Monday, February 9, 2015

The Fixed-Ratio Massive Transfusion Answer

After years of wondering and wandering, we finally have the definitive answer for how best to resuscitate the severely-injured trauma patient – transfusion ratios best mimicking whole blood.  You know, just as we all expected, just as these authors hoped, and just what's been reported from prior observational series and military combat experience.

More or less.

Regardless, this study – the Pragmatic, Randomized, Optimal Platelet and Plasma Ratios (PROPPR) trial – was a remarkable undertaking in logistics.  Each participating Level 1 trauma center incorporated sealed coolers into their ready blood supply, providing a random allocation of product ratio when the massive transfusion protocol was activated.  As transfusion continued, more coolers with the same ratio arrived.  As best as can be implemented, this reduces the immortality bias seen in other observational series – where survivors were survivors in part, basically, because they survived.

This trial randomized patients to 1:1:1 vs. 1:1:2 – that is, equal numbers of FFP, platelets and RBCs, or half as much FFP and platelets as RBCs.  Ultimately, it didn't precisely test those same ratios, except as the initial resuscitation strategy.  Following the intervention period, the 1:1:2 arm caught up a bit with plasma and FFP – but the quantities transfused were not substantial.

Technically, this is a negative trial – the mortality advantage favoring the 1:1:1 cohort did not reach statistical significance at 24 hours or 30 days.  However, the authors powered the study expecting a 10% mortality advantage – and instead it was only 4.2% (95% CI -1.1 to 9.6) and 3.7% (95% CI -2.7 to 10.2) at each time point, respectively.  We are then left with the question whether this small difference reflects the underlying truth or chance.

Do the secondary aspects of these data validate the difference?  The expected advantage of 1:1:1 resuscitation is the warding off of evil spirits associated with transfusion-related coagulopathy – and we see in this study the primary driver of differences in mortality was related to deaths secondary to exsanguination.  Likewise, a greater number in the 1:1:1 group achieved satisfactory hemostasis.  So, using a Bayesian approach to interpreting the statistical tests for mortality, it is reasonable to adopt approaches based initial 1:1:1 resuscitation when massive transfusion is necessary, despite the limitations of the evidence.

One oddity worth noting in these data were the relatively small differences in sepsis and ARDS in the 1:1:1 group.  Increased use of FFP and, in particular, platelets are associated with these transfusion-related complications – and it has always been of particular interest whether a 1:1:1 ratio is safe, for precisely these reasons.  The inclusion of platelets in the 1:1:1 randomization may also be a matter for debate; few patients had any indication for platelets following the intervention, and further work could consider the relative utility of aggressive use of platelets.

Overall, however, this is best evidence to date the 1:1:1 ratio is a worthy initial target.

“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”

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