Massive transfusion refers to the infusion of a large volume of blood products over a relatively short period of time, in response to a clinical situation of massive haemorrhage.1 Massive bleeding leads to high mortality rates, partly as a result of the “lethal triad” (hypothermia, acidosis and coagulopathy).2 In trauma patients, uncontrolled bleeding may account for 50% of deaths occurred within the first 24h.3,4

Several studies have shown that an early and aggressive transfusion policy has a direct impact on patient survival.5,6 In fact, European guidelines for management of traumatic bleeding and coagulopathy recommend the development and implementation of local massive bleeding protocols (MBP), which should be activated soon after the patient admittance, or the awareness of a massive bleeding situation (GRADE 1C recommendation). Such a protocol should include a damage control strategy, restrictive fluid resuscitation, frequent coagulation monitoring, rational but optimal blood product usage, and early use of adjunctive haemostatics agents.6–8 Local Spanish recommendations have also become available, addressing requirements for transfusion support in massive bleeding situations.9

Transfusion strategy within MBPs has been designed based on the military trauma experience, where whole blood is used for transfusion support.10 Since the use of whole blood is considered unsafe and impractical in the civilian scenario,11–13 guidelines recommend the combined use of blood products aiming at a specific fresh frozen plasma-to-red blood cells ratio (FFP:RBC), attempting to emulate whole blood. Although several randomized controlled trials and meta-analysis have been conducted on this matter, the optimal FFP:RBC ratio remains to be established.14–17

Complementing transfusion support, the adjunctive co-administration of fibrinogen concentrates and antifibrinolytics have been included in the protocols, as both have proven to reduce mortality in massive transfusion trials.18–21 Prothrombin complex concentrate (PCC) and recombinant activated factor VII (rFVII) may also be useful when FFP is insufficient to provide coagulation factors to revert coagulopathy.22–25

Specific studies or recommendations for management of massive hemorrhage in medical or surgical patients were scarce, until recently.14,26–28 We report the use of a non-trauma MBP protocol in a single tertiary center, which has significantly impacted blood product usage and patient outcome.

From a total of 324 patients with massive hemorrhage, 20 died shortly after MBP activation and were excluded from the study. For the remaining 304, there were virtually no differences in demographic and clinical data or baseline laboratory parameters between groups or sub-groups (Table 1).

A summary of the characteristics and the quantity of blood products used are summarized in supplementary Table 1. From the safety point of view, only 2 cases of transient pulmonary edema were reported during the study period, no transfusion related-lung injury (TRALI) was demonstrated based on anti-HLA antibody testing. Non-haemolytic transfusion-related reactions were seen in approximately 0.2% of patients, mostly hyperthermia and urticarial reactions that resolved quickly with symptomatic treatment (supplementary Table 1).

Globally, 82% of massive bleeding events occurred in surgical patients. The remaining 18% of cases were non-surgical, mostly gastro-intestinal bleeding in cirrhotic patients. Among patients from Group 2, MBP was proactively triggered in 42 out 22 (20%), without differences between sub-groups (Table 1).

For the whole series, the absolute frequency of haemostatic agents used was high (60%), without group differences in median doses used. A significant time-dependent increase in fibrinogen, antifibrinolytics and PCC usage, together with a reduction in rFVIIa usage, was observed since MBP implementation (Table 1). As shown in Table 2, blood component requirements were comparable among groups and subgroups. Overall, an increase in FFP:RBC ratio (p=0.053) and a significant decrease in time to transfusion of the first FFP unit (p=0.001) were found after MBP implementation, without differences in PLT:RBC ratio.

Compared to automatic activation, proactive MBP triggering was consistently associated with increased use of RBC, FFP, higher FFP:RBC transfusion ratio and shorter to first FFP unit transfusion (Fig. 2).

Figure 2.

Effect of proactive MTP activation. RBC (A) and FFP (B) usage was increased in proactively activated MTP, together with a reduction in time to first FFP unit (C) and an improvement in FFP:RBC ratio (D) (*p<0.05; **p<0.01).

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Overall, 24-h mortality was 2.6% and 30-day mortality 20.4%. The greatest reduction of 30-day mortality was observed at the end of the observation period (Group 2B), particularly for non-surgical patients (Fig. 3A); yearly evolution of 24-h and 30-day mortality is also depicted in Fig. 3B. After MBP implementation, a significant time-dependent decrease in 24-h mortality rate (7.3–1.1%) and 30-day mortality rate (30.2–13.0%, p=0.02) were observed (Table 2).

Figure 3.

Reduction on 30-day mortality after MTP implementation (A), in the global cohort and within patient subgroups (surgical and medical); Group 1 (2005–2006); Group 2A (2007–2009); Group 2B (2010–2012). Yearly 24-h and 30-day mortality rates (B) are also shown.

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In the bivariate analysis, non-surgical bleeding, oncological surgery, lower hematimetric values, prolonged coagulation times, total blood products, and rFVIIa usage were associated with 30-day mortality, whereas MBP use appeared as protective factor (Table 3). Noteworthy, FFP:RBC ratio (≥1:2) and PLT:RBC ratio (≥1:5) were not associated with 30-day mortality in the bivariate analysis (Table 3). In the multinomial logistic regression analysis only non-surgical bleeding and rFVII use were independently associated with an increased OR for 30-day mortality, whereas MBP implementation was associated with a reduction in OR for 30-day mortality (Table 4).

No clinically evident thromboembolic complications were seen 24h after MTP deactivation.

We describe the experience of a single-center where the implementation of a MBP in non-trauma patients was associated with a significant reduction of 30-day mortality (an absolute 14% reduction compared to historical controls) together with improved transfusion dynamics and better transfusion ratios.

