Effect of a chitosan-based hemostatic dressing on blood loss and survival in a model of severe venous hemorrhage and hepatic injury in swine

BACKGROUND: Hemorrhage is a leading cause of death from trauma. An advanced hemostatic dressing could augment available hemostatic methods. We studied the effects of a new chitosan dressing on blood loss, survival, and fluid use after severe hepatic injury in swine. METHODS: Swine received chitosan dressings or gauze sponges. Standardized, severe liver injuries were induced. After 30 seconds, dressings were applied and resuscitation initiated. Blood loss, hemostasis, resuscitation volume, and 60-minute survival were quantified. RESULTS: Posttreatment blood loss was reduced ( p< 0.01) in the chitosan group (264 mL; 95% confidence interval [CI], 82-852 mL) compared with the gauze group (2,879 mL; 95% CI, 788-10,513 mL). Fluid use was reduced ( p= 0.03) in the chitosan group (1,793 mL; 95% CI, 749-4,291) compared with the gauze group (6,614 mL; 95% CI, 2,519-17,363 mL). Survival was seven of eight and two of even in the chitosan and gauze groups ( p= 0.04), respectively. Hemostasis was improved in the chitosan group ( p= 0.03). CONCLUSION: A chitosan dressing reduced hemorrhage and improved survival after severe liver injury in swine. Further studies are warranted.     

Controlled resuscitation for uncontrolled hemorrhagic shock

OBJECTIVE: To test the hypothesis that controlled resuscitation can lead to improved survival in otherwise fatal uncontrolled hemorrhage. METHODS: Uncontrolled hemorrhage was induced in 86 rats with a 25-gauge needle puncture to the infrarenal aorta. Resuscitation 5 minutes after injury was continued for 2 hours with lactated Ringer's solution (LR), 7.3% hypertonic saline in 6% hetastarch (HH), or no fluid (NF). Fluids infused at 2 mL x kg(-1) x min(-1) were turned on or off to maintain a mean arterial pressure (MAP) of 40, 80, or 100 mm Hg in six groups: NF, LR 40, LR 80, LR 100, HH 40, and HH 80. Blood loss was measured before and after 1 hour of resuscitation. RESULTS: Survival was improved with fluids. Preresuscitation blood loss was similar in all groups. NF rats did not survive 4 hours. After 72 hours, LR 80 rats (80%) and HH 40 rats (67%) showed improved survival over NF rats (0%) (p < 0.05). Rebleeding increased with MAP. Attempts to restore normal MAP (LR 100) led to increased blood loss and mortality. CONCLUSION: Controlled resuscitation leads to increased survival compared with no fluids or standard resuscitation. Fluid type affects results. Controlled fluid use should be considered when surgical care is not readily available.     

Fibrin sealant foam sprayed directly on liver injuries decreases blood loss in resuscitated rats

OBJECTIVE: The majority of early trauma deaths are attributable to uncontrolled hemorrhage from truncal sites. A hemorrhage-control technique that reduced bleeding in the prehospital phase of treatment without requiring manual compression may improve the outcome of these patients. We conducted this preliminary study to determine whether an expanding fibrin sealant foam (FSF) would reduce bleeding from a severe liver injury even during resuscitation. METHODS: Rats (n = 31; 291 +/- 5 g; 37.4 +/- 0.3 degrees C; mean +/- SEM), underwent a 60 +/- 5% excision of the median hepatic lobe. The animals received one of three treatments: (1) FSF, (2) immunoglobulin G placebo foam (IgGF), or (3) no treatment. All animals were resuscitated with 40 degrees C lactated Ringer's solution at 3.3 mL/ min/kg to a mean arterial pressure of 100 mm Hg. Total blood loss, mean arterial pressure, and resuscitation volume were recorded for 30 minutes. A qualitative measure of foam coverage and adherence to the cut liver edge was recorded. RESULTS: The total blood loss was less (p < 0.01) in the FSF group (21.2 +/- 5.0 mL/kg) than in either IgGF (41.4 +/- 4.3 mL/kg) or the no treatment group (44.6 +/- 4.7 mL/kg), which did not differ. The resuscitation volume was not different. The amount of foam used in the treated groups, 9.1 +/- 1.0 g in the FSF group and 10.0 +/- 1.0 g in the IgGF group, did not differ. Survival for 30 minutes was not different among groups. There was no difference in the amount of cut liver covered by either foam, but the clots were more adherent (p < 0.05) in the FSF group than in the IgGF group. CONCLUSION: In rats with a severe liver injury, spraying fibrin foam directly on the cut liver surface decreased blood loss when compared with placebo foam and no treatment. This pilot study suggests a future possible treatment for noncompressible truncal hemorrhage.     

