An FFP:PRBC Transfusion Ratio ≥1:1.5 Is Associated With A Lower Risk Of Mortality After Massive Transfusion : Journal of Trauma and Acute Care Surgery

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Original Articles

An FFP:PRBC Transfusion Ratio ≥1:1.5 Is Associated With A Lower Risk Of Mortality After Massive Transfusion

Sperry, Jason L. MD, MPH; Ochoa, Juan B. MD; Gunn, Scott R. MD; Alarcon, Louis H. MD; Minei, Joseph P. MD; Cuschieri, Joseph MD; Rosengart, Matthew R. MD, MPH; Maier, Ronald V. MD; Billiar, Timothy R. MD; Peitzman, Andrew B. MD; Moore, Ernest E. MD The Inflammation the Host Response to Injury Investigators

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The Journal of Trauma: Injury, Infection, and Critical Care: November 2008 - Volume 65 - Issue 5 - p 986-993
doi: 10.1097/TA.0b013e3181878028
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Abstract

The effects of coagulopathy, hypothermia, and acidosis, touted as the “lethal triad,” are well-known markers for mortality after traumatic hemorrhage.1–4 Increasing attention has recently been paid to the correction of the coagulopathy that complicates massive transfusion and damage control resuscitation after severe injury.5–8 Importantly, coagulopathy has been shown to be present early after injury, at the time of trauma admission, even further substantiating the importance of early initiation of treatment and the prevention of coagulopathy.7,9–11 Both allogeneic blood and fresh frozen plasma (FFP) transfusions have been shown to be independent risk factors for poor outcome in the critically ill.12–16 Despite these inherent risks, the acutely exsanguinating injured patient at times requires large volumes of these transfusion components until hemostasis can be obtained.17–19 Recent military experience suggests that, in patients who require massive transfusion, a high FFP: packed red blood cell (PRBC) transfusion ratio, in the first 24 hours postinjury, is associated with improved survival.20 However, the appropriate ratio in which these transfusion products should be given remains controversial,21 and the associated risks attributable to a high FFP:PRBC transfusion ratio have not been adequately characterized for a civilian population.

The main objective of this current analysis was to determine whether ≥1:1.5 FFP:PRBC transfusion ratio (high F:P ratio), in patients who required massive transfusion after injury, was associated with a lower risk of mortality. Additionally, the associated risks of multiple organ failure (MOF), nosocomial infection (NI), and acute respiratory distress syndrome (ARDS) attributable to high F:P transfusion ratio were independently characterized to determine whether those who survive their initial injury are at additional risk because of this type of transfusion practice. We hypothesized that patients who received a high F:P ratio would be at a lower risk of mortality, yet those who do survive, would have a higher risk of subsequent complications.

METHODS

Data were derived from the ongoing multicenter prospective cohort study known as the Inflammation and the Host Response to Injury Large Scale Collaborative Program (www.gluegrant.org) supported by the National Institute of General Medical Sciences (NIGMS), which is designed to characterize the genomic and proteomic response in injured patients at risk for MOF after traumatic injury and hemorrhagic shock.22 Standard operating procedures were developed and implemented across all institutional centers to minimize variation in postinjury care, including early goal directed resuscitation, strict glycemic control, venous thromboembolism prophylaxis, appropriate low tidal volume ventilation, ventilator-associated pneumonia management, and restrictive transfusion guidelines.22–27 Patients admitted to one of seven institutions, during a 3.5-year period (November 2003–March 2007), were included in the analysis. Inclusion criteria for the overall cohort study included blunt mechanism of injury, presence of prehospital or emergency department systolic hypotension (<90 mm Hg) or an elevated base deficit (≥6 meq/L), blood transfusion requirement within the first 12 hours, and any body region exclusive of the brain with an abbreviated injury score (AIS) ≥2, allowing exclusion of patients with isolated traumatic brain injury. Patients younger than 16 years or older than 90 years and those with cervical spinal cord injury were also excluded from enrolment. For the current study, only patients who required ≥8 units of PRBCs within the first 12 hours from injury were included in the analysis. Clinical data were entered and stored in TrialDb, a web-based data collection platform, by trained research nurses.28 Integrity of the data were maintained through ongoing curation and external data reviewed by an independent chart abstractor.

