MILITARY MEDICINE, 175, 4:280, 2010

Comparative Testing of New Hemostatic Agents in a SwineModel of Extremity Arterial and Venous Hemorrhage

Capt Jared G. Clay, USAF MC*; J. Kevin Grayson, DVM, PhDf; Maj Dustin Zierold, USAF MC

ABSTRACT Objective: To compare advanced hemostatic dressings: HemCon (HC). QuikClot ACS+ (advanced clot-ting sponge, and two granular agents: Celox (CX) and WoundStat (WS), with a .standard field dressing in a swine modelof extremity hemorrhage. Methods: We randomized 30 animals to treatment with a standard dressing or a hemostaticagenl applied to a 2 x 6-mm injury in Ihe femoral anery and vein after 45 s of free bleeding. Animals received 500 mLHextend 15 min after the bleeding commenced without further resuscitation. End point was survival to 120 min or non-survivable blood pressure. Results: Survival to 120 min among treatment groups was 100% (WS), 83% (CX). 67% (HC),and 50% (ACS+). No control animals survived. Postinjury blood loss (mLAg) was 4.6 (WS), 12.9 (CX). lO.O (HC), and15.8 (ACS+) compared to 27.0 for controls. Conclusion: All hemostatic dressings result in significantly less blood lossand improved survival over standard gauze dressing.

INTRODUCTIONUncontrolled bleeding is the leading cause of death in mil-itary trauma cases'- and the second leading cause of deathin civilian trauma.' In recent military operations, hemorrhageresistant to standard hemostatic techniques continues to bethe number one cause of battlefield death."" Early and effectivecontrol of hemorrhage can theoretically save more lives thanany other measure.** The mortality from traumatic injuries hasdiminished markedly in recent military operations, due to sev-eral factors including routine vi-ear of hody armor, judicioususe of tourniquets for extremity hemorrhage, rapid casualtyevacuation, and aggressive use of blood products in hemor-rhagic shock.'' Advanced hemostatic agents further reducehemorrhage and death when applied to wounds not amenableto treatment with a tourniquet.

The ideal hemostatic agent, as defined by Pusateri andcolleagues,'' should include the ability to rapidly stop large-vessel arterial and venous hieeding even when applied througha pool of blood, be ready for use with no mixing or specialpreparation, simple to apply, lightweight, and durable, stableat various temperatures and humidities, harmless to both thewounded individual and the one giving aid, and inexpensive.

Several advanced hemostatic agents have been developedwith varying mechanisms of action. Many of these have proveneffective in a variety of injury models.^ - We conducted a ran-domized study comparing four hemostatic agents that areFDA approved for the treatment of external hemorrhage andhave proven efficacy (Table I). We used a bulky gauze con-

*David Grant Medical Center 60MSGS/SGCQ 101 Bodin Circle, TravisAFB,CA 94535.

t David Grant Medical Center. Clinical Investigation Facility. 60MDSS/SGSE 101 Bodin Circle, Travis AFB. CA 94535.

Presented ¡it the 55Lh Symposium of the Society of Air Force ClinicalSurgeons. Denver. CO, April 9. 2009.

The views expressed iti this article are those of the authors, and donol reflect the official policy or position of the United States Air Force,Department of Defense, or the U.S. Government.

trol dressing for reference in a swine model of lethal groininjury—a similar model that has been used in previous testsof hemostatic agents.'^-' Our goal was to compare the effi-cacy of these agents with regard to blood loss, maintenanceof blood pressure, survival, and wound site temperature in amodel that avoided intensive fiuid therapy, thereby approxi-mating prehospital conditions.

MATERIALS AND METHODSThis study was approved by the Institutional Animal Care andUse Committee and all animals received humane care in com-pliance with the Guide for the Care and Use of LaboratoryAnimals (National Institutes of Health publication 86-23,revised 1996). All animal handling and research was con-ducted in our facility, which is accredited by the Associationfor the Assessment and Accreditation of Laboratory AnimalCare International. The office of the Surgeon General of theAir Force provided all funding for this study.

Hemostatic AgentsWe compared several hemostatic agents with demonstratedefficacy that had been FDA approved for control of externalhemorrhage. We used a standard army field dressing (AFD)(Conterra Inc., Bellingham. Washington) as a control dress-ing. This is a bulky gauze dressing with bandage straps, whichwere removed before use in this study. An AFD was alsoapplied over each of the hemostatic agents to enhance bloodcollection and distribute pressure.

