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Year : 2011  |  Volume : 4  |  Issue : 2  |  Page : 207-211
The effects of blood pressure on rebleeding when using ExcelArrest™ in a porcine model of lethal femoral injury

1 William Beaumont Army Medical Center, Ft Bliss, El Paso, TX, USA
2 Tripler Army Medical Center, Honolulu, HI, USA
3 FT Sam Houston, San Antonio, TX, USA

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Date of Submission08-May-2010
Date of Acceptance23-Sep-2010
Date of Web Publication18-Jun-2011


Background : Uncontrolled hemorrhage is one of the leading causes of death in both combat and civilian trauma. This study was designed to compare the arterial blood pressures at which rebleeding occurred when a hemostatic agent, ExcelArrest™, was used compared with a standard pressure dressing. Materials and Methods : This study was a prospective, experimental, and mixed research design. Swine were assigned to one of two groups: ExcelArrest™ (n=5) or a control consisting of standard pressure dressings (n=5). Investigators generated a complex groin injury. The femoral artery and vein were transected and allowed to bleed for 60 s in each pig. After 60 s, ExcelArrest™ was poured into the wound. The control group underwent the same procedures, but without treatment with the hemostatic agent. After 5 min of direct pressure, a standard pressure dressing was applied. After 30 min, dressings were removed and the systolic blood pressure (SBP) was increased incrementally using intravenous phenylephrine until rebleeding occurred. Statistical Analysis : A multivariate ANOVA and a least significant difference were used to analyze the data. Results : ExcelArrest™ was more effective in preventing rebleeding compared to a standard pressure dressing (P<0.05). The means and standard deviations in mmHg for SBP and mean arterial pressure (MAP) for rebleeding were as follows: ExcelArrest™ (SBP=206.4, SD±11.6; MAP=171.4, SD±12.5); for the control group (SBP=89.40±3.58, MAP=58.60±12.86). Conclusions : ExcelArrest™ was more effective in preventing rebleeding compared to the standard dressing with elevated blood pressures. There may be protective benefits in using this hemostatic agent against elevated blood pressures provided by ExcelArrest™.

Keywords: Emergency room, hemorrhage, hemostasis, porcine, trauma

How to cite this article:
Hirst H, Brinkman J, Beasley A, Crocker R, O'Sullivan J. The effects of blood pressure on rebleeding when using ExcelArrest™ in a porcine model of lethal femoral injury. J Emerg Trauma Shock 2011;4:207-11

How to cite this URL:
Hirst H, Brinkman J, Beasley A, Crocker R, O'Sullivan J. The effects of blood pressure on rebleeding when using ExcelArrest™ in a porcine model of lethal femoral injury. J Emerg Trauma Shock [serial online] 2011 [cited 2020 May 25];4:207-11. Available from:

   Introduction Top

Uncontrolled hemorrhage is the major cause of death in trauma patients with trauma representing one of the leading causes of morbidity and mortality in both the civilian and military populations. [1] Historically, 20% of combat casualties were killed in action with 90% of the deaths occurring in the pre-hospital setting. [2] The primary causes of these deaths were attributed to hemorrhage. Up to 40% of soldiers in Vietnam, who died of exsanguination, had a source of hemorrhage that could have been stopped or controlled by a hemostatic agent. [3]

Today in Operations Iraqi Freedom and Enduring Freedom, up to 50% of the battlefield deaths that occur prior to evacuation are due to uncontrolled bleeding. [4] According to COL John Holcomb (Retired), former Trauma Consultant to the US Army Surgeon General, the majority of casualties on the battlefield with potentially survivable injuries died of hemorrhage. [4] Recent doctrinal shifts in the priority of care of a trauma patient call for hemorrhage control before all other interventions. [2] In separate studies, Heckbert and Alam emphasize that the control of hemorrhage is essential, not only to sustain life, but also to facilitate optimal recovery. [5] Alam also stresses that there are two effective methods that can be utilized to control hemorrhage. One is the use of a tourniquet; the other is the application of a hemostatic agent. [2] Ward indicates that hemostatic agents may be better at controlling hemorrhage from areas that are not controlled by a tourniquet. For example, a tourniquet cannot be effectively used to control hemorrhage in an upper femoral arterial bleed because of anatomical limitations. [6] Alam emphasizes the fact that no ideal hemostatic agent currently exists, and of those that are available, rebleeding remains a major concern. [2]

