The PROPPR Randomized Clinical Trial

Copyright 2015 American Medical Association. All rights reserved.
Transfusion of Plasma, Platelets, and Red Blood Cells in a 1:1:1
vs a 1:1:2 Ratio and Mortality in Patients With Severe Trauma
The PROPPR Randomized Clinical Trial
John B. Holcomb, MD; Barbara C. Tilley, PhD; Sarah Baraniuk, PhD; Erin E. Fox, PhD; Charles E. Wade, PhD; Jeanette M. Podbielski, RN;
Deborah J. del Junco, PhD; Karen J. Brasel, MD, MPH; Eileen M. Bulger, MD; Rachael A. Callcut, MD, MSPH; Mitchell Jay Cohen, MD;
Bryan A. Cotton, MD, MPH; Timothy C. Fabian, MD; Kenji Inaba, MD; Jeffrey D. Kerby, MD, PhD; Peter Muskat, MD; Terence O’Keeffe, MBChB, MSPH;
Sandro Rizoli, MD, PhD; Bryce R. H. Robinson, MD; Thomas M. Scalea, MD; Martin A. Schreiber, MS; Deborah M. Stein, MD; Jordan A. Weinberg, MD;
Jeannie L. Callum, MD; John R. Hess, MD, MPH; Nena Matijevic, PhD; Christopher N. Miller, MD; Jean-Francois Pittet, MD; David B. Hoyt, MD;
Gail D. Pearson, MD, ScD; Brian Leroux, PhD; Gerald van Belle, PhD; for the PROPPR Study Group
IMPORTANCE Severely injured patients experiencing hemorrhagic shock often require
massive transfusion. Earlier transfusion with higher blood product ratios (plasma, platelets,
and red blood cells), defined as damage control resuscitation, has been associated with
improved outcomes; however, there have been no large multicenter clinical trials.
OBJECTIVE To determine the effectiveness and safety of transfusing patients with severe
trauma and major bleeding using plasma, platelets, and red blood cells in a 1:1:1 ratio
compared with a 1:1:2 ratio.
DESIGN, SETTING, AND PARTICIPANTS Pragmatic, phase 3, multisite, randomized clinical trial
of 680 severely injured patients who arrived at 1 of 12 level I trauma centers in North America
directly from the scene and were predicted to require massive transfusion between August
2012 and December 2013.
INTERVENTIONS Blood product ratios of 1:1:1 (338 patients) vs 1:1:2 (342 patients) during
active resuscitation in addition to all local standard-of-care interventions (uncontrolled).
MAIN OUTCOMES AND MEASURES Primary outcomes were 24-hour and 30-day all-cause
mortality. Prespecified ancillary outcomes included time to hemostasis, blood product
volumes transfused, complications, incidence of surgical procedures, and functional status.
RESULTS No significant differences were detected in mortality at 24 hours (12.7% in 1:1:1 group
vs 17.0% in 1:1:2 group; difference, −4.2% [95% CI, −9.6% to 1.1%]; P = .12) or at 30 days (22.4%
vs 26.1%, respectively; difference, −3.7% [95% CI, −10.2% to 2.7%]; P = .26). Exsanguination,
which was the predominant cause of death within the first 24 hours, was significantly
decreased in the 1:1:1 group (9.2% vs 14.6% in 1:1:2 group; difference, −5.4% [95% CI, −10.4% to
−0.5%]; P = .03). More patients in the 1:1:1 group achieved hemostasis than in the 1:1:2 group
(86% vs 78%, respectively; P = .006). Despite the 1:1:1 group receiving more plasma (median of
7 U vs 5 U, P < .001) and platelets (12 U vs 6 U, P < .001) and similar amounts of red blood cells
(9 U) over the first 24 hours, no differences between the 2 groups were found for the 23
prespecified complications, including acute respiratory distress syndrome, multiple organ
failure, venous thromboembolism, sepsis, and transfusion-related complications.
CONCLUSIONS AND RELEVANCE Among patients with severe trauma and major bleeding, early
administration of plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio
did not result in significant differences in mortality at 24 hours or at 30 days. However, more
patients in the 1:1:1 group achieved hemostasis and fewer experienced death due to
exsanguination by 24 hours. Even though there was an increased use of plasma and platelets
transfused in the 1:1:1 group, no other safety differences were identified between the 2 groups.
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01545232
JAMA. 2015;313(5):471-482. doi:10.1001/jama.2015.12
Supplemental content at
jama.com
Author Affiliations: Author
affiliations are listed at the end of this
article.
Group Information: The Pragmatic,
Randomized Optimal Platelet and
Plasma Ratios (PROPPR) Study Group
members are listed at the end of this
article.
Corresponding Author: John B.
Holcomb, MD, Center for
Translational Injury Research,
University of Texas Health
Science Center, 6410 Fannin St,
Houston, TX 77030
(john.holcomb@uth.tmc.edu).
Research
Original Investigation
(Reprinted) 471
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF SYDNEY LIBRARY User on 09/20/2015
Copyright 2015 American Medical Association. All rights reserved.
I
n the United States, injury is the leading cause of death
among individuals between the ages of 1 and 44 years, it is
the leading cause of years of life lost for those younger than
75 years, and it is the third leading cause of death overall.1
Deaths from injury have increased 23% during the last decade.2
Approximately 20% to 40% of trauma deaths occurring after
hospital admission involve massive hemorrhage from truncal
injury and are potentially preventable with rapid hemorrhage
control and improved resuscitation techniques.3
Damage control resuscitation is defined as rapid hemorrhage
control through early administration of blood products
in a balanced ratio (1:1:1 for units of plasma to platelets to red
blood cells [RBCs]; a ratio that is the closest approximation to
reconstituted whole blood), prevention and immediate correction
of coagulopathy, and minimization of crystalloid
fluids.4 Damage control resuscitation was developed to treat
intravascular volume deficits, the acute coagulopathy of
trauma, preserve oxygen-carrying capacity, repair the endothelium,
and prevent dilutional coagulopathy.4,5
Damage control resuscitation was codified as a US Department
of Defense clinical practice guideline in 20046 and has
become the standard of care for battlefield resuscitation that
is now used in many civilian trauma centers. Damage control
resuscitation principles have been associated with improved
outcomes compared with more traditional transfusion
practices.7-12 Conversely, other studies have reported beneficial
outcomes across a wider range of blood product ratios or
goal-directed approaches.13,14 However, concerns about the
safety of exposing injured patients to large amounts of plasmacontaining
blood products were difficult to address in previous
retrospective studies.
There are no large, multicenter, randomized clinical trials
with survival as a primary end point that support optimal
trauma resuscitation practices with approved blood products.
As a result, there are multiple and often conflicting recommendations
promulgated by various organizations.15-18The
Prospective Observational Multicenter Major Trauma Transfusion
(PROMMTT) study demonstrated that clinicians generally
were transfusing patients with a blood product ratio of
1:1:1 or 1:1:2 and that early transfusion of plasma (within minutes
of arrival to a trauma center) was associated with improved
6-hour survival after admission.10,19
The Pragmatic, Randomized Optimal Platelet and Plasma
Ratios (PROPPR) trial was designed to address the effectiveness
and safety of a 1:1:1 transfusion ratio compared with a 1:1:2
transfusion ratio in patients with trauma who were predicted
to receive a massive transfusion.
Methods
Study Design and Intervention
A pragmatic, phase 3, multisite, randomized trial, the PROPPR
study compared the effectiveness and safety of a 1:1:1 transfusion
ratio of plasma, platelets, and RBCs to a 1:1:2 ratio.20 Patients
were randomized within each site, and the intervention
consisted of containers of blood products prepared by each
site’s blood bank and delivered to the bedside within 10 minutes
(DJ Novak et al and the PROPPR Study Group, unpublished
data, 2015; Supplement 1). The initial container was
sealed to blind the physicians to treatment assignment. The
patient was declared randomized when the seal was broken.
The blood products were transfused in a prespecified order designed
to maintain the appropriate assigned ratio.
All containers for the 1:1:1 group included 6 U of plasma,
1 dose of platelets (a pool of 6 U on average), and 6 U of RBCs,
which were transfused in the following order: platelets first,
then alternating RBC and plasma units. The initial and all
subsequent odd-numbered containers for the 1:1:2 group
included 3 U of plasma, 0 doses of platelets, and 6 U of RBCs,
which were transfused in the following order: alternating 2 U
of RBCs and 1 U of plasma. The second and all subsequent
even-numbered containers included 3 U of plasma, 1 dose of
platelets (a pool of 6 U on average), and 6 U of RBCs, which
were transfused in the following order: platelets first,
then alternating 2 U of RBCs and 1 unit of plasma. Patients
with multiple intravenous lines could receive blood products
simultaneously, otherwise patients received products
sequentially.
Transfusion of all study blood products was stopped when
clinically indicated, irrespective of ratio or partial blood container
use.20Transfusion of study blood products ended in several
ways: achievement of hemostasis, death, declaration of
treatment futility, no need for further blood products after randomization,
or protocol violations.
No other resuscitation, pharmacological, or clinical treatment
was controlled by the trial protocol (Supplement 1). The
study was approved by the US Food and Drug Administration
(FDA) (Investigational New Drug No. 14929), Health Canada,
the Department of Defense, and all site institutional review
boards. In addition, the study was monitored by an external
data and safety monitoring board appointed by the National
Heart, Lung, and Blood Institute and used exception from informed
consent, including community consultation with delayed
patient or legally authorized representative consent.21
Study Population
Patients included in the PROPPR trial were severely injured and
met the local criteria for highest level trauma activation at 1
of 12 participating level I trauma centers in North America.
