The Research Review
by Kenny Navarro
04/16/2015

When to use hemostatic agents in EMS


Hemorrhage is responsible for about 40 percent of the deaths following traumatic injury, with 33 to 56 percent of those deaths occurring during the prehospital period (Kauvar, Lefering, & Wade, 2006). Early trauma care stresses the importance of minimizing blood loss in the prehospital environment. There is no debate about the importance of hemorrhage control as a first step in reducing death following traumatic injury.

Hemostatic agents and EMS
Increasingly, EMS systems across the country are adding topical hemostatic agents to their prehospital treatment of hemorrhage (Kerby & Cusick, 2012). Topical hemostatic agents are available as powders, granules or dressings composed of traditional gauze or dressings impregnated with the active agent. The ideal agent (Granville-Chapman, Jacobs, & Midwinter, 2011) should be:

  • Able to stop hemorrhage from large arteries and veins within two minutes of application
  • Capable of effective application through pools of blood, packaged as a ready to use agent
  • Simple to use even by non-medically trained responders
  • Lightweight and durable
  • Capable of extended storage under a wide range of temperatures
  • Inexpensive
  • Free from bacterial or viral risk

To date, no topical hemostatic agent meets all these criteria. However, there are a number of agents available on the market. Physicians categorize these agents into one of three groups based on the mechanism of action: mucoadhesive agents, factor concentrators, or procoagulant supplements (Granville-Chapman, Jacobs, & Midwinter, 2011).

Mucoadhesive agents: Using salt to promote clotting
Mucoadhesive agents react with blood to create a seal over the wound, which arrests continuing blood flow. Both HemCon® and Celox™ utilize a granular chitosan salt derived from the shells of marine arthropods (Granville-Chapman, Jacobs, & Midwinter, 2011). These salts, which are positively charged, react with and bind to negatively charged red blood cells rapidly forming a cross-linked barrier clot which seals the injured vessel (Burkatovskaya et al., 2006; Kozen, Kircher, Henao, Godinez, & Johnson, 2008).

Researchers found HemCon® to be clinically superior to standard gauze in a low-pressure, high-flow model of venous bleeding (Pusateri et al., 2003), although this type of injury might not represent the injury patterns encountered in the prehospital environment (Lawton, Granville-Chapman, & Parker, 2009). In a high-pressure model of uncontrolled arterial hemorrhage, HemCon® was initially effective at controlling but could not sustain hemostasis (Kheirabadi, Acheson, Sondeen, Ryan, & Holcomb, 2004).

Despite this failure, a retrospective review of 34 cases of hemorrhage treated with HemCon® by Portland, Ore. firefighters revealed bleeding control in 79 percent of the cases (Brown, Daya, & Worley, 2009). On the other hand, in a side by side comparison of commonly used topical hemostatic agents in a swine model of uncontrolled hemorrhage, Celox™ was the only agent that improved short term survival (Kozen, Kircher, Henao, Godinez, & Johnson, 2008).

Factor concentrators: Super dehydrator
Factor concentrators, such as QuikClot® rapidly absorb water from the blood at the injury site, which concentrates platelets and other intrinsic clotting factors resulting in faster clot formation. The active ingredient in QuikClot® is zeolite, an inert volcanic mineral that rapidly absorbs water in an exothermic (heat-producing) reaction.

In addition to its water absorbing properties, an in vitro examination revealed zeolite also rapidly increases calcium ion concentration of blood, which promotes rapid clot formation (Li et al., 2013). In the first generation of QuikClot®, healthcare providers poured the zeolite granules directly into the wound. However, physicians soon found the exothermic reaction was significant enough to cause burns and tissue necrosis (McManus, Hurtado, Pusateri, & Knoop, 2007; Rhee, et al., 2008; Wright et al., 2004). As a result, the granular form of QuikClot® is no longer available.

The second generation of QuikClot® replaced the granules with larger zeolite beads and packed them into a small mesh bag (QuikClot® ACS+™) that was inserted into the bleeding wound. The bag facilitates removal of the product during surgery. Changes in the second generation of the product reduced the temperatures created by the reaction and produced a safer topical agent (Ahuja et al., 2006).

