Intensive Care Unit-Like Care of Nonhuman Primates with Ebola Virus Disease.

BACKGROUND: Ebola virus disease (EVD) supportive care strategies are largely guided by retrospective observational research. This study investigated the effect of EVD supportive care algorithms on duration of survival in a controlled nonhuman primate (NHP) model. METHODS: Fourteen rhesus macaques were challenged intramuscularly with a target dose of Ebola virus (1000 plaque-forming units; Kikwit). NHPs were allocated to intensive care unit (ICU)-like algorithms (n = 7), intravenous fluids plus levofloxacin (n = 2), or a control group (n = 5). The primary outcome measure was duration of survival, and secondary outcomes included changes in clinical laboratory values. RESULTS: Duration of survival was not significantly different between the pooled ICU-like algorithm and control groups (8.2 vs 6.9 days of survival; hazard ratio; 0.50; P = .25). Norepinephrine was effective in transiently maintaining baseline blood pressure. NHPs treated with ICU-like algorithms had delayed onset of liver and kidney injury. CONCLUSIONS: While an obvious survival difference was not observed with ICU-like care, clinical observations from this model may aid in EVD supportive care NHP model refinement.

Efficacy of intermittent versus standard resuscitative endovascular balloon occlusion of the aorta in a lethal solid organ injury model.

BACKGROUND: High-grade solid organ injury is a major cause of mortality in trauma. Use of resuscitative endovascular balloon occlusion of the aorta (REBOA) can be effective but is limited by ischemia-reperfusion injury. Intermittent balloon inflation/deflation has been proposed as an alternative, but the safety and efficacy prior to operative hemorrhage control is unknown. METHODS: Twenty male swine underwent standardized high-grade liver injury, then randomization to controls (N = 5), 60-min continuous REBOA (cR, n = 5), and either a time-based (10-minute inflation/3-minute deflation, iRT = 5) or pressure-based (mean arterial pressure<40 during deflation, iRP = 5) intermittent schedule. Experiments were concluded after 120 minutes or death. RESULTS: Improved overall survival was seen in the iRT group when compared to cR (p < 0.01). Bleeding rate in iRT (5.9 mL/min) was significantly lower versus cR and iRP (p = 0.02). Both iR groups had higher final hematocrit (26% vs. 21%) compared to cR (p = 0.03). Although overall survival was lower in the iRP group, animals surviving to 120 minutes with iRP had decreased end organ injury (Alanine aminotransferase [ALT] 33 vs. 40 in the iRT group, p = 0.03) and lower lactate levels (13 vs. 17) compared with the iRT group (p = 0.03). No differences were seen between groups in terms of coagulopathy based on rotational thromboelastometry. CONCLUSION: Intermittent REBOA is a potential viable adjunct to improve survival in lethal solid organ injury while minimizing the ischemia-reperfusion seen with full REBOA. The time-based intermittent schedule had the best survival and prolonged duration of tolerable zone 1 placement. Although the pressure-based schedule was less reliable in terms of survival, when effective, it was associated with decreased acidosis and end-organ injury.

Lifesaving interventions in blackout conditions using night vision technology: Come to the dark side.

BACKGROUND: During military combat operations and civilian night-time aeromedical transport, medical providers are frequently required to perform lifesaving interventions (LSIs) in low-light environments. Because definitive surgical care is often delayed until a white light environment is permissible, we sought to determine if night optical device (NOD) technology could enable surgical capabilities in blackout conditions. METHODS: Using a crossover design, six surgeons performed 11 different procedures on six swine, three in normal light conditions (LC) and 3 in blackout conditions (BC) using two-chamber NODs after familiarization with the procedures in both conditions on manikins. Successful completion and procedural times were compared between groups. RESULTS: Blackout conditions were confirmed with ambient light reading of 0.2 lux during BC versus 3962.9 lux for LC (p < 0.001). There were no significant differences in success rates for any procedure. There were no differences in operative times between BC and LC for extremity tourniquet placement, femoral artery cut-down and clamping, resuscitative thoracotomy, or percutaneous resuscitative endovascular balloon occlusion of the aorta placement. The following procedures took significantly longer in BC vs. LC: Focused Assessment with Sonography for Trauma examination (98 seconds vs. 62 seconds), peripheral IV placement (140 seconds vs. 35 seconds), intraosseous access (51 seconds vs. 26 seconds), jugular vein cut-down and access (237 seconds vs. 104 seconds), laparotomy and packing (71 seconds vs. 51 seconds), stapled splenectomy (137 seconds vs. 74 seconds), resuscitative endovascular balloon occlusion of the aorta placement via cutdown (1,008 seconds vs. 338 seconds), and cricothyroidotomy (177 seconds vs. 109 seconds) (all p < 0.05). CONCLUSION: Lifesaving interventions can be safely and effectively performed in blackout conditions using NODs, although increased difficulty with select procedure types was identified. Focused training and technological improvements to currently available devices are needed. LEVEL OF EVIDENCE: Basic science.

