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Postinjury Life Threatening Coagulopathy: Is 1:1 Fresh Frozen Plasma: Packed Red Blood Cells the Answer?

Kashuk, Jeffry L. MD; Moore, Ernest E. MD; Johnson, Jeffrey L. MD; Haenel, James RRT; Wilson, Michael MD; Moore, John B. MD; Cothren, C Clay MD; Biffl, Walter L. MD; Banerjee, Anirban PhD; Sauaia, Angela MD, PhD

The Journal of Trauma: Injury, Infection, and Critical Care: August 2008 - Volume 65 - Issue 2 - p 261-271
doi: 10.1097/TA.0b013e31817de3e1
Original Articles
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Background: Recent military experience suggests that immediate 1:1 fresh frozen plasma (FFP); red blood cells (RBC) for casualties requiring >10 units packed red blood cells (RBC) per 24 hours reduces mortality, but no clinical trials exist to address this issue. Consequently, we reviewed our massive transfusion practices during a 5-year period to test the hypothesis that 1:1 FFP:RBC within the first 6 hours reduces life threatening coagulopathy.

Methods: We queried our level I trauma center’s prospective registry from 2001 to 2006 for patients undergoing massive transfusion. Logistic regression was used to evaluate the independent effect of FFP:RBC in 133 patients who received >10 units RBC in 6 hours on (1) Coagulopathy (international normalized ratio [INR] >1.5 at 6 hours), controlling for our previously described risk factors predictive of coagulopathy, as well as RBC, FFP, and platelet administration (2) Death (controlling for all variables plus age, crystalloids per 24 hours, INR >1.5 at 6 hours).

Results: Overall mortality was 56%; 50% died from acute blood loss in the operating room. Over 80% of the RBC transfusions were completed in the first 6 hours: (Median RBC: 18 units) Median FFP:RBC survivors, 1:2, nonsurvivors: 1:4. (p < 0.001) INR >1.5 at 6 hours occurred in 30 (23%); 81% died. Regarding mortality, logistic regression showed significant variables (p < 0.05) included: RBC per 6 hours (OR = 1.248, 95%CI: 1.957–53.255), INR at 6 hours >1.5 (OR = 10.208, 95% CI: 1.957–53.255), ED temperature <34°C (OR = 15.491, 95% CI 1.376–174.396), and age >55 years (OR = 40.531, CI 5.315–309.077). The adjusted OR for FFP:RBC ratio including the quadratic term was found to follow a U-shaped association (quadratic term estimate 0.6737 ± 0.0345, p = 0.0189).

Conclusion: Although our data suggest that 1:1 FFP:RBC reduced coagulopathy, this did not translate into a survival benefit. Our findings indicate that the relationship between coagulopathy and mortality is more complex, and further clinical investigation is necessary before recommending routine 1:1 in the exsanguinating trauma patient.

From the Department of Surgery and Surgical Research (J.L.K., E.E.M., J.L.J., J.H., J.B.M., C.C.C., W.L.B., A.B.), Denver Health Medical Center; Division of Health Care Policy and Research (A.S.), Department of Medicine; and Department of Pathology and Laboratory Services (M.W.), Denver Health Medical Center, University of Colorado at Denver Health Sciences Center, Denver, Colorado.

Submitted for publication October 18, 2007.

Accepted for publication February 7, 2008.

Presented at the 66th Annual Meeting of the American Association for the Surgery of Trauma, September 27–29, 2007, Las Vegas, Nevada.

Address for reprints: Jeffry L. Kashuk, MD, FACS, Department of Surgery, Denver Health Medical Center, 777 Bannock Street, MC 0206, Denver, CO 80204-4507; email: Jeffry.Kashuk@dhha.org.