While patients were admitted to the intensive care unit (ICU), multiple organ dysfunction scores for renal, hepatic, cardiovascular, metabolic, hematologic, respiratory, and neurologic systems were determined daily.29–31 All nosocomial infectious complications were monitored and recorded (infection type, culture specimen source, and bacteriology). The diagnosis of MOF required a maximum Marshall Multiple Organ Dysfunction score >5, whereas the diagnosis of NI required specific clinical criteria along with positive culture evidence. ARDS was defined as a Pao2/Fio2 ratio <200, bilateral infiltrates on X-ray, a measured pulmonary artery occlusion pressure <18 mm Hg or the absence of clinical evidence for elevated left atrial pressure. All time variables to the respective outcome event were determined from the day of initial injury, whereas the time to the first NI was used in those patients with multiple infections. Diagnosis of a ventilator-associated pneumonia required a quantitative culture threshold of ≥ 104 CFU/mL for bronchoalveolar lavage specimens.24 Diagnosis of catheter-related blood stream infections required positive peripheral cultures with the identical organism obtained from either a positive semiquantitative culture (>15 CFU/segment), or positive quantitative culture (>103 CFU/segment) from a catheter segment specimen. Urinary tract infections required >105 organisms/mL of urine.

Each individual patients transfusion requirements for FFP and PRBCs (per unit) in the initial 12 hours after injury were used to determine an FFP:PRBC ratio. As this was a continuous variable, a specific cut point was required to categorize patients into the comparison groups (Fig. 1). Those patients who received at least an FFP:PRBC ratio of 1:1.50 were categorized as the high F:P ratio group. Patients who required an FFP:PRBC transfusion ratio of 1:1.51 or less were categorized as low F:P patients. Similar decimal place cutoffs (x.50–x.51) were used for the stratified group analysis (see below).

F1-3
Fig. 1.:
FFP:PRBC group stratification.

Patients who received a high F:P ratio within the first 12 hours postinjury versus those patients who received a low F:P ratio were compared in a univariate fashion, and crude rates for mortality (in hospital), MOF ARDS and the development of NI were then determined and compared. The FFP:PRBC variable, specifically the low F:P group, was then categorized as 1:2 (1:1.51–1:2.50, n = 105), 1:3 to 4 (1:2.51–1:4:50, n = 111), and ≤1:5 (≤1:4.51, n = 97) groups, and the time course of mortality risk associated with the FFP:PRBC transfusion ratio groups was characterized using Kaplan-Meier survival analysis. Cox proportional hazard regression modeling was then used to characterize the independent risk of mortality (in hospital) associated with a high F:P ratio relative to patients who received a low F:P ratio, after adjusting for important confounders. Then after stratification of the low F:P group, a similar regression analysis was performed. Confounders for the multivariate models were chosen to adjust for differences in injury characteristics, shock severity, operative and ICU interventions, and important comorbidities. Particular attention was paid to those factors that would alter the early coagulation status of the patient. Confounders for the final regression model included patient age, gender, Injury Severity Score (ISS), acute physiology and chronic health evaluation (APACHE) II score, presenting Glasgow Coma Score (GCS) and head AIS score, crystalloid, platelet and cryoprecipitate requirements (within 12 hours postinjury), worst base deficit and blood gas pH in the first 12 hours, lowest core body temperature, initial coagulation status (international normalized ratio [INR]), the requirement of early operative intervention (exploratory laparotomy or thoracotomy or sternotomy), early vasopressor (<24 hours) requirements, and a history of liver disease. Clinically relevant interaction terms were tested and kept in the final model if statistically significant (p < 0.05).

Cox proportional hazard regression was then also used to determine the independent associated risks of MOF, ARDS, and NI attributable to a high F:P ratio after controlling for important confounders. Patients who died or who were discharged from the hospital without a respective outcome event were censored, thus adjusting for any effect of early death on subsequent MOF, ARDS, and NI calculated risks.