These site-specific criteria, reviewed by the American College
of Surgeons, are based on heart rate, blood pressure, respiratory
rate, and mechanism of injury and are used clinically to
ensure trauma teams are present before these critically injured
patients arrive at the emergency department. The research
personnel were notified along with the trauma teams.
The goal was to rapidly enroll patients with severe hemorrhage
who were nonmoribund, regardless of injury type.
To facilitate rapid identification of patients with severe
bleeding, inclusion criteria included the patient having at least
1 U of any blood component transfused prior to hospital arrival
or within 1 hour of admission and prediction by an Assessment
of Blood Consumption score22 of 2 or greater or by
physician judgment of the need for a massive transfusion (defined
as ≥10 U of RBCs within 24 hours). The complete inclusion
and exclusion criteria are listed in the Box.
Research Original Investigation Transfusion in Patients With Severe Trauma
472 JAMA February 3, 2015 Volume 313, Number 5 (Reprinted) jama.com
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF SYDNEY LIBRARY User on 09/20/2015
Copyright 2015 American Medical Association. All rights reserved.
Outcomes and Other Variables of Interest
The primary outcomes included absolute percentage group differences
for 24-hour and 30-day mortality. These 2 outcome
measures tested 2 separate questions regarding short-term effectiveness
and long-term safety without adjustment for multiple
comparisons per protocol.23 Each death was adjudicated
by a clinician blinded to group assignment and external
to the trial site and 1 or more causes of death were assigned.
Ancillary outcomes were prespecified to evaluate the effectiveness
and safety of the transfusion ratios and included
(1) time to hemostasis; (2) the number and type of blood products
used from randomization until hemostasis was achieved;
(3) the number and type of blood products used after hemostasis
was achieved up to 24 hours postadmission; (4) 23 complications;
(5) hospital-, ventilator-, and ICU-free days (within
the first 30 days or hospital discharge, whichever occurred
first); (6) incidence of major surgical procedures; and (7) functional
status at hospital discharge or 30 days, whichever occurred
first, asmeasured by discharge destination and Glasgow
Outcome Scale-Extended.
Blood product ratios were calculated as 2 separate ratios:
plasma to RBCs and platelets to RBCs. For example, a 1:1 ratio
of plasma to RBCs is equivalent to 1.0 and represents equal total
units of plasma and RBCs within the specified interval. A
1:2 ratio is equivalent to 0.5 and represents twice as many total
RBC units as plasma units. Ratios for patients who received no
RBCs within a specified interval cannot be calculated because
the denominator is zero, and therefore are not included
in the calculation of cumulative ratios of blood products
in that interval.
Race and Hispanic ethnicity were collected by patient
self-report or hospital staff determination and were included
to identify disparities in treatment or outcome. The Injury
Severity Score is an anatomic scoring system used for
patients with multiple injuries, correlates with mortality,
and has a range of 0 (uninjured) to 75 (usually unsurvivable
injuries).24 The critical administration threshold represents
the trauma subset at highest risk of hemorrhagic mortality25
and denotes patients receiving more than 3 U of RBCs within
at least 1 hour during the first 24 hours after admission. The
Assessment of Blood Consumption score has a range of 0 to
4 with scores of 2 or greater associated with the need for a
massive transfusion.22
Anatomic hemostasis in the operating room was defined
as an objective assessment by the surgeon indicating that bleeding
within the surgical field was controlled and no further hemostatic
interventions were anticipated. In the interventional
radiology suite, anatomic hemostasis was defined as
achieving resolution of contrast blush after embolization.
Sample Size
The initial sample size of 580 was planned to detect a clinically
meaningful 10% difference in 24-hour mortality (11% vs
21%) and a 12% difference in 30-day mortality (23% vs 35%),
which was supported by prior data.26,27 Sample size was increased
to 680 by the data and safety monitoring board according
to the trial’s adaptive design. With 680 patients and
given the final observedmortality proportions in the 1:1:1 group,
the PROPPR trial had 95% power to detect the prespecified 10%
difference at 24 hours and 92% power to detect the prespecified
12% difference at 30 days, if such differences existed.
Statistical Analysis
The primary analysis separately compared 24-hour and
30-day mortality in the 2 transfusion ratio groups using a
2-sided Mantel-Haenszel test adjusting for site. For the 4 patients
missing a primary outcome, a sensitivity analysis using
all possible combinations (n = 16) of outcomes was performed
and a range of intent-to-treat P values for the hypotheticalMantel-Haenszel
tests are presented.28The critical level
for significance (P ≤ .044) was adjusted for 2 interim analyses,
and all tests were conducted using 2-sided tests.29 In Cox
analyses, the 4 patients missing a 30-day outcome were censored
at the last known follow-up time.30 Lack of protocol compliance
was measured by the per-patient percentage of blood
products given out of order. A sensitivity analysis compared
treatment groups excluding these patients.
Box. Inclusion and Exclusion Criteria for the Pragmatic,
Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial
Eligible Patients Met All of the Following:
Highest trauma level activation
Estimated age of 15 years or older or weight of 50 kg or greater if age
unknown
Received directly from the injury scene
Initiated transfusion of at least 1U ofblood component within the first
hour of arrival or during prehospital transport
Predicted to receive a massive transfusion by exceeding the threshold
score of either the Assessment of Blood Consumption score of 2
or greater or based on the attending trauma physician’s judgment
Patients Who Were Ineligible Met at Least 1 of the Following:
Received a lifesaving intervention from an outside hospital or health
care facility
Had devastating injuries and expected to die within 1 hour of admission
(eg, lethal traumatic brain injury)
Directly admitted from a correctional facility
Required a thoracotomy prior to receiving randomized blood products
in the emergency department
Younger than 15 years or weighed less than 50 kg if age unknown
Known pregnancy in the emergency department
Had burns covering greater than 20% total body surface area
Suspected inhalation injury
Received greater than 5 consecutiveminutes of cardiopulmonary resuscitation
(with chest compressions) prior to arriving at the hospital
or within the emergency department
Known do-not-resuscitate order prior to randomization
Enrolled in a concurrent, ongoing, interventional, randomized clinical
trial
Activated the opt-out process for the PROPPR trial (usually by wearing
a bracelet given out at a community consent presentation)
More than 3 U of red blood cells given before randomization
Transfusion in Patients With Severe Trauma Original Investigation Research
jama.com (Reprinted) JAMA February 3, 2015 Volume 313, Number 5 473
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF SYDNEY LIBRARY User on 09/20/2015
Copyright 2015 American Medical Association. All rights reserved.
All analyses were generated using SAS version 9.3 (SAS Institute
Inc). Additional details regarding the study design and
analysis were published previously.20
Results
From August 3, 2012, to December 2, 2013, a total of 14 313
highest-level trauma activations occurred at the 12 enrolling
sites, of which 78% were screened. A total of 680 patients
were randomized (338 to the 1:1:1 group and 342 to the 1:1:2
group; Figure 1). Randomized blood products were transfused
to 669 patients. No differences were detected between
treatment groups in baseline characteristics (Table 1).
Themajority of patientsweremalewith similar ages in both
groups. Patients in both groups were profoundly injured with
a median Injury Severity Score of 26 and severely bleeding
based on the critical administration threshold (87% positive
based on this threshold overall). The initial hemoglobin level
was 11.7 g/dL (37% had hemoglobin levels <11 g/dL) in the 1:1:1
group and 11.9 g/dL (38.8% had hemoglobin levels <11 g/dL)
in the 1:1:2 group. Seventy-five percent of patients required an
interventional radiology or operating room procedure within
2 hours of admission (data not shown).
The primary trial outcomes of mortality at 24 hours and
30 days were obtained on 100% and 99.4% of patients, respectively.
No significant differences in mortality were detected at
24 hours (12.7% in the 1:1:1 group vs 17.0% in the 1:1:2 group;
difference, −4.2% [95% CI, −9.6% to 1.1%) or at 30 days (22.4%
vs 26.1%, respectively; difference, −3.7% [95% CI, −10.2% to
2.7%) (Table 2).31 The range of intent-to-treat P values computed
for all possible combinations of 30-day outcomes for the
4 patients with missing values did not change these results.
The P values ranged from 0.21 to 0.36 (eTable 1 in Supplement
2). The Kaplan-Meier curves (Figure 2) show a separation in survival
between the 2 treatment groups across the follow-up period,
but the difference was not significant (unadjusted logrank
test, P = .21).
Sensitivity analyses excluding patients who received blood
products given out of order yielded results similar to the main
analysis. Themean percentages of intervention units given out
of order per patient (protocol noncompliance) were significantly
lower in the 1:1:1 group (4%; 95% CI, 3.2%-5.7%) vs the
1:1:2 group (7%; 95% CI, 6.1% to 8.5%) (P = .01).
Exsanguination, the predominant cause of death within
the first 24 hours, was decreased in the 1:1:1 group (9.2%) vs
the 1:1:2 group (14.6%) (difference, −5.4% [95% CI, −10.4% to
−0.5%], P = .03); the median time to death due to exsanguination
was 106 minutes (interquartile range [IQR], 54 to 198
minutes) and 96 minutes (IQR, 43 to 194 minutes), respectively.
