Haemoglobin transfusion threshold in traumatic brain injury optimisation (HEMOTION): a multicentre, randomised, clinical trial protocol

Alexis F Turgeon, Dean A Fergusson, Lucy Clayton, Marie-Pier Patton, Ryan Zarychanski, Shane English, Annemarie Docherty, Timothy Walsh, Donald Griesdale, Andreas H Kramer, Damon Scales, Karen E A Burns, John Gordon Boyd, John C Marshall, Demetrios J Kutsogiannis, Ian Ball, Paul C Hébert, Francois Lamontagne, Olivier Costerousse, Maude St-Onge, Paule Lessard Bonaventure, Lynne Moore, Xavier Neveu, Andrea Rigamonti, Kosar Khwaja, Robert S Green, Vincent Laroche, Alison Fox-Robichaud, Francois Lauzier, HEMOTION Trial Team, the Canadian Critical Care Trials Group, the Canadian Perioperative Anesthesia Clinical Trials Group and the Canadian Traumatic Brain Injury Research Consortium, Alexis F Turgeon, Dean A Fergusson, Lucy Clayton, Marie-Pier Patton, Ryan Zarychanski, Shane English, Annemarie Docherty, Timothy Walsh, Donald Griesdale, Andreas H Kramer, Damon Scales, Karen E A Burns, John Gordon Boyd, John C Marshall, Demetrios J Kutsogiannis, Ian Ball, Paul C Hébert, Francois Lamontagne, Olivier Costerousse, Maude St-Onge, Paule Lessard Bonaventure, Lynne Moore, Xavier Neveu, Andrea Rigamonti, Kosar Khwaja, Robert S Green, Vincent Laroche, Alison Fox-Robichaud, Francois Lauzier, HEMOTION Trial Team, the Canadian Critical Care Trials Group, the Canadian Perioperative Anesthesia Clinical Trials Group and the Canadian Traumatic Brain Injury Research Consortium

Abstract

Introduction: Traumatic brain injury (TBI) is the leading cause of mortality and long-term disability in young adults. Despite the high prevalence of anaemia and red blood cell transfusion in patients with TBI, the optimal haemoglobin (Hb) transfusion threshold is unknown. We undertook a randomised trial to evaluate whether a liberal transfusion strategy improves clinical outcomes compared with a restrictive strategy.

Methods and analysis: HEMOglobin Transfusion Threshold in Traumatic Brain Injury OptimizatiON is an international pragmatic randomised open label blinded-endpoint clinical trial. We will include 742 adult patients admitted to an intensive care unit (ICU) with an acute moderate or severe blunt TBI (Glasgow Coma Scale ≤12) and a Hb level ≤100 g/L. Patients are randomly allocated using a 1:1 ratio, stratified by site, to a liberal (triggered by Hb ≤100 g/L) or a restrictive (triggered by Hb ≤70 g/L) transfusion strategy applied from the time of randomisation to the decision to withdraw life-sustaining therapies, ICU discharge or death. Primary and secondary outcomes are assessed centrally by trained research personnel blinded to the intervention. The primary outcome is the Glasgow Outcome Scale extended at 6 months. Secondary outcomes include overall functional independence measure, overall quality of life (EuroQoL 5-Dimension 5-Level; EQ-5D-5L), TBI-specific quality of life (Quality of Life after Brain Injury; QOLIBRI), depression (Patient Health Questionnaire; PHQ-9) and mortality.

Ethics and dissemination: This trial is approved by the CHU de Québec-Université Laval research ethics board (MP-20-2018-3706) and ethic boards at all participating sites. Our results will be published and shared with relevant organisations and healthcare professionals.

Trial registration number: NCT03260478.

Keywords: Adult intensive & critical care; INTENSIVE & CRITICAL CARE; Neurological injury; TRAUMA MANAGEMENT.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Flow diagram. GCS, Glasgow Coma Scale; Hb, haemoglobin; ICU, intensive care unit; TBI, traumatic brain injury.
Figure 2
Figure 2
Potential protocol deviations and violations. ICU, intensive care unit.

