Received: 31 December 2020 Revised: 24 January 2021 Accepted: 26 January 2021

DOI: 10.1111/trf.16453

SUPPLEMENT ARTICLE

A new definition for massive transfusion in the modern era

of whole blood resuscitation

Parker Hu1 | Rindi Uhlich2 | Jonathan Black1 | Jan O. Jansen1 |

Jeffrey Kerby1 | John B. Holcomb1

1
Center for Injury Science & Division of
Acute Care Surgery, Department of
Surgery, University of Alabama at
Birmingham, Birmingham,
Alabama, USA
2 tration threshold (CAT), and resuscitation intensity (RI). All fail to account for
Department of Surgery, University of
Alabama at Birmingham, Birmingham,
Alabama, USA
Correspondence
Parker Hu, 1808 7th Ave South, BDB
D603, Birmingham, AL 35233, USA.
Email: phu@uabmc.edu
Abstract
Background: Multiple thresholds are defined to identify patients at risk of
death from hemorrhage, including massive transfusion (MT), critical adminis-
the use of whole blood (WB). We hypothesized that a definition including WB
transfusion would better predict early mortality following trauma.
Methods: This is a retrospective review of all trauma patients with activation
of the MT protocol from December 2018 to February 2020. Combinations of
WB, RBCs, and fresh frozen plasma (FFP) units transfused during the initial
hour of resuscitation were compared using receiver operating characteristic
and area under the receiver curve (AUC) for 3- and 6-h mortality. WB massive
transfusion (WB MT) score was defined as the sum of each unit RBC plus three
times each unit of WB transfused within the first hour of resuscitation.
Results: There were 235 patients eligible for analysis with 60 resuscitated
using ≥1 unit of WB. Overall, 27 and 29 patients died in the first 3 and 6 h,
respectively. WB MT ≥7 had the greatest 3-h and 6-h mortality AUC values
(0.78 and 0.79, respectively) when compared to MT, CAT, RI4+, and other
attempted definitions using units of WB, RBC, and FFP. Compared to WB
MT
, WB MT+ patients died at significantly higher rates at 3 h (28.9%
vs. 3.1%, p < .001), 24 h (35.5% vs. 5.7%, p < .001), and 28 days (42.1%
vs. 11.9%, p < .001).
Conclusion: WB MT is the first measure of massive resuscitation to incorpo-
rate WB and better identifies early mortality than other definitions.

KEYWORDS
Hemorrhage, Massive Transfusion Protocol, Trauma, Whole Blood

Abbreviations: AUC, Area under the curve; ED, Emergency department; CAT, Critical administration threshold; FFP, Fresh frozen plasma; MTP,
Massive transfusion protocol; MT, Massive transfusion; RBC, Red blood cells; RI+, Resuscitation intensity; ROC, Receiver operating characteristic;
TAC, Trauma associated coagulopathy; UAB, University of Alabama at Birmingham; WB MT, Whole blood massive transfusion; WB MT+, Whole
blood massive transfusion positive; WB MT-, Whole blood massive transfusion negative; WB, Whole blood.

Our work has no outside sources of support or funding to report. It has not been presented at any meeting.

S252 © 2021 AABB wileyonlinelibrary.com/journal/trf Transfusion. 2021;61:S252–S263.