Hemodynamic and metabolic effects of resuscitation in an uncontrolled hemorrhage model of severe rat liver injury

Purpose: The benefits of fluid resuscitation have become controversial for noncompressible uncontrolled hemorrhage. The effect of delayed access to definitive care is an additional confounding variable. Rural and military environments often entail delayed access to surgical care, and current recommendations are for ongoing fluid resuscitation to a normal blood pressure during transport. This approach has been proposed to increase survival time, at the expense of increased blood loss. This study was designed to evaluate the hemodynamic and metabolic response to resuscitation in a rat model of severe liver injury and uncontrolled hemorrhage over 4 hours.MethodsAll animals (N = 21, 275 ± 15 g), underwent a reproducible excision of the median hepatic lobe. The animals received either no resuscitation (NR) or 40°C lactated Ringer’s solution at 1 ml/min, starting at 2.5 minutes after the injury (LR). The end point of resuscitation was a return to the immediate preinjury mean arterial pressure (MAP). Total blood loss, MAP, survival time, fluid volume infused, serum lactate, arterial blood gasses, intra-abdominal pressure, and hematocrit were measured preinjury and at 4 hours or death.ResultsBlood loss was greater (p < 0.01) in the LR group (37.8 ± 13.5 ml/kg) than in the NR group (15.9 ± 5.9). Final Pao₂ was lower (p < 0.01) in the LR group (55.0 ± 21.5 mm Hg) than in the NR group (92.2 ± 17). No differences were noted between groups in the amount of hepatic median lobe excised (60% ± 7%), overall survival time (86.3 ± 66.0 min), MAP nadir (35.2 ± 0.7 mm Hg at 1.9 ± 0.7 min postinjury), final pH (7.04 ± 0.14), final base excess (−16.5 ± 4.5 mmol/l), final intra-abdominal pressure (2.2 ± 1.4 mm Hg), and final serum lactate (6.8 ± 4.0 mmol/l).ConclusionsIn this model of uncontrolled hemorrhage from a solid organ, fluid resuscitation provided no survival or metabolic advantage, serving only to increase blood loss and decrease Pao₂. Vigorous resuscitation may not provide benefit when significant injury and prolonged transport times are combined.     

Blood loss after fluid resuscitation with isotonic or hypertonic saline for the initial treatment of uncontrolled hemorrhage induced by spleen rupture

BACKGROUND: It has been suggested that fluid resuscitation for the prehospital management of hypotensive trauma victims increases bleeding. In a model of uncontrolled hemorrhage induced by complete splenic laceration with a hilar vascular injury, we hypothesized that small-volume hypertonic saline or large-volume lactated Ringer's solution may provide sustained hemodynamic benefits despite promoting increases in intra-abdominal bleeding. METHODS: Forty anesthetized, spontaneously breathing dogs (18 +/- 1 kg) underwent laparotomy. A suture line was placed around the spleen to produce a splenic rupture with hilar vascular injury by pulling the exteriorized lines after incision closure. Intra-abdominal blood loss was measured directly, immediately after the animal was killed. Dogs were randomly assigned to four groups (n = 10 per group): Untreated controls were killed 20 (CT20) or 40 (CT40) minutes after splenic rupture to measure blood loss directly. Treatment groups received (20 minutes after spleen rupture) lactated Ringer's (LR), 33 mL/kg over 15 minutes, or 7.5% NaCl/6% dextran 70 (HSD), 4 mL/kg over 4 minutes. Blood loss was measured 40 minutes after spleen rupture. RESULTS: Mean arterial pressure dropped from an average value of 103 +/- 3 mm Hg to 67 +/- 5 mm Hg during the first 20 minutes and was partially restored afterward in all groups, with no significant differences between them. No resuscitation was associated with low cardiac output, whereas HSD restored and LR overshot baseline cardiac output. Intra-abdominal blood loss was 30 +/- 4, 38 +/- 4, 43 +/- 5, and 42 +/- 5 mL/kg for groups CT20, CT40, HSD, and LR, respectively, with no statistical significance between groups. CONCLUSION: No-fluid resuscitation in uncontrolled hemorrhage from splenic rupture resulted in a low-flow state, whereas resuscitation with small volumes of HSD or large volumes of LR produced hemodynamic benefits without significant increases in bleeding.     

