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Author Manuscript
JAMA Surg. Author manuscript; available in PMC 2014 February 01.
Published in final edited form as:
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Corresponding author: John B. Holcomb, MD, FACS, Vice Chair and Professor of Surgery, Chief, Division of Acute Care Surgery,
Director, Center for Translational Injury Research, Jack H. Mayfield Chair in Surgery, University of Texas Health Science Center,
Houston, TX, 77030, 713-500-5493.
Previous Presentation of the Information Reported in the Manuscript: Portions of these data were presented at the Advanced
Technology Applications for Combat Causality Care (ATACCC) Annual Scientific Meeting, August 15–18, 2011, Fort Lauderdale,
FL.
Disclaimer: The views and opinions expressed in this manuscript are those of the authors and do not reflect the official policy or
NIH-PA Author Manuscript
position of the Army Medical Department, Department of the Army, the Department of Defense, or the United States Government.
Online-only Material: eFigure 1 are available at http://www.jama.com.
Author Contributions: Drs del Junco and Fox had full access to all the data in the study and take responsibility for the integrity of
the data and the accuracy of the data analysis. Dr Rahbar served as PI of PROMMTT and is the senior author on this manuscript.
Study concept and design: Holcomb, del Junco, Rahbar, Fox, Zhang
Acquisition of data: Alarcon, Bai, Brasel, Bulger, Cohen, Cotton, Holcomb, Matijevic, Muskat, Myers, Phelan, Schreiber, White
Analysis and interpretation of data: del Junco, Fox, Rahbar, Holcomb, Wade
Drafting of the manuscript: Holcomb, Fox, del Junco, Wade
Critical revision of the manuscript for important intellectual content: del Junco, Holcomb, Fox, Rahbar, Wade, Alarcon, Bai, Brasel,
Bulger, Cohen, Cotton, Matijevic, Muskat, Myers, Phelan, Schreiber, White, Zhang
Statistical analysis: del Junco, Fox, Rahbar
Obtained funding: Rahbar
Administrative, technical, or material support: Rahbar, Holcomb, Fox, del Junco, Alarcon, Bai, Brasel, Bulger, Cohen, Cotton,
Muskat, Myers, Phelan, Schreiber, Wade, White, Zhang,
Study supervision: Rahbar, Holcomb
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of
Interest. Dr Holcomb reported serving on the board for Tenaxis, the Regional Advisory Council for Trauma, and the National Trauma
Institute; providing expert testimony for the Department of Justice; grants funded by the Haemonetics Corporation, and KCI USA,
Inc. and consultant fees from the Winkenwerder Company. Dr Wade reported serving on the Science Board for Resuscitation
Products, Inc. and the Advisory Board for Astrazeneca. No other disclosures were reported.
Holcomb et al. Page 2
6Department of Pathology and Laboratory Medicine, Medical School, University of Texas Health
Science Center at Houston
7Division of Trauma and Critical Care, Department of Surgery, Medical College of Wisconsin
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8Division
of Trauma and Critical Care, Department of Surgery, School of Medicine, University of
Washington
9Divisionof Trauma/Critical Care, Department of Surgery, College of Medicine, University of
Cincinnati
10Division
of Trauma, Department of Surgery, School of Medicine, University of Texas Health
Science Center at San Antonio
11Division
of Burn/Trauma/Critical Care, Department of Surgery, Medical School, University of
Texas Southwestern Medical Center at Dallas
12Department of Surgery, Brooke Army Medical Center, Fort Sam Houston, Texas
13School of Biomedical Informatics, University of Texas Health Science Center at Houston
14Divisionof Epidemiology, Human Genetics and Environmental Sciences, School of Public
Health, University of Texas Health Science Center at Houston
Abstract
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Context—Hemorrhagic shock is the leading potentially preventable cause of death after injury.
Transfusion of early and increased ratios of plasma and platelets to red blood cells (RBCs) has
been associated with decreased mortality; however conflicting reports and the time-varying nature
of transfusions and hemorrhagic death raise concern for the validity of the clinical conclusions
drawn from the retrospective data.
Objective—To relate in-hospital mortality to: 1) early transfusion of plasma and/or platelets and
2) time-varying plasma:RBC and platelet:RBC ratios.
Design—Prospective cohort study documenting the timing of transfusions during active
resuscitation and patient outcomes. Data were analyzed using time-dependent proportional hazards
models.
Setting—Ten US Level 1 trauma centers.
Patients—Adult trauma patients surviving for 30 minutes after admission, transfused at least 1
unit RBC within 6 hours of admission (n=1245, the original study group) and at least 3 total units
(of RBC, plasma or platelets) within 24 hours (n=905, the analysis group).