HU ET AL.
1 | INTRODUCTION
Trauma is a leading cause of death in the United States,
and importantly, blood loss, or hemorrhage, is the leading
cause of potentially preventable death.1–5 Early resuscitation
with blood, reversal of trauma-associated coagulopathy
(TAC), and early hemorrhage control are essential to
improve survival in patients with ongoing bleeding.
Although hemorrhage is the leading cause of preventable
death among the severely injured, the incidence of life-
threatening hemorrhage remains less than 5% among those
requiring trauma evaluation.6 The majority of those deaths
occur within the first 3–6 h of injury.7,8 Time to recognition
and differentiation of these patients at risk for death from
blood loss is essential to improve survival in this population
and decrease the estimated 30,000 preventable deaths due
to hemorrhage after injury.9
Quantitative assessment of the resuscitative efforts in
the immediate post-injury period has long been used as
an easily available tool to identify patients with life-
threatening hemorrhage requiring massive transfusion
(MT). The definition of MT was developed and defined
during the Vietnam War as transfusion of 10 units of
whole blood (WB) in a 24 h period.10,11 Although the
classic definition of MT was significantly associated with
coagulopathy and mortality, it requires that patients live
long enough to receive 10 units of blood.12 Recognition of
the survival bias inherent in MT, as well as evidence that
most mortality from hemorrhage occurs within the first
6 h of injury, led to the development of earlier markers of
massive resuscitation such as critical administration
threshold (CAT) and resuscitation intensity (RI+).13–16
Both CAT and RI+ measure the intensity of early resusci-
tative efforts, measured over the first minutes and hours
following arrival, and offer improvement in sensitivity
and specificity in prediction of mortality compared with
MT.17,18
One aspect of MT classification that lags behind
current resuscitation practice is how the use of WB
factors into the definition of MT. Since the middle of
the Vietnam War, transfusion policy shifted to favor
the separation of WB into its components for banking
and subsequent transfusion.19 The current definitions
(MT, CAT, RI+) retained the number of red units, but
changed from WB to packed red blood cells. A unit of
WB is clearly different from a unit of RBCs. As the use
of WB in the resuscitation of the severely injured has
increased, the need for a definition of MT incorporat-
ing the use WB is required. We hypothesized that the
addition of WB to resuscitative volume measurement
would allow for development of a definition for whole
blood massive transfusion (WB MT) with improvement
S253
in sensitivity and specificity for mortality over existing
measurement tools.
2 | METHODS
We performed a retrospective review of all trauma
patients with activation of the massive transfusion proto-
col (MTP) at our institution from December 2018 to
February 2020. Approval of the Institutional Review
Board of the University of Alabama at Birmingham was
obtained prior to proceeding with this review. With
almost 5000 annual trauma activations, the University
Hospital at the University of Alabama at Birmingham
(UAB) is a busy, urban trauma center and the only Amer-
ican College of Surgeons verified Level 1 trauma center
in central Alabama. Only patients with activation of MTP
at the time of arrival in the trauma bay were eligible for
inclusion.
2.1 | Massive transfusion protocol
Resuscitation of the acutely injured patients arriving at
UAB occurs in one of four trauma bays within the
emergency department (ED). Emergency release blood
products (two units RBC, two units thawed plasma) are
available for immediate use within the ED. Following
arrival of the patient with suspected hemorrhagic
shock, house staff and faculty may activate the MTP.
Blood products are delivered in coolers of RBCs,
thawed fresh frozen plasma (FFP), and platelets in a
ratio of 6:6:1.
Since August 2019, UAB has added WB as an option
to our MTP for exclusive use by the Division of Acute
Care Surgery in the immediate resuscitation of patients
with life-threatening hemorrhage. The WB is low titer
(<256), O negative, and leukocyte reduced. WB is deliv-
ered in coolers with four units WB. MTP utilizing WB is
the default selection for the initial cooler of MTP until all
local supplies are exhausted. Delivery of six units WB
from the American Red Cross occurs on a twice weekly
basis.
2.2 | Patient selection and analysis plan
Patients with activation of MTP during the study period
were identified. Data extracted from the medical record
include demographic and injury characteristics and
severity, transfusion quantities and timing, hematologic
data, results of hemolysis testing, and patient outcomes.
S254
Traumatic arrest prior to arrival, transfusion of pre-
hospital blood products, age ≤ 18 years, pregnancy, and
imprisonment were used to exclude patients from final
analysis.
MT was defined as the transfusion of 10 units of RBCs
within 24 h of patient arrival. CAT was defined as the
transfusion of at least three units of RBCs in 1 h within
the first 3 h following arrival to the hospital.13 The total
number of CAT-positive hours was also quantified. RI+
was calculated as the sum of the products (one point
each: 1000 ml crystalloid, 500 ml colloid, one unit RBC,
one unit plasma, or one unit platelets) administered
within the first 30 min following arrival to the hospital.14
The WB MT score (range from 0 to 47) was developed
to incorporate the strengths of existing measures of resus-
citation while also factoring in the use of WB. The first
hour of resuscitation was scored as a pragmatic measure
to improve ease of calculation and use while avoiding the
survival bias inherent in 24 h scores. Calculations were
performed with different combinations of WB, RBCs, and
FFP and then compared by area under the receiver curve
(AUC) for 3 and 6 h mortality. Units of WB were not reg-
arded as equivalent to units of RBCs given the additional
plasma, platelets, and coagulation factors inherently
included within each unit of WB compared to RBCs. Differ-
ing weights (3 or 2) were applied to the units of WB to
account for the additional blood volume (or plasma and
platelets) in each unit of WB. The WB MT score was thus
defined as the sum of the number of units of RBCs and 3
the number of units of WB transfused. Based on these
results, a WB MT score of 7 was used to define WB MT pos-
itive (WB MT+) and negative (WB MT
). The equation for
WB MT may be demonstrated as follows:
WB MT ¼ 3  units WB þ units RBC
WB MT ðþÞ ¼ WB MT score ≥ 7
WB MT ð
Þ ¼ WB MT score < 7:
Bivariate comparisons of each cohort were performed
using Pearson's Chi-square or Fischer's exact and Mann–
Whitney U tests for categorical and continuous data,
respectively. Data were displayed as the number and pro-
portion or as median and interquartile range for categori-
cal and continuous data, respectively. Differences in the
diagnostic accuracy of different measures of MT (WB MT
+, CAT, RI+, and MT) for mortality at 3 h were the pri-
mary outcome of interest. Receiver operating characteris-
tic (ROC) curves were created to compare the measures
of MT. Kaplan–Meier survival curves were created to
HU ET AL.
demonstrate differences in early survival comparing
patients WB MT+ and WB MT
. All analyses were per-
formed using IBM SPSS Statistics for Windows, Version
26.0 (IBM Corp., Armonk, NY).
3 | RESULTS
Since December 2018, there have been 10,790 trauma evalua-
tions with 8325 admissions. During that period, 269 patients
required activation of MTP with 235 eligible for final analy-
sis. Of those patients, 25.5% (n = 60) received at least one
unit of WB during the initial 3 h of resuscitation. A majority
of patients, 79.6% (n = 187), were male with a median age of
36 years. Patients suffered a similar proportion of blunt and
penetrating injuries (47.2% vs. 52.8%) with a majority requir-
ing either operative or angiographic intervention from the
trauma bay (66.4%, n = 156).
There were 36 (15.3%) patients with activation of
MTP who died within 24 h of admission to the trauma
bay. A large majority of these patients, 75–81% died
within 3 (n = 27) to 6 (n = 29) h of arrival. Only 10.7% of
MTP activation patients who survived the first 6 h after
admission would die within 28 days of admission.
There were no significant differences in the propor-
tion of patients injured by penetrating mechanisms
(p = .28) between those patients who were WB MT+
and those who were WB MT
(Table 1). WB MT+
patients demonstrated similar ISS (p = .10) to WB
MT
patients, but significantly higher NISS scores
(p = .005). WB MT+ patients had significantly lower
admission MAPs (p < .001), higher INR (p < .001), and
were significantly more acidotic with lower admission
base excess (p < .001).
Comparing the traditional measures of massive resus-
citation, RI4+ was the most sensitive predictor of both 3-
and 6-h mortality (Tables 2 and 3). MT was the most spe-
cific predictor of 3-h mortality while RI4+ was the most
specific for 6-h mortality.
This WB MT formula resulted in scores ranging from
0 to 47 with corresponding increasing rates of mortality
(Table 4, Figure 1). Using a threshold of 7 for the WB MT
score was the most accurate predictor of early mortality
in comparison with other equations by AUC analysis (3-h
mortality AUC = 0.78, 6-h mortality AUC = 0.79)
(Tables 1 and 2). Furthermore, it demonstrated high sen-
sitivity (81.5% and 82.8%) and specificity (74.0% and
74.8%) for both 3- and 6-h mortality with superior ROC
curves in comparison with traditional measures (MT,
CAT, and RI) (Figures 2 and 3).
The median WB MT score was 11 [8, 16] compared to
3 [2, 5] in patients WB MT+ versus WB MT
(Table 5).
HU ET AL. S255

