PROPPR: Transfusion Ratios in Severe Trauma (2015)

“In patients with severe trauma and major bleeding, we found no significant differences in 24-hour or 30-day mortality between patients receiving blood products in a 1:1:1 ratio and those receiving them in a 1:1:2 ratio. However, more patients in the 1:1:1 group achieved hemostasis and fewer experienced death due to exsanguination by 24 hours.”

  • The PROPPR Study Group

1. Publication Details

  • Trial Title: Transfusion of Plasma, Platelets, and Red Blood Cells in a 1:1:1 vs a 1:1:2 Ratio in Patients with Severe Trauma: The PROPPR Randomized Clinical Trial
  • Citation: Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015;313(5):471-482. DOI: 10.1001/jama.2015.12
  • Published: February 3, 2015, in The Journal of the American Medical Association (JAMA)
  • Author: John B. Holcomb, M.D., on behalf of the PROPPR Study Group
  • Funding: United States National Heart, Lung, and Blood Institute (NHLBI); US Department of Defense; and others.

2. Keywords

  • Trauma, Hemorrhage, Massive Transfusion, Damage Control Resuscitation, Plasma, Platelets, Red Blood Cells, Randomized Controlled Trial

3. The Clinical Question

  • In adult trauma patients with major bleeding who are predicted to require a massive transfusion (Population), does a resuscitation strategy using a 1:1:1 ratio of plasma, platelets, and red blood cells (Intervention) compared to a strategy using a 1:1:2 ratio (Comparison) reduce 24-hour and 30-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Uncontrolled hemorrhage is a leading cause of preventable death in trauma. The concept of “damage control resuscitation,” which emphasizes early and aggressive correction of coagulopathy, had gained traction, largely based on military experience. This led to the practice of transfusing plasma and platelets in addition to red blood cells in a balanced ratio to mimic whole blood.
  • Knowledge Gap: The optimal ratio of blood products was a major clinical controversy. While a 1:1:1 ratio was physiologically appealing, it was more resource-intensive than a more red-cell-heavy ratio. There was no high-quality evidence from a large, multicenter randomized trial to guide this critical aspect of massive transfusion protocols.
  • Proposed Hypothesis: The authors hypothesized that a transfusion strategy using a 1:1:1 ratio would be superior to a 1:1:2 ratio in reducing mortality.

5. Study Design and Methods

  • Design: A multicenter, pragmatic, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 12 level 1 trauma centers in North America.
  • Trial Period: Enrollment ran from August 2012 to December 2013.
  • Population:
    • Inclusion Criteria: Adult trauma patients who arrived directly from the scene and were predicted to require a massive transfusion (defined as receiving ≥3 units of blood products within the first hour).
    • Exclusion Criteria: Included patients with non-survivable injuries or those who had received a massive transfusion before arrival.
  • Intervention: Patients were randomized to receive blood product coolers containing plasma, platelets, and red blood cells in a 1:1:1 ratio.
  • Control: Patients were randomized to receive blood product coolers containing the same components in a 1:1:2 ratio.
  • Management Common to Both Groups: All other aspects of trauma care, including damage control surgery and the use of tranexamic acid, were at the discretion of the treating clinicians.
  • Power and Sample Size: The authors calculated that a sample size of 680 patients would provide 90% power to detect a 10% absolute risk reduction in 24-hour mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: 24-hour all-cause mortality.
    • Secondary Outcomes: Included 30-day mortality and the time to hemostasis.