A fixed moderate-dose combination of tiletamine+zolazepam outperforms midazolam in induction of short-term immobilization of ball pythons (Python regius).

Laboratory animals are commonly anesthetized to prevent pain and distress and to provide safe handling. Anesthesia procedures are well-developed for common laboratory mammals, but not as well established in reptiles. We assessed the performance of intramuscularly injected tiletamine (dissociative anesthetic) and zolazepam (benzodiazepine sedative) in fixed combination (2 mg/kg and 3 mg/kg) in comparison to 2 mg/kg of midazolam (benzodiazepine sedative) in ball pythons (Python regius). We measured heart and respiratory rates and quantified induction parameters (i.e., time to loss of righting reflex, time to loss of withdrawal reflex) and recovery parameters (i.e., time to regain righting reflex, withdrawal reflex, normal behavior). Mild decreases in heart and respiratory rates (median decrease of <10 beats per minute and <5 breaths per minute) were observed for most time points among all three anesthetic dose groups. No statistically significant difference between the median time to loss of righting reflex was observed among animals of any group (p = 0.783). However, the withdrawal reflex was lost in all snakes receiving 3mg/kg of tiletamine+zolazepam but not in all animals of the other two groups (p = 0.0004). In addition, the time for animals to regain the righting reflex and resume normal behavior was longer in the drug combination dose groups compared to the midazolam group (p = 0.0055). Our results indicate that midazolam is an adequate sedative for ball pythons but does not suffice to achieve reliable immobilization or anesthesia, whereas tiletamine+zolazepam achieves short-term anesthesia in a dose-dependent manner.

Extending the golden hour for Zone 1 resuscitative endovascular balloon occlusion of the aorta: Improved survival and reperfusion injury with intermittent versus continuous resuscitative endovascular balloon occlusion of the aorta of the aorta in a porcine severe truncal hemorrhage model.

BACKGROUND: Noncompressible hemorrhage can be controlled using resuscitative endovascular balloon occlusion of the aorta (REBOA). Prolonged ischemia limits REBOA application during Zone 1 deployment. Intermittent inflation/deflation may effectively mitigate this problem. METHODS: A lethal abdominal vascular injury was created in 28 swines. Animals were randomized to controls (n = 7), 60 minutes full REBOA (FR, n = 5), time-based intermittent REBOA (iRT, n = 7), and pressure-based REBOA (iRP, n = 9). Intermittent groups had an initial inflation for 15 minutes, followed by 10-minute inflation: 3-minute deflation cycles (iRT), or an inflate/deflate schedule based on mean arterial pressure (MAP) less than 40 mm Hg (iRP). Experiments were concluded after 120 minutes or death (MAP < 20 mm Hg). RESULTS: Intermittent REBOA animals all survived to 120 minutes versus 15 minutes for controls and 63 minutes for FR (p < 0.001). After 60 minutes, FR animals were more hypotensive (MAP 20 mm Hg vs. 80 mm Hg [iRP] and 100 mm Hg [iRT]; p < 0.001), had lower cardiac output (1.06 mL/min vs. 5.1 L/min [iRP] and 8.2 L/min [iRT]; p < 0.001), higher lactate (12.5 mg/dL vs. 8.5 mg/dL [iRP], p = 0.02), and decreased clot firmness on rotational thromboelastometry than iRP/T (64 mm vs. 69 mm [iRP] and 69 mm [iRT], p = 0.04). Acidosis was worse in iRT versus iRP at 120 minutes (pH 7.28 vs. pH 7.12; p = 0.02), improved lactate (11.9 mg/dL vs. 16.3 mg/dL; p = 0.04), and decreased whole blood resuscitation (452 mL vs. 646 mL, p = 0.05). Blood loss (clot weight) was higher in controls (2.0 kg) versus iRT and iRP (1.16 kg and 1.23 kg; p < 0.01) and not different from FR (0.87 kg; p = 0.10). CONCLUSION: Intermittent REBOA can maintain supraceliac hemorrhage control while decreasing distal ischemia in a swine model. Prolonged survival times, decreased acidosis, and lower resuscitation requirements indicate that this technique could potentially extend Zone 1 REBOA deployment times. Schedules based on MAP may be superior to time-based regimens.

Mobile forward-looking infrared technology allows rapid assessment of resuscitative endovascular balloon occlusion of the aorta in hemorrhage and blackout conditions.

