DELAYED TUMOR-NECROSIS-FACTOR-ALPHA BLOCKADE ATTENUATES PULMONARY DYSFUNCTION AND METABOLIC-ACIDOSIS ASSOCIATED WITH EXPERIMENTAL GRAM-NEGATIVE SEPSIS

Objective: To ascertain the effect of delayed tumor necrosis factor al pha (TNF-alpha) on the evolution of systemic and pulmonary injury afte r the onset of sepsis. Design: Prospective controlled trial. Intervent ion: Anesthetized swine were made septic with a 1-hour infusion of liv e Pseudomonas aeruginosa, following which a treatment group received a n infusion of anti-TNF-alpha monoclonal antibody (5 mg/kg). Control an imals received 0.9% saline. Results: Delayed anti-TNF-alpha treatment had no effect on septic pulmonary hypertension or decline in cardiac o utput. Late recovery in systemic arterial hypotension was associated w ith a reversal of arterial acidosis (P<.05 by t test and analysis of v ariance 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 baselin e following anti-TNF-alpha treatment (1.5 +/- 0.1 vs 1.6 +/- 0.2, not significant). Characteristic septic neutropenia was dramatically rever sed by anti-TNF-alpha treatment and was associated with downregulation (P<.05 by t test and analysis of variance) of polymorphonuclear neutr ophil (PMN) leukocyte CD18 adhesion receptors and reduction (P<.05 by t test and analysis of variance) in lung PMN sequestration measured by myeloperoxidase activity. The mean (+/- SEM) decrease in bronchoalveo lar lavage protein indicated an attenuated permeability injury in anti -TNF-alpha animals (septic animals at 5 hours compared with baseline v alue, 1044 +/- 270 vs 149 +/- 28 mu g/mL; control animals at 5 hours c ompared with baseline value, 217 +/- 83 vs 129 +/- 19 mu g/mL; P<.05 b y t test and analysis of variance). Conclusions: These data show that delayed anti-TNF-alpha treatment reversed metabolic acidosis associate d with sepsis. Furthermore, anti-TNF-alpha treatment reversed septic n eutropenia, reduced PMN sequestration, and was associated with attenua ted lung injury in a model of fulminant sepsis. This supports evidence of PMN-mediated tissue injury in sepsis and suggests mechanisms for p otential therapeutic benefit of anti-TNF-alpha treatment in clinical p ractice.