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Differential susceptibility of rhesus monkeys to high doses of endotoxin

Division of Medicine, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, Texas, Center for Biologics Evaluation and Research, FDA, Bethesda, Maryland, USA

S. Denny

Division of Medicine, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, Texas, Center for Biologics Evaluation and Research, FDA, Bethesda, Maryland, USA

T.M. Cosgriff

Division of Medicine, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, Texas, Center for Biologics Evaluation and Research, FDA, Bethesda, Maryland, USA

H.D. Hochstein

Division of Medicine, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, Texas, Center for Biologics Evaluation and Research, FDA, Bethesda, Maryland, USA

We investigated susceptibility of rhesus monkeys (Macaca mulatta) to Escherichia coli endotoxin (ETX) in two ways. We infused 8 monkeys (group A) with various doses of ETX (1.0-7.5 mg/kg) to assess the effect of dose on shock severity; and we infused 6 monkeys (group B) with 1.0 mg ETX/kg to test biological variability to ETX challenge. Controls were 7 saline-infused monkeys. Systolic pressure, heart rate (HR), temperature, plasma ETX and inflammatory markers — tumor necrosis factor- (TNF), interleukin-1 (IL-1) and IL-6 — were quantified before and at 1.5, 2.5, 6 and 26 h after infusion. The highest plasma concentrations of ETX (at 1.5 h) — < 8% that infused — correlated well with the infused doses. ETX elicited hypotension and increases in HR in all monkeys. Fever did not occur. The degree of hypotension and increase in HR and death did not correlate with ETX dose (or plasma ETX concentrations). The response of inflammatory cytokines to ETX was greater in nonsurvivors than in survivors. The observed low mortality rate (4/14) suggests that rhesus monkeys are rather resistant to high endotoxin concentrations similar to baboons but unlike humans or chimpanzees. The lack of correlation between ETX dose and shock severity suggests that there is a critical ETX concentration in each animal that leads to controllable or uncontrollable cytokine elevation in plasma, with reversible or irreversible shock, and resulting survival or death.

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