Please see later in the article for the Editors' Summary

The association of transfusion with all-cause mortality appears to vary according to the predicted risk of death. Transfusion may reduce mortality in patients at high risk of death but increase mortality in those at low risk. The effect of transfusion in low-risk patients should be further tested in a randomised trial.

A secondary analysis of the CRASH-2 trial (which originally evaluated the effect of tranexamic acid on mortality in trauma patients) was conducted. The trial included 20,127 trauma patients with significant bleeding from 274 hospitals in 40 countries. We evaluated the association of RBC transfusion with mortality in four strata of predicted risk of death: <6%, 6%–20%, 21%–50%, and >50%. For this analysis the exposure considered was RBC transfusion, and the main outcome was death from all causes at 28 days. A total of 10,227 patients (50.8%) received at least one transfusion. We found strong evidence that the association of transfusion with all-cause mortality varied according to the predicted risk of death (p-value for interaction <0.0001). Transfusion was associated with an increase in all-cause mortality among patients with <6% and 6%–20% predicted risk of death (odds ratio [OR] 5.40, 95% CI 4.08–7.13, p<0.0001, and OR 2.31, 95% CI 1.96–2.73, p<0.0001, respectively), but with a decrease in all-cause mortality in patients with >50% predicted risk of death (OR 0.59, 95% CI 0.47–0.74, p<0.0001). Transfusion was associated with an increase in fatal and non-fatal vascular events (OR 2.58, 95% CI 2.05–3.24, p<0.0001). The risk associated with RBC transfusion was significantly increased for all the predicted risk of death categories, but the relative increase was higher for those with the lowest (<6%) predicted risk of death (p-value for interaction <0.0001). As this was an observational study, the results could have been affected by different types of confounding. In addition, we could not consider haemoglobin in our analysis. In sensitivity analyses, excluding patients who died early; conducting propensity score analysis adjusting by use of platelets, fresh frozen plasma, and cryoprecipitate; and adjusting for country produced results that were similar.

Haemorrhage is a common cause of death in trauma patients. Although transfusions are extensively used in the care of bleeding trauma patients, there is uncertainty about the balance of risks and benefits and how this balance depends on the baseline risk of death. Our objective was to evaluate the association of red blood cell (RBC) transfusion with mortality according to the predicted risk of death.

Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001664 .

These findings show that RBC transfusion is associated with an increase in all-cause deaths among patients with trauma and major bleeding with a low predicted risk of death, but with a reduction in all-cause deaths among patients with a high predicted risk of death. In other words, these findings suggest that the effect of RBC transfusion on all-cause mortality may vary according to whether a patient with trauma has a high or low predicted risk of death. However, because the participants in the CRASH-2 trial were not randomly assigned to receive a RBC transfusion, it is not possible to conclude that receiving a RBC transfusion actually increased the death rate among patients with a low predicted risk of death. It might be that the patients with this level of predicted risk of death who received a transfusion shared other unknown characteristics (confounders) that were actually responsible for their increased death rate. Thus, to provide better guidance for clinicians caring for patients with trauma and hemorrhage, the hypothesis that RBC transfusion could be harmful among patients with trauma with a low predicted risk of death should be prospectively evaluated in a randomised controlled trial.

The CRASH-2 trail included 20,127 patients with trauma and major bleeding treated in 274 hospitals in 40 countries. In their risk-stratified analysis, the researchers investigated the effect of RBC transfusion on CRASH-2 participants with a predicted risk of death (estimated using a validated model that included clinical variables such as heart rate and blood pressure) on admission to hospital of less than 6%, 6%–20%, 21%–50%, or more than 50%. That is, the researchers compared death rates among patients in each stratum of predicted risk of death who received a RBC transfusion with death rates among patients who did not receive a transfusion. Half the patients received at least one transfusion. Transfusion was associated with an increase in all-cause mortality at 28 days after trauma among patients with a predicted risk of death of less than 6% or of 6%–20%, but with a decrease in all-cause mortality among patients with a predicted risk of death of more than 50%. In absolute figures, compared to no transfusion, RBC transfusion was associated with 5.1 more deaths per 100 patients in the patient group with the lowest predicted risk of death but with 11.9 fewer deaths per 100 patients in the group with the highest predicted risk of death.