TABLE 1 Comparison of demographics between patients whole blood massive transfusion positive and negative

All patients WB MT positive WB MT negative

(n = 235) (n = 76) (n = 159) p
Demographics
Age 36 [27, 54] 37 [25, 49] 36 [28, 55] .33
Gender, n (%)
Male 187 (79.6) 61 (80.3) 126 (79.2) .86
Female 48 (20.4) 15 (19.7) 33 (20.8)
Race, n (%)
Caucasian 111 (47.2) 33 (43.4) 78 (49.1) .16
Black 120 (51.1) 40 (52.6) 80 (50.3)
Hispanic 4 (1.7) 3 (3.9) 1 (0.6)
Injury
Mechanism of injury, n (%)
Blunt 111 (47.2) 32 (42.1) 79 (49.7) .28
Penetrating 124 (52.8) 44 (57.9) 80 (50.3)
Injury severity score 21 [13, 29] 22 [15, 34] 19 [13, 29] .10
Major trauma (≥15) 157 (66.8) 57 (75.0) 100 (63.3) .07
New Injury Severity Score 27 [17, 38] 29 [22, 43] 27 [17, 34] .005
TRISS 0.94 [0.79, 0.98] 0.93 [0.76, 0.96] 0.96 [0.83, 0.98] .03
AIS 1 0 [0, 2] 0 [0, 1] 0 [0, 3] .050
AIS 3 2 [0, 3] 2 [0, 3] 3 [0, 3] .95
AIS 4 2 [0, 3] 3 [0, 4] 2 [0, 3] .01
Initial heart rate (BPM) 104 [86, 125] 106 [86, 131] 104 [86, 123] .68
Initial mean arterial pressure (mmHg) 70 [55, 86] 61 [48, 74] 75 [59, 93] <.001
Initial Glasgow Coma Scale Score 14 [3, 15] 11 [3, 15] 15 [8, 15] .002
Laboratory
Hemoglobin 12 [10.0, 13.1] 11 [9.9, 12.9] 12 [10.0, 13.3] .09
Platelets 213 [165, 254] 182 [152, 240] 224 [173, 263] .002
Serum creatinine 1.2 [1.00, 1.50] 1.3 [1.08, 1.53] 1.2 [1.00, 1.50] .33
INR 1.2 [1.10, 1.40] 1.3 [1.19, 1.74] 1.2 [1.08, 1.32] <.001
TEG
R 4 [3.0, 5.0] 4 [3.8, 5.0] 4 [3.0, 5.0] .07
K 2 [1.0, 2.0] 2 [1, 2] 1 [1, 2] .24
AA 69 [64, 72] 68 [64, 71] 70 [64, 73] .09
MA 59 [55, 64] 59 [55, 64] 60 [54, 64] .88
LY30 0 [0, 2] 0 [0, 1] 1 [0, 2] .004
Lactate 5.1 [2.6, 8.7] 5.4 [3.0, 8.6] 4.9 [2.5, 8.7] .63
Base excess (mEq/L)
7.3 [
12.00,
3.40]
10.1 [
14.95,
6.65]
5.6 [
9.72,
2.73] <.001
Acidotic on arrival (BE <
6 mEq/L) 142 (60.4) 62 (86.1) 80 (51.3) <.001

