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.

Does small-volume resuscitation with crystalloids or colloids influence hemostasis and survival of rabbits subjected to lethal uncontrolled hemorrhage?

BACKGROUND: Prehospital, small-volume resuscitation of combat casualties with a synthetic colloid (6% hydroxyethyl starch [HES] 670/0.75) has been recommended when blood or blood components are unavailable. We studied hemostatic effects of a newer synthetic colloid (6% HES, 130/0.4) compared with either a natural colloid (albumin) or to crystalloids in an uncontrolled hemorrhage model. METHODS: Spontaneously breathing New Zealand white rabbits (3.4 ± 0.1 kg) were anesthetized, instrumented, and subjected to a splenic injury with uncontrolled bleeding. Fifteen minutes after injury, rabbits were in shock (mean arterial pressure [MAP] = 26 ± 1.3 mm Hg, and received colloids (6% HES, 130/0.4 or 5% albumin at 15 mL/kg), or crystalloids (normal saline at 30 mL/kg or 5% hypertonic saline at 7.5 mL/kg) for resuscitation in two intravenous bolus injections (15 minutes apart) to raise their MAP to 65 mm Hg, n = 9/group. Animals were monitored for 2.5 hours or until death, and blood losses were measured. Blood samples were analyzed for arterial blood gas, complete blood count, and coagulation measures. RESULTS: There were no differences among groups in baseline measures and initial hemorrhage volume (11.9 ± 0.6 mL/kg) at 15 minutes postinjury. Twenty minutes after fluid resuscitation (1 hour postinjury), MAP was higher, shock indices were lower, and blood pH was higher in colloids versus. crystalloids groups (p < 0.05). Administration of 6% HES 130/0.4 colloid produced the largest hemodilution (54% decrease in hematocrit, p < 0.05 vs. hypertonic saline). Activated partial thromboplastin time increased approximately 35% above baseline in all groups except in 6% HES 130/0.4 group in which it doubled. Clot strength was reduced (15%) only in the 6% HES 130/0.4 group. 6% HES 130/0.4 resuscitation produced the largest blood loss and 33% survival rate that was not different than the crystalloid groups. Albumin produced the best hemostatic and survival outcomes (78%). CONCLUSION: Small-volume resuscitation with crystalloids appeared inadequate to treat hypovolemic shock and prevent death. 6% HES 130/0.4 was effective hemodynamically but detrimental to hemostasis. Albumin produced the best outcomes consistent with our previous observations. Further studies are needed to prove benefit of albumin solution as a possible resuscitation fluid for treating combat casualties at the point of injury.

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.

Is limited prehospital resuscitation with plasma more beneficial than using a synthetic colloid? An experimental study in rabbits with parenchymal bleeding.

BACKGROUND: Reports of survival benefits of early transfusion of plasma with red blood cells (1:1 ratio) in trauma patients suggest that plasma may be a better fluid to replace Hextend for battlefield resuscitation. We studied possible advantages of prehospital resuscitation with plasma compared with Hextend or albumin in a model of uncontrolled hemorrhage. METHODS: Male New Zealand white rabbits (3.3 ± 0.1 kg) were anesthetized, instrumented, and subjected to a splenic injury with uncontrolled bleeding. Ten minutes after injury (mean arterial pressure [MAP] < 40 mm Hg), the rabbits received small and equal volumes (15 mL/kg) of rabbit plasma (n = 10), Hextend (n = 10), or 5% human albumin (n = 9) or no fluid. Fluids were administered in two bolus injections (20 minutes apart) and targeted to a MAP of 65 mm Hg. Animals were monitored for 2.5 hours or until death, and their blood losses were measured. Arterial blood samples were collected at different times and analyzed for ABG, CBC, and coagulation tests. RESULTS: There were no differences in baseline measures among groups. Splenic injury caused similar hemorrhages (9.1 ± 0.4 mL/kg at 10 minutes) and decreased MAP in all subjects. Subsequent resuscitation initiated additional bleeding. At 60 minutes after injury (20 minutes after resuscitation), longer activated partial thromboplastin time and lower fibrinogen concentrations were apparent compared with baseline values with differences among groups. Thrombelastography analysis indicated faster and stronger clot formation with plasma and albumin resuscitation than with Hextend use. Shock indices were increased in all groups, but smaller changes were measured in the albumin group. Total blood loss did not differ among resuscitated rabbits but was higher (p < 0.05) than among nonresuscitated animals. Survival rates were 11% (untreated), 40% (Hextend and plasma), and 89% (albumin, p < 0.05). CONCLUSION: Resuscitation with plasma or albumin better preserved coagulation function than did Hextend. However, despite these improvements, plasma resuscitation did not reduce blood loss or improve survival, while albumin administration seemed beneficial.