6. Key Results

  • Enrollment and Baseline: 680 patients were randomized (338 to the 1:1:1 group and 342 to the 1:1:2 group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 24-hour mortality. 48 of 338 patients (14.2%) in the 1:1:1 group died, compared with 58 of 342 patients (17.0%) in the 1:1:2 group (p=0.30). There was also no significant difference in 30-day mortality.
  • Secondary Outcomes: A key secondary finding was that a significantly higher proportion of patients in the 1:1:1 group achieved hemostasis (86% vs. 78%; p=0.006), and death due to exsanguination within the first 24 hours was significantly lower (9.2% vs. 14.6%; p=0.03).
  • Adverse Events: There were no significant differences in the rates of complications, including ARDS or venous thromboembolism, between the two groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute mortality rates and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.30 for the primary outcome is much higher than the 0.05 threshold, indicating that the result was not statistically significant and likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures (for the secondary outcome of death from exsanguination):
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 14.6% – 9.2% = 5.4%.
      • Clinical Meaning: For every 100 patients treated with a 1:1:1 ratio, about 5 additional deaths from bleeding were prevented.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.054 = 18.5, which is rounded down to 18.
      • Clinical Meaning: You would need to treat 18 patients with a 1:1:1 ratio to prevent one additional death from exsanguination.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized controlled design provided high-quality evidence on a critical clinical question.
  • Generalizability: The pragmatic design and inclusion of 12 major North American trauma centers make the findings highly generalizable to similar high-resource settings.
  • Statistical Power: The study was large and adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The study focused on the crucial outcome of mortality.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which introduces a risk of performance bias.
  • External Validity (Generalizability): The findings are specific to trauma resuscitation and do not apply to other causes of major hemorrhage.
  • Other: The trial was technically “negative” for its primary outcome. The actual ratio of products delivered to the two groups was closer than the intended 1:1:1 vs. 1:1:2, which may have biased the result towards the null.

10. Conclusion of the Authors

  • The authors concluded that among patients with severe trauma and major bleeding, there was no significant difference in 24-hour or 30-day mortality between a transfusion strategy of a 1:1:1 ratio versus a 1:1:2 ratio of plasma, platelets, and red blood cells.

11. To Summarize

  • Impact on Current Practice: This was a landmark trial that, despite its neutral primary outcome, was profoundly influential. The strong positive signal for the secondary outcome of reduced death from bleeding provided the first high-quality evidence to support the widespread adoption of a balanced, 1:1:1-style massive transfusion protocol.
  • Specific Recommendations:
    • Patient Selection: For adult trauma patients with major hemorrhage requiring massive transfusion.
    • Actionable Intervention: A massive transfusion protocol targeting a 1:1:1 ratio of plasma, platelets, and red blood cells is a reasonable and likely beneficial strategy.
  • What This Trial Does NOT Mean: This trial does NOT mean that the exact ratio of blood products does not matter. It only suggests that a 1:1:1 ratio was not statistically superior to a 1:1:2 ratio for all-cause mortality, but it was for bleeding-related death.
  • Implementation Caveats: The key takeaway is the importance of a protocolized, balanced resuscitation strategy that provides early and aggressive replacement of all blood components, not just red blood cells.

12. Context and Related Studies

  • Building on Previous Evidence: The PROPPR trial (2015) was designed to provide high-quality RCT evidence to support the principles of damage control resuscitation that had been developed based on military experience and observational data.
  • Influence on Subsequent Research: The findings of this trial have been a cornerstone of all subsequent international trauma and transfusion guidelines, which now universally recommend a balanced, hemostatic resuscitation strategy with a high ratio of plasma and platelets to red blood cells.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal role of whole blood transfusion as an alternative to component therapy, and the best way to guide resuscitation using viscoelastic assays (e.g., TEG/ROTEM) in conjunction with fixed ratios, remain areas of investigation.
  • Future Directions: Future research is focused on more personalized approaches to trauma resuscitation, including the use of point-of-care coagulation testing and the early administration of other hemostatic agents.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a fundamental and life-saving aspect of modern trauma care.
  • Methods: The large, multicenter, pragmatic RCT design was appropriate and robust. The main methodological weakness is the open-label design. A key point for interpretation is that the actual separation in the ratios of products delivered was less than planned, which may have made it more difficult to find a difference.
  • Results: The study was negative for its primary outcome of all-cause mortality. However, the statistically significant and clinically important benefit for the secondary outcome of death from exsanguination is a powerful and persuasive finding.
  • Conclusions and Applicability: The authors’ conclusion is a fair and accurate reflection of the primary outcome data. However, the clinical community has largely interpreted the totality of the evidence from this trial as being strongly supportive of a 1:1:1 strategy due to the clear benefit in controlling hemorrhage. The findings are broadly applicable to all major trauma centers.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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