Note: Units displayed as the number (%) or median [IQR] for categorical or continuous data, respectively. Whole blood massive transfusion score = 3*units
whole blood + units packed red blood cells in first hour after arrival (Positive: WB MT ≥ 7. Negative: WB MT < 7).

WB MT+ patients were transfused significantly greater 24 h. There were significantly more patients who also quali-
numbers of WB (p < .001), RBC (p < .001), FFP (p < .001), fied for traditional MT in those WB MT+ (55.3% vs. 19.7%,
platelets (p = .001), and cryoprecipitate (p < .001) within p < .001). Similarly, there were more patients who qualified
S256 HU ET AL.

TABLE 2 Comparison of accuracy of different measures of transfusion requirements in predicting 3-h mortality

Traditional measures of massive resuscitation

Positive Negative
predictive predictive
Sensitivity Specificity value value AUROC
a
Massive transfusion 51.9 73.6 20.3 92.2 0.63
Critical administrationb threshold 81.5 44.7 16.1 94.9 0.63
c
Resuscitation intensity 4+ 88.9 32.2 14.5 95.7 0.61

Whole blood included

Positive Negative Positive Negative

predictive predictive predictive predictive
Sensitivity Specificity value value AUROC Sensitivity Specificity value value AUROC

2*WB + RBC 2*WB + RBC + FFP

≥1 100 11.1 12.7 100 0.56 100 10.6 12.7 100 0.55
≥2 100 17.8 13.6 100 0.59 100 12.0 12.9 100 0.56
≥3 92.6 31.7 15.0 97.1 0.62 96.3 20.2 13.5 97.7 0.58
≥4 88.9 41.3 16.4 96.6 0.65 96.3 20.7 13.6 97.7 0.59
≥5 85.2 57.2 20.5 96.7 0.71 85.2 30.8 13.8 94.1 0.58
≥6 85.2 64.4 23.7 97.1 0.75 85.2 36.5 14.8 95.0 0.61
≥7 74.1 76.9 29.4 95.8 0.76 85.2 46.6 17.2 96.0 0.66
≥8 70.4 81.3 32.8 95.5 0.76 85.2 47.6 17.4 96.1 0.66
≥9 66.7 87.0 40.0 95.3 0.77 85.2 47.6 17.4 96.1 0.71
≥10 63.0 88.0 40.5 94.8 0.76 81.5 64.4 22.9 96.4 0.73
3*WB + RBC (WB MT) 3*WB + RBC + FFP
≥1 100 11.1 12.7 100 0.56 100 10.6 12.7 100 0.56
≥2 100 17.8 13.6 100 0.59 100 12.0 12.9 100 0.56
≥3 92.6 31.7 15.0 97.1 0.62 96.3 20.2 13.5 97.7 0.58
≥4 88.9 41.3 16.4 96.6 0.65 96.3 20.7 13.6 97.7 0.59
≥5 88.9 52.4 19.5 97.3 0.71 88.9 30.3 14.2 95.5 0.60
≥6 88.9 63.9 24.2 97.8 0.76 88.9 35.6 15.2 96.1 0.62
≥7 81.5 74.0 28.9 96.9 0.78 85.2 42.8 16.2 95.7 0.64
≥8 74.1 77.9 30.3 95.9 0.76 85.2 47.6 17.4 96.1 0.66
≥9 66.7 84.1 35.3 95.1 0.75 85.2 57.7 20.7 96.8 0.71
≥10 63.0 86.1 37.0 94.7 0.75 85.2 61.1 22.1 96.9 0.73
a
Massive transfusion = 10 units packed red blood cells transfused in initial 24 h after presentation.
b
Critical administration threshold = 3 units of packed red blood cells in first hour after arrival.
c
Resuscitation intensity = 1 point for each of the following infused in the first 30 min following arrival (1000 ml crystalloid, 500 ml colloid, 1 unit of red blood cells,
fresh frozen plasma, or platelets).

