Research

JAMA Surgery | Original Investigation

Association Between Ratio of Fresh Frozen Plasma

to Red Blood Cells During Massive Transfusion and Survival
Among Patients Without Traumatic Injury
Tomaz Mesar, MD; Andreas Larentzakis, MD, PhD; Walter Dzik, MD; Yuchiao Chang, PhD;
George Velmahos, MD, PhD; Daniel Dante Yeh, MD

Invited Commentary
IMPORTANCE Hemostatic resuscitation has been shown to be beneficial for patients with page 580
trauma, but there is little evidence that it is equally beneficial for bleeding patients without Supplemental content
trauma. The practice of a high transfusion ratio of fresh frozen plasma (FFP) to red blood cells
CME Quiz at
(RBCs) has spread to other surgical and medical fields.
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OBJECTIVE To identify whether ratio-based resuscitation in patients without trauma is

associated with improved survival.

DESIGN, SETTING, AND PARTICIPANTS This study is a retrospective review of all massive
transfusions provided in an urban academic hospital from January 1, 2009, through
December 31, 2012. Massive transfusion was defined as the transfusion of at least 10 U of
RBCs in the first 24 hours after a patient’s admission to the operating room, emergency
department, or intensive care unit. All patients who received massive transfusions within the
study period and survived more than 30 minutes after hospital arrival were counted (n=865).
Patients were grouped into those with trauma and those without trauma. Sources of data
included the Research Patient Data Registry, patients’ medical records, and blood bank
records. All data collection occurred between April 26, 2013, and April 26, 2015. Data analysis
took place from April 27, 2015, and June 22, 2016.

MAIN OUTCOMES AND MEASURES Examination of FFP:RBC transfusion ratios for patients
without trauma.

RESULTS There were 865 massive transfusion events that occurred within 4 years,
transfusing 16 569 U of RBCs, 13 933 U of FFP, 5228 U of cryoprecipitate, and 22 635 U of
platelets. Most of these transfusions were received by patients without trauma (767
[88.7%]), by men (582 [67.3%]), and for intraoperative bleeding (544 [62.9%]). The FFP:RBC
ratios of survivors and nonsurvivors were nearly identical: the ratio for survivors was 1:1.5
(interquartile range [IQR], 1:1.1-1:2.2) and for nonsurvivors was 1:1.4 (IQR, 1:1.1-1:1.9; P = .43).
Among the 767 patients without trauma, there was no difference in the adjusted odds ratio
(aOR) for 30-day mortality when comparing the high FFP:RBC ratio vs the low FFP:RBC ratio
Author Affiliations: Division of
subgroups (aOR, 1.10; 95% CI, 0.72-1.70; P = .65). In vascular surgery, the aOR for death Trauma, Department of Surgery,
favored the high FFP:RBC ratio subgroup (aOR, 0.16; 95% CI, 0.03-0.79; P = .02). However, Emergency Surgery and Surgical
in general surgery and medicine, the aOR for death favored the low FFP:RBC ratio subgroup; Critical Care, Massachusetts General
Hospital and Harvard Medical School,
general surgery: aOR, 4.27 (95% CI, 1.28-14.22; P = .02); medicine: aOR, 8.48 (95% CI, Boston (Mesar, Larentzakis,
1.50-47.75; P = .02). Velmahos, Yeh); Department of
Pathology and Transfusion Medicine,
Massachusetts General Hospital and
CONCLUSIONS AND RELEVANCE High FFP:RBC transfusion ratios are applied mostly to
Harvard Medical School, Boston
patients without trauma, who account for nearly 90% of all massive transfusion events. (Dzik); Department of Medicine,
Thirty-day survival was not significantly different in patients who received a high FFP:RBC Massachusetts General Hospital,
ratio compared with those who received a low ratio. Boston (Chang).
Corresponding Author: Daniel Dante
Yeh, MD, Division of Trauma,
Department of Surgery, Emergency
Surgery and Surgical Critical Care,
Massachusetts General Hospital and
Harvard Medical School, 165
JAMA Surg. 2017;152(6):574-580. doi:10.1001/jamasurg.2017.0098 Cambridge St, Room 810, Boston, MA
Published online March 8, 2017. 02114 (dyeh2@partners.org).

