The effects of BleedArrest on hemorrhage control in a porcine model.
|Publication:||Name: U.S. Army Medical Department Journal Publisher: U.S. Army Medical Department Center & School Audience: Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2012 U.S. Army Medical Department Center & School ISSN: 1524-0436|
|Issue:||Date: Oct-Dec, 2012|
Trauma represents the leading cause of morbidity and mortality in
all populations with uncontrolled hemorrhage as the major cause of
complications and death. (1-6) Historically, 20% of combat casualties
were killed in action. Ninety percent of those casualties never reached
a field hospital with hemorrhage as the major cause of death. (5) In
Vietnam, almost 40% of Soldiers who died of exsanguination had a source
of bleeding that could possibly have been controlled by a hemostatic
agent. (6) Uncontrolled hemorrhage accounts for almost 50% of the
battlefield deaths prior to evacuation in the more recent conflicts of
Iraq and Afghanistan. (3)
If trauma victims survive the initial blood loss and injury, they are prone to hypothermia, coagulopathy, acidosis, infection, and multiple organ failure. These complications result in an increase in morbidity and mortality even after successful resuscitation. (1,2,7-9) Therefore, rapid hemostasis and control of bleeding is not only essential for initial survival, but also for optimal recovery.
Several hemostatic agents have been investigated in multiple animal models over the past decade with mixed and inconclusive results. (7,10-26) The purpose of this study was to examine the effectiveness of the hemostatic agent BleedArrest (Hemostasis LLC, Saint Paul, MN). The mechanism of action of BleedArrest is based on the absorbance of plasma by amylopectin, a plant-based starch. The result is the concentration of platelets and coagulation factors at the site of injury supporting the formation of a robust clot. The research question guiding this study was: Is there a statistically significant difference in the amount of bleeding between BleedArrest and the control group?
MATERIALS AND METHODS
This study was a within and between subjects experimental design employing an established porcine model of uncontrolled hemorrhage. The research protocol was approved by the Institutional Animal Care and Use Committee. The animals received care in accordance with the Animal Welfare Act and The Guide for the Care and Use of Laboratory Animals. Twenty male Yorkshire swine weighing between 70 kg and 89 kg were randomly assigned (n=10 per group) to one of 2 groups, BleedArrest or the control group. The rationale for using swine of this size was that they represent the average weight of the US Army Soldier. (27) The swine were observed for 3 days to ensure a good state of health, fed a standard diet, and were NPO [no food or water] after midnight the day of the experiment. This study was conducted in 4 phases: induction/stabilization, hemorrhage, hemostasis, and blood loss.
The induction phase started with an intramuscular injection of ketamine (20 mg/kg) and atropine (0.04 mg/kg). Subjects were placed supine on a litter and transported to an operating room followed by inhaled isoflurane (4% to 5%). After placement of an endotracheal tube, a peripheral IV catheter was inserted and the isoflurane concentration was reduced to 1% to 2% for the remainder of the experiment. The swine were ventilated with a standard Narkomed anesthesia machine (Drager, Telford, PA). Heart rate, electrocardiography, blood pressure, oxygen saturation, end-tidal carbon dioxide, and rectal temperatures were continuously monitored for the remainder of the experiment. A Thermal Industries of Florida (TIF) scale, Model 9010A, (SPX Service Solutions, Owatonna, MN) was placed between the litter and operating room table. The TIF scale is an electronic scale that measures pressure applied in pounds per square inch and is precise within 0.5 oz and accurate within 0.5%. The scale was zeroed per manufacturer's instructions. While manual pressure was applied to the wound during the experiment, the scale was observed to ensure pressure was maintained at 25 psi within [+ or -] 0.5 oz to ensure continuity from subject to subject.
