Skip to main content
  • Review
  • Published:

Methods for improved hemorrhage control

Abstract

Trauma is the leading cause of death from age 1 to 34 years and is the fifth leading cause of death overall in the USA, with uncontrolled hemorrhage being the leading cause of potentially preventable death. Improving our ability to control hemorrhage may represent the next major hurdle in reducing trauma mortality. New techniques, devices, and drugs for hemorrhage control are being developed and applied across the continuum of trauma care: prehospital, emergency room, and operative and postoperative critical care. This brief review focuses on drugs directed at life-threatening hemorrhage. The most important of these new drugs are injectable hemostatics, fibrin foams, and dressings. The available animal studies are encouraging and human studies are required.

Introduction

Trauma is the leading cause of death from age 1 to 34 years and is the fifth leading cause of death overall in the USA [1]. However, because injury is primarily a disease of young people, trauma is the leading cause of years of potential life lost and cost to society. Traumatic injuries killed 147 891 people in the USA in 1995, with uncontrolled hemorrhage being the leading cause of potentially preventable death [1].

Not all trauma victims who are bleeding can be saved with improved care. Many bleed to death before care reaches them. Unfortunately, some bleed to death during transport to appropriate care. Improving our ability to control hemorrhage in individuals with injuries that are otherwise survivable may represent the next major hurdle in reducing trauma mortality. New techniques, devices, and drugs for hemorrhage control are being developed and applied across the continuum of trauma care: prehospital, emergency room, and operative and postoperative critical care. To decrease the mortality from hemorrhage, modern methods of hemostasis should be applied not only in the operating room but also throughout the trauma care system. This brief review focuses on drugs directed at life-threatening hemorrhage rather than the more common 'bothersome' bleeding encountered routinely in ambulances, emergency departments (EDs), and operating rooms. To be truly efficacious in the acute trauma situation, these drugs must be simple to store and use, and must be rapidly effective. The most important of these new drugs are injectable hemostatics, fibrin foams, and dressings. The complementary hemorrhage control strategies of hypotensive resuscitation, damage control techniques, and angiographic embolization are beyond the scope of this limited review.

Prehospital care

Conventional prehospital care for hemorrhagic injury consists of maintenance of the airway and ventilation; control of accessible hemorrhage with bandages, direct pressure, and occasionally tourniquets; and treatment of shock with intravenous fluids. Despite this care, approximately 30–40% of civilian and fully 90% of military casualties who die will do so before they reach the hospital [2, 3]. Unfortunately, the materials and methods available to stop bleeding in the prehospital care setting (gauze dressings, direct pressure, and tourniquets) have not changed greatly in 2000 years [4]. Are there strategies, techniques, drugs, or devices that can be used to improve the outcome in this and similar situations? The answer appears to be 'yes' on all counts. The drugs for improved hemorrhage control described here can be effectively utilized in the prehospital arena.

Emergency room care

In the urban environment, rapid transport of seriously injured patients routinely results in delivery of critically ill individuals to the ED. In some locations, the development of very rapid transport systems has only changed the location of death from the street to the ED. Upon arrival, patients must be kept alive while they undergo diagnostic assessment, resuscitation, and preparation for surgery. The critical therapeutic decision required while managing acutely hemorrhaging patients in the ED is which patients are stable enough to undergo further evaluation and which patients need to go immediately to the operating room to stop the bleeding. Hemodynamically stable patients may undergo deliberate evaluation and intervention. For patients with severe injuries or profound shock, the decision to intervene rapidly often leads to the strategies and procedures of 'damage control' surgery.

Under the old Advanced Trauma Life Support guidelines [5], patients arriving in the ED who were hemorrhaging or in shock immediately received fluids through two large-bore intravenous lines. Fluids were followed by packed red cells if patients did not improve promptly. A negative relationship exists, however, between the number of units of blood administered and patient outcome [6, 7]. Even the ubiquitous crystalloid solutions appear to make activated white cells more adherent and potentiate their effects in multiple organ failure [8]. Most clinicians now recognize that attempting to raise blood pressure to normal before definitive hemostasis only serves to increase bleeding. For all of these reasons, the new Advanced Trauma Life Support guidelines [9] are less emphatic about the need for blood and fluids and stress early definitive hemorrhage control as a priority.