Long-term effects of Combat Ready Clamp application to control junctional hemorrhage in swine.

BACKGROUND: Groin application of Combat Ready Clamp (CRoC) in pigs elicits an acute inflammation in underlying ischemic tissues. This study examined functional recovery of pigs' hind leg(s) following 2 hours of CRoC application. METHODS: Left femoral arteries were isolated and injured in anesthetized pigs. Following 25% hemorrhage, CRoC was applied on the inguen for 2 hours (n = 6), and wounds were covered with combat gauze (CG). Bleeding was treated in the control animals (n = 5) with CG only. Next, CRoC and CG were removed, arteries were repaired and reflowed, and animals were recovered. The legs' mobility was scored daily, and their neuromuscular functions were measured on Days 7 and 14. Computed tomographic angiography and blood analysis were performed on Days 0, 2, 7, and 14. Pigs were then euthanized, and tissues were collected for histology. Umbilicus application of CRoC was also tested in four pilot experiments. RESULTS: Inguinal application of CRoC with 524 ± 12 mm Hg pressure occluded iliac arteries and collateral circulation. Following surgical repair, blood flow to the arteries was restored, and five of six CRoC-applied legs recovered full mobility within 9 days. Control-treated legs recovered full function in 3 days (p = 0.001). At 2 weeks, muscle strength of CRoC-applied legs was diminished (p < 0.05 vs. baselines or controls). Injury biomarkers in the CRoC group increased severalfold compared with the controls on Day 2 but returned to baseline afterward. Histologic changes were mostly mild and indicative of ischemia in the CRoC group. Umbilical application of CRoC required higher pressure (625 ± 8 mm Hg) and caused gross ischemic necrosis of lumbar muscles with significant disabilities. CONCLUSION: Two-hour inguinal application of CRoC caused mild and reversible ischemic injuries, which delayed full recovery of the limb function by a few days. In contrast, 2-hour umbilicus application of CRoC resulted in extensive muscle necrosis with functional disabilities. While CRoC seems safe and effective for inguinal application, other tourniquets should be evaluated for treating bilateral junctional bleeding.

Vented versus unvented chest seals for treatment of pneumothorax and prevention of tension pneumothorax in a swine model.

BACKGROUND: Unvented chest seals (CSs) are currently recommended for the management of penetrating thoracic injuries in the battlefield. Since no supporting data exist, we compared the efficacy of a preferred unvented with that of a vented CS in a novel swine model of pneumothorax (PTx). METHODS: An open chest wound was created in the left thorax of spontaneously air-breathing anesthetized pigs (n = 8). A CS was applied over the injury, then tension PTx was induced by incremental air injections (0.2 L) into the pleural cavity via a cannula that was also used to measure intrapleural pressure (IP). Both CS were tested on each pig in series. Tidal volume (V(T)), respiratory rate, IP, heart rate, mean arterial pressure, cardiac output, central venous pressure, pulmonary arterial pressure, venous and peripheral oxygen saturations (SvO2, SpO2) were recorded. Tension PTx was defined as a mean IP equal to or greater than +1 mm Hg plus significant (20-30%) deviation in baseline levels of the previously mentioned parameters and confirmed by chest x-ray study. PaO2 and PaCo2 were also measured. RESULTS: PTx produced immediate breathing difficulty and significant rises in IP and pulmonary arterial pressure and falls in V(T), SpO2, and SvO2. Both CSs returned these parameters to near baseline within 5 minutes of application. After vented CS was applied, serial air injections up to 2 L resulted in no significant change in the previously mentioned parameters. After unvented CS application, progressive deterioration of all respiratory parameters and onset of tension PTx were observed in all subjects after approximately 1.4-L air injection. CONCLUSION: Both vented and unvented CSs provided immediate improvements in breathing and blood oxygenation in our model of penetrating thoracic trauma. However, in the presence of ongoing intrapleural air accumulation, the unvented CS led to tension PTx, hypoxemia, and possible respiratory arrest, while the vented CS prevented these outcomes.

