Endovascular Embolization Techniques in a Novel Swine Model of Fatal Uncontrolled Solid Organ Hemorrhage and Coagulopathy.

BACKGROUND: Endovascular embolization is increasingly used in treating traumatic hemorrhage and other applications. No endovascular-capable translational large animal models exist and coagulopathy's effect on embolization techniques is unknown. We developed a coagulation-adaptable solid organ hemorrhage model in swine for investigation of embolization techniques. METHODS: Anesthetized swine (n = 26, 45 ± 3 kg) had laparotomy and splenic externalization. Half underwent 50% isovolemic hemodilution with 6% hetastarch and cooling to 33-35°C (COAG group). All had controlled 20 mL/kg hemorrhage and endovascular access to the proximal splenic artery with a 4F catheter via a right femoral sheath. Splenic transection and 5 min free bleeding were followed by treatment (n = 5/group) with 5 mL gelfoam slurry, three 6-mm coils, or no treatment (n = 3, control). Animals received 15 mL/kg plasma resuscitation and were monitored for 6 hr. Splenic blood loss was continuously measured and angiograms were performed at specified times. RESULTS: Coagulopathy was successfully established in COAG animals. Pre-treatment blood loss was greater in COAG (11 ± 6 mL/kg) than non-COAG (7 ± 3 mL/kg, P = 0.04) animals. Splenic hemorrhage was universally fatal without treatment. Non-COAG coil survival was 4/5 (326 ± 75 min) and non-COAG Gelfoam 3/5 (311 ± 67 min) versus non-COAG Control 0/3 (82 ± 18 min, P < 0.05 for both). Neither COAG Coil (0/5, 195 ± 117 min) nor COAG Gelfoam (0/5, 125 ± 32 min) treatment improved survival over COAG Control (0/3, 56 ± 19 min). Post-treatment blood loss was 4.6 ± 3.4 mL/kg in non-COAG Coil and 4.6 ± 2.9 mL/kg in non-COAG Gelfoam, both lower than non-COAG Control (18 ± 1.3 mL/kg, P = 0.05). Neither COAG Coil (8.4 ± 5.4 mL/kg) nor COAG Gelfoam (15 ± 11 ml/kg) had significantly less blood loss than COAG Control (20 ± 1.2 mL/kg). Both non-COAG treatment groups had minimal blood loss during observation, while COAG groups had ongoing slow blood loss. In the COAG Gelfoam group, there was an increase in hemorrhage between 30 and 60 min following treatment. CONCLUSIONS: A swine model of coagulation-adaptable fatal splenic hemorrhage suitable for endovascular treatment was developed. Coagulopathy had profound negative effects on coil and gelfoam efficacy in controlling bleeding, with implications for trauma and elective embolization procedures.

Plasma and Urinary Glycosaminoglycans as Evidence for Endotheliopathy in a Swine Burn Model.

BACKGROUND: The endothelial glycocalyx controls vascular permeability, cellular signaling, blood-endothelial cell adhesion, extravasation, and transmission of shear stress signals. Burn injury compromises integrity of this layer increasing vascular permeability, which is further exacerbated by large volumes of (intravenous) crystalloids. We have shown that enteral resuscitation is able to reverse burn-induced acute kidney injury (AKI), and herein, we present a follow-up examination of the integrity of the glycocalyx layer and its relationship with renal dysfunction after burn injury. MATERIALS AND METHODS: Anesthetized Yorkshire pigs sustained 40% total body surface area full-thickness contact burns and recovered in metabolic cages for one of three treatments: no fluids (oral or intravenous); (n = 6), ad libitum water (n = 6), or volume-matched oral rehydration solution (ORS; n = 6) for 48 h. Urine and blood were collected at baseline (BL), 6, 12, 24, 32, and 48 h after burn at which point kidneys were harvested. RESULTS: In no fluid and water groups (but not ORS), plasma levels of glycosaminoglycans (GAGs) were elevated after burn (P ≤ 0.031). Syndecan-1 was elevated by 6 h after burn in all animals, but levels declined by 24 h with enteral fluids. Urinary GAGs in the no-fluid group were elevated after burn. No differences among treatments were detected in syndecan-1 levels, or glomerular lectin within the kidney. CONCLUSIONS: Collectively, these data demonstrate that ORS prevented increases in circulating GAGs. Furthermore, an inexpensive and simple method for detecting GAGs provides a sensitive measure of endotheliopathy after burn.