One factor concentrator that does not produce an exothermic reaction is WoundStat™, which is a biodegradable powder composed of smectite clay mineral and a cross-linked poly-acrylic acid (Lawton, Granville-Chapman, & Parker, 2009). Smectite particles have a negative charge which activates coagulation pathways and promotes clotting (Kheirabadi et al., 2010).

Although early animal studies demonstrated the effectiveness of WoundStat™ in controlling hemorrhage and improving survival (Clay, Grayson, & Zierold, 2010; Kheirabadi et al., 2009; Ward et al., 2007), a subsequent study demonstrated the active particles in WoundStat™ damaged blood vessel linings, caused occlusive thrombus in injured vessels and migrated to the pulmonary vasculature (Kheirabadi et al., 2010). As a result, this product was removed from the market (Kerby & Cusick, 2012).

Other factor concentrators, such as TraumaDex™, use microporous polysaccharide hemospheres derived from potato starch. When compared to QuikClot® in a swine groin wound model, this product proved less effective and in fact, was no better than standard gauze dressings (Alam et al., 2003).

Procoagulant supplements: Faster clotting
Procoagulant supplements deliver additional clotting factors to the wound which then combine with clotting factors already present. Together, these clotting factors increase the rate of blood clot formation. Some of the products deliver human clotting factors while others deliver factors derived from bovine blood (Granville-Chapman, Jacobs, & Midwinter, 2011).

The only procoagulant supplement approved by the Food and Drug Administration is Combat Gauze™ (Littlejohn, Bennett, & Drew, 2015). This product is actually the third generation of QuikClot® products in which the manufacturer replaced the zeolite with kaolin, a clay containing the active ingredient aluminum silicate. Combat Gauze™ uses gauze dressings impregnated with kaolin. An animal model determined Combat Gauze™ to be as effective as the second generation QuikClot® at controlling hemorrhage without producing excessive heat (Baker, Sawvel, Zheng, & Stucky, 2007).

Researchers conducting an evidence-based review in an attempt to determine if Combat Gauze™ was safe for controlling hemorrhage in the prehospital setting determined that although not conclusive, the results in support of the product were promising (Gegel, Austin, & Johnson, 2013).

A side-by side comparison of four hemostatic dressings in an animal model of arterial hemorrhage demonstrated survival superiority associated with the use of Combat Gauze™ (Kheirabadi, Scherer, Estep, Dubick, & Holcomb, 2009).  In this study, researchers planned to test each of the products in 10 animals.  However, two of the chitosan-based products (HemCon® and Celox™-D) failed to achieve hemostasis in the first six tests and all of the animals died.  As a result, the researchers did not test those products in the final four animals.

In a similar study, researchers found rebleeding after initial hemostasis in 33% of the animals treated with Celox™ gauze compared to no rebleeding seen in animals treated with Combat Gauze™(Rall et al., 2012).

In an animal model of uncontrolled hemorrhage, researchers tested whether Combat Gauze™ produced a more stable clot compared to standard wound packing practices (Gegel et al., 2012).  After achieving hemostasis, the researchers moved the animals affected leg to simulate movement that might occur during evacuation and transportation to more definitive care.  The number of movements required to produce rebleeding after using Combat Gauze™ was significantly higher compared to standard wound packing therapy.

Clinicians have even reported success in using Combat Gauze™ to control bleeding related to percutaneous catheter insertion sites for patients undergoing extracorporeal membrane oxygenation (ECMO) support (Lamb, Pitcher, Cavarocchi, & Hirose, 2012). Use of safe and effective hemostatic dressings for patients undergoing ECMO has the potential to reduce the need for blood transfusions, surgical exploration, overall healthcare costs, and promote faster patient recovery.

Tactical Combat Casualty Care guidelines developed by the United States Special Operations Command recommend Combat Gauze™  as the hemostatic dressing of choice (Bennett et al., 2014).  However, the guidelines allow for alternative use of Celox™ gauze and ChitoGauze® in the event Combat Gauze™ is not available.