From 24 hours through 30 days, the numbers of additional
all-cause deaths were similar (32 for the 1:1:1 group vs
31 for the 1:1:2 group). Over 30 days, deaths due to exsanguination
occurred in 10.7% of patients in the 1:1:1 group vs 14.7%
in the 1:1:2 group, whereas deaths due to traumatic brain injury
were 8.1% vs 10.3%, respectively. Additional causes of
Figure 1. Flow of Patients in the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial
11185 Patients assessed for eligibility
10505 Excluded
7027 Did not receive at least 1 U of a blood component within
the first hour after arrival or during prehospital transport
1655 Not received directly from the injury scene
882 Not predicted to receive a massive transfusion
277 Age <15 y (or weight <50 kg)
154 Patient improved, did not require further transfusion
130 Devastating injury, expected to die within 1 h of ED admission
129 PROPPR products not given within 2-h period
65 Patient did not require highest level of trauma activation
49 Received CPR for >5 min
48 Required an emergency thoracotomy
36 Institutionalized in prison
32 Fourth unit of RBCs was transfused before randomization
21 Other reasonsa
680 Randomized
30-d Mortality
18 Withdrew consentb
3 Lost to follow-up
338 Included in mortality analysis
30-d Mortality
17 Withdrew consentb
1 Lost to follow-up
342 Included in mortality analysis
24-h Mortality
3 Withdrew consentb
0 Lost to follow-up
338 Included in mortality analysis
24-h Mortality
2 Withdrew consentb
0 Lost to follow-up
342 Included in mortality analysis
338 Randomized to 1:1:1 group 342 Randomized to 1:1:2 group
CPR indicates cardiopulmonary
resuscitation; ED, emergency
department; RBC, red blood cell.
a Included patients with the
following: 6 known pregnancies,
5 with physicians who refused to
randomize, 4 with known
do-not-resuscitate order prior to
randomization, 3 with burns
covering more than 20% of total
body surface area, 1 with a
documented inhalation injury, 1 who
opted out upon arrival to the ED,
1 unknown reason.
b The vital statistic data were
obtained for patients who withdrew
consent when available. Patients
who withdrew consent at 24 hours
are included in the count of those
who withdrew at 30 days.
Research Original Investigation Transfusion in Patients With Severe Trauma
474 JAMA February 3, 2015 Volume 313, Number 5 (Reprinted) jama.com
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF SYDNEY LIBRARY User on 09/20/2015
Copyright 2015 American Medical Association. All rights reserved.
death were infrequent and are shown in Table 3. More patients
achieved anatomic hemostasis in the 1:1:1 group (86.1%
vs 78.1% in the 1:1:2 group, P = .006) with a median time of 105
minutes (IQR, 64 to 179 minutes) vs 100 minutes (IQR, 56 to
181minutes), respectively (P = .44) in those who achieved anatomic
hemostasis (Table 2).
Cumulative transfusion ratios and the distribution of
blood product amounts (prerandomization, during the intervention,
and postintervention) are shown in Figure 3 and
Figure 4. During the intervention, patients received median
ratios of plasma to RBCs of 1.0 in the 1:1:1 group and 0.5 in the
1:1:2 group. The median ratios of platelets to RBCs during the
Table 1. Patient Characteristics by Treatment Group
1:1:1 Group
(n = 338)
1:1:2 Group
(n = 342)
Age, median (IQR), ya 34.5 (25 to 51) 34 (24 to 50)
Male sex, No. (%) 263 (77.8) 283 (82.7)
Race, No. (%)b
White 210 (62.1) 224 (65.5)
Black 94 (27.8) 93 (27.2)
Other 35 (10.4) 25 (7.3)
Hispanic ethnicity, No. (%)c 61 (18.0) 59 (17.3)
Glasgow Coma Scale score, median (IQR) 14 (3 to 15) 14 (3 to 15)
Systolic blood pressure, No. of patients 330 328
Median (IQR), mm Hgd 102 (81 to 126) 102 (80 to 125)
No. (%) with ≤90 mm Hg 127 (38.5) 128 (39.0)
Diastolic blood pressure, No. of patients 284 279
Median (IQR), mm Hgd 70 (53 to 90) 68 (50 to 91)
Heart rate, No. of patients 336 341
Median (IQR), beats/mind 115 (97 to 135) 113 (93 to 130)
No. (%) with ≥120 beats/min 148 (44.0) 152 (44.6)
Respiratory rate, No. of patients 308 313
Median (IQR), breaths/min 20 (17.5 to 26.0) 20 (17 to 26)
Assessment of Blood Consumption score ≥2, No. (%)22,e 215 (63.6) 223 (65.2)
Mechanism of injury, No. (%)
Any blunt injury 185 (54.7) 173 (50.6)
Any penetrating injury 157 (46.4) 173 (50.6)
Time to randomization, median (IQR), min 27.5 (17 to 47) 25.5 (16 to 41)
Hemoglobin level, No. of patients 327 325
Median (IQR), g/dL 11.7 (10.1 to 13.4) 11.9 (10.1 to 13.2)
No. (%) with ≤11 g/dL 121 (37.0) 126 (38.8)
International normalized ratio, No. of patients 218 218
Median (IQR) 1.3 (1.2 to 1.5) 1.3 (1.2 to 1.5)
No. (%) with ratio >1.5 57 (26.1) 59 (27.1)
Thromboelastography R time, No. of patients 276 279
Median (IQR), min 3.8 (2.9 to 4.6) 3.8 (2.8 to 4.7)
No. (%) with time >8 min 12 (4.3) 12 (4.3)
Platelet count, No. of patients 317 317
Median (IQR), in thousands 213 (164 to 261) 212 (164 to 264)
No. (%) with count <150 in thousands 54 (17.0) 60 (18.9)
Base excess, No. of patients 318 301
Median (IQR), mmol/L −8 (−12.5 to −3.8) −8.5 (−12.8 to −4.7)
No. (%) with score ≤−4 mmol/L 238 (74.8) 239 (79.4)
Injury Severity Score, median (IQR)f 26.5 (17 to 41) 26 (17 to 38)
Revised Trauma Score, No. of patientsg 303 304
Median (IQR) 6.8 (4.1 to 7.8) 6.4 (4.1 to 7.8)
Resuscitation indicators, No. (%)
Massive transfusionh 153 (45.3) 160 (46.8)
Critical administration thresholdi 281 (83.1) 314 (91.8)
Abbreviations: IQR, interquartile
range; RBC, red blood cell.
a One patient was missing a verified
age so it was imputed using the
median of the interval for estimated
age.
bMore than 1 race could be selected
per patient, therefore percentages
may exceed 100%. Other included
American Indian/Alaskan
Native/Aboriginal, Asian, Native
Hawaiian/other Pacific Islander,
other, and unknown.
c Determined by either self-report
from the patient or family or direct
observation by medical staff.
dPatients with blood pressure and
heart rate that was not recorded,
measured, detectable, or palpable
were excluded from the median
calculations and the Wilcoxon rank
sum test.
e The score range was 0 to 4. Patients
with a score of 0 (n = 50) and 1
(n = 192) were enrolled in the trial as
physician overrides, which was
defined as a score of less than 2 and
attending physician determination
that a massive transfusion was
needed.
f The score range was 0 to 75. A score
greater than 15 indicates major
trauma.
g The score range was 0 to 7.8. A
higher score is associated with
better survival probability.
hDefined as 10 U or greater of RBCs
received within first 24 hours.
Includes observations made
postrandomization.
i Defined as 3 U or greater of RBCs
received at least once per 1-hour
interval during the first 24 1-hour
periods. One patient in each
treatment group did not receive any
RBCs. Includes observations made
postrandomization.
Transfusion in Patients With Severe Trauma Original Investigation Research
jama.com (Reprinted) JAMA February 3, 2015 Volume 313, Number 5 475
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF SYDNEY LIBRARY User on 09/20/2015
Copyright 2015 American Medical Association. All rights reserved.
intervention were 1.5 for the 1:1:1 group and 0.4 for the 1:1:2
group. Higher cumulative plasma and platelet ratios in the
1:1:2 group vs the 1:1:1 group were seen during the postintervention
period.
Similar amounts of total blood products (median of 2 U)
were delivered prerandomization to both groups (eFigure in
Supplement 2). Themedian total blood product amounts transfused
were 16 U in the 1:1:1 group and 15 U in the 1:1:2 group
during the intervention period. Patients in the 1:1:1 group received
fewer blood products during the postintervention period
than the 1:1:2 group (median of 1 U vs 2 U, respectively).
The median total for blood products transfused up to 24 hours
after admission was 25.5 U in the 1:1:1 group and 19 U in the
1:1:2 group. Total plasma (median of 7 U in the 1:1:1 group vs
5 U in the 1:1:2 group, P < .001) and platelets (12 U vs 6 U, respectively,
P < .001) transfused within the first 24 hours were
higher in the 1:1:1 group, but similar for RBCs (9 U) (eTable 2
in Supplement 2). Use of tranexamic acid and other procoagulants
was similar.
Differences were not detected in any of the 23 complications
at 30 days (Table 4), including acute respiratory distress
syndrome, multiple organ failure, venous thromboembolism,
sepsis, and transfusion-related complications. The overall
rate of complications was high (89% of patients). One patient
in the 1:1:1 group died from transfusion-associated
circulatory overload. Significant differences between groups
in the other ancillary outcomes focusing on safety were not
detected and are shown in Table 2.
