So often in the management of the critically ill we are forced to choose between the lesser of two evils. The transfusion of blood products in the face of hemorrhagic shock is in some ways the best compromise of less than ideal choices. Every drop of resuscitative fluid given that does not mimic the blood a patient has recently lost further dilutes their already diminished coagulative capabilities. And yet an overtly zealous administration of blood products has the potential to cause a multitude of adverse events downstream, further complicating the patient’s potentially arduous recovery. That being said, the endeavor to replenish as close a surrogate to whole blood as logistically possible is an extremely feasible concept to accept as beneficial. Yet despite this strong biological plausibility, the balanced administration of packed red blood cells (PRBCs), plasma and platelets has never been demonstrated to be efficacious beyond this physiologic reasoning. A number of retrospective trials examining this concept have claimed benefit(1,2,3,4), but their results are so confounded by survivor bias, it is difficult to interpret their true meaning (8). Even the PROMMTT trial, the largest trial to examine this question in a prospective fashion, failed to include a prospectively randomized control group and as such, its results were equally limited. With the publication of the PROPPR trial, the first large RCT to evaluate the efficacy of a balanced transfusion strategy, we finally have some strong data to guide us (6). On first glance this well-done RCT seems to have vindicated those in support of the 1:1:1 transfusion strategy, but I fear, in reality it may have left us with more questions than answers.
The Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial by Holcomb et al, published in JAMA on February 3, 2015, sought to identify the preferential ratio of plasma, platelets, and blood cells when resuscitating the critically ill trauma patient. The authors randomized 680 patients to either a 1:1:1 or 1:1:2 ratio of plasma, to platelets, to PRBCs. Inclusion criteria included; patients identified as having severe bleeding or being at risk of severe bleeding (defined as having at least 1 U of any blood component transfused prior to hospital arrival or within one hour of admission and prediction by an Assessment of Blood Consumption score of 2 or greater or by physician judgment of the need for a massive transfusion). Although authors specified the order and ratio that blood components should be transfused, the decision to administer products was left to the discretion of the treating physician. Using this pragmatic trial design authors hoped to examine the effects of each transfusion strategy on the primary endpoints, 24-hour and 30-day mortality. Holcomb et al also examined a number of secondary endpoints of importance including, time to hemostasis and the number and type of blood products administered until hemostasis was achieved.
On first glance the difference in transfusion strategies did not seem to make a difference, as the authors failed to find statistical significance in either of their two primary endpoints. A closer look reveals that this was more likely due to the authors overestimation of the true effect size of the 1:1:1 ratio rather than a lack of efficacy for this balanced transfusion strategy. Specifically the 24-hour mortality was 12.7% and 17.0% in the 1:1:1 and 1:1:2 groups respectively. Though not statistically significant this 4.3% absolute difference in favor of the more aggressive transfusion strategy clearly trends towards clinical relevance. Especially given that the rate of death due to exsanguination (9.2% vs 14.6%) and the percentage of patients who achieved hemostasis (86.1% vs 78.1%) were noticeably improved. Likewise though the 30-day mortality failed to reach statistical significance, it did maintain a robust absolute difference of 3.7% in favor of the 1:1:1 group.
As far as the transfusion related adverse events, the 1:1:1 strategy appears to be safe when compared to a less aggressive protocol. None of the 23 adverse events prospectively recorded seemed to occur with a greater regularity in patients randomized to the more aggressive strategy. There was a slight non-significant surge in the rate of systemic inflammatory response syndrome (SIRS) (5.2% absolute increase) in patients randomized to the 1:1:1, but it is hard to make much of this as the rates of both sepsis and acute respiratory distress syndrome seem equivalent.
It is important to note, despite the authors best intentions, this trial did not truly compare 1:1:1 vs 1:1:2 resuscitative strategies. Rather Holcomb et al examined a protocol intending to give 1:1:1 vs 1:1:2. In reality neither group truly reached their proportional expectations. The 1:1:1 group in actuality was given products closer to a 2:1:2 ratio, while the 1:1:2 group only received products in a 2:1:4 ratio. It is difficult to know how these shortcomings affected outcomes.