Hextend attenuates hypercoagulability after severe liver injury in swine

BACKGROUND: Hypercoagulability is a major source of morbidity and mortality after injury. A resuscitation regimen that modulates this coagulopathy may prove beneficial. We sought to evaluate the effects of lactated Ringer's (LR) solution and Hextend on the resuscitation of uncontrolled hemorrhagic shock. METHODS: Twenty swine underwent invasive line placement, midline celiotomy, and splenectomy. After a 15-minute stabilization period, we recorded a baseline mean arterial pressure and created a grade V liver injury. The animals bled freely for 30 minutes, after which we measured the initial blood loss (that after injury). We blindly randomized the swine to receive LR solution or Hextend to achieve and maintain the baseline mean arterial pressure for 90 minutes postinjury. Laboratory values were obtained at baseline and on completion of the 2-hour study period. RESULTS: The initial blood loss (before resuscitation) was 22 mL/kg in both treatment groups (p = 0.97). Animals required 119 +/- 78 mL/kg of fluid in the LR group and 40 +/- 21 mL/kg in the Hextend group (p = 0.01). After resuscitation, the secondary blood loss was 3.7 +/- 1.7 mL/kg in the LR group and 4.7 +/- 1.1 mL/kg in the Hextend group (p = 0.1). Thrombelastography revealed a hypercoagulable state in all animals after injury. This was less pronounced in those animals resuscitated with Hextend. Routine tests of coagulation did not reveal a hypercoagulable state. CONCLUSION: Modulation and restoration of normal coagulation is critical in the management of trauma patients. The patient's coagulation profile might determine the type of fluid to be used at various times during their course. Thrombelastography is superior to routine coagulation assays for the detection of a hypercoagulable state. Resuscitation with Hextend results in a decreased fluid requirement and attenuation of hypercoagulability after injury without increased blood loss.     

Advanced hemostatic dressing development program: animal model selection criteria and results of a study of nine hemostatic dressings in a model of severe large venous hemorrhage and hepatic injury in Swine

BACKGROUND: An advanced hemostatic dressing is needed to augment current methods for the control of life-threatening hemorrhage. A systematic approach to the study of dressings is described. We studied the effects of nine hemostatic dressings on blood loss using a model of severe venous hemorrhage and hepatic injury in swine. METHODS: Swine were treated using one of nine hemostatic dressings. Dressings used the following primary active ingredients: microfibrillar collagen, oxidized cellulose, thrombin, fibrinogen, propyl gallate, aluminum sulfate, and fully acetylated poly-N-acetyl glucosamine. Standardized liver injuries were induced, dressings were applied, and resuscitation was initiated. Blood loss, hemostasis, and 60-minute survival were quantified. RESULTS: The American Red Cross hemostatic dressing (fibrinogen and thrombin) reduced (p < 0.01) posttreatment blood loss (366 mL; 95% confidence interval, 175-762 mL) and increased (p < 0.05) the percentage of animals in which hemostasis was attained (73%), compared with gauze controls (2,973 mL; 95% confidence interval, 1,414-6,102 mL and 0%, respectively). No other dressing was effective. The number of vessels lacerated was positively related to pretreatment blood loss and negatively related to hemostasis. CONCLUSION: The hemorrhage model allowed differentiation among topical hemostatic agents for severe hemorrhage. The American Red Cross hemostatic dressing was effective and warrants further development.     

Fluid resuscitation improves hemodynamics without increased bleeding in a model of uncontrolled hemorrhage induced by an iliac artery tear in dogs