Discussion
Transfusion for patients with severe trauma and major bleeding
has been predominantly guided by tradition rather than
evidence from large, multicenter randomized trials. Over the
last decade, transfusion therapy has undergone a significant
change with many patients receiving less crystalloid and early,
more balanced transfusion ratios attempting to reconstitute
whole blood.4-12,27,32-41 This change has largely been associated
with decreased transfusion amounts, fewer inflammatory
complications, and improved survival.4-12,27,32-41
To our knowledge, the PROPPR trial was the first multicenter
randomized trial using approved blood products to compare
2 transfusion ratioswithmortality as the primary end point.
Among the 680 patients predicted to receive a massive transfusion
and transfused with a 1:1:1 or 1:1:2 ratio, no significant
differences in overall mortality at 24 hours or 30 days were detected.
However, more patients achieved hemostasis in the
Table 2. Trial Outcomes by Treatment Group
1:1:1 Group
(n = 338)
1:1:2 Group
(n = 342) Difference (95% CI), % Adjusted RR (95% CI) P Valuea
24-h Mortality, No. (%)b 43 (12.7) 58 (17.0) −4.2 (−9.6 to 1.1) 0.75 (0.52 to 1.08) .12
30-d Mortality, No. (%)b 75 (22.4) 89 (26.1) −3.7 (−10.2 to 2.7) 0.86 (0.65 to 1.12) .26
Achieved hemostasis
No. (%) 291 (86.1) 267 (78.1) .006
Anatomic, median (IQR), minc 105 (64 to 179) 100 (56 to 181) .44
Hospital-free days, median (IQR)c,d 1 (0 to 17) 0 (0 to 16) .83
Ventilator-free daysd
Total No. of patients 337 340
Median (IQR)c 8 (0 to 16) 7 (0 to 14) .14
ICU-free daysd
Total No. of patients 337 340
Median (IQR)c 5 (0 to 11) 4 (0 to 10) .10
Incidence of primary surgical procedure 290 (85.8) 284 (83.0) 2.8 (−2.8 to 8.3)
Disposition at 30 d, No. (%)e
Home 118 (34.9) 105 (30.7)
.37
Remained hospitalized 82 (24.3) 77 (22.5)
Otherf 59 (17.5) 71 (20.8)
Morgue 75 (22.2) 89 (26.0)
Unknown 4 (1.2) 0
Glasgow Outcome Scale-Extended score
Total No. of patientsg 30 28
Median (IQR)c 4 (3 to 6) 4.5 (3.5 to 7.0) .11
a Calculated using the Mantel-Haenszel test for binary outcomes measured
from randomization, adjusting for site.
bBreslow-Day test for homogeneity, χ 2
11: 24-hour P = .51, 30-day P = .65.
c The van Elteren test31 was used to compare medians, adjusting for site.
d Individuals who died within the first 24 hours from admission were assigned
zero ICU-, ventilator-, and hospital-free days.
e A generalized logit model was fit to test for treatment differences.
f Includes long-term care facility, skilled nursing facility, rehabilitation
facility, acute care hospital, assisted living, psychiatric facility,
and jail.
gObtained only on discharged patients who had a head injury.
Research Original Investigation Transfusion in Patients With Severe Trauma
476 JAMA February 3, 2015 Volume 313, Number 5 (Reprinted) jama.com
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF SYDNEY LIBRARY User on 09/20/2015
Copyright 2015 American Medical Association. All rights reserved.
1:1:1 group, fewer patientsdied of exsanguination, and this transfusion
ratio appears to be safe.Results from thePROMMTT study
showed that earlier use of higher amounts of plasma and platelets
(albeit without consistent ratios) was associated with improved
survival during the first 6 hours after admission.10,19Data
from the PROPPR trial evaluated the effect of early transfusion
of different but consistent ratios in patients predicted to receive
a massive transfusion. Taken together, these data support
early (withinminutes of hospital arrival) use of a 1:1:1 transfusion
ratio in patients with rapid bleeding.
Despite significant concerns that the 1:1:1 group would experience
higher rates ofmultiple inflammatory-mediated complications
such as acute respiratory distress syndrome, multiple
organ failure, infection, venous thromboembolism, and
sepsis,13,14,42-45 no differences were detected between the 2
treatment groups. Furthermore, the rates ofmultiple organ failure
(5%) and acute respiratory distress syndrome (14%) were
lower than in recent studies in similarly injured patient
populations,46,47whichmay be attributable to delivering blood
to the bedside earlier (median of 8minutes)20 and limited crysFigure
2. Kaplan-Meier Failure Curves for Mortality at 24 Hours and 30 Days
0.30
0.35
0.25
0.20
0.15
0.10
0.05
0
0
342
338
24
284
295
12
291
300
18
286
297
6
296
305
Probability of Death
Time to Death From Randomization, h
No. at risk
1:1:2
1:1:1
1
322
327
3
304
318
24-h Mortality
0.30
0.35
0.25
0.20
0.15
0.10
0.05
0
0
342
338
30
252
260
20
253
263
Probability of Death
Time to Death From Randomization, d
10
261
269
30-d Mortality
1:1:2 Group
1:1:1 Group
The colored areas indicate 95% confidence bands, which were calculated using
the Hall-Wellner method. The Hall-Wellner bands extend to the last event
(death) in each group. For 24-hour mortality, the Cox proportional hazards
regression model, adjusted for site as a random effect, produced a hazard ratio
(HR) of 0.72 (95% CI, 0.49-1.07). There were no patients lost to follow-up
during the first 24 hours from randomization. For 30-day mortality, the Cox
proportional hazards regression model, adjusted for site as a random effect,
produced an HR of 0.83 (95% CI, 0.61-1.12). Between 24 hours and 30 days, 4
patients were lost to follow-up and were censored when they withdrew consent
or were last known to be alive (3 in the 1:1:1 group and 1 in the 1:1:2 group).
Table 3. Adjudicated Cause of Death by Treatment Group and Period From Randomization
First 24 Hours 30 Days
No. (%)
Difference (95% CI),%a
No. (%)
Difference (95% CI), %a
1:1:1 Group
(n = 338)
1:1:2 Group
(n = 342)
1:1:1 Group
(n = 335)
1:1:2 Group
(n = 341)
Total No. of deaths 43 58 75 89
Cause of deathb
Exsanguination 31 (9.2) 50 (14.6) −5.4 (−10.4 to −0.5) 36 (10.7) 50 (14.7) −3.9 (−9.1 to 1.2)
Traumatic brain injury 11 (3.3) 12 (3.5) −0.3 (−3.2 to 2.7) 27 (8.1) 35 (10.3) −2.2 (−6.7 to 2.2)
Respiratory, pulmonary contusion,
or tension pneumothorax
3 (0.9) 1 (0.3) 0.6 (−0.9 to 2.4) 5 (1.5) 2 (0.6) 0.9 (−0.8 to 3.0)
Sepsis 0 0 0 (−1.1 to 1.1) 1 (0.3) 2 (0.6) −0.3 (−1.9 to 1.2)
Multiple organ failure 0 0 0 (−1.1 to 1.1) 10 (3.0) 8 (2.3) 0.6 (−2.0 to 3.4)
Type of cardiovascular event
Stroke 0 1 (0.3) −0.3 (−1.7 to 0.9) 2 (0.6) 1 (0.3) 0.3 (−1.1 to 1.9)
Myocardial infarction 1 (0.3) 1 (0.3) 0 (−1.4 to 1.4) 1 (0.3) 2 (0.6) −0.3 (−1.9 to 1.2)
Pulmonary embolism 0 1 (0.3) −0.3 (−1.7 to 0.9) 0 1 (0.3) −0.3 (−1.7 to 0.9)
Transfusion-related fatality 0 0 0 (−1.1 to 1.1) 1 (0.3) 0 0.3 (−0.8 to 1.7)
a Calculated using exact unconditional methods based on the Farrington-Manning score statistic.
bA patient may have had more than 1 cause of death.
Transfusion in Patients With Severe Trauma Original Investigation Research
jama.com (Reprinted) JAMA February 3, 2015 Volume 313, Number 5 477
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF SYDNEY LIBRARY User on 09/20/2015
Copyright 2015 American Medical Association. All rights reserved.
talloid exposure (median, 6.3-6.6 L) during the first 24 hours
of care. In this trial, the early availability of blood products administered
within minutes of arrival using a transfusion ratio
of 1:1:1 was associated with more patients achieving hemostasis
and decreased hemorrhage-related deaths over the first 24
hours with no differences in complications. Therefore, patient
safety was not compromised over 30 days.
Transfusing patients based on an empirical ratio rather
than guided solely by laboratory data (goal-directed) is considered
controversial by some researchers.44,45,48 This trial
was not designed to study this question. However, after the
controlled, ratio-driven intervention was completed, clinicians
treated patients based on local laboratory-guided
standard-of-care practice.49 It appears that laboratorydirected
catching up occurred in the 1:1:2 group with plasma
and platelets approaching a cumulative ratio of 1:1:1. Other
studies have shown similar results with laboratory-directed
resuscitation.11 This catching up after the completion of randomized
blood product transfusion may have decreased the
ability to detect differences in mortality at 24 hours and 30
days or in the prespecified ancillary outcomes.