INTRODUCTION: Objective assessment of final resuscitative endovascular balloon occlusion of the aorta (REBOA) position and adequate distal aortic occlusion is critical in patients with hemorrhagic shock, especially as feasibility is being increasingly investigated in the prehospital setting. We propose that mobile forward-looking infrared (FLIR) thermal imaging is a fast, reliable, and noninvasive method to assess REBOA position and efficacy in scenarios applicable to battlefield and prehospital care. METHODS: Ten swine were randomized to a 40% hemorrhage group (H, n = 5) or nonhemorrhage group (NH, n = 5). Three experiments were completed after Zone I placement of a REBOA catheter. Resuscitative endovascular balloon occlusion of the aorta was deployed for 30 minutes in all animals followed by randomized continued deployment versus sham in both light and blackout conditions. Forward-looking infrared images and hemodynamic data were obtained. Images were presented to 62 blinded observers for assessment of REBOA inflation status. RESULTS: There was no difference in hemodynamic or laboratory values at baseline. The H group was significantly more hypotensive (mean arterial pressure 44 vs. 60 mm Hg, p < 0.01), vasodilated (systemic vascular resistance 634 vs. 938dyn·s/cm, p = 0.02), and anemic (hematocrit 12 vs. 23.2%, p < 0.01). Hemorrhage group animals remained more hypotensive, anemic, and acidotic throughout all three experiments. There was a significant difference in the temperature change (ΔTemp) measured by FLIR between animals with REBOA inflated versus not inflated (5.7°C vs. 0.7°C, p < 0.01). The H and NH animals exhibited equal magnitudes of ΔTemp in both inflated and deflated states. Blinded observer analysis of FLIR images correctly identified adequate REBOA inflation and aortic occlusion 95.4% at 5 minutes and 98.8% at 10 minutes (positive predictive value at 5 minutes = 99% and positive predictive value at 10 minutes = 100%). CONCLUSIONS: Mobile thermal imaging is an easy, rapid, and reliable method for assessing distal perfusion after occlusion by REBOA. Smartphone-based FLIR technology allows for confirmation of adequate REBOA placement at the point of care, and performance was not degraded in the setting of major hemorrhage or blackout conditions.

Plasma coadministration improves resuscitation with tranexamic acid or prothrombin complex in a porcine hemorrhagic shock model.

BACKGROUND: Traumatic coagulopathy has now been well characterized and carries high rates of mortality owing to bleeding. A 'factor-based' resuscitation strategy using procoagulant drugs and factor concentrates in lieu of plasma is being used by some, but with little evidentiary support. We sought to evaluate and compare resuscitation strategies using combinations of tranexamic acid (TXA), prothrombin complex concentrate (PCC), and fresh frozen plasma (FFP). METHODS: Sixty adult swine underwent 35% blood volume hemorrhage combined with a truncal ischemia-reperfusion injury to produce uniform shock and coagulopathy. Animals were randomized to control (n = 12), a single-agent group (TXA, n = 10; PCC, n = 8; or FFP, n = 6) or combination groups (TXA-FFP, n = 10; PCC-FFP, n = 8; TXA-PCC, n = 6). Resuscitation was continued to 6 hours. Key outcomes included hemodynamics, laboratory values, and rotational thromboelastometry. Results were compared between all groups, with additional comparisons between FFP and non-FFP groups. RESULTS: All 60 animals survived to 6 hours. Shock was seen in all animals, with hypotension (mean arterial pressure, 44 mm Hg), tachycardia (heart rate, 145), acidosis (pH 7.18; lactate, 11), anemia (hematocrit, 17), and coagulopathy (fibrinogen, 107). There were clear differences between groups for mean pH (p = 0.02), international normalized ratio (p < 0.01), clotting time (CT; p < 0.01), lactate (p = 0.01), creatinine (p < 0.01), and fibrinogen (p = 0.02). Fresh frozen plasma groups had significantly improved resuscitation and clotting parameters (Figures), with lower lactate at 6.5 versus 8.4 (p = 0.04), and increased fibrinogen at 126 versus 95 (p < 0.01). Rotational thromboelastometry also demonstrated shortened CT at 60 seconds in the FFP group vs 65 seconds in the non-FFP group (p = 0.04). CONCLUSION: When used to correct traumatic coagulopathy, combinations of FFP with TXA or PCC were superior in improving acidosis, coagulopathy, and CT than when these agents are given alone or in combination without plasma. Further validation of pure factor-based strategies is needed.

The effects of hemorrhage on the pharmacokinetics of tranexamic acid in a swine model.