The left carotid artery was cannulated with a 20 guage (Ga) angio-catheter using a cut down technique. A central venous catheter was inserted using a modified Seldinger technique for fluid volume management and blood sampling. The catheters were attached to a hemodynamic monitoring system (Hewlett Packard, Palo Alto, CA) for continuous monitoring of the arterial blood pressures. All catheters were continuously flushed with 0.9% saline solution (5 mL per hour) to maintain patency. Following line placement, the NPO fluid deficit was corrected with 0.9% normal saline, per the Holliday-Segar formula. The investigators used an activated clotting time (ACT) test to screen all subjects for coagulopathy prior to procedures. The upper limit in this study for all subjects was an ACT less than 150 seconds. Subjects were further monitored for 30 minutes to ensure hemodynamic stability prior to intervention. Body temperature was monitored via a rectal probe and maintained at greater than 36.0[degrees]C using a forced-air warming blanket. A complex groin injury as described by Alam and colleagues was generated to simulate a penetrating injury. (12,13) The injury included dissection of the proximal thigh soft tissues including the skin, quadriceps, and adductor muscles to expose the femoral artery and vein just below the inguinal ligament. All subjects were hemodynamically stable prior to intervention.
Following the 30-minute stabilization period, the exposed femoral artery and vein were transected with a scalpel blade. The swine were allowed to hemorrhage for one minute simulating the response time of a battlefield health care provider. Blood was collected by gauze, absorbent pads underneath the animals, and in a suction canister by use of a suction tip catheter placed in the distal portion of the wound.
After one minute of hemorrhage, proximal pressure was applied to the transected femoral vessels, and 4 in by 4 in gauze was used to blot the blood from the wound per the hemostatic agent manufacturer's guidelines. At this time, the hemostatic agent was poured into the wound followed by standard wound packing including a layer of petroleum gauze and roller gauze (Kerlix, Covidien, Mansfield, MA). The control group received proximal pressure and standard wound packing. Firm manual pressure of 25 psi was applied for 5 minutes to the injury site as measured by the TIF scale. (28) After 5 minutes, all groups received a pressure dressing of rolled gauze and a 10-pound sandbag. This dressing was left in place for 30 minutes. 500 mL of 6% Hextend in lactated ringer's solution (Hospira, Inc., Lake Forest, IL) IV was administered to all subjects in accordance with current battlefield resuscitation protocol recommended by the Committee on Tactical Combat Casualty Care. (29)
BLOOD LOSS PHASE
After 35 minutes of pressure on the wound (5 minutes manual pressure plus 30 minutes with the pressure dressing), the standard pressure dressing was removed being careful to keep the clot intact. The rationale for using the petroleum gauze was that it allowed removal of the pressure dressing with minimal clot disruption. For the purposes of this study, hemostasis was defined as a clot formation with oozing of no more than 2% of the swine's total blood volume over a 5-minute period (approximately 100 mL in a 70 kg pig). Blood loss was measured over 2 time periods: the initial injury to intervention and postintervention to the completion of the study. Blood loss was calculated by weighing the dressings, the absorbent pads underneath the animals, and blood suctioned from the distal portion of the wound before and after transection of the femoral vessels.
RESULTS AND COMMENT
The minimum number of animals was used to obtain a statistically valid result. A large effect size was determined for this experiment based upon previous work by Alam and Pusateri.7,13,19,30 Using G-Power 3.00 for Windows (Institut Fur Experimentelle Psychologie, Dusseldorf, FRG), an effect size of 0.6, a power of 0.80, and an alpha of 0.05, it was determined that a sample size of 10 swine per group was needed for this study. Investigators evaluated coagulation studies with all subjects. There were no statistically significant differences between the groups in reference to the amount of initial bleeding after one minute (P=.533): BleedArrest group ranged from 492 to 1569 mL (mean=789.22, SD [+ or -] 121.60 mL) and control group ranged from 100 to 992 mL (mean=601.50, SD [+ or -] 84.03 mL). The body weights, core body temperatures, amount of blood volume, and the amount of the initial one minute hemorrhage were analyzed using a multivariate analysis of variance. There were no statistically significant differences between the groups (P>.05) indicating that the groups were equivalent on these parameters. Blood loss after 35 minutes of pressure on the wound (manual pressure and pressure dressing) was calculated for each group over a five minute observation period following removal of dressings and exposure of the formed clot. The amount of bleeding BleedArrest group ranged from 0 to 648 mL (mean=72, SD[+ or -]72 mL) and control group ranged from 0 to 1002 mL (mean=317.30, SD[+ or -]112.02 mL). A repeated analysis of variance test was used to analyze the data, the one minute and 5 minute hemorrhage postintervention, and indicated a significant difference between the BleedArrest and control groups (P=.033). The results are summarized in the Figure.