Recent military experience indicates that for patients with combat-related trauma requiring massive transfusion, an initial fresh frozen plasma (FFP):red blood cells (RBC) transfusion ratio of 1:1, (damage control resuscitation) is independently associated with improved survival.1–5 Contemporary civilian studies appear to support the damage control resuscitation policy,6 although the scientific basis for this policy remains to be established. Our group has had a long-standing interest in postinjury life threatening coagulopathy. In 1981, at this meeting,7 we reported that in a subset of patients sustaining major vascular trauma, persistent hemorrhage associated with acidosis, hypothermia, and coagulopathy (bloody vicious cycle) often resulted in death despite surgical control of the vascular injuries. A decade ago, we presented at this meeting8 the specific factors predictive of postinjury coagulopathy using a multiple logistic regression (MLR) analysis: (1) pH <7.10, (2) Temp <34°C, (3) injury severity score (ISS) >25, and (4) systolic blood pressure (SBP) <70 mm Hg. In our model, the conditional probability of developing coagulopathy when all four risk factors were present was 98%. Although these data invoked hypothermia, protracted shock, and acidosis as potent triggers of this process, they also emphasized the significant role of tissue injury in the pathophysiology of coagulopathy.

Recent reports provide compelling evidence that the synergistic effects of tissue injury and hypovolemic shock rather than a depletion or dilution of coagulation factors are critical in the genesis of early postinjury coagulopathy. Specifically, investigators have demonstrated activated protein C consumption concurrent with an increase in tissue plasminogen activator inhibitor; the net result is a hypocoagulable state.9,10 Finally, the potential adverse effects of FFP administration must be considered, as we11–13 and others14–24 have shown that FFP and platelets, as well as RBC are independent risk factors for the development of transfusion associated lung injury (TRALI) and multiple organ failure (MOF). In sum, although most civilian transfusion guidelines embrace liberal FFP administration in acutely injured patients with massive blood loss, the ideal ratio for this patient population remains to be analyzed.25–29

The purpose of this study was to review our recent 5 year massive transfusion practices for the acutely injured patient with the objective of evaluating the impact of FFP:RBC ratio on coagulopathy and mortality. Specifically, we sought to analyze whether current military findings indicating improved survival with early 1:1 FFP:RBC should be translated to the civilian population.

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METHODS

After appropriate IRB submission and approval, we queried our level I trauma center’s prospective registry as well as the transfusion registry maintained by our blood bank for all patients admitted to the Denver Health Medical Center from 2001 to 2006 undergoing massive transfusion, defined as greater than 10 units of RBC’s during the initial 6 hours after admission. We chose 6 hours because our ongoing MOF database indicates this is the critical time period which analyzes life threatening coagulopathy and its direct effects on mortality. Systematic review of the medical records of these patients was conducted to provide (1) demographic characteristics (age, gender), (2) anatomic injury severity (ISS), (3) blunt or penetrating injury mechanism, (4) the presence of hypovolemic shock:SBP, (5) fluids administered and blood products transfused (crystalloid, RBC, FFP, cryoprecipitate, apheresis platelets), and (6) coagulation related variables (blood pH, body temperature, International Normalized Ratio [INR], partial thromboplastin time [PTT]) at emergency department (ED), 6 hours and 24 hours, and (7) indices of perfusion: base deficit and lactate. In addition, the following outcome measures were collected for all patients (1) severe coagulopathy (defined as INR >1.5 at 6 hours), (2) death, (3) length of stay, and (4) survival time. Deaths were further categorized according to location as: operating room (OR), intensive care unit (ICU), and other. Exclusion criteria were (1) severe head injury judged to be the primary case of death, (24 patients, 18%, had associated head injuries not judged to be the primary case of death), (2) emergency department resuscitative thoracotomy, (3) documented severe chronic medical conditions including chronic obstructive pulmonary disease, coronary artery disease, chronic renal failure, and cirrhosis of the liver. After exclusions, 133 patients were eligible for this study. The independent effects of FFP:RBC ratio on coagulopathy (defined as INR >1.5 at 6 hours) and mortality was categorized by dividing the units transfused into 1:1, 1:2, 1:3, 1:4, and 1:5 or greater. All analyses were performed using SAS version 9.1 for Windows (SAS Institute Inc., Cary, NC, 2002–2003). Data were expressed as mean ± SEM if normally distributed, or as median and lower (25%)/upper (75%) quartiles (interquartile range) if the distribution was not known.

