Prehospital adenosine, lidocaine, and magnesium has inferior survival compared with tactical combat casualty care resuscitation in a porcine model of prolonged hemorrhagic shock.

BACKGROUND: Adenosine, lidocaine, and magnesium (ALM) is a cardioplegic agent shown to improve survival by improving cardiac function, tissue perfusion, and coagulopathy in animal models of shock. We hypothesized prehospital ALM treatment in hemorrhagic shock would improve survival compared to current Tactical Combat Casualty Care (TCCC) resuscitation beyond the golden hour. METHODS: Swine were randomized to: (1) TCCC, (2) 2 mL·kg vehicle control (VC), (3) 2 mL·kg ALM + drip, (4) 4 mL·kg ALM + drip, 5) 4 mL·kg ALM + delayed drip at 0.5 mL·kg·h, 6) 4 mL/kg VC, 7) 4 mL·kg ALM for 15 minutes + delayed drip at 3 mL·kg·h. Animals underwent pressure controlled hemorrhage to mean arterial pressure (MAP) of 30 mm Hg (S = 0). Treatment was administered at T = 0. After 120 minutes of simulated prehospital care (T = 120) blood product resuscitation commenced. Physiologic variables were recorded and laboratories were drawn at specified time points. RESULTS: Tactical Combat Casualty Care demonstrated superior survival to all other agents. The VC and ALM groups had lower MAPs and systolic blood pressures compared with TCCC. Except for the VC groups, lactate levels remained similar with correction of base deficit after prehospital resuscitation in all groups. Kidney function and liver function remained comparable across all groups. Compared with baseline values, TCCC demonstrated significant hypocoagulability. CONCLUSION: Adenosine, lidocaine, and magnesium, as administered in this study, are inferior to current Hextend-based resuscitation for survival from prolonged hemorrhagic shock in this model. In survivors, ALM groups had lower systolic blood pressures and MAPs, but provided a protective effect on coagulopathy as compared to TCCC. Adenosine, lidocaine, and magnesium do not appear to be a suitable low volume replacement to current TCCC resuscitation. The reduced coagulopathy compared to TCCC warrants future studies of ALM, perhaps as a therapeutic adjunct.

Whole blood and Hextend: Bookends of modern tactical combat casualty care field resuscitation and starting point for multifunctional resuscitation fluid development.

BACKGROUND: Hemorrhage is the leading cause of preventable death in traumatically injured civilian and military populations. Prehospital resuscitation largely relies on crystalloid and colloid intravascular expansion, as whole blood and component blood therapy are logistically arduous. In this experiment, we evaluated the bookends of Tactical Combat Casualty Care Guidelines recommendations of prehospital resuscitation with Hextend and whole blood in a controlled hemorrhagic shock model within non-human primates, as means of a multifunctional resuscitative fluid development. METHODS: In the nonhuman primate, a multiple injuries model was used, consisting of a musculoskeletal injury (femur fracture), soft tissue injury (15-cm laparotomy), and controlled hemorrhage to a mean arterial pressure of 20 mm Hg, demarcating the beginning of the shock period. Animals were randomized to prehospital interventions of whole blood or Hextend at T = 0 minutes, and at T = 90 minutes definitive surgical interventions and balanced sanguineous damage control resuscitation could be implemented. All animals were euthanized at T = 480 minutes. Data are expressed as mean ± SEM; significance, p < 0.05. RESULTS: No significant differences in survival (83% vs. 100%; p = 0.3), tissue perfusion (EtCO2 and StO2) or endpoints of resuscitation (base deficit, lactate, pH) between Hextend and whole blood were identified. Second, whole blood compared with Hextend demonstrated significantly earlier normalization of clot formation time, maximal clot firmness, and α angle. CONCLUSION: A future multifunctional resuscitative fluid including an asanguineous, oncotic, non-oxygen-carrying component to facilitate intravascular volume expansion, and a component with synthetic coagulation factors and fibrinogen to deter coagulopathy may show equivalence to whole blood. LEVEL OF EVIDENCE: N/A: Study type: translational animal model.

Control of severe intra-abdominal hemorrhage with an infusible platelet-derived hemostatic agent in a nonhuman primate (rhesus macaque) model.