Hemostatic agents: Current recommendation
A panel of experts in prehospital trauma care convened by the American College of Surgeons recently recommended the prehospital use of topical hemostatic agents in conjunction with direct pressure for controlling hemorrhage in injuries where direct pressure alone is ineffective or not practical and in cases where tourniquet application is not possible due to anatomic limitations (Bulger et al., 2014). Although not endorsing the use of a specific product, the panel recommended that EMS systems choose a product with demonstrated efficacy that is available in gauze format, which permits wound packing.

References

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Alam, H. B., Uy, G. B., Miller, D., Koustova, E. Hancock, T., Inocencio, R., Anderson, D., Llorente, O., & Rhee, P. (2003). Comparative analysis of hemostatic agents in a swine model of lethal groin injury. Journal of Trauma-Injury Infection & Critical Care, 54(6), 1077-1082. doi:10.1097/01.TA.0000068258.99048.70

Baker, S. E., Sawvel, A. M., Zheng, N., & Stucky, G. D. (2007). Controlling bioprocesses with inorganic surface: Layered clay hemostatic agents. Chemistry of Materials, 19(18), 4390-4392. doi:10.1021/cm071457b

Bennett, B. L., Littlejohn, L. F., Kheirabadi, B. S., Butler, F. K., Kotwal, R. S., Dubick, M. A., & Bailey, J. A. (2014). Management of external hemorrhage in tactical combat casualty care: Chitosan-based hemostatic gauze dressings - TCCC Guidelines-Change 13-05. Journal of Special Operations Medicine, 14(3), 40-57.

Brown, M. A., Daya, M. R., & Worley, J. A. (2009). Experience with chitosan dressings in a civilian EMS system. Journal of Emergency Medicine, 37(1), 1-7. doi:10.1016/j.jemermed.2007.05.043

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Burkatovskaya, M., Tegos, G. P., Swietlik, E., Demidova, T. N., P Castano, A., & Hamblin, M. R. (2006). Use of chitosan bandage to prevent fatal infections developing from highly contaminated wounds in mice. Biomaterials, 27(22), 4157–4164. doi:10.1016/j.biomaterials.2006.03.028

Clay, J. G., Grayson, J. K., & Zierold, D. (2010). Comparative testing of new hemostatic agents in a swine model of extremity arterial and venous hemorrhage. Military Medicine, 175(4), 280–284.

Gegel, B. T., Austin, P. N., & Johnson, A. D. (2013). An evidence-based review of the use of a combat gauze (QuikClot) for hemorrhage control. AANA Journal, 81(6), 453-458.

Gegel, B., Burgert, J., Gasko, J., Campbell, C., Martens, M., Keck, J., Reynolds, H., Loughren, M., & Johnson, D. (2012). The effects of QuikClot Combat Gauze and movement on hemorrhage control in a porcine model. Military Medicine, 177(12), 1543-1547.

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Kerby, J. D., & Cusick, M. V. (2012). Prehospital emergency trauma care and management. Surgical Clinics of North America, 92(4), 823–841 doi:10.1016/j.suc.2012.04.009

Kheirabadi, B. S., Acheson, E. M., Sondeen, J. L., Ryan, K. L., & Holcomb, J. B. (2004). Hemostatic effect of two advanced dressings in an aortic hemorrhage model in swine [abstract]. Journal of Trauma-Injury Infection & Critical Care, 57(2), 439.

Kheirabadi, B. S., Scherer, M. R., Estep, J. S., Dubick, M. A, & Holcomb, J. B. (2009). Determination of efficacy of new hemostatic dressings in a model of extremity arterial hemorrhage in swine. Journal of Trauma-Injury Infection & Critical Care, 67(3), 450-459. doi:10.1097/TA.0b013e3181ac0c99

Kheirabadi, B. S., Edens, J. W., Terrazas, I. B., Estep, J. S., Klemcke, H. G., Dubick, M. A., & Holcomb, J. B. (2009). Comparison of new hemostatic granules/powders with currently deployed hemostatic products in a lethal model of extremity arterial hemorrhage in swine. Journal of Trauma-Injury Infection & Critical Care, 66(2), 316-328. doi:10.1097/TA.0b013e31819634a1

