex area.

Figure 1-6 The larynx.
Correct positioning of patients increases their comfort while maximizing the examiner’s view of the larynx. The legs should be uncrossed and placed firmly on the footrest. The back should be straight with the hips planted firmly against the chair. Patients, while leaning slightly forward from the waist, should place their chin upward so that the examiner’s light source is illuminating the oropharynx well. After discussing the examination procedure with the patient, the patient’s tongue is pulled forward by the examiner, who uses a gauze sponge between the thumb and index finger. This allows the physician’s long middle finger to retract the patient’s upper lip superiorly. A warm dental mirror (to prevent fogging) is placed in the oropharynx and elevates the uvula and soft palate to view the larynx ( Fig. 1–7 ). The patient with a strong gag reflex may benefit from a small spray of local anesthetic to help suppress the reflex.
There are some maneuvers that will allow better visualization of the larynx and its related structures. Panting, quiet breathing, and phonating with a high-pitched E aid in assessing true vocal fold function.
The epiglottis should be crisp and whitish. An erythematous, edematous epiglottis may signify epiglottitis, a serious infection or inflammation that mandates consideration of airway control. The petiole of the epiglottis is a peaked structure on the laryngeal surface of the epiglottis above the anterior commissure of the true vocal folds. It may be confused for a cyst or mass but is a normal prominence. Irregular

Figure 1-7 The laryngeal examination.

mucosal lesions may be carcinomas and require further evaluation.
In the posterior glottis, movement of the arytenoids allows determination of true vocal fold mobility. The interarytenoid mucosa may be edematous or erythematous, sometimes representing gastroesophageal reflux laryngitis. The mucosa over the arytenoids may be erythematous as a result of rheumatoid arthritis or as a result of recent intubation trauma. Posterior glottic webs or scars also may be present.
The true vocal folds should have translucent white, crisp borders that meet each other. Edema of the folds that extends for the entire fold length often is caused by Reinke’s edema, seen in tobacco users. Actual polypoid degeneration of the vocal cord with obstructing polyps may occasionally be seen in patients and may be a result of tobacco use or hypothyroidism. Ulcerative or exophytic lesions deserve further investigation, usually requiring operative direct laryngoscopy. True vocal fold paralysis and subtle gaps present between the folds during cord adduction should be noted.
During abduction of the cords, the subglottic area may be viewed. A prominent cricoid cartilage, seen inferiorly to the anterior commissure, may be mistaken for a subglottic stenosis. It is difficult to fully inspect the subglottic area in the office setting. Any concerns about subglottic inflammatory swelling, masses, or stenosis should be addressed in an operative setting or with radiographic imaging.
Flexible endoscopy
Perhaps the best technique to evaluate the function of the larynx uses the flexible fiberoptic nasopharyngolaryngoscope. In conjunction with a strong light source, this allows a more complete evaluation of the structures of the larynx than a mirror examination.
A topical decongestant and anesthetic spray usually is applied to the nares, and the patient is asked to gently sniff these nose sprays. One percent pontocaine and 2% lidocaine are commonly used as topical anesthetics. Another way to administer anesthesia is to carefully apply a viscous 2% lidocaine solution to the nares with a cotton-tipped applicator. It is important to allow time for these topical agents to anesthetize the nasal mucosa, and while the physician is waiting, the scope can be prepared. The focus ring is used to get the brightest possible image. Often there is a small amount of residue at the end of the fiberoptic scope, and this can be carefully removed using either a pencil eraser or an alcohol swab. If the image is not clear when the scope is out of the nose, it will not allow for a useful image when the fiberoptic scope has been passed through the nares. Once the best possible focus has been obtained, a small amount of water-soluble lubricant should be applied approximately 1 cm from the tip of the scope. This is to prevent breakage of the fiberoptic component of the scope while it is passed through the nose.
The laryngoscope then is gently passed along the floor of the nose, and with the instrument tip held above the epiglottis, the larynx may be viewed. Pooling of secretions in the pyriform sinuses is abnormal and is common in patients with decreased laryngeal sensation, neurologic impairment, or tumors. Saliva freely flowing in and out of the true cords is another indication of decreased laryngeal function. In some patients, having patients inhale and hold their breath often aids in viewing the pyriform sinuses. Asking the patient to cough and swallow and then viewing the residual saliva or phlegm also is helpful. The flexible fiberoptic examination enables the patient to freely phonate, unlike with the mirror examination, and the true vocal folds may be assessed by moving the instrument tip into the laryngeal vestibule for closer inspection.
Rigid telescopic examination with 70°, 90°, and 110° telescopes is performed in a similar fashion to the mirror examination. It permits photographic documentation of the laryngeal examination. In patients with trismus, this is better tolerated than the mirror examination, and a minimal amount of local anesthetic usually is necessary.
Anterior rhinoscopy, using a headlight and nasal speculum allows assessment of the nasal septum and inferior turbinates. The speculum should be directed laterally to avoid touching the sensitive septum with the metal edges. The point wherein numerous small branches of the external and internal carotid arteries meet, or Kesselbach’s plexus, is the most common site for epistaxis; prominent vessels in this area should be noted. Anterior septal deviations and bony spurs often are evident. The characteristics of the mucosa of the inferior turbinate may range from the boggy, edematous, pale mucosa seen in those with allergic rhinitis to the erythematous, edematous mucosa seen in those with sinusitis.
Rhinorrhea often reveals important clinical information. Clear mucus often is associated with allergic rhinitis or chronic vasomotor rhinitis. Yellow or green mucopurulence is common with sinusitis. Clear watery rhinorrhea may represent spinal fluid and may indicate a cerebrospinal fluid leak.
Nasal endoscopy using rigid endoscopes allows thorough examination of even the most posterior portions of the nasal cavity. After applying a local anesthetic to the nares, either lidocaine or pontocaine spray or topical 4% cocaine, the rigid 0° endoscope may be passed into the nose along the floor of the nasal vault. The septum, inferior turbinate, and eustachian tube orifices in the nasopharynx may be seen this way. Often, at this time, it is necessary to spray a decongestant to shrink the nasal mucosa. It is helpful to attempt to view the nasal anatomy in the native state and after the decongestant so that the effect of the decongestant may be seen. After inspecting both sides, the endoscope is placed above the inferior turbinate to view the middle turbinate. Accessory ostia from the maxillary sinus often are present, especially in patients with chronic sinusitis. These openings into the lateral nasal wall often are mistaken for the true maxillary ostium.

The nasopharynx extends from the skull base to the soft palate. This is a challenging area to examine, but with the available technology, there are many ways to approach this region. The technique used often will depend on the anatomy of the patient. In the patient with a high posterior soft palate and small tongue base, an otolaryngologist with a headlight may use a small dental mirror to visualize the nasopharynx. By having the patient sit upright in the chair, the physician may firmly pull the tongue forward while opening the mouth to place the mirror just posterior to the soft palate. In a manner analogous to that used to view the larynx with a mirror, the structures in the nasopharynx will be seen when the mirror is oriented upward.
Another method uses a fiberoptic nasopharyngoscope, which allows excellent visualization of this area. After anesthetizing the nares with either topical cocaine (on pledgets) or applying lidocaine spray, many otolaryngologists will spray the nares with a decongestant. The flexible fiberoptic scope then is gently passed along the floor of the nostril beneath the inferior turbinate. The eustachian tube orifice, torus tubarius, and fossa of Rosenmueller should be inspected on each side. This may be accomplished by using the hand control to turn the tip of the scope from side to side. The midline also should be inspected for any masses, ulcerations, or bleeding areas. Rigid endoscopes offer good visualization also, although the ability to view both sides of the nasopharynx often means passing the endoscope through each nostril. The endoscopes have various angles, such as 70°, 90°, and 110°.
Arguably, the best view of all may be obtained using a 90° rigid scope in the oropharynx. By advancing the rigid scope through the mouth and by placing the beveled edge posterior to the soft palate, the nasopharynx may be seen in its entirety. Both sides of the nasopharynx may be compared for symmetry using this technique.
Whereas children will have adenoid tissue present, adults should not have much adenoid tissue remaining in this area. Thus, adenoid tissue should not be a cause of nasal or eustachian tube obstruction in adults. One possible exception is patients with HIV infections, who may manifest adenoid hypertrophy as part of their disease. Nonetheless, adults with an otitis media, especially unilateral in nature, should have their nasopharynx inspected for possible nasopharyngeal masses. If present, it is important to diagnose nasopharyngeal carcinomas, which are most common lateral to the eustachian tube orifice in the fossa of Rosenmueller. In young male patients, nasopharyngeal angiofibromas are locally aggressive, but histologically benign masses that are most commonly present in the posterior choana or nasopharynx. These masses should not be missed. Another malignancy to consider is non-Hodgkin’s lymphoma. Cysts in the superior portion of the nasopharynx may represent a benign Tornwaldt cyst or a malignant craniopharyngioma.

TABLE 1-3 — Neurologic examination
Cranial nerves
Sense of smell to several substances
Do not use ammonia (common chemical sense caused by CN V stimulation)
Visual acuity
Visual fields
Inspect optic fundi
Extraocular movements in six fields of gaze
Pupillary reaction to light
Palpate temporal and masseter muscles
Patient should clench teeth
Test forehead, cheeks, jaw for pain, temperature and light (cotton) touch
Corneal reflex (blinking in response to cotton touching the cornea)
Near reaction to light
Ptosis of upper eyelids
Symmetry of face in repose
Raise eyebrows, frown, close eyes tightly, smile, puff out cheeks
Auditory—Tuning fork tests for hearing
Vestibular—Nystagmus on lateral gaze; Hallpike-Dix test; headshaking; Caloric testing; Frenzel lenses
True vocal cord mobility
Gag reflex (CN IX or X)
Movement of soft palate and pharynx
Shrug shoulders against examiner’s hand (trapezius muscle)
Turn head against examiner’s hand (sternocleidomastoid muscle)
Stick tongue out
Tongue deviates toward side of lesion
Tongue atrophy, fasciculations

Table 1–3 outlines the basics of a neurologic examination appropriate for most head and neck patients. Certainly, patients presenting with vertigo or disequilibrium require a highly specialized neurologic examination, but that is beyond the scope of this chapter. Much valuable clinical information can be obtained with an evaluation of the cranial nerves.
This chapter serves as an outline for approaching the head and neck examination. There are many ways to perform the examination and to take the patient’s history. This chapter is not meant as an exhaustive review of all the examination techniques available, and the order in which the head and neck regions are examined can be changed to suit the physician. Remember to be consistently thorough with each patient. Developing a competently performed, routine examination increases the probability of discovering important clinical information.

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ICU & Fluids – Electrolytes – Nutrition

ICU & Fluids – Electrolytes – Nutrition:

Edited by Andy S. Binder, MD, Pulmonologist, Critical Care.  Contents:  Electrolytes:  Fluids:  Dehydration:  Shock:  Nutrition & Vitamins:  Common Conversions: Therapeutic Levels:  Hypoxemia: Hypoxia:  Pulse Oximetry: Hypercapnea:  Intubation:  Mechanical Ventilation: Sedation: Vascular Access: PA Cath Patterns:  Acid-Base Physiology:  Preamble & Abbrev & Labs:    9-08-01.

Serum Electrolytes:

Links:  Sodium (Na):   Magnesium (Mg):   Potassium (K):   Calcium (Ca):   Phosphate (P):   Always repeat to r/o artifact (laboma).

Chloride (Cl):  closely related to Na metabolism.  Requirements:  adult –> 90-120 mEq/d.  Child–> 5-7 mEq/kg/d.  Bicarbonate: Major extracellular anion with Cl.

Sodium (Na) Metabolism:

Links:  FENa:   Hyponatremia:   SIADH:   Hypernatremia:

Major determinant of body tonicity, primarily an extracellular cation.  Serum Na reflects body water.

Na requirements:  3 mEq/L ECF = 0.6 X wt in kg X 3.    Adults need ~75-150 mEq/d.  Child needs 3-5 mEq/kg/d.   1 teaspoon table salt = 100 mEq of Na.   1g salt = 17  1 mEq of Na.   1g Na = 43.5 mEq of Na.

FENa: [UrNa X SCr/ SNa X UCr] X 100–> <1 = pre-renal.  > 1= renal (ATN).  FENa is the fraction of Na in the urine filtered by the glomerulus and not reabsorbed. Corrected Na = (0.016 X BS) – 100 + Na (measured). As Na falsely decreases 1.6 mEq/L for each 100mg/dL inc glucose over 100mg/dL.


Links:  Etiology:  S/s:  W/u:  Spot Ur Na:  Ur Osm:  Tx:  Hypotonic (Hyposmotic hyponatremia):  SIADH: Isotonic (Isosmotic hyponatremia): Hypertonic (Hyperosmotic hyponatremia):

Too much extracellular water relative to Na.   Na <136 mEq/L (mmol/L) (normal = 136-145).  Na+ deficit: 0.6 X (wt in kg) X (140- Na).  The tonicity (osmolality) is usually low (hypotonic), but may be normal or high.

Causes:  ACEi. Renal Na loss–> diuretic, adrenal insufficiency, RTA, salt losing nephritis.  Nonrenal Na loss–> emesis, diarrhea, pancreatitis, rhabdo, burns.  Water excess–> SIADH, secondary adrenal insuf.  Hypovolemic –> Saline excess with dec ECV–>  CHF, cirrhosis, nephrotic syndrome.   Saline Excess w/o dec ECV–>  ARF, CRF.

S/s: muscle twitching, inc DTR, sz, HTN (20 to inc ICP), salivation, lacrimation, watery diarrhea.    Na <120 w/o sx, then gradual depletion.

W/u: get initial wt, daily wts, check serum osmolality, Ur Osm, Chem 7, Alb, Ca, Mg, FENa, spot urine Na/ K/ Cl/ Cr.  Step #1: Assess serum osmolality:   A. Normal (280-295) = isoosmotic hyponatremia (pseudohyponatremia) and is due to either 1. Hyperproteinemia or 2. Hyperlipidemia.     B. Elevated (>295) = hypertonic hyponatremia and is due to either 1. Hyperglycemia (no osmolar gap) or 2. Hypertonic infusions (mannitol, glycine).   C. Low (<280) = hypotonic hyponatremia. —->  Step #2: Assess volume status and Ur-Na.  A. Hypovolemic = total body depletion of Na disproportionately to water losses, due to 1. Urine Na >20-renal loss (osmotic diuresis, salt-losing nephropathy, diuretic, proximal RTA, adrenal insufficiency, vomiting with bicarbonaturia and obligate Na loss).  2. Urine Na <20 = extrarenal loss (vomiting, diarrhea, third-spacing).  Or B. Hypervolemic = retention of free water. 1. Urine Na >20 = renal failure.  2. Urine Na <20 = nephrotic syndrome, CHF, cirrhosis.  Or C. Euvolemic = a mixed bag.   1. Urine Na >20 = renal failure, SIADH, hypothyroidism, pain/emotional stress, various drugs (amitriptyline, carbamazepine, clofibrate, Cytoxan, morphine, vincristine), selective glucocorticoid deficiency.   2. Urine Na <20 = water intoxication.

Calculating the Na (mEq) deficit:  Not very accurate as it assumes a closed system (kidneys clamped), in real life the kidneys assist in correcting the deficit much quicker.   Na deficit = 0.6 x (wt kg) x (desired [Na] – actual [Na]).  Ex: if wt is 64kg and serum Na is 113–>  0.6 (113)  X 140-113 = 38.4 X 27 = ~1040.  If have 154 mEq Na in NS, then 1040 / 154 = ~6.7 L NS needed to correct.   To estimate the effect of 1L of infusate on serum Na:    Change in Na = [(infusate Na +K) — serum Na] / (total body water —1).

Spot Ur NA in Hyponatremia:  Interpret based on estimated volume status. Ur Na reflects aldo effect.  1. Inc Extracellular Volume (Hypervolemic): <10-20 mEq/L –> CHF, Cirrhosis, Nephrotic, hypo-albumen.   >20-40 mEq/L –> Renal Failure (acute or chronic).

2. Dec Extracellular Volume (Hypovolemic): <10-20 mEq/L –> Emesis, diarrhea, pancreatitis, lung/ skin loss (burns).   >20-40 mEq/L –> Renal Loss: Na-wasting nephropathy, osmotic diuretics, obstruction, RTA, adrenal insufficiency.

3. Isovolumic (Euvolemic):  <10-20 mEq/L –> Water intoxication.   >20-40 mEq/L –> Renal failure, hypothyroid, pain, SIADH, emotion, adrenal insufficiency, post-op states.  Variable Urine-Na concentration with decreased solute intake, psychogenic polydipsia and resetting of osmostat (pregnancy, psychiatric disorders).

Urine Osmolality:  reflects ADH effect.   Normal is >700-1400 mOsm/kg.  If 600-700 then minimal impairment in renal concentrating ability.  If 400-600 moderate impairment.  If <400 mOsm/kg then severe impairment.   In complete diabetes insipidus (DI) Ur Osm 50-200.  In partial DI 250-500.  In Nephrogenic DI 100-200.  In primary (psychogenic) polydipsia Ur Osm are 700-1200 mOsm/kg.  In high-set osmoreceptor DI it is 700-1400.

Tx:  Correct underlying d/o with volume and correct the cause.  Water restricting to <800-1000 ml/d will ameliorate all forms of hyponatremia, but it is not considered the optimal therapy as uncomfortable to the pt (only ice chips if IV at “keep vein open”) and slow (1mEq/d).  Loop diuretics with hourly K and Na replacement in hypervolemic forms.

If symptomatic–>  Hypertonic saline (3-5%) @ 2ml/kg/hr, to inc Na by a max 1-2 mEq/h, up to serum Na of 125-130.    The initial rate of correction can be 1-2 mmol/L/hr in patients with severe sx’s, but the maximum rate of correction should not exceed 8 mmol/L on any day of treatment.   Max rate of infusion of 100ml of 5% saline/h to avoid central pontine myelinolysis (demyelination, think hypo – pons, hyper = edema- cerebral).   Rule of thumb:  1ml/kg 3%NS raises serum Na by 1mEq/L.  Correct slowly over 48hr.  To raise the sodium 1mEq/hr infuse at rate of–>  (wt in kg X 0.6) / (0.513 mEq/L X 1hr). Or take the amount of NS calculated from the deficit and divide by 24hr.  The pt usually correct faster as the calculations are based on the kidneys being clamped, so re-check in 4-6hr to make sure not correcting too quick as you may need to add free water (½NS or D5W).

1.  Hypotonic (Hyposmotic hyponatremia):  Plasma Osm <280 mOsm/kg (normal = 280-295). Check Uosm –> if <150, then psychogenic polydipsia as appropriate dilution.  If Uosm >150–>  assess renal function to r/o primary renal dz.  If normal renal function, assess extracellular volume status.

W/u:   Check urine Osm, if <150 mOsm/kg then psychogenic polydipsia.  If >150 mOsm/kg assess renal function.  If inc BUN or Cr, then primary renal dz.  If normal renal function, assess extracellular fluid volume, check UrNa.  Consider the Cosyntropin Stimulation Test for adrenal insufficiency.

Etiology of Hypotonic Hyponatremia:   1. Excessive water intake:  primary polydipsia, accidental intake of water (swimming lessons), dilute infant formula, Na-free irrigant solutions during surgery, multiple tap-water enemas.

2.  Impaired capacity of renal water excretion:     A.  Decreased Volume of Extracellular Fluids (Hypovolemic):   Loss of isotonic fluids or replacement with inadequate volume of excessively hypotonic fluid. GI loss (vomit, diarrhea), skin, lungs, kidneys (diuretics, RTA, diuretic phase of ATN, adrenal insufficiency, hypo-aldo), third spacing.    Tx: 3% NS.

B.  Increased Volume of ECF (Hypervolemic):  Due to fluid retaining states such as CHF, nephrotic syndrome, hepatic failure (cirrhosis), malnutrition, acute/ chronic renal failure, pregnancy.    Tx: water restrict, consider diuresis.

C.  Normal ECF Volume (Isovolumic): Iatrogenic free water overloading, SIADH (unable to dilute urine in response to a water load), renal insufficiency, dec K (sensitizes kidney to ADH), thiazides, hypothyroid, adrenal insufficiency.   Tx: restrict water, consider hypertonic saline if sx’s.

Other:   Oxytocin: Used to induce labor, has an ADH effect, mimics SIADH.   Avoid giving Oxytocin with hypotonic fluids.  Tx:  D/c Oxytocin.

Cyclophosphamide: has antidiuretic effect and pt’s encouraged to drink fluid to avoid chemical cystitis.  Tx:  3% NS and Furosemide.

Psychotic Self Induce Water Intoxication:  Polydipsia (>1L/hr).

Tx: monitor diurnal wt for early detection.  Avoid antidiuretic meds, water restrict.  R/o SIADH.

Marathon runner:  especially if uses NSAIDs before race and female.  Pain and stress + ECF depletion due to salt loss (minimal contributor as if lose 9L sweat, only lose 1/17 of total body sodium), sugar water consumed during race + volume expansion from lots of fluid (excess hydration with plain water) –>  promotes ADH (vasopressin) release–>  hyponatremia and risk of cerebral edema and sz.  Whenever an athlete collapses, the first step is to place in Trendelenburg, then check a rectal temperature (if >39C, treat as heat illness).

Tx:  3% NS if sz’s.  Isotonic saline and water restriction if milder sx’s.  If post race Na >130, then observe pt.   If 126-130 give NS IV by estimating ECFV.    If <126 give 100ml of 3%NS IV qh until Na >130 (takes 3-5h).

Syndrome of Inappropriate Antidiuretic Hormone (SIADH):

Criteria:  1.  Hypotonic Hyponatremia (Na <125 mEq/L) and hypo-osmolarity (<270-280 mOsm/kg).   2.  Urine osmolality greater than appropriate (>75-100 mOsm/kg = 75-100 mmol/kg, usually >400 mOsm/kg, but less than maximally dilute) for the degree of systemic hypotonicity.    3.  Urinary Na excretion is high, usually >20-40 mEq/d. May go to 154 if pt treated with NS.     4. Absence of volume contraction (no extracellular fluid depletion). Euvolemic appearing (really volume expanded as have low uric acid level). Uric acid is low in SIADH (<2.5) (Hypouricemia in SIADH. NEJM 301:528, 1979).   5. R/o other causes:  normal renal, adrenal, thyroid, cardiac, hepatic function.

Etiology of SIADH:  Cancer –> lung (small cell) >pancreas> duodenum> bladder> prostate> lymphoma/ leukemia> thymoma> mesothelioma> Ewings.   Any pulmonary lesion–>  TB, CF, any type of pneumonia, abscess, asthma, positive pressure mechanical ventilation, acute respiratory failure.    Endocrine–>  hypothyroid, glucocorticoid def (hypopituitarism).   Neurologic d/o–>  psychosis, any CNS lesions (neoplasia, vascular, trauma), stroke, Guillan-Barre’s, infection (meningitis, abscess), hydrocephalus, MS.  Drugs–>  chlorpropamide (Diabinese), tolbutamide, clofibrate, antineoplastic (vincristine, cyclophosphamide, vinblastine), antidiuretic hormones (oxytocin, DDAVP, Vasopressin), tricyclics, Haldol, nicotine, phenothiazines, carbamezapine (Tegretol), opiates, bromocriptine, NSAIDs, SSRI’s.  Other–>  Idiopathic, surgical (post-op)/ emotional stress, pain, nausea, porphyria, delirium tremens, AIDS, decreased intake of solutes (beer potomania, tea-and-toast diet).  Postoperative–>  vasopressin secreted in response to surgical stress, free water from hypotonic IV fluids.

Tx: 3% saline and Furosemide (Lasix makes the kidneys excrete ½NS as get dec Na in the urine).   Avoid hypotonic fluids (D5W, 0.45% saline) and excessive volumes of isotonic (LR, NS).  The osmostat often resets to the lower serum Na level.  Demeclocycline: 150-300mg PO BID-QID, indefinitely.

2.  Isotonic (Isosmotic hyponatremia):  (250-280 mOsm/L)  “Pseudohyponatremia”, see in presence of inc Trig (serum Na decreases by 1mmol/L for each inc serum lipids of 4.6g/L), inc protein. Or isotonic infusions of glucose, mannitol, glycine, glycerol, sorbitol, ethanol, methanol.   Due to lab artifact as plasma water as smaller fraction than normal leading to an underestimation of true Na concentration.   Suspect when the serum is milky appearing.  Need to compare measured plasma osmolarity with calculated or measure plasma Na with a direct-reading Na electrode.

3.  Hypertonic (Hyperosmotic hyponatremia): Posm >285.

Due to a non-Na hyperosmotic infusion of a substance that has an intracellular water osmotic redistribution (glucose, mannitol, glycine, isopropyl, ethylene glycol, sorbitol).  For each 100mg/dL greater than 100, serum Na decreases by 3 mEq/L.  Hyperglycemia–>  anticipate 3 mEq/L inc Na for every 200mg/dL reduction in BS.  IV Mannitol–>  water shift from ICF to ECF as with hyperglycemia.  Should be rapidly excreted if normal renal function. IVIG–> maltose in the solution acts like mannitol.    Irrigant absorption–> seen in prostatectomy and intrauterine surgery.  The solute (glycine, mannitol or sorbitol) is initially confined to ECF causes dec Na with little change in plasma osmolarity.   Glycine is a neurotoxin and causes blindness, it is metabolized to ammonia and may cause encephalopathy.

**Ref:(Hyponatremia. N Eng J Med 2000;342:21) (Ann IM 1990;113:417-19) (J IM 1994;235:497) (Hyponatremia: age-related risk factors and therapy decisions.  Geriatrics. 1998;53:32-8) (Beer potomania: two cases and review of the literature.  Clin Nephrol. 1996;45:61-4) (Severe hyponatremia in the polydipsia-hyponatremia syndrome.  J Clin Psychiatry. 1994;55:355-61) (Acute hyponatremia in ultra-endurance athletes.  Am J Emerg Med. 1994;12:441-4) (Management of symptomatic hyponatremia: dependence on the duration of development. J Intern Med. 1994;235:497-501) (Hyponatremia: epidemiology, pathophysiology, and therapy.  Curr Opin Nephrol Hypertens. 1993;2:636-52)


Links:  Etiology:  S/s:  Labs:  W/u & Tx:

Na >145-150 mEq/L (mmol/L).  Free water deficit or water loss (>Na loss) or a Na gain with free water restriction.  Always associated with a hyperosmolar state (hypertonic hyperosmolality) leading to at least a transient state of cellular dehydration.

Etiology:  1. Net Water Loss:  neurogenic/ nephrogenic diabetes insipidus, renal diuresis (osmotic, Loop diuretics), postobstructive diuresis, polyuric phase of ATN, intrinsic renal dz, GI or cutaneous losses.  Poor fluid intake–> mental or physical disability, limited access to fluids, inadequate thirst response.     Free Water loss–> osmotic diuresis (DM, DI), diuretic use, febrile illness (unreplaced insensible losses).      2.  Hypertonic Sodium Gain:  Salt poisoning–> inappropriate administration of hypertonic salt solution (hemodialysis pt).  Hypertonic NaHCO3 infusion, hypertonic feeding preparations, ingestion of salt or seawater, hypertonic saline enemas, primary hyperaldosteronism, Cushings syndrome.

S/s: restlessness, sz, coma, delirium, mania, sticky mucous membranes, dec salivation/lacrimation, inc temp, red/swollen tongue, thirst, weakness.  In infants it causes hyperpnea, weakness, high-pitched cry, insomnia, lethargy and coma.   In elderly there may be few sx’s until Na >160. Brain shrinkage may cause vascular rupture leading to a cerebral bleed or a SAH.

Lab: Elev Na (>145 mEq/L), inc serum Osm, inc Ur Osm (if extrarenal losses), inc Ur Na (if renal losses), dec GFR.  Check ADH (vasopressin) level on admission labs (low in central DI, high in nephrogenic DI). Step #1:  assess volume status. This helps to determine underlying cause. A. Hypovolemia–> usually from Na (and hence H2O) losses with H2O losses predominating.   Urine Na >20 meq/L reflects renal losses from diuretics, glycosuria, mannitol, renal failure, etc. Urine volume also tends to be high with high osmolality.    Urine Na <10 meq/L reflects extrarenal losses (sweat, GI, insensible). Urine volume is low with high osmolality.    B. Isovolemia–> reflects loss of free water.  R/o diabetes insipidus (DI), consider extrarenal losses-skin & respiratory insensible losses.   C. Hypervolemia–> usually from net Na gain, can be iatrogenic-IVF with hypertonic saline or NaHCO3, NaCl tablets, hypertonic IVF (e.g. cryoprecipitate with Nacitrate anticoagulant), dialysis with hypertonic solutions or from mineralocorticoid excess-primary hyperaldosteronism, Cushing’s disease, congenital adrenal hyperplasia

Tx:   Links:  Step #1: FWD:  Step #2: Volume Status: Hypovolemic:  Isovolumic: Hypervolemic:

Basics:  correct free water deficit slowly with ½ the calculated amount over 8hr, then reassess and give remaining ½ over 16-24hr.  If too rapid correction, cerebral edema may result.  Hypotonic fluids such as D5W, dextrose are metabolized in the liver to leave electrolyte free water.  May need to stop GI losses, control pyrexia, hyperglycemia and treat the possible associated inc Ca and dec K.  Isotonic fluids if there is significant depletion of extracellular fluid as to cause hemodynamic compromise.

Step #1: Free (body) Water Deficit (FWD) in Liters:   FWD in Hypernatremia:  FWD = [Serum Na (measured) – serum Na (normal) x 0.6 Wt in kg/ normal serum Na].     Also written as, FWD = [(Na-140)/140] baseline wt X F. (F = fraction of wt that is water, 0.6 for male, 0.5 for females).  Also written as, FWD = FWD  = 0.6 X wt in kg X (1- 140/Na).   Kg is estimated wt when fully hydrated.  Generally, about half of deficit can be replaced in the first 24 hours; rest over 1-2 days.  Avoid correcting the serum Na concentration >1mEq/L/hr.

Step #2: Determine patients specific etiology & volume status: Hypovolemic:  Electrolyte-free water loss.  If UrNa >20–> renal loss (diuretic, glycosuria, RF, diabetes insipidus, excess urea excretion).

If <10–> extrarenal loss (GI, sweating, repiratory loss, fever). Labs seen with low volume status: dec Ur Na, Ur Osm >400mOsm/kg.   Diuretic use:  Ur Na >20, Ur Osm +300 mOsm/kg (isotonic), serum Osm is variable depending on free water loss.   If pt awake & alert, nl BP, no sx’s–> free water, PO 300 ml q2hr during waking hours for a total daily intake of 2.4-2.7 L.  Replace ½ the deficit and decrease the serum Na by 3/d.  If pt obtunded or comatose–> 5% dextrose in water IV at no more than 12 mEq/d for 72hr.  Monitor serum Na q8-12hr, switch to PO when tolerated.  If pt severely dehydrated, postural hypotension, tachycardia and high BUN/Cr ratio. –> Rapidly administer NS until tissue perfusion adequate, then immediately exchange to 5% Dextrose as for obtunded pt.   If pt has DM–> add small amounts of regular insulin to IV solution PRN.  If pt has Central DI, inc Ur Na, Ur Osm <150, inc serum Osm, Vasopressin level low after 8hr water deprivation test–> Vasopressin 5 U SC q 24-72hr or Desmopressin 5-10 ug intranasal or 0.1-0.4 mg PO BID.  If pt has Nephrogenic DI, same labs as central but normal vasopressin level –> Hydrochlorothiazide 25mg PO BID, low Na diet.

Isovolumic:  Loss of water or inadequate intake.  Hypotonic losses.   If UrNa >20–> renal loss (Diabetes insipidus, glycosuria, mannitol, glycerol, diuretics).  If <10–> insensible skin (sweat), repiratory, upper GI, osmotic cathartics loss.  Variable Urine-Na with renal loss and hypothalamic disorders.

Tx: water replacement, D5W + vasopressin for central DI.

Hypervolemic:  gain water +Na. Salt poisoning.   If UrNa >20–> Iatrogenic (NaCl tablets, hypertonic solutions such as 3-5% saline, hypertonic NaHCO3), Mineralocorticoid (adrenal, Cushings, primary hyperaldosterone), hemodialysis with hypertonic dialysate.

Tx: diuretics + dialysis.

**Ref:(Hypernatremia. N Engl J Med 2000;342:20) (Ann IM 1996;124:197) (Hypernatremia.  Semin Nephrol. 1998;18:20-30) (Hyponatremia and hypernatremia.  Med Clin North Am. 1997;81:585-609) (Hypernatremia in hospitalized patients.  Ann Intern Med 1996;124:197-203)

Magnesium (Mg) Metabolism:

Links:  Hypomagnesemia:  Hypermagnesemia:

Mg is the 2nd most abundant intracellular cation.  It plays a crucial role in enzymatic reactions utilized in storing and using energy.  The average dietary intake is 25mEq/d, which only marginally meets the requirements. 54% is in bone and teeth (~14g), 46% in cells (~12g) and 1% extracellular.  Normal serum level is ~1.6-2.6 mg/dL


Links:  Ddx:  S/s:  Dx:  Tx:

Distribution is similar to K, effects similar to Ca.   Require 20 mmol/d.  Rarely sx’s unless <1mg/dL.  Often due to dec Alb as it is protein bound like calcium.

Ddx:  Malnutrition (ETOHism, prolonged fasting, TPN w/o replacement, short gut syndrome, malabsorption, fistulas), ETOH (causes renal loss), burns, pancreatitis, chronic diarrhea and fistulas, SIADH, vigorous diuresis, primary hyperaldosteronism, post- parathyroidectomy, Meds (AmphoB, Cisplatin, Aminoglycosides, Dig, Foscarnet, Cyclosporin, Pentamidine, Diuretics), s/p ATN, NG drainage, DKA.

Bartter Syndrome: a familial hypokalemic, hypochloremic metabolic alkalosis.  Due to ion channel abnormalities in of renal tubular cells.

S/s:  HTN is not present, despite high renin and angiotensin II levels. Delayed growth, mild cognitive developmental deficits, polyuria and polydipsia, rare tetany.  Hypomagnesemia in ~20%.  Normal to high urine calcium (nephrocalcinosis variable), high urine prostaglandins.  Renin, aldosterone & angiotensin II markedly elevated.  Tx:  correcting sx’s and electrolyte anomalies.  Indomethacin to inhibit prostaglandin secretion is variably effective.  Gitelman Syndrome:  a variant of Barrter syndrome, presents in childhood or adolescence.  S/s: pt has normal growth and cognitive development, polyuria and polydipsia may be present.  Prominant neuromuscular irritability with positive Chvostek and Trousseau signs (with normal serum calcium levels), tremor, fasciculations and tetany is common.  Hypomagnesemia in ~100%.  Chondrocalcinosis occurs as dec Mg blunts release and function of parathyroid hormone, this can lead to hypocalcemia.   They have a low urine calcium, normal urine prostaglandins.  Renin & angiotensin II are elevated, aldosterone is normal to high.  Tx: Correct electrolyte anomalies

S/s: Weakness, muscle fasciculation’s/ tremor/ tetany, apathy, MS changes, sz, hyperreflexia, cardiac dysrhythmia, inc QT, dec K, dec Ca, N/V, ileus.

Dx: Serum Mg may not reflect intracellular, if the serum Mg is equivocal consider measuring a 24hr Urine Mg and Cr (to ensure adequate collection).   If the Ur-Mg is 10 mg–> then poor intake, GI malabsorption, small bowel dz, redistribution or normo- magnesemic Mg depletion.   If >20mg–> then due to primary renal tubular defect, inc Ca, saline infusion, diuretics, Cisplatin toxicity, aminoglycoside toxicity or Barters syndrome.   Or can do a Mg load study by giving 60mEq in 500ml D5W over 12hr, if > ½ is excreted in 24hr then depletion.

Tx:  IV:  PO:   Most cases need no supplements unless <1.0, sx’s or causing dec K or arrhythmia.  Correct slowly over days by giving 50-60 mEq/d X 5-6 days, caution if pt has chronic renal failure (reduce dose by ~50%). Consider adding a K-sparing diuretic if already taking a thiazide or loop diuretic.

IV: 1-2g MgSO4 (22mg or 4ml of 50% MgSO4) in 100ml D5W as 10% solution over 15 min. Can give 4g/hr, if acute situation (i.e. Torsades) give 1-2g over 1min IVP. Follow with a continuos infusion over the next 6hr of 5g diluted in NS or D5W.   Monitor closely if oliguric.  Follow replacement with dec patellar reflexes, serial serum and sx’s resolution.  Check EKG if large doses.  MgSO4 for IV comes in amps, 1 amp = 1 gram (8 mEq). You may write a sliding scale in the units. Serum Mg–> gm of MgSO4 to give IV. If 1.8-1.9–> 2. 1.6-1.7–> 3. 1.4-1.5–> 4. 1.2-1.3–> 5. <1.2–> 6 & call HO.

PO Forms: ~500mg PO qd-BID.  Mg Oxide: 400 mg (20mEq = 70% of RDA/tab) or 420 mg (240 mg elemental Mg) at a max of 4-6X/d.  A laxative, the sulfate or gluconate forms may cause less diarrhea.  Beelith: 600mg Mg-oxide = 362 mg of elemental Mg (30mEq = 90% RDA).

Slow Mag (Mg-Cl): 64mg of Mg (5.3 mEq or 16% of RDA) + 110mg Ca carbonate per tab.    Mag-Tab (Mg-lactate): 84mg of Mg per tab (=7 mEq or 21% of RDA).  Give 2 tabs TID-QID if severe or 2 tabs qd-BID if mild asymptomatic dz.    Mag complex: 300 mg elemental Mg @ 1-2 tab qd.   Mag gluconate: 500 mg (27 mg elemental Mg) @ 1-2 tab qd.


Ddx: Renal insufficiency, antacid abuse, rhabdo, tumor lysis, burns, tissue trauma, hypothyroid, adrenal insufficiency, excessive intake (tx of eclampsia), cathartic abuse.

Sx: N/V, weakness, MS changes lethargy, coma, hyporeflexia, respiratory depression, dec BP, arrhythmia, inc QT, AVB.

Tx: Stop external sources (antacids, cathartics), IV CaGluconate: 10ml of 10% solution IVP.  Or CaCl (10%) @ o.2-0.3 ml/kg (max 5ml) IV.   Volume expansion with NS, IV Lasix if good renal function, dialysis in renal failure.

**Ref: (Hypomagnesemic hypocalcemia in chronic renal failure.  Am J Kidney Dis. 1993;21:167-71) (Cecil Textbook of Medicine 2000, 21st ed, Saunders, pp1137-39) (Magnesium: physiology and pharmacology. Br J Anaesth 1999;83:302-20)


Links:  TTKG:  Foods:  Hypokalemia:   Hyperkalemia:

90% K is intracellular. A major cation along with Mg.   Normal value is 3.6-5.2 mmol/L.   Serum level does not reflect intracellular level; 1 mEq/L ECF = 200 mEq/L ICF.  Level is influenced by the kidneys, intestines, endocrine, acid-base status.  Both high and low may lead to arrhythmia’s.  Important in glucose transport, intracellular protein depolarization, and myoneural conduction.  Requirements:  2 mEq/l ICF : 0.4 X wt in kg X 2.   Or  ~50-100 mEq/d adult, and 2-3 mEq/kg/d as child.

Transtubular Potassium Gradient (TTKG):

Normal = 4-14, varies with diet.  = (UrK / PlasmaK) / (Uosm / Posm).

If Dec K: <2, GI loss.  >4, renal loss or excess aldo.

If Inc K: Helps to determine if the hyperkalemia is of renal or extrarenal origin.   If TTKG is <6, suggests a renal cause (dec aldo or lack of response). If the renin is normal it suggests hypoaldosteronism. If serum aldo is low and the renin is also low, it suggests hyporeninemic hypoaldosteronism. If the serum aldo is normal it suggests a renal tubular deficit.  If >6-10 suggests non renal, normal aldo effect. Such as increased K intake in diet, hemolysis or rhabdo.

Foods with High Potassium (K):

Highest (>10mg/g) –> dried figs, molasses, seaweed.

Very High (>5mg/g) –> dried dates/ prunes, nuts, avocados, bran cereals, wheat germ, lima beans.   High (>2.5 mg/g) –> vegetables such as spinach, tomatoes, broccoli, squash, beets, carrots, cauliflower, potatoes.   Fruits such as banana, cantaloupe, kiwi, oranges, mango.    Meats such as beef, pork, veal, lamb.


Links:  Ddx:  S/s:  Tx:

K <3.6 mmol/L.  The most common electrolyte abnormality in clinical practice as it occurs in 25% of pt’s treated with thiazide diuretics.

Ddx: dec intake, Lab error, hyperthyroidism (thyrotoxicosis related dec K), decreased Mg (must repleat this 1st as there are Mg dependent ATPases in the renal tubules).   Hypokalemic periodic paralysis (Mostly seen in Asians with thyrotoxicosis, have severe weakness that spares the CN’s and diaphragm, no precipitants, lasts 2-3d, replete K).  Inc GI loss–> gastric/ diarrhea/ laxative abuse (very low Ur sodium)/ bile/ fistula/ vomiting/ geophagia (very low UrCl, low serum Cl & Na).    Inc Renal Loss–> diuretic abuse (high UrCl and UrNa./ dec Mg / RTA/ steroid excess (Cushings/ Conn’s/ Hyperaldosterone/ CAH/ Adenoma/ renovascular HTN/ vasculitis).    Bartters Syndrome–> (Hypokalemia + metabolic alkalosis + hyper-reninimeic hyperaldosteronism.  HypoMg common.  3 gene defects cause, renal K loss.  Presents in childhood with growth failure and weakness.).  Liddle’s Syndrome–> an inherited tubular d/o with dec K, metabolic alkalosis, HTN and subnormal aldo secretion.   Inc Skin loss–> sweat,/ burns.   Redistribution (cellular shifts) –> Metabolic Alkalosis (hyperventilation/ resp or metabolic–> cells remove the inc H+, K is drawn into cell), OD of insulin/ Verapamil/ Chloroquine, B12, beta2-Agonist, periodic paralysis (familial or thyroid dz), tocolytic such as Ritodrine, theophylline, caffeine (even 1-2 cups).  Type I RTA (metabolic acidosis).  Drugs–> barium, mineralocorticoid effects (licorice, Fludrocortisone), amphotericin, diuretics, phenolphthalein, Na-polystyrene, high dose Abx (PCN, Nafcillin, Ampicillin, Carbenicillin), Mg depletion (aminoglycosides, Cisplatin, Foscarnet, Ampho-B), toluene, Verapamil OD, thyroid hormone, theophylline OD, Chloroquine.

Thyrotoxic Periodic Paralysis:  acquired, sporadic disease associated with underlying thyrotoxicosis and resolves with tx of thyrotoxicosis.  Always associated with hypokalemia.  About 95% of cases occur in men, more common in Asians.  Suspect dx pt who developes periodic paralysis after age 30yo as typical signs and symptoms of thyrotoxicosis are often completely lacking.  Dx:  Low TSH with increased radioiodine uptake by thyroid.   Tx:  aimed at thyroid dysfunction, beta-adrenergic blockers can be of some benefit prior to definitive therapy.

Hypokalemic Periodic Paralysis:  attacks of weakness occur during periods of hypokalemia.  About 2/3 of patients have a FHx of the dz, remainder likely due to spontaneous mutations.  Onset of sx’s usually before age 20, but as early as age 3-4, always begin before age 30.  S/s:  severe weakness of the limbs occurs spontaneously, paralysis occurs without pain or changes in level of consciousness.  The limbs are primarily affected (facial and respiratory muscles usually spared), pt’s may become temporarily quadriplegic.  Attacks typically last for 3-4 hours, but may persist up to 24 hours, worse in males than females.  Attacks usually follow exercise (at rest), or during sleep.   Serum K+ level usually low, but may be low normal, during an attack, reducing K+ levels will precipitate an attack.  Weakness improves with gentle exercise.  Common to have eyelid myotonia is often present even between attacks.   A d/o of voltage-gated calcium (Ca2+) channel gene, CACNL1A3, chromosome 1q, the physiologic basis remains unclear.   Tx:  Oral potassium loading during attacks will shorten duration, IV K+ should be avoided (dextrose solutions will reduce serum K+ levels).  Attacks are prevented by acetazolamide, yet may worsen some pt’s (Triampterene or spironolactone will usually be effective).  Low carbohydrate, low Na+ diet recommended.

S/s Dec K:  Mild depletion: (3-3.5 mmol/L) usually have no sx’s.   Moderate depletion (2.5-3 mmol/L) get nonspecific sx’s such as weakness, lassitude and constipation, thirst, HTN.  Risk of cardiac arrhythmia if have underlying CHF, ischemia or LVH.  Inc Digitalis SE’s.  Severe depletion: (2-2.5) get myonecrosis, paresthesias, hyporeflexia, confusion, ileus.   Very severe: (<2 mmol/L) get an ascending paralysis and impaired respirations, coma.  Limb and trunk paralysis with “hypokalemic periodic paralysis”, due to acute dec K associated with high carb meal.  ECG changes:  Flat T’s on EKG, PVC’s, U wave, dec ST segment, wide QRS.  Does not correlate well with serum levels.  Check Chem 7.

if dec HCO2–> then likely due to metabolic acidosis (renal failure, Addisons, DKA).  If dec HCO2 & inc Cl- –> Resp Alk or diarrhea.

if Inc CO2 & dec Cl–> diuretics, vomit, laxative, licorice, Aldo.

Tx: Ensure proper renal function first:  Deficit usually greater than serum value indicated because of depleted body stores.  Check Mg level or give empirically as K gets lost via Mg-dependent ATPase.  Consider ABG to r/o acidosis or LDH to r/o hemolysis of the specimen sent.  Check Urine K, if low (<20) then non renal loss.   KCl @ 7.5-10 mEq IV in 50-100ml D5W over 1hr with peripheral IV.  Up to 20mEq/hr if central line.  Kphos if dec phosphate too.    Enteral: PO K-Dur @20-40mEq doses.    10mEq needed for each 0.1 mmol serum depletion.    A “K” of 3.0 needs ~350 mEq and a K of 2.5 needs eventually needs 500-600.    Serum K–> mEq KCl to give PO/IV:   3.8-3.9–> 20.  3.6-3.7–> 40.  3.4-3.5–> 60. 3.2-3.3–> 80. 3.0-3.1–> 100. <3.0–> 120 & call HO.

Total body potassium deficit (mEq/L)= (4 — K) X 350.  At a normal pH, a deficit of 350mEq/L occurs for each 1 mEq/L drop in the serum K below 4 mEq/L.  A low Na diet will stop renal K wasting.

Tabs–> 6.7mEq (Kaon-Cl), 8 mEq (Klor-Con, Slow-K, Micro-K) 10 mEq (K-tab, K-Dur, Ten-K, Micro-K, Kaon-Cl, Kor-Con, Klotrix).   20mEq (K-Dur).      Liquids–> 20 mEq/15ml (Cena-K, Kaochlor, Kay Ciel, Klorvess, Kaon).   40 mEq/L (Cena-K, Kaon-Cl).

Powder–> 15, 20, 25 mEq/pack.  Acetazolamide is useful for the prevention of periodic paralysis.


Links:  Etiology:  S/s:  Tx:

Even slightest hemolysis raises K.  Levels increase aa change from supine to upright position.   Inc 0.6 mEq/L per 0.1 dec pH or 10 mOsm inc.  Inc 0.15 per 100 X10-9th platelets/L increase.

Etiology: acidosis, tissue necrosis (rhabdo, infarct), hemolysis, blood transfusion, GI bleed, RF (acute/ chronic), DKA, pseudohyperkalemia (leuko/ thrombocytosis), lab error, dec mineralocorticoid activity (Addison’s, Hyperaldo).  Hyperkalemic periodic paralysis (diurese and give Kayexolate). Meds –> High dose PCN, succinylcholine, ACEi & ARB’s, NSAIDs, K-sparing diuretic (spironolactone >Triamterene >Amiloride), TMP-SMX , Pentamidine, Heparin (aldo suppression), Digitalis, beta-blocker, stored PRBC’s, salt substitutes (K-Cl), Cyclophosphamide and Tacrolimus.

S/s: Usually asymptomatic, weakness, paresthesias, paralysis, confusion, arrhythmia, resp alk (diaphragm paralysis).   EKG –> peaked T@ 5-6 mEq/L, inc PR interval and QT @6-6.5, dec ST, small P waves @ 6.5-7.   Inc intraventricular conduction @ 7-7.5.   Wide QRS, ST and T’s merge @ 7.5-8.    Sine wave @ >10.    Brady, cardiac arrest.  Absence of ECG changes means nothing as can go from normal to VF in seconds.

Tx: EKG monitor, correct acidosis or hypovolemia (hydration & forced diuresis).    #1: CaGluconate: 1 or 2 ampules (10ml of 10% solution) IVP q1hr as needed for K>6 or EKG changes. Or give 10% (100mg/ml) @ 20mg/kg IV over 5min. Avoid if pt is on Digoxin as worsens any Dig toxicity.  Onset immediate, lasts 30-60min to counteract the electrophysiologic effects of inc K, stop infusion if heart rate <100.     #2: Sodium Bicarb: 7.5% (1mEq/ml) @ 1-2 mEq/kg (Or 1-2 amps) IV over 10-20min.  Causes K to move into cells.  Do not give simultaneously with Ca-Gluconate or will precipitate. Onset 20 min, lasts 2hrs.   #3: Insulin with Glucose: 1amp D50 (1-2g/kg) with 10-15 U (0.3 U/g glucose) regular Insulin IVP q2-3hrs as needed.  Onset in 20min, lasts 3-6hr.   #4: Na-Polystyrene (Kayexalate):  20-50g (1g/kg PO) in 100-200ml 20-70% Sorbitol PO q3-6hr.  Often comes in 15g jars mixed with sorbitol.  Removes K from body.  Will remove 1 mEq of K/g of resin.  1g of resin = 4.1 mEq Na (Watch for volume overload), takes 4-6hr.  Retention Enema: 50g Kayexalate in 200cc water with 50g Sorbitol or 200ml of 20% Dextrose solution q1hr.     #5: Albuterol (beta-agonist): 10-20 mg nebulized or 0.5mg IV, causes redistribution.  #6: Dialysis.