Differing Resuscitation With Aortic Occlusion in a Swine Junctional Hemorrhage Polytrauma Model.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) and Abdominal Aortic and Junctional Tourniquet (AAJT) have received much attention in recent as methods for temporary control of junctional hemorrhage. Previous studies typically used the animal's shed blood for resuscitation. With current interest in moving REBOA to prehospital environment, this study aimed to evaluate the hemodynamic and metabolic responses to different resuscitation fluids used with these devices. METHODS: In swine (Sus scrofa), shock was induced using a controlled hemorrhage, femur fracture, and uncontrolled hemorrhage from the femoral artery. Infrarenal REBOA or AAJT was deployed for 60 min during which the arterial injury was repaired. Animals were resuscitated with 15 mL/kg of shed whole blood (SWB) or fresh frozen plasma (FFP) or 30 mL/kg of a balanced crystalloid (PlasmaLyte). RESULTS: Animals in the AAJT and REBOA groups did not show any measurable differences in hemodynamics, metabolic responses, or survival with AAJT or REBOA treatment; hence, the data are pooled and analyzed among the three resuscitative fluids. SWB, FFP, and PlasmaLyte groups did not have a difference in survival time or overall survival. The animals in the SWB and FFP groups maintained higher blood pressure after resuscitation, (P < 0.001) and required significantly less norepinephrine to maintain blood pressure than those in the PlasmaLyte group (P < 0.001). The PlasmaLyte resuscitation prolonged prothrombin time and decreased thromboelastography maximum amplitude. CONCLUSIONS: After 60 min, infrarenal REBOA or AAJT aortic occlusion SWB and FFP resuscitation provided better blood pressure support with half of the resuscitative volume of PlasmaLyte. Swine resuscitated with SWB and FFP also had a more favorable coagulation profile. These data suggest that whole blood or component therapy should be used for resuscitation in conjunction with REBOA or AAJT, and administration of these fluids should be considered if prehospital device use is pursued.

Burn-induced reductions in mitochondrial abundance and efficiency are more pronounced with small volumes of colloids in swine.

Severe burn injury results in systemic disruption of metabolic regulations and impaired cardiac function. Restoration of hemodynamic homeostasis utilizing intravenous (IV) fluids is critical for acute care of the burn victim. However, the effects of burns and resuscitation on cardiomyocyte mitochondria are currently unknown. The purpose of this study is to determine cardiac mitochondrial function in a swine burn model with subsequent resuscitation using either crystalloids or colloids. Anesthetized Yorkshire swine (n = 23) sustained 40% total body surface area burns and received IV crystalloids (n = 11) or colloids (n = 12) after recovery from anesthesia. Non-burned swine served as controls (n = 9). After euthanasia at 48 h, heart tissues were harvested, permeabilized, and analyzed by high-resolution respirometry. Citrate synthase (CS) activity was measured, and Western blots were performed to quantify proteins associated with mitochondrial fusion (OPA1), fission (FIS1), and mitophagy (PINK1). There were no differences in state 2 respiration or maximal oxidative phosphorylation. Coupled complex 1 respiration decreased, while uncoupled state 4O and complex II increased significantly due to burn injury, particularly in animals receiving colloids (P < 0.05). CS activity and electron transfer coupling efficiency were significantly lower in burned animals, particularly with colloid treatment (P < 0.05). Protein analysis revealed increased FIS1 but no differences in mitophagy in cardiac tissue from colloid-treated compared with crystalloid-treated swine. Taken together, severe burns alter mitochondrial respiration in heart tissue, which may be exacerbated by early IV resuscitation with colloids. Early IV burn resuscitation with colloids may require close hemodynamic observation. Mitochondrial stabilizing agents incorporated into resuscitation fluids may help the hemodynamic response to burn injury.