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 Association of Ratio-Based Massive Transfusion With Survival Among Patients Without Trauma
M
assive transfusion (MT) is defined as transfusion of at
least 10 U of red blood cells (RBCs) within a 24-hour pe-
riod, although alternate definitions, such as 3 U/h (criti-
cal administration threshold), are also used to more accurately
reflect most transfusions that occur in the first 6 hours.1 In addi-
tion to RBCs, fresh frozen plasma (FFP) and platelets may be trans-
fused as a ratio of RBCs in an approach termed balanced resusci-
tation. For example, transfusing 1 U of FFP for every 2 U of RBCs
is a 1:2 strategy. Although ratio-based resuscitation is not a new
concept,2 interest was rekindled in the past decade when retro-
spective studies from the US military reported improved survival
when massively transfused injured soldiers received resuscita-
tion with higher (compared with lower) amounts of FFP to RBCs
(FFP:RBC ratio).3 Additional reports from civilian trauma centers
supported these findings, and the practice of transfusing higher
FFP:RBC ratios was quickly embraced by the trauma surgery and
anesthesia community, with many hospitals implementing for-
mal massive transfusion protocols (MTPs) with high FFP:RBC
ratios.4,5 Until recently, high-quality evidence supporting this
practice had been lacking. The Prospective, Observational, Mul-
ticenter, Major Trauma Transfusion (PROMMTT) study described
transfusion ratios and clinical outcomes in a prospective obser-
vational manner and concluded that higher ratios of FFP and
platelets administered early in resuscitation were associated with
decreased mortality in the first 24 hours.6 However, the subse-
quent Pragmatic Randomized Optimal Platelet and Plasma Ra-
tios (PROPPR) trial found no difference in 24-hour or 30-day sur-
vival outcomes when comparing a 1:1:1 (FFP to platelets to RBCs)
resuscitation strategy with a 1:1:2 strategy.7 While it is now com-
mon practice for trauma patients who require MT to receive ratio-
based resuscitation, the exact ratio continues to be explored.
We have observed that the strategy of transfusing a high
ratio of FFP:RBC has begun to be practiced in yet-to-be-
studied populations, such as patients who underwent non-
trauma surgery, nonsurgical patients, and even patients who
do not need MT. Others have also observed this practice.8,9 The
issue has broad implications because recent studies docu-
ment that most MT cases are not associated with trauma.8,10,11
Little research has been reported on the effect of blood-
component ratios on other patient populations, and extrapo-
lation from the trauma setting may be inappropriate. Aggres-
sive transfusion of FFP and platelets may not be beneficial and,
at worst, might be harmful.12-14
The primary aim of our study was to examine blood-
component transfusion ratios in all patients receiving MT in a
major urban academic hospital that supports both trauma and
nontrauma services. Secondary exploratory aims were to test
the hypothesis that higher FFP:RBC ratios are associated with
improved survival, similar to the original findings in patients
with trauma. We hypothesized that the practice of using high
FFP:RBC transfusion ratio has spread to other fields of sur-
gery and medicine.
Methods
We conducted a retrospective review of all MTs provided at
Massachusetts General Hospital, Boston, from January 1, 2009,
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Original Investigation Research
Key Points
Question Is hemostatic resuscitation being practiced for rapidly
bleeding patients without trauma?
Findings In this retrospective study of 865 massive transfusion
events in an urban academic hospital, nearly 90% of all massive
transfusions were received by patients without trauma, but there
was no evidence that a ratio-based transfusion strategy of high
fresh frozen plasma to red blood cells ratio improved survival.
Meaning The practice of hemostatic resuscitation has spread to
other patient populations without supporting evidence of benefit.
to December 31, 2012. The hospital is an urban academic hos-
pital in which approximately 37 000 operations are per-
formed per year, including 1600 cardiac, 5500 general (elec-
tive and emergency), 1500 vascular, 2500 gynecologic, and 560
burn surgical procedures as well as 70 liver transplants. All data
collection occurred between April 26, 2013, and April 26, 2015.
Data analysis took place from April 27, 2015, and June 22, 2016.
This study was approved by the Massachusetts General Hos-
pital Institutional Review Board, which waived the require-
ment for patient informed consent.
In this study, MT is defined as the transfusion of at least
10 U of RBCs in the first 24 hours of a patient’s admission to
the operating room, emergency department, or intensive care
unit. All patients with trauma who were pronounced dead in
less than 30 minutes after arrival to the hospital were ex-
cluded to reduce survival bias. Data were retrieved from the
Research Patient Data Registry, patients’ medical records, and
blood bank records. Data collected included age, sex, admit-
ting service, type of operation, 30-day mortality, bleeding on-
set location (intraoperative, prehospital, postoperative, and
other), and number of transfused blood products (including
RBCs, FFP, platelets, and cryoprecipitate). In addition, if in-
traoperative blood recovery (transfusion of washed, autolo-
gous recovered red cells [Cell Saver; Haemonetics]) was used
during an operation, the transfused ratio was corrected for the
units transfused through blood recovery. For each patient, the
ratio of transfused FFP to RBCs was calculated.
Intraoperative transfusion practice for all patients is
guided by a combination of point-of-care testing (eg, hemo-
globin, electrolytes, blood gas, and lactate values) and tradi-
tional coagulation testing. Viscoelastic testing is not used.
Anesthesiologists who treat rapidly bleeding patients with
trauma using the MTP also treat patients without trauma.
However, there is no explicit ratio-defined transfusion pro-
tocol for patients without trauma. For major operations with
historically large volumes of blood loss (eg, thoracoabdomi-
nal aneurysm repair, aortic root replacement, and sacral
chordoma resection) or operations on patients with coagu-
lopathy (eg, liver transplant), it is common practice to
request delivery to the operating room of 10 U of RBCs and
10 U of thawed plasma to have on hand in advance of the
operation. Transfusion of washed, autologous recovered
RBCs (ie, Cell Saver) was occasionally performed, and these
units were included in the calculations of ratios.
(Reprinted) JAMA Surgery June 2017 Volume 152, Number 6 575
 Research Original Investigation Association of Ratio-Based Massive Transfusion With Survival Among Patients Without Trauma