BACKGROUND: Fluid resuscitation administered before hemorrhage control for trauma victims sustaining penetrating abdominal injury is controversial. Our objective was to evaluate intra-abdominal blood loss and hemodynamic and metabolic effects of no fluid resuscitation, small-volume 7.5% sodium chloride/6% dextran-70 (HSD), or large-volume lactated Ringer's (LR) solution during intra-abdominal vascular injury and uncontrolled hemorrhage. METHODS: In pentobarbital-anesthetized dogs (n = 26, 17 +/- 0.3 kg), a suture was placed through the common iliac artery to produce a 3-mm tear when the exteriorized suture lines were pulled after incision closure. Dogs were randomized to three groups, according to the treatment used after 20 minutes of uncontrolled hemorrhage: controls, no fluid resuscitation (CT group) (n = 6); the HSD group (4 mL/kg over 4 minutes, n = 6); and the LR group (32 mL/kg over 15 minutes, n = 6). After 40 minutes of uncontrolled bleeding, animals were killed, and intra-abdominal blood loss was measured. RESULTS: Eight dogs died from severe hemorrhagic shock before randomization and were excluded. After 20 minutes, animals presented lower blood pressure (approximately 35 mm Hg), low cardiac output (approximately 1.0 L/min/m(2)), and metabolic acidosis (pH approximately 7.23, base excess approximately -9 mmol/L). After HSD and LR solution, arterial pressure presented a transient increase, but remained below baseline. Two animals died before the end of the experiment, both in the LR group. Cardiac index was partially improved in the LR and HSD groups, whereas the CT group sustained a low-flow state. There were no significant differences between groups regarding intra-abdominal blood loss (CT group, 47.8 +/- 5.9 mL/kg; HSD group, 41.7 +/- 2.3 mL/kg; and LR group, 49.4 +/- 0.7 mL/kg). CONCLUSION: Fluid resuscitation with either large-volume LR solution or small-volume HSD, during uncontrolled hemorrhage from intra-abdominal vascular injury, produced hemodynamic and metabolic benefits, without additional blood loss, whereas no fluid resuscitation was associated with sustained low cardiac output and hypotension.     

Application of a granular mineral-based hemostatic agent (QuikClot) to reduce blood loss after grade V liver injury in swine

BACKGROUND: Uncontrolled hemorrhage is a leading cause of death in cases of trauma. Many products currently are under development to control traumatic bleeding. One such Food and Drug Administration (FDA)-approved product is QuikClot. This study determined the efficacy of QuikClot, a hemostatic agent, in reducing blood loss and mortality in a standardized model of severe liver injury as well as the consequences of its use. METHODS: Swine received either QuikClot or gauze treatment after induction of grade V liver injuries. Hemostasis, blood loss, resuscitation volume, 60-minute survival, and peak tissue temperatures were measured. RESULTS: Hemostasis was improved with QuikClot (p < 0.05), and resuscitation volume was consequently reduced (p < 0.05). Posttreatment blood loss was reduced (p < 0.01) with QuikClot (1,397 mL), as compared with gauze (5,338 mL). The survival rate was seven of eight in the QuikClot group and one of eight in the gauze group (p < 0.01). Peak temperature at the tissue interface was increased (p < 0.01) with QuikClot (93.3 +/- 10.5 degrees C), as compared with gauze (37.5 +/- 6.5 degrees C). QuikClot use was associated with both macro- and microscopic tissue damage caused by the exothermic reaction. CONCLUSION: QuikClot provides hemostasis and decreased mortality in this model of severe liver injury. The beneficial aspects of QuikClot treatment must, however, be balanced against the tissue-damaging effects of the exothermic reaction.     

Initial resuscitation volume in uncontrolled hemorrhage: effects on organ function

Conventional resuscitation of hypovolemia due to hemorrhage has consisted of aggressive fluid administration. Recent studies have suggested that surgical control of bleeding before fluid resuscitation might improve early survival. The effects of limited resuscitation on organ function have not been assessed in these studies. We developed a model of moderate intraperitoneal hemorrhage designed to evaluate long-term end-organ function after various resuscitation protocols. Male Sprague-Dawley rats underwent ketamine anesthesia, followed by placement of femoral artery and vein lines. Intraperitoneal hemorrhage was induced by division of distal branches of the ileocolic artery and vein. After 5 minutes of bleeding, the animals were randomized to one of three resuscitation groups: Group 1 received no fluid resuscitation before surgical control of the hemorrhage; Group 2 received 0.5 mL of lactated Ringer's solution (LR) every 5 minutes for a mean arterial pressure (MAP) of less than 80 mm Hg; Group 3 received 2.0 mL of LR every 5 minutes for a MAP of less than 80 mm Hg. In all three groups, after 20 minutes, the bleeding was surgically controlled. All rats were then resuscitated with LR to a MAP of 80 mm Hg. The intravascular lines were removed, and the rats were allowed to recover from anesthesia and were returned to animal holding. On the 7th day, survivors were sacrificed, and their blood was assayed for hematocrit and serum levels of bilirubin, alanine aminotransferase, urea nitrogen, and creatinine. Kidneys, lungs, and liver were harvested for microscopic examination. Survival was lower in Group 2 than in the other groups (90%, 60%, and 100%, respectively; P = 0.04), but all deaths occurred within 3 hours of hemorrhage and were due to either hypovolemia or anesthetic complications. No histologic abnormalities were identified in the livers of the animals that survived, but pulmonary atelectasis and mild-to-moderate renal tubular necrosis were identified uniformly. No histologic differences could be discerned between the groups. Hematocrit and indices of liver and renal function were similar in all groups, and no animal developed organ dysfunction. In this model of moderate uncontrolled intraperitoneal hemorrhage, the volume of fluid resuscitation, or the absence of resuscitation, had an inconsistent effect of 7-day survival and did not influence function or histologic appearance of the liver, lungs, or kidneys 7 days after hemorrhage.     