Crude bivariate associations with the outcomes (death and coagulopathy defined as INR >1.5 at 6 hours) were evaluated using the Kruskal-Wallis Test (the nonparametric equivalent of analysis of variance [ANOVA]) for continuous variables and the Chi-square test for categorical variables. Significance was set at the 0.05 level. MLR was used to control the association of the main variable (FFP:RBC ratio at 6 hours) with the outcomes for multiple confounders. The best format for which to include the independent variables in the MLR models (categorical, continuous, polynomials) was decided based on (1) graphic examination to analyze the shape of its association with the outcome, and (2) comparison of the goodness-of-fit of the models with the different formats. For example, the FFP:RBC ratio at 6 hours had a linear relationship with early coagulopathy, better represented by having the ratio variable in a continuous format. On the other hand, a U-shaped curve seemed to fit better with the association of FFP:RBC ratio with death; this was tested by including a quadratic term (square of the variable) and comparing the models’ goodness-of-fit. Other variables were also tested for higher order terms but none were significant. Predicted probabilities, adjusted for all other variables in the model, were analyzed using the MLR models.30 For negative results of interest, a power analysis was conducted using PASS versus 6.0 (NCSS, Kaysville, UT, 1998).

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RESULTS

During the 5 years of this review 133 patients received greater than 10 units of RBCs within 6 hours of hospital admission and were eligible for the study. Of note, most of the RBCs, FFP, and platelets were transfused within the first 6 hours of admission with a median of 100% for all three blood products (lower quartile: 85% for RBC, 78% for FFP, and 67% for platelet units; upper quartile: 100% for all) (See Fig. 1). These results further strengthen our contention that massive transfusion for the purposes of studying postinjury coagulopathy should be defined as greater than 10 units of packed red blood cells (RBCs) within 6 hours of hospital admission. Figure 2 shows our transfusion practices for the 5-year time period of this study. Of note, there was no significant difference in FFP:RBC ratio, FFP and RBC at 6 hours and at 24 hours administered during this time period. When we evaluated the mean crystalloid administration during the first 24 hours for patients in each ratio group, no significant difference was noted.

Fig. 1.

Fig. 1.

Fig. 2.

Fig. 2.

The overall mortality was 56%, death from penetrating injuries occurred in 30 (41%) of 74 patients and after blunt trauma in 44 (59%). The distribution of place of death by FFP:RBC ratio is shown in Figure 3. As anticipated, patients who died in the OR were more likely to die from penetrating injuries and less likely to receive additional FFP at the time of RBC resuscitation. Figure 4 correlates location of death with time to death. As expected, patients died rapidly of exsanguinating vascular injuries in the OR, and those that were transferred to the ICU died many hours later. Descriptive characteristics for severity of injury, vital signs, laboratory values, resuscitation indices, survival statistics, and transfusion ratios are summarized in Tables 1 and 2. Of note, the median RBC units administered in 6 hours was 18 (LQ = 14, UQ = 25). In the emergency department, the mean SBP was 91.7 mm Hg ± 3 mm Hg, temperature 35.9°C ± 0.1, pH 7.1 ± 0, and the mean initial INR was 1.4 ± 0, increasing to 2.4 ± 0.9 by 6 hours after presentation.

Fig. 3.

Fig. 3.

Fig. 4.

Fig. 4.