The frequency of massive hemorrhage events was 40.5 cases per year (0.75 cases per week), similar to previous reports with comparable patient characteristics.29 Overall, our results show lower 24-h (2.6%) and 30-day mortality rates (20.4%) compared to similar series.30,31 This is likely to depend on differences in MBP activation criteria (e.g., remote activation after transfusion of 8 RBC units at our center) and patient characteristics (mostly oncological and cardiovascular surgery in our series). A previous study compared the use of an MBP between trauma and non-trauma bleeding events, reporting higher 24-h mortality in non-trauma patients (59% vs. 35%), without differences in 30-day mortality (59% vs. 51%).31 Another retrospective study compared the results of MBP activation in trauma vs. non-trauma patients, and found no differences in blood product usage or in-hospital mortality between groups (33.9% vs. 36.5%). However, trauma patients were more likely to die in the first 24h than non-trauma patients (27.4% vs. 11.1%).30 Although no definitive conclusion can be made regarding the utility of MBP in non-trauma patients, the use of a non-MBP cohort in our study strengthen the results obtained regarding the potential role of a MBP in non-surgical bleeding scenarios.

It has been proposed that beneficial effects of any MBP are mainly derived from the improvement in transfusion ratios and the early administration of FFP.11,12,16,17,32,33 In our series, there was a noticeable effect of MBP implementation on transfusion practices (FFP:RBC ratio and time to first FFP unit), but multivariate regression analysis showed that 30-day mortality reduction (survival effect) was only independently associated with MBP implementation. Although improvements in transfusion support might have contributed to mortality reduction, many other unmeasured variables associated with MBP may have contributed equally to the observed results (e.g., haemostatic agent administration, medical support and increased MBP awareness).18,34,35

The FFP:RBC 1:1 ratio target in our MBP was based on several reports suggesting early used of balanced transfusions as a central aspect of haemostatic resuscitation.8,14,34,35 Despite the 1:1 target, our best performance was only 1:1.5, with the majority of patients between 1:1.5 and 1:3 ratio (a FFP:RBC ratio ≥1:2 was attained in 40% of patients after MBP implementation). This observation likely reflects late activation of the MBP, with unbalanced RBC transfusion starting with moderate but continuous bleeding until the MBP alarm is triggered (typically after 8 RBC units). Several authors have reported on MBP use in trauma and non-trauma cohorts where only 50–60% of patients effectively received a FFP:RBC ratio of 1:2 and only 8–12% of patients achieved a 1:1 ratio.27,30,36 Additionally, a large randomized trial has recently showed no benefit of 1:1:1 RBC:FFP:PLT ratio over 2:1:1 ratio in terms of mortality.36 Based on the available evidence, many centers have modified local protocols accordingly.27,34,36–39

From the implementation perspective, the low percentage of proactive MBP triggering is probably a consequence of a slow gain of compliance with the protocol, which has been considered sub-optimal after 6 years of clinical use. This finding may also help to explain the lack of association between the improvement in transfusion support and mortality. We believe that appropriate training, education and awareness among the medical staff and nurses may be useful for improving compliance with the MBP and patient outcome.

The application of a computer-generated alarm system for the triggering of the MBP and the leading role of the hematologist on the clinical decision making during the transfusion act should be emphasized as part of a successful MBP implementation. Although these items may represent an unmeasured variable that may have contributed to the clinical benefit observed, we believe that it is an uttermost important part of the care of patients with massive bleeding.

In our series, global use of RBC units was lower than that typical reported for MBP use in trauma, thus underlining the differences in the characteristics of massive bleeding between trauma and medical populations.30,40 Additionally, the numbers of transfused blood components remained stable after MBP implementation (Table 1); this was an unexpected finding, as the MBP implementation was expected to increase overall blood product usage as the transfusion ratios improve.36

As for recombinant factor VII (rFVII), it was typically used as a last resort haemostatic agent and, therefore, the higher mortality rate observed among patients receiving rFVII was not surprising. However, the evidence for the use of rFVII is scarce and, in our center, it has become anecdotal since 2010.

The use of viscoelastic tests (e.g., TEG®/ROTEM®) to guide transfusion practice has been preconized in recent studies.41,42 However, a Cochrane systematic review found that while transfusion guided by TEG or ROTEM may reduce bleeding, it does not improve morbidity or mortality.43 In this regard, it is worth emphasizing that only standard coagulation tests were used for decision-making within our MBP (APTT, PT and fibrinogen). The results seem to support the use of laboratory coagulation parameters within a goal-directed transfusion strategy, as recommended by recent UK guidelines,26 particularly in centers where there is rapid turnaround time for laboratory tests.

Our results have the limitations proper of a single-center retrospective analysis, such as the possibility of unmeasured variables, selection bias and the lack of statistical power to draw definitive conclusions about mortality. Although an independent association has been found between MBP implementation and mortality, the study design provide results of associative nature and therefore no cause-effect relationship can be firmly established.

In conclusion, our results show that implementation of an institutional MBP for prompt and aggressive management of non-trauma, massive bleeding patients was associated with a lower rate of mid-term mortality. This change in mortality rates could be driven by the improvement in patient support together with improved FFP availability, better FFP:RBC transfusion ratios and increased use of pro-haemostatic agents. Further studies are required to prospectively confirm the effect of MBP in non-trauma patients.

No funding was required for the development of this work.

NM performed data review and wrote the manuscript, FH designed the MTP and wrote the manuscript, AA performed data review and reviewed the manuscript, MH designed MTP and managed blood bank requests, MM helped with statistical analysis and reviewed the manuscript, JAP and RL designed the MTP and reviewed the manuscript.

The authors declare no conflicts of interests.