In critically injured trauma patients requiring massive transfusion, does a ratio of 1:1:1 of plasma, platelets and RBCs respectively improve all-cause mortality at 24 hours or 30 days as compared to a 1:1:2 product ratio?
Trauma is very common and hemorrhage is a major cause of death in trauma. In fact, it is the number one cause of death and life years lost in young people in America. However, we actually know surprisingly little about the optimum resuscitation strategies for these patients.
In the ancient past, whole blood was transfused, then in the 1970s we began separating blood into its component products –Plasma, Platelets and RBCs – but how to best transfuse these different products is unknown. Damage Control resuscitation strategies have posited that nearer-to-whole-blood ratios may reduce mortality.
The PROMMTT trial in 2013 provided observational data on what was being done in the nation’s top trauma centers, and there was suggestion that 1:1:1 ratios performed better than 1:1:2. The PROPPR trial aimed to provide definitive RCT to answer this question.
Pragmatic, multicenter, randomized controlled trial. Blinding was broken once the first pre-packaged box of product was opened. In the 1:1:1 group, 6 units of platelets, followed by alternating units of RBCs and Plasma were given. In the 1:1:2 group, 2 units of RBCs followed by 2 units of Plasma and 0 units of platelets were transfused initially, followed by subsequent product packages which included 3 units plasma, 6 units platelets and 6 units of RBCs, administering the platelets first. Transfusions were stopped when clinically indicated, and all other interventions were at the discretion of the treating physician. They powered the trial at 95% to detect a 10% absolute difference in 24-hour mortality (21%-->11%) with a margin of error, so 680 patients were enrolled.
Inclusion: Subjects were highest level trauma activations taken from scene directly to one of 12 level 1 trauma centers in the US. All received a transfusion prehospital or within one hour of reaching the trauma center. They had an ABC score ≥2 or physician gestalt that they would require a massive transfusion defined as >10 units RBCs in 24 hours.
Exclusion: Age <15, pregnant, prisoners, burns >20% or inhalation injuries, moribund, >3u RBCs prior thoracotomy prior to randomization
They collected a large amount of baseline data about demographics, injury severity and, laboratory data, randomization details, interventions and 23 complications. Their primary outcomes were mortality at 24 hours and at 30 days.
Ancillary outcomes were pre-specified to evaluate the effectiveness and safety of the transfusion ratios and included (1) time to hemostasis; (2) the number and type of blood products used from randomization until hemostasis was achieved; (3) the number and type of blood products used after hemostasis was achieved up to 24 hours post-admission; (4) 23 complications; (5) hospital-, ventilator-, and ICU-free days (within the first 30 days or hospital discharge, whichever occurred first); (6) incidence of major surgical procedures; and (7) functional status at hospital discharge or 30 days, whichever occurred first, as measured by discharge destination and Glasgow Outcome Scale-Extended.
Groups were well matched. Patients were very sick with mean ISS of 26. Kaplan Meier curves and adjusted risk ratios were employed (using a logit model to account for treatment differences) and a Mantel-Haenszel test which measures binary outcomes but accounts for differences between sites.
Primary Outcomes: No statistically significant difference for mortality at 24 hours (12.7% vs 17.0% p=0.12) or 30 days (22.4% vs 26.1% p=0.26). Patients were analyzed in an intention to treat analysis.
Secondary Outcomes: More patients achieved homeostasis and fewer died from exsanguination in the 1:1:1 group. This effect seemed to occur within the first 6 hours, when most patients were expected to die from hemorrhagic causes. No differences in adverse events were detected.
a) Internal Validity: While the authors appropriately conclude no difference in their primary outcomes, they still exalt the benefits of 1:1:1 by claiming the reduction in hemorrhagic death and anatomic homeostasis is important. While that may be true, if those patients all die from head injuries rather than liver lacerations, we have not truly done them much good. That said, though they did not demonstrate a 10% absolute reduction in mortality, they did show a 4% difference. That reduction could still be considered clinically important, if not statistically significant (though potentially attributable to chance due to lack of power).
Further, the study confounds two variables by changing the way in which products were delivered between the two groups. In the 1:1:1 group, platelets were given up front, all at once. In the 1:1:2 group, platelets were not given until the second box of blood at which time the ratios were allowed to work toward goal. This introduces serious confounding: is it the ratio that matters more or is it that giving platelets early and aggressively is more likely to achieve homeostasis, which is certainly physiologically plausible? The trial design raises some concerns about bias. However, the physiologic plausibility for 1:1:1’s superiority is bolstered by the fact that most of the “catching up” which occurred after the intervention window was directed by visco-elastic testing.
Finally, The 1:1:1 group in actuality was given products closer to a 2:1:2 ratio, while the 1:1:2 group only received products in a 2:1:4 ratio.
External Validity: Multiple prior studies purporting to show a benefit for 1:1:1 have been so confounded by survival bias as to make them uninterpretable. This is one of the few to show an improvement. Further, other studies have shown higher complications rates with 1:1:1 ratios, which were not demonstrated here, though this trial was dramatically underpowered to detect such differences. Also, in an evolving era of visco-elastography guided resuscitation, it is unclear to me what role empiric ratios will play in the future.
Based on current data and in the absence viscoelastic directed resuscitation, 1:1:1 should be the empiric ratio of choice for massive transfusion, with platelets administered first. But be mindful that patients often succumb to non-hemorrhagic deaths even if they survive their first hours in hospital.
PROPPR #FOAMed Elsewhere on the Web
EMCrit Podcast 144 – The PROPPR trial with John Holcomb
St. Emlyn's JC: Getting the Balance Right: The PROPPR Trial
R.E.B.E.L EM: The PROPPR Randomized Clinical Trial
EM Nerd: The Adventure of the Blanched Soldier
SGEM: One Platelet, One Plasma and One RBC–PROPPR Trial
CORE EM: PROPPR – Transfusion Ratios in Trauma