**Ref: (Drug-induced hyperkalemia.  Am J Med 2000;109) (Hypokalemia. N Engl J Med 1998;339:7) (Bartter’s syndrome: the unsolved puzzle.  Am J Kidney Dis. 1995;25:813-23) (Potassium homeostasis in the elderly.  QJM. 1997;90:487-92) (Hypokalemia and hyperkalemia. Med Clin North Am 1997;81:611-39) (Hypokalemia–consequences, causes, and correction. J Am Soc Nephrol. 1997;8:1179-88)

Calcium Metabolism:

Links:   Labs:  Ca & P:  W/u:    Hypercalcemia:   Hypocalcemia:

99% of the bodies Ca is in bone (~1300g), 0.1% in extracellular and 1% is intracellular.  Ca has 3 forms ionized (“free”, active form), Protein bound (40%), anion bound (15%, bicarb, phosphate, citrate), need to correct for albumen level.   Levels regulated by PTH (low Ca and high P –> inc PTH –> increase resorption bone and Ca in DCT, inc V-D hydroxylation in PCT–> inc gut/bone Ca absorption).   Important in neuromuscular and enzyme physiology.  Body stores 1-1.2 kg.   Require 1-3g/d PO or 7-10 mmol/d IV.

Labs:   Ionized Ca is usefull if hypo/hypercalcemia, borderline serum Ca or altered serum proteins.  50% of Ca is ionized, 40% is bound to albumin and 10% is bound to other anions.  The ionized fraction is the only fractioon that is physiologically active.  Always check serum pH as acidosis increases it and alkalosis decreases it.   The normal level is 1.15-1.35 in adults.

Corrected Ca:   Correct for Low albumin –> adjust serum Ca by 0.8mg/dl for each 1g that Albumin is above or below 4g/dl. = (normal alb – Pt’s alb) X 0.8) + Pt’s Ca. =   (3.5- pt’s Alb) X 0.8 + pt’s Ca.      0.8 is the amount of Ca bound to albumen.  Ca: dec 0.8mg% per g% dec alb.  Dec 0.16mg% per g% inc globulins.  Dec 0.12mg% per 0.1 dec pH or per 10 inc mOsm.

Calcium and Phosphate Control:

PTH–> Causes inc serum Ca and dec P.  inc bone resorption of Ca & P.  Inc renal tubular Ca reabsorption.  Dec renal Ca reabsorption.  Inc renal production of 1,25(OH)2D.   1,25-Dihydroxyvitamin D–> Causes inc serum Ca & P.  inc renal reabsorption of Ca & P.  Inc bone resorption of Ca & P.  Inc gut absorption of Ca & P.  Dec parathyroid production of PTH.  Dec renal production of 1,25(OH)2D.    Calcitonin–> Causes dec serum Ca & P.   Dec bone, gut and renal absorption.   Calcium–> dec PTH, dec 1,25(OH)2D, dec P and dec Calcitonin.  Phosphate–> inc PTH, dec1,25(OH)2D, dec Ca.

W/u: CBC, Alb, total protein, Ca, P, ALT, AST, AP, Cr, TSH, UA with micro, CXR.   Check “intact” PTH, if very high–> likely PHPT (get FHx to r/o MEN syndromes.    If marginally high or nl Ca–> may still be PHTP, consider FHPC if young and asymptomatic–> if 24hr Ca <100, only thiazides or FHCP).   Low PTH –> check PTH-RP(RP=related peptide), which will be elevated in carcinoma.  Check 1,25(OH)2D will be inc in granulomatous and V-D intox.  Check 25-(OH)D: nl in granulomatous, high in V-D intox.   Check Urinary cAMP: if dec and have dec PTH likely an osteolytic process of V-D intox.   Other Labs:  SPEP, UPEP, V-A level, best-carotene, ACE, 24hr Ur Ca & Cr, bone scan, renal U/S, CT abd, mammogram, ACTH stim, PPD.

Primary –> Hyperparathyroidism –> Intact PTH: Inc. PTHrP: Dec. 1,25(OH)2D: Inc. Ca:  Inc.  PTHrP malignancy –> Intact PTH: Dec.  PTHrP: Inc. 1,25(OH)2D: Dec. Ca:  Inc.  Non-PTHrP malignancy –> Intact PTH: Dec. PTHrP: Dec. 1,25(OH)2D: Dec. Ca:  Inc.


Links:  Ddx:  S/s:  Tx:   Milk Alkali:  Hyperparathyroidism:  Malignancy: Familial Hypocalciuric Hypercalcemia:

Total Ca >10.5 mg/dL or ionized Ca >2.7 mEq/L (1.3 mmol/L). Hypercalcemic Crisis:  (>12)  (critical 16-20mg/dl)

Ddx:  “SHAMPOO DIRT” –> Sarcoid.  Hyperparathyroidism/ hyperthyroid.  Addisons dz, AIDS.  Metastases/ myeloma, milk-alkali syndrome.   Pagets dz, parenteral nutrition, pheo, parathyroid dz.   Osteogenesis imperfecta, Osteoporosis.    D-vitamin toxicity.  Immobility, inflammatory d/o. RTA, rhabdomyolysis. Thiazides and other drugs (Li), thyrotoxicosis.

Ddx by Mechanism:   Inc Bone resorption–> hyperparathyroid, mets, thyrotoxicosis, pheo, V-A intake >50,000 IU/d, immobilization, humeral hypercalcemia of malignancy.  Increased renal reabsorption or dec excretion–> rhabdo, thiazides, Milk-alkali syndrome, renal failure, familial hypocalciuric hypercalcemia.  Increases gut absorption–> candidiasis, coccidiomycosis, histoplasmosis, sarcoidosis, eosinophilic granuloma, berylliosis, V-D intake > 50,000 IU/wk, TB, inflammatory d/o. AIDS, lymphoma.  Unknown Etiology–> VIPoma, theophylline, Li, Addisons, parenteral nutrition, estrogen and antiestrogens.  Drugs: thiazides, Li, V-A or D intoxication.

Sx’s: Stones, bones, abdominal groans, and psychic overtones. N/V/C, dry mouth, confusion, weakness, sz, H-A, hyporeflexia, HTN, dec QT interval, brady, AVB, polyuria, polydipsia, pruritis.  If chronic: osteoporosis/ bone pain, stones, pancreatitis.   Inc Ionized Ca & inc P & inc PTH–> CRF, lithium therapy.

Labs: total and ionized Ca+, Mg+, P, lytes, AP, creatinine.   Consider PTH,TSH.  With hyperparathyroidism also have dec HCO3, inc Cl, inc AP.

Serum Phos –> PTH-mediated: Dec. Non-PTH mediated: Inc/dec or normal.  Serum Cl –> PTH-mediated: Inc.  Non-PTH mediated: Often <100 mEq/dL.  Met Acidosis –> PTH-mediated: Mild. Non-PTH mediated: None.  Serum Cl / PO4 –> PTH-mediated: >33. Non-PTH mediated: <33.  PTH –> PTH-mediated: Inc.  Non-PTH mediated: Dec.

Tx:  0.9NS hydration 1-2 L over 2-3hr, then 150-350ml/hr (2.5-4L in 24 hr, some need 10L) to promote calciuresis and correct hypovolemia, then once volume is repleated, use forced diuresis with Lasix @20-60mg IVP (often need 80-100mg IV q2hr), maintain UO @ 100-200ml/hr. Replace urine losses iv 0.45 NS + 20 mEq KCl/L with careful monitoring of CVP and Ca q4-6hrs.  Dialysis for renal failure.  Replete Mg.

Calcitonin-Salmon (Calcimar, Miacalcin): Adult @ 200 units/ml inj.  For hypercalcemia give 4 units/kg SC or IM q12 hr.  Will work in a few hours, but max drop in serum Ca of only 0.5 mmol/L.  Can increase the dose to 8 U/kg SC/IM q12hr in 1-2 days if not responding then 8 units/kg q6hr in 2 more days if still unresponsive.   Also use in Paget’s dz and osteoporosis.  Can add Prednisone 40-60mg/d PO.   SE: N/V, dermatologic reaction, nocturia, eye pain, feverish sensation.   Action: Inhibits bone resorption, decreases serum Ca, and increases excretion of P, Ca, and Na by decreasing tubular reabsorption.

Bisphosphanates (Didronel, Aredia): (inhibit osteoclast activity, slow onset (days) but safe @90mg in a single IV 24hr infusion and lasts weeks, can retreat in 7 days.  Etidronate: 7.5mg/kg with 3L NS over 24hr, repeat qd X 3d.    Mithramycin: inhib RNA synthesis in osteoclasts, if malignancy or unresponsive to other tx @ 15-25mg/kg IV over 4-6hr, takes 120, peaks in 36hr , lasts 4days, BM depression a SE.  Steroids if MM, lymphoma, V-d intox @ 100mg hydrocortisone BID IV Treat underlying disorder.  Can also use Gallium Nitrate, IV Phosphate, Dialysis, EDTA.

Other (long term): d/c thiazide diuretics, drink lots of fluids and avoid Ca+ in diet, mobilization, oral phosphates (K-phos 3 tabs TID).

Milk Alkali Syndrome:    Secondary to ingestion of excess Ca (milk) and Alkali (antacids), often in attempt to self tx PUD or GERD.

S/s: anorexia, constipation, dehydration, dizzy, H-A, irritable, abnormal taste, MS changes, myalgias, polyuria/polydipsia, N/V, weakness.

Lab: inc Ca, inc HCO3, normocalcuria, dec urine P, inc BUN/Cr, normal Alk phosphatase (AP).

Tx: Stop milk/antacids, tx inc Ca PRN with Lasix and NS, monitor kidney function, urine electrolytes, urine output.

Primary hyperparathyroidism (PHPT): (oversecreter PTH)   Dx: inc “intact” PTH. Vs.     See Endocrine Section.

Secondary HPT: Inc PTH secretion in response to: dec Ca, inc P, low calcitriol (all 3 conditions seen in CRF, most common cause). Vs.

Tertiary HPT: spontaneous change from dec Ca–> inc Ca.  PTH usually 10-20X nl.

Malignancy:  (Mets–> breast/ MM/ lymphoma/ prostate/ lung/ thyroid) or Humoral Hypercalcemia of malignancy (HHM) seen in SC Ca producing PTH related peptide.     3. Granulomatous dz: (TB, sarcoid, disseminated fungal, berylliosis, lymphoma, from V-D via macrophages)

Familial Hypocalciuric Hypercalcemia (FHHC or FHH):  Seen in young pt’s with FHx (AD) kidney reabsorbs too much Ca, check 24hr UR Ca (should be <100) with nl PTH. These pt’s are not at risk of making stones as they do not have an elevated urinary Ca.  Their disorder is thought to be a defect in the parathyroid calcium receptor.  Can mimic primary hyperparathyroidism.  Due to a defective Ca sensor on the membranes of the parathyroid and renal tubular cells.  Leads to dec renal clearance of Ca (low Ur Ca), a normal-high level of PTH, mild inc Mg, nl-dec P and FECa <1%.

**Ref: (N Engl J Med 1992;326:1196-1203) (End Clin NA 1993;22:343-62) (Hypercalcemia.  Endocrinol Metab Clin North Am. 1989;18:601-832) (Clinical manifestations of cancer-related hypercalcemia.  Semin Oncol. 1990;17(2 Suppl 5):16-25) (Hypercalcemia of malignancy.  Am J Med. 1997;103:134-45) (Hypercalcemia: mechanisms, differential diagnosis, and remedies. Postgrad Med 1996;100:119-26)


Links:  S/s:  Lab:  Tx:  Ddx:

Total Ca <8.5, or ionized <2 mEq/L (1 mmol/L).   Asymptomatic until serum <8mEq/dl.

S/s: numb/ tingling extremities, circumoral paresthesias, muscle/ abd cramps, tetany, inc DTR’s, sz, laryngospasm.   Chvosteks sign: twitching facial muscles after percussion of masseter muscle just anterior to the ear below the zygomatic bone. (normal in 15-25% of pop, also seen with diptheria, whopping cough, measles, scarlet fever and myxedema).    Trousseau’s sign: More specific than Chvosteks, carpopedal spasm induced by inflation of BP cuff above SBP for 3 min. Also seen with dec Mg. EKG: inc QT without U waves if <6.

Lab: check serum Mg (parathyroid needs Mg to work), dec K, inc P. Total Ca <8.5, or ionized <2 mEq/L (1 mmol/L). Ca & P:

Tx: If sx’s mix as bolus in 100ml of NS over 10min of 200mg (max 15mg/kg) elemental Ca (8ml of 10% CaCl or 22ml of CaGluconate), then follow with a continuous infusion of 1-2mg elemental Ca/kg/hr for 6-12hr.

CaCl: (max of 0.2-0.3ml/kg = 5-10ml) IVP 10ml of 10% solution = 6.5mmole (27mg (1.36mEq)/ml elemental Ca).  Risk of possible tissue necrosis if infiltrated. 1g = 13.6 mEq Ca.  Give 1-2g in 50ml over 1hr or slow IVP up to 16mEq/min.  Comes in 10ml vials = 100mg/ml.

CaGluconate (max 0.5-1ml/kg = 5-10ml) 10% soln 10ml IVP =2.2mmole of Ca (9mg (0.46mEq)/ml of elemental Ca). Less irritating if using peripheral vein. 1g = 4.5 mEq. Also used to tx inc K.

PO: Tums: 1 tab= 0.5 g CaC03 = 200mg Ca, OsCal, 1 tab= 1.25g CaC03= 500mg Ca. CaGluconate syrup: 5ml gives 115mg Ca.  1/3 of Ca is absorbed.   Phosphate binding antacids improve GI absorption of Ca.

V-D (Calciferol) -begin once phosphate is nl.  Start @50,000U/d, increase up to 200,000U as needed.  Ca may potentiate digoxin.

Ddx: hypoalbuminemia with nl ionized fraction.  May have nl serum Ca, but low ionized in acute alkalosis.  If albumen is nl–> check PTH (low PTH: hypo PTHism, dec Mg)  (high PTH: pancreatitis, inc P, dec V-D, citrated blood transfusion, renal insufficiency (CRF).  If inc PTH–> check P, Cr, LFT’s, AP, total protein, Mg, see above.  Other–> soft tissue infection, rhabdo, tumor lysis syndrome.  Drugs–> Cimetidine, Cisplatin, Dilantin, phenabarititol, glucagon, protamine, theophylline, NE, nitroprusside, heparin, loop diuretics gentamicin.

**Ref:(Hypocalcemia.  Semin Nephrol. 1992;12:146-58) (Hypocalcemic crisis.  Crit Care Clin. 1991;7:191-200) (Hypocalcemic emergencies.  Endocrinol Metab Clin North Am. 1993;22:363-75)

Phosphate Metabolism:

Links: Hypophosphatemia:   Hyperphosphatemia:

Phosphorus is the form of phosphate it the principle intracellular anion.  It has a central role in the cytoplasm as a buffer, energy carrier (ATP) and molecular switching (phosphorylation).  In the blood it is principally unbound like Mg. 86% of phosphate is in the bone (600g), 14% in cells (100g) and 0.03% in the extracellular fluid.

Calcium and Phosphate Control:

PTH–> Causes inc serum Ca and dec P.  inc bone resorption of Ca & P.  Inc renal tubular Ca reabsorption.  Dec renal Ca reabsorption.  Inc renal production of 1,25(OH)2D.   1,25-Dihydroxyvitamin D–> Causes inc serum Ca & P.  Inc renal reabsorption of Ca & P.  Inc bone resorption of Ca & P.  Inc gut absorption of Ca & P.  Dec parathyroid production of PTH.  Dec renal production of 1,25(OH)2D.    Calcitonin–> Causes dec serum Ca & P.   Dec bone, gut and renal absorption.   Calcium–> dec PTH, dec 1,25(OH)2D, dec P and dec Calcitonin.  Phosphate–> inc PTH, dec1,25(OH)2D, dec Ca. W/u:


Links:  Etiology: S/s:  Tx:

Phosphorous:  important mediator of cellular energy, metabolism is related to Ca.  The most abundant intracellular anion (as is protein), require 30mmole/d.  700g in the body, 80% in bone, 9% in skeletal muscle, <1% in the plasma.  Very hard not to get enough in ones diet.

Etiology: dec Phosphate absorption–> malabsorption, PO4 binding in gut (antacids), steatorrhea, V-D Defic, hyperalimentation, inadequate intake.  Inc Renal excretion–> alcoholism, alkaluria, diuretics, Fanconi syndrome, inc Ca, hyperparathyroidism, metabolic acidosis, renal tubular defect (ATN), glucocorticoid/ mineralocorticoid therapy, PTH-related protein, renal transplantation, volume expansion. Other–> dec Mg, dec K, hemodialysis, thyrotoxicosis, pancreatitis, extensive burns.   Intracellular shift–> carbohydrate infusion, Calcitonin, catecholamines, glucagon, insulin, respiratory alkalosis (gout, sepsis, panic attack, heat stroke, salicylate OD), EPO therapy, leukemic blast crisis. Refeeding Syndrome:

S/s Hypophosphatemia: Usually no sx’s unless <1, severe if <0.5.  Neurologic – areflexic paralysis, confusion, Guillain-Barre syndrome, weakness to ascending paralysis, paresthesias, CNS dysfunction (irritability, confusion, sz, coma). Cardiac – decreased myocardial function, cardiac arrest, arrhythmias, myocardial depression (CHF from low ATP).  Hematologic – altered RBC morphology, hemolytic anemia, platelet/ granulocyte dysfunction, shift in oxyhemoglobin (from dec 2,3 DPG). Hepatic – liver dysfunction (especially in cirrhotics).  Muscular – rhabdomyolysis, weakness.  Respiratory – acute ventilatory failure.  Skeletal – bone pain, osteomalacia (long term hypophosphatemia).  GI – nausea, vomiting, poor GI motility, anorexia.

Tx:  PO:   IV:    PO Phosphate repletion: Achieved over 7-10 days, give 60 mmol in 3-4 divided doses.  Give 15mg/kg = 1g PO4 = 30 mmol, = 1 qt of milk, this raises the serum P by 1.  Use Na-P if renal failure or inc K.

Neutra-Phos (NaP): @ 2caps BID-TID with water. Has 250mg/ packet of P + 7.1 mEq Na + 7.1 mEq K.  Phospho-Soda: 5ml BID-TID. Has 150 mg/ml P + 4.8 mEq/ml Na.   Skim Cows Milk: 1g/L P + 28 mEq/L Na + 38 mEq/L K.  Neutra-Phos K: 250mg/cap P + 14.25 mEq/cap K.  K-Phos Original: 150 mg/cap P + 3.65 mEq/cap K.  K-Phos Neutral: 250 mg/tab + 13 mEq/tab Na + 1.1 mEq/tab K.

IV Phosphate repletion:  If unable to take PO or severely symptomatic (levels <1mg/dL).  It is with Na or K.    Give ~2.5mg/kg body wt over 6h if no overt clinical manifestation.   Give 5mg/kg over 6h if an emergency.

Na-Phos or K-phos (has 93mg =3mmol/ml + 4mEq Na or K) @15-30 mmol in 100ml over 4hr, max 100mm/d. Typically give ~”15-30 mmoles over 6 hours”.  If very low can write “NS with 10 ml of K-Phos/L @ 125ml/h”.    NaPhos–> 3 mmoles Phos + 4 mEq Na (so 21 of Phos with 28 of Na).    Kphos–> 3 mmoles Phos + 4.4 mEq K (so 21 of Phos with 30.8 of K).

If having adverse effects and PO4<2mg/dL–> 0.9mg (0.03mmol)/ kg/hr, slower if renal dysfunction, monitor serum P q6hr.

If recent onset–> 0.08-0.20mM/kg over 6hr,  If Prolonged–> 0.16-0.24mM/ kg over 6hr.

Can also give Neutral NK-PO3 with 0.09 mmol/ml P + 0.02 mEq/ml K + 0.2 mEq/ml Na.  Or Neutral Na-P which has 1.1 mmol P + 0.2 mEq/ ml Na.


Laxative abuse, PO4 salts for inc Ca Rx, renal insufficiency, hypoparathyroid, catabolism, V-D metabolites, sepsis, rhabdo, tumor lysis, hypo/ hyperthermia, inc GH.

Sx: same as dec Ca, may produce ectopic calcifications.

Tx: restrict diet/ external sources, P-binding antacid (Amphojel, Alternagel).  Volume expansion if normal renal function.  Al-Hydroxide @ 30cc PO q2-4hr, Acetazolamide if sx’s @ 15mg/kg IVSS q4hr, Dialysis.

**Ref:(Severe hypophosphatemia presentation and treatment.  Medicine 2000;79:1) (Tumor lysis syndrome.  Semin Nephrol. 1993;13:273-80) (Endocrine crises. Hypophosphatemia and hyperphosphatemia.  Crit Care Clin. 1991;7:201-14)

Body Fluids:

Links:  Compartments:  Free Water:  Normal Losses:  Maintenance: Other: Hypervolemia: Hypovolemia:  Dehydration:  Oral Rehydration:   IV Solutions:

Tips on correcting FEN abnormalities:   R/o Laboma–> lab error, re-check lab 1st.  Correlate to the pt’s condition.  Correct ½ the deficit, reassess the labs, then correct the remaining.  If multiple problems correct 1st Volume >pH > K/Ca/Mg > Na/Cl (osmolarity).

Serum Uric Acid:  level is a rough correlate with intravascular volume, but a need baseline to compare too.

Total Body Water (TBW): ~60% Ideal Body Weight. Increased with inc muscle mass (600ml/kg in male, 500ml in female), dec with age (highest in newborn, @ ~77%).    TBW = 0.6 in child or non-elderly male.  TBW = 0.5 in an elderly male or a non-elderly female.  0.45 in elderly females. Normally the intracellular + extracellular fluid = 40-60% of the TBW.

Desired TBW: (Measured Na X current TBW)/ normal serum Na.

Body Water Deficit:  Desired TBW- current TBW.

Intracellular Fluid (ICF): 40% of body wt or 66% of TBW, ~28 L, primarily in muscle, 160ml/kg.

Extracellular Fluid (ECF): 33% of TBW.  Interstitial is 15-20% TBW (~8 L).  Intravascular (Plasma) is 5% TBW, ~3-4 L (plasma volume is 38ml/kg, blood volume is 70ml/kg).

Free Water:  water in the body that can be removed by ultrafiltration and in which substances can be dissolved.

Free (body) Water Deficit (FWD) in Liters:   FWD in Hypernatremia:  FWD = [Serum Na (measured) – serum Na (normal) x 0.6 Wt in kg/ normal serum Na].     Also written as, FWD = [(Na-140)/140] baseline wt X F. (F = fraction of wt that is water, 0.6 for male, 0.5 for females).  Also written as, FWD = FWD  = 0.6 X wt in kg X (1- 140/Na).   Kg is estimated wt when fully hydrated.      FWD in Hyperglycemia:  Use corrected Na if necessary, particularly if hyperglycemia is present–> FWD = ( baseline wt in kg — 0.45) — [(290/Eosm) X current wt X 0.45]. Effective osm = 2 X (Na+K) + (glucose/18) = TBW in kg X 0.6 (1- normal Osm/observed Osm). Generally, about half of deficit can be replaced in the first 24 hours; rest over 1-2 days.  Avoid correcting the serum Na concentration >1mEq/L/hr.

Free Water Clearance (FWC): Used to asses a solute Vs water diuresis when have polyuria (>3L/d).  FWC = Ur volume in 1 day – Osmolar clearance.  Osmolar Clearance = (Ur Osm X Ur volume)/ plasma Osm.  No FWC if Ur Osm >300 mOsm/kg H2O.  Excess FWC if Ur Osm <150 mOsm/kg H2O.

Normal Losses of Fluid:  Insensible = stool + skin = ~500ml/d.  Stool–> ~300ml/d.  Renal excretion–> 1-1.5L/d.   Insensible Loss–> 400ml/m2/d (~750ml/d for adults = 10ml/kg/d, 60% as free water vapor from lungs, 40% perspiration). Increased Loss of Fluid:  fever–> Inc 15% =~150ml insensible loss/ 1 deg C above 37.  (or 100ml/deg F >98.6), tachypnea.  Inc 50% for each doubling of RR, evaporation (perspiration, ventilator, open wounds), GI (fistula, emesis, diarrhea, NGT), third space, operative loss (~800ml/hr for major abd surgery).

Maintenance Fluid:   If wt>20kg, simplify 4:2:1 rule by   adding 40  to pts weight  in kilograms = ml/hr.   Maintenance:  D5-1/4NS (= D5-.2NS) with 25 mEq K.    If >20kg.   Maintenance = 110 + wt in kg.   Daily Fluid Volume:  100ml/kg/d  (4cc/hr) for 1st 10kg + 50ml/kg/d (2cc/hr) for 2nd 10kg + 20ml/kg/d (1cc/hr) any kg >20.   Average adult needs:  30-35ml/kg/d water (1500ml/m2/d).  35 kcal/kg/d.  Need ~1g Na/ 160 kcals.    70kg Male–> D5 ½NS +20mEq KCL/L  @125ml/hr = ~3L free water.  Goal:  maintain urine output of 1-1.5L/d.

Other Info: Body Surface Area (BSA) = square root of (Ht in cm X wt in kg)/ 3600.   BSA (m2)= 0.007184 X wt- 0.425th X Ht- 0.725th.  (Use wt in kg, ht in cm).

Banana Bag: MVI 1 amp + 100mg Thiamine + 1mg Folate + 2g MgSO4 @ 100-125 ml/hr X 3d.

Urine Volume: should be 0.5-1 ml/kg/hr if adequate intravascular volume, renal function, cardiac output.

Anion Gap: Na – (Cl + HCO3).  Normal 8-16 mEq/L.

Osmol Gap: Measured Osm – Calculated Osm–> if 0-10= normal, if >10 abnormal, if <0 lab/ calculation error.

Serum Osmolality: tonicity of body fluids.    Calculated Osmolality (mOsm/L): 2(Na) + Glucose/18 + BUN/2.8.   For “effective osmols”, need to add in mannitol (mOsm) + Sorbitol + Glycerol as these solutes do not easily cross into muscle cells.

Fractional Excretion of Sodium (FENa %):   (UNa X PlCr)/ (PlNa X UCr) X 100.  (<1=prerenal, >1=renal).


Usually secondary to parenteral overhydration, fluid retaining states (CHF, Acute RF), or mobilization of previously sequestered fluid.

S/s:  wt gain, pedal/sacral edema, rales/wheezing, JVD, inc CVP and PCWP.

Lab: dec HCT, dec albumen, inc/ dec Na.

Tx: water restrict to 1500ml/d, diuretics, Na restrict to 0.5g/d, anasarca may respond to combined colloid (albumen) infusion with parenteral loop diuretics.


Seen in trauma (crush injury, burn), GI loss (vomit, NGT, diarrhea), third spacing (ascites, effusions, bowel obstruction), inc insensible losses.

Mild–> 4% of Total Body Water (TBW), 15% blood volume.    Mod–> 6% TBW, 15-30% blood volume.   Severe–> 8% TBW, 30-40% blood volume.  Shock–> >8% TBW, >40% blood volume.

S/s: sleepy, apathy, coma, OH, tachycardia, dec pulse pressure, dec CVP and PCWP, dec skin turgor, hypothermia, pale extremities, dry tongue, dec fontanelle in infant, ileus, oliguria, weakness.

Lab: BUN:Cr is >20:1, inc Hct (3% for each Liter deficit), FENa <1%, inc Ur sg.

Tx:  Bolus therapy with NS or LR.  Replace free water loss with D5W or D5W ¼ NS.


Links:  S/s:  ORT:  Other: IV Solutions: Pediatric:

Dehydration:  loss of intracellular water that ultimately causes cellular dessication and inc’s the plasma Na and osmolality. Seen mostly in the elderly with infections and poor access to water.   No circulatory instability, should get 5% Dextrose slowly.  Yet most also have volume depletion and need NS (Hypovolemia refers to both conditions).

Volume Depletion: loss of Na from the extracellular space (intravascular, interstitial fluid) after GI hemorrhage, vomiting, diarrhea, diuresis.  Have circulatory instability and need NS rapidly.

Adults–> check bicarb & BUN/Cr ratio (>25 suggests dehydration or renovascular dz).    Stool specimens on need if bloody stool  or signs of invasive bacteria (abrupt onset, diarrhea precedes vomiting).  Screen with FWBC test (inc in bacterial).  Elderly: susceptible as dec thirst sensation & kidney ability, debilitating illness, meds.

S/s: Everything must be interpreted in context.    Dry axilla & dry MM’s are both unrealiable. Tongue furrows can be seen, but mouth breathing can cause this.  Cap refill and skin turgor are not good signs in the elderly.   Normal elderly may have sunken eyes, tenting (lose elastin fibers with age), tachycardia, concentrated urine and orthostatics.  Look for tongue furrows & dryness, upper body weakness, speech difficulties, confusion.  Other signs include >5% wt loss in 30d, dizziness, failure to eat, febrile illness, problems with hand dexterity, uncontrolled DM, UTI.

Labs:  Check lytes for inc Na & BUN.  Yet BUN not reliable as both starvation & liver dysfunction prevent its rising commensurate with volume loss. Measure serum Osm & urine Na.  A Ur s.g. >1.020 is dehydrated.  Urine output <2ml/kg/hr is oligouria.  Each kg BW loss is ~1L deficit.

Oral Rehydration Therapy (ORT):

Diarrhea is #1 cause.  Best if used with any diarrhea to prevent dehydration.   Advantages: less $ than IV, less complications than IV, can be used at home. Contra: severe dehydration, shock, intractable vomiting, lack of personnel to administer ORT.  Need 75-90mEq/L of Na. 2-2.5g/dL glucose (High glucose content in soda & juices –> inc osmolality–> osmotic diarrhea.), 300-330 mOsm/L.

Dietary Adjustments: inc salt with boiled starches, boiled vegetables, soups, yogurt, bananas, avoid Lactose until formed stools developed.

Rehydralyte or WHO Oral Rehydration Solution (ORS) formula and :

Home ORS Formulas:

May be given by bottle, cup, spoon, syringe, or NGT.  Give frequent small amounts, ~10ml q 10min, can inc rate by 5ml q min at tolerated.

¾-1 level tsp (3.5g) salt + ½-1 tsp baking soda + 8oz water (or OJ) + 4 level tbsp sugar + 4 tsp Cream of Tartar (KCl, K bitartrate).  Can replace the sugar with 50-60g of cereal flour or 200g mashed potatoes to make a food-based formula.

Or 1 qt water + ¾ tsp salt substitute (KCl) + ½ tsp Baking soda + 3 Tbs Karo Syrup (White Corn Syrup) + 1 packet unsweetened powdered drink mix (Kool-Aid) or fruit juice concentrate.

Or   8oz fruit beverage (OJ, apple)+ 8 oz water + ½ tsp honey/ corn syrup + pinch NaCl + ¼ tsp baking soda.     Carb-Na ratio of <2:1.

Or  (8:1 sugar:salt): 2 tsp sugar + ¼ tsp salt + squeeze lime in 8oz water.

Comparison of the Composition of Solutions:

Solution –> Na (mEq/L)\ K (mEq/L)\ Cl (mEq/L)\ Bicarb (mEq/L)\ Glucose (g/dL):    ECF –>142\4\103\27.1.  LR –> 130\109\28.  0.9% NaCl ( NS) –> 154\154.  Chicken Broth –> 250\5-8\-\-\-.  WHO-ORS –> 90\20\80\-\2.  Pedialyte –> 45\20\35\30\2.5.  Gatorade –> 28\2\-\-\2.1.  Ginger Ale –> 4.2\-\-\9.  Coke/Pepsi –> 2.5.5\9\10\10.5.  Apple Juice –> 3\17\-\-\12.  Grape Juice –> 3\25\-\-\15.  Jell-O –> 24\1.5\-\-\16.

Alternative Hydration Methods:

Hypodermoclysis:  use #21-25g butterfly needle inserted into SC skin at anterior chest, abd wall infraclavicular or scapular regions.  Can run at 80-250ml/hr (0.5-3L/d)

Proctoclysis:  rectal hydration using a #22F NGT inserted 40cm into rectum.  Use NS or tap water starting at 100ml/hr, increase to 400ml/hr if tolerated.  Can also be used to raise the core body temp.

Osteoclysis:  interosseous infusion of fluids.  Need a bone injection gun.

IV Solutions:

Links: Crystalloid:  Colloid:  Compositions:

Crystalloid Solutions:  Includes: Dextrose, NaCl, plasmalyte A, ringers.    Only 25-33% stays in the intravascular compartment.  A person who has lost 2 units of blood (1000ml) would need 3-4L of crystalloid for volume resuscitation.  ½NS provides only ½ of what LR or NS provides/L.  D5W is the worst for trying to give intravascular volume (gives 80ml/L, the rest to the cells and interstitium).   Replace 3rd space losses with isotonic crystalloids–> LR or NS.

Lactated Ringer (LR) –> 130 Na mEq/L, 4 K, 109 Cl, 28 Lactate, 3 Ca, 9 kcal/L, 272 osmol, 100ml free water, pH = 6.5).  Contra: renal failure (potassium), citrated blood to same line (Ca).  More physiological level of electrolytes, better for trauma.

0.9% NaCl (NS = normal saline) –> 154 Na mEq/L,154 Cl, 208 osmol, no free water, pH = 5.    Contra: prolonged/fast infusion may cause hyperchloremic metabolic acidosis and hypokalemia (as normal serum has Cl of only 100mEq/L).  Better for pt with protracted vomiting.

½NS–> 450ml free water.

Plasmalyte A: 140 Na mEq/L, 98 Cl, 5 K, 294 Osm, pH = 7.4.  5% Dextrose (D5W) –> 1000ml free water, 5,000mg/dL dextrose, 170 kcal/L, 250 mOsm/L.  10% Dextrose (D10W) –> 1000ml free water, 340 kcal/L, 500 mOsm/L.   D5 ½NS–> 800ml free water.      1L of D50 = 1700 kcal.

**Ref: (Critical Care Clinics 1992;8;2) (Critical Care Clinics 1993;9:2) (Dehydration: evaluation and management in older adults. JAMA 1995;274:1552-6)

Composition of Common Fluids (mEq/L):

Fluid –> Na/ K/ Cl/ HCO3/ Vol/24hr/ mOsm/L:  Extracellular –> 40\4.5\108\-\- \290. Saliva –> 20-60\15\15-30\40\1-2L\-.  Stomach –> 40-99\5-15\15-20\~2L\-.  Pancreas –> 135\4-6\40-75\95\1-2L\-.  Sweat –> 40-50\5-10\40-60\-\-.  Diarrhea –> 50-60/ 45/ 35-45/ 55/-/-.

Na/ K/ Cl/ HCO3/ Glucose/ mOsm/L / Kcal:  D5W –> 0\50 g\252\170.  D10W –> 0\100\505\340. ½NS (0.45%) –> 77\77\154. NS (0.9%) –> 154\1540\308. 3% NS –> 513\513\1026. D5 1/4NS (0.2%) –> 38\38\50\329\170.  D5 ½NS –> 77\77\50\404\170. LR –> 130\4\110\27\272\10.  D5 LR –> 130\4\110\27\50\524\180.  Albumin –> 145\145\-\-.

Colloid Solutions:  Used because crystalloids would be required in such great amount that have risk of fluid overload.  Plasma volume expanders. Albumin, Hetastarch (Hextend) (6%), Pentastarch (10%), Dextran (40, 70), Gelatins, Blood products (whole blood used if >25% of total volume is lost), plasma protein fractions and synthetic blood substitutes.

Albumin:  Typical order: 25g of 25% IV q6-12hr X 4-6 doses.  It is the major protein produced by the liver (50%), 8% turnover each day.  584 amino acids.  Accounts for 80% of plasma colloid oncotic pressure.  40% is distributed intravascular, 60% interstitial.   Each gram holds 18ml of fluid in the intravascular space.Human serum albumin is available as 5 or 25% solution, from human plasma donors.  T-½ is 18d, colloid oncotic pressure is 19mmHg. 25% Albumin Dilution:   Avoid hypotonic plasma/ hemolysis if use 0.9% NaCl instead of H2O in 1:4 dilution to make 5% albumin.  The oncotic effect of 100ml of 25% = 500ml of plasma.

Hydroxyethyl Starch (Hetastarch, HES):  synthetic molecule similar to glycogen.  In a 6% solution in NS.  Has an oncotic pressure of 30mmHg with Osm of 310.  Effects last 3-24h.   Less expensive than albumin.  May decrease platelet count and inc PTT with large volumes.

Pentastarch: 10% solution, more predictable excretion compared to hetastarch.  Volume expanding effects last 12h.

Dextran:  a mixture of glucose polymers produced by the bacteria Leuconostoc mesenteroides when grown in sucrose.  Dextran 70 has a slower excretion rate than Dextran 40.  1L of Dextran 70 will increase the plasma volume 790ml.  T½ ~7h.  Has been uses as DVT prophylaxis.  Complications:  ARF, anaphylaxis, bleeding diathesis.


Links: Septic: Cardiogenic:  Hypovolemic:  Labs:  Tx:  Vasopressors:  Pulmonary & Cardiac Parameters:

Failure of the circulatory system to maintain adequate cellular perfusion and function.  Due to impaired blood flow to vital organs and tissues.

Ddx:  “SHOCK”: Sepsis, Hypovolemia, Other (Addisons, drugs), CNS(spinal shock), “K” cardiogenic (MI).  Anaphylaxis –> DOC is Epi.  Massive PE or TCA OD –> drug of choice (DOC) is NE.

Obstructive Shock:   Vascular etiology.  Consider aortic stenosis, PE or tamponade from tension pneumo–> inc HR, dec heart sounds, distended neck veins, +pulsus paradoxus (dec SBP >10 during insp), Kussmauls sign (inc venous pressure with insp).

Neurogenic Shock:  (dec symp tone) –> dec BP but normal HR and pulse pressure, no vasoconstriction.  Doapmine is the drug of choice.

Distributive Shock (Septic):  50% due to G-, 25% G+, from endotoxemia that leads to vascular collapse and multiple organ failure.  Hypotension from vasodilators (lipopolysaccharide, TNF, C3a, C5a).  Positive blood Cx in <50%.   Hypotension, mildly inc HR, warm, pink, wide pulse pressure.  Initial tx is an attempt to eradicate the infection via Abx + surgical drainiage.  If severe met acidosis (pH <7.2) consider bicarb. Use Dobutamine + epinephrine or Norepinephrine.  Phenylephrine @ 20-200 ug/min (pure alpha-1 agonist) has a theoretical advantage as it maintains a near normal gastric pH.  Dopamine is often used, but may not be as efficacious at reversing the hemodynamic abnormalities.

Cardiogenic Shock: Commonly seen with >35% loss of functioning of LV after an AMI.  Get dec CO and lactic acidosis due to tissue hypoxia.  MR occurs frequently with inferoposterior MI.  Ruptured LV wall may occur.   During Tx aim for a LV filling pressure of 15-18 mmHg and CI of >2.2 L/min/M2.  Start vasopressors and inotropic agents if SBP low despite fluids.  If SBP >80mmHg use dobutamine (unless tachy, arrhythmia or vasoconstriction) as it increases coronary blood flow.  If SBP <80 mmHg use Dopamine as need some additional vasoconstriction of peripheral vessels to maintain vital organ perfusion.  If SBP <70 or refractory hypotension use NE as it will rise MAP & SVR.   Consider adding a low-dose DA drip.  An intraaortic ballon pump (IABP) may be needed (see AMI) to dec systemic afterload and inc diastolic perfusion pressure as a bridging device to revascularization.  Give volume resuscitation if no pulmonary edema, correct electrolyte abnormalities, hold antihypertensives meds.

Hypovolemic Shock:  loss of >40% of circulating blood volume.  Hypotension, profound tachycardia.  Usually due to bleeding, severe diarrhea or emesis, burns, or redistribution of body fluids.

Pearl:  If can feel radial pulse–> BP must be at least 80-90mmHg.  Femoral–> 70mmHg.    Carotid only–> 50mmHg.   In shock BP is usually <70mmHg.

Labs:  CBC, lytes, blood sugar, ECG, CXR.  If bleeding get T&C.

Tx: Hemodynamic monitoring–> Swan-Ganz or bedside parameters such as UO, acid-base status, level of sensorium, skin temp.  Step #1 is Fluid resuscitation: NS or LR generously (~2L in adults) but cautiously to raise SBP to 90-100 mmHg.  If develops SOB, rales, distended neck veins then overhydration has occurred (consider a PA cath to guide therapy).   Aim for a mean arterial pressure of 65mmHg to maintain cerebral perfusion.    If the pressure fails to rise after 2L IVF, then start vasopressors.  Consider intra-arterial pressure monitoring.  If unresponsive to initial fluids and altered MS or UGI bleed, consider ETT and ventilator support.


Autonomic Nervous System:   Adrenergic Receptors:  alpha-1–> constricts the peripheral vascular and coronary smooth muscle.  Beta-1–> acts on myocardium to increase rate and contractility.   Beta-2–> dilates bronchial, peripheral vascular and coronary smooth muscle.  Dopamine–> dilates renal vasculature and GI smooth muscle, shown to decrease mortality.

Dopamine (DA, Intropin): 5-20 ug/kg/min.  0.5-2 ug/kg/min = Renal Dose, for oligouria despite “normal” BP as dopaminergic.  2-10 ug/kg/min is Beta-1.  10-20 ug/kg/min is Alpha-1 (high arrhythmogenic potential).    2-15 for emergency tx of hypotension of any cause.  1-10 for hypotension due to sepsis.

Dobutamine (Dobutrex): 2.0-20 ug/kg/min.  For cardiogenic shock, cardiac induced pulmonary edema (CHF), not used alone if pt is hypotensive as only increased CO, not SBP. Beta-1 and Beta-2.  Good if hypertensive or normotensive.

Norepinephrine (NE, Levophed): 0.5-30 ug/min IV.  For emergency tx of hypotension from any cause, especially sepsis. Alpha-1 & Beta-1.

Epinephrine (Levarterenol): 0.5-10 ug/min for anaphylaxis, pulseless arrest and sepsis. Alpha-1, Beta-1 and Beta-2.  High arrhythmogenic potential.

Phenylephrine (Neo-Synephrine): 0.1-0.5 mg IV, then 0.05-0.2 mg/min for neurogenic shock (usual dose is 10-200 ug/min). Pure alpha-1.

Isoproterenol (Isuprel): 1-10 ug/min for bradycardia.  Beta-1 and Beta-2.  High arrhythmogenic potential.

Metaraminol (Aramine): 0.5-5 mg IV bolus, then 5-15 ug/kg/min for neurogenic shock.

Hemodynamic Profiles:   Drug –>\SVR\CO\HR\Inotropy\VO2.  DA- low –>\dec\inc\inc\inc\Inc.  DA- high –>\3+ inc\2+ inc\2+ inc\2+ inc\2+ inc.  Dobutamine –>\dec\2+ inc\2+ inc\2+ inc\3+ inc.  Epi –>\2+ inc\2+ inc\3+ inc\2+ inc\3+ inc. NE –>\3+ inc\inc\3+ inc\2+ inc\Inc.  Isuprel –>\2+ dec\2+ inc\3+ inc\inc\3+ inc.

Phosphodiesterase Inhibitors:   Amrinone (Inocor): 0.75 mg/kg IV over 3min, then 5-15 ug/kg/min as short term inc cardiac contractility when catecholamine therapy is hazardous such as arrhythmia or ischemia.   Has no adrenergic effects.

Milrinone (Primacor): 50 ug/kg IV over 10min, then 0.5 ug/kg/min.

**Ref: (The case of dehydration versus volume depletion.  An Intern Med 1997:127:848-53) (The Medical Abacus, by D. Rifkind, Parthenon Publishing 2000, NY) (Dehydration. Evaluation and management in older adults. Council on Scientific Affairs, American Medical Association. JAMA. 1995;274:1552-6) (Colloidal and crystalloid fluid resuscitation in shock associated with increased capillary permeability. Curr Stud Hematol Blood Transfus. 1986;:86-100) (Emergency fluid management for hypovolemia.  Postgrad Med. 1996;100:243-54) (Crystalloid or colloid?  Br J Hosp Med. 1986;35:217) (Fluid resuscitation with colloid or crystalloid solutions.  BMJ. 1998;317:278) (Cardiogenic shock: therapy and prevention.  Clin Cardiol. 1998;21:72-80)  (Septic shock.  Crit Care Clin. 1997 ;13:553-74)   (Septic shock.  Lancet. 1998;351:1501-5) (Fluid-electrolyte balance during labor and exercise: concepts and misconceptions.  Int J Sport Nutr. 1999;9:1-12)  (Subcutaneous infusion or hypodermoclysis: a practical approach.  J Am Geriatr Soc. 1999;47:93-5)  (Abnormalities of water metabolism in the elderly.  Semin Nephrol. 1996;16:277-88) (Serum osmolality. N Engl J Med 1984;310:102-05) (Emergency fluid management for hypovolemia. Postgrad Med 1996;100:243-51) (Cardiogenic shock. Ann Intern Med 1999;131:47-59) (Hypouricemia in the syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med 301:528, 1979). (Managing shock: the role of vasoactive agents.  J Critical Care Med 2001;16:6 & 7)


Links:  Types:  ORT:  Severity:  Composition of Solutions:

Dehydration:  loss of intracellular water that ultimately causes cellular dessication and inc’s the plasma Na and osmolality. Seen mostly in the elderly with infections and poor access to water.   No circulatory instability, should get 5% Dextrose slowly.  Yet most also have volume depletion and need NS (Hypovolemia refers to both conditions).

Volume Depletion: loss of Na from the extracellular space (intravascular, interstitial fluid) after GI hemorrhage, vomiting, diarrhea, diuresis.  Have circulatory instability and need NS rapidly.

Average child has 1-2 episodes/yr for 1st 5yrs of life.  85% of dehydration due to Viral (Rota, Norwalk, Adeno, astrovirus).   Most of deaths in age <12mo –> vulnerable as inc metabolic rate (loses water), immature immune system, reticence to PO when not feeling well.

For hypovolemic shock –> bolus with 20ml/kg isotonic fluids.

PE: eyes sunken back into skull, skin tents/ loses elasticity, lips parched, inability to produce tears when cry, recessed fontanelle.  Ur s.g. >1.020 is dehydrated.  Urine output <2ml/kg/hr is oliguria.  Each kg BW loss is ~1L deficit, can estimate deficit from current wt- birth wt if an infant.

Types of Dehydration:

Hyponatremic (Hypotonic):  Na < 130 mEq/L. Seen in 5%.  Physio: Na loss exceeds water loss.  ECF loss >> ICF loss

S/s: inc HR, dec BP, comatose, skin tenting and clammy

Tx: All with isotonic fluid X 1-2hr (NS or LR), then D5 in NS X 12hr, then D5 0.45% NS for balance of fluids. Inc Na to 120 mEq/L over 12hr, then to 130 over next 24-36hr. 3%NS if severe sx.

Isonatremic (Isotonic):  Na is normal Seen in 80%.  Physio: Equal Na and water loss, no fluid shifts, mod ECF depletion

S/s: inc HR, dec BP, somnolent, dec skin turgor, dry skin and MM’s

Tx: All with isotonic fluid X 1-2hr (NS or LR), then ORT OK if  <10% dehydration.  D5 in 0.45% NS X 12hr Then D5 in 0.225 NS. + 25 mEq/L Bicarb, then add 30mEq KCl once voided.  Replace ½ Na deficit over 12hr, then ¼ over next 12hr.

Hypernatremic (Hypertonic): Na >150, Seen in 15%. Physio: Water loss > Na loss.  ICF loss > than ECF.

S/s: Mild inc HR, dec BP, irritable, doughy skin.  Parched MM’s

Tx: All with isotonic fluid X 1-2hr (NS or LR), then D5 in 0.225% NS.  Add 40mEq/l KCl.  Dec Na slowly (< 10mEq/l/d over 36-48hr).  Avoid rapid correction.  Assume 4ml/kg free water deficit for each 1mEq/L Na >145.

Five steps:  1.  Asses Severity of dehydration:

Mild (3-5%): normal BP/ HR/ MS/ skin turgor, but slightly dry MM & dec  UO.   Most are isonatremic and no electrolyte or labs determination needed.  Need to replace 50ml/kg given in 4-6hr, add 10ml/kg stool for ongoing loss.

Moderate (6-9%): Need to replace 80-100ml/kg in 4-6hr with volume for volume stool/ emesis loss.    Have nl BP, but inc HR & dec fontanel/ MS/ UO/ skin turgor, dry MM, absent tearing, cap refill >2 sec, generally ill appearing.   Heck Electrolytes to determine baseline & guage clinical progress.   If ingesting hyperosmolar liquids (fruit juices) that cause free water to move into gut, then likely Hypernatremia (Na >150mEq/L).  Will have contraction of vascular space –> irritable, feverish, sz, delirium, coma.  Need slow rehydration.   Hyponatremia (Na<125mEq/L) –> More common, from consumption of free water or low Na intake.