The US Army's goal is for each Soldier to carry a hemostatic agent, but research should be conducted to determine the most efficacious and cost effective agent. In addition, many civilian disaster teams and first responders are exploring the potential for hemostatic agent use in the prehospital setting. Pusateri outlined the ideal qualities of hemostatic agents for civilian and military use. These include (1) the ability to rapidly stop large vessel arterial and venous bleeding within 2 minutes of application when applied to an actively bleeding wound through a pool of blood; (2) no requirement for mixing or preapplication preparation; (3) simplicity of application by wounded victim, buddy, or medic; (4) lightweight and durable; (5) long shelf life in extreme environments; (6) safe to use with no risk of injury to tissues or transmission of infection; and (7) inexpensive. (31) This study compared BleedArrest against a standard pressure dressing control in a porcine model of uncontrolled hemorrhage. A complex groin injury was generated simulating penetrating trauma in an anatomical area not protected by conventional body armor or amenable to use of a tourniquet. The hemostatic agent BleedArrest rapidly controlled arterial and venous bleeding. It was statistically and clinically superior at controlling hemorrhage compared to the standard pressure dressing control group. BleedArrest is packaged in a 250 g easy-to-open envelope. The investigators used enough of the hemostatic agent, mean weight of 24.3 g, to completely fill the groin injury cavity. Standard packaging of the agent in small waterproof packets would allow it to be easily carried by Soldiers, medics, and other healthcare providers in pockets, backpacks, or medic bags. BleedArrest has a shelf life of 3 years and is approved by the Federal Drug Administration (FDA). Investigators noted that the agent did not produce any exothermic reaction when applied to the wound, there were no obvious signs of tissue damage, and does not carry a risk of infection. This hemostatic agent is relatively inexpensive, costing less than $30.00 for a single application. (32)
BleedArrest was statistically and clinically superior at controlling hemorrhage compared to the standard pressure dressing control group. This hemostatic agent is simple to use, lightweight, demonstrates no known risk of tissue injury, has a long shelf life with FDA approval, and isrelatively inexpensive. Based on this study and the requirements outlined by Pusateri, BleedArrest is an effective hemostatic agent for use in the management of hemorrhage and trauma.
This research was sponsored by the TriService Nursing Research Program, Uniformed Services University of the Health Sciences. However, the information or content and conclusions do not necessarily represent the official position or policy of, nor should there be any inference of official endorsement by the TriService Nursing Research Program, Uniformed Services University of the Health Sciences, the Department of Defense, or the US Government.
The investigators acknowledge the following students in the US Army Graduate Program in Anesthesia who participated in the study:
MAJ Travis Hawksley, AN, USA
MAJ Matthew Ruemmler, AN, USA
CPT Chris Angeles, AN, USA
CPT Frances Bradley, AN, USA
CPT William Corona, AN, USA
CPT Alenka Vale-Dominguez, AN, USA
1LT Elizabeth Hawksley, AN, USA
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Brian Gegel, MSN, CRNA
James Burgert, MSNA, CRNA
LTC Michael Loughren, AN, USA
Don Johnson, PhD
Mr Gegel is co-owner of Veteran Anesthesia Services, PLLC, San Antonio, Texas.
Mr Burgert is a member of the Adjunct Clinical Faculty, Brooke Army Medical Center, Fort Sam Houston, Texas.
LTC Loughren is a member of the Faculty of the US Army Graduate Program in Anesthesia Nursing, Fort Sam Houston, Texas.
Dr Johnson is Director of Research of the US Army Graduate Program in Anesthesia, Fort Sam Houston, Texas.
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