Rolf Rossaint

Background: Trauma is a leading cause of mortality and morbidity, with traumatic brain injury (TBI) and uncontrolled hemorrhage responsible for the majority of these deaths. Recombinant activated factor VIIa (rFVIIa) is being investigated as an adjunctive hemostatic treatment for bleeding refractory to conventional replacement therapy in trauma patients. TBI is a common component of polytrauma injuries. However, the combination of TBI with polytrauma injuries is associated with specific risk factors and treatment modalities somewhat different from those of polytrauma without TBI. Although rFVIIa treatment may offer added potential benefit for patients with combined TBI and polytrauma, its safety in this population has not yet been assessed. We conducted a post hoc sub analysis of patients with TBI and severe blunt polytrauma enrolled into a prospective, international, double-blind, randomized, placebo-controlled study. Methods: A post hoc analysis of study data was performed for 143 patients with severe blunt trauma enrolled in a prospective, randomized, placebo-controlled study, evaluating the safety and efficacy of intravenous rFVIIa (200 + 100 + 100 μg/kg) or placebo, to identify patients with a computed tomography (CT) diagnosis of TBI. The incidences of ventilator-free days, intensive care unit-free days, and thromboembolic, serious, and adverse events within the 30-day study period were assessed in this cohort. Results: Thirty polytrauma patients (placebo, n = 13; rFVIIa, n = 17) were identified as having TBI on CT. No significant differences in rates of mortality (placebo, n = 6, 46%, 90% confidence interval (CI): 22% to 71%; rFVIIa, n = 5, 29%, 90% CI: 12% to 56%; P = 0.19), in median numbers of intensive care unit-free days (placebo = 0, rFVIIa = 3; P = 0.26) or ventilator-free days (placebo = 0, rFVIIa = 10; P = 0.19), or in rates of thromboembolic adverse events (placebo, 15%, 90% CI: 3% to 51%; rFVIIa, 0%, 90% CI: 0% to 53%; P = 0.18) or serious adverse events (placebo, 92%, 90% CI: 68% to 98%; rFVIIa, 82%, 90% CI: 60% to 92%; P = 0.61) were observed between treatment groups. Conclusion: The use of a total dose of 400 (200 + 100 + 100) μg/kg rFVIIa in this group of hemodynamically unstable polytrauma patients with TBI was not associated with an increased risk of mortality or with thromboembolic or adverse events.

Purpose: The purpose of this study was to assess the cost-effectiveness of recombinant activated factor VII (rFVIIa) as adjunctive therapy for the control of bleeding in patients with severe blunt trauma injuries in Germany. The primary outcome measure was incremental cost per quality-adjusted life-year (QALY) gained. Materials and Methods: We developed a cost-effectiveness model based on patient-level data from a 30 day international, randomized, placebo-controlled phase II trial. The data were supplemented with secondary data from the German Trauma Register and German life tables to estimate lifetime costs and benefits. We assumed that the non-significant difference in mortality observed in the phase II trial of 5% in favor of rFVIIa could be verified in the ongoing, much larger follow-up trauma study. We adopted the perspective of third-party payers in Germany, and included all trauma-related healthcare costs. Results: The incremental cost per QALY gained with rFVIIa relative to placebo was e29,451. The probability that this was below e30,000 and e40,000 was 51 and 58%, respectively. The estimates were sensitive to the differences observed in mortality and the applied discount rate. Conclusions: Based on preliminary evidence from a phase II trial, we conclude that, relative to placebo, rFVIIa may be a cost-effective therapy from the thirdparty payer perspective in Germany.

Introduction: Evidence-based recommendations can be made with respect to many aspects of the acute management of the bleeding trauma patient, which when implemented may lead to improved patient outcomes. Methods: The multidisciplinary Task Force for Advanced Bleeding Care in Trauma was formed in 2005 with the aim of developing guidelines for the management of bleeding following severe injury. Recommendations were formulated using a nominal group process and the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) hierarchy of evidence and were based on a systematic review of published literature. Results: Key recommendations include the following: The time elapsed between injury and operation should be minimised for patients in need of urgent surgical bleeding control, and patients presenting with haemorrhagic shock and an identified source of bleeding should undergo immediate surgical bleeding control unless initial resuscitation measures are successful. A damage control surgical approach is essential in the severely injured patient. Pelvic ring disruptions should be closed and stabilised, followed by appropriate angiographic embolisation or surgical bleeding control, including packing. Patients presenting with haemorrhagic shock and an unidentified source of bleeding should undergo immediate further assessment as appropriate using focused sonography, computed tomography, serum lactate, and/or base deficit measurements. This guideline also reviews appropriate physiological targets and suggested use and dosing of blood products, pharmacological agents, and coagulation factor replacement in the bleeding trauma patient. Conclusion: A multidisciplinary approach to the management of the bleeding trauma patient will help create circumstances in which optimal care can be provided. By their very nature, these guidelines reflect the current state-of-the-art and will need to be updated and revised as important new evidence becomes available.

