Evaluation of unfractionated heparin and recombinant hirudin on survival in a sustained ovine endotoxin shock model

OBJECTIVE: To compare and evaluate the potential benefit of two different anticoagulation regimens during endotoxemia in an ovine model. DESIGN: Animal prospective randomized and controlled study following preliminary dose-range study conforming with the Guide for the Care and Use of Laboratory Animals as promulgated by the Council of the American Physiologic Society and reviewed by the Ethical Committee for Animal Research of our institution. SETTING: Laboratories of anesthesiological investigations and hemostasis, primary care university medical center. SUBJECTS: Twenty-two adult sheep of either sex, weighing 29-42 kg (mean 35.8 kg), surgically instrumented for chronic studies and randomly allocated to receive three different treatment groups: unfractionated heparin (40 units.kg.hr; n = 7), recombinant hirudin (500 units.kg.hr; n = 7), or saline (nonanticoagulated controls; n = 8). INTERVENTIONS: Ovine model of severe endotoxin shock induced by a continuous intravenous endotoxin infusion over 72 hrs (10 ng.kg.min ). MEASUREMENTS AND MAIN RESULTS: Endotoxin infusion alone produced a progressive hypotensive, hyperdynamic shock state with right ventricle failure leading to the death of all animals of the control group within 44 hrs (median, 12 hrs). Heparin profoundly improved survival rate in this model, whereas effective anticoagulation with hirudin did not significantly increase the survival rate compared with controls. Animals in the control group died from disseminated intravascular coagulation, metabolic acidosis, and hemorrhagic pulmonary edema, whereas sheep treated with hirudin died from severe pulmonary edema (hypoxemia, increased alveoloarterial oxygen gradient associated with an increased wet/dry lung weight ratio) in the absence of disseminated intravascular coagulation. CONCLUSIONS: We conclude that systemic anticoagulation with the thrombin inhibitor hirudin is without benefit in this sheep model of lethal endotoxemia, whereas anticoagulation with heparin affords not only effective prevention of endotoxin-induced coagulation disorders but also global protection with prevention of respiratory decompensation and thus markedly improves survival rate in this situation.