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Complement components

Disseminated intravascular coagulation

Complement components

Leukocytes attracted to lung tissue

Lysosomal enzymes released from leukocytes

Disseminated intravascular coagulation

Depletion Tissue of clotting damage proteins from clots in capillaries

Increased capillary leakage of plasma

LUNG TISSUE DAMAGE HEMORRHAGE

Figure 28.3 Events in Gram-Negative Septicemia

Macrophages also synthesize and secrete complement, which is activated by endotoxin. Components of activated complement attract leukocytes and cause them to release tissue-damaging lyso-somal enzymes. Activated complement also causes capillaries to leak excessive amounts of plasma. ■ complement, p. 381

The circulating proteins responsible for blood clotting are also activated by endotoxin. Activation causes small clots to form, which plug capillaries, cutting off blood supply and causing tissue necrosis. Paradoxically, this condition, called disseminated intravascular coagulation (DIC), is often accompanied by hemorrhage, bleeding. This is because not enough clotting proteins are left to stop blood from flowing out of damaged blood vessels.

These harmful effects of endotoxemia, endotoxin circulating in the bloodstream, are made worse by the hypotension, low blood pressure, that usually is present. The hypotension is caused by decreased muscular tone of the heart and blood ves sel walls, and the low blood volume that results from leakage of plasma out of the blood vessels. Current evidence indicates that the release of cytokines and their effects on the heart and blood vessels play a key role in causing hypotension in Gramnegative septicemia. Shock results when the blood pressure falls so low that vital organs are no longer supplied with adequate amounts of blood to maintain their function.

Although multiple organs are affected by endotoxemia, the lung is particularly vulnerable to serious, irreversible damage because of its high concentrations of tissue macrophages. Cytokines released from these macrophages in response to endotoxin attract leukocytes, which in turn discharge tissue-destroying enzymes. The resulting damage to lung tissue often results in death of an individual despite successful cure of their infection and correction of shock.

Epidemiology

Gram-negative septicemia is mainly a nosocomial disease, reflecting the high incidence of Gram-negative bacteremia in hospitalized patients with impaired host defenses. Patients with cancers and other malignancies, diabetes, and organ transplants are particularly vulnerable. There is a general trend toward an increasing incidence of the disease that relates to increasing life span, antibiotic suppression of normal flora, immunosuppressive medications, and medical equipment where biofilms readily develop, such as respirators, and catheters placed in blood vessels and the urinary system.

Prevention and Treatment

Prevention of septicemia depends largely on the prompt identification and effective treatment of localized infections, particularly in people whose host defenses are impaired. Also, conditions such as bedsores and pyelonephritis, which commonly lead to septicemia in patients with cancer and diabetes, can usually be prevented. For treatment, antimicrobial medications directed against the causative organism are given. Measures are taken to correct shock and poor oxygenation. Despite these treatments, the mortality rate remains high, generally 30% to 50%, partly because most of the patients have serious underlying conditions. Treatment with monoclonal antibody directed against endotoxin or TNF has shown some benefit when given early in the illness before shock develops. Drotrecogin alpha, another medication being evaluated, is activated human protein C produced by recombinant technology. Protein C normally acts to oppose the effects of cytokines such as TNF and IL-1. Evaluation of these kinds of treatments is difficult because many of the patients have underlying life-threatening illnesses in addition to their septicemia. ■ pyelonephritis, p. 636 ■ monoclonal antibodies, p. 427

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