Large Animal Models of Proximal Aortic Balloon Occlusion in Traumatic Hemorrhage: Review and Identification of Knowledge Gaps Relevant to Expanded Use.

BACKGROUND: The aim of this study was to review and summarize the large animal data on resuscitative endovascular balloon occlusion of the aorta (REBOA) for traumatic hemorrhage and identify knowledge gaps pertinent to the proposed broader use of the technique in prehospital situations. METHODS: A review of published large animal models of traumatic hemorrhage incorporating REBOA with a primary outcome of the effect of aortic occlusion was performed. Data were collected on experimental protocols, hemodynamic effects, resuscitation requirements, mortality, metabolic and tissue consequences of induced ischemia-reperfusion, and effects on hemorrhage volume and other injuries. RESULTS: A limited number of REBOA studies exist, and there is variability in the species and size of animals used. Various controlled and uncontrolled hemorrhage protocols have been studied, and a number of balloon devices used. Hemodynamic effects of occlusion were consistent as were basic systemic physiological effects. Minimal study of the effects of partial aortic occlusion and hemodynamic and metabolic physiology distal to the balloon has been performed, and partial or complete occlusion times >90 min have not been studied. CONCLUSIONS: Significant knowledge gaps exist, which are potentially relevant to the expanded use of REBOA. Investigation into the physiology of partial occlusion and the metabolic effects and potential mitigation strategies for large-scale ischemia and reperfusion are particularly needed.

Proceedings of the Food and Drug Administration's public workshop on new red blood cell product regulatory science 2016.

The US Food and Drug Administration (FDA) held a workshop on red blood cell (RBC) product regulatory science on October 6 and 7, 2016, at the Natcher Conference Center on the National Institutes of Health (NIH) Campus in Bethesda, Maryland. The workshop was supported by the National Heart, Lung, and Blood Institute, NIH; the Department of Defense; the Office of the Assistant Secretary for Health, Department of Health and Human Services; and the Center for Biologics Evaluation and Research, FDA. The workshop reviewed the status and scientific basis of the current regulatory framework and the available scientific tools to expand it to evaluate innovative and future RBC transfusion products. A full record of the proceedings is available on the FDA website (http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/ucm507890.htm). The contents of the summary are the authors' opinions and do not represent agency policy.

Long-term consequences of abdominal aortic and junctional tourniquet for hemorrhage control.

BACKGROUND: Specialized tourniquets have been deployed to the battlefield for the control of junctional/pelvic hemorrhage despite limited knowledge concerning their safety and duration of use. This study investigated long-term effects of abdominal application of the abdominal aortic and junctional tourniquet (AAJT) in a swine survival model. METHODS: Anesthetized spontaneously air-breathing swine were subjected to bilateral femoral artery injuries and subsequent 40% hemorrhage. Further hemorrhage was controlled by applying the AAJT on the lower abdomen for 0 h (n = 2, controls), 1 h (n = 6), 1.5 h (n = 6), or 2 h (n = 3). Before tourniquet release, arterial injuries were repaired, and mechanical ventilation and rapid crystalloid fluid were provided for at least 5 min. Additional fluid and 500 mL autologous blood were transfused after restoring blood flow. Animals were recovered and their mobility and health monitored up to 2 wk. RESULTS: AAJT application occluded the infrarenal abdominal aorta and stopped bilateral groin hemorrhage with rapid reversal of hemorrhagic shock and improved cranial blood pressure. All animals including controls recovered overnight but regaining hind leg function varied among AAJT-treated groups. In contrast to 1 h AAJT-treated swine that recovered full mobility in 1 wk, 2 h animals developed persistent hind leg paraplegia concurrent with urinary retention and ischemic necrosis of lumber muscles and had to be euthanized 3 d after surgery. Half of the 1.5-h group also had to be euthanized early due to paraplegia, whereas the other half recovered motor function within 2 wk. CONCLUSIONS: The results of this animal study indicated that ischemic reperfusion injuries associated with abdominal application of the AAJT were time-dependent. To avoid permanent injuries, AAJT application on the abdomen to control a groin hemorrhage could not be longer than 1 h. This was consistent with recent instructions for application of this tourniquet on the abdomen in patients.