Theconceptsofdamagecontrol resuscitation anddata from
the PROMMTT study formed the biological basis of the PROPPR
trial, ie, both early initiation (withinminutes of arrival) and increased
ratios of plasma and platelets would decrease death
from hemorrhage by improving hemostasis.4-12,27,32-41Recent
trauma resuscitationstudieshavedemonstrated thatmost early
deaths due to hemorrhage occur within 2 to 3 hours.3,10,27,50,51
The PROMMTT study demonstrated a median time to hemorrhagic
death from admission of 2.6 hours,10 and in the
PROPPR trial, the median time was 2.3 hours. In recognition
of the known physiology of patients with major bleeding, the
FDA recently recommended moving the end point of hemostasis
in a pivotal phase 3 prothrombin complex concentrate
trial to within 4 hours of the intervention.52 These data support
recent recommendations by the FDA to include a 3-hour
end point for intervention studies focusing on traumatic
hemorrhage.53
In the current study, the FDA only allowed 2 separate
primary end points (24 hours and 30 days) in recognition of
the assumed time frame of death from hemorrhage after
injury.3,10,54 However, most outcomes relevant to hemorrhage
control occurred early (within the initial 2-3 hours
after randomization). Thereafter, the number of patients
who died was similar between groups, explaining the
diminished effects at 24 hours and 30 days. This pattern of
Figure 3. Distribution of Cumulative Blood Product Ratios Within Period up to 24 Hours After Admission
4.0
2.0
2.5
3.5
3.0
1.5
1.0
0.5
0
Ratio of Plasma to RBCs
No.
1:1:1
1:1:2
Prerandomization
324 321
Postintervention
133 114
7.5
6.0
4.5
3.0
1.5
0
Ratio of Platelets to RBCs
No.
Prerandomization
324 321
Postintervention
133 114
Ratio of plasma to RBCs Ratio of platelets to RBCs
During
Intervention
326 332
During
Intervention
326 332
Prerandomization blood products
include those given prior to hospital
arrival. Patients who received no red
blood cells (RBCs) within an interval
were excluded because RBCs are in
the ratio denominator. The lower and
upper edges of the boxes are the
25th and 75th percentiles, the
whiskers extend to ± 1.5 × the
interquartile range, and the points
outside are the outliers. The thick line
inside the box represents the median
and the circle is the mean.
Figure 4. Distribution of Blood Product Amounts Within Period up to 24 Hours After Admission
70
40
50
60
30
20
10
0
Amount Given, U
Prerandomization
No.
70
40
50
60
30
20
10
0
Amount Given, U
During intervention
No.
RBCs
70
40
50
60
30
20
10
0
Amount Given, U
Postintervention
No.
Plasma Platelets RBCs
316
Plasma Platelets
305
Plasma Platelets RBCs
342
Platelets
338
Plasma RBCs
1:1:1
Plasma Platelets
342
RBCs
1:1:2 1:1:1 1:1:2 1:1:1 1:1:2
Platelets RBCs
338
Plasma
Prerandomization blood products include those given prior to hospital arrival.
The lower and upper edges of the boxes are the 25th and 75th percentiles, the
whiskers extend to ± 1.5 × the interquartile range, and the points outside are
the outliers. The thick line inside the box represents the median and the circle is
the mean. Five or 6 U pools of whole blood–derived platelets were considered
equivalent to 1 U of apheresis platelets (eg, an adult dose of platelets).
Research Original Investigation Transfusion in Patients With Severe Trauma
478 JAMA February 3, 2015 Volume 313, Number 5 (Reprinted) jama.com
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF SYDNEY LIBRARY User on 09/20/2015
Copyright 2015 American Medical Association. All rights reserved.
traumatic death is consistent with previous randomized
resuscitation studies.51,55,56
This trial had a number of strengths. The trial addressed
most of the limitations found in previous randomized trauma
resuscitation trials, including lack of blinded treatment assignment,
enrollment after bleeding slowed, survival and selection
biases, and small sample size.48,55-61The trial was performed
under exception from informed consent so that patients
with severe bleeding could be enrolled rapidly and required
that all blood products be immediately available for infusion
within 10 minutes of calling the blood bank (Supplement 1).
The selection criteria used in this study resulted in the rapid
enrollment of patients who were severely bleeding, critically
injured, in shock, and transfused with a median greater than
19 U of blood products. Separation of the ratio groupswasmaintained
during the intervention period.
Another strength of the trial was the high degree of compliance
with treatment protocols while simultaneously caring
for patients with severe injuries. Follow-up at 24 hours was
complete in both intervention groups, and only 4 patients were
lost to follow-up at 30 days. Additionally, we blinded clinicians
to treatment assignment until infusion of randomized
products and used direct observation for accurate data collection
of blood product delivery.
Limitations include power to detect differences smaller
than the effect size we considered to be both clinically meaningful
and affordable to study when we designed the trial. The
PROPPR trial had 95% power to detect the prespecified 10%
difference at 24 hours and 92% power to detect the prespecified
12% difference at 30 days, if such differences existed. As
in many studies, observed mortality in the comparison group
(1:1:2) was lower than expected, whereas in the 1:1:1 group, observed
mortality was similar to what was projected. A total
sample size of 2968 would have been required to detect the
observed difference of 4.2% given the observed 24-hour mortality
of 12.7% in the 1:1:1 group with 90% power. A further limitation
is the inability to independently examine the effects of
plasma and platelets on outcomes. To enroll patients withmassive
bleeding, the protocol required transfusion of at least 1 U
of any blood product and no more than 3 U of RBCs prior to
randomization, resulting in an inability to use randomized
blood products starting with the first transfusion.
Table 4. Incidence of Prespecified Complications by Treatment Group
1:1:1 Group (n = 338) 1:1:2 Group (n = 342) Difference Between
Groups in Percentage
of Patients With Event,
% (95% CI)c
Total No. of
Eventsa
No. (%) of
Patientsb
Total No. of
Eventsa
No. (%) of
Patientsb
Systemic inflammatory response syndrome 265 231 (68.3) 239 216 (63.2) 5.2 (−2.1 to 12.3)
Sepsis 110 99 (29.3) 102 91 (26.6) 2.7 (−4.2 to 9.5)
Infection (urinary tract infection, wound, line, other) 155 98 (29.0) 146 106 (31.0) −2.0 (−8.9 to 5.0)
Death 75 75 (22.2) 89 89 (26.0) −3.8 (−10.3 to 2.7)
Acute kidney injury 87 74 (21.9) 93 85 (24.9) −3.0 (−9.4 to 3.5)
Ventilator-associated pneumonia 70 62 (18.3) 65 58 (17.0) 1.4 (−4.4 to 7.2)
Transfusion-related metabolic complication (hypocalcemia
or hyperkalemia)
53 53 (15.7) 60 59 (17.3) −1.6 (−7.2 to 4.1)
Acute lung injury 56 47 (13.9) 66 57 (16.7) −2.8 (−8.3 to 2.7)
Acute respiratory distress syndrome 55 46 (13.6) 57 48 (14.0) −0.4 (−5.7 to 4.9)
Deep vein thrombosis 28 25 (7.4) 24 24 (7.0) 0.4 (−3.6 to 4.4)
Abdominal complication 29 24 (7.1) 23 22 (6.4) 0.7 (−3.3 to 4.6)
Cardiac arrest 25 23 (6.8) 30 27 (7.9) −1.1 (−5.2 to 3.0)
Multiple organ failure 24 20 (5.9) 18 15 (4.4) 1.5 (−1.9 to 5.1)
Symptomatic pulmonary embolism 14 14 (4.1) 13 13 (3.8) 0.3 (−2.8 to 3.5)
Additional bleeding after hemostasis requiring
interventional radiology or operating room procedure
13 13 (3.8) 18 16 (4.7) −0.8 (−4.1 to 2.4)
Asymptomatic pulmonary embolism 11 11 (3.3) 11 11 (3.2) 0 (−2.8 to 2.9)
Stroke 9 8 (2.4) 11 11 (3.2) −0.8 (−3.6 to 1.8)
Abdominal compartment syndrome 3 3 (0.9) 3 3 (0.9) 0 (−1.8 to 1.8)
Delayed serological transfusion reaction 2 2 (0.6) 0 0 0.6 (−0.5 to 2.1)
Transfusion-related allergic reactions 2 2 (0.6) 1 1 (0.3) 0.3 (−1.1 to 1.9)
Hypernatremia (associated with hypertonic saline) 1 1 (0.3) 4 4 (1.2) −0.9 (−2.7 to 0.6)
Febrile nonhemolytic transfusion reaction 1 1 (0.3) 1 1 (0.3) 0 (−1.4 to 1.4)
Transfusion-associated circulatory overload 1 1 (0.3) 0 0 0.3 (−0.8 to 1.7)
Myocardial infarction 0 0 2 2 (0.6) −0.6 (−2.1 to 0.6)
Any prespecified complications 1089 297 (87.9) 1076 310 (90.6) −2.8 (−7.6 to 1.9)
a A patient may have had multiple complications of the same type.
bPercentages may add to more than 100% because a patient may have had
more than 1 complication.
c Calculated using exact unconditional methods based on the
Farrington-Manning score statistic.
Transfusion in Patients With Severe Trauma Original Investigation Research
jama.com (Reprinted) JAMA February 3, 2015 Volume 313, Number 5 479
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF SYDNEY LIBRARY User on 09/20/2015
Copyright 2015 American Medical Association. All rights reserved.
Even though the study was blinded until the opening of
the containers, another limitation was that clinicians could not
be blinded after the containers were opened without altering
patient care. This trial was also limited by an inability to completely
exclude patients with an unsurvivable brain injury; 23%
of deaths at 24 hours and 38% of all deaths at 30 days were associated
with traumatic brain injury. Last, the issue of competing
risks of death from hemorrhage and traumatic brain injury
in trauma studies that require rapid enrollment before
definitive diagnosis of allmajor injuries is well-known and will
continue to be an issue in future trauma studies unless novel
regulatory, study design, or technological solutions are developed
to solve this issue.3,54
Given the lower percentage of deaths from exsanguination
and our failure to find differences in safety, clinicians
should consider using a 1:1:1 transfusion protocol, starting with
the initial units transfused while patients are actively bleeding,
and then transitioning to laboratory-guided treatment once
hemorrhage control is achieved. Future studies of hemorrhage
control products, devices, and interventions should concentrate
on the physiologically relevant period of active bleeding
after injury and use acute complications and later deaths
(24 hours and 30 days) as safety end points.
