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Dynamic Impact of Transfusion Ratios on Outcomes in Severely Injured Patients: Targeted Machine Learning Analysis of the PROPPR Randomized Clinical Trial
Nguyen M, Pirracchio R, Kornblith LZ, Callcut R, Fox EE, Wade CE, Schreiber M, Holcomb JB, Coyle J, Cohen M, et al
J Trauma Acute Care Surg. 2020
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Abstract
BACKGROUND Massive transfusion protocols to treat post-injury hemorrhage are based on pre-defined blood product transfusion ratios followed by goal-directed transfusion based on patient's clinical evolution. However, it remains unclear how these transfusion ratios impact patient outcomes over time from injury. METHODS The Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) is a phase 3, randomized controlled trial, across 12 level-I trauma centers in North America. From 2012 to 2013, 680 severely injured patients required massive transfusion. We used semi-parametric machine learning techniques and causal inference methods to augment the intent-to-treat analysis of PROPPR, estimating the dynamic relationship between transfusion ratios and outcomes: mortality and hemostasis at different time-points during the first 24 hours after admission. RESULTS In the intention-to-treat analysis, the 1:1:1 group tended to have decreased mortality, but with no statistical significance. For patients in whom hemostasis took longer than 2 hours, the 1:1:1 ratio was associated with a higher probability of hemostasis, statistically significant from the 4 hour on. In the per-protocol, actual-transfusion-ratios-received analysis, during four successive time intervals, no significant association was found between the actual ratios and mortality. When comparing patient groups who received both high plasma:PRBC and high platelet:PRBC ratios to the group of low ratios in both, the relative risk of achieving hemostasis was 2.49 (95% CI = 1.19-5.22) during the 3 hour after admission, suggesting a significant beneficial impact of higher transfusion ratios of plasma and platelets on hemostasis. CONCLUSIONS Our results suggest that the impact of transfusion ratios on hemostasis is dynamic. Overall, the transfusion ratios had no significant impact on mortality over time. However, receiving higher ratios of platelets and plasma relative to red blood cells hastens hemostasis in subjects who have yet to achieve hemostasis within 3 hours after hospital admission. LEVEL OF EVIDENCE Prognostic, level III.
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A comparison of resuscitation intensity (RI) and critical administration threshold (CAT) in predicting early mortality among bleeding patients: a multicenter validation in 680 major transfusion patients
Meyer DE, Cotton BA, Fox EE, Stein D, Holcomb JB, Cohen M, Inaba K, Rahbar E
The Journal of Trauma and Acute Care Surgery. 2018;85((4):):691-696
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Abstract
BACKGROUND To address deficiencies associated with the classic definition of massive transfusion, Critical Administration Threshold and Resuscitation Intensity were developed to better quantify the overall severity of illness and predict the need for transfusions and early mortality. We sought to evaluate these as more appropriate replacements for MT in defining mortality risk in patients undergoing major transfusions. METHODS Patients predicted to receive MT at 12 Level-1 trauma centers were randomized in the PROPPR trial. MT: ≥10U RBC in 24 hours; CAT+: ≥3U RBC in the first hour; and RI: total products in the first 30 minutes (1U RBC, 1U plasma, 1000mL crystalloid, 500mL colloid each valued at 1U). RI was evaluated as a continuous variable and dichotomized as RI4+, where RI≥4 U. Each metric was evaluated for its ability to predict mortality at 3, 6, and 24 hours, and at 30 days. RESULTS Of the 680 patients, 301 patients met MT definition, 521 were CAT+, and 445 were RI4+. Of those that died, 23% never reached MT threshold, but all were captured by CAT+ and RI4+. The 3-hr (9 vs. 9%), 6-hr (14 vs. 14%), 24-hr (17 vs. 18%), and 30-day mortality rates (28 vs. 29%) were similar between CAT+ and RI4+ patients. When RI was evaluated as a continuous variable, each unit increase was associated with a 20% increase in hemorrhage-related mortality (OR 1.20, 95% CI [1.15-1.29], p<0.05).CONCLUSIONBoth RI and CAT are valid surrogates for early mortality in patients undergoing major transfusion, capturing patients omitted by the MT definition. CAT+ showed the best sensitivity; RI4+ demonstrated better specificity and good PPV and NPV. While CAT+ may be suited for patients receiving a RBC-dominant resuscitation, RI4+ is more comprehensive. RI can also be used as a continuous variable to provide quantitative as well qualitative risk of death.LEVEL OF EVIDENCELevel III, Prognostic.