EBQ:PROPPR Trial

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Complete Journal Club Article
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 and Mortality in Patients With Severe Trauma". JAMA. 2015. 313(5):471-482.
PubMed Full text

Clinical Question

  • Compare 1:1:1 vs 1:1:2 in safety and efficacy in trauma rescus

Conclusion

  • No significant differences in mortality at 24 hours or at 30 days between two groups
  • More patients in the 1:1:1 group achieved hemostasis and fewer experienced death due to exsanguination by 24 hours (86% vs 78%; p=0.006)
  • Exsanguination in first 24 hours decreased in the 1:1:1 group (9.2% vs 14.6%; p=0.03)
  • No other safety differences were identified between the two groups

Major Points

  • This was a negative trial - the 1:1:1 was as safe as 1:1:2
  • They did not meet the 10% mortality advantage which the study was powered to but found 4.2% improvement in the 1:1:1 group at 24hr and 3.7% at 30d

Study Design

  • Randomized clinical trial
  • Blood product protocol
    • 1:1:1 = 6 plt, (1 RBC, 1 FFP) x 6, 6 plt...
    • 1:1:2 = (2 RBC, 1 FFP) x 3, 6 plt, (2 RBC, 1 FFP) x 3, 6 plt...

Population

  • 680 patients from of 12 participating level I trauma centers in North America

Patient Demographics

No differences were detected between treatment groups in baseline characteristics

Characteristics 1:1:1 1:1:2
Age 34.5 (25-51) 34 (24-50)
Male 263 (77.8%) 283 (82.7%)
Race - White 210 (62.1%) 224 (65.5%)
Race - Black 94 (27.8%) 93 (27.2%)
Race - Other 35 (10.4%) 25 (7.3%)

Inclusion Criteria

  • Highest trauma level activation
  • ≥15 yo or weight ≥50 kg if age unknown
  • Received directly from the injury scene
  • Transfusion initiated with at least 1 U of blood component within the first hour of arrival
  • Predicted to receive a massive transfusion

Exclusion Criteria

  • Received a lifesaving intervention from OSH
  • Terminal injuries and expected to die within 1 hour of admission (eg, lethal traumatic brain injury)
  • Directly admitted from a correctional facility
  • Required a thoracotomy prior to randomization
  • <15 yo or <50 kg if age unknown
  • Pregnant
  • Burns >20% total BSA
  • Suspected inhalation injury
  • >5 mins of CPR
  • DNR
  • Enrolled in a concurrent, ongoing, interventional, randomized clinical trial
  • >3 U of pRBC given before randomization

Interventions

  • Two cohorts received blood product ratios of 1:1:1 (n=338) vs 1:1:2 (n=342) during active resuscitation

Outcomes

Primary Outcome

  • Absolute percentage group differences for 24-hour and 30-day mortality
Time Period 1:1:1
n=338
1:1:2
n=342
Difference Adjusted RR p value
24h mortality 43 (12.7%) 58 (17.0%) −4.2 (−9.6-1.1) 0.75 (0.52-1.08) 0.12
30d mortality 75 (22.4%) 89 (26.1%) −3.7 (−10.2-2.7) 0.86 (0.65-1.12) 0.26

Secondary Outcomes

  1. Time to hemostasis
    • 1:1:1 - 291 (86.1%)
    • 1:1:2 - 267 (78.1%)
    • p=0.006
  2. Exsanguination within first 24h
    • 1:1:1 - 9.2%
    • 1:1:2 - 14.6%
    • p=0.03
  3. Exsanguination within 30d
    • 1:1:1 - 10.7%
    • 1:1:2 - 14.7%
    • p value no reported
  4. Number and type of blood products used from randomization until hemostasis was achieved
    • 1:1:1 - 25.5 units (pRBC 9u, FFP 7u, Plt 12u)
    • 1:1:2 - 19 units (pRBC 9u, FFP 5u, Plt 6u)
    • p=0.001 for units of platelets
  5. Number and type of blood products used after hemostasis was achieved up to 24 hours postadmission
    • 1:1:1 group received fewer blood products during the postintervention period than the 1:1:2 group (median of 1 U vs 2 U, respectively)
  6. Analysis of 23 complications
    • Differences were not detected in any of the 23 complications at 30 days
  7. Incidence of major surgical procedures
    • 1:1:1 - 290 (85.8%)
    • 1:1:2 - 284 (83.0%)
  8. Functional status at hospital discharge or 30 days (median , whichever occurred first
    • 1:1:1 - 4 (3-6)
    • 1:1:2 - 4.5 (3.5-7.0)
    • p=0.11
  9. Hospital-free days, ventilator-free days, and ICU-free days
1:1:1 1:1:2 p value
Hospital-free days 1 (0-17) 0 (0-16) 0.83
Ventilator-free days 8 (0-16) 7 (0-14) 0.14
ICU-free days 5 (0-11) 4 (0-10) 0.10

Criticisms & Further Discussion

  • This was ultimately an unblinded and was a negative primary outcome due to the powering to detect only an absolute difference of 10% in mortality. To reach statistical significance for a small effect, 2968 patients would have been required to detect the observed difference of 4.2% (24 hour mortality) with 90% power. Regardless this is the best evidence to date the 1:1:1 ratio is a safe and effective treatment. [1]
  • The 1:1:1 group received platelets first (six units) followed by alternating RBCs and plasma. However, the 1:1:2 group received two unis RBCs first followed by 1 unt of plasma. Patients were not given until the patient received 9 units of other blood products. This makes interpretation of the results unclear since the platelets not the ratio may have been responsible for the early hemostasis achieved.
  • Study design was randomized, multi-centre, and pragmatic, with minimal loss to 30 day followup, and allocation concealed during trial duration.
  • Transfusion complications may be more likely related to the increased use of platelets in the treatment arm.
  • This trial did not truly compare 1:1:1 vs 1:1:2 resuscitative strategies. Rather Holcomb et al examined a protocol intending to give 1:1:1 vs 1:1:2. In reality, neither group truly reached their proportional expectations. The 1:1:1 group in actuality was given products closer to a 2:1:2 ratio, while the 1:1:2 group only received products in a 2:1:4 ratio. [2]
  • Lab guided strategies in smaller sample sizes have not demonstrated 1:1:1 to be superior[3]

External Links

Funding

  • US National Heart, Lung, and Blood Institute grant U01HL077863
  • Department of Defense
  • The Defence Research and Development Canada in partnership with the Canadian Institutes of Health Research-Institute of Circulatory and Respiratory Health (grant CRR-120612)

References

  1. Radecki R. The Fixed-Ratio Massive Transfusion Answer. http://www.emlitofnote.com/2015/02/the-fixed-ratio-massive-transfusion.html
  2. EM Nerd. The Adventure of the Blanched Soldier. http://emnerd.com/adventure-blanched-soldier/
  3. Bartolomeu et al. “Effect of a Fixed-Ratio (1:1:1) Transfusion Protocol Versus Laboratory-Results–guided Transfusion in Patients with Severe Trauma: a Randomized Feasibility Trial.” CMAJ : Canadian Medical Association Journal 185.12 (2013): E583–E589. PMC. Web. 6 Feb. 2015.