Table 1. Massive Transfusions by Service

30-Day Survival
For the entire cohort, when survivors were compared with non-
Service No. (%) survivors, the patients who died were older (mean [SD] age,
Cardiac surgery 272 (31.4) 59.6 [16.9] vs 63.5 [17.4] years) and received more units of RBCs
Liver transplant surgery 114 (13.2) (median [IQR], 15.0 [12.0-21.0] vs 20.0 [13.7-32.8] U; P < .001),
Trauma surgery 98 (11.3) FFP (11.0 [6.0-19.0] vs 15.0 [8.0-27.0] U; P < .001), and cryo-
General surgery 86 (9.9) precipitate (median [95th-99th percentile], 0.0 [20-40] U for
Vascular surgery 78 (9.0) those who survived compared with 0.0 [30-80] U for those who
Medicine 76 (8.8) died; P = .008) (Table 2). Note that the FFP:RBC ratios of sur-
Orthopedic surgery 56 (6.5) vivors and nonsurvivors were nearly identical: the median
Cardiopulmonary transplant surgery 37 (4.3) (IQR) FFP:RBC ratio for survivors was 1:1.5 (1:1.1-1:2.2) and for
Obstetrics/gynecology 14 (1.6) nonsurvivors was 1:1.4 (1:1.1-1:1.9) (P = .43).
Urology 10 (1.2)
Neurosurgery 9 (1.0) FFP: RBC Transfusion Ratios
Burns 6 (0.7) The median (IQR)–calculated FFP:RBC transfusion ratio for pa-
Thoracic surgery 6 (0.7) tients with trauma was 1:1.7 (1:1.3-1:2.7) and for all other sur-
Otolaryngology 3 (0.3)
gical services was 1:1.4 (1:1.0-1:2.0) (P = .002). Transfusion ra-
tios by surgical specialty are displayed in Table 3. Cardiac,
Total 865
cardiopulmonary transplant, general, liver transplant, and vas-
cular surgery cases transfused substantially more FFP to RBCs
Continuous variables were summarized using mean (SD) than did the trauma service, whereas medicine and otolaryn-
or median (interquartile range [IQR]) and compared using gology transfused substantially less FFP to RBCs than did the
2-sample t tests or Wilcoxon rank sum tests, as appropriate. trauma service. There were no differences in median FFP:
Categorical variables were summarized using frequencies with RBC transfusion ratios for thoracic, orthopedic, obstetric/
percentages and compared using χ2 or Fisher exact tests, as ap- gynecology, neurosurgery, burns, and urology surgeries.
propriate. Prespecified subgroups were patients with trauma Patients were divided into 3 groups using the tertiles of
and patients without trauma. The median FFP:RBC transfu- FFP:RBC ratio from patients without trauma. The 3 sub-
sion ratio was compared between patients with trauma and pa- groups were defined by the following median (IQR) FFP:RBC
tients from each nontrauma service using Wilcoxon rank sum ratios: high FFP to RBCs, 1:0.9 (1:0.4-1:1.1); medium FFP to
tests. On the basis of the FFP:RBC ratio tertiles from patients RBCs, 1:1.4 (1:1.2-1:1.7); and low FFP to RBCs, 1:3.0 (1:1.7-1:21)
without trauma, patients were divided into high, medium, and (Table 4). The high FFP:RBC subgroup received substantially
low FFP:RBC groups, and patient characteristics were com- more units of RBCs compared with the low FFP:RBC sub-
