Search

Uncontrolled hemorrhage is a leading cause of death in trauma situations. Developing solutions to automate hemorrhagic shock resuscitation may improve the outcomes for trauma patients. However, testing and development of automated solutions to address critical care interventions, oftentimes require extensive large animal studies for even initial troubleshooting. The use of accurate laboratory or in-silico models may provide a way to reduce the need for large animal datasets. Here, a tabletop model, for use in the development of fluid resuscitation with physiologically relevant pressure-volume responsiveness for high throughput testing, is presented. The design approach shown can be applied to any pressure-volume dataset through a process of curve-fitting, 3D modeling, and fabrication of a fluid reservoir shaped to the precise curve fit. Two case studies are presented here based on different resuscitation fluids: whole blood and crystalloid resuscitation. Both scenarios were derived from data acquired during porcine hemorrhage studies, used a pressure-volume curve to design and fabricate a 3D model, and evaluated to show that the test platform mimics the physiological data. The vessels produced based on data collected from pigs infused with whole blood and crystalloid were able to reproduce normalized pressure-volume curves within one standard deviation of the porcine data with mean residual differences of 0.018 and 0.016, respectively. This design process is useful for developing closed-loop algorithms for resuscitation and can simplify initial testing of technologies for this life-saving medical intervention., (© 2022 IOP Publishing Ltd.)

Introduction: Current agents for the intravascular embolization of traumatic hemorrhage are used off-label and have been minimally studied with respect to their performance under differing coagulation conditions. We studied the hemorrhage control efficacy of a novel, liquid, polyethylene glycol-based hydrogel delivered as two liquid precursors that polymerize within the target vessel in a unique animal model of severe solid organ injury with and without dilutional coagulopathy., Methods: Anesthetized swine (n = 36, 45 ± 3 kg) had laparotomy and splenic externalization. Half underwent 50% isovolemic hemodilution with 6% hetastarch and cooling to 33°C-35°C (coagulopathic group). All animals had controlled 20 mL/kg hemorrhage and endovascular proximal splenic artery access with a 4F catheter via a right femoral sheath. Splenic transection and 5-minute free bleeding were followed by treatment (n = 5/group) with 5 mL of gelfoam slurry, three 6-mm coils, up to 6 mL of hydrogel, or no treatment (n = 3, control). Animals received 15 mL/kg plasma and were monitored for 6 hours with continuous blood loss measurement., Results: Coagulopathy was successfully established, with coagulopathic animals having greater pretreatment blood loss and earlier mean time to death regardless of the treatment group. All control animals died within 100 minutes. Overall survival without coagulopathy was 5/5 for hydrogel, 4/5 for coil, and 3/5 for gelfoam. With coagulopathy, one hydrogel animal survived to the end of the experiment, with 2/4 hydrogel deaths occurring in the final hour of observation. In noncoagulopathic animals, hydrogel demonstrated improved survival time ( P  < .01) and post-treatment blood loss (1.46 ± 0.8 mL/kg) over controls (18.8 ± 0.7, P  = .001), gelfoam (4.7 ± 1.3, P > .05), and coils (4.6 ± 1.5, P > .05). In coagulopathic animals, hydrogel had improved survival time ( P  = .003) and decreased blood loss (4.2 ± 0.8 mL/kg) compared with control (20.4 ± 4.2, P  = .003)., Conclusions: The hydrogel demonstrated equivalent hemorrhage control performance to standard treatments under noncoagulopathic conditions and improved performance in the face of dilutional coagulopathy. This agent should be explored as a potential preferable treatment for the embolization of traumatic solid organ and other injuries. (JVS-Vascular Science 2021;2:43-51.)., Clinical Relevance: In a translational model of severe solid organ injury hemorrhage with and without coagulopathy, a novel hydrogel transarterial embolization agent demonstrated equivalent hemorrhage control performance to standard agents under noncoagulopathic conditions and improved performance in the face of dilutional coagulopathy. This agent represents a promising future treatment for the embolization of traumatic solid organ and other injuries.

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., (Published by Elsevier Inc.)

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., (Published by Elsevier Inc.)