Prehospital Application of Hemostatic Agents in Iraq and Afghanistan.

INTRODUCTION: Hemorrhage is the leading cause of death on the battlefield. Development of chitosan- and kaolin-based hemostatic agents has improved hemorrhage control options. Sparse data exists on the use of these agents in the prehospital, combat setting. We describe recent use of these agents and compare patients receiving hemostatic to the baseline population. METHODS: We used a series of emergency department (ED) procedure codes to identify patients within the Department of Defense Trauma Registry (DODTR) from January 2007 to August 2016. We only included patients for whom the DODTR specified the hemostatic agent utilized (chitosan or kaolin). We defined a serious injury by body region as an Abbreviated Injury Score (AIS) of 3 or greater. RESULTS: Our predefined search codes captured 28,222 patients. Of those, 258 (0.9%) patients had documented hemostatic use: 58 chitosan, 201 kaolin, and one subject received both. Patients undergoing hemostatic agent application were more likely to be injured by gunshot wound or explosive. Patients with hemostatic application had higher median composite Injury Severity Scores (10 vs. 9, p < 0.001), and higher AIS for the abdomen, extremity and superficial body regions with higher rates of blood product utilization. Proportions of patients suffering traumatic amputations and undergoing tourniquet application were higher in the hemostatic agent group than the baseline population (11.6% vs. 6.7%, p = 0.002 and 43.4% vs. 13.8%, p < 0.001, respectively). CONCLUSIONS: Hemostatic agents were infrequently utilized to manage traumatic hemorrhage during the recent conflicts in Afghanistan and Iraq. Hemostatic agent use was more frequent in casualties with gunshot wounds, traumatic amputations, concomitant tourniquet application, and greater blood product administration."

The Cutaneous Microbiome and Wounds: New Molecular Targets to Promote Wound Healing.

The ecological community of microorganisms in/on humans, termed the microbiome, is vital for sustaining homeostasis. While culture-independent techniques have revealed the role of the gut microbiome in human health and disease, the role of the cutaneous microbiome in wound healing is less defined. Skin commensals are essential in the maintenance of the epithelial barrier function, regulation of the host immune system, and protection from invading pathogenic microorganisms. In this review, we summarize the literature derived from pre-clinical and clinical studies on how changes in the microbiome of various acute and chronic skin wounds impact wound healing tissue regeneration. Furthermore, we review the mechanistic insights garnered from model wound healing systems. Finally, in the face of growing concern about antibiotic-resistance, we will discuss alternative strategies for the treatment of infected wounds to improve wound healing and outcomes. Taken together, it has become apparent that commensals, symbionts, and pathogens on human skin have an intimate role in the inflammatory response that highlights several potential strategies to treat infected, non-healing wounds. Despite these promising results, there are some contradictory and controversial findings from existing studies and more research is needed to define the role of the human skin microbiome in acute and chronic wound healing.

Molecular mechanisms of trauma-induced acute kidney injury: Inflammatory and metabolic insights from animal models.

Trauma-induced acute kidney injury (AKI), such as after hemorrhagic shock (HS) or burn, remains a significant problem in the intensive care unit and is associated with increased mortality. The pathophysiology that drives AKI post-trauma is multi-factorial, and includes both inflammatory and metabolic alterations. Identifying the systemic profile that contributes to AKI is crucial not only for early diagnosis, but also for identifying treatments that improve kidney function and maintaining long-term patient health. In an effort to elucidate this molecular pathophysiology researchers have utilized a variety of animal models including chemically-induced (i.e., cisplatin), blocking renal perfusion (i.e., arterial clamping) and inducing burn or HS. As the latter burn and HS models are unequivocally applicable to studying AKI in the context of traumatic injury, this review will summarize the inflammatory and metabolic insights associated with AKI gained with these animal models. Moreover, novel therapeutic strategies brought forth with these models will be discussed.

