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Delayed Tumor Necrosis Factor α 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. doi:10.1001/archsurg.1994.01420250092012.
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Objective:  To ascertain the effect of delayed tumor necrosis factor α (TNF-α) 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-α monoclonal antibody (5mg/kg). Control animals received 0.9% saline.

Results:  Delayed anti—TNF-α 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 τ 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-α treatment (1.5±0.1 vs 1.6±0.2, not significant). Characteristic septic neutropenia was dramatically reversed by anti—TNF-α treatment and was associated with downregulation (P<.05 by τ test and analysis of variance) of polymorphonuclear neutrophil (PMN) leukocyte CD18 adhesion receptors and reduction (P<.05 by τ 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-α 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 τ test and analysis of variance).

Conclusions:  These data show that delayed anti—TNF-α treatment reversed metabolic acidosis associated with sepsis. Furthermore, anti—TNF-α 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-α treatment in clinical practice.(Arch Surg. 1994;129:80-89)


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