Transition of Resuscitative Endovascular Balloon Occlusion of the Aorta from Zone 3 to Zone 1 to Treat Hemodynamic Collapse during Continued Hemorrhage.

INTRODUCTION: Noncompressible torso hemorrhage (NCTH) accounts for most potentially survivable deaths on the battlefield. Treatment of NCTH is challenging, especially in far-forward environments with limited capabilities. Resuscitative endovascular balloon occlusion of the aorta (REBOA) has shown promise in the care of patients with NCTH. REBOA involves introducing a balloon catheter into the descending aorta in a specific occlusion region (zones 1, 2, or 3) and acts as a hemorrhage control adjunct with resuscitative support. The balloon is placed in zone 3 in the infrarenal aorta for high junctional or pelvic injuries and in zone 1 proximal to the diaphragm for torso hemorrhage. Zone 1 REBOA provides more resuscitative support than zone 3; however, the potential for ischemia and reperfusion injuries is greater with zone 1 than with zone 3 REBOA placement. This study aims to determine the possible benefit of transitioning the REBOA balloon from zone 3 to zone 1 to rescue a patient with ongoing venous bleeding and impending cardiovascular collapse. MATERIALS AND METHODS: Yorkshire male swine (70-90 kg, n = 6 per group) underwent injury to the femoral artery, which was allowed to bleed freely for 60 s, along with a simultaneous controlled venous hemorrhage. After 60 s, the arterial bleed was controlled with hemostatic gauze and zone 3 REBOA was inflated. Five hundred milliliters of Hextend was used for initial fluid resuscitation. The controlled venous bleed continued until a mean arterial pressure (MAP) of 30 mmHg was reached to create an impending cardiovascular collapse. The animals were then randomized into either continued zone 3 REBOA or transition from zone 3 to zone 1 REBOA. Following 30 min, a "hospital phase" was initiated, consisting of cessation of the venous hemorrhage, deflation of the REBOA balloon, and transfusion of one unit of whole blood administered along with saline and norepinephrine to maintain a MAP of 60 mmHg or higher. The animals then underwent a 2-h observation period. Survival, hemodynamics, and blood chemistries were compared between groups. RESULTS: No significant differences between groups were observed in hemodynamic or laboratory values at baseline, postinitial injury, or when MAP reached 30 mmHg. Survival was significantly longer in animals that transitioned into zone 1 REBOA (log-rank analysis, P = .012). The average time of survival was 14 ± 10 min for zone 3 animals vs. 65 ± 59 min for zone 1 animals (P = .064). No animals in the zone 3 group survived to the hospital phase. Zone 1-treated animals showed immediate hemodynamic improvement after transition, with maximum blood pressure reaching near baseline values compared to those in the zone 3 group. CONCLUSIONS: In this swine model of NCTH, hemodynamics and survival were improved when the REBOA balloon was transitioned from zone 3 to zone 1 during an impending cardiovascular collapse. Furthermore, these improved outcome data support the pursuit of additional research into mitigating ischemia-reperfusion insult to the abdominal viscera while still providing excellent resuscitative support, such as intermittent or partial REBOA.

Testing and Evaluation of a Novel Hemostatic Matrix in a Swine Junctional Hemorrhage Model.

INTRODUCTION: In an ongoing effort to improve survival and reduce blood loss from hemorrhagic injuries on the battlefield, new hemostatic dressings continue to be developed. This study aimed to determine the efficacy of a novel silicon dioxide-based hemostatic matrix (HM) and compare it with the current military standard Quikclot Combat Gauze (QCG) utilizing a lethal femoral artery injury model. MATERIALS AND METHODS: The femoral arteries of 20 anesthetized swine were isolated, and an arteriotomy was performed. After a 45 s free bleed, the wound was treated with either HM or QCG (n = 10 per group). Following a 60-min observation period, ipsilateral leg manipulations and angiography were performed. Animal survival, hemostasis, blood loss, exothermic reaction, and femoral artery patency were analyzed. RESULTS: Despite a volumetric size discrepancy between the two products tested, the survival rate was similar between the two groups (80% HM, 90% QCG, n = 10, P = 0.588). Immediate hemostasis was obtained in 50% of HM animals and 40% of QCG animals. There was no difference in total blood loss recorded between the two groups (P = 0.472). Femoral artery patency rates following ipsilateral leg manipulations were similar between the two groups (50% HM, 33% QCG, P = 0.637), with no contrast extravasation in HM-treated wounds (0% HM, 33% QCG, P = 0.206). There was no significant difference in either pretreatment or posttreatment laboratory values, and there were no exothermic reactions in either group. CONCLUSIONS: The SiOxMed HM demonstrated comparable hemostatic efficacy to QCG. The tested form of HM may be appropriate for surgical or topical hemostasis applications, and with further product development, it could be used for battlefield trauma implementation.

