New Agents In The Treatment Of Sepsis

Recent advances in molecular biology and immunology suggest that the host's inflammatory response to infection contributes substantially to the development of septic shock. Standard sepsis treatment strategies include the use of life support procedures, antibiotics to kill invading bacteria, and surgical procedures to eradicate the nidus of infection. Despite these aggressive measures, the mortality rate of septic shock remains high. The development of new interventions is based on the premise that neutralizing bacterial toxins and the potentially harmful host mediators could stop or slow this syndrome. Researchers have targeted interventions at all three phases of the host's inflammatory responses. Interventions targeting the induction phase include all those against the endotoxin's lipopolysaccharide molecule. This category includes E5 and HA-1A therapy monoclonal antibodies. Therapies targeting cytokine synthesis include pentoxifylline, b-agonists (amrinone and dobutamine), and corticosteroids. Therapies directed against the cascade phase of sepsis include monoclonal antibodies to TNF- and lL-1-receptor antagonist, monoclonal antibodies against the neutrophil CD11/18 adhesion complex, nitric oxide synthase inhibitors, and cyclooxygenase inhibitors.

Currently, none of the therapies aimed at single targets in the inflammatory cascade has been proven to be effective in the treatment of septic shock in humans. In the cases of interventions that are directed at endogenous inflammatory mediators, none of the studies has produced unequivocal benefit in the treatment of sepsis. Great potential danger exists in altering the natural balance of inflammatory mediators. These mediators perform important functions, such as clearing bacterial toxins and the mobilization of the host defenses that control the infection. Attempting to block the harmful effect of inflammatory mediators may compromise host defenses and ultimately worsen the outcome. Successful therapeutic approaches may depend on determining which inflammatory mediators should be inhibited or augmented and when to do so. In almost all the animal models, anti-LPS therapy is only effective if given before or simultaneously with LPS challenge. Thus, it is very unlikely that anti-LPS treatment alone will change outcome in patients in shock and with organ failure. The situations in which these agents may be the most effective are those in which the patients are in early gram-negative sepsis or as a prophylaxis for high-risk patients.

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