References

    1. Hyder AA, Wunderlich CA, Puvanachandra P, et al. . The impact of traumatic brain injuries: a global perspective. NeuroRehabilitation 2007;22:341–53. 10.3233/NRE-2007-22502
    1. Chodobski A, Zink BJ, Szmydynger-Chodobska J. Blood-brain barrier pathophysiology in traumatic brain injury. Transl Stroke Res 2011;2:492–516. 10.1007/s12975-011-0125-x
    1. Smith MJ, Stiefel MF, Magge S, et al. . Packed red blood cell transfusion increases local cerebral oxygenation. Crit Care Med 2005;33:1104–8. 10.1097/01.CCM.0000162685.60609.49
    1. Zygun DA, Nortje J, Hutchinson PJ, et al. . The effect of red blood cell transfusion on cerebral oxygenation and metabolism after severe traumatic brain injury. Crit Care Med 2009;37:1074–8. 10.1097/CCM.0b013e318194ad22
    1. Leal-Noval SR, Rincón-Ferrari MD, Marin-Niebla A, et al. . Transfusion of erythrocyte concentrates produces a variable increment on cerebral oxygenation in patients with severe traumatic brain injury: a preliminary study. Intensive Care Med 2006;32:1733–40. 10.1007/s00134-006-0376-2
    1. Utter GH, Shahlaie K, Zwienenberg-Lee M, et al. . Anemia in the setting of traumatic brain injury: the arguments for and against liberal transfusion. J Neurotrauma 2011;28:155–65. 10.1089/neu.2010.1451
    1. Boutin A, Chassé M, Shemilt M, et al. . Red blood cell transfusion in patients with traumatic brain injury: a systematic review and meta-analysis. Transfus Med Rev 2016;30:15–24. 10.1016/j.tmrv.2015.08.004
    1. Desjardins P, Turgeon AF, Tremblay M-H, et al. . Hemoglobin levels and transfusions in neurocritically ill patients: a systematic review of comparative studies. Crit Care 2012;16:R54. 10.1186/cc11293
    1. Robertson CS, Hannay HJ, Yamal J-M, et al. . Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial. JAMA 2014;312:36–47. 10.1001/jama.2014.6490
    1. Carney N, Totten AM, O'Reilly C, et al. . Guidelines for the management of severe traumatic brain injury, fourth edition. Neurosurgery 2017;80:6–15. 10.1227/NEU.0000000000001432
    1. Vlaar AP, Oczkowski S, de Bruin S, et al. . Transfusion strategies in non-bleeding critically ill adults: a clinical practice guideline from the European society of intensive care medicine. Intensive Care Med 2020;46:673–96. 10.1007/s00134-019-05884-8
    1. Boutin A, Moore L, Green RS, et al. . Hemoglobin thresholds and red blood cell transfusion in adult patients with moderate or severe traumatic brain injuries: a retrospective cohort study. J Crit Care 2018;45:133–9. 10.1016/j.jcrc.2018.01.023
    1. Boutin A, Moore L, Lauzier F, et al. . Transfusion of red blood cells in patients with traumatic brain injuries admitted to Canadian trauma health centres: a multicentre cohort study. BMJ Open 2017;7:e014472. 10.1136/bmjopen-2016-014472
    1. Hébert PC, Wells G, Blajchman MA, et al. . A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. transfusion requirements in critical care Investigators, Canadian critical care trials group. N Engl J Med 1999;340:409–17. 10.1056/NEJM199902113400601
    1. Carson JL, Stanworth SJ, Dennis JA, et al. . Transfusion thresholds for guiding red blood cell transfusion. Cochrane Database Syst Rev 2021;12:CD002042. 10.1002/14651858.CD002042.pub5
    1. Lessard Bonaventure P, Lauzier F, Zarychanski R, et al. . Red blood cell transfusion in critically ill patients with traumatic brain injury: an international survey of physicians' attitudes. Can J Anaesth 2019;66:1038–48. 10.1007/s12630-019-01369-w