Performance of a novel temporary arterial shunt in a military-relevant controlled hemorrhage swine model.

BACKGROUND: In military trauma, temporary vascular shunts restore arterial continuity until delayed vascular reconstruction, often for a period of hours. A novel US Air Force-developed trauma-specific vascular injury shunt (TS-VIS) incorporates an accessible side port for intervention or monitoring, which may improve patency under adverse hemodynamic conditions. Our objective was to evaluate TS-VIS patency in the setting of volume-limited resuscitation from hemorrhagic shock. METHODS: Female swine (70-90 kg) underwent 30% hemorrhage and occlusion of the left external iliac artery for 30 minutes. Animals were allocated to one of three groups (n = 5 per group) by left external iliac artery treatment: Sundt shunt (SUNDT), TS-VIS with arterial pressure monitoring (TS-VIS), or TS-VIS with heparin infusion (10 µ/kg per hour, TS-VISHep). Animals were resuscitated with up to 3 U of whole blood to maintain a mean arterial pressure (MAP) of >60 mm Hg and were monitored for 6 hours. Bilateral femoral arterial flow was continuously monitored with transonic flow probes, and shunt thrombosis was defined as the absence of flow for greater than 5 minutes. RESULTS: No intergroup differences in MAP or flow were observed at baseline or following hemorrhage. Animals were hypotensive at shunt placement (MAP, 35.5 ± 7.3 mm Hg); resuscitation raised MAP to >60 mm Hg by 26.5 ± 15.5 minutes. Shunt placement required 4.5 ± 1.8 minutes with no difference between groups. Four SUNDT thrombosed (three before 60 minutes). One SUNDT thrombosed at 240 minutes, and two TS-VIS and one TS-VISHep thrombosed between 230 and 282 minutes. Median patency was 21 minutes for SUNDT and 360 minutes for both TS-VIS groups (p = 0.04). While patent, all shunts maintained flow between 60% and 90% of contralateral. CONCLUSION: The TS-VIS demonstrated sustained patency superior to the Sundt under adverse hemodynamic conditions. No benefit was observed by the addition of localized heparin therapy over arterial pressure monitoring by the TS-VIS side port.

Conversion of the Abdominal Aortic and Junctional Tourniquet (AAJT) to Infrarenal Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) Is Practical in a Swine Hemorrhage Model.

BACKGROUND: Two methods of controlling pelvic and inguinal hemorrhage are the Abdominal Aortic and Junctional Tourniquet (AAJT; Compression Works) and resuscitative endovascular balloon occlusion of the aorta (REBOA). The AAJT can be applied quickly, but prolonged use may damage the bowel, inhibit ventilation, and obstruct surgical access. REBOA requires technical proficiency but avoids many of the complications associated with the AAJT. Conversion of the AAJT to REBOA would allow for field hemorrhage control with mitigation of the morbidity associated with prolonged AAJT use. METHODS: Yorkshire male swine (n = 17; 70-90kg) underwent controlled 40% hemorrhage. Subsequently, AAJT was placed on the abdomen, midline, 2cm superior to the ilium, and inflated. After 1 hour, the animals were allocated to an additional 30 minutes of AAJT inflation (continuous AAJT occlusion [CAO]), REBOA placement with the AAJT inflated (overlapping aortic occlusion [OAO]), or REBOA placement following AAJT removal (sequential aortic occlusion [SAO]). Following removal, animals were observed for 3.5 hours. RESULTS: No statistically significant differences in survival, blood pressure, or laboratory values were found following intervention. Conversion to REBOA was successful in all animals but one in the OAO group. REBOA placement time was 4.3 ± 2.9 minutes for OAO and 4.1 ± 1.8 minutes for SAO (p = .909). No animal had observable intestinal injury. CONCLUSIONS: Conversion of the AAJT to infrarenal REBOA is practical and effective, but access may be difficult while the AAJT is applied.

