A Regional Massive Hemorrhage Protocol: Designed with a Modified Delphi Technique to Obtain Consensus
Authors: Callum Jeannie , Yeh Calvin , McVey Mark , Petrosoniak Andrew , Cope Stephanie , Thompson Troy , Chin Victoria , Karkouti Keyvan , Nathans Avery , Murto Kimmo , Beno Suzanne , Pendergrast Jacob , McDonald Andrew , Adhikari Neil , Alam Asim , Arnold Donald M. , Barratt Lee , Beckett Andrew , Brenneman Sue , Chaudhry Hina , Collins Allison , Harvey Margaret , Lampron Jacinthe , MacDonald Russell , Margarido Clarita , McFarlan Amanda , Nascimento Barto , Owens Wendy , Pai Menaka , Rizoli Sandro , Ruijs Theodora , Skeate Robert , Skelton Teresa , Sholzberg Michelle , Syer Kelly , Viveiros Jami-Lynn , Theriault Josee , Tinmouth Alan T. , Van Heest Rardi , White Susan , Zeller Michelle P. , Pavenski Katerina 
Published: November 2019

Background: The cornerstone of a massive hemorrhage protocol (MHP) is the rapid delivery of blood components to mitigate the consequences of hemorrhagic shock, coagulopathy, and hypothermia in the exsanguinating patient pending definitive hemorrhage control. MHPs are used to facilitate protocol activation/termination, mobilize an interdisciplinary team, provide immediate access to blood, prioritize rapid blood testing, and commence hypothermia-prevention strategies. Non-randomized, before-after implementation studies have found an association between MHPs and improved patient outcomes, including mortality. There is variability in MHP implementation rates, content, and protocol compliance due to challenges presented by infrequent activation, variable team performance, and patient acuity.
Methods: We used a modified Delphi technique to establish the framework for a standardized Provincial MHP toolkit and develop quality indicators. We assembled a panel of 36 content experts to represent relevant stakeholders at 150 Ontario hospitals.
Panelists included physicians, nurses, and technologists from anesthesia, trauma, obstetrics, hematology, transfusion, emergency, transport, critical care, as well as representation by blood suppliers and patients. The group represented the diverse geographic healthcare program including academic, pediatric, suburban, and small rural hospitals.
Panelists were required to attend a two-day MHP forum and complete all rounds of the Delphi. Panelists used digital surveys (LimeSurvey, Hamburg, Germany) to independently review 43 statements and 8 quality indicators drafted by a steering committee. Each statement was rated on a 7-point Likert scale from "definitely should not" to "definitely should include".
Disposition of items was based on critieria determined a priori on the median Likert score. Round 1: (1) score at least >5.5 incorporated as written, (2) 2.6-5.4, discussed at the forum with all panelists, with a 2nd round revision, (3) <2.5, removed from further rounds, unless there was a strong opposition by the panel and a revision drafted for the second round. Novel statements and quality indicators could be added in the first round. No additional statements were added after round two. For the 2nd and 3rd rounds: (1) >5.5, accepted, (2) 2.4-5.4, rewritten and sent for round 3, (3) <2.4, removed. Merging or division of statements could occur where appropriate.
Results: After 3 rounds, consensus was reached for 42 statements and 8 quality indicators. A 100% response rate was achieved from panelists in all three rounds.
There were four main areas that required additional rounds and major modifications: (1) selection of the name of the protocol; (2) selection of the laboratory resuscitation targets; (3) determination of the pack configurations; and, (4) clarification of the role of rVIIa. The obstacle to selecting a unified name for the protocol was that many of the hospitals already had longstanding MHPs with specific names. Consensus on the laboratory targets and pack configuration was achieved by splitting statements into sub-sections. The rVIIa statement required three rounds of review to ensure the phrasing satisfied all the panelists for this controversial therapy.
Interpretation: We believe that harmonization of MHPs in our region will simplify training, increase uptake of evidence-based interventions, enhance communication, improve patient safety, and ultimately improve outcomes. We highlight areas that need additional study: (1) RCTs are needed to determine if MHPs improve patient outcomes. (2) A "streamlined" version for community hospitals for stabilization before transfer to a tertiary care centre must be tested. (3) Activation and termination criteria have not been validated. (4) The frequency and type of laboratory testing has not been investigated. (5) Laboratory targets for resuscitation must be tested. (6) Does maintaining normothermia decrease transfusion? (7) Can fibrinogen concentrates and PCCs can be considered equivalent to cryoprecipitate and plasma, respectively? (8) Does compliance with the selected quality indicators result in improved outcome? These MHP recommendations will provide the basis for the design of local MHPs including specific recommendations for pediatric patients and for hospitals where definitive hemorrhage control may not be available.

Disclosures
Arnold: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Rigel: Consultancy, Research Funding; Principia: Consultancy. Pai:Novartis: Honoraria. Sholzberg:Takeda: Honoraria, Research Funding; Baxalta: Honoraria, Research Funding; Baxter: Honoraria, Research Funding. Zeller:Canadian Blood Services: Consultancy; Pfizer: Other: Advisory Board; Ontario Ministry of Health and Long Term Care: Consultancy. Pavenski:Ablynx: Honoraria, Research Funding; Bioverativ: Research Funding; Shire: Honoraria; Alexion: Honoraria, Research Funding; Octapharma: Research Funding.