Principal component analysis of a swine injury model identifies multiple phenotypes in trauma.

BACKGROUND: Trauma is the third leading cause of death in the United States and the primary cause of death for people between the ages of 1 year and 44 years. In addition to tissue damage, trauma may also activate an inflammatory state known as trauma-induced coagulopathy (TIC) that is associated with clotting malfunctions, acidemia, and end-organ dysfunction. Prior work has also demonstrated benefit to acknowledging the type and severity of endothelial injury, coagulation derangements, and systemic inflammation in the management of trauma patients. This study builds upon prior work by combining laboratory, metabolic, and clinical metrics into an analysis of trauma phenotypes, evolution of phenotypes over time after trauma, and significance of trauma phenotype on mortality. METHODS: Seventy 3-month-old female Yorkshire crossbred swine were randomized to injury and resuscitation groups. Principal component analysis (PCA) of longitudinal swine TEG data (Reaction time, Alpha-Angle, Maximum Amplitude, and Clot Lysis at 30 minutes), pH, lactate, and MAP was completed in R at baseline, 1 hour postinjury, 3 hours postinjury, 6 hours postinjury, and 12 hours postinjury. Subjects were compared by principal component factor scores to assess differences in survival, injury severity, and treatment group. RESULTS: Among injured animals, three phenotypes were observed at each time point. Five phenotypes were associated with differences in survival, and of these, four were associated with differences in injury severity. Phenotype alignment was not significantly different by treatment group. CONCLUSION: This application of PCA to a set of coagulation, hemodynamic, and organ perfusion variables has identified multiple evolving phenotypes after trauma. Some of these phenotypes may correlate with injury severity and may have implications for survival. Next steps include validating these findings over greater numbers of subjects and exploring other machine-learning techniques for phenotype identification. LEVEL OF EVIDENCE: Level IV, Therapeutic/Care Management.

FFP maintains normal coagulation while Kcentra induces a hypercoagulable state in a porcine model of pulmonary contusion and hemorrhagic shock.

BACKGROUND: Moderate injury can lead to a coagulopathy. Fresh frozen plasma (FFP) corrects coagulopathy by means of a balanced array of clotting factors. We sought to compare the late effects of FFP and a prothrombin complex concentrate (PCC) on the coagulopathy of trauma using a porcine model of pulmonary contusion (PC) and hemorrhagic shock (HS) designed to evaluate the organ protective effects of these treatments. METHODS: Female Yorkshire swine (40-50 kg) were randomized to receive PC + HS or control (instrumented and uninjured). A blunt PC was created using a captive bolt gun. To induce HS, a liver crush injury was performed. Eighty minutes after injury, swine were treated with 25 U·kg-1 PCC, 1 U FFP, or 50 mL lactated Ringer's vehicle in a blinded manner. Arterial blood samples were drawn every 6 hours. Swine were euthanized 48 hours postinjury. Data were analyzed by Pearson χ2, analysis of variance and Kruskal-Wallis tests with Tukey's or Mann-Whitney U tests for post hoc analysis. RESULTS: Twenty-seven swine received PC + HS, 3 groups of 9 per group received PCC, FFP, or vehicle. Nine were noninjured controls. When compared with control, PC + HS swine had significantly shortened R time at 6 hours, 36 hours, and 42 hours, decreased LY30 at 12 hours, shortened K time at 30 hours and reduced α angle at 42 hours. PC + HS swine showed significant differences between treatment groups in K and α angle at 3 hours, LY30 at 12 hours and 18 hours, and MA at 12 hours, 18 hours, and 30 hours. Post hoc analysis was significant for higher α angle in PCC versus vehicle at 3 hours, higher MA in vehicle versus PCC at 12 hours and 18 hours, and higher LY30 in PCC versus vehicle at 18 hours (p < 0.012) with no significant differences between FFP and vehicle. CONCLUSION: Severe injury with HS induced a coagulopathy in swine. While FFP maintained normal coagulation following injury, PCC induced more rapid initial clot propagation in injured animals.