pared between patients with high FFP:RBC ratios and pa- group (16.0 vs 12.0 U; P < .001) as well as more units of FFP
tients with low FFP:RBC ratios. To control for potential con- (21.0 vs 5.0 U; P < .001), cryoprecipitate (4.0 vs 0.0 U; P < .001),
founding effects, multivariable logistic regression models were and platelets (30.0 vs 12.0 U; P < .001). Overall, there was no
used to compare the effect of FFP:RBC ratio group on 30-day difference in 30-day mortality between the high FFP:RBC ra-
mortality, adjusting for patient age and total RBC use. Regres- tio and the low FFP:RBC ratio groups (27% vs 22%; P = .16).
sion analysis was also conducted for the specialties with 20 However, statistically significant differences in 30-day mor-
or more mortality cases individually. All analyses were con- tality rates were observed within individual services. Among
ducted using SAS software version 9.4 (SAS Institute Inc), and patients in vascular surgery, 30-day mortality rates increased
a 2-sided P ≤ .05 was considered statistically significant. as the FFP:RBC ratio decreased (high ratio, 14%; medium ra-
tio, 26%; and low ratio, 42%; P = .045). However, the oppo-
site trend in 30-day mortality was noted among patients in gen-
eral surgery, orthopedic surgery, and medicine. In each of these
Results categories, transfusion of higher ratios of FFP:RBC was asso-
Overall Transfusions, Demographics, ciated with increased 30-day mortality (Table 4).
and Bleeding Onset Location Because patient age and total RBC use might confound the
In the 4-year period studied (2009-2012), there were 865 MT observed association between high FFP:RBC ratios and mor-
events, resulting in the transfusion of 16 569 U of RBCs, 13 933 tality, a regression analysis was performed to adjust for the ef-
U of FFP, 5228 U of cryoprecipitate, and 22 635 U of platelets. fect of these factors. Among all patients without trauma
Of these transfusions, 767 events were for patients without (n = 767), after adjusting for patient age and total units of RBCs
trauma. The mean (SD) age of the transfused patient was 60.6 transfused, the adjusted odds ratio (aOR) for 30-day mortal-
(17) years, and 582 (67.3%) of MTs occurred in men. Most MTs ity was not substantial for low ratio vs high ratio subgroups
occurred for intraoperative bleeding (544 [62.9%]), followed (aOR, 1.10; 95% CI, 0.72-1.70; P = .65). For cardiac surgery, the
by prehospital bleeding (187 [21.6%]) (eFigure in the Supple- aOR was not significantly different, either (aOR, 0.98; 95% CI,
ment). The distribution of MT by service is displayed in Table 1, 0.45-2.14; P = .96 for high vs low ratio). For general surgery and
and the distribution of bleeding onset location by service is dis- medicine, the aOR for death remained significantly higher for
played in the eTable in the Supplement. the high FFP:RBC ratio subgroup (aOR, 4.27; 95% CI, 1.28-

