A novel, reverse-phase-shifting, thermoreversible foaming hydrogel containing antibiotics for the treatment of thermal burns in a swine model - A pilot study.

BACKGROUND: This study compared a novel topical hydrogel burn dressing (CI-PRJ012) to standard of care (silver sulfadiazine) and to untreated control in a swine thermal burn model, to assess for wound healing properties both in the presence and absence of concomitant bacterial inoculation. METHODS: Eight equal burn wounds were created on six Yorkshire swine. Half the wounds were randomized to post-burn bacterial inoculation. Wounds were subsequently randomized to three treatments groups: no intervention, CI-PRJ012, or silver sulfadiazine cream. At study end, a blinded pathologist evaluated wounds for necrosis and bacterial colonization. RESULTS: When comparing CI-PRJ012 and silver sulfadiazine cream to no treatment, both agents significantly reduced the amount of necrosis and bacteria at 7 days after wound creation (p < 0.01, independently for both). Further, CI-PRJ012 was found to be significantly better than silver sulfadiazine (p < 0.02) in reducing bacterial colonization. For wound necrosis, no significant difference was found between silver sulfadiazine cream and CI-PRJ012 (p = 0.33). CONCLUSIONS: CI-PRJ012 decreases necrosis and bacterial colonization compared to no treatment in a swine model. CI-PRJ012 appeared to perform comparably to silver sulfadiazine. CI-PRJ012, which is easily removed with the application of room-temperature water, may provide clinical advantages over silver sulfadiazine.

A Novel Peritoneal Packing Method for Management of Hyperkalemia During Acute Kidney Injury in Trauma.

INTRODUCTION: United States Military operations in resource limited areas are increasing. Furthermore, future peer or near-peer conflicts will require caring for larger numbers of casualties with limited resources. In this setting, traditional renal replacement therapy is not feasible and novel methods are required to address severe acute kidney injury in austere environments lacking definitive therapies. Here, we describe experiments designed to determine the efficacy of a novel peritoneal packing material (Potassium Binding Pack-PBP, CytoSorbents INC) for the acute management of severe hyperkalemia. MATERIALS AND METHODS: Male swine (52 ±1 kg) were nephrectomized via midline laparotomy under a plane of anesthesia and randomized into one of two experimental groups (PBP & CON). Exogenous potassium was infused to achieve a serum potassium level of 7.5 mEq/L. Novel potassium absorbing packs (PBP) or sham packs (CON) were placed in the right and left upper quadrants, and the right and left paracolic gutters of the abdomen to simulate four-quadrant packing (n = 6, n = 5, respectively). Two liters of peritoneal dialysis fluid was instilled into the abdomen and temporary closure performed. Animals were observed for 12 hours. Serum and peritoneal fluid (dialysate) potassium levels were sampled at T = 15, 30, 60 min, and Q60min thereafter. Animals were humanely euthanized at the end of the observation period. RESULTS: Baseline characteristics were similar between groups. Pairwise analysis showed that serum potassium concentrations were significantly lower in the PBP group compared to CON at T = 540 and T = 720 (P = 0.006 and P = 0.015, respectively). Potassium concentrations were significantly lower in dialysate of the PBP group compared to CON at all time points after T = 15 (T = 30, P = 0.017; T = 60 through T = 720, P < 0.001). CONCLUSIONS: This is the first demonstration of an effective technology for the management of hyperkalemia in trauma in the absence of standard of care; renal replacement therapy. We identified that PBP was able to consistently maintain a concentration gradient between dialysate in the peritoneum and system potassium concentration throughout the experiment. Furthermore, systemic potassium concentrations were reduced in a clinically relevant manner in the PBP group compared to CON. This suggests that peritoneal packing technology for the management of metabolic disturbances in trauma has potential for clinical application. These results are preliminary and should be interpreted with caution.

Thermoreversible Reverse-Phase-Shift Foam for Treatment of Noncompressible Torso Hemorrhage, a Safety Trial in a Porcine Model.