for CAT (75.0% vs. 50.3%, p < .001) and RI4+ (89.5% vs.
61.0%, p < .001) in those patients WB MT+.
WB MT+ patients had significantly poorer outcomes
than those who required less transfusion intensity. Those
with WB MT+ had significantly fewer hospital (p = .04),
ICU (p = .001), and ventilator free days (p = .01). Most
important, there were significant differences in morality
at all measured time points (p = .001).
The median time to death for WB MT+ patients was
1.4 h compared to 1.6 h for WB MT
patients (Table 6).
WB MT+ patients demonstrated significant differences
on survival analysis for 3 h (p < .001), 6 h (p < .001), and
24 h (p < .001) (Figures 4–6).
4 | DISCUSSION
We performed a retrospective review of all trauma
patients requiring activation of the MTP on arrival to our
facility over a 3-year period to develop a new scoring
HU ET AL. S257

TABLE 3 Comparison of accuracy of different measures of transfusion requirements in predicting 6-h mortality

Traditional measures of massive resuscitation

Positive Negative
predictive predictive
Sensitivity Specificity value value AUROC
a
Massive transfusion 55.2 74.3 29.4 92.2 0.65
b
Critical administration threshold 82.8 45.1 17.5 94.9 0.64
c
Resuscitation intensity 4+ 89.7 32.5 15.8 95.7 0.61

Whole blood included

Positive Negative Positive Negative

predictive predictive predictive predictive
Sensitivity Specificity value value AUROC Sensitivity Specificity value value AUROC

2*WB + RBC 2*WB + RBC + FFP

≥1 100 11.2 13.7 100 0.56 100 10.7 13.6 100 0.55

≥2 100 18.0 14.6 100 0.59 100 12.1 13.8 100 0.56

≥3 93.1 32.0 16.2 97.1 0.63 96.6 20.4 14.6 97.7 0.59

≥4 89.7 41.7 17.8 96.6 0.66 96.6 20.9 14.7 97.7 0.59

≥5 86.2 57.8 22.3 96.7 0.72 86.2 31.1 15.0 94.1 0.59

≥6 86.2 65.0 25.8 97.1 0.76 86.2 36.9 16.1 95.0 0.62

≥7 75.9 77.7 32.4 95.8 0.77 86.2 47.1 18.7 96.0 0.67

≥8 69.0 81.6 34.5 94.9 0.75 86.2 48.1 18.9 96.1 0.67

≥9 65.5 87.4 42.2 94.7 0.76 82.8 60.7 22.9 96.2 0.72

≥10 62.1 88.3 42.9 94.3 0.75 82.8 65.0 25.0 96.4 0.74

3*WB + RBC (WB MT) 3*WB + RBC + FFP

≥1 100 11.2 13.7 100 0.56 100 10.7 13.6 100 0.56

≥2 100 18.0 14.6 100 0.59 100 12.1 13.8 100 0.56
≥3 93.1 32.0 16.2 97.1 0.63 96.6 20.4 14.6 97.7 0.59

≥4 89.7 41.7 17.8 96.6 0.66 96.6 20.9 14.7 97.7 0.59

≥5 89.7 52.9 21.1 97.3 0.71 89.7 30.6 15.4 95.5 0.60

≥6 89.7 52.9 21.1 97.3 0.77 89.7 35.9 16.5 96.1 0.63

≥7 82.8 74.8 31.6 96.9 0.79 86.2 43.2 17.6 95.7 0.65

≥8 72.4 78.2 31.8 95.3 0.75 86.2 48.1 18.9 96.1 0.67

≥9 65.5 84.5 37.3 94.6 0.75 86.2 58.3 22.5 96.8 0.72

≥10 62.1 86.4 39.1 94.2 0.74 86.2 61.7 24.0 96.9 0.74

a
Massive transfusion = 10 units packed red blood cells transfused in initial 24 h after presentation.
b
Critical administration threshold = 3 units of packed red blood cells in first hour after arrival.
c
Resuscitation intensity = 1 point for each of the following infused in the first 30 min following arrival (1000 ml crystalloid, 500 ml colloid, 1 unit of red blood cells, fresh
frozen plasma, or platelets).

system for MT incorporating the use of WB. Our study
demonstrated that the sum of the number of units of
RBCs and three times the number of units of WB was the
most accurate predictor of early mortality (measured at
3 and 6 h following arrival to the trauma bay). Setting the
WB MT score threshold at 7 for WB MT+ and WB MT

demonstrated a superior AUC for early mortality com-
pared with traditional measures of MT and our other
equations incorporating WB. Patients that are WB MT+
demonstrated fewer hospital, ICU, and ventilator free
days compared with those WB MT
. Most importantly,
patients who are WB MT+ demonstrated significantly
increased rates of mortality for both early (3–24 h) and
late (7 and 28 days) mortality.
The use of WB to define massive resuscitation in
trauma is not a novel concept. WB was previously used
from the start of the 20th century up until the
1970s.19,20 At that time, MT was defined as transfusion
of 10 units of WB within a 24-h period. Given that units
of WB were 500 ml, 10 units of WB represented the
S258 HU ET AL.