    1. Hansson L, Hedner T, Dahlöf B. Prospective randomized open blinded end-point (probe) study. A novel design for intervention trials. Blood Press 1992;1:113–9. 10.3109/08037059209077502
    1. Chan A-W, Tetzlaff JM, Gøtzsche PC, et al. . Spirit 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ 2013;346:e7586. 10.1136/bmj.e7586
    1. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974;2:81–4. 10.1016/s0140-6736(74)91639-0
    1. Moher D, Hopewell S, Schulz KF, et al. . Consort 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010;340:c869. 10.1136/bmj.c869
    1. Kramer AH, Diringer MN, Suarez JI, et al. . Red blood cell transfusion in patients with subarachnoid hemorrhage: a multidisciplinary North American survey. Crit Care 2011;15:R30. 10.1186/cc9977
    1. Maas AIR, Harrison-Felix CL, Menon D, et al. . Standardizing data collection in traumatic brain injury. J Neurotrauma 2011;28:177–87. 10.1089/neu.2010.1617
    1. Asselin M, Lachance Y, Lalonde G, et al. . Long-term functional outcome in adults with severe TBI: a meta-analysis. Crit Care 2013;17:S127. 10.1186/cc12272
    1. Jennett B, Snoek J, Bond MR, et al. . Disability after severe head injury: observations on the use of the glasgow outcome scale. J Neurol Neurosurg Psychiatry 1981;44:285–93. 10.1136/jnnp.44.4.285
    1. Pettigrew LEL, Wilson JTL, Teasdale GM. Reliability of ratings on the glasgow outcome scales from in-person and telephone structured interviews. J Head Trauma Rehabil 2003;18:252–8. 10.1097/00001199-200305000-00003
    1. Levin HS, Boake C, Song J, et al. . Validity and sensitivity to change of the extended glasgow outcome scale in mild to moderate traumatic brain injury. J Neurotrauma 2001;18:575–84. 10.1089/089771501750291819
    1. Wright DW, Yeatts SD, Silbergleit R, et al. . Very early administration of progesterone for acute traumatic brain injury. N Engl J Med 2014;371:2457–66. 10.1056/NEJMoa1404304
    1. Nichol A, French C, Little L, et al. . Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised controlled trial. Lancet 2015;386:2499–506. 10.1016/S0140-6736(15)00386-4
    1. Roquilly A, Moyer JD, Huet O, et al. . Effect of continuous infusion of hypertonic saline vs standard care on 6-month neurological outcomes in patients with traumatic brain injury: the cobI randomized clinical trial. JAMA 2021;325:2056–66. 10.1001/jama.2021.5561
    1. Andrews PJD, Sinclair HL, Rodriguez A, et al. . Hypothermia for intracranial hypertension after traumatic brain injury. N Engl J Med 2015;373:2403–12. 10.1056/NEJMoa1507581
    1. Cooper DJ, Nichol AD, Bailey M, et al. . Effect of early sustained prophylactic hypothermia on neurologic outcomes among patients with severe traumatic brain injury: the polar randomized clinical trial. JAMA 2018;320:2211–20. 10.1001/jama.2018.17075
    1. Keith RA, Granger CV, Hamilton BB, et al. . The functional independence measure: a new tool for rehabilitation. Adv Clin Rehabil 1987;1:6–18.
    1. Livingston DH, Lavery RF, Mosenthal AC, et al. . Recovery at one year following isolated traumatic brain injury: a Western trauma association prospective multicenter trial. J Trauma 2005;59:1298–304. 10.1097/01.ta.0000196002.03681.18
    1. Zhu XL, Poon WS, Chan CCH, et al. . Does intensive rehabilitation improve the functional outcome of patients with traumatic brain injury (TBI)? A randomized controlled trial. Brain Inj 2007;21:681–90. 10.1080/02699050701468941