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INTRODUCTION
Injury is increasing in incidence, the second leading cause of death worldwide, and the
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leading cause of years of life lost in the United Sates.1,2 Uncontrolled hemorrhage after
injury is the leading cause of potentially preventable death.3–9 As opposed to other major
causes of traumatic death (e.g., traumatic brain injury and multiple organ failure (MOF)),
hemorrhagic deaths occur quickly, and are frequently associated with massive transfusion
(MT, traditionally defined as ≥ 10 units of red blood cells (RBCs) in 24 hours).10,11 Current
transfusion practices consist of infusing crystalloid, RBCs, plasma, and platelets, and date
back to the 1970s when separation of donated whole blood into its component parts became
commonplace.12–16
A new resuscitation strategy, termed damage control resuscitation, is challenging the status
quo.17 The term originated in the U.S. military and refers to the guidelines developed for
combat casualties suffering substantial bleeding in Iraq and Afghanistan. Among other
interventions, this approach recommends earlier and more balanced transfusion of plasma
and platelets along with the first units of RBCs (i.e., maintaining plasma:platelet:RBC ratios
closer to the 1:1:1 ratio of whole blood), while simultaneously minimizing crystalloid
use18–27 in patients in order to avert or reverse the triad of coagulopathy, acidosis, and
hypothermia25,28–30 and decrease endothelial permeability.31–33
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Conflicting findings regarding the association between transfusion ratios closer to 1:1 and
survival in massively transfused trauma patients have been reported29,34–36 and attributed to
multiple issues, including survival bias.34,35,37,38 Survival bias, also known as reverse
causation, is a prevalent, important, and often-neglected problem in clinical observational
studies, systematic reviews, and comparative effectiveness research.39,40 In trauma
resuscitation research, the conundrum of reverse causation is whether treatment caused
patients to survive longer or patients received treatment only because they survived long
enough. Without compelling evidence to guide uniform transfusion practice for trauma
patients with substantial bleeding after injury, considerable variation persists across Level 1
trauma centers.14,19,41
Utilizing prospective, minute-to-minute observational data from ten Level 1 trauma centers,
our objective was to accurately describe when RBCs, plasma, and platelets were infused and
assess the association between inhospital mortality and the timing and amount of blood
products. One purpose of observational clinical studies is to inform the design of future
randomized trials, and exploratory analysis can provide critical information regarding trial
feasibility, realistic estimates of expected effect size, and unique insights from real-world
healthcare settings. Thus, we describe the rationale, results, and lessons learned from our
exploratory analyses of observational PROMMTT data.42 We hypothesized that early
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transfusion of plasma and platelets in higher ratios would be associated with decreased in-
hospital mortality in bleeding patients.
METHODS
Study Samples
PROMMTT was a prospective, multicenter observational cohort study conducted at ten
Level 1 trauma centers in the US. At each study site and the Data Coordinating Center
(DCC), the local institutional review board approved the study. The US Army Human
Research Protections Office provided a second level review and approval.42
Trauma patients were enrolled in PROMMTT and data collection was begun upon ED
arrival. Patients were eligible if they required the highest level of trauma activation, were
age 16 or older, and were transfused at least one unit of RBCs in the first six hours after
admission. Patients were excluded if: 1) transferred from other facilities; 2) declared dead
within 30 minutes of admission; 3) received more than five minutes of CPR prior to or
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within 30 minutes of admission; 4) prisoners; 5) burn injury > 20% of total body surface
area; 6) inhalation injury diagnosed by bronchoscopy; or 7) pregnant. If ineligibility was
first identified sometime after enrollment, the patient was withdrawn from the study and
post-enrollment data was destroyed. No changes in clinical practice were implemented in
this observational study. All participating centers had massive transfusion protocols in
place.42
ascertained by data collectors. The DCC audited study data for missing values and
outliers.42 Some severely injured patients did not undergo routine baseline assessments (e.g.,
base deficit, temperature, international normalized ratio, pH) due to the emergent nature of
their injuries (Table 1).
Statistical Analysis
The primary outcome of interest was in-hospital mortality. In the original analysis plan, the
primary independent variables were single plasma:RBC and platelet:RBC transfusion
ratios.42 Under the assumption that each patient would receive constant ratios of plasma and
platelets during the period of active resuscitation, PROMMTT was designed to enroll 1200
transfused and 300 MT patients. Previous retrospective studies suggested higher plasma and
platelet ratios occurred in about 25–50% of MT patients19 and were associated with at least
a 50% decrease in mortality relative to lower ratios.19,23,43 Thus, at the .05 significance
level, a total of at least 300 PROMMTT MT patients was expected to provide 80% power44
to detect differences of at least 50% in mortality between two groups of patients classified
by transfusion ratios (ratios closer to 1:1 vs. ratios closer to 1:2).
