REBEL Cast Ep60: COMBAT and PAMPer – Prehospital Plasma in Trauma

05 Nov
November 5, 2018

Background: Care of trauma patients with severe bleeding has advanced in recent years with a focus on damage control resuscitation which includes permissive hypotension, hemostatic resuscitation (blood component resuscitation), and hemorrhage control. Minimizing crystalloids in favor of blood component-based resuscitation in the prehospital setting has the potential to reduce downstream complications by intervening closer to the time of injury before the development of coagulopathy, irreversible shock, and inflammatory response.  There is a paucity of high level evidence showing the efficacy and safety of plasma transfusions in the prehospital setting including retrospective studies which suffered from survivor bias (patients had to survive long enough to receive plasma) and small randomized clinical trials not showing survival benefit.  This has led to the publication of two randomized controlled trials: COMBAT and PAMPer.

REBEL Cast Episode 60 – COMBAT and PAMPer  Prehospital Plasma in Trauma

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Control of Major Bleeding After Trauma (COMBAT) Trial [1]

What They Did:

  • Pragmatic, randomized, placebo-controlled clinical trial based at a single institution in the USA, which was a level 1 trauma center
  • Patients randomized to 250mL of AB plasma vs 250mL of frozen water + normal saline per standard care

Outcomes:

  • Primary: 28 day mortality after injury
  • Secondary:
    • Composite multiple organ failure (MOF), death, or both by day 28
  • Exploratory:
    • Time from injury to need for 1stRBC transfusion
    • TEG indices
    • Number of ventilation-free days
    • Number of intensive-care-free days
    • Development of MOF
  • Safety:
    • Development of acute lung injury within 28d
    • Development of possible transfusion-related acute lung injury

 Inclusion:

  • Adults (Age >18 years) suffering trauma
  • SBP ≤ 70 mm Hg or 71 – 90mmHg + HR ≥108 BPM

Exclusion:

  • Prisoner
  • Pregnant
  • Isolated GSW to head
  • Asystole or cardiopulmonary resuscitation before randomization
  • Objection to blood products

Results:

  • 144 eligible patients (Intention to Treat Analysis)
    • Plasma 1st: 75 patients
    • Saline Control: 69 patients
  • Median time from injury to hospital arrival:
    • Plasma 1st: 28min
    • Saline Control: 24min
  • Median transport time:
    • Plasma 1st: 19min
    • Saline Control: 16min
  • Time from injury to 1stplasma unit
    • Plasma 1st: 24min
    • Saline Control: 59min
  • 28 day mortality:
    • Plasma 1st: 15%
    • Saline Control: 10%
    • 95% CI 0.60 – 3.98
    • P = 0.37
  • No difference in mortality at 24h, ALI within 28 days, ventilator free days or ICU free days

Strengths:

  • Asks a clinically important question
  • Pragmatic, randomized, placebo controlled trial
  • Independent data and safety monitoring board oversaw the trial and reviewed all suspected adverse events and interim analyses
  • Study funder had no role in study design, data collection, data analysis, data interpretation or writing of the report

Limitations:

  • Single center study
  • It is unclear if outcome assessors were blinded as it was stated in the manuscript
  • No attempt at blinding patient’s and clinicians (i.e. Potential unmasking of groups due to the appearance of plasma and saline having different colors
  • Trial was underpowered as it required 150 patients to provide an 80% power to determine a 19% difference in mortality
  • Patients were not completely balanced at baseline with patients in the plasma group being more hypotensive and having slightly more hyperfibrinolysis, which would bias the results to favor the saline crystalloid control group
  • Patients randomized to control arm, did not require defrosting procedures which may have allowed paramedics to focus on other tasks that may have resulted in improved outcomes in this arm

Discussion:

  • Prehospital administration of plasma reduced time to transfusion by 30 minutes but did not improve clinical outcomes
  • NS was limited in the non-plasma group which shows a great deal of restraint on the part of the paramedics
  • Study terminated early for futility because outcomes had not differed in any of the interim analyses
  • Hypotension and tachycardia are not specific of hemorrhage in trauma, therefore some patients included in this trial may not have been due to hemorrhage and may have been one cause of a lack of effect seen with plasma-first resuscitation
  • Finally, there was no difference in the intention to treat analysis vs the per-protocol analysis

Author Conclusion:“During rapid ground rescue to an urban level 1 trauma centre, use of prehospital plasma was not associated with survival benefit.  Blood products might be beneficial in settings with longer transport times, but the financial burden would not be justified in an urban environment with short distances to mature trauma centres.”

Prehospital Air Medical Plasma (PAMPer) Trial [2]

What They Did:

  • Pragmatic, multicenter, cluster-randomized, phase 3 trial of trauma patients at risk for hemorrhagic shock during air medical transport to a trauma center
  • Patients randomized to 2 units of thawed plasma (plasma group) vs standard care resuscitation (Standard care group)

Outcomes:  

  • Primary: 30 day mortality
  • Secondary:
    • Mortality at 24 hours
    • In-hospital mortality
    • Volume of blood components and resuscitation fluid administered within 24hrs after enrollment
    • Incidence of multiorgan failure, acute lung injury, acute respiratory distress syndrome, transfusion-related acute lung injury, and nosocomial infection
    • Indexes of coagulopathy and results of thromboelastography

Inclusion:

  • One episode of hypotension (SBP <90mmHg) and/or tachycardia HR >108 BPM)
  • Any severe hypotension (<70mmHg)

Exclusion:

  • <18 years or >90 years of age
  • Inability to establish IV or IO access
  • Isolated fall from standing
  • Documented cervical cord injury
  • Prisoner
  • Pregnant
  • Traumatic cardiac arrest lasting longer than 5 min
  • Penetrating brain injury
  • Injury due to isolated drowning or hanging
  • Burns >20% BSA

Results:

  • 564 patients were eligible
    • Plasma group: 230 patients
    • Standard care group: 271 patients
    • Blunt Trauma: 82.4% of patients
    • Median Injury Severity Score = 22
    • Overall 30d Mortality = 29.6%
    • Required Intubation = 51.1%
    • Required Red-Cell Transfusion = 34.7%
  • 30 day mortality (Primary Outcome)
    • Plasma Group = 23.2%
    • Standard Care Group = 33.0%
    • 95% CI = -18.6 to -1.0%
    • P = 0.03
  • 24hr Mortality
    • Plasma Group = 13.9%
    • Standard Care Group = 22.1%
    • P = 0.02
  • In-Hospital Mortality
    • Plasma Group = 22.2%
    • Standard Care Group = 32.5%
    • P = 0.01
  • Adverse Events
    • Plasma Group = 6 Patients
    • Standard Care Group = 2 Patients
    • All reactions deemed minor

Strengths:

  • Asks a clinically important question
  • Pragmatic, multicenter randomized trial
  • External data and safety monitoring committee performed regular safety surveillance
  • Pre-specified subgroup analyses showed a consistent survival benefit in the plasma group across various injury types, suggesting generalizability of results
  • Prehospital personnel and receiving physicians were not blinded to trial intervention, but personnel who assessed trial outcomes were

Limitations:

  • Study groups were imbalanced in volume of crystalloid and patients receiving red-cell transfusions before arrival at the trauma center which may have biased results of the study
  • The inclusion of transfer patients in the trial had the potential to introduce bias owing to differences in treatment before arrival at the trauma center (i.e. it is not clear what treatments these patients received while at the originating ED)

Discussion:

  • 111 patients transferred from outside referral ED (i.e. Hospital to Hospital Transfer vs Scene to Hospital Transfer)
    • Prehospital Transport Times to Trauma Center = 52min vs 39min
    • Prehospital Intubation = 37.3% vs 51.9%
  • Median Prehospital Volume of Crystalloid
    • Plasma Group = 500cc
    • Standard Care Group = 900cc
  • Prehospital Red Cell Transfusion
    • Plasma Group = 26.1%
    • Standard Care Group = 42.1%

Author Conclusion: “In injured patients at risk for hemorrhagic shock, the prehospital administration of thawed plasma was safe and resulted in lower 30-day mortality and a lower median prothrombin-time ration than standard-care resuscitation.”

Different Outcomes in COMBAT and PAMPer:

  • Patients slightly older in PAMPer Trial vs COMBAT Trial (40’s vs 30’s)
  • More Crystalloid used in PAMPer Trial vs COMBAT Trial (500 – 900cc vs 150 – 250cc)
  • More Blunt Injury in PAMPer Trial vs COMBAT Trial (>80% vs ≈50%)
  • Transport Times Longer in PAMPer Trial vs COMBAT Trial 39 – 52min vs 16 – 28min

Clinical Take Home Point:

In injured patients at risk for hemorrhagic shock, pre-hospital administration of thawed plasma appears to be a safe and efficacious practice in reducing mortality. The difference in mortality outcomes between the COMBAT and PAMPer trials may simply be the  longer transport times and the amount of crystalloids, which begs the question of whether we should be resuscitating these patients with crystalloid fluids at all?

Guest Expert

Ashley Liebig, RN, BSN, CCRN
Clinical Supervisor
STAR Flight
Austin, TX
Twitter: ashleyliebig

  • Transport times were longer in the PAMPer trial vs the COMBAT Trial (39 – 52min vs 16 – 28min). I think this was one of the key differences between the studies.  The PAMPer trial was an aeromedical prehospital study and the COMBAT Trial was more a ground transportation trial.  Do you think pre-hospital plasma is something we should be putting on all prehospital vehicles or just the ones that will have the longest transport times (Aeromedical vs Ground)?

Ashley’s Response: This is about logistics and utilization of resources.  If your system has longer transport times, it may be worthwhile to have blood products.  This should be based on historical analysis within your system. Blood products are precious resources and there has to be a proven need in order to place them in a prehospital system.

  • As we move away from crystalloid infusion in trauma patients, it is also interesting that in the PAMPer trial many patients got 500 – 900cc of crystalloid compared to 150 – 250cc of crystalloid in the COMBAT trial. This is incredible restraint by the pre-hospital personnel in the COMBAT trial. What are your thoughts on this?

Ashley’s Response: It depends on what the system protocols are.  Most systems will titrate to a SBP of 80 – 90mmHg. In PAMPer, patients received more crystalloid and reported a median SBP of 71mmHg.  In COMBAT, patients received less crystalloid and reported a median SBP of 64mmHg on scene and 96mmHg at arrival.  In this context, the amount seems very reasonable in each of the studies.

  • Finally, defrosting frozen plasma may take the focus of paramedics away from the patient to the procedure of thawing the plasma.Is thawing plasma something you are doing in practice and if so, how hard and long does it take to make this happen?

Ashley’s Response: In the US, aeromedical prehospital transport use liquid plasma not frozen plasma. Thawed plasma has to be used within 5 days, but liquid plasma has a 26 day shelf life.  In a paper published in 2012 [3], the hemostatic profile of liquid plasma was better and sustained 5x longer than thawed plasma.  Ashley contacted her local blood blank who stated there is no difference in cost and liquid plasma has a longer shelf life.  Ashley also asked some of her Australian aeromedical colleagues and they stated that it was not possible to get liquid plasma.  So there may be challenges in acquiring liquid plasma in other countries.

Ergonomics and precision are key in dealing with critically ill trauma patients.  So when you only have two providers, you need efficiency.  The additional step of thawing is concerning, due to the  multistep process of warming and administering thawed plasma in an already chaotic environment.  Hopefully, one day we will transition to whole blood in the prehospital system.

Take Home Message From Ashley: Blood products in any form are a precious resource, and only available through the gift of others, so if able go out and donate.

References:

  1. Moore HB et al. Plasma-First Resuscitation to Treat Haemorrhagic Shock During Emergency Ground Transportation in an Urban Area: A Randomised Trial. Lancet 2018. PMID: 30032977
  2. Sperry JL et al. Prehospital Plasma During Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock. NEJM 2018. PMID: 30044935
  3. Matijevic N et al. Better Hemostatic Profiles of Never-Frozen Liquid Plasma Compared with Thawed Fresh Frozen Plasma. J Trauma Acute Care Sure 2013. PMID: 23271081

For More Thoughts on This Topic Checkout:

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)

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Salim Rezaie

Emergency Physician at Greater San Antonio Emergency Physicians (GSEP)
Creator & Founder of R.E.B.E.L. EM
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