Effect of the Abdominal Aortic and Junctional Tourniquet on chest compressions in a swine model of ventricular fibrillation.

INTRODUCTION: Mortality for out-of-hospital cardiac arrest is high when traditional chest compressions are used without adjuncts. The abdominal aortic and junctional tourniquet (AAJT) is a device with a wedge-shaped air bladder that occludes the aortic bifurcation, augmenting blood flow to the heart and brain. Previously, the addition of AAJT during chest compression led to an increase in rate of survival in a model of traumatic cardiac arrest. HYPOTHESIS: This study was designed to determine if application of the AAJT would lead to more effective chest compressions as measured by improved hemodynamic parameters and an increased rate of return of spontaneous circulation (ROSC). METHODS: Yorkshire swine (n = 6 per group) underwent general anesthesia and instrumentation. Ventricular fibrillation (Vfib) was electrically induced and animals were allocated into groups with or without the AAJT. The AAJT was inflated if selected after four minutes of compressions. Following a total of ten minutes of compressions, the animals entered into a ten-minute advanced cardiac life support phase. Hemodynamics and blood gas measurements were compared between groups. RESULTS: ROSC or cardioversion from Vfib was not achieved in either group. The AAJT group had improved hemodynamic parameters with significantly higher carotid diastolic pressure and higher blood flow in the carotid artery (p = 0.016 and 0.028 respectively). However, no significant differences were observed with coronary perfusion pressure or end tidal CO2. CONCLUSION: The AAJT did not confer a survival advantage during chest compressions, but hemodynamic improvements were observed while the AAJT was in place.

Extracorporeal Filtration of Potassium in a Swine Model of Bilateral Hindlimb Ischemia-Reperfusion Injury With Severe Acute Hyperkalemia.

Introduction: Options for the treatment of hyperkalemia in the pre-hospital setting are limited, particularly in the context of natural disaster or during combat operations. Contemporary interventions require extensive resources and technical expertise. Here we examined the potential for a simple, field deployable bridge-dialysis as a countermeasure for acute hyperkalemia induced by prolonged ischemia-reperfusion. Methods: Twenty female swine were randomized into two experimental groups undergoing a 2-hour bilateral hindlimb ischemia-reperfusion injury. Subsequent to injury, hemoperfusion was performed in the presence (Column) and absence (Sham Control) of a high-affinity potassium-binding column (CytoSorbents, Monmouth Junction, NJ, USA). Serial blood gas and chemistries were sampled. Primary endpoint was changed in serum potassium concentrations post-injury and filtration. Results: Serum potassium was significantly elevated following ischemia-reperfusion injury in both groups (149% (12) and 150% (22), p < 0.05 vs respective baseline values). There were no differences observed between groups in respect to physiologic parameters; mean arterial pressure, heart rate, systemic vascular resistance, cardiac output, or central venous oxygenation. Filtration resulted in a significant relative decrease in potassium compared with controls after the first hour as determined by repeated measures two-way ANOVA (p < 0.0001) which continued through end of the study. Significant thrombocytopenia was observed in animals undergoing filtration with a mean reduction in platelets measured at T = 480 minutes (168 × 103µL, p < 0.0001 vs baseline). Conclusions: We demonstrate that serum potassium can be filtered via hemoperfusion utilizing a simple extracorporeal potassium-binding platform, though evolution of this technology will be required to achieve meaningful reduction of potassium in clinically significant hyperkalemia after trauma.