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To test the hypothesis that plasma:RBC and platelet:RBC ratios closer to 1:1 were
independently and jointly associated with lower in-hospital mortality than transfusion ratios
closer to 1:2, we reasoned that only PROMMTT patients surviving long enough to receive at
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least 3 blood product units (including one RBC) should be eligible to be included in the
analysis. Patients transfused less than 3 units by hour 24 (or death) had no opportunity to
attain 1:1 ratios for both plasma:RBC and platelet:RBC (i.e., the same ratios as whole
blood). Follow-up time at risk of death for each patient began at minute 31 or the start of the
third unit transfused, whichever occurred last because eligible PROMMTT patients had to
survive the first 30 minutes after admission and long enough to receive at least 3 units of
blood product. Cumulative ratios of plasma:RBC and platelet:RBC and summed counts of
blood products transfused were computed at baseline (entry to follow-up) and for up to 14
consecutive time intervals: 1) two 15-minute intervals between minute 31 and hour 1; 2) ten
30-minute intervals between >1 and 6 hours; 3) one 18-hour interval between >6 and 24
hours; 4) one 29-day interval between >24 hours and 30 days. The timing of transfusion was
defined by the time of initiation of each transfusion. Cell-saver transfusions were not
enumerated or combined with donor blood products in these analyses.
We first examined whether transfusion ratios among PROMMTT patients in the analysis
cohort were constant across time by using mixed linear regression models46 for both
continuous plasma:RBC and platelet:RBC ratios. We then performed multi-level time-
dependent Cox proportional hazards regression which uses time as a continuous variable to
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accommodate 1) varying entry times for this dynamic analysis cohort, 2) time-varying
cumulative sums of transfusion, plasma:RBC ratios and platelet:RBC ratios, 3) important
patient baseline covariates, and 4) any residual variation in mortality rates due to
unmeasured center influences. Center random effects were assessed using shared frailty,
which assumed a single hazard factor (e.g., unmeasured clinical practices) for each trauma
center shared by all of its patients. Hazard ratios (as an estimate of standard relative risk),
95% confidence intervals, and p-values were estimated.
Similar to previous retrospective studies of the association between transfusion ratios and in-
hospital mortality among trauma patients,19 our initial time- dependent Cox analysis
spanned the entire follow-up period of 30 days, and a separate analysis focused on the first
24 hours after ED admission. The proportional hazards assumption was tested using
Schoenfeld residuals for each covariate and the global test proposed by Grambsch and
Therneau.47 Results from these tests suggested significant violations of the assumptions
underlying the Cox models for both the full 30 day period (global test, p=.0002) and the first
24 hours of follow-up (global test, p=.0004), so subsequent analyses are presented in three
intervals (30 minutes to 6 hours, > 6 hours to 24 hours, and > 24 hours to 30 days). In the
models stratified by these time intervals, the proportional hazards assumptions were not
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violated (global test, p=.127, .484 and .402 respectively). Because transfusions were
generally completed by 6 hours, only the proportional hazards model for the first interval
(30 minutes to 6 hours) included time-dependent covariates.
We applied purposeful variable selection strategies48 which retained in all models the
plasma and platelet ratios as the primary independent variables of interest, and the sum of
transfusions, age, time period at cohort entry and injury severity score (ISS) as the primary
potential confounders of interest. The remaining covariates of head, chest and limb bleeding
sites were retained in all models because they were significant at the .05 level and changed
the magnitude of the plasma or platelet ratio coefficients by more than 20% when compared
with models excluding them for one or more of the separate time intervals examined. The
other candidate covariates listed in Table 1 did not change the magnitude of the plasma or
platelet ratio coefficients by more than 20% and were not significant when compared with
models excluding them; they were therefore not retained in the final models.49 No
interactions (each transfusion ratio multiplied by the alternate ratio or a primary covariate)
were significant at the .05 level. The transfusion ratios were also modeled categorically,
using clinically relevant cut-points. The lowest ratios (< 1:2) defined the referent group;
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ratios > 1:2 and <1:1 defined the moderate group; and ratios > 1:1 defined the high group.
Patients discharged in less than 30 days were censored alive at 30 days.
All analyses were performed using SAS/STAT50 and Stata/MP software packages.46
Manuscript preparation was guided by the STROBE statement for the reporting of cohort
studies in epidemiology51 and the SQUIRE standards for the reporting of improvement
studies in health care.52
RESULTS
There were 34,362 trauma admissions in the 10 centers over an average of 58 weeks. Data
collection was initiated on 12,560 patients; of these, 11,315 became ineligible and were
withdrawn from the study and 1,245 met all PROMMTT eligibility criteria. Of these, 905
were transfused three or more units of blood products, thus meeting the eligibility criteria for
the analysis cohort. Overall in-hospital mortality was 21% for all 1245 transfused patients
and 25% for patients included in the analysis cohort (Table 1).
Among cohort patients, 94% of hemorrhagic deaths occurred within 24 hours, the majority
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of these deaths (58%) occurred within three hours of admission (Table 2), and the median
time to hemorrhagic death was 2.6 hours (interquartile range (IQR): 1.7–5.4). The principal
causes of in-hospital death after 24 hours were MOF and brain injury.
Neither plasma:RBC nor platelet:RBC ratios were constant across the first 24 hours among
individual patients (Figure 1) (p<.001 for each patient in the analysis cohort). The time-
varying nature of plasma and platelet transfusion practice across the analysis cohort is
illustrated in Figure 2. Thirty minutes after admission, 67% of cohort patients had not
received plasma, while 99% had not received platelets. Three hours after admission (the
peak time of hemorrhagic death), 10% of surviving cohort patients had not received any
plasma, while 28% of survivors had not received platelets. For each successive hour
survived (up to hour six), patients were more likely to receive plasma and platelets and
hence were more likely to approach ratios of 1:1. By 30 minutes, 1 hour, 2 hours, 3 hours
and 6 hours after admission, ratios exceeded 1:2 in 29%, 47%, 69%, 78%, and 84% of
surviving cohort patients for plasma and in 1%, 14%, 40%, 60%, and 80% for platelets,
respectively.