IV Therapy if: Severe (10-15%): Need to replace 110-130ml/kg given via IV or interosseous infusion of NS or LR @ 20-40ml/kg/hr, repeated until signs of rehydration are evident. Replace 50% of loss in 1st 8hr, remaining 50% over next 16hr.  Begin PO fluids once consciousness has improved and condition stabilized.     Pt has nl to dec BP, inc HR, dry MM, oliguria, fontanel, MS, skin turgor.  ORT Failure: clinical deterioration, failure to rehydrate within 8hr, intractable vomiting.   Will also need IV therapy if have profuse diarrhea or are vomiting relentlessly.  Exhibit a marked change in mental status.   Suffer from a medical illness or physical disability that interferes with oral therapy.  Exhibit marked change in mental status.  Unreliable caregivers or simply refuse to drink.  Re-evaluate lytes periodically.

2. Rehydrate: Over 4 hours, reassess status every 1-2hr, when clinically rehydrated proceed to maintenance.   Mild: 50ml/kg + 10ml/kg stool + Est of emesis.     Moderate: 100ml/kg +10ml/kg stool + Est emesis.

3.  Maintain hydration: take Ad Lib with goal of maintenance + ongoing losses.  @40-60mEq/L Na content, 2-2.5g/dL glucose, 215-260 mOsm/L.

4. Early Re-feeding: –> dec stool output.  Best to continue breast feeding throughout/ resume with full strength milk (80% will do well, lactose intolerance is rare) Foods should be complex carbo’s, lean meats, fruits, vegies, yogurt, low fat (BRAT diet along with wheat noodles & potatoes). Formula fed infants should alternate feedings of ORS and formula.

5.  Non-use of pharmacologic agents: children more susceptible to toxicity, decreased motility may inc risk for bacterial invasion.  Abx only if bacterial (cholera, travelers, dysentery, protozoal).

6.   F/u: reassess via telephone.  RTC if diarrhea lingers >10-14d.

Composition of Solutions:    Solution –> Na (mEq/L)\K (mEq/L)\Cl (mEq/L)\Bicarb (mEq/L)\Glucose (g/dL).   ECF –> 142\4\103\27.1.   LR –> 130\ 109\ 28.   0.9% NaCl (NS) –> 154\154.   Chicken Broth –> 250\5-8\-\-\-.   WHO-ORS –> 90\20\80\-\2.   Lytren –> 50\25\45\30\2.   Pedialyte –> 45\20\35\30\2.5.   Rehydralyte –> 75\20\65\30\2.5.   Resol –> 50\20\50\34\2.   Ricelyte –> 50\25\45\10\3.   Infalyte –> 50\20\40\-\2.  Gatorade –> 28\2\-\-\2.1.   Ginger Ale –> 4.2\-\-\9.  Coke/Pepsi –> 2.5.5\9\10\10.5.  Apple Juice –> 3\17\-\-\12.  Grape Juice –> 3\25\-\-\15.  Jell-O –> 24\1.5\-\-\16.  Infant Caravel’s –> 81\61\20\4.65.  Child Caravel’s –> 132\3.8\109\27\4.8.

**Ref:  (Dehydration in young children.  Acta Paediatr. 1997;86:337-8) (Oral rehydration for children with diarrhea. JAMA. 1991;266:517) (Update on medications used to treat gastrointestinal disease in children. Curr Opin Pediatr. 1999;11:396-401)


Links:  Essential Nutrients:  Vitamins & Nutrients:  Signs of Deficiencies:  Vitamin Toxicity:  Caffeine:  Basal Metabolic Rate:   Assessment:   Nutritional Support:  Enteral:  Oral: TPN:  PPN:   Healthy Diet:   Vegetarians: Refeeding Syndrome:

Roughly 30% of Americans use at least one vitamin or mineral supplement in a given month.   The highest use is seen in non-Hispanic whites (42.6%) (Arch Fam Med 2000;9:258-62)

Dietary Reference Intakes (DRI’s):

Quantitative estimates of nutrients intake, useful for planning and assessing diets for healthy people.  Comprises 4 different values:

1. Estimated Average Requirement (EAR): intake of a nutrient adequate to meet the requirement of ½ the healthy population.

2.  Recommended Daily Allowance (RDA): dietary intake sufficient to meet the requirements of nearly all (97-98%) healthy persons in a particular life-stage and gender group.  RDA= EAR + 2SD  or   RDA= 1.2 X EAR.

3.  Adequate intake (AI): based on observed or experimentally derived estimates of nutrient intake by a group or groups of healthy people.  It is used when scientific evidence is insufficient to determine an EAR or RDA.  It is less precise

4.  Tolerable Upper Intake Level (UL): the highest level of daily nutrient intake likely to pose no risks of adverse health effects to most of the population.  Ex: Niacin–> flushing, B6–> sensory neuropathy, Folic Acid mask anemia dx from B12 def, Choline in large doses–> fishy body odor.

Nutrients Requirements and & Assessment:

Determining factors an individuals requirements:   gender, age & stage of life cycle (fetus, pregnant, lactating, child, adult, elder), disease states (malabsorption, maldigestion), inborn errors of metabolism, lifestyle (smoker, ETOH), medications, bioavailability, quantity required to fulfill physiologic roles, the extent to which the body can recycle micronutrient, the distribution & storage.

Known Essential Nutrients:  There are 45 essential micronutrients in humans (15 vitamins, 20 minerals, 8 AA’s, 2 fatty acids) that must be obtained from food as the body cannot manufacture them.  Amino Acids (L forms) –> threonine, valine, isoleucine, lysine, tryptophan, methionine-cyteine, Phenylpthaline-tyrosine, histidine.     Fatty acid –> Linoleic acid.    Vitamins –> thiamine, niacin, riboflavin, pyridoxine, folic acid, B12, ascorbic acid, biotin, pantothenic acid, V-A, V-D, V-E, V-K.   Elements–> Na, K, Ca, Mg, Cl, P, Fe, Cu, Zn, Manganese, Selenium, molybdenum, iodine, fluoride.

Common Nutrients:……Links: Ascorbic Acid (Vit-C): Vitamin A: Thiamine (B1): Riboflavin (B2): Niacin (B3): Pyridoxine (B6): Vit B-12: Biotin: Calcium: Coenzyme Q10: Creatine: L-Carnitine: Chromium: Chloride: Cobalt: Copper: Vitamin D: Fatty Acids: Fluoride: Folic Acid: Vit E: Iodine: Iron: Vit K: Magnesium: Manganese: Molybdenum: Pantothenic Acid: Phosphorus: Potassium: Selenium:  Sodium: Sulfur:  Zinc:

Ascorbic Acid (Vit-C): 75 mg/d for women, 90mg/d in men (Max of 2g/d).  Found in citrus fruits, raw cabbage, tomatoes, strawberries, peppers, greens, potato, kiwi. Used in microsomal electron transport, tyrosine, tryptophan, DA synthesis, steroid synthesis, hydroxylation of collagen proline and lysine and folic acid metabolism.

Defic: Scurvy.   Gingival hypertrophy, bleeding gums, petechiae, perifollicular hemorrhages (often on posterior thigh), curled hair follicles (corkscrew hairs), ecchymosis, osteopenia with subperiosteal hemorrhages, poor wound healing.  Toxic effects include nephrolithiasis and diarrhea.  Normal levels: 0.5-1 mg/dL in serum, 15-30 mg/dL in WBC.

Vitamin A (V-A, Retinol, Retinoic Acid, Beta carotene):   RDA is 300-500ug in child, 900ug in male >14yo and 700ug in female, 1200ug if lactating.   ~= 4,000-5,000 IU/d (800-1000 mg RE) .  Found in green leafy vegetables, dairy, yellow fruits and vegetables, liver.  Needed for light sensitive pigments in the retina, epithelial maintenance (retinoic acid), immune function.  Normal level: 20-60 ug/dL (-.7-2 umol/L).   Defic:  Keratomalacia:  (dry conjunctiva, corneal ulcers and prolapse of the iris), Bitot’s spots (white/ yellow spots under the conjunctiva), gingivitis, dry skin with hyperkeratinization, night blindness.  Some carotenoids, most notably beta-carotene, are metabolized into compounds with vitamin A activity and are considered to be provitamin A compounds. Vitamin A is an integral component of rhodopsin and iodopsin, light-sensitive proteins in retinal rod and cone cells.   Toxicity: In adults, >500,000 IU may cause acute toxicity: intracranial hypertension, skin exfoliation, and hepatocellular necrosis. Chronic toxicity may occur with habitual daily intake of >25,000 IU: alopecia, ataxia, dermatitis, pseudotumor cerebri, hepatocellular necrosis, and hyperlipidemia. Daily ingestion of >15,000 IU during early pregnancy can be teratogenic. Excessive intake of most carotenoids causes a benign, yellowish discoloration of the skin. Large doses of canthaxanthin, a carotenoid, can induce retinopathy.

Beta-Carotene: 5-6mg/d.  Antioxidant, can be converted to V-A.  Found in carrots, sweet potatoes, yellow-green veges, mangoes, apricots, papaya.  Defic: same as V-A.

Thiamine (B1):  1-1.5mg/d.  Found in pork, enriched breads/ cereals, wheat germ, organ meats, nuts, legumes, beans and peas.  Cofactor for transketolase, pyruvate to metabolize branched chain ketoacids.  Essential for glucose and alcohol metabolism.  A water-soluble compound containing substituted pyrimidine and thiazole rings and a hydroxyethyl side chain. The coenzyme form is thiamine pyrophosphate (TPP). Serves as a coenzyme in many alpha-keto-acid decarboxylation and transketolation reactions. Defic:   Inadequate thiamine availability leads to impairment of the above reactions and consequently to inadequate ATP synthesis and abnormal carbohydrate metabolism.  Lactic acidosis, Wernicke-Korsakoff syndrome (ophthalmoplegia- CN VI loss, nystagmus, ataxia, amnesia, confusion, confabulation), Wet beriberi (high output CHF, edema, peripheral vasodilation), Dry beriberi (peripheral neuropathy, muscle wasting), hyperglycemia (impaired insulin secretion). Normal levels: 8-15 IU ETK or <10% TPP effect.   Tx of Defic: 50-100mg IV/IM qd X 7-14d, then PO.  Must be given before or concurrent with dextrose fluids as a glucose load will inc metabolic demand for thiamine. The most effective measure of B1 status is the erythrocyte transketolase activity coefficient, which measures enzyme activity before and after addition of exogenous TPP: RBCs from a deficient individual express a substantial increase in enzyme activity with addition of TPP.  Toxicity: excess intake is largely excreted in the urine although parenteral doses >400 mg/d are reported to cause lethargy, ataxia, and reduced tone of the gastrointestinal tract.

Riboflavin (B2):  1.3-1.7 mg/d.  Found in dairy foods, organ meats, enriched cereals, green leafy veges, eggs, nutritional yeast, fortified soy milks, vegetarian burger patties, ready-to-eat breakfast cereals and peanuts. If pt limits animal products in their diets, they should take supplements or eat fortified food.   Used as electron transporter in flavin metabolism. Can be synthesized from tryptophan in foods. A compound consisting of a substituted isoalloxazine ring with a ribitol side chain. Serves as a coenzyme for diverse biochemical reactions. The primary coenzymatic forms are flavin mononucleotide and flavin adenine dinucleotide. Riboflavin holoenzymes participate in oxidation-reduction reactions in myriad metabolic pathways.   Deficiency: Susually found in conjunction with deficiencies of other B vitamins. Isolated deficiency of riboflavin produces hyperemia and edema of nasopharyngeal mucosa, cheilosis, angular stomatitis, glossitis, seborrheic dermatitis, and a normochromic, normocytic anemia. Soreness and burning of the mouth from cheilosis, angular stomatitis, gingivitis, atrophic lingular papillae, hypertrophy of filiform and fungiform papillae, seborrheic dermatitis, conjunctivitis, photophobia, anemia.   Toxicity: not reported in humans.  Assessment:  the most common assessment is determining the activity coefficient of glutathione reductase in RBCs (the test is invalid for individuals with glucose-6-phosphate dehydrogenase deficiency). Measurements of blood and urine concentrations are less desirable methods.

Niacin (B3, Nicotinic Acid):  13-20 mg/d.  Found in meats, peanuts, liver, enriched grains/ breads.  Used in electron transport for NAD and NADP.   Defic:  = Pellagra:  4 D’s–> Dermatitis (hyperpigmented, weeping, edema with fissuring, common on the head & neck or sun exposed areas), Dry MM’s, Diarrhea, Dementia. Fissured tongue with atrophy of lingular papillae, scaling/ dry/ atrophic/ thickened/ hyperpigmented skin, dementia, diarrhea. Most common in alcoholics.  Often affects populations where corn is the major source of energy endemic in parts of China, Africa, and India.  Normal levels: 4-9 ug/ml. Blood levels of vitamin not reliable. Measurements of urinary excretion of the niacin metabolites N-methylnicotinamide and 2-pyridone are thought to be the most effective means of assessment at present. Refers to nicotinic acid and the corresponding amide nicotinamide. The active coenzymatic forms are composed of nicotinamide affixed to adenine dinucelotide to form NAD or NADP. Over 200 apoenzymes use these coenzymes as electron acceptors or hydrogen donors. The essential amino acid tryptophan is used as a precursor of niacin; 60 mg of dietary tryptophan yields approximately 1 mg of niacin. Dietary requirements depend partly on the tryptophan content of diet.

Toxicity:  hypolipidemic effects. Includes vasomotor phenomenon (flushing), hyperglycemia, parenchymal liver damage, and hyperuricemia.

Pyridoxine (B6):  2mg/d in men, 1.6mg/d in women.  Found in pork, glandular meats, bananas, bran/germ cereals, milk, egg yolk, oatmeal and legumes.  Cofactor for enzymes such as transaminase, phosphorlyase and oxidases for protein (AA) metabolism, heme synthesis, reduces blood homocysteine levels. Several derivatives of pyridine, including pyridoxine, pyridoxal, and pyridoxamine. The co enzymatic forms are pyridoxal-5-phosphate (PLP) and pyridoxamine-5-phosphate. As a coenzyme, B6 is involved in many transamination reactions (and thereby in gluconeogenesis), in the synthesis of niacin from tryptophan, and in the synthesis of several neurotransmitters, and delta-aminolevulinic acid (and therefore in heme synthesis).   Defic: seen in conjunction with other water-soluble vitamin deficiencies. Glossitis, peripheral neuropathy, dementia, MCHC anemia, sz, N/V, cheilosis, depression.  A normochromic, normocytic anemia has been reported in severe deficiency. Abnormal EEGs and, in infants, convulsions have been observed. Some sideroblastic anemias respond to B6 administration. Isoniazid, cycloserine, penicillamine, ethanol, and theophylline can inhibit B6 metabolism.    Normal levels: EGOT index <1.5.   Plasma or erythrocyte PLP levels are most common. Urinary excretion of xanthurenic acid after an oral tryptophan load or activity indices of RBC alanine or aspartic acid transaminases (ALT and AST, respectively) all functional measures of B6 -independent enzyme activity. Toxicity: chronic use with doses exceeding 200 mg/d (in adults) may cause peripheral neuropathies and photosensitivity.@Assessment of Status Many laboratory methods of assessment exist.

Vitamin B-12 (Cobalamin): 2-3ug/d.  Found in meats, milk, eggs, fish, cheese, poultry.  Used as a methyl donor in carboxylation reactions such as DNA synthesis (with folate), reduces blood homocysteine levels.   Strict vegetarians and elderly (>60yo have atrophic gastritis and cannot absorb) need supplements.   Defic: glossitis, optic neuritis, hyporeflexia, dementia, ataxia, anorexia, loss of proprioception and vibration sense, megaloblastic/ pernicious anemia.  7 P’s of pancytopenia, peripheral neuropathy, pyramidal tract signs, papillary atrophy, pH elevation (GI), psychosis and posterior column disease =subacute combined degeneration (stocking-glove paresthesias, clumsiness, ataxia, weakness and spasticity).  Nl level: 200-900 pg/ml.

Biotin: 50-200ug/d.  Found in most foods such as liver, egg yolk, mushrooms, fruits, peanuts, dark green veg.  Used as cofactor in carboxylation of pyruvate and acetyl CoA, works with B vitamins.  Defic: alopecia, seb derm, neuritis, dry skin, alterations in mental status, myalgias, hyperesthesias, and anorexia occur  Normal levels: 200-500 pg/ml.  Plasma and urine concentrations of biotin are diminished in the deficient state. Elevated urine concentrations of methyl citrate, 3-methylcrotonylglycine, and 3-hydroxyisovalerate are observed in deficiency

A bi-cyclic compound consisting of a uredio ring fused to a substituted tetrahydrothiophene tring. Most dietary biotin is linked to lysine, a compound called biotinyl lysine, or biocytin. The lysine must be hydrolyzed by an intestinal enzyme called biotinidase before intestinal absorption occurs. Acts primarily as a coenzyme for several carboxylases; each holoenzyme catalyzes an ATP-dependent CO2 transfer. The carboxylases are critical enzymes in carbohydrate and lipid metabolism. Toxicity:  not been reported in humans with doses as high as 60 mg/d in children.

Calcium: 800-1200mg/d. Found in milk, broccoli, sardines, clams, kale, turnip greens, mustard greens.  Body contains 600 g, 99% in bones.  Used for blood clotting, nerve and muscle function.  Defic–> osteomalacia, tetany.  Normal = 8.6-10.8 mg/dL (2.2-2.7 mmol/L) if normal serum albumen.  Need to take in 400-600 IU of V-D.

Ca Content of Food: 1 cup skim milk or 8 oz yogurt has 300mg.  1 oz of Swiss or Gruyere cheese or 10 figs has 280mg.  ½ cup of tofu or _ cup of Ca fortified cereal has 250mg.  1 oz cheddar or mozzarella or 6 oz of fortified orange juice has 200mg.  ½ cup of collards or 1 oz of American cheese has 175mg.  ½ cup of mustard greens, kale or broccoli has 50mg.

Ca intake (mg/d): Age 11-24–> 1200-1500mg/d.  Pregnancy–> 1,200.   25-50yo–> 1000mg/d.  50+–> 1500 if on ERT need 1000mg (men need same amounts).  1000mg Ca = 1qt milk (3-4 8oz glasses), 2.7# of broccoli.

Ca Carbonate (Caltrate, Os-Cal, Tums): inexpensive, but less soluble, requires gastric acid for absorption, lowers Thyroxine absorption.

Ca Citrate (Citracal): is more soluble and not affected by stomach acid.  Good for elderly pt’s and those on H2 blockers.

Ca Gluconate and Lactate: soluble, but give less Ca per tablet.

Ca Glubionate (Neo-Calglucon): comes in a syrup, good for kids.

Coenzyme Q10 (Ubiquinol): essential for mitochondria, 40% HTN and 60% CAD are deficient.  Takes 4-6 weeks to lower BP @50-150mg BID.  Insufficient evidence to recommend.  Fairly safe drug.

Creatine: an amino acid (methylguanidine acetic acid). Not routinely incorporated into proteins.  Endogenously synthesized from glycine, arginine and methionine. Taken orally, it will increase total muscle creatinine 20%, with 20% of that increase in the form of creatinine phosphate.   Increases energy substrate to muscle in order to delay fatigue.  May increase power and strength.  Increases wt due to water retention (not muscle), may cause dehydration, cramps and strains.

95% is in skeletal muscle as phosphocreatine, supports synth of ATP, may or may not help in recovery of muscle strength or improve performance, yet incr in body weight (fluid retention and/or stim Protein synthesis).  Naturally in meat, milk and some fish (½# raw meat has 1g creatine).  Gain 1-3# in first week, then 10# by 6wks.  Used for intermittent high intensity exercise (soccer, basketball)  Load dose of 5g QID for 5-7d, then 2-3g/d maintenance. (should use BW dose of 0.3g/kg load, .03g/kg maint), monitor LFT’s and BUN/Cr. The safest form is the monohydrate powder, which is usually mixed with 4-8 oz of juice.  When stopped creatine levels rapidly decrease in 4-12 days to normal levels. No known serious adverse effects. 25% of people do not respond to high muscle creatinine levels.

Lutein:  a carotenoid found in green and yellow veges.  Some studies show benefit in cataract and macular degeneration.  6mg/d.

L-Carnitine (Levocarnitine): helps metab FA’s by transporting free fatty acids into mitochondrial cytosol for oxidation.   Normally synthesized in the liver from Lysine.  S/s:  weakness, fatigue, cramps.    Essential to supplement if deficient.  However w/o the genetic d/o, there is little to no loss from skeletal m during high or low intensity exercise.  Even massive doses increase levels by only 1-2%.  Depletion is common in those on hemodialysis.  300-330-500mg PO TID.  2g IV with each dialysis.  Comes in 1g/10ml solution.  Mix with juice or liquids.

Androstenedione:  androgen derived from plants at 100-300mg/d.  In its natural form it is produced by the adrenal glands and gonads.  It may increase muscle mass and serum testosterone levels.  SE: dec HDL, behavioral changes, acne, testicular atrophy, premature closure of epiphysial plates.

Chromium: 50-200ug/d.  Found in corn oil, clams, whole grain cereals, meats, brewers yeast.  6mg in body, used as part of glucose receptor.   Defic: glucose intolerance.  Normal levels: 2-4ng/ml (35-73 nmol/L) plasma.   Element #24.  Dietary intake should be 50-200ug/d.  enhances insulin action to increase AA uptake in order to lose fat and gain muscle.   Deficiency may cause anemia, chromosomal damage, cognitive impairment and interstitial nephritis.  Usually combined with picolate to increase GI absorption.   Found in:  liver, American cheese, brewer’s yeast, wheat germ, meats, alfalfa, apples with skins, brown sugar, carrots, potatoes.    No proven benefit unless deficient. Deficiency seen with long-term TPN.  Advice to diabetics:  it is inexpensive, can try adding 300-1000 ug/d once BS is stable on traditional meds, if see no measurable improvement in diabetics parameters, then stop taking.

Chloride (Cl): 2-5g/d.  Found in table salt, seafood, milk, meats, eggs.  80g in body, main extracellular cation.  Defic: metabolic alkalosis.  Nl: 89-106 mEq/L.

Cobalt: 3ug/d.  Found in liver, kidney, shellfish, poultry, milk, and veges (depending on soil).  80ug in body, used as a cofactor in B12.  Defic: no know.  Normal levels: 2-5 ng/ml.

Copper (Cu): 2-3mg/d.  Found in liver, shellfish, whole grains, cherries, legumes, kidney, poultry, oysters, chocolate, nuts.  100mg in body, used as cofactor in lysyl oxidase for collagen synthesis and in cytochrome.  Defic: has been observed in premature and low-birthweight infants fed exclusively a cow’s milk diet and in individuals receiving long-term TPN lacking copper.  Get anemia, neutropenia, osteopenia in children, depigmentation of skin and hair, neurologic disturbances.  Normal levels: 90-130 ug/dL (14-20 umol/L). Deficiency is reliably detected by diminished serum copper and ceruloplasmin concentrations, as well as by low erythrocyte superoxide dismutase activity. Absorbed by a specific intestinal transport mechanism. It is carried to the liver, where it is bound to ceruloplasmin, which circulates systematically and delivers copper to target tissues in the body. Excretion of copper is largely through bile into feces. Toxicity:    absorption of copper salts applied to burned skin. Milder manifestations include nausea, vomiting, epigastric pain, and diarrhea; coma and hepatic necrosis may ensue in severe cases. Toxicity may be seen with doses as low as 70 mug/kg/d. Chronic toxicity is also described. Wilson disease is a rare, inherited disease associated with abnormally low ceruloplasmin levels and accumulation of copper in the liver and brain, eventually leading to damage to these two organs.

Vitamin D (V-D): 200-400 IU/d, 5-10mg/d). A group of sterol compounds whose parent structure is cholecalciferol (vitamin D3 ). Cholecalciferol is formed in the skin from 7-dehydrocholesterol by exposure to UV-B radiation. A plant sterol, ergocalciferol, can be similarly converted into vitamin D2 and has similar vitamin D activity. Maintains intracellular and extracellular concentrations of calcium and phosphate by enhancing intestinal absorption of the two ions and, in conjunction with parathormone, promoting their mobilization from bone mineral. Needed for Ca, P and Mg metabolism and absorption from the gut as well as Ca deposition in the bone.  Normal levels: 10-80 ng/ml (25-200 nmol/L). The serum concentration of the major circulating metabolite, 25-hydroxyvitamin D, indicates systemic status, except in chronic renal failure, n which the impairment in renal 1-hydroxylation results in disassociation of the monohydroxy- and dihydroxyvitamin concentrations. Measuring the serum concentration of 1,25-dihydroxyvitamin D is then necessary.     Daily V-D intake of 400-800 U/d–> 3.5oz Cod Liver Oil: 8,500 IU.   Herring (3.5oz): 900 IU.   Salmon (3.5oz) 600 IU.   Margarine (3.5oz): 320 IU.  Milk (1 cup): 100 IU.  Swill Cheese (3.5oz): 100 IU.   Egg (1 whole): 27 IU.   Defic: osteomalacia in adults, muscle weakness/ hypotonia, rickets in children. Expansion of the epiphyseal growth plates and replacement of normal bone with unmineralized bone matrix are the cardinal features.  D1 = Dihydrotachysterol (DHT): 0.6mg qd in osteoporosis.  0.1-0.6mg qd in renal osteodystrophy.   D2 = Ergocalciferol: 250 ug IM qd or 12,000-500-000 IU PO qd for osteomalacia/ rickets.  50,000-200,000 IU PO qd + 500mg Ca 6X/d for hypoparathyroidism.  10,000-80,000 IU PO qd + 1-2g Phos for familial hypophosphatemia. Dietary Sources of V-D (units of V-D):  Cod Liver Oil, 3.5 oz (8,500), Herring, 3.5oz (900), Salmon, 3.5oz (600), MVI with 100% RDA (400), Margarine, 3.5oz (320), Sardines, 3.5oz (300), Milk, 1cup (100), Swiss Cheese, 3.5oz (100), Chicken Liver, 3.5oz (67), Breakfast Cereal (40), One Whole Egg (27).  Toxicity: Excess amounts result in abnormally high serum concentrations of calcium and phosphate; metastatic calcifications, renal damage, and altered mentation may ensue.

Nutritional Rickets: Failure of calcification of osteoid in growing child, called osteomalacia in adult.  Caused by deficient V-D metabolites, rarely by deficient Ca or P.  Can be due to V-D def, resistance to V-D, GI d/o renal osteodystrophy or associated with other d/o (fibrous dysplasia, neurofibromatosis, malignancy, anticonvulsant tx).   Risk: darker skinned (blocks light penetration), breast fed and no oral supplements, inner city, kept inside. Milk sold in USA has 400 IU (10ug)/ qt.  D3 formed in skin–> hydroxylated in liver to 25-, then kidney to 1,25-= Calcitriol, this acts at 3 sites promotes Ca & P absorption in intestines, P reabsorption in kidney, acts to release bone Ca & P.   Clinical: generalized muscular hypotonia, ittitability, apathy, lethargy, failure to thrive, craniotabes, thick wrists and ankles, bowlegs (genu varum), rachitic rosary (knobby deformity of chest), frequent fx’s.

Lab: initially low Ca, then nl, always low P, AP elevated, low calcidiol, inc PTH, generalized aminoaciduria. Dec in 25(OH)-Vit-D3 and 1,23(OH)-Vit-D3.  X-ray: AP of knees show widened, frayed and cupped metaphyses, osteopenia (especially juxtra-articular), bowing of the long bones.

Tx: V-D 125-250 ug (5000-10,000 U) daily for 2-3mo until healing documented on Xray and AP normalizes or 15,000 ug (600,000 U) in single day in 4-6 PO doses (avoid suspension in propylene glycol, best to use 50,000 U capsules of ergosterol softened in water and fed blended in applesauce.  Prevent with 20 min UV light/ day or 10ug (400 U) V-D.  (Nutritional rickets. Am J Ortho 2000;3:214-18)

Essential Fatty Acids:1-2% of kcals. Omega-3 (alpha-linolenic acid) & Omega-6 (linoleic acid).    Found in vegetable oils (use olive/ canola oils).  Components of all lipid membranes, precursors of prostaglandins.    Defic: scaly dermatitis, Triene:tetraene ratio >0.7.   Normal levels = treine-letraene ratio >0.4, plasma or RBC membrane.   Fatty acids:  used either as stored fuel or as precursors for essential compounds such as prostaglandins, leukotrienes and thromboxane.  Can be classified by chain length:  Short–> 2-5 carbons.  Medium–> 6-11 carbons.  Long–> 12-26 carbons.  Also classified on presence of double bonds (unsaturated).  Saturated fats found in beer, pork shops, chicken/ turkey thighs.  Lower saturated levels in chicken breast, veal and pork tenderloin.     Poly or mono unsaturated depending on the number of double bonds.  Omega 3, 6 or 9 by location of the double bond when count carbons from the noncarboxyl end.   Humans can only synthesize double bonds at position #7, but can elongate or desaturate linoleic acide & alpha-linoleic acid to make others.  Whole milk is 3.3% fat and has 8.2 fat grams (150 cal) per 8oz compared to 2.6g (102 cal)in 1%.  Cheddar cheese 1oz has 9 fat g, Swiss has 8, Mozzarella has 6.

Omega-3 Fatty Acids: cold water fish *mackerel, lake trout, herring, sardines, albacore tuna, salmon, halibut), flax seed oil.   750-1,000mg will reduce the risk of sudden cardiac death.  Vegetarians can use flaxseed oil.    Three common types:  EPA= eicosapentaenoic acid found in fish and plankton, DHA = docosahexaenoic acid found in fish, plankton, algae, ALA = alpha-linolenic acid, found in flaxseed (linseed) oil, soybean, canola and walnuts, all metabolized to DHA.  Cardioprotective as slows heart rate, increases left ventricular diastolic filling, lowers postprandial triglyceride levels, reduces transcription of inflammatory cytokines and decreases secretion of platelet-derived growth factor to ¯ fibrinogen, BP and CAD.  One g/d is a safe target in adults, this can be obtained by consumer four 3oz servings/wk.  Most standard fish oil concentrates contain 300mg EPA & DHA / 1g capsule (30%).  Thus would need 10-12 cap/d.  One can get concentrates that are 50 or 80%. Olive Oil has highest content of monounsaturated fat (72%) than other sources, Canola has 62% mono, Peanut 49%, Palm 39%, Corn 26%, Soybean 24%, Sunflower 20%, Cottonseed 19%, Safflower 12%. (Heart Dz 1999;1) (JAMA 1998;279) (Mayo Clin Proc 2000;75:607-14)

Fluoride:  1.5-4mg/d.  Too much while teeth still forming beneath gum line–> fluorosis, use pea sized amount of toothpaste.  May need supplement if low intake and risk factors for dental caries (clean mouth, FHx of parents/ siblings with cavities).  2.2mg Sodium Fluoride contains 1mg Fluoride. Only 5% of bottled water contains the recommended amount of fluoride, compared to nearly 100% found in tap water.

Daily Fluoride Supplementation by Age per water content:

Age –> <0.3 ppm\ 0.3-0.6 ppm\ >0.6ppm:   ½-3yo –> 0.25 mg/d.  3-6yo –> 0.5.5.  >6yo –> 1.5.

Folic Acid (Folate):    200 ug/d (400ug if childbearing age).  Found in liver, meats, kidney/ lima beans, green leafy vegetables, wheat, lentils, eggs.  Used as a cofactor for purine and pyrimidine synthesis, need for metabolism of serine, histidine, homocystine. Reduces blood levels of homocysteine.  Defic: megaloblastic anemia due to defects in RBC’s and mucous membranes, birth defects.  Normal levels: 3-9 ng/ml serum, 150-600 ng/nl RBC. High doses may give nausea/ anorexia/ flatulence/ lower sz threshold in epileptics.  Toxicity:  a dose >400 mug/d may partially correct the anemia of B12 deficiency and mask (and perhaps exacerbate) the associated neuropathy. Doses >400 mug are also reported to lower the seizure threshold in individuals prone to seizures. Rarely, parenteral administration is reported to cause allergic phenomena,

Vitamin E (V-E, Tocopherol):  RDA for male or female is 15 mg/d (22 IU) of alpha-TE in adults, which is equivalent to 2 IU of “Natural” V-E (d-alpha-tocopherol, the RRR isomer of alpha-tocopherol, provides 0.67 mg/IU) or 33 IU of “Synthetic” V-E (d-l-alpha-tocopherol, has 8 different isomers, provides 0.45mg/IU).  The synthetic form has inactive isomers.  A group of at least 8 naturally occurring compounds that share a spectrum of biologic activities.  The natural form is what is found naturally in food and is the only type the body used.  Found in wheat germ, vegetables, milk, fat, egg yolk.  Prevents peroxidation of polyunsaturated lipids, may protect against atherosclerosis.   1200 IU/d decreases CRP levels in diabetics.  Defic: rare in developed countries, usually affects premature infants, get a hemolytic anemia of newborns, dystrophic changes in retinal and posterior column nuclei.      Etiology of Defic:  CF, chronic cholestatic hepatobiliary dz, chronic intestinal mucosal absorption defects (short bowel syndrome, celiac sprue, hypobetalipoproteinemia, other malabsorption), liver dz (Wilsons, hepatitis), chronic pancreatitis, lymphatic obstruction (Whipples dz, intestinal lymphangiectasia), Familia isolated V-E Defic.

Neurological findings:  early–> hyporeflexia, dec proprioception/vibratory sense, distal muscle weakness, night blindness (nyctalopia).   Middle–> truncal/limb ataxia, limited upward gaze, nystagmus, diffuse muscle weakness.   Late findings–> areflexia, loss of proprioception/ vibratory sense, dysphagia, dysarthria, arrhythmia, ophthalmoplegia, blindness, dementia.  Normal levels = 0.02-0.03 mmol/L (0.8-1.2 mg/dL), 10% hemolysis.  Max of 1500 IU/d of “d” form or 1100 if “di” form) Plasma or serum concentration of alpha-tocopherol is most commonly used. Additional accuracy is obtained by expressing this value per mg of total plasma lipid. The RBC peroxide hemolysis test is not entirely specific, but is a useful functional measure of antioxidant potential of cell membranes.   Toxic effects:   include headaches and V-K antagonism via depressed levels of vitamin K-dependent procoagulants and potentiation of oral anticoagulants have been reported, as has impaired leukocyte function. Doses of 50 IU/d may slightly increase the incidence of hemorrhagic stroke.

Iodine: 150 ug/d.  Found in iodized table salt, seafood, water and vegetables in non mountainous regions.  30mg in body.  Defic: cretinism’s, hypothyroidism, obesity, mental retardation.  T4 for levels.

Iron (Fe): RDA of 18 mg/d for women age 19-50.  27mg/d if pregnant.  8mg/d if male.  Found in liver, meats, egg yolk, legumes, whole/ enriched grains, dark green veges, dark molasses, seafood.  4g in body used as heme compounds, cytochrome enzymes and storage.  Defic: MCHC anemia, immunocompetence.  10% of women of childbearing age are deficient, 3.5% have anemia compared to 1% of males.

Vitamin K (Phytonadione):  40-80 mg/d.  Found in green leafy veges, wheat bran, cheese, egg yolk, liver (K1) and intestinal bacteria (K2).  Synthesis of clotting F (2), 7, 9, 10 and possibly 5 as wll a protein C & S.  Menaquinone (K2) is the form produced by bacteria.   Defic:  uncommon except in (1) breast-fed newborns, in whom it may cause “hemorrhagic disease of the newborn”; (2) adults with fat malabsorption or who are taking drugs that interfere with vitamin K metabolism (coumarin, phenytoin, broad-spectrum antibiotics); and (3) individuals taking large doses of vitamin E and anticoagulant drugs. Excessive hemorrhage is the usual manifestation. Occurs in the skin or GI, epistaxis, ecchymosis.  Normal: PT <1sec over control.  Abnormal if >2sec.  Dietary Sources of V-K (ug/100g):  Green tea (712), Turnip greens (650), Avocado (634), Brussel Sprouts (317), Chickpeas (220), Broccoli (200), Cauliflower (192), Lettuce (129), Cabbage/ Kale (125), Spinach (92), Asparagus/ Watercress (57), Green Beans (14), Potatoes (3).   Toxicity:  rapid intravenous infusion of K1 has been associated with dyspnea, flushing, and cardiovascular collapse, probably related to dispersing agents in the solution. Can be given PO, SC, IV, IM. Given PO (2.5mg) will lower the INR in 12-48hr.  Takes 4 days if just stop Warfarin intake.   Give 1-2.5mg PO if INR 5-10 w/o bleeding, give 3-5mg PO if INR >9.   Onset of IV is faster (2-3hr to dec INR, max effect in 27hrs) than PO, however it has higher risks (2%) such as anaphylaxis and allergic reactions.  Reserved for high risk patients, infuse at rate <1mg/min, get return of therapeutic INR in 4.1 days (Mayo Clin Proc 2001;76:260). (Arch Intern Med 1998; 158)

Magnesium (Mg): 300-400 mg/d (toward the higher range as age.  Found in whole grains, cereals, nuts, meat, milk, green veges, legumes.  25g in body, a cofactor for enzymes (phosphorylase, V-D hydroxylase).

Defic: tetany, weakness due to dec K & Ca.  Nl: 1.3-2.5 mg/dL.

Manganese: 2-5mg/d.  Found in blueberries, whole grains, nuts, fruit, legumes, tea, beans.  20mg in body.  A component of several metalloenzymes used as a cofactor in lipid, cholesterol, mucopolysaccharide synthesis.  Defic: hypocholesterolemia, weight loss, hair and nail changes, dermatitis, and impaired synthesis of vitamin K-dependent proteins. Abnormal clotting, not corrected by V-K, abnormal blood glucose.  Normal levels: 6-10 ng/ml.  Toxicity:  unknown in humans. Toxic inhalation causes hallucinations, other alterations in mentation, and extrapyramidal movement disorders.

Molybdenum: 0.15-0.5 mg/d.  Found in legumes, cereals, dark green leafy vegetables, organ meats.  5mg in body, used as cofactor in Xanthine oxidase and sulfite oxidase.  Defic: delirium due to inc methionine.  Normal levels: 0.5-2 ng/ml.   Toxicity:   may interfere with copper metabolism at high doses.

Pantothenic Acid: 4-10 mg/d.  Found in most foods, especially eggs, salmon, yeast and organ meats.  Converted to coenzyme A, hormone production.    Defic:  Usually seen in conjunction with other water-soluble vitamin, may see irritability, paresthesias, cramps, muscle wasting.    Normal levels: 150-400 ng/ml. Whole blood and urine concentrations of pantothenate are indicators of status; serum levels are not accurate.    Consists of pantoic acid linked to beta-alanine through an amide bond. Pantothenate serves as an essential precursor of CoA. CoA is essential for the synthesis and beta-oxidation of fatty acids and the synthesis of cholesterol, steroid hormones, vitamins A and D, and other isoprenoid derivatives. CoA is also involved in the synthesis of several amino acids and delta-aminolevulinic acid, a precursor for the corrin ring of vitamin B12 and the porphyrin ring of heme and the cytochromes. CoA is also necessary for the acetylation and fatty acid acylation of a variety of proteins.Toxicity: doses exceeding 10 g/d may induce diarrhea.

Phosphorus: 800-1200mg/d.  600g in body, 85% in bone, used for high energy phosphate bonds, chief intracellular anion.  Defic: osteomalacia, hemolytic anemia, dec HbO2 dissociation, dec phagocytosis.  Normal levels: 2.5-4.5 mg/dL (0.8-1.5 mmol/L).

Potassium (K): 2-5g/d.  Found in fruits/ vegetables (apricots, OJ, potatoes, carrots, cantaloupe, melons, mushrooms, dried beans & peas, artichokes, tomatoes), meats, milk, cereals, legumes, salt substitutes.  165g in body, the main intracellular cation.  Defic: rare in North America except in individuals receiving long-term TPN lacking selenium. Such individuals have myalgias and/or cardiomyopathies.  Weakness, arrhythmia, metabolic alkalosis.  Normal level: 3.5-5 mEq/L.

Selenium:  55 ug/d for men and women.  Found in whole grains, onions, meats (seafood, liver, chicken), milk and veges (depending on soil).  Used as cofactor in glutathione peroxidase, antioxidant similar to V-E.  This enzyme appears to prevent oxidative and free radical damage to various cell structures. Evidence suggests that the antioxidant protection conveyed by selenium operates in conjunction with vitamin E because deficiency of one seems to enhance damage induced by a deficiency of the other. Selenium also participates in the enzymatic conversion of thyroxine to its more active metabolite triiodothyronine.   Defic: weakness, hemolytic anemia, cardiac problems. Normal levels: 0.02ng/ml.   Erythrocyte glutathione peroxidase activity and plasma, or whole blood, selenium concentrations are moderately accurate indicators of status.   Toxicity:  If take >400 ug/d, nausea, diarrhea, alterations in mental status, peripheral neuropathy, and loss of hair and nails.

Sodium (Na): 1-3g/d.  Found in table salt, seafoods, animal products, milk, eggs, cheese, dried fruits, MSG, mustard, pickles, ketchup, olives, preserved meats, soy sauce, snack foods, salad dressing, bouillon, canned foods, packaged foods, most foods except fruit.  100g in body, a main extracellular cation.  Defic: low circulating blood volume, BP and urine output.  Normal levels: 135-145 mEq/L.

Sulfur:  Found in meats, milk, egg, cheese, legumes, nuts.  180g in body, found in methionine, cyteine, thiamine, insulin, chondroitin sulfate.

Zinc (Zn):  RDA of 2-3mg/d for 0-1yo, 3mg 1-3yo, 5mg 4-8yo, 8mg 9-13yo, 11mg males >14yo.  8mg for females >9yo.  12mg/d if pregnant or lactating.   Found in milk, liver, shellfish, herring, wheat bran.  1-2g in body, functions as an enzyme activator and cofactor.  Absorbed via ligand binding.  Defic: dec Intake–> poor appetite, diet high in fiber, P, Fe, Cu, tannates, oxalates, Ca.   Low protein (histidine, cysteine). Dec absorption–> lack of zinc binding ligand (acrodermatitis enterhaepatica), malabsorption syndromes.   Inc Gut losses–> prolonged NGT, high fistulas, exudative enteropathy.  Inc Urinary loss–> alcoholism, cirrhosis, nephrotic syndrome, CRF.     S/s:  4 D’s–> diarrhea, dermatitis, depression, dementia.   Alopecia, night blindness, tremor, loss of taste, poor wound healing.   Tx: zinc sulfate 3-6g/d.

Clinical Signs of Possible Nutrient Deficiency:

Hair:   Transverse depigmentation–> Protein, copper.  Easily pluckable–> Protein. Sparse and thin–> Protein, zinc, biotin.

Skin:    Dry, scaling–> Zinc, V-A, essential fatty acids.  Flaky paint dermatitis–> Protein, niacin, riboflavin.  Follicular hyperkeratosis–> V-A and C.  Perifollicular petechiae–> V-C.  Petechiae, purpura–> V-C and K.  Pigmentation, desquamation–> Niacin. Nasolabial seborrhea–> Niacin, riboflavin, pyridoxine. Pallor–> Iron, folate, V-B12, copper.  Scrotal/vulvar dermatoses–> Riboflavin.  Subcutaneous fat loss–> Calorie.

Nails:  Spooning–> Iron. Transverse lines, ridging–> Protein-calorie.

Head:  Temporal muscle wasting–> Protein-calorie.  Parotid enlargement–> Protein.

Eyes:  Night blindness–> V-A, zinc. Corneal vascularization–> Riboflavin.  Xerosis, Bitot spots–> V-A.  Keratomalacia, Conjunctival inflammation–> Riboflavin.

Mouth:  Glossitis (scarlet, raw) –> Niacin, pyridoxine, riboflavin, V-B12, folate.   Bleeding gums–> V-C, riboflavin.   Cheilosis–> Riboflavin.  Angular stomatitis–> Riboflavin, iron.  Atrophic lingual papillae–> Niacin, iron, riboflavin, folate, V-B12.  Hypogeusia –> Zinc, V-A.   Tongue fissuring–> Niacin

Neck:  Goiter–> iodine.      Chest:  Thoracic rosary–> V-D.

Heart:  High-output failure–> Thiamin.   Dec output–>Protein-calorie.

Abdomen:  Hepatosplenomegaly –> Protein-calorie.  Distention –> Protein-calorie.  Diarrhea –> Niacin, folate, V-B12.

Extremities:  Muscle tenderness, pain –> Thiamin, V-C.  Muscle wasting –> Protein-calorie. Edema –> Protein, thiamine.  Bone tenderness –> V-D, V-C, Ca, P.

Neurologic:  Hyporeflexia –> Thiamin.  Decreased position and vibratory –> V-B12, thiamine. Paresthesias –> V-B12, thiamine, niacin.   Confabulation, disorientation –> Thiamin. Dementia –> Niacin.  Ophthalmoplegia –> Thiamin, phosphorus. Tetany –> Ca, Mg.

Other:  Delayed wound healing –> Zinc, protein-calorie, V-C. Protein Calorie Deficiency –> brittle, fine, dry hair, enlargement of parotid gland edema, muscle wasting, weakness, loss of SC fat, hepatomegaly, diarrhea.

Vitamin Toxicity:

V-A:   Acute: >1mil IU for adult, >80,000 IU for child –> inc ICP with H-A, irritability, lethargy, ophthalmoplegia, papilledema.  Later get thinning hair, peeling skin and hepatomegaly.   Chronic: >30,000 IU/d in adult, >18,000 in child –> inc ICP, pseudotumor cerebri.  Dry, peeling skin, hair loss, brittle nails, cheilitis, stomatitis, gingivitis, hepatomegaly, N/V, + inc LFT.   Later get hepatic fibrosis, ascites, cirrhosis, esophageal varices, bone pain, cortical hyperostosis, premature epiphyseal closure. Teratogenic: >10,000 IU/d will cause facial, CNS and cardiac anomalies, but less than isotretinoin.

V-D: >60,000 IU/d adult, >1800 child. –> inc Ca, hypercalciuria, nephrolithiasis, metastatic calcifications of heart and vessels.

V- E:   >800-3000 IU/d –> contact dermatitis, H-A, weakness, nausea, cramps, diarrhea, inc effects of anticoagulants.

Niacin (B3): >3-4.5g/d. –> alopecia, pruritis, flushing, thrombocytopenia, A fib, gout, myopathy.

B6 (pyridoxine): >120-500mg/d. –> peripheral sensory neuropathy, porphyria cutanea tarda.

V-K: therapeutic IV dose. –> cutaneous hypersensitivity, anaphylactoid reaction.

erythematous plaques, localized urticaria, pseudo-scleroderma,

V-C: >4g/d. –> nausea, cramping, diarrhea, nephrolithiasis, hemolysis (if G6PD Defic).

Others with toxic doses:  zinc (500mg), selenium (1mg), P (12g), Mg (6g), Fe (100mg), I (2mg), Cu (100mg), Ca (12g), biotin (50mg), Folate (400mg), pantothenic acid (1g), riboflavin (1g).

Caffeine Content in mg:

180ml cup.   Brewed coffee = 80-140 mg.  Instant = 60-100.  Decaf = 1-6.  Leaf tea = 30-80.  Tea bags = 25-75.  Instant tea = 30-60.  Cocoa = 10-50.  Cola drink = 15-50.  1oz chocolate = 20.  Excedrine = 60mg.  Cafergot = 100mg.

**Ref:  (Arch Fam Med 1999;8:386-90) (Nutritional aspects of exercise. Clin Sport Med 1999;18:3) (Vitamin supplements. The Med Letter 1998;40:75) (Vitamin supplementation therapy in the elderly.  Drugs Aging. 1997;11:433-49) (Adult scurvy.  J Am Acad Dermatol. 1999;41:895-906) (Aging and the immune system: the role of micronutrient nutrition.  Nutrition. 1999;15:593-5)  (Vitamin supplementation in the elderly: a critical evaluation. Gastroenterologist. 1996;4:262-75) (Chromium.  Hosp Practice 2000;2:15) (Chromium.  Diabetes 1997;46:1786) (Creatine use in sports. Am J Med Sports 2000;2)

Estimating Nutritional Requirements:

Step #1:  Calculate Resting energy expenditure for caloric requirements.

“Small” calorie = 4.184 J and “large” Calorie = 1 kilocalorie (kcal), but when specifying energy content of foods, 1 calorie (cal) = 1 kcal.

Basal Energy Expenditure/ Requirements:

(Harris Benedict Equation):  W = IBW in kg, A = age in yrs, H = ht in cm.

BMR for Male: 66 + (13.7 X W) + (5XH) – (6.8 X A)= kcal/d.

BMR for Female: 655 + (9.6 X W) + (1.8XH) – (4.7 X A).

Multiply X activity level / stress level:   Well nourished and unstressed = 1.  Confined to bed or minor surgery = 1.2.   Out of bed =  1.3.   Mild starvation = 0.85-1.  Bone trauma = 1.35.  Major sepsis = 1.6.  Severe burn = 2.1.        Or use 25 X IBW wt in Kg.

Basal Metabolic Rate (BMR) –> 50 kg male = 1485 kcal/d, female = 1399.  60 kg male = ~1630 kcal/d, female = 1544.  70kg male = 1750, female = 1680.   78 kg male = 1900, female = 1781.