Low-volume resuscitation with normal saline is associated with microvascular endothelial dysfunction after hemorrhage in rats, compared to colloids and balanced crystalloids.

BACKGROUND: Restoration of endothelial glycocalyx (EG) barrier may be an essential therapeutic target for successful resuscitation. The aim of this study was to compare in vivo the effects of resuscitation with normal saline (NS) to lactated Ringer's solution (LR), 5% albumin and fresh frozen plasma (FFP) on their ability to maintain EG and barrier function integrity, mitigate endothelial injury and inflammation, and restore vascular homeostasis after hemorrhagic shock. METHODS: Anesthetized rats (N = 36) were subjected to hemorrhagic shock (bled 40% of total blood volume), followed by resuscitation with 45 ml/kg NS or LR, or 15 ml/kg 5% albumin or FFP. Microhemodynamics, EG thickness, permeability, leukocyte rolling and adhesion were assessed in >180 vessels from cremaster muscle, as well as systemic measures. RESULTS: After hypotensive resuscitation, arterial pressure was 25% lower than baseline in all cohorts. Unlike FFP, resuscitation with crystalloids failed to restore EG thickness to baseline post shock and shedding of glycocalyx proteoglycan was significantly higher after NS. NS decreased blood flow and shear, and markedly increased permeability and leukocyte rolling/adhesion. In contrast, LR had lesser effects on increased permeability and leukocyte rolling. Albumin stabilized permeability and white blood cell (WBC) rolling/adhesion post shock, comparable to FFP. CONCLUSIONS: Resuscitation with NS failed to inhibit syndecan-1 shedding and to repair the EG, which led to loss of endothelial barrier function (edema), decline in tissue perfusion and pronounced leukocyte rolling and adhesion. Detrimental effects of NS on endothelial and microvascular stabilization post shock may provide a pathophysiological basis to understand and prevent morbidity associated with iatrogenic resuscitation after hemorrhagic shock.

Bleeding Control With Limb Tourniquet Use in the Wilderness Setting: Review of Science.

The purpose of this review is to summarize tourniquet science for possible translation to wilderness settings. Much combat casualty data has been studied since 2005, and use of tourniquets in the military has changed from a last resort to first aid. The US Government has made use of tourniquets a health policy aimed to improve public access to bleeding control items. International authorities believe that education in first aid should be universal, as all can and should learn first aid. The safety record of tourniquet use is mixed, but users are reliably safe if trained well. Well-designed tourniquets can reliably attain bleeding control, may mitigate risk of shock progression, and may improve survival rates, but conclusive proof of a survival benefit remains unclear in civilian settings. Even a war setting has a bias toward survivorship by sampling mostly survivors in hospitals. Improvised tourniquets are less reliable than well-designed tourniquets but may be better than none. The tourniquet model used most often in 2016 by the US military is the Combat Application Tourniquet (C-A-T), and civilians use an array of various models, including C-A-T. Evidence on tourniquet use to date indicates that most uses are safe and effective in civilian settings. Future directions for study relevant to the wilderness setting include consideration of research priorities, study of the burdens of injury or capability gaps in caregiving for various wilderness settings, determination of the skill needs of outdoor enthusiasts and wilderness caregivers, and survey of wilderness medicine stewards regarding bleeding control.

Belts Evaluated as Limb Tourniquets: BELT Study Comparing Trouser Supporters Used as Medical Devices in a Manikin Model of Wound Bleeding.