The protective association between higher transfusion ratios and mortality in the first time
interval (minute 31 to hour 6) diminished over the next two time intervals (Table 3). The
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trend for plasma ratios suggested that the decreased mortality risk observed during the first 6
hours (adjusted HR=0.31, p=<.001) switched direction and became non-significant (adjusted
HR=1.21, p=.20) by the final follow-up period of >24 hours- 30 days. The association
between platelet:RBC ratio and mortality remained below the null but was not significant for
either of the later time periods. Additionally, bleeding from the chest was associated with
higher mortality during the first 6 hours; in contrast, among patients who survived longer
than 6 hours, bleeding from the chest was associated with lower mortality.
To facilitate clinical use, we repeated the same Cox models but substituted patients’
continuous transfusion ratio values with three categorical ones (Table 3). In the initial 6-
hour time interval, patients in the moderate or high ratio group had lower mortality rates
than the low ratio group, (p<.001 for each of the higher plasma ratio groups; p=.040 for the
high platelet ratio group). In both subsequent time intervals, mortality among survivors was
not associated with the categorical ratios.
DISCUSSION
In-hospital mortality among 1245 trauma patients receiving at least a single unit of RBCs
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within 6 hours of admission was 21% (Table 1) while cohort patients with ≥ 3 units
transfused had in-hospital mortality of 25%, among the highest of any acute surgical disease
process. The major findings were 1) patients did not receive a constant ratio during the
period of active resuscitation, and 2) early infusion of higher plasma and platelets ratios was
associated with decreased mortality within six hours of admission, during which 77% of the
hemorrhagic deaths had occurred (Table 2).
The protective association between higher transfusion ratios and in-hospital mortality 1)
appears strongest within 6 hours, and 2) diminishes over time as the primary causes of
mortality shift from exsanguination to head injury, respiratory distress, organ failure and
infection after the first 24 hours. These time trends reflect heterogeneity as the dynamic
cohort of injured patients changes over the course of hospitalization in composition and risk
profile due to mortality. Survivors avoiding early hemorrhage-related mortality face the
longer-term competing risks of death from complications (e.g., MOF) or multiple injuries
(e.g., head injury). The significant protective association between higher blood product
ratios and mortality that we observed was concentrated in the first 24 hours for plasma and
first 6 hours for platelets. Thereafter, during the later time periods of high competing risks
for non-hemorrhagic causes of death among severely injured patients, plasma and platelet
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Survival bias may have threatened previous studies that used 1) the traditional definition of
MT and therefore excluded patients who suffered substantial bleeding but died
early;19,29,34,35,53 2) a single cumulative ratio for plasma or platelets up to the time of death
or 6–24 hours after admission and therefore not accounting for time-dependent
treatment;19,23,29,35,36,54–57 and 3) 30-day or overall in-hospital mortality as the primary
endpoint, which conflates competing mortality risks.19,23,28,29,34–36,53–58 Our prospective
study design, detailed real-time data collection methods and analysis strategies attempted to
minimize the effect of survival bias.
In rapidly and substantially bleeding trauma patients, inadequate transfusion of plasma and
platelets is associated with early death. However, the actual transfusion of blood products is
a complicated balance between rapid recognition of need, ordering of appropriate products,
product availability in the blood bank and ED, obtaining those products quickly, and
appropriate infusion. Unless these steps are orchestrated in an integrated fashion, delayed
infusion and sub-optimum ratios will occur (Figures 1 and 2). Clinicians must rapidly
identify patients who are substantially bleeding, and several predictive algorithms have been
developed to do this.59–69
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Once bleeding patients have been identified, constant ratios are not infused and
heterogeneous transfusion practice persists (Figure 2). Clinicians at PROMMTT Level 1
trauma centers ultimately delivered plasma ratios of 1:1 and 1:2 within 6–24 hours to
surviving patients, but platelet infusion lagged behind with only 72% of patients receiving
platelets by hour three, the median time to hemorrhagic death.
Stratifying by time interval and including time-dependent covariates (Table 3) revealed how
early infusion and increased ratios were associated with decreased mortality (30 minutes to 6
hours). However, it is difficult to translate hazard ratios for continuous variables into a
physician’s order to the blood bank for the delivery of specific blood product amounts.
Therefore, we created three clinically-relevant categories and found a 1:1 ratio of plasma
and platelets was associated with decreased early mortality compared with lower ratios
(Table 3).