Conclusions
Among patients with severe trauma and major bleeding, early
administration of plasma, platelets, and RBCs in a 1:1:1 ratio
compared with a 1:1:2 ratio did not result in significant differences
in mortality at 24 hours or at 30 days. However, more
patients in the 1:1:1 group achieved hemostasis and fewer experienced
death due to exsanguination by 24 hours. Even
though there was an increased use of plasma and platelets
transfused in the 1:1:1 group, no other safety differences were
identified between the 2 groups.
ARTICLE INFORMATION
Author Affiliations: Center for Translational Injury
Research, Division of Acute Care Surgery,
Department of Surgery, Medical School, University
of Texas Health Science Center, Houston (Holcomb,
Fox, Wade, Podbielski, del Junco, Cotton,
Matijevic); Division of Biostatistics, School of Public
Health, University of Texas Health Science Center,
Houston (Tilley, Baraniuk); Division of Trauma and
Critical Care, Department of Surgery, Medical
College of Wisconsin, Milwaukee (Brasel); Division
of Trauma and Critical Care, Department of Surgery,
School of Medicine, University of Washington,
Seattle (Bulger); Division of General Surgery,
Department of Surgery, School of Medicine,
University of California, San Francisco (Callcut,
Cohen); Division of Trauma and Surgical Critical
Care, Department of Surgery, College of Medicine,
University of Tennessee Health Science Center,
Memphis (Fabian, Weinberg); Division of Trauma
and Critical Care, University of Southern California,
Los Angeles (Inaba); Division of Trauma, Burns and
Surgical Critical Care, Department of Surgery,
School of Medicine, University of Alabama,
Birmingham (Kerby); Division of Trauma/Critical
Care, Department of Surgery, College of Medicine,
University of Cincinnati, Cincinnati, Ohio (Muskat,
Robinson); Division of Trauma, Critical Care and
Emergency Surgery, Department of Surgery,
University of Arizona, Tucson (O’Keeffe); Trauma
and Acute Care Surgery, St Michael’s Hospital,
University of Toronto, Toronto, Ontario, Canada
(Rizoli); R. Adams Cowley Shock Trauma Center,
Program in Trauma, University of Maryland School
of Medicine, Baltimore (Scalea, Stein); Division of
Trauma, Critical Care and Acute Care Surgery,
School of Medicine, Oregon Health & Science
University, Portland (Schreiber); Sunnybrook
Research Institute, Department of Clinical
Pathology, Sunnybrook Health Sciences Centre,
Toronto, Ontario, Canada (Callum); Department of
Laboratory Medicine, School of Medicine,
University of Washington, Seattle (Hess);
Department of Emergency Medicine, College of
Medicine, University of Cincinnati, Cincinnati, Ohio
(Miller); Division of Critical Care and Perioperative
Medicine, Department of Anesthesiology, School of
Medicine, University of Alabama, Birmingham
(Pittet); American College of Surgeons, Chicago,
Illinois (Hoyt); Division of Cardiovascular Sciences,
National Heart, Lung, and Blood Institute, National
Institutes of Health, Bethesda, Maryland (Pearson);
Department of Biostatistics, School of Public
Health, University of Washington, Seattle (Leroux,
van Belle); Department of Environmental and
Occupational Health Sciences, School of Public
Health, University of Washington, Seattle
(van Belle). Dr Brasel is now with the Division of
Trauma, Critical Care and Acute Care Surgery,
School of Medicine, Oregon Health & Science
University, Portland. Dr Muskat is now with the
Division of General Surgery, Department of Surgery,
School of Medicine, University of California,
San Francisco.
Author Contributions: Drs Tilley and Baraniuk had
full access to all of the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Holcomb, Tilley,
Baraniuk, Wade, del Junco, Bulger, Cohen, Cotton,
Kerby, Muskat, Rizoli, Robinson, Scalea, Schreiber,
Stein, Callum, Hess, Miller, Pittet, Hoyt, Pearson,
Leroux, van Belle.
Acquisition, analysis, or interpretation of data: Tilley,
Baraniuk, Fox, Wade, Podbielski, del Junco, Brasel,
Bulger, Callcut, Cohen, Cotton, Fabian, Inaba, Kerby,
Muskat, O’Keeffe, Rizoli, Robinson, Scalea,
Schreiber, Stein, Weinberg, Callum, Hess, Matijevic,
Miller, Pittet, Hoyt, Leroux, van Belle.
Drafting of the manuscript: Holcomb, Tilley,
Baraniuk, Fox, Wade, Podbielski, Callcut, Cohen,
Cotton, Robinson, Stein, Hess, Pearson, van Belle.
Critical revision of the manuscript for important
intellectual content: Tilley, Baraniuk, Fox, Wade,
del Junco, Brasel, Bulger, Callcut, Cohen, Cotton,
Fabian, Inaba, Kerby, Muskat, O’Keeffe, Rizoli,
Robinson, Scalea, Schreiber, Stein, Weinberg,
Callum, Hess, Matijevic, Miller, Pittet, Hoyt,
Pearson, Leroux, van Belle.
Statistical analysis: Tilley, Baraniuk, Fox, Wade,
Fabian, van Belle.
Obtained funding: Holcomb, Wade, Cotton,
Schreiber, van Belle.
Administrative, technical, or material support: Tilley,
Wade, Podbielski, del Junco, Bulger, Callcut, Cohen,
Cotton, Kerby, Muskat, O’Keeffe, Rizoli, Robinson,
Scalea, Stein, Weinberg, Callum, Hess, Matijevic,
Miller, Pittet, Hoyt, Pearson, Leroux,
Study supervision: Holcomb, Tilley, Wade, Bulger,
Callcut, Muskat, Rizoli, Robinson, Schreiber,
Weinberg, Callum, Hess, Matijevic, Pittet, Hoyt,
van Belle.
Conflict of Interest Disclosures: The authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Dr
Rizoli reported receiving grant funding from TEM
International and CSL Behring. Dr Stein reported
serving as an advisor for Decisio Health for which
she receives travel reimbursement. No other
disclosures were reported.
Funding/Support: This work was supported with
grant U01HL077863 from the US National Heart,
Lung, and Blood Institute and funding from the US
Department of Defense, the Defence Research and
Development Canada in partnership with the
Canadian Institutes of Health Research-Institute of
Circulatory and Respiratory Health (grant CRR-
120612).
Role of the Funder/Sponsor: The US National
Heart, Lung, and Blood Institute (NHLBI) and the
US Department of Defense had a role in the study
design but had no role in the conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication. However, Dr
Pearson is employed by the NHLBI and she did
participate in the review and approval of the
manuscript.
Group Information: The PROPPR Study Group:
Clinical Coordinating Center, University of Texas
Health Science Center, Houston: John B. Holcomb,
MD, Charles E. Wade, PhD, Deborah J. del Junco,
PhD, Erin E. Fox, PhD, Nena Matijevic, PhD
(laboratory committee co-chair), Jeanette M.
Podbielski, RN, Angela M. Beeler, BS. Data
Coordinating Center, University of Texas Health
Science Center, Houston: Barbara C. Tilley, PhD,
Sarah Baraniuk, PhD, Stacia M. DeSantis, PhD,
Hongjian Zhu, PhD, Joshua Nixon, MS, Roann Seay,
MS, Savitri N. Appana, MS, Hui Yang, MS, Michael O.
Gonzalez, MS. Core Laboratory, University of Texas
Health Science Center, Houston: Lisa Baer, MS,
Research Original Investigation Transfusion in Patients With Severe Trauma
480 JAMA February 3, 2015 Volume 313, Number 5 (Reprinted) jama.com
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF SYDNEY LIBRARY User on 09/20/2015
Copyright 2015 American Medical Association. All rights reserved.
Yao-Wei Willa Wang, MD, Brittany S. Hula, MS, Elena
Espino, BS, An Nguyen, BS, Nicholas Pawelczyk, BS,
Kisha D. Arora-Nutall, BS, Rishika Sharma, MD,
Jessica C. Cardenas, PhD, Elaheh Rahbar, PhD,
Tyrone Burnett Jr, BS, David Clark, BS. Resuscitation
Outcomes Consortium, University of Washington:
Gerald van Belle, PhD, Susanne May, PhD, Brian
Leroux, PhD, David Hoyt, MD, Judy Powell, BSN,
RN, Kellie Sheehan, BSN. Systems Biology
Committee, University of California, Berkeley: Alan
Hubbard, PhD (co-chair), Adam P. Arkin, PhD.
Transfusion Committee: John R. Hess, MD, MPH
(co-chair, University of Washington), Jeannie L.
Callum, MD (co-chair, Sunnybrook Health Sciences
Centre). Anesthesiology Committee: Jean-Francois
Pittet, MD (chair, University of Alabama,
Birmingham). Emergency Medicine Committee:
Christopher N. Miller, MD (chair, University of
Cincinnati). PROPPR Clinical Sites (listed in order of
number of patients enrolled): University of Texas
Health Science Center, Houston: Bryan A. Cotton,
MD, MPH, Laura Vincent, BSN, RN, CCRP, Timothy
Welch, Tiffany Poole, DC, Evan G. Pivalizza, MD,
Sam D. Gumbert, MD, Yu Bai, MD, PhD, James J.