Treatment of uncontrolled hemorrhagic shock after liver trauma: fatal effects of fluid resuscitation versus improved outcome after vasopressin

In a porcine model of uncontrolled hemorrhagic shock, we evaluated the effects of vasopressin versus an equal volume of saline placebo versus fluid resuscitation on hemodynamic variables and short-term survival. Twenty-one anesthetized pigs were subjected to severe liver injury. When mean arterial blood pressure was <20 mm Hg and heart rate decreased, pigs randomly received either vasopressin IV (0.4 U/kg; n = 7), an equal volume of saline placebo (n = 7), or fluid resuscitation (1000 mL each of lactated Ringer's solution and hetastarch; n = 7). Thirty minutes after intervention, surviving pigs were fluid resuscitated while bleeding was surgically controlled. Mean (+/- SEM) arterial blood pressure 5 min after the intervention was significantly (P < 0.05) higher after vasopressin than with saline placebo or fluid resuscitation (58 +/- 9 versus 7 +/- 3 versus 32 +/- 6 mm Hg, respectively). Vasopressin improved abdominal organ blood flow but did not cause further blood loss (vasopressin versus saline placebo versus fluid resuscitation 10 min after intervention, 1343 +/- 60 versus 1350 +/- 22 versus 2536 +/- 93 mL, respectively; P < 0.01). Seven of 7 vasopressin pigs survived until bleeding was controlled and 60 min thereafter, whereas 7 of 7 saline placebo and 7 of 7 fluid resuscitation pigs died (P < 0.01). We conclude that vasopressin, but not saline placebo or fluid resuscitation, significantly improves short-term survival during uncontrolled hemorrhagic shock. IMPLICATIONS: Although IV fluid administration is the mainstay of nonsurgical management of trauma patients with uncontrolled hemorrhagic shock, the efficacy of this strategy has been discussed controversially. In this animal model of severe liver trauma with uncontrolled hemorrhagic shock, vasopressin, but not saline placebo or fluid resuscitation, improved short-term survival.     

Protective effects of preheparinization on the microvasculature during and after hemorrhagic shock.

Despite the fact that trauma patients are not heparinized at the time of injury, most models of hemorrhagic shock involve heparinization before the initiation of hemorrhage. To determine whether preheparinization has any effects on the microvasculature of organs during or after hemorrhage, rats (with and without preheparinization) were bled to a mean arterial blood pressure (BP) of 40 mm Hg. In two groups, this pressure was maintained by withdrawing additional blood until BP could no longer be maintained at 40 mm Hg (maximal bleedout, MB). In another two groups, the BP was maintained at 40 mm Hg until 40% of the MB volume was returned in the form of lactated Ringer's solution. The rats were then resuscitated with four times the volume of MB with lactated Ringer's. At MB or immediately after resuscitation, colloidal carbon black was rapidly infused and the liver, kidney, and spleen were excised, fixed, and sectioned. In additional animals, blood samples for platelet counts and total body fibrinogen estimates were taken before hemorrhage and at MB or at the end of resuscitation. The results indicate that at MB, microvascular patency in the kidney and liver was significantly depressed in the nonheparinized rats but not depressed in the preheparinized rats. This protective effect of heparin is not directly attributable to its anticoagulant properties, since there were no differences in the consumption of platelets or fibrinogen between the nonheparinized and preheparinized groups. Although the microvascular patency improved with resuscitation in the nonheparinized group, the glomeruli counts and perfusion of the spleen remained significantly lower than in the preheparinized group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Isotonic saline resuscitation in uncontrolled hemorrhage under various anesthetic conditions.