The strengths of this study are its prospective multicenter design and teaming a dedicated
data coordinating center (epidemiologists, informatics experts, and biostatisticians) with a
group of Level 1 trauma centers. By identifying patients who received at least 3 units of
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In summary, these prospective data suggest the association between earlier and higher ratios
of plasma and platelets and decreased in-hospital mortality is concentrated in the first 6
hours in patients with substantial bleeding. In the first 6 hours, patients with ratios < 1:2
were 3–4 times more likely to die than patients with ratios ≥1:1. Among survivors at 6
hours, the subsequent risk of death by hour 24 was higher for patients with low plasma
ratios. Among survivors at 24 hours, the subsequent risk of death by day 30 was not
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associated with plasma or platelet ratios. Furthermore, these data highlight the serious
problems of survival bias and competing risks in most previous trauma resuscitation
studies37,58 and emphasize the need for definitive comparative effectiveness trauma
transfusion research.
Survival bias can be eliminated only in a randomized trial with appropriate design and
analysis strategies. However, it can threaten even a randomized trial if study patients are
stratified by post-randomization events such as the conventional MT definition. This study
supports a potential net survival benefit of early and higher plasma and platelet ratios to be
assessed in a randomized trial.71 Our findings offer guidance and evidence for designing a
rigorous, multicenter randomized transfusion trial by identifying: 1) transfusion ratios in
common use at Level 1 trauma centers, 2) well-defined endpoints (e.g. 3, 6 and 24 hours and
30 day mortality), 3) appropriate data analysis strategies accounting for time-varying
covariates, 4) effect size estimates for power and sample size considerations, 5) patients for
whom interventions should be targeted and 6) procedures that promote integrated, consistent
transfusion practices across individual clinicians, blood banks, research teams and trauma
centers.
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Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
Funding/Support: This project was funded by the U.S. Army Medical Research and Materiel Command
subcontract W81XWH-08-C-0712. Infrastructure for the Data Coordinating Center was supported by CTSA funds
from NIH grant UL1 RR024148.
Role of the Sponsor: The sponsors did not have any role in the design and conduct of the study; collection,
management, analysis and interpretation of the data; preparation, review or approval of the manuscript; or the
decision to submit this manuscript for publication.
References
1. Lopez AD, Mathers CD. Measuring the global burden of disease and epidemiological transitions:
NIH-PA Author Manuscript
9. Gruen RL, Jurkovich GJ, McIntyre LK, Foy HM, Maier RV. Patterns of errors contributing to
trauma mortality: lessons learned from 2,594 deaths. Ann Surg. 2006; 244(3):371–380. [PubMed:
16926563]
10. Demetriades D, Murray J, Charalambides K, et al. Trauma fatalities: time and location of hospital
deaths. J Am Coll Surg. 2004; 198(1):20–26. [PubMed: 14698307]
11. Moore FA, Nelson T, McKinley BA, et al. Massive transfusion in trauma patients: tissue
hemoglobin oxygen saturation predicts poor outcome. J Trauma. 2008; 64(4):1010–1023.
[PubMed: 18404069]
12. Counts RB, Haisch C, Simon TL, Maxwell NG, Heimbach DM, Carrico CJ. Hemostasis in
massively transfused trauma patients. Ann Surg. 1979; 190(1):91–99. [PubMed: 464685]
13. Ledgerwood AM, Lucas CE. A review of studies on the effects of hemorrhagic shock and
resuscitation on the coagulation profile. J Trauma. 2003; 54(5 Suppl):S68–S74. [PubMed:
12768106]
14. Malone DL, Hess JR, Fingerhut A. Massive transfusion practices around the globe and a
suggestion for a common massive transfusion protocol. J Trauma. 2006; 60(6 Suppl):S91–S96.
[PubMed: 16763487]
15. Moore FA, McKinley BA, Moore EE. The next generation in shock resuscitation. Lancet. 2004;
363(9425):1988–1996. [PubMed: 15194260]
NIH-PA Author Manuscript
16. American College of Surgeons Committee on Trauma. Advanced Trauma Life Support for Doctors
Student Manual. 8. Chicago: American College of Surgeons; 2008.
17. Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation: directly addressing the early
coagulopathy of trauma. J Trauma. 2007; 62(2):307–310. [PubMed: 17297317]
18. Duchesne JC, Barbeau JM, Islam TM, Wahl G, Greiffenstein P, McSwain NE Jr. Damage control
resuscitation: from emergency department to the operating room. Am Surg. 2011; 77(2):201–206.