INTRODUCTION: Noncompressible torso hemorrhage is the leading cause of exsanguination on the battlefield. A self-expanding, intraperitoneal deployed, thermoreversible foam has been developed that can be easily administered by a medic in austere settings to temporarily tamponade noncompressible torso hemorrhage. The purpose of this study was to assess the long-term safety and physical characteristics of using Fast Onset Abdominal Management (FOAM; Critical Innovations LLC) in swine. MATERIALS AND METHODS: Yorkshire swine (40-60 kg) were sedated, intubated, and placed on ventilatory support. An external jugular catheter was placed for sampling of blood. Continuous heart rate, temperature, saturation of peripheral oxygen, end-tidal carbon dioxide, and peak airway pressures were monitored for a 4-hour period after intervention (i.e., FOAM agent injection or a sham introducer without agent delivery). The FOAM agent was injected to obtain an intra-abdominal pressure of 60 mmHg for at least 10 minutes. After 4 hours, the animals were removed from ventilatory support and returned to their housing for a period of 7-14 days. Group size analysis was not performed, as this was a descriptive safety study. Blood samples were obtained at baseline and at 1-hour post-intervention and then on days 1, 3, 7, and 14. Euthanasia, necropsy, and harvesting of samples for histologic analysis (from kidneys, terminal ilium, liver, pancreas, stomach, spleen, and lungs) were performed upon expiration. Histologic scoring for evidence of ischemia, necrosis, and abdominal compartment sequela was blinded and reported by semi-quantitative scale (range 0-4; 0 = no change, 1 = minimal, 2 = mild, 3 = moderate, and 4 = marked). Oregon Health & Science University's Institutional Animal Care and Use Committee, as well as the U.S. Army Animal Care and Use Review Office, approved this protocol before the initiation of experiments (respectively, protocol numbers IP00003591 and MT180006.e002). RESULTS: Five animals met a priori inclusion criteria, and all of these survived to their scheduled endpoints. Two animals received sham injections of the FOAM agent (one euthanized on day 7 and one on day 14), and three animals received FOAM agent injections (one euthanized on day 7 and two on day 14). A transitory increase in creatinine and lactate was detected during the first day in the FOAM injected swine but resolved by day 3. No FOAM agent was observed in the peritoneal cavity upon necropsy at day 7 or 14. Histologic data revealed no clinically relevant differences in any organ system between intervention and control animals upon sacrifice at day 7 or 14. CONCLUSIONS: This study describes the characteristics, survival, and histological analysis of using FOAM in a porcine model. In our study, FOAM reached the desired intra-abdominal pressure endpoint while not significantly altering basic hematologic parameters, except for transient elevations of creatinine and lactate on day 1. Furthermore, there was no clinical or histological relevant evidence of ischemia, necrosis, or intra-abdominal compartment syndrome. These results provide strong support for the safety of the FOAM device and will support the design of further regulatory studies in swine and humans.

Development of a Novel Epidural Hemorrhage Model in Swine.