Resting Metabolic Rate:

Age in Years –> Male (kcal)\Female (kcal):   3-10 yo –> W X 22.7 + 505\W X 20.3 + 486.  10-18 –> W X 17.7 + 659\W X 13.4 + 693.  18-30 –> W X 15.1 + 693\W X 14.8 + 487.  30-60 –> W X 11.5 + 1113\W X 8.1 + 846. >60 yo –> W X 11.7 + 588\W X 9.1 + 659.

Daily energy required for maintenance = BMR X stress factor X 1.25 (an additional 25% for hospital activity, not added if paralyzed on a ventilator or heavily sedated.

Daily energy requirements for wt gain = maintenance + 750 kcal.

Step #2: Calculate protein requirements: Normal: 0.8-1 g/kg/d protein (up to 60-70g/d).   Moderate depletion/ stress: 1-1.5 g/kg/d.  Severe: 1.5-2.  Non protein (Carbs + Lipids): 25-30 kcal/kg/d.  Protein is 16% Nitrogen.   Calculate grams of nitrogen = grams of protein/ d/ 6.25.  Nitrogen-to-calorie ratio is usually 1gN to every 150 kcal (1:150).  Need less protein with renal failure before dialysis and hepatic encephalopathy.

Multiple trauma/ burn/ sepsis –> 30-50 non protein and 1.5-3 protein.

Metabolic Requirements During Stress:   Stress Level –> Non-protein\ BMR\ Nonprotein Calorie:nitrogen\ Amino Acids g/kg/d:   Starvation –> 25\1\150:1\1.  Low –> 25\1.25\100:1\1.25.  Moderate –> 30\1.25\100:1\1.5.  High –> 35\2\80:1\1.5-2.

Fat Requirements:  >40% calories as fat may decrease the immune response.   Fat calories help decrease the risk of carb overload and keep total fluid down.  Need a minimum of 4% of total calories as essential fatty acids (Linoleic).

Vitamins, minerals and trace elements:  Use RDA’s.  Can get catabolism and loss of lean body mass if low in K, Mg, Zn, P, sulfur.

Calorie Value of Macronutrients (kcal/g):

Fat –> 9.  Ethanol –> 7.  Protein –> 4.   Carbohydrates –> 4.  IV Dextrose –> 3.4 . 1ml of 10% fat emulsion –> 1.1.    0.8X (Proof of beverage / 2) X dL drank = kcal = g of alcohol X7.

Nutritional Assessment (Protein Energy Malnutrition):

Hx:  Dietary changes relative to usual intake, duration of changes and type of diet (hypocaloric, starvation, suboptimal solid), supplements taken.  GI sx’s that have persisted >2 wks (N/V/D/ pain).  Functional capacity (bedridden, ambulatory, working suboptimally).  Medical dz and its relation to nutritional requirements (no stress, moderate stress, high stress such as burns/ trauma/ sepsis).  Physical status (wasting, ascites, edema, mucosal lesions, cutaneous changes, loss of SC fat).

1.  Albumin:  T-½ = 3wks.  3-3.5g/dL mild, 2-3 mod, <2.5 severe malnutrition.  Can be deceptive, as pre-albumen both may be normal in starvation, or be markedly low in an acute illness or increase with dehydration.  Must use in combo with other clinical assessments.Level does not change with aging.

Pre-albumen: T-½ = 2-3 days.  Best lab to use.  Transferrin has T-½ =  8d. False elevation with renal dysfunction.   All three will decrease with microvascular permeability and stress.

2.  Nitrogen (Protein) Balance: = Nin – Nout = (protein intake(g)/6.25) – (UN ( 24hr UUN collection) + 4).  The “4” is added to represent the insensible nitrogen lost other than UUN, >2/3 of nitrogen derived from protein breakdown is excreted in the urine.   Since protein is 16% nitrogen, each gram of urinary nitrogen (UN) = 6.25mg of degraded protein.    The goal of nitrogen balance is to maintain a positive balance of 4g.     85% of the nitrogen in the urine is contained in urea, the remainder in ammonia and creatinine.   UUN can underestimate the urinary nitrogen losses in ICU pts (may need to add the urinary ammonia excretion).    Normal metabolism you want 0.8-1g/kg protein intake, if hypercatabolism, you need 1.2-1.6g/kg.  Growing children need 2g/kg/d.  The healthy 70kg adult excretes (urea, feces, skin) 30g of protein/d = 0.4g/kg, not all dietary protein is digestible, thus the RDA calls for 0.8g/kg/d.

3.  Total Lymphocyte Count: <1000-1200 /uL =mod to severe malnutrition.

4.  Serum Transferrin: < 100-200 = mod to severe malnutrition.

5.  % Weight loss: compare current to usual  outpatient/ preinjury wt (not IBW):   %Wt change = (usual wt / actual wt) /usual wt X100.

Significant wt loss –> 2% @1wk, 5% @1mo, 7.5% @3mo, 10% @6mo.  Severe wt loss if higher.  % Ideal Body Weight = actual wt/ IBW X 100.

6. Total Cholesterol:  <160 mg/dL in the frail elderly is associated with poor nutritional intake as well as increased mortality.  Other –> thyroid binding globulin, retinol binding protein, delayed cutaneous hypersensitivity (anergy), Triceps skinfold (Men should have 8-23mm, women 10-30mm).

Nutritional Support:

Links: Enteral:  Oral: TPN:   PPN:  Healthy Diet:

Refeeding Syndrome:  hungry bone syndrome (the opposite of tumor lysis syndrome).  Occurs with refeeding of pt’s with severe wt loss, anorexia (main cause in USA), cancer, chronic infections (including HIV), starvation conditions (kwashiorkor and classic marasmus), chronic underfeeding, chronic alcoholism, morbid obesity with massive weight loss, prolonged fasting or underfeeding (>7-10 days).   S/s:   Hypokalemia, hypomagnesemia, severe hypophosphatemia, vitamin deficiency (thiamine deficit) and fluid shifts (edema).  Refeeding adds carbohydrates to blood, increased insulin secretion, carbs cause inc uptake of electrolytes (phosphorus, K+, Mg2+) into cells with depletion of phosphorylated intermediates (ATP, 2,3 DPG).   If there is concern for development of refeeding syndrome, check a full panel electrolytes including phosphate, Ca2+, Mg2+ qd x 1 week, begin low calorie feeding with gradual increase, administer vitamins routinely including thiamin >100mg/day and follow urinary electrolytes including phosphate.

Enteral Nutrition Support:

Links:  Common Supplements: Feeding Tubes:  PEG:  PEGJ:  DPEJ:

By tube or by mouth.  Medicare covers 80% of cost if needed >3mo and pt requires >20 cal/kg/d because of an anatomic defect (poor appetite and anorexia nervosa not covered).

Requirements:  hemodynamically stable, no massive GI bleeds, intestinal obstruction, Abx induced/ severe idiopathic diarrhea, high-output enteric fistula or abd distention.

Assess GI function:  GI output should be <600ml/d via NGT, ostomy or rectal tube.   Check bowel sounds (does not correlate with peristalsis), passage of flatus or stool is better marker.

Start infusion –> @ 10-20ml/hr. of isotonic solution (300mOsm/kg) for 1st 24h. Day #1 at up to 30ml/h, 60ml on day #2, 90ml on day #3.  If intragastric can go up to 480 mOsm/kg (max of 300 if intrajejunal).

All pt’s have inc risk of aspiration, place pt in semi-recumbant position with HOB elevated to 30-40 deg.   Monitor for tube migration into the stomach.

Residual volumes: Check q6hr –> Before each feeding, delay feeding if >200ml.  Make sure tube is distal to the ligament of Treitz and HOB is elevated. If inc aspiration risk, get tube into jejunum by 1st placing tube in stomach (confirm by pH of aspirate), then placing pt on their R side for 2h and 1-2X in next 24h, then check X-ray.   If still not passed, give 10mg Reglan IV.  Can add 3-5ml of contrast into tube to verify position.  May need endoscopy.  Consider a prokinetics or avoiding narcotics to prevent gut stasis. Consider using a low fat formula.   Flush tube with 100 ml of water after each bolus. Check BS <200 as hyperglycemia causes gastroparesis.  IV dopamine may cause gut dysfunction.

Hyperglycemia is the most common metabolic abnormality seen. Try to use a formula with 30-50% of calories as fat.  May need insulin SC @ 5 U q4-6h for glucose 200-250mg/dL, 7.5 U if 250-300, 10 U if 300-350.  When the next days solution is ordered give half the SC quantity of insulin added to the bag. If need >100 U/d give a separate insulin drip/ infusion.   If severe glucose intolerance, limit the rate of administered glucose to 5mg/kg/min (~500mg/d) and give extra calories as a fat emulsion.  Need to monitor serum triglycerides and hold emulsion temporarily if it exceeds 500 mg/dL.

Indications of Intolerance: May need parenteral nutrition if –> vomiting, severe cramps, residual volume >50% of administered volume in past 4h, increasing distention, worsening diarrhea.

Complications:  Large bore NGT causing pharyngeal irritation, otitis media, sinusitis.  Obstruction of tube lumen, gastric aspiration, tube displacement.

Aspiration –> add food coloring or methylene blue to liquid, see if detect in pharyngeal or tracheal secretions.  Risks: depressed sensorium, inc GERD, h/o aspiration, meds such as theophylline, CCB, anticholinergics, beta adrenergic agonist, alpha antagonist.

Symptomatic Medications:

If get N/V, cramping, bloating –> reduce rate or concentration, use lactose free formula, bring formula to room temp before use.

If get diarrhea –> (=stool wt >300g/d or volume >30ml) –> inc rate or concentration, use continuous infusion, mix formula better, r/o Abx induced.  Use a lactose free or elemental diet, clean equipment.  Can add an antidiarrheal such as Kaolin-pectin 30ml or in J-tube q3-6h followed by 25ml NS irrigation.  If not improved in 48h add Paregoric (opiate) @1ml/100ml formula. Check C. diff assay and fecal fat content.  Avoid H2 blockers as may lead to bacterial overgrowth, if need them, titrate to gastric pH of 4.5-6.5).  Or Loperamide (Imodium) 24 mg PO or in J-tube q6h, max 16 mg/d prn OR Diphenoxylate/atropine (Lomotil) 5-10 mL (2.5 mg/5 mL) PO or in J-tube q4-6h, max 12 tabs/d.

Constipation –> increase free water intake, stool softener, fiber containing formula, prune juice, increase physical activity.

Tube clogging –> add routine irrigation with 20-25ml of NS or water after each feeding.

Special Medications:  Metoclopramide (Reglan) 10-20 mg PO, IM, IV, or in J tube q6h.  Cimetidine (Tagamet) 300 mg PO tid-qid or 37.5-100 mg/h IV or 300 mg IV q6-8h OR  Ranitidine (Zantac) 50 mg IV q6-8h or 150 mg in J-tube bid.

Specific Oral Nutritional Support:

Links: Common Supplements:

Nutrient intake is increased due to the increased nutrient density of the supplements.  Intermittent bolus feeding via 8-10F NGT.  Avoid aspiration by elevating the HOB and checking for residuals.  If need long-term feeding such as in dementia, neurological impairment a gastrostomy tube may be placed.  Caloric density: of most is 1 kcal/ml.

Modified diets: elemental diet.  Hepatic, stress and renal diets.

Thickened Feeding:  for those with dysphagia.  Start with intro Stage I: puree diet of pureed foods (mashed potatoes, yogurt, pudding, veges, meats).  Stage II is textured puree such as egg salad, cottage cheese, finely chopped & drained fruits.   Stage III is gound diet such as ground meats with gravy.  Stage IV is chopped foods such as finger sandwich, bread, scambled eggs, chopped pancakes.   Always avoid foods that melt (ice cream, ice chips, gelatin).   Liquids: can either purchase nectar consistency liquids such as Kerns fruit nectar, V-8, Ensure Plus, Nepro, Creamed soups, carrot juice with pulp, egg nog or take thinner liquids and “thicken” them with tapioca or a commercial thickener (Thick-it, Nutra-Thick, Thicken Up).   Super thick liquids are a honey consistence, can be purchased as “Resource” brand.

Hepatic formula: if in failure or hypercatabolic or encephalopathic.  Have increased amounts of branched-chain AA’s (BCAA’s) as they undergo little metabolism by the liver (also beneficial if septic or critically ill).  Also have dec aromatic AA’s (phenylthaline, tyrosine, tryptophan) and sulfur containing (methionine).  For impaired liver function use Hepatic-aid II, Nutrihep or Travasorb Hepatic.

Renal Formula: all essential AA’s, but no nonessential.  Indicated if renal failure and do not need dialysis and not on broad-spectrum Abx.

Most give 2cal/ml.  Deliver 2.0, Magnacal Renal, Nepro, Novasource renal, Suplena or Renalcal.

GI dysfunction:  use medium chain triglycerides (MCT’s) as more easily absorbed and metabolized than long-chain (LCT’s).

Diarrhea –> Isotonic, lactose free 1cal/cc formulas such as Isosource standard, Isosource HN, Isocal, Isocal HN, Osmolite, Osmolite HN, Promote or Nutren 1.0.

Impaired Fat absorption –> use MCT’s.  Lipisorb, Subdue, Peptamen, Sandosource peptide, Reabilan or Travasorb MCT.

Constipation/ Diarrhea –> use high fiber formula.  Ensure/f, Boost/f, Nuren/f, Relpete/f, Nubasics/f, Sustacal/f, Fibersource, Fibersource HN, Jevity 1.5, Jevity Plus, Poralance or Ultracal.

Fluid Restriction –> use 2 cal/cc products.  Deliver 2.0, Twocal HN, Nutren 2.0 or Novasource 2.0.

Diabetes/ hyperglycemia –> use formula with high fat and low carbs.  Choice DM, DiabetiSOurce, Glucerna, Glyctol, Resource Diabetic.

Stress –> use peptides or free AA’s as protein source.  Criticare HN, Tolerex, Petamen, Vital HN, Sanosource peptide, Vivonex Plus or TEN.

High stress and hypermetabolic –> use peptides/ free AA’s.  Alitraq, Crucial, Peptamin VHP or 1.5, Perative, Reabilan HN or Replete.

HIV Infection –> use omega-3 fatty acids.  Advera, Impact or Impact 1.5

Glutamine: the most abundant AA in the body.  Acts as the main fuel source and as a biosynthetic precursor in the gut and immune system.  Forms glutathione for antioxidants, used in acid base metabolism to release ammonia in the kidney.

Arginine: required for growth and secretion of GH, insulin, glucagon, prolactin, and somatostatin.

Enteral Feeding Formulations:

Type –> Carb g per L\ Prot g per L\ Fat g per L\ Kcal per ml\ Water ml per L:    Ensure –> 145\37\37\1.06\845.  For maintenance cals & protein, low residue.  Ensure Plus –>   200\55\53\1.5\769. High cal for maintenance proteine, low residue.  Jevity –> 152\44\36\1.06\835. High protein and fiber, 20% of fat as MCT.  For Tube feed, not PO.   Glucerna –> 94\42\56\1\870. High fat, low carb for those with abnormal glucose tolerance. Promote with fiber –> 139/62/28/1/830 Incr protein, maintenance cals with fiber in a low nutrient base for nonambulatory pt’s.   Nepro –> 215\70\95\2\700.  High cal, mod protein, low electolytes, low fluid for acute/chronic renal failure.   Nutrihep –> 290\40\20\1.5\760. High branched chain AA, low aromatic, low ammonia to support lean body mass during liver failure or stress.  Vital HN –> 185\42\11\1\860. With peptides, free AA’s and MCT oil to enhance nitrogen uptake in malabsorption states or impaired GI function.  Optimental –> 138\51\28\1\830. For malabsorption states.   Perative –>177/67/37/1.3/790  For metabolically stressed, for tube feed only, has arginine, beta-carotene, carnitine, trace minerals.  Isocal –> 135\34\44\1.06\840.  Isosource –> 170\43\41\1.2\819.  Sustacal –> 140\61\23\1.01\850.  Ultracal –> 123\44\45\1.06\850.  Osmolite –> 145\37\38\1.06\841.  Preattain –> 60\20\20.5\930.  Promote –> 130\63\26\1.0\840.  Replete –> 113\62\34\1.0\844.  Resource –> 140\37\37\1.06\842.  Nutren 1.0 –> 127\40\38\1.0\852.  Deliver –> 200\75\102\2.0\710.  Magnacal –> 250\70\80\2.0\700.  TwoCal –> 217\84\91\2.0\712.  Pediasure with fiber  –>109/30/490/1/840.  Maintenance cals.  Peptamen Junior–>   137/30/360/1/850.  Pediatric tube feeds, 60% fats as MCT for malabsorption or imparied GI function.

Additonal Additives:  Protein–> Promod powder with 3g protein/tbsp.    Carbs –> polycose liquid with 60 cal/30ml.  Fat –> MCT oil at 230 cal/30ml.

Common Oral Supplements:

Type –> Kcal per 8oz\ Gm protein per 8oz\ Other Features:   Ensure –> 254\8.9\Low residue. Ensure Plus –> 360\13.3\High cal/ protein, low residue. Pudding –> 250\6.8\Low residue.  Sustacal –> 242\14.6\High protein, low residue.  Sustacal Plus –> 365\14.6\High cal/ protein, low residue.  Pudding –> 240\6.8\Low residue. Citricource –> 180\8.8\Clear, low residue.   Other:  Boost, Mighty Shakes (milk-based, tastes better).

Dry Powder Product –> Cal per mL\ Protein g per L (%)\ Carbs g per L (%)\ Fat g per L (%):   Carnation Instant Breakfast Liquid –> 0.73\10 g/8 oz (25%)\25/8 oz. (62.5%)\2.4/ 8oz. (13.5%).   Carnation Instant Breakfast Powder –> 1\63.3\149.6 \34.6.  Carnation Instant Breakfast No Sugar Added Powder –> 0.7\62.5 \86.3 \20.8.   Forta Shake Powder (reconst with 1 cup whole milk) –> 140 / 1.4 oz mix\9/ 1.4 oz mix\26/ 1.4 oz mix\< 1/ 1.4 oz mix.  Meritene Powder –> 1.06\69 (26%)\120 (45%)\34 (29%).  Sustacal Powder (reconst with skim milk) –> 1.09\79 (29%)\180 (66%)\5.6 (5%).  Other:  Boost.

Medicare’s Enteral Product Categories:

Standard (I) –> $0.61/ 100cal, Fibersource, Isocal, Jevity, Osmolite, Promote, Resource, Ultracal.

Natural Standard (II) –> $1.71/ 100cal, Compleat Modifies.

Calorie Dense (IIb) –> $0.51, Comply, Deliver, Magnacal Renal, Nutren 1.5, Two Cal NH.

Hydrolyzed (III) –> $1.74, Criticare HN, Reabilan, Vital HN.

Disease Specific (IV) –> $1.12, Advera, Alitraq, Choice DM, Glucerna, Diabetasource, Hepatic Aid, Impact, Pulmocare, Vivonex.

Modular (V) –> $0.87, MTC oil, Microlipid, Promod.

Specialized Nutrients (VI) –> $1.24/ 100cal, Tolerex, Travasorb STD.

Total Parenteral Nutrition (TPN):

Links:  Indications:  Method: The Calculation:  Infusion:  Monitoring:  Risk:  Composition:  Standard Solutions:  Special Formulations: PPN:

Indications: Pt unable to eat or absorb nutrients for an indefinite period (permanent neurologic impairment, prematurity in infant, oropharyngeal dysfunction, short gut syndrome), severely malnourished and undergoing major surgery, major trauma, BM transplant undergoing chemo.

Unproven indications:  CA pt not tolerating PO >7-10d, AIDS pt, liver/renal failure, critically ill and NPO >7d, GI tract dysfunction (Crohns).

(N Engl J Med 1997;336:1)

Method:  Centrally administered into vena cava at a constant rate.  Reserve for pt that has nonfunctional GI tract –> Acute GI bleed, +ileus, small bowel obstruction (SBO), ischemic bowel, chylothorax.  Lines:  Tip of catheter should be in the innominate vein or SVC (avoid R atrium and subclavian vein).  Can be from a peripherally inserted central catheter (PICC).   Long term catheters (Hickman or Portacath) avoid catheter clotting.  If in groin, need to replace q2-3d due to infection risk.

Calculation:   Step #1: Determine pt’s weight.  Use actual body wt on admission unless >20% from IBW, in which case use adjusted body wt.

Step #2: Determine calorie requirements with Harris-Benedict equation and multiply by any stress factors. At rest BMR is 25 kcal/kg/d, up to 35 with increasing metabolic stress. This drops to 20 kcal/kg/d in the critically ill as stress metabolism already leads to high levels of serum glucose and triglycerides.  Kg needs to be adjusted to IBW.

Step #3: Determine Protein Requirements (g/kg/d):  Renal dysfunction @ 0.5-0.8.  Dialysis @ 1.  Maintenance (rest) @ 0.8-1.  Mod depletion/ stress @ 1-1.5.  Severe depletion/ stress @ 1.5-2 g/kg/d.

Step #4: Decide how Fat content supplied:  If 10% = 550 kcal in 500ml.  If 20% = 1000 kcal in 500ml.  Fats given a minimum of 2X/wk and should never exceed 50% of total daily calories.  High dose lipids may be immunosuppresive in critically ill pt’s, thus no more than 1g/kg/d of IV lipids should be given.

Step #5: Daily requirement — cal supplied by fat = calories supplied by TPN.

Step #6:  Calculate Flow rate:  Based on fluid requirements.  Central –> (TPN cal needed X 1000)/ 1020 kcal/L X 24h = ml/h.  Peripheral –> (TPN cal needed X 1000)/ 510 kcal/L X 24h = ml/h.  Max recommended peripheral rate is 125ml/h.

Step #7:  Additives such as lytes vitamins and trace elements as needed.

Infusion:  start @ 40-50ml/h (except renal @ 30ml/h as inc glucose, advance 10ml/d), inc at increments of 20-25ml/hr q 8hr (if controlled blood sugar or else add insulin) until caloric needs are matched.

Monitoring: VS q6hr X6 sets, then per routine.  I&O q8hr, wt QOD, finger glucose q6h, twice weekly lytes, CBC, PT, PTT, LFT, Ca, P, pre-alb.

Risks:  PTX (<3%), thrombosis of subclavian vein (tx with local heat, removal, heparin), catheter sepsis, hyperglycemia (SC insulin, inc insulin/L of solution), inc infectious, metabolic and fluid complications (cholestatic liver dz, CHF, inc Trig’s), all known nutrients not provided.  Cost 4X enteral.  Refeeding Syndrome:  a starved pt get a drop in K and P due to fluid shifts.  Avoid by starting low and going slow.

Composition:  Carbs (dextrose) concentration 15-47%,

Amino Acids (balanced or dz specific such as renal (dec AA, inc glucose)/ hepatic/ stress).

Lipid emulsions (10 or 20% solutions at 1 or 2 kcal/ml.  Can provide 20-60% of calories as lipids, only need 100ml of 10% solution/wk to prevent essential fatty acid Defic.), minor components ( V-K 5mg qMonday).  Intralipid 20% 500 mL/d IVPB infused in parallel with standard solution at 1 mL/min x 15 min. If no adverse reactions, increase to 20-50 mL/hr. Serum triglyceride level should be checked 6h after end of infusion (maintain <250 mg/dL).

Electrolytes (mEq/L) –> Na 20-80 (0-150 range).  Potassium (K): 13-40 (0-80). Magnesium –> 8.0 mEq  Chloride (Cl) 10-80 (0-150) since Cl losses are increased with NGT suction, most salts should be administered as Cl.    Phosphate (P) in mMol 14 (45-220).  Usually given as potassium salt, NaP is used if K is contraindicated.   Ca 4.7 (0-10), Mg 8 (0-15), Acetate 45-81mEq (45-220).

Other:  Regular Insulin 0-25 U/L.  1 unit per 10-15g of glucose. Bicarb is incompatible with nutrient solutions.

Standard Solution per Liter:  850kcal/L.  Amino acid solution (Aminosyn) –> 7-10% 500 mL or 5% AA (50g/L).  Trace elements (to 1st bottle each day) –> Zn 3mg (inc risk of zinc Defic in alcoholic, pancreatic insufficiency with malabsorption, renal failure with dialysis and nephrotic syndrome), Cu 1.2mg (inc risk of copper def with short bowel syndrome, jejunoileal bypass, malabsorption), Cr 12ug, Mg 0.3mg, Se 60mg, MVI 1amp. Vitamin B 12 –> 1000 mcg/week. V-K (phytonadione): 10mg is given 1X/wk unless pt is receiving Warfarin.

General Patient –> 25% Dextrose and AA 4-5% with a high carb to fat ration.  500ml D50 + 500ml 8.5% AA + multivitamin at rate (ml/hr) = [calories required — 500] / 20.

Special Formulations:  Hepatic Dysfunction –> add folate, Thiamine, V-K and reduce protein and aromatic AA.  500ml D70 + 500ml AA 7-8% hepatic formula + multivitamin at rate (ml/hr) = [calories required —500] / 29.

Fluid restriction –> increase the concentration of glucose and lipid calories.  500ml D70 + 500ml AA 10-15% + multivitamin at rate = [cal required — 500] / 29.

Pulmonary Dysfunction –> reduce carbs and increase lipids to decrease the CO2 production from excess carbs.  500ml D30 + 500ml 8.5-15% AA + multivitamin at rate of [cal req — 1000] / 12.

Head Trauma –> may need increased protein and lipids with decreased fluids and carbs.  500ml D30 + 500 ml 10-15% AA plus multivitamin at rate of [cal req — 1000] / 12.

Renal Dysfunction –> Pt need increased folate with decreased V-K, P, Mg along with close electrolyte adjustments.  500ml D70 + 500ml 8.5% AA [;us multivitamin a rate of [calories required — 500] / 20.

Cyclic Total Parenteral Nutrition: 12-hour night schedule; taper continuous infusion in morning by reducing rate to half original rate for 1 hour. Further reduce rate by half for an additional hour, then discontinue. Restart TPN in evening. Taper at beginning and end of cycle. Final rate should be 185 mL/hr for 9-10h with 2 hours of taper at each end, for total of 2000 mL.

Peripheral parenteral nutrition (PPN):

For calculations see:  TPN:

Standard solution contains:  3% AA (ProCalamine) (30g/L) (or 4.25% has 510 kcal/L) in 10% Dextrose (D10, 100g/L) @ 350kcal/L.  Osm 600-900 mOsm/kg.  If fat emulsion infused via piggyback give during an 8-12h period ending at 3 AM so the hypertriglyceridemia will not interfere with blood sampling. Max flow rate: 125ml/h = 3L/d = 1530 kcal/d.

Indicated in: malnourished, minimally stressed patients for 3-5d of support when PO intake is inadequate and have inc risk of complications of malnutrition.    Can combine 500 mL amino acid solution 7% or 10% (Aminosyn) and 500 mL 20% dextrose and electrolyte additive and infuse at up to 100 cc/hr in parallel with: Intralipid 10% or 20% at 1 mL/min for 15 min (test dose), if no adverse reactions, infuse 500 mL/d at 20 mL/hr.

**Ref: (J Parenteral Enteral Nutrition 1997;21:133) (Parenteral nutrition. Clin Perspect Gastroen 2000;12) (Sci America 1999;8:1-16) (Nutritional support in hospitalized patients. Dis Mon 1997;43:6) (Home artificial nutrition.  Curr Opin Clin Nutr Metab Care. 1999;2:387-93) (Parenteral iron supplementation.  Nutr Clin Pract. 1996;11:139-46) (Current uses and abuses of total parenteral nutrition.  Adv Surg. 1996;29:165-89) (Enteral feeding in critical care, gastrointestinal diseases, and cancer.  Gastrointest Endosc Clin N Am. 1998;8:623-43) (Nutrition in the elderly. J Clin Gastro 2000;30:4)

Healthy Diets:

Low fat diets are out as ave American has reduced their fat intake from 41 –> 32% over the last 20 years, yet has gained 8 more lbs.

Bad = saturated and partially hydrogenated fats.

Good = polyunsaturated (Eskimo diet, marine omega-3 FA’s) & monounsaturated (Mediterranean diet) fats as have cardioprotective effects.  Eat lots of the good fats found in fruits, vegies, whole grains and beans (except coconut, palm oils), and nuts.  Reduce your intake of bad fats found in chicken, meats, whole milk dairy products, eggs, solid margarine, prepared foods, bakery goods and cereals made with trans fats.  Eat no more than two 4oz servings of red meat/wk.   <30% of calories should come from fat, 60% from carbs, 12% from protein.   Eat more fresh and homemade foods (not processed foods).   Eat lots of whole grains, vegetables, beans and fruits, these have the correct types of  fat and are full of complex carbo’s, and phytochemicals that help protect from dz.   Deep sea fish have omega-3 oils that prevent clotting if taken twice a week, aim for 4oz.

Weight loss: see obesity in Endocrine section.  Avoid untested food supplements, including megavitamins, Herb’s, food extracts and amino acids.   If want to lower cholesterol, lower intake of calories and fat, eat no more than 1 egg yolk/d (including those in baking and cooking).

Fiber Content: need at least 25-30g/d.  Fiber is found only in plants, most is in the bran of whole grains and in the stems & leaves of vegetables, fruits, nuts and seeds.  Soluble fiber –> Gums (oat, beans, legumes, guar), pectin (apples, citrus fruit, carrots, potatoes, green beans), mucilage (psyllium).  Metabolized by bacteria, add little to fecal bulk.

Insoluble fiber –> Hemicellulose (barley, wheat bran, whole grains, brussel sprouts), Lignin (strawberries, peaches, pears, radish, green beans), Cellulose (broccoli, apples, corn, peas, root vegetables, beans, peppers).  Not metabolized by human or bacteria.  Increases the water content and bulk of the stool to shorten the intestinal transit time.

Weight Watchers Diet:  Attend weekly meetings, can only eat a certain number of food points from each category.  A healthy diet low in calories.

Jenny Craig Diet:  carbs are 60%, concentrating on complex ones.  Low fat foods.  A healthy diet low in calories.

Dean Ornish Diet:  avoid fat.  Eat healthy natural food like fruits and vegetables, oatmeal, soy.  Very healthy, but hard to maintain.

Zone diet: (40/30/30 diet), 40% complex carbs, 30% Protein/fat, with each meal in proper ration to avoid carbo craving from insulin bumps. Low carbs, but balance it with amount of fat and protein.  Lean meats with high protein.   Fairly healthy diet.

Body For Life:   by Bill Phillips of EAS Company.  A practical book that gives a healthy diet and exercise program that patients can follow.

Low Carbohydrate Diet’s: Best just to advise pt’s who are interested in low carb diets to limit potaties, reduce intake of white bread, white pasta and white rice.  They should select up to 4 servings of whole grains and at least 5 servings of nonstarchy fruits & vegetables (such as berries or cruciferous).  Cut back on simple sugar and hydrogenated vegetable fats. Substitute chicken, legumes, nuts and fish for red meat.  Eggs or high fiber cereals can be eaten for breakfast.  Lunch can be a salad, lean protein, nuts, cheese stick and vegetables.  For snacks eat yogurt, fruit, vegetables, for dinner can be flexible with soup with a clear broth base, a salad & vegetable eaten fist, then a protein and a starch.   Need to limit potatoes, carrots, squash and parsnips.  Atkins Diet high Protein low carbs (<20g/d)  Can eat bacon, eggs, cheeseburger, shrimp, fish, steak, cheese, sugarless foods.   Similar to Sugar Busters Diet and Carb Addict’s Diet and Schwarzbein Diet.  Have risk of loss of V-B, Ca and P due to low carbs.  Induces a ketosis that leads to water loss and anorexia.  SE of fatigue, constipation, orthostatic hypotension and renal calculi.

Suzanne Summers Diet:  No fats with carbs and if eat fruit need to wait at least 20 min before eat more carbs.

Sucralose (Splenda): artificial sweetener, no calories, no tooth decay, no effect on serum BS.

Other Common “FAD” Diets:  Zen Macrobiotic Diet: a 10 stage diet where food are eliminated progressively and replaced with grain products.  Can be hazardous to growing children.

Anti-allergenic diet:  attempt to avoid the “nightshade food” such as potatoes, tomatoes, eggplant and pepper.

Anti-Arthritis Diet:  no red meat, fruits, dairy, herb, spices, preservatives, additives or alcohol.

Vegetarian Diets:

All consume predominately plant foods: fruits, grains, legumes, nuts, seeds, vegetables.  May include eggs and dairy products.   Choose to omit animal products for religious, health, environmental, humanitarian, ethical, economic, political reasons.   Vegetarian is often used loosely as many may occasionally consume beef, fish, poultry and still consider themselves vegetarian.

Vegan:  (no meat/ poultry/ fish/ eggs/ milk)  The strictest vegetarian, as no animal products at all. Some will not eat honey or yeast products nor will they wear or use animal products such as leather, silk or wool.   Need fortified cereals/ soy drinks or supplements.

Ovovegetarian:  (no meat/ poultry/ fish/ milk) A vegan who consumes eggs.

Lactovegetarian:  (no meat/ poultry/ fish/ eggs) A vegan who consumes milk.

Lacto-ovovegetarian:  (no meat/ poultry/ fish) A vegan who eats milk and eggs, most vegetarians fall into this category.

Pescetarian: a vegetarian who eats fish.   V-D –> if Vegan need supplements or fortified foods.   Ca –> spinach, kale, broccoli, legumes, soy/ tofu.   Zinc –> need supplement or alternative source from grains, nuts, legumes. Protein –> lots in whole grains, legumes, vegetables, seeds, nuts.   Fe –> dried beans, spinach, enriched products, yeast, dried fruit.   V-B12 –> only from animal sources.

**Ref: (Diet and the prevention of cancer. BMHJ 1998;317:1636) (Mediterranean diet and the rate of cardiovascular complications. Circulation 1999;99:779) (Development of a vegetarian food guide.  Am J Clin Nutr. 1994;59:1248S-1254S) (Nutrition therapy for the cancer patient.  Hematol Oncol Clin North Am. 1996;10:221-34)

Common Conversions:

Link:  Pound to Kg:  Temp:  American to SI:  Fluids:  Milligrams: Solutions:  Drips:

Apothecary doses with metric equivalents:  1oz = 30g = 30ml.   1 grain = 60mg.  30 grains = 2000mg = 2g.  1/60 grain = 1mg = 0.001g.

Pounds to Kilograms:   Pt’s Wt in Kg = (lb/2)- 1/10 (Ex: 160= 80-8=72kg).   1 # (lb) = 0.454kg.   1 kg = 2.2# .

# = Kg –> 4 = 1.8, 6 = 2.7, 8 = 3.6, 10 = 4.5, 15 = 6.8, 20 = 9.1, 25 = 11.4, 30 = 13.6, 35 = 15.9, 40 = 18.2, 45 = 20.2, 50 = 22.7, 55 = 25, 60 = 27.3, 65 = 29.5, 70 = 31.8, 80 = 36.3, 90 = 40.9, 100 = 45.4, 125 = 56.7, 150 = 68.2, 175 = 79.5, 200 = 91.

Temperature:  F –> C: 5/9(F-32).    C –> F: (2C- 1/10) +32.

C = F –> 40.5 = 105, 40 = 104, 39.9 = 103.8, 39.7 = 103.5, 39.5 = 103.1, 39.2 = 102.6, 39.1 = 102.4, 39 = 102.2, 38.9 = 102, 38.6 = 101.5, 38.5 = 101.3, 38.4 = 101.1, 38 = 100.4, 37.9 = 100.2, 37.5 = 99.5, 37 = 98.6, 36 = 96.8.

American (Traditional) –> SI units:

SI unit = Traditional Unit / (relative or molecular atomic mass X Factor).  There are 7 fundamental (base) SI units, meter, kg, sec, ampere, kelvin, mol, candela (luminous intensity).

Common SI prefixes:  10-11st = deci, 10–2nd = centi, 10–3rd = mili, 10–6th = micro, 10–9th = nano (billionth), 1011st = deca, 10-2nd = hecto, 10-3rd = kilo, 10-6th = mega, 10-9th = giga, 10-12th = tera.

Traditional Unit –> SI Unit:    “–“ = minus.

nmol/L –> Umol/l –> Mmol/L –> mol/L:   pg/ml –> 1 –> 10-3 rd –> 10-6 th –> 10-9 th.   pg/dL –> 10-2nd –> 10-5 th –> 10-8 th –> 10-11 th.  pg/L –> 10-3rd –> 10-6 th –> 10-9 th –> 10-12 th. ng/ml –> 10–3rd –> 1 –> 10-3 rd –> 10-6 th.  ng/dL –> 10–1st –> 10-2 nd –> 10-5 th –> 10-8 th.  ng/L –> 1 –> 10-3 rd –> 10-6 th –> 10-9 th.  ug/ml –> 10–6th –> 10–3 rd –> 1 –> 10-3 rd.  ug/dL –> 10–4 th –> 10–1 –> 10-2 nd 10-5 th.  ug/L –> 10–3rd –> 1 –> 10-3 rd –> 10-6 th.  mg/ml –> 10–9 th –> 10–6 th –> 10–3 rd –> 1.  mg/dL –> 10–7 th –> 10–4 th –> 10–1 st 10-2nd.  mg/L –> 10–6 th –> 10–3 rd –> 1 –> 10-3 rd. g/ml –> 10–12 th –> 10–9 th –> 10–6 th –> 10–3 rd.  g/dl –> 10–10 th –> 10–7 th –> 10–4 th –> 10–1st.  g/L –> 10–9 th –> 10–6 th –> 10–3 rd –> 1.

Fluids:  1 tsp = 5ml.  1tbl = 15ml.  15 drops (gtt) = 1 ml or 1 cc.  1 tsp = 5 tbs.  1 tbs = 15ml.  1oz = 30ml = 0.0625 liquid pints = 0.03125 qt = 0.0296 L = 1.805 in2.    1dram = 4ml. 1L = 1000ml.  1 glass = 8oz = 240 ml.  1 pint = 16 oz = 480 ml.  1 quart = 32 oz = 960 ml.  1 gallon = 128 oz = 4 quarts = 8 pints = 3840 ml = 3.8L.

Milligram (mg) = 0.001g = 1000ug = 0.015grain.  Microgram (ug) = 0.001mg.  1ug/ml = 0.1mg% = 0.1mg/dL = 1mg/L. Nanogram (ng) = 0.001ug.  1ng/ml = 0.001ug/ml = 0.1ug = 0.1ug/dL.

Percent Solution: 1% solution = 1g/100ml = 10mg/ml = 10mg/L.   1mg% = mg/100ml = 10ug/ml = 1mg/dL = 10mg/L.  Deciliter (dl) = 100ml.  1mg/dL = 1mg/100ml = 1mg% = 10ug/ml.  1ppm = 1mg/L = 0.1mg% = 1ug/ml. 1 mole = mol wt in mg/dL. 1 millimole = MW in gm/L.

Drug Infusion Rates:    ug/kg/min = 16.7 X drug conc in mg/ml X rate in ml/hr // wt in kg.   ml/hr = Desired ug/kg/min X wt in kg X 60 // drug conc in ug/ml.

Other:  1km = 0.6 mi.  1 meter = 39.4 in.  1cm = 0.4 in.

Commonly Used Drug Therapeutic Range (Levels):

Acetaminophen–> 10-20 mg/L, toxic @ >150 mg/L 5 hr after ingestion. Alcohol–> 0, toxic @ 150-300 mg/dl: confusion, 300-450: stupor, >400: coma/ death.  Amikacin –>     Peak 25-30, trough <10 ug/mL.  Amiodarone –>   1-3.0 ug/mL.  Amitriptyline  –> 100-250 ng/mL.  Amobarbital–> 7-15 µg/ml. Bromide–> 20-120 mg/dl, toxic @ >150 mg/dl. Carbamazepine –>   4-10 ug/mL.  Chloramphenicol –>   Peaks 10-15, trough <5 ug/mL. Clonazepam–> 0.02-0.10 µg/ml.  Cyclosporine –> 100-300 ng/ml (50-150 renal transplant, 150-250 heart or liver).  Desipramine –>   150-300 ng/mL.  Digoxin –>   0.8-2.0 ng/mL.  Digitoxin–> 5-40 ng/ml. Diphenylhydantoin–> 10-20 µg/ml.  Disopyramide –>   2-5 ug/mL.  Doxepin –>   75-200 ng/mL. Ethosuximide–> 40-100 µg/ml. Flecainide –>   0.2-1.0 ug/mL.  Gentamicin –>   Peaks 6-8.0, trough <2.0 ug/mL. Glutethimide–> 1-7 µg/ml.  Imipramine –>   150-300 ng/mL.  Lidocaine –>   2-5 ug/mL.  Lithium –>   0.5-1.4 mEq/L, toxic @ 2.0 mEq/L.  Meprobamate–> 10-20 µg/ml, toxic @ 30-70 µg/ml: coma.  Mexiletine –> 1-2 ug/ml.  Nortriptyline –>   50-150 ng/mL. Pentobarbital–> 4-6 µg/ml.  Phenobarbital –>   10-30 mEq/mL (µg/ml), toxic @ >40 µg/ml. Phenytoin –> 8-20 ug/mL, 4-10 if azotemia or dec alb. Primidone–> 4-12 µg/ml.  Prograf –>    5-10 ng/ml.  Procainamide –>  4-8.0 ug/mL. Propranolol–> 50-100 ng/ml. Quinidine –>   2.5-5.0 ug/mL, toxic @ >8 µg/ml. Salicylate –> 15-25 mg/dL, toxic @ 300 mg/L.  Secobarbital–>  3-5 µg/ml.  Streptomycin –> Peak 10-20, trough <5 ug/ml.  Theophylline –>    8-20 ug/mL.  Tocainide –> 4-10 ug/ml.  Valproic acid –>    50-100 ug/mL.  Vancomycin –>   Peaks 30-40, trough <10 ug/mL.   ***All levels may vary depending on the reference lab.

Hypoxemia (Dec PaO2):

Links:  5 Mechanisms:  Labs:  Hypoxia: Cyanosis:  Pulse Oximetry:  Methemoglobin:

Decrease O2 in the tissue.  Subnormal oxygenation of arterial blood (dec delivery from the atm to the blood).  Low PO2 in arterial/ capillary or venous blood.  Short of anoxia.    Normal PAO2 = 80-100mmHg. To determine PaO2: subtract 1mmHg for each decade of age.  (or 100- 1/3Age) Subtract 3mmHg for every 1000 ft of altitude.   Usually accompanied by an acidosis (pH <7.2), base deficit >5mEq with bicarb <20.  AG >8 mEq/L, blood lactate >2mEq/L.  Ventilatory control is 3 main components:  chemosensors (carotid body senses PaO2 & H+.  Medullary senses PaCO2 & H+), the central controller (respiratory center in brainstem) and the effectors (respiratory muscles such as the diaphragm, intercostals and abd muscles).

5 Main Mechanisms of Hypoxemia:

1.  Ventilation-Perfusion (V/Q) mismatch:  airway secretions, pulmonary embolism, bronchospasm (asthma, COPD), pneumonia, CHF, ARDS, tumor-filled alveoli.   Causes >95% of hypoxemia.  Ventilation to a region of the lung is decreased in comparison to perfusion.  Have normal / dec/ inc PaCO2, inc A-aDO2, good response to inc FiO2.

2.  Shunt (R to L):  V/Q ~ = 0.  Atelectasis, pneumonia, pulmonary edema, ARDS, intracardiac shunt. This occurs when systemic venous blood enters the L heart w/o prior oxygenation.  Ventilation =0, but perfusion continues.   Shunts will not significantly correct with 100% O2 (unlike V/Q mismatch and diffusion defects).  Has normal/ dec PaCO2, inc A-aDO2, minimal response to inc FiO2.

3.  Low Inspired PO2:  high altitude.  Has normal or dec PaCO2, normal A-aDO2, good response to inc FiO2.  Normal A-a gradient.

4.  Alveolar Hypoventilation:  COPD, low respiratory drive from sedation (overdose narcotics) or hypothyroid or idiopathic alveolar hypoventilation or central (brain stem) dz, mechanical breathing problem (GBS, polio, MG, kyphoscoliosis, Pickwickian syndrome, myopathy, chest wall abnormality, crushed thoracic cage).  Has inc PaCO2, normal A-aDO2, with good response to inc FiO2. Normal A-a gradient.

S/s: H-A, somnolence, dec cognitive ability, constriced pupils, asterixis, coma, diaphoresis, tachycardia, arrythmia, cor pulmonale (late), polycythemia.

5.  Diffusion Defect: interstitial lung dz, PCP pneumonia. Has normal – dec PaCO2, inc A-aDO2, good response to inc FiO2.

Labs:  Abnormality –> PO2\ PCO2\ Room air O2/ Aa Gradient\ 100% O2 PaO2:   Hypoventilation –> dec\ inc\ Nl\ improves. V/Q Mismatch –> dec\ Inc-Dec\ inc\ improves.   Fixed Shunt –> dec\ dec or nl\ inc\ minimal Inc.  Diffusion Barrier –> dec\ nl\ inc\ Nl.  Dx of Hypoxemia:   PaO2 <60mmHg or SaO2<90%.


Usually due to the dec delivery of O2 to the tissue (shock, anemia).  Hypoxemia can occur independently, but hypoxia is often the result of severe hypoxemia.

Types of Hypoxia:   Hypoxemic Hypoxia –> a lower than normal PaO2 (hypoxemia).    Anemic Hypoxia –> dec RBC count, carboxy-Hgb, hemoglobinopathy. Circulatory Hypoxia –> dec cardiac output, dec local perfusion.   Affinity Hypoxia –> dec release of O2 from Hgb to tissues.  Histotoxic Hypoxia –> cyanide poisoning.

Respiratory Failure –> NM blockage (aminoglycosides, succinylcholine, Gallamine, Dimethyltubocurare, CCB, Mg sulfate, Nicotine, macrolides, Penicillamine, Polymyxin B).  CNS depression (sedatives, narcotics, hypnotics, ETOH, TCA’s, O2).  Inhibition of transmission at neuromuscular junction (Captopril, Cytosine-arabinoside, Danazol, Gold, Phenytoin, Vincristine), respiratory muscle myopathy (beta agonists like fenoterol, corticosteroids, Clofibrate, diuretics, narcotics, Pancuronium, Procainamide).

S/s of Hypoxia:  acute hepatic necrosis, ATN, agitation, altered MS, angina, anxiety, arrythmias, claudication, coma, confusion, cyanosis, diaphoresis, dizziness, gangrene, HTN, hypotension, lactic acidosis, sz, somnolence, syncope, tachycardia, tachypnea.


Becomes clinically apparent when there is >5g/dL of unsaturated Hgb, which corresponds to a pAO2 of <50 torr (50% of Hgb w/o O2) or SaO2 <85%.  It may not be apparent in pt has a coexisting anemia.

Central: seen in the nailbeds and mucous membranes (tongue, conjunctiva) under natural light.  Occurs in warm and cold areas.  If fingers are pink but the toes are cyanotic, consider a persistent ductus arteriosus with a reversible R-L shunt seen in pulmonary HTN (Eisenmengers syndrome).

Peripheral: seen in cool exposed areas such as fingers, earlobes, tip of nose, cheeks, outer surface of the lips.  It is due to increased capillary O2 extraction secondary to poor perfusion, and may be obliterated by warming or massaging the area.

Ddx:  Shock, arterial insufficiency, asthma, COPD, hypoventilation, methemoglobinemia, Patent ductus arteriosis, SVC obstruction, tricuspid insufficiency, tracheal obstruction, intrapulmonary shunting, polycythemia vera, R-to-L cardiac shunt, pulmonary embolism, arterial insufficiency, upper airway obstruction, respiratory failure.

Harlequin cyanosis:  one arm only, seen in aortic dissection, patent ductus arteriosis with pulmonary HTN and with embolic arterial occlusion.

Pseudo-cyanosis:  seen with Amiodarone deposits in the skin.  Silver rubbed into skin gives a blue discoloration when exposed to sun.

**Ref: (Neurologic manifestations of pulmonary disease. Neurol Clin. 1989;7:605-16) (Cecil’s Textbook of Medicine, 21st ed, 2000, Saunders, pp379-83) (Consultation with the specialist: nonrespiratory cyanosis. Pediatr Rev. 1999;20:350-2) (Pleuropulmonary manifestations of systemic lupus erythematosus. Thorax. 2000;55:159-66)

Pulse Oximetry:

The absorption characteristics of oxyhemoglobin and deoxy-hemoglobin (reduced) are at different wavelengths (660nm, red and 940, infrared).  The oximeter uses the light to estimate the ratio (assuming that the pulsatile portion represents arterial and the nonpulsatile is a mixture) to give an estimate of the SaO2.   The pulse ox is calibrated to a blood cooximeter (a spectrophotometer) that measures reduced Hgb, oxy-Hgb, Met-Hgb, carboxy-Hgb.   There is excellent correlation between 75-100% saturation, otherwise it is a nonlinear relationship.   O2 Sats (normal is 80-100%):  50% –> ~27mmHg.   60% –> ~30. 75% –> ~40.  85% –> 55mmHg. 90% –> 60.  95% –> 80.  97% –> 100mmHg.

Beer’s Law:  the concentration of an unknown solute dissolved in a solvent can be determined by light absorption.

May fail if:  pt with hypotension/ hypothermia/ shock (low perfusion states) or perfusion of vasoconstrictors, as vasoconstriction leads to underestimation of O2 sat.  Not calibrated for extremely low saturation levels (<70%).  Motion artifacts.  Erroneous reading when Hgb <5g/dL, conditions with inc venous pulsations (TR, R heart failure, a tourniquet or BP cuff above the probe), excessive light (surgical lamp, direct sunlight), dyes & pigments (methylene blue, indigo carmine, indocyanine green, nail polish), met-Hgb interferes with reading (local anesthetics, nitrates, Metoclopramide, sulfa drugs, Ca-EDTA).  Darkly pigmented skin and anemia also affect the accuracy.