[PubMed: 21337881]
19. Holcomb JB, Wade CE, Michalek JE, et al. Increased plasma and platelet to red blood cell ratios
improves outcome in 466 massively transfused civilian trauma patients. Ann Surg. 2008; 248(3):
447–458. [PubMed: 18791365]
20. Johansson PI, Stensballe J. Effect of Haemostatic Control Resuscitation on mortality in massively
bleeding patients: a before and after study. Vox Sang. 2009; 96(2):111–118. [PubMed: 19152603]
21. Maegele M, Lefering R, Paffrath T, Tjardes T, Simanski C, Bouillon B. 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 fur
Unfallchirurgie. Vox Sang. 2008; 95(2):112–119. [PubMed: 18557827]
22. Shaz BH, Dente CJ, Nicholas J, et al. Increased number of coagulation products in relationship to
NIH-PA Author Manuscript
red blood cell products transfused improves mortality in trauma patients. Transfusion. 2010; 50(2):
493–500. [PubMed: 19804568]
23. Borgman MA, Spinella PC, Perkins JG, et al. The ratio of blood products transfused affects
mortality in patients receiving massive transfusions at a combat support hospital. J Trauma. 2007;
63(4):805–813. [PubMed: 18090009]
24. Cotton BA, Gunter OL, Isbell J, et al. Damage control hematology: the impact of a trauma
exsanguination protocol on survival and blood product utilization. J Trauma. 2008; 64(5):1177–
1182. [PubMed: 18469638]
25. Duchesne JC, Islam TM, Stuke L, et al. Hemostatic resuscitation during surgery improves survival
in patients with traumatic-induced coagulopathy. J Trauma. 2009; 67(1):33–37. [PubMed:
19590305]
26. Cotton BA, Reddy N, Hatch QM, et al. Damage control resuscitation is associated with a reduction
in resuscitation volumes and improvement in survival in 390 damage control laparotomy patients.
Ann Surg. 2011; 254(4):598–605. [PubMed: 21918426]
27. Holcomb JB, Zarzabal LA, Michalek JE, et al. Increased platelet:RBC ratios are associated with
improved survival after massive transfusion. J Trauma. 2011; 71(2 Suppl 3):S318–S328.
[PubMed: 21814099]
28. Gonzalez EA, Moore FA, Holcomb JB, et al. Fresh frozen plasma should be given earlier to
NIH-PA Author Manuscript
36. Scalea TM, Bochicchio KM, Lumpkins K, et al. Early aggressive use of fresh frozen plasma does
not improve outcome in critically injured trauma patients. Ann Surg. 2008; 248(4):578–584.
[PubMed: 18936570]
37. Ho AM, Dion PW, Yeung JH, et al. Prevalence of Survivor Bias in Observational Studies on Fresh
Frozen Plasma: Erythrocyte Ratios in Trauma Requiring Massive Transfusion. Anesthesiology.
2012
38. Dimick JB, Livingston EH. Comparing treatments using observational study designs: what can we
do about selection bias? Arch Surg. 2010; 145(10):927. [PubMed: 20956759]
39. van WC, Davis D, Forster AJ, Wells GA. Time-dependent bias was common in survival analyses
published in leading clinical journals. J Clin Epidemiol. 2004; 57(7):672–682. [PubMed:
15358395]
40. Austin PC, Platt RW. Survivor treatment bias, treatment selection bias, and propensity scores in
observational research. J Clin Epidemiol. 2010; 63(2):136–138. [PubMed: 20122500]
41. Wade CE, del Junco DJ, Holcomb JB, et al. Variations between level I trauma centers in 24-hour
mortality in severely injured patients requiring a massive transfusion. J Trauma. 2011; 71(2 Suppl
3):S389–S393. [PubMed: 21814110]
NIH-PA Author Manuscript
42. Rahbar MH, Fox EE, delJunco DJ, et al. Coordination and management of multicenter clinical
studies in trauma: Experience from the PRospective Observational Multicenter Major Trauma
(PROMMTT) Study. Resuscitation. 2011 In press.
43. Duchesne JC, Kimonis K, Marr AB, et al. Damage control resuscitation in combination with
damage control laparotomy: a survival advantage. J Trauma. 2010; 69(1):46–52. [PubMed:
20622577]
44. Hintze, J. Pass. Vol. 11. Kaysville, UT: NCSS, LLC; 2011.
45. Holcomb JB, Weiskopf R, Champion H, et al. Challenges to effective research in acute trauma
resuscitation: consent and endpoints. Shock. 2011; 35(2):107–113. [PubMed: 20926987]
46. Stata Statistical Software: Release 11. College Station, TX: StataCorp LP; 2009.
47. Grambsch PM, Therneau TM, Fleming TR. Diagnostic plots to reveal functional form for
covariates in multiplicative intensity models. Biometrics. 1995; 51(4):1469–1482. [PubMed:
8589234]
48. Bursac Z, Gauss CH, Williams DK, Hosmer DW. Purposeful selection of variables in logistic
regression. Source Code Biol Med. 2008; 3:17. [PubMed: 19087314]
49. Hosmer, DW.; Lemeshow, S. Applied Survival Analysis: Regression Modeling of Time to Event
Data. New York: John Wiley & Sons; 1999.
50. SAS/STAT software for Windows. Version 9.2. Cary, NC: SAS Institute, Inc; 2008.
NIH-PA Author Manuscript
51. Von EE, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. The Strengthening
the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for
reporting observational studies. J Clin Epidemiol. 2008; 61(4):344–349. [PubMed: 18313558]
52. Ogrinc G, Mooney SE, Estrada C, et al. The SQUIRE (Standards for QUality Improvement
Reporting Excellence) guidelines for quality improvement reporting: explanation and elaboration.
