Neurologic Function and Health-Related Quality of Life in Patients Following Targeted Temperature Management at 33°C Vs 36°C After Out-Of-Hospital Cardiac Arrest

Supplementary Online Content

Cronberg T, Lilja G, Horn J, et al; TTM Trial Investigators. Neurologic function and health-related quality of life in patients following targeted temperature management at 33°C vs 36°C after out-of-hospital cardiac arrest. JAMA Neurol. Published online April 6, 2015. doi:10.1001/jamaneurol.2015.0169.

eAppendix.

eTable 1. Outcome Assessments and Questionnaires at 180 Days in the Target Temperature Management Trial

eTable 2. Comparison Between Observed Data and Data Obtained by Imputing Missing Values Using Multiple Imputations of Data From Patients Alive at the Date of Follow-up

eTable 3. Relation and Meeting Frequency Between Informant and Patient: IQCODE

eTable 4. Factors Potentially Influencing Neurological and Cognitive Testing

eTable 5. Outcomes of Cognitive Function and Health-Related Quality of Life at Follow-up: Complete Case Analysis

eTable 6. Analysis of MMSE and IQCODE per Category: Complete Case Analysis

eReferences

This supplementary material has been provided by the authors to give readers additional information about their work.

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Coordinating hospital...... 2 Chief investigator and contact ...... 2 Steering group ...... 2 Statistician...... 2 Independent Data Monitoring and Safety Committee ...... 2 Follow>up coordinator ...... 2 Trial coordinators ...... 2 Sites, principal investigators and investigators ...... 2 Supporting methods ...... 4 Details of the intervention ...... 4 Supporting results ...... 5 Supporting tables ...... 6 References ...... 11

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Chief investigator and contact Niklas Nielsen, MD, PhD, DEAA, EDIC, Department of Anesthesiology and Intensive Care, Helsingborg Hospital, S Vallgatan 5, 251 87, Helsingborg, Sweden; Department of Clinical Sciences, Lund University, Lund, Sweden, [email protected]

Steering group Niklas Nielsen, Department of Anesthesiology and Intensive Care, Helsingborg hospital, Helsingborg, Sweden (Chair and Chief Investigator); Tobias Cronberg, Department of Neurology, Skåne University Hospital, Lund, Sweden; David Erlinge, Department of Cardiology, Skåne University Hospital, Lund, Sweden; Hans Friberg, MD, PhD, Department of Anesthesiology and Intensive Care, Skåne University Hospital, Lund, Sweden (Senior Investigator); Christian Hassager, The Heart Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Janneke Horn, Department of Intensive Care, Academic Medical Centre, Amsterdam, The Netherlands; Jan Hovdenes, Department of Anesthesiology, Rikshospitalet, Oslo University Hospital, Oslo, Norway; Jesper Kjaergaard, The Heart Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Michael Kuiper, Department of Intensive Care, Leeuwarden Hospital, Leeuwarden, The Netherlands; Yvan Gasche, Department of Intensive Care, Geneva University Hospital, Geneva, Switzerland; Thomas Pellis, Department of Intensive care, Santa Maria degli Ángeli, Pordenone, Italy; Pascal Stammet, Department of Anesthesiology and Intensive Care, Centre Hospitalier de Luxembourg, Luxembourg; Michael Wanscher, The Heart Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Jørn Wetterslev, Copenhagen Trial Unit, Rigshospitalet, Copenhagen, Denmark; Matt P Wise, Adult Critical Care, University Hospital of Wales, Cardiff, United Kingdom; Anders Åneman, Department of Intensive Care, Liverpool Hospital, Sydney, Australia

Statistician Per Winkel, Copenhagen Trial Unit, Rigshospitalet, Copenhagen, Denmark

Independent Data Monitoring and Safety Committee Professor Lars V Køber (Chair), University of Copenhagen, Denmark, Professor Djillali Annane, University of Paris, France, Professor Jan Wernerman, Karolinska Institute, Sweden, Associate professor Theis Lange, Department of Biostatistics, University of Copenhagen, Denmark (statistician).

Follow-up coordinator Gisela Lilja, department of Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden

Trial coordinators Ulla-Britt Karlsson, Helsingborg Hospital, Sweden; Liz Jergle-Almqvist, Region Skåne FOU-center, Sweden; Berit Grevstad, Copenhagen Trial Unit, Denmark; Kate Whitfield, Copenhagen Trial Unit, Denmark. Australian management: Anders Åneman, Sharon Micallef, Parisa Glass, John Myburgh, Manoj Saxena, Antony Stewart, Simon Finfer, Gillian Bishop, Dorrilyn Rajbhandari, Naomi Hammond, Lynsey Willenberg.

Sites, principal investigators and investigators Australia: Department of Intensive Care, St George Hospital, Sydney: Manoj Saxena (PI), Jennene Miller, Deborah Inskip; Department of Intensive Care, North Shore Hospital, Sydney: Lewis Macken © 2015 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 10/01/2021 (PI), Simon Finfer, Noel Eatough, Naomi Hammond, Frances Bass, Elizabeth Yarad, Anne O'Connor, Simon Bird, Timothy Jewell, Gareth Davies, Karl Ng, Sharon Coward; Department of Intensive Care, Liverpool Hospital, Sydney: Anders Åneman (PI), Antony Stewart, Sharon Micallef, Sharyn Parker, Dennis Cortado; The George Institute of Global Health: Sharon Micallef, Ann Gould, Meg Harward, Kelly Thompson, Naomi Hammond, Parisa Glass, John Myburgh. Czech republic: 2nd Department of Internal Medicine, Cardiology and Angiology, General University Hospital in Prague, Prague: Ondrej Smid (PI), Jan Belholavek, Marketa Kreckova, Ales Kral, Jan Horak, Michal Otahal, Jan Rulisek, Jan Malik, Martin Prettl. Denmark: Departments of Cardiology and Cardiothoracic Anesthesiology, The Heart Center, Copenhagen University Hospital Rigshospitalet, Copenhagen: Jesper Kjaergaard (PI), Christian Hassager, Michael Wascher, Soeren Boesgaard, Jacob E Moller, John Bro- Jeppesen, Ane Loof Johansen. Italy: Department of Intensive Care, Ospedale Universitario di Cattinara, Trieste: Vincenzo Campanile (PI), Alberto Peratoner, Francesca Verginella , Daniele Leone; Department of Intensive Care, Santa Maria degli Angeli Hospital, Pordenone: Thomas Pellis (PI), Andrea Roncarati, Eliana Franceschino, Anna Sanzani, Alice Martini , Micol Perlin; Department of Anesthesia and Intensive Care, IRCCS San Martino IST, Genoa: Paolo Pelosi (PI), Iole Brunetti, Angelo Insorsi, Stefano Pezzato, Giorgio De Luca, Emanuela Gazzano, Gian Andrea Ottonello, Andrea Furgani, Rosanna Telani, Simona Maiani. Luxembourg: Department of Anesthesiology and Intensive Care, Medical Centre, Luxembourg: Pascal Stammet (PI), Christophe Werer, Jaqueline Kieffer. The Netherlands: Department of Intensive Care, AMC Amsterdam: Janneke Horn (PI), Annelou L vd Veen, Tineke Winters, Nicole P Juffermans; Department of Intensive Care, Leeuwarden Hospital, Leeuwarden: Michael Kuiper (PI), PH Egbers, EC Boerma, RT Gerritsen, H Buter, C de Jager, F de Lange, M Loos, PM Koetsier, WP Kingma, N Bruins, L de Kock, M Koopmans; Department of Intensive Care, Rijnstaate Hospital, Arnhem: Frank Bosch (PI), Monique AM Raaijmakers, SWL Metz- Hermans; Department of Intensive Care, Onze Lieuwe Vrouwe Gasthuis, Amsterdam: Henrik Endeman (PI), Saskia Rijkenberg, Addy Bianchi. Norway: Department of Anesthesiology and Intensive Care, Oslo University Hospital: Jan Hovdenes (PI), Jan Frederik Bugge, Hilde Norum, Andreas Espinoza, Viesturs Kerans, Helene Brevik, Morten Svalebjørg, Guro Grindheim, Arne Jan Petersen, Andreas Baratt-Due, Jon Henrik Laake, Ulrik Spreng, Marte Marie Wallander Karlsen; Department of Heart Diseases, Haukeland University Hospital, Bergen: Jørund Langøren (PI), Rune Fanebust, Marianne Sætrang Holm, Stine Iren Flinterud, Carsten Wickman. Sweden: Department of Anesthesiology and Intensive Care, Helsingborg Hospital, Helsingborg: Jesper Johnsson (PI), Florian Ebner, Nerida Gustavsson, Heléne Petersson, Jörgen Petersson, Faezheh Nasiri, Frida Stafilidou; Department of Anesthesiology and Intensive Care, Karlstad Hospital, Karlstad: Kristine Edqvist (PI), Sven Uhlig, Gunilla Sköld, Johan Sanner; Department of Anesthesiology and Intensive Care, Kungälv Hospital, Kungälv: Jesper Wallskog (PI), Department of Intensive Care, Linköping University Hospital, Linköping: Nicholas Wyon (PI), Martin Golster, Anders Samuelsson, Carl Hildebrand, Taichi Kadowaki, Jessica Larsson- Viksten, Lina De Geer, Patrik Hansson, Henrik Appelberg, Anders Hellsten, Susanne Lind; Department of Anesthesiology and Intensive Care, Skåne University Hospital, Lund: Malin Rundgren (PI), Thomas Kander, Johan Persson, Martin Annborn, Anne Adolfsson, Ingrid Corrigan, Tobias Cronberg, Hans Friberg, Irina Dragancea; Department of Anaesthesiology and Intensive Care, Skåne University Hospital, Malmö: Johan Undén (PI), Marina Larsson, Michelle Chew, Mårten Unnerbäck; Department of Anesthesiology and Intensive Care, Norra Älvsborgs Län Hospital: Per Petersen (PI), Anna Svedung-Rudebou; Department of Anesthesiology and Intensive Care, Vrinnevi Hospital, Norrköping: Robert Svensson (PI), Hilde Elvenes, Carl Bäckman; Department of Anesthesiology and Intensive Care, Sahlgrenska University Hospital, Gothenburg: Christian Rylander (PI), Patrik Martner, Louise Martinell, Björn Biber, Marita Ahlqvist, Caisa Jacobson, Marie-Louise Forsberg, Roman Desta Lindgren, Fatma Bergquist; Department of Thoracic Anesthesiology and Intensive Care, Sahlgrenska University Hospital, Gothenburg: Anders Thorén (PI), Martin Fredholm, Johan Sellgren, Lisa Hård af Segerstad, Mikael Löfgren, Ingvor Gustavsson, Christina Henström, Marita Ahlqvist; Department of Anesthesiology and Intensive Care, Sahlgrenska University Hospital Östra, Gothenburg: Bertil Andersson (PI), Karin Thiringer, Nadja Rydholm; Department of Anesthesiology and Intensive Care, Örebro University Hospital, Örebro: Stefan Persson (PI), Jawad Jawad, Ingela Östman, Ida Berglind, Eric Bergström, Annika Andersson, Cathrine Törnqvist. Switzerland: Department of Anesthesiology, Pharmacology and Intensive Care, Geneva University Hospital, Geneva: Yvan Gasche (PI), Nubia Lafayete Marques de Mello, Valérie Gardaz; Department of Intensive Care, Hospital St Gallen, St Gallen: Gian-Reto Kleger (PI), Claudia Schrag, Edith Fässler; © 2015 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 10/01/2021 Department of Intensive Care, Hospital La Chaux de Fonds, Hervé Zender (PI). United Kingdom: Adult Critical Care, University Hospital of Wales, Cardiff: Matthew Wise (PI), Nicki Palmer (nee Haskins), Jen Fouweather, Jade M Cole, Eve Cocks, Paul J Frost, Anton G Saayman, Tom Holmes, Christopher D Hingston, Gareth M Scholey, Helen Watkins, Stephen Fernandez; Department of Intensive Care, Royal Berkshire Hospital, Reading: Andrew Walden (PI), Jane Atkinson, Nicola Jacques, Abby Brown; Department of Intensive Care, Royal Bournemouth Hospital, Bournemouth: Julius Cranshaw (PI), Peter Berridge, Robert McCormick, Martin Schuster-Bruce, Michelle Scott, Nigel White, Emma Vickers; Department of Intensive Care, Guy's and St Thomas NHS Trust, London: Guy Glover (PI), Marlies Ostermann, Paul Holmes, Michael Koutroumanidis, Katie Lei, Barnaby Sanderson, John Smith; Department of Intensive Care, St George’s Hospital, London: Nawaf Al-Subaie (PI), Matthew Moore, Paul Randall, Johannes Mellinghoff, Azul Forti Buratti, Chris Ryan, Jonathan Ball, Gaynor Francis.

Supporting methods

Complete exclusion criteria: obvious or suspected pregnancy, known bleeding diathesis (medically induced coagulopathy did not exclude the patient), suspected or confirmed acute intracranial bleeding, suspected or confirmed acute stroke, unwitnessed cardiac arrest with initial rhythm asystole, known limitations in therapy and Do Not Resuscitate-order, known disease making 180 days survival unlikely, known pre-arrest Cerebral Performance Category 3 or 4, and systolic blood pressure <80 mm Hg in spite of fluid loading/vasopressor and/or inotropic medication/intra aortic balloon pump that did not recover during the 240 minute inclusion window.

Details of the intervention The intervention period of 36 hours commenced at the time of randomization. All patients, in both intervention groups, were sedated until the end of the intervention period. The choices of sedatives, analgesics and neuromuscular blocking agents were at the discretion of the treating physician. Core body temperature was measured with a temperature probe in the urinary bladder, or with an esophageal or intravascular probe in patients with low urinary output. The goal of the intervention was to achieve the allocated temperature as rapidly as possible using ice-cold fluids, ice-packs, and intravascular or surface temperature management devices at the discretion of the site. Patients with an initial body temperature between 30°C and 33°C were actively rewarmed to 33°C at a maximum rate of 0.5°C per hour in both groups. For patients allocated to the 36°C-group, passive rewarming to 36°C was mandated in the range from 33°C to 36°C, after which controlled temperature management was commenced and continued throughout the intervention period. After 28 hours gradual rewarming to 37°C by a maximum of 0.5°C per hour was commenced in both groups. At 36 hours mandatory sedation was discontinued or tapered. After the intervention period the intention was to maintain the body temperature for unconscious patients below 37.5°C until 72 hours post-cardiac arrest, using fever control measures at the discretion of the sites. Concomitant intensive care, cardiological and neurological treatment followed standard practice.

Neurological prognostication All patients in the trial were actively treated until a minimum 72 hours after the intervention period, i.e. 108 hours after randomization, when neurological evaluation was done on patients not regaining consciousness. Exceptions from this rule were 1) patients with myoclonus status in the first 24 hours and 2) patients who became brain dead due to cerebral herniation and 3) because of ethical reasons described below. External physicians, blinded to intervention assignment, evaluated the patient at the end of phase 3 and made a statement on neurological prognosis. At that time-point, limitations in and withdrawal of therapy could be instituted by the treating physicians. The neurological evaluation was based on clinical neurological examination, SSEP and electroencephalogram (EEG).1,2 Biomarkers for brain damage were not used for operational prognostication. Findings allowing for discontinuation of active intensive care: brain death due to © 2015 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 10/01/2021 cerebral herniation, severe myoclonus status in the first 24 hours after admission and a bilateral absence of N20- peak on median nerve SSEP, persisting coma with a Glasgow Motor Score 1-2 and bilateral absence of N20- peak on median nerve SSEP, persisting coma with a Glasgow Motor Score 1-2 and a treatment refractory status epilepticus. Patients with Glasgow Motor Score 1-2 at 72 hours or later after the end of the intervention period who had retained N20-peak on the SSEP, or patients in hospitals where SSEP was not available, were re- examined daily and the limitations/withdrawal of intensive care considered if GCS-Motor did not improve and metabolic and pharmacological affection was ruled out. Active treatment could be withdrawn prior to 72 hours after the intervention period for ethical reasons (for instance: previously unknown information about disseminated end-stage cancer or refractory shock with end-stage multiorgan failure). However assumptions of a poor neurological function were not allowed be the sole reason for withdrawal of active treatment prior to 72 h after the intervention period (exception: brain death and early myoclonus status including a negative SSEP).

Supporting results

Post hoc power calculations The sample size of 939 patients in this study was determined in a power calculation for the primary outcome of the Target Temperature Management after Cardiac Arrest trial: survival until end of the trial. The different outcomes in this study were thus not subject to a priori power calculations. Post hoc power calculations were performed indicating a minimal detectable difference in MMSE, IQCODE, TSQ and the summary scores of SF-36: MCS and PCS between the 33°C and the 36°C group, with a type-1 risk (alpha) of 0.05 and a power (beta) of 80% given by the sample size of 939 and the control group (36°C) mean and standard deviation or event rate, not adjusted for multiplicity. The minimal detectable differences are for MMSE 2.5 points, IQCODE 4.6 points, MCS 2.5 points, PCS 2.1 points, TSQ-1 5.9% and TSQ-2 8.8%.

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eTable 1. Outcome Assessments and Questionnaires at 180 Days in the Target Temperature Management Trial

Abbr. Score Cut-off level Area Test administration

PRO PerfO ObsRO ClinRO

© Short Form Questionniare-36 SF-36v2 36 questions measure 8 health-domains <47 (mean T-scores) Generic ! © 1 version 2 (Physical functioning, Role-Physical, indicates worse health Health-status Bodily Pain, General Health, Vitality, than the general Social Functioning, Role-Emotional, population Mental Health). Quality Metrics Health Outcomes™ Scoring Software version 4.5 calculates Age comparable norm- norm-based T-scores for each domain mean and construct two composite scores of PCS (T-scores) 65-74: overall health; the Mental Component 45.6 Summary (MCS) and the Physical >75: 43.11 Component Summary (PCS). The norm MCS (T-scores) 65-74: mean is equal to a T-score of 50. 53.71 >75: 53.4

Downloaded From: https://jamanetwork.com/ on 10/01/2021 2 3 Two Simple Questions , TSQ Possible answers are; Yes or No Yes, to question 1 Neurological ! 1“In the last two weeks, did recoded to a binary variable AND 1.1, or No to outcome you require help from another question 2 is (everyday person for your everyday considered a worse activities/me activities?” outcome than before ntal recovery) If the answer to (1) is “Yes”; the CA 1.1, “Is this a new situation following your heart arrest?” 2.”Do you feel that you have made a complete mental recovery after your heart arrest?”

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Informant Questionnaire on IQCODE 26 questions (items) rated at a 5-point 26-78 Everyday ! 4 Cognitive Decline scale (1 much better 3 no change 5 No decline or better memory and much worse). The total score represent 79-83 function the sum of all items (range 26-130) Minor decline 84-86 Moderate decline 87- 130 Major decline

A cut-off value of >83 is used to identify mild cognitive impairment 5

MiniMental Status Examination MMSE The total sum (range 0-30) of 11 items 27-30 normal Screening of ! 6 assessed with 30 questions/tasks scored: 21-26 mild impairment overall correct (1) or incorrect (0) 11-20 moderate cognitive impairment ability 0-11 major impairment (orientation, registration, A cut-off of 24 is most attention, widely used in recall, screening for dementia language, visuospatial ability)

Downloaded From: https://jamanetwork.com/ on 10/01/2021 Cerebral Performance Category CPC 5 point scale: 1-2 good outcome, General ! 7 1, conscious and alert with good 3-4 poor outcome neurological cerebral performance, 5 dead outcome 2, conscious and alert with moderate cerebral performance, 3, conscious with severe cerebral disability 4, comatose or in a persistent vegetative state

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5, brain dead 8, 9 modified Rankin Scale mRS 7 point scale: 0-3 good outcome General ! outcome 0, no symptoms at all, 4-5 poor outcome

1, no significant disability 6 dead despite symptoms, 2, slight disability,

3, moderate disability, 4, moderately severe

disability 5, severe disability ,

PRO= Patient-reported outcome (subjective) PerfO= Performance outcome ObsRO= Obsever-reported outcome (by an informant) ClinRO= Clinican-reported outcome. Cut –off values and categorical values are based on the references shown in the Table.

Downloaded From: https://jamanetwork.com/ on 10/01/2021 eTable 2. Comparison Between Observed Data and Data Obtained by Imputing Missing Values Using Multiple Imputations of Data From Patients Alive at the Date of Follow-up Quantity Percent missing Mean/proportion of Mean of imputed a values original data values IQCODE 11 83.9 87.3 MMSE 16 27.2 23.9 PCS 10 47.6 41.0 MCS 10 49.4 42.3 TSQ-1 8 17.0% 25.8% TSQ-2 8 65.1% 52.9% a) The multiple imputation was confined to data from patients belonging to the modified intention tor treat population, who were alive at the date of follow-up (N = 491).

Downloaded From: https://jamanetwork.com/ on 10/01/2021 eTable 3. Relation and Meeting Frequency Between Informant and Patient: IQCODE* 33°C 36°C Number of informants answering test – no. 223 219 Living together – no. 167 164 Not living together – no. 56 55

-Meet every day 6 10 -Meet several times a week 27 21 -Meet once a week 10 7 -Several times a month 6 4 -Meet once a month 1 5 -Meet more seldomly 6 7 *IQCODE denotes Informant Questionnaire of Cognitive Decline in the Elderly

Downloaded From: https://jamanetwork.com/ on 10/01/2021 eTable 4. Factors Potentially Influencing Neurological and Cognitive Testing 33°C 36°C Factor – no. Neurological disease 24 21 Memory problems before cardiac arrest 9 9 Dyslexia 9 3 Hearing problem 19 14 Vision problem 19 24 Speech problem 11 11 Paresis 9 6

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33°C 36°C P -value

Performance measures MMSE (all patients) Median 0 0 ## Interquartile range [0-28] [0-28] 0.79 Mean±SD 12.7±13.8 12.7±13.9 MMSE (alive at follow up) Median 28 29 ## Interquartile range [26-30] [26-30] 0.65 Mean±SD 27.1±4.1 27.2±4.2

Observer reported measures IQCODE (all patients) ## Median 130 130 0.52 Interquartile range [80-130] [80-130] Mean±SD 107.6±25.0 108.3±24.2 IQCODE (alive at follow up) ## Median 79 80 0.04 Interquartile range [78.0-85.0] [78.0-86.0] Mean±SD 83.1±10.6 83.7±10.5

Patient reported measures (alive at follow up) TSQ1: Did you during the two last weeks need help for everyday activities?# N (% of alive at follow up) †† 41 (19) 36 (16) 0.55 TSQ2: Do you feel that you have made a complete mental recovery after the cardiac arrest? N (% of †† alive at follow up) 152 (67) 143 (63) 0.41 SF-36v2® MCS (alive at follow-up) ## Median 53.0 52.0 0.71 Interquartile range [42.8-58.0] [43.8-58] Mean 49.6±10.8 49.3±10.9 SF-36v2® PCS (alive at follow-up) ## Median 48 50 0.60 Interquartile range [40-55] [41-56] Mean±SD 47.4±9.8 47.9±9.7 *IQCODE denotes Informant questionnaire for the elderly, MMSE-mini mental state exam, SF-36® - short form 36, SD-standard deviation, TSQ-two simple questions. All analyses were performed on the complete case data set. †Includes six patients lost to follow-up for evaluation of neurological function and quality-of-life that were alive at time of follow up. #The number excludes patients that did need help for everyday activities, but when this situation was not new after the cardiac arrest. ††P-values obtained by Chi-square test ##P-values obtained by Wilcoxon-Mann-Whitney test

Downloaded From: https://jamanetwork.com/ on 10/01/2021 eTable 6. Analysis of MMSE and IQCODE per Category: Complete Case Analysis*

MMSE Normal Mild Moderate Major Missing Dead P-value impairment impairment impairment (27-30) (21-26) (11-20) (0-11) 33°C N (%) 150 (32) 44 (9) 13 (3) 1 (>1) 37 (8) 228 (48) 36°C N (%) 148 (32) 41 (9) 12 (3) 3 (>1) 42 (9) 220 (47) 0.96

IQCODE No decline Minor Moderate Major Dead (26-78) decline decline decline (79-83) (84-86) (87-130) 33°C N (%) 100 (21) 58 (12) 15 (3) 47 (10) 25 (5) 228 (48) 36°C N (%) 74 (16) 72 (15) 19 (4) 49 (11) 35 (7) 220 (47) 0.37 *MMSE denotes Mini mental state exam, IQCODE – Informant questionnaire of cognitive decline for the elderly. All analyses were performed on the complete case data set. Numbers in italics are reference values. P- values obtained by Cochran-Armitage trend test.

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eReferences

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