McCarthy, MD, Amy Noland, MD, Rhonda Hobbs,
MT(ASCP)SBB. University of Washington: Eileen M.
Bulger, MD, Patricia Klotz, RN, Lindsay Cattin, BA,
Keir J. Warner, BS, Angela Wilson, BA, David Boman,
BA, Nathan White, MD, MS, Andreas Grabinsky, MD,
Jennifer A. Daniel-Johnson, MBBS. University of
California, San Francisco: Mitchell Jay Cohen, MD
(systems biology and laboratory committee
co-chair), Rachael A. Callcut, MD, MSPH, Mary
Nelson, RN, MPA, Brittney Redick, BA, Amanda
Conroy, BA, Marc P. Steurer, MD, DESA, Preston C.
Maxim, MD, Eberhard Fiebig, MD, Joanne Moore,
Eireen Mallari, MT. University of Cincinnati: Peter
Muskat, MD, Jay A. Johannigman, MD, Bryce R. H.
Robinson, MD, Richard D. Branson, MSc, RRT, Dina
Gomaa, BS, RRT, Christopher Barczak, BS, MT
(ASCP), Suzanne Bennett, MD, Patricia M. Carey,
MD, Helen Hancock, BS, MT(ASCP), Carolina
Rodriguez, BA. University of Southern California:
Kenji Inaba, MD, Jay G. Zhu, MD, Monica D. Wong,
MS, Michael Menchine, MD, MPH, Kelly Katzberg,
MD, FACEP, Sean O. Henderson, MD, Rodney
McKeever, MD, Ira A. Shulman, MD, Janice M.
Nelson, MD, Christopher W. Tuma, BA, MT(ASCP),
SBB, Cheryl Y. Matsushita, BS, MT(ASCP). Shock,
Trauma and Anesthesiology Research-Organized
Research Center, R. Adams Cowley Shock Trauma
Center, University of Maryland Medical Center:
Thomas M. Scalea, MD, Deborah M. Stein, MD,
MPH, Cynthia K. Shaffer, MS, MBA, Christine Wade,
BA, Anthony V. Herrera, MS, Seeta Kallam, MBBS,
Sarah E. Wade, BS, Samuel M. Galvagno Jr, DO, PhD,
Magali J. Fontaine, MD, PhD, Janice M. Hunt, BS,
MT(ASCP) SBB, Rhonda K. Cooke, MD. University of
Tennessee Health Science Center, Memphis:
Timothy C. Fabian, MD, Jordan A. Weinberg, MD,
Martin A. Croce, MD, Suzanne Wilson, RN,
Stephanie Panzer-Baggett, RN, Lynda WaddleSmith,
BSN, Sherri Flax, MD. Medical College of
Wisconsin: Karen J. Brasel, MD, MPH, Pamela
Walsh, AS, CCRC, David Milia, MD, Allia Nelson, BS,
BA, Olga Kaslow, MD, PhD, Tom P. Aufderheide, MD,
MS, Jerome L. Gottschall, MD, Erica Carpenter,
MLS(ASCP). University of Arizona: Terence
O’Keeffe, MBChB, MSPH, Laurel L. Rokowski, RN,
BSN, MKT, Kurt R. Denninghoff, MD, Daniel T.
Redford, MD, Deborah J. Novak, MD, Susan Knoll,
MS, MT(ASCP)SBB. University of Alabama,
Birmingham: Jeffrey D. Kerby, MD, PhD, Patrick L.
Bosarge, MD, Albert T. Pierce, MD, Carolyn R.
Williams, RN, BSN, BSME, Shannon W. Stephens,
EMTP, Henry E. Wang, MD, MS, Marisa B. Marques,
MD. Oregon Health & Science University: Martin A.
Schreiber, MD, Jennifer M. Watters, MD, Samantha
J. Underwood, MS, Tahnee Groat, MPH, Craig
Newgard, MD, MPH, Matthias Merkel, MD, PhD,
Richard M. Scanlan, MD, Beth Miller, MT(ASCP)SBB.
Sunnybrook Health Science Center: Sandro Rizoli,
MD, PhD, Homer Tien, MD, Barto Nascimento, MD,
MSc, CTBS, Sandy Trpcic, Skeeta Sobrian-Couroux,
RN, CCRP, BHA, Marciano Reis, Adic Pérez, MD,
Susan E. Belo, MD, PhD, Lisa Merkley, BA, MLT,
CBTS, Connie Colavecchia, BSc, MLT.
Disclaimer: The content is the sole responsibility of
the authors and should not be construed as official
or as reflecting the views of any of the sponsors.
Additional Contributions: We thank the members
of the data and safety monitoring board (Lance
Becker, Charles Cairns, Ralph D’Agostino, Karl Jern,
Nigel Key, Laurence McCullough, Jeremy Perkins,
Herbert Wiedemann, Janet Wittes, and Jay Mason)
and the external advisory committee (Kenneth G.
Mann, Kathleen Brummel, Beth Hartwell, Charles
Esmon, Morris Blajchman, Andrew P. Cap, Andrei
Kindzelski, and Anthony E. Pusateri) for their time
and effort. We also thank the Resuscitation
Outcomes Consortium protocol review committee
for their important contributions as well as
COL Dallas Hack and COL Robert Vandre for their
extraordinary commitment and unwavering
support for this trial. We could not have
successfully completed this study without the help
of hundreds of unnamed clinical personnel and we
thank them for their sustained efforts.
Additional Information: We dedicate this work to
the US Soldiers, Sailors, Airmen, and Marines who
put their lives on the line every day. We hope this
effort will help improve the care of seriously injured
patients, both military and civilian.
REFERENCES
1. US Centers for Disease Control and Prevention.
Injury prevention and control: data and statistics,
2012. http://webappa.cdc.gov/cgi-bin/broker.exe.
Accessed December 21, 2014.
2. Rhee P, Joseph B, Pandit V, et al. Increasing
trauma deaths in the United States. Ann Surg. 2014;
260(1):13-21.
3. Tisherman SA, Schmicker RH, Brasel KJ, et al.
Detailed description of all deaths in both the Shock
and Traumatic Brain Injury Hypertonic Saline Trials
of the Resuscitation Outcomes Consortium
[published online July 28, 2014]. Ann Surg. doi:10
.1097/SLA.0b013e3181df0401.
4. 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.
5. Holcomb JB, Pati S. Optimal trauma
resuscitation with plasma as the primary
resuscitative fluid: the surgeon’s perspective.
Hematology Am Soc Hematol Educ Program. 2013;
2013:656-659.
6. US Army Institute of Surgical Research. Joint
Theater Trauma System Clinical Practice Guideline:
damage control resuscitation at level IIb and III
treatment facilities. http://www.usaisr.amedd.army
.mil/assets/cpgs/Damage%20Control
%20Resuscitation%20-%201%20Feb%202013
.pdf. Accessed December 21, 2014.
7. 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.
8. Shaz BH, Dente CJ, Nicholas J, et al. Increased
number of coagulation products in relationship to
red blood cell products transfused improves
mortality in trauma patients. Transfusion. 2010;50
(2):493-500.
9. 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.
10. Holcomb JB, del Junco DJ, Fox EE, et al;
PROMMTT Study Group. The Prospective,
Observational, Multicenter, Major Trauma
Transfusion (PROMMTT) study: comparative
effectiveness of a time-varying treatment with
competing risks.JAMA Surg. 2013;148(2):127-136.
11. Johansson PI, Sørensen AM, Larsen CF, et al.
Low hemorrhage-related mortality in trauma
patients in a level I trauma center employing
transfusion packages and early
thromboelastography-directed hemostatic
resuscitation with plasma and platelets. Transfusion.
2013;53(12):3088-3099.
12. Langan NR, Eckert M, Martin MJ. Changing
patterns of in-hospital deaths following
implementation of damage control resuscitation
practices in US forward military treatment facilities.
JAMA Surg. 2014;149(9):904-912.
13. 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.
14. Johnson JL, Moore EE, Kashuk JL, et al. Effect
of blood products transfusion on the development
of postinjury multiple organ failure. Arch Surg.
2010;145(10):973-977.
15. American Society of Anesthesiologists Task
Force on Perioperative Blood Transfusion and
Adjuvant Therapies. Practice guidelines for
perioperative blood transfusion and adjuvant
therapies: an updated report by the American
Society of Anesthesiologists Task Force on
Perioperative Blood Transfusion and Adjuvant
Therapies. Anesthesiology. 2006;105(1):198-208.
16. Dzik WH, Blajchman MA, Fergusson D, et al.
Clinical review: Canadian National Advisory
Committee on Blood and Blood Products—massive
transfusion consensus conference 2011: report of
the panel. Crit Care. 2011;15(6):242.
17. American Society of Anesthesiologists.
Standards, guidelines, statements and other
documents. https://www.asahq.org/For-Members
/Standards-Guidelines-and-Statements.aspx.
Accessed September 1, 2014.
18. Spahn DR, Bouillon B, Cerny V, et al.
Management of bleeding and coagulopathy
following major trauma: an updated European
guideline. Crit Care. 2013;17(2):R76.