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 Association of Ratio-Based Massive Transfusion With Survival Among Patients Without Trauma Original Investigation Research

Table 2. Demographic Characteristics and Ratios According to Survival Status

Characteristic Survived (n = 636) Died (n = 229) P Value

Age, mean (SD), y 59.6 (16.9) 63.5 (17.4) .003
Male, No. (%) 429 (67) 153 (67) .84
Location of bleeding, No. (%) <.001
Prehospital 116 (18) 71 (31)
Intraoperative 434 (68) 110 (48)
Postoperative 60 (9) 32 (14)
FFP:RBCs, median (IQR) 1:1.5 (1.1-2.2) 1:1.4 (1.1-1.9) .43
RBCs, median (IQR) 15.0 (12.0-21.0) 20.0 (13.7-32.8) <.001
FFP, median (IQR) 11.0 (6.0-19.0) 15.0 (8.0-27.0) <.001
Cryoprecipitate, median (95th-99th 0.0 (20-40) 0.0 (30-80) .008
percentile) Abbreviations: FFP, fresh frozen
plasma; IQR, interquartile range;
Platelets, median (IQR) 18.0 (6.0-30.0) 18.0 (6.0-36.0) .32
RBCs, red blood cells.

14.22; P = .02) than for the low FFP:RBC ratio subgroup (aOR,
Table 3. FFP:RBC Transfusion Ratios by Service
8.48; 95% CI, 1.50-47.75; P = .02). For vascular surgery, the aOR
for death remained significantly lower (aOR, 0.16; 95% CI, 0.03- FFP:RBC Ratio,
Service (No. of Patients) Median (IQR) P Valuea
0.79; P = .02 for high vs low ratio). The aORs for each spe- Cardiac surgery (272) 1:1.4 (1.1-1.8) <.001
cialty comparing the high vs low FFP:RBC ratios are dis-
Liver transplant surgery (114) 1:1.0 (0.8-1.3) <.001
played graphically in the Figure.
Trauma surgery (98) 1:1.7 (1.3-2.7) NA
General surgery (86) 1:1.3 (0.9-2.4) .01
Vascular surgery (78) 1:1.3 (1.0-1.7) <.001
Discussion Medicine (76) 1:3.3 (1.7-10.0) <.001
Orthopedic surgery (56) 1:1.9 (1.3-2.6) .45
The practice of ratio-based resuscitation has now become
Cardiopulmonary transplant surgery (37) 1:1.4 (1.2-1.6) .005
firmly established in trauma resuscitation as a result of
Obstetrics/gynecology (14) 1:1.5 (1.1-1.8) .13
nearly a decade of research. This strategy of resuscitation for
hemorrhage is also widely practiced in other surgical and Urology (10) 1:1.9 (1.6-2.5) .47

medical fields, but with little supporting evidence. Our Neurosurgery (9) 1:2.0 (1.3-5.0) .36

results found no evidence that a high FFP:RBC ratio transfu-
sion strategy improved survival in a large cohort of non-
trauma MT recipients and even demonstrated worse out-
comes for several subgroups.
Although most of the published literature on MT has focused
on trauma patients, we found that, at Massachusetts General Hos-
pital, patients with trauma accounted for only one-tenth of MTs.
This result is consistent with other recently reported findings
about MT that note that trauma patients comprise the minority
of patients who receive MT.10,11 This observation is relevant be-
cause the hemostatic features of patients who are injured may
be very different from those of patients without traumatic injury.
Thus, the results obtained in blood resuscitation studies among
trauma patients may not apply directly to most hospital patients
who receive MT.
First, it is widely recognized that retrospective studies of
blood-component ratios in trauma surgery may have been con-
founded by survivorship bias, which occurs when patients in
the emergency department receive only RBCs while waiting
for FFP to thaw and when those patients with the greatest in-
jury burden die early. Our results, which analyze outcomes in
scheduled surgery, are likely to be far less subject to survivor-
ship bias because RBCs and FFP are frequently requested and
prepared before the start of cardiac surgery, liver transplant,
and other major surgical procedures.
Second, there may be inherent differences in demograph-
ics, comorbid illness, and physiology that distinguish bleed-
ing patients with trauma from bleeding patients without
Burns (6) 1:2.9 (1.7-4.0) .08
Thoracic surgery (6) 1:1.2 (1.1-2.0) .34
Otolaryngology (3) 1:5.0 (3.7-11.0) .02
Abbreviations: FFP, fresh frozen plasma; IQR, interquartile range; NA, not
applicable; RBC, red blood cell.
a
Comparisons calculated vs trauma.
trauma. The two largest subgroups of patients receiving MT
were patients undergoing cardiac surgery and liver trans-
plant surgery. In cardiac surgery, coagulopathy is thought to
arise mainly because of the effects of cardiopulmonary by-
pass on platelets and coagulation factors and the require-
ment for intraoperative anticoagulation. In liver transplant sur-
gery, bleeding is associated with advanced liver disease,
large-vessel anastomoses, and the complete absence of the liver
during the anhepatic phase of surgery.
Third, the observed differences may be in bleeding location
onset. In our study, 22% of patients who received MT had a pre-
hospital onset of bleeding, although prehospital bleeding was the
predominant location for bleeding among patients with trauma
(>90%). In contrast, most of the bleeding among patients with-
out trauma began in the operating room and likely involved
causes of bleeding that were distinct from massive blunt trauma
or devastating penetrating trauma. Despite these differences, the
practice of high FFP:RBC ratio transfusion has been adopted by
nontrauma surgeons and anesthesiologists.
Only a few studies have examined survival and blood-
component ratios outside of trauma. In a retrospective study

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 Research Original Investigation Association of Ratio-Based Massive Transfusion With Survival Among Patients Without Trauma

Table 4. Blood Product Transfusions and 30-Day Mortality by FFP:RBC Ratio Tertile Excluding Patients
With Trauma

