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Association of Prehospital Plasma Transfusion With Survival in Trauma Patients With Hemorrhagic Shock When Transport Times Are Longer Than 20 MinutesA Post Hoc Analysis of the PAMPer and COMBAT Clinical Trials

Educational Objective To identify the outcomes when transport times are longer for injured patients who received plasma during transport.
1 Credit CME
Key Points

Question  Is prehospital plasma administration more beneficial when patient transport times are longer?

Findings  This post hoc analysis was performed using harmonized data from 2 randomized clinical trials, Control of Major Bleeding After Trauma and Prehospital Air Medical Plasma, which included 626 patients with trauma and hemorrhagic shock. Patients who received prehospital plasma transfusion had significantly reduced 28-day mortality compared with standard care when prehospital transport times were longer than 20 minutes.

Meaning  Prehospital plasma administration is associated with reduced mortality in patients with trauma and significant hemorrhage when transport times are prolonged.


Importance  Both military and civilian clinical practice guidelines include early plasma transfusion to achieve a plasma to red cell ratio approaching 1:1 to 1:2. However, it was not known how early plasma should be given for optimal benefit. Two recent randomized clinical trials were published, with apparently contradictory results. The Prehospital Air Medical Plasma (PAMPer) clinical trial showed a nearly 30% reduction in mortality with plasma transfusion in the prehospital environment, while the Control of Major Bleeding After Trauma (COMBAT) clinical trial showed no survival improvement.

Objective  To facilitate a post hoc combined analysis of the COMBAT and PAMPer trials to examine questions that could not be answered by either clinical trial alone. We hypothesized that prehospital transport time influenced the effects of prehospital plasma on 28-day mortality.

Design, Setting, and Participants  A total of 626 patients in the 2 clinical trials were included. Patients with trauma and hemorrhagic shock were randomly assigned to receive either standard care or 2 U of thawed plasma followed by standard care in the prehospital environment. Data analysis was performed between September 2018 and January 2019.

Interventions  Prehospital transfusion of 2 U of plasma compared with crystalloid-based resuscitation.

Main Outcomes and Measures  The main outcome was 28-day mortality.

Results  In this post hoc analysis of 626 patients (467 men [74.6%] and 159 women [25.4%]; median [interquartile range] age, 42 [27-57] years) who had trauma with hemorrhagic shock, a Cox regression analysis showed a significant overall survival benefit for plasma (hazard ratio [HR], 0.65; 95% CI, 0.47-0.90; P = .01) after adjustment for injury severity, age, and clinical trial cohort (COMBAT or PAMPer). A significant association with prehospital transport time was detected (from arrival on scene to arrival at the trauma center). Increased mortality was observed in patients in the standard care group when prehospital transport was longer than 20 minutes (HR, 2.12; 95% CI, 1.05-4.30; P = .04), while increased mortality was not observed in patients in the prehospital plasma group (HR, 0.78; 95% CI, 0.40-1.51; P = .46). No serious adverse events were associated with prehospital plasma transfusion.

Conclusions and Relevance  These data suggest that prehospital plasma is associated with a survival benefit when transport times are longer than 20 minutes and that the benefit-risk ratio is favorable for use of prehospital plasma.

Trial Registration  ClinicalTrials.gov identifiers: NCT01838863 (COMBAT) and NCT01818427 (PAMPer)

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: October 6, 2019.

Corresponding Author: Anthony E. Pusateri, PhD, US Army Institute of Surgical Research, 3698 Chambers Pass, Bldg 3611, Ste B, JBSA-Fort Sam Houston, San Antonio, TX 78234 (anthony.e.pusateri.civ@mail.mil).

Published Online: December 18, 2019. doi:10.1001/jamasurg.2019.5085

Author Contributions: Dr Pusateri had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Pusateri, E. Moore, H. Moore, Le, Guyette, Chapman, Brown, Miller, Claridge, Sperry.

Acquisition, analysis, or interpretation of data: Pusateri, Le, Guyette, Chapman, Sauaia, Ghasabyan, Chandler, McVaney, Brown, Daley, Harbrecht, Claridge, Phelan, Witham, Putnam, Sperry.

