Ho and colleagues predicted 1 to 1.5 units FFP to each RBC to prevent dilutional coagulopathy in mathematical models [55].Since 2007, growing numbers of retrospective Brefeldin A clinical military and civilian papers have studied early formula-driven haemostatic resuscitation with different FFP:RBC ratios (mostly near 1:1) and mortality [11-20,56,57]. Overall, these studies demonstrate a significant association between higher ratios and lower mortality in massive traumatic bleedings, with absolute mortality reductions ranging between 15 and 62% [11-20]. These figures surpass any predictions of potentially preventable deaths in trauma [47]. While the survival advantage of early and aggressive FFP transfusion in early formula-driven resuscitation cannot be ignored, the evidence behind it has limitations that are discussed next.

Survival advantageBorgman and colleagues reviewed 246 massively transfused (��10 units RBC/24 hours) combatants and analysed mortality at three different FFP:RBC ratios (1:8, 1:2.5 and 1:1.4) [11]. A 55% absolute reduction in mortality occurred between the highest and lowest ratios. While mortality reduction was impressive, patients with a higher FFP:RBC ratio (1:1.4) had a longer median time to death (38 hours) than those with a lower ratio (2 hours). These data suggest that lower ratio patients may not have lived long enough to receive FFP. Another study by the same group on civilian trauma patients reported a similarly impressive survival advantage for higher ratios than lower ratios, but also a markedly dissimilar time to death (35 hours versus 4 hours) [58].

Both studies disclose survivorship bias, where arguably patients had to survive long enough to receive FFP, thus questioning their conclusions.Addressing survivorship biasTwo studies specifically addressed the survivorship bias in high-FFP:RBC studies. Scalea and colleagues used stepwise logistic regression analysis on 806 patients, demonstrating no survival benefit for higher ratios when early deaths were excluded [56]. This study has its own limitations, however, including a failure to report the time to intensive care unit admission, an inability to include major factors (acidosis and coagulation) in the statistical model and a surprisingly low mortality (6%) for massive transfusions. Snyder and colleagues also attemp-ted to correct for survivorship bias in another study where mortality in high (>1:2) and low (<1:2) ratios was compared in regression models [57]. Using the FFP:PRBC ratio as a fixed value at 24 hours, as in many studies on this topic, the high ratio resulted in better survival. This survival advantage was lost, however, when the ratio was treated as a time-dependent Brefeldin_A variable (relative risk = 0.84, 95% confidence interval = 0.47 to 1.5).