Our results indicate that for patients with significant traumatic injuries requiring massive transfusion, a higher plasma to RBC ratio is independently associated with improved survival, primarily decreasing early (<4 hours from admission) death from hemorrhage. The patients with the lowest mortality rate in our study were transfused a median plasma to RBC ratio of 1:1.4. This study supports recent reports in the literature that have called for the increased transfusion of coagulation factors for patients requiring massive transfusion1,15,25,26,35,36 and that have raised concerns about the increased use of RBCs and crystalloids in critically ill patients.26,35,37–50
Earlier massive transfusion protocols developed for patients bleeding a large amount of whole blood, did not replace whole blood, but rather called for a much greater percentage of RBC units.35 Such protocols recommended that FFP only be transfused if prothrombin time (PT) or partial thromboplastin time (PTT) was 1.5 times normal, or after 10 RBC units were transfused. Additionally, these massive transfusion protocols called for 1 unit of FFP to be given for every 4 to 10 RBC units and platelets to be infused at less than 50,000 to 100,000.35,52,53
The standard clinical practice guidelines for optimally diagnosing and treating seriously injured casualties are based on expert opinion and theoretical assumptions rather than robust laboratory or clinical data.35,52,54 Furthermore, they have frequently been extrapolated from elective operative settings, and may not be applicable to the patient with severe trauma who is in a hypocoagulable state and in hemorrhagic shock. Given these concerns, there has been recent controversy in the approach to patients requiring massive transfusions after injury.
Several current clinical practice guidelines have called for a strategy of aggressive early correction of coagulation factors in a 1:1:1 ratio (i.e., plasma:RBC:platelets) in patients with severe trauma or requiring massive transfusions.1,25 These recommendations are echoed in a clinical practice guideline instituted in September 2004 at US combat hospitals, which support the early use of a 1:1:1 ratio of plasma to RBC to platelets for patients at high risk of requiring a massive transfusion based upon clinical or laboratory data. The majority of these recommendations are based upon expert opinion or computer modeling. This study is the first to support, with comparative ratio data in three equally injured groups of patients and regression analysis, the concept that early and aggressive replacement of coagulation factors may improve survival by decreasing death from hemorrhage for patients requiring massive transfusions based on data from a large population with traumatic injuries. Interestingly, our results support a report by Hirshberg et al. that used a computer simulation model and found that a plasma to RBC ratio of 2:3 was necessary to effectively minimize coagulopathy in exsanguinating hemorrhage.55
Previous reports of the outcomes of patients requiring massive transfusion have documented similar results in smaller populations. Lucas and Ledgerwood found that coagulopathy was exacerbated in several studies in which trauma patients were transfused less plasma relative to RBCs.53,54 Cinat et al., in a study of 45 massively transfused patients reported the plasma to RBC ratio for survivors was 1:1.8 compared with 1:2.5 in nonsurvivors (p = 0.06).57 Cosgriff et al. in a prospective cohort of 56 massive transfusion patients found significant coagulopathy in 47% of patients, predicted by persistent hypothermia and progressive metabolic acidosis.10 Several other retrospective studies have confirmed the presence of coagulopathy in patients requiring massive transfusion31 and have called for increased use of coagulation factors.2,14,17,44,58,59
There was an absolute and relative reduction in mortality of 55% and 60%, respectively, in the high (1:1.4) plasma to RBC ratio group compared with in the low (1:8) plasma to RBC ratio group. The correction of the coagulopathy of trauma must begin early, before the patient enters the “bloody vicious cycle”. Our results reinforced this approach, as those in the low plasma to RBC ratio group died from uncontrolled hemorrhage within a median of 2 hours. Other studies have demonstrated that the coagulopathy of trauma occurs early in patients with severe trauma and that the severity of coagulopathy is associated with mortality.10,11,14,58,60,61 Early and appropriate use of plasma in the high ratio group likely prevented the start of this cycle. Gonzalez et al. have recently elegantly demonstrated that trauma patients who arrive in the intensive care unit with a persistent coagulopathy have increased mortality rates and they recommend earlier and more aggressive use of plasma.36
Our population of patients also received an increased amount of aPLT and cryoprecipitate. One apheresis platelet unit usually also contains 250 to 350 mL of plasma. This increased use of plasma, in addition to platelets and cryoprecipitate, supports the concept of damage control or hemostatic resuscitation.15,26,28 This approach emphasizes the aggressive diagnosis and treatment of coagulopathy in patients at high risk of requiring massive transfusion before it occurs or early in the resuscitation. If successful it will prevent and treat the lethal triad of trauma, which includes the early coagulopathy of trauma, from occurring.15,18,28,62 Similar in philosophical approach to damage control surgery the concept is to “stay out of trouble rather than get out of trouble”.