Use of bilobed partial resuscitative endovascular balloon occlusion of the aorta is logistically superior in prolonged management of a highly lethal aortic injury.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a viable technique for management of noncompressible torso hemorrhage. The major limitation of the current unilobed fully occlusive REBOA catheters is below-the-balloon ischemia-reperfusion complications. We hypothesized that partial aortic occlusion with a novel bilobed partial (p)REBOA-PRO would result in the need for less intraaortic balloon adjustments to maintain a distal goal perfusion pressure as compared with currently available unilobed ER-REBOA. METHODS: Anesthetized (40-50 kg) swine randomized to control (no intervention), ER-REBOA, or pREBOA-PRO underwent supraceliac aortic injury. The REBOA groups underwent catheter placement into zone 1 with initial balloon inflation to full occlusion for 10 minutes followed by gradual deflation to achieve and subsequently maintain half of the baseline below-the-balloon mean arterial pressure (MAP). Physiologic data and blood samples were collected at baseline and then hourly. At 4 hours, the animals were euthanized, total blood loss and urine output were recorded, and tissue samples were collected. RESULTS: Baseline physiologic data and basic laboratories were similar between groups. Compared with control, interventions similarly prolonged survival from a median of 18 minutes to over 240 minutes with comparable mortality trends. Blood loss was similar between partial ER-REBOA (41%) and pREBOA-PRO (51%). Partial pREBOA-PRO required a significantly lower number of intraaortic balloon adjustments (10 ER-REBOA vs. 3 pREBOA-PRO, p < 0.05) to maintain the target below-the-balloon MAP. The partial ER-REBOA group developed significantly increased hypercapnia, fibrin clot formation on TEG, liver inflammation, and IL-10 expression compared with pREBOA-PRO. CONCLUSION: In this highly lethal aortic injury model, use of bilobed pREBOA-PRO for a 4-hour partial aortic occlusion was logistically superior to unilobed ER-REBOA. It required less intraaortic balloon adjustments to maintain target MAP and resulted in less inflammation.

Efficacy of the Abdominal Aortic Junctional Tourniquet-Torso Plate in a Lethal Model of Noncompressible Torso Hemorrhage.

BACKGROUND: The Abdominal Aortic Junctional Tourniquet, when modified with an off-label, prototype, accessory pressure distribution plate (AAJT-TP), has the potential to control noncompressible torso hemorrhage in prolonged field care. METHODS: Using a lethal, noncompressible torso hemorrhage model, 24 male Yorkshire swine (81kg-96kg) were randomly assigned into two groups (control or AAJT-TP). Anesthetized animals were instrumented and an 80% laparoscopic, left-side liver lobe transection was performed. At 10 minutes, the AAJT-TP was applied and inflated to an intraabdominal pressure of 40mmHg. At 20 minutes after application, the AAJT-TP was deflated, but the windlass was left tightened. Animals were observed for a prehospital time of 60 minutes. Animals then underwent damage control surgery at 180 minutes, followed by an intensive care unit-phase of care for an additional 240 minutes. Survival was the primary end point. RESULTS: Compared with Hextend, survival was not significantly different in the AAJT-TP group (ρ = .564), nor was blood loss (3.3L ± 0.5L and 3.0L ± 0.5L, respectively; p = .285). There was also no difference in all physiologic parameters between groups at the end of the study or end of the prehospital phase. Three of 12 AAJT-TP animals had an inferior vena cava thrombus. CONCLUSION: The AAJT-TP did not provide any survival benefit compared with Hextend alone in this model of noncompressible torso hemorrhage.

Efficacy of the perfluorocarbon dodecafluoropentane as an adjunct to pre-hospital resuscitation.

BACKGROUND: Hemorrhage is the most common cause of preventable death in the pre-hospital phase in trauma, with a critical capability gap optimizing pre-hospital resuscitation in austere environments. One promising avenue is the concept of a multi-functional resuscitation fluid (MRF) that contains a blood product backbone with agents that promote clotting and enhance oxygen delivery. Oxygen therapeutics, such as hemoglobin based oxygen carriers(HBOCs) and perfluorocarbons(PFCs), may be a critical MRF component. Our purpose was to assess the efficacy of resuscitation with a PFC, dodecafluoropentane(DDFPe), compared to fresh whole blood(FWB). METHODS AND FINDINGS: Forty-five swine(78±5kg) underwent splenectomy and controlled hemorrhage via femoral arterial catheter until shock physiology(lactate = 7.0) was achieved prior to randomization into the following groups: 1) Control-no intervention, 2)Hextend-500mL, 3)FFP-500mL, 4)FFP+DDFPe-500mL, 5)FWB-500mL. Animals were observed for an additional 180 minutes following randomization. RESULTS: Baseline physiologic values did not statistically differ. At T = 60min, FWB had significantly decreased lactate(p = 0.001) and DDFPe was not statistically different from control. There was no statistical significance in tissue oxygenation(StO2) between groups at T = 60min. Survival was highest in the FWB and Hextend groups(30% at 180min). Kaplan-Meier analysis showed decreased survival of DDFPe+FFP in comparison to FWB(p<0.05) and was not significantly different from control or FFP. Four animals who received DDFPe died within 10 minutes of administration. This study was limited by a group receiving DDFPe alone, however this would not be feasible in this lethal swine model as DDFPe given its small volume. CONCLUSION: DDFPe administration with FFP does not improve survival or enhance tissue oxygenation. However, given similar survival rates of Hextend and FWB, there is evidence that an ideal MRF should contain an element of volume expansion to enhance oxygen delivery.