Our study represents a civilian investigation to analyze the impact of initial presumptive FFP:RBC transfusion ratios on ultimate survival. Although many investigators2–5,25,28–30 suggest liberal transfusion of coagulation factors for this group, the recent military experience indicating a survival advantage for initial 1:1 FFP:RBC is becoming the standard for civilian resuscitation as well.6 In fact, in 2001, we recommended empiric 1:1 FFP:RBC for initial resuscitation in major pelvic fractures based upon our observations of early coagulopathy in these patients.31 This policy may have had a “halo effect” on our general massive transfusion practices (Fig. 2), as there was no significant difference in FFP, RBC, or FFP:RBC transfused during the 5-year time period of this study. Our findings of a U-shaped association between mortality risk and ratio (Figs. 7 and 8) was reinforced by MLR analysis and further confirmed via quadratic term estimate, controlling for multiple risk factors predictive of coagulopathy including SBP, ISS, pH, and temperature.8 The overall median FFP:RBC ratio for all survivors in this series was 1:2 and for nonsurvivors, 1:4 (Table 6). Based upon these results, showing the lowest predictive probability of mortality of 0.2 to 0.3, we think that the critical threshold for survival in civilian patients sustaining postinjury life threatening coagulopathy may be in the range of 1:2 and 1:3 FFP:RBC. Our study also found that in excess of 80% of transfusion requirements were completed within the first 6 hours after emergency department admission. On this basis, we think that the common definition of massive transfusion as 10 units of RBC per 24 hours should be changed to 10 units RBC per 6 hours to better reflect the dominant time period of the acute hemorrhagic event, as well as the associated physiologic consequences. Our study also showed that crystalloid infusion was not an independent predictor of coagulopathy. Although we were only able to evaluate crystalloid infusion during 24 hours because of data collection limitations of this retrospective analysis, this finding could indicate that the dilutional effects of crystalloid administration on coagulopathy may not be as dominant within the 6 hour time frame of our study. When we performed MLR analysis for the endpoint of coagulopathy, (defined as INR >1.5 at 6 hours) with FFP:RBC ratio, a linear relationship resulted, although a sample of about 1,400 patients would be required to further confirm the significance of this association.
Reporting on extensive animal studies of hypovolemic shock and resuscitation, Lucas and Ledgerwood34,35 questioned the appropriate ratio of FFP:RBC in massive transfusion, recommending two units of FFP after six units of RBCs, with a subsequent ratio in massive transfusion of 2:5. In 1981, we reported our experiences with major abdominal vascular trauma in a series of patients treated with component therapy. We recognized at that time that many patients died of persistent coagulopathy with associated acidosis, and hypothermia despite surgical control of their vascular injuries, which we termed “the bloody vicious cycle.”7,8,36 Subsequently, through the 1990s to the current era, progressive coagulopathy has remained the most prevalent and compelling reason for damage control staged laparotomy, and these techniques have become standard in the military, particularly in blast injury, as well as in the civilian sector for patients receiving massive transfusion. It is now widely recognized that the decision to abort operative intervention in this setting must occur early in the procedure, before clinical or laboratory evidence of advanced coagulopathic derangements is overt.36
In response to the military experience described, a recent consensus conference on massive transfusion called for a common massive transfusion protocol to be applied to the civilian sector, based on a 1:1 ratio, emphasizing the need for additional FFP in an attempt to approximate concentrations found in whole blood.3,19,29,32,33 It is difficult to develop a consistent and predictable “whole blood substitute” from components because the need for RBCs to transport oxygen may not correspond to the need for other blood components based upon laboratory coagulation studies. On the basis of these observations, we think that the use of fresh whole blood in selected use for massive transfusion should be re-examined.