Our results indicate that the rate per hour of crystalloid and blood products was decreased with higher plasma to RBC ratios. We hypothesize that the early, increased use of plasma in these severely injured patients helped control the coagulopathy of trauma more efficiently, and, as a result required less crystalloid and RBCs per hour during the first 24 hours of resuscitation. Additionally, the use of plasma instead of crystalloids and RBCs helped prevent or limit the development of dilutional coagulopathy.15 Conversely, we believe that patients who received less plasma and more crystalloid and RBCs in the low and medium plasma to RBC ratio groups entered the “bloody vicious cycle”, and died significantly sooner from uncontrolled hemorrhagic shock. The rate of blood products and crystalloid may have also been reduced for the survivors in the high plasma to RBC ratio group as a result of not requiring active resuscitation during the entire 24 hours after initiating a massive transfusion. We suspect that both improved hemostasis and survival, and the lack of need to be actively resuscitated contributed to the decreased rate of products and crystalloid transfused in the high plasma to RBC ratio group.
Patients who received low or medium plasma to RBC ratios died predominantly of hemorrhage at a median of 2 to 4 hours. This supports the concept that patients who require massive transfusion are at risk of early (<6 hours from admission) death from hemorrhage,30 and indicates rapid treatment of coagulopathy with a higher ratio of plasma to RBC prevents early death from hemorrhage. This was evidenced by the median time to death of 38 hours in the high ratio group. Patients who received high plasma to RBC ratios had a higher incidence of death from sepsis and multiorgan failure versus hemorrhage as a result of surviving long enough to develop these complications. This is supported by the median time to death in the low and medium ratio groups compared with in the high ratio group. This relationship was noted in another similar study evaluating the effect of blood products on mortality.63 Because of the retrospective nature of this study, we cannot rule out the possibility that the increased use of plasma, apheresis platelets, and cryoprecipitate may have contributed to these results, as has been previously reported.64
Our results are subject to limitations inherent in retrospective studies, including incomplete data collection, lack of standard timing for measuring variables, and lack of a massive transfusion protocol that was consistently applied to patients. The variable with the highest percentage of missing data was the admission platelet concentration at 30%. It is possible that the exclusion of these missing values may have affected our results, but because ISS and mechanism of injury were equal in all three groups, it is likely that there was a comparable degree of coagulopathy, as has been shown previously.14 Another potential confounder is the possibility that the patients who did not receive plasma did not primarily as a function of dying before they had a chance to receive plasma. These patients may have been more critically ill than the others who were able to wait for plasma to be thawed. Although this is possible, all available indicators of severity of injury including ISS, systolic blood pressure, base deficit, and INR were equal between the three groups of patients which makes this potential confounder less likely.
Despite these limitations, this study is currently one of the largest reviews of patients with massive transfusion in trauma to analyze the effects of blood product transfusion and mortality. Additionally, we were able to adjust for many confounding variables in our regression analysis to include thoracic AIS values, admission hemoglobin concentrations, and rFVIIa use, which were each different in the low, medium, and high ratio groups that were compared. In addition to adjusting for thoracic AIS score in the regression model, we also analyzed the relationship between ratio of plasma to RBCs transfused with the exclusion of patients with severe thoracic injuries. In this analysis, the relationship of increased plasma to RBC ratio and decreased mortality remained between the low and high ratio groups (Table 3).