TABLE 4 Comparison of outcomes between patients at different whole blood massive transfusion score thresholds

WB MT ≥ 3 WB MT ≥ 5 WB MT ≥ 7 WB MT ≥ 9 WB MT ≥ 11
(n = 167) (n = 123) (n = 34) (n = 41) (n = 34)
Mortality, n (%)
3h 25 (15.0) 24 (19.5) 22 (28.9) 18 (35.3) 15 (36.6)
6h 27 (16.2) 26 (21.1) 24 (31.6) 19 (37.3) 16 (39.0)
24 h 31 (18.6) 29 (23.6) 27 (35.5) 21 (41.2) 17 (41.5)
28 days 43 (25.7) 39 (31.7) 32 (42.1) 24 (47.1) 20 (48.8)

Note: Whole blood massive transfusion score = 3*units whole blood + units packed red blood cells in first hour after arrival.

F I G U R E 1 Proportion of patients
with death within 24 h per whole blood
massive transfusion score

F I G U R E 2 Receiver operating
characteristic for major transfusion criteria and
identification of 6-h mortality

average blood volume of an adult patient. The use of a
24-h period was both easily collected from nurse's char-
ting and blood bank records and thus reproducible
across centers, but it failed to account for the physiol-
ogy of death due to hemorrhage and contributed to
substantial survival bias.
Given the economics of blood donation, separation,
and the demand generated by increased use of chemo-
therapy, transfusion policy in the 1970s shifted to favor
the separation of WB into its component products.
Unfortunately, the definition for MT shifted to the use
of RBCs rather than WB as well. One problem with this
transition was that transfusion of 10 units of RBCs for
MT represents significantly less blood volume com-
pared with 10 units of WB (2500 ml vs. 4500 ml). Addi-
tionally, as demonstrated by Chang et al., the majority
of deaths from hemorrhage occur within the first 3–6 h
following injury.7 Furthermore, the use of WB as an
HU ET AL.
F I G U R E 3 Receiver operating
characteristic for major transfusion criteria and
identification of 3-h mortality
early resuscitative fluid is increasing across the United
States, driven by the recent and robust military experi-
ence.21–23 Given the increase in use of WB and the sur-
vival bias that prompted the development of CAT and
RI4+, we identified a need for a marker of massive
resuscitation incorporating the use of WB that could be
measured over a short interval immediately following
patient arrival.
Based on our calculations, numerous combinations of
the sum of the units of WB, RBC, platelets,
cryoprecipitate, and FFP provide either increased sensi-
tivity or specificity for early mortality. The use of 3 WB
appeared to increase the predictive ability of the equa-
tions over WB or 2 WB. This seems appropriate given
that each unit of WB provides both additional blood vol-
ume as well as platelets and coagulation factors. Neither
FFP nor platelets significantly improved the diagnostic
accuracy when added to our equations. The AUC values
of all equations including FFP were lower than those
including only WB and RBC. In the current era of 1:1:1
resuscitation, FFP and platelet administration are mat-
ched to RBC, making it likely a collinear variable to
RBCs in our equation.
Patients in our study, and most others, commonly
received a mix of WB and component products following
activation of MTP. Those who were WB MT+ were trans-
fused significantly greater amounts of WB, RBC, FFP,
platelets, and cryoprecipitate within 24 h. Our resuscita-
tion volumes are similar to a recently published study uti-
lizing Trauma Quality Improvement Program (TQIP)
data, in which patients resuscitated with WB were found
to receive a median of one unit of WB during their initial
trauma resuscitation. Given this, our mix of WB and
component resuscitation in patients with MTP similarly
S259
reflects current resuscitation strategies in the country. As
WB becomes more available, it is likely that the amounts
of WB will increase and that other products will
decrease.
Similar to the use of CAT and RI4+, WB MT high-
lights the importance of early recognition of massive
resuscitation to identify patients at risk of exsanguinating
hemorrhage. Of the patients in our study who died, a
large majority died within the first 3 h of arrival to the
trauma bay. Patients who were WB MT+ demonstrated
significantly faster time to death in Kaplan–Meier analy-
sis. Furthermore, WB MT+ provides the most accurate
marker for early mortality, surpassing traditional mea-
sures of massive resuscitation.
Review of the times to death among MT-positive and
MT-negative patients compared to patients with
and without WB MT, CAT, and RI highlights the main
problem with use of MT as a definition for massive resus-
citation. For example, MT suffers from survivor bias as
patients must live long enough to have received an ade-
quate number of red blood cells to be classified as MT
positive.15 Paradoxically, patients with a greater injury
burden and more severe hemorrhage may die sooner and
fail to be transfused 10 units of RBCs as required to be
MT+. WB MT, similar to CAT and RI4+, does not appear
to have the same problem with survival bias, as
evidenced by the shorter time to death among patients
WB MT+ than WB MT
patients. Instead, it appears to
successfully identify patients at risk of early death due
to hemorrhagic shock.
WB MT fills a demonstrable need in the current era
of modern civilian trauma resuscitation. Importantly,
WB MT captures additional patients that previously
would not have been identified by other measures of
S260 HU ET AL.

