Effect of recombinant FVIIa in hypothermic, coagulopathic pigs with liver injuries.

BACKGROUND: Previous experiments with diverse pig models to evaluate the ability of rFVIIa to reduce hemorrhage have provided divergent results. The current study was conducted to address concerns related to previous work by using larger sample sizes, and an extended observational period of 4 hours post-injury. The objectives were to evaluate further the hemostatic efficacy and safety of rFVIIa administration after traumatic, uncontrolled hemorrhage. METHODS: Anesthetized, splenectomized pigs (36.6 +/- 0.3 kg; n = 18/group) underwent an approximately 50% isovolemic blood exchange with 33 degrees C 6% hetastarch, and body temperature was adjusted to 32.5 +/- 0.5 degrees C. Subsequently, a Grade V liver injury was inflicted. After 30 seconds, either vehicle or treatment (180 microg/kg or 720 microg/kg rFVIIa) was administered intravenously as a bolus. Concomitantly, laparotomy pads were packed around the liver. Resuscitation with 33 degrees C lactated Ringer's solution (260 mL/min) was initiated and pigs were monitored for 4 hour post-injury or until death. Tissues were collected and examined histologically to assess the presence of disseminated intravascular coagulation (DIC). RESULTS: Liver injuries were comparable among all groups (p = 0.89). Measures associated with in vitro coagulation (prothrombin time, activated partial thromboplastin time, thromboelastographic split-point and R times) were enhanced by rFVIIa administration (p < 0.05). However, neither percent survival (p = 0.82), survival time (p = 0.56), nor blood loss (p = 0.63) were affected by treatment. DIC was not evident in lung or kidney tissue. CONCLUSIONS: These data indicate an inability of rFVIIa at these doses to reduce blood loss, or to increase survival time or percent survival in this pig model. Absence of DIC provides evidence for safe use of rFVIIa under conditions specific to this study.

Evaluation of commercially available fluid-warming devices for use in forward surgical and combat areas.

The fluid-warming capabilities of four individual fluid warmers, i.e., Level 1, FMS 2000, Thermal Angel, and Ranger, were compared to evaluate their potential for medical use in forward military echelons of care. Lactated Ringer's solution (LR) and Hextend at room temperature (20 degrees C) or refrigerated temperature (4-7 degrees C) and packed red blood cells at 4 degrees C to 7 degrees C were used with each warmer at two different flow rates. The FMS 2000 consistently warmed all fluids to approximately 37 degrees C, regardless of the starting temperature or flow rate. The Level 1 and Ranger also efficiently warmed all fluids except cold LR to approximately 37 degrees C. The Thermal Angel generally warmed room temperature fluid, cold Hextend, and packed red blood cells to at least 33 degrees C to 34 degrees C but could not warm cold LR. The clinical standard is to have fluids warmed to 32 degrees C at a minimum and more preferably to 34 degrees C to 35 degrees C. Of the fluid warmers tested, only the Thermal Angel failed to achieve such a temperature in warming cold LR. Data from the present study suggest the Ranger and FMS 2000 to be operationally adaptable to at least echelons 1 and 2, respectively, whereas far-forward use of the Thermal Angel has limitations.

The effect of recombinant factor VIIa on noncoagulopathic pigs with grade V liver injuries.

BACKGROUND: Recombinant Factor VIIa (rFVIIa) has been used to decrease bleeding in a number of settings, including hemophilia, liver transplantation, intractable bleeding, and cirrhosis. It has also been shown to reduce bleeding in coagulopathic pigs with Grade V liver injuries when used as an adjunct to packing. This study was performed to determine if rFVIIa would reduce blood loss after a Grade V liver injury in noncoagulopathic pigs when used as sole therapy. STUDY DESIGN: Thirty normothermic animals were randomized to receive either 150 microg/kg of rFVIIa or normal saline intravenously. After laparotomy and splenectomy, a standardized Grade V liver injury was made with a liver clamp. Thirty seconds after injury, blinded therapy was given. Blood loss was measured 15 minutes after injury and the abdomen was closed. Animals were resuscitated to their baseline blood pressure and the study was continued for 2 hours. Serial coagulation parameters were obtained. Following the study period, blood loss was measured and an autopsy was performed. Grossly normal areas of lung were examined for evidence of intravascular thrombosis. RESULTS: Mean Factor VII:C levels increased 155-fold in the treatment group after infusion of rFVIIa. The mean prothrombin time in the treatment group decreased from 9.8 +/- 0.4 seconds to 7.3 +/- 0.2 seconds and remained significantly different from the control group throughout the study (p < 0.01). There were no differences in other coagulation parameters. Mean initial blood loss was 822 +/- 266 mL in the treatment group and 768 +/- 215 mL in the control group (p = 0.6). Rebleeding blood volume was 397 +/- 191 mL in the treatment group and 437 +/- 274 mL (p = 0.6) in the control group. Lung histology revealed no evidence of abnormal microvascular thrombosis. CONCLUSIONS: rFVIIa does not reduce blood loss after Grade V liver injury when it is used as sole therapy in warm noncoagulopathic pigs.

The effect of recombinant factor VIIa on coagulopathic pigs with grade V liver injuries.

BACKGROUND: Recombinant factor VIIa (rFVIIa) has been used to decrease bleeding in a number of settings including hemophilia, liver transplantation, intractable bleeding, and cirrhosis. Experience in the trauma setting is limited. This study was performed to determine whether rFVIIa would reduce bleeding after a grade V liver injury in hypothermic, dilutionally coagulopathic pigs when used as an adjunct to abdominal packing and to determine whether increasing the dose of the drug increased its hemostatic efficacy. METHODS: Thirty animals were randomized to receive 180 microg/kg of rFVIIa, 720 microg/kg of rFVIIa, or vehicle buffer control. After laparotomy and splenectomy, animals underwent a 60% blood volume isovolemic exchange transfusion with 5% human albumin. The animals' temperature was maintained at 33 degrees C and a standardized grade V liver injury was made with a liver clamp. Thirty seconds after injury, the abdomen was packed with laparotomy sponges, resuscitation was initiated, and blinded therapy was given. Animals were resuscitated to their baseline mean arterial pressure and the study was continued for 2 hours. Serial coagulation parameters were measured at the temperature they were drawn. After the study period, surviving animals were killed, posttreatment blood loss was measured, and an autopsy was performed. RESULTS: Ten animals were randomized to each group. After administration of study drug, factor VII clotting activity (FVII:C) was higher in the 720 microg/kg group than in the 180 microg/kg group (p < 0.01). FVII:C was higher in both treatment groups than in the control group (p < 0.01). The mean prothrombin time was shorter in the treatment groups than in the control group (p < 0.05). Mean arterial pressure was lower in the control group than in the treatment groups throughout the study (p < 0.01). Mean blood loss was less in the treatment groups than in the control group (p = 0.03). Mortality was not different between groups. There were no differences between the groups that received rFVIIa in any measured parameters except for FVII:C. Liver injuries were similar between groups and there was no evidence of microthrombosis on lung histology. CONCLUSION: rFVIIa reduces blood loss in hypothermic, dilutionally coagulopathic pigs with grade V injuries when used as an adjunct to packing. Increasing the dose does not enhance the hemostatic effect.