BACKGROUND: The early use of tranexamic acid (TXA) is strongly advocated in patients who are likely to require massive transfusion to decrease mortality. This study determines the influence of hemorrhage on the pharmacokinetics of TXA in a porcine model. METHODS: The investigation was a prospective experimental study in Yucatan minipigs. First, in vitro plasma-cell partitioning of TXA was evaluated by inoculating whole blood with known aliquots, centrifuging, and measuring the supernatant with high-performance liquid chromatography with mass spectrometry (HPLC-MS). Then, using in vivo modeling, normovolemic and hypovolemic (35% reduction in blood volume) swine (n = 4 per group) received 1 g of intravenous TXA and had blood sampled at 14 time points over 4 hours to determine baseline clearance via HPLC-MS. Additional swine (n = 4) were hemorrhaged 35% of their blood volume, and TXA was administered as a 15 mg/kg infusion over 10 minutes followed by infusion of 1.875 mg/kg per hour to simulate massive hemorrhage scenario. During the first hour of TXA administration, one total blood volume was hemorrhaged and simultaneously replaced with TXA free blood. Serial blood samples and the hemorrhaged blood were analyzed by HPLC-MS to determine the percentage of dose lost via hemorrhage. RESULTS: Clearance of TXA was diminished in the hypovolemic group compared with the normovolemic group (115 ± 4 vs 70 ± 7 mL/min). Percentage of dose lost via hemorrhage averaged 25%. The lowest measured plasma level during the exchange transfusion was 34 µg/mL. CONCLUSION: Mean 25% of the present 2017 Joint Trauma System Clinical Practice Guideline dosing of TXA can be lost to hemorrhage if a blood volume is transfused within an hour of initiating therapy. In the case of TXA, which has limited distribution and is administered during active hemorrhage and massive blood transfusions, replacement strategies should be developed and tested to find simple methods of adjusting the current dosing guidelines to maintain therapeutic plasma concentrations. LEVEL OF EVIDENCE: Therapeutic, level II.

Evaluation of a novel thoracic entry device versus needle decompression in a tension pneumothorax swine model.

INTRODUCTION: Tension pneumothorax (tPTX) remains a major cause of preventable death in trauma. Needle decompression (ND) has up to a 60% failure rate. METHODS: Post-mortem swine used. Interventions were randomized to 14G-needle decompression (ND, n = 25), bladed trocar with 36Fr cannula (BTW, n = 16), bladed trocar alone (BTWO, n = 16) and surgical thoracostomy (ST = 11). Simulated tPTX was created to a pressure(p) of 20 mmHg. RESULTS: Success (p < 5 mmHg by 120 s) was seen in 41 of 68 (60%) interventions. BTW and BTWO were consistently more successful than ND with success rates of 88% versus 48% in ND (p < .001). In successful deployments, ND was slower to reach p < 5 mmHg, average of 82s versus 26s and 28s for BTW and BTWO respectively (p < .001). Time to implement procedure was faster for ND with an average of 3.6s versus 16.9s and 15.3s in the BTW and BTWO (p < .001). Final pressure was significantly less in BTW and BTWO at 1.7 mmHg versus 7 mmHg in ND animals (p < .001). CONCLUSION: Bladed trocars can safely and effectively tPTX with a significantly higher success rates than needle decompression.

No intravenous access, no problem: Intraosseous administration of tranexamic acid is as effective as intravenous in a porcine hemorrhage model.

BACKGROUND: The acute coagulopathy of trauma is often accompanied by hyperfibrinolysis. Tranexamic acid (TXA) can reverse this phenomenon, and, when given early, decreases mortality from bleeding. Establishing intravenous (IV) access can be difficult in trauma and intraosseous (IO) access is often preferred for drug administration. Currently, there are no data on the efficacy of IO administered TXA. Our objectives were to compare serum concentrations of TXA when given IV and IO and to compare the efficacy of IO administered TXA to IV at reversing hyperfibrinolysis. METHODS: Using a porcine hemorrhage and ischemia-reperfusion model, 18 swine underwent hemorrhagic shock followed by a tissue plasminogen activator infusion to induce hyperfibrinolysis. Animals then received an IV or tibial IO infusion of TXA over 10 minutes. Blood was then analyzed using rotational thromboelastometry to monitor reversal of hyperfibrinolysis. Serum was analyzed for drug concentrations. RESULTS: After hemorrhage and ischemia-reperfusion, there were no significant differences in mean arterial pressure (48 vs. 49.5), lactate (11.1 vs. 10.8), and pH (7.20 vs. 7.22) between groups. Intraosseous TXA corrected the lysis index at 30 minutes in EX-TEM and IN-TEM, like IV infusion. Peak serum levels of TXA after IV and IO administration show concentrations of 160.9 µg/mL and 132.57 µg/mL respectively (p = 0.053). Peak levels occurred at the completion of infusion. Drug levels were tracked for four hours. At the end of monitoring, plasma concentrations of TXA were equivalent. CONCLUSION: Intraosseous administration of TXA is as effective as IV in reversing hyperfibrinolysis in a porcine model of hemorrhagic shock. Intraosseous administration was associated with a similar peak levels, pharmacokinetics, and clearance. Intraosseous administration of TXA can be considered in hemorrhagic shock when IV access cannot be established.

Reproducing severe acute subglottic stenosis in a rabbit model.

