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Date: February 28th, 2015

Guest Skeptic: Dr. Salim R. Rezaie. Salim is faculty member at University of Texas Health Science Center at San Antonio, TX. He is currently the creator/founder of REBEL EM blog and REBEL Cast available on iTunes.

Case: 28 year-old male is involved in an altercation and shot multiple times in the chest and presents to the emergency department. His initial vital signs include a BP 72/46, HR 140, RR 30, O2 sat 89% on NRB and a temp of 98.7F. You intubate the patient successfully, begin intravenous fluids, and place bilateral chest tubes with significant blood return from the right chest tube. Due to the patients blood loss you initiate damage control resuscitation including: permissive hypotension, source control of bleeding, and a massive transfusion protocol.

Background: 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 Prospective 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 (plasma, platelets, RBC) and that early transfusion of plasma and platelets was associated with improved 6-hour survival after admission. 

Clinical Question: What is the effectiveness and safety of transfusing adult patients with severe trauma and major bleeding using plasma, platelets, and red blood cells in a 1:1:1 ratio vs. with a 1:1:2 ratio?

Reference: 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 February 2015

  • ExclusionsPopulation: 680 patients age ≥ 15 years of age and/or ≥ 50kg meeting highest level of trauma activation
    • Inclusion: Requiring at least 1 U of any blood component within the first hour of arrival or during pre-hospital transport and/or predicted by the ABC Score≥2 or clinical gestalt to need massive transfusion (≥10 U RBC within 24hrs)
    • Exclusion: See list
  • Intervention: Platelet, plasma and red blood cell transfusion in a 1:1:1 ratio
  • Comparison: Plasma, platelet, and red blood cell transfusion in a 1:1:2 ratio
  • Outcome:
    • Primary Outcome: All cause mortality at 24 hour and 30 day
    • Secondary Outcomes: Ancillary outcomes were time to hemostasis, blood product volumes transfused, and complications.

Authors’ Conclusions: Among patients with severe trauma and major bleeding, early administration of plasma, platelets and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio did not result in significant differences in mortality at 24 hours or at 30 days. However more patients in the 1:1:1 group achieved hemostasis and fewer experienced death due to exsanguination by 24 hours. Even though there was an increased use of plasma and platelets transfused in the 1:1:1 group, no other safety differences were identified between the 2 groups.

Quality Checklist for Randomized Clinical Trials:

  1. checklist-cartoonThe study population included or focused on those in the ED. YES, but specifically 1 of 12 emergency departments that were designated level one trauma centers in North America
  2. The patients were adequately randomized. YES
  3. The randomization process was concealed. Unsure, the initial container of blood products was prepared by the sites blood bank and sealed to blind physicians to treatment assignment, but once transfusion protocol started, physicians were unblinded.
  4. The patients were analyzed in the groups to which they were randomized. YES
  5. The study patients were recruited consecutively (i.e. no selection bias). YES
  6. The patients in both groups were similar with respect to prognostic factors. YES, the majority of patients were male with similar ages in both groups and no differences were detected between treatment groups in baseline characteristics.
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. YES
  8. All groups were treated equally except for the intervention. Unsure, the pragmatic part of the trial left the management after randomization up to the treating clinician
  9. Follow-up was complete (i.e. at least 80% for both groups). YES, Follow up was excellent with 100% 24 hour follow up 99.4% 30 day follow up.
  10. All patient-important outcomes were considered. YES, Mortality at 24 hours and 30 days.
  11. The treatment effect was large enough and precise enough to be clinically significant. NO, although this is the largest randomized clinical trial to date looking at mortality in massive transfusion protocols, the study population was not large enough to detect a difference in mortality of less than 10%.

Key Results: No statistically significant difference in mortality at 24 hours or at 30 days.

  • Primary Outcome Mortality:
    • 24 hours: 12.7% in 1:1:1 group vs. 17.0% in 1:1:2 group (CI -9.6% – 1.1%) [p=0.12]
    • 30 days: 22.4% in 1:1:1 group vs. 26.1% in the 1:1:2 group (CI -10.2% – 2.7%) [p=0.26]
  • Secondary Outcomes:
    • Exsanguination in first 24 hours significantly decreased in the 1:1:1 group (9.2%) vs. the 1:1:2 group (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 U vs. 5 U) and platelets (median 12 U vs. 6 U) were used in the 1:1:1 ratio vs. 1:1:2 ratio respectively
  • Complications:
    • No difference in complications between the two transfusion strategies

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It is great to have a large randomized control trial looking at such an important topic. These studies take a tremendous effort to coordinate and do well. Congratulations to Dr. Holcomb and his team at University of Texas.

This trial was designed to test if a 1:1:1 protocol was superior to a 1:1:2 protocol and safety. They powered the study at about 600 patients to detect a 10% difference. Their primary outcome of all cause mortality at 24hr and 30days was not statistically significant.

This does not mean there is no difference between the two protocols. The only conclusion that can be made is there was not a >10% difference.

This is an important concept of trial design and evidence based medicine. A 10% mortality difference would be huge. They demonstrated only a difference of about 4% at 24hrs and 30days favoring 1:1:1. They would have needed a much larger trial (n=3,000) to confirm this 4% difference that would give an NNT of 25.

There was a problem of un-blinding of the trial once the transfusion protocol was started. This had the potential for interfering with the treatment of the patients once they were assigned to each of the protocols.