Comparison of zone 3 Resuscitative Endovascular Balloon Occlusion of the Aorta and the Abdominal Aortic and Junctional Tourniquet in a model of junctional hemorrhage in swine.

BACKGROUND: Traumatic injuries to the pelvis and high junctional injuries are difficult to treat in the field; however, Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) and the Abdominal Aortic and Junctional Tourniquet (AAJT) constitute two promising treatment modalities. The aim of this study is to use a large animal model of pelvic hemorrhage to compare the survival, hemostatic, hemodynamic, and metabolic profile of both techniques. METHODS: Yorkshire swine (n = 10, 70-90 kg) underwent general anesthesia, instrumentation, and surgical isolation of the femoral artery. Uncontrolled hemorrhage was initiated by an arteriotomy. Animals were randomly allocated to either REBOA or AAJT. Following completion of device application, both groups received a 500 mL Hextend bolus. After 1 hour, the injured femoral artery was ligated to simulate definitive hemostasis followed by a second Hextend bolus and device removal. Animals were observed for two more hours. Physiological data were collected throughout the experiments and compared between groups. RESULTS: Both techniques achieved 100% hemostasis, and all animals survived the entire experiment except one in the REBOA group. During the hour treatment phase, the AAJT group had a higher mean arterial pressure than the REBOA group (59.9 ± 16.1 versus 44.6 ± 9.8 mm Hg, respectively; P < 0.05). The AAJT-treated group had higher lactate levels than the REBOA-treated group (4.5 ± 2.0 versus 3.2 ± 1.3 mg/dL, respectively; P < 0.05). CONCLUSIONS: Despite their mechanistic differences, both techniques achieved a similar hemostatic, hemodynamic, and metabolic profile. Some differences do exist including lactate levels and blood pressure.

Evaluation of XSTAT® and QuickClot® Combat Gauze® in a Swine Model of Lethal Junctional Hemorrhage in Coagulopathic Swine.

BACKGROUND: Hemorrhage is associated with most potentially survivable deaths on the battlefield. Effective and field-tested products are lacking to treat junctional and noncompressible injuries. XSTAT® is a newly developed, U.S. Food and Drug Administration-approved product designed to treat junctional hemorrhage. The Committee on Tactical Combat Casualty Care has recently approved the product for use as part of its treatment guidelines, but data are lacking to assess its efficacy in different wounding patterns and physiologic states. METHODS: Dilutional coagulopathy was induced in 19 large (70-90kg), healthy, male swine by replacing 60% of each animal's estimated blood volume with room temperature Hextend ®. After dissection, isolation, and lidocaine incubation, uncontrolled hemorrhage was initiated by transection of both axillary artery and vein. Free bleeding was allowed to proceed for 30 seconds until intervention with either XSTAT or QuickClot® Combat Gauze® (CG) followed by standard backing. Primary outcomes were survival, hemostasis, and blood loss. RESULTS: XSTAT-treated animals achieved hemostasis in less time and remained hemostatic longer than those treated with CG. Less blood was lost during the first 10 minutes after injury in the XSTAT group than the CG group. However, no differences in survival were observed between XSTAT-treated and CG-treated groups. All animals died before the end of the observation period except one in the XSTAT-treated group. CONCLUSION: XSTAT performed better than CG in this model of junctional hemorrhage in coagulopathic animals. Continued testing and evaluation of XSTAT should be performed to optimize application and determine appropriate indications for use.

A comparison of Selective Aortic Arch Perfusion and Resuscitative Endovascular Balloon Occlusion of the Aorta for the management of hemorrhage-induced traumatic cardiac arrest: A translational model in large swine.