Enhanced HemCon (HC) dressing (HemCon MedicalTechnologies, Inc.. Portland Oregon) is a 4 x 4-inch lightweightchitosan dressing that is nontoxic. Its primary mechanism ofhemostasis is a strong adherence to tissue when wet with bloodor other fluid, thus creating a seal and preventing further hemor-rhage. Several studies have reported its efficacy.̂ -"•̂ '' HemConhas modified the dressing to he thinner and more pliahle to cre-ate a better seal. The dressing was FDA approved in February2003 and is currently deployed hy the U.S. Army.

280 MILITARY MEDICINE, Vol. 175, April 2010

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Comparison of Hemostatic Agents

TABLE I. Hemostatic Agents

Agenl

Army Field DressingQuikClot ACS-i-

Enhanced HemCon

Celux

WoundStat

Form

GauzeZeolite granules contained in a porous bag

Single-sided chitosan wafer

Fine chitosan granules

Smectite granules

Mechanism of Action

AbsorptionZeolite granules rapidly absorb water upon contact with blood.

concentraling platelets and clotting factors.Positively charged chitosan forms strong seal with negatively

charged blood ceîls upon contact.Positively charged chilosan granules bt)nd with negatively

charged blood cells forming a gel-like seal in the wound.Snieciiie granules rapidly absorb water upon contact with blood.

concentrating plaielets and clotting factors; granules form aclay-like seal in the wound.

QuikClot ACS-f (advanced clotting sp(mge) (Z-Medica,Wallingford. Connecticut) is a modiiied version ot the origi-nal zeolite granules that act by rapid absorption of water—concentrating platelets, red blood cells, and clotting factors inan exothermic reaction. ACS-i- is packaged in a porous fabricbag of four compartments to ease product removal. The zeo-lite granules have been modified to diminish the amount ofheal generated. A recent study demonstrated that ACS was aseffective as the original QuikClot beads in providing hemo-stasis and improving survival.-" ACS+ was FDA approved inJuly 2006. QuikClot products are currently deployed by mul-tiple branches of the U.S. Armed Forces as part of a standardfirst aid kit.

Celox (CX) granules (Medtrade Products Ltd.. Crewe,United Kingdom) are chitosan-based granules that were FDAapproved in June 2006. They are positively charged particlesthat attract to negatively charged red blood cells and subse-quently undergo chemical and mechanical linkages to form abarrier at the site of injury. The efficacy of these granules haverecently been reported in a large animal model."

WoundStat(WS)granules(TraumaCure.Bethesda,Maryland)is a smectile-based granular product approved by the FDA inAugust 2{X)7. It acts partially by rapid absorption of water thatcauses the granules to swell and lake on a clay-like consistencywith tissue adherence properties. The granules are negativelycharged, which may also activate the intrinsic clotting pathway.This dressing has proven efficacy in recent tests.'''-^

Animai Handling and PreparationWe used 30 female or castrate male Yorkshire crossbred com-mercial swine {Sus scrofä), weighing 43 ± 6 kg. The animalswere fed a commercial diet and observed for 7 days beforeinitiating the study. The animals were fasted 12 hours beforesurgery with unrestricted access to water. On the day of sur-gery, animals were premedicated with tilet;imine/zolazepam4.4 mg/kg IM (Telazol, Fort Dodge Laboratories. Fort Dodge.Iowa) and glycopyrrolate 0.1 mg/kg IM (Baxter HealthcareCoiporation. Deerfield. Illinois). Anesthesia was induced with5% isoflurane in oxygen by nose cone, Endotracheal intuba-tion was followed by 3% isoflurane in oxygen for anestheticmaintenance. Mechanical ventilation was set for tidal vol-

umes of 7-10 mL/kg and a respiratory rate of 10-15 breathsper minute. A rectal temperature probe measured core tem-perature, which was maintained between 36°C and 38°C witha water-filled warming blanket.