**Ref: (Pulse oximetry.  Respir Care Clin N Am. 1995;1:77-105) (Methemoglobinemia: etiology, pharmacology, and clinical management. Ann Emerg Med 1999;34:646-56)

Hypercapnia = Hypercarbia (Inc PaCO2):

Links:  Causes: Tx:

Abnormally increased arterial carbon dioxide tension.   PaCO2  >45 mmHg (Torr).  The opposite of hyperventilation (PaCO2 <35 = hypocapnia).  Tends to be more tolerated than hypoxia or acidosis.  Usually the result of hypoventilation and should be suspected in a patient with:  Opioid OD, airway obstruction, brain/ spinal cord damage, bilateral phrenic nerve damage.  Inc Temp 1 deg C –> 13% inc production.

Causes of CO2 retention:   1. Inc CO2 production wit no ventilatory response.   2. dec minute ventilation.  3.  Inc dead space ventilation.

Inc CO2 production –> hyperthermia, sepsis (most common), hypertonic dextrose, trauma, burns, excess carbohydrates, post-op state, organic acidosis, increased work of breathing.  Normal lungs –> Depression of central controller by drugs (narcotics, sedatives), metabolic alkalosis, CNS dz (medullary infarct/ tumor).  Dec minute ventilation see with –> CNS depression, cervical spinal cord injury, MG, GBS, diaphragm fatigue, obstructed hypopharynx.   Abnormal N-M function –> spinal cord injury >C3 level), anterior horn cell dz (polio, ALS), peripheral neuropathy (GBS), other (MG, MD, myopathy).   Structural change in Chest Wall –> kyphoscoliosis, obesity.  Acute Ventilatory Failure –> Primary Resp. Acidosis –> inc PaCO2, dec pH, normal HCO3.     Chronic Ventilatory Failure –> Compensated Respiratory Acidosis –> inc PaCO2, normal/ dec pH, inc HCO3.  Seen in COPD, end stage ILD.  Iatrogenic–> narcotics, sedatives, paralytics.  Metabolic derangements –> myxedema, Met. Alkalosis, dec K/ P/ Mg.   Abnormal Ventilatory Control  –> primary/ central alveolar hypoventilation, morbid obesity, severe OSA.  Inc V/Q ratio –> inc dead space ventilation.  Dec CO2 elimination –> PE, asthma, bronchiolitis, shock. Other –>Cardiogenic (LV CHF), acute lung injury (overwhelming pneumonia), respiratory muscle failure, chest wall injury.

Tx: inc pulmonary blood flow with inc vascular volume, Inotropes, remove obstructive cause, bronchodilators.

**Ref: (The causes and evaluation of chronic hypercapnea.  Chest 1987;91:755-9) (Hypercapnia.  N Engl J Med. 1989;321:1223-31) (Irwin and Rippe’s Intensive Care Medicine, 4th ed, 1999, Lippincott-Raven)


Links: Indications:  Equipment:  Equipment by Age:  Airway Assessment:  Special Conditions: Difficult Pediatric:  Adult Rapid Sequence: After Intubation: Pediatric: Drugs Used:  Emergency Airways: Laryngeal Mask: Mechanical Ventilation: Sedation:

Indications:  Provide patent airway, prevent aspiration, facilitate positive pressure ventilation, when airway maintenance using a mask is difficult, need for prolonged mechanical ventilation.   Apnea –> RR <4.  Acute hypoxemia –> PO2 <55mmHg.    Upper airway obstruction –> Fb aspiration, edema due to anaphylaxis, trauma, inhalational injury or bleeding.   Acute Respiratory Insufficiency –> PCO2 >50 mmHg.  Acute reduction in pH.  RR >35.  Chest wall trauma (flail chest), to prevent unnecessary chest wall movement.    Airway protection –> CNS d/o, deep coma, prevention of aspiration pneumonia.  Inc ICP to hyperventilate.  General anesthesia.  Hypothermia (core rewarming).

Equipment: 2 wall suction devices with Yankauer tips, laryngoscope (check lights), appropriate size ET tube with backup 0.5-1 size smaller, + stylet, check integrity of inflatable cuff (no cuff if age <8yo).  Adult Female –> 7.5-8.5 ETT, ~21cm in length. Adult Male –> 8-9.0 ETT, ~23cm length.   A size #9 is 2X normal airway resistance, 4X the work of breathing if use size #7.

Estimate of ETT size: Internal Diameter (mm) =  (age in yr/4) + 4. May also may use size of patient’s fifth digit.

Depth of Insertion (cm): (Age in yr/2) +12 Or Internal Diameter (mm) X3.

Age 12-18yo (32-40kg) –> (Green) 6.0 ETT, size 3 laryngoscope (Miller or Macintosh), 12F suction cath, 14F stylet, 18F NG tube, 16F urine cath, 32-40F chest tube, 3 laryngeal mask. 700-800ml boluses of NS to resuscitate.

Age 8-10yo (25-32kg) –> (Orange) 5.5 ETT, size 2-3 laryngoscope, 10F suction cath, 14F stylet, 14-18F NTG, 12-14F urine cath, 28-32F chest tube. 550cc NS boluses.

Age 5-8yo (18-24kg) –> (Blue) 5.5 uncuffed ETT, 16cm long, 14F stylet, 10F suction catheter, 18-20 IV cath, 12-14F NGT, 24-32F chest tube.

Age 3-5yo (14-18kg) –> (White) 4.5 ETT, size laryngoscope, 10F suction cath, 6F stylet, 10-12F NGT, 10-12F urine cath, 20-24F chest tube.  300-450 ml boluses of NS for resuscitation.

Age 1-2yo (11-14kg) –> (Yellow) 3.5-4.5 ETT, 1-2 Miller blade, 8-10F suction cath, 6F stylet, 8-10F NGT, 8-10F urine cath, 16-24F CT. 160-280 ml NS.

Age <1yo (8-11kg) –> (Purple) 4.0 ETT, 11-12cm length, 1 Miller, 8F suction cath, 6F stylet, 5-8F NGT/ urine cath, 16-20F chest tube, 100-140ml boluses.

Neonate/ Premature –> (Red) 2.5 premature, 3-3.5 (term) ETT, 10-11cm length.6F stylet, 8F suction, 22-24 IV cath, 5-8F NGT, Infant paddle until 1yo, 10-12F chest tube.

Pediatric laryngoscope size: Use straight blade until age 4.  Newborn 0, 6mos-2yrs 1, 3-5 years 2, 6-12 years 2-3, 12-16 years 3-4.

Airway Assessment: examine/ asses mobility of neck, mandible.  Size of tongue and mandible.  Dental condition and configuration.

Difficult Adult Airway:  <40cm from chin to hyoid cartilage (<3 finger breadths),  <40cm from upper to lower incisors.  Large tongue or inability to see uvula & tonsillar pillars with mouth opened.   Limited hinge movement of TMJ joint.   If pt is unable to flex chin to chest, expect a difficult intubation.

Mallampati Class:

Rated Class I-IV for Difficulty to Intubation by anatomy of airway by visualizing 3 structures, the uvula, soft palate and palatoglossal/ palatopharyngeal pillars.   Class I:  minimal difficulty, has visible soft palate, tonsillar pillars and uvula.    Class II: uvula is masked and only the pillars and soft palate are visible.  Class III:  only the soft palate is visible, severe difficulty with intubation.   Class IV: has visible hard palate only. (Can Anesth Soc 1985;32)

Neck Trauma:

Use “over the wire” retrograde intubation or insert a “lighted stylet” blindly until see light area at larynx, then ok to pass ETT over the top.  Or use fiberoptic bronchoscopy.

Head Injury patient:  Use Thiopental: Adults @3-5mg/kg IVP over 1-2 min.  Peds @3-4mg/kg IVP over 2-3 min.  Infants @5-8mg/kg IVP over 3-5 min.  Can use +Fentanyl: 2-3mcg/kg IV and Versed: 0.15mg/kg IV over 1 min.   Avoid Ketamine.

Asthma or Hypotension:  Use Ketamine: Adults or peds @1-2mg/kg IV over 1 min.  Avoid Thiopental.   Can use Versed: IV 0.15mg/kg over 1min.  Succinylcholine: Adult @0.6-1.5mg/kg IV, Peds @2mg/kg if < 10yo.  Then Vecuronium: Adult & Peds @0.1mg/kg IV.

Difficult Pediatric Airway:

Inability to visualize tonsillar pillars/ uvula/ soft palate on oropharyngeal exam.   Extension <35 deg at atlanto-occipital joint.  Thyromental distance: with neck in neutral position should be >2 adult fingerwidths (3cm) from mandibular ramus –> thyroid cartilage.  If infant >1 fingerwidth (1.5cm).   TMJ with limited hinge movement (JRA, scoliosis, fx, trismus from infection).  Congenital airway abnormality (cleft palate, micrognathia, macroglossia, glossoptosis).  Maxillary abnormality (protruding maxillary incisors or trauma).  Upper airway swelling/ obstruction (bleeding, infection, burn, inhalational injury).

Adult Rapid Sequence Intubation:

Patient preparation –>  1.  Adjust bed to comfortable height (pt’s nose at intubators xiphoid).  Establish IV, EKG monitor, pulse oximetry, have suction set up.

2. Prepare alternate airway plan: transtracheal jet intubation, cricothyrotomy (if age >8), tracheostomy. Give Lidocaine 1.5mg/kg if pt has a head injury (to attenuate rise in ICP and blunt the CV responses).

3.  Estimate pts wt. (Breslow tape).  4.  Confirm working pulse Ox & cardiac monitor.

5.  Specify personnel for cricoid pressure, neck immobilization if trauma, handling of ETT, watching O2 sats & cardiac monitor, medications.

6.  Pre-oxygenate with 100% O2 X 3-4min via BVM (if time permits).   7.  Draw up all drugs into syringes & secure IV access.  Premedicate if appropriate with Fentanyl 2-3 ug/kg IV over 3-5min or Thiopental 2-5mg/kg rapid IV push.  Lidocaine 1.5-2 mg/kg IV over 45sec.

8.  Position head to sniffing position if no trauma.   9.  Optional:  Defasciculating med (Pancuronium/ Vecuronium @ 0.01mg/kg IV).

10.  Paralyze after sedation:  Succinylcholine 1.5mg/kg IVP.  Asses for apnea, jaw relaxation, dec resistance to bag-mask.

11.  Perform Sellick maneuver (cricoid pressure) as consciousness is lost.

Intubate:  Lift upward (do not rotate the laryngoscope) to visualize vocal cords.  Straight blade (Miller) goes in front of the epiglottis, thus will see cords only.  The curved blade (Macintosh) goes under epiglottis, need to lift epiglottis to visualize the cords)  Advance tube through the vocal cords. Inflate cuff with 5-10cc air.  Ventilate with ambu bag.

After Intubation:   1. Check tube placement (5-point auscultation:  breath sounds at bilateral chest & axilla, no low pitched gurgling sounds in the stomach, check with end-tidal CO2 detector). See symmetric chest wall movement, no bulging in epigastrium with ventilation. If unilateral BS only are heard, tube may in a mainstem bronchus, withdraw slightly and re-check    If “breath sounds” are heard in stomach and not in lungs the tube may be in the esophagus.   2.  Inflate cuff, then release cricoid pressure, stabilize tube with tape or commercial holder.

3.  Measure & record tube depth (Distance in cm from mid-trachea to incisors/ gum line = 3(ETT internal D in mm) or = 12+age in yrs)/2 or = (ht in cm)/10 +5.  Or Mid-trachea to nares = 12 + (age)/2.

4. Reassess pt’s clinical status. Pulse Ox should improve.   5. Check CXR to verify correct placement depth.   Tip of tube should be 3-5cm above the carina (T4-5 interspace, at the level of aortic arch) and 3 cm below the vocal cords.  Vocal cords are at C4-5 interspace as is inferior border of mandible when in neutral position.  Head flexed –> tube descends 2cm, head extended –> tube ascends 2cm (follows the chin).    6.  Consider longer-acting sedative & paralytic.

Pediatric Rapid Sequence Intubation:

1.  Atropine 0.01-.02 mg/kg IV (minimum dose of 0.1mg, max 0.5mg) if <5yo to block vagal reflex and thus prevent bradycardia.

2. defasciculating –> Pancuronium @ 0.01mg/kg IV, not needed if <4yo.

3.  Pre-oxygenate.    4.  Sedation –> Thiopental @ 4-6mg/kg or Ketamine 1-2mg/kg.   5.  Paralyzing –> Succinylcholine 1-2mg.kg or Pancuronium 0.04-0.1mg/kg.  See above for post-intubation checks.

Drugs for Rapid Sequence Intubation:

Links:  Defasciculating:  Reversing NM Block:  Paralyzing (NM Block):

Defasciculating drugs:

Always use defasciculating dose if pt has ruptured globe:

Pancuronium 0.01mg/kg IV, onset 3min, (SE: histamine release, tachy).

Rocuronium 0.06mg/kg IV, onset 2-3min

Vecuronium 0.01mg/kg, 3min, SE: mild tachycardia. No refrig needed.

Succinylcholine 0.1mg/kg IV, onset 3min, (SE: fasciculations, inc BP/ ICP/ IOP, GI, MH.  Contra: inc K, burns, trauma, NMD, eye injury). Keep refrigerated.   All may occasionally cause paralysis, if need to

Reverse the neuromuscular blockage:

Anticholinesterase drug. –> Always use with Glycopyrrolate (Robinol): 0.01mg/kg or Atropine 0.02mg/kg to block the muscarinic SE’s (salivation, bronchospasm, bradycardia, urination) as only want nicotinic effects.  Or Scopolamine.

Neostigmine (Prostigmine):   0.07mg/kg, onset 7-10min, may take 40min. Or    Pyridostigmine (Mestinon): 0.1mg/kg IV.  Onset 12-15min.   Or

Edrophonium (Tensilon): 0.75-1mg/kg IV, onset 3-5min.

Paralyzing Drugs (Neuromuscular Blockers):

Links: TOF:  Indications:  Depolarizing = Succinylcholine:  Non-Depolarizing: Duration of Action:

Muscle Relaxants. Degree of neuromuscular blockage is assessed by electrical stimulation of peripheral motor nerves –>

Train-of-four (TOF): ulnar nerve is given 4 twitches at 2Hz over 2 sec, observe the # of twitches in the thumb.  If have 2 twitches =75% of receptors blocked to decrease the twitch responses.   Goal is 1 twitch, =90-95% to block neuromuscular transmission but prevents over paralysis. Check q1h.

Troubleshooting:  proper electrode placement over nerve, more power, weak battery, dry electrodes (change qd), disease states.   Can also monitor facial nerve at orbicularis oculi, the posterior tibial nerve with plantar flexion of great toe or peroneal nerve with dorsiflexion of great toe.

Indications for paralysis: Short term –> intubation (prevent laryngospasm and relax airway structures), transport stability, immobility during procedures, suppression of shivering in hypothermia (O2 requirements inc 40%), status epilepticus and status asthmaticus as adjuncts.    Long term –> optimize ventilation (prevent bucking after use of narcotics and sedatives, dec airway pressure, minimize barotrauma, inc chest wall compliance, use of controlled ventilation), control ICP, tetanus, dec energy expenditure (burn patients).

Extra ICU Care with NMB: occular lubricant, frequent turning to avoid pressure ulcer, ETT suctioning as cannot swallow, DVT prophylaxis, physical therapy. Talk to the patient, explain to the family, adequate sedation.

Sequence of paralysis:  Occular muscles –> digits –> abdomen –> intercostals –> diaphragm.

Depolarizing agent: mimics the action of acetylcholine.  1st cause a contraction, then relaxation.

Succinylcholine  (Anectine): 1-2mg/kg IV, onset ~45sec, lasts 5-15min, (use 2mg/kg if <10kg & 1.5 mg/kg if defasciculating agent used)

Precautions with inc K, renal failure, severe trauma, disuse atrophy, extensive burns, open eye injury (inc IOP), spinal cord or peripheral nerve injury, malignant hyperthermia, intra-abdominal infections, preexisting N-M dz.   Mimics the action of acetylcholine by depolarizing the postsynaptic membrane at the neuromuscular junction, it is metabolized by pseudocholinesterase.   SE: Cardiac –> Sinus bradycardia, junctional rhythm, sinus arrest. Ganglionic stimulation may increase heart rate and blood pressure in adults.   High K –> muscle releases potassium to raise serum potassium by 0.5 mEq/L.   Massive release with thermal injuries, massive trauma, severe intra-abdominal infection, neurologic disorders (spinal cord injury, encephalitis, stroke, Guillain-Barre syndrome, severe Parkinson’s disease), ruptured cerebral aneurysm, polyneuropathy, myopathy (eg, Duchennes dystrophy) and tetanus. Other –> inc ICP and IOP, myalgia, myoglobinuria, fasciculations (prevented by pretreatment with a nondepolarizing relaxant), trismus, malignant hyperthermia.    Drug that potentiate the NM block such as antibiotics (streptomycin’s, colistin, polymyxin, tetracycline, lincomycin, clindamycin), antidysrhythmic (quinidine, lidocaine, calcium channel blockers), antihypertensives (trimethaphan), cholinesterase inhibitors, furosemide, inhalational anesthetics, local anesthetics, lithium, and magnesium.

Non-depolarizing agents: compete for cholinergic receptors (competitive antagonists of acetylcholine) on the post-synaptic membrane.

Dosing:  can give intermittent injections (if healthy use Pancuronium, if multi-organ system failure use Pancuronium or Doxacurium) or can give continuous infusion (if healthy use Atracurium or Vecuronium, if MOSF use Atracurium).

Pancuronium (Pavulon): 0.04-0.1mg/kg IV onset 1-5min, DUO: 60min. (SE: tachy & HTN as vagolytic, prolonged action)

Rocuronium (Zemuron): 0.6-1.2mg/kg, onset in 30-90sec, lasts only 25-60min.

Vecuronium (Norcuron): 0.1-0.2mg/kg, onset in 1-4min, lasts 30min. (SE: prolonged action).

Atracurium (Tracrium): 0.3-5mg/kg.  Onset 2-3min, lasts 30min.  Less histamine release than others.

Pipecuronium: 0.07-0.085mg/kg, onset 2-3min, DOA is 60-100min.

Doxacurium: 0.025-0.08mg/kg, onset in 4-5 min, DOA 55-160 min., Mivacurium.

Duration of action:   Ultrashort (5-8min) –> Succinylcholine.  Short (15-20min) –> Mivacurium.    Intermediate (20-30min) –> Atracurium, Rocuronium, Vecuronium.    Long (45-60min) –> Doxacurium, Pancuronium, Pipecuronium.

Post Paralysis Syndrome:  all agents with prolonged exposure, diffuse proximal & distal muscle weakness.  Myopathic process on EMG with preserved nerve conduction and sensory function.  Slow clinical recovery.

**Ref:  (New neuromuscular blocking drugs. N Engl J Med 1995;332:1691-99)  (Am Rev Resp Dis 1993;147:234-36) (Intubation. Mayo Clin 1992; 67:569-576)  (EM Clinic of NA 1988;6)

Emergency Airway Options:

Links:  Needle Crico:  Surgical Crico:  Tracheostomy:

1.  Awake Intubation (no sedation): used for difficult airway (congenital anomaly, trauma, burns), hemodynamically unstable pt (hypotensive), unconscious pt, newborns.

2.  Rapid Sequence Intubation (Crash): Use pharmacological paralysis/ sedation/ cricoid pressure.  For bowel obstruction, peritonitis, pregnancy (>2nd tri), inc ICP, undocumented fasting (or documented of <8hr fast of solid food), multiple trauma, pain.

3.  General anesthesia: need OR, anesthesiologist, for airway obstruction (acute epiglottitis), Fb aspiration.

4.  Sedation & Paralysis: elective intubation (prior to gastric lavage, radiographic procedure, cardioversion), emergent intubation in hemodynamically stable pt.

Needle Cricothyroidotomy:

Similar to percutaneous tracheostomy kits.   Using “Transtracheal Jet Ventilation”:   Buys time until definitive airway provided.  Poor CO2 elimination, thus useful for only 30-45min.

Equipment: alcohol or provodine-iodine pads, #11 scalpel, small syringe, 25g needle, lidocaine, 4″ hemostat, 5-6mm ETT or a tracheostomy tube.  Step #1:  Place pt supine, extend neck.   Betadine X3 neck. Inject 2% lidocaine with epinephrine if the patient is awake.

Step #2:  Cricothyroid Membrane identified between cricoid and thyroid cartilages.  Stabilize thyroid cartilage with opposite hand.  Make a 3-4cm vertical skin incision then a 1-2cm horizontal cricothyroid membrane incision.

Step #3:  Place 12-14g IV cannula “catheter-over-needle” (Angiocath or Jelco) attached to 3-5ml syringe through cricothyroid membrane.  Puncture vertically at midline.   Aspirate as advance needle syringe until air is  aspirated.    Advance cannula 45 deg caudally (inferiorly) and tape in place.    Can adapt Ambu bag onto this.

Step #4:  Remove needle, confirm catheter placement by aspirating air.  Attach 3mm ETT adapter (on any ped tube) to IV catheter or a 3ml locking syringe (w/o plunger).  Attach to 14g angiocath and bag pt.

Step #5:  Attach high flow oxygen source @10-50 psi 100% via O2 tubing @15L/min via a Y connector or with a hole cut into the side of the tubing.   The open end of the Y is occluded for 1sec (“on”) out of every 5s (4 sec “off”) to allow O2 to enter the pt, deliver O2 at 20 bursts/min.  On release of the hole, passive exhalation occurs.   Age <5 –> initial psi of 5, 100ml tidal volume.   Age 5-8yo –> 5-10psi, 240-340 ml TV.    Age 8-12 –> 10-25 initial psi, 340-625 TV.      Age >12yo –> 30-50 psi, 700-1000ml TV.  Eventually end up getting hypercarbia in 30-45min.

Surgical Cricothyroidotomy:

Indications: Excessive ENT hemorrhage, massive regurgitation, airway obstruction such that ETT intubation is unsuccessful.  C-spine fx and nasotracheal intubation unsuccessful.   Contra: fx or serious injury to larynx or cricoid cartilage (needs tracheostomy).

Equipment: #11 blade, Scalpel, Trousseau dilator, Tracheostomy tube (Silex or Portex), (Or a standard #5-8 size ETT that has been cut), small curved hemostats, prep solution, 4X4 gauze, scissors, 10ml syringe, tracheal suction catheter, tracheal hook, Lido with epi (if pt awake and have time)

Step #1:  Aseptically infiltrate with local anesthetic.   Step #2:  Hold larynx between thumb and middlefinger, hold membrane with index finger.  Make a transverse stab incision of 2-3cm through the skin and then the cricothyroid membrane, avoiding the large vessels that are located laterally.

Step #3:  Keep scalpel in place and insert tracheal hook into hold and retract upward before removing the blade.   (To avoid losing the tract from the skin to the trachea). Can dilate if necessary with a hemostat or by rotating the scalpel handle 90 deg to open the membrane perpendicular to the incision.

Step #4:   Insert tube of appropriate size under direct visualization.  Inflate cuff and secure.   Asses ventilation by listening for breath sounds. Should be replaced with a formal tracheostomy within a few hours.

Other:  Tracheostomy or pass wire through a catheter out the mouth then pass ETT over and into the trachea.  “Over the wire”

X-ray findings:  The tracheostomy tube is located halfway between the stoma and the carina, it should be parallel to the long axis of the trachea and be approximately 2/3 of width of the trachea.  The cuff should not cause bulging of the trachea walls. Check for subcutaneous air in the neck tissue and for mediastinal widening secondary to air leakage. Stabilization:  trach ties should be secure enough to prevent movement, but loosse enough to allow one finger width of play to decrease risk of skin necrosis.    Decannulation:  accidental removal of the reach tube.  Can occur with a strong cough, pt movement if not well-secured and with routine trach care.  Stoma Care: suction as needed.  Remove old dressing & ties (one side at a time) with constant stabelization.  Always have a spare tube nearby in case of decannulation.   Clean site with 4X4 moistened with H2O2 with single pass for each pad.  Look for swelling, redness or pulsations at site.  Next use cotton tipped applicator moistened with H2O2 to clean around the stoma & flanges of trach tube.  Rinse with sterile water and pat dry.  Never apply non-water soluble ointment. Use only dressings designed for trach or drains.  Never cut a gauze pad to fit the site as small cotton filaments get absorbed into the stoma and lead to microabcesses.

Laryngeal Mask Airway (LMA):

Intermediate between an ETT and facemask.  It is inserted blindly into the pharynx where it lies in the hypopharynx to form a low-pressure seal around the laryngeal inlet.    Technique:  get appropriate size base on wt.  Lubricate with K-Y jelly.  Sedate pt.   Place pt in sniffing position and preoxyginate.  Hold it “like a pen” with the opening facing forward and the black line of the air tube facing toward the upper lip in an anterior position.  Use your index finger to guide it in over the tongue as press the distal tip against the hard palate.  Advance until feel the “typical” resistance and inflate the cuff to around 60 cm H2O (4-40ml depending on size).  Connect to anesthesia circuit and check for proper breath sounds.  Insert bite block.  There are alternative methods of insertion.  After procedure remove when pt able to cough and swallow.   Advantages:  avoids most of the complications seen with ETT.  Disadvantage:  unable to protect airway from aspiration (2-3%).  Not effective if poor lung complinat or inc airway resistance such as in COPD or pulmonary edema.

Mask Size –>  Pt’s wt (kg) @ Internal Diameter (mm)@  Cuff Volume (ml):  1 –> <6.5kg@ 5.25@ 2-5.   2 –>  6.2-20@. 7@ 7-10.   2.5 –> 20-30@ 8.4@ 14.   3 –> 30-70@ 10@ 15-20. 4 –> 70-90@ 12@ 25-30.    5 –> >90@ 11.5@ 30-40.

**Ref:  (Retrograde intubation of the pharynx: an unusual complication of emergency cricothyrotomy.  Ann Emerg Med. 1992;21:220-2) (Emergency cricothyroidotomy.  J Laryngol Otol. 1992;106:479-80) (Emergency cricothyroidotomy.  Am Surg. 1997;63:346-9)

Initiating Mechanical Ventilation:

Links:  Criteria:  Types of Ventilators:  Ventilatory Modes:   Non-invasive Ventilation:  Initial Settings:  Monitoring:   Respiratory Physiology:  Complications of Ventilators:  Other Ventilator Considerations:   Trouble Shooting:  Weaning:  Sedation:  Intubation:

Criteria Parameters:

RR >35/min.  PaCO2 >50mmHg & pH < 7.30.   VC < 10-15 ml/kg.   VD/VT = dead space/ tidal volume >0.60.   FEV1 <10 ml/kg.   Resting Minute Ventilation >20 or ❤ L/min.   Max Insp Press < -20 cm H2O.   A-a gradient >450 mmHg.  PaO2 with O2 supplement <55-60 mm Hg.

Other Indications:   To improve pulmonary gas exchange in resp. failure of pulmonary or extrapulmonary (chest bellow, central resp. drive) etiology, to inc PAO2 and dec PaCO2.   To relieve respiratory distress, dec O2 cost of breathing. To reverse respiratory muscle fatigue.  To alter pressure-volume relationships, prevent and reverse atelectasis, improve lung compliance.  Reduced CNS resp. drive (intoxication, brainstem CVA).  To treat inc ICP by hyperventilating to reduce cerebral blood flow.  Prophylactic –> sepsis, shock, upper GI bleed with aspiration risk (varices), obtundation with loss of protective airway reflexes.

Tips:  Always consider individual pt’s characteristics, e.g. PCO2 of 55 in a young asthmatic indicates impending resp. failure, whereas in an elderly COPD’er it may be their baseline.   Consider alternative methods of non-invasive ventilation with BiPAP.

Types of ventilators:   Vent Modes:

Negative Pressure Ventilator:  Non-invasive negative pressure ventilation (NINPV). The iron lung used during polio epidemic in 1950’s.   Positive Pressure Ventilator:  Raise airway pressure to create inspiratory flow that inflates the lungs, used with cuffed ET tubes.    Divided into 4 categories:

1.  Time Cycle –> Timed delivery of gas flow.  TV = Flow rate X insp time.  Delivers a relatively constant TV to allow for precise control and variability in waveform of delivered gas.

2. Volume-cycled –> most common, reliably delivers set volume of gas at a pre-set flow regardless of pressure.  TV (tidal volume) is constant despite fluctuations in respiratory mechanics. TV will not vary with changes in pressure (compliance), unless pressure limit is reached.

3.  Pressure-cycled –> Triggered by pt’s inspiratory effort to deliver air at until a preset airway pressure is reached.  Inspiration stops when preset pressure reached.  TV = Flow rate X Time until pressure reached.  Will have variable volume if circuit pressure varies (compliance).

4.  High Frequency Ventilators:  jet ventilation, oscillation, percussive ventilation.  Have low mean airway pressure, but volume increases.  Used for closed head injuries, large pulmonary air leaks/ flail chest and refractory respiratory failure.

Ventilatory modes:

Links:  AC:  IPPC/CMV:  PCV:  PC-IRV:  IMV:  SIMV:  PSV:  PEEP:  Non-Invasive: Initial Settings:  Monitoring: Complications: Extubation Criteria:

Paralysis, sedation, controlled ventilation all lead to respiratory muscle atrophy.

Assist Control (AC) (Assisted Mandatory Ventilation = AMV or ACV) –> A combined mode of ventilation.  Pt makes a respiratory effort, vent is triggered to deliver a positive pressure breath at a preset TV. Ventilator assists if pt breaths on own.  Usually combine with minimal CMV (back-up rate) so that if pt doesn’t initiate a breath for a given period of time (e.g. 6 sec. if the RR is set at 10/min), the vent delivers a “backup” breath at the preset TV. Used for sick pt’s with CHF, sepsis or ARDS.  Risk of hypocapnia from low CO2 as even a small breath can trigger a full TV.

Intermittent Positive Pressure (Controlled Mechanical) Ventilation (IPPC/CMV) –> A mandatory mode with preset ventilatory patterns.  Either volume or pressure controlled.   Pt unable to interact with the machine, requires sedation or paralysis.  Has variable peak airway pressure.

Pressure Controlled Ventilation (PCV): where a specific pressure is set and the machine delivers a preset flow until that pressure is reached at which point inspiration ends and exhalation begins.   Uncomfortable as does not allow for spontaneous breathing.  Insufficient TV’s if pt fights the breath, low lung compliance or increased airway resistance causing inspiration to end prematurely.  Appropriate for initial control of pt with little ventilatory drive, severe lung injury (ARDS), gas trapping or circulatory instability.  PCV often combined with inverse ration ventilation (IRV) to get PCIRV in pt’s with ARDS to avoid barotrauma.

Pressure Control Inverse Ratio Ventilation (PC-IRV) –> A salvage mode.  It is contrary to the normal state, inspiration phase lasts longer (50-75% of the respiratory cycle) than the expiratory phase.  We set the vent to deliver a set amount of pressure above the PEEP level and lengthen the inspiratory phase so that I:E = 1:1 or 2:1 or 3:1.  The inversion holds the lungs at peak inflation pressure for a longer period of time to increase the mean airway pressure w/o inc PIP to improve oxygenation.  The pt must be sedated and paralyzed as uncomfortable.  Can lead to auto-PEEP, worsening hypercapnea or barotrauma.

Intermittent Mandatory Ventilation (IMV) –> Vent delivers breaths at set volume and rate at predetermined time intervals.  Pt may take additional breaths but they’re not assisted, so they entail more work than pt initiated breaths in AC mode-provides “workout” of resp. muscles, especially if RR is set below pt’s spontaneous RR.  Better than AC for pts with auto-PEEP or with high spont. RR, e.g. anxiety (b/c may get severe resp. alkalosis with AC).   May get patient-vent dyssynchrony so use SIMV.

Synchronized Intermittent Mandatory Ventilation (SIMV) –> delivers a mandatory set number of mechanically imposed breaths of predetermined TV and therfore achieves a predetermined minimum mandatory minute volume (MMV).   Allows for spontaneous pressure supported breathing with minimal bucking of the ventilator as will not deliver a breath during a spontaneous breath.  Helps to add pressure support (PSV) of ~5ml to overcome tube resistance.   Useful for a pt with minimal sedation, drug overdoses and when weaning. Easy to wean, just dec the rate.

Pressure Support Ventilation (PSV) –> Inspiratory effort by the pt triggers the vent to supply a preset level of positive pressure until inspiration ceases (flow varies to meet pressure).  TV remains dependent on pt’s effort.   Pt controls the RR, inspiratory time and flow.  Helps decrease the work of breathing.  An ETT size 8 adds 5cm, size 7 requires 10-12 PSV to overcome the tube resistance, thus always add back when weaning.  No breaths are delivered in the absence of spontaneous inspirations  If have secretions or a sudden drop in compliance will not get aeration, thus only for clear airways.  Used with SIMV and for weaning and for pts who have been intubated purely for airway protection.  Can use in combination with IMV, giving some (but not full) assistance with pt-initiated breaths.   Use 5-20 cm H2O, 25= full support.

Positive End-Expiratory Pressure (PEEP) –> Positive airway pressure applied throughout the respiratory cycle during mandatory invasive ventilation. No affect on ventilation, but improves oxygenation by splinting (recruiting) open collapsed alveoli (to inc FRC) and dec V/Q mismatching to drive fluid into interstitium, allowing for reduction of FiO2. Physiologic PEEP is 3cm.  SE:  May dec CO, risk of barotrauma (PTX, lung cyst, pneumomediastinum).

Noninvasive Ventilation:  Alternative to an ET tube:

(Bi PAP) ventilator or continuous positive airway pressure (CPAP) device. Uses a silicone mask or a mouthpiece. Can use oronasal or nasal masks.  Head straps must be used, pt must keep their mouth closed.   Can use either volume or pressure cycled ventilator.

Noninvasive Positive-Pressure Ventilation (NIPPV) –> Delivers a set pressure with each breath. Delivered via a bilevel positive airway pressure (insp Vs exp).   Has fewer complications and shorter ICU stay compared to conventional ventilation.

BIPAP:  Bilevel PAP allows independent control of inspiratory and expiratory pressures, when pt initiates breath a sensor initiates a predetermined amount of inspiratory pressure.  Can be administered in either a spontaneous or timed setting or both. Can use a nasal or face mask.  Typical start level is with an IPAP (inspiritory, like pressure support) @ 10 (8-15 cm H2O) and an EPAP (expiratory, like CPAP) @ 3-8.  Short-term Indications:  acute respiratory failure due to COPD, particularly if symptomatic with inc PaCO2.  Acute hypoxic respiratory failure, status asthmaticus, cardiogenic pulmonary edema.  Long-term indications:  chronic respiratory failure due to NM dz, thoracic deformity or idiopathic hypoventilation, severe stable COPD.  Benefits:  Delivery of assisted ventilation w/o ETT.  Dec the length of ICU stay, reduced mortality, fewer nosocomial infections, less sedation needed.  Succes rates: 93% with acute cardiogenic pulmonary edema, 88% with status asthmaticus, 81% with acute-on-chronic resp failures, 66% with acute hypoxemia or mixed resp failure.  Key:  exclude pt’s with hemodynamic instability and those with little improvement in 2-3 days.  Will likely fail if agitation, ARDS, severe acidemia/ encephalopathy.   Allow pt to accomidate to mask (may need to change types).  Contra: respiratory arrest, acute cardiac ischemia, AMI, inadequate airway protective reflexes, impaired mental status, inability to wear mask due to claustrophobia or facial abnormality.  Disadvantages:  tidal volume is variable, no alarms, no monitors.

Problems:  patient-ventilator asynchrony (PVA) –> avoid by starting at a PEEP of 2-3 cm H2O and slowly titrate to 4-8.  Avoid mask leakage wich leads the vent to fail in detecting end-inspiration (adjust size, remove NGT, consider chin strap, change type, dec PSV).  Portable units –> most unable to deliver high FiO2, most lack waveform displays, have the potential for rebreathing exhaled gas.  Other: discourages coughing and clearance of bronchial secretions.  The can be uncomfortable and claustrophobic.  Can cause eye irritation, nasal abrasions and sinus congestion.

Continuous Positive Airway Pressure (CPAP) –> same objective as PEEP in a spontaneous breathing pt, it is applied to a pt breathing via ETT or nasal/ face mask. A flow generator entrains air to the desires FiO2 & pressure.  Positive pressure is typically set at 5-10cm H2O (dec risk of barotrauma).Good for pt’s with low FRC. Use carefully in pts with bronchospasm or risk of air trapping.  Used during weaning trials with PSV (=PSSV).

**Ref:  (N Engl J Med 1998; 339:429) (Mayo Clin 1999; 74:817-820) (N Engl J Med 1994; 330:1056) (Keys to effective noninvasive ventilation.  J Crit Illness 2001;16:2&3) (Advances in mechanical ventilation.  N Engl J Med 2001;344:26)

Initial Post-intubation Settings for Adults: Links: Monitoring: Vent Modes: Weaning:

Mode: Assist control (AC) and IMV are commonly used.   Use control if pt cannot breath on own, paralyzed or heavy sedation.

Tidal Volume (TV): start with 7-10ml/kg as sick pt’s tend to have stiffer lungs.  10-15ml/kg if routine surgery in healthy. (7-10 if inc peak airway pressures like in asthma, less if have ARDS). >20 causes barotrauma. Actual TV delivered may vary from setting due to pulmonary compliance, thus always measure exhaled volume.  In ARDS use 6ml/kg (based on IBW) tidal volume (~400-500ml) to avoid over-stretching the lungs which decreases shunting, hypoxemia and alveolar capillary damage.  Let the pH and CO2 be secondary concerns, if pH <7.15 give bicarb.

Respiratory Rate (RR):  12-20/min for adult and 14-25 for child.  >20 should be avoided as ventilatory efficiency will drop off.  If using ACV set at 4/min unless not breathing spontaneous and need to set at 10.  No rate is set in PSV.

FiO2: start with 100%, wean downward to <50% (to avoid O2 toxicity) ASAP keeping sats >90%.  0.6 is the threshold for toxic concentration.

PEEP: none or @ 5cm H20 if PaO2 <60 or FiO2  >50%, avoid going higher.   Increase in increments of 2-3cm until pulmonary shunt <15-20% or PaO2/FiO2 ratio exceeds 250.  May also help to reduce auto-PEEP.

Inspiratory / Expiratory (I:E) Time:  1:2 (reverse ration of >2:1 if ARDS or pulmonary edema).  Regulates respiratory rate.  Usually 0.5-3.  Increased inspiratory time leads to improved oxygenation.

Insp flow Rate: During ACV or SIMV.  50-60 L/min (if too slow, leaves inadequate time for exhalation).  In COPD often set at 100.  Higher flow rates deliver a tidal volume in a shorter period of time, leaving more time for exhalation, which favors complete emptying of the lung. But have inc peak pressures and in VQ mismatch.  Inc rate –> inc PIP.

COPD on Vent:  keep peak flow <50 as air trap can increase expiration by decreasing the rate or decrease the TV or decrease the I/E ratio.

Commonly set the TV 0.5L,  FIO2 @ 0.5, CMV 12, 5 PEEP, and write “check for auto-PEEP q12, if >5 call MD”.  If chronically acidotic (pH 7.38 and CO2 56), avoid overventilation or will get post hypercapnea metabolic alkalosis.  Thus aim to normalize their acute change in pH, not their CO2.  Predicted range of normal CO2  = (HCO3 X 1.5) +8 +2.  Insp pause:  none (leads to uneven ventilation and air trapping).

Peak Inspiratory Pressure (PIP):  start @20-30cm if pressure cycled ventilator. Keep <45 to minimize barotrauma.  Influenced by TV, inspiratory flow rate and inspiratory wave pattern.  May prevent premature collapse of airway).   Sensitivity:  to trigger an assisted breath in ACV or PSV, pt need to lower airway pressure to open a “demand valve”.  Usually set at —1 to —3 cm H2O.  Aim for plateau pressure of <30 = the elastic recoil of the lungs, a pressure measured after inspiration using a 1sec breathhold.

Neonates & Infant –> ventilator pressure limited if <10kg, rate of 30-40/min, Insp/expiratory (I:E) ratio of 1:2, settings: begin peak inspiratory pressure at 16mmHg and inc by 2mmHg until good excursion.  Start PEEP at 3-4cm H2O.  FiO2 at 5-10% above preintubation FiO2.

Older Child –> use volume limited ventilator, normal respiratory rate for age, I:E ratio of 1:2, tidal volume 10-12ml/kg, 3-4cm H2O PEEP, adjust FiO2 to O2 SATs.

Adjusting the settings:   Frequent reassessment (2-3X/24h) is the key to good results.  Two key categories, those that change the minute ventilation (=RR X TV) to change the pt’s pCO2 and pH and those that change oxygenation (FiO2, PEEP, I:E ratio).   Oxygenation:  Sats > 90% don’t significantly inc tissue oxygenation.   Sat is mostly a function of FiO2 rather than TV or RR.  If you need FiO2 >60% consider second-line approach to improving oxygenation –> Ventilation:   getting rid of CO2.   A function of alveolar minute ventilation = RR x TV.

Permissive Hypercapnea Technique:  low TV often lead to dec ventilation and inc PaCO2.  Must focus on the pH rather than PaCO2 to determine pt’s status.  Can give IV bicarb if pH is <7.15   A controlled hypoventilation by limiting TV to 5-7ml/kg.  Accept some hypercapnia in exchange for lower PIP and lower risk of barotrauma.  May exacerbate pulm HTN and cause an inc ICP (avoid if head injury).


ABG: 30-60 min post any changes in vent settings, then periodically.  CXR: daily to monitor ETT position ans r/o PTX, SC emphysema, pneumomediastinum or subpleural air cysts. Lung infiltrates or atelectasis may diminish or disappear after initiation of mechanical ventilation because of increased aeration of the affected lung lobe.  O2 sat: at all times except in stable long-term vent pts.   RR: is pt overbreathing the vent? Check daily.   PIP: should be < 30mm H2O.

Auto-PEEP (Intrinsic PEEP):  Develops due to incomplete emptying of local lung units and air trapping.  Can be due to a ventilatory delivery prior to complete expiration of previous breath.  Seen in pt’s with inc minute ventilation (ARDS) and those with airflow limitations such as chronic pulmonary dz (COPD & asthma) where dynamic airway compression is present or in a rapid RR or large VT when expiratory time is inadequate.  Most vents can measure, need the application of an end-inspiratory hold.  Causes same complications as PEEP and more work to trigger the vent.

Tx of Auto-PEEP: bronchodilator, dec rate (to 8-10 to allow exhalation), sedate, paralyze, fluids for hypotension, chest PT, larger size ETT, inc exp time (dec rate or tidal volume), dec Insp time (inc peak flow, use low compressible volume circuit), allow PCO2 to rise above 60mmHg (dec rate or tidal volume), normalize pH(bicarb if met acidosis, purposeful hyperventilation), add PEEP or CPAP to decrease the work of breathing.

Tracheal cuff pressures: should allow a little leak, <15mm Hg.

Hemodynamic parameters: BP, UO, CO and PCWP in selected cases. PA Catheter indicated if PEEP >15cm H2O, cardiac dz, intracranial injury or questionable fluid status.

Fluids & Electrolytes:  mech. ventilation can cause Na and fluid retention.

Pearls:   Prophylactic H2-blockers (better at preventing ulcer than sucralfate, may have slight inc risk of infection (N Engl J Med 1998; 338:791). Carafate 1g in 5-10ml sterile H2O via NGT q6h (avoid 2h from dig, Coumadin, theo, Quinolone). DVT prophylaxis with pneumatics or Lovenox 40mg SC qd.   Check back side QOD for decubiti.  HOB at >30 deg if possible, to reduce risk of aspiration.   Adequate nutritional support.  Sedation PRN.

Respiratory Physiology:

Respiratory Exchange Ratio (RER): ~ = Respiratory Quotient. =VCO2/ VO2 = 0.8-0.85.  If eat pure carbos, will be 1.0.

Compliance = Change in volume / change in pressure.

Static Compliance (C-stat): change in vol / change in pressure. At a no flow state.  For most lungs = 50-100ml/cmH2O.  = VT / (Plateau pressure — PEEP) = 50-85 ml/cm H2O.  Reflects pulmonary parenchymal changes.  Abnormal in pneumonia, pulmonary edema, ARDS, atelectasis, intubation, PTX.  Plateau pressure is measured during the no flow state.   C-stat determines plateau pressure at end-inspiration for given TV.

Dynamic compliance (Cdyn):   Due to airways compliance resistance.  Can get high peak proximal airway pressure if this is low, e.g. in asthma. = Vt / (peak insp press – PEEP).  Inc flow or inc resistance or dec compliance all inc PIP.

Complications of Mechanical Ventilation: Other Ventilator Considerations:   Trouble Shooting:  ….Common complications include respiratory muscle deconditioning, psychological trauma.  Dec CO (need to dec PEEP, VT, PIP and bolus with fluids to inc CVP), barotrauma (PTX, SC emphysema, pneumomediastinum, interstitial emphysema, pneumoperitoneum).  Avoid PEEP >15, PIP >45 and FiO2 >50%), V/Q mismatch (need to inc PEEP and VT).  Nosocomial infection.

If Inc PIP’s (peak inspiratory pressure): inc risk of barotrauma.  Limiting PIP’s may or may not change outcomes, e.g. mortality or incidence of pneumothorax (N Engl J Med 1998; 338:355 and 335:341).   Etiology: High airways resistance (severe asthma), low lung compliance (pulmonary edema), relatively short expiratory time, use of PEEP, auto-PEEP, “Fighting the vent”.

Tx:  Sedation if fighting the vent, inc expiratory time by either dec TV, dec RR or inc inspiratory flow rate.  Change from AC to IMV so some breaths are unassisted.  Give fluid if BP is low from high PIP.

Hypotension: due to dec systemic venous return and thus dec preload, with compensatory Na and H2O retention.

Other:  Barotrauma (pneumothorax, pneumomediastinum, sub-Q emphysema).     O2 toxicity (occurs with FiO2 > 60% for > 72h, avoid by using lowest FiO2 that will give sat >90).  Auto-Peep, gas-trapping in alveoli (due to airways disease).  Get persistent positive alveolar pressure at end of exhalation (in nl people, end-expiratory alv. pressure = atmospheric pressure)   Makes it harder for pt to trigger the vent b/c pt has to generate more negative pressure (has to generate neg. pressure equivalent to the amount of Auto-PEEP plus the amount required to trigger vent), which inc effective dead space (due to inc vent and dec perfusion).  Tx:  Add extrinsic PEEP, which can make it easier to trigger vent.

Ventilator-Associated Pneumonia:  mortality rate of 30%.   Can reduce incidence by adequate handwashing, semirecumbent positioning to avoid aspiration, good nutritional support, avoid gastric distention, early removal of ETT and NGT, continuous subglottic suctioning, using Sucralfate instead of H2 blockers for stress ulcer prophylaxis, chlorhexidine oral rinses.

Other Ventilator Considerations:

Agitation:  r/o drug/ substance withdrawal, hypoxemia, meds, pneumonia.  Consider decreasing the PEEP or changing to pressure support.

Increased PaCO2:  R/o obstruction, cuff leak, PTX, right mainstem intubation.  Consider decreasing sedation, increasing rate, increasing TV, initiating NGT suction (to lower any distention and acid load), if pt has COPD consider increasing the peak flow. R/o overfeeding.

Hypotension:  r/o occult bleeding, AMI, steroid withdrawal, PTX, auto-PEEP.  Consider Narcan, giving PRBC and fluids or decreasing the PEEP.

Metabolic Alkalosis:  consider decreasing the NGT suction, adding Diamox or decreasing diuretics. Diamox 250mg IVP q12h x3 with 20 mEq KCl via NGT.

Decreased PaCO2:  Check for pain or sepsis.  Consider decreasing the rate, TV or adding sedation.  Measure Ve, consider changing to IMV or add a dead space of 6 inches every day up to 24 inches.

Decreased PaO2: r/o atelectasis, mucous plug, PTX, R mainstem intubation, cuff leak, pneumonia, fluid overload, CHF, dec CO, PE.   Sedate the pt if severe agitation.  Can try increasing the TV, rate, FIO2 or PEEP.  Can consider diuresing the pt or suctioning or using bronchodilator.

Increased Airway Pressure:  R/o mucous plugging of ETT, bronchospasm, auto-PEEP, ARDS, R mainstem intubation, PTX.  Consider sedating the patient adding bronchodilation or bronchoscopy.

Troubleshooting Respiratory Distress in the Ventilated Patient:

The rapidity of onset of the problem is a key clue.  If deterioration occurs over several hours, it is likely progression of the underlying dz.

Abrupt onset:  Examine pt and all circuits. Check CXR (infiltrate, PTX, tube).

Consider swan readings if suspect progression of dz.

High Pressure Alarm: high peak pressure from airway resistance.  Check the ETT, r/o bronchospasm.

Low Pressure Alarm: is the pt disconnected, is there inadequate flow rate.

Hypoxemia: Make dx.  Can increase PEEP incrementally up to 18cm H2O or titrate up the inspired O2.  Consider the prone position, increasing cardiac output.

Hypotension: is there volume depletion (consider fluid bolus), sedation, increased intrathoracic pressure.  May need to reduce PEEP or minute volume.  R/o PTX or auto-PEEP.

Hypercapnea: May need bicarb if acidotic.  Ok to accept mild hypercapnea in the 50-80 m Hg range.

