PEG-BP-30 MONOTHERAPY ATTENUATES THE CYTOKINE-MEDIATED INFLAMMATORY CASCADE IN BABOON ESCHERICHIA-COLI SEPTIC SHOCK

Septic shock following gram-negative infection is a leading cause of m ortality in critically ill patients, accounting for nearly 200,000 dea ths a year. The exaggerated production of tumor necrosis factor-alpha (TNF alpha) is known to contribute to hemodynamic collapse and the hem atological dyscrasia associated with gram-negative sepsis. Although pr evious studies have shown TNF alpha antibodies and TNF immunoadhesins to be effective in experimental gram-negative sepsis, we postulated th at administration of a novel construct of two modified soluble p55 rec eptors linked to polyethylene glycol (PEG-BP-30) would also attenuate the hemodynamic and hematologic alterations to lethal Escherichia coli septic shock in nonhuman primates. Nine adult female and male baboons (Papio anubis), weighing 10-17 kg, were anesthetized and invasively m onitored. The nine animals were randomized to receive either 0.2 mg/kg body wt PEG-BP-30 (n = 3), 5.0 mg/kg body wt PEG-BP-30 (n = 3), or pl acebo (n = 3). One hour after pretreatment, animals were infused with 5-10 X 10(10) CFU/kg of live E. coli iv and vital signs were recorded for the next 8 hr. Arterial blood was drawn for baseline parameters an d throughout the study to obtain total and differential white blood ce ll and platelet counts and cytokine levels (TNF alpha, IL-1 beta, IL-6 , IL-8). E. coli bacteremic baboons receiving only placebo demonstrate d a significant fall in mean blood pressure and leukopenia. Two of the three animals expired. In contrast, five of the six baboons receiving the PEG-BP-30 survived and these animals exhibited markedly attenuate d declines in blood pressure and leukocyte numbers. Septic baboons als o manifested monophasic plasma TNF alpha, IL-1 beta, IL-6, and IL-8 re sponses that were significantly attenuated by PEG-BP-30 pretreatment i n a dose-dependent manner. We conclude from these data that the admini stration of PEG-BP-30 improves survival and attenuates the TNF alpha-m ediated pathophysiology in E. coli sepsis. (C) 1995 Academic Press, In c.