In vivo assessment of the Combat Ready Clamp to control junctional hemorrhage in swine.

BACKGROUND: Junctional wounds and associated hemorrhage have become more common and more lethal in the current war. The Combat Ready Clamp (CRoC) has been developed and deployed for treating junctional hemorrhage on the battlefield. This study examined the efficacy of CRoC and its acute effects in an animal model. METHODS: Anesthetized pigs (n = 6) were subjected to laparotomy, splenectomy, and abdominal closure. Next, coagulopathy was induced in animals by hemodilution and hypothermia. The left femoral artery was isolated, punctured (6-mm hole), and allowed to bleed for 15 seconds. The groin wound was packed with gauze, and a CRoC applied and tightened until hemorrhage stopped. It was kept in place for 1 hour (treatment period) and then released for another hour or less (control-period) if animal exsanguinated. Fluid resuscitation was administered, and vascular blood flow was examined by Doppler and CT scans. After death, local tissues were collected for histology. RESULTS: CRoC generated 800 to 900 mm Hg pressure on the wounds, which stopped the hemorrhage and prevented rebleeding during the first hour in all animals. Blood loss was minimal (≤137 mL), and mean arterial pressure remained at or higher than the target level (65 mm Hg) during this period. Removal of the clamp promptly led to rebleeding and exsanguination of five of six pigs during the second hour despite fluid resuscitation. Blood loss, survival, shock indices, and other measures were significantly (p < 0.01) different between the two periods. Doppler tests and CT scans showed no blood flow in the proximal, distal, and collateral arteries of the clamped leg. Minor inflammation was seen on blood vessels (endothelium) and nerves. CONCLUSION: CRoC functioned as an effective hemostatic adjunct for compression and control of groin hemorrhage. Although no acute histological damages were seen in compressed tissues, the short- and long-term effects of CRoC application (e.g., total ischemia) on limb function remain unknown and warrant investigation.

Negative-pressure wound therapy: a hemostatic adjunct for control of coagulopathic hemorrhage in large soft tissue wounds.

BACKGROUND: Negative-pressure wound therapy has been commonly used for treating chronic wounds and recently applied for treatment of traumatic wounds. We investigated the potential hemostatic benefit of negative-pressure wound therapy for control of refractory hemorrhage in a soft tissue wound model in swine. METHODS: Coagulopathy was induced in pigs (n = 38, 36 kg) by hemodilution and hypothermia. Next, a large soft tissue wound (diameter, approximately 20 cm) was created by slicing the gluteus maximus muscle. Free bleeding was allowed for 1 minute, and wounds were then randomly dressed with either laparotomy gauze (G) alone or TraumaPad (TP, a kaolin-coated dressing) alone or in combination with negative pressure (NP, approximately -500 mm Hg). All wounds were sealed with adhesive drapes. Fluid resuscitation was administered and targeted to mean arterial pressure of 60 mm Hg. Pigs were observed for 150 minutes or until death after which tissues were sampled for histologic examination. RESULTS: Induced coagulopathy as measured by increases in prothrombin time (12%) and activated partial thromboplastin time (22%) and decreases in fibrinogen (48%) were similar in all groups. There were no differences in initial bleeding rates (4.5 mL/kg/min). Dressing the wounds with G or TP produced hemostasis only in one pig (1 of 18 pigs). Addition of NP to these dressings secured hemostasis in 70% (G) and 90% (TP) of animals with average hemostasis time of 34 minutes and 25 minutes, respectively. Blood losses and fluid resuscitation requirements were significantly less, and survival times were significantly longer in NP adjunct groups than in the other groups. Survival rates were 80% (G+NP) and 90% (TP+NP) versus 0% (G) and 10% (TP) in the respective groups. Histologic examination showed similar superficial myofibril damages in all groups. CONCLUSION: To our knowledge, the present data provide the first evidence that NP serves as an effective hemostatic adjunct and when combined with standard hemostatic dressing it is able to stop lethal coagulopathic bleeding in large soft tissue wounds.

