GRAM-NEGATIVE BACTEREMIA AND THE SEPSIS CASCADE
More than 300,000 episodes of gram-negative bacteremia occur yearly in the United States, and the incidence of the problem has increased, especially among persons age 65 years and older. Despite the availability of potent antimicrobial drugs and sophisticated life-support facilities, 20% to 25% of all patients with this condition succumb, and approximately 50% of bacteremic patients who also experience severe sepsis expire; among geriatric patients with gram-negative bacteremia in whom severe sepsis and the adult respiratory distress syndrome (ARDS) develop, the mortality rate can approach 90%. Finally, although this chapter focuses on gram-negative bacteremia, it must be emphasized that contemporary studies of blood-borne infection have shown that the prevalence of bacteremia (and the associated sepsis) caused by gram-positive microbes, such as staphylococci and enterococcci, is increasing; indeed, in some recent surveys of bacteremia, the frequency of blood-borne infections due to gram-positive microbes has exceeded that of disease caused by gram-negative organisms.
The urinary tract is the most common source of both community-acquired and nosocomial gram-negative bacteremia. Bacteremia frequently complicates bladder catheterization or surgical manipulation. Gram-negative bacteria can also invade the bloodstream following infection of the lungs (pneumonia), hepatobiliary system (cholecystitis, cholangitis), abdominal cavity (abscess, perforated viscus, peritonitis), skin (decubitus ulcer, surgical wounds, burns), and female reproductive organs (pelvic abscess). In hospitalized patients, bacteremia can result from infected intravascular catheters—both peripheral and central lines. Infected pacemaker wires and endovascular prostheses (cardiac valves, arterial grafts) are uncommon causes of gram-negative bacteremia that are very difficult to cure. On occasion, diagnostic procedures, such as upper gastrointestinal endoscopy, can produce life-threatening hematogenous infection. In some patients, especially those with granulocytopenia, bacteremia can occur in the absence of an apparent focus of infection; in that circumstance, the lower gastrointestinal tract is the source of the problem.
The risk for a gram-negative bacteremia appears to be greatest in patients of advanced age who are hospitalized for long periods of time, who have received prior antimicrobial therapy, and who have serious underlying diseases, such as neoplasms, renal failure, cirrhosis, diabetes mellitus, congestive heart failure, and skin lesions (burns, decubitus ulcers). The incidence of bacteremia has been noted to be up to fourfold greater in geriatric patients than in younger adults; however, underlying diseases and other factors beyond advanced age play substantial roles in placing a geriatric patient at risk. Medical interventions that disrupt host defenses, such as catheterization of the urinary tract, corticosteroid administration, and surgical procedures, clearly increase the likelihood of bacteremia. Nevertheless, granulocytopenia (cell counts of 38°C) or hypothermia (20/min), and tachycardia (>90/min); obviously, SIRS can occur in the absence of an infectious illness, and the condition can be precipitated by pancreatitis, trauma, and burns. Severe sepsis is the presence of sepsis plus evidence of hypotension or hypoperfusion leading to organ dysfunction (e.g., altered mental status, hypoxia, oliguria, increased plasma lactate). Septic shock is severe sepsis plus hypotension and organ dysfunction refractory to fluid resuscitation. These distinctions are useful because data have shown that even if it is precipitated by infection, the sepsis cascade can become self-perpetuating; indeed, by the time that sepsis becomes clinically manifest, the triggering infection may not be apparent. As a result, in the setting of sepsis, severe sepsis, or septic shock, therapies beyond antimicrobials are necessary to increase the likelihood of survival.
Septic shock occurs in 25% to 40% of patients with gram-negative bacteremia, usually within the first 12 hours of infection. Factors that predispose to shock are advanced age, a history of prior therapy with antimicrobials or immunosuppressive agents (corticosteroids, antimetabolites, cytotoxic drugs), and the presence of diabetes mellitus, congestive heart failure, azotemia, or a rapidly fatal illness. The risk for shock does not seem to be influenced by the magnitude of the bacteremia, species of the bacterium, or presence of detectable quantities of endotoxin.
Derived from the cell wall of gram-negative bacteria, endotoxin contains lipopolysaccharide (LPS), outer-membrane structures, and capsular polysaccharides. LPS consists of a core polysaccharide, O (somatic) antigen side chains, and lipid A. LPS plays the central role in precipitating the sepsis cascade; for example, many of the manifestations of sepsis can be induced in laboratory animals by the administration of cell wall fragments, LPS, or lipid A. Of note, the components of gram-positive bacteria that can precipitate sepsis include cell wall constituents (e.g., peptidoglycan) and extracellular products, such as the superantigens, pyrogenic exotoxin A (elaborated by Streptococcus pyogenes), and toxic shock toxin 1 (produced by S. aureus).