OBJECTIVE: The purpose of the present study is to compare several models of commercially designed belts as used as a tourniquet. METHODS: In the Belts Evaluated as Limb Tourniquets (BELT) study, an experiment was designed to test the effectiveness of pants belts as nonimprovised medical devices to control hemorrhage in a manikin. Models of belts included Tourni-belt, Tourniquet Belt, ParaBelt, and Battle Buddy. Data collected included effectiveness, time to stop bleeding, total time of application, pressure, blood loss, and composite results (score count of good results; composite outcome good if every component was good). RESULTS: Differences in effectiveness percentages among models were not statistically significant. The difference in mean between users was statistically significant for stop time, total time, pressure, blood loss, composite score, and composite outcome. Mean time to stop bleeding differed for only 1 pair of models after the Tukey-Kramer adjustment; ParaBelt was faster than Tourniquet Belt. Mean total time of application differed between ParaBelt-Tourniquet Belt and Tourni-belt-Tourniquet Belt; the former model in both pairs was faster. No significant difference in mean blood loss measured by model was found. For composite outcome score, no pairwise difference between models was significant. For composite outcome (good-bad), ParaBelt had good results in 75% of tests; the other 3 models had significantly worse results. CONCLUSIONS: In a preliminary laboratory analysis of belt tourniquet models using a manikin, performance differed by model. ParaBelt performed better than other models for the composite outcome.

Plasma syndecan-1 and heparan sulfate correlate with microvascular glycocalyx degradation in hemorrhaged rats after different resuscitation fluids.

The endothelial glycocalyx plays an essential role in many physiological functions and is damaged after hemorrhage. Fluid resuscitation may further change the glycocalyx after an initial hemorrhage-induced degradation. Plasma levels of syndecan-1 and heparan sulfate have been used as indirect markers for glycocalyx degradation, but the extent to which these measures are representative of the events in the microcirculation is unknown. Using hemorrhage and a wide range of resuscitation fluids, we studied quantitatively the relationship between plasma biomarkers and changes in microvascular parameters, including glycocalyx thickness. Rats were bled 40% of total blood volume and resuscitated with seven different fluids (fresh whole blood, blood products, and crystalloids). Intravital microscopy was used to estimate glycocalyx thickness in >270 postcapillary venules from 58 cremaster preparations in 9 animal groups; other microvascular parameters were measured using noninvasive techniques. Systemic physiological parameters and blood chemistry were simultaneously collected. Changes in glycocalyx thickness were negatively correlated with changes in plasma levels of syndecan-1 (r = -0.937) and heparan sulfate (r = -0.864). Changes in microvascular permeability were positively correlated with changes in both plasma biomarkers (r = 0.8, P < 0.05). Syndecan-1 and heparan sulfate were also positively correlated (r = 0.7, P < 0.05). Except for diameter and permeability, changes in local microcirculatory parameters (red blood cell velocity, blood flow, and wall shear rate) did not correlate with plasma biomarkers or glycocalyx thickness changes. This work provides a quantitative framework supporting plasma syndecan-1 and heparan sulfate as valuable clinical biomarkers of glycocalyx shedding that may be useful in guiding resuscitation strategies following hemorrhage.

Extracorporeal Carbon Dioxide Removal Enhanced by Lactic Acid Infusion in Spontaneously Breathing Conscious Sheep.