Background: Junctional hemorrhage is a leading contributor to battlefield mortality. The Abdominal Aortic and Junctional Tourniquet (AAJT) and infrarenal (zone III) resuscitative endovascular balloon occlusion of the aorta (REBOA) are emerging strategies for controlling junctional hemorrhage, with AAJT currently available in select forward deployed settings and increasing interest in applying REBOA in the military prehospital environment. This study compared the hemostatic, hemodynamic, and metabolic effects of these devices used for junctional hemorrhage control., Methods: Shock was induced in anesthetized, mechanically ventilated swine with a controlled hemorrhage (20 mL/kg) and closed femur fracture followed by uncontrolled hemorrhage from a partial femoral artery transection (40% total hemorrhage volume). Residual femoral hemorrhage was recorded during 60-minute AAJT (n = 10) or zone III REBOA (n = 10) deployment, and the arterial injury was repaired subsequently. Animals were resuscitated with 15 mL/kg autologous whole blood and observed for 6 hours., Results: One animal in each group died during observation. Both devices achieved hemostasis with mean residual femoral blood loss in the AAJT and REBOA groups of 0.38 ± 0.59 mL/kg and 0.10 ± 0.07 mL/kg (p = 0.16), respectively, during the 60-minute intervention. The AAJT and REBOA augmented proximal blood pressure equally with AAJT allowing higher distal pressure than REBOA during intervention (p < 0.01). Following device deflation, AAJT animals had transiently lower mean arterial blood pressure than REBOA pigs (39 ± 6 vs. 54 ± 11 mm Hg p = 0.01). Both interventions resulted in similar degrees of lactic acidemia which resolved during observation. Similar cardiac and renal effects were observed between AAJT and REBOA., Conclusion: The AAJT and REBOA produced similar hemostatic, resuscitative, and metabolic effects in this model of severe shock with junctional hemorrhage. Both interventions may have utility in future military medical operations.

Background: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is accepted as a resuscitation adjunct and bridge to definitive hemostasis. The ischemic burden of REBOA may be mitigated by a partial REBOA (P-REBOA) strategy permitting longer occlusion times and military use for combat trauma. We evaluated REBOA and P-REBOA in a swine multiple trauma model with uncontrolled solid organ hemorrhage and delayed resuscitation and surgical hemostasis., Methods: Anesthetized swine (51.9 ± 2.2 kg) had 20 mL/kg hemorrhage and closed femur fracture. Splenic transection was performed and free bleeding permitted for 10 minutes. Controls (n = 5) were hemorrhaged but had no REBOA, REBOA (n = 8) had 60 minutes complete zone 1 occlusion, P-REBOA (n = 8) had 15 minutes complete occlusion and 45 minutes 50% occlusion. Splenectomy was performed and plasma (15 mL/kg) resuscitation initiated 5 minutes prior to deflation. Resuscitation goal was 80 mm Hg systolic with epinephrine as needed. Animals were monitored for 6 hours., Results: An initial study with 120-minute occlusion had universal fatality in three REBOA (upon deflation) and three P-REBOA animals (after 60 minutes inflation). With 60-minute occlusion, mortality was 100%, 62.5%, and 12.5% in the control, REBOA, and P-REBOA groups, respectively (p < 0.05). Survival time was shorter in controls (120 ± 89 minutes) than REBOA and P-REBOA groups (241 ± 139, 336 ± 69 minutes). Complete REBOA hemorrhaged less during inflation (1.1 ± 0.5 mL/kg) than Control (5.6 ± 1.5) and P-REBOA (4.3 ± 1.4), which were similar. Lactate was higher in the REBOA group compared with the P-REBOA group after balloon deflation, remaining elevated. Potassium increased in REBOA after deflation but returned to similar levels as P-REBOA by 120 minutes., Conclusion: In a military relevant model of severe uncontrolled solid organ hemorrhage 1-hour P-REBOA improved survival and mitigated hemodynamic and metabolic shock. Two hours of partial aortic occlusion was not survivable using this protocol due to ongoing hemorrhage during inflation. There is potential role for P-REBOA as part of an integrated minimally invasive field-expedient hemorrhage control and resuscitation strategy.