Although RBC transfusion can save the lives of patients with trauma who are bleeding, there is considerable uncertainty regarding the balance of risks and benefits associated with this procedure. RBC transfusion, which is an expensive intervention, is associated with several potential adverse effects, including allergic reactions and infections. Moreover, blood supplies are limited, and the risks from transfusion are high in low- and middle-income countries, where most trauma-related deaths occur. In this study, which is a secondary analysis of data from a trial (CRASH-2) that evaluated the effect of tranexamic acid (which stops excessive bleeding) in patients with trauma, the researchers test the hypothesis that RBC transfusion may have a beneficial effect among patients at high risk of death following trauma but a harmful effect among those at low risk of death.

Trauma—a serious injury to the body caused by violence or an accident—is a major global health problem. Every year, injuries caused by traffic collisions, falls, blows, and other traumatic events kill more than 5 million people (9% of annual global deaths). Indeed, for people between the ages of 5 and 44 years, injuries are among the top three causes of death in many countries. Trauma sometimes kills people through physical damage to the brain and other internal organs, but hemorrhage (serious uncontrolled bleeding) is responsible for 30%–40% of trauma-related deaths. Consequently, early trauma care focuses on minimizing hemorrhage (for example, by using compression to stop bleeding) and on restoring blood circulation after blood loss (health-care professionals refer to this as resuscitation). Red blood cell (RBC) transfusion is often used for the management of patients with trauma who are bleeding; other resuscitation products include isotonic saline and solutions of human blood proteins.

Funding: This study was supported by PROGRESS Medical Research Council Prognosis Research Strategy (PROGRESS) Partnership [G0902393/99558]. DA, PC, and IR are UK NIHR Senior Investigators. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. Freebird ( http://freebird.lshtm.ac.uk ) is a website that allows the sharing of injury and emergency research data and has the data from CRASH-2 trial.

Copyright: © 2014 Perel et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

It is possible that the effect of RBC transfusion on mortality depends on the underlying risk. We hypothesized that there may be a beneficial effect among patients at high risk of death but a harmful effect in those patients at low risk of death. Even if the relative effect is similar, the absolute effect and cost-effectiveness could vary according to underlying risk, and so a stratified approach to RBC transfusion might be justified. To the best of our knowledge, this hypothesis has not been tested before in trauma patients. Using a large international cohort of trauma patients with bleeding, we evaluated the association of RBC transfusion with mortality according to the predicted risk of death.

However, most RBC transfusion in trauma patients occurs early after hospital admission, when haematocrit level is not a reliable indicator of the extent of bleeding, and clinicians must use physical signs, diagnostic tests, and clinical judgment to decide whether or not a RBC transfusion is indicated [8] .

A systematic review showed that RBC transfusion is associated with increased morbidity and mortality in critically ill patients, including trauma patients [6] . Nevertheless, the included studies were observational, and it is likely that some of the effect observed was due to confounding by indication, with transfusion being offered to more severely ill patients. A more recent systematic review of randomised trials evaluated the effect of different haemoglobin or haematocrit thresholds for blood transfusion in haemodynamically stable critically ill patients. It found that a more restrictive approach (transfusion only when haemoglobin levels were below 70 or 80 g/l) reduced in-hospital mortality without any increase in adverse events [7] .

RBC transfusion is a scarce and expensive intervention with potential adverse effects, including allergic reaction, transfusion-related lung injury, graft versus host disease, and infection. Furthermore, supplies of blood are lower, and the risks from transfusion higher, in low- and middle-income countries, where most bleeding deaths occur [5] .

Haemorrhage is a leading cause of death in trauma patients, responsible for approximately 30% to 40% of trauma-related deaths [1] , [2] . Although red blood cell (RBC) transfusion is often used in the management of bleeding trauma patients, there is considerable uncertainty regarding the balance of risks and benefits [3] , [4] .

Finally, to take into account potential confounding by geographical variation in the types of blood products used for transfusion, we adjusted the comparison within each predicted risk group by use of platelets, fresh frozen plasma, and cryoprecipitate and by country using logistic regression.

To examine the impact of possible confounding by indication, we calculated propensity scores for all patients using logistic regression, with blood transfusion as the outcome. Factors included in the model were those likely to influence the decision to transfuse, including age, gender, income region (high, middle, or low), systolic blood pressure, heart rate, respiratory rate, Glasgow Coma Scale, type of injury (penetrating or blunt), time since injury, and tranexamic acid use. The distribution of propensity scores amongst all transfused and non-transfused patients was then compared, and we excluded all patients with scores in the upper and lower 5% of the score distribution. Any patients whose propensity scores were outside the overlapping area of the distributions of transfused and non-transfused patients were also excluded, to avoid making comparisons between patients with too many underlying differences. With this reduced study population, we then evaluated the association of transfusion with all-cause mortality according to the predicted risk of death in each of the pre-specified mortality strata, adjusting by the propensity score (as a continuous variable).