INTRODUCTION: Traumatic brain injury is a major public health concern. Among patients with severe traumatic brain injury, epidural hemorrhage is known to swiftly lead to brain herniation and death unless there is emergent neurosurgical intervention. However, immediate neurosurgeon availability is frequently a problem outside of level I trauma centers. In this context, the authors desired to test a novel device for the emergent management of life-threatening epidural hemorrhage. A review of existing animal models determined that all were inadequate for this purpose, as they were found to be either inappropriate or obsolete. Here, we describe the development of a new epidural hemorrhage model in swine (Sus scrofa, 18-26 kg) ideal for translational device testing. MATERIALS AND METHODS: Vascular access was achieved using an ultrasound-guided percutaneous Seldinger catheter-over-wire technique with 5 Fr catheters placed in the bilateral carotid arteries, for continuous blood pressure and to allow for withdrawal of blood for creation of epidural hemorrhage. To simulate an actively bleeding and life-threatening epidural hemorrhage, unadulterated autologous blood was infused from the vascular access point into the epidural space. To be useful for this application and clinical scenario, brain death needed to occur after the planned intervention time but before the end of the protocol period (if no intervention took place). An iterative approach to model development determined that this could be achieved with an initial infusion rate of 1.0 mL/min, slowed to 0.5 mL/min after the first 10 minutes, paired with an intervention time at 15 minutes. All experiments were performed at Oregon Health & Science University, an Association for Assessment and Accreditation of Laboratory Animal Care accredited facility. Oregon Health & Science University's Institutional Animal Care and Use Committee, as well as the United States Army Animal Care and Use Review Office, reviewed and approved this protocol before the initiation of experiments (respectively, protocol numbers IP00002901 and 18116010.e001). RESULTS: The final developed model allows for the infusion of a known volume of autologous, unadulterated blood directly into the epidural space, without the use of a balloon or other restricting membranes, and is rapidly fatal in the absence of intervention. CONCLUSIONS: This animal model is the first to mirror the expected clinical course of epidural hemorrhage in a physiologically relevant manner, while allowing translational testing of emergency devices. This model successfully allowed the initial testing of a novel interventional device for the emergent management of epidural hemorrhage that was designed for use in the absence of traditional neurosurgical capabilities.

Efficacy of past, present, and future fluid strategies in an improved large animal model of non-compressible intra-abdominal hemorrhage.

BACKGROUND: Noncompressible hemorrhage is a leading cause of potentially survivable combat death, with the vast majority of such deaths occurring in the out-of-hospital environment. While large animal models of this process are important for device and therapeutic development, clinical practice has changed over time and past models must follow suit. Developed in conjunction with regulatory feedback, this study presents a modernized, out-of-hospital, noncompressible hemorrhage model, in conjunction with a randomized study of past, present, and future fluid options following a hypotensive resuscitation protocol consistent with current clinical practice. METHODS: We performed a randomized controlled experiment comparing three fluid resuscitation options in Yorkshire swine. Baseline data from animals of same size from previous experiments were analyzed (n = 70), and mean systolic blood pressure was determined, with a permissive hypotension resuscitation target defined as a 25% decrease from normal (67 mm Hg). After animal preparation, a grade IV to V liver laceration was induced. Animals bled freely for a 10-minute "time-to-responder" period, after which resuscitation occurred with randomized fluid in boluses to the goal target: 6% hetastarch in lactated electrolyte injection (HEX), normal saline (NS), or fresh whole blood (FWB). Animals were monitored for a total simulated "delay to definitive care" period of 2 hours postinjury. RESULTS: At the end of the 2-hour study period, 8.3% (1 of 12 swine) of the HEX group, 50% (6 of 12 swine) of the NS group, and 75% (9 of 12 swine) of the FWB had survived (p = 0.006), with Holm-Sidak pairwise comparisons showing a significant difference between HEX and FWB and (p = 0.005). Fresh whole blood had significantly higher systemic vascular resistance and hemoglobin levels compared with other groups (p = 0.003 and p = 0.001, respectively). CONCLUSION: Survival data support the movement away from HEX toward NS and, preferably, FWB in clinical practice and translational animal modeling. The presented model allows for future research including basic science, as well as translational studies of novel diagnostics, therapeutics, and devices.

Femoral vascular access for endovascular resuscitation.

ABSTRACT: Endovascular resuscitation is an emerging area in the resuscitation of both severe traumatic hemorrhage and nontraumatic cardiac arrest. Vascular access is the critical first procedural step that must be accomplished to initiate endovascular resuscitation. The endovascular interventions presently available and emerging are routinely or potentially performed via the femoral vessels. This may require either femoral arterial access alone or access to both the femoral artery and vein. The time-critical nature of resuscitation necessitates that medical specialists performing endovascular resuscitation be well-trained in vascular access techniques. Keen knowledge of femoral vascular anatomy and skill with vascular access techniques are required to meet the needs of critically ill patients for whom endovascular resuscitation can prove lifesaving. This review article addresses the critical importance of femoral vascular access in endovascular resuscitation, focusing on the pertinent femoral vascular anatomy and technical aspects of ultrasound-guided percutaneous vascular access and femoral vessel cutdown that may prove helpful for successful endovascular resuscitation.

