The PROPPR Randomized Clinical Trial

In the United States, trauma is the leading cause of death among patients between the ages of 1 and 44 years of age and the third leading cause of death overall. Approximately 20 to 40% of trauma deaths occur after hospital admission and are a result of massive hemorrhage.  There have been no large, multi-center, randomized clinical trials with survival as a primary end point that support optimal trauma resuscitation practices with approved blood products and therefore there are many conflicting recommendations. The Prosective Observational Multicenter Major Trauma Transfusion (PROMMT) Trial demonstrated that many clinicians were transfusing patients with blood products in a ratio of 1:1:1 or 1:1:2 and that early transfusion of plasma was associated with improved 6-hour survival after admission.

The Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial was designed to address the effectiveness and safety of 1:1:1 transfusion ratio vs 1:1:2 in patients with trauma who were predicted to receive a massive transfusion.

What is Damage Control Resuscitation (DCR)? [1]

Damage Control Resuscitation (DCR) is the concept of rapid hemorrhage control through:

1. Permissive Hypotension
2. Hemostatic Resuscitation (Massive Transfusion Protocol)
3. Hemorrhage Control (Damage Control Surgery)

Early administration of blood products in a balanced ratio (1:1:1 for units of plasma to platelets to red blood cells helps treat intravascular volume deficits, acute coagulopathy of trauma, preserve oxygen-carrying capacity, and prevention of dilutional coagulopathy.

What is the definition of a massive transfusion? [2]

Historically, massive transfusion is defined as the replacement of > 10 Units of PRBCs within 24 hours or arbitrarily defined as:

1. The replacement of a patient’s total blood volume in less than 24 hours
2. The acute administration of more than half the patient’s estimated blood volume over 3 hours

What is the Basic Breakdown of The PROPPR Randomized Clinical Trial? JAMA Feb 2015

What they Did:

• Determine the effectiveness and safety of transfusing patients with severe trauma and major bleeding using plasma, platelets, and red blood cells in a 1:1:1 ratio vs 1:1:2 ratio
• Phase 3, multisite, randomized clinical trial of 680 severely injured patients
• 12, level 1 trauma centers in North America

Primary Outcome:

• 24-hour and 30-day all-cause mortality

Secondary Outcomes:

• Time to hemostasis
• Blood product volumes transfused
• Complications
• Incidence of surgical procedures
• Functional status

Results:

• No statistically significant difference in mortality at 24 hours or at 30 days
• Exsanguination in first 24 hours (secondary outcome) significantly decreased in the 1:1:1 group vs 1:1:2 group (9.2% vs 14.6%; p = 0.03)
• More patients achieved hemostasis in the 1:1:1 group vs 1:1:2 group (86% vs 78%; p = 0.006)
• More plasma (Median 7 Units vs 5 Units) and platelets (Median 12 Units vs 6 Units) were used in the 1:1:1 ratio vs 1:1:2 ratio
• No difference in complications between the two strategies

Limitations:

• This study was appropriately powered to detect a 10% difference in mortality between the 1:1:1 and 1:1:2 groups, however the study could not definitively establish a benefit < 10%
• Physicians not blinded once transfusion protocol begun
• Unable to completely exclude patients with an unsurvivable brain injury (23% of deaths at 24 hrs and 38% of deaths at 30 days)

Study Conclusion: Among patients with severe trauma and major bleeding, early administration of plasma, platelets, and red blood cells in a 1:1:1 ratio vs 1:1:2 ratio did not result in significant differences in mortality at 24 hours or 30 days. However, more patients in the 1:1:1 group achieved hemostasis and fewer experienced death due to exsanguination at 24 hours.

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Take Home Message

Ultimately, this was an underpowered study to determine < 10% mortality benefit at 24 hours and 30 days, however the 1:1:1 transfusion strategy decreases death from exsanguination at 24 hours, achieves more rapid hemostasis, and has no additional complications associated with it.

References:

1. Pohlman TH et al. Damage Control Resuscitation. Blood Rev 2015. PMID: 25631636
2. Hardy JF et al. Massive Transfusion and Coagulopathy: Pathophysiology and Implications for clinical Management. Can J Anaesth 2014. PMID: 15064258
3. Holcomb JB et al. 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: The PROPPR Randomized Clinical Trial. JAMA 2015. PMID: 25647203

For More Thoughts Check Out:

• Rory Spiegel at EM Nerd: The Adventure of the Blanched Soldier
• Ryan Radecki at EM Literature of Note: The Fixed-Ratio Massive Transfusion Answer
• Richard Carden at St. Emlyn’s: JC: Getting the Balance Right: The PROPPR Trial 
• The Bottom Line: PROPPR: 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. The PROPPR Randomized Clinical Trial
• Scott Weingart at EMCrit: Podcast 144 – The PROPPR Trial with John Holcomb
• Ken Milne at The SGEM: SGEM#109 – One Platelet, One Plasma and One RBC – PROPPR Trial