Surgical ProcedureA peripheral arterial catheter was surgically placed in the rightsaphenous artery and mean arterial pressure (MAP) was trans-duced continuously. A right neck dissection was performedwith insertion of a second arterial catheter into the carotidartery anda 14-gaugecatheter into the jugular vein. When suf-fering hemorrhagic stress, a swine's spleen may actively con-tract creating an auto-transfusion. To decrease variability fromthis unpredictable phenomenon (as has been done in similarstudies"* '''-'). spleneclomy was performed via a midline lapa-rotomy, and a volume of lactated Ringer's solution equal tothree times the spleen weight was infused. The abdomen wasclosed with perforating towel clamps. A right groin dissec-tion was then conducted with removal of the adductor mus-cle overlying the femoral canal, and the femoral artery andvein were isolated. The first four animals in each group hada temperature probe sutured to the muscle and nerve adjacentto the artery. To simulate a near-transection. we used a 2 x6-mm aortic punch (Scanlan, Saint Paul, Minnesota) to createa standardized injury in both the femoral artery and vein. Weallowed 45 s of free bleeding before application of the studydressing. The dressings were studied in random order, and thesurgeon was blinded to the dressing until after the wound hadbeen created and free bleeding hud occurred.

Animals in the control group hud the AFD applied directlyto the wound and manual pressure sufficient to stop the bleed-ing wus held for 6 min. The hemostatic agents were appliedaccording to the manufacturers' directions and then coveredwith an AFD through which manual pressure was applied.Specifically. HC was cut in half to create a 2 x 4-inch dressingand pressure was held for 2 min. ACS+ (100 g) was applieddirectly to tbe wound and pressure was provided for 3 min.CX (70 g) was applied and manually formed to the woundfollowed by pressure for the remainder of 5 min. WS (150 g)was applied and manually formed to the wound followed bypressurefortberemainder of 3 min. For granular applications.

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Comparison ofHemostatic Agents

molding of the agent generally took 15-30 s. We allowed onlya single application of each dressing.

Pressure was then released for all dressings and the AFDand test agent were left undisturbed. Any blood loss was col-lected into a suction canister. Fifteen minutes after the bleedingcommenced, each animal received 500 mL of 6% hetastarchsolution (Hextend, Hospira, Inc.. Lake Forest. Illinois). Noother fluids were given. The animal was monitored under gen-eral anesthesia for 2 h or until a nonsurvivable blood pres-sure was reached, which we defined as a MAP <20 mmHg for5 min or a MAP <10 mmHg at any time. Upon reaching eitherend point, a lethal dose of pentobarbital veterinary euthana-sia solution (170 mg/kg) was administered intravenously andnonrecovery was ensured with bilateral thoracotomy.

Dafa CollectionBefore injury, we recorded weight, temperature, carotid andsaphenous MAP, heart rate, oxygen saturation, completeblood count, fibrinogen. activated clotting time, and arterialblood gases. Dressings and suction canisters were weighedbefore use and afterward to determine the volume of bloodlost. Pre- and post-treatment blood losses were measured sep-arately. Vital signs (heart rate, carotid and saphenous MAP.and oxygen saturation) were recorded before injury, at thetime of injury, every minute for 30 inin postinjury. and thenevery 5 min until an end point was reached. Wound site tem-

perature was recorded for the first 10 min. Repeat assays offihrinogen, activated clotting time, and complete blood countwere obtained at 30 and 60 min postinjury.

Statistical AnalysisThe primary outcome measures were blood loss standardizedto body weight and survival. For the former, descriptive statis-tics were computed and then compared using analysis of vari-ance with post hoc pairwise tests. Overall survival rates wereevaluated using Pearson's x^ test. Survival curves were gen-erated using a commercial software package (STATA, StataCorp. College Station, Texas) and the equality of the survivorfunctions was tested using log-rank tests.

RESULTSAll 30 animals (6 per group) completed the study with noexclusions. No significant differences existed between groupsfor any preinjury physiologic or hématologie parameter mea-sured (see Table II). Pretreatment blood loss averaged 7.1 mL/kgwith no significant differences between the groups. Postinjurycharacteristics are described in Table III. There were no sig-nificant differences in core temperature, blood counts, fibrino-gen, or activated clotting time at 30 min postinjury betweenthe treatment groups.

Overall survival to 120 min and actual survival time weresignificantly better for all hemostatic agents compared to the

Weight {kg)Preinjury MAP (mmHg)Preinjury Temperature ("C)Preinjury ACT (seconds)Preinjury WBC(xlOVnL)Preinjury Hemalocrit (%)Preinjury Platelets (xlOV^L)Preinjury Fibrinogen (mg/dL)Pretreatment Blood Loss (niL/kg)

TABLE II.