Operating room care

When discussing hemorrhage control, it is useful to analyze the modern treatment of severe liver injury because it is the most commonly injured solid abdominal organ. All measures initially utilized to treat liver injuries are directed at hemorrhage control. Although specialized injuries such as pelvic fractures are treated differently, many of the principles of hemorrhage control apply to other injuries.

Liver injuries are graded from I to VI based on the wound depth and the location of the involved injured vessels [10]. Low-grade injuries involving minor capsular lacerations usually resolve spontaneously. Deep lacerations involving major vessels may not stop bleeding spontaneously and often require operative intervention. Thus, a stable patient whose computed tomography (CT) scan reveals a laceration of grade IV or less with no evidence of 'pooling' of intravenous contrast material can usually be managed with observation alone [11]. On the other hand, grade V injuries involving major lobar vessels can be fatal if not surgically treated. Many patients do not fall neatly into one of these categories and must be treated based on their evolving hemodynamic status. Thus, for the hemodynamically 'stable' patient, the invasive radiologist can utilize a large number of new devices and procedures. For the truly unstable patient, immediate operative intervention is required.

For the hypotensive and unstable liver injury patient, the overriding goal is rapid control of hemorrhage. The operative procedure of choice is rapid gauze packing. Under the best of circumstances, the procedure is effective and results in 40% mortality [12]; however, it is associated with complications such as infection, biliary and enteric fistula formation, and the need to reoperate to remove the gauze packing within 24–72 hours. This latter requirement can itself become a vicious cycle of rebleeding during unpacking, requiring repacking and reoperation.

Such procedures currently represent the limit of modern trauma surgery. These maneuvers may soon be augmented or replaced by one or, more likely, a combination of the hemostatic drugs, foams, and dressings currently being developed and evaluated.

Drugs

Pharmacologic manipulation of the coagulation cascade has been all but ignored in the previously normal surgical patient. In a variety of elective surgical situations, clot-stabilizing drugs reduce blood loss. Reduced transfusion requirements with the use of aprotinin have been documented in cardiac surgery, hepatic resection, hepatic transplantation, lung transplantation, and orthopedic surgery [13–16]. Similar results using tranexamic acid have been documented in cardiac surgery, liver transplantation, and orthopedic surgery [13]. ε-Aminocaproic acid has been effective in cardiac surgery [17]. None of these drugs were found to have increased complications after use but they have exhibited various levels of effectiveness. Inhibiting the fibrinolytic pathway or, alternatively, enhancing the speed and/or strength of the endogenous clots of hemorrhaging patients may decrease transfusion and improve survival.

Perhaps most intriguing is the use of recombinant factor VIIa (rFVIIa) as an intravenous adjunct for hemorrhage control [18, 19]. While approved by the US Food and Drug Administration for use in hemophiliacs, this drug has recently been utilized in nonhemophiliac patients undergoing liver transplantation, gastrointestinal bleeding, and severe trauma [20]. Originally, rFVIIa was isolated and later cloned to treat hemophilia patients with inhibitors to factors VIII and IX during critical bleeding episodes or major surgery. Freiderich and coworkers [21] recently reported their positive experience in the first prospective, randomized, double-blind, placebo-controlled trial of the use of rFVIIa in radical prostate surgery patients. A placebo treatment was compared with two doses (20 and 40 μg/kg) of rFVIIa. Blood loss was decreased in the rFVIIa groups (P < 0.01), and transfusions were eliminated in the higher dose group. Operative time decreased in the rFVIIa group (120 min versus 180 min; P < 0.05). No deleterious safety issues were identified, and in this group of older males those receiving rFVIIa did not develop the complications associated with hypercoagulopathy. It has been used in previously normal patients to stop bleeding by reversing the acquired dilutional and hypothermic induced coagulopathies [22]. Furthermore, rFVIIa has been used to reverse warfarin anticoagulation rapidly in healthy volunteers and to correct prothrombin times in cirrhotic patients [23].

