[en] [en] BACKGROUND: Sedation is often provided to resuscitated out-of-hospital cardiac arrest (OHCA) patients to tolerate post-cardiac arrest care, including temperature management. However, the evidence of benefit or harm from routinely administered deep sedation after cardiac arrest is limited. The aim of this trial is to investigate the effects of continuous deep sedation compared to minimal sedation on patient-important outcomes in resuscitated OHCA patients in a large clinical trial.
METHODS: The SED-CARE trial is part of the 2 × 2 × 2 factorial Sedation, Temperature and Pressure after Cardiac Arrest and Resuscitation (STEPCARE) trial, a randomized international, multicentre, parallel-group, investigator-initiated, superiority trial with three simultaneous intervention arms. In the SED-CARE trial, adults with sustained return of spontaneous circulation (ROSC) who are comatose following resuscitation from OHCA will be randomized within 4 hours to continuous deep sedation (Richmond agitation and sedation scale (RASS) -4/-5) (intervention) or minimal sedation (RASS 0 to -2) (comparator), for 36 h after ROSC. The primary outcome will be all-cause mortality at 6 months after randomization. The two other components of the STEPCARE trial evaluate sedation and temperature control strategies. Apart from the STEPCARE trial interventions, all other aspects of general intensive care will be according to the local practices of the participating site. Neurological prognostication will be performed according to European Resuscitation Council and European Society of Intensive Care Medicine guidelines by a physician blinded to the allocation group. To detect an absolute risk reduction of 5.6% with an alpha of 0.05, 90% power, 3500 participants will be enrolled. The secondary outcomes will be the proportion of participants with poor functional outcomes 6 months after randomization, serious adverse events in the intensive care unit, and patient-reported overall health status 6 months after randomization.
CONCLUSION: The SED-CARE trial will investigate if continuous deep sedation (RASS -4/-5) for 36 h confers a mortality benefit compared to minimal sedation (RASS 0 to -2) after cardiac arrest.
Disciplines :
Anesthesia & intensive care
Author, co-author :
Ceric, A ; Anesthesia and Intensive Care, Department of Clinical Sciences, Lund University, Skane University Hospital, Malmö, Sweden
Dankiewicz, J; Department of Clinical Sciences Lund, Section of Cardiology, Skåne University Hospital, Malmö, Sweden
Hästbacka, J; Faculty of Medicine and Health Technology, Tampere University Hospital, Wellbeing Services County of Pirkanmaa and Tampere University, Tampere, Finland
Young, P; Intensive Care Unit, Wellington Hospital, Wellington, New Zealand ; Medical Research Institute of New Zealand, Wellington, New Zealand ; Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia ; Department of Critical Care, University of Melbourne, Melbourne, Victoria, Australia
Niemelä, V H ; Department of Anaesthesia and Intensive Care, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
Bass, F; The George Institute for Global Health, Sydney, Australia ; Royal North Shore Hospital, Sydney, Australia
Skrifvars, M B ; Department of Anaesthesia and Intensive Care, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
Hammond, N; Critical Care Program, The George Institute for Global Health, UNSW, Sydney, Australia ; Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, Australia
Saxena, M; Critical Care Division and Department of Intensive Care Medicine, The George Institute for Global Health and St George Hospital Clinical School, University of New South Wales, Sydney, Australia
Levin, H; Department of Clinical Sciences Lund, Lund University, Lund, Sweden ; Department of Research, Development, Education and Innovation, Skåne University Hospital, Lund, Sweden
Lilja, G; Neurology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden ; Department of Neurology, Skåne University Hospital, Lund, Sweden
Moseby-Knappe, M; Department of Clinical Sciences Lund, Lund University, Lund, Sweden ; Department of Neurology and Rehabilitation, Skåne University Hospital, Lund, Sweden
Tiainen, M; Department of Neurology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