TABLE 5 Comparison of outcomes between patients with and without whole blood massive transfusion (WB MT ≥ 7)

All patients WB MT positive WB MT negative

(n = 235) (n = 76) (n = 159) p
Treatment
Required OR, n (%) 142 (60.4) 56 (73.7) 86 (55.5) .008
Required IR, n (%) 12 (5.1) 5 (6.8) 7 (6.1) .85
Resuscitative units—3 h
Whole blood 0 [0, 1] 2 [0, 4] 0 [0, 0] <.001
Packed red blood cells 5 [2, 8] 9 [4, 17] 4 [2, 6] <.001
Fresh frozen plasma 4 [2, 8] 8 [4, 16] 3 [2, 6] <.001
Platelets 1 [0, 1] 1 [0, 2] 0 [0, 1] .001
Cryoprecipitate 0 [0, 0] 0 [0, 0] 0 [0, 0] <.001
Resuscitative units—24 h
Whole blood 0 [0, 1] 2 [0, 4] 0 [0, 0] <.001
Packed red blood cells 6 [3, 11] 10 [6, 22] 5 [3, 8] <.001
Fresh frozen plasma 6 [3, 10] 8 [6, 20] 4 [2, 8] <.001
Platelets 1 [0, 2] 1 [1, 3] 1 [0, 2] <.001
Cryoprecipitate 0 [0, 0] 0 [0, 2] 0 [0, 0] <.001
WB MT score 5 [2, 8] 11 [8, 16] 3 [2, 5] <.001
a
Massive transfusion , n (%) 42 (55.3) 27 (17.0) <.001
CATb, n (%)
Hour 1 137 (58.3) 57 (75.0) 80 (50.3) <.001
Hour 2 56 (23.8) 29 (38.2) 27 (17.0) <.001
Hour 3 29 (12.3) 14 (8.8) 15 (19.7) .02
Resuscitation intensityc, n (%)
Score
4+ 165 (70.2) 68 (89.5) 97 (61.0) <.001
6+ 72 (30.6) 25 (32.9) 47 (29.6) .60
8+ 57 (24.3) 22 (28.9) 35 (22.0) .25
Outcomes
Hospital free days 9 [0, 19] 0 [0, 10] 14 [1, 20] <.001
ICU free days 15 [0, 22] 0 [0, 16] 18 [6, 23] <.001
Ventilator free days 23 [0, 26] 9 [0, 25] 25 [17, 27] <.001
Mortality, n (%)
3h 27 (11.5) 22 (28.9) 5 (3.1) <.001
6h 29 (12.3) 24 (31.6) 5 (3.1) <.001
24 h 36 (15.3) 27 (35.5) 9 (5.7) <.001
7 days 43 (18.3) 30 (39.5) 13 (8.2) <.001
28 days 51 (21.7) 32 (42.1) 19 (11.9) <.001

Note: Units displayed as the number (%) or median [IQR] for categorical or continuous data, respectively. Whole blood massive transfusion score = 3*units
whole blood + units packed red blood cells in first hour after arrival. (Positive: WB MT ≥ 7. Negative: WB MT < 7).
a
Massive transfusion = 10 units packed red blood cells transfused in initial 24 h after presentation.
b
Critical administration threshold = 3 units of packed red blood cells in first hour after arrival.
c
Resuscitation intensity = 1 point for each of the following infused in the first 30 min following arrival (1000 ml crystalloid, 500 ml colloid, 1 unit of red blood
cells, fresh frozen plasma, or platelets).
HU ET AL. S261

TABLE 6 Comparison of median time to death in hours based on different major transfusion criteria

Total n = 235 Yes No p

Measure of massive resuscitation Median time to death
WB MT 76 (32.3) 1.4 [0.83, 2.93] 1.6 [0.60, 12.33] .77
MTa 69 (29.4) 2.5 [1.14, 5.37] 0.9 [0.72, 2.28] .04
CAT1b 137 (58.3) 1.5 [0.83, 2.93] 2.5 [0.60, 12.33] .57
c
RI4 165 (70.2) 1.3 [0.82, 2.95] 6.4 [0.66, 14.44] .37
RI6 72 (30.6) 1.1 [0.82, 4.26] 1.6 [0.72, 4.87] .95
RI8 56 (23.8) 2.0 [0.82, 5.92] 1.5 [0.78, 3.25] .69

Note: Units displayed as the number (%) or median [IQR] for categorical or continuous data, respectively. Whole blood massive transfusion score = 3*units
whole blood + units packed red blood cells in first hour after arrival. (Positive: WB MT ≥ 7. Negative: WB MT < 7).
a
Massive transfusion = 10 units packed red blood cells transfused in initial 24 h after presentation.
b
Critical administration threshold = 3 units of packed red blood cells in first hour after arrival.
c
Resuscitation intensity = 1 point for each of the following infused in the first 30 min following arrival (1000 ml crystalloid, 500 ml colloid, 1 unit of red blood
cells, fresh frozen plasma, or platelets).