All data were summarized as mean ± SD, median (interquartile range), or percentage (%). Student’s t or Mann-Whitney statistical tests were used to compare continuous variables, whereas χ2 or Fisher’s exact tests were used for categorical variables. The institutional review board of each participating center approved the cohort study, while the institutional review board at the University of Pittsburgh Medical Center approved this current analysis.

RESULTS

Of the 1,036 blunt injured patients enrolled during the study period, 415 patients had a blood transfusion requirement of ≥8 units within the initial 12 hours after injury, and constituted the study population. In this cohort, 39 patients received no FFP within the first 12 hours from injury (FFP:PRBC ratio = 0) despite having a ≥8 unit blood transfusion requirement. The overall mortality for the study population was 33.5%, whereas the overall complication rates for MOF, NI, and ARDS were 56.4%, 46.5%, and 29.6%, respectively. This cohort of patients requiring massive transfusion had a median age of 41 years (IQR 25–54) and were significantly injured with a median ISS of 34 (IQR 22–43). An early (with 48 hours) exploratory laparotomy was required in 63% of patients, whereas 16% required an early thoracotomy or sternotomy. The median blood transfusion requirement in first 12 hours postinjury was 14 units (IQR 14–22) for the entire study cohort.

Those patients who received a high F:P ratio when compared with those who received a low F:P ratio were similar in age, gender, mechanism of injury, presenting base deficit and INR, level of acidosis, and prehospital comorbidities (Table 1). Those who received a high F:P ratio had higher ISS score and extremity AIS scores, higher APACHE II scores, lower GCS scores, and had lower nadir core body temperature measurements in the first 24 hours postinjury. They also had greater length of stay, ICU, and ventilator requirements; however, these comparisons would be inaccurate if an early mortality difference existed between the two groups. Hospital free days, ICU free days, and ventilator free days were compared with adjust for any such difference and confirmed that high F:P ratio patients had fewer hospital, ICU, and ventilator free days. Although not statistically different, high F:P ratio patients were less likely to undergo early laparotomy and had clinically higher head AIS scores. Crude rate comparison for mortality did not reach statistical significance, but high F:P ratio patients did have a significantly higher incidence of NI and ARDS, whereas a clear trend existed for having a higher rate of MOF (Table 2). Although no statistical differences in mortality were found between those who received a high F:P ratio versus those who did not, the clinically relevant difference in crude mortality between the comparison groups highlights the importance of the use of Cox proportional hazard regression, which allows patients who die before a respective outcome event to be appropriately censored, when determining complication risks.

T1-3
Table 1:
Baseline Demographics and Characteristics for Patients Who Received a High F:P vs. a Low F:P Transfusion Ratio
T2-3
Table 2:
Crude Complication Rate Comparison for Patients Who Received a High F:P vs. a Low F:P Transfusion Ratio

Transfusion and resuscitation requirements compared across the two groups revealed that those who received a high F:P ratio had a reduced blood transfusion requirement at both 12 hours and 24 hours postinjury (Table 3). A significantly higher amount of cryoprecipitate was also given to the high F:P group; however, no differences were found in platelet or crystalloid administration. It is apparent that the vast majority of transfusion products and crystalloid were given within the first 12 hours after injury as the average requirements increased only slightly when analyzed at 24 hours out from injury.

T3-3
Table 3:
Transfusion Requirements at 12 h and 24 h Postinjury

Kaplan-Meier time to event analysis revealed early separation of survival curves for high F:P ratio patients relative to those who received a low F:P ratio (Fig. 2). Although the survival curves overall were not statistically different (log-rank: p = 0.119), the mortality rate at day 1 postinjury was significantly lower in the high F:P group (3.9% vs. 12.8%, p = 0.012). Although underpowered to be statistically different, when the FFP:PRBC variable was stratified into groups (high F:P, 1:2, 1:3–4, and ≤1:5), similar findings with early separation of the survival curves are apparent at day 1 postinjury, with a dose response being demonstrated, based on the transfused FFP:PRBC ratio (Fig. 3).