Reinikainen, M; Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland ; Department of Anaesthesiology and Intensive Care, Kuopio University Hospital, Kuopio, Finland
Holgersson, J; Department of Clinical Sciences Lund, Anesthesia and Intensive Care, Lund University, Lund, Sweden ; Department of Anesthesia and Intensive Care, Helsingborg Hospital, Helsingborg, Sweden
Kamp, C B; Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark ; Department of Regional Health Research, The Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
Wise, M P; Adult Critical Care, University Hospital of Wales, Cardiff, UK
McGuigan, P J; Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK ; Regional Intensive care Unit, Royal Victoria Hospital, Belfast, United Kingdom
White, J ; Adult Critical Care, University Hospital of Wales, Cardiff, UK
Sweet, K; University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
Keeble, T R; Essex Cardiothoracic Centre, MSE NHSFT, Essex, UK ; Anglia Ruskin School of Medicine & MTRC, ARU, Chelmsford, Essex, United Kingdom
Glover, G; Department of Critical Care, Guy's and St Thomas NHS Foundation Trust, London, UK
Hopkins, P; Faculty of Life, Sciences and Medicine, King's College, Intensive Care Medicine, Centre for Human and Applied Physiological Sciences, School of Basic and Medical Biosciences, London, UK ; Intensive Care Medicine, King's Critical Care, King's College Hospital, NHS Foundation Trust, London, UK
Remmington, C; Department of Pharmacy and Adult Critical Care, Guy's and St Thomas' NHS Foundation Trust, London, UK ; Institute of Pharmaceutical Sciences, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK
Cole, J M; Critical Care, University Hospital of Wales, Cardiff, UK
Gorgoraptis, N; BartsHealth NHS Trust, London, UK
Pogson, D G; Department of Critical Care, Portsmouth University Hospitals Trust, Portsmouth, UK
Jackson, P; Leeds Teaching Hospitals NHS Trust, Leeds, UK
Düring, J; Department of Clinical Sciences, Anesthesia and Intensive Care, Lund University, Skåne University Hospital, Malmö, Sweden
Lybeck, A ; Anesthesia and Intensive Care, Department of Clinical Sciences Lund, Lund University, Skane University Hospital, Lund, Sweden
Johnsson, J; Department of Anaesthesiology and Intensive Care, Helsingborg Hospital, Helsingborg, Sweden
Unden, J; Department of Operation and Intensive Care, Hallands Hospital, Halmstad, Sweden ; Department of Intensive and Perioperative Care, Skåne University Hospital, Lund University, Lund, Sweden
Lundin, A ; Department of Anaesthesiology and Intensive Care Medicine, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Kåhlin, J; Perioperative Medicine and Intensive Care (PMI), Karolinska University Hospital, Stockholm, Sweden ; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
Grip, J; Function Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden ; Department of Clinical Science, Interventionand Technology, Karolinska Institute, Stockholm, Sweden
Lotman, E M; North Estonia Medical Centre, Tallinn, Estonia
Romundstad, L; Department of Anesthesia and Intensive Care medicine, Division of Emergencies and Critical care, Oslo University Hospital, Oslo, Norway ; Lovisenberg Diaconal University College, Oslo, Norway
Seidel, P; Department of Intensive Care Medicine, Stavanger University Hospital, Stavanger, Norway
STAMMET, Pascal ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM) > Medical Education ; Department of Anaesthesia and Intensive Care Medicine, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg
Graf, T; University Heart Center Lübeck, University Hospital Schleswig-Holstein, Schleswig-Holstein, Germany ; German Center for Cardiovascular Research (DZHK), Hamburg/Lübeck/Kiel, Germany
Mengel, A; Department of Neurology and Stroke, University Hospital Tuebingen, Hertie Institute of Clinical Brain Research, Tuebingen, Germany
Leithner, C; Charité-Universitätsmedizin Berlin, Department of Neurology, Freie Universität and Humboldt-Universität zu Berlin, Berlin, Germany
Nee, J; Department of Nephrology and Medical Intensive Care, Charité-Universitaetsmedizin Berlin, Berlin, Germany
Druwé, P ; Department of Intensive Care Medicine, Ghent University Hospital, Ghent, Belgium
Ameloot, K; Department of Cardiology, Ziekenhuis Oost-, Genk, Limburg, Belgium