Another concern about PROPPR is why compare 1:1:1 to 1:1:2? The hypothesis was generated from the PROMMTT study but this was a prospective observational trial showing an associated benefit of earlier and higher ratios of plasma and platelets. There could have been confounding factors responsible for this observed mortality benefit.

Others may argue that they should have compared 1:1:1 to a goal direct approach or “usual care” to find out if this protocol was superior. They addressed this briefly in their discussion. This trial cannot speak to usual care or a goal directed approach.

We have seen sepsis care over the last decade go through a transition. It started with usual care not being that great. Dr. River’s paper demonstrated a protocol with a bundle of steps could be significantly better in treating septic patients. However, last year major trials like ProCESS and ARISE showed two things. Usual septic care is now much better and that all parts of the bundle are not necessary. A similar story could emerge as more information becomes available on what is the best approach to patients requiring massive transfusions.

Another issue is the two different transfusion protocols can be deceiving if not read in detail. They say they study compares a 1:1:1 protocol to a 1:1:2 protocol. However, there were some important differences not just in the ratios but in the order patients received blood products.

  • Initial Containers:
    • 1:1:1 got PLATELETS first (6 units) followed by alternating RBC and plasma.
    • 1:1:2 got 2 units of RBC first and 1 unit of plasma. Platelets were not transfused until after 9 units of other blood products
  • Subsequent Containers:
    • Even number – 3 units plasma, 1 dose (6 units) platelets and 6U RBC with platelets given first then alternating 2 units RBC and 1 unit plasma
    • Odd Numbers – 2 units of RBC and 1 unit plasma

I think this is a key piece of information and could explain why the 1:1:1 achieved homeostasis and fewer exsanguinations. It is possible the platelets given first in the 1:1:1 treatment group was responsible for the earlier hemostasis and fewer deaths due to exsanguination by 24 hours.

Looking at the Kaplan-Meier Curves the lines deviated between one and three hours but otherwise remained parallel. Could it have been the earlier transfusion of platelets in the 1:1:1 protocol that explains this anomaly in the results?

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A minor point is they used the definition of “massive transfusion” as those patients requiring ≥10U RBC in the first 24hrs. The median transfusions of RBCs in the study were only 9 units. There are other definitions for massive transfusions but at least half their patients in their study did not reach the definition they decided to use.

Another comment about this study is that it was a “pragmatic” trial. This has both strengths and weaknesses. After the randomization process they left the treatment decisions up to the attending physician. This would be more “real” world practice but makes it more difficult to interpret the results. A more rigorous but less pragmatic approach would have been to treat both groups equally except for the intervention.

Their study objective was to compare the effectiveness of a 1:1:1 transfusion ratio of plasma, platelets and RBCS to a 1:1:2 ratio. They did appear to achieve these ratios with plasma to RBC. However, the median ratios of platelets to RBCs were 1.5 for the 1:1:1 group and 0.4 for the 1:1:2 group. So patients received more platelets than they were supposed to in the 1:1:1 group and less platelets than they were supposed to in the 1:1:2 group.

An online supplemental eTable 2 showed total blood products up to 24hrs after admission. The 1:1:1 group got a mean of 7 units plasma, 12 units platelets and 9 units RBC. In comparison the 1:1:2 group received a mean of 5 units plasma, 6 units platelets and 9 units RBC.

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They explain this in the discussion suggesting that after the intervention stage of the study there was a catching up of products based on laboratory-directed care. This resulted in the 1:1:2 group receiving more plasma and platelets products and a final ratio approaching 1:1:1.

The other objective of the PROPPR study was to determine the safety of the transfusion strategies. It is important to note that they found no differences in the 23 prespecified complications.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree that a plasma:platelet:red blood cell massive transfusion protocol in a 1:1:1 vs. 1:1:2 does not result in a greater than 10% difference in mortality at 24 hours or at 30 days, but smaller differences in mortality may be possible.

SGEM Bottom Line: A 1:1:1 transfusion strategy is a reasonable approach to adult patients who require a massive transfusion and seems to achieve more hemostasis and less death from exsanguination at 24 hours without increased complications.

Case Resolution: Unfortunately our patient did not survive. He was started on a massive transfusion protocol of 1:1:1 and had an emergency department thoracotomy performed, but ultimately all the bleeding could not be stopped and the patient coded.

Clinical Application: For adult patients who require massive transfusions a 1:1:1: is not superior to a 1:1:2 strategy. The PROPPR data suggests giving platelets earlier and in higher ratios. Local protocols will need to be developed using available resources and expertise to guide care of these critically ill patients.

Dr. Salim Rezaie

Dr. Salim Rezaie

What Do I Tell My Patient? Your family member has been shot. They are critically injured. There is a lot of bleeding and they require a massive transfusion. The US Department of Defense has come up with a treatment called damage control resuscitation. It involves early transfusion of different types of blood products (platelet cells that help stop bleeding, red blood cells that carry oxygen to the body and plasma that fills up their tank). We are going to use this balanced approach to try and save their life.

There have been a number of FOAMy reviews of the PROPPR Trail. I will put up a list of those in the show notes including the .

FOAMed PROPPR Reviews: FOAM logo

Keener Kontest: Last weeks’ winner was Dr. Hector Singson from Freeport, Bahamas.. Hector knew that the posterior canal is the most commonly affected semicircular canal in benign paroxysmal positional vertigo.

Listen to the podcast to hear this weeks keener/gunner question. If you know the answer send me email to TheSGEM@gmail.com with “keener” or “gunner” in the subject line. The first person with the correct answer will receive a cool skeptical prize. 

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

Conferences:

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