Background: Tranexamic acid (TXA) is an antifibrinolytic drug that was shown to increase survival in trauma patients, but the mechanisms remain unclear. The purpose of this double-blinded, randomized placebo-controlled study was to determine if TXA with hypotensive resuscitation with Hextend (HEX) or fresh frozen plasma (FFP) reduced blood loss (BL) and improved survival in a model of uncontrolled hemorrhage., Methods: Instrumented, anesthetized pigs (n = 11 per group) were subjected to 24-mL/kg controlled hemorrhage, followed by transection of the spleen. After 15 minutes of bleeding, TXA (1.43 mg/kg/min) or normal saline (NS) was given over 10 minutes, and then 15-mL/kg HEX or FFP was administered. At 90 minutes, a second infusion of TXA or NS was given. BL, coagulation status, and 5-hour survival were determined. Tissue plasminogen activator (tPA) was added to blood samples collected before and after TXA administration to confirm that the TXA inhibited fibrinolysis. In addition, a comparison of a dose response to tPA-induced fibrinolysis was made between swine and human plasma in vitro., Results: TXA prevented the rise in d-dimers that occurred after spleen injury. However, there was no significant effect of TXA on survival or BL compared with NS with HEX (HEX + NS, 17 ± 2 mL/kg vs. HEX + TXA, 17 ± 2 mL/kg) or FFP (FFP + NS, 7 ± 2 mL/kg vs. FFP + TXA, 12 ± 3 mL/kg), while FFP significantly reduced BL and increased survival compared with HEX in the NS-treated animals. The tPA-induced fibrinolysis was inhibited in the blood from TXA-treated animals, yet in fibrinolysis sensitivity studies, human plasma was 30 times more sensitive to tPA-induced fibrinolysis than swine plasma., Conclusion: TXA did not reduce BL, even though TXA was antifibrinolytic in the pigs. The possibility remains that the pig is highly resistant to fibrinolysis and not a good model to study the effects of antifibrinolytics or that fibrinolysis is not a major factor in bleeding from splenic injury.

During the past several years, trauma resuscitation in human patients has evolved from decreased use of crystalloids to increased use of blood products. Of high interest is the role of platelets in trauma resuscitation. Because conducting prehos- pital resuscitation in human trauma patients is very difficult, swine are often the animal model of choice for such studies because their coagulation and hemodynamic systems are similar to those in humans. However, consistent production of sufficient swine platelets for such studies has not previously been achieved. We developed a method for producing swine platelets by using standard human techniques and equipment. We assessed pH, pO2, pCO2, lactate, thromboelastography, and platelet aggregation over 5 d of storage to determine whether the swine platelet product met the American Association of Blood Banks (AABB) standards for transfusion. Swine platelets met AABB standards at 24 h but not at later time points. In addition, we fluorescently labeled nonautologous platelets and then measured their percentage recovery over 5 h (the time used in subsequent experimental studies) when transfused into a recipient pig. We showed that 80% of the platelets stored for 24 h remained in the circulation and increased the recipient pigs' thromboelastographic responses, indicating that the platelets were viable and active. Therefore, swine platelets stored for 24 h by using standard human products met the AABB criteria and were functional.

Background: Tranexamic acid (TXA) is an antifibrinolytic agent that reduces blood loss during surgery, decreases mortality in civilian and military trauma populations, was adopted for prehospital use by the British military, and is now issued to U.S. Special Operations Forces for use on the battlefield., Objective: This study tested whether storage of TXA ampoules at four temperatures (-20°C, 4°C, 22°C, or 50°C) for 1, 2, 4, and 12 weeks would result in chemical degradation and the loss of activity to block streptokinase-induced fibrinolysis in human plasma., Methods: For each temperature and storage duration, normal plasma, plasma plus streptokinase (SK) (50 units/mL), and plasma + SK + TXA (0.2 μg/mL, n = 4) were tested for D-dimer (DD), for fibrin degradation products (FDP), by thromboelastography (to measure the units/mL of SK needed to get 100% fibrinolysis at 60 minutes [LY60]), and by high-performance liquid chromatography (HPLC). The results were similar for all temperatures and storage durations, and were therefore combined., Results: Streptokinase led to a rise in LY60, DD, and FDP that was significantly (p < 0.05) attenuated with TXA. The results in the three test conditions were LY60: 0.00% ± 0.00%, 70.52% ± 4.7%, 0.02% ± 0.01%; DD: 0.23 ± 0.1, 205.05 ± 101.59, 0.31 ± 0.01 mg/L; and FDP: <10, >40, and <10 μg/mL, respectively. The HPLC results showed no chemical breakdown of TXA. All TXA glass ampoules at -20°C were cracked by week 1., Conclusions: Except for the finding that TXA ampoules cracked when frozen, this study indicated that the drug remains effective when stored under conditions likely to be encountered in the prehospital environment and outside the manufacturer's recommended temperature range for at least 12 weeks.