F2-3
Fig. 2.:
Kaplan-Meier survival analysis comparing high F:P and low F:P transfusion ratios.
F3-3
Fig. 3.:
Kaplan-Meier survival analysis comparing stratified FFP:PRBC transfusion ratio groups.

Cox proportional hazard regression revealed that a high F:P ratio, relative to patients who received a low F:P ratio, was independently associated with a 52% lower risk of mortality (HR 0.48, p = 0.002, 95% CI 0.3–0.8), after controlling for important confounders. To verify that this finding held true irrespective of the amount of blood transfusion a patient required, the amount of blood (per unit) required at 12 hours postinjury was added as a covariate and the hazard ratio for high F:P ratio patients remained significant with the protective effect for mortality being unaltered (HR 0.57, p = 0.026, 95% CI 0.35–0.93). When complications including MOF and the development of NI were added to the model, no changes occurred and the hazard ratio for a high F:P ratio also remained unaltered, suggesting that these findings are not attributable to the development of these clinically outcomes. Similar to the results from the Kaplan-Meier analysis, when patients who died within the first 48 hours postinjury were excluded, the hazard ratio for a high F:P ratio became nonsignificant (HR 0.70, p = 0.241, 95% CI 0.4–1.2), indicating that, in part, the protective effect associated with a high F:P ratio was relevant to mortality early after injury, within the first 48 hours. Interestingly, when only patients who received ≥4 and <8 units of blood (n = 307) were included in the model, the protective effects associated with a high F:P ratio were no longer present (HR 0.95, p = 0.894, 95% CI 0.4–2.0), suggesting that these findings hold true only when a patient requires massive transfusion. When the FFP:PRBC ratio was further stratified into groups (high F:P, 1:2, 1:3–4, and ≤1:5), relative to patients who received <1:5 FFP:PRBC ratio, the hazard ratios for mortality also demonstrated a dose response relationship with a high F:P ratio remaining a significant independent predictor or survival (mortality HR 0.38, p = 0.002, 95% CI 0.2–0.7, Fig. 4).

F4-3
Fig. 4.:
Independent risk of mortality associated with stratified FFP:PRBC transfusion ratios using Cox proportional hazard regression modeling (relative to a FFP:PRBC <1:5). Additional covariates included in the regression model: age, gender, Injury Severity Score, APACHE II score, ED Glasgow Coma Score and head AIS, 12 hour crystalloid, platelet and cryoprecipitate requirements, worst base deficit, and blood gas pH in the first 12 hours, lowest core body temperature in 24 hours, ED coagulation status (INR), the requirement of early operative intervention (exploratory laparotomy or thoracotomy or sternotomy), early vasopressor (<24 hours) requirements, and a history of liver disease.

To determine the potential risks associated with the proportion of FFP and PRBCs a patient receives, Cox proportional hazard regression was also used to determine the independent associated risks for MOF, NI, and ARDS attributable to receiving a high F:P ratio relative to a low F:P ratio. After controlling for differences in age, gender, injury severity, initial base deficit, and APACHE II score, a high F:P ratio was not significantly associated with a higher risk of MOF or NI (Fig. 5). However, a high F:P ratio was associated with almost a twofold higher risk of ARDS, after controlling for important confounders (Table 4). Finally, to characterize the time course at which this higher risk of ARDS occurs after injury, Kaplan-Meier analysis revealed significantly different (log rank: p = 0.001) (Fig. 6) time to event curves with separation around day 4 postinjury, signifying that this higher risk of pulmonary complications occurs soon after injury and were not a delayed outcome effect.

F5-3
Fig. 5.:
Risk of complications associated with a high F:P (≥1:1.5) transfusion ratio.
T4-3
Table 4:
Cox Proportional Hazard Regression Model With ARDS as Dependent Variable
F6-3
Fig. 6.:
Kaplan-Meier time to event analysis for the development of ARDS for high F:P and low F:P transfusion ratios.