OBJECTIVE: The authors evaluated the effect of early fluid resuscitation with isotonic saline (NaCl, 0.9%) on uncontrolled hemorrhage in rats under different anesthetic conditions. SUMMARY/BACKGROUND DATA: Recently, it has been suggested that administration of fluids to patients during uncontrolled hemorrhage may produce adverse effects, and a postponement of resuscitation until surgical control of bleeding was recommended. Past clinical trials were inconclusive, and the results of recent experimental studies were affected by use of vasoactive anesthetics. METHODS: One hundred thirty-five female Sprague-Dawley rats were randomly divided into three groups: group 1--unanesthetized; group 2--anesthetized with sodium pentobarbital; and group 3--anesthetized with a mixture of droperidol and ketamine. Uncontrolled hemorrhage was initiated with a 75% tail resection, and each group was further subdivided into three subgroups for the following treatment: (A) no resuscitation; (B) 40 mL/kg of isotonic saline; or (C) 80 mL/kg of isotonic saline, administered 15 minutes after the initiation of hemorrhage. Blood loss volume and survival time were recorded, and animals were observed up to 360 minutes. RESULTS: At 6 hours, nonresuscitated animals of all groups exhibited the highest mortality rates (93%, 73%, 100% in groups 1, 2, and 3, respectively). Resuscitation significantly improved the survival; lowest mortality rates were observed after resuscitation with 80 mL/kg in groups 1 and 3 (33%) and 40 mL/kg in group 2 (40%). Fluid infusion increased hemorrhage rates in all anesthetized rats. No such increases in bleeding were observed in group 1. CONCLUSIONS: Resuscitation with isotonic saline improved mortality in uncontrolled hemorrhage, even with concomitant increases in hemorrhage rates, under all three anesthetic conditions tested. Unanesthetized rats bled less than the animals under anesthesia and did not exhibit an increased blood loss in response to fluid infusion.     

Damage control management of experimental grade 5 renal injuries: further evaluation of FloSeal gelatin matrix

BACKGROUND: We developed a porcine grade 5 renal laceration damage control model to evaluate the hemostatic efficacy of FloSeal gelatin matrix (Baxter Healthcare, Corp., Deerfield, Ill). METHODS: Ten commercial swine underwent celiotomy, contralateral nephrectomy, and cooling to 32 degrees C after a well-established hypothermia protocol to simulate a damage control scenario. Following prospective randomization, a complex grade 5 renal injury was uniformly produced on the remaining kidney. Control animals (group 1, n = 5) were treated with direct manual compression with a gelatin sponge. Experimental animals (group 2, n = 5) were treated by application of FloSeal gelatin matrix followed by direct compression with a gelatin sponge. Operative blood loss and efficacy of hemostasis were compared. Creatinine levels were obtained daily until postoperative day 7. Abdominal computed tomography was performed at 10 days. RESULTS: Use of FloSeal gelatin matrix hemostatic sealant resulted in significantly less mean blood loss than gelatin sponge bolster compression alone (202.4 mL vs. 540.4 mL, respectively, p = 0.016). Hemostasis was complete in 60% (three out of five) of experimental animals after 2 minutes, but was incomplete in all control animals. After an initial increase, serum creatinine approached baseline by postoperative day 7 in all animals. Axial imaging 10 days postoperatively revealed no evidence of significant delayed perirenal hemorrhage. CONCLUSIONS: FloSeal gelatin matrix performed well as a rapidly deployable, effective hemostatic agent in a hypothermic grade 5 renal injury damage control model. The absence of delayed bleeding and nephrotoxicity suggests a possible increased role for FloSeal in the treatment of devastating renal injuries in damage control surgery.     

Comparative analysis of hemostatic agents in a swine model of lethal groin injury

