Evaluation of a novel hydrogel intravascular embolization agent in a swine model of fatal uncontrolled solid organ hemorrhage and coagulopathy.

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.

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.

Should Albumin be Considered for Prehospital Resuscitation in Austere Environments? A Prospective Randomized Survival Study in Rabbits.

BACKGROUND: The new guidelines for prehospital care of combat casualties in shock recommend administration of whole blood or blood components to increase blood pressure to a permissible hypotensive level (i.e., hypotensive resuscitation [HR]). We investigated if 2 h of HR using limited volumes of whole blood, plasma, or albumin would lead to full recovery and long-term survival of rabbits subjected to severe hemorrhagic shock (HS). METHODS: Following instrumentation, laparotomy was performed on IV-anesthetized spontaneously breathing New Zealand white rabbits (3.0 kg -3.5 kg). Next, ∼40% of rabbits' blood volume was removed producing HS (mean arterial pressure [MAP]∼20 mm Hg). Fifteen minutes later, rabbits were resuscitated with a limited volume (12.5 mL/kg) of rabbit whole blood (fresh whole blood [FWB]), rabbit fresh frozen plasma (FFP), or 5% human albumin (ALB) to a target pressure (MAP) of 60 mm Hg (n=8/grp) and monitored for 2 h. Liver bleeding time was measured at baseline and 10 min after HR. Subsequently, animals were fully resuscitated (blood + lactated Ringer [LR]), surgically repaired, and recovered for 8 days. An untreated group (n = 6) was also included. RESULTS: Following HS, lactate and base deficit levels were increased to 8.2 ±â€Š1.6 and 12.9 ±â€Š3.1 mM respectively with no difference among groups. A lower volume of FWB volume was required to reach the target MAP (P < 0.05 vs. ALB) but MAP declined during the HR period (P < 0.01 vs. ALB). FWB provided higher hematocrit and platelets but it did not reduce lactate level faster than other fluids. Beside higher fibrinogen, no differences were found in hemostatic or resuscitative effects of FFP versus ALB. Bleeding time was prolonged with ALB and FFP fluids but unchanged with FWB. Untreated rabbits died during shock or shortly after. All treated rabbits except one recovered and lived for 8 days with normal blood tests and similar tissue histology. CONCLUSIONS: Two hours of HR using a limited volume of FWB, FFP, or ALB led to full recovery and long-term survival of rabbits subjected to HS. Apart from bleeding time, no clinically significant differences were found among the three fluids. Five percent human albumin solutions are isotonic, iso-oncotic, ready-to-use, stable, and compatible with all blood types and should be considered for prehospital resuscitation where blood products are not available or not accepted.

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.

Do vented chest seals differ in efficacy? An experimental evaluation using a swine hemopneumothorax model.

OBJECTIVE: Airways compromise was the second leading cause of potentially preventable death among combat casualties. We investigated the ability of five Food and Drug Administration-approved nonocclusive chest seals (CSs) to seal a bleeding chest wound and prevent tension hemopneumothorax (HPTX) in a swine model. METHODS: Following instrumentation, an open chest wound was created in the left thorax of spontaneously air-breathing anesthetized pigs (n = 26; 43 kg). Autologous fresh blood (226 mL) was then infused into the pleural cavity to produce HPTX. The chest wounds were then sealed with CSs. The sealant strength and venting function of CSs were challenged by infusion of 50 mL more blood directly into the chest wound and incremental air injections into the pleural cavity. Tension HPTX was defined as intrapleural (IP) pressure equal to or more than +1 mm Hg and more than 20% deviation in physiologic measurements. RESULTS: An open chest wound with HPTX raised IP pressure (~ -0.7 mm Hg) and caused labored breathing and reductions in PaO2 and SvO2 (p < 0.01). Sealing the wounds with the CSs restored IP pressure, and improved breathing and oxygenation. Subsequent blood infusion into the wound and IP air injections produced CS-dependent responses. Chest seals with one-way valves (Bolin and SAM) did not evacuate the blood efficiently; pooled blood either detached the CSs from skin and leaked out (75%), or clotted and clogged the valve and led to tension HPTX (25%). Conversely, CSs with laminar venting channels allowed escape of blood and air from the pleural cavity and maintained IP pressure and oxygenation near normal levels. Success rates were 100% for Sentinel and Russell (6/6); 67% for HyFin (4/6); 25% for SAM (1/4); and 0% for Bolin (0/4) CSs (p = 0.002). CONCLUSION: The sealant and valve function of vented CS differed widely in the presence of bleeding chest wounds. Medics should be equipped with more effective CSs for treating HPTX in the field.

