Correlation analysis of variables resulted in eight variables as candidates for further multivariate analysis. These included hemoglobin, platelets, INR, base deficit, FFP, ISS, F:R ratio (continuous), and F:R ratio (high/low). The F:R ratio (high/low) variable had a higher correlation coefficient than F:R ratio (continuous) variable (−0.247 vs. −0.178) and was, therefore, chosen for multivariate analysis over the continuous F:R ratio variable. The INR variable showed a significant positive correlation (0.290) to mortality, but was excluded for low sample size (168 of 252). Recombinant Factor VIIa use was not correlated with mortality in this analysis and was therefore not a candidate for multivariate logistic regression.
Backward and forward regression analysis resulted in the base deficit, ISS, and F:R ratio (high/low), as the best predictors of mortality with a receiver operating characteristic curve area of 0.71 (95% confidence interval 0.63–0.79; Fig. 4 and Table 3). Hosmer and Lemeshow tests showed a good model fit with a χ2 of 3.17 (p = 0.92). The model correctly predicted 93% (10 of 147) of survivors and 29% (17 of 50) of deaths in the sample set using a 0.5 predictive positive cutoff. Mortality rate predicted increased to 56% (33 of 59) using a 0.3 positive cutoff value (survival rate decreased to 76%, correct predictions were obtained in 36 of 147).
Our results are consistent with the studies above in that they demonstrate that an increased amount of fibrinogen in relation to the amount of RBCs transfused was independently associated with survival in combat casualties requiring massive transfusions. This is important since the majority of preventable deaths in combat are due to hemorrhage and strategies that can decrease death from hemorrhage in combat will significantly impact survival in this population. To the best of our knowledge, this is the first article to demonstrate the association of high levels of transfused fibrinogen on the survival of casualties requiring massive transfusion.
Recombinant Factor VIIa (NovoSeven, NovoNordisk, Princeton, NJ) is another clotting factor available in lyophilized powder form that many trauma centers have recently integrated into their massive transfusion protocols. Recombinant Factor VIIa reduces the total number of red cell units transfused in combat casualties,36 decreases death in combat casualties requiring massive transfusion,4 and requires adequate levels of platelets and fibrinogen in place to achieve hemostasis.40,41 Administering recombinant Factor VIIa in the face of low fibrinogen levels may not produce the desired hemostatic effect; in addition, acidosis should be reversed and platelet deficiencies corrected either simultaneously with or before recombinant Factor VIIa administration.41
Although our data reveal a strong association between a high F:R transfusion ratio and survival, that association does not necessarily imply causation. During the data collection period from January 2004 through October 2005, platelet availability varied, and deployed U.S. military medical personnel shifted progressively away from crystalloid toward more plasma and whole blood in factor-specific targeted resuscitation of combat casualties. Progressively smaller amounts of crystalloid infused may also have contributed to these results.42,43
Although the sample size in this study is small, our data demonstrate that transfusion of a high F:R ratio (≥0.2 g of fibrinogen per red cell unit transfused) was independently associated with survival to hospital discharge, primarily by decreasing death from hemorrhage. One 15-mL cryoprecipitate bag containing 250 mg of fibrinogen can be transfused per unit of RBCs to achieve this ratio; plasma and whole blood seem to be just as capable of supplying the needed fibrinogen. Clinicians can meet this requirement by (1) transfusing 1 unit of FFP for every 2 units of red cells transfused, or (2) transfusing 1 unit of whole blood for every 4 units of red cells transfused (Table 1), or (3) transfusing one 10-unit bag of cryoprecipitate for every 10 units of red cells transfused. Whether the survival benefit of the increased F:R ratio is a result of fibrinogen alone or to fibrinogen working with the other clotting factors present in plasma and whole blood is unknown. More prospective studies are needed to evaluate the best source of fibrinogen and the optimal empiric ratio of fibrinogen to RBCs in patients requiring massive transfusion.
We thank Ms. Lindsey Stinger for assistance with data collection and Ms. Amy Newland for support, helpful discussions, and critical evaluation of this article.
1. Bellamy RF. The causes of death in conventional land warfare: implications for combat casualty care research. Mil Med.
2. Holcomb JB, Caruso J, McMullin NR, et al. Causes of death in Special Operations Forces on the modern battlefield: 2001–2006. Ann Surg.
3. Demetriades D, Martin M, Salim A, et al. Relationship between American College of Surgeons trauma
center designation and mortality in patients with severe trauma
(ISS >15). J Am Coll Surg.
4. Spinella PC, Perkins JG, McLaughlin DF, et al. The effect of recombinant activated factor VII on mortality in combat-related casualties with severe trauma
and massive transfusion
. J Trauma.
5. Borgman M, Spinella PC, Perkins JG, et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma.
6. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy
. J Trauma.
7. McLeod JB, Lynn M, McKenney MG, Cohn SM, Murtha M. Early coagulopathy
predicts mortality in trauma
. J Trauma.
8. Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, Pittet JF. Acute traumatic coagulopathy
: initiated by hypoperfusion: modulated through the protein C pathway? Ann Surg.
9. Gonzalez EA, Moore FA, Holcomb JB, et al. Fresh frozen plasma should be given earlier to patients requiring massive transfusion
. J Trauma.
10. Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation: directly addressing the early coagulopathy
. J Trauma.
11. Malone DL, Holcomb J, Fingerhut A. Massive transfusion
practices around the globe and a suggestion for a common massive transfusion
protocol. J Trauma.
12. Phillips TF, Soulier G, Wilson RF. Outcome of massive transfusion
exceeding two blood volumes in trauma
and emergency surgery. J Trauma.
13. Wudel JH, Morris JA Jr, Yates K, Wilson A, Bass SM. Massive transfusion
: outcome in blunt trauma
patients. J Trauma.
14. Como JJ, Dutton RP, Scalea TM, Edelman BB, Hess JR. Blood transfusion rates in the care of acute trauma
15. 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.
16. 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.
17. Peng R, Chang C, Gilmore D, Bongard F. Epidemiology of immediate and early trauma
deaths at an urban level 1 trauma
center. Am Surg.
18. Demetriades D, Murray J, Charalambides K, et al. Trauma
fatalities: time and location of hospital deaths. J Am Coll Surg.
19. Sauaia A, Moore FA, Moore EE, et al. Epidemiology of trauma
deaths: a reassessment. J Trauma.
20. Engstrom M, Schott U, Romner B, Reinstrup P. Acidosis impairs the coagulation: a thromboelastographic study. J Trauma.
21. 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.
22. DeLoughery TG. Coagulation defects in trauma
patients: etiology, recognition, and therapy. Crit Care Clin.
23. Ferrara A, MacArthur JD, Wright HK, Modlin IM, McMillen MA. Hypothermia and acidosis worsen coagulopathy
in the patient requiring massive transfusion
. Am J Surg.
24. McMullin NR, Holcomb J, Sondeen J. Hemostatic resuscitation. In: Vincent J, ed. Yearbook of Intensive Care and Emergency Medicine.
New York: Springer; 2006:265–278.
25. Hirshberg A, Dugas M, Banez EI, Scott BG, Wall MJ Jr, Mattox KL. Minimizing dilutional coagulopathy
in exsanguinating hemorrhage: a computer simulation. J Trauma.
26. Ho AM, Dion PW, Cheng CA, et al. A mathematical model for fresh frozen plasma transfusion strategies during major trauma
resuscitation with ongoing hemorrhage. Can J Surg.
27. Ketchum L, Hess JR, Hiippala S. Indications for early fresh frozen plasma, cryoprecipitate
, and platelet transfusion in trauma
. J Trauma.
28. Kelley DL. Update on plasma and cryoprecipitate
transfusion. Trans Med Update.
29. Hiippala ST, Myllyla GJ, Vahtera EM. Hemostatic factors and replacement of major blood loss with plasma-poor red cell concentrates. Anesth Analg.
30. Armand R, Hess JR. Treating coagulopathy
patients. Transfus Med Rev.
31. Collins JA. The pathophysiology of hemorrhagic shock. Prog Clin Biol Res.
32. Martini WZ, Chinkes DL, Pusateri AE, et al. Acute changes in fibrinogen
metabolism and coagulation after hemorrhage in pigs. Am J Physiol Endocrinol Metab.
33. Martini WZ, Chinkes DL, Sondeen J, Dubick MA. Effects of hemorrhage and lactated Ringer’s resuscitation on coagulation and fibrinogen
metabolism in swine. Shock.
34. Fries D, Krismer A, Klinger A, et al. Effect of fibrinogen
on reversal of dilutional coagulopathy
: a porcine model. Br J Anaesth.
35. Fries D, Innerhofer P, Reif C, et al. The effect of fibrinogen
substitution on reversal of dilutional coagulopathy
: an in-vitro model. Anesth Analg.
36. Perkins J, Schreiber M, Wade C, Holcomb J. Early versus late recombinant factor VIIa (rFVIIa) in combat trauma
patients requiring massive transfusion
. J Trauma.
37. Martini WZ, Holcomb JB. Acidosis and coagulopathy
: the differential effects on fibrinogen
synthesis and breakdown in pigs. Ann Surg.
38. Martini WZ, Dubick MA, Pusateri AE, et al. Does bicarbonate correct coagulation function impaired by acidosis in swine? J Trauma.
39. Martini WZ, Dubick MA, Wade CE, Holcomb JB. Evaluation of tris-hydroxymethylaminomethane on reversing coagulation abnormalities caused by acidosis in pigs. Crit Care Med.
40. Mannucci PM, Levi M. Prevention and treatment of major blood loss. NEJM.
41. Dempfle CE, Borggrefe M. Acidosis and impaired blood coagulation: what and how to correct before using recombinant human factor VIIa. Crit Care Med.