OBJECTIVES: The objectives of this study were to develop an animal model with consistent, severe subglottic stenosis (SGS), and to develop the timeline needed for intervention to limit rabbit mortality. METHODS: Subglottic stenosis was created endoscopically using either a nylon or polypropylene brush in sixteen New Zealand White rabbits. The subglottic cross-sectional area was measured endoscopically using a right-angled probe and an open source image analysis software The cross-sectional areas of the stenotic and native airways were compared to calculate the subglottic stenosis percentage and Myer-Cotton grade classification. RESULTS: The average diameter of the native subglottis was 4.7 mm (SD 0.4). The mean subglottic stenosis percentage was 73% (SD 32) for all rabbits. The three rabbits injured with the nylon brush had 30, 52, and 76% stenosis. Nine of the 12 surviving rabbits (75%) injured with the polypropylene brush had a >86% subglottic stenosis. Four rabbits in the polypropylene brush cohort died from procedural complications. CONCLUSION: This study demonstrates a reliable model using a polypropylene brush to create severe acute subglottic stenosis. Cartilage exposure after creating the injury was associated with more severe stenosis. Mortality rate may have been reduced if endoscopic balloon dilation was performed electively seven days after injury, rather than emergently nine days after injury. LEVEL OF EVIDENCE: 4.

Smartphone-based mobile thermal imaging technology to assess limb perfusion and tourniquet effectiveness under normal and blackout conditions.

BACKGROUND: Over the past decade, there has been a resurgence of tourniquet use in civilian and military settings. Several key challenges include assessment of limb perfusion and adequacy of tourniquet placement, particularly in the austere or prehospital environments. We investigated the utility of thermal imaging to assess adequacy of tourniquet placement. METHODS: The FLIR ONE smartphone-based thermal imager was utilized. Ten swine underwent tourniquet placement with no associated hemorrhage (n = 5) or with 40% hemorrhage (n = 5). Experiment 1 simulated proper tourniquet application, experiment 2 had one of two tourniquets inadequately tightened, and experiment 3 had one of two tourniquets inadequately tightened while simulating blackout-combat conditions. Static images were taken at multiple time points up to 30 minutes. Thermal images were then presented to blinded evaluators who assessed adequacy of tourniquet placement. RESULTS: The mean core temperature was 38.3 °C in non-hemorrhaged animals versus 38.2 °C in hemorrhaged animals. Hemorrhaged animals were more hypotensive (p = 0.001), anemic (p < 0.001), vasodilated (p = 0.008), and had a lower cardiac output (p = 0.007) compared to non-hemorrhaged animals. The thermal imaging temperature reading decreased significantly after proper tourniquet placement in all animals, with no difference between hemorrhaged and non-hemorrhaged groups at 30 minutes (p = 0.23). Qualitative thermal image analysis showed clearly visible perfusion differences in all animals between baseline, adequate tourniquet, and inadequate tourniquet in both hemorrhaged and non-hemorrhaged groups. Ninety-eight percent of blinded evaluators (n = 62) correctly identified adequate and inadequate tourniquet placement at 5 minutes. Images in blackout conditions showed no adverse impact on thermal measurements or in the ability to accurately characterize perfusion and tourniquet adequacy. CONCLUSIONS: A simple handheld smartphone-based forward looking infrared radiometry device demonstrated a high degree of accuracy, reliability, and ease of use for assessing limb perfusion. Forward looking infrared radiometry also allowed for rapid and reliable identification of adequate tourniquet placement that was not affected by major hemorrhage or blackout conditions.

Three- versus four-factor prothrombin complex concentrates for "factor-based" resuscitation in a porcine hemorrhagic shock model.

BACKGROUND: Bleeding is a leading cause of preventable death after severe injury. Prothrombin complex concentrates (PCC) treat inborn coagulation disorders and reverse oral anticoagulants, but are proposed for use in "factor-based" resuscitation strategies. Few studies exist for this indication in acidosis, or that compare 3-factor PCC (3PCC) versus 4-factor PCC (4PCC) products. We aimed to assess and compare their safety and efficacy in a porcine model of severe hemorrhagic shock and coagulopathy. METHODS: Twenty-five adult Yorkshire swine underwent 35% volume hemorrhage, ischemia-reperfusion injury, and protocolized crystalloid resuscitation. Seventeen animals were randomized at 4 hours after model creation to receive a 45-IU/kg dose of either 3PCC or 4PCC. An additional eight animals received autologous plasma transfusion before 4PCC to better characterize response to PCC. Individual factor levels were drawn at 4 hours and 6 hours. RESULTS: The model created significant acidosis with mean pH of 7.21 and lactate of 9.6 mmol/L. After PCC, 66.7% of 3PCC animals and 25% of 4PCC animals (regardless of plasma administration) developed consumptive coagulopathy. The animals that developed consumptive coagulopathy had manifested the "lethal triad" with lower temperatures (36.3°C vs. 37.8°C), increased acidosis (pH, 7.14 vs. 7.27; base excess, -12.1 vs. -6.5 mEq/L), and worse coagulopathy (prothrombin time, 17.1 vs. 14.6 seconds; fibrinogen, 87.9 vs. 124.1 mg/dL) (all p < 0.05). In the absence of a consumptive coagulopathy, 3PCC and 4PCC improved individual clotting factors with transient improvement of prothrombin time, but there was significant depletion of fibrinogen and platelets with no lasting improvement of coagulopathy. CONCLUSION: PCC failed to correct coagulopathy and was associated with fibrinogen and platelet depletion. Of greater concern, PCC administration resulted in consumptive coagulopathy in the more severely ill animals. The incidence of consumptive coagulopathy was markedly increased with 3PCC versus 4PCC, and these products should be used with caution in this setting.