    1. EuroQol Group . EuroQol--a new facility for the measurement of health-related quality of life. Health Policy 1990;16:199–208. 10.1016/0168-8510(90)90421-9
    1. Salbach NM, Mayo NE, Hanley JA, et al. . Psychometric evaluation of the original and Canadian French version of the activities-specific balance confidence scale among people with stroke. Arch Phys Med Rehabil 2006;87:1597–604. 10.1016/j.apmr.2006.08.336
    1. von Steinbüchel N, Wilson L, Gibbons H, et al. . Quality of life after brain injury (QOLIBRI): scale validity and correlates of quality of life. J Neurotrauma 2010;27:1157–65. 10.1089/neu.2009.1077
    1. Fann JR, Bombardier CH, Dikmen S, et al. . Validity of the patient health questionnaire-9 in assessing depression following traumatic brain injury. J Head Trauma Rehabil 2005;20:501–11. 10.1097/00001199-200511000-00003
    1. Turgeon AF, Lauzier F, Zarychanski R, et al. . Prognostication in critically ill patients with severe traumatic brain injury: the TBI-prognosis multicentre feasibility study. BMJ Open 2017;7:e013779. 10.1136/bmjopen-2016-013779
    1. Lachin JM. Introduction to sample size determination and power analysis for clinical trials. Control Clin Trials 1981;2:93–113. 10.1016/0197-2456(81)90001-5
    1. Murray GD, Barer D, Choi S, et al. . Design and analysis of phase III trials with ordered outcome scales: the concept of the sliding dichotomy. J Neurotrauma 2005;22:511–7. 10.1089/neu.2005.22.511
    1. Steyerberg EW, Mushkudiani N, Perel P, et al. . Predicting outcome after traumatic brain injury: development and international validation of prognostic scores based on admission characteristics. PLoS Med 2008;5:e165. 10.1371/journal.pmed.0050165
    1. Little RJ, Rubin DB. Statistical analysis with missing data. John Wiley & Sons, 2019.
    1. Brant R. Assessing proportionality in the proportional odds model for ordinal logistic regression. Biometrics 1990;46:1171–8. 10.2307/2532457
    1. Ha D, Jeong J-H, Lee Y. Statistical modelling of survival data with random effects. Springer, 2017.
    1. Schandelmaier S, Briel M, Varadhan R, et al. . Development of the instrument to assess the credibility of effect modification analyses (ICEMAN) in randomized controlled trials and meta-analyses. CMAJ 2020;192:E901–6. 10.1503/cmaj.200077
    1. DAMOCLES Study Group, NHS Health Technology Assessment Programme . A proposed charter for clinical trial data monitoring committees: helping them to do their job well. Lancet 2005;365:711–22. 10.1016/S0140-6736(05)17965-3
    1. Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Br J Radiol 1971;44:793–7. 10.1259/0007-1285-44-526-793
    1. Peto R, Pike MC, Armitage P, et al. . Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design. Br J Cancer 1976;34:585–612. 10.1038/bjc.1976.220
    1. Cook D, Lauzier F, Rocha MG, et al. . Serious adverse events in academic critical care research. CMAJ 2008;178:1181–4. 10.1503/cmaj.071366
    1. Brain injury Canada. Available: [Accessed 16 June 2022].
    1. Lacroix J, Hébert PC, Fergusson DA, et al. . Age of transfused blood in critically ill adults. N Engl J Med 2015;372:1410–8. 10.1056/NEJMoa1500704
    1. English SW, Fergusson D, Chassé M, et al. . Aneurysmal subarachnoid hemorrhage-red blood cell transfusion and outcome (Sahara): a pilot randomised controlled trial protocol. BMJ Open 2016;6:e012623. 10.1136/bmjopen-2016-012623

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