There is a growing trend towards a one to one ratio of fresh frozen plasma (FFP) to red blood cells (RBCs) when transfusing during the first 24 h of haemorrhage. Conventional management, according to current guidelines, recommends a 1: 6 FFP: RBC ratio The question arises whether the use of a higher ratio is just a fashion or is based on sound science.
Borgman et al.1 published the first study to suggest benefit from a 1: 1 FFP: RBC ratio. Their data from a combat support hospital found that mortality in patients receiving massive transfusions (>10 RBC within 24 h) was lowest for a FFP: RBC ratio approaching 1: 1.4. Subsequently, this was corroborated by several reports showing that plasma infusion at high ratios was associated with a significant reduction in mortality.2 The meta-analysis of studies enrolling trauma patients requiring massive blood transfusion confirmed that plasma transfusion at ratios greater than 1: 3 was indeed associated with a significant reduction in mortality.3
However, most of the data come from flawed retrospective observational studies that have missing data and analytical bias, limiting the interpretation of the results. The most important source of bias comes from the impact of survival. Individuals who die are participants for a shorter time than those who survive, and the longer an individual survives, the greater the likelihood that they will receive more FFP.4 This creates an association of survival with higher FFP: RBC ratio, but without making it clear whether this is a cause or an effect. To accommodate the possibility that the ratio for a given individual may change with time, it is necessary, in the statistical analysis, to treat the ratio as a time-dependent variable. When this is done, the survival benefit associated with the high ratio disappears. Patients did not die early because they had a low ratio, but a low ratio was recorded because they died ‘early’.
A further difficulty comes from results that are contradictory and study groups that are heterogenous. Whereas studies on combat casualties underlined the benefit of a 1: 1 ratio, this advantage was not seen as clearly in analyses of data from civilians. Indeed, the two cannot be compared because combat casualties are young, male and in good health, whereas civilians form a more varied group, tending to be older and with concomitant disease. Penetrating trauma was the major injury in 94% of combat casualties, but in only 10% of civilians. The management of combat casualties was also different in that many received not only activated recombinant factor VII, but also total blood or thawed plasma, which was not the case for injured civilians.
Given the weaknesses that exist in methods and analyses, it is too soon to adopt a 1: 1 ratio as a firm recommendation for haemorrhage management. First-class evidence requires prospective randomised trials to confirm these results, but given the nature of the problem under study, they are unlikely to be forthcoming. Therefore, the existing publications, with all their problems, can still help us to improve our transfusion practices, provided we interpret their results with caution and objectivity. High ratio management cannot yet be applied to all bleeding patients across the board. It is appropriate to consider what the ideal ratio and transfusion therapy might be for any individual under treatment.
Studies suggesting that a high ratio is of benefit include only those requiring massive transfusion. They are trauma victims or patients with ruptured abdominal aortic aneurysm.2,3,5 They arrive with very early coagulation disorders, which are not corrected by conventional management that adheres to current guidelines (FFP 1: 6 RBC). As this coagulopathy occurs very rapidly, FFP transfusion is required early and in greater volume than generally recommended. Regardless of definition, those requiring massive transfusion account for just 3–10% of admissions to trauma centres. Thus, the need for high ratio applies to only a small fraction of patients.
In contrast, in patients undergoing surgery without massive transfusion, there was a trend towards increased mortality in those transfused with plasma.3 There are no available data to inform on scheduled surgery outcomes with severe blood loss. There is insufficient evidence of benefit from plasma transfusion, but adverse effects are reported. Although, with current therapies, the risk of infectious disease transmission is very low, other adverse effects are described. Several studies have found a relationship between the FFP: RBC ratio and hospital-acquired infections, pneumonia, acute respiratory distress syndrome (ARDS), transfusion-related acute lung injury (TRALI) or multiorgan failure.6 Increasing the ratio leads also to transfusion of ABO non-identical units. A recent observational study suggests that ABO compatible but non-identical FFP transfusion is associated with increased mortality.7
The optimal FFP: RBC ratio providing benefit to trauma victims has not been definitively ascertained. Several teams favour a 1: 1 ratio, but the 1: 1 ratio has not always come out best. A comparison involving 259 multiple trauma victims receiving massive transfusions and FFP: RBC ratios in excess of 1: 1 showed that the lowest mortality rate was associated with a ratio between 1: 1.5 and 1: 1.8 In another comparison of 133 multiple trauma victims, the probability of death was higher for ratios over 1: 1 than for ratios of 1: 2 and 1: 3.9 The optimal ratio remains to be decided, and the use of 1: 1 is by no means established and could even be challenged.
One of the points to emerge from this concerns the timing of plasma transfusion. As early deaths have occurred with no or little plasma replacement, the question arises whether outcomes might have been better if plasma could have been immediately available. FFP cannot be given prior to thawing and cross-matching, making immediate availability a major issue.
Reducing transfusion delay can be achieved through a carefully constructed massive transfusion protocol that incorporates a local agreement with the blood bank to make plasma available in 20–30 min rather than the 60–90 min commonly required.2 Protocols should extend to the provision of successive shipments of FFP and RBC in fixed proportions. A ratio of 2 FFP to 5 RBC decreased the quantity of blood components used and also costs.10 Cotton et al.11 used blood products in a close predefined ratio of 4 FFP to 10 RBC to 2 platelet units and observed a reduction in overall blood product consumption as well as decreased 30-day mortality. Patient prognosis was significantly better, yet the FFP: RBC ratio was less than 1: 2. We can conclude that the prognosis in haemorrhagic shock can be improved through the implementation of a transfusion protocol while we await stronger evidence for the efficacy of high FFP: RBC ratios. These protocols specify the number and administration sequence of products. They describe hospital blood product circuits and indicate the position and tasks of the health professionals involved.12
All these algorithms include initial transfusion with thawed plasma. Immediate availability of plasma is the only way to achieve the early massive plasma transfusion that is required for the management of preexisting coagulopathy. It also reduces the amount of crystalloid administered, reducing in turn, dilution and the use of coagulation factor concentrates.13 The use of thawed AB group plasma stored for immediate availability together with O group RBC concentrates should form part of the local agreement. After thawing, the activity of coagulation factors in plasma stored at 4°C over 6 days decreases moderately at first and then remains stable and above 70%.14 The effectiveness is, thus, preserved for a few days, allowing storage in trauma resuscitation unit refrigerators. Good stock management will limit waste and ensure sufficient active plasma supplies for immediate availability. This approach is already used in some American and European centres.
Similarly, the use of freeze-dried plasma that can be stored for up to 2 years, allows, after rehydratation, immediate availability of clotting factors for any blood type in less than 3 min.15 This plasma product is used by Belgian and French armies as well as the Australian Red Cross and represents a practical alternative solution in small centres where massive transfusion is rare.
Finally, the use of radio wave-based technology allows thawing in 8 min, with FV and FVIII rates greater than 90% compared to levels before freezing.16
Traditional practices for resuscitation in massive bleeding are changing. Published data suggest that plasma transfusion should be more aggressive. Higher ratios are not the only goal. Implementation of comprehensive massive transfusion protocols is mandatory. Plasma must be immediately available, with thawed plasma, freeze-dried plasma and thawing microwaves available for faster release, making early management with high ratios a reality.
A.G. has received lecture fees from LFB, Octapharma and CSL-Behring. Y.O. has a consultancy contract with LFB and has received lecture fees from LFB. S.S. has received lecture fees from LFB.
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