The change to component therapy during the past 30 years has resulted in a steady increase in the clinical use of FFP worldwide.40–43 Despite this, the clinical efficacy of FFP remains largely unproven,44 with most evidence for FFP administration from observational data.44,45 Recognizing this lack of evidence based data, recently published European massive transfusion guidelines,46–48 have stopped short of recommending routine 1:1 FFP:RBC in their protocols. Of note, TRALI has become the most important cause of transfusion related morbidity and mortality in the Unites States.49–53 FFP infusion has been suggested to triple the risk of TRALI in patients mechanically ventilated.54 Furthermore, the known independent risk factors for MOF previously attributed to RBC transfusion12,13,17,18,53–55, may also be significantly associated with FFP and platelet administration from leukocyte-alloimmunized donors.48,50,51,56–59
Our study has several limitations, besides the known inherent problems with a retrospective study. First, although it is a 5 year review of massive transfusion practices within a single institution by one group of trauma surgeons, no consistent transfusion protocol existed for the time of this review, although our transfusion protocol for pelvic fractures was operative.31 Second, this prospective chart review contains several areas of incomplete data collection, as previously described. In addition, this study focused only on acute hemorrhage and coagulopathy and did not examine the impact of transfusion on late deaths from complications related to MOF, a well established complication of massive transfusion. Despite these limitations, we think our findings suggesting increased mortality with the addition of FFP below the 1:2 range to be concerning for the civilian population. Accordingly, based upon our collective data analysis, we currently employ a protocol of 1:2 FFP:RBC for massive transfusion. Although protocols may vary depending upon institutional policy, we think that certain principles are essential, including rapid notification and close cooperation between surgery, anesthesia, and the blood bank via a well defined delivery schedule. Finally, although prompt surgical control of hemorrhage remains paramount, monitoring of ongoing hemorrhage and physiologic derangements to guide resuscitative therapy is a core principal to the success of the massive transfusion event. Recognizing that massive transfusion represents less than 5% of most trauma center experience, the validation of our findings must be confirmed with multicenter investigation via a prospective randomized study.
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Dr. John B. Holcomb (San Antonio, Texas): The Denver group has a long and distinguished history of close inspection of severely-injured and coagulopathic patients. This report of plasma to red cell ratios adds to that legacy.
The authors compared their five-year history of 133 patients with various plasma and red cell ratios to those currently recommended by the U.S. military in Iraq and Afghanistan (Borgman et al., J Trauma, Oct 2007). The overall question was, does increased plasma red cell ratio improve survival.
The data presented by Dr. Moore suggests that 1:1 has a higher mortality than 1:2, while the military data, shared previously with the Denver group, shows that 1:1 significantly improves survival.
The military data that Dr. Moore referred to will be published next month (Oct 2007) in the Journal of Trauma and served as the basis for the all Army message and the clinical practice guideline that is widely practiced in Iraq and Afghanistan and was shown on your first slide.
Basically, the Army data shows transfusing plasma:RBC in a 1:1 ratio significantly improves survival compared to 1:2 or 1:4. These data were based on 246 massive transfusions with a 95 percent penetrating rate and a 19 percent mortality in the 162 patients who received 1:1 ratio.
There are several significant differences between the civilian and military data. Accrual time was five years versus 18 months. Massive transfusion was redefined as greater than 10 units of red cells in 6 hours versus the more standard definition, and the one that we used, of 10 units in 24 hours.
Severe head injuries were excluded in the Denver data and included in the military. And cause and time of death was not reported in the Denver data and is in the military.
Have you looked at these differences? And how would your conclusions differ if you compared apples to apples and oranges to oranges rather than with changing definitions?
I think the cause of and time of death, whether it be hemorrhage, brain injury or multi-organ failure, must be evaluated and reported when reporting these type of data. Changing times and causes need to be described in relation to changing resuscitation strategies.
The last and most important is really simply numbers and statistical power. The Denver group with their five-year review had 11 patients in the 1:1 group and the military data had 162 casualties over 18 months in their 1:1 data. The final conclusions must be interpreted with these differences in mind.
