Anti-L-selectin antibody treatment of hemorrhagic-traumatic shock in baboons

Abstract

Objectives: The adhesion molecule L-selectin plays an important role in leukocyte-endothelium interactions, thereby contributing to inflammatory reactions. We tested the hypothesis that humanized anti-L-selectin antibodies reduce trauma-associated organ damage and mortality.

Design: Prospective, randomized experimental study.

Setting: Independent nonprofit research laboratory in a trauma hospital (Ludwig Boltzmann Institute) and a contract research institute (Biocon).

Subjects: Twenty-eight male baboons (Papio ursinus), 18 to 29 kg.

Interventions: Hemorrhagic-traumatic shock was created by complement activation with cobra venom factor, followed by withdrawal of blood to a mean arterial pressure of 35 to 45 mm Hg. Blood and lactated Ringer's solution were reinfused. Animals were randomized to receive either 2 mg/kg humanized anti-L-selectin antibody (HuDREG-55 [Ab]) or placebo (lactated Ringer's solution [LRS]).

Measurements and main results: Treatment with humanized anti-L-selectin antibody decreased mortality (Ab 21% vs. LRS 71%; p = .011) and improved survival time (p = .016). A trend toward reduced organ damage, especially in the adrenal glands (score 1.2 +/- 0.2 placebo vs. 1.0 +/- 0.1 antibody; p = .059) was seen, and at 24 hrs was accompanied by significantly increased mean arterial pressure (Ab 99 +/- 6 mm Hg vs. LRS 79 +/- 8 mm Hg; p = .023), cardiac output (Ab 3.4 +/- 0.2 L/min vs. LRS 2.4 +/- 0.3 L/min; p = .007), core temperature (p = .048), and improved perfusion, with less negative base excess (Ab 2.9 +/- 1.1 vs. LRS 2.1 +/- 1.7; p = .019) and a trend toward less lactate (p = .065). These improvements were accompanied by significantly (p = .006) decreased fluid requirements in the treatment group (Ab 11.7 +/- 2.5 mL/kg/hr vs. LRS 23.0 +/- 2.3 mL/kg/hr). There were also fewer circulating leukocytes (p = .042) in the treatment group at 24 hrs.

Conclusion: Humanized anti-L-selectin antibody has beneficial effects on survival in a long-term in vivo model of hemorrhagic. traumatic shock.