DISCUSSION

Despite the significant advances in trauma care delivery and postinjury management practices that have occurred during the last decade, uncontrolled hemorrhage remains one of the leading causes of trauma-related deaths.4,32–34 A significant amount of attention has been paid recently to the prevention and early treatment of the coagulopathy that complicates severe injury and damage control resuscitation.6,19,35,36 Historically, postinjury coagulopathy was thought to be a secondary event, resulting from resuscitative hemodilution, ongoing acidosis, and iatrogenic hypothermia.1,2,4 Recent evidence suggests that coagulopathy should be thought of as a primary event, as it occurs early after injury, even at the time of admission before major volume resuscitation, and is independently associated with detrimental outcomes.7,9–11 Recent military experience has provided strong evidence for a survival benefit associated with a high FFP:PRBC transfusion ratio (median, 1:1.4) in patients who require massive transfusion.20 This cohort of military patients were primarily injured via a penetrating mechanism, had a median age of 24 years, and were predominantly men. The survival benefit was most pertinent to mortality that occurred within the first 4 hours from injury, primarily decreasing early death from ongoing hemorrhage.

The results of this current analysis complement these prior findings and verifies that a high F:P (≤1:1.5 FFP:PRBC) ratio is associated with a lower risk of mortality in a civilian population, who were somewhat older, were more typically split across gender, and who all had a blunt mechanism of injury. Similarly, these current results suggest that the protective effects associated with a high F:P ratio were most relevant to mortality within 48 hours from the time of injury, suggesting that the higher mortality risk associated with an FFP:PRBC transfusion ratio <1:1.5 occurs earlier, possibly secondary to ongoing coagulopathy and uncontrollable hemorrhage. Despite crude mortality rates between the comparison groups not reaching statistical difference, the significant early mortality differences (with in first 24 hours) was likely responsible for this overall mortality risk reduction. These protective effects were not found in those who required <8 units of blood in the initial 12 hours from injury, and verifies that it is the massive transfusion population where prevention and early correction of coagulopathy seems most efficacious. These results add to our current understanding of the benefits associated with aggressive prevention and treatment of coagulopathy after injury and massive transfusion and additionally offers insight into the potential complications and risks attributable to this type of resuscitative practice.

Despite high F:P ratio patients having higher crude rates of NI, ARDS, and a trend toward a higher rate of MOF, after controlling for important confounders, there was no greater risk of MOF and NI attributable to a high F:P ratio found in multivariate regression analysis. These findings were apparent even though high F:P patients had a significantly greater hospital length of stay, higher ICU days, and more time required on the ventilator. Importantly, these length of stay differences were not simply due to a higher mortality rate in the low F:P ratio groups as hospital, ICU, and ventilator free days were also found to be less in the high F:P group. An almost twofold greater independent risk of ARDS, however, was found to be attributable to high F:P ratio. This finding was independent of the quantity of crystalloid a patient received and the severity of chest injury sustained. This greater risk was apparent very early in the patients hospital course, within 4 days from the time of injury, temporally related to the transfusion product administration rather than a delayed outcome event. In a recent publication by Khan et al.,16 FFP and platelet transfusions were found to be independent risk factors for acute lung injury and ARDS, each having a higher risk relative to PRBC transfusion in critically ill medical patients. Exclusive of this study, a relative paucity of high-level evidence exists on the potential benefits or risks associated with transfusion products other than blood, particularly after injury.37,38 As this represents the first analysis to characterize the risks associated with a high FFP:PRBC ratio, further studies are required to verify these findings and to advance our understanding and insight into the risks associated with plasma-rich transfusion products (FFP, platelets, and cryoprecipitate) and the proportion in which they are and should be given with blood transfusions after injury.

