A controlled trial of HA-1A in a canine model of gram-negative septic shock
Z. M. Quezado, C. Natanson, D. W. Alling, S. M. Banks, C. A. Koev, R. J. Elin, J. M. Hosseini, J. D. Bacher, R. L. Danner and W. D. Hoffman
Department of Critical Care Medicine, National Institutes of Health, Bethesda, MD 20892.
OBJECTIVE--To investigate the therapeutic efficacy and microbiological and
physiological effects of a human IgM monoclonal antibody (HA-1A) 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 with Escherichia coli O111: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-1A 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-1A
in non-infected animals. CONCLUSION--In a canine model of E coli sepsis,
HA-1A did not alter levels of bacteremia or endotoxemia and actually
decreased survival. If these data are relevant to human septic shock, HA-1A
therapy should be limited until the conditions under which this monoclonal
antibody has beneficial or deleterious effects are more completely defined.