Efficacy of a novel chest tube system in a swine model of hemothorax.

BACKGROUND: Tube thoracostomy is the definitive treatment for most significant chest trauma, including injuries resulting in pneumothorax, hemothorax, and hemopneumothorax. However, traditional chest tubes fail to sufficiently remove blood up to 20% of the time (i.e., retained hemothorax), which can lead to empyema and fibrothorax, as well as significant morbidity and mortality. Here we describe the use of a novel chest tube system in a swine model of hemothorax. METHODS: This was an intra-animal-paired, randomized-controlled study of hemothorax evacuation using the PleuraPath™ Thoracostomy System (PPTS) compared to a traditional chest tube in large Yorkshire-Landrace swine (75-85 kg). One liter of autologous whole blood was infused into each pleural cavity simultaneously with subsequent drainage from each device individually monitored for a total of 120 minutes, before the end of the experiment and necroscopy. RESULTS: Six animals completed the full protocol. On average, the PPTS removed 17% more blood (P=0.049) and left 19.1% less residual hemothorax (P=0.023) as compared to the standard of care during the first two hours of use. No complications or iatrogenic injury were identified in any animal for either device. CONCLUSIONS: The novel PPTS device was superior to the traditional chest tube drainage system in this acute, large-animal model of retained hemothorax. While this study supports clinical translation, further research will be required to assess efficacy and optimize device use in humans.

State-of-the-Art Review-Endovascular Resuscitation.

ABSTRACT: The emerging concept of endovascular resuscitation applies catheter-based techniques in the management of patients in shock to manipulate physiology, optimize hemodynamics, and bridge to definitive care. These interventions hope to address an unmet need in the care of severely injured patients, or those with refractory non-traumatic cardiac arrest, who were previously deemed non-survivable. These evolving techniques include Resuscitative Endovascular Balloon Occlusion of Aorta, Selective Aortic Arch Perfusion, and Extracorporeal Membrane Oxygenation and there is a growing literature base behind them. This review presents the up-to-date techniques and interventions, along with their application, evidence base, and controversy within the new era of endovascular resuscitation.

Thermoreversible Reverse-Phase-Shift Foam for Treatment of Noncompressible Torso Hemorrhage.

BACKGROUND: Noncompressible torso hemorrhage (NCTH) is a leading cause of traumatic exsanguination, requiring emergent damage control surgery performed by a highly trained surgeon in a sterile operating environment. A self-expanding, intraabdominally deployed, thermoreversible foam is one proposed method to potentially task shift temporizing hemostasis to earlier providers and additional settings. The purpose of this study was to assess the feasibility of using Fast Onset Abdominal Management (FOAM) in a lethal swine model of NCTH. METHODS: This was a proof-of-concept study comparing FOAM intervention in large Yorkshire swine to historical control animals in the established Ross-Burns model of NCTH. After animal preparation, a Grade IV liver laceration was surgically induced, followed by a free bleed period of 10 min. FOAM was then deployed to a goal intraabdominal pressure of 60 mm Hg for 5 min, followed by a total 60-min observation period following injury. RESULTS: At the end of the experiment, the FOAM agent was found to be distributed throughout the peritoneal cavity in all animals, without signs of iatrogenic injury. The FOAM group demonstrated a significantly higher mean arterial pressure compared with historical controls and a trend toward improved survival: 82% (9/11) compared with 50% for controls (7/14; P = 0.082). CONCLUSIONS: This is the first study to describe the use of a thermoresponsive foam to manage NCTH and successfully demonstrated proof-of-concept feasibility of FOAM deployment. These results provide strong support for future, higher-powered studies to confirm improved survival with this novel intervention.