AFD

43.2 ±1.465.0 ± 3.636.6 ± 0.266.7 ± 3.615.8 ±0.526.2 ±1.4272 ± 33267 ± 728.3 ±0,8

Pretreatment Animal Characteristics

ACS+

42.3 ±1.170.5 ± 4.536.9 ± 0.270.5 ± 4.617.0 ±2.726.2 ± 1.3244 ± 16270 ± 676.4 ± 0.9

HC

43.7 ±0.863.2 ±4.636.6 ± 0.273.0 ± 6.215.5 ±0.525.5 ± 1.2239 ± 20280 ± 537.3 ±1.2

CX

43.2 ±1.769.2 ± 3.936.2 ± 0.377.7 ± 3.714.8 ±0.8

26 ±0.8253 ±19233 ± 567.6 ± 0.8

WS

43.5 ±1.760.5 ± 6.036.9 ± 0.369.2 ± 5.617.7 ±2.225.9 ± 0.8262 ± 29400 ±526.0 ± 1.3

ANOVA/; value

0.9670.4440.2550.5740.7050.9900.8680.2800.522

AFD, army field dressing; ACS+, QuikClot advanced clotting sponge +; HC. enhanced HemCon dressing; CX, Celox granules; WS, WouiidStat granules; ACT.activated cloUing time; WBC, white blood cell count.

Temperature ("C) at 10 minMAP (mmHg) at 30 minACT (seconds) al 30 minWBC(xlOVnL)at3OminHematocrit (%) at 30 minPla[elels(xlO-VnL)at3OminFibrinogen (mg/dL) at 30 minSurvival Time (min)Survival to 120 minPosi-Trealment Blood Loss (mL/kg)

TABLE III.

AFD

36.5 ± 0.322.057.0

5.920.7

196200

21.5 ±6.40/6

27.0 ± 2.7

Post-Treatment Animal Characteristics

ACS+

36.8 ±0.154.0 ± 9.052.0 ±1.421.7 ±3.422.5 ±1.4233 ± 24200 ±41

64.5 ± 24.83/6

15.8 ±3.6

HC

36.6 ±0.252.3 ±0.854.8 ± 2.514.1 ±0.723.8 ± 0.8I60±40375 ±14783.2 ± 23.3

4/610.0 ±3.6

CX

36.2 ± 0.349.0 ± 3.163.6 ±6.816.4 ± 1.423.5 ± 0,8228 ± 14440± 149IIO±IO

5/612.9 ±4.9

WS

36.8 ± 0.350.8 ± 4.355.2 ± 2.417.7 ±2.623.7 ± 1.2220 ± 14216±70120 ±0

6/64.6 ±2.3

ANOVA p value

0.4060.1950.5600.1530.8040.3930.6370.0020.0050.002

AFD. army field dressing; ACS+. QuikClnt advanced clotting sponge; HC, enhanced HemCon dressing; CX. Celox granule.s; WS. WoundStat granules; ACT,activated clotting time; WBC, while blood cell count. Data included only for animals surviving to given time point. Single surviving animal in AFD group at30 min precludes confidence inlervals.

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Comparison of Hemostatic Agents

AFD; a survival curve is shown in Figure 1. WS was the onlyagent to achieve 100% survival followed by CX (83%), HC(67%). then ACS-i- (50%). Five of six AFD animals died by18 min with a single pig surviving 53 min. In pairwise com-parisons survival time for the WS group was significantlybetter than for ACS-i- (p = 0.05), but there were no other sig-nificant differences between the other dressings.

Post-treatment blood loss was significantly improved for allhemostatic agents when compared with the AFD. As shown inTable III, WS had the lowest blood loss followed by HC, CX.and then ACS-t-. Tbe WS group had significantly less bloodloss than ACS-i- {p = 0.02), and there were no significant dif-ferences in blood loss between the other groups.

A graph of mean arterial pressure (MAP) over time for allgroups is shown in Figure 2, The control group rebled shortlyafter release of pressure with resultant drop in MAR Otherthan one late rebleed and death in the CX group from 40 to

Percent of pigs surviving to 120 minutes post groin injury

WoundStat

8-

Celox

Hem con

Ouickclot ACS*

Army Field Bandage

p = 0.0072

0 5 1015202530 40 50 60 70 80 90 100 110 120

Survival Time {min)

FIGURE 1. Percentage of pigs surviving to 120 min post groin injury.

P 0 5 1015 20 25 30 40 50 60 70 80 90 100 110 120

Time (minutes)

FIGURE 2. Mean arterial pressure in pigs receiving either army fielddressing I AFD). HemCon (HC), QuikCloI advanced cloUing sponget (ACS),Celüx (CX). or WoundStal (WS).