Resuscitative endovascular balloon occlusion of the aorta for major abdominal venous injury in a porcine hemorrhagic shock model.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a rescue maneuver for unstable patients with noncompressible hemorrhage below the diaphragm. The efficacy of REBOA in the setting a major abdominal venous injury is unknown. Our objective was to examine the use of REBOA in a large animal model of major abdominal venous injury and characterize any impact on the hemodynamics, rate and volume of hemorrhage, and survival. METHODS: Ten swine (35-55 kg) underwent a controlled and validated hemorrhage and ischemia/reperfusion injury protocol to produce shock physiology. Animals were randomly assigned to a control arm (N = 5) or a treatment (REBOA) arm (N = 5). An injury was then created in the common iliac vein. Bleeding was allowed for 60 seconds and the balloon was then inflated in the REBOA arm. Hemodynamics were recorded for 45 minutes or until death. Blood loss was verified post-mortem and bleeding rate calculated. RESULTS: All animals demonstrated shock physiology at the time of randomization. There were no differences between control versus REBOA animals in baseline mean arterial pressure (42 vs. 50), pH (7.29 vs. 7.26), lactate (6.19 vs. 6.26), or INR (1.2 vs. 1.3, all p = NS). REBOA animals demonstrated immediate improvements in mean arterial pressure (50.6 vs. 97.2, p = 0.04). The mean survival time was 4.1 minutes for controls (100% died) versus 40.1 minutes for REBOA (p < 0.01). There was no difference in total blood loss (mean 630 mL for both). The rate of bleeding was significantly lower in the REBOA animals (control 197 mL/min vs. REBOA 14 mL/min, p = 0.02). CONCLUSION: In the setting of an abdominal venous injury, REBOA improved hemodynamics and lengthened survival time. Blood loss was similar between groups but the rate of bleeding was markedly decreased with REBOA. REBOA appears effective for central venous injuries and provides a sustained period of stabilization and window for surgical intervention.

There's an app for that: A handheld smartphone-based infrared imaging device to assess adequacy and level of aortic occlusion during REBOA.

BACKGROUND: Advances in thermal imaging devices have made them an appealing noninvasive point-of-care imaging adjunct in the trauma setting. We sought to assess whether a smartphone-based infrared imaging device (SBIR) could determine presence and location of aortic occlusion in a swine model. We hypothesized that various levels of aortic occlusion would transmit significantly different heat signatures at various anatomical points. METHODS: Six swine (35-50 kg) underwent sequential zone 1 (Z1) aortic cross clamping as well as zone 3 (Z3) aortic balloon occlusion (resuscitative endovascular balloon occlusion of the aorta [REBOA]). SBIR images and readings (FLIR One) were taken at five anatomic points (axilla [A], subcostal [S], umbilical [U], inguinal [I], medial malleolar [M]) and were used to determine significant thermal trends 5 minutes to 10 minutes after Z1 and Z3 occlusion. Significant (p ≤ 0.05) thermal ratio patterns were identified and compared among groups, and images were reviewed for obvious qualitative differences at the various levels of occlusion. RESULTS: Body temperatures were similar during control (CON), Z1 occlusion, and Z3 occlusion, ranging from 94.0 °F to 100.9 °F (p = 0.126). No significant temperature differences were found among A, S, U, I, M points prior to and after aortic occlusions. Among the anatomical 2-point ratios evaluated, A/M and S/M ratios were the best predictors of aortic occlusion, whether at Z1 (8.2 °F, p < 0.01; 10.9 °F, p < 0.01) or Z3 (7.3 °F, p < 0.01; 8.4 °F, p < 0.01), respectively. The best predictor of Z1 versus Z3 level of occlusion was the S/I ratio (5.2 °F, p < 0.05 vs. 3.4 °F, p = 0.27). SBIR generated qualitatively different thermal signatures among groups. CONCLUSION: SBIR was capable of detecting thermal trends during Z1 and Z3 aortic occlusion by using an anatomical 2-point thermal ratio. There were also easily recognized qualitative differences between control and occlusion images that would allow immediate determination of adequate occlusion of the aorta. SBIR represents a potential inexpensive and accurate tool for assessing perfusion, adequate REBOA placement, and even the aortic level of occlusion.