When bound to exposed tissue factor (TF), normally expressed factor VIIa activates the extrinsic clotting system at the site of injury without causing systemic hypercoagulability [18]. rFVIIa is an attractive therapeutic candidate for coagulopathy because it bypasses much of the intrinsic coagulation system, is only active in the presence of exposed TF, and has a rapid onset and a short half-life [18]. TF is not normally expressed in the intact vascular space but exists in high concentrations in the media and is exposed upon vessel injury. TF can be expressed on the surface of activated monocytes after sepsis, but the significance of this is unclear because activated TF activity (the biologically functional form of the molecule) has not been measured [24]. An alternative hypothesis is that rFVIIa acts by binding to activated platelets and activating factor Xa on the platelet surface, independent of the usual TF cofactor [22]. In addition to the perceived beneficial effects of an intravenous procoagulant, there has not been a significant number of reported complications related to intravascular coagulation.

A large animal model of grade V liver injury combined with hypothermia and hemodilution was recently utilized to demonstrate the effectiveness of rFVIIa when used as an adjunct to gauze packing. In this realistic injury model, blood loss was decreased by 46% in the rFVIIa group as compared with the saline control group [25]. Schreiber and coworkers [26] described no effect of the drug when used in isolation for grade V liver injury. Conversely, Jeroukhimov and coworkers [27] documented that very large doses (720 μg/kg) decreased blood loss and improved mortality when used as sole therapy in a pig model of grade IV liver injury.

Martinowitz and colleagues [28, 29] presented a series of case reports highlighting the usefulness of rFVIIa in massively transfused trauma patients. Based on these and other case reports, a prospective and appropriately controlled human damage control trauma study has been presented to the US Food and Drug Administration. A similar multinational trauma trial is nearing completion outside the USA. The drug not only appears to enhance the strength of the natural clot but it also appears to be rapidly effective despite the presence of a hypothermic and dilutional coagulopathy [30]. A prospective appropriately controlled study is sorely needed in the USA, and would allow clinicians the opportunity to determine the usefulness of this drug based on data rather than on the currently available series of anecdotal case reports.

Fibrin sealants formulated as a self-expanding foam (fibrin-fix-a-flat) have been designed to fill a cavity and reduce blood loss by binding to damaged surfaces. Successful application of this concept was recently demonstrated in a rat liver trauma model [31]. After spraying the fibrin foam directly onto the cut liver surface, the foam contributed to the speed and strength of the natural surface clot. Questions to be resolved with this technique include amount of foam required and effect of combining increased intra-abdominal pressure with systemic hypotension. This technique may be more applicable in the prehospital and ED arena, where methods of intra-cavitary hemorrhage control must be developed. Safe deployment of this and other 'radical' concepts are required because 99% of life-threatening hemorrhages occur in body cavities outside the 'reach' of nonsurgical personnel.

The US Army Institute of Surgical Research demonstrated that hemorrhage from grade V liver injuries in a realistic animal model can be consistently and immediately stopped with new hemostatic dressings [32–36]. These dressings are an example of a procoagulant medical device that is applicable in the prehospital and hospital settings. Designed to be used like the typical gauze dressing, the new hemostatic and absorbable bandages achieve hemorrhage control after manual compression and can be left in place, which eliminates the need for reoperation solely for gauze pack removal. When the device is pressed into a wound, blood dissolves the proteins and leads to immediate activation and rapid clot formation. Resuscitation may then proceed without fear of rebleeding. Similar benefits may be possible in other problematic clinical situations, such as open fractures of the pelvic ring and injuries in the mediastinum or thoracic outlet. Animal studies utilizing these bandages demonstrate that they can rapidly and safely control massive bleeding from large arterial injuries or extensive soft tissue injuries when the bandage is applied with a minute or two of direct pressure. Human trauma studies evaluating the efficacy of these dressings are required.