Nichol, A; University College Dublin Clinical Research Centre at St Vincent's University Hospital, University College Dublin, Dublin, Ireland ; The Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Australia ; The Alfred Hospital, Melbourne, Australia
Haenggi, M; Institute of Intensive Care Medicine University Hospital Zurich, Zurich, Switzerland
Hilty, M P; Institute of Intensive Care Medicine, University Hospital Zurich, Zurich, Switzerland
Iten, M ; Department of Intensive Care Medicine, Inselspital University Hospital Bern, Bern, Switzerland
Schrag, C; Klinik für Intensivmedizin, Kantonsspital St. Gallen, St. Gallen, Switzerland
Nafi, M ; Istituto Cardiocentro Ticino, Lugano, Switzerland
Joannidis, M ; Division of Intensive Care and Emergency Medicine, Department of Internal Medicine, Medical University Insbruck, Innsbruck, Austria
Robba, C; IRCCS Policlinico San Martino, Genova, Italy. Dipartimento di Scienze Chirurgiche Diagnostiche Integrate, University of Genova, Genova, Italy
Pellis, T; Anaesthesia and Intensive Care, Pordenone Hospital, Azienda Sanitaria Friuli Occidentale, Pordenone, Italy
Belohlavek, J; First Faculty of Medicine, Charles University in Prague, Institute for Heart Diseases, Prauge, Czech Republic ; Second Department of Internal Medicine, Cardiovascular Medicine, General University Hospital, Wroclaw Medical University, Wroclaw, Poland
Rob, D; Second Department of Medicine, Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic
Arabi, Y M ; King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
Buabbas, S; Department of Anestesia, Critical Care and Pain Medicine, Jaber Alahmad Alsabah Hospital, Kuwait City, Kuwait
Yew Woon, C; Tan Tock Seng Hospital, Singapore, Singapore ; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore ; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
Aneman, A ; Intensive Care Unit, Liverpool Hospital, South Western Sydney Local Health District, Sydney, New South Wales, Australia ; South Western Clinical School, University of New South Wales, Sydney, New South Wales, Australia ; The Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia
Stewart, A; Liverpool Hospital, Liverpool, Australia
Reade, M; Medical School, University of Queensland, Level 9, Health Sciences Building, Royal Brisbane and Women's Hospital, Brisbane, Australia
Delcourt, C; The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, Australia ; Department of Clinical Medicine, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia
Delaney, A; Critical Care Program, The George Institute for Global Health. Malcolm Fisher Depratment of Intensive Care Medicine, Royal North Shore Hospital. Northern Clinical School, Sydney Medical School, University of Sydney, Sydney, Australia
Ramanan, M; Caboolture and Royal Brisbane and Women's Hospitals, Metro North Hospital and Health Service, Brisbane, Queensland, Australia ; School of Clinical Medicine, Queensland University of Technology, Brisbane, Queensland, Australia ; Critical Care Division, The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia
Venkatesh, B; The George Institute for Global Health, Sydney, Australia
Navarra, L; Medical Research Institute of New Zealand, Wellington, New Zealand
Crichton, B; Medical Research Institute of New Zealand, Wellington, New Zealand
Williams, A; Middlemore Hospital, Auckland, New Zealand
Knight, D; Department of Intensive Care, Christchurch Hospital, Christchurch Central City, New Zealand
Tirkkonen, J; Intensive Care Unit, Tampere University Hospital, Tampere, Finland
Oksanen, T; Department of Anaesthesia and Intensive Care, Jorvi Hospital, University Hospital of Helsinki and University of Helsinki, Espoo, Finland
Kaakinen, T; Research Unit of Translational Medicine, Research Group of Anaesthesiology, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland ; OYS Heart, Oulu University Hospital, MRC Oulu and University of Oulu, Oulu, Finland
Bendel, S; Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland ; Department of Anaesthesiology and Intensive Care, Kuopio University Hospital, Kuopio, Finland
Friberg, H; Anesthesia and Intensive Care, Department of Clinical Sciences Lund, Lund University, Lund, Sweden ; Intensive and Perioperative Care, Skåne University Hospital, Malmö, Sweden