Qual Saf Health Care. 2008; 17 (Suppl 1):i13–i32. [PubMed: 18836062]
53. Riskin DJ, Tsai TC, Riskin L, et al. Massive transfusion protocols: the role of aggressive
resuscitation versus product ratio in mortality reduction. J Am Coll Surg. 2009; 209(2):198–205.
[PubMed: 19632596]
54. Cinat ME, Wallace WC, Nastanski F, et al. Improved survival following massive transfusion in
patients who have undergone trauma. Arch Surg. 1999; 134(9):964–968. [PubMed: 10487591]
55. Duchesne JC, Hunt JP, Wahl G, et al. Review of current blood transfusions strategies in a mature
level I trauma center: were we wrong for the last 60 years? J Trauma. 2008; 65(2):272–276.
[PubMed: 18695461]
56. Gunter OL Jr, Au BK, Isbell JM, Mowery NT, Young PP, Cotton BA. Optimizing outcomes in
damage control resuscitation: identifying blood product ratios associated with improved survival. J
Trauma. 2008; 65(3):527–534. [PubMed: 18784564]
57. Wafaisade A, Maegele M, Lefering R, et al. High plasma to red blood cell ratios are associated
NIH-PA Author Manuscript
with lower mortality rates in patients receiving multiple transfusion (4</=red blood cell units<10)
during acute trauma resuscitation. J Trauma. 2011; 70(1):81–88. [PubMed: 21217485]
58. Kent DM, Alsheikh-Ali A, Hayward RA. Competing risk and heterogeneity of treatment effect in
clinical trials. Trials. 2008; 9:30. [PubMed: 18498644]
59. Yucel N, Lefering R, Maegele M, et al. Trauma Associated Severe Hemorrhage (TASH)-Score:
probability of mass transfusion as surrogate for life threatening hemorrhage after multiple trauma.
J Trauma. 2006; 60(6):1228–1236. [PubMed: 16766965]
60. Schreiber MA, Perkins J, Kiraly L, Underwood S, Wade C, Holcomb JB. Early predictors of
massive transfusion in combat casualties. J Am Coll Surg. 2007; 205(4):541–545. [PubMed:
17903727]
61. Nunez TC, Dutton WD, May AK, Holcomb JB, Young PP, Cotton BA. Emergency department
blood transfusion predicts early massive transfusion and early blood component requirement.
Transfusion. 2010; 50(9):1914–1920. [PubMed: 20456707]
62. Nunez TC, Voskresensky IV, Dossett LA, Shinall R, Dutton WD, Cotton BA. Early prediction of
massive transfusion in trauma: simple as ABC (assessment of blood consumption)? J Trauma.
2009; 66(2):346–352. [PubMed: 19204506]
NIH-PA Author Manuscript
63. McLaughlin DF, Niles SE, Salinas J, et al. A predictive model for massive transfusion in combat
casualty patients. J Trauma. 2008; 64(2 Suppl):S57–S63. [PubMed: 18376173]
64. Rainer TH, Ho AM, Yeung JH, et al. Early risk stratification of patients with major trauma
requiring massive blood transfusion. Resuscitation. 2011; 82(6):724–729. [PubMed: 21458905]
65. Borgman MA, Spinella PC, Holcomb JB, et al. The effect of FFP:RBC ratio on morbidity and
mortality in trauma patients based on transfusion prediction score. Vox Sang. 2011; 101(1):44–54.
[PubMed: 21438884]
66. Larson CR, White CE, Spinella PC, et al. Association of shock, coagulopathy, and initial vital
signs with massive transfusion in combat casualties. J Trauma. 2010; 69 (Suppl 1):S26–S32.
[PubMed: 20622616]
67. Cancio LC, Wade CE, West SA, Holcomb JB. Prediction of mortality and of the need for massive
transfusion in casualties arriving at combat support hospitals in Iraq. J Trauma. 2008; 64(2
Suppl):S51–S55. [PubMed: 18376172]
68. Maegele M, Lefering R, Wafaisade A, et al. Revalidation and update of the TASH-Score: a scoring
system to predict the probability for massive transfusion as a surrogate for life-threatening
haemorrhage after severe injury. Vox Sang. 2011; 100(2):231–238. [PubMed: 20735809]
69. Krumrei NJ, Park MS, Cotton BA, Zielinski MD. Comparison of massive blood transfusion
predictive models in the rural setting. J Trauma. 2012; 72(1):211–215.
NIH-PA Author Manuscript
70. Mackenzie EJ, Rivara FP, Jurkovich GJ, et al. A national evaluation of the effect of trauma-center
care on mortality. N Engl J Med. 2006; 354(4):366–378. [PubMed: 16436768]
71. [Accessed March 8, 2012] Pragmatic, Randomized Optimal Platelets and Plasma Ratios
(PROPPR). http://clinicaltrials.gov/ct2/show/NCT01545232
Medical College of Wisconsin: Karen J. Brasel, MD, MPH (principal investigator); Pamela
Walsh (study coordinator).
University of Texas Health Science Center at San Antonio: John G. Myers, MD (co-
principal investigator); Ronald M. Stewart, MD (co-principal investigator); Rick L.