19. del Junco DJ, Holcomb JB, Fox EE, et al;
PROMMTT Study Group. Resuscitate early with
plasma and platelets or balance blood products
Transfusion in Patients With Severe Trauma Original Investigation Research
jama.com (Reprinted) JAMA February 3, 2015 Volume 313, Number 5 481
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF SYDNEY LIBRARY User on 09/20/2015
Copyright 2015 American Medical Association. All rights reserved.
gradually: findings from the PROMMTT study.
J Trauma Acute Care Surg. 2013;75(1)(suppl 1):S24-
S30.
20. Baraniuk S, Tilley BC, del Junco DJ, et al;
PROPPR Study Group. Pragmatic Randomized
Optimal Platelet and Plasma Ratios (PROPPR) Trial:
Design, rationale and implementation. Injury. 2014;
45(9):1287-1295.
21. US Department of Health and Human
Services; US Food and Drug Administration.
Guidance for institutional review boards, clinical
investigators, and sponsors: exception from
informed consent requirements for emergency
research, 2013. http://www.fda.gov/downloads
/RegulatoryInformation/Guidances/UCM249673
.pdf. Accessed September 1, 2014.
22. 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.
23. O’Brien PC. The appropriateness of analysis of
variance and multiple-comparison procedures.
Biometrics. 1983;39(3):787-794.
24. Baker SP, O’Neill B, Haddon W Jr, Long WB.
The injury severity score: a method for describing
patients with multiple injuries and evaluating
emergency care.J Trauma. 1974;14(3):187-196.
25. Savage SA, Zarzaur BL, Croce MA, Fabian TC.
Redefining massive transfusion when every second
counts.J Trauma Acute Care Surg. 2013;74(2):396-
400.
26. Farrington CP, Manning G. Test statistics and
sample size formulae for comparative binomial
trials with null hypothesis of non-zero risk
difference or non-unity relative risk. Stat Med.
1990;9(12):1447-1454.
27. 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.
28. Hollis S. A graphical sensitivity analysis for
clinical trials with non-ignorable missing binary
outcome. Stat Med. 2002;21(24):3823-3834.
29. O’Brien PC, Fleming TR. A multiple testing
procedure for clinical trials. Biometrics. 1979;35(3):
549-556.
30. Klein JP, Moeschberger ML. Survival Analysis:
Techniques for Censored and Truncated Data. 2nd ed.
New York, NY: Springer; 2003.
31. van Elteren PH. On the combination of
independent two-sample tests of Wilcoxon. Bull Int
Stat Inst. 1960;37:351-361.
32. Ho AM, Karmakar MK, Dion PW. Are we giving
enough coagulation factors during major trauma
resuscitation? Am J Surg. 2005;190(3):479-484.
33. Huber-Wagner S, Qvick M, Mussack T, et al;
Working Group on Polytrauma of German Trauma
Society (DGU). Massive blood transfusion and
outcome in 1062 polytrauma patients:
a prospective study based on the Trauma Registry
of the German Trauma Society. Vox Sang. 2007;92
(1):69-78.
34. Duchesne JC, Hunt JP, Wahl G, et al. Review of
current blood transfusion strategies in a mature
level I trauma center: were we wrong for the last 60
years? J Trauma. 2008;65(2):272-276.
35. Sperry JL, Ochoa JB, Gunn SR, et al;
Inflammation and the Host Response to Injury
Investigators. An FFP:PRBC transfusion ratio
>/=1:1.5 is associated with a lower risk of mortality
after massive transfusion.J Trauma. 2008;65(5):
986-993.
36. 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.
37. Perkins JG, Cap AP, Spinella PC, et al.
An evaluation of the impact of apheresis platelets
used in the setting of massively transfused trauma
patients [published correction appears in J Trauma.
2009;67(6):1453].J Trauma. 2009;66(4)(suppl):
S77-S84.
38. Holcomb JB, Zarzabal LA, Michalek JE, et al;
Trauma Outcomes Group. Increased platelet:RBC
ratios are associated with improved survival after
massive transfusion.J Trauma. 2011;71(2)(suppl 3):
S318-S328.
39. Kautza BC, Cohen MJ, Cuschieri J, et al;
Inflammation and the Host Response to Injury
Investigators. Changes in massive transfusion over
time: an early shift in the right direction? J Trauma
Acute Care Surg. 2012;72(1):106-111.
40. Radwan ZA, Bai Y, Matijevic N, et al. An
emergency department thawed plasma protocol
for severely injured patients.JAMA Surg. 2013;148
(2):170-175.
41. Robinson BR, Cotton BA, Pritts TA, et al;
PROMMTT study group. Application of the Berlin
definition in PROMMTT patients: the impact of
resuscitation on the incidence of hypoxemia.
J Trauma Acute Care Surg. 2013;75(1)(suppl 1):S61-
S67.
42. Watson GA, Sperry JL, Rosengart MR, et al;
Inflammation and Host Response to Injury
Investigators. Fresh frozen plasma is independently
associated with a higher risk of multiple organ
failure and acute respiratory distress syndrome.
J Trauma. 2009;67(2):221-227.
43. Roback JD, Caldwell S, Carson J, et al; American
Association for the Study of Liver; American
Academy of Pediatrics; US Army; American Society
of Anesthesiology; American Society of
Hematology. Evidence-based practice guidelines
for plasma transfusion. Transfusion. 2010;50(6):
1227-1239.
44. Pieracci FM, Kashuk JL, Moore EE. Postinury
hemotherapy and hemostasis. In: Mattox KL,
Moore EE, Feliciano DV, eds. Trauma. 7th ed. New
York, NY: McGraw-Hill; 2012:216-235.
45. Kelly JM, Callum JL, Rizoli SB. 1:1:1-warranted or
wasteful? even where appropriate, high ratio
transfusion protocols are costly: early transition to
individualized care benefits patients and
transfusion services. Expert Rev Hematol. 2013;6
(6):631-633.
46. Park PK, Cannon JW, Ye W, et al. Transfusion
strategies and development of acute respiratory
distress syndrome in combat casualty care.
J Trauma Acute Care Surg. 2013;75(2)(suppl 2):
S238-S246.
47. Sauaia A, Moore EE, Johnson JL, et al.
Temporal trends of postinjury multiple-organ
failure: still resource intensive, morbid, and lethal.
J Trauma Acute Care Surg. 2014;76(3):582-592.
48. Nascimento B, Callum J, Tien H, et al. Effect of
a fixed-ratio (1:1:1) transfusion protocol versus
laboratory-results-guided transfusion in patients
with severe trauma: a randomized feasibility trial.
CMAJ. 2013;185(12):583-589.
49. Johansson PI, Stensballe J, Oliveri R, Wade CE,
Ostrowski SR, Holcomb JB. How I treat patients
with massive hemorrhage. Blood. 2014;124(20):
3052-3058.
50. Hoyt DB, Bulger EM, Knudson MM, et al. Death
in the operating room: an analysis of a multi-center
experience.J Trauma. 1994;37(3):426-432.
51. Bulger EM, May S, Kerby JD, et al; ROC
Investigators. Out-of-hospital hypertonic
resuscitation after traumatic hypovolemic shock:
a randomized, placebo controlled trial. Ann Surg.
2011;253(3):431-441.
52. Sarode R, Milling TJ Jr, Refaai MA, et al. Efficacy
and safety of a 4-factor prothrombin complex
concentrate in patients on vitamin K antagonists
presenting with major bleeding: a randomized,
plasma-controlled, phase IIIb study. Circulation.
2013;128(11):1234-1243.
53. US Food and Drug Administration. Product
development program for interventions in patients
with severe bleeding due to trauma or other causes,
2010. http://www.fda.gov/BiologicsBloodVaccines
/NewsEvents/WorkshopsMeetingsConferences
/ucm241913.htm. Accessed December 21, 2014.
54. 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.
55. Moore EE, Moore FA, Fabian TC, et al;
PolyHeme Study Group. Human polymerized
hemoglobin for the treatment of hemorrhagic
shock when blood is unavailable: the USA
multicenter trial. J Am Coll Surg. 2009;208(1):1-13.
56. Hauser CJ, Boffard K, Dutton R, et al;
CONTROL Study Group. Results of the CONTROL
trial: efficacy and safety of recombinant activated
factor VII in the management of refractory
traumatic hemorrhage.J Trauma. 2010;69(3):489-
500.
57. Silverman T, Aebersold P, Landow L, Lindsey K.
Regulatory perspectives on clinical trials for trauma,
transfusion, and hemostasis. Transfusion. 2005;45
(1)(suppl):14S-21S.
58. Dutton R, Hauser C, Boffard K, et al; CONTROL
Steering Committee. Scientific and logistical
challenges in designing the CONTROL trial:
recombinant factor VIIa in severe trauma patients
with refractory bleeding. Clin Trials. 2009;6(5):
467-479.
59. Snyder CW, Weinberg JA, McGwin G Jr, et al.
The relationship of blood product ratio to mortality:
survival benefit or survival bias? J Trauma. 2009;66
(2):358-362.
60. 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;116(3):716-728.
61. del Junco DJ, Fox EE, Camp EA, Rahbar MH,
Holcomb JB; PROMMTT Study Group. Seven deadly
sins in trauma outcomes research: an epidemiologic
post mortem for major causes of bias.J Trauma
Acute Care Surg. 2013;75(1)(suppl 1):S97-S103.
Research Original Investigation Transfusion in Patients With Severe Trauma
482 JAMA February 3, 2015 Volume 313, Number 5 (Reprinted) jama.com
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF SYDNEY LIBRARY User on 09/20/2015
TO GET YOUR ASSIGNMENTS DONE AT A CHEAPER PRICE,PLACE YOUR ORDER WITH US NOW