Kheirabadi, B. S., Mace, J. E., Terrazas, I. B., Fedyk, C. G., Estep, J. S., Dubick, M. A., & Blackbourne, L. H. (2010). Safety evaluation of new hemostatic agents, smectite granules, and kaolin-coated gauze in a vascular injury wound model in swine. Journal of Trauma-Injury Infection & Critical Care, 68(2), 269–278. doi:10.1097/TA.0b013e3181c97ef1

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Lawton, G., Granville-Chapman, J., & Parker, P. (2009). Novel haemostatic dressings. Journal of the Royal Army Medical Corps, 155(4), 309-314 doi:10.1136/jramc-155-04-13

Li, J., Cao, W., Lv, X. X., Jiang, L., Li, Y. J., Li, W. Z., Chen, S. Z., & Li, X. Y. (2013). Zeolite-based hemostat QuikClot releases calcium into blood and promotes blood coagulation in vitro. Acta Pharmacologica Sinica, 34(3), 367-372. doi:10.1038/aps.2012.159

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McManus, J., Hurtado, T., Pusateri, A., & Knoop, K. J. (2007). A case series describing thermal injury resulting from zeolite use for hemorrhage control in combat operations. Prehospital Emergency Care, 11(1), 67–71. doi:10.1080/10903120601021176

Pusateri, A. E., McCarthy, S. J., Gregory, K. W., Harris, R. A., Cardenas, L., McManus, A. T., & Goodwin, C. W. Jr. (2003). Effect of a Chitosan-based hemostatic dressing on blood loss and survival in a model of severe venous hemorrhage and hepatic injury in swine. Journal of Trauma, 54(1), 177-182.

Rall, J. M., Cox, J. M., Songer, A. G., Comeaux, J. A., Estep, S., Cestero, R. F., & Ross, J. D. (2012).  Comparison of novel hemostatic gauzes to Quickclot Combat Gauze in a standardized swine model of uncontrolled hemorrhage (Technical Report No. TR-2012-22). San Antonio, TX: Naval Medical Research Unit

Rhee, P., Brown, C., Martin, M., Salim, A., Plurad, D., Green, D., Chambers, L., Demetriades, D., Velmahos, G., & Alam, H. (2008). QuikClot use in trauma for hemorrhage control: Case series of 103 documented uses. Journal of Trauma-Injury Infection and Critical Care, 64(4), 1093–1099. doi:10.1097/TA.0b013e31812f6dbc

Ward, K. R., Tiba, H., Holbert, W. H., Blocher, C. R., Draucker, G. T., Proffitt, E. K., Bowlin, G. L., Ivatury, R. R., & Diegelmann, R. F. (2007). Comparison of a new hemostatic agent to current combat hemostatic agents in a swine model of lethal extremity arterial hemorrhage. Journal of Trauma-Injury Infection & Critical Care, 2007; 63(2), 276-284. doi:10.1097/TA.0b013e3180eea8a5

Wright, J. K., Kalns, J., Wolf, E. A., Traweek, F., Schwarz, S., Loeffler, C. K., Snyder, W., Yantis, L. D. Jr., & Eggers, J. (2004). Thermal injury resulting from application of a granular mineral hemostatic agent. Journal of Trauma-Injury Infection and Critical Care, 57(2), 224–230. doi:10.1097/01.TA.0000105916.30158.06

Kenny Navarro is an Assistant Professor in the Department of Emergency Medicine at the University of Texas Southwestern Medical School at Dallas. He also serves as the AHA Training Center Coordinator for Tarrant County College. Mr. Navarro serves as an Emergency Cardiovascular Care Content Consultant for the American Heart Association, served on two education subcommittees for NIH-funded research projects, as the Coordinator for the National EMS Education Standards Project, and as an expert writer for the National EMS Education Standards Implementation Team. Send correspondence concerning any articles in this section to Kenneth W. Navarro, The University of Texas Southwestern Medical School at Dallas, 5323 Harry Hines Blvd MC 8890, Dallas, Texas 75390-8890, or e-mail kenny.navarro@ems1.com.

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