Despite all of the technology currently available in our modern hospitals and Emergency Medical Service systems to treat trauma patients, hemorrhage control is still a major problem in emergency medical care. As many as 51% of all deaths in the first 48 hours of hospitalization are related to lack of hemostasis [2]. Failure to stop bleeding within the first 24 hours is almost uniformly fatal. Unfortunately, the methods we currently utilize to stop otherwise fatal hemorrhage are hundreds of years old. Multiple research avenues exist to improve our care.

Conclusion

The best way to prevent hemorrhagic death is to prevent injury. Once injury has occurred, however, we are convinced that the best way to break the feedback loop – the 'bloody vicious cycle' of bleeding and resuscitation, resulting in coagulopathy, acidosis and hypothermia, leading to more bleeding – is to stop bleeding early. This will best be accomplished by focusing research activity on developing innovative new concepts and technologies that allow control of hemorrhage in the earliest phases of care.

If possible, hemostatic maneuvers should be initiated in the prehospital phase of care, extending active measures of hemorrhage control outside the operating room to the point of injury. Providing time-sensitive interventions outside the hospital has proven life-saving for cardiac patients, whereas treatment of stroke victims has moved from the intensive care unit to the ED. The hemorrhaging trauma patient deserves the same aggressive approach. We expect that wide implementation of advances such as integrated trauma management, hypotensive resuscitation, damage control surgery, pharmacologic modulation of the clotting cascade, fibrin foams, and hemostatic dressings will have positive effects on patient outcome.

Abbreviations

ED:

emergency department

rFVIIa:

recombinant factor VIIa

TF:

tissue factor.

References

  1. Committee on Injury Prevention and Control: magnitude and costs: In: Reducing the Burden of Injury: Advancing Prevention and Treatment. Edited by: Bonnie RJ, Fulco CE, Liverman CT. 1999, National Academy Press: Washington, 41-59.

    Google Scholar 

  2. Sauaia A, Moore FA, Moore EE, Moser KS, Brennan R, Read RA, Pons PT: Epidemiology of trauma deaths: a reassessment. J Trauma. 1995, 38: 185-193.

    Article  CAS  PubMed  Google Scholar 

  3. Bellamy RF: The causes of death in conventional land warfare: implications for combat casualty care research. Mil Med. 1984, 149: 55-62.

    CAS  PubMed  Google Scholar 

  4. Zimmerman LM, Veith I: Great Ideas in the History of Surgery. 1961, Baltimore: The Williams and Wilkins Company

    Google Scholar 

  5. American College of Surgeons. Committee on Trauma: Advanced Trauma Life Support Program for Doctors: ATLS. 1985, Chicago, IL: American College of Surgeons

    Google Scholar 

  6. Armand R, Hess JR: Treating coagulopathy in trauma patients. Transfus Med Rev. 2003, 17: 223-231. 10.1016/S0887-7963(03)00022-1.

    Article  PubMed  Google Scholar 

  7. Hess JR, Thomas MJ: Blood use in war and disaster: lessons from the past century. Transfusion. 2003, 43: 1622-1633. 10.1046/j.1537-2995.2003.00576.x.

    Article  CAS  PubMed  Google Scholar 

  8. Koustova E, Stanton K, Gushchin V, Alam HB, Stegalkina S, Rhee PM: Effects of lactated Ringer's solutions on human leukocytes. J Trauma. 2002, 52: 872-878.

    Article  CAS  PubMed  Google Scholar 

  9. American College of Surgeons. Committee on Trauma: Advanced Trauma Life Support Program for Doctors: ATLS. 1997, Chicago, IL: American College of Surgeons, 6

    Google Scholar 

  10. Pachter HL, Spencer FC, Hofstetter SR, Liang HG, Coppa GF: Significant trends in the treatment of hepatic trauma. Experience with 411 injuries. Ann Surg. 1992, 215: 492-500. discussion 500–502

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Pachter HL, Knudson MM, Esrig B, Ross S, Hoyt D, Cogbill T, Sherman H, Scalea T, Harrison P, Shackford S, et al: Status of non-operative management of blunt hepatic injuries in 1995: a multi-center experience with 404 patients. J Trauma. 1996, 40: 31-38.

