Pathogenetic Mechanisms of Septic Shock

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Abstract
Dr. Parrillo (May 20 issue)1 raises an important issue concerning the use of inhibitors of nitric oxide synthase in septic shock in his article “Pathogenetic Mechanisms of Septic Shock.” The view that these inhibitors may be harmful in the treatment of septic shock is based on experiments in animals given 2 to 4 mg of endotoxin per kilogram of body weight. These amounts of endotoxin are 1 million times greater than those that cause cardiovascular changes in humans2. In contrast, only concentrations of endotoxin measurable in picograms per milliliter have been detected in the serum of patients with septic shock. Although the administration of very high doses of endotoxin to animals results in marked cardiac decompensation that is not influenced by or attributable to nitric oxide synthase inhibitors,3 in animals given lower doses of endotoxin or cytokines that are known to mediate septic shock, these inhibitors are potent and potentially useful pressor agents4. In preliminary studies of patients with septic shock, the administration of NG-monomethyl-L-arginine, an inhibitor of nitric oxide synthesis, resulted in a prompt increase in blood pressure5. Although inhibitors of nitric oxide synthase are a novel class of drugs and specific compounds may have unexpected toxic effects, they may be useful for a condition that is difficult to treat and associated with a high mortality.