BACKGROUND: The authors studied the effects on membrane lung carbon dioxide extraction (VCO2ML), spontaneous ventilation, and energy expenditure (EE) of an innovative extracorporeal carbon dioxide removal (ECCO2R) technique enhanced by acidification (acid load carbon dioxide removal [ALCO2R]) via lactic acid. METHODS: Six spontaneously breathing healthy ewes were connected to an extracorporeal circuit with blood flow 250 ml/min and gas flow 10 l/min. Sheep underwent two randomly ordered experimental sequences, each consisting of two 12-h alternating phases of ALCO2R and ECCO2R. During ALCO2R, lactic acid (1.5 mEq/min) was infused before the membrane lung. Caloric intake was not controlled, and animals were freely fed. VCO2ML, natural lung carbon dioxide extraction, total carbon dioxide production, and minute ventilation were recorded. Oxygen consumption and EE were calculated. RESULTS: ALCO2R enhanced VCO2ML by 48% relative to ECCO2R (55.3 ± 3.1 vs. 37.2 ± 3.2 ml/min; P less than 0.001). During ALCO2R, minute ventilation and natural lung carbon dioxide extraction were not affected (7.88 ± 2.00 vs. 7.51 ± 1.89 l/min, P = 0.146; 167.9 ± 41.6 vs. 159.6 ± 51.8 ml/min, P = 0.063), whereas total carbon dioxide production, oxygen consumption, and EE rose by 12% each (223.53 ± 42.68 vs. 196.64 ± 50.92 ml/min, 215.3 ± 96.9 vs. 189.1 ± 89.0 ml/min, 67.5 ± 24.0 vs. 60.3 ± 20.1 kcal/h; P less than 0.001). CONCLUSIONS: ALCO2R was effective in enhancing VCO2ML. However, lactic acid caused a rise in EE that made ALCO2R no different from standard ECCO2R with respect to ventilation. The authors suggest coupling lactic acid-enhanced ALCO2R with active measures to control metabolism.

Intramuscular versus Intraosseous Delivery of Nerve Agent Antidote Pralidoxime Chloride in Swine.

OBJECTIVE: Exposure to nerve agents requires prompt treatment. We hypothesized that intraosseous (IO) injections of drug antidotes into the vascularized bone marrow will provide a more rapid and effective means to treat exposure to nerve agents than standard intramuscular (IM) injections. We compared the pharmacokinetics of IM and IO administration of pralidoxime chloride (2-PAM Cl) during normovolemia and hypovolemia, as well as their combined administration during normovolemia in swine. METHODS: Ten normovolemic swine were randomly administered 2 mL, 660 mg 2-PAM Cl via the IM or IO route and monitored for 180 minutes. IM versus IO also was compared in 8 hypovolemic swine bled to a mean arterial pressure of 50 mmHg. In a combined group, an IO injection was administered followed by an IM injection 60 minutes later. Blood samples were collected at times over a 180-minute period to calculate standard pharmacokinetic variables to compare the 2 routes of administration. RESULTS: In the normovolemic swine, IM injection achieved therapeutic levels (4 µg/mL) in 2 minutes, whereas IO infusion achieved these levels in less than 15 seconds. 2-PAM-Cl concentrations fell below these levels at 60 minutes post-injection in both groups. In the hypovolemic swine, IM injection achieved therapeutic levels in 4 minutes compared to less than 15 seconds in the IO group. 2-PAM-Cl concentrations fell below therapeutic levels at 12 and 90 minutes post-injection in the IM and IO groups, respectively. In the combined IO-IM treatment, plasma levels remained above therapeutic levels for the entire experiment and had two concentration peaks that corresponded to IO and IM injections. CONCLUSIONS: The IO route for the delivery of 2-PAM Cl provides a significant time and high initial blood concentrations advantage compared to the IM route for the prehospital treatment of nerve agent exposure even under hypovolemic conditions. The initial concentration peak associated with IO, but not IM, may provide greater initial therapy at the most critical time.

Postischemic conditioning does not reduce muscle injury after tourniquet-induced ischemia-reperfusion injury in rats.