    Article  CAS  PubMed  Google Scholar 

  12. Fabian TC, Croce MA, Stanford GG, Payne LW, Mangiante EC, Voeller GR, Kudsk KA: Factors affecting morbidity following hepatic trauma. A prospective analysis of 482 injuries. Ann Surg. 1991, 213: 540-547. discussion 548

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Porte RJ, Leebeek FW: Pharmacological strategies to decrease transfusion requirements in patients undergoing surgery. Drugs. 2002, 62: 2193-2211.

    Article  CAS  PubMed  Google Scholar 

  14. Landis RC, Asimakopoulos G, Poullis M, Haskard DO, Taylor KM: The antithrombotic and antiinflammatory mechanisms of action of aprotinin. Ann Thorac Surg. 2001, 72: 2169-2175. 10.1016/S0003-4975(01)02821-1.

    Article  CAS  PubMed  Google Scholar 

  15. Findlay JY, Kufner RP: Aprotinin reduces vasoactive medication use during adult liver transplantation. J Clin Anesth. 2003, 15: 19-23. 10.1016/S0952-8180(02)00475-0.

    Article  CAS  PubMed  Google Scholar 

  16. Capdevila X, Calvet Y, Biboulet P, Biron C, Rubenovitch J, d'Athis F: Aprotinin decreases blood loss and homologous transfusions in patients undergoing major orthopedic surgery. Anesthesiology. 1998, 88: 50-57. 10.1097/00000542-199801000-00010.

    Article  CAS  PubMed  Google Scholar 

  17. Chen RH, Frazier OH, Cooley DA: Antifibrinolytic therapy in cardiac surgery. Tex Heart Inst J. 1995, 22: 211-215.

    PubMed Central  CAS  PubMed  Google Scholar 

  18. Hedner U: NovoSeven® as a universal haemostatic agent. Blood Coagul Fibrinolysis. 2000, Suppl 1: S107-S111.

    Article  Google Scholar 

  19. Lynn M, Jeroukhimov I, Klein Y, Martinowitz U: Updates in the management of severe coagulopathy in trauma patients. Intensive Care Med. 2002, Suppl 2: S241-S247. 10.1007/s00134-002-1471-7.

    Article  Google Scholar 

  20. Dejgaard A: Update on Novo Nordisk's clinical trial programme on NovoSeven. Blood Coagul Fibrinolysis. 2003, Suppl 1: S39-S41. 10.1097/00001721-200306001-00010.

    Article  Google Scholar 

  21. Friederich PW, Henny CP, Messelink EJ, Geerdink MG, Keller T, Kurth KH, Buller HR, Levi M: Effect of recombinant activated factor VII on perioperative blood loss in patients undergoing retropubic prostatectomy: a double-blind placebo-controlled randomised trial. Lancet. 2003, 361: 201-205. 10.1016/S0140-6736(03)12268-4.

    Article  CAS  PubMed  Google Scholar 

  22. Meng ZH, Wolberg AS, Monroe DM, Hoffman M: The effect of temperature and pH on the activity of FVIIa: implications for the efficacy of high-dose FVIIa in hypothermic and acidotic patients. J Trauma. 2003, 50: 721-729.

    Google Scholar 

  23. Deveras RA, Kessler CM: Reversal of warfarin-induced excessive anticoagulation with recombinant human factor VIIa concentrate. Ann Intern Med. 2002, 137: 884-888.

    Article  CAS  PubMed  Google Scholar 

  24. Rapaport SI, Rao LV: The tissue factor pathway: how it has become a 'prima ballerina'. Thromb Haemost. 1995, 74: 7-17.

    CAS  PubMed  Google Scholar 

  25. Martinowitz U, Holcomb JB, Pusateri AE, Stein M, Onaca N, Freidman M, Macaitis JM, Castel D, Hedner U, Hess JR: Intravenous rFVIIa administered for hemorrhage control in hypothermic coagulopathic swine with grade V liver injuries. J Trauma. 2001, 50: 721-729.