It is intriguing that a lower risk of mortality was still demonstrated for those who received a high F:P ratio, despite these patients being more severely injured by ISS, having higher APACHE II scores, and lower GCS scores at admission. Similarly, the blood transfusion requirement, beginning as early as 12 hours postinjury, is unexpectedly lower in the high F:P patients based on these same group differences. Importantly, the protective effect attributable to a high FFP:PRBC was independent of the amount of blood transfusion required. This suggests that our findings were not due to differences in blood transfusion between the comparison groups and were most strongly dependent on the proportion of FFP relative to PRBC’s a patient received. This analysis represents one of the largest that has analyzed transfusion product ratios in patients who require massive transfusion, but the secondary nature of this current analysis is unable to definitively prove that a high F:P ratio is causally responsible for these findings. Despite this limitation, proposed criteria39 including consistency across different data sets, theoretical plausibility, the temporal relationship of the associations, the dose-response relationship in early survival, and finally the strength of the associations even after controlling for important confounders, does give precedence to the causality argument and justifies future higher level, prospective analyses, to provide more definitive answers concerning a high FFP:PRBC transfusion practice.

This analysis does have several potential limitations. First, this study is a secondary analysis of a prospective cohort study looking at the genomic and proteomic response after severe injury and hemorrhagic shock. As with any secondary analysis, data were not recorded to answer our specific hypothesis stated for this study. Potential unknown or unmeasured confounding variables may be responsible for the associations described and the conclusions formulated. Factor VIIa use was not originally a data point recorded for the overall cohort analysis. As its use and relevance has increased after injury, it was added as an important variable to be recorded but this prospectively occurred only as recently as December 2006. The data analyzed included patients upto April 2007. The use of factor VIIa in this small subset of patients was not different (high F:P-0% vs. low F:P-1%, p = 0.326) form those in whom prospectively recorded data exist; however, this represents incomplete data, and differences in factor VIIa use may be an important confounder and represents a significant limitation of this analysis. Despite similar comparison group characteristics overall and adjustment for differences that were apparent using multivariate regression analysis, patients who received a high F:P ratio soon after injury may be an inherently different population relative to those who received a low F:P ratio, as they were not randomized. Those patients who received a high F:P ratio were clinically less likely to undergo exploratory laparotomy (56% vs. 66% p = 0.060) and our results could be biased despite adjusting for this potential confounder in our regression models. Finally, the time of death (in hours) during the initial days of injury was not prospectively recorded in the data set. It may be that those patients most likely to die early due to uncontrolled hemorrhage were less likely to receive greater amounts of FFP secondary to time restraints or other unknown factors. However, all analyzed patients received at least 8 units of PRBC’s within the first 12 hours from the time of injury, and those who received a low F:P ratio were given even greater amounts of blood at 12 hours and 24 hours, making any potential time to death difference between the comparison groups a less likely confounder.

In conclusion, patients who received an FFP:PRBC transfusion ratio ≥1:1.5, relative to patients who received <1:1.51 FFP:PRBC ratio, had a significant lower risk of in-hospital mortality following massive transfusion after controlling for important confounders. This protective effect was most pertinent for mortality within the first 48 hours after injury and was independent of the blood transfusion requirement each individual patient received. Although crude mortality differences between the high F:P and low F:P groups did not reach statistical significance, the significant difference in early (24 hour) mortality was likely responsible for this overall mortality risk reduction. As the FFP:PRBC ratio became smaller (less FFP relative to PRBCs) a dose-response relationship was demonstrated for mortality, with those patients who received minimal or no FFP having the highest early mortality. Those who survived their initial injury were almost at a twofold higher risk of ARDS, independent of important confounders. These results suggest that the mortality risk associated with an FFP:PRBC transfusion ratio <1:1.5 may be secondary to inadequate correction of coagulopathy and uncontrollable hemorrhage. Patients who receive ≥1:1.5 FFP:PRBC transfusion ratio and survive their initial injury are almost at a twofold higher risk of ARDS. This analysis provides further justification for the prospective trial investigation to evaluate the safety and efficacy of the incorporation of a high FFP:PRBC into massive transfusion practice.

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Keywords:

Massive transfusion; Transfusion ratio; Plasma; Cox proportional hazard regression

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