42. Cotton BA, Guy JS, Morris JA Jr, et al. The cellular, metabolic and systemic consequences of aggressive fluid resuscitation strategies. Shock.
43. Rhee P, Wang D, Ruff P, et al. Human neutrophil activation and increased adhesion by various resuscitation fluids. Crit Care Med.
Dr. Myung S. Park (Wilford Hall Medical Center, San Antonio, TX): I would like to thank Dr. Stinger and his co-authors for tackling the much debated issue of how much of which blood components do we give to an exsanguinating trauma patient requiring massive transfusion. In their review of 252 patients who received massive transfusions (10 or more RBC units within 24-hour period) at the combat support hospital in Baghdad, they found that the ratio of fibrinogen per unit of RBCs transfused (F:R ratio) differed significantly between survivors and nonsurvivors. Specifically, patients who received <200 mg of fibrinogen per unit of RBC had a mortality rate of 52% versus 24% in those who received >200 mg of fibrinogen per unit of RBC. The percentage of death by hemorrhage was even more striking with mortality rate of 85% versus 44%, respectively. Furthermore, in multiple logistic regression, they found that the high fibrinogen-to-RBC ratio (>200 mg/unit) was an independent additive predictor of survival. Thus far, this is the first clinical study that has shown the survival benefit of fibrinogen during massive transfusions. This study supports the important concept of damage control hemostatic resuscitation as currently practiced in military combat support hospitals where plasma (containing 400 mg fibrinogen per unit) is given in 1:1 ratio to RBCs.
Based on this study, the authors recommend that we give at least 200 mg fibrinogen per unit of RBC transfused. As the authors note, “Although compelling, our results are limited by the fact that fibrinogen was administered as cryoprecipitate, plasma, platelets, and whole blood, with each product containing other coagulation factors in varying amounts.” Because of their small sample size of 252 patients, comparisons between different fibrinogen sources were not made. Despite this shortcoming, I think this study delineates the importance of adequate fibrinogen supplementation in massive transfusions.
I have two questions: (1) Significant number of patients in this study received rFVIIa, especially in those who received the high F:R ratio. How can you attribute the improvement in survival to the latter when rFVIIa may be a contributor to increased survival? It is likely that both are important factors in improving the outcome of the exsanguinating trauma patients, but it is hard to discern the two based on the study presented. (2) Will the authors look into any mortality difference between patients who received fibrinogen from different sources, i.e., cryoprecipitate, plasma, whole blood, etc. using a larger cohort of patients?
Again, I would like to commend the authors for sharing with us their data that support fibrinogen is one of the key components in the resuscitation strategy.
Dr. Harry K. Stinger (Brooke Army Medical Center, Fort Sam Houston, TX): Thanks for your comments, Dr. Park. This analysis documented rFVIIa use versus nonuse in the 252 massive transfusion patients; it did not assess the timing or the dose of rFVIIa administered. In our analysis, the rate of rFVIIa use was similar (between survivors [51 of 177, 29%] and nonsurvivors [22 of 75, 29%]). However, a much higher percentage of patients in the high F:R ratio group (77 of 200, 38.5%) received rFVIIa than in the low F:R ratio group (5 of 52, 9.6%; p < 0.001). This issue is one limitation mentioned in the discussion section above, that is, was it the fibrinogen in the various blood products that positively impacted survival, or was it the other clotting factors present in those blood products—especially in plasma and in whole blood—that conferred the survival advantage? Recombinant Factor VIIa is a clotting factor that, along with fibrinogen, may have conferred a survival benefit.
At least in theory, rFVIIa needs adequate serum levels of fibrinogen and platelets in a normothermic, nonacidotic patient to work. I suspect that at least part of the survival benefit in the high F:R ratio category was the synergistic result of high serum levels of rFVIIa, plasma clotting factors, platelets and fibrinogen all working together to achieve hemostasis, and not the result of any single clotting factor operating alone. Separating out the effects of each factor individually is a challenge that would require a prospective randomized trial of massive transfusion casualties, hypothetically by assigning the various fibrinogen sources to separate treatment arms. Recombinant Factor VIIa use could then be evaluated by further subdividing each treatment arm into Factor VIIa use and nonuse categories, and looking at the effect of mortality in each group. Again, as stated in the article, the likelihood of such a trial being conducted is low for ethical reasons.
With regard to fibrinogen administration, based on these preliminary findings, we recommend transfusing a minimum of 200 mg of fibrinogen per red cell unit. Clinicians can meet this requirement by (1) transfusing 1 unit of FFP for every 2 units of red cells, (2) transfusing 1 unit of whole blood for every 4 units of red cells, or (3) transfusing one 10-unit bag of cryoprecipitate initially and then just before every subsequent 10th unit of red cells. Keep in mind that this is a preliminary recommendation based on this analysis only; we plan to analyze larger JTTR data sets in the near future to further refine this recommendation.