Cronberg, T; Neurology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden ; Department of Neurology, Skåne University Hospital, Lund, Sweden
Jakobsen, J C; Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark ; Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
Nielsen, N; Department of Clinical Sciences Lund, Anesthesia and Intensive Care, Lund University, Lund, Sweden ; Department of Anesthesia and Intensive Care, Helsingborg Hospital, Helsingborg, Sweden
Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics – 2012 update: a report from the American Heart Association. Circulation. 2012;125(1):e2-e220. doi:10.1161/CIR.0b013e31823ac046
Atwood C, Eisenberg MS, Herlitz J, Rea TD. Incidence of EMS-treated out-of-hospital cardiac arrest in Europe. Resuscitation. 2005;67(1):75-80. doi:10.1016/j.resuscitation.2005.03.021
Rea TD, Eisenberg MS, Sinibaldi G, White RD. Incidence of EMS-treated out-of-hospital cardiac arrest in the United States. Resuscitation. 2004;63(1):17-24. doi:10.1016/j.resuscitation.2004.03.025
Thomassen A, Wernberg M. Prevalence and prognostic significance of coma after cardiac arrest outside intensive care and coronary units. Acta Anaesthesiol Scand. 1979;23(2):143-148. doi:10.1111/j.1399-6576.1979.tb01434.x
Dragancea I, Horn J, Kuiper M, et al. Neurological prognostication after cardiac arrest and targeted temperature management 33°C versus 36°C: results from a randomised controlled clinical trial. Resuscitation. 2015;93:164-170. doi:10.1016/j.resuscitation.2015.04.013
Nolan JP, Sandroni C, Bottiger BW, et al. European Resuscitation Council and European Society of Intensive Care Medicine guidelines 2021: post-resuscitation care. Intensive Care Med. 2021;47(4):369-421. doi:10.1007/s00134-021-06368-4
Callaway CW, Donnino MW, Fink EL, et al. Part 8: post-cardiac arrest care: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2015;132(18 suppl 2):S465-S482. doi:10.1161/CIR.0000000000000262
Jarpestam S, Martinell L, Rylander C, Lilija L. Post-cardiac arrest intensive care in Sweden: A survey of current clinical practice. Acta Anaesthesiol Scand. 2023;67(9):1249-1255. doi:10.1111/aas.14298
Celis-Rodríguez E, Díaz Cortés JC, Cárdenas Bolívar YR, et al. Evidence-based clinical practice guidelines for the management of sedoanalgesia and delirium in critically ill adult patients. Med Intensiva. 2020;44(3):171-184. doi:10.1016/j.medin.2019.07.013
DAS-Taskforce 2015, Baron R, Binder A, et al. Evidence and consensus based guideline for the management of delirium, analgesia, and sedation in intensive care medicine. Revision 2015 (DAS-guideline 2015) - short version. Ger Med Sci. 2015;13:Doc19. doi:10.3205/000223
Devlin JW, Skrobik Y, Gelinas C, et al. Clinical practice guidelines for the prevention and Management of Pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018;46(9):e825-e873. doi:10.1097/CCM.0000000000003299
Sandroni C, Nolan JP, Andersen LW, et al. ERC-ESICM guidelines on temperature control after cardiac arrest in adults. Intensive Care Med. 2022;48(3):261-269. doi:10.1007/s00134-022-06620-5
Hirsch KG, Abella BS, Amorim E, et al. Critical care management of patients after cardiac arrest: a scientific statement from the American Heart Association and neurocritical care society. Circulation. 2024;149(2):e168-e200. doi:10.1161/CIR.0000000000001163
Lybeck A, Friberg H, Aneman A, et al. Prognostic significance of clinical seizures after cardiac arrest and target temperature management. Resuscitation. 2017;114:146-151. doi:10.1016/j.resuscitation.2017.01.017
Vossler DG, Bainbridge JL, Boggs JG, et al. Treatment of refractory convulsive status epilepticus: a comprehensive review by the American Epilepsy Society Treatments Committee. Epilepsy Curr. 2020;20(5):245-264. doi:10.1177/1535759720928269
Hausburg MA, Banton KL, Roman PE, et al. Effects of propofol on ischemia-reperfusion and traumatic brain injury. J Crit Care. 2020;56:281-287. doi:10.1016/j.jcrc.2019.12.021
Oddo M, Crippa IA, Mehta S, et al. Optimizing sedation in patients with acute brain injury. Crit Care. 2016;20(1):128. doi:10.1186/s13054-016-1294-5
Jessen NA, Munk AS, Lundgaard I, Nedergaard M. The glymphatic system: a Beginner's guide. Neurochem Res. 2015;40(12):2583-2599.
