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Military protocol may benefit civilians in need of massive blood transfusion
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Damage control resuscitation, an emergency procedure used in the military to try to save the lives of injured personnel with massive blood loss, may be a viable option in civilian hospitals, according to results of a randomized phase 3 trial.
“Bleeding to death is the leading, potentially preventable, cause of death in military and civilian trauma patients,” John B. Holcomb, MD, director of the division of acute care surgery at The University of Texas Health Medical School, said in a press release. “If I needed a massive blood transfusion, I would want damage control resuscitation.”
John B. Holcomb
Damage control resuscitation calls for the administration of equal parts plasma, platelets and red blood cells (1:1:1), whereas the normal ratio calls for twice as many blood cells as plasma and platelets for patients who have massive blood loss (1:1:2).
Observational studies have shown that the earlier transfusion with the higher ratio improved outcomes, but no large multicenter trials have been conducted.
In the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial, Holcomb and colleagues assessed the efficacy and safety of the 1:1:1 strategy compared with the 1:1:2 strategy for patients with trauma predicted to require a massive transfusion.
Mortality at 24 hours and 30 days served as the primary outcome measures. Secondary outcomes included time to hemostasis, blood product volumes transfused, complications, incidence of surgery and functional status.
The investigators identified 680 patients who sustained severe injuries between August 2012 and December 2013. All patients arrived at one of 12 participating trauma centers in the United States and Canada directly from the scene of their injuries, and they all were predicted to require a massive blood transfusion.
All patients received local standard-of-care interventions; 338 patients received blood product ratios of 1:1:1, and 342 received blood product ratios of 1:1:2.
In the 1:1:1 arm, each container prepared by the institution’s blood bank that was administered to the patient with 10 minutes of their arrival at the facility included 6 units of plasma, one dose of platelets (a pool of an average of 6 U) and 6 units of red blood cells.
Those were administered simultaneously if possible; if not, platelets were administered first, followed by alternating red blood cells and plasma.
In the 1:1:2 cohort, there were two subgroups. In one subgroup, patients received 3 units of plasma, zero doses of platelets and 6 units of red blood cells, alternating 2 units of red blood cells with every 1 unit of plasma. In the other subgroup, patients received 3 units of plasma, one dose of platelets (a pool of 6 U on average) and 6 units of red blood cells, which were transfused with the platelets first followed by alternating 2 units of red blood cells with 1 unit of plasma.
Researchers reported no significant differences in mortality between the two arms at 24 hours, with a rate of 12.7% in the 1:1:1 arm and 17% in the 1:1:2 arm (difference, –4.2%; 95% CI, –9.6 to 1.1). Similarly, there was no significant difference in 30-day mortality, with a rate of 22.4% in the 1:1:1 arm and 26.1% in the 1:1:2 arm (difference, –3.7%; 95% CI, –10.2 to 2.7).
The primary cause of death in the first 24 hours was exsanguination. Researchers reported a lower rate of death due to exsanguination in the 1:1:1 group than the 1:1:2 group (9.2% vs. 14.6%; difference, –5.4%; 95% CI, –10.4 to –0.5).
The median time to death by exsanguination was 106 minutes (range, 54-198 minutes) in the 1:1:1 arm and 94 minutes (range, 43-194 minutes) in the 1:1:2 arm.
A greater percentage of patients administered the 1:1:1 transfusion protocol achieved anatomic hemostasis (86.1% vs. 78.1%; P = .006).
Although patients in the 1:1:1 group received more plasma and platelets and similar amounts of red blood cells during the first 24 hours than patients in the 1:1:2 group, researchers observed no differences in 23 prespecified complications, such as organ failure, sepsis, venous thromboembolism and acute respiratory distress syndrome.
“This study represents a translation of practice from what has been learned during wartime into civilian practice after scientific evaluation,” David Hoyt, MD, executive director of the American College of Surgeons, said in a press release. “The lessons learned have definitely changed practice and saved lives. Perhaps, as has been said before, this is the only good thing to come out of war.” – by Anthony SanFilippo
Disclosure: The researchers report grant funding from TEM International and CSL Behring, as well as advisory roles with Decisio Health.
Perspective
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Jed B. Gorlin, MD, MBA
As transfusion service medical director at a level one trauma hospital that has more than 100 massive transfusion events annually, I looked forward with great anticipation to the release of the conclusions of this large and logistically complex trial.Briefly, almost 700 severely injured, massively bleeding patients were randomly assigned to receive coolers of blood providing either an equal or a 2:1 ratio of red cells to plasma and the equivalent of a pool of 6 whole blood platelets (or, in the vast majority of cases, one apheresis unit) for every 6 units of plasma. During the intervention period, the ratio was intended to be driven by how the products were provided and not laboratory value directed, although clinicians were neither blinded to the ratio nor the patients lab values as pragmatic exigencies would require.
Researchers observed no significant differences in mortality at 24 hours or 30 days, nor in any of 24 pre-specified variables. The authors observe that, although statistical significance was not achieved between the two groups, the better-than-expected outcome for the 1:2 group limited the power to detect differences. If the groups were much larger, perhaps the apparent trend visible in the survival curves might have achieved significance. For example, the authors focus on the observation that statistically significantly more patients (50 vs. 31) died early — typically in the first couple of hours — of hemorrhage in the group that got less plasma. Conversely, a few more died of pulmonary complications in the higher plasma group.
Curiously, what the patients actually received as opposed to what they were intended to receive is not expanded upon by the study authors. The median number of plasma units transfused was 7 units (1:1) vs. 5 units (1:2), but the median number of platelets transfused differed twofold! The median number of platelets was 12 units in the 1:1 group vs 6 units in the 1:2 group, even though the ratio of platelets was intended to be identical for the two groups.
Hence, given more early exsanguination in the 1:2 group — which got 40% more plasma but 100% more platelets — I might be inclined to wonder if the more aggressive platelet therapy, as opposed to higher ratio of plasma, might be worth exploring as a contributor to restoring hemostasis earlier.
In short, although one might reasonably conclude that this study supports a 1:1 ratio, the truly dispassionate observer might want additional data before abandoning alternative approaches that achieve rapid dispensing of coolers in a timely fashion.
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