TRANSIENT INHIBITION OF CD18-DEPENDENT LEUKOCYTE FUNCTIONS AFTER HEMORRHAGE AND POLYMICROBIAL SEPSIS

Background. The goals were (I) to characterize physiologic changes aft er a combined insult of hemorrhage plus sepsis in a large animal model and (2) to determine whether transient inhibition of the neutrophil C D18 adherence receptor during fluid resuscitation impairs host defense during recovery from this injury. Methods. Two series of experiments were performed in anesthetized swine. In the first series (n = 22), th e cecum was ligated and incised immediately before 35% hemorrhage. Aft er 1 hour, shed blood plus supplemental fluid was administered to rest ore and stabilize hemodynamics. On the basis of these results, a secon d series examined effects of anti-CD18 (2 mg/kg R15.7; n = 9) or its s aline placebo (n = 10) administered during fluid resuscitation. Result s. In the first series the mortality rate was 41% (9 of 22). Early dea ths occurred 3.0 +/- 0.8 days after injury and were distinguished by s ignificantly lower neutrophil counts on resuscitation. Those alive at 7 days had intraabdominal abscesses and bacteremia. Alveoli and peribr onchial spaces were congested, with edema and fibrin deposition in cap illaries and alveoli. Livers were congested with biliary stasis. Despi te these pathologic findings, hemodynamic, electrolyte, and serum enzy me changes were minimal. In the second series the mortality rate at 4 days war 30% with placebo (3 of 10) versus 33% with anti-CD18 (3 of 9) . Lung changes (i.e., pneumonia, pleuritis, thrombosis, and edema) wer e similar in both groups, but liver congestion and hemorrhage were att enuated by anti-CD18. Some aspects of host defense were altered by ant i-CD18. At 24 and 48 hours the oxidative burst potential for circulati ng granulocytes was 208% +/- 57% and 383% +/- 73% with placebo versus 1273% +/- 351% and 762% +/- 226% in anti-CD18. At 72 hours the granula rity of circulating neutrophils was unchanged from baseline with place bo but was reduced to 82% +/- 5% by anti-CD18. At 48 hours lipopolysac charide-evoked tumor necrosis factor production in vitro was reduced t o 62% +/- 22% with placebo but was increased to 148% +/- 16% with anti -CD18. Conclusions. Anti-CD18 during fluid resuscitation did not incre ase vulnerability to endogenous pathogens because the transient inhibi tion of neutrophil demargination was balanced by enhanced oxidative bu rst, degranulation, and production of tumor necrosis factor in circula ting cells later during recovery Thus a single administration of antia dhesion therapy does not worsen posttrauma outcome even if given durin g ongoing sepsis.