Historically, high volume fluid resuscitation in the treatment of hemorrhagic shock was widely practiced. The metabolic benefit of aggressive fluid resuscitation was demonstrated in the animal model and implemented in patients with uncontrolled hemorrhagic shock. However, aggressive fluid resuscitation increases the blood pressure, dislodges the newly formed clot causing rebleeding resulting in increased morbidity and mortality. [1],[7],[8],[9]

Recently, research has shown that the metabolic benefits of fluid resuscitation are accepted and must be balanced against the poor outcomes associated with rebleeding. [7],[8],[9],[10] To maximize the metabolic benefits of fluid resuscitation without causing rebleeding, it is vital to determine if there is a reproducible blood pressure at which clot failure occurs with the use of hemostatic agents. Investigators have found that further research is needed to determine the best hemostatic agent for hemorrhage control, cost effectiveness, and limited rebleeding. [11],[12],[13] The ideal hemostatic agent would be inexpensive, highly effective, simple to utilize, and fully absorbable without antigenic properties. The ideal agent does not exist. There are many types of topical hemostatic agents, and readers are referred to an excellent review article by Achneck et al. [14] for further information. In brief, hemostatic trauma agents in the field can be grouped into four major groups; fibrin, chitin, chitosan, and mineral zelolite dressings. They have different mechanisms of action, as well as different advantages and disadvantages which are beyond the scope of this article.

The theoretical framework for this study is based on the clotting cascade, mechanisms of action of the hemostatic agent, ExcelArrest™, and how these perform under increasing arterial blood pressures. ExcelArrest™, a chitin-based hemostatic agent made from the exoskeleton of shrimp, concentrates platelets and coagulation factors at the site of injury, and forms adhesive complexes. [15] The platelets undergo this process of adhesion, activation, and aggregation resulting in a platelet plug within seconds to minutes depending on the severity of the vascular insult. Coagulation occurs by the binding of the platelet's Glycoprotein IIb/IIIa complex to fibrin to form a complex mesh of platelets and fibrin strands creating a robust clot. It is unknown whether the clot, with or without the hemostatic agent, will maintain integrity or rebleed in the presence of increasing arterial pressures. [10] Side effects from ExcelArrest™ application has not been investigated, although research has shown difficulties with debridement of other agents, problems with healing and closure of the wound site, contraindicated to allergies to shellfish and most significantly, granules entering the systemic circulation and causing distal thrombosis in organs. [16]

There has only been one study designed to evaluate hemostatic agents in regards to the blood pressure at which rebleeding occurs, and although the clot failed at a much higher pressure with both agents studied: Celox™ (a chitosan type of agent) = mean SBP 166.40; SD = ±40.92, Traumadex™ (a biodegradable organic polysaccharide hemosphere agent) = mean SBP 152.20; SD = ±59.05 while the control group's mean SBP = 88.25; SD = ±2.80, no studies have examined the effect of ExcelArrest™ on rebleeding. [10] It is unknown at which arterial blood pressure rebleeding occurs when using ExcelArrest™ in hemorrhage control. Continued research is vital to examine the other hemostatic agents available and the effect of arterial blood pressure on rebleeding.

   Materials and Methods Top

Study design

This study was a prospective, experimental, mixed research design. The Institutional Animal Care and Use Committee (IACUC) approved the protocol. The animals received care in compliance with the Animal Welfare Act and the Guide for the Use of Laboratory Animals. The minimum number of animals was used to obtain a statistically valid result. A large effect size was calculated for this experiment based upon previous work by Burgert et al. [10] Using the effect size of 0.6, a power of 0.8, and an alpha of 0.05, it was determined that a sample size of five swine per group (10 total) was needed for this study.


Ten Yorkshire-Cross swine weighing 60-80 kg were randomly assigned (n=5 per group) to one of the two groups: ExcelArrest™ or control group. The reason for using swine of this size is that it represents the average weight of the US Army soldier. [17] In addition, male swine were used to decrease possible effects from female hormones. The swine were observed for 3 days to ensure good state of health, fed a standard diet, and remained NPO after midnight the day of the experiment.


Anesthesia was induced with an intramuscular injection of ketamine (10 mg/kg), atropine (0.05 mg/kg), isoflurane (4%), and 100% oxygen. After intubation, isoflurane was reduced to 0.5-2% for the remainder of the experiment. A peripheral IV catheter was started with a continuous infusion of lactated Ringer's solution at a rate of 3 mL/kg/min. The animals were ventilated (tidal volume 8-10 mL/kg, respiratory rate 10-14 bpm) with a standard Narkomed anesthesia machine (Drager, Telford, PA) and continuously monitored with the following standard monitors: HR, BP, ECG, SpO 2 , ETCO 2 , and rectal temperature. The left carotid artery was cannulated with a 20-G angio-catheter using a cut down technique. Blood pressure was continuously monitored by the use of the carotid arterial line connected to the Marquette Solar 800 Medical System (It is precise within 1 mmHg and accurate within 2 mmHg). A left triple-lumen central venous catheter was inserted using a modified Seldinger technique for central venous pressure monitoring, fluid volume management, and blood sampling.