Introduction: We conducted a post-hoc analysis on the effect of recombinant factor VIIa (rFVIIa) on coagulopathic patients from two randomized, placebo-controlled, double-blind trials of rFVIIa as an adjunctive therapy for bleeding in patients with severe trauma. Methods: Blunt and penetrating trauma patients were randomly assigned to rFVIIa (200 + 100 + 100 μg/kg) at 0, 1, and 3 hours after transfusion of 8 units of red blood cells (RBCs) or to placebo. Subjects were monitored for 48 hours post-dosing and followed for 30 days. Coagulopathy was retrospectively defined as transfusion of fresh frozen plasma (FFP) (>1 unit of FFP per 4 units of RBCs), FFP in addition to whole blood, and transfusion of platelets and/or cryoprecipitate. Results: Sixty rFVIIa-treated and 76 placebo subjects were retrospectively identified as being coagulopathic. No significant differences were noted in baseline characteristics. The rFVIIa-treated coagulopathic subgroup consumed significantly less blood product: RBC transfusion decreased by 2.6 units for the whole study population (P = 0.02) and by 3.5 units among patients surviving more than 48 hours (P < 0.001). Transfusion of FFP (1,400 versus 660 ml, P < 0.01), platelet (300 versus 100 ml, P = 0.01), and massive transfusions (29% versus 6%, P < 0.01) also dropped significantly. rFVIIa reduced multi-organ failure and/or acute respiratory distress syndrome in the coagulopathic patients (3% versus 20%, P = 0.004), whereas thromboembolic events were equally present in both groups (3% versus 4%, P = 1.00). Conclusion: Coagulopathic trauma patients appear to derive particular benefit from early adjunctive rFVIIa therapy.

Introduction: Recombinant activated factor VII (rFVIIa) has been used as adjunctive therapy in trauma patients with severe bleeding. However, its pharmacokinetics profile remains unknown. Methods: In two placebo-controlled studies in patients with blunt and penetrating trauma, the pharmacokinetics of rFVIIa given at an initial dose of 200 μg.kg^-1 after transfusion of eight red blood cell units, followed by additional doses of 100 μg.kg^-1, one and three hours later, have been studied, based on the FVII coagulant activity assay. Both non-compartment and population pharmacokinetic analyses were performed. A two-compartment, population pharmacokinetic model was used to estimate a population profile for the rFVIIa dosing regimen. Data are population means (percent coefficient of variation (CV)). Results: Based on the two-compartment population model, the estimated pharmacokinetic parameters were: clearance 40 (30% CV) ml.kg^-1.h^-1; central volume of distribution 89 (32% CV) ml.kg^-1; inter-compartmental clearance 24 ml.kg^-1.h^-1; and peripheral compartment volume 31 ml.kg^-1. Baseline FVII coagulant activity was estimated at 0.29 (39% CV) U.ml^-1, initial half-life was 0.6 (34% CV) hours, and terminal half-life 2.4 (50% CV) hours. High intra- and inter-patient variability was noted in volume of distribution and clearance, which was in part correlated with the transfusion requirements as the single significant covariate. The non-compartmental analysis led to almost identical estimates of key parameters. Conclusion: A high intra- and inter-patient variability was noted in the volume of distribution and clearance of rFVIIa in trauma patients with severe bleeding, mainly related with the transfusion requirements and thus blood loss and/or bleeding rate.

Background: All general anesthetics used are known to have a negative inotropic side effect. Since xenon does not have a negative inotropic effect, it could be an interesting future general anesthetic. The aim of this clinical multicenter trial was to test the hypothesis of whether recovery after xenon anesthesia is faster compared with an accepted, standardized anesthetic regimen and that it is as effective and safe. Method: A total of 224 patients in six centers were included in the protocol. They were randomly assigned to receive either xenon (60 +/- 5%) in oxygen or isoflurane (end-tidal concentration, 0.5%) combined with nitrous oxide (60 +/- 5%). Sufentanil (10 mcirog) was intravenously injected if indicated by defined criteria. Hemodynamic, respiratory, and recovery parameters, the amount of sufentanil, and side effects were assessed. Results: The recovery parameters demonstrated a statistically significant faster recovery from xenon anesthesia when compared with isoflurane-nitrous oxide. The additional amount of sufentanil did not differ between both anesthesia regimens. Hemodynamics and respiratory parameters remained stable throughout administration of both anesthesia regimens, with advantages for the xenon group. Side effects occurred to the same extent with xenon in oxygen and isoflurane-nitrous oxide. Conclusion: This first randomized controlled multicenter trial on the use of xenon as an inhalational anesthetic confirms, in a large group of patients, that xenon in oxygen provides effective and safe anesthesia, with the advantage of a more rapid recovery when compared with anesthesia using isoflurane-nitrous oxide.