A controlled trial of HA-1A in a canine model of gram-negative septic shock.
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.


METHODS
Blinded, placebo-controlled 28-day trial.


METHODS
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.


METHODS
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.


CONCLUSIONS
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.
Quezado
Z M
ZM
Department of Critical Care Medicine, National Institutes of Health, Bethesda, MD 20892.
Natanson
C
C
Alling
D W
DW
Banks
S M
SM
Koev
C A
CA
Elin
R J
RJ
Hosseini
J M
JM
Bacher
J D
JD
Danner
R L
RL
Hoffman
W D
WD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D004195:Disease Models, Animal; D004285:Dogs; D004731:Endotoxins / Q000276:immunology*; D004927:Escherichia coli Infections / Q000188:drug therapy; D005260:Female; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D006801:Humans; D007075:Immunoglobulin M / Q000494:pharmacology; D008297:Male; D012709:Serum Albumin / Q000494:pharmacology; D012772:Shock, Septic / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D016019:Survival Analysis
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004731:Endotoxins; D007075:Immunoglobulin M; D012709:Serum Albumin; C068069:nebacumab