The experiment was conducted in three major phases: In phase one, a blast wound was simulated with the complete transection of the femoral artery and vein then allowed to bleed for 60s. This site was chosen because the groin is not protected by conventional body armor and is a common site of combat injury. Furthermore, hemorrhage cannot be controlled with a tourniquet at this site. [7] A suction catheter was placed distal to the wound used to collect blood. A stopwatch was used to measure the time for stabilization, hemorrhage, observation of homeostasis, and the increments in blood pressure (The stopwatch is precise within one-hundredth of a second and accurate within one-tenth of a second). After 60 s of bleeding, in the ExcelArrest™ Group, the agent was placed over the wound followed by standard packing and 5 min of manual pressure at 25 pounds per square inch (psi). Constant manual pressure in the groin wound was maintained with the use of a TIF scale (precise within 10 mg and accurate within 500 mg) placed under the affected area. The control group only received wound packing and manual pressure. Following 5 min of manual pressure, a pressure dressing was applied with Coban for 30 min. Five hundred milliliter of Hextend (Hospira, Inc., Lake Forrest, IL) was administered during the hemorrhage phase as recommended by the Committee on Tactical Combat Casualty Care treatment protocol. [18] Hextend, a volume expander containing 6% hetastarch in a lactated electrolyte solution, is an ideal choice because it allows for rapid intravascular volume expansion as opposed to the use of a crystalloid which would demand more volume (3:1) thus increasing risks of third spacing and dilution clotting factors. Hextend stays in the intravascular space up to 24 h versus 20 min with crystalloids. Hextend has not been reported to have any adverse effects on the coagulation system; [1],[19] however, high volumes of high molecular weight hetastarch (15 cc/kg) have been documented to effect blood coagulation, specifically von Willebrand factor and factor VIII. [20] Low volumes of hetastarch are much less likely to induce a clinically relevant coagulation defect. [21]

In phase two, the dressings were removed. Hemostasis was observed and defined as blood loss of ≤2% of total blood volume during a 5-min period. If hemostasis was not achieved, then the experiment concluded for that subject. In the final phase of data collection, a phenylephrine infusion was initiated on swine that achieved hemostasis. Phenylephrine is a direct acting selective α-1 adrenergic agonist. It causes marked arterial smooth muscle vasoconstriction and only causes β-receptor activation at much higher concentrations. It was specifically chosen for the use in this study due to its ability to easily titrate to our required increasing blood pressures. Phenylephrine was titrated to increase systolic blood pressure (SBP) in increments of 10 mmHg up to a maximum SBP of 210 mmHg. Each blood pressure manipulation was maintained for 3 min, and the wound observed for rebleeding. A multivariate ANOVA (MANOVA) was used to determine if there were differences in the groups relative to the outcome variables of mean arterial pressure (MAP) and SBP. Rebleeding was defined as blood loss greater than 2% of total blood volume in over a 5-min period. If rebleeding occurred, the experiment was terminated. The dressings and suction canisters were then weighed by a second TIF Scale and the difference subtracted to determine the total amount of blood loss for rebleeding during the 5-min period.

   Results Top

Prior to the experiment, each swine was checked for normal coagulation function using the activated clotting time (ACT) test. This test is usually used in humans to test heparin anticoagulation levels; however, it is commonly used as a very accurate coagulation test in large animal research. ACT values are prolonged with hemodilution, hypothermia, platelet dysfunction, hypofibrinogenemia, antiphospholipid antibodies, and other coagulopathies. The baseline ACT should be shorter than 200 s. All swine had ACT values <200 s. An ANOVA was used to analyze the pretest variables of laboratory values, weight, and NPO deficit replacement. There were no statistically significant differences between the groups (P>0.05) indicating the two groups were equivalent within these parameters. Similar weight and size of the swine were in each group. The ExcelArrest™ group ranged from 64 to 76 kg (mean=68.9, SD±4.9 kg), and the control group ranged from 72 to 84 kg (mean=77.9, SD±4.9 kg).

