PROPPR

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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. 313(5):471-482.
PubMedFull text

Clinical Question

In severely injury trauma patients with major bleeding receiving massive transfusion, is a 1:1:1 ratio of plasma:platelets:red blood cells non-inferior to a 1:1:2 ratio?

Bottom Line

Among patients with trauma suffering hemorrhagic shock, there was no difference in mortality at 24 hours or 30 days between a 1:1:1 and 1:1:2 administration of plasma, platelets, and red blood cells

Major Points

Optimal blood product transfusion ratios in bleeding major trauma patients are not known. 1:3 ratios of plasma to RBCs have historically been used, but more recent data from military studies supports a ratio more similar to whole blood (i.e. 1:1:1). Published in 2015, the PROPPR study randomized 680 severely injured patients to receive plasma:platelets:RBC in a 1:1:1 or 1:1:2 fashion. There was no significant difference was found in mortality or adverse events between groups. However, the 1:1:1 group had greater proportion of hemostasis and lower mortality due to exsanguination at 24 hours.

Guidelines

At the time of writing a review of available guidelines from the Eastern Association for the Surgery of Trauma (EAST) and the National Guidelines Clearinghouse did not reveal specific recommendations for massive transfusion product ratios. It should be noted that most institutions have massive transfusion protocols which will stipulate the recommended ratio.

Design

  • Pragmatic, phase 3, multisite, randomized clinical trial
  • 680 patients (11,185 screened)
    • 1:1:1 arm (n=338)
    • 1:1:2 arm (n=342)
  • 12 level I trauma centers in North America
  • Enrollment: 2012-2013
  • Follow up done at 24 hours and 30 days
  • Follow up rate: 100% at 24 hours, 99.4% at 30 days
  • Primary outcome: 24 hour and 30 day mortality

Population

Inclusion Criteria

  • Highest level trauma activation available at the facility
  • Estimated age 15 or older or weight 50 kg or greater if age unknown
  • Received at Trauma Center directly from scene of injury
  • At least 1 unit of any blood component transfused prior to hospital arrival or within 1 hour of admission
  • Assessment of Blood Consumption score of 20 or greater or clinician judgment that there is a need for massive transfusion (greater than or equal to 10 units of RBCs within 24 hours)

Exclusion Criteria

  • Received a lifesaving intervention from an outside hospital or health care facility
  • Had devastating injuries and expected to die within 1 hour of admission (e.g. lethal traumatic brain injury)
  • Directly admitted from a correctional facility
  • Required a thoracotomy prior to receiving randomized blood products in the emergency department
  • Younger than 15 years or weight less than 50 kg if age unknown
  • Known pregnancy in the emergency department
  • Had burns covering greater than 20% total body surface area
  • Suspected inhalation injury
  • Received greater than 5 consecutive minutes of cardiopulmonary resuscitation (with chest compressions) prior to arriving at the hospital or within the emergency department
  • Known do-not-resuscitate order prior to randomization
  • Enrolled in a concurrent, ongoing, interventional, randomized clinical trial
  • Activated the opt-out process for the PROPPR trial (usually by wearing a bracelet given out at a community consent presentation)
  • More than 3 units of red blood cells given before randomization

Baseline Characteristics

There were no significant differences between the groups at baseline. Below numbers denote 1:1:1 group and 1:1:2 group respectively

  • Both groups were predominantly male (77.8% and 82.7% respectively) and young (median age 34.5 and 34 respectively)
  • Median HR 115 and 113 respectively, median SBP 102 and 102 respectively, median DBP 70 and 68 respectively
  • Similar division of blunt (54.7% vs. 50.6%) vs. penetrating (46.4% vs. 50.6%) injury
  • Initial hemoglobins were similar (median 11.7 g/dL vs. 11.9 g/dL)
  • Injury Severity Scores were similar (median 26.5 vs. 26)

Interventions

  • Randomized patients to transfusion of blood products using 1:1:1 (plasma, platelets, red blood cells) vs. 1:1:2 ratio
  • Patients in the 1:1:1 group were dispatched containers of 6 units of plasma, 1 dose of platelets (a pool of 6 units on average) and 6 units of RBCs: which were transfused as platelets first, then alternating RBC and plasma units.
  • Patients in the 1:1:2 group were dispatched odd numbered containers (including the initial container) with 3 units of plasma, no platelets, and 6 units of RBCs, transfused as alternating 2 units of RBCs and 1 unit of plasma. Even numbered containers for 1:1:2 patients contained 3 units of plasma, 1 dose of platelets (a pool of 6 units on average) and 6 units of RBCs, transfused as platelets followed by alternating 2 units RBCs and 1 unit plasma.
  • For both groups transfusion was terminated at the discretion of the treating clinician when clinically indicated irrespective of ratio or partial blood container use.

Outcomes

Primary Outcome

Absolute percentage group differences for 24 hour and 30 day mortality based on 2-sided Mantel-Haenszel test adjusting for site

  • 24 hours: 12.7% in 1:1:1 group vs. 17.0% in 1:1:2 group (-4.2% absolute difference, 95 percent confidence interval: 9.6% to 1.1%)
  • 30 days: 22.4% in 1:1:1 group vs. 26.1% in 1:1:2 group (-3.7% absolute difference, 95 percent confidence interval: -10.2% to 2.7%)
  • P-values ranged from 0.21 to 0.36

Secondary Outcomes

*All comparisons are made 1:1:1 group vs. 1:1:2 group respectively

  • Achievement of hemostasis at 24 hours: 86.1% vs 78.1% (p=0.06)
  • Median time to hemostasis: 105 minutes in 1:1:1 group vs. 100 minutes in 1:1:2 group (p=0.44)
  • Median ventilator free days: 8 vs. 7 (p=0.14)
  • Median ICU-free days: 5 vs. 4 (p=0.10)
  • Disposition at 30 days: No significant differences
  • Median Glasgow Outcome Scale-Extended Score: 4 vs. 4.5 (p=0.11)
  • 23 pre-specified complications
  • Incidence of major surgical procedures: 290 vs. 284 (95% confidence interval -2.8 to 8.3)
  • Protocol non-compliance was significantly lower in the 1:1:1 group than the 1:1:2 group (4% vs. 7%, p=0.01)
  • Rate of death due to exsanguination at 24 hours was significantly lower in the 1:1:1 group (9.2%) vs the 1:1:2 group (14.6%) (p=0.03). No other causes of death were significantly different at 24 hours, and no causes of death were significantly different at 30 days, including exsanguination.

Subgroup Analysis

No subgroup analyses were reported

Adverse Events

The 95% confidence intervals for difference in rate of all prespecified complications between treatment groups crossed 0 (i.e. there were no significant differences in rates of any of the measured complications). 23 discrete complications were measured, a few notable results include:

All comparisons are 1:1:1 group vs. 1:1:2 group respectively with 95% confidence intervals for differences in complication rate

  • Transfusion-related metabolic complication (hypocalcemia or hyperkalemia): 15.7% vs. 17.3% (-7.2 to 4.1)
  • Acute Lung Injury: 13.9% vs. 16.7% (-8.3 to 2.7)
  • Acute Respiratory Distress Syndrome: 13.6% vs. 14.0% (-5.7 to 4.9)
  • Transfusion-Associated Circulatory Overload: 0.3% vs. 0% (-0.8 to 1.7)
  • Any complication: 87.9% vs. 90.6% (-7.6 to 1.9)

Criticisms

Rebel EM WessexICS

  • Powered to detect a 10% difference, but could not detect smaller benefits.
  • Not powered to be a safety study (i.e. differences in rare complications would likely be undetected)
  • Clinicians were unblinded after randomization by delivery of blood products from blood bank.
  • The timing of blood product administration was affected by the study protocol, with the 1:1:1 group likely receiving platelets earlier and the 1:1:2 group receiving plasma earlier

Funding

"PROPPR is a Resuscitation Outcomes Consortium (ROC) Protocol. ROC is funded by the National Heart, Lung, and Blood Institute (NHLBI), the United States' Department of Defense (DoD) and the Defence Research and Development Canada" per ClinicalTrials.gov

Further Reading