title: Transient inhibition of CD18-dependent leukocyte functions after hemorrhage and polymicrobial sepsis.
abstract: BACKGROUND
  The goals were (1) to characterize physiologic changes after a combined insult of hemorrhage plus sepsis in a large animal model and (2) to determine whether transient inhibition of the neutrophil CD18 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), the cecum was ligated and incised immediately before 35% hemorrhage. After 1 hour, shed blood plus supplemental fluid was administered to restore and stabilize hemodynamics. On the basis of these results, a second series examined effects of anti-CD18 (2 mg/kg R15.7; n = 9) or its saline placebo (n = 10) administered during fluid resuscitation.
  
  
  RESULTS
  In the first series the mortality rate was 41% (9 of 22). Early deaths occurred 3.0 +/- 0.8 days after injury and were distinguished by significantly lower neutrophil counts on resuscitation. Those alive a 7 days had intraabdominal abscesses and bacteremia. Alveoli and peribronchial spaces were congested, with edema and fibrin deposition in capillaries and alveoli. Livers were congested with biliary stasis. Despite these pathologic findings, hemodynamic, electrolyte, and serum enzyme changes were minimal. In the second series the mortality rate at 4 days was 30% with placebo (3 of 10) versus 33% with anti-CD18 (3 of 9). Lung changes (i.e., pneumonia, pleuritis, thrombosis, and edema) were similar in both groups, but liver congestion and hemorrhage were attenuated by anti-CD18. Some aspects of host defense were altered by anti-CD18. At 24 and 48 hours the oxidative burst potential for circulating granulocytes was 208% +/- 57% and 383% +/- 73% with placebo versus 1273% +/- 351% and 762% +/- 226% in anti-CD18. At 72 hours the granularity of circulating neutrophils was unchanged from baseline with placebo but was reduced to 82% +/- 5% by anti-CD18. At 48 hours lipopolysaccharide-evoked tumor necrosis factor production in vitro was reduced to 62% +/- 22% with placebo but was increased to 148% +/- 16% with anti-CD18.
  
  
  CONCLUSIONS
  Anti-CD18 during fluid resuscitation did not increase vulnerability to endogenous pathogens because the transient inhibition of neutrophil demargination was balanced by enhanced oxidative burst, degranulation, and production of tumor necrosis factor in circulating cells later during recovery. Thus a single administration of antiadhesion therapy does not worsen posttrauma outcome even if given during ongoing sepsis.
authors.affiliation: Department of Surgery, University of Tennessee, Memphis, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Lyden
authors.forename: J H
authors.initials: JH
authors.lastname: Patton
authors.forename: D N
authors.initials: DN
authors.lastname: Ragsdale
authors.forename: M A
authors.initials: MA
authors.lastname: Croce
authors.forename: T C
authors.initials: TC
authors.lastname: Fabian
authors.forename: K G
authors.initials: KG
authors.lastname: Proctor
mesh_terms: D000818:Animals; D018821:CD18 Antigens / Q000502:physiology*; D005260:Female; D006470:Hemorrhage / Q000097:blood*; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D008297:Male; D009504:Neutrophils / Q000502:physiology*; D018805:Sepsis / Q000097:blood*; D013552:Swine
chemical_list: D018821:CD18 Antigens; D018799:Intercellular Adhesion Molecule-1