Clot-inducing minerals versus plasma protein dressing for topical treatment of external bleeding in the presence of coagulopathy.

BACKGROUND: Previous studies identified WoundStat (WS, smectite) and Combat Gauze (CG, kaolin-coated gauze) as the most effective available agents for controlling arterial bleeding with potential utility in casualty care. Tissue sealant properties of WS suggested its potential advantage over clot-promoting CG for treating coagulopathic bleeding. This study compared the efficacy of CG and WS with a fibrinogen-based (FAST) dressing to control bleeding in coagulopathic animals. METHODS: Coagulopathy was induced in pigs (n = 55, 35 kg) by ∼50% isovolemic hemodilution and hypothermia (core temperature, 33°C ± 0.5°C). A 6-mm arteriotomy was made in the femoral artery and free bleeding allowed for 30 seconds. A test agent (n = 13-15 per group) or control product (gauze, GZ, n = 12) was applied to the wounds and compressed with a Kerlix gauze for 2 minutes. Fluid resuscitation was given, titrated to a mean arterial pressure of 65 mm Hg. Animals were observed for 180 minutes or until death. Angiography using the computed tomography method was performed on survivors, and local tissues were collected for histology. RESULTS: No differences were seen in baseline measures. Coagulopathy, confirmed by a 31% increase in prothrombin time and a 28% reduction in clotting strength (maximum amplitude, thrombelastography assay), was similar in all groups before injury. The average pretreatment blood loss was 11.9 mL/kg ± 0.4 mL/kg with no difference among groups. Posttreatment blood loss, however, was significantly different (p = 0.015) ranging from 18.2 mL/kg ± 8.8 mL/kg (FAST) to 63.3 mL/kg ± 10.2 mL/kg (GZ controls). Stable hemostasis was achieved in 10 of 13 (FAST), 5 of 15 (CG), 2 of 15 (WS), and 1 of 12 (GZ) animals in each group, resulting in significantly different survival rates (8-77%; p = 0.001). The average survival times were 145 (FAST), 119 (CG), 75 (WS), and 74 (GZ) minutes for different groups (p < 0.002). The outcomes with the FAST dressing were significantly better than with WS or GZ in this coagulopathic bleeding model. Essentially, no difference was found between WS and GZ control. Computed tomography images showed limited blood flow only through the vessels treated with FAST dressings. Histologic observations of the vessels indicated minimal damage with FAST and CG and greater injury with WS with some residues present on the tissues. CONCLUSION: The tissue sealant property of WS is apparently mediated by clot formation in the wound; therefore, it was ineffective under coagulopathic conditions. CG was partially effective in maintaining blood pressure up to 1 hour after application. FAST dressing showed the highest efficacy because of the exogenous delivery of concentrated fibrinogen and thrombin to the wound, which bypasses coagulopathy and secures hemostasis.

Safety evaluation of new hemostatic agents, smectite granules, and kaolin-coated gauze in a vascular injury wound model in swine.