BACKGROUND: Techniques for better hemorrhage control after injury could change outcome. A large-animal model of lethal, uncontrolled hemorrhage was developed to test whether the use of various hemostatic agents would decrease bleeding and improve early survival. METHODS: A complex groin injury was created in 30 Yorkshire swine (42-55 kg) to produce uncontrolled hemorrhage. This injury included semitransection of the proximal thigh and complete division of the femoral artery and vein. After 5 minutes, the animals were randomized to (n = 6 animals per group) no dressing (ND), standard dressing (SD), SD and Rapid Deployment Hemostat (RDH) bandage, SD and QuikClot hemostatic agent (QC), or SD and TraumaDEX (TDEX). Limited volume 0.9% saline (1,000 mL over 30 minutes) resuscitation was started 30 minutes after injury. We measured blood loss, early mortality (180 minutes), and physiologic markers of hemorrhagic shock (e.g., cardiac output, blood pressure, hemoglobin, metabolic acidosis). RESULTS: Application of wound dressing decreased mortality in all groups compared with the ND group (83% mortality). However, this difference was significant (p < 0.05) only for the QuikClot hemostatic agent (0% mortality). Before the application of dressing (first 5 minutes), there were no differences in blood loss between the groups. After application of dressings, the QC group had the lowest blood loss (4.4 +/- 1.4 mL/kg). CONCLUSION: Of the hemostatic agents tested, QuikClot improved survival and decreased bleeding in a swine model of lethal vascular and soft tissue injury.     

电针足三里穴对致死性失血性休克延迟补液大鼠生存率和脏器功能指标的影响

目的:研究电针足三里穴对致死性失血性休克延迟补液大鼠生存率和脏器功能指标的影响,探讨其对液体复苏疗法的替代作用.方法:36只SD雄性大鼠,体重(270±20)g,按全血容量的45%放血制成致死性失血性休克模型.随机分为3组:即刻补液组、非经非穴+延迟补液组和足三里+延迟补液组,每组12只.即刻补液组于失血后10 min...     

A pilot study on early versus delayed hypertonic saline dextran resuscitation in a porcine model of near-lethal liver injury: early hemodynamic response and short-term survival

BACKGROUND: We studied the effects of early versus delayed fluid resuscitation on hemodynamic response and short-term survival in a porcine model of severe hepatic injury associated with hemorrhagic shock. MATERIALS AND METHODS: Eighteen anesthetized swine were randomized after standardized liver injury into two groups: early resuscitation (ER, n = 9) and delayed resuscitation (DR, n = 9). The ER and DR groups were resuscitated with hypertonic saline dextran (HSD) 20 min and 40 min after the injury, respectively. Mean arterial pressure (MAP), cardiac output (CO), and arterial blood gases were measured in addition to vascular blood flow rates in the aorta, hepatic artery and portal vein. The duration of follow-up was 100 min. RESULTS: MAP decreased from 112 +/- 4 to 23 +/- 2 mmHg (P < 0.05) during 20 min after the injury. Bolus infusion of HSD significantly elevated MAP, CO, and flow rates in the aorta, portal vein and common hepatic artery in both groups. Portal vein flow remained relatively high during the shock. Intra-abdominal bleeding (ER, 701 +/- 42 mL; DR 757 +/- 78 mL) and the mortality rate (ER 44%; DR 33%) did not differ between the groups 100 min after injury (P > 0.05). Aortic flow, portal vein flow, common hepatic artery flow, MAP, CO, PaO(2), PaCO(2), base deficit, pH, hemoglobin measurements, and the volume of blood shed into the intraperitoneal cavity did not affect survival in the Cox regression analysis. CONCLUSIONS: Early versus delayed fluid infusion with HSD resulted in a comparable hemodynamic response and survival 100 min after injury. No rebleeding was observed.     

Irreversible shock is not irreversible: a new model of massive hemorrhage and resuscitation

BACKGROUND: Existing shock models do not address the patient with massive hemorrhage (> 1 blood volume). Such patients often die from irreversible shock. This model simulates the clinical scenario of massive hemorrhage and resuscitation (MHR) to determine if irreversible shock can be reversed. METHODS: Lewis rats were bled at a rate of 1 estimated blood volume (EBV) per hour for 2 hours with simultaneous infusion of resuscitation mixture (RM) consisting of red blood cells and crystalloid. Blood pressure was maintained at a mean arterial pressure (MAP) of 50 mm Hg during the 2 hours of hemorrhage. Hemorrhage was stopped and resuscitation continued for 1 hour until 6, 8, or 10 x EBV of RM was infused. Control animals were subjected to a traditional fixed pressure hemorrhage to MAP of 50 mm Hg for 2 hours followed by resuscitation to MAP > 90 mm Hg for 1 hour with crystalloid alone. Two-week survival was compared using a chi2 test. RESULTS: Control animals (n = 13) were hemorrhaged 48% +/- 5% of EBV and had a mortality rate of 23%. MHR animals had severity and duration of hypotension identical to that of controls but were hemorrhaged 214% +/- 8% of EBV. Despite receiving 390 mL/kg of RM and a final hematocrit of 37%, 14 of 15 animals resuscitated with 6 x EBV died from "irreversible" shock (mortality, 93%; p < 0.001 vs. controls). When very large volumes of resuscitation were used, survival rates improved significantly. The 10 x EBV group received 120% of lost red blood cells and 530 mL/kg of crystalloid and had 64% survival at 2 weeks (p < 0.01 vs. 6 x EBV group). CONCLUSION: This MHR model is much more lethal than a traditional severe hemorrhage model and reproduces the clinical picture of irreversible shock. This irreversible shock can be reversed with very large volumes of resuscitation.     