Novel use of XSTAT 30 for mitigation of lethal non-compressible torso hemorrhage in swine.

BACKGROUND: Management of Non-Compressible Torso Hemorrhage (NCTH) consists primarily of aortic occlusion which has significant adverse outcomes, including ischemia-reperfusion injury, in prolonged field care paradigms. One promising avenue for treatment is through use of RevMedx XSTAT 30™ (an FDA approved sponge-based dressing utilized for extremity wounds). We hypothesized that XSTAT 30™ would effectively mitigate NCTH during a prolonged pre-hospital period with correctable metabolic and physiologic derangements. METHODS AND FINDINGS: Twenty-four male swine (53±2kg) were anesthetized, underwent line placement, and splenectomy. Animals then underwent laparoscopic transection of 70% of the left lobe of the liver with hemorrhage for a period of 10min. They were randomized into three groups: No intevention (CON), XSTAT 30™-Free Pellets (FP), and XSTAT 30™-Bagged Pellets (BP). Animals were observed for a pre-hospital period of 180min. At 180min, animals underwent damage control surgery (DCS), balanced blood product resuscitation and removal of pellets followed by an ICU period of 5 hours. Postoperative fluoroscopy was performed to identify remaining pellets or bags. Baseline physiologic and injury characteristics were similar. Survival rates were significantly higher in FP and BP (p<0.01) vs CON. DCS was significantly longer in FP in comparison to BP (p = 0.001). Two animals in the FP group had pellets discovered on fluoroscopy following DCS. There was no significant difference in blood product or pressor requirements between groups. End-ICU lactates trended to baseline in both FP and BP groups. CONCLUSIONS: While these results are promising, further study will be required to better understand the role for XSTAT in the management of NCTH.

Novel method for action potential measurements from intact cardiac monolayers with multiwell microelectrode array technology.

The cardiac action potential (AP) is vital for understanding healthy and diseased cardiac biology and drug safety testing. However, techniques for high throughput cardiac AP measurements have been limited. Here, we introduce a novel technique for reliably increasing the coupling of cardiomyocyte syncytium to planar multiwell microelectrode arrays, resulting in a stable, label-free local extracellular action potential (LEAP). We characterized the reliability and stability of LEAP, its relationship to the field potential, and its efficacy for quantifying AP morphology of human induced pluripotent stem cell derived and primary rodent cardiomyocytes. Rise time, action potential duration, beat period, and triangulation were used to quantify compound responses and AP morphology changes induced by genetic modification. LEAP is the first high throughput, non-invasive, label-free, stable method to capture AP morphology from an intact cardiomyocyte syncytium. LEAP can accelerate our understanding of stem cell models, while improving the automation and accuracy of drug testing.

Selective aortic arch perfusion with fresh whole blood or HBOC-201 reverses hemorrhage-induced traumatic cardiac arrest in a lethal model of noncompressible torso hemorrhage.