Drafting of the manuscript: Pusateri, E. Moore, H. Moore, Le, Sauaia, Ghasabyan, Miller, Sperry.

Critical revision of the manuscript for important intellectual content: Pusateri, E. Moore, Le, Guyette, Chapman, Chandler, McVaney, Brown, Daley, Harbrecht, Claridge, Phelan, Witham, Putnam, Sperry.

Statistical analysis: Pusateri, Le, Sauaia, Brown.

Obtained funding: E. Moore, Claridge, Sperry.

Administrative, technical, or material support: E. Moore, H. Moore, Le, Guyette, Chapman, Ghasabyan, Chandler, McVaney, Daley, Harbrecht, Phelan, Putnam, Sperry.

Supervision: Chapman, Ghasabyan, McVaney, Phelan, Witham, Sperry.

Conflict of Interest Disclosures: Dr H. Moore reported owning financial shares in Thrombo Therapeutics and providing consulting services to Instrumentation Laboratory outside the submitted work. Dr Guyette reported receiving grants from the Department of Defense during the conduct of the study. Dr Chapman reported receiving grants from the Department of Defense during the conduct of the study and serving on the board of Thrombo Therapeutics and providing consulting services to Haemonetics and Instrumentation Laboratory outside the submitted work. Dr Sauaia reported receiving grants from the National Institutes of Health and the Department of Defense during the conduct of the study. Dr McVaney reported receiving grants from the Department of Defense during the conduct of the study. Dr Daley reported receiving grants from the Department of Defense during the conduct of the study. Dr Harbrecht reported receiving grants from the National Institutes of Health and the Department of Defense during the conduct of the study and grants from the National Institutes of Health and the Department of Defense outside the submitted work. Dr Claridge reported receiving grants from the Department of Defense during the conduct of the study. Dr Sperry reported receiving grants from the Department of Defense during the conduct of the study. No other disclosures were reported.

Funding/Support: This work was supported by grants W81XWH-12-2-0028 (Control of Major Bleeding After Trauma clinical trial) and W81XWH-12-2-0023 (Prehospital Air Medical Plasma clinical trial) from the US Army Medical Research and Materiel Command and grant UM1 HL120877-05 (Trans-Agency Consortium for Trauma-Induced Coagulopathy) from the National Heart, Lung, and Blood Institute.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content of this article is the sole responsibility of the authors and does not represent the views or policies of the US Department of Defense, the US Army Institute of Surgical Research, the Denver Health Medical Center, the University of Pittsburgh Medical Center, the University of Tennessee Health Science Center, the Vanderbilt University Medical Center, the University of Louisville, Case Western Reserve University, the University of Texas Southwestern, the Texas Health Harris Methodist Hospital, or the National Institutes of Health.

Data Sharing Statement: See Supplement 3.

Additional Contributions: Duncan Donahue, PhD (Center for Environmental Health Research, Fort Detrick, MD), Charles Peterson, MD (Telemedicine and Advanced Technology Research Center, Fort Detrick, MD), Basil Golding, MD (Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD), and Wilbur Malloy, MA (Congressionally Directed Medical Research Program, US Army Medical Research and Materiel Command, Fort Detrick, MD), assisted with the planning of the study harmonization; Stephen Wisniewski (University of Pittsburgh, Pittsburgh, PA) helped with database management; Andrei Kindzelski, MD, PhD (National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources, Bethesda, MD), assisted with the Trans-Agency Consortium for Trauma-Induced Coagulopathy program coordination; and Richard Weiskopf, MD (University of California, San Francisco, CA), contributed to the planning and critical review of this article. No compensation was received.