Artificial airway problems:Malposition of the tube (should be 2-5cm above carina as flex neck tip moves 3cm down, extend and it moves 5cm up).   Inspissated secretions (need frequent suction, saline instillation and nebs), Cuff or ETT failure (cuff pressure should be <25cm or tamponade local tissue causing tracheomalacia.  Pt may bite the tube.  If cuff leak will hear bubble sounds).   T-E fistula (risks: steroids, hypotension with intermittent ischemia and poor nutrition).   Pain & cough (give 3ml of 1% Lido before suction).

External Ventilator Problems: leaks or disconnects (ask resp tech to asses).  In-line nebulizer (goofs up measured VT and VE on PSV, triggering alarm).  Tube Condensate (can prevent triggering).

Ventilator Failure: rare, if in doubt bag pt with 100% O2 and see if improves.

Patient-Ventilator System Problem: Asynchronous/ dyssynchronous breathing (“Fighting”), may need to use sedation or paralyze.  Ask resp tech to match TV to flow rate of pt. Check the trigger sensitivity, Check for Auto-PEEP, barotrauma, and inspiratory flow rate.  Consider switching to synchronized IMV, PS or PC modes.

Weaning: Extubation Criteria:

Overall clinical assessment is the most important thing.   CV stable and original problem that resulted in intubation is reversed.  Asses mental status (AAO), adequacy of secretion clearance.   Ventilatory supply, respiratory muscle and pulmonary function meets demand (high O2-consumption states, such as sepsis).   Priority –> 1. dec FiO2 to <50-60% with PaO2 > 60-80 Torr.    2. dec Mechanical rate.   3.  dec PEEP in increments of 2-3cm.  4. Ventilatory capacity: self support for >30min on T-tube with acceptable gases.

Weaning trials:   Commonly give trial of spontaneous breathing with either a T-piece or pressure support for 1-2 h.    Terminate if: RR>35/min, SATs <90%, HR >140/min, SBP >200 mmHg or have agitation and diaphoresis.  If fail, consider etiology:  poor nutrition, electrolyte abnormality, cardiac disease, neuromuscular dysfunction, excessive secretions, residual sedation, unresolved primary illness.  Can re-institute daily trials of spontaneous breathing or add additional weaning protocols such as using pressure support to keep RR <30/min, lowering the pressure by 2-4cm H2O BID to <10 or using T-piece or SIMV.

T-Piece trial –> Trial of spontaneous breathing for up to 2h qd.   Pt breathes spontaneously through T-tube connected to humidified air source for a preset duration.  Start at 5 min., not to fatigue patient, gradually lengthening.   Advantages: pt doesn’t need to work to open any demand valve.   Disadvantages: no alarms, have to stay at bedside in case poops out.  Fails to provide physiologic levels of PEEP, promoting alveolar collapse.   May shorten duration on vent (4.5 vs. 6d) and lower incidence of complications (reintubation, vent x >3wks, etc.) (N Engl J Med 1996; 335:1864)

SIMV –> Ventilations are mandatory, preset tidal volume at preset rate delivered at gradually decreasing rate. Gradually decrease the number of machine-delivered breaths.  Final rate usually 0.5-1/minute, timed not to be in synch with pt’s own efforts.  Pt breathes spontaneously on his/her own between IMV breaths.  Can take several days or more.  RR > 25 indicates failure.   Once SIMV is at 0, can gradually remove pt from pressure support until get to 5-7cm H2O, then can extubate.

Pressure support –> Pt breathes spontaneously at their own pace, each of pt’s inspirations augmented by preset positive pressure from vent.  Can result in varying tidal volumes if pt’s resp. mechanics are unstable.   Advantages: more comfortable for pt avoids asynchrony, allows pt to regulate TV, RR and inspiratory flow rate/ time.    Disadvantages: can get variable tidal volumes.

CPAP trial + PSSV –> Start with IMV of 6 for 30min if tolerate –> set CPAP 3 with PSV 3 (more if small ETT) to overcome ETT resistance.  It is like pressure support, but with positive pressure during exhalation too.  Advantages: alarms, pt is monitored by vent.   Disadvantages: pt must work to open vent’s demand valve.

Extubation –> May need ETT after weaning from vent if upper airway is obstructed, full of secretions, no gag reflex, etc.  Return of swallowing function may take hours-days, don’t rush start of oral intake.

Criteria for Extubation –> Weaning Parameters:  Opposite of intubation criteria.

Category –> Parameter:   Resp Function: Neg Inspiratory Force (NIF) –> Good: < -20 cm H2O. (nl = -60 -100).  No good: > -20. Respiratory Rate –> Good: 12-26. No good:  >35.

Ventilatory demand:  Spontaneous RR –> Good: < 30/min. No good: > 35/min. Minute vent (VE) –> Good: < 10 L/min. No good: > 10 L/min  Vd/Vt (nl = 0.3) –> Good: < 0.4. No good: > 0.6.

Ventilatory ability: Vital capacity (nl = 65-75) –> Good: > 15 ml/kg . No good: < 10 ml/kg .

Oxygenation: FiO2 <40 –> Good: < 60%. No good: > 60%.

R-L shunt –> Good: < 20%. No good: > 60%.

Other: Spontaneous TV > 5ml/kg.    RR/TV over 1min of unassisted breathing >2X resting Minute vent. of <100/min.

Sedating Drugs (IV Anesthesia):

Links:   Ramsay Scale:  Indications in ICU:  Adult Meds:  Pediatric:

Guidelines:  Scheduled bolus injections or continuous infusions of morphine or lorazepam should be administered in pt’s receiving propofol for >72h.  The level of sedation should be monitored using the Ramsay Scale.   Pt’s should be awakened from sedation qd to asses respiratory and neurologic function.    Morphine for analgesia should be used in any pt with perceived agitation secondary to pain.

Ramsay Scale for Assessment of Sedation:

Level/score:  1 –> anxious and agitated.  2 –> cooperative, oriented, tranquil.  3 –> responds only to verbal commands.  4 –> asleep with brisk response to light stimulation.  5 –> Asleep with sluggish response to stimulation.  6 –> Asleep w/o response to stimulation.

Bispectral Index (BIS):  Uses EEG leads.

Indications for Sedation in ICU:  pt is danger to self/ others, anxiety is worsening the underlying pathology, initial ETT tolerance, NMB, part of program to restore day/night cycling, protection from withdrawal syndromes.    Contra: respiratory insufficiency, CV instability, specific drug intolerance, need for “barnacle therapy (unwanted meds).

Ddx of ICU Agitation:  hypoxia, hypercarbia, hypoglycemia, encephalopathy, drug/ ETOH withdrawal, CNS catastrophes, ICU psychosis, pain, anxiety or disorientation.

Ultrashort-acting Barbiturates:   Can be used as an anesthetic induction agent.

Thiopental (Pentothal): 2-5mg/kg over 30-45s.  Onset 45s, DUO 5-10min.    SE: myocardial/respiratory depression, peripheral vasodilation.  Decreases cerebral blood flow and ICP.   Use cautiously if CAD or shock.

Methohexital (Brevital): 1mg/kg.  Immediate onset, used for induction and intubation.   SE:  myocardial depression, hypotension.

Contra: porphyria.

Narcotics:  Naloxone (Narcan): to reverse –> 0.1-2mg IV, titrate to response, may repeat in 2-3min intervals to max of 10mg.

Fentanyl (Sublimize): 0.4mg/kg IV.  50-75X more potent than morphine.  Minimal myocardial effects. Duration of analgesia is ~1h.   SE:  respiratory depression, muscle rigidity, hypotension, bradycardia, truncal rigidity (“wooden chest”).   Reverse with Naloxone (0.4mg/kg IVP).   Analgesic dose @0.05-0.1mg (2-10ug/kg) (1-2ml).

Morphine Sulfate (MSO4): 2.5-15mg IV.  SE: hypotension, bradycardia, biliary tract spasms.

Meperidine (Demerol): 0.5-2mg/kg IV/IM/PO.

Benzodiazepines:   Good amnesia.

Diazepam (Valium): 10mg IM 1-2hr pre-op or 5-10mg slow IVP for sedation.  Give 5-10mg q2-4h.  Onset in 1-5 min.  with caution in elderly.  SE: respiratory depression, disorientation, unpredictable IM absorption.  Inexpensive, but long T-½.

Midazolam (Versed): 0.1-0.2 mg/kg deep IV, onset 1-3min, IM/IV 1-2hr pre-op for sedation.   Can give constant infusion of 50-100mg/100ml D5W or NS.  1-5mg/hr.Short DUO, predictable IM absorption, anterograde amnesia.  Reduce dose 50% in elderly. SE: hypotension, respiratory and CV depression.

Lorazepam (Ativan): 0.05mg/kg (max 4mg) IM 2hr pre-op.  Contra: egg allergy. 1-4mg IV push q1-6h. No active metabolites, expensive.

Other Agents:  Ketamine (Ketalar): 1.5-5mg/kg (max 13mg/kg) IM, onset 4-10min.   0.5-1mg IV (max 4.5mg/kg).  Onset 45s-7min.  Dissociative anesthetic with good analgesia.  Maintains hypoxic pulmonary vasoconstrictor reflexes.  Does not relieve visceral sensation.  Useful in burn, peds, thoracic surgery.  Has bronchodilator effect (safe is asthma).  SE:  tachycardia, HTN, inc ICP, inc CO and myocardial O2 demand.  Inc Saliva.  Respiratory depression.  Hallucinations can be avoided by pre-treatment with benzo. 20% have unpleasant dreams on waking.  Contra:  HTN, eclampsia, inc ICP, cardiovascular dz.

Propofol (Diprivan): 2-2.5mg/kg.  Start at 5 ug/kg/min infusion, titrate by 5-10 ug q5-10min to maintenance infusion of 5-50 ug/kg/min.   Hypnotic, onset in 45s.  Very short acting (may awaken in 8-15 min, Vs 60-90 min with Midazolam).  Pharmacokinetics not changed by chronic hepatic or renal failure.  Lacks analgesic and amnestic properties. SE: hypotension, may be painful to inject unless preceded by IV lidocaine (max dose of 4mg/kg). Should be used for no longer than 72h.  “Milk of Amnesia”.  Has 1.1 fat cal/ml.  Do not use for pediatric ICU sedation.

Etomidate:  0.2-0.4mg/kg IV.   Onset in 30-90sec.  For induction and intubation. Minimal BP effects.  SE:  inc/dec BP, adrenocortical suppression.

Neuroleptic Analgesia:  Combo of tranquilizer and narcotic analgesia.

Droperidol + Fentanyl (Innovar):  50:1.  A preanesthetic, causes amnesia, analgesia, somnolence w/o unconsciousness.

Haloperidol (Haldol):  a butyrophenone, DA agonist-antagonist.  Can be given IM/PO/IV.  Causes CNS depression at subcortical levels (midbrain and RAS).  Has antiemetic properties.  Onset in minutes IV @2.5-5mg, 10min IM, 2-3h PO.  Start at 2-5mg, increase by 5mg q20min until agitation subsides.  Repeat doses q4-6h around the clock.  Can rarely cause tardive dyskinesia, NMS, dystonic reactions. T-½ of 18-54h.

Scopolamine:  3-6ug/kg.  Onset in seconds, last 2-3h, hepatic metabolism.  A natural antimuscarinic from belladonna plant.  A mydriatic, antisialogogue,  bronchodilator, vagolytic, anhidrotic.  No cardiac depression.  Can be used as ICU sedation.

Conscious Sedation in Ped’s:   Included for the purpose of completion.  All conscious sedation should be done in a hospital setting under proper monitoring with anesthesiology.

Indicated for:  BM aspiration, cardiac cath, BAE potentials, CT, dental procedure, echo, endoscopy, EEG, laceration repair, liver Bx, LP, ortho manipulation, sexual abuse exam, wound debridement, VCG.

Ketamine:  6mo-8yo, 4mg/kg IM + 0.01mg/kg Atropine Sulfate (IM/IV).  Or PO 6-10mg/kg or IV 0.5-1mg/kg.   Get vitals q5min until discharge. Onset in 3 min, lasting ~80 min, gives a Dissociative, trancelike state with rare respiratory depression, usually increasing the HR and BP from catecholamine release.   SE:  Bad dreams and hallucinations rare in children (1-2%) The inc airway secretions (hypersalivation) dec by anticholinergics like atropine or glycopyrrolate.  Excellent for burn patients needing dressing changes.

Compared to IM MCP: (2mg/kg meperidine, 1mg/kg promethazine, 1mg/kg chlorpromazine with respiratory depression, dystonic reaction, lowered sz threshold) (Arch Ped & Adol 1996, 150).

For IV: use 1-2mg/kg (additional 0.5-1 prn) Ketamine and 0.05-.1mg/kg Midazolam (max 4mg) for reduced dysphoric reactions and 90% optimal sedation. (Peds 1997:99).

Chloral Hydrate: sedative/ hypnotic, onset 15-60min, DUA: 2-8hr, dose: 50-100mg/kg (max 2000mg) PO/ PR.  SE: paradoxical hyperactivity, N/V.  Most effective for children <2yo an radiological studies.  Not good for suturing or other “noxious” procedures.  Best to have pulse ox as respiratory depression at high doses.  Unpredictable GI absorption rate.

Nitrous Oxide: 50/50 mix of 02 and NO (Nitrox).  Inhalation, short term use only.   Not a good analgesic, but effective sedation.  SE:  N/V.

Fentanyl (Sublimaze): 1-2ug/kg IV (max 5uf-kg), onset in 2-3 min, DUA: 45-60min.  SE:  respiratory depression, chest wall rigidity. Lollipop: 200, 300, 400ug doses.  Great for BM bx’s.

Midazolam (Versed): 0.05-0.15mg/kg IV onset in 3-5min, DUA: 1-2 hr.  Can also add to juice @0.5-1mg/kg PO or slowly drip into nostrils @0.2-0.5mg/kg or give IM.  SE:  respiratory depression if used in combination with opiates.

Methohexital (Brevital): 1-1.5mg/kg IV lasts 5 min.  Can be given rectally via an 8F feeding tube at dose of 25mg/kg (max 500mg) 15 min before a procedure such as CT scan.  (Pediatrics 2000;105:1110-4)

Reversal:  Flumazenil (Romazicon) @0.01 mg/kg or 0.2mg IV –> Benzo’s.    Narcan (Naloxone) @ 0.1mg/kg (max 2mg) IV/ IM –> Opioids.

Demerol-Phenergan-Thorazine (DPT): IM, unpredictable.

**Ref:  (Mechanical ventilation. Hosp Med 1999;12:26-36) (Weaning from mechanical ventilation–the team approach and beyond.  Intensive Care Med. 1994;20:317-8) (Issues in ventilator weaning.  Chest. 1999;115:1215-6) (Clinical management of weaning from mechanical ventilation.  Intensive Care Med. 1998;24:999-1008) (Weaning from mechanical ventilation. N Engl J Med. 1991;324:1496-8) (Hospital Medicine, by Wachter, 2000, Lippincott, p108-112) (Sedation in the intensive care unit, a systematic review. JAMA 2000;283:11) (Prolonged sedation with midazolam or propofol.  Crit Care Med. 1997;25:556-7) (Mechanical ventilation. Hosp Med 1999;12:26-36)

Vascular Access:

Links:  Venous cutdown:   Arterial Lines:   Femoral Artery:   Central Lines:  Vascular Anatomy:  EJ:   IJ:   SC:   PA Cath:   Pulmonary & Cardiac Parameters:   PA Cath Patterns:   CVP:  Catheter Sizes:

Venous Cutdown:

Equipment: a prepackaged cutdown tray, or a minor procedure tray and instrument tray with a silk suture (3-0, 4-0) and a catheter. Sterile gloves, sterile towels/drapes, 4 x 4 gauze sponges, povidone-iodine solution, 5 ml syringe, 25 gauge needle, 1% lidocaine with epi, adhesive tape, scissors, needle holder, hemostat, scalpel and blade, suture.

Step #1: Apply a tourniquet proximal to the site, and identify the vein. Prep the skin with povidone-iodine solution and drape the area. Infiltrate the skin with 1% lidocaine, then incise the skin transversely.

Step #2: Spread the incision long-wise in the direction of the vein with a hemostat and dissect any adherent tissue from the vein. Lift the vein and pass two chromic or silk ties (3-0 or 4-0) behind the vein.

Step #3: Tie off the distal suture, using the upper tie for traction. Make a transverse nick in the vein. If necessary, use a catheter introducer to hold the lumen of the vein open.

Step #4: Make a small stab incision in the skin distal to the main skin incision, and insert a plastic catheter or IV cannula through the incision, then insert it into vein. Tie the proximal suture, and attach IV fluid, release the tourniquet.  Suture skin with silk or nylon, and apply dressing.

Arterial Line Placement:  Link:  Femoral Artery:

Indication:  continuous monitoring of arterial pressure, serial ABG/ lytes/ Hct/ glucose measuring.  Informed consent is required.

Contra: poor collateral circulation (Allen test), local infection, need for AV fistula or shunt, bleeding d/o.

Equipment:  20 g 1 ½-2″ catheter over needle assembly (Angiocath), arterial line setup (transducer, tubing and pressure bag containing heparinized saline), arm board, sterile dressing, lidocaine, 3ml syringe, 25g needle, 3-O nylon suture with curved cutting needle.

Step #1:  Use the Allen test to verify patency of the radial and ulnar arteries. Immobilize the wrist on an arm board with a gauze (Kerlix) roll behind the wrist to maintain hyperextension.   Prep the skin with povidone-iodine and drape, infiltrate with 2-3ml of 1% Lido using a 25g needle down to the periosteum on either side of the artery, aspirating before each injection.

Anatomy:  The radial artery runs deep along the lateral aspect of the volar forearm between the radial styloid and flexor carpi radialis tendon.  Max pulsation is usually 1-2cm proximal to the transverse wrist crease.  Choose site where the artery appears most superficial and distal.  Have the pressure tubing flushed with heparin and calibrate the transducer.

Step #2:  Palpate the artery with the left hand, and advance (“dart”) the catheter-over-needle assembly into the artery at a 30-45 deg angle to the skin. When a flash of blood is seen, hold the needle in place and decrease the angle to 25 deg as advance the cath into the artery. Occlude the artery with manual pressure while the pressure tubing is connected.   If no blood is seen slowly advance until hit periosteum, then slowly withdraw to just under the skin before re-aiming.   If after the artery has been entered and are unable to thread the cath or a hematoma forms, withdraw everything and hold pressure for 10min.

Step #3: Advance the guide-wire into the artery, and pass the catheter over the guide-wire. Hook up and look for the sharp arterial tracing.  Suture the catheter in place with 3-0 silk and apply dressing.

F/u: check pt q4h for perfusion, change dressing qd. Change cath q3-4d.

Femoral Artery A-line:

Equipment:  19-20 g Teflon catheter, ~16cm (6 in)long.  A flexible guidewire small enough to pass through the catheter and needle

20-gauge needle, ~5cm long.   IV fluid and tubing.

Procedure:  Step #1: Locate the femoral artery approximately 2cm below the inguinal ligament or near the inguinal fold.

Femoral Triangle –> NAVEL –> Lat to Med.  Nerve, Artery, Vein (to draw blood, stick the needle medial to the artery), Empty (femoral canal/ hernia), Lymphatics.  Shave the groin and cleanse/prepare the area with Betadine X 3, don a mask and sterile gloves, drape the area.

Step #2: Anesthetize the area of insertion with 1% lidocaine. Place your 2nd, 3rd and 4th fingers along the course of the femoral artery beyond the inguinal ligament, the index finger is held slightly apart.   Step #3: Insert the needle between your index and middle fingers using the Seldinger technique, enter the skin and artery at 45degs.  When a free flow of blood spurts from the end of the needle, insert the wire through the needle (or catheter-over-needle) well into the artery, then remove the needle (should be no resistance).  (If the artery is not entered, insert the needle deeply until it can go no further then slowly withdraw the needle until free arterial flow is obtained).

Step #4: remove the needle and insert the catheter over the wire then remove the wire and attach the connecting tubing.  Be sure to have control of the wire at all times.  Note: if the artery is not entered, withdraw the needle completely, redetermine the location of the artery and make another attempt.  If the artery is entered but the wire/catheter cannot be passed, remove the needle and hold pressure for 5-10minutes before making another attempt.  Step #5:  Connect to IV tubing then suture the catheter in place, the cover the insertion site with povidone-iodine and a sterile dressing.

Complications:  Thrombosis, particularly if pt has peripheral vascular disease or after repeated attempts or following excessive pressure to control bleeding; the larger the catheter used, the greater the incidence.   Embolism from a thrombus that formed around the Cath may embolize to the lower leg producing gangrene, thus if any loss/weakening of lower extremity pulses, remove the Cath.   Hematoma and hemorrhage can be minimized by holding pressure over the femoral artery for 10min after removing the catheter, do not obliterate the pulse since that can lead to thrombosis.  Arteriovenous fistula may occur when large catheter is used.

Central Venous Lines:  Links: Types: Complications:

A catheter placed in a major vein such a subclavian, internal jugular or femoral.  Indications:  Monitoring of central venous pressures (CVP) in shock or heart failure, management of fluid status,  insertion of a transvenous pacemaker, administration of long term TPN, administration of irritant meds (chemotherapeutic agents), hypovolemia an unable to perform peripheral Cath.    Contra:  no absolute.  Avoid preexisting site infections, anatomic anomalies, coagulopathy.

Vascular Anatomy:

Complications: vessel trauma, thrombosis, PTX, nosocomial infection (line sepsis), cardiac dysrhythmia, air embolism, hemorrhage/ hematoma formation, catheter embolism.  The line is changed every 4-7 days, sooner if sx’s of septicemia, or local infection.

Placement:  Seldinger Technique: placement of a central line by first placing a guide wire in the vein, then the catheter over the wire.  Tip should be outside the heart (except PA catheter), stopping in the SVC 3-5cm above R atrium.  Some have tips that measure a R atrial ECG such that it has a maximal P-wave amplitude at entry into the atrium, catheter is then pulled back 3cm.   External jugular or internal jugular approach is preferable in pt’s with coagulopathy or thrombocytopenia because of the ease of external compression for hemostasis. In patients with unilateral lung pathology or a chest tube already in place, the catheter should be placed on the side of predominant pathology or on the side with the chest tube if present.

X-ray:  Catheter should be located well above the right atrium, and not in a neck vein.  Ideal location is distal to the innominate or in the proximal SVC.  Cardiac tamponade or arrhythmia if tip erodes the cardiac wall.  (Can check a lead II, if in the R atrium will see huge P waves.  Rule out PTX by checking that the lung markings extend completely to the rib cages on both sides. An upright, x-ray may be helpful, examine for hydropericardium (“water bottle” sign, mediastinal widening).

Pulmonary Artery Catheter:  tips should be located centrally and posteriorly, and not more than 3-5 cm from midline.

Estimation of insertion length:  R subclavian:  (Ht in cm/ 10) — 2cm.   For R IJ, just use Ht —10cm.

Types:  Links:  EJ:   IJ:   SC:

Femoral Venous:  Associated with a higher risk of infection and throbotic complications compared to sites in the upper extremity veins.  Major femoral or retroperitoneal hematoma in up to 1.3% of cases, infectious complications in 19.8% Vs 4.5% (JAMA 2001;286:700). For anatomy see:  Femoral Artery:..For technique use the Seligner technique as with other central venous catheters.

Hickman-Broviac Catheter:  double-lumen catheter, the smaller Broviac line is often used for the administration of IV therapy; the larger Hickman line is reserved for additional venous access and blood withdrawal. This catheter is generally inserted into the cephalic, subclavian, external, or internal jugular vein with the distal tip advanced to just above the right atrium. The proximal end exits via a subcutaneous tunnel from the lower anterior chest wall. A felt cuff (Dacron) is used to anchor it in place subcutaneously . The Hickman-Broviac catheter is made of polymeric silicone rubber that is of low thrombogenic potential but extremely flexible and soft. Because of the pliability of the material, the catheter must be treated gently. Clearing an obstructed catheter with a guidewire may cause catheter perforation. Similarly, forcing fluid through the catheter by positive pressure is contraindicated because of the risk of catheter rupture or catheter embolus. For this reason, no syringe larger than 5 ml should be used for irrigation.  Routine Care and Use. This line should be irrigated with 6 ml of normal saline solution between different infusions to prevent mixing of incompatible solutions, development of precipitation, and resultant catheter occlusion. The larger Hickman line should be used to withdraw blood. This line should be irrigated with 6 ml of heparinized saline after blood withdrawal to prevent clot formation in the catheter lumen. When a clamp is used, it should be placed over a piece of tape wrapped around the line. The clamp should have a smooth surface; those with teeth or prongs may sever or abrade the line.

Cook / Vygon/ Bard: external central line tunneled under the skin with a cuff (to prevent bacterial contamination and to hold in place).  Commonly used as widespread, experienced use.  Needs regular flushing with heparin (50 u/ml) weekly.  Inexpensive, but higher risk of infection than other long-term access lines, may interfere with activities.

Subcutaneous Ports:  Portacath:  the port is buried under the skin and thus must be accessed percutaneously.  Need special needles.  Infection worse if it occurs.  Expensive but low maintenance.  Flush with heparin (100 U/ml) qmo.

Mediport: has an injection port with the catheter.

Groshong:  a single thin-walled silicone rubber catheter designed for prolonged venous cannulation that differs from the Hickman-Broviac catheter in insertion, design, and maintenance. A decreased outer diameter-to-inner diameter ratio allows insertion into a smaller vein through a smaller introducer sheath. The catheter can be inserted at the bedside under local anesthesia without fluoroscopy using the Seldinger technique and a peel-away catheter introducer sheath. After placement of the catheter in the subclavian, internal, or external jugular vein, a subcutaneous tunnel is created with a stainless steel tunneling device through which the catheter is threaded. A cuff (Dacron) stabilizes the catheter’s placement in subcutaneous tissues and reduces the chance of inadvertent removal or retrograde infection.  The Groshong catheter is constructed with a closed end and a vocal cord-type integral valve at the distal end . This pressure-sensitive two-way valve at the intravascular end minimizes back-bleeding, eliminating the need for heparin flushes or external clamping, but permits blood sampling with gentle negative pressure. Patency of the catheter is maintained with 5 ml of saline flush once a week. A 20 ml saline irrigation is necessary after any blood transfusion or if blood is observed in the catheter lumen. A 30 ml saline irrigation is performed before blood sampling after infusion of hyperalimentation solutions.  Groshong catheters offer the advantage of bedside placement, minimal back-bleeding, elimination of heparin flushes, and elimination of external clamping when changing injection caps or connecting tubing. A lower incidence of complete obstruction to flow from clots or precipitants within the catheter lumen, however, has not been proved.Groshong catheters are otherwise subject to the same complications as described for Hickman-Broviac catheters.  Less frequent need for flushing, can use saline flush qwk, less risk of bleeding or air embolism with valve.  Easier to insert percutaneously, but smaller than a Hickman.

Quinton-Mahurkar Catheter:  the method of choice in providing immediate vascular access for hemodialysis. Its advantages include bedside placement and a functional life up to 18 months.  The Quinton-Mahurkar catheter is a single flexible polyurethane cannula with two separate D-shaped channels. Each lumen is connected by a molded Y-piece to a color-coded external port. As a precaution against a disconnected cap, each limb of the Y-piece has an attached clamp. The Quinton-Mahurkar catheter is most commonly placed in the subclavian vein and less commonly in the femoral vein by the Seldinger technique.

Apheresis: Large bore, permits high blood flow rate.   Flush with heparin (100 u/ml) 2X/wk.  Uncomfortable to pt, limited line survival.

Cimino-Brescia Fistula and Prosthetic Bridge Fistula:  the preferred means of vascular access for long-term hemodialysis. The fistula is created by using a side-to-side and side-to-end anastomosis using the radial artery and the cephalic forearm vein. The high blood flow and pressure on the venous side of the fistula “arterialize” the veins, a process that takes 3 to 5 weeks.

Complications of Catheters:   Erosions: of endocardium may cause perforation in 1-7 days if tip in contact with the heart.  Presents as dyspnea, pleural effusion, tamponade.

Catheter Sepsis:  Presents with F/C, leukocytosis and glucose intolerance.  If s/s of infection in pt, check CBC and UA.  If blood Cx needed, use a peripheral vein.  If no evidence of infection at catheter site can leave intact.  If blood Cx is +, remove catheter.  If blood Cx are negative, can change catheter over a wire and culture tip (bacteria and fungal).  Wait 24h before starting a new line, obtain blood cultures X3d to r/o recurrent bacteremia or fungemia.  If marked hyperpyrexia or hypertension remove all catheters.

Approach to Catheter Occlusion: clots/ precipitants within the catheter lumen, and mechanical obstruction. Cath that painlessly accept infusions at normal rates but cannot be aspirated, consider: cath lodged against the wall of the vessel, occluding fibrin sheath around the cath tip, ball valve or mural thrombus, and central vein thrombosis.   Pt’s who have intermittent complete occlusion and withdrawal occlusion have a type of mechanical obstruction called “pinch-off syndrome.” Clots within the catheter lumen, obstructing fibrin sheaths, and ball valve/mural thrombus often respond to low-dose intracatheter urokinase; central vein thrombosis, precipitants in the catheter lumen, and mechanical obstruction do not.   Precipitants within the catheter lumen are most commonly the result of failure to clear the line with saline after total parenteral nutrition and flushing of the line with a heparin solution instead. Heparin combines with total parenteral nutrition fluid-producing precipitants. Clots within the catheter lumen most commonly result from failure to flush the line with a heparinized saline solution after blood aspiration.  A CXR to confirm catheter position and integrity, the tip should be positioned just above the right atrium.  If the catheter is lodged against the vessel wall, the pt’s changing body position, raising the arms above the head, or performing a Valsalva maneuver may relieve withdrawal occlusion. If this is unsuccessful:   try low-dose intracatheter Urokinase (5,000 U) should be injected into the catheter and left for 30 minutes before aspiration is again attempted. If it is unsuccessful, a second dose of urokinase can be injected and the procedure repeated. Contra to thrombolytic agents should be considered, although low-dose therapy for occluded catheters appears well tolerated.   Mechanical obstruction can be due to a variety of causes, including pinch-off syndrome, in which the catheter lumen is compromised as the result of mechanical forces acting on it between the clavicle and the first rib. The catheter is intermittently obstructed during both administration and withdrawal of fluids. A chest roentgenogram demonstrates narrowing of the catheter lumen as it passes between the clavicle and the first rib. This condition is most commonly detected within 3 weeks after catheter placement; the catheter must be removed because of the frequency of fragmentation or embolization if left in place.   Because engorged collateral circulation or swelling in the affected extremity is not universally present with subclavian vein thrombosis, this diagnosis should be considered in all patients who are unresponsive to declotting attempts. Catheter removal and systemic heparinization or maintenance of the catheter’s placement and treatment with high-dose thrombolytic therapy is a therapeutic option for subclavian vein thrombosis.  Mechanical occlusion is rare and requires catheter replacement with a surgical approach. Because of variations in approach by different consultants, it is recommended that the EP seek early consultation in patients who have occluded central venous catheters.

Catheter-Related Infections:   categorized as local or systemic. Local infections primarily involve the skin and subcutaneous tissues surrounding the exit site with erythema, tenderness, and no clinical or laboratory evidence of sepsis. Skin organisms are primarily responsible for local infections, especially coagulase-negative staphylococci. Studies show that local infections usually do not require catheter removal and resolve with antibacterial therapy alone.   The source of systemic infection are urinary tract, anorectal area, upper respiratory tract, and, finally, central venous catheter. The most common organisms causing catheter infection are coagulase-negative staphylococci, S. aureus, and Candida albicans. In immunocompromised pt’s, G+ have now replaced G- bacteria as most often responsible for sepsis. Accordingly, initial empiric therapy should include an antistaph drug, in addition to G- coverage.  Get Bx X2 with Bx drawn simultaneously through the cath and from a peripheral blood vessel may assist in determining whether the cath is the source of infection. Studies now indicate that infections that do not extend through the vessel wall (“pericatheter infections”) can be successfully treated without catheter removal. Catheter removal is mandatory in patients with continued positive blood culture results despite therapy and in those with vascular access infections caused by Candida species. Catheter-related septic central venous thrombosis can progress through and around the vessel wall to cause a perivascular infection or abscess.  This rare but devastating complication is associated with serious morbidity and a reported mortality as high as 83%.  Because of the lack of specific clinical findings, the most prominent diagnostic feature is continued bacteremia after catheter removal. Diagnosis is confirmed by venography or CT scan.  Removal of the catheter, IV administration of antibiotics, and anticoagulation constitute appropriate initial therapy. Surgical treatment with thrombectomy and possible abscess drainage is indicated after failure of an adequate course of antibiotics and anticoagulation. Several studies have used thrombolytic agents as an adjunct to the management of catheter-related septic venous thrombosis, but the risk-to-benefit ratio of this approach has not been established. In patients who require removal of the catheter, a quantitative culture of the number of organisms on the surface of the removed vascular catheter correlates well with a positive blood culture result for the same organism.  This technique involves rolling the catheter on a culture medium. Broth culture of catheter tips may be less reliable in determining whether the catheter is the source of infection.

External Jugular (EJ) Vein Catheter:

Advantages:  it may be utilized in pt’s with clotting abnormalities, it is part of the surface anatomy, has minimal risk of PTX.

Disadvantage: it often takes an unpredictable course into the central compartment as there is a sharp angle where it emerges from the subclavian leads to 15% entering arm or looping cephalad.

External Jugular V:  Often can visualize the vein surface.  Safer in cases of coagulopathy, less risk of PTX.  Can be difficult to get into central vein as the catheter often turns into the subclavian.

Equipment: prep solution, drapes, gloves, mask.  A short intracath 8-12 inches and suture to secure catheter.  A J-wire and a scalpel.

Step #1: The right side is best. Pt is supine in 15 deg Trendelenburg with head turned away from the side of approach (distends the vein and minimizes air embolism). Locate the EJ, it runs from the angle of the mandible infero-laterally to the clavicle, crossing the sternocleidomastoid (SCM) 5cm above the clavicle, then behind the clavicle to join the subclavian. Cleanse skin with Betadine X3. Sterile technique, inject 1% lidocaine to produce a skin weal.  Apply digital pressure with your index finger to the external jugular vein above the clavicle to distend the vein and keep it from rolling. The valsalva maneuver may help locate the vein.

Step #2: :  With a 16-gauge thin wall needle enter with a firm and quick thrust where it courses over the anterior portion of the clavicular head of the SCM above the clavicle.  Advance the needle in the axis of the vein at 200 to the frontal plane.  Expel the skin plug once through the skin.   Once see free backflow of blood advance and additional 2mm.  Insert the J-wire (soft, flexible end first) through the needle and advance.  If any resistance is met, tilt (not rotate) to the head to straighten the IEJ as it enters the subclavian vein.   Never force it.

Step #3: Remove the needle, maintaining control over the guide wire at all times.  Make a small incision with a No. 11 scalpel blade to facilitate entry of the catheter, thread the catheter over the J-wire and into place (be sure to always have control of the wire).

Step #4: Remove the guide wire after the catheter is in place. Cover the catheter hub with a finger to prevent air embolization.  Suture catheter in place with 2-0 silk suture and tape. Attach the catheter to intravenous infusion. Check CXR to r/o hemothorax or PTX. The catheter should be replaced weekly or if there is any sign of infection.

Complications:  tearing of the subclavian vein by the wire or catheter (avoidable with careful technique). Internal carotid puncture, must apply local pressure for 10min.

Internal Jugular Vein:

Relatively contraindicated in patients with carotid bruits, stenosis, or aneurysm.   The right side is better as can access ( “straight shot”) R atrium w/o encountering major angles.

Advantage: less risk of pleural puncture, easy to compress a hematoma, easy landmarks.

Disadvantages: difficult to cannulate if hypovolemic, a “blind” puncture, risk of carotid injury, restriction of the pt’s neck mobility.

Anatomy: positioned behind the sternocleidomastoid muscle lateral to the carotid artery. The catheter should be placed at a location at the upper confluence of the two bellies of the sternocleidomastoid, at the level of the cricoid cartilage.

Step #1:  Place the patient in Trendelenburgs position and turn the patient’s head to the contralateral side.  Choose a location on the right or left. If lung function is symmetrical and no chest tubes are in place, the right side is preferred because of the direct path to the superior vena cava. Prepare the skin with Betadine solution using sterile technique and a drape. Infiltrate the skin and deeper tissues with 1% lidocaine.

Step #2:   3 main approaches:   All use the same landmarks, but differ in entry site and needle angle. While aspirating, advance the 22g scout needle until the vein is located and blood flows back into the syringe.

Anterior –> Enter at the midpoint of the sternal head of the SCM, ~5cm from both the angle of the mandible and the sternum.  Palpate the carotid and enter at 40 deg angle 1cm lateral and parallel (directed caudally and toward ipsilateral nipple).  Hit IJ in 2-4cm.

Posterior –> Enter 1cm dorsal to where the EJ crosses the posterior border of the clavicular head of the SCM (~5cm cephalad of the clavicle). Direct needle caudally toward the sternal notch at 45 deg angle.  Hit IJ in 5-7cm.

Central –> Skin puncture is at the apex of the triangle formed by the two bellies of the SCM and the clavicle.  Needle enters at 40 deg angle with the frontal plane and directed toward the ipsilateral nipple.  Hit IJ in 3-5cm.

Step #3: Now can either remove the finer “scout” needle and advance a 16-gauge, thin wall catheter-over- needle (directly above it)  with an attached syringe along the same path as the scout needle. Or remove the finer needle and introduce the larger one in the same plane.  When back flow of blood is noted into the syringe, advance the catheter into the vein. Remove the needle and confirm back flow of blood through the catheter and into the syringe. Remove the syringe, and use a finger to cover the catheter hub to prevent air embolization.

Step #4: With the 16 g catheter in position, advance a spring guide wire (0.89 mm x 45 cm) through the catheter. The guidewire should advance easily without resistance. With the guidewire in position, remove the catheter and use a No. 11 scalpel blade to nick the skin.

Step #5: Place the central vein catheter over the wire, holding the wire secure at all times. Pass the catheter into the vein, remove the guidewire, and suture the catheter with 0 silk suture, tape, and connect it to an IV infusion. Obtain a CXR to rule out PTX and confirm position of the catheter.

Subclavian Vein:

Advantage: remains open even with profound circulatory collapse.  Less restricting to the pt. Good choice in emergency situation as placement will not interfere with airway management.

Disadvantage: Has increased risk of PTX in patients with emphysema or bullae as the pleural space is easily entered with the “blind” stick. Difficult to apply pressure if the artery becomes punctured.   It is located in the angle formed by the med 1/3 of the clavicle and the first rib.

Step #1: Position the patient supine with a rolled towel located between the patient’s scapulae, and turn the patient’s head towards the contralateral side. Prepare the area with Betadine X3, using sterile technique, drape the area and infiltrate 1% lidocaine into the skin and tissues.

Step #2: The needle enters at the tubercle of the clavicle, palpated on the inferior surface ~1/3 to 1/2  the length of the clavicle form the sternum.  Depress under the clavicle distal to this area with your thumb as your pointer finger rest at the angle of Louis.   Advance the 16-gauge catheter-over-needle, with syringe attached until the clavicle bone and needle come in contact.

Step #3: Slowly probe (walk) down with the needle until the needle slips under the clavicle, and advance it slowly (should feel no resistance) towards the finger resting on the sternal notch at a 25 deg angle to the thorax (parallel to the bed).  Keep bevel pointed inferomedial to encourage the guidewire to enter the innominate vein.  Advance until see a back flow of venous blood enters the syringe.  Remove the syringe, and cover the catheter hub with a finger to prevent air embolization. Ask the pt to hum or hold breath as you pull the needle out and cover it.

Step #4: With the 16-gauge catheter in position, advance a 0.89mm x 45cm spring guide wire through the catheter. The guide wire should advance easily without resistance.  With the guide wire in position, remove the catheter, and use a #11 scalpel blade to nick the skin.

Step #5: Place the central line catheter over the wire, holding the wire secure at all times. Pass the catheter into the vein, and suture the catheter with 2-0 silk suture, tape, and connect to an IV infusion. Check CXR to confirm position and rule out PTX.

Pulmonary Artery Catheterization:  PA Cath Patterns:

Contra: none are absolute.  Preexisting site infection, known or suspected anatomic abnormality, coagulopathy, LBBB, pulmonic stenosis, pacemaker wires. Step #1: Using sterile technique, cannulate a central vein using one of the above techniques.   Step #2:  Advance a guide wire through the cannula, then remove the cannula, but leave the guide wire in place. Keep the guide wire under control at all times. Nick the skin with a number #11 scalpel blade adjacent to the guide wire, and pass a number 8 French introducer over the wire into the vein. Remove the wire and connect the introducer to an IV fluid infusion, and suture with 2-0 silk.

Step #3: Pass the proximal end of the pulmonary artery catheter (Swan Ganz) to an assistant for connection to a continuous flush transducer system.    Step #4: Flush the distal and proximal ports with heparin solution, remove all bubbles, and check balloon integrity by inflating 2ml of air. Check pressure transducer by quickly moving the distal tip and watching monitor for response.

Step #5: Pass the catheter through the introducer into the vein, then inflate the balloon with 1.0ml of air one passed the introducer, and advance the catheter until the balloon is in or near the right atrium. The catheter is marked at 10cm intervals to aid in determining the depth of insertion.  Step #6: The approximate distance to the entrance of the right atrium is

determined from the site of insertion:  Right IJ vein –> 10-15 cm.  Subclavian vein –> 10 cm.  Femoral vein –> 35-45 cm.

Step #7:  Advance the inflated balloon, while monitoring pressures and wave forms as the PA catheter is advanced. Watch for ventricular ectopy during insertion. Advance the catheter through the right ventricle into the main pulmonary artery until the catheter enters a distal branch of the pulmonary artery and is stopped (as evidenced by a pulmonary wedge pressure waveform).

Other: Do not advance catheter while the balloon is deflated, and do not withdraw the catheter with the balloon inflated. After placement, obtain a chest X-ray to ensure that the tip of catheter is no farther than 3-5 cm from the mid-line, and no PTX is present.  It shouldn’t take >1ml to wedge.  Measures pulmonary venous pressure ~= L atrial pressure ~= LV end-diastolic pressure, false readings if have mitral stenosis.  Also uses a Thermaster to determine cadiac parameters via temperature dilution.  Give a bolus of fluid to R atrium (CVP port) at room temp, simultaneously measure temp in pulmonary artery (tip), there is a smaller temp change with inc cardiac output.  False readings with TR and VSD.

**Ref:(Irwin and Rippe’s Intensive Care Medicine, 4th ed, 1999, Lippincott-Raven) (Infections related to central venous catheters.  Mayo Clin Proc. 1990;65:979-86) (Intravenous and central catheter infections.  Surg Clin North Am. 1994;74:557-70) (Central venous catheter placement and complications.  Crit Care Med. 1994;22:1516-18) (Arterial cannulation: how to do it. Br J Hosp Med 1997;57:497-9) (Arterial cannulation. Anesthesia 1995;50:576)

Normal Pulmonary Artery Catheter & Cardiac Parameters:  Link: PA Cath Patterns: PA Cath:

Directly measured and most important are the CO, PAP and PCWP.

Fick Principle:  the uptake of a substance by an organ is a product of blood flow and the arteriovenous (A-V) substance difference across the organ.  For CO = 100 X O2 Consumption / (arterial O2 content – venous O2 content).  The blood O2 content (Vol %) is calculated from the saturation % X Hemoglobin (g/dL) X 1.36.  Venous blood is from the PA, arterial blood is from the periphery.

Cardiac Output (CO): HR X stroke volume.  Nl = 3.5-8 L/min. Total body perfusion.    CO l/min = 125 mL O2 /min/M 2 x 100 = 8.5 {(1.36)(Hgb)(SaO2 ) – (1.36)(Hgb)(SvO2)}. Measured by either Fick method or thermodilution (invalid with tricuspid regurge). Stroke Volume: CO / HR = 55-100 mL.  Stroke Index:  30-65 ml/beat/m2.   Cardiac Index (CI): CO/ BSA. Nl = 2-4 L/min/m2.  Double Product: (HRXSBP)/ 100. Nl 60-140, relative myocardial O2 use.

Mean arterial Press (MAP):  (SBP + 2DBP) / 3 or [(SBP — DBP)/3] + DBP.  = 85-95mmHg.  End organ perfusion.

Systemic Vascular Resistance (SVR): [ 80 X (MAP – CVP)] / CO. Nl = 700-1600 dynes/sec/cm-5.  Geometry of systemic arterioles.  Calculated value, need to take with a grain of salt.

SVR Index (SVRI): = SVR X BSA (in m2).  Normal SVRI = 2130 +450 dyn/d/cm-5/m2.

Left Ventricular Stroke Volume (LVSV): range of 70-94 ml.   LVSVI (Index): range of 30-65 mL/m2.

Total Pulmonary Vascular Resistance (PVR):  [ 80 X (MPAP — PCWP)] / CO.   = [(PA – PCW) X 80] / CO.  Normal is ~1/6 the SVR = 100-300 dyn/sec/cm-5.  Pulmonary Vascular Resistance is 20-130.  Geometry of pulmonary arterioles.  It is elevated in shunts, myocardial dz, pulmonary vasculature obstruction, hypoxemia, toxins and primary pulmonary HTN.  PVRI = 80 X (mean PAP — PAWP) / CI = 80-240 dynes-sec/cm2/m2.

Arterial O2 Content (CaCO2): (Hgb X 1.36) SaO2 + (PaO2 X 0.0031) = 16-22 ls O2/ dL blood or vol%.

Mixed Venous O2 content (CvO2): (Hgb X 1.36) SvO2 + (PvO2 X 0.0031) = 12-17 mL O2/dL blood.  A measurement of overall tissue oxygenation extraction.  Calculated using the Fick equation after measuring the mixed venous saturation.  Mixed Venous O2 sat (Pulmonary artery):  75%.

Arterial oxygen capacity =(Hg(gm)/100 mL) x 1.36 mL O2 /gm Hg.  O2 carrying capacity is mostly due to Hgb as O2 sats have little affect.

DO2: O2 delivery: CaO2 X CO X 10.   nl = 640-1400 mL/min.

VO2: O2 uptake: C(a-v)O2 X CO X 10.  Nl = 180-280 mL/min.  The best hemodynamic parameter to asses if shock is present.

Oxygen Consumption Index (VO2I): range of 113-148 ml/min X m2.  Arteriovenous O2 Difference:  30-50 ml/L.

Measured Parameters:

Central Venous Pressure (CVP = Right Atrial Pressure): 0-8mmHg. RV preload.  If >11 and in CHF give 80mg Lasix q8hr.

Pulmonary Artery Pressure (PAP) Mean: 9-20 mmHg.  Pulmonary artery SBP (PAS): PAP Systolic: 15-30 mmHg. >35 = pulmonary HTN.  Pulmonary artery DBP (PAD): PAP Diastolic: 4-15 mmHg. Should be a points above the PCWP, can be used instead of a wedge.

Pulmonary Cap Wedge Press (PCWP): 6-12 mmHg (~16 with AMI). Preload of LV, a hydrostatic gradient.  PCWP is the dampened LA pressure (indirect measure of LA pressure) which reflects LVEDP, which reflects LVEDV.   Not a valid measurement when intrathoracic pressure exceeds the distending pressure of the pulmonary capillary bed (parenchymal lung dz, severe volume depletion, pulmonary vascular dz, catheter tip malposition).  Pearls: the diastolic pressures will be = in all 4 chamber with pericardial tamponade or constrictive pericarditis.   Normally the diastolic PA pressure = PCWP (except with pulmonary HTN).   If have an inferior AMI and see a dec CO & PCWP with inc RA pressure you have a RV infarction (check R-side ECG).  If have dec CO with inc PCWP and RA pressure then have biventricular failure due to cardiogenic shock.

Right Atrial (RA) pressure: 1-7 mmHg, if elevated, then suggests RV failure, should see JVD. The mean RA pressure is a measure of both the hydrostatic pressure on the systemic veins & RV end-diastolic (filling) pressure.   RV Pressure (RVP) Systolic: 15-30 mmHg.  RVP Diastolic: 0-8 mmHg = RV end-diastoli.  LV Systolic Pressure: 100-140 mHg.  LV End-diastolic: 3-12 mmHg.  Aortic Systolic @ 100-140, diastolic @ 60-90, mean @ 70-105.

PA Catheter Patterns:

Links:  Conditions:  Swan Orders:  CVP:  Shock:  Pulmonary & Cardiac Parameters:  PA Cath Placement:

PCWP = Wedge pressure = Pulmonary artery wedge pressure (PAWP = LAP, L atrial pressure, in mm Hg, pulmonary artery diastolic pressure may be used instead). Cardiac Index (CI). Pulmonary artery pressure (PAP = MAP).  Central Venous Pressure (CVP = RAP, R atrial pressure).  Systemic Vascular Resistance (SVR):  multiply by 80 to give SI units of dynes/sec/cm-5, normal = 1000 dyn). Almost all above conditions will have inc HR, dec venous compliance (except septic shock), dec CaO2 and dec DO2.

Various Shock States –> CO / SVR/ CVP (RAP)/ PCWP/ O2 consumption:

Hemorrhagic –> dec / inc/ dec/ dec/ inc.

Cardiogenic –>  dec/ inc/ inc or dec/ inc/ inc.

Septic  –> inc/ dec/ inc or dec/ inc or dec/ inc then dec.

Neurogenic –> dec/ inc or dec/ dec/ inc or dec/ inc or dec.

Specific Conditions –> PCWP/ CI/ SVR/ Other:

Normal –> 6-12/ 3.5L/ 11-18/ PAP 14, CVP 5-10.