Substantial insight into the molecular mechanisms through which endotoxin or LPS precipitates the sepsis cascade has been gained, and new observations concerning mediators of the syndrome and their interactions are being published regularly. In general, once in the circulation, LPS binds to LPS-binding protein (LBP), and the LPS-LBP complex attaches to specific receptors on monocytes and macrophages, stimulating the release of a large number of biologically active molecules. The endogenous mediators induced by LPS-LBP include tumor necrosis factor (TNF), interleukin-1, -2, and -6 (IL-1, IL-2, IL-6), and platelet-activating factor; TNF and IL-1 represent the most important proinflammatory cyokines released in response to LPS. The endogenous mediators in turn activate a variety of cellular and humoral inflammatory systems, including T lymphocytes, neutrophils, platelets, endothelial cells, and the coagulation and complement cascades. Furthermore, endotoxin and the inflammatory mediators increase the expression of nitric oxide synthetase found in vascular smooth muscle; that enzyme in turn results in an overproduction of nitric oxide, a potent vasodilator recently implicated in the pathogensesis of septic shock. The activation of these inflammatory systems leads to DIC, ARDS, and circulatory collapse. With insight into the pathogenesis of septic shock, researchers have attempted to alter the course of the condition by blocking the effects of mediators. Unfortunately, controlled clinical trials have failed to demonstrate a benefit of monoclonal or polyclonal antibodies to endotoxin, monoclonal antibodies to TNF, or antagonists to platelet-activating factor and the IL-1 receptor.
The biologic effects of the potent endogenous mediators result in increased cellular metabolism and therefore increased oxygen requirements. They also produce an increase in capillary permeability, a peripheral vasodilation, a fall in systemic vascular resistance, and a global depression of myocardial contractility. These cardiovascular changes contribute to septic shock. By extension, the goals of therapy of septic shock include a restoration of adequate tissue perfusion and oxygen delivery. The rapid administration of large volumes of fluid is essential. Although the roles of crystalloids versus colloids (e.g., hydroxyethyl starch solutions) remain controversial, the importance of monitoring the progress of fluid administration with a pulmonary artery (Swan-Ganz) catheter is widely accepted. These catheters allow measurements of wedged pulmonary artery pressures and so permit an accurate assessment of left ventricular filling pressures. In general, a wedged pulmonary artery pressure of 12 to 14 mm Hg should be maintained, although higher levels may be required in some patients. An improved mental status, a urine output of 40 to 50 mL/h, and a decline in serum lactate concentration are indicative of a favorable response.
Vasoactive drugs must be administered if volume expansion does not result in a prompt clinical improvement, including a rise in systolic blood pressure to about 100 mm Hg. The adrenergic agent of choice, dopamine, produces a variety of dose-dependent effects on the cardiovascular system. At low doses (2 to 5 g/kg per minute), dopamine raises the heart rate and enhances cardiac contractility, resulting in increases in stroke volume and cardiac index; it also augments renal blood flow and the glomerular filtration rate. At higher doses, dopamine produces generalized vasoconstriction. If hypotension persists despite administration of high doses of dopamine (20 to 25 g/mL), treatment with norepinephrine should be initiated. The roles of other agents, including the combination of dobutamine and norepinephrine, vasopressin, and nitric oxide synthetase inhibitors, remain under study.
To ensure the delivery of sufficient oxygen to tissues, a hemoglobin saturation approaching 100% is essential. To achieve an arterial hemoglobulin saturation of greater than 90%, the arterial oxygen tension must be maintained above 60 mm Hg. Accordingly, endotracheal intubation and mechanical ventilation are usually indicated in patients in whom respiratory insufficiency, progressive hypoxemia, and an arterial oxygen tension of less than 50 mm Hg develop. The addition of positive end-expiratory pressure is often required to maintain an arterial oxygen tension of 60 to 70 mm Hg without increasing the fraction of inspired oxygen to above 50%.
A variety of additional therapeutic interventions are often required to address the multiple manifestations of septic shock: insulin for hyperglycemia; glucose for hypoglycemia; platelet and red blood transfusions for thrombocytopenia with active bleeding; fresh-frozen plasma, platelets, and RBC transfusions for DIC with active bleeding; nasogastric lavage, histamine2-receptor antagonists and RBC transfusions for upper gastrointestinal bleeding; and glucocorticoids for acute adrenal insufficiency, an overlooked condition in this setting that can lead to refractory hypotension. (A.L.E.)
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