Gurney  JM, Spinella  PC.  Blood transfusion management in the severely bleeding military patient.  Curr Opin Anaesthesiol. 2018;31(2):207-214. doi:10.1097/ACO.0000000000000574PubMedGoogle ScholarCrossref
Cannon  JW, Khan  MA, Raja  AS,  et al.  Damage control resuscitation in patients with severe traumatic hemorrhage: a practice management guideline from the Eastern Association for the Surgery of Trauma.  J Trauma Acute Care Surg. 2017;82(3):605-617. doi:10.1097/TA.0000000000001333PubMedGoogle ScholarCrossref
Joint trauma system clinical practice guidelines (CPGs). Department of Defense Center of Excellence for Trauma website. https://jts.amedd.army.mil/index.cfm/PI_CPGs/cpgs. Updated August 6, 2019. Accessed June 12, 2019.
Butler  FK, Holcomb  JB, Schreiber  MA,  et al.  Fluid resuscitation for hemorrhagic shock in tactical combat casualty care: TCCC guidelines change 14-01–2 June 2014.  J Spec Oper Med. 2014;14(3):13-38.PubMedGoogle Scholar
Maegele  M, Lefering  R, Paffrath  T, Tjardes  T, Simanski  C, Bouillon  B; Working Group on Polytrauma of the German Society of Trauma Surgery (DGU).  Red-blood-cell to plasma ratios transfused during massive transfusion are associated with mortality in severe multiple injury: a retrospective analysis from the Trauma Registry of the Deutsche Gesellschaft für Unfallchirurgie.  Vox Sang. 2008;95(2):112-119. doi:10.1111/j.1423-0410.2008.01074.xPubMedGoogle ScholarCrossref
Zink  KA, Sambasivan  CN, Holcomb  JB, Chisholm  G, Schreiber  MA.  A high ratio of plasma and platelets to packed red blood cells in the first 6 hours of massive transfusion improves outcomes in a large multicenter study.  Am J Surg. 2009;197(5):565-570. doi:10.1016/j.amjsurg.2008.12.014PubMedGoogle ScholarCrossref
Holcomb  JB, del Junco  DJ, Fox  EE,  et al; PROMMTT Study Group.  The prospective, observational, multicenter, major trauma transfusion (PROMMTT) study: comparative effectiveness of a time-varying treatment with competing risks.  JAMA Surg. 2013;148(2):127-136. doi:10.1001/2013.jamasurg.387PubMedGoogle ScholarCrossref
Brown  JB, Cohen  MJ, Minei  JP,  et al; Inflammation and the Host Response to Injury Investigators.  Pretrauma center red blood cell transfusion is associated with reduced mortality and coagulopathy in severely injured patients with blunt trauma.  Ann Surg. 2015;261(5):997-1005. doi:10.1097/SLA.0000000000000674PubMedGoogle ScholarCrossref
Shackelford  SA, del Junco  DJ, Powell-Dunford  N,  et al.  Association of prehospital blood product transfusion during medical evacuation of combat casualties in Afghanistan with acute and 30-day survival.  JAMA. 2017;318(16):1581-1591. doi:10.1001/jama.2017.15097PubMedGoogle ScholarCrossref
Sperry  JL, Guyette  FX, Brown  JB,  et al; PAMPer Study Group.  Prehospital plasma during air medical transport in trauma patients at risk for hemorrhagic shock.  N Engl J Med. 2018;379(4):315-326. doi:10.1056/NEJMoa1802345PubMedGoogle ScholarCrossref
O’Reilly  DJ, Morrison  JJ, Jansen  JO, Apodaca  AN, Rasmussen  TE, Midwinter  MJ.  Prehospital blood transfusion in the en route management of severe combat trauma: a matched cohort study.  J Trauma Acute Care Surg. 2014;77(3)(suppl 2):S114-S120. doi:10.1097/TA.0000000000000328PubMedGoogle ScholarCrossref
Peters  JH, Smulders  PSH, Moors  XRJ,  et al.  Are on-scene blood transfusions by a helicopter emergency medical service useful and safe? a multicentre case-control study.  Eur J Emerg Med. 2019;26(2):128-132. doi:10.1097/MEJ.0000000000000516PubMedGoogle ScholarCrossref