There were statistically significant differences between the groups in reference to highest MAP and rebleeding as well as the SBP and rebleeding (P=0.00). The ExcelArrest™ group's MAP ranged from 153 to 184 mmHg (mean=171.4, SD±12.5 mmHg), and the control group's MAP ranged from 40 to 75 mmHg (mean=58.6, SD±12.8 mmHg) for rebleeding to occur. The ExcelArrest™ group's SBP ranged from 186 to 216 mmHg (mean=206.4, SD±11.6 mmHg) while the control group's SBP ranged from 84 to 94 mmHg (mean=89.4, SD=3.5 mmHg) for rebleeding to occur [Figure 1]. Rebleeding was measured after 5 min of pressure on the wound (manual pressure at 25 psi) and was calculated for each group. Rebleeding in the control group over the 5-min period had a mean of 339.2 mL with a SD 126.7 mL. The ExcelArrest™ group did not have rebleeding (>2% blood volume) despite mean SBP and MAP of 206.4 and 171.4 mmHg, respectively. The control group had lower pressures for rebleeding with a mean SBP of 89.4 and a mean MAP of 58.6 mmHg [Figure 2].
Figure 1: Minimum and maximum SBP and MAP before rebleeding in control and ExcelArrest™ groups

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Figure 2: Mean SBP and mean MAP of rebleeding between groups

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In summary, data collection of SBP or MAP was terminated on any swine if either of two events occurred. First, if rebleeding occurred after removal of the dressing or at any time during the hypertension challenge, or second, if rebleeding did not occur at the maximum SBP (around 200 millimeters of mercury). Also, examined were baseline blood pressures to determine if there existed statistical differences between groups. As [Table 1] shows, there were no statistical differences between groups except relating to the blood pressures at which rebleeding occurred.
Table 1: Means and standard deviation of systolic blood pressure and MAP by group

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   Discussion Top

Continued advancement in technology and materials to control hemorrhage is of obvious benefit and remains a top priority in the care of trauma patients. The recent trend to diverge from massive fluid resuscitation to permissive hypotension has lead to decreased rebleeding and mortality from organ failure. [7] The metabolic benefits of fluid resuscitation must be balanced against the poor outcomes associated with rebleeding. Aggressive fluid resuscitation increases arterial blood pressure and organ perfusion but raises BP which leads to dislodgement of the newly formed clot. From the work of Sondeen, a reproducible blood pressure in which rebleeding occurred was concluded in a swine model of uncontrolled hemorrhage. They determined a MAP equal to 64±2, SBP equal to 94±3, and a diastolic blood pressure (DBP) of 45±2 mm Hg lead to rebleeding. It is suggested that the optimal fluid resuscitation should stop below reaching this rebleeding pressure. [22] Aggressive volume resuscitation is no longer recommended prior to definitive control of hemorrhage. Consequently, permissive hypotension using low-volume colloid fluids are given to achieve the therapeutic goals of SBP ~ 90 and a MAP ~ 60 mmHg to sustain life. Moreover, recent studies suggest that resuscitation to normal blood pressures may not be beneficial prior to definitive surgical control. The blood pressure is maintained at the minimal goals to prevent rebleeding; however, when ExcelArrest™ is used then it provides a higher safety margin. Using a hemostatic agent as opposed to a standard pressure dressing may allow for initial fluid resuscitation benefits with less concern in raising BP and dislodging the clot. Healthcare providers need to know at what arterial blood pressure rebleeding occurs following the use of hemostatic agents such as ExcelArrest™. Studies relative to the hemostatic agents Celox™ and Traumadex™ have been done relating to blood pressure challenges, but none has been implemented using ExcelArrest™. ExcelArrest™ demonstrated a statistically significant difference compared to the control group in the prevention of rebleeding at higher blood pressures.

   Conclusion Top

As uncontrolled hemorrhage in trauma remains a constant problem in both civilian and military healthcare sectors, it is essential that providers have access to optimal modalities of treatment for such vascular injuries. As this study demonstrates, ExcelArrest™ is a promising agent for the control of bleeding and the prevention of rebleeding as arterial blood pressures increase. Within the confines of our study, ExcelArrest™ treated subjects had significantly higher MAP and SBP with no rebleeding vs. rebleeding to occur with the control group.

