A Controlled Trial of HA-1A in a Canine Model of Gram-negative Septic Shock

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Abstract
Objectvie. —To investigate the therapeutic efficacy and microbiological and physiological effects of a human IgM monoclonal antibody (HA-1 A) directed against the lipid A component of endotoxin in a canine model of sepsis that simulates the cardiovascular abnormalities of human septic shock. Design. —Blinded, placebo-controlled 28-day trial. Interventions. —Purpose-bred beagles were implanted with an intraperitoneal clot infected withEscherichia coliO111:B4. At clot placement, animals received HA-1A (10 mg.kg-1), control human IgM antibody (10 mg.kg-1), or control human serum albumin intravenously. All animals were given antibiotic and fluid therapy. Measures. —Survival and microbiological and physiological events. Results. —Only two (15%) of 13 animals in the HA-1A group, compared with eight (57%) of 14 control animals (combined control human IgM antibody and control human serum albumin groups) (P=.05), survived 28 days. At 24 hours, the HA-1A group had lower mean arterial pressure (P=.04) and cardiac index (P=.004) and higher lactate levels (P=.05) compared with the combined-controls group. In addition, these parameters in the HA-1A group were significantly more predictive of death. The HA-1 A and combined-controls groups had similar significant increases in the level of endotoxemia and bacteremia. Studies of toxic effects showed no harmful effects of control human IgM antibody in infected animals or HA-1 A in noninfected animals. Conclusion. —In a canine model ofE colisepsis, HA-1 A did not alter levels of bacteremia or endotoxemia and actually decreased survival. If these data are relevant to human septic shock, HA-1 A therapy should be limited until the conditions under which this monoclonal antibody has beneficial or deleterious effects are more completely defined. (JAMA. 1993;269:2221-2227)

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