By all intents and purposes it seems the rate of adverse reactions was not significantly increased when a more aggressive use of plasma and platelets was administered, though these results may too have been biased by the less than stringent implementation of each groups assigned blood product ratio. Throughout the intervention period the 1:1:1 group received a significantly higher ratio of PRBCs to plasma and PRBCs to platelets than the 1:1:2 group. However this ratio was reversed when the post-intervention period was examined. During the post-intervention period the treating physicians were able to select blood products in any ratio they deemed clinically relevant, and as such they attempted to replenish all the plasma and platelets they were restricted from giving during the intervention period. Though the total quantity was far less than what was given in the intervention period, the PRBCs to plasma to platelets ratio was higher in the 1:1:2 group during the post-intervention period. This in and of itself may have led to an increase in the rates of adverse events observed in the 1:1:2 group without providing the coagulative benefits the early administration of these products provided in the 1:1:1 group.
Despite some minor inconsistencies, the results appear to be a validation of the balanced transfusion strategy. And yet one has to ask, “what did these authors truly demonstrate?” Holcomb et al compared a 1:1:1 strategy to the slightly more conservative 1:1:2 strategy. Ideally the only difference in these two groups should have been that the 1:1:1 group received marginally more platelets and plasma during the initial resuscitation. Are these two transfusion strategies really dissimilar enough to demonstrate a clinically relevant difference? Should they have compared a balanced transfusion strategy to a reaction method where platelets and plasma are only administered when patients develop a coagulopathy? More importantly is any empirically chosen ratio the ideal strategy in today’s age of point of care testing? In 2013 CMAJ published a trial by Bartolomeu et al that compared a fixed ratio similar to that used by Holcomb et al (1:1:1) to a laboratory-guided transfusion strategy (7). In this laboratory-guided strategy, blood product administration was guided by INR, PTT, Hb and platelet values. Although the trial was far too small to be definitive (n=67), the results were interesting nonetheless. The mortality in the laboratory-guided group was far less at 14.3% when compared to the 32.5% observed in the 1:1:1 strategy. Although a lab value guided resuscitation strategy is clearly impractical in the acute resuscitation period, a point-of-care based system like TEG may provide us with the instantaneous feedback we require to tailor our resuscitation strategies to the specific needs of the patient rather than the empiric strategy currently advised.
I doubt these results will lead to a significant change in practice. It seems the 1:1:1 massive transfusion strategy has become firmly entrenched in trauma resuscitation dogma. At least the PROPPR trial offers support to the notion that if one is going to use an empirically based transfusion strategy, striving for a equal ratio of cells, plasma and platelets appears to be of some benefit.
1. Holcomb JB, Wade CE, Michalek JE, Chisholm GB, Zarzabal LA, Schreiber MA et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg 2008; 248: 447–458.
2. Borgman, M.A., Spinella, P.C., Perkins, J.G. et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma 2007; 63: 805–813.
3. Holcomb, J.B., Wade, C.E., Michalek, J.E. et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg 2008; 248: 447–458.
4. Maegele, M., Lefering, R., Paffrath, T. et al. Red-blood-cell to plasma ratios transfused during massive transfusion are associated with mortality in severe multiple injury: a retrospective analysis from the Trauma Registry of the Deutsche Gesellschaft für Unfallchirurgie. Vox San. 2008; 95: 112–119.
5. Holcomb, J.B., del Junco, D.J., Fox, E.E. et al. The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) study. JAMA Surg 2013; 148: 127–136.
6. Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA 2015;313:(5)471-82.
7. Bartolomeu et al. “Effect of a Fixed-Ratio (1:1:1) Transfusion Protocol Versus Laboratory-Results–guided Transfusion in Patients with Severe Trauma: a Randomized Feasibility Trial.” CMAJ?: Canadian Medical Association Journal 185.12 (2013): E583–E589. PMC. Web. 6 Feb. 2015.
8. Ho AM, Zamora JE, Holcomb JB, Ng CS, Karmakar MK, Dion PW. The Many Faces of Survivor Bias in Observational Studies on Trauma Resuscitation Requiring Massive Transfusion. Ann Emerg Med 2015.