BACKGROUND: Hemorrhage-induced traumatic cardiac arrest (HiTCA) has a dismal survival rate. Previous studies demonstrated selective aortic arch perfusion (SAAP) with fresh whole blood (FWB) improved the rate of return of spontaneous circulation (ROSC) after HiTCA, compared with resuscitative endovascular balloon occlusion of the aorta and cardiopulmonary resuscitation (CPR). Hemoglobin-based oxygen carriers, such as hemoglobin-based oxygen carrier (HBOC)-201, may alleviate the logistical constraints of using FWB in a prehospital setting. It is unknown whether SAAP with HBOC-201 is equivalent in efficacy to FWB, whether conversion from SAAP to extracorporeal life support (ECLS) is feasible, and whether physiologic derangement post-SAAP therapy is reversible. METHODS: Twenty-six swine (79 ± 4 kg) were anesthetized and underwent HiTCA which was induced via liver injury and controlled hemorrhage. Following arrest, swine were randomly allocated to resuscitation using SAAP with FWB (n = 12) or HBOC-201 (n = 14). After SAAP was initiated, animals were monitored for a 20-minute prehospital period prior to a 40-minute damage control surgery and resuscitation phase, followed by 260 minutes of critical care. Primary outcomes included rate of ROSC, survival, conversion to ECLS, and correction of physiology. RESULTS: Baseline physiologic measurements were similar between groups. ROSC was achieved in 100% of the FWB animals and 86% of the HBOC-201 animals (p = 0.483). Survival (t = 320 minutes) was 92% (11/12) in the FWB group and 67% (8/12) in the HBOC-201 group (p = 0.120). Conversion to ECLS was successful in 100% of both groups. Lactate peaked at 80 minutes in both groups, and significantly improved by the end of the experiment in the HBOC-201 group (p = 0.001) but not in the FWB group (p = 0.104). There was no significant difference in peak or end lactate between groups. CONCLUSION: Selective aortic arch perfusion is effective in eliciting ROSC after HiTCA in a swine model, using either FWB or HBOC-201. Transition from SAAP to ECLS after definitive hemorrhage control is feasible, resulting in high overall survival and improvement in lactic acidosis over the study period.

Extracorporeal potassium binding for the management of hyperkalemia in an anephric model of crush injury.

BACKGROUND: Potassium-binding polymers have shown promising results in an anephric porcine hyperkalemia model. The benefits of the polymer in a clinically relevant injury model remain unknown. We hypothesized that potassium-binding cartridges would control serum potassium concentration in a porcine hemorrhagic shock model with supraceliac aortic occlusion and a limb crush injury. METHODS: Ten Yorkshire-cross swine were anesthetized and instrumented. Pigs underwent splenectomy and bilateral nephrectomy. Hemorrhagic shock was induced for 30 minutes while a leg compression device was applied. Pigs underwent supraceliac aortic occlusion for 60 minutes and were resuscitated with shed blood. The leg compression device was removed 20 minutes after balloon deflation. After 20 minutes of reperfusion, animals were randomized to extracorporeal circulation with (treatment) or without (control) the potassium binding cartridges. In both groups, blood was circulated through a hemodialyzer with a peristaltic pump. In the treatment group, the ultrafiltrate was diverted from the hemodialyzer through cartridges containing the polymer and returned to the extracorporeal circuit. Animals were resuscitated with 0.9% saline boluses and a norepinephrine infusion. The change in serum potassium concentration (ΔK) was calculated as serum [K]T390 - serum [K]T0. RESULTS: There was a significant difference in serum potassium concentration between groups (p < 0.001). ΔK was significantly higher in the control than the treatment group (3.75 [3.27-4.42] and 1.15 [0.62-1.59] mmol/L, respectively; p = 0.03). There were no differences in mean arterial pressure (p = 0.14), isotonic crystalloids requirement (p = 0.51), or norepinephrine dose (p = 0.83) between groups. Serum lactate concentration was significantly higher in the control group (p < 0.001). At the end of the experiment, the [K] was reduced by 25% (24.9%-27.8%) across the cartridges. CONCLUSION: The cartridges controlled serum potassium concentrations without dialysate and retained potassium binding capabilities over 4 hours. There were no deleterious effects on hemodynamic parameters. Those cartridges might be beneficial adjuncts for hyperkalemia management in austere environments. LEVEL OF EVIDENCE: Translational science study, level I.

A Novel Perfusion System for Damage Control of Hyperkalemia in Swine.