Stamatakis EA, Adapa RM, Absalom AR, Menon DK. Changes in resting neural connectivity during propofol sedation. PLoS One. 2010;5(12):e14224.
Treggiari MM, Romand JA, Yanez ND, et al. Randomized trial of light versus deep sedation on mental health after critical illness. Crit Care Med. 2009;37(9):2527-2534. doi:10.1097/CCM.0b013e3181a5689f
Kress JP, Pohlman AS, O'Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med. 2000;342(20):1471-1477. doi:10.1056/NEJM200005183422002
Shehabi Y, Chan L, Kadiman S, et al. Sedation depth and long-term mortality in mechanically ventilated critically ill adults: a prospective longitudinal multicentre cohort study. Intensive Care Med. 2013;39(5):910-918. doi:10.1007/s00134-013-2830-2
SRLF Trial Group. Impact of oversedation prevention in ventilated critically ill patients: a randomized trial-the AWARE study. Ann Intensive Care. 2018;8(1):93. doi:10.1186/s13613-018-0425-3
Maagaard M, Barbateskovic M, Andersen-Ranberg NC, et al. Dexmedetomidine for the prevention of delirium in adults admitted to the intensive care unit or post-operative care unit: a systematic review of randomised clinical trials with meta-analysis and Trial sequential analysis. Acta Anaesthesiol Scand. 2023;67(4):382-411. doi:10.1111/aas.14208
Wijdicks EF, Hijdra A, Young GB, Bassetti CL, Wiebe S. Quality standards subcommittee of the American Academy of Neurology. Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the quality standards subcommittee of the American Academy of Neurology. Neurology. 2006;67(2):203-210. doi:10.1212/01.wnl.0000227183.21314.cd
Sandroni C, D'Arrigo S, Cacciola S, et al. Prediction of poor neurological outcome in comatose survivors of cardiac arrest: a systematic review. Intensive Care Med. 2020;46(10):1803-1851. doi:10.1007/s00134-020-06198-w
Wimmer H, Stensønes SH, Benth JŠ, et al. Outcome prediction in comatose cardiac arrest patients with initial shockable and non-shockable rhythms. Acta Anaesthesiol Scand. 2024;68(2):263-273. doi:10.1111/aas.14337
Sessler CN, Gosnell MS, Grap MJ, et al. The Richmond agitation-sedation scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 2002;166(10):1344-1348. doi:10.1164/rccm.2107138
Riker RR, Picard JT, Fraser GL. Prospective evaluation of the sedation-agitation scale for adult critically ill patients. Crit Care Med. 1999;27(7):1325-1329. doi:10.1097/00003246-199907000-00022
Butcher NJ, Monsour A, Mew EJ, et al. Guidelines for reporting outcomes in trial protocols: the SPIRIT-outcomes 2022 extension. Jama. 2022;328(23):2345-2356. doi:10.1001/jama.2022.21243
Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c332.
Kahan BC, Hall SS, Beller EM, et al. Reporting of factorial randomized trials: extension of the CONSORT 2010 statement. Jama. 2023;330(21):2106-2114.
Wijdicks EF, Bamlet WR, Maramattom BV, Manno EM, McClelland RL. Validation of a new coma scale: the FOUR score. Ann Neurol. 2005;58(4):585-593. doi:10.1002/ana.20611
Devlin JW, Skrobik Y, Gélinas C, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018;46(9):e825-e873.
Badjatia N, Strongilis E, Gordon E, et al. Metabolic impact of shivering during therapeutic temperature modulation: the bedside shivering assessment scale. Stroke. 2008;39(12):3242-3247. doi:10.1161/STROKEAHA.108.523654
Sandroni C, Cariou A, Cavallaro F, et al. Prognostication in comatose survivors of cardiac arrest: an advisory statement from the European Resuscitation Council and the European Society of Intensive Care Medicine. Intensive Care Med. 2014;40(12):1816-1831. doi:10.1007/s00134-014-3470-x
Haywood K, Whitehead L, Nadkarni VM, et al. COSCA (core outcome set for cardiac arrest) in adults: an advisory statement from the international liaison committee on resuscitation. Circulation. 2018;137(22):e783-e801. doi:10.1161/cir.0000000000000562
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727-1736. doi:10.1007/s11136-011-9903-x
Cook D, Lauzier F, Rocha MG, Sayles MJ, Finfer S. Serious adverse events in academic critical care research. Cmaj. 2008;178(9):1181-1184. doi:10.1503/cmaj.071366
Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). Jama. 2016;315(8):801-810.
GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993;329(10):673-682.
van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19(5):604-607. doi:10.1161/01.str.19.5.604
Olsen MH, Jensen AKG, Dankiewicz J, et al. Interactions in the 2×2×2 factorial randomised clinical STEPCARE trial and the potential effects on conclusions: a protocol for a simulation study. Trials. 2022;23(1):889. doi:10.1186/s13063-022-06796-7
Ameloot K, De Deyne C, Eertmans W, et al. Early goal-directed haemodynamic optimization of cerebral oxygenation in comatose survivors after cardiac arrest: the neuroprotect post-cardiac arrest trial. Eur Heart J. 2019;40(22):1804-1814. doi:10.1093/eurheartj/ehz120
Jakkula P, Pettila V, Skrifvars MB, et al. Targeting low-normal or high-normal mean arterial pressure after cardiac arrest and resuscitation: a randomised pilot trial. Intensive Care Med. 2018;44(12):2091-2101. doi:10.1007/s00134-018-5446-8
Díaz M, Becker DE. Thermoregulation: physiological and clinical considerations during sedation and general anesthesia. Anesth Prog. 2010;57(1):25-33.
Reade MC, Bass F, Howe B, Seppelt I, Shehabi Y. Considerations for co-enrolment in randomised controlled effectiveness trials in critical care: the SPICE-8 co-enrolment guidelines. Crit Care Resusc. 2017;19(2):110-114.
Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369(23):2197-2206. doi:10.1056/NEJMoa1310519
Dankiewicz J, Cronberg T, Lilja G, et al. Hypothermia versus normothermia after out-of-hospital cardiac arrest. New Eng J Med. 2021;384(24):2283-2294. doi:10.1056/nejmoa2100591
Dankiewicz J, Cronberg T, Lilja G, et al. Targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest (TTM2). A randomised clinical trial – rationale and design. Am Heart J. 2019;217:23-31.
Nielsen N, Hovdenes J, Nilsson F, et al. Outcome, timing and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest. Acta Anaesthesiol Scand. 2009;53(7):926-934. doi:10.1111/j.1399-6576.2009.02021.x
Pareek N, Kordis P, Beckley-Hoelscher N, et al. A practical risk score for early prediction of neurological outcome after out-of-hospital cardiac arrest: MIRACLE2. Eur Heart J. 2020;41(47):4508-4517. doi:10.1093/eurheartj/ehaa570
World Medical Association. World medical association declaration of Helsinki: ethical principles for medical research involving human subjects. Jama. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053
Gordon Lan KK, Demets DL. Discrete sequential boundaries for clinical trials. Biometrika. 1983;70(3):659-663. doi:10.1093/biomet/70.3.659
Haywood K, Whitehead L, Nadkarni VM, et al. COSCA (core outcome set for cardiac arrest) in adults: an advisory statement from the international liaison committee on resuscitation. Resuscitation. 2018;127:147-163. doi:10.1016/j.resuscitation.2018.03.022