Zielinski  MD, Smoot  DL, Stubbs  JR, Jenkins  DH, Park  MS, Zietlow  SP.  The development and feasibility of a remote damage control resuscitation prehospital plasma transfusion protocol for warfarin reversal for patients with traumatic brain injury.  Transfusion. 2013;53(suppl 1):59S-64S. doi:10.1111/trf.12037PubMedGoogle ScholarCrossref
Zielinski  MD, Stubbs  JR, Berns  KS,  et al.  Prehospital blood transfusion programs: Capabilities and lessons learned.  J Trauma Acute Care Surg. 2017;82(6S)(suppl 1):S70-S78. doi:10.1097/TA.0000000000001427PubMedGoogle ScholarCrossref
Chen  J, Benov  A, Nadler  R,  et al.  Prehospital blood transfusion during aeromedical evacuation of trauma patients in Israel: the IDF CSAR experience.  Mil Med. 2017;182(S1):47-52. doi:10.7205/MILMED-D-16-00081PubMedGoogle ScholarCrossref
Malsby  RF  III, Quesada  J, Powell-Dunford  N,  et al.  Prehospital blood product transfusion by US army MEDEVAC during combat operations in Afghanistan: a process improvement initiative.  Mil Med. 2013;178(7):785-791. doi:10.7205/MILMED-D-13-00047PubMedGoogle ScholarCrossref
Holcomb  JB, Donathan  DP, Cotton  BA,  et al.  Prehospital transfusion of plasma and red blood cells in trauma patients.  Prehosp Emerg Care. 2015;19(1):1-9. doi:10.3109/10903127.2014.923077PubMedGoogle ScholarCrossref
Spinella  PC, Pidcoke  HF, Strandenes  G,  et al.  Whole blood for hemostatic resuscitation of major bleeding.  Transfusion. 2016;56(suppl 2):S190-S202. doi:10.1111/trf.13491PubMedGoogle ScholarCrossref
Mayne  T. Ranger Whole Blood Program wins an Army's Greatest Innovation award. US Army website. https://www.army.mil/article/184219/ranger_whole_blood_program_wins_an_armys_greatest_innovation_award. Published March 14, 2017. Accessed September 30, 2018.
Moore  HB, Moore  EE, Chapman  MP,  et al.  Plasma-first resuscitation to treat haemorrhagic shock during emergency ground transportation in an urban area: a randomised trial.  Lancet. 2018;392(10144):283-291. doi:10.1016/S0140-6736(18)31553-8PubMedGoogle ScholarCrossref
Pusateri  AE, Homer  MJ, Rasmussen  TE, Kupferer  KR, Hoots  WK.  The interagency strategic plan for research and development of blood products and related technologies for trauma care and emergency preparedness 2015-2020.  Am J Disaster Med. 2018;13(3):181-194. doi:10.5055/ajdm.2018.0299PubMedGoogle ScholarCrossref
National Heart, Lung, and Blood Institute. The TACTIC Project. TACTIC Project website. https://www.tacticproject.org/ Published 2019. Accessed May 25, 2019.
Cannon  JW.  Prehospital damage-control resuscitation.  N Engl J Med. 2018;379(4):387-388. doi:10.1056/NEJMe1805705PubMedGoogle ScholarCrossref
Makris  M, Iorio  A.  Prehospital fresh frozen plasma: universal life saver or treatment in search of a target population?  Res Pract Thromb Haemost. 2018;3(1):12-14. doi:10.1002/rth2.12172PubMedGoogle ScholarCrossref
Naumann  DN, Doughty  H, Cotton  BA.  No gains with plasma-first resuscitation in urban settings?  Lancet. 2018;392(10144):255-256. doi:10.1016/S0140-6736(18)31565-4PubMedGoogle ScholarCrossref
Moore  EE, Chin  TL, Chapman  MC,  et al.  Plasma first in the field for postinjury hemorrhagic shock.  Shock. 2014;41(suppl 1):35-38. doi:10.1097/SHK.0000000000000110PubMedGoogle ScholarCrossref
Brown  JB, Guyette  FX, Neal  MD,  et al.  Taking the blood bank to the field: the design and rationale of the Prehospital Air Medical Plasma (PAMPer) trial.  Prehosp Emerg Care. 2015;19(3):343-350. doi:10.3109/10903127.2014.995851PubMedGoogle ScholarCrossref
