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


METHODS
Prospective, randomized experimental study.


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


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


METHODS
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]).


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.


CONCLUSIONS
Humanized anti-L-selectin antibody has beneficial effects on survival in a long-term in vivo model of hemorrhagic. traumatic shock.
Schlag
G
G
Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria.
Redl
H R
HR
Till
G O
GO
Davies
J
J
Martin
U
U
Dumont
L
L
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018988:Bacterial Translocation / Q000187:drug effects; D003167:Complement Activation / Q000187:drug effects; D003169:Complement Inactivator Proteins; D004546:Elapid Venoms; D004727:Endothelium / Q000276:immunology; D006439:Hemodynamics / Q000187:drug effects; D019041:L-Selectin / Q000276:immunology*; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D010215:Papio; D011446:Prospective Studies; D011897:Random Allocation; D012771:Shock, Hemorrhagic / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D012774:Shock, Traumatic / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016019:Survival Analysis; D018746:Systemic Inflammatory Response Syndrome / Q000276:immunology / Q000473:pathology
D000911:Antibodies, Monoclonal; D003169:Complement Inactivator Proteins; D004546:Elapid Venoms; C016310:cobra venom factor; D019041:L-Selectin