The Denver group has appropriately highlighted the 6-hour timeframe as important, and this time point deserves further exploration in other similar efforts. I think this is one of the new findings that’s coming out of this data analysis and likely represents a new, clinically-relevant end-point that many of the future studies dealing in this area of early hemorrhagic shock and massive transfusion need to further evaluate.
The authors appropriately call into question the transfer of practices from military to civilian populations. This question is currently under evaluation in a very large retrospective study enrolling at 20 centers and currently encompasses 485 massive transfusion patients. The early analysis of those data, while not complete, suggests that more plasma is better than less plasma. We will hear more about that later. It is interesting to know that every time we have looked for differences in outcomes between military and civilian populations, we have seen more similarities than differences.
Dr. Moore appropriately cautions us with giving “unbridled plasma.” This really translates to: What is the rate of TRALI in trauma patients? The rate is from 1:60,000 to 1:10,000. TRALI doesn’t happen very often. And yet some of the data presented here and in subsequent papers at this meeting suggest that giving more plasma significantly improves 30 day mortality. While there is a risk benefit ratio to everything we do, it seems from the available data that the benefit currently falls on the side of more plasma.
We agree with Dr. Moore’s final conclusion that prospective studies are needed. We will learn how to optimally treat these patients as we gather prospective data in this critically-injured group of patients.
Dr. Charles E. Lucas (Detroit, Michigan): The largest database on massive transfusion was put together by myself and Dr. Ledgerwood. Based upon analysis of over 500 patients of prospectively monitored we determined that the ratio of plasma to red cells was best at a 1.5:2 which is comparable to that reported today.
This achieved two things. It restored the absolute coagulation factors to greater than 25 percent of activity. Jeffry and Gene, did you measure your activity? And, secondly, it reduced the forced relocation of proteins out of the vascular system due to the increased oncotic pressure when you give large amounts of protein. This reduced the incidence of multiple organ failure, particularly to the kidney, the lungs, and to the heart. So I support your regime and believe that you have the right answer.
Dr. Ernest E. Moore (Denver, Colorado) and Dr. Jeffry L. Kashuk(Denver, Colorado): We thank the discussants and particularly Dr. Holcomb for his critical review of our work. First of all, we want to emphasize that we in no way are challenging the military policy.
They shared their data with us. We believe it. And in no way are we suggesting that there is anything awry with the military data. We have done the best we can with our database to analyze it in the civilian population and clearly need to move on to multicenter trials to answer all of these questions.
We do believe that there may be material differences in injury patterns. Some of us have been fortunate enough to spend time in Landstuhl and have seen the extensive injuries that have challenged the military, particularly blast injuries and so on and they have some unique aspects to their injury pattern.
We should emphasize that we didn’t exclude all head injuries from this analysis. We only excluded head injuries that we in retrospect believe materially contributed to their mortality.
In fact, if we add all head injuries and then used 24 hours rather than 6 hours, we would have had over 500 patients in this series but we believe that’s a lot of noise that only confuses us. So we tried to distill it down to what we thought was the best database.
The 11 patients, you’re absolutely correct, we’re concerned about. But I would emphasize that the statistical analysis, as you know, is based on the entire pool, not simply an isolated group.
So we look forward to your prospective trial and commend you for your leadership in this area and asking the important question that all of us need now to take home and address scientifically.
Dr. Lucas, we’re quite aware of your pioneering work in this area. Some of us of gray hair sat around here 25 years ago and listened to your report on your studies and then extrapolated that over into the clinical arena.
We applaud you again for your leadership. It is interesting that we’ve come full circle in almost 25 years.
We now believe, however, that for us to move ahead we need to implement point of care treatment and the new rapid thrombelastogram. We have begun studying this prospectively. The Europeans are very enthused with this modality.
And I think if all of us go into the emergency department and begin to study our patients from a scientific viewpoint we’ll surely improve the outcome of our patients.