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Background: Although 17α-ethinyl estradiol-3-sulfate (EES) reduces mortality in animal models of controlled hemorrhage, its role in a clinically relevant injury model is unknown. We assessed the impact of EES in a swine model of multiple injuries and hemorrhage., Methods: The study was performed under Good Laboratory Practice, with 30 male uncastrated swine (25-50 kg) subjected to tibial fracture, pulmonary contusion, and 30% controlled hemorrhage for an hour. Animals were randomized to one of five EES doses: 0 (control), 0.3, 1, 3, and 5 mg/kg, administered postinjury. Subjects received no resuscitation and were observed for 6 hours or until death. Survival data were analyzed using Cox-proportional hazard regression. Left ventricular pressure-volume loops were used to derive preload recruitable stroke work as a measure of cardiac inotropy. Immediate postinjury preload recruitable stroke work values were compared with values at 1 hour post-drug administration., Results: Six-hour survival for the 0, 0.3, 1, 3, and 5 mg/kg groups was 0%, 50%, 33.3%, 16.7%, and 0%, respectively. Following Cox regression, the hazard (95% confidence interval) of death was significantly reduced in the 0.3 (0.22 [0.05-0.93]) and 1 (0.24 [0.06-0.89]) mg/kg groups but not the 3 (0.49 [0.15-1.64]) and 5 (0.46 [0.14-1.47]) mg/kg groups. Mean survival time was significantly extended in the 1 mg/kg group (246 minutes) versus the 0 mg/kg group (96 minutes) (p = 0.04, t test). At 1 hour post-drug administration, inotropy was significantly higher than postinjury values in the 0.3 and 1 mg/kg groups (p = 0.003 and p < 0.001, respectively). Inotropy was unchanged in the 3 and 5 mg/kg groups but significantly depressed in the control (p = 0.022)., Conclusion: Administration of EES even in the absence of fluid resuscitation reduces mortality and improves cardiac inotropy in a clinically relevant swine model of multiple injuries and hemorrhage. These findings support the need for a clinical trial in human trauma patients., (Copyright © 2021 American Association for the Surgery of Trauma.)

Background: In locations in which access to resuscitative therapy may be limited, treating polytraumatized patients present a challenge. There is a pressing need for adjuncts that can be delivered in these settings. To assess these adjuncts, a model representative of this clinical scenario is necessary. We aimed to develop a hemorrhage and polytrauma model in the absence of fluid resuscitation., Materials and Methods: This study consisted of two parts: pulmonary contusion dose-finding (n = 6) and polytrauma with evaluation of varying hemorrhage volumes (n = 6). We applied three, six, or nine nonpenetrating captive bolt-gun discharges to the dose-finding group and obtained computed tomography (CT) images. We segmented images to assess contusion volumes. We subjected the second group to tibial fracture, pulmonary contusion, and controlled hemorrhage of 20%, 30%, or 40% and observed for 3 hours or until death. We used Kaplan-Meier analysis to assess survival. We also assessed hemodynamic and metabolic parameters., Results: Contusion volumes for three, six, and nine nonpenetrating captive bolt-gun discharges were 24 ± 28, 50 ± 31, and 63 ± 77 cm3, respectively (p = .679). Animals receiving at least six discharges suffered concomitant parenchymal laceration, whereas one of two swine subjected to three discharges had lacerations. Mortality was 100% at 12 and 115 minutes in the 40% and 30% hemorrhage groups, respectively, and 50% at 3 hours in the 20% group., Conclusion: This study characterizes a titratable hemorrhage and polytrauma model in the absence of fluid resuscitation. This model can be useful in evaluating resuscitative adjuncts that can be delivered in areas remote to healthcare access., (2021.)

Abstract: Exsanguination leading to cardiac arrest is the terminal phase of uncontrolled hemorrhage. Resuscitative interventions have focused on preload and afterload support. Outcomes remain poor due to several factors but poor coronary perfusion undoubtedly plays a role. The aim of this study is to characterize the relationship between arterial pressure and flow during hemorrhage in an effort to better describe the terminal phases of exsanguination.Male swine weighing 60 kg to 80 kg underwent splenectomy and instrumentation followed by a logarithmic exsanguination until asystole. Changes in hemodynamic parameters over time were compared using one-way, repeated measures analysis of variance.Nine animals weighing 69 ± 15 kg were studied. Asystole occurred at 53 ± 13 min when 52 ± 11% of total blood volume has been shed. The greatest fall in mean hemodynamic indices were noted in the first 15 min: SBP (80-42 mm Hg, P = 0.02), left ventricular end-diastolic volume (94-52 mL, P = 0.04), cardiac output (4.8-2.4 L/min, P = 0.03), coronary perfusion pressure (57-30 mm Hg, P = 0.01), and stroke volume (60-25 mL, P = 0.02). This corresponds to the greatest rate of exsanguination. Organized cardiac activity was observed until asystole without arrythmias. Coronary flow was relatively preserved throughout the study, with a precipitous decline once mean arterial pressure was less than 20 mm Hg, leading to asystole.In this model, initial hemodynamic instability was due to preload failure, with asystole occurring relatively late, secondary to failure of coronary perfusion. Future resuscitative therapies need to directly address coronary perfusion failure if effective attempts are to be made to salvage these patients., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by the Shock Society.)