Preperitoneal balloon tamponade for lethal closed retroperitoneal pelvic hemorrhage in a swine model: A comparable and minimally invasive alternative to open pre-peritoneal pelvic packing.

BACKGROUND: The management of massive pelvic fracture-associated hemorrhage is extremely challenging, particularly in the unstable patient. We sought to characterize and compare the efficacy of a minimally invasive preperitoneal balloon technique (MIB) to standard open packing. METHODS: Twenty-six swine were randomized to control (C), open preperitoneal packing technique (OP), and MIB groups. A closed extraperitoneal iliac vascular injury followed by intervention + resuscitation over a 120-minute OP and MIB efficacy was assessed by procedure time, hemodynamics, extraperitoneal tamponade pressures (ETPs), blood loss, and survival. Angiography was performed in select animals, and ETPs were also measured in humans undergoing MIB placement for an elective procedure. RESULTS: Baseline parameters (mean arterial pressure [MAP] 29, 38, and 38 mm Hg; cardiac index [CI] 3.5, 3.8, and 4.2; and EPTs 5, 4, and 5 mm Hg) were similar among C, OP, and MIB groups, respectively (all p's > 0.05). The OP and MIB groups had markedly improved MAP and CI versus C. MIB generated significantly higher ETP (28 vs 17 mm Hg), was faster to deploy (164 vs 497 seconds), and had lower total blood loss versus OP (0.7 vs 1.2 L, all p's < 0.05). OP and MIB had equivalent survival times that were significantly improved versus C (91 and 116 vs 43 minutes, p < 0.05). Survival to 2 hours was 80% with OP versus 100% in the MIB group. Angiography showed no active extravasation in both study groups, but controlled partial deflation of the MIB allowed easy visualization of extravasation. Minimally invasive preperitoneal balloon inflation in five human subjects demonstrated a significant increase in mean ETP from 2.4 to 31 mm Hg (p < 0.01). CONCLUSION: Minimally invasive preperitoneal balloon tamponade was as effective as OP in improving hemodynamics and prolonging survival times, and performed superiorly to OP in time to placement, blood loss, and generation of tamponade pressures. The MIB allows for controlled deflation and reinflation to facilitate angiographic interventions, and may represent a promising new bedside intervention in this patient population.

Inducing metabolic suppression in severe hemorrhagic shock: Pilot study results from the Biochronicity Project.

BACKGROUND: Suspended animation-like states have been achieved in small animal models, but not in larger species. Inducing metabolic suppression and temporary oxygen independence could enhance survivability of massive injury. Based on prior analyses of key pathways, we hypothesized that phosphoinositol-3-kinase inhibition would produce metabolic suppression without worsening organ injury or systemic physiology. METHODS: Twenty swine were studied using LY294002 (LY), a nonselective phosphoinositol-3-kinase inhibitor. Animals were assigned to trauma only (TO, n = 3); dimethyl sulfoxide only (DMSO, n = 4), LY drug only (LYO, n = 3), and drug + trauma (LY + T, n = 10) groups. Both trauma groups underwent laparotomy, 35% hemorrhage, severe ischemia/reperfusion injury, and protocolized resuscitation. Laboratory, physiologic, cytokine, and metabolic cart data were obtained. Histology of key end organs was also compared. RESULTS: Baseline values were similar among the groups. Compared with the TO group, the LYO group had reversible decreases in heart rate, mean arterial pressure, cardiac output, oxygen consumption, and carbon dioxide production. Compared with TO, LY + T showed sustained decreases in heart rate (113 vs. 76, p = 0.03), mean arterial pressure (40 vs. 31 mm Hg, p = 0.02), and cardiac output (3.8 vs. 1.9 L/min, p = 0.05) at 6 hours. Metabolic parameters showed profound suppression in the LY + T group. Oxygen consumption in LY + T was lower than both TO (119 vs. 229 mL/min, p = 0.012) and LYO (119 vs. 225 mL/min, p = 0.014) at 6 hours. Similarly, carbon dioxide production was decreased at 6 hours in LY + T when compared with TO (114 vs. 191 mL/min, p = 0.043) and LYO (114 vs. 195 mL/min, p = 0.034) groups. There was no worsening of acidosis (lactate 6.4 vs. 8.3 mmol/L, p = 0.4) or other endpoints. Interleukin 6 (IL-6) showed a significant increase in LY + T when compared with TO at 6 hours (60.5 vs. 2.47, p = 0.043). Tumor necrosis factor α and IL-1ß were decreased, and IL-10 increased in TO and LY + T at 6 hours. Markers of liver and kidney injury were no different between TO and LY + T groups at 6 hours. CONCLUSIONS: Phosphoinositol-3-kinase inhibition produced metabolic suppression in healthy and injured swine without increasing end-organ injury or systemic physiologic markers and demonstrated prolonged efficacy in injured animals. Further study may lead to targeted therapies to prolong tolerance to hemorrhage and extend the "golden hour" for injured patients.