BACKGROUND: Hemorrhage remains the leading cause of potentially survivable trauma mortality. Recent reports indicate that injuries sustained in noncompressible anatomic locations (i.e., truncal and junctional) account for 86.5% of hemorrhage-related deaths. Infusible human platelet-derived hemostatic agents (hPDHAs) represent a promising strategy to reduce blood loss from noncompressible injuries. Here, we evaluate the hemostatic efficacy of a lyophilized hPDHA in a rhesus macaque model of severe, uncontrolled hemorrhage. METHODS: Hemorrhage was induced via laparoscopic 60% left-lobe hepatectomy in anesthetized rhesus macaques (T = 0 minute). Treatment infusion began with an 11-mL bolus (T = 5-6 minutes) of either 5% albumin solution (control; n = 8) or hPDHA (1.2 × 10(10) platelet equivalents, n = 8), followed by 2.8-mL/min 0.9% normal saline at T = 6-20 minutes. Resuscitation continued with normal saline (0.22 mL/kg/min) to a total volume of 20 mL/kg at T = 120 minutes, at which time surgical hemostasis was achieved and percent blood loss quantified. Animals were monitored until T = 480 minutes and then euthanized, and necropsy was performed with emphasis on intravascular and end-organ thrombi. Data are expressed as mean ± SEM; significance, p < 0.05. RESULTS: Both groups exhibited a ∼70% decrease in mean arterial pressure (MAP) from T = 0-5 minutes. Percent blood loss was 44.2 ± 3.9% in hPDHA animals, and 44.3 ± 3.3% in controls. Survival rates were 4 of 8 for hPDHA animals and 7 of 8 for controls. Regardless of treatment, percent blood loss was greater (p < 0.02) in nonsurviving animals (55 ± 2%, n = 5) compared with surviving animals (42% ± 3%, n = 11). No pathologic intravascular thrombi were observed in either group. CONCLUSION: The isolated administration of hPDHA did not significantly reduce blood loss; however, thrombocytopenia was not present in the model, and clinically, platelets would be administered in combination with plasma. Mortality was not statistically different between groups (p = 0.14) but was related to blood loss. Future studies should consider the use of hPDHA in combination with additional therapeutics (e.g., factors) and a model that incorporates thrombocytopenia or platelet dysfunction.

Development of a Nonhuman Primate (Rhesus Macaque) Model of Uncontrolled Traumatic Liver Hemorrhage.

Hemorrhage is the leading cause of potentially survivable trauma mortality, necessitating the development of improved therapeutic interventions. The objective of this study was to develop and characterize a reproducible clinically translatable nonhuman primate model of uncontrolled severe hemorrhage. Such a model is required to facilitate the development and meaningful evaluation of human-derived therapeutics. In Rhesus macaques, a laparoscopic left-lobe hepatectomy of 25% (n = 2), 50% (n = 4), or 60% (n = 6) was performed at T = 0 min, with no attempt at hemorrhage control until T = 120 min. A constant-rate infusion of normal saline was administered between T = 15 and 120 min to a total volume of 20 mL/kg. At T = 120 min, a laparotomy was performed to gain surgical hemostasis and quantify blood loss. Physiological parameters were recorded, and blood samples were collected at defined intervals until termination of the study at T = 480 min. Statistical analyses used Student t tests, with P < 0.05 considered statistically significant. Results are reported as mean ± SEM. The calculated percent blood loss for the 25% hepatectomy group was negligible (2.3% ± 0.2%), whereas the 50% and 60% hepatectomy groups exhibited 26.6% ± 7.1% and 24.9% ± 3.8% blood loss, respectively. At T = 5 min, blood pressure for the 25%, 50%, and 60% hepatectomy groups was reduced by 13.8%, 60.8%, and 63.2% from the respective baseline values (P < 0.05). In the 60% hepatectomy group, alterations in thromboelastometry parameters and systemic inflammatory markers were observed. The development of a translatable nonhuman primate model of uncontrolled hemorrhage is an ongoing process. This study demonstrates that 60% hepatectomy offers a significant reproducible injury applicable for the evaluation of human-derived therapeutics.