   References Top

1.Pope AF, Longnecker D. Fluid Resuscitation: State of the science for treating combat casualities and civilian injuries. Washington, DC: National Academy Press; 1999.  Back to cited text no. 1
2.Alam HB, Burris D, DaCorta JA, Rhee P. Hemorrhage control in the battlefield: Role of new hemostatic agents. Mil Med 2005;170:63-9.  Back to cited text no. 2
3.Mabry RL, Holcomb JB, Baker AM, Cloonan CC, Uhorchak JM, Perkins DE, et al. United States Army Rangers in Somalia: An analysis of combat casualties on an urban battlefield. J Trauma 2000;49:515-28.  Back to cited text no. 3
4.Holcomb J. Recombinant Factor VII History, Use in Civilian Trauma, Combat Operations, Complications and Outcomes, Testimony to congress. Washington, DC: 2006.  Back to cited text no. 4
5.Heckbert SR, Vedder NB, Hoffman W, Winn RK, Hudson LD, Jurkovich GJ, et al. Outcome after hemorrhagic shock in trauma patients. J Trauma 1998;45:545-9.  Back to cited text no. 5
6.Ward KR, Tiba MH, Holbert WH, Blocher CR, Draucker GT, Proffitt EK, et al. Comparison of a new hemostatic agent to current combat hemostatic agents in a Swine model of lethal extremity arterial hemorrhage. J Trauma 2007;63:276-83.  Back to cited text no. 6
7.Bickell WH, Bruttig SP, Millnamow GA, O'Benar J, Wade CE. The detrimental effects of intravenous crystalloid after aortotomy in swine. Surgery 1991;110:529-36.  Back to cited text no. 7
8.Pepe PE. Management of trauma: Changing perspectives. Curr Opin Crit Care 2002;8:549-50.  Back to cited text no. 8
9.Pepe PE, Mosesso VN Jr, Falk JL. Prehospital fluid resuscitation of the patient with major trauma. Prehosp Emerg Care 2002;6:81-91.  Back to cited text no. 9
10.Burgert JM, Gegel BT, Austin R 3 rd , Davila A, Deeds J, Hodges L, et al. Effects of arterial blood pressure on rebleeding using Celox and TraumaDEX in a porcine model of lethal femoral injury. AANA J 2010;78:230-6.  Back to cited text no. 10
11.Beekley AC, Martin MJ, Spinella PC, Telian SP, Holcomb JB. Predicting resource needs for multiple and mass casualty events in combat: Lessons learned from combat support hospital experience in Operation Iraqi Freedom. J Trauma 2009;66:S129-37.  Back to cited text no. 11
12.Beekley AC, Sebesta JA, Blackbourne LH, Herbert GS, Kauvar DS, Baer DG, et al. Prehospital tourniquet use in Operation Iraqi Freedom: Effect on hemorrhage control and outcomes. J Trauma 2008;64:S28-37.  Back to cited text no. 12
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14.Achneck HE, Sileshi B, Jamiolkowski RM, Albala DM, Shapiro ML, Lawson JH. A comprehensive review of topical hemostatic agents: Efficacy and recommendations for use. Ann Surg 2010;251:217-28.  Back to cited text no. 14
15.Pusateri AE, McCarthy SJ, Gregory KW, Harris RA, Cardenas L, McManus AT, et al. Effect of a chitosan-based hemostatic dressing on blood loss and survival in a model of severe venous hemorrhage and hepatic injury in swine. J Trauma 2003;54:177-82.  Back to cited text no. 15
16.Kheirabadi BS, Mace JE, Terrazas IB, Fedyk CG, Estep JS, Dubick MA, et al. Safety evaluation of new hemostatic agents, smectite granules, and kaolin-coated gauze in a vascular injury wound model in swine. J Trauma 2010;68:269-78.  Back to cited text no. 16
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19.Petroni KG, Birmingham S. Hextend is a safe alternative to 5% human albumin for patients undergoing elective cardiac surgery. Anesthesiology 2001;95:198-203  Back to cited text no. 19
20.Jamnicki M, Bombeli T, Seifert B, Zollinger A, Camenzind V, Pasch T, et al. Low- and medium-molecular-weight hydroxyethyl starches: Comparison of their effect on blood coagulation. Anesthesiology 2000;93:1231-7.  Back to cited text no. 20
[PUBMED]  [FULLTEXT] Jonge E, Levi M. Effects of different plasma substitutes on blood coagulation: A comparative review. Crit Care Med 2001;29:1261-7.  Back to cited text no. 21
22.Shires GT, Canizaro PC. Fluid resuscitation in the severely injured. Surg Clin North Am 1973;53:1341-66.  Back to cited text no. 22

Correspondence Address:
Joseph O'Sullivan
FT Sam Houston, San Antonio, TX
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0974-2700.82207

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  [Figure 1], [Figure 2]

  [Table 1]

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