BACKGROUND: In 2007, a potent procoagulant mineral called WoundStat (WS), consisting of smectite granules, received clearance from the Food and Drug Administration for marketing in the United States for temporary treatment of external hemorrhage. Previously, we found that microscopic WS particles remained in the injured vessels that were treated, despite seemingly adequate wound debridement. Thus, we investigated the thromboembolic risk of using WS when compared with kaolin-coated gauze, Combat Gauze (CG); or regular gauze, Kerlix (KX) to treat an external wound with vascular injuries in pigs. METHODS: The right common carotid artery and external jugular vein of pigs were isolated and sharply transected (50%). After 30 seconds of free bleeding, the neck wounds were packed with WS, CG, or KX and compressed until hemostasis was achieved (n = 8 per group). Wounds were debrided after 2 hours, and vascular injuries were primarily repaired with suture. Blood flow was restored after infusing 1 L of crystalloid (no heparin or aspirin) and the wounds were closed. Two hours later, computed tomographic angiography was performed, and the wounds were reopened to harvest the vessels. The brains and lungs were recovered for gross and microscopic examination after euthanasia. RESULTS: No differences were found in baseline measurements. Thrombelastography showed similar hypercoagulability of the final blood samples when compared with baselines in all groups. All vessels treated with KX or CG were patent and had no thrombus or blood clot in their lumen. In contrast, seven of eight carotid arteries and six of eight jugular veins treated with WS developed large occlusive red thrombi and had no flow. Small clots and WS residues were also found in the lungs of two pigs. Histologically, significant endothelial and transmural damage was seen in WS-treated vessels with luminal thrombi and embedded WS residues. CONCLUSION: WS granules caused endothelial injury and significant transmural damage to the vessels that render them nonviable for primary surgical repair. The granules can enter systemic circulation and cause distal thrombosis in vital organs. More relevant in vitro and in vivo safety tests should be required for clearance of new hemostatic agents.

Comparison of new hemostatic granules/powders with currently deployed hemostatic products in a lethal model of extremity arterial hemorrhage in swine.

BACKGROUND: HemCon bandage (HC) and QuikClot granules (QC) have been deployed for the past 5 years for treating external hemorrhage in combat casualties. We examined efficacy and initial safety of three new hemostatic granules/powders in a swine extremity arterial hemorrhage model that was 100% fatal with army standard gauze treatment. The new products were compared with the most advanced forms of HC and QC products. METHODS: Anesthetized pigs (37 kg, n = 46) were instrumented, splenectomized, and their femoral arteries were isolated and injured (6 mm arteriotomy). After 45 seconds free bleeding, a test agent [WoundStat (WS), super quick relief (SQR), Celox (CX)] or a control product [HC or QC bead bags (advanced clotting sponge plus)] was applied to the wounds and compressed with a large gauze for 2 minutes. Fluid resuscitation (colloid and crystalloid) was given and titrated to a mean arterial pressure of 65 mm Hg. Animals were observed for 180 minutes or until death. Computed tomography angiography was performed on survivors and tissue samples were collected form wounds for histologic examination. RESULTS: No differences were found in baseline measurements and pretreatment blood loss (17.4 mL/kg +/- 0.5 mL/kg, mean +/- SEM) among groups. Advanced clotting sponge plus testing was halted after six unsuccessful attempts (no hemostasis observed) whereas other agents were tested each in 10 animals. Stable hemostasis was achieved in 10 (WS), 7 (SQR), 6 (CX), and 1 (HC) subjects in each group, resulting in the recovery of mean arterial pressure and survival of the animals for 3 hours (p < 0.05, SQR or WS vs. HC). Posttreatment blood loss was significantly reduced with the use of the new agents (CX = 40 +/- 16.6, SQR = 34.5 +/- 16.3, WS = 9.5 mL/kg +/- 5.2 mL/kg) as compared with HC (85.6 mL/kg +/- 10 mL/kg, p < 0.05). The granular treated animals lived for 180 (WS), 164 +/- 8.2 (SQR) and 138 +/- 17.7 (CX) minutes, significantly (p < 0.05) longer than the HC (83.3 +/- 12 minutes) group. A significant (p < 0.05) rise in temperature (53.5 degrees C +/- 1.8 degrees C) over baseline (36.5 degrees C +/- 0.3 degrees C) was measured only in the wounds treated with SQR. Computed tomography images showed no blood flow through treated vessels. Histologic evidence indicated the least tissue damage with HC, moderate damage with WS and CX, and most damage including axonal necrosis with SQR. CONCLUSION: The new hemostatic agents are significantly more effective in treating arterial hemorrhage than currently deployed products. Among them, WS granules appear to be most efficacious, followed by SQR and CX powders. The clinical significance of tissue damage caused by these agents and any potential risk of embolism with procoagulant granular/powder products are unknown and warrant survival studies.