BACKGROUND: Survival rates remain low after hemorrhage-induced traumatic cardiac arrest (TCA). Noncompressible torso hemorrhage (NCTH) is a major cause of potentially survivable trauma death. Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) at the thoracic aorta (Zone 1) can limit subdiaphragmatic blood loss and allow for IV fluid resuscitation when intrinsic cardiac activity is still present. Selective Aortic Arch Perfusion (SAAP) combines thoracic aortic balloon hemorrhage control with intra-aortic oxygenated perfusion to achieve return of spontaneous circulation (ROSC) when cardiac arrest has occurred. METHODS AND FINDINGS: Male Yorkshire Landrace cross swine (80.0 ± 6.0 kg) underwent anesthesia, instrumentation for monitoring, and splenectomy. TCA was induced by laparoscopic liver lobe resection combined with arterial catheter blood withdrawal to achieve a sustained systolic blood pressure <10 mmHg, cardiac arrest. After 3 min of arrest, swine were allocated to one of three interventions: (1) REBOA plus 4 units of IV fresh whole blood (FWB), (2) SAAP with oxygenated lactated Ringer's (LR), 1,600 mL/2 min, or (3) SAAP with oxygenated FWB 1,600 mL/2 min. Primary endpoint was survival to the end of 60 min of resuscitation, a simulated prehospital phase. Thirty animals were allocated to 3 groups (10 per group)-5 protocol exclusions resulted in a total of 35 animals being used. Baseline measurements and time to cardiac arrest were not different amongst groups. ROSC was achieved in 0/10 (0%, 95% CI 0.00-30.9) REBOA, 6/10 (60%, 95% CI 26.2-87.8) SAAP-LR and 10/10 (100%, 95% CI 69.2-100.0) SAAP-FWB animals, p < 0.001. Survival to end of simulated 60-minute prehospital resuscitation was 0/10 (0%, 95% CI 0.00-30.9) for REBOA, 1/10 (10%, 95% CI 0.25-44.5) for SAAP-LR and 9/10 (90%, 95% CI 55.5-99.7) for SAAP-FWB, p < 0.001. Total FWB infusion volume was similar for REBOA (2,452 ± 0 mL) and SAAP-FWB (2,250 ± 594 mL). This study was undertaken in laboratory conditions, and as such may have practical limitations when applied clinically. Cardiac arrest in this study was defined by intra-aortic pressure monitoring that is not feasible in clinical practice, and as such limits the generalizability of findings. Clinical trials are needed to determine if the beneficial effects of SAAP-FWB observed in this laboratory study will translate into improved survival in clinical practice. CONCLUSIONS: SAAP conferred a superior short-term survival over REBOA in this large animal model of hemorrhage-induced traumatic cardiac arrest with NCTH. SAAP using an oxygen-carrying perfusate was more effective in this study than non-oxygen carrying solutions in TCA. SAAP can effect ROSC from hemorrhage-induced electrocardiographic asystole in large swine.

Hemodynamic effects of the Abdominal Aortic and Junctional Tourniquet in a hemorrhagic swine model.

BACKGROUND: Torso hemorrhage constitutes a leading cause of battlefield mortality. The Abdominal Aortic and Junctional Tourniquet (AAJT) uses a pneumatic bladder to compress the aorta reducing pelvic and lower extremity perfusion; however, concern exists over the risk of caval compression exacerbating hypotension after application. METHODS: Male swine (70-90 kg) were randomized into four groups of 10: presence or absence of hemorrhage and AAJT placement. After a 40% hemorrhage, a 15-min period of hypovolemia was observed before the AAJT application. All animals received two 500 mL boluses of Hextend separated by 30 min. Cardiovascular, pulmonary, and oxygenation values were compared among groups. RESULTS: The AAJT was effective in reducing blood flow to the femoral arteries in both hemorrhaged and nonhemorrhaged animals (P < 0.001 for both groups). Hemorrhage resulted in significant decrease in mean arterial pressure compared with sham controls (23.5 ± 2.4 versus 61.6 ± 7.8 mm Hg, respectively, P < 0.001). AAJT application, compared with untreated controls, resulted in a significant increase in mean arterial pressure and systemic vascular resistance but not in cardiac output, oxygenation, and central venous pressure. Furthermore, no indication of overresuscitation injury was present as evidenced by pulmonary artery pressure and pulmonary histology. CONCLUSIONS: AAJT application in an animal model of severe shock results in a favorable hemodynamic profile because of afterload support. The present study did not demonstrate any adverse consequences because of caval compression, bowel injury, or pulmonary dysfunction. In addition, there does not appear to be any particular intravenous fluid economy achieved by AAJT application.