INTRODUCTION: The standard of care for refractory hyperkalemia is renal replacement therapy (RRT). However, traditional RRT requires specialized equipment, trained personnel, and large amounts of dialysate. It is therefore poorly suited for austere environments. We hypothesized that a simplified hemoperfusion system could control serum potassium concentration in a swine model of acute hyperkalemia. METHODS: Ten pigs were anesthetized and instrumented. A dialysis catheter was inserted. After bilateral nephrectomy, animals received intravenous potassium chloride and were randomized to the control or treatment group. In both groups, blood was pumped through an extracorporeal circuit (EC) with an in-line hemodialyzer. In the treatment arm, ultrafiltrate from the hemodialyzer was diverted through cartridges containing novel potassium binding beads and returned to the EC. Blood samples were obtained every 30 min for 6 h. RESULTS: Serum potassium concentration was significantly lower in the treatment than in the control group over time (P = 0.02). There was no difference in serum total calcium concentration for group or time (P = 0.13 and 0.44, respectively) or platelet count between groups or over time (P = 0.28 and 1, respectively). No significant EC thrombosis occurred. Two of five animals in the control group and none in the treatment group developed arrhythmias. All animals survived until end of experiment. CONCLUSIONS: A simplified hemoperfusion system removed potassium in a porcine model. In austere settings, this system could be used to temporize patients with hyperkalemia until evacuation to a facility with traditional RRT.

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.

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.

Molecular Architecture of the Essential Yeast Histone Acetyltransferase Complex NuA4 Redefines Its Multimodularity.

Conserved from yeast to humans, the NuA4 histone acetyltransferase is a large multisubunit complex essential for cell viability through the regulation of gene expression, genome maintenance, metabolism, and cell fate during development and stress. How the different NuA4 subunits work in concert with one another to perform these diverse functions remains unclear, and addressing this central question requires a comprehensive understanding of NuA4's molecular architecture and subunit organization. We have determined the structure of fully assembled native yeast NuA4 by single-particle electron microscopy. Our data revealed that NuA4 adopts a trilobal overall architecture, with each of the three lobes constituted by one or two functional modules. By performing cross-linking coupled to mass spectrometry analysis and in vitro protein interaction studies, we further mapped novel intermolecular interfaces within NuA4. Finally, we combined these new data with other known structural information of NuA4 subunits and subassemblies to construct a multiscale model to illustrate how the different NuA4 subunits and modules are spatially arranged. This model shows that the multiple chromatin reader domains are clustered together around the catalytic core, suggesting that NuA4's multimodular architecture enables it to engage in multivalent interactions with its nucleosome substrate.

Hyperkalemia in Combat Casualties: Implications for Delayed Evacuation.

OBJECTIVE: Fixed facilities and rapid global evacuation ensured that delayed complications of trauma, such as hyperkalemia, occurred late in the evacuation chain where renal replacement therapies were available. However, future conflicts or humanitarian disasters may involve prolonged evacuation times. We sought to quantify one potential risk of delayed evacuation by assessing hyperkalemia in combat casualties. METHODS: Retrospective study of military members admitted to intensive care units in Iraq and Afghanistan from February 1, 2002, to February 1, 2011. This study was approved by the U.S. Army Medical Research and Materiel Command Institutional Review Board. Demographics, injury severity score, burn injury, mechanism of injury, vital signs, creatinine, and potassium were collected. Logistic regression models were used to identify incidence and risk factors for hyperkalemia. RESULTS: Of 6,011 patient records, 1,472 had sufficient data to be included for analysis. Hyperkalemia occurred in 5.8% of patients. Those with hyperkalemia had higher injury severity scores, higher shock index, were more likely to have acute kidney injury, and were more likely to die. On multivariate analysis, acute kidney injury and shock index were significantly associated with the development of hyperkalemia. In a subgroup of patients with data on creatine kinase, rhabdomyolysis was associated with hyperkalemia in the univariate model, but was not significant after adjustment. CONCLUSION: Hyperkalemia occurred in 5.8% of patients in our cohort of critically injured combat casualties. The development of hyperkalemia was independently associated with acute kidney injury and shock index. In future conflicts, with prolonged evacuation times, mitigation strategies should be developed to treat hyperkalemia in casualties before arrival at definitive care.

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.