Physiological Consequences of Abdominal Aortic and Junctional Tourniquet (AAJT) Application to Control Hemorrhage in a Swine Model.

INTRODUCTION: Specialized tourniquets such as Abdominal Aortic and Junctional Tourniquet (AAJT) have been deployed for control of junctional hemorrhage with limited information concerning their efficacy and safety. We examined physiological effects of a 2-h abdominal application of AAJT to control groin hemorrhage in a swine model. METHODS: Anesthetized pigs were subjected to 25% controlled hemorrhage and a groin arterial injury. Resulting hemorrhage from the groin wound was controlled for 2 h by applying AAJT on each pig's abdomen. After AAJT removal, the artery was repaired and blood flow was fully restored for 1 h. CT angiography and blood analyses were done and tissues collected for histology. Experiments were conducted in three groups of pigs (n = 6/group): mechanically ventilated (MV); spontaneously breathing (SB); and spontaneously breathing during AAJT application but transitioned to mechanical ventilation (SB-MV) before AAJT release. RESULTS: AAJT application produced sharp increases in blood pressure and heart rate. SB animals experienced labored and rapid respiration, but their PaO2 and PaCO2 were unaffected. Their respiration suddenly stopped when the AAJT was released requiring manual respiratory assistance. However, three pigs in SB group eventually died from cardiac and respiratory arrests, which coincided with hyperkalemia and metabolic acidosis that occurred after reflow. These changes were less severe in other groups. Other measures including increased hematocrit, tissue injury biomarkers, and kidney function indicators were similar in all groups. Histological changes were mild and reversible. CONCLUSION: The ischemia-induced hyperkalemia and metabolic acidosis associated with AAJT application are life-threatening in spontaneously breathing subjects. Cardiopulmonary resuscitation appears necessary when AAJT is released to prevent life-threatening consequences.

Influences of limited resuscitation with plasma or plasma protein solutions on hemostasis and survival of rabbits with noncompressible hemorrhage.

BACKGROUND: Plasma infusion with or without red blood cells is the current military standard of care for prehospital resuscitation of combat casualties. We examined possible advantages of early and limited resuscitation with fresh plasma compared with a single plasma protein or crystalloid solutions in an uncontrolled hemorrhage model in rabbits. METHODS: Anesthetized spontaneously breathing rabbits (3.3 ± 0.1 kg) were instrumented and subjected to a splenic uncontrolled hemorrhage. Rabbits in shock were resuscitated at 15 minutes with Plasma-Lyte (PAL; 30 mL/kg), PAL + fibrinogen (PAL + F; 30 mL + 100 mg/kg), fresh rabbit plasma (15 mL/kg), or 25% albumin (ALB; 5 mL/kg) solution, all given in two bolus intravenous injections (15 minutes apart) to achieve a mean arterial pressure of 65 mm Hg, n = 8 to 9/group. Animals were monitored for 2 hours or until death, and blood loss was measured. Blood samples and tissues were collected and analyzed. RESULTS: There were no differences among groups in baseline measures and their initial bleeding volume at 15 minutes. At 60 minutes after injury, mean arterial pressure was higher with ALB than with crystalloids (PAL or PAL + F), but shock indices were not different despite the large differences in resuscitation volumes. Fibrinogen addition to PAL only increased clot strength. Plasma resuscitation increased survival rate (75%) without significant improvement in coagulation measures. Albumin administration replenished total plasma protein and increased survival rate to 100% (p < .05 vs. crystalloids). No histological adverse events were identified in the vital organs. CONCLUSIONS: Fibrinogen administration added to a compatible crystalloid did not improve hemostatic outcomes. Plasma resuscitation increased survival rate; however, its effects did not differ from those obtained with 25% ALB at one-third of the volume. The ALB advantage was consistent with our previous findings in which 5% ALB was used at a volume equal to plasma. The benefit of plasma for resuscitation may be mostly due to its ALB content rather than its coagulation proteins.