FIGURE 4 Kaplan–Meier analysis for 3-h

survival

FIGURE 5 Kaplan–Meier analysis for 6-h

survival

massive resuscitation. Nearly 50% of patients who are hemostasis and living. Furthermore, nearly 30% of
WB MT+ would fail to reach the threshold for a tradi- patients would not qualify for CAT and 10% would not
tional MT, either dying before 24 h or achieving be identified by RI4+.
S262
In addition to fulfilling a need for trauma providers,
adoption of WB MT may also serve as an important tool
in quality control in transfusion medicine. Despite its
benefits, the use of type O WB does expose patients to a
small, but potential risk of autoimmune hemolytic reac-
tions (AHR) that may result in uncontrolled hemolytic
anemia, coagulopathy, renal failure, and death.24–26
Compared to units of type O RBCs, units of type O WB
contain both type O RBCs and type O plasma (itself con-
taining both anti-A and anti-B antibodies). It remains
uncertain how many units of WB may be transfused
without risking AHR. Previous reports of military use of
WB from WWII through the Vietnam War suggest that
massive resuscitations utilizing WB may be accomplished
with minimal incidence of AHR.27,28 Currently, many
centers using WB either limit the number of units of WB
that may be transfused, monitor for evidence of hemoly-
sis, or both. Going forward, WB MT may be a useful tool
in identifying those patients most at risk of AHR that
require ongoing monitoring.
Our study has multiple limitations that have the
potential to impact generalizability in future studies.
Given that we offer the perspective of a single center, our
results reflect the resuscitation practices of our trauma
center. Importantly, our use of rapidly available emer-
gency release RBCs and FFP may affect the outcomes of
patients resuscitated with WB. Similarly, as the majority
of our patients received a mix of WB and component
products, a pure comparison of patients based on WB or
component product resuscitation is not possible. How-
ever, this likely represents the current resuscitation prac-
tices at most centers given the current relative national
scarcity of WB compared to component products.29
Another limitation to our study is that we chose not to
include patients who received blood products prior
to arrival at our hospital. Although we recognize that
HU ET AL.
FIGURE 6 Kaplan–Meier analysis for 24-h
survival
many trauma centers treat patients who receive blood
products prior to arrival, we felt that for this initial attempt
to define WB MT, inclusion of these patients may compli-
cate the analysis. Subsequent studies should measure the
impact of prehospital transfusion to help validate WB
MT. Finally, our measure of massive resuscitation is likely
not translatable to centers that do not utilize WB, where
CAT may be optimal. Other definitions for massive resusci-
tation account for volume of crystalloid, which we do not
utilize and may affect the diagnostic accuracy of WB
MT. Lastly, given the small numbers of patients, we did not
use a naive data set to test our results.
To our knowledge, this study offers the first examination
of a massive resuscitation score accounting for the use of
WB transfusion. Patients who are WB MT+ are at signifi-
cantly increased risk of early and late mortality with
improved diagnostic accuracy over existing measures of mas-
sive resuscitation. Further validation is needed through a
multicenter analysis to provide generalizability of this model.
CONFLICT OF INTEREST
Dr. John B. Holcomb is a co-founder and on the Board of
Directors of Decisio Health, on the Board of Directors
of QinFlow and Zibrio, a Co-inventor of the Junctional
Emergency Tourniquet Tool, an adviser to Arsenal
Medical, Cellphire, Spetrum, PotentiaMetrics, and Wake
Forest Institute of Regenerative Medicine. Dr. Jan
O. Jansen is a consultant for CSL Behring. The remaining
authors declare no conflicts of interest.
ORCID
Parker Hu https://orcid.org/0000-0002-2491-6107
Rindi Uhlich https://orcid.org/0000-0001-7797-4397
Jan O. Jansen https://orcid.org/0000-0001-8863-4398
John B. Holcomb https://orcid.org/0000-0001-8312-
9157
HU ET AL.
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How to cite this article: Hu P, Uhlich R, Black J,
Jansen JO, Kerby J, Holcomb JB. A new definition
for massive transfusion in the modern era of whole
blood resuscitation. Transfusion. 2021;61:
S252–S263. https://doi.org/10.1111/trf.16453