Hypovolemia –> dec/ dec/ Nl-inc/ Pt is dry.

LV Failure –> inc/ dec/ inc.

Primary RV Failure (RV AMI) –> Nl-dec/ dec/ Nl/ dec RA press, steep Y-descent, RV diastolic dip and plateau.

Secondary RV Failure (LV Failure) –> nl-inc/ dec/ Nl-inc/ inc PVR, inc RA.

Tamponade –> inc/ dec/ inc/ RA=wedge, dec y-descent, inc x-descent, pulsus paradoxus always present.

Constrictive Pericarditis –> inc/ nl- dec/ Nl/M or W shape JVP, steep y-descent, Kussmauls, pulsus paradoxus in 1/3.

Acute MR –> inc, peaked v-wave so/dec/inc/Post MI, tall V-waves.

Acute VSD –> inc/ dec/ inc /Post MI, O2 step up from RA to RV to PA.

Sepsis –> dec/ nl- inc/ Nl- dec/ +F/C, Blood Cx.

ARDS –> Nl-dec /inc/ dec/ Inc / dec/ Pulmonary infiltrates with progressive hypoxemia.

Massive PE –> Nl/ dec/ inc / inc PA pressure.

COPD exac. –> 4/ inc/ dec/ inc CVP, PAP, CO.

Typical Swan Ganz Parameters Orders:  You can choose the no sleep option or write:   Maintain PCWP at 14-18 mmHg.  If PCWP <12-14 give 250 NS bolus and/or increase IV NS at 75-80 ml/hr.   If PCWP 14-15 give IV NS at 40 ml/hr.  If PCWP 16-18 TKO or dec IVF.  If PCWP >18-20 give Lasix 20-40 mg IV q6-8hr, if initial dose ineffective repeat in 1-2hr or write “If PCWP 1hr after Lasix is >18, call”.  If urine output (UO) <30-40 ml/hr >2hr call (if PCWP >12-15 consider Lasix.  If <12 give fluids & albumen).

Central Venous Pressure (CVP): varies with respiration.  When lying down it is 6-8 mmHg.  The upper limit of normal for an ill person is 10mmHg.  When on mechanical ventilation with PEEP and needing volume, commonly use 20.  If exceeds 15-18, commonly need PCWP to follow in order to precisely titrate fluids.   In normal conditions the L atrial pressure is within 2-3mmHg of the R atrial pressure.  Thermodilution techniques can be used to estimate the CO.

Catheter Sizes:

French Size–>   Outside Diameter = OD (mm) X 3 = French Inches / Millimeter.  1 –> 0.1 / 0.3. 4 –> 0.05 / 1.3. 8 –> 0.1 / 2.6. 10 –> 0.13 / 3.3. 12 –> 0.16 / 4.0. 16 –> 0.21 / 5.3. 18 –> 0.23 / 6. 20 –> 0.26 / 6.6. 22 –> 0.28 / 7.3.  30 –> 0.41 / 10.6. 38 –> 0.5 / 12.6.

Guage–> Outside Diameter:  Inches / mm. 26 –> 0.018 / 0.45. 25 –> 0.02 / .05. 24 –> 0.022 / 0.56. 23 –> 0.024 / 0.61. 22 –> 0.028 / 0.71. 20 –> 0.036 / 0.91. 18 –> 0.048 / 1.22. 16 –> 0.064 / 1.62. 14 –> 0.08 / 2.03. 12 –> 0.104 / 2.64. 10 –> 0.128 / 3.25.

**Ref: (Pulmonary artery catheters in the critically ill. An overview using the methodology of evidence-based medicine. Crit Care Clin 1996;12:777-94) (Cardiovascular-pulmonary monitoring in the ICU. Chest 1984;85:537-668) (Irwin and Rippe’s Intensive Care Medicine, 4th ed, 1999, Lippincott-Raven) (Am Fam Phys 1996;54:3) (Bedside Critical Care Manual, 1998, Hanley & Belfus, pp62-69) (Cardiac complications in the intensive care unit. Clin Chest Med 1999;20:269-85)

Acid-Base Physiology:

Links:  Evaluation Step #1: Compensation:  Anion Gap (AG):  Urinary Electrolytes:   Mixed Disorders:  Respiratory Acidosis:   Metabolic Acidosis:  Metabolic Alkalosis:  Respiratory Alkasosis:  Arterial Blood Gas (ABG): Osmolarity:  Osmolar Gap:  References:

The daily diet generates CO2 (from carbo & fat metabolism) and H+ (from protein metabolism).   Ventilation allows for the excretion of CO2.  The kidneys must deal with the acid by reclaiming filtered bicarb (HCO3-) or end up gaining H=.  Most of the acid load is excreted as ammonium.  40% is excreted as titratable acids (phosphoric and sulfuric).  The carbonic acid-bicarb system is the bodies principle buffer.    Cations: Na (140), K (4).  Anions: Bicarb (25), Cl (100).  Pearls:  in pulmonary embolus there is a mild-mod respiratory alkalosis and hypoxemia that correlates with the size of the embolus.  A pO2 >90 mmHg on room air virtually excludes a lung problem.  In acute pulmonary congestion the CO2 is not increases unless the situation is grave, hypoxemia is common.   In COPD can be either pink puffer (mild hypoxemia, nl pH, nl pCO2) or blue bloater (hypoxemia, inc pCO2, if nl pH the compensation, if low pH then decompensation).  In sepsis may have an unexplained respiratory alkalosis as the earliest sign, this progresses to a metabolic acidosis, the mixed picture may have a normal pH.  With asthma see a low pCO2 (<35) due to hyperventilation, if it rises (>40 mmHG) the impending respiratory failure.  See hypoxia even with mild attack.   With neuro d/o get a high pCO2, low pH and nl HCO3, get acidosis before hypoxemia and a rising CO2 means deterioration.   With salicylate poisoning have a poor correlation of serum level and acidosis.  In adults you usually see a respiratory alkalosis, this may progress to a metabolic acidosis if severe.

Acidosis –> inc K, Ca & Mg.   Alkalosis –> dec K, Mg & Ca.

Step #1:  pH: acidosis or alkalosis.   Step #2: Is the primary process Respiratory or Metabolic or both. Use Bicarb & PCO2.

Acid-base Disturbances:

Respiratory Acidosis: Often from COPD, hypoventilation.   Uncompensated –> inc PaCO2, nl HCO3-, dec pH.  Partially Compensated –> inc PaCO2, inc HCO3-, dec pH.  Fully Compensated –> inc PaCO2, inc HCO3-, Nl pH.

Respiratory Alkalosis: Often from PE, cirrhosis, sepsis, pregnancy.  Uncompensated –> dec PaCO2, nl HCO3-, inc pH.  Partially Compensated –> dec PaCO2, dec HCO3-, inc pH.  Fully Compensated –> dec PaCO2, dec HCO3-, Nl pH.

Metabolic Acidosis: Often from hypotension, severe diarrhea, renal failure, sepsis.  Uncompensated –> Nl PaCO2, dec HCO3-, dec pH.  Partially Compensated –> dec PaCO2, dec HCO3-, dec pH.  Fully Compensated –> dec PaCO2, dec HCO3-, Nl pH.

Metabolic Alkalosis:  Often from vomiting, diuretic use cause contraction alkalosis.  Uncompensated –> Nl PaCO2, inc HCO3-, inc pH.  Partially Compensated –> inc PaCO2, inc HCO3-, inc pH.  Fully Compensated –> inc PaCO2, inc HCO3-, Nl pH.

Step #3: Degree of Compensation.  A predictable and adaptive response to acid-base d/o by the kidney and lungs.

Met Acidosis: PCO2 = 1.3 X (dec HCO3), lose CO2 from tachypnea.     Met Alkalosis: inc PCO2 = 0.6 X (inc HCO3).

Resp Acididosis: Acute –> for every PCO2 inc of 10mmHg, HCO3 will inc by 1mEq/L.   Chronic –> every PCO2 inc of 10, HCO3 will inc by 4.

Resp Alkalosis: Acute –> for every PCO2 dec of 10, HCO3 dec by 2mEq/L.  Chronic –> for every PCO2 dec of 10, HCO3 will dec by 4 mEq/L.

Step #4: Calculate Anion Gap: = Na – (HCO3 + Cl).   Links:  Abnormal AG: Normal AGMA:   Increased AG:  Osmolarity:  Osmolar Gap:  Decreased AG:   Urinary Gap:  Delta Gap:

Normal gap = 6-12 mEq/L an is due to unmeasured anions and cations. The difference between the anions (neg charge, protein, organic acids, phosphates, sulfates) and cations (+, Ca, K, Mg).    If >25, then always metabolic acidosis.  For each 100 mg/dL increase in glucose, Na decreases by 1.6 mEq/L.

Step #5:   Determine if there is a 1:1 relationship between anions in the blood.   Inc AG Met acidosis (AGMA): every 1pt inc AG, should have dec 1mEq/L in bicarb.    Normal AG Metabolic Acidosis (Hyperchloremic): every 1 mEq/L inc Cl, have 1mEq/L dec HCO3.  Usually due to: RTA, diarrhea or carbonic anhydrase inhibitor.   Traditionally, the normal anion gap has been 12 ± 4 meq/L. With the new generation of autoanalyzers, the reference range may be lower (6 ± 1 meq/L), primarily from an inc in Cl– values. Despite its usefulness, the serum anion gap can be misleading. Non-acid-base disorders that may contribute to an error in anion gap interpretation include hypoalbuminemia, antibiotic administration (carbenicillin is an unmeasured anion, polymyxin is an unmeasured cation), hypernatremia, or hyponatremia. Decreased AG:

Increased Anion Gap Acidosis (Inc Unmeasured Anions):

The hallmark of this disorder is that metabolic acidosis (thus low HCO3–) is associated with normal serum Cl–, so that the anion gap increases. Normochloremic metabolic acidosis generally results from addition to the blood of nonchloride acids such as lactate, acetoacetate, b-hydroxybutyrate, and exogenous toxins. An exception is uremia, with underexcretion of organic acids and anions.  Pseudometabolic acidosis is caused by underfilling Vacutainer tubes. If 1 mL of blood is put into a 10-mL red-top Vacutainer tube, a significant decline in HCO3– with an increase in anion gap occurs.

Abnormal anion gap (AG):   Inc (>12 mEq):  Anion gap metabolic acidosis = “MUDPILES”    = Methanol, Uremia, Diabetic ketoacidosis (ETOH or starvation ketosis), Paraldehyde, Isoniazid, Lactic acidosis, Ethylene glycol, Salicylates.    Other:  Metabolic anion, Renal insufficiency (PO43–, SO42–), Drug or chemical anion, Salicylate intoxication, Sodium carbenicillin therapy, Methanol (formic acid), Ethylene glycol (oxalic acid), Metformin, Cyanide, Carbenicillin, Acetaminophen (ingestion >75g), Amiloride, Ascorbic acid, CO, Dapsone, Ibuprofen (ingestion >300mg/kg), Iodine, Iron, Ketamine, Ketoprofen, Niacin, Phenol, Propofol, Strychnine, Toluene, verapamil, Zinc, Phenformin (lactic acidosis), aminoglycosides (uremic agents), generalized sz (often from toxin-induced).   ***Note in metabolic alkalosis (inc number of neg charges on the albumen protein).

Lab W/u:  serum ketones (DKA, AKA, starvation), salicylate (ASA) level, measured osmolarity, serum alcohol level, lactate level (nl 1-3 mmol/L), anion gap metabolic acidosis, check osmolal gap (nl <10).  Osmolarity = 2 [Na+] + [glucose]/ 18 + [BUN]/ 2.8.     Check for calcium oxalate crystals (antifreeze) or fluorescence of urine under a Woods lamp.  Abnormal osmolal gap w/o metabolic acidosis seen with ethyl alcohol, isopropyl alcohol.   Must use corrected osmolal gap for combined ingestion:   Osmolarity = 2 [Na+] + [glucose]/ 18 + [BUN]/ 2.8 + ETOH/ 4.6.

Osmolal Gap:  Measured Osm – Calculated Osm –> if 0-10= normal, if >10 abnormal, if <0 lab/ calculation error.  If >10-15 there is an unmeasured osmole such as methanol, paraldehyde, ethylene glycol or mannitol.   Only low MW substances are osmotically active in the serum.

Drugs that cause Osmolar Gap:  “ME DIE”  Methanol, Ethanol, Diuretics (Mannitol, Sorbitol), Isopropanol (acetone), Iodine (questionable), Ethylene glycol.  Other: Glycerol, Hypermagnesemia (>9.5 mEq/L), hyperlipidemia.  If have both an osmolal gap & anion gap then likely due to either methanol or ethelyne glycol.

Decreased Anion Gap (AG):   Links:  Normal AGMA:  Narrow Gap Metabolic Acidosis:

Can occur because of a decrease in unmeasured anions or an inc in unmeasured cations.  The major unmeasured cations are calcium (5 meq/L), magnesium (2 meq/L), gamma globulins, and potassium (4 meq/L).   The major unmeasured anions are negatively charged albumin (2 meq/L per g/dL), phosphate (2 meq/L), sulfate (1 meq/L), lactate (1–2 meq/L), and other organic anions (3–4 meq/L).   Drugs causing dec AG: acidosis, Acetazolamide, Ammonium chloride, Bromide, Iodine, Lithium, Polymyxin B, Spironolactone, Sulindac, Tromethamine.

Dec AG (< 6 mEq):  Hypoalbuminemia (dec unmeasured anion, common), Plasma cell dyscrasias, Monoclonal protein (cationic paraprotein) (accompanied by chloride and bicarbonate), Bromide intoxication.

Dec Unmeasured Anions: If the sodium concentration remains normal but HCO3– and Cl– increase, the anion gap will dec. This is seen when there dec unmeasured anions, especially in hypoalbuminemia. For every 1 g/dL decline in serum albumin, a 2 meq/L dec in anion gap will occur. The new reference range for anion gap diminishes the usefulness of a low anion gap categorization except to detect an increased anion gap acidosis mimicking a normal anion gap acidosis.

Inc Unmeasured Cations: If the sodium concentration falls because of addition of unmeasured cations but HCO3– and Cl– remain unchanged, the anion gap will dec. This is seen in severe inc Ca, inc Mg, or inc K, IgG myeloma, where the immunoglobulin is cationic in 70% of cases, and Li toxicity.

Decreased (Low, Narrow) Anion Gap Metabolic Acidosis:    Renal causes –> urine pH usually >6 with RTA, Diamox, early renal failure, urinary tract obstruction, toluene inhalation, Ampho-B.   GI causes –> urine pH of around 5.  Bicarb rich diarrhea, pancreatic fluid, ureteral diversions.    “HARD-UP AC”, use the Urine AG to determine cause.   Hyperalimentation/ hyperventilation (chronic),   Aldosterone inhibitors (Spironolactone), RTA,  Diarrhea, Ureterosigmoidostomy,  Pancreatic fistula/ small bowel fistula, Addisons, Carbonic anhydrase inhibitors (Diamox = Acetazolamide).    “USED CARPS”: Ureteroenterostomy, Small bowel fistula, Extra chloride (bromism, iodide, hyperlipidemia), Diarrhea, Carbonic anhydrase inhibitors, Adrenal insufficiency, RTA, Pancreatic fistula, Saline load (chloride load causes acidosis).

Urinary Electrolytes:

Urinary Anion Gap (UAG): = urinary anions (UA) – urinary cations (UC) = UNa + UK – UCl.   Normal = -30 to –50 mEq/L.    Used to determine the cause of non-AG acidosis:  If it’s a (+)#, then RTA (renal loss).  If it’s a (-)#, then likely G.I. loss (diarrhea or pancreatic fistula).  Ammonia is the major urinary cation.  Want to see if kidney is making NH3.   If urinary acidification is deranged as in RTA, the UC is decreased, thus get an increased primary urinary AG as it becomes more positive.    In Metabolic Acidosis the kidney makes NH3, Cl enter the urine and the kidney excretes acid like it should.   A useful calculation in pt with non-AG acidosis to determine if renal or GI loss of bicarb.  If not making enough NH3:  lack mineralocorticoid or kidney not responding to it or proximal RTA.  A normal UAG is seen with hyperchloremic metabolic acidosis due to GI loss of bicarb in the presence of normal kidneys that are producing and excreting NH4.   Negative Urinary AG: Urine pH <5.5 –> normal.  Urine pH >5.5 –> diarrhea/ GI loss.  Positive Urinary AG and Urine pH>5.5 –> type 1 RTA.

Volume Depletion: Na 0-10 mEq/L –> extrarenal Na loss.  >10 –> renal salt wasting or Addisons.

Acute Oliguria:  Na 0-10 –> pre-renal azotemia.  >30 –> ATN.

Hyponatremia:  Na 0-10 –> intravascular volume depletion.  Na > 11-15 –> SIADH or Addisons.

Hypokalemia:  K 0-10 –> extrarenal K loss.  >10 –> renal K wasting.

Metabolic Acidosis: Cl 0-10 –> Cl responsive alkalosis.   Cl >10–> Cl resistant alkalosis.

Is There a Mixed Acid-Base Disorder?:

Calculate whether the secondary response is within range of that expected for the primary disturbance.  Measure the “Delta” Gap = “Change in” AG – “change in” HCO3 = (AG observed – AG ULN) – HCO3 LLN – HCO3 observed).  AG ULN = 12.  HCO3 LLN = 24.   Delta Gap = 0, then simple AGMA.   Delta Gap >0, mixed AGMA + primary metabolic alkalosis.  Or a mixed AGMA + chronic respiratory alkalosis with compensation.   Delta Gap <0, mixed AGMA + chronic respiratory alkalosis with compensatory non-AGMA.

Short Cut Method:  If the Delta AG + HCO3 normal –> AGMA only.   Delta AG + HCO3 > normal –> AGMA + met alk.   Delta AG + HCO3 < normal –> AGMA + non-AGMA.

Ddx:  Inc pCO2:   Dec pH –> resp acidosis w/ or w/o incompletely compensated met alk or coexisting met acidosis.  Nl pH–> resp acid and compensated met alk.  Inc pH –> met alk with incompletely compensated resp acid or coexisting resp acid.

Nl pCO2:  Dec pH –> metabolic acidosis.  Nl pH –> NORMAL.   Inc pH –> met alk.

Dec pCO2:  Dec pH –> met acid ww/ incompletely compensated resp alk or coexisting resp alk.  Nl pH –> resp alk and compensated met acid.  Inc pH –> resp alk w/ or w/o incompletely compensated met acid or coexisting met alk.

Respiratory Acidosis:

PH <7.4 with PCO2 >40.  Get inc HCO3 with compensation.   Acute: Inc 1 mEq/L HCO3 = 10 mmHg PaCO2.   Chronic: inc 3.5-4 mEq/L HCO3 = inc 10 mmHg PaCO2.

Ddx: acute airway obstruction (asthma, COPD), lung dz, pleural effusions, PTX, thoracic cage abnormality (flail chest, rib fx, kyphoscoliosis, scleroderma), hypoventilation (narcotics, CVA, sedatives, tranquilizers, paralysis, neuropathy), dec K, dec P, dec Mg, muscular dystrophy.

Step #1:  Calculate ratio:  (PCO2 – 40) / (HCO3 – 25).    If 10/ <1 –> acute respiratory acidosis + metabolic acidosis. Check A-a gradient.   If 10/1 –> acute respiratory acidosis.  Check A-a gradient.  10/1 – 10/3 –> acute and chronic resp acidosis.  Check A-a and consider chronic pulmonary system disorders.  10/3 – 10/3.5 –> chronic respiratory acidosis.  10/ >3.5 –> chronic respiratory acidosis + metabolic alkalosis.

Causes of Chronic Pulmonary Disease:  COPD, OSA, obesity hypoventilation, NM dz (ALS, MD), or chronic ILD.  Check PFTs, CXR, neuro exam, consider sleep study.

Arterial-alveolar (A-a) Gradient: >15 –> consider acute parenchymal lung dz such as COPD flare, severe asthma, pulmonary edema, drug OD, ARDS or pneumonia.     <15 –> acute hypoventilation from NM dz (Guillain Barre, MG), drug OD, brainstem injury or airway obstruction.  Check CXR, PFT’s, tox screen, neuro exam.  Intubate or use non-invasive ventilation if signs of fatigue, depressed mental status, rising PCO2 despite tx, PO2 <55 despite O2 or VC <10-15 ml/kg.

Metabolic Acidosis:

Links:   Lactic Acidosis:    Alcoholic Ketoacidosis:  Uremic:  Toxins:  Anion Gap:  DKA – See Endocrine.

PH <7.35, dec HCO3 (acute), dec PaCO2 to compensate 1-1.5 for change in HCO3.   Step #1:  Determine the Anion Gap.    Consider bicarb replacement:  HCO3 deficit (mEq) = 24- HCO3 (0.4) wt in kg). One amp bicarb raises the serum HCO3 1mEq.  Put 3 amps in 1L of D5W as a volume expander, also corrects the hyperkalemia.   Inc serum K inhibits production of NH3, which can cause met acidosis.   Anion Gap Acidosis is usually one of four things, lactic acidosis (most common), ketoacidosis, toxins/ drugs and uremia.

Lactic Acidosis:

One of the most common causes of AGMA.   Arterial lactate level >5 mmol/L and pH <7.35.    Lactic acid is formed from pyruvate in anaerobic glycolysis.   Most lactate is produced in tissue with high rates of glycolysis (gut- 50% of lactate production), skeletal muscle, brain, skin, and erythrocytes).    Lactate levels usually low (1 meq/L), as metabolism of lactate is principally by the liver through gluconeogenesis or oxidation via the Krebs cycle. The kidneys metabolize about 30% of lactate.  In lactic acidosis, lactate levels rise to >4–5 meq/L but often 10–30 meq/L.  Any level >4 means tissue ischemia, usually from anaerobic metabolism.   There are two basic types of lactic acidosis, both associated with increased lactate production and decreased lactate utilization fro poor perfusion or mitochondrial dz.  Up to 30% may not have a anion gap.

Type A (Hypoxic or hypoperfusion): have hypoxia or dec tissue perfusion (dec O2 content).  More common than type B.  Often resulting from poor tissue perfusion, cardiogenic, septic, or hemorrhagic shock, CO poisoning, severe anemia/ hypoxemia, pulmonary edema. These conditions not only cause lactic acid production to increase peripherally but, more importantly, hepatic metabolism of lactate to decrease as liver perfusion declines. Severe acidosis also impairs the ability of the liver to extract any perfused lactate.

Type B (Impaired O2 utilization and/or lactate metabolism) –> not due to hypoxia.  May be due to metabolic causes, such as DKA, liver disease/ failure, renal failure, infection (sepsis, Malaria), cancer, strenuous exercise, sz, pheochromocytoma, congenital enzyme defects, toxicity from biguanides therapy, Thiamine def., leukemia, or lymphoma or as a result of toxicity from ethanol, methanol, salicylates, INH, Niacin, Nitroprusside, Cocaine, Cyanide, Acetaminophen, Streptozotocin, AZT, ASA, Nalidixic Acid or phenformin, also seen in  AIDS.  Tissue oxygen utilization is impaired.   Or from congenital erros of metabolism.

Idiopathic lactic acidosis, usually in debilitated patients, has an extremely high mortality rate.

Alcoholic Ketoacidosis (AKA):

This is a common disorder of chronically malnourished patients who consume large quantities of alcohol daily. Most of these patients have mixed acid-base disorders (10% have a triple acid-base disorder). Usually have a dec HCO3-, but half the patients may have normal or alkalemic pH.

The primary ketones produced in AKA are b-hydroxybutyrate (bHB) and acetoacetate (AcAc). The ratio of bHB to AcAc depends on the ratio of NADH to NAD. Because of dehydration, the ratio of NADH to NAD in alcoholic ketoacidosis is often elevated, resulting in a higher percent of ketones as bHB.   The nitroprusside test used for ketones detects only AcAc, patients with AKA may have falsely low to negative tests for ketones. The ratio of bHB to AcAc reverses with reversal of dehydration, which can produce an apparently “worse” laboratory ketone value with clinical improvement alcoholic ketoacidosis.  AKA may present with alkalemia or a mixed acid-base disorder, secondary to contraction alkalosis form profuse vomiting  A mild lactic acidosis, secondary to ethanol use, can also compound the patient’s acid-base status.  Both Inc/dec Phos have also been noted in patients with AKA.  Serum K level may be falsely elevated.  Mild elevations in LFT’s and/or pancreatic enzymes, may be seen secondary to ethanol use.

Three types:        1. Ketoacidosis: due to b-hydroxybutyrate and acetoacetate excess.    2. Lactic acidosis: Alcohol metabolism inc NADH:NAD ratio, causing increased production and decreased utilization of lactate. Moderate to severe elevations of lactate (> 6 mmol/L) are seen with concomitant disorders such as sepsis, pancreatitis, or hypoglycemia.

3. Hyperchloremic metabolic acidosis due to bicarb loss in the urine associated with ketonuria. If lose HCO3, the kidneys retain Cl in 1:1 ratio.  Metabolic alkalosis occurs from volume contraction and vomiting. Respiratory alkalosis results from alcohol withdrawal, pain, or associated disorders such as sepsis or liver disease. Half of the patients have either hypoglycemia or hyperglycemia. When serum glucose levels are >250 mg/dL, the distinction from diabetic ketoacidosis is difficult. The diagnosis of alcoholic ketoacidosis is supported by absence of a diabetic history and by no evidence of glucose intolerance after initial therapy.  Ddx of Hyperchloremic MA: RTA –> proximal or distal.     Acid loads –> ammonium chloride, arginine or lysine hydrochloride, sulfur, hyperalimentaion, methionine sulfate, ketoacidosis with renal ketone loss.  Bicarb loss –> diarrhea, pancreatic/ biliary/ small bowel fistulas or drainage, ureterosigmoidostomy, drugs (CaCl, MgSO4, Cholestyramine), posthypocapnea).

W/u: if low or normal plasma K, check Ur pH during acidosis.  If >5.5, then distal RTA.  If <5.5, then r/o proximal RTA, measure ammonium and titratable acidity, measure urine PCO2 during bicarb infusion to look for a rate dependent defect.

Tx:  IV hydration is the mainstay of treatment for alcoholic ketoacidosis.    Crystalloid with supplemental glucose, such as D5NS, is the fluid of choice.  Thiamine 100 mg IV or IM to prevent the development of Wernicke-Korsakoff syndrome.  Multivitamins, Mg and folate supplementation.  K replacement started as soon as adequate urine output is established, as the K+ value will fall with correction of the acidosis.   Hyperphosphatemia will usually resolve with treatment of the dehydration. Phosp is indicated in patients whose level is less than 1 mEq/L.  Benzo’s may be required for the prevention of DTs.   Treatment should be continued until dehydration, acidosis and electrolyte abnormalities have been reversed, good oral intake is established (usually requires 12-24 hrs IVF).

Diabetic Ketoacidosis:   Seen Endocrine/ diabetes complications.

Uremic Acidosis:

At glomerular filtration rates below 20 mL/min, the inability to excrete H+ with retention of acid anions such as PO43– and SO42– result in an anion gap acidosis, which rarely is severe. The unmeasured anions “replace” HCO3– (which is consumed as a buffer). Hyperchloremic normal anion gap acidosis may be seen in milder cases of renal insufficiency.


Multiple toxins and drugs can inc AG gap by increasing endogenous acid production. Methanol (metabolized to formic acid), ethylene glycol (glycolic and oxalic acid), and salicylates (salicylic acid and lactic acid), which can cause a mixed disorder of metabolic acidosis with respiratory alkalosis.

Metabolic Alkalosis:

Alkalosis:   Often associated with low K+ and low Cl- contraction alkalosis.   Metabolic alkalosis is often precipitated by ongoing failure of kidneys to excrete HCO3, due to volume contraction and hypokalemia.  Can be due to:  Loss of acid –> vomit, NGT, gastrocolic fistula, villous adenoma, aciduria (from K depletion).  Excess base –> admin of antacids (bicarb or milk-alkali), some vegetarian diets,  admin of salts of weak acids (Na-lactate, Na or K-citrate).  Potassium depletion (causes H+ & Na to enter cells) –> GI loss with diarrhea, poor intake, diuretics, chronic alkalosis, glycogen deposition, mineralcorticoid excess (primary aldo, Cushings, steroids, licorice), K losing nephropathy.

Ddx:  Choride-responsive: volume depleted (dehydration), responds to NaCl or KCl, (urine Cl <10 mEq/L) –> Vomiting, nasogastric suction, diuretics, post-hypercapnic alkalosis, stool loss (laxative abuse, CF, villous adenoma), massive blood transfusion, exogenous alkali administration.  Serum albumen will be elevated which will expose more binding sites and can create a GAP-alkalosis.

Ddx: Chloride-resistant:  profound dec K (800-100 mEq deficit), hyperadrenocorticoid states such as Cushing’s syndrome, primary hyperaldosteronism, secondary mineralocorticoidism such as licorice, chewing tobacco (Ur Cl >20 mEq/L) –> Hypomagnesemia, hypokalemia, Bartter’s syndrome.

Unclassified Causes:  alkali administration, recovery from organic acidosis, antacids and exchange resins administered in renal failure, Milk-Alkali syndrome, large doses of carbenicillin or PCN, glucose ingestion after starvation, nonparathyroid hypercalcemia.

Tx:  Varies depending on the cause.  Cl-responsive give saline, correct accompanying hypokalemia.  Cl-resistant correct of underlying cause, correct K depletion.  Can follow urine Cl as indicator of repletion of volume status. Diamox 250mg IVP q12h x3 with 20 mEq KCl via NGT.  Short-term improvements can be seen with adding 3 amps Bicarb/ L NS.

Bartter Syndrome: a familial hypokalemic, hypochloremic metabolic alkalosis.  Due to ion channel abnormalities in of renal tubular cells.

S/s:  HTN is not present, despite high renin and angiotensin II levels. Delayed growth, mild cognitive developmental deficits, polyuria and polydipsia, rare tetany.  Hypomagnesemia in ~20%.  Normal to high urine calcium (nephrocalcinosis variable), high urine prostaglandins.  Renin, Aldosterone & Angiotensin II markedly elevated.  Tx:  correcting sx’s and electrolyte anomalies.  Indomethacin to inhibit prostaglandin secretion is variably effective.

Respiratory Alkalosis:

Sx:  perioral and peripheral paresthesias, hyperreflexia, tetany, seizures, arrhythmias

Etiology: hypoxemia (pneumonia, PE, atelectasis, high altitudes), psychogenic hyperventilation (hysteria, anxiety, pain), drugs (salicylates, xanthines, progesterone, epinephrine, thyroxine, nicotine), CNS disorders (CVA, trauma, tumor, infections), hepatic encephalopathy (inc NH3), progesterone, hypoxia, early G- sepsis, hyponatremia, sudden recovery from metabolic acidosis, assisted ventilation, pregnancy, anemia, emboli, CHF.

Tx:  underlying cause.  If psychogenic hyperventilation rebreathe to increase. PCO2 (paper bag, breathing 5% CO2 via mask).

Arterial Blood Gas (ABG) Sampling:

Links:  A-a Gradient:  Procedure: ……  Reason:  to asses if adequate gas exchange.

Abbreviations:  PB = barometric pressure (mm Hg).  FIO2 = inspired oxygen fraction (0.21 = room air).  PaCO2 = partial pressure of carbon dioxide in arterial blood (mm Hg).  PACO2 = partial pressure of carbon dioxide in alveolar gas (mm Hg).  PaO2  = partial pressure of oxygen in arterial blood (mm Hg).  PAO2  = partial pressure of oxygen in alveolar gas (mm Hg).

Normal values at sea level room air (FIO2 = 0.21):  PaO2 –> 80-95 mmHg.  The oxygenation.   PaCO2 –> 35-45 mmHg. The ventilation.  SaO2 –> 96-99%.    pH –> 7.40 +0.02.  HCO3 –> 22-28 mEq/L  Base excess or deficit: ­-3 to +3 mEq/L.

Values should not change with age except dec PaO2.    For age 40-90yo, PaO2 = 108.75 – 0.39 X age. (Or ~100-1/3 age)

Mixed venous O2 tension (PVO2): 35-50mmHg.   Mixed venous O2 concentration (CVO2): 12-15ml/dL. Or 70-75% sat.

Arterial O2 concentration (CaO2): 17-20 ml/dL.

Arteriovenous O2 difference = C(a-v)O2: 4-5ml/dL.

Alveolar-arterial O2 Gradient (A-a)     (FIO2 X 713) – 1.25(PaCO2) – PaO2. (PAO2 is calc, PaO2 is measured.)

Normal = 4 + [(age-20) x .3]   Normal is <10-20 mmHg breathing room air at sea level for any age , or 10-60 on 100% O2.  If elevated, it indicates respiratory dz that is interfering with gas exchange.  If on O2, can remove and the O2 sat will equilibrate in 5 min, as hard to interpret unless on RA or 100%.  = 148 – 1.2(PaCO2) – PaO2.    148 = 713 X FiO2.   = PAO2 – PaO2.  Short-cut estimate:  150 – (1.25 PaCO2).  P(A-a) in adolescents = <10 mm Hg, adults <40 yo = 10 mmHg, >40 yo = 10-15.

ABG Procedure:  Best to use radial > femoral or brachial artery.   Contra: +Allen test, ESRD (may need shunt or fistula site), bleeding d/o.  Equipment: 3-5ml plastic syringe X2, one with 2ml of 1% Lido.  Two 25g, ½” needles, ice, ETOH or Iodine, drape, 1ml of Heparin 10,000 U/ml, sterile gloves, 2X2’s, towel, tape.

Step #1: Check Allen Test: asses patency of collateral circulation.  Occlude both radial & ulnar arteries with firm pressure at distal forearm.  Elevate arm, pt make a few fists to drain blood.  Release pressure on ulnar side, should pink up hand in <6sec.

Step #2: Place rolled towel under hyperextended wrist, tape to back board.  Palpate radial artery as it lies between styloid process of radius & flexor carpi ulnaris tendon.  PMI should be just proximal to transverse wrist crease.

Step #3: Don sterile gloves.  Wet the syringe with Heparin and evacuate the extra (extra heparin left in syringe –> dec pH).

Prep area with Betadine or ETOH, then give local anesthetic (optional), infiltrate skin and then down to periosteum or radius on either side of the artery with 1%Lido (may dec vasospasm).

Step #4: Tell pt to expect some discomfort but to keep as still as possible. Relocate PMI with nondominant hand as face the patient.   Hold syringe like-a-dart, insert bevel up into skin at 60 deg pointing proximally.  Slowly advance until 1-2ml of pulsatile blood fills syringe passively.

If no blood advance until hit bone, then slowly pull back to skin (may have pierced the artery), once needle is just beneath skin, repalpate artery and redirect.    Step #5: withdraw needle, apply firm pressure to area for 5-10 min.  Remove all air bubbles (affects PO2) from syringe, remove needle and apply rubber stopper.  Label and place on ice or send to lab ASAP (within 20min) as WBC’s metabolically active.  Can use elastic ace wrap and gauze pad to apply pressure, best not to let pt do it, can use an assistant.

Complications:  Pain, infection, local bleeding, venous or air contamination.  Distal ischemia if over traumatize the artery (rotate sites, avoid brachial artery).  AV fistula or false aneurysm (from over sampling same site)   Re-check pt in 15-20 min to r/o wrist hematoma and adequate perfusion.   If unable to use radial artery due to +Allen, or local infection.

Brachial Artery: use 22g 1.5”.  Consult a vascular surgeon ASAP if get transient spasm, occlusion or clotting of brachial artery.  Distal embolization with blood or cholesterol emboli, ischemia or gangrene of hand or forearm.

Femoral Artery: Commonly use is hypovolemia or shock.  Can use blind sampling of the best estimated position of the femoral artery.  Postion of vascular structure:  Lat –> Med: NAVAL:  Nerve, artery, vein, empty space, lymphatics.  If no pulse palpable –> divide the distance between ASIS & Pubic tubercle in thirds.  The artery lies at a point where the inner 1/3 and middle 1/3 meets.

***Ref: (Acid base disorders, The Principles and Practice of Nephrology, 1995, Mosby)  (Anion gap, Kidney Int 1985;27:472) (Postgrad Med 2000;107:3) (Acid-base. Arch IM 1992;152:1625-29)  (Medicine 1980;59:161-187) (Acid-base disorders: classification and management strategies.  Am Fam Physician. 1995;52:584-90) (The cellular basis of metabolic alkalosis.  Kidney Int. 1996;49:906-17) (Metabolic acidosis with extreme elevation of anion gap: case report and literature review. Am J Med Sci. 1999;317:38-49) (An approach to clinical acid-base problem solving.  Compr Ther. 1998;24:553-9) (Protection of acid-base balance by pH regulation of acid production. N Engl J Med 1998;339:12) (Arch IM 1992;152;1625-29) (The urine anion gap.  Am J Med 1986;292:198-202)

Nasogastric Tubes (NGT):

Two clinical uses, for dx of upper GI bleed and for gastric decompression.  Rule of 9’s for NGT:  1 liter of gastric fluid contains 9 mEq K, 45 mEq Na, 90 mEq Cl.    Easy NGT Placement:  Step #1: estimate the distance of insertion, usually 50cm in adults, then apply a slight caudal curve to the tip.  Can stiffen a soft tube by mixing in ice.   Step #2:  Lubricate distal 15cm of the tube with KY. Numb nostril first by squirting 3-5ml 2% Lido through a 22g needle.  If available create a 50/50 mixture by injecting 4% Lido into Afrin bottle and spray/  inject into nares. For improved ease of tube placement can add atomized 4% lidocaine:  1.5ml into nasopharynx + 3ml into oropharynx.

Step #3: For easier insertion have pt suck water out of a 30cc syringe to initiate swallow reflex and lubricate.  As swallow tube and keep neck flexed to close the epiglottis and avoid tracheal intubation.  In uncooperative, attach a 20cc with water, when pt starts to gag withdraw slightly and instill a few drops of water to trigger the swallow reflex.

Step #4: Auscultate over the stomach as inject 50cc of air to confirm placement.   Aspirate the GI contents and check pH.  Tape tube to nose.  Before using a feeding tube, always check a low CXR to confirm placement.  Preferred site is the antral or fundic pool.  If becomes clogged, use a saline flush to clear it.

Complications:  nasotracheal intubation, epistaxis, esophageal/ nasal/ gastric erosion with prolonged use, otitis media, excessive gagging (encourage the pt to deep breath or pant through the mouth after the tube passes.

Feeding Tubes:  correct location is anywhere from stomach to proximal jejunum.  Only postpyloric placement helps reduce risk of reflux and aspiration pneumonia.  Before feed, must confirm enteral position with a low CXR.  No benfit in advanced dementia.  Informed consent about the benefits, burdens and alternatives is often only brushed upon.

Percutaneous Endoscopic Gastrostomy (PEG):   Placed with an endoscope in stomach a needle is percutaneously pushed into stomach, a tube is inserted using the Seldinger technique.   Usually a 18-28F, large enough for fiber enriched or blenderized enteral formulas as well as medications.  Allows for continuous or intermittent feedings.  Since pt’s usually have a severe stroke or advanced dementia the 1yr mortality rate is 50%.  Pt’s wt at 4mo is usually unchanged, 10% have improved ADL’s and 30% have inc serum albumin. (J Am Ger Soc 2000;48)   Indications:  need nutritional support > 4wks.  Consider in any pt with a functional GI tracts unable to consume sufficient calories to meet metabolic demands.  Frequent indications include impaired swallowing due to neurological or neoplastic dz, head/ facial trauma or catabolic conditions.  0.1-1% procedure mortality rate, 3-6% morbidity rate.    Contra:  prior gastric resection, high risk for aspiration.  Ascites, hepatomegaly and severe obesity may impede gastric transillumination.   Complications: 8% overall, risk intra-abdominal leakage, peritonitis, site infection, tube displacement, aspiration.  Often get excoriation at the insertion site, diarrhea, tube gets pulled out requiring restraints.    If PEG falls out:  insert a new one, can check placement by having pt swallow (if able) a dose of acetaminophen elixir, if able to aspirate a pink liquid then tube is correctly in place.  At least insert a Foley to keep the tract open and to use as a temporary tube.

Endoscopically Positioned Transgastric Jejunal Tube (PEGJ):  A tube is inserted via an existing gastrostomy and the tip is positioned distal to the ligament of Treitz.  Small (<12F), >50% have tube dysfunction in 1 yr.

Direct Percutaneous Endoscopic Jejunostomy (DPEJ):   Feeding tube inserted directly into the jejunum with endoscopic assistance.  Mores stable access to the jejunum.  Tubes are smaller (9-12F) and thus more prone to clogging.   More prone to malabsorption diarrhea if feeding intolerance.

**Ref: (Diagnosing ant treating pt’s with refractory functional GI disorder, Annu Rev Med 1998;49:175-93)  (Cecils Textbook of Medicine 2000, 21st ed, WB Saunders, pp 667-723) (Nasogastric and feeding tubes.  Postgrad Med 1996;99:5)

Methemoglobin-forming Gases:   Met-Hgb is produced when nitric oxide or nitrogen dioxide transforms the iron if heme from ferrous (Fe2+) to ferric (Fe3+). Causes anemia because can’t carry O2, also causes O2-Hgb dissoc curve to shift to L.

Sources:   Nitrites/ ates –> contaminated well water, meat preservatives, carrot juice/ spinach, silver nitrate burn tx, industrial salts, room deodorizer propellants, amyl nitrite (cyanide antidote kits, sexual enhancers), NTG meds.  Other Inducers –> laundry ink (aniline, aminophenol)), industrial solvents/ gun cleaners (nitrobenzene), mothballs (Naphthalene), local anesthetics (lidocaine, benzocaine), Pyridium, Sulfonamides, Chloroquine, Primaquine, Dapsone, phenytoin, nitroprusside, Benzocaine/Hurricaine spray, Fungicides for plants/ seeds (copper sulfate), Resorcinol (anti-seborrheic/ pruritic/ septic), Chlorates (explosives, matches, pyrotechnics), combustion products (fires).

S/s:  parallels those of CO poisoning.  Inc Met-Hgb levels –> cyanosis and chocolate-brown discoloration of venous blood –> cyanosis without abnormal dec in arterial pO2 (except with severe anemia).  Dx is on this basis & other signs of O2 delivery.    Degree of MetHb is expressed in % of total Hgb.   1-2%= normal,  >15% get sx (DOE, inc HR, HTN, H-A.  >35% also get metabolic acidosis, agitation, sz, coma, death.       Also Dx if place drop of pt’s blood on filter paper, when dry it turns deep chocolate brown or slate gray.   Pulse Ox is unreliable and tends to overestimate the O2 sats.   ABG: see normal PO2, but dec O2 sats (both must be measured, not calculated).  Levels @ 10-20% –> mild, avoid nitrates in food/ water, give 100% O2.   If 20-45% –> moderate, likely have CNS depression, H-A, dizziness fatigue, lethargy, syncope, dyspnea.    45-55% –> coma, lactic acidosis, arrhythmia, shock, convulsions.    >70% high risk of mortality.

Tx: Give IV 1% methylene blue in NS 1-2ml/kg over 5-10min (avoid if deficiency in G6PD or methemoglobin reductase), causes ferric –> ferrous.  100% O2.  Hyperbaric O2, exchange transfusions.

Preamble and List of Abbreviations Used:

Links:   Disclaimer:   Lab Values:  Abbreviations:

Written by Carl G. Weber MD, Internal Medicine.   Any feedback is appreciated:  CGWEBER@POL.NET.   Remember, paying the nominal download fee contributes to the ongoing improvement of this text and entitles you to free email upgrades for 1 year.   Purchase at PalmGear.com, look under “clinical”.  If you have any pearls, illustrations or knowledge that you wish to add send it to me.  If it is good, I will add it and send the update back to you as soon as possible and subsequently include it in further updates.   If it is a significant contribution, I will prolong your update period (possible indefinitely) and give you recognition as a contributor.  Let’s make this book our own, we can save trees and the weight of carrying books around.  Please include any citations as evidence-based medicine is our ultimate goal.

Preamble to Book:  Thank you for supporting the production of this text.   It is called shareware, not because you can “share” it freely with others, but in order to simplify the transmittal of my frequent email updates to those who purchase it.   I hope you find it useful.   This text is designed as a quick and yet extensive reference for the diagnosis and treatment of the majority of problems that may present in a primary care physician’s practice.  It is intended to aid providers in their pursuit of optimal patient care.   This book provides concise, quick information that can be used during a busy clinical day with the goal of efficient work-ups, accurate diagnosis, and effective treatment that hopefully leads to well-informed, healthy patients, healthy families and a satisfied physician.  The information in this guide (the ultimate peripheral brain) has been culled from peer-reviewed articles and manuscripts, key textbooks and review courses published within the last few years.The goal is for these texts is to have 95% of clinical info you need at your fingertips. If you have any pearls, illustrations or knowledge that you wish to add send it to me.  If it is good, I will add it and send the update back to you as soon as possible and subsequently include it in further updates.   If it is a major contribution, I can prolong your update period.  Let’s make this book our own, we can save trees and the weight of carrying books around.

Purpose of Book:   I believe this is the first electronic textbook available that adequately summarizes medical information in a concise and easy to read format.    This book is directed at practicing clinicians.  It is also useful to residents and medical students doing clinical rotations.  It includes differential diagnosis, basic pathophysiology, clinical pearls, physical diagnostic findings as well as evaluations and treatments of a multitude of medical conditions.   This book will allow primary care physicians to interface with the specialist, and assist in deciding when referral is necessary.

Book Disclaimer:   Medicine is a constantly changing science with a continuing better understanding of disease processes and newer and diagnostic and treatment modalities emerging almost every day.  The authors, editors, and publisher of this text have given their best efforts to provide accurate, up-to-date, information that is considered to be within current medical standards. The approaches to medical problems are referenced with supporting studies, and further reading is encouraged.   Human error is always possible and the authors, editors, and publisher of this text do not warrant the information as being absolutely complete, nor are they responsible for omissions or errors in the text or for the results of using this information.  This book should not take the place of your own clinical judgment or the advice of specialists. We have tried with great fervor to limit errors, misinformation, and copyright infringement in the text.   We would greatly appreciate feedback regarding any problems you discover while perusing these pages.

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Lab Values:  Links:  Hematology:  Endocrinology:

Common Laboratory Values:  Chem 7  = basic metabolic panel, 17 = comprehensive, which includes electrolytes, renal and liver function tests.  New Medicare Labs:  **Electrolyte Panel (#4): Na, K, Cl, CO2.  **BMP: #8: Chem 7 (SMA-7) with Ca.   **Renal Panel: #10 BMP + Alb & PO4.   **CMP #14: BMP + Alb, AP, AST, ALT, Tb, Dbili.   **ECMP #17: CMP +Mg, P, LDH.  **Hepatic: Alb, Tbili, Dbili, AP, Tp, ALT, AST.

Acetoacetate:  0.3-2.0 mg/dl.

Acid phosphatase:  0-0.8 U/ml (0-5.5 U/L).

Acid phosphatase, prostatic:  2.5-12.0 IU/L.

Albumin (Alb): 3.0-5.5 g/dl.

Aldolase:  1-6 IU/L.

Alkaline phosphatase (AP):  15-20 years @ 40-200 IU/L (U/L), 20-101 years @ 35-125 IU/L.

Alpha-1 antitrypsin: 200-500 mg/dl.

Aminotransferases:   AST (SGOT): 0-35 U/L (IU/L), ALT (SGPT): 0-40 U/L.

Ammonia:  11-35 µmol/L = 80-110 mcg/dL.

Amylase:  2-40 U/L.

Anion gap: 8-12 mEq/L (mmol/L).

Ascorbic acid:  0.4-1.5 mg/dl.

AST:  5-40 IU/L.

Bilirubin:  Total @ 0.2-1.2 mg/dl, Direct @ 0-0.4 mg/dl, Indirect @ 0.2-0.7 mg/dL.

Calcium:  8.7-10.6 mg/dl.

Carbon dioxide:  18-30 mEq/L (mmol/L).

Carcinoembryonic antigen, serum (CEA):  <25. µg/dl.

Carotene (carotenoids):  50-300 µg/dl.

C3 complement: 55-120 mg/dl.  C4 @ 14-51 mg/dl.

Ceruloplasmin:  15-60 mg/dl.

Chloride:  95-106 mEq/L (mmol/L).

Cholesterol Total: <200 mg/dL, 12-19 yo @ 120-230 mg/dl, 20-29 yo @ 120-240 mg/dl, 30-39 yo @ 140-270 mg/dl, 40-49 yo @150-310 mg/dl. 50-59 yo @ 160-330 mg/dl.  HDL: 30-90 mg/dL, LDL: 50-160 mg/dL.

Copper:  100-200 µg/dl.

Creatine kinase, total (CPK):  20-200 IU/L (25-145 U/L).

Creatine kinase, isoenzymes:  MM fraction @ 94%-95%, MB @ 0%-5%, BB @ 0%-2%.  Normal values in the heart @ 80% MM, 20% MB, in the brain @ 100% BB, in the skeletal muscle @ 95% MM, 2% MB.

Creatinine (Cr):  Female adult @ 0.5-1.3 mg/dl, Male adult @ 0.7-1.5 mg/dl.

Delta-aminolevulinic acid (ALA):  <200 µg/dl

Alpha-Fetoprotein, serum:  <40 µg/dl.

Ferritin: 15-200 ng/mL.

Folate: 1.9-14.0 ng/ml.

Gamma glutamyl transpeptidase (GGT or GGTP):  Male @ 12-38 IU/L, Female @ 9-31 IU/L.