Hemorrhage is responsible for a large percentage of trauma-related deaths but the mechanisms underlying tissue ischemia are complex and not well understood. Despite the evidence linking glycocalyx degradation and hemorrhagic shock, there is no direct data obtained in vivo showing glycocalyx thickness reduction in skeletal muscle venules after hemorrhage. We hypothesize that damage to the endothelial glycocalyx is a key element in hemorrhage pathophysiology and tested the hypothesis that hemorrhage causes glycocalyx degradation in cremaster muscle microvessels. We utilized intravital microscopy to estimate glycocalyx thickness in 48 microvessels while other microvascular parameters were measured using non-invasive techniques. Systemic physiological parameters and blood chemistry were simultaneously collected. We studied 27 post-capillary venules (<16 μm diameter) of 8 anesthetized rats subjected to hemorrhage (40% of total blood volume). Six control rats were equally instrumented but not bled. Dextrans of different molecular weights labeled with FITC or Texas Red were injected. Glycocalyx thickness was estimated from the widths of the fluorescence columns and from anatomical diameter. While control rats did not show remarkable responses, a statistically significant decrease of about 59% in glycocalyx thickness was measured in venules after hemorrhagic shock. Venular glycocalyx thickness and local blood flow changes were correlated: venules with the greatest flow reductions showed the largest decreases in glycocalyx. These changes may have a significant impact in shock pathophysiology. Intravital microscopy and integrated systems such as the one described here may be important tools to identify mechanisms by which resuscitation fluids may improve tissue recovery and outcome following hemorrhage., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Damage control resuscitation recommends use of more plasma and less crystalloid as initial resuscitation in treating hemorrhage. The purpose of this study was to evaluate resuscitation with either blood components or conventional fluids on coagulation and blood loss., Study Design and Methods: Isofluorane-anesthetized, instrumented pigs (eight per group) underwent controlled hemorrhage of 24 mL/kg, 20-minute shock period, splenic injury with 15-minute initial bleeding, and hypotensive fluid resuscitation. Lactated Ringer's (LR) was infused at 45 mL/kg while hetastarch (high-molecular-weight hydroxyethyl starch 6%, Hextend, Hospira, Inc., Lake Forest, IL) and blood component (fresh-frozen plasma [FFP], 1:1 FFP:[red blood cells] RBCs, 1:4 FFP : RBCs, and fresh whole blood [FWB]) were infused at 15 mL/kg. Postresuscitation blood loss (PRBL), hemodynamics, coagulation, hematocrit, and oxygen metabolism were measured postinjury for 5 hours., Results: Resuscitation with any blood component reduced PRBL of 52% to 70% compared to Hextend, with FFP resulting in the lowest PRBL. PRBL with LR (11.5 ± 3.0 mL/kg) was not significantly different from Hextend (17.9 ± 2.5 mL/kg) or blood components (range, 5.5 ± 1.5 to 8.6 ± 2.6 mL/kg). The volume expansion effect of LR was transient. All fluids produced similar changes in hemodynamics, oxygen delivery, and demand despite the oxygen-carrying capacity of RBC-containing fluids. Compared with other fluids, Hextend produced greater hemodilution and reduced coagulation measures, which could be caused by an indirect dilutional effect or a direct hypocoagulable effect., Conclusions: These data suggest that blood products as initial resuscitation fluids reduced PRBL from a noncompressible injury compared to Hextend, preserved coagulation, and provided sustained volume expansion. There were no differences on PRBL among RBCs-to-FFP, FWB, or FFP in this nonmassive transfusion model., (© 2010 American Association of Blood Banks.)