We believe that our results support the development of randomized controlled trials in animal and human subjects that will evaluate the effect of plasma to RBC ratios transfused to patients at risk of requiring massive transfusions. Ratios tested should also include plasma to RBC ratios of greater than 1:1 to evaluate if more plasma than RBCs would improve survival in coagulopathic patients with severe traumatic injury. Strategies that aggressively treat the coagulopathy of trauma and decrease the use of stored RBCs in patients with severe traumatic injuries including early and increased use of plasma, platelets, cryoprecipitate, or fresh whole blood if available, and the aggressive treatment of hypothermia, metabolic acidosis, and hypocalcemia need continued study to determine whether they can improve outcomes.
Based upon these data the US Army Surgeon General has recently distributed a policy recommending that a 1:1 plasma to RBC ratio be transfused to all patients with significant trauma and who are at risk for requiring a massive transfusion.
Recent literature demonstrates that the risk of requiring a massive transfusion can be rapidly identified and death from hemorrhage occurs quickly for patients with severe traumatic injuries requiring massive transfusion. The transfusion of plasma to RBCs in a 1:1 ratio is a rapid treatment that improves survival for patients at risk of hemorrhagic shock. We suggest that the empiric ratio of plasma to RBC should approximate 1:1 for patients with traumatic injuries requiring massive transfusions. Future prospective randomized controlled trials are needed to compare empiric plasma to RBC ratios for patients with severe traumatic injuries.
1. Malone DL, Hess JR, Fingerhut A. Massive transfusion practices around the globe and a suggestion for a common massive transfusion protocol. J Trauma
2. Phillips TF, Soulier G, Wilson RF. Outcome of massive transfusion exceeding two blood volumes in trauma
and emergency surgery. J Trauma
3. Wudel JH, Morris JA Jr, Yates K, Wilson A, Bass SM. Massive transfusion: outcome in blunt trauma
patients. J Trauma
4. Como JJ, Dutton RP, Scalea TM, Edelman BB, Hess JR. Blood transfusion rates in the care of acute trauma
5. Malone DL, Dunne J, Tracy JK, Putnam AT, Scalea TM, Napolitano LM. Blood transfusion, independent of shock severity, is associated with worse outcome in trauma
. J Trauma
. 2003;54:898–905; discussion 905–907.
6. Huber-Wagner S, Qvick M, Mussack T, et al. Massive blood transfusion and outcome in 1062 polytrauma patients: a prospective study based on the Trauma
Registry of the German Trauma
Society. Vox Sang
7. Sauaia A, Moore FA, Moore EE, et al. Epidemiology of trauma
deaths: a reassessment. J Trauma
8. Perkins J, Schreiber M, Wade C, Holcomb J. Early versus late recombinant factor VIIa (rFVIIa) in combat trauma
patients requiring massive transfusion. J Trauma
. 2007;62:1095–1099; discussion 1099–1101.
9. Engstrom M, Schott U, Romner B, Reinstrup P. Acidosis impairs the coagulation: a thromboelastographic study. J Trauma
10. Cosgriff N, Moore EE, Sauaia A, Kenny-Moynihan M, Burch JM, Galloway B. Predicting life-threatening coagulopathy
in the massively transfused trauma
patient: hypothermia and acidoses revisited. J Trauma
. 1997;42:857–861, discussion 861–862.
11. DeLoughery TG. Coagulation defects in trauma
patients: etiology, recognition, and therapy. Crit Care Clin
12. Ferrara A, MacArthur JD, Wright HK, Modlin IM, McMillen MA. Hypothermia and acidosis worsen coagulopathy
in the patient requiring massive transfusion. Am J Surg
13. Kaufmann CR, Dwyer KM, Crews JD, Dols SJ, Trask AL. Usefulness of thrombelastography in assessment of trauma
patient coagulation. J Trauma
. 1997;42:716–720, discussion 720–722.
14. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy
. J Trauma
15. Hess JR, Holcomb JB, Hoyt DB. Damage control resuscitation: the need for specific blood products to treat the coagulopathy
16. Hess JR, Lawson JH. The coagulopathy
versus disseminated intravascular coagulation. J Trauma
17. Hewson JR, Neame PB, Kumar N, et al. Coagulopathy
related to dilution and hypotension during massive transfusion. Crit Care Med
18. Martinowitz U, Michaelson M. Guidelines for the use of recombinant activated factor VII (rFVIIa) in uncontrolled bleeding: a report by the Israeli Multidisciplinary rFVIIa Task Force. J Thromb Haemost
19. Rohrer MJ, Natale AM. Effect of hypothermia on the coagulation cascade. Crit Care Med
20. Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, Pittet J. Acute traumatic coagulopathy
: initiated by hypoperfusion: modulated through the protein C pathway? Ann Surg
21. Coates JB. Blood Program in World War II. Washington, DC: Office of the Surgeon General, Dept. of the Army; United States Army Medical Service; 1964.
22. Pfeffermann R, Rozin RR, Durst AL, Marin G. Modern war surgery: operations in an evacuation hospital during the October 1973 Arab-Israeli war. J Trauma
23. Repine TB, Perkins JG, Kauvar DS, Blackborne L. The use of fresh whole blood in massive transfusion. J Trauma
24. Dutton RP, Carson JL. Indications for early red blood cell transfusion. J Trauma
25. Ketchum L, Hess JR, Hiippala S. Indications for early fresh frozen plasma
, cryoprecipitate, and platelet transfusion in trauma
. J Trauma
26. Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation: directly addressing the early coagulopathy
. J Trauma
27. Holcomb JB, McMullin N, Pearse L, et al. Causes of death in US Special Operations Forces in the Global War on Terrorism: 2001–2004. Ann Surg
28. McMullin NR HJ, Sondeen J. Hemostatic resuscitation. In: Vincent J, ed. Yearbook of Intensive Care and Emergency Medicine. New York: Springer; 2006:265–278.
29. Bellamy RF. The causes of death in conventional land warfare: implications for combat casualty care research. Mil Med
30. Moore FA. Need for massive transfusion can be predicted early after trauma
center arrival [abstract]. J Trauma
31. Yucel N, Lefering R, Maegele M, et al. Trauma
Associated Severe Hemorrhage (TASH)-Score: probability of mass transfusion as surrogate for life threatening hemorrhage after multiple trauma
. J Trauma
. 2006;60:1228–1236, discussion 1236–1237.
32. Drews RE. Critical issues in hematology: anemia, thrombocytopenia, coagulopathy
, and blood product transfusions in critically ill patients. Clin Chest Med
33. Mohr R, Martinowitz U, Lavee J, Amroch D, Ramot B, Goor DA. The hemostatic effect of transfusing fresh whole blood versus platelet concentrates after cardiac operations. J Thorac Cardiovasc Surg
34. Watts DD, Trask A, Soeken K, Perdue P, Dols S, Kaufmann C. Hypothermic coagulopathy
: effect of varying levels of hypothermia on enzyme speed, platelet function, and fibrinolytic activity. J Trauma
35. Ho AM, Karmakar MK, Dion PW. Are we giving enough coagulation factors during major trauma
resuscitation? Am J Surg
36. Gonzalez EA, Moore FA, Holcomb JB, et al. Fresh frozen plasma
should be given earlier to patients requiring massive transfusion. J Trauma
37. Basran S, Frumento RJ, Cohen A, et al. The association between duration of storage of transfused red blood cells and morbidity and mortality after reoperative cardiac surgery. Anesth Analg
38. Hebert PC, Fergusson DA, Stather D, et al. Revisiting transfusion practices in critically ill patients. Crit Care Med
. 2005;33:7–12, discussion 232–233.
39. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med
40. Ho J, Sibbald WJ, Chin-Yee IH. Effects of storage on efficacy of red cell transfusion: when is it not safe? Crit Care Med
41. Marik PE, Sibbald WJ. Effect of stored-blood transfusion on oxygen delivery in patients with sepsis. JAMA
42. Napolitano LM, Corwin HL. Efficacy of red blood cell transfusion in the critically ill. Crit Care Clin
43. Zallen G, Offner PJ, Moore EE, et al. Age of transfused blood is an independent risk factor for postinjury multiple organ failure. Am J Surg
44. Harvey MP, Greenfield TP, Sugrue ME, Rosenfeld D. Massive blood transfusion in a tertiary referral hospital. Clinical outcomes and haemostatic complications. Med J Aust
45. McIntyre LA, Hebert PC. Can we safely restrict transfusion in trauma
patients? Curr Opin Crit Care
46. Tinmouth A, Fergusson D, Yee IC, Hebert PC. Clinical consequences of red cell storage in the critically ill. Transfusion
47. Alam HB, Rhee P. New developments in fluid resuscitation. Surg Clin North Am
. 2007;87:55–72, vi.
48. Hoyt DB. Fluid resuscitation: the target from an analysis of trauma
systems and patient survival. J Trauma
49. Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med
50. Cotton BA, Guy JS, Morris JA Jr, Abumrad NN. The cellular, metabolic, and systemic consequences of aggressive fluid resuscitation strategies. Shock
51. Spinella PC, Perkins JG, Grathwohl KW, et al, and the 31st CSH Research Working Group. The risks associated with fresh whole blood and red blood cell transfusions in a combat support hospital. Crit Care Med
. 2007;(in press).
52. Robb WJ. Massive transfusion in trauma
. AACN Clin Issues
. 1999;10:69–84, quiz 138–140.
53. Ledgerwood AM, Lucas CE. A review of studies on the effects of hemorrhagic shock and resuscitation on the coagulation profile. J Trauma
54. Montenegro L, Jobes D. Complications of massive transfusion. In: Atlee JL, ed. Complications in Anesthesia. Philadelphia: Elsevier/Saunders; 1999:668–673.
55. Hirshberg A, Dugas M, Banez EI, Scott BG, Wall MJ Jr, Mattox KL. Minimizing dilutional coagulopathy
in exsanguinating hemorrhage: a computer simulation. J Trauma
56. Lucas CE, Ledgerwood AM. Clinical significance of altered coagulation tests after massive transfusion for trauma
. Am Surg
57. Cinat ME, Wallace WC, Nastanski F, et al. Improved survival following massive transfusion in patients who have undergone trauma
. Arch Surg
. 1999;134:964–968, discussion 968–970.
58. Faringer PD, Mullins RJ, Johnson RL, Trunkey DD. Blood component supplementation during massive transfusion of AS-1 red cells in trauma
patients. J Trauma
. 1993;34:481–485, discussion 485–487.
59. Mitchell KJ, Moncure KE, Onyeije C, Rao MS, Siram S. Evaluation of massive volume replacement in the penetrating trauma
patient. J Natl Med Assoc
60. Martinowitz U, Zaarur M, Yaron BL, Blumenfeld A, Martonovits G. Treating traumatic bleeding in a combat setting: possible role of recombinant activated factor VII. Mil Med
. 2004;169(Suppl):16–18, 4.
61. Rugeri L, Levrat A, David JS, et al. Diagnosis of early coagulation abnormalities in trauma
patients by rotation thrombelastography. J Thromb Haemost
62. Malone DL HJ, Fingerhut A. Massive transfusion practices around the globe and a suggestion for a common massive transfusion protocol. J Trauma
63. Moore FA, Moore EE, Sauaia A. Blood transfusion. An independent risk factor for postinjury multiple organ failure. Arch Surg
. 1997;132:620–624, discussion 624–625.
64. MacLennan S, Williamson LM. Risks of fresh frozen plasma
and platelets. J Trauma