Sambucini, RN, BS (study coordinator); Marianne Gildea, RN, BSN, MS (study
coordinator); Mark DeRosa CRT (study coordinator); Rachelle Jonas, RN, BSN (study
coordinator); Janet McCarthy, RN (study coordinator).
Figure 1. Blood product use in the 1st 6 hours in two PROMMTT patients
Patient A had an ISS of 48 and died of hemorrhage at 1 hour, 7 minutes after ED admission.
Patient B had an ISS of 57 and was discharged to another acute care hospital at 27 days.
Note the constantly changing ratios over time. For example, patient A received cumulative
plasma:platelet:RBC ratios of 0:0:1, 0:0:3, 0:0:6, 4:6:6, and 5:6:6 at 15, 30, 45, 60 and 75
minutes respectively, while patient B received 0:0:1, 0:0:4, 0:0:4, 2:0:6, and 2:0:10 at those
same time points.
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Figure 2.
The bars represent cumulative ratios at the start of each time interval. The majority of
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patients received 1:2 plasma:RBC ratio or higher by three hours and for platelets:RBC, by
six hours. In the last time interval (24 hours), the percentage for patients receiving 0 platelets
or plasma increases, reflecting the dynamic cohort with newly eligible patients entering and
others exiting due to death in the previous interval.
Table 1
Admission and treatment characteristics and unadjusted survival in 1245 PROMMTT patients
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Bleeding sitesa
Head, No. (%) 181 (14.5) 1245 128 (14.1) 905
Face, No. (%) 340 (27.3) 1245 246 (27.2) 905
Neck, No. (%) 57 (4.6) 1245 41 (4.5) 905
Chest, No. (%) 299 (24.0) 1245 237 (26.2) 905
Abdomen, No. (%) 396 (31.8) 1245 320 (35.4) 905
Pelvis, No. (%) 164 (13.2) 1245 143 (15.8) 905
Limb, No. (%) 441 (35.4) 1245 334 (36.9) 905
Unknown, No. (%) 121 (9.7) 1245 79 (8.7) 905
Treatment characteristics
Damage control surgery performed, No. (%) 239 (19.3) 1241 222 (24.6) 904
Time to first RBC transfused, min 30 (12–99) 1222 25 (11–77) 905
Time to first plasma transfused, min 69 (35–133) 815b 69 (35–130) 778b
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Time to first platelet transfused, min 123 (81–190) 357b 121 (80–187) 343b
6-hour RBC unit total 4 (2–7) 1224 5 (3–9) 905
6-hour plasma unit total 2 (0–5) 1224 4 (2–7) 905
6-hour platelet unit total 0 (0–6) 1224 0 (0–6) 905
24-hour RBC unit total 5 (2–9) 1244 6 (4–11) 905
24-hour plasma unit total 4 (0–8) 1245 5 (2–9) 905
24-hour platelet unit total 0 (0–6) 1245 0 (0–6) 905
Unadjusted in-hospital mortality
30 minute – 6-hour mortality, No. (%) 102 (8.2) 1245 95 (10.5) 905
>6 hour – 24-hour mortality, No. (%) 46 (4.0) 1143 37 (4.6) 810
>24 hour – 30-day mortality, No. (%) 112 (10.2) 1097 88 (11.4) 773
Overall cumulative mortality, No. (%) 266 (21.4) 1245 226 (25.0) 905
Table 2
Distribution of reported cause of death for decedent patients in the analysis cohort by the time period surviveda
> 0.5 – ≤ 1 hour >1 – ≤ 3 hours > 3 – ≤ 6 hours > 6 – ≤ 12 hours > 12 – ≤ 24 hours > 24 – ≤ 72 hours > 72 hours– ≤ 30 days 30+ days
Cause of death,b No. (%) N=8 N=55 N=32 N=21 N=16 N=21 N=67 N=6
Holcomb et al.
a
Column percentages sum to greater than 100% because patients may have more than one contributing cause of death
b
Not centrally adjudicated
Table 3
Multivariable Cox regression models examining the association of plasma and platelet transfusion ratios with in-hospital mortality
B. Time Interval 2: Hour >6 to hour 24 post ED admissiond (N=809)e Low <1:2 Moderate ≥ 1:2–<1:1 High ≥1:1
6-hour cumulative plasma:RBC ratio 0.34 0.14 0.81 .02 1.00 Ref 0.79 0.63 0.55 0.23
6-hour cumulative platelet:RBC ratio 0.81 0.46 1.43 .46 1.00 Ref 0.79 0.56 0.49 0.19
C. Time Interval 3: Hour >24 to day 30 post ED admissionf (N=773)g Low <1:2 Moderate ≥ 1:2–<1:1 High ≥1:1
24-hour cumulative plasma:RBC ratio 1.21 0.90 1.61 .20 1.00 Ref 1.41 0.33 1.47 0.26
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24-hour cumulative platelet:RBC ratio 0.78 0.57 1.06 .11 1.00 Ref 1.23 0.46 0.69 0.19