Table 1

Table 1

Table 2

Table 2

The results of continuous data analyses of independent variables in this study for each ratio are summarized in Table 3. Differences between ratio groups were noted in pH and temperature at ED presentation, INR at 6 hours, FFP and platelet transfusion at 6 hours and 24 hours, RBC, FFP, and platelets administered from 7 hours to 24 hours, INR at 6 hours, total crystalloids administered at 24 hours, and survival in hours. These differences became less apparent when the ratios of 1:1 to 1:3 are compared with 1:4 and greater. The relationships of the risk factors for coagulopathy defined by INR >1.5 at 6 hours for all ratio categories in this study are depicted in Figure 5. As expected, those patients who had higher FFP:RBC ratios had a higher incidence of risk factors.

Table 3

Table 3

Fig. 5.

Fig. 5.

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Coagulopathy as an Endpoint

Summarized in Table 4 and Figure 5 are the results of MLR analysis performed for the endpoint of coagulopathy defined as INR >1.5 at 6 hours after ED presentation. Of note, ED temperature <34°C was significant, whereas ISS >25 and number of platelet units transfused in 6 hours were marginally significant for the development of coagulopathy as an endpoint. Interestingly, crystalloid infusion was not found to be an independent risk factor for coagulopathy, although this comparison was underpowered. Figure 6 demonstrates the predicted probability of coagulopathy for each level of FFP:RBC ratio administered. Although this relationship appears linear, its significance was not established, possibly because of limited sample size and the high correlation of the variable of interest (FFP:RBC ratio) with the other independent variables (R2 = 0.80).

Table 4

Table 4

Fig. 6.

Fig. 6.

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Death as an Endpoint

The MLR analysis for death as an outcome is shown in Table 5. The significant independent variables (p < 0.05), (OR 95%) included: RBC transfused at 6 hours (OR = 1.248, 95% CI: 1.038–1.501), INR at 6 hours >1.5 (OR = 10.208 95% CI: 1.957–53.255), ED temperature <34°C (OR = 15.49195% CI 1.376–174.396), and age >55 years (OR = 40.531, CI 5.315–309.077). Of note, the adjusted odds ratios for the variable of FFP:RBC ratio including the quadratic term could not be expressed in a simple table, because instead of a linear correlation, the FFP:RBC ratio at 6 hours was found to follow a U-shaped relationship with death as an endpoint (Fig. 7), as demonstrated by the significance of the quadratic term (p < 0.027). Furthermore, the lowest predicted mortality probability, (0.35, trendline) was found to correlate with transfusion ratios in the range of 1:2 to 1:3. This U shaped relationship was further strengthened when patients who died in the OR from exsanguinating penetrating wounds were excluded (Fig. 8). Interestingly, in this group, the predicted probability of mortality further decreased to 0.2 (trend line) over the transfusion ratio range 1:2 to 1:3. The importance of clearly delineating transfusion ratios is emphasized in Figure 9. As noted, when we combined the 1:1 and 1:2 ratios, the U-shaped association was lost, and the relationship of mortality to ratio appears to follow a linear trend. Table 6 illustrates the impact of transfusion ratio on survival for all patients in this study. As noted, the median FFP:RBC ratio for all survivors was 1:2, and for all nonsurvivors, 1:4. This further re-enforces our belief that the critical ratio for survival in this series appears to be in the range of 1:2 to 1:3, as mentioned above.

Table 5

Table 5

Fig. 7.

Fig. 7.

Fig. 8.

Fig. 8.

Fig. 9.

Fig. 9.

Table 6

Table 6

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DISCUSSION

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.

Although the ideal resuscitation transfusion for critically injured patients is fresh whole blood1,20,32,33 this product is generally only available in combat settings. In the civilian sector, logistic challenges of collection and current concerns for infectious transmission limit the practical use of this product. Accordingly, in the civilian sector, use of fresh whole blood is currently precluded by regulatory requirements, because of collection issues and infectious concerns.