Tranexamic acid does not prevent rebleeding in an uncontrolled hemorrhage porcine model

BACKGROUND: Fluid resuscitation after uncontrolled hemorrhage might promote rebleeding and irreversible shock. Tranexamic acid is a procoagulant drug that limits blood loss after surgery of the hip, knee, and heart. We hypothesized that pretreatment with tranexamic acid reduces the rebleeding in uncontrolled hemorrhage and thereby allows safe administration of crystalloid fluid resuscitation. METHODS: A 120-minute intravenous infusion of 100 mL/kg of Ringer's solution was given to 24 pigs (mean weight, 20 kg) 10 minutes after lacerating the infrarenal aorta. The animals were randomized to receive an intravenous injection of 15 mg/kg of tranexamic acid or placebo just before starting the resuscitation. Rebleeding events were monitored by two ultrasonic probes positioned proximal and distal to the laceration. RESULTS: Tranexamic acid had no effect on the number of rebleeding events, bled volume, or mortality. The initial bleeding stopped within 4 minutes after the injury. The five animals that died suffered from 4.4 rebleeding events on average, which tripled the total blood loss, whereas the survivors had only 1.3 such events during fluid resuscitation (p < 0.02). At autopsy, death was associated with a larger total hemorrhage; the blood recovered from the abdomen weighed 1.4 kg (median) in nonsurvivors and 0.6 kg in survivors (p < 0.001), with the difference being attributable to rebleeding. CONCLUSION: Rebleeding events increased the amount of blood lost and the mortality in uncontrolled aortic hemorrhage. Tranexamic acid offered no benefit.     

Resuscitation-induced pulmonary apoptosis and intracellular adhesion molecule-1 expression in rats are attenuated by the use of Ketone Ringer's solution

BACKGROUND: Resuscitation with Lactated Ringer's solution after hemorrhagic shock in rats has been shown to cause early cellular injury in the lung. We hypothesized that the use of energy substrates, such as ketone bodies, in the resuscitation fluids would protect against this injury. As markers of cellular injury we measured the induction of apoptotic cell death and the expression of Intracellular Adhesion Molecule-1 (ICAM-1). STUDY DESIGN: Male Sprague Dawley rats (n = 35) under inhaled isoflurane anesthesia had placement of femoral arterial and venous catheters. A three-stage hemorrhage model was used for this experiment. There was an initial hemorrhage of 27 mL/kg for 10 minutes. During the next 75 minutes another 8 mL/kg of blood was withdrawn at a steady rate. The resuscitation fluids were then infused for 45 minutes during which the third continuous hemorrhage of 8 mL/kg was performed. The animals were randomized to five groups: 1) sham hemorrhage (n = 6); 2) sham resuscitation (n = 7); 3) Lactated Ringer's resuscitation, three times the volume of shed blood (n = 8); 4) Ketone Ringer's (containing 28 mEq/L of beta-hydroxybutyrate) resuscitation, three times the volume of shed blood (n = 7); and 5) plasma resuscitation, volume equal to shed blood (n = 7). The animals were sacrificed 1 hour after resuscitation and lungs were harvested. Western blot technique was used for the determination of proapoptotic protein (bax), antiapoptotic protein (bcl-2), apoptotic fragments of poly ADP-ribose polymerase, and ICAM-1. Sections of lung were also subjected to immunostaining using antibodies to bax and ICAM-1 proteins (reported as number of positive cells/mm2). RESULTS: Lactated Ringer's resuscitation caused a significant increase in pulmonary apoptosis and ICAM-1 expression compared with the sham hemorrhage group. Animals resuscitated with Ketone Ringer's solution and plasma did not show this injury pattern. CONCLUSIONS: Substitution of lactate with ketone bodies in the resuscitation fluid attenuates the expression of cellular injury markers in the lung.