BACKGROUND: The widespread application of tourniquets has reduced battlefield mortality related to extremity exsanguinations. Tourniquet-induced ischemia-reperfusion injury (I/R) can contribute to muscle loss. Postischemic conditioning (PostC) confers protection against I/R in cardiac muscle and skeletal muscle flaps. The objective of this study was to determine the effect of PostC on extremity muscle viability in an established rat hindlimb tourniquet model. METHODS: Rats were randomly assigned to PostC-1, PostC-2, or no conditioning ischemic groups (n = 10 per group). Postischemic conditioning, performed immediately after tourniquet release, consisted of four 15-second cycles (PostC-1) or eight 15-second cycles (PostC-2) of alternating occlusion and perfusion of hindlimbs. Twenty-four hours later, muscles were excised. The primary end points were muscle edema and viability; secondary end points were histologic and markers of oxidative stress. RESULTS: Ischemia-reperfusion injury decreased viability in all tourniquet limbs, but viability was not improved in either PostC group. Likewise, I/R resulted in substantial muscle edema that was not reduced by PostC. The predominant histologic feature was necrosis, but no significant differences were found among groups. Markers of oxidative stress were increased similarly among groups after I/R, although myeloperoxidase activity was significantly increased only in the no conditioning ischemic group. A protective effect from PostC was not observed in our model suggesting that PostC was not effective in reducing I/R skeletal muscle injury or any benefits of PostC were not sustained for 24 hours when tissues were assessed. CONCLUSION: These negative findings are pertinent as the military investigates different strategies to extend the safe time for tourniquet application.

Vitamin and Trace Element Loss from Negative-Pressure Wound Therapy.

OBJECTIVE: This study investigated select vitamin and trace element loss from wound exudates in burn and trauma patients treated with negative-pressure wound therapy (NPWT). DESIGN: A prospective observational study was performed using wound exudate samples. SETTING: A level I trauma center acute care hospital. PARTICIPANTS: The study was composed of 8 patients with open abdomens and 9 patients with 12 soft-tissue wounds. MAIN OUTCOME MEASURES: The goal was to collect wound exudate samples daily for 3 days, then every other day to day 9 or until NPWT was discontinued, and to analyze for vitamins A (retinol), C, and E and zinc (Zn), iron (Fe), and copper (Cu). Daily loss of each micronutrient was calculated from their concentration and 24-hour volumes of the exudates. MAIN RESULTS: Exudate loss in the open-abdomen group was significantly higher than in the patients with soft-tissue wounds (900 ± 547 vs 359 ± 246 mL/d). The mean 24-hour loss of vitamins A, C, and E were 0.3, 2.8, and 11 mg, respectively, in the open-abdomen group. Over the same period, the losses of Zn, Fe, and Cu were 0.5, 0.4, and 0.25 mg, respectively, in these patients. Micronutrient 24-hour loss was significantly lower in the soft-tissue wound patients than in the open-abdomen group. CONCLUSIONS: The data support the concept that significant amounts of micronutrients can be lost from NPWT wound exudates, particularly in open abdomens. These losses should be considered in the nutritional support of these patients who typically are in a hypermetabolic and catabolic state.

Transfusion for shock in US military war casualties with and without tourniquet use.

STUDY OBJECTIVE: We assess whether emergency tourniquet use for transfused war casualties admitted to military hospitals is associated with survival. METHODS: A retrospective review of trauma registry data was made of US casualties in Afghanistan and Iraq. Patients with major limb trauma, transfusion, and tourniquet use were compared with similar patients who did not receive tourniquet use. A propensity-matching analysis was performed by stratifying for injury type and severity by tourniquet-use status. Additionally, direct comparison without propensity matching was made between tourniquet use and no-tourniquet use groups. RESULTS: There were 720 casualties in the tourniquet use and 693 in the no-tourniquet use groups. Of the 1,413 casualties, 66% (928) also had nonextremity injury. Casualties with tourniquet use had worse signs of hemorrhagic shock (admission base deficit, admission hemoglobin, admission pulse, and transfusion units required) than those without. Survival rates were similar between the 2 groups (1% difference; 95% confidence interval -2.5% to 4.2%), but casualties who received tourniquets had worse shock and received more blood products. In propensity-matched casualties, survival rates were not different (2% difference; 95% confidence interval -6.7% to 2.7%) between the 2 groups. CONCLUSION: Tourniquet use was associated with worse shock and more transfusion requirements among hospital-admitted casualties, yet those who received tourniquets had survival rates similar to those of comparable, transfused casualties who did not receive tourniquets.