    Article  CAS  PubMed  Google Scholar 

  26. Schreiber MA, Holcomb JB, Hedner U, Brundage SI, Macaitis JM, Aoki N, Meng ZH, Tweardy DJ, Hoots K: The effect of recombinant factor VIIa on noncoagulopathic pigs with grade V liver injuries. J Am Coll Surg. 2003, 196: 691-697. 10.1016/S1072-7515(02)01835-5.

    Article  PubMed  Google Scholar 

  27. Jeroukhimov I, Jewelewicz D, Zaias J, Hensley G, MacLeod J, Cohn SM, Rashid Q, Pernas F, Ledford MR, Gomez-Fein E, Lynn M: Early injection of high-dose recombinant factor VIIa decreases blood loss and prolongs time from injury to death in experimental liver injury. J Trauma. 2002, 53: 1053-1057.

    Article  CAS  PubMed  Google Scholar 

  28. Martinowitz U, Kenet G, Lubetski A, Luboshitz J, Segal E: Possible role of recombinant activated factor VII (rFVIIa) in the control of hemorrhage associated with massive trauma. Can J Anaesth. 2002, 49: S15-S20.

    PubMed  Google Scholar 

  29. Martinowitz U, Kenet G, Segal E, Luboshitz J, Lubetsky A, Ingerslev J, Lynn M: Recombinant activated factor VII for adjunctive hemorrhage control in trauma. J Trauma. 2001, 51: 431-438. discussion 438–439

    Article  CAS  PubMed  Google Scholar 

  30. Schreiber MA, Holcomb JB, Hedner U, Brundage SI, Macaitis JM, Hoots K: The effect of recombinant factor VIIa on coagulopathic pigs with grade V liver injuries. J Trauma. 2002, 53: 252-257. discussion 257–259

    Article  CAS  PubMed  Google Scholar 

  31. Holcomb JB, McClain JM, Pusateri AE, Beall D, Macaitis JM, Harris RA, MacPhee MJ, Hess JR: Fibrin sealant foam sprayed directly on liver injuries decreases blood loss in resuscitated rats. J Trauma. 2000, 49: 246-250.

    Article  CAS  PubMed  Google Scholar 

  32. Holcomb J, MacPhee M, Hetz S, Harris R, Pusateri A, Hess J: Efficacy of a dry fibrin sealant dressing for hemorrhage control after ballistic injury. Arch Surg. 1998, 133: 32-35. 10.1001/archsurg.133.1.32.

    Article  CAS  PubMed  Google Scholar 

  33. Holcomb JB, Pusateri AE, Harris RA, Reid TJ, Beall LD, Hess JR, MacPhee MJ: Dry fibrin sealant dressings reduce blood loss, resuscitation volume, and improve survival in hypothermic coagulopathic swine with grade V liver injuries. J Trauma. 1999, 47: 233-240. discussion 240–242

    Article  CAS  PubMed  Google Scholar 

  34. Pusateri AE, Modrow HE, Harris RA, Holcomb JB, Hess JR, Mosebar RH, Reid TJ, Nelson JH, Goodwin CW, Fitzpatrick GM, McManus AT, Zolock DT, Sondeen JL, Cornum RL, Martinez RS: 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. J Trauma. 2003, 55: 518-526.

    Article  CAS  PubMed  Google Scholar 

  35. Sondeen JL, Pusateri AE, Coppes VG, Gaddy CE, Holcomb JB: Comparison of 10 different hemostatic dressings in an aortic injury. J Trauma. 2003, 54: 280-285.

    Article  PubMed  Google Scholar 

  36. Pusateri AE, McCarthy SJ, Gregory KW, Harris RA, Cardenas L, McManus AT, Goodwin CW: 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: 177-182.

    Article  PubMed  Google Scholar 

Download references

Acknowledgement

The opinion expressed herein is that of the author and is not to be construed as official or reflecting the views of the US Department of Defense. This is a US Government work and is not copyrighted.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to John B Holcomb.

Additional information

Competing interests

None declared.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Holcomb, J.B. Methods for improved hemorrhage control. Crit Care 8 (Suppl 2), S57 (2004). https://doi.org/10.1186/cc2407

Download citation

  • Published:

  • DOI: https://doi.org/10.1186/cc2407

Keywords