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Delayed Tumor Necrosis Factor  Blockade Attenuates Pulmonary Dysfunction and Metabolic Acidosis Associated With Experimental Gram-negative Sepsis
Alastair C. J. Windsor, MD;
Patrick G. Mullen, MD;
Ciaran J. Walsh, MD;
Bernard J. Fisher;
Charles R. Blocher;
Gary Jesmok, PhD;
Alpha A. Fowler, III, MD;
Harvey J. Sugerman, MD
Arch Surg. 1994;129(1):80-89.
Abstract
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Objective
To ascertain the effect of delayed tumor necrosis factor  (TNF-) on the evolution of systemic and pulmonary injury after the onset of sepsis.
Design
Prospective controlled trial.
Intervention
Anesthetized swine were made septic with a 1-hour infusion of live Pseudomonas aeruginosa, following which a treatment group received an infusion of anti—TNF- monoclonal antibody (5mg/kg). Control animals received 0.9% saline.
Results
Delayed anti—TNF- treatment had no effect on septic pulmonary hypertension or decline in cardiac output. Late recovery in systemic arterial hypotension was associated with a reversal of arterial acidosis (P<.05 by  test and analysis of variance with Tukey's Studentized Range Test) compared with unprotected septic animals. Septic animals had a significant increase in mean (±SEM) plasma lactate levels at 5 hours compared with baseline values (3.8±0.7 vs 2±0.4, P<.05), but remained unchanged from baseline following anti—TNF- treatment (1.5±0.1 vs 1.6±0.2, not significant). Characteristic septic neutropenia was dramatically reversed by anti—TNF- treatment and was associated with downregulation (P<.05 by test and analysis of variance) of polymorphonuclear neutrophil (PMN) leukocyte CD18 adhesion receptors and reduction (P<.05 by test and analysis of variance) in lung PMN sequestration measured by myeloperoxidase activity. The mean (±SEM) decrease in bronchoalveolar lavage protein indicated an attenuated permeability injury in anti—TNF- animals (septic animals at 5 hours compared with baseline value, 1044 ±270 vs 149 ±28 µg/mL; control animals at 5 hours compared with baseline value, 217±83 vs 129±19 µg/mL; P<.05 by test and analysis of variance).
Conclusions
These data show that delayed anti—TNF- treatment reversed metabolic acidosis associated with sepsis. Furthermore, anti—TNF- treatment reversed septic neutropenia, reduced PMN sequestration, and was associated with attenuated lung injury in a model of fulminant sepsis. This supports evidence of PMN-mediated tissue injury in sepsis and suggests mechanisms for potential therapeutic benefit of anti—TNF- treatment in clinical practice.
(Arch Surg. 1994;129:80-89)
Author Affiliations
From the Departments of Surgery (Drs Windsor, Mullen, Walsh, and Sugerman and Mr Blocher) and Internal Medicine (Mr Fisher and Dr Fowler), Medical College of Virginia, Virginia Commonwealth University, Richmond; and Miles Inc, West Haven, Conn (Dr Jesmok).
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