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

Despite advances in the surgical approach to coagulopathy via damage control during the past 20 years, many recommendations to guide current transfusion and resuscitation therapy lack solid scientific evidence and current guidelines are largely expert opinion rather than evidence based. Cinat et al.,37 in a series of patients with >50 units massive transfusion, noted a ratio of 1:1.8 in survivors versus 1:2.5 in nonsurvivors. Gonzalez et al.,6 concluded that persistent coagulopathy for patients arriving in the ICU greater than 6 hours after initial presentation to the trauma center was an independent risk factor for mortality, and suggested that earlier aggressive use of FFP; approaching ratios of 1:1 would improve the later survival in this group. Although logical, this suggestion was made without direct investigation of the relationship of early transfusion practice to ultimate survival.

Borgman et al.,1 recently reported a retrospective review of 246 patients at a US Army combat support hospital who received a massive transfusion, defined as >10 units of RBCs within a 24-hour period. After dividing their patients into three groups according to high (approaching 1:1), medium (1:2–3), and low (1:5 and greater) ratios, they concluded that ratios approaching 1:1 (damage control resuscitation) were independently associated with survival. Despite these excellent results from the military, we think that several differences between the military study and our civilian group are evident and must be considered when evaluating whether such a policy can readily be applied to a civilian cohort. As pointed out previously, and in contrast to current civilian practice, the military uses fresh whole blood when available. Additionally, as mentioned by the authors, when fresh whole blood and thoracic trauma were excluded from their analysis, mortality rates between the medium and high ratio lost statistical significance. Of note, the medium ratio of FFP:RBC in their study was similar to our range of 1:2 to 1:3 which we think may be the critical threshold for survival. Other differences between these studies are the inclusion of primary neurosurgical trauma and predominance of thoracic as well as pelvic and extremity injuries in the military. The latter may reflect the contributions of blast injury to this group, a pattern not currently seen in civilian trauma. Significant differences between conventional trauma and blast injury have been described that likely impact resuscitation strategies.38,39 In addition, although extensive soft tissue injury is potentially amenable to hemorrhage control via direct pressure or tourniquet, such injuries probably contribute to coagulation factor consumption. We think the differences between the civilian and military sector to be important when evaluating whether the successful damage control resuscitation policy of the military can be applied to our civilian population.

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

Recent reports9,10,60 suggest that trauma patients manifest early abnormalities in coagulation profiles, before crystalloid or blood administration. Shock and associated tissue injury and acidosis likely trigger an early acute endogenous coagulopathy independent of clotting factor deficiency. Further insights into this alternative pathway were suggested by Ganter et al.,61. Brohi et al.,10 have noted that hypoperfusion results in reduced protein C in these patients, may lead to a state of anticoagulation and hyperfibrinolysis, suggesting a mechanism modulated by the thrombomodulin pathway. These results provide further support that early aggressive pre-emptive administration of FFP, despite the absence of coagulation factor depletion may be ineffective or potentially deleterious in this group (FFP resistant, see Fig. 10). Given the complexity of mechanisms contributing to this system, accurate on-going monitoring of the process is essential to guide management protocols. Although PTT and INR are the most commonly used tests to assess coagulation function, their principle use has been for anticoagulation therapy and their reliability in massive transfusion of trauma patients remains to been proven.46,62 Although previously described,63 there has been renewed interest in thromboelastography as a potentially more accurate method of evaluating hemostatic function.64 Emerging evidence suggests that the newer point of care (POC) rapid thromboelastography may provide more timely and accurate determinations of qualitative and dynamic thrombostatic homeostasis in this patient group, and could potentially guide more accurate resuscitation guidelines. Most of the evidence to support this concept is from Europe65–68 but experience is beginning to emerge in the United States. We have acquired this equipment and initiated a prospective study to analyze its role in managing postinjury coagulopathy. Furthermore, this technology may be valuable in the treatment of postinjury hypercoagulability.

Fig. 10.

Fig. 10.

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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DISCUSSION

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.

Keywords:

Postinjury; Coagulopathy; Plasma; Transfusion

© 2008 Lippincott Williams & Wilkins, Inc.