Recombinant Activated Factor VII Increases Survival Time in a Model of Incompressible Arterial Hemorrhage in the Anesthetized Pig

Abstract

Hemorrhage is the leading cause of death in battlefield casualties and the second leading cause of death after civilian trauma. Evacuation time for military casualties to surgical care can be prolonged and improved hemostasis could greatly reduce mortality. There are several anecdotal reports that recombinant activated factor VII (rFVIIa) may arrest uncontrolled bleeding after trauma. However, the majority of prospective randomized controlled trials show little benefit in survival. The aim of this study was to determine whether rFVIIa could increase survival time within a clinically relevant time scale for military practice and reduce the volume of blood loss in a model of incompressible arterial hemorrhage. A secondary aim was to determine the effects of hypotensive versus normotensive resuscitation on the effectiveness of rFVIIa. Terminally anaesthetized Large White pigs were randomly allocated to one of four treatment groups. All animals received a controlled hemorrhage of 40% of the total estimated blood volume. They were given either rFVIIa (180 microg/kg) or placebo (saline 0.3 mL/kg) intravenously and a 4 to 5 mm longitudinal aortotomy created in the infra renal aorta before resuscitation commenced with 0.9% saline to one of two target systolic arterial blood pressures (SBPs): 110 mm Hg (normotensive) or 80 mm Hg (hypotensive). Group sizes were as follows: placebo/normotensive (6), placebo/hypotensive (7), rFVIIa/normotensive (7), and rFVIIa/hypotensive (7). Survival was monitored for a maximum of 6 hours after the onset of resuscitation. rFVIIa was associated with a significantly prolonged survival time in animals managed hypotensively (214 [79-349] vs. 35 [19-52] minutes mean [95% confidence interval] rFVIIa vs. placebo, p = 0.03 Peto log rank test). There was no significant difference in survival time between those given rFVIIa and placebo in groups managed normotensively (128 [6-249] vs. 40 [15-66] minutes respectively, p = 0.27). Both rFVIIa and hypotensive management were associated with reduced uncontrolled hemorrhage volumes. There was no evidence of inappropriate intravascular thrombi or microthrombi associated with the use of rFVIIa. rFVIIa, combined with hypotensive resuscitation, can increase survival time and reduce hemorrhage in a model of arterial hemorrhage. The increase in survival time is clinically relevant for military evacuation of battlefield casualties to surgical care.