60 min, tbe MAP curves for tbe bemostatic agents approximateeach other closely from 25 min until the end of observation.

Application site temperatures for AFD, CX, HC. and WSwere all below 99°F. Peak temperatures in ACS-i- applicationsoccurred between 2 and 4 min. Tbe highest recorded tempera-ture for ACS+ of 105.9°F occurred at 4 min and decreased to103.8°F by 10 min. This heat could be felt through tbe overly-ing APT) but was not uncomfortable.

Altbough blood flow distal to the site of injury and hemo-static agent was not directly measured in this study, an arterialcatheter in tbe ipsilateral thigh demonstraled diminished butmeasurable arterial pressures in all groups (data not shown).

DISCUSSIONThis study demonstrates the superiority of newer bemostaticagents compared to the standard field dressing. While tour-niquets are being applied in military field conditions for themajority of exsanguinating extremity trauma, hemostaticagents may play a significant role treating anatomic sites tbatare not amenable to tourniquet usage sucb as tbe groin oraxilla. The model of swine groin injury we used is based uponsimilar studies'"'''^' with some modifications. We simulateda complex groin injur>' with a reproducible near-transectionof tbe femoral artery and vein, causing life-threatening hem-orrhage that would be difficult or impossible to treat with atourniquet. The purpose of the near-transection injury is toprevent vessel retraction, which has contributed to prematurebemostasis in studies employing a complete femoral transec-tion model."'•"''^-- While all animal models are necessarilyartificial, our modifications were intended to more closelyapproximate real-world conditions. Specifically, we did notadminister lidocaine. thus allowing vasospasm to occur aswould be expected in a traumatic injury. This resulted in lesspretreatment blood loss than noted in other studies (7.1 mL/kgcompared with approximately 16-18 mL/kg).'**'"̂

Furthermore, rather than giving large volumes of saline toachieve a particular MAP (over 120 mL/kg administered insome .studies).'^''' we limited fluids to 500 mL of hetastarcbsolution beginning 15 min after injury, which is more con-sistent with a field resuscitation scenario. This resulted in aMAP of approximately 55 mmHg at 60 min in surviving ani-mals, whereas the above-noted studies resuscitated to a goalMAP of 65 mmHg. However, our results demonstrate thatthis model provided a rigorous challenge for tbe bemostaticagents, as evidenced by tbe separation between the variousdressings in terms of overall survival and blood loss. This maybe due to our addition of a venotomy wbere previous incom-plete transection studies used an arteriotomy only."*'"*'̂ ^

The handling characteristics of these agents differ remark-ably. The improved handling of the ACS-i- allowed it to beremoved completely and far more easily than the otheragents. Additionally, the beat generated was much less thantbe original QuikClot granules. The enhanced HemConbandage was tbinner and more pliable and formed a tight sealto the injury that is difficult to remove. In several cases it tore

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Comparison of Hemostatic Agents

during removal, but we were always able to completely removethe dressing. Celox produced a sticky granular gelatinous sub-stance that was difficult to remove completely given the widespread of the granules throughout the wound. WoundStatswelled slightly and developed a red clay-like texture that waseasily molded to the wound. It was more difficult to removethan Celox, and both of these substances would require copi-ous irrigation for complete removal. Overall, none of thesedressings should be considered definitive care, and all wouldrequire removal for operative exploration and repair.

Based on blood loss and survival data, all tested agents aresuperior to a standard gauze dressing. In addition, WoundStatwas superior lo the QuikClot ACS+ dressing with a trend towardsuperiority when compared to the other dressings; however, thisstudy was not sufficiently powered to determine this statistically.

We made no evaluation of the toxicity of these dressings.A recent study at the Army Institute of Surgical Research hasshown a moderate inflammatory reaction associated with Celoxand tissue damage associated with WoundStat. while ACS-t-and HemCon cause minimal histologie changes.-^ Furthermore,despite some differences in the model utilized, their findingswith regard to efficacy are consistent with, and reinforce, thetrends and findings in our study. Further work is needed todetermine the long-term effects, if any, of retained agent andwhether granular emboiization may cause adverse events.

ACKNOWLEDGMENTSThe animals involved in this study were procured, maintained, and used inaccordance with the Laboratory Animal Welfare Act of 1966, as amended.and National Institutes of Health 80-23. Guide for the Care and Use ofLaboratory Animals, National Research Council. The work reported hereinwas perfbrmctl under United Slates Air Force Surgeon General-approvedClinical Investigation No. FDG2OOíí(XH)2A.

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