FFP:RBC Ratio
High Medium Low
Variable (n = 257) (n = 254) (n = 256) P Valuea
Median (IQR) FFP:RBC ratio 1:0.9 (1:0.4-1:1.1) 1:1.4 (1:1.2-1:1.7) 1:3.0 (1:1.7-1:21)
RBCs transfused, median (IQR), U 16.0 (12.0-24.0) 15.0 (12.0-22.0) 12.0 (11.0-16.0) <.001
FFP transfused, median (IQR), U 21.0 (15.0-30.0) 12.0 (9.0-18.0) 5.0 (2.0-8.0) <.001
Cryoprecipitate transfused, 4.0 (0.0-10.0) 0.0 (0.0-10.0) 0.0 (0.0-5.0) <.001
median (IQR), U
Platelets transfused, 30.0 (18.0-48.0) 18.0 (12.0-36.0) 12.0 (0.0-24.0) <.001
median (IQR), U
Mortality rate, No. (%)
All nontrauma 70 (27) 62 (24) 56 (22) .16
Cardiac 27 (31) 30 (28) 19 (24) .39
Liver transplant 10 (14) 2 (8) 4 (27) .25
General 17 (52) 7 (28) 5 (18) .008
Vascular 4 (14) 8 (26) 8 (42) .045
Medicine 8 (80) 4 (40) 14 (25) .002
Orthopedics 3 (43) 5 (25) 2 (7) .04
Cardiopulmonary transplant, 0 5 (23) 1 (17) .40
No. (%)
Obstetrics/gynecology 0 0 0 NA
Urology 0 0 1 (17) >.99
Abbreviations: FFP, fresh frozen
Neurosurgery 0 0 0 NA plasma; IQR, interquartile range;
Burns NA 1 (50) 2 (50) NA NA, not applicable; RBC, red blood
cell.
Thoracic 1 (50) 0 (0) 0 >.99
a
Comparing highest with lowest
Otolaryngology NA NA 0 NA
tertile.

Figure. Adjusted Odds Ratio (OR) for Death

No. of Adjusted OR Favors High Favors Low

Surgical Service Patients (95% CI) FFP:RBC Ratio FFP:RBC Ratio
Vascular surgery 78 0.16 (0.03-0.79)
Medicine 76 8.48 (1.50-47.75)
Trauma surgery 99 0.63 (0.17-2.35) Overall, no benefit was observed for
General surgery 86 4.27 (1.28-14.22) high or low fresh frozen plasma (FFP)
Cardiac surgery 272 0.98 (0.45-2.14) to red blood cells (RBC) ratio. In
All patients without trauma 767 1.10 (0.72-1.70) vascular surgery, a high FFP:RBC ratio
was associated with a survival
0.01 0.1 1.0 10 100 benefit. In medicine and general
Adjusted OR (95% CI) surgery, a high FFP:RBC ratio was
associated with increased mortality.

of a 2-year period at a level I trauma center, Baumann and
colleagues8 found that one-half of all MTP activations oc-
curred for patients without trauma (63 of 125 total MTP acti-
vations). The most common causes of bleeding were vascular
rupture (23 patients [37%]), gastrointestinal bleeding (16 [25%]),
cardiothoracic surgery (11 [17%]), and obstetric bleeding (5
[8%]). The remaining patients without trauma were catego-
rized under thrombosis (n = 2), orthopedic (n = 1), and other
conditions (ie, septic shock, splenic rupture, exploratory lapa-
rotomy, neurosurgery, and liver disease without bleeding iden-
tified [1 patient each]). Patients without trauma received FFP
and platelets in ratios similar to those received by patients with
trauma for whom MTP activation occurred during the same pe-
riod. Similar to our findings, no association was found be-
tween mortality and blood-component transfusion ratios.8
Our retrospective analysis provides some initial insight into
the effect on survival of blood ratios in nontrauma MT. We ob-
served no 30-day survival advantage when 257 patients with
nontrauma MT transfused at a median ratio of 1 FFP to 0.9 RBC
were compared with 256 patients with nontrauma MT trans-
fused at a median ratio of 1 FFP to 3 RBCs (27% vs 22%; P = .16).
Furthermore, even among patients with trauma receiving MT,
we did not observe a survival advantage associated with higher
FFP to RBC (Figure). This result is consistent with the failure
of a 1:1 vs 1:2 ratio of FFP to RBCs to improve the 30-day sur-
vival of patients with trauma, as documented in the prospec-
tive PROPPR trial.7
Of particular interest in our data set was the exploratory
observation that certain categories of patients without trauma
might have improved or worsened survival when transfused

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 Association of Ratio-Based Massive Transfusion With Survival Among Patients Without Trauma Original Investigation Research

with high ratios of FFP to RBCs. When we examined 30-day
mortality adjusted for patient age and total blood RBC use, we
found no effect of FFP:RBC ratios in trauma or cardiac sur-
gery. We found a beneficial effect for high FFP:RBC ratios
among patients undergoing vascular surgery, which others have
also reported.15 However, of some concern, we found that high
FFP:RBC ratios were associated with greater 30-day mortal-
ity for patients in general surgery and medicine who were un-
dergoing MT. These observations suggest that high FFP:RBC
ratio transfusion strategies should not be assumed to be ben-
eficial or to be harmless and that more studies are needed to
examine clinical outcomes among different patient groups un-
dergoing MT.
Limitations
Our single-site, retrospective study is subject to several limi-
tations. First, because of the retrospective nature of data col-
lection, we were unable to verify exact times of transfusion
of each blood product; thus, we cannot account for time-
varying treatment and time-dependent confounding.16 Simi-
larly, we could not discern the strategy or thought process of
the clinician giving the transfusions. Second, because most
of the patients without trauma had bleeding that initiated in
the operating room, the risk of survival bias was minimized.
We attempted to further minimize this risk in the group of
patients with trauma by excluding patients who died within
30 minutes of hospital arrival. We only examined 30-day all-
cause mortality, which can be influenced by factors other
than blood resuscitation strategies. We did not collect data on
the exact time of death or the cause of death, as this was not
the primary focus of our study. Third, transfusions were
given according to the decisions of the caregivers and were
not part of a strict transfusion protocol. Our definition of MT
(>10 U of RBCs transfused in a 24-hour period) has been the
most common definition used in the literature but has been
criticized. Specifically, the 24-hour time frame may be too
long, as most bleeding occurs in the first 6 hours, and this
definition does not account for the rate of bleeding. Alterna-
tive definitions have been proposed but, to our knowledge,
none have been universally adopted as a standard.1,17 Fourth,
our patient population was heterogeneous, as were the loca-
tion and cause of bleeding. The inclusion of washed, autolo-
gous recovered RBCs in our analysis may be considered a
potential confounding factor on outcomes; however, we
believed it was important to include those operations in
which Cell Saver was used because it reflects real-world prac-
tice. Fifth, although the overall data set of MT was large, indi-
vidual patient groups may not have had a sufficient sample
size to allow for observation of a treatment effect. Despite
these limitations, our study represents the largest report of
the effect of blood-component ratios on nontrauma MT and
suggests future studies that can be conducted to define best
practices.
Conclusions
At Massachusetts General Hospital, high FFP:RBC transfu-
sion ratios are being used in patients without trauma, who
account for nearly 90% of all MT events. Thirty-day survival
was not significantly different in patients receiving a high
FFP:RBC ratio compared with those receiving a low ratio.
Additional studies are necessary to refine MTPs in non-
trauma specialties.

ARTICLE INFORMATION
Accepted for Publication: December 27, 2016.
Published Online: March 8, 2017.
doi:10.1001/jamasurg.2017.0098
Author Contributions: Dr Yeh had full access to all
the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data
analysis.
Study concept and design: Mesar, Velmahos, Yeh.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Mesar, Dzik, Yeh.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Mesar, Chang.
Administrative, technical, or material support:
Larentzakis, Dzik.
Study supervision: Velmahos, Yeh.
Conflict of Interest Disclosures: None reported.
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1. Savage SA, Zarzaur BL, Croce MA, Fabian TC.
Redefining massive transfusion when every second
counts. J Trauma Acute Care Surg. 2013;74(2):
396-402.
2. Motschman TL, Taswell HF, Brecher ME, Rettke
SR, Wiesner RH, Krom RA. Blood bank support of a
liver transplantation program. Mayo Clin Proc. 1989;
64(1):103-111.
3. 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.
4. Schuster KM, Davis KA, Lui FY, Maerz LL, Kaplan
LJ. The status of massive transfusion protocols in
United States trauma centers: massive transfusion
or massive confusion? Transfusion. 2010;50(7):
1545-1551.
5. Cotton BA, Gunter OL, Isbell J, et al. Damage
control hematology: the impact of a trauma
exsanguination protocol on survival and blood
product utilization. J Trauma. 2008;64(5):
1177-1183.
6. 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.
7. Holcomb JB, Tilley BC, Baraniuk S, et al; PROPPR
Study Group. 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. JAMA. 2015;313(5):
471-482.
8. Baumann Kreuziger LM, Morton CT,
Subramanian AT, Anderson CP, Dries DJ. Not only in
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24(3):162-168.
9. Pacheco LD, Saade GR, Costantine MM, Clark SL,
Hankins GD. The role of massive transfusion
protocols in obstetrics. Am J Perinatol. 2013;30(1):
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10. Dzik WS, Ziman A, Cohen C, et al; Biomedical
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1360 cases. Transfusion. 2016;56(3):
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11. Halmin M, Chiesa F, Vasan SK, et al.
Epidemiology of massive transfusion: a binational
study from Sweden and Denmark. Crit Care Med.
2016;44(3):468-477.
12. 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.
13. Inaba K, Branco BC, Rhee P, et al. Impact of
plasma transfusion in trauma patients who do not
require massive transfusion. J Am Coll Surg. 2010;
210(6):957-965.

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 Research Original Investigation Association of Ratio-Based Massive Transfusion With Survival Among Patients Without Trauma

14. Sambasivan CN, Kunio NR, Nair PV, et al;
Trauma Outcomes Group. High ratios of plasma and
platelets to packed red blood cells do not affect
mortality in nonmassively transfused patients.
J Trauma. 2011;71(2)(suppl 3):S329-S336.
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early plasma transfusion on mortality in patients
with ruptured abdominal aortic aneurysm. Surgery.
2010;148(5):955-962.
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Holcomb JB; PROMMTT Study Group. Seven deadly
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Acute Care Surg. 2013;75(1)(suppl 1):S97-S103.
17. Moren AM, Hamptom D, Diggs B, et al;
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920-924.

Invited Commentary

Applying Trauma Transfusion Practices to Nontrauma Care

A Cautionary Tale
Tanya N. Rinderknecht, MD; Sherry M. Wren, MD

The publication by Borgmann et al1 changed combat casualty
care, shifting transfusion practices to a more balanced ratio of
plasma to red blood cells. The crossover into civilian trauma
quickly ensued and even continued after 2 key trials (Prospec-
tive, Observational, Multi-
center, Major Trauma Trans-
Related article page 574 fusion and P ragmatic
Randomized Optimal Plate-
let and Plasma Ratios) showed no 30-day survival benefits.2,3
A subsequent expansion to nontrauma massive transfusion
cases followed. In this issue of JAMA Surgery, Mesar and
colleagues4 describe transfusion ratios in all patients with mas-
sive transfusions and assess survival benefit through hospital
specialty and ratios.
Not surprisingly, a more balanced transfusion practice was
present in most specialties and multiple specialties trans-
fused average higher fresh frozen plasma to packed red blood
cell ratios than the trauma service. Overall, more balanced
transfusion ratios showed no improvements in survival; how-
ever, in certain specialties, the ratios significantly affected sur-
vival. Lower transfusion ratios benefitted medical and gen-
eral surgery patients, while higher ratios improved survival for
vascular patients. These findings prompt the question of why
certain subgroups fare differently and, more importantly, how
to determine the optimal transfusion needs of patients.
The implications of these subgroup analyses, if reproduc-
ible, are directly clinically relevant and should lead to future
prospective trials. Factors such as the location of initial bleed-
ing (prehospital, intraoperative, postoperative) and coagula-
tion profiles, including thromboelastography, may be in-
cluded factors in future analyses. The authors have provided
fascinating retrospective data that the “optimal ratio” may vary
not only between trauma and nontrauma patients, but also be-
tween subpopulations of bleeding patients. We should strive
to determine the most expeditious and effective transfusion
strategies for these subgroups.

ARTICLE INFORMATION
Author Affiliations: Department of Surgery,
Stanford University School of Medicine, Stanford,
California (Rinderknecht, Wren); Surgical Service,
Palo Alto Veterans Health Care System, Palo Alto,
California (Wren).
Corresponding Author: Sherry M. Wren, MD,
Stanford Surgery, G112 PAVAHCS, 3801 Miranda
Ave, Palo Alto, CA 94304 (swren@stanford.edu).
Published Online: March 8, 2017.
doi:10.1001/jamasurg.2017.0091
Conflict of Interest Disclosures: None reported.
REFERENCES
1. 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.
2. 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.
3. Holcomb JB, Tilley BC, Baraniuk S, et al; PROPPR
Study Group. 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. JAMA. 2015;313(5):471-482.
4. Mesar T, Larentzakis A, Dzik W, Chang Y,
Velmahos G, Yeh DD. Association between ratio of
fresh frozen plasma to red blood cells during
massive transfusion and survival among patients
without traumatic injury [published online March 8,
2017]. JAMA Surg. doi:10.1001/jamasurg.2017.0098

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© 2017 American Medical Association. All rights reserved.

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