COMBINED IBUPROFEN AND MONOCLONAL-ANTIBODY TO TUMOR-NECROSIS-FACTOR-ALPHA ATTENUATE HEMODYNAMIC DYSFUNCTION AND SEPSIS-INDUCED ACUTE LUNG INJURY

A number of key mediators are implicated in the pathophysiology of sep sis. In previous studies of a septic porcine model, ibuprofen pretreat ment prevented the early but not the late rise in pulmonary vascular r esistance index (PVRI) and the early but not the late fall in arterial PO2 (PaO2), whereas monoclonal antibody to tumor necrosis factor alph a (anti-TNFalpha) prevented the late but not the early rise in PVRI an d the late but not the early fall in PaO2. This study examined the imp act of pretreatment with combined ibuprofen and anti-TNF-alpha on the course of sepsis and acute lung injury (ALI) in pigs. Three groups wer e studied for 5 hours. Groups I (n = 9) and II (n = 5) received a 1-ho ur infusion of Pseudomonas aeruginosa. Group II received ibuprofen (12 .5 mg/kg) and anti-TNF-alpha (5 mg/kg) before P. aeruginosa, and a fur ther bolus of ibuprofen at 120 minutes. Group III (n = 11) received st erile saline. Group I demonstrated a significant (p < 0.05) rise in pl asma TNF-alpha that was abolished in group II. The SVRI in group II di d not change significantly from baseline through the study and the SVR I rose sharply in group I following onset of the infusion of P. aerugi nosa, as did PVRI. There was no significant change in PVRI from baseli ne in group II, except for the final 60 minutes; PVRI in group II was significantly less than in group I throughout the study. The protein ( BAL-P) and neutrophil (BAL) contents in bronchoalveolar lavage fluid i n group II were significantly less than in group I at the study conclu sion. However, neutrophil superoxide production in group II at 300 min utes was not attenuated. In conclusion, combined ibuprofen and anti-TN F-alpha moderate the hemodynamic response to sepsis and offer greater protection against acute lung injury than either agent used alone. The loss of ibuprofen-mediated inhibition of neutrophil superoxide genera tion represents a significant interaction between these agents that wa rrants further investigation.