Gastrin:  150 pg/ml.

Glucose, serum (fasting, blood sugar = FBS): 70-115 mg/dl.  Subtract 15-20% if a plasma value.

Glucose-6-phosphate dehydrogenase: 5-10 IU/g Hb.

G6PD screen, qualitative:  Negative.

Haptoglobin:  100-300 mg/dl.   Hemoglobin A2 @ 0%-4% of total Hb.  Hemoglobin F @ 0%-2% of total Hb.

Immunoglobulin, quantitation:  IgG @ 700-1500 mg/dl, IgA @ 70-400 mg/dl, IgM @ Male = 30-250 mg/dl, Female = 30-300 mg/dl, IgD @  0-40 mg/dl.

Insulin, fasting: 6-20 µU/ml

Iron-binding capacity:  250-400 µg/dl (250-450 mcg/dL). Iron Saturation: 20-45.

Iron, total, serum (Fe):  40-150 µg/dl (80-180 mcg/dL).

Lactic acid:  0.6-1.8 mEq/L.

LDH: 20-220 IU/L.   LDH isoenzymes: LDH1  @ 20%-34%, LDH2 @ 28%-41%, LDH3 @ 15%-25%, LDH4 @ 3%-12%, LDH5 @ 6%-15%.

Leucine aminopeptidase (LAP):  30-55 IU/L.

Lipase: 4-24 IU/dl (49-220 U/L).

Magnesium (Mg): 1.6-2.6 mg/dL.

5′-Nucleotidase:   0.3-3.2 Bodansky units.

Osmolality: 285-295 mOsm/kg serum water.

Phenylalanine:  3 mg/dl.

Phosphorus (P): 2.5-4.5 mg/dL.

Potassium, plasma:  3.1-4.3 mEq/L.

Potassium, serum:  3.5-5.2 mEq/L.

Protein:  2-55 yo @ 5.0-8.0 g/dl, 55-101 yo @ 6.0-8.3 g/dl.

Protein electrophoresis, serum (SPEP):  Albumin @ 3.2-5.2 g/dl, Alpha-1 @ 0.6-1.0 g/dl, Alpha-2 @ 0.6-1.0 g/dl, Beta @ 0.6-1.2 g/dl, Gamma                           0.7-1.5 g/dl.

Sodium (Na): 136-145 mEq/L.

Sulfate:  0.5-15 mg/dl.

T3 uptake:  25%-45%.

T4:  4-11 µg/dl.

Triglycerides (Trig): <60 mg/dL.  2-29 yo @ 10-140 mg/dl, 30-39 yo @ 20-150 mg/dl, 40-49 yo @ 20-160 mg/dl, 50-59 yo @ 20-190 mg/dl, 60-101 yo @ 20-200 mg/dl.

Urea nitrogen,  serum (BUN):  2-65 yo @ 5-22 mg/dl.

Uric acid:  10-59 yo:  Male @ 2.5-9.0 mg/dl, Female @ 2.0-8.0 mg/dl.  60-101 yo:  Male @ 2.5-9.0 mg/dl, Female @ 2.5-9.0 mg/dl.

Viscosity:  1.4-1.8 (serum compared to H2O).

Vitamin A:  0.15-0.60 µg/ml.

Vitamin B12:  200-850 pg/ml.

Hematology Labs:

Complete blood count:  Male / Female.   Hematocrit (%): 40-52 / 38-48.

Hemoglobin (g/dl):  13.5-18.0 / 12-16.

Erythrocyte count (x 10-12th cells/L): 4.6-6.2 / 4.2-5.4.

Reticulocyte count (%):  0.6-2.6 / 0.4-2.4.

MCV (fL): 82-98 / 82-98.  MCH (pg): 27-32 / 27-32.  MCHC (g/dl): 32-36 / 32-36.

WBC (x 109 cells/L): 4.5-11.0 / 4.5-11.0.  Segmented neutrophils: 1.8-7.7 / 1.8-7.7. Ave %: 40-60 / 40-60. Bands (cells):  0-0.3 / 0-0.3. Ave (%): 0-3 / 0-3.  Eosinophils (cells x 10-9th/L): 0-0.5 / 0-0.5. Ave %:  0-5 / 0-5.  Basophils (cells x 10-9th/L):  0-0.2 / 0-0.2. Ave %:  0-1 / 0-1. Lymphocytes (cells x 109/L):  1.0-4.8 / 1.0-4.8.  Ave %: 20-45 / 20-45. Monocytes (cells x 10-9th/L): 0-0.8 /  0-0.8. Ave %:  2-6 / 2-6.

Platelet count (cells x 10-9th/L): 150-350 / 150-350.

Coagulation Normal Values:  Template bleeding time: 3.5-7.5 min.   Clot retraction, qualitative:  Apparent in 30-60 min; complete in 24 hr, usually in 6 hr.  Coagulation time (Lee-White), in glass tubes: 5-15 min, in siliconized tubes:  20-60 min.  Euglobulin lysis time: 120-240 min.

Factors II, V, VII, VIII, IX, X, XI, or XII: 100% or 1.0 unit/ml.

Fibrin degradation products:  <10 µg/ml or titer  1.4.

Fibrinogen:  200-400 mg/ml.

Partial thromboplastin time, activated (aPTT): 20-40 sec.

Prothrombin time (PT): 11-14 sec.

Thrombin time: 10-15 sec.

Whole blood clot lysis time:  >24 hr.

Acid hemolysis test (Ham): No hemolysis.

Carboxyhemoglobin: Nonsmoker @ <1%, Smoker @ 2.1%-4.2%.

Cold hemolysis test: No hemolysis

Erythrocyte life span: Normal @120 days, 51Cr-labeled half-life @ 28 days.

Erythropoietin by radioimmunassay:  9-33 mU/dl.

Ferritin (serum): Male @ 15-200 µg/L, Female @ 12-15O µg/L.

Folate, RBC: 120-670 ng/ml.

Fragility, osmotic:  Hemolysis begins @ 0.45%-0.38g% NaCl, completed @ 0.33%-0.30% NaCl.

Haptoglobin: 100-300 mg/dl.

Hemoglobin:  Hemoglobin A1C @ 0%-5% of total, A2 by column @ 2%-3% of total, fetal @ <1% of total, plasma @ 0%-5% of total, serum @ 2-3 mg/ml.

Iron:  Male @ 75-175 µg/dl, Female @ 65-165 µg/dl.

Iron-binding capacity, tota (TIBC): 250-450 µg/dl.

Iron turnover rate (plasma):  20-42 mg/24 hr.

Leukocyte alkaline phosphatase (LAP) score: 30-150.  Elevated in polycythemia vera, myeloid metaplasia and some inflammatory diseases.  Dec in CML, PNH, Wilson’s dz and occasionally in Hodgkins.

Methemoglobin:  <1.8%.

Schilling test: urinary excretion of radiolabeled vitamin B12 after “flushing” IM injection of B12 @ 6%-30% of oral dose within 24 hr.

Sedimentation rate:  Male / Female.  Wintrobe:  0-5 mm/hr / 0-15 mm/hr.   Westergren: 0-15 mm/hr / 0-20 mm/hr.

Transferrin saturation, serum: 20%-50%.

Volume:  Male / Female.  Blood:  52-83 ml/kg / 50-75 ml/kg.  Plasma: 25-43 ml/kg / 28-45 ml/kg.  Red cell: 20-36 ml/kg /19-31 ml/kg.

Differential cell count of bone marrow:   Myeloid cells:  Neutrophilic series:  Myeloblasts: 0.3%-5.0%, Promyelocytes:  1%-8%, Myelocytes:  5%-19%, Metamyelocytes:  9%-24%, Bands:  9%-15%, Segmented cells:  7%-30%, Eosinophil precursors:  0.5%-3.0%, Eosinophils:  0.5%-4.0%, Basophilic series:  0.2%-0.7%.

Erythroid cells:  Pronormoblasts:  1%-8%, Polychromatophilic normoblasts    7%-32%, Megakaryocytes: 0.1%.

Lymphoreticular cells:   Lymphocytes:  3%-17%, Plasma cells:  0%-2%, Reticulum cells:  0.1%-2.0%, Monocytes:  0.5%-5.0%, Myeloid/erythroid ratio:  0.6-2.7.

Endocrine Labs:

Adrenocorticotropin (ACTH):  15-100 pg/ml

Calcitonin:  Basal @ 0.15-0.35 ng/ml, stimulated @ <0.6 ng/ml.

Catecholamines, free urinary:  <110 µg/24 hr

Chorionic gonadotropin (hCG):   Pregnancy 1st mo @ 10-10,000 mIU/ml, 2nd-3rd @ 10,000-100,000 mIU/ml.  2nd trimester @ 10,000-30,000 mIU/ml, 3rd trimester @ 5000-15,000 mIU/ml.  Nonpregnant @ ❤ mIU/ml.

Cortisol:  8 AM @ 5-25 µg/dl, 8 PM @<10 µg/dl.   Cosyntropin stimulation @ >10 µg/dl rise over baseline (30-90 min after 0.25 mg cosyntropin IM/IV).  Overnight suppression (8 AM  after 1 mg dexamethasone PO at 11 PM) @ 5 µg/dl.   Urine @ 20-70 µg/24 hr.

C-peptide:  0.28-0.63 pmol/ml.

11-Deoxycortisol:  Basal @ 0-1.4 µg/dl.  Metyrapone stimulation (30 mg/kg PO 8 hr prior to level) @ >7.5 µg/dl.

Epinephrine, plasma:  <35 pg/ml.

Estradiol:  Male @ 20-50 pg/ml.  Female @ 25-200 pg/ml.

Estrogens, urine:  inc during pregnancy, dec after menopause.  Male / Female.   Total @ 4-25 µg/24 hr / 5-100 µg/24 hr.  Estriol @ 1-11 µg/24 hr / 0-65 µg/24 hr. Estradiol @ 0-6 µg/24 hr / 0-l4 µg/24 hr.  Estrone @ 3-8 µg/24 hr / 4-31 µg/24 hr.

Etiocholanolone, serum: <1.2 µg/dl.

Follicle-stimulating hormone (FSH):  Male @ 2-18 mIU/ml.  Female Follicular phase @ 5-20 mIU/ml.  Peak midcycle @ 30-50 mIU/ml.  Luteal phase @ 5-15 mIU/ml.  Postmenopausal  @ >50 mIU/ml.

Free thyroxine index: 1-4 ng/dl.

Gastrin, serum (fasting): 30-200 pg/ml.

Growth hormone:   Adult, fasting @ <5 ng/ml.  Glucose load (100 g orally) @ <5 ng/ml.

Levodopa stimulation test: serum growth hormone after 0.5 g (500mg) levodopa PO while fasting @ >5 ng/ml rise over baseline within 2hr.

17-Hydroxycorticosteroids, urine:  Male @ 2-12 mg/24 hr.  Female @ 2-8 mg/24 hr.

5′-Hydroxyindoleacetic acid (5′-HIAA), urine: 2-9 mg/24 hr.

Insulin, plasma:  Fasting @ 6-20 µU/ml.  Hypoglycemia (serum glucose <50 mg/dl) @ <5 µU/ml.

17-Ketosteroids, urine:  <8 yo @ 0-2 mg/24 hr.  Adolescent @ 0-18 mg/24 hr.  Adult Male @ 8-18 mg/24 hr.  Female @ 5-15 mg/24 hr.

Luteinizing hormone (LH):  Male adult @ 2-18 mIU/ml.   Female adult Basal @ 5-22 mIU/ml, Ovulation @ 30-250 mIU/ml, Postmenopausal @ >30 mIU/ml.

Metanephrines, urine:  <1.3 mg/24 hr.

Norepinephrine:  Plasma @ 150-450 pg/ml.  Urine @ <100 µg/24 hr.

Parathyroid hormone:  C-terminal @ 150-350 pg/ml.  N-terminal @ 230-630 pg/ml.

Pregnanediol, urine:  Female Follicular phase @ <1.5 mg/24 hr, Luteal phase @ 2.0-4.2 mg/24 hr,  Postmenopausal @ 0.2-1.0 mg/24 hr.  Male @<1.5 mg/24 hr.

Progesterone:  Female Follicular phase @ 0.02-0.9 ng/ml, Luteal phase @ 6-30 ng/ml.  Male @ <2 ng/ml.

Prolactin:  Nonpregnant day @ 5-25 ng/ml, night @ 20-40 ng/ml.   Pregnant @ 150-200 ng/ml.

Radioactive iodine (131I) uptake (RAIU): 5%-25% at 24 hr (varies with iodine intake).

Testosterone, total plasma:  Bound in adolescent male @ <100 ng/dl.  Adult male @ 300-1100 ng/dl.  Female @ 25-90 ng/dl.  Unbound adult male @ 3-24 ng/dl. Female @ 0.09-1.30 ng/dl.

Thyroid-stimulating hormone:  <10 µU/ml.

Thyroxine (T4):  Total @ 4-11 µg/dl,  Free @ 0.8-2.4 ng/dl.

Thyroxine-binding globulin capacity: 15-25 µg T4/dl.

Thyroxine index, free:  1-4 ng/dl.

Tri-iodothyronine (T3):  70-190 ng/dl.

T3 resin uptake:  25%-45%.

Vanillylmandelic acid (VMA), urine:  1-8 mg/24 hr.

Glucocorticoid suppression:  overnight dexamethasone suppression test (8 AM serum cortisol after 1 mg dexamethasone orally at 11 PM) @ 5 µg/dl.

Glucocorticoid stimulation: cosyntropin stimulation test (serum cortisol 30-90 min after 0.25 mg cosyntropin IM or IV) @ >10 µg/ml more than baseline serum cortisol.

Metyrapone test:  8 AM serum deoxycortisol after 30 mg/kg metyrapone PO at midnight)@ >7.5 µg/dl.

Aldosterone suppression: sodium depletion test (urine aldosterone collected on day 3 of 200 mEq day/sodium diet) @ <20 µg/24 hr.

Glucose tolerance test:  serum glucose after 100 g glucose PO.  60 min after ingestion @ <180 mg/dl.  90 min @ <160 mg/dl.  120 min @ <125 mg/dl.  Add 10 mg/dl for each decade over 50 years of age.

Growth hormone suppression: glucose tolerance test (serum growth hormone after 100g glucose orally after 8 hr fast) @ <5 ng/ml within 2 hr.

Luteinizing hormone (LH) stimulation: gonadotropin releasing hormone (GnRH) test (serum LH after 100 µg GnRH IM/IV) @ 4- to 6-fold rise over baseline.

Thyroid-stimulating hormone (TSH) stimulation: thyrotropin-releasing hormone (TRH) stimulation test (serum TSH after 400 µg TRH IV) @ >2-fold rise over baseline within 2hr.

Radioactive iodine uptake (RAIU): suppression test (RAIU on day 7 after 25 µg tri-iodothyronine PO 4 times daily) @ <10% to <50% baseline.

Commonly Used Abbreviations:   Links:  E:   J:  N:  S:

1/2 NS = 0.45% saline solution

5-HIAA = 5-hydroxyindoleacetic acid

5-HT = serotonin

17-OHCS = 17-hydroxcorticosteroids

AAA = apply to affected area, abd aortic aneurysm

ac = ante cibum (before meals)

ABG = arterial blood gas

Ab = antibody

ABI = ankle brachial index (in PVD)

Abx = antibiotics

ac = before meals

ACD = anemia of chronic dz

ACT = activated clotting time

ACTH = adrenocorticotropic hormone

Ad = R ear (aurio dextra)

ad lib = as needed or desired

AD = autosomal dominant

ADH = antidiuretic hormone

ADL = activities of daily living

AF = atrial fibrillation

AFB = acid fast bacillus

AK = actinic keratosis

AP = alkaline phosphatase

AR – autosomal recessive

ALL = acute lymphocytic leukemia

ALT = alanine amino-transferase

am = morning

AMA = against medical advice

AMI = acute myocardial infarction

AML = acute myelogenous leukemia

amp = ampule

AMV = assisted mandatory (mode) ventilation

ANA = antinuclear antibody

ante = before

AP = anteroposterior, alk phos

AR = autosomal recessive

ARB = angiotensin receptor blocker

ARDS = adult respiratory distress syndrome

ARF = acute renal failure

ASA = acetylsalicylic acid, aspirin

ASO = antistreptolysin

AST = aspartate amino-transferase

AVB = atriovenous block

AVM = atrial venous malformation

AVN = avascular necrosis

BAL = blood alcohol level

BBB = bundle branch block

BCC = basal cell carcinoma

BID = bis in die (twice a day)

B12 = vitamin B-12

BM = bowel movement, bone marrow

BMD = bone mineral density

BMR = basal metabolic rate

BMT = bone marrow transplant

BP = blood pressure

BPH = benign prostatic hypertrophy

BS = bowel sounds

BUN = blood urea nitrogen

BSA = body surface area

Bx = biopsy

CA = cancer

Cal = calorie (kilocalorie)

c/o = complaint of

c cum (with)

C/ S or C & S = culture and sensitivity

C = centigrade

Ca = calcium

CAD = coronary artery disease

cap = capsule

CBC = complete blood count

CBZ = carbamezapine

cc = cubic centimeter, creatinine clearance

CCB = calcium channel blocker

CCU = coronary care unit

CF = cystic fibrosis

CFU = colony forming units

Chem 7  = basic metabolic panel, 17 = comprehensive, which includes electrolytes, renal and liver function tests.  New Medicare Labs:  **Electrolyte Panel (#4): Na, K, Cl, CO2.  **BMP: #8: Chem 7 with Ca.   **Renal Panel: #10 BMP + Alb & PO4.   **CMP #14: BMP + Alb, AP, AST, ALT, Tb, Dbili.   **ECMP #17: CMP +Mg, P, LDH.  **Hepatic: Alb, Tbili, Dbili, AP, Tp, ALT, AST.

cm = centimeter

CMV = cytomegalovirus

CNS = central nervous system

CO2 = carbon dioxide

COPD = chronic obstr pulm dz

CP = chest pain

CPK-MB = myocardial-specific CPK

Cr = creatinine

CrCl = creatinine clearance

CRF = chronic renal failure

CSF = cerebrospinal fluid

CT = computerized tomography

CTA = cotton tip applicator

CTD = connective tissue disease

CTX = contraction

CV = cardiovascular

CVA = cerebrovascular accident, costovertebral angle

CVD = cardiovascular disease

CVP = central venous pressure

Cx = culture

CXR = chest x-ray

DA = dopamine

d/c = discharge or discontinue

D5W = 5% dextrose water solution

DBP = diastolic blood pressure

DIC = dissemin. Intravasc Coagulation

Diff = differential cell count

DHP = dihydropteridine

DJD = degenerative joint disease

DKA = diabetic ketoacidosis

dL = deciliter

DM = diabetes mellitus

DNR = do not resuscitate

DOC = drug of choice

DOE = dyspnea on exertion

DOT = directly observed therapy

Doxy = doxycycline

DT’s = delirium tremens

DTR = deep tendon reflex

DVT = deep vein thrombosis

Dx = diagnosis

Ddx = differential diagnosis

DUB = dysfunctional uterine bleeding

Dz = disease

EBV = Epstein Barr virus

ECG = electrocardiogram = EKG

ECT = electroconvulsive therapy

EDC = estimated date of confinement (due date)

EE = ethinyl estradiol

EEG = electroencephalogram

EGA = estimated gestational age

ELISA = enzyme-linked immunoabsorbant assay

EM = erythema multiforme

EMB = endometrial biopsy

Emyc = erythromycin

EPO = erythropoietin

EPS = extra pyramidal symptoms

ERCP = endoscopic retrograde cholangiopancreatography

ERT = estrogen replacement therapy

ESR = erythrocyte sedimentation rate

ET = endotracheal tube

ETD = eustachian tube dysfunction

ETOH = alcohol

Fb = foreign body

FBS = fasting blood sugar

F/C = fever and chills

FEV1 = forced expiratory volume (1 sec)

FHT/ FHR = fetal heart tones/ rate

FiO2 = fractional inspired oxygen

FOB = fecal occult blood

FSP = fibrin split product

FVC = functional vital capacity

Fx = fracture

G = gram(s)

GC = gonococcal; gonococcus

GBS = GBBHS = Group B Beta Hem Strep

GFR = glomerular filtration rate

GH = growth hormone

GI = gastrointestinal

gm = gram

GN = glomerular nephritis

gt = drop

gtt = drops

GU = genitourinary

h or hr = hour

H20 = water

HA = headache

Hb = hemoglobin concentration

HCO3 = bicarbonate

HCG = human chorionic gonadotropin

HCT hematocrit

HCTZ = hydrochlorothiazide or hydrocortisone

HCW = Health Care Worker

HDL = high-density lipoprotein

HF = heart failure

Hg = mercury

HI = homicidal ideation

HIV = human immunodeficiency virus

hr = hour

HOCM = HCM = hypertrophic cardiomyopathy

HR = heart rate

HRT = hormone replacement therapy

HS = hora somni (bedtime)

HSM = hepato-splenomegaly

HSP = Henoch-Schonlein purpura

HTN = hypertension

HUS = hemolytic uremic syndrome

Hx = history

ICP = intracranial pressure

IBD = inflammatory bowel disease

IBS = irritable bowel syndrome

ICP = intracranial pressure

IDA = iron deficiency anemia

ILD = interstitial lung disease

IM = intramuscular

I & D = incision and drainage

I & O =intake and output

IOP = intraocular pressure

IU = international units

ICU = intensive care unit

IgM = immunoglobulin M

IMV = intermittent mandatory ventilation

INH = isoniazid

INI = if not improved, RTC.

INR = International normalized ratio

IV = intravenous or intravenously

IVD = intravenous drug

IVF = intravenous fluids, in-vitro fertilization

IVP = intravenous pyelogram, intravenous piggyback

JRA = juvenile rheumatoid arthritis

K = potassium

kcal = kilocalorie

KCL = potassium chloride

KOH = potassium hydroxide

KUB = x-ray of abdomen

L = liter

LBBB = left bundle branch block

LPB = lower back pain

LDH = lactate dehydrogenase

LDL = low-density lipoprotein

LE = lower extremity

LFT = liver function tests

liq = liquid

LLSB = left lower sternal border

LLQ = left lower quadrant

LMN = lower motor neuron

LMP = last menstrual period

LN2 = liquid nitrogen

LOC = loss of consciosness

LP = lumbar puncture,

LR = lactated Ringer’s

LV = left ventricle

LVH = left ventricular hypertrophy

mEq = milliequivalent

MD = muscular dystrophy

Mg = magnesium, milligram, myasthenia gravis

MgSO4 = Magnesium Sulfate

MI = myocardial infarction

MIC = minimum inhibitory concentration

mL = milliliter

mm = millimeter, multiple myeloma

MOM = Milk of Magnesia

MR = mitral regurg

MRI = magnetic resonance imaging

MS = mitral stenosis, multiple sclerosis, mental status, morphine sulfate

MSE = mental status exam

MTX = methotrexate

MVP mitral valve prolapse

Na = sodium

NaHCO3 = sodium bicarbonate

NE = norepinephrine

Neuro = neurologic

NCV = nerve conduction velocity

NGT = nasogastric tube

NKA = no known allergies

NM(J) = neuro muscular (junction)

NMT = no more than (maximum dose)

NLT = no less than (minimum age to use drug)

NPH = neutral protamine, normal pressure hydrocephalus

NPO = nulla per os (nothing by mouth)

NS = normal saline solution (0.9%)

NSAIDs = nonsteroidal anti-inflammatory drugs

NTG = nitroglycerine

N/V/D = nausea, vomiting, diarrhea

NWB = non-weight bearing.

OCD = obsessive compulsive disorder

OCP = oral contraceptive pill

OD = right eye, overdose, optometrist

oint = ointment

OS = left eye (oculus sinister)

Osm = osmolality

OT = occupational therapy

OTC = over the counter

OU = each eye

oz = ounce

p = post after, Phosphate

pc = post cibum (after meals)

PA = posteroanterior, pulmonary artery

PAC = premature atrial contraction

PaO2 = arterial oxygen pressure

pAO2 = partial pressure of oxygen

pc = after meals

PCA = patient controlled anesthesia

PCN = penicillin

pCO2 = partial pressure of carbon dioxide

PE = pulmonary embolism, physical exam

PEEP positive end-expiratory pressure

per = by

PFS = patella-femoral syndrome

PFT = pulmonary function test

PG or PGE = prostaglandin

pH = hydrogen ion concentration (H+)

PID = pelvic inflammatory disease

pm = afternoon

PND = paroxysmal nocturnal dyspnea

PO = orally, per os

pO2 = partial pressure of oxygen

Post cib = after meals (post cibos)

polys = polymorphonuclear leukocytes

PP = pathophysiology

PPD = purified protein derivative

PPI = proton pump inhibitor

PR = per rectum

prn = pro re nata (as needed)

PT = physical therapy, pro-thrombin time

PTCA = percutaneous transluminal coronary angioplasty

PTT = partial thromboplastin time

PV or Px = prevention

PUD = peptic ulcer disease

PVC = premature ventricular contraction

PVD = peripheral vascular disease

q = (every) q6h, q2h every 6 hours, every 2h

QID = quarter in die (four times a day)

qAM = every morning

qd = quaque die (every day)

qh = every hour

qHS = every night before bedtime

QID = 4 times a day

Ql = as much as desired (quantum libet)

QOD = every other day

qs = quantity sufficient

qt = quart

R = right

RAD = right axis deviation

RAE = right atrial enlargement

R/O = rule out

RA = rheumatoid arthritis, room air, right atrial

RAST = radioallergosorbent test

RF = rheumatic fever

RMSF = rocky mountain spotted fever

RPR = syphilis test

RR = Respiratory rate

ROM = range of motion

RSD = reflex sympathetic dystrophy

RTA = renal tubular acidosis

RTC = return to clinic (pt to come back)

RV = right ventricle, residual volume

s = sine (without)

s/p = status post

sat = saturated

SBE: subacute bacterial endocarditis

SBP = systolic blood pressure

SC = subcutaneously

SE = side effect

SED = SE discussed (chart if start a new med), ESR

SES = socioeconomic status

SI = suicidal ideation

SIADH = syndrome of inappropriate antidiuretic hormone

SJS = Stevens Johnson syndrome

SK = seborrheic keratosis

SL = sublingually under tongue

SLE = systemic lupus erythematosus, slit lamp exam

SMA-7, 10, 17 = sequential multiple analysis

SMX = sulfamethoxazole

SOB = shortness of breath = DOE

sol = solution

SPEP = serum protein electrophoresis

SQ = under the skin

SR = sustained release

S(S)RI = selective serotonin reuptake inhibitor

S/s = signs and symptoms of disease

SSC = squamous cell carcinoma

STAT = statim (immediately)

STD = sexually transmitted disease

susp = suspension

T-½ = half life (of a drug)

TCN = tetracycline

TID = ter in die (three times a day)

T4 = Thyroxine level

tab = tablet

TB = tuberculosis

Tbsp = tablespoon

TCA = tricyclic antidepressant

Temp = temperature

TIA = transient ischemic attack

TKO = to keep open, an infusion rate (~500 mL/24h) just enough to keep the IV from clotting, not the same as saline lock or Heplock.

TL = toxic level

TMJ = temporomandibular joint

TMP = trimethoprim

TMP-SMX = trimethoprim-sulfa-methoxazole

TPA = tissue plasminogen activator

TS/ TR = tricuspid stenosis/ regurge

TSH thyroid-stimulating hormone

tsp = teaspoon

TPN = total parenteral nutrition

TSS = toxic shock syndrome

TT = thrombin time

TTP = tender to palpation

Tx = treatment

U = units

UA = uric acid

U/A or Ua = urinalysis

UC = ulcerative colitis

UD = as directed

UDS = urine drug screen (tox)

ug = microgram

UFH = unfractionated heparin

ULN = upper limits of normal

um = micrometer

UO = urine output

URI = upper respiratory infection

UPEP = urine protein electrophoresis

U/S = ultrasound

UTI = urinary tract infection

UV = ultraviolet light

V = vitamin, V-C, V-E, V-B6 etc

VAC vincristine, adriamycin, and cyclophosphamide

vag = vaginal

VC = vital capacity

VDRL = Venereal Disease Research Laboratory

V fib = ventricular fibrillation

VGE = viral gastroenteritis

VLDL = very low-density lipoprotein

Vol = volume

VS = vital signs

VSD = ventricular septal defect

VT = ventricular tachycardia

WBC = white blood count

X = times

Zn = zinc


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Harrison’s Manual of Medicine




Adverse drug reactions are among the most frequent problems encountered clinically and represent a common cause for hospitalization. They occur most frequent in pts receiving multiple drugs and are caused by

Errors in self-administration of prescribed drugs (quite common in the elderly).

Exaggeration of intended pharmacologic effect (e.g., hypotension in a pt given antihypertensive drugs).

Concomitant administration of drugs with synergistic effects (e.g., aspirin and warfarin).

Cytotoxic reactions (e.g., hepatic necrosis due to acetaminophen).

Immunologic mechanisms (e.g., quinidine-induced thrombocytopenia, hydralazine-induced SLE).

Genetically determined enzymatic defects (e.g., primaquine-induced hemolytic anemia in G6PD deficiency).

Idiosyncratic reactions (e.g., chloramphenicol-induced aplastic anemia).
RECOGNITION   History is of prime importance. Consider (1) nonprescription drugs and topical agents as potential offenders; (2) previous reaction to identical drugs; (3) temporal association between drug administration and development of clinical manifestations; (4) subsidence of manifestations when the agent is discontinued or reduced in dose; (5) recurrence of manifestations with cautious readministration (for less hazardous reactions); (6) rare: (a) biochemical abnormalities, e.g., red cell G6PD deficiency as cause of drug-induced hemolytic anemia, (b) abnormal serum antibody in pts with agranulocytosis, thrombocytopenia, hemolytic anemia.
Table 202-1 lists a number of clinical manifestations of adverse effects of drugs. It is not designed to be complete or exhaustive.

Table 202-1

Clinical Manifestations of Adverse Reactions to Drugs


Iodinated drugs or contrast media
ACE inhibitors
Drug-induced lupus erythematosus
Aminosalicylic acid
Amphotericin B
Serum sickness

Addisonian-like syndrome
Galactorrhea (may also cause amenorrhea)
Tricyclic antidepressants
Calcium channel antagonists
Sexual dysfunction
Beta blockers
Major tranquilizers
Oral contraceptives
Thyroid function tests, disorders of
Colestipol and nicotinic acid
Gold salts
Oral contraceptives

Antacids with absorbable alkali
Vitamin D
Ethacrynic acid
Growth hormone
Oral contraceptives
Oral hypoglycemics
ACE inhibitors
Digitalis overdose
Potassium preparations including salt substitute
Potassium salts of drugs
Alkali-induced alkalosis
Amphotericin B
Laxative abuse
Mineralocorticoids, some glucocorticoids
Osmotic diuretics
Vitamin B12
Ethacrynic acid


Salt wasting
Metabolic acidosis

Anabolic and androgenic steroids
Oral contraceptives
Oral contraceptives (withdrawal)
Cream and lotion perservatives
Topical antihistamines
Topical antimicrobials
Topical local anesthetics
Erythema multiforme or Steven Johnson syndrome
Erythema nodosum
Oral contraceptives
Exfoliative dermatitis
Gold salts
Fixed drug eruptions
Chloroquine and other antimalarials
Gold salts
Hypervitaminosis A
Oral contraceptives
Lichenoid eruptions
Aminosalicylic acid
Gold salts
Nalidixic acid
Oral contraceptives
Tetracyclines, particularly demeclocycline
Purpura (see also thrombocytopenia)
Rashes (nonspecific)
Skin necrosis
Toxic epidermal necrolysis (bullous)
Nalidixic acid

Agranulocytosis (see also Pancytopenia)
Gold salts
Tricyclic antidepressants
Clotting abnormalities/hypothrombinemia
Aminosalicylic acid
Erythromycin estolate
Hemolytic anemia
Aminosalicylic acid
Mefenamic acid
Hemolytic anemias in G6PD deficiency
See Table 58-3
Megaloblastic anemia
Folate antagonists
Nitrous oxide
Oral contraceptives
Pancytopenia (aplastic anemia)
Gold salts
Zidovudine (AZT)
Pure red cell aplasia
Thrombocytopenia (see also Pancytopenia)
Gold salts
Phenytoin and other hydantoins

Angina exacerbation
Alpha blockers
Beta blocker withdrawal
Excessive thyroxine
Antiarrhythmic drugs
Beta blockers
Thyroid hormone
Tricyclic antidepressants
AV block
Fluid retention or congestive heart failure
Beta blockers
Calcium antagonists
Calcium antagonists
Citrated blood
Clonidine withdrawal
Monoamine oxidase inhibitors with sympathomimetics
Oral contraceptives
Tricyclic antidepressants with sympathomimetics
Oral contraceptives

Airway obstruction
Beta blockers
Cholinergic drugs
Tartrazine (drugs with yellow dye)
ACE inhibitors
Pulmonary edema
Contrast media
Pulmonary infiltrates
Carmustine (BCNU)
Mitomycin C

Cholestatic jaundice
Anabolic steroids
Erythromycin estolate
Gold salts
Oral contraceptives
Constipation or ileus
Aluminum hydroxide
Barium sulfate
Calcium carbonate
Ferrous sulfate
Ion exchange resins
Tricyclic antidepressants
Diarrhea or colitis
Antibiotics (broad-spectrum)
Magnesium in antacids
Diffuse hepatocellular damage
Acetaminophen (paracetamol)
Aminosalicylic acid
Erythromycin estolate
Monoamine oxidase inhibitors
Sodium valproate
Zidovudine (AZT)
Intestinal ulceration
Solid KCl preparations
Aminosalicylic acid
Antibiotics (broad-spectrum)
Nausea or vomiting
Ferrous sulfate
Potassium chloride
Oral conditions

Gingival hyperplasia
Calcium antagonists

Salivary gland swelling

Taste disturbances

Gentian violet
Isoproterenol (sublingual)
Ethacrynic acid
Oral contraceptives
Peptic ulceration or hemorrhage
Ethacrynic acid

Bladder dysfunction
Monoamine oxidase inhibitors
Tricyclic antidepressants
Vitamin D
Concentrating defect with polyuria (or nephrogenic diabetes insipidus)
Vitamin D
Hemorrhagic cystitis
Interstitial nephritis
Penicillins, esp. methicillin
Due to analgesics (e.g., phenacetin)
Nephrotic syndrome
Gold salts
Obstructive uropathy
Extrarenal: methysergide
Intrarenal: cytotoxics
Renal dysfunction
Renal tubular acidosis
Amphotericin B
Degraded tetracycline
Tubular necrosis
Amphotericin B
Radioiodinated contrast medium

Exacerbation of myasthenia
Extrapyramidal effects
Butyrophenones, e.g., haloperidol
Oral contraceptives
Tricyclic antidepressants
Ergotamine (withdrawal)
Glyceryl trinitrate
Peripheral neuropathy
Nalidixic acid
Polymyxin, colistin
Tricyclic antidepressants
Pseudotumor cerebri (or intracranial hypertension)
Glucocorticoids, mineralocorticoids
Hypervitaminosis A
Oral contraceptives
Nalidixic acid
Tricyclic antidepressants
Oral contraceptives

Color vision alteration
Corneal edema
Oral contraceptives
Corneal opacities
Vitamin D
Optic neuritis
Aminosalicylic acid

Ethacrynic acid
Vestibular disorders

Bone disorders


Aluminum hydroxide
Myopathy or myalgia
Amphotericin B
Oral contraceptives

Delirious or confusional states
Sedatives and hypnotics
Amphetamine withdrawal
Beta blockers
Centrally acting antihypertensives (reserpine, methyldopa, clonidine)
Anxiolytic drugs
Major tranquilizers
Tricyclic antidepressants
Hallucinatory states
Beta blockers
Tricyclic antidepressants
Hypomania, mania, or excited reactions
Monoamine oxidase inhibitors
Tricyclic antidepressants
Schizophrenic-like or paranoid reactions
Lysergic acid
Monoamine oxidase inhibitors
Tricyclic antidepressants
Sleep disturbances
Monoamine oxidase inhibitors

SOURCE: Adapted from AJJ Wood: HPIM-15, pp. 432–436.


For a more detailed discussion, see Wood AJJ: Adverse Reactions to Drugs, Chap. 71, p. 430, in HPIM-15.

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Harrison’s Manual of Medicine



Clinical Features

Narcotics, or opiates, bind to specific opioid receptors in the CNS and elsewhere in the body. These receptors mediate the opiate effects of analgesia, euphoria, respiratory depression, and constipation. Endogenous opiate peptides (enkephalins and endorphins) are natural ligands for the opioid receptors and play a role in analgesia, memory, learning, reward, mood regulation, and stress tolerance.
The prototypic opiates, morphine and codeine, are derived from the juice of the opium poppy, Papaver somniferum. The semisynthetic drugs produced from morphine include hydromorphone (Dilaudid), diacetylmorphine (heroin), and oxycodone. Purely synthetic agents are meperidine (Demerol), propoxyphene (Darvon), and methadone. All of these substances produce analgesia and euphoria as well as physical dependence when taken in high enough doses for prolonged periods of time.
1% of the U.S. population meets criteria for narcotic abuse or dependence at some time in their lives. 70% of narcotic-addicted individuals have another psychiatric disorder (usually major depression, alcoholism, or a personality disorder). Three groups of abusers can be identified: (1) “medical” abusers—pts with chronic pain syndromes who misuse their prescribed analgesics; (2) physicians, nurses, dentists, and pharmacists with easy access to narcotics; and (3) “street” abusers. The street abuser is typically a higher functioning individual who began by using tobacco, alcohol, and marijuana and then moved on to opiates.
Clinical Features
Acutely, all opiates have the following CNS effects: sedation, euphoria, decreased pain perception, decreased respiratory drive, and vomiting. In larger doses, markedly decreased respirations, bradycardia, pupillary miosis, stupor, and coma ensue. Additionally, the adulterants used to “cut” street drugs (quinine, phenacetin, strychnine, antipyrine, caffeine, powdered milk) can produce permanent neurologic damage, including peripheral neuropathy, amblyopia, and myelopathy. The shared use of contaminated needles is a major cause of brain abscesses, acute endocarditis, hepatitis B, AIDS, septic arthritis, and soft tissue infections. At least 25% of street abusers die within 10–20 years of starting active opiate abuse.
Chronic use of opiates will result in tolerance (requiring higher doses to achieve psychotropic effects) and physical dependence. With shorter-acting opiates such as heroin, morphine, or oxycodone, withdrawal signs begin 8–12 h after the last dose, peak at 2–3 days, and subside over 7–10 days. With longer- acting opiates such as methadone, withdrawal begins 2–4 days after the last dose, peaks at 3–4 days, and lasts several weeks.
Withdrawal produces diarrhea, coughing, lacrimation, rhinorrhea, diaphoresis, twitching muscles, piloerection, fever, tachypnea, hypertension, diffuse body pain, insomnia, and yawning. Relief of these exceedingly unpleasant symptoms by narcotic administration leads to more frequent narcotic use. Eventually, all of the person’s efforts are consumed by drug-seeking behavior.

Overdose High doses of opiates, whether taken in a suicide attempt or accidentally when the potency is misjudged, are frequently lethal. Toxicity occurs immediately after IV administration and with a variable delay after oral ingestion. Symptoms include miosis, shallow respirations, bradycardia, hypothermia, stupor or coma, and pulmonary edema. Treatment requires cardiorespiratory support and administration of the opiate antagonist naloxone (0.4 mg IV repeated in 3–10 min if no or only partial response). Because the effects of naloxone diminish in 2–3 h compared with longer-lasting effects of heroin (up to 24 h) or methadone (up to 72 h), pts must be observed for at least 1–3 days for reappearance of the toxic state.
Withdrawal or Abstinence Syndromes Clonidine is effective in decreasing the sympathetic nervous system hyperactivity observed in opiate withdrawal. Doses of 0.3–0.5 mg/d are used for the 2–3 weeks of the withdrawal period. Although it is highly unpleasant, opiate withdrawal is not physically dangerous or life-threatening per se in adults (unlike alcohol withdrawal). However, withdrawal syndromes in newborns of street abusers are fatal in 3–30% of cases.
Methadone maintenance (to avoid withdrawal or abstinence syndromes) is a widely used treatment strategy in the management of opiate addiction. Long-acting oral methadone is most convenient: 1 mg methadone is equivalent to 3 mg morphine, 1 mg heroin, or 20 mg meperidine. Most patients receive 10–25 mg methadone bid, with higher doses given if withdrawal symptoms break through. Although methadone has mood-elevating effects in some individuals, maintenance nevertheless leads to reduced opiate and nonopiate drug use, reduced criminal behavior, and decreased symptoms of depression.
L-Alpha-acetylmethadol (LAAM) is a long-acting synthetic narcotic that may be given only 3 times a week; however, some pts experience nervousness and stimulation on LAAM. Buprenorphine is a partial receptor agonist that blocks some of the subjective effects of narcotics and may be as effective as low-dose methadone in maintenance treatment.
To help prevent relapses in the abstinent pt, the oral antagonist naltrexone is used in doses of 50–150 mg/d. It blocks the euphoric and analgesic effects of the opiate when a pt relapses and uses narcotics.
Chronic Pain Syndromes   Physicians should avoid encouraging narcotic addiction in pts with established chronic pain syndromes (this is to be distinguished from prescribing adequate analgesia in pts with acute pain). Once tolerance and physical dependence are established in the pt with a chronic pain syndrome, withdrawal and abstinence syndromes will intensify the pt’s pain and confuse the management of an already difficult problem. Pts should be educated that medications will be used to minimize the effects of pain on their physical function but that they will not abolish the pain entirely. Nonpharmacologic approaches to pain management should also be part of the treatment plan.
Identification of the Chronic Narcotic User Blood and urine screens for opiates, or the naloxone challenge test, can be used to identify chronic narcotic users. In the naloxone challenge test, 0.4 mg is given slowly IV over 5 min, and the pt is observed for 1–2 h for signs of withdrawal.
Realistic expectations for rehabilitation are possible only when the pt is motivated to make a long-term commitment to a drug-free lifestyle. Specialized counseling and peer programs, including Narcotics Anonymous, are a mainstay of treatment. In many cases, adjunctive pharmacologic management is helpful, either to block the euphoric effects of opiates or to impede withdrawal/abstinence syndromes (discussed above). Any co-morbid psychiatric diagnoses (the “dual diagnosis” pt) must be evaluated and treated vigorously.
Special issues exist for medical staff. Physicians should never prescribe opiates for themselves or members of their families. Medical organizations need to be prepared to identify and rehabilitate substance-impaired physicians as quickly as possible.


For a more detailed discussion, see Shuckit MA, Segal DS: Opioid Drug Abuse and Dependence, Chap. 388, p. 2567, in HPIM-15.

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Harrison’s Manual of Medicine



Clinical Features
Laboratory Findings

Alcoholism and alcohol abuse are defined by the regular and excessive use of alcohol with concomitant social, occupational, and/or physical problems; alcohol is associated with half of all traffic fatalities and half of all homicides. In alcohol dependence, the regular use of alcohol has resulted in a state of physiologic tolerance and dependence. A pt may never suffer from withdrawal symptoms and still meet criteria for alcohol abuse.
Alcoholism is a multifactorial disorder in which genetic, biologic, and sociocultural factors interact. Typically, the first major life problem from excessive alcohol use appears in early adulthood, followed by periods of exacerbation and remission; the lifespan of the alcoholic is shortened by an average of 15 years due to increased risk of death from heart disease, cancer, accidents, or suicide.
Clinical Features
One out of five of the average physician’s pts will suffer from alcoholism. Routine medical care requires attention to potential alcohol-related illness and to alcoholism itself:

Neurologic—blackouts, seizures, delirium tremens, cerebellar degeneration, neuropathy, myopathy

Gastrointestinal—esophagitis, gastritis, pancreatitis, hepatitis, cirrhosis, GI hemorrhage

Cardiovascular—hypertension, cardiomyopathy

Hematologic—macrocytosis, folate deficiency, thrombocytopenia, leukopenia

Endocrine—gynecomastia, testicular atrophy, amenorrhea, infertility

Skeletal—fractures, osteonecrosis

Cancer—breast cancer, oral and esophageal cancers, rectal cancers.
Most alcoholic pts do not have dramatic physical symptoms but instead present with psychosocial difficulties. Most common are marital difficulties, job problems (tardiness, absenteeism), and legal problems resulting from driving while intoxicated. A positive answer to any of the “CAGE questions” indicates a high probability of alcoholism: Are you . . . Cutting down, or feel the need to? Annoyed when people criticize your drinking? Guilty about your drinking? Eye-opening with a drink in the morning? Typically, pts will describe a host of difficulties but will then deny that they have a problem with alcohol abuse. Denial is a characteristic, if not the core, symptom of alcoholism.
Alcohol is a CNS depressant that acts on receptors for g-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the nervous system. Behavioral, cognitive, and psychomotor changes can occur at blood alcohol levels as low as 4–7 mmol/L (20–30 mg/dL), a level achieved after the ingestion of one or two typical drinks. Mild to moderate intoxication occurs at 17–43 mmol/L (80–200 mg/dL). Incoordination, tremor, ataxia, confusion, stupor, coma, and even death occur at progressively higher blood alcohol levels.
Chronic alcohol use produces CNS dependence. In such individuals, the earliest sign of alcohol withdrawal is tremulousness (“shakes” or “jitters”), which usually occurs 8–24 h after the last drink. This may be followed by generalized seizures (“rum fits”) in the first 24–48 h; these do not require initiation of anti-seizure medications. With severe withdrawal, autonomic hyperactivity ensues (sweating, hypertension, tachycardia, tachypnea, fever), accompanied by insomnia, nightmares, anxiety, and GI symptoms.
Delirium tremens (DTs), which may begin 3–5 days after the last drink, is a very severe withdrawal syndrome characterized by profound autonomic hyperactivity, extreme confusion, agitation, vivid delusions, and hallucinations (often visual and tactile); mortality is 5–15%. Wernicke’s encephalopathy is an alcohol-related syndrome characterized by ataxia, ophthalmoplegia, and confusion, often with associated nystagmus, peripheral neuropathy, cerebellar signs, and hypotension; there is impaired short-term memory, inattention, and emotional lability. Korsakoff’s syndrome follows as the encephalopathy and ocular findings resolve; it is characterized by anterograde and retrograde amnesia and confabulation. Wernicke-Korsakoff’s syndrome is caused by chronic thiamine deficiency, resulting in damage to thalamic nuclei, mamillary bodies, and brainstem and cerebellar structures.
Laboratory Findings
Clues to alcoholism include mild anemia with macrocytosis, folate deficiency, thrombocytopenia, granulocytopenia, abnormal LFTs, hyperuricemia, and elevated triglycerides. Decreases in serum K, Mg, Zn, and PO4 levels are common. Diagnostic studies such as GI radiology or endoscopy, abdominal ultrasound or CT, liver-spleen scan, liver biopsy, ECG, echocardiogram, brain CT or MRI, EEG, and nerve conduction studies may show evidence of alcohol-related organ dysfunction.

Acute Withdrawal Acute alcohol withdrawal is treated with thiamine (50–100 mg IV or 100 mg PO daily for 5 d) to replenish depleted stores; if Wernicke-Korsakoff’s syndrome is suspected, the IV route must be used, since intestinal absorption is unreliable in alcoholics. CNS depressant drugs that enhance GABA-mediated inhibition are used when seizures or autonomic hyperactivity are present. These drugs halt the rapid state of withdrawal in the CNS and allow for a slower, more controlled reduction of the substance. Low-potency benzodiazepines with long half-lives are the medication of choice (e.g., diazepam, chlordiazepoxide), because they produce fairly steady blood levels of drug and there is a wide dose range within which to work. These benefits must be weighed against the risk of overmedication and oversedation, which occur less commonly with shorter-acting agents (e.g. oxazepam, lorazepam). Typical doses are diazepam 5–10 mg or chlordiazepoxide 25–50 mg PO every 1–4 h prn objective signs of alcohol withdrawal (such as pulse < 90). Extremely high doses are sometimes required for the chronic alcoholic.
In severe withdrawal or DTs, the physician must also look for evidence of trauma or infection that may be masked by prominent withdrawal symptoms or that contribute to the pt’s debilitated state. Fluid and electrolyte status and blood glucose levels should be closely followed as well. Cardiovascular and hemodynamic monitoring are crucial, as hemodynamic collapse and cardiac arrhythmia are not uncommon.
Recovery and Sobriety The definitive treatment of alcoholism requires a successful confrontation of the pt’s denial, followed by the pt’s motivation to change. It may take multiple encounters between physician and pt over a period of years for a pt to achieve this level of motivation. Once pts commit to treatment, an initial stage of recovery (early abstinence) is followed by ongoing sobriety. The physician should counsel the pt about the need for continued abstinence as a primary treatment goal and about the usefulness of regular participation in self-help resources such as AA (and Alanon for family members).
Once sobriety has been achieved, pts should be evaluated for the presence of any other underlying psychiatric disorder (such as major depression) and vigorously treated. The physician should also recognize the relapsing/remitting nature of alcoholism, and be prepared to help pts reenter treatment periodically.
Disulfiram (Antabuse), a drug that inhibits aldehyde dehydrogenase and results in toxic symptoms (nausea, vomiting, diarrhea, tremor) if the pt consumes alcohol, is used in some centers but is not an effective therapy in the absence of psychosocial intervention. Preliminary studies show that naltrexone and acamprosate may reduce recidivism in abstinent alcoholics.


For a more detailed discussion, see Schuckit MA: Alcohol and Alcoholism, Chap. 387, p. 2561, in HPIM-15.