Comparison of novel hemostatic dressings with QuikClot combat gauze in a standardized swine model of uncontrolled hemorrhage.

BACKGROUND: Uncontrolled hemorrhage is the leading cause of preventable death on the battlefield. The development, testing, and application of novel hemostatic dressings may lead to a reduction of prehospital mortality through enhanced point-of-injury hemostatic control. This study aimed to determine the efficacy of currently available hemostatic dressings as compared with the current Committee for Tactical Combat Casualty Care Guidelines standard of treatment for hemorrhage control (QuikClot Combat Gauze [QCG]). METHODS: The femoral artery of anesthetized Yorkshire pigs was isolated and punctured. Free bleeding was allowed to proceed for 45 seconds before packing of QCG, QuikClot Combat Gauze XL (QCX), Celox Trauma Gauze (CTG), Celox Gauze (CEL), or HemCon ChitoGauze (HCG), into the wound. After 3 minutes of applied, direct pressure, fluid resuscitation was administered to elevate and maintain a mean arterial pressure of 60 mm Hg or greater during the 150-minute observation time. Animal survival, hemostasis, and blood loss were measured as primary end points. Hemodynamic and physiologic parameters, along with markers of coagulation, were recorded and analyzed. RESULTS: Sixty percent of QCG-treated animals (controls) survived through the 150-minute observation period. QCX, CEL, and HCG were observed to have higher rates of survival in comparison to QCG (70%, 90%, and 70% respectively), although these results were not found to be of statistical significance in pairwise comparison to QCG. Immediate hemostasis was achieved in 30% of QCG applications, 80% of QCX, 70% of CEL, 60% of HCG, and 30% of CTG-treated animals. Posttreatment blood loss varied from an average of 64 mL/kg with CTG to 29 mL/kg with CEL, but no significant difference among groups was observed. CONCLUSION: These results suggest that the novel hemostatic devices perform at least as well as the current Committee on Tactical Combat Casualty Care standard for point-of-injury hemorrhage control. Despite their different compositions and sizes, the lack of clear superiority of any agent suggests that contemporary hemostatic dressing technology has potentially reached a plateau for efficacy.

Intrahippocampal infusion of a cyclooxygenase-2 inhibitor attenuates memory acquisition in rats.

Cyclooxygenase-2 (COX-2) inhibitors have been shown to block memory retention in rodents following Morris water maze training and in chicks following a passive avoidance task. However, the role of COX-2 in acquisition has not been analyzed. We show that pre-training intrahippocampal infusion of a COX-2 specific inhibitor (celecoxib) attenuated water maze acquisition. These findings, along with previously published reports, implicate COX-2 activity in both memory acquisition and retention.

High-density microarray analysis of hippocampal gene expression following experimental brain injury.

Behavioral, biophysical, and pharmacological studies have implicated the hippocampus in the formation and storage of spatial memory. Traumatic brain injury (TBI) often causes spatial memory deficits, which are thought to arise from the death as well as the dysfunction of hippocampal neurons. Cell death and dysfunction are commonly associated with and often caused by altered expression of specific genes. The identification of the genes involved in these processes, as well as those participating in postinjury cellular repair and plasticity, is important for the development of mechanism-based therapies. To monitor the expression levels of a large number of genes and to identify genes not previously implicated in TBI pathophysiology, a high-density oligonucleotide array containing 8,800 genes was interrogated. RNA samples were prepared from ipsilateral hippocampi 3 hr and 24 hr following lateral cortical impact injury and compared to samples from sham-operated controls. Cluster analysis was employed using statistical algorithms to arrange the genes according to similarity in patterns of expression. The study indicates that the genomic response to TBI is complex, affecting approximately 6% (at the time points examined) of the total number of genes examined. The identity of the genes revealed that TBI affects many aspects of cell physiology, including oxidative stress, metabolism, inflammation, structural changes, and cellular signaling. The analysis revealed genes whose expression levels have been reported to be altered in response to injury as well as several genes not previously implicated in TBI pathophysiology.