Efficacy of a novel fluoroscopy-free endovascular balloon device with pressure release capabilities in the setting of uncontrolled junctional hemorrhage.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) has emerged as an alternative to gauze packing (GP) in the setting of noncompressible torso hemorrhage. Our objective was to describe placement and physiologic impact of a novel REBOA device during uncontrolled junctional hemorrhage. We hypothesized that REBOA could be deployed without fluoroscopic guidance or intra-aortic barotrauma and could increase survival in the setting of profound shock physiology. METHODS: Fourteen adult swine (35-50 kg) underwent a hemorrhage and ischemia/reperfusion injury protocol to produce shock physiology and dilutional coagulopathy and randomized to REBOA (n = 8) or standard GP (n = 6) groups. A complex contralateral groin soft tissue and vascular injury was then created, followed by 30 seconds of free bleeding and GP for 5 minutes. The REBOA group had the aortic balloon inflated in aortic Zone III until the pressure release valve opened, followed by 45-minute postpacking survival, after which native and balloon-exposed aortae were harvested for histologic analysis. RESULTS: Control and REBOA groups had similar baseline hemodynamics (mean arterial pressure, 32 mm Hg vs. 43 mm Hg; p = 0.228), levels of coagulopathy (international normalized ratio, 1.3 vs. 1.2, p = 0.476; fibrinogen, 108 vs. 135 mg/dL, p = 0.747), and hemorrhage/ischemia/reperfusion insult (lactate, 7 vs. 7, p = 0.950; base deficit, 9 vs. 5, p = 0.491). No histologic barotrauma was identified, and 88% of the REBOA devices were successfully deployed into the Zone III of the aorta. The REBOA group had significantly decreased hemorrhage volumes (0.5 L vs. 0.2 L, p = 0.014) and increased survival times (45 minutes vs. 8 minutes, p < 0.001). CONCLUSION: This study reinforces results found in previous studies that REBOA is an effective method to increase survival in the setting of noncompressible torso hemorrhage and is the first to show that this specific REBOA device can be blindly guided into the appropriate zone of the aorta without generating aortic wall injury during unmeasured balloon inflation.

Measurement of fecal corticosterone metabolites as a predictor of the habituation of rhesus macaques (Macaca mulatta) to jacketing.

Jacket use in NHP is a common practice and is often considered a form of refinement during experiments necessitating extended periods of catheterization. An important consideration when using jackets is the physiologic effects that jacketing has on NHP and its potential to confound research. Several studies have evaluated the stress response and habituation of NHP to various forms of restraint, but none have looked directly at the timeframe necessary for the habituation of rhesus macaques (Macaca mulatta) to jackets. We set out to determine whether 3 d was a sufficient timeframe for this species to become habituated to a jacket, with or without an undershirt, by evaluating 2 major physiologic parameters. After jacket placement, we measured food consumption and collected fecal samples to measure fecal corticosterone metabolites (FCM) daily for 2 wk. FCM measurements for NHP without undershirts were significantly increased for days 2 and 3 after jacketing before returning to baseline levels. FCM measurements for NHP with undershirts were significantly increased for only 1 d after jacketing, suggesting that the undershirt has a positive effect on jacket habituation. There were no measurable differences in food consumption during the jacket habituation period. Furthermore, no significant differences were noted between sexes. These findings suggest that FCM levels return to baseline 3 d after jacketing and could be a useful predictor of jacket habituation in rhesus macaques.

Euthanasia assessment in ebola virus infected nonhuman primates.

Multiple products are being developed for use against filoviral infections. Efficacy for these products will likely be demonstrated in nonhuman primate models of filoviral disease to satisfy licensure requirements under the Animal Rule, or to supplement human data. Typically, the endpoint for efficacy assessment will be survival following challenge; however, there exists no standardized approach for assessing the health or euthanasia criteria for filovirus-exposed nonhuman primates. Consideration of objective criteria is important to (a) ensure test subjects are euthanized without unnecessary distress; (b) enhance the likelihood that animals exhibiting mild or moderate signs of disease are not prematurely euthanized; (c) minimize the occurrence of spontaneous deaths and loss of end-stage samples; (d) enhance the reproducibility of experiments between different researchers; and (e) provide a defensible rationale for euthanasia decisions that withstands regulatory scrutiny. Historic records were compiled for 58 surviving and non-surviving monkeys exposed to Ebola virus at the US Army Medical Research Institute of Infectious Diseases. Clinical pathology parameters were statistically analyzed and those exhibiting predicative value for survival are reported. These findings may be useful for standardization of objective euthanasia assessments in rhesus monkeys exposed to Ebola virus and may serve as a useful approach for other standardization efforts.