To take into account a potential survival bias we also reported the association of RBC transfusion with all-cause mortality excluding patients who died on day “0” (first day of hospital arrival).

To identify a potential non-linear interaction between transfusion and baseline risk, patients were also categorised into ten risk groups containing approximately one-tenth of the primary outcome each, and the association of RBC transfusion with death from all causes was evaluated within each of these categories.

Because RBC transfusion practices vary and could be associated with different risks according to the region of the world, we also examined the association with death from all causes separately for four geographical regions.

The number of patients and number of deaths were tabulated by transfusion status. Odds ratios (ORs) and risk differences, together with 95% confidence intervals, comparing RBC transfusion to no RBC transfusion were calculated within each of the pre-specified risk categories as defined previously [10] . Interaction tests were conducted using logistic regression to formally assess whether the impact of RBC transfusion differed according to underlying risk, with risk considered as a continuous variable.

For each patient we estimated the predicted risk of death from all causes using a validated model, and categorised patients into four pre-specified strata (<6%, 6%–20%, 21%–50%, and >50%). The prognostic model we used was developed using 20,127 trauma patients with, or at risk of, significant bleeding within 8 h of injury. The model development was conducted with a backward stepwise approach, and the predictors included in the final model were Glasgow Coma Scale, age, heart rate, systolic blood pressure, time since injury, type of injury, and geographical region. Full details of model development and validation have been published elsewhere [10] (see Text S1 ). Although risk is a continuous variable, we decided to use risk categories for simplifying its use in clinical practice. The risk categories used were identical to the ones reported in the original prognostic model, and the cutoffs were decided with the feedback from prognostic model users and by looking at previous publications [10] .

The characteristics of patients were tabulated and compared according to whether the patient underwent a transfusion. Univariable comparisons were made using a logistic regression model by treating each variable as a categorical or continuous co-variate as appropriate.

We compared the association of RBC transfusion with the outcomes versus that of no RBC transfusion. For this analysis we compared two groups: those who received at least one RBC transfusion (transfused) versus those patients who did not receive any RBC transfusion (non-transfused).

The primary outcome of this analysis was death from all causes stratified by baseline risk. We also reported specific causes of death (bleeding, head injury, multi-organ failure, myocardial infarction, stroke, pulmonary embolism, and other causes), and we conducted a secondary analysis exploring the association of RBC transfusion with fatal and non-fatal vascular occlusive events including myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism. All events were measured at 28 days or hospital discharge. Cause of death was defined by the investigators using their clinical judgment.

The study cohort included all patients from the CRASH-2 clinical trial. The trial included 20,127 trauma patients with, or at risk of, significant bleeding within 8 h of injury, and evaluated the effect of tranexamic acid on all-cause mortality. The trial was undertaken in 274 hospitals in 40 countries. Detailed information on the methods and results of the CRASH-2 trial have been published previously [9] .

The primary objective of the study was to evaluate the association of RBC transfusion with all-cause mortality at 28 days (or hospital discharge) according to predicted risk of death at hospital admission. The secondary objective was to evaluate the association of RBC transfusion with fatal and non-fatal vascular occlusive events.

Results

The baseline characteristics of CRASH-2 trial patients according to their RBC transfusion status are displayed in Table 1. A total of 10,227 patients (50.8%) received RBC transfusion. Patients from high-income countries, and those who arrived at hospital more than 3 h after the injury, had lower systolic blood pressure or Glascow Coma Score, had higher heart rate or respiratory rate, or had blunt injury were more likely to receive RBC transfusion (p<0.0001 for all comparisons, except p = 0.010 for blunt versus penetrating injuries). Patients in the lowest predicted risk of death category (<6%) were less likely to receive RBC transfusions.

All-cause mortality was higher in patients who received RBC transfusion (Table 2). A total of 2,021 (19.8%) patients who received a RBC transfusion died, while 1,055 (10.7%) patients who did not receive RBC transfusion died (OR 2.06, 95% CI 1.91–2.24, p<0.0001). Deaths from bleeding (OR 3.16, 95% CI 2.74–3.64, p<0.0001), multi-organ failure (OR 3.44, 95% CI 2.74–4.30, p<0.0001), myocardial infarction (OR 3.05, 95% CI 1.30–7.13, p = 0.010), and other causes (OR 2.80, 95% CI 2.12–3.69, p<0.0001) were more frequent in patients who received a RBC transfusion than in those who did not receive one.

A total of 267 (2.6%) patients who received RBC transfusion had a fatal or non-fatal vascular occlusive event, in comparison to 102 (1.0%) of those patients who did not receive a RBC transfusion (OR 2.58, 95% CI 2.05–3.24, p<0.0001).

As shown in Table 3 we found strong evidence that the association of RBC transfusion with all-cause mortality differed according to the predicted risk of death (p-value for interaction <0.0001). A total of 270 patients were excluded from this analysis because at least one variable of the prognostic model was missing (Table S1 provides details of patient characteristics for individuals with missing data). The risk of all-cause mortality associated with RBC transfusion was increased in patients with <6% predicted risk of death, (217 [6.4%] in transfused group versus 66 [1.2%] in non-transfused group; OR 5.40, 95% CI 4.08–7.13, p<0.0001). RBC transfusion was also associated with an increase in all-cause mortality in patients with 6%–20% predicted risk of death (591 [15.1%] in transfused group versus 211 [7.2%] in non-transfused group; OR 2.31, 95% CI 1.96–2.73, p<0.0001). Among patients with a predicted risk of death of 21%–50%, all-cause mortality was similar in the two groups (557 [31.6%] in transfused group versus 334 [33.5%] in non-transfused group; OR 0.92, 95% CI 0.78–1.08, p = 0.31), while the risk of all-cause mortality was significantly decreased with RBC transfusion in patients with >50% predicted risk of death (566 [59%] in transfused group versus 413 [70.8%] in non-transfused group; OR 0.59, 95% CI 0.47–0.74, p<0.0001).

In absolute terms, there were 5.1 (95% CI 4.3 to 6.0) more deaths per 100 patients associated with RBC transfusion in the group with the lowest predicted risk of death but 11.9 (95% CI 7.1 to 16.7) fewer deaths per 100 patients associated with RBC transfusion in the group with the highest predicted risk.

The sensitivity analysis (excluding 1,086 patients who died at day 0) showed similar results, indicating that the association of RBC transfusion with all-cause mortality differed according to the predicted risk of death (p-value for interaction <0.0001) (Table 4). Propensity score analysis (excluding 2,011 patients with extreme propensity score values) showed similar results, with strong evidence of interaction of the association of RBC transfusion with all-cause mortality according to the predicted risk of death (p-value for interaction <0.0001) (Table 5). The sensitivity analysis adjusting for use of platelets, fresh plasma, and cryoprecipitate and for country also showed a similar pattern and strong evidence of interaction (Table 6).

To explore the association of RBC transfusion with all-cause mortality further, we created ten groups of predicted risk of death containing approximately one-tenth of the primary outcome each. As can be seen in Figure 1, RBC transfusion showed a trend from a positive association (harmful) to a negative association (beneficial) with all-cause mortality according to predicted risk of death. RBC transfusion was associated with an increase in all-cause mortality at low predicted risk of death and a decrease in all-cause mortality at high predicted risk of death. The change in direction of the association of transfusion (from harmful to beneficial) with all-cause mortality occurred around a predicted risk of death of about 25%.

We found strong evidence that the association of RBC transfusion with all-cause mortality differed according to the predicted risk of death (p-value for interaction <0.0001) for each of geographical regions considered (Table 7). Although effect estimates and confidence intervals varied by geographical region, we found the same pattern of association of RBC transfusion and all-cause mortality (positive at low predicted risk of death and negative at high predicted risk of death).

We also found strong evidence that the association of RBC transfusion with vascular occlusive events differed according to the predicted risk of death (p-value for interaction <0.0001) (Table 8). The risk associated with RBC transfusion was significantly increased for all the predicted risk of death categories, but the relative increase was higher for those with the lowest predicted risk of death. The OR of vascular occlusive events associated with RBC transfusion was 4.92 (95% CI 2.80–8.65, p<0.0001) in patients with <6% predicted risk of death, 1.66 (95% CI 1.13–2.46, p = 0.009) in patients with 6%–20% predicted risk of death, 1.80 (95% CI 1.16–2.80, p = 0.006) in patients with 21%–50% predicted risk of death, and 1.58 (95% CI 0.93–2.68, p = 0.081) in patients with >50% predicted risk of death