Targeted Hypothermia Versus Targeted Normothermia After Out-of-hospital Cardiac Arrest
NCT ID: NCT02908308
Last Updated: 2023-04-03
Study Results
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Basic Information
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COMPLETED
NA
1900 participants
INTERVENTIONAL
2017-11-18
2022-12-31
Brief Summary
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Detailed Description
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The TTM1 trial (NCT01020916) was a multicenter, multinational, outcome assessor-blinded, parallel group, randomised clinical trial comparing two strict target temperature regimens of 33°C and 36°C in adult patients, who have sustained return of spontaneous circulation and are unconscious after out-of-hospital cardiac arrest, when admitted to hospital. The trial did not demonstrate any difference in survival until end of trial (Hazard Ratio with a point estimate in favour of 36°C of 1.06 (95% confidence interval 0.89-1.28; P=0.51) or neurologic function at six months after the arrest, measured with CPC and mRS.
The planned study is a international, multicenter, parallel group, non-commerical, randomized, superiority trial in which a target temperature om 33°C after cardiac arrest will be compared to normothermia and early treatment of fever.
Patients eligible for inclusion will be unconscious adult patients with OHCA of a presumed cardiac cause with stable return of spontaneous circulation. Randomization will be performed by a physician in the emergency department, in the angiography suite or in the intensive care unit via web-based application using permuted blocks with varying sizes, stratified by site. Due to the nature of the intervention, health care staff will not be blinded to the intervention. However, the physicians who will assess outcomes will be blinded to temperature allocation, as will those who perform prognostication.
The intervention period will commence at the time of randomization. Cooling in the hypothermia group will achieved by means of cold fluids and state-of-the-art cooling devices (intravascular or body-surface applied closed loop systems). The initial aim will be to achieve a body temperature of 33.0°C. When this has been achieved, the target temperature will be 33°C until 28 hours after randomisation. When 28 hours have passed, gradual rewarming at a rate of 1/3°C per hour will commence, this will allow 12 hours for rewarming.
In the normothermia arm the aim will be to avoid a temperature greater than or equal to 37.8°C using conservative measures. If a single temperature of 37.8° or greater is measured, active cooling with a device should be initiated and maintained until 40 hours after randomization.
All participants will be sedated, mechanically ventilated and hemodynamically supported throughout the intervention period of 40 hours. Participants in both arms who remain comatose after 40h should be kept at a normothermic level (36.5 - 37.7°C) until 72h after randomization and active warming should be avoided.
Participants who remain unconscious four days after randomization will be assessed according to a conservative protocol based on the European Resuscitation Council's recommendations for withdrawal of life sustaining therapies.
Follow up will be performed at:
1 month (face-to-face or telephone), Assessment according to the modified Rankin scale (mRS)
6 moths (face-to-face), Assessment according to the mRS-scale. Assessment of health-related quality of life using EQ5D-5L.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
TRIPLE
Study Groups
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Normothermia
Standard care with early treatment of fever. Active temperature control with a device will be used if the patient develops a temperature greater than or equal 37.8°C.
Standard care with early treatment of fever
Normothermia and standard care - use of a device for temperature control if temperature is greater than or equal to 37.8°C
Hypothermia
Targeted temperature management to 33°C for up to 28h.
Targeted temperature management to 33°C
Rapid cooling to below 33°C, followed by temperature control at 33°C for up to 28h.
Interventions
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Targeted temperature management to 33°C
Rapid cooling to below 33°C, followed by temperature control at 33°C for up to 28h.
Standard care with early treatment of fever
Normothermia and standard care - use of a device for temperature control if temperature is greater than or equal to 37.8°C
Eligibility Criteria
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Inclusion Criteria
* Presumed cardiac cause of cardiac arrest
* Unconscious with a FOUR-score \<M4 (not obeying verbal commands)
* Stable return of spontaneous circulation (20 min)
* Eligible for intensive care treatment without restrictions
* Inclusion within 180 minutes of ROSC
Exclusion Criteria
* Temperature on admission \<30°C.
* On ECMO prior to ROSC
* Obvious or suspected pregnancy
* Intracranial bleeding
* On ECMO prior to ROSC
* Severe chronic obstructive pulmonary disorder (COPD) with long-term home oxygen therapy
18 Years
ALL
No
Sponsors
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Lund University
OTHER
Region Skåne - Skånevård SUND
UNKNOWN
Copenhagen Trial Unit, Center for Clinical Intervention Research
OTHER
Clinical Trials Sweden, Forum South
UNKNOWN
Integrated Biobank of Luxembourg
OTHER
Helsingborgs Hospital
OTHER
Responsible Party
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Niklas Nielsen
MD, PhD, Associate professor
Principal Investigators
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Niklas Nielsen, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Helsingborgs lasarett, Region Skåne, Sweden
Hans Friberg, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Lund University Hospital, Lund, Sweden
Tobias Cronberg, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Lund University Hospital, Lund, Sweden
Jan Hovdenes, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Oslo University Hospital, Oslo, Norway
Matt P Wise, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
University Hospital of Wales, Cardiff, UK
Clifton W Callaway, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
University of Pittsburgh, Pittsburgh, USA
Christian Storm, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Charité-University Medicine (Berlin, Germany)
Alain Cariou, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Université Paris Descartes, France
David Erlinge, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Lund University Hospital, Lund, Sweden
Christian Rylander, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Sahlgrenska University Hospital
Josef Dankiewicz, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Skåne University Hospital Lund
Mauro Oddo, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Université de Lausanne, Lausanne, Switzerland
Manoj Saxena, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
The George Institute for Global Health (Sydney, Australia)
Per Nordberg, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Södersjukhuset, Stockholm
Fabio Taccone, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Hopital Erasme, Brussles, Belgium
Paolo Pelosi, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
San Martino University Hospital, Genoa
Michael Ioannidis, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Innsbruck University Hospital
Jan Belholavek, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Prague University Hospital
Paul Young, MD
Role: PRINCIPAL_INVESTIGATOR
Wellington Regional Hospital
Hans Kirkegaard, MD,PhD
Role: PRINCIPAL_INVESTIGATOR
Aarhus University Hospital
Alistair Nichol, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Department of Anaesthesia and Intensive Care Medicine, St Vincent's University Hospital
Locations
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Mayo Clinic Hospital-St. Mary's Campus
Rochester, New York, United States
UPMC-Presbyterian
Pittsburgh, Pennsylvania, United States
John Hunter Hospital
Newcastle, New South Wales, Australia
Concord Repatriation General Hospital
Sydney, New South Wales, Australia
Liverpool Hospital
Sydney, New South Wales, Australia
St Vincent's Hospital
Sydney, New South Wales, Australia
Princess Alexandra Hospital
Brisbane, Queensland, Australia
Northern Hospital
Epping, Victoria, Australia
The Alfred
Melbourne, Victoria, Australia
Austin Hospital
Melbourne, , Australia
Nepean Hospital
Sydney, , Australia
Royal North Shore Hospital
Sydney, , Australia
Innsbruck University Hospital
Innsbruck, , Austria
Erasme Hospital
Brussels, , Belgium
Ziekenhuis Oost-Limburg
Genk, , Belgium
Hradec Kralove Hospital
Hradec Králové, , Czechia
Liberec Hospital
Liberec, , Czechia
General University Hospital
Prague, , Czechia
Aarhus University Hospital
Aarhus, , Denmark
Chu Dupuytren
Limoges, , France
CHU Nantes
Nantes, , France
Cochin University Hospital
Paris, , France
Lariboisière Hospital
Paris, , France
Versailles Hospital
Versailles, , France
Charité, Campus Virchow
Berlin, , Germany
San Martino Hospital
Genova, , Italy
Modena NOCSAE Hospital
Modena, , Italy
Christchurch Hospital
Christchurch, , New Zealand
Wellington Hospital
Wellington, , New Zealand
Sorlandet Hospital
Arendal, , Norway
Haukeland Hospital
Bergen, , Norway
Oslo University Hospital
Oslo, , Norway
St. Olav's University Hospital
Trondheim, , Norway
Hallands Hospital
Halmstad, Halland County, Sweden
Skane University Hospital - Lund
Lund, Skåne County, Sweden
Skane University Hospital - Malmö
Malmo, Skåne County, Sweden
Sahlgrenska University Hospital
Gothenburg, , Sweden
Helsingborgs Hospital
Helsingborg, , Sweden
Centralsjukhuset i Karlstad
Karlstad, , Sweden
Linköping University Hospital
Linköping, , Sweden
Örebro University Hospital
Örebro, , Sweden
Skaraborgs sjukhus
Skövde, , Sweden
Capio St:Göran
Stockholm, , Sweden
Södersjukhuset
Stockholm, , Sweden
Norra Älvsborgs Länssjukhus (NÄL)
Trollhättan, , Sweden
Akademiska Sjukhuset
Uppsala, , Sweden
University Hospital Bern, Inselspital
Bern, , Switzerland
University Hospital of Lausanne
Lausanne, , Switzerland
Cardiocentro Ticino
Lugano, , Switzerland
Kantonsspital St.Gallen
Sankt Gallen, , Switzerland
Zurich University Hospital
Zurich, , Switzerland
Basildon and Thurrock Hospitals NHS Foundation Trust - Essex CTC
Basildon, , United Kingdom
Royal Victoria Hospital
Belfast, , United Kingdom
Birmingham University Hospital
Birmingham, , United Kingdom
Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust
Bournemouth, , United Kingdom
Bristol Royal Infirmary
Bristol, , United Kingdom
University Hospital of Wales
Cardiff, , United Kingdom
Manchester Royal Infirmary
Manchester, , United Kingdom
Queen Alexandra Hospital
Portsmouth, , United Kingdom
Royal Berkshire Hospital
Reading, , United Kingdom
Countries
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References
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Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, Horn J, Hovdenes J, Kjaergaard J, Kuiper M, Pellis T, Stammet P, Wanscher M, Wise MP, Aneman A, Al-Subaie N, Boesgaard S, Bro-Jeppesen J, Brunetti I, Bugge JF, Hingston CD, Juffermans NP, Koopmans M, Kober L, Langorgen J, Lilja G, Moller JE, Rundgren M, Rylander C, Smid O, Werer C, Winkel P, Friberg H; TTM Trial Investigators. Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest. N Engl J Med. 2013 Dec 5;369(23):2197-206. doi: 10.1056/NEJMoa1310519. Epub 2013 Nov 17.
Admiraal MM, Backman S, Annborn M, Borgquist O, Dankiewicz J, During J, Legriel S, Lilja G, Lindehammer H, Nielsen N, Rossetti AO, Unden J, Cronberg T, Westhall E; TTM2-trial investigators. Electrographic and Clinical Determinants of Good Outcome After Postanoxic Status Epilepticus. Neurology. 2025 Mar 11;104(5):e210304. doi: 10.1212/WNL.0000000000210304. Epub 2025 Feb 11.
Taccone FS, Cariou A, Zorzi S, Friberg H, Jakobsen JC, Nordberg P, Robba C, Belohlavek J, Hovdenes J, Haenggi M, Aneman A, Grejs A, Keeble TR, Annoni F, Young PJ, Wise MP, Cronberg T, Lilja G, Nielsen N, Dankiewicz J. Hypothermia versus normothermia in patients with cardiac arrest and shockable rhythm: a secondary analysis of the TTM-2 study. Crit Care. 2024 Oct 15;28(1):335. doi: 10.1186/s13054-024-05119-3.
Heimburg K, Blennow Nordstrom E, Dankiewicz J, Friberg H, Grejs AM, Hanggi M, Keeble TR, Kirkegaard H, Nielsen N, Rylander C, Tornberg AB, Ullen S, Wise MP, Cronberg T, Lilja G. Low physical activity level in out-of-hospital cardiac arrest survivors with obesity, mobility problems and cognitive impairment: Results from the TTM2 trial. Resuscitation. 2024 Nov;204:110407. doi: 10.1016/j.resuscitation.2024.110407. Epub 2024 Oct 4.
Battaglini D, Schiavetti I, Ball L, Jakobsen JC, Lilja G, Friberg H, Wendel-Garcia PD, Young PJ, Eastwood G, Chew MS, Unden J, Thomas M, Joannidis M, Nichol A, Lundin A, Hollenberg J, Hammond N, Saxena M, Martin A, Solar M, Taccone FS, Dankiewicz J, Nielