Association Between Ratio of Fresh Frozen Plasma to Red Blood Cells During Massive Transfusion and Survival Among Patients Without Traumatic Injury

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.

Importance  Hemostatic resuscitation has been shown to be beneficial for patients with trauma, but there is little evidence that it is equally beneficial for bleeding patients without trauma. The practice of a high transfusion ratio of fresh frozen plasma (FFP) to red blood cells (RBCs) has spread to other surgical and medical fields.

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 subgroups (aOR, 1.10; 95% CI, 0.72-1.70; P = .65). In vascular surgery, the aOR for death favored the high FFP:RBC ratio subgroup (aOR, 0.16; 95% CI, 0.03-0.79; P = .02). However, in general surgery and medicine, the aOR for death favored the low FFP:RBC ratio subgroup; general surgery: aOR, 4.27 (95% CI, 1.28-14.22; P = .02); medicine: aOR, 8.48 (95% CI, 1.50-47.75; P = .02).

Conclusions and Relevance  High FFP:RBC transfusion ratios are applied mostly to patients without trauma, who account for nearly 90% of all massive transfusion events. Thirty-day survival was not significantly different in patients who received a high FFP:RBC ratio compared with those who received a low ratio.

Massive transfusion (MT) is defined as transfusion of at least 10 U of red blood cells (RBCs) within a 24-hour period, although alternate definitions, such as 3 U/h (critical administration threshold), are also used to more accurately reflect most transfusions that occur in the first 6 hours.¹ In addition to RBCs, fresh frozen plasma (FFP) and platelets may be transfused as a ratio of RBCs in an approach termed balanced resuscitation. 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 retrospective studies from the US military reported improved survival when massively transfused injured soldiers received resuscitation 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 formal 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, Multicenter, Major Trauma Transfusion (PROMMTT) study described transfusion ratios and clinical outcomes in a prospective observational manner and concluded that higher ratios of FFP and platelets administered early in resuscitation were associated with decreased mortality in the first 24 hours.⁶Quiz Ref ID However, the subsequent Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial found no difference in 24-hour or 30-day survival 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 common 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 nontrauma 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 document 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 extrapolation from the trauma setting may be inappropriate. Aggressive 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 surgery and medicine.

We conducted a retrospective review of all MTs provided at Massachusetts General Hospital, Boston, from January 1, 2009, to December 31, 2012. The hospital is an urban academic hospital in which approximately 37 000 operations are performed per year, including 1600 cardiac, 5500 general (elective 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 Hospital Institutional Review Board, which waived the requirement for patient informed consent.

Quiz Ref IDIn 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 excluded 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, admitting service, type of operation, 30-day mortality, bleeding onset location (intraoperative, prehospital, postoperative, and other), and number of transfused blood products (including RBCs, FFP, platelets, and cryoprecipitate). In addition, if intraoperative blood recovery (transfusion of washed, autologous 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, hemoglobin, electrolytes, blood gas, and lactate values) and traditional 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 protocol for patients without trauma. For major operations with historically large volumes of blood loss (eg, thoracoabdominal aneurysm repair, aortic root replacement, and sacral chordoma resection) or operations on patients with coagulopathy (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.

Continuous variables were summarized using mean (SD) or median (interquartile range [IQR]) and compared using 2-sample t tests or Wilcoxon rank sum tests, as appropriate. Categorical variables were summarized using frequencies with percentages and compared using χ² or Fisher exact tests, as appropriate. Prespecified subgroups were patients with trauma and patients without trauma. The median FFP:RBC transfusion ratio was compared between patients with trauma and patients from each nontrauma service using Wilcoxon rank sum tests. On the basis of the FFP:RBC ratio tertiles from patients without trauma, patients were divided into high, medium, and low FFP:RBC groups, and patient characteristics were compared between patients with high FFP:RBC ratios and patients with low FFP:RBC ratios. To control for potential confounding effects, multivariable logistic regression models were used to compare the effect of FFP:RBC ratio group on 30-day mortality, adjusting for patient age and total RBC use. Regression analysis was also conducted for the specialties with 20 or more mortality cases individually. All analyses were conducted using SAS software version 9.4 (SAS Institute Inc), and a 2-sided P ≤ .05 was considered statistically significant.

In the 4-year period studied (2009-2012), there were 865 MT events, resulting in the transfusion of 16 569 U of RBCs, 13 933 U of FFP, 5228 U of cryoprecipitate, and 22 635 U of platelets. Of these transfusions, 767 events were for patients without trauma. The mean (SD) age of the transfused patient was 60.6 (17) years, and 582 (67.3%) of MTs occurred in men. Most MTs occurred for intraoperative bleeding (544 [62.9%]), followed by prehospital bleeding (187 [21.6%]) (eFigure in the Supplement). The distribution of MT by service is displayed in Table 1, and the distribution of bleeding onset location by service is displayed in the eTable in the Supplement.

Quiz Ref IDFor the entire cohort, when survivors were compared with nonsurvivors, the patients who died were older (mean [SD] age, 59.6 [16.9] vs 63.5 [17.4] years) and received more units of RBCs (median [IQR], 15.0 [12.0-21.0] vs 20.0 [13.7-32.8] U; P < .001), FFP (11.0 [6.0-19.0] vs 15.0 [8.0-27.0] U; P < .001), and cryoprecipitate (median [95th-99th percentile], 0.0 [20-40] U for those who survived compared with 0.0 [30-80] U for those who died; P = .008) (Table 2). Note that the FFP:RBC ratios of survivors and nonsurvivors were nearly identical: the median (IQR) FFP:RBC ratio for survivors was 1:1.5 (1:1.1-1:2.2) and for nonsurvivors was 1:1.4 (1:1.1-1:1.9) (P = .43).

The median (IQR)–calculated FFP:RBC transfusion ratio for patients with trauma was 1:1.7 (1:1.3-1:2.7) and for all other surgical services was 1:1.4 (1:1.0-1:2.0) (P = .002). Transfusion ratios by surgical specialty are displayed in Table 3. Quiz Ref IDCardiac, cardiopulmonary transplant, general, liver transplant, and vascular surgery cases transfused substantially more FFP to RBCs than did the trauma service, whereas medicine and otolaryngology transfused substantially less FFP to RBCs than did the trauma service. There were no differences in median FFP:RBC transfusion ratios for thoracic, orthopedic, obstetric/gynecology, neurosurgery, burns, and urology surgeries.

Patients were divided into 3 groups using the tertiles of FFP:RBC ratio from patients without trauma. The 3 subgroups were defined by the following median (IQR) FFP:RBC ratios: high FFP to RBCs, 1:0.9 (1:0.4-1:1.1); medium FFP to RBCs, 1:1.4 (1:1.2-1:1.7); and low FFP to RBCs, 1:3.0 (1:1.7-1:21) (Table 4). The high FFP:RBC subgroup received substantially more units of RBCs compared with the low FFP:RBC subgroup (16.0 vs 12.0 U; P < .001) as well as more units of FFP (21.0 vs 5.0 U; P < .001), cryoprecipitate (4.0 vs 0.0 U; P < .001), and platelets (30.0 vs 12.0 U; P < .001). Overall, there was no difference in 30-day mortality between the high FFP:RBC ratio and the low FFP:RBC ratio groups (27% vs 22%; P = .16). However, statistically significant differences in 30-day mortality rates were observed within individual services. Among patients in vascular surgery, 30-day mortality rates increased as the FFP:RBC ratio decreased (high ratio, 14%; medium ratio, 26%; and low ratio, 42%; P = .045). However, the opposite trend in 30-day mortality was noted among patients in general surgery, orthopedic surgery, and medicine. In each of these categories, transfusion of higher ratios of FFP:RBC was associated with increased 30-day mortality (Table 4).

Because patient age and total RBC use might confound the observed association between high FFP:RBC ratios and mortality, a regression analysis was performed to adjust for the effect of these factors. Among all patients without trauma (n = 767), after adjusting for patient age and total units of RBCs transfused, the adjusted odds ratio (aOR) for 30-day mortality was not substantial for low ratio vs high ratio subgroups (aOR, 1.10; 95% CI, 0.72-1.70; P = .65). For cardiac surgery, the aOR was not significantly different, either (aOR, 0.98; 95% CI, 0.45-2.14; P = .96 for high vs low ratio). For general surgery and medicine, the aOR for death remained significantly higher for the high FFP:RBC ratio subgroup (aOR, 4.27; 95% CI, 1.28-14.22; P = .02) than for the low FFP:RBC ratio subgroup (aOR, 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, 0.03-0.79; P = .02 for high vs low ratio). The aORs for each specialty comparing the high vs low FFP:RBC ratios are displayed graphically in the Figure.

The practice of ratio-based resuscitation has now become firmly established in trauma resuscitation as a result of nearly a decade of research. This strategy of resuscitation for hemorrhage is also widely practiced in other surgical and medical fields, but with little supporting evidence. Quiz Ref IDOur results found no evidence that a high FFP:RBC ratio transfusion strategy improved survival in a large cohort of nontrauma MT recipients and even demonstrated worse outcomes for several subgroups.

Although most of the published literature on MT has focused on trauma patients, we found that, at Massachusetts General Hospital, 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 because 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 confounded 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 injury burden die early. Our results, which analyze outcomes in scheduled surgery, are likely to be far less subject to survivorship 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 demographics, comorbid illness, and physiology that distinguish bleeding patients with trauma from bleeding patients without trauma. The two largest subgroups of patients receiving MT were patients undergoing cardiac surgery and liver transplant surgery. In cardiac surgery, coagulopathy is thought to arise mainly because of the effects of cardiopulmonary bypass on platelets and coagulation factors and the requirement for intraoperative anticoagulation. In liver transplant surgery, 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 prehospital 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 without 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 of a 2-year period at a level I trauma center, Baumann and colleagues⁸ found that one-half of all MTP activations occurred for patients without trauma (63 of 125 total MTP activations). 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 categorized under thrombosis (n = 2), orthopedic (n = 1), and other conditions (ie, septic shock, splenic rupture, exploratory laparotomy, neurosurgery, and liver disease without bleeding identified [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 period. Similar to our findings, no association was found between 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 observed 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 transfused 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 survival of patients with trauma, as documented in the prospective 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 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 surgery. 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 mortality for patients in general surgery and medicine who were undergoing MT. These observations suggest that high FFP:RBC ratio transfusion strategies should not be assumed to be beneficial or to be harmless and that more studies are needed to examine clinical outcomes among different patient groups undergoing MT.

Our single-site, retrospective study is subject to several limitations. First, because of the retrospective nature of data collection, 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 Similarly, 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. Alternative 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 location and cause of bleeding. The inclusion of washed, autologous 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 practice. Fifth, although the overall data set of MT was large, individual 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.

At Massachusetts General Hospital, high FFP:RBC transfusion 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 nontrauma specialties.

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 Cambridge St, Room 810, Boston, MA 02114 (dyeh2@partners.org).

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.