Meyer  DE, Vincent  LE, Fox  EE,  et al.  Every minute counts: time to delivery of initial massive transfusion cooler and its impact on mortality.  J Trauma Acute Care Surg. 2017;83(1):19-24. doi:10.1097/TA.0000000000001531PubMedGoogle ScholarCrossref
Wandling  MW, Nathens  AB, Shapiro  MB, Haut  ER.  Association of prehospital mode of transport with mortality in penetrating trauma: a trauma system–level assessment of private vehicle transportation vs ground emergency medical services.  JAMA Surg. 2018;153(2):107-113. doi:10.1001/jamasurg.2017.3601PubMedGoogle ScholarCrossref
Brown  JB, Gestring  ML, Guyette  FX,  et al.  Helicopter transport improves survival following injury in the absence of a time-saving advantage.  Surgery. 2016;159(3):947-959. doi:10.1016/j.surg.2015.09.015PubMedGoogle ScholarCrossref
Galvagno  SM  Jr, Haut  ER, Zafar  SN,  et al.  Association between helicopter vs ground emergency medical services and survival for adults with major trauma.  JAMA. 2012;307(15):1602-1610. doi:10.1001/jama.2012.467PubMedGoogle ScholarCrossref
Morrison  JJ, Oh  J, DuBose  JJ,  et al.  En-route care capability from point of injury impacts mortality after severe wartime injury.  Ann Surg. 2013;257(2):330-334. doi:10.1097/SLA.0b013e31827eefcfPubMedGoogle ScholarCrossref
Henriksen  HH, Rahbar  E, Baer  LA,  et al.  Pre-hospital transfusion of plasma in hemorrhaging trauma patients independently improves hemostatic competence and acidosis.  Scand J Trauma Resusc Emerg Med. 2016;24(1):145. doi:10.1186/s13049-016-0327-zPubMedGoogle ScholarCrossref
Kozar  RA, Peng  Z, Zhang  R,  et al.  Plasma restoration of endothelial glycocalyx in a rodent model of hemorrhagic shock.  Anesth Analg. 2011;112(6):1289-1295. doi:10.1213/ANE.0b013e318210385cPubMedGoogle ScholarCrossref
Pati  S, Potter  DR, Baimukanova  G, Farrel  DH, Holcomb  JB, Schreiber  MA.  Modulating the endotheliopathy of trauma: factor concentrate versus fresh frozen plasma.  J Trauma Acute Care Surg. 2016;80(4):576-584. doi:10.1097/TA.0000000000000961PubMedGoogle ScholarCrossref
Peng  Z, Pati  S, Potter  D,  et al.  Fresh frozen plasma lessens pulmonary endothelial inflammation and hyperpermeability after hemorrhagic shock and is associated with loss of syndecan 1.  Shock. 2013;40(3):195-202. doi:10.1097/SHK.0b013e31829f91fcPubMedGoogle ScholarCrossref
Potter  DR, Baimukanova  G, Keating  SM,  et al.  Fresh frozen plasma and spray-dried plasma mitigate pulmonary vascular permeability and inflammation in hemorrhagic shock.  J Trauma Acute Care Surg. 2015;78(6)(suppl 1):S7-S17. doi:10.1097/TA.0000000000000630PubMedGoogle ScholarCrossref
Ban  K, Peng  Z, Pati  S, Witkov  RB, Park  PW, Kozar  RA.  Plasma-mediated gut protection after hemorrhagic shock is lessened in syndecan-1−/− mice.  Shock. 2015;44(5):452-457. doi:10.1097/SHK.0000000000000452PubMedGoogle ScholarCrossref
D’Alessandro  A, Moore  HB, Moore  EE,  et al.  Plasma first resuscitation reduces lactate acidosis, enhances redox homeostasis, amino acid and purine catabolism in a rat model of profound hemorrhagic shock.  Shock. 2016;46(2):173-182. doi:10.1097/SHK.0000000000000588PubMedGoogle ScholarCrossref
Holcomb  JB, Pati  S.  Optimal trauma resuscitation with plasma as the primary resuscitative fluid: the surgeon’s perspective.  Hematology Am Soc Hematol Educ Program. 2013;2013:656-659. doi:10.1182/asheducation-2013.1.656PubMedGoogle ScholarCrossref
Pusateri  AE, Butler  FK, Shackelford  SA,  et al.  The need for dried plasma—a national issue.  Transfusion. 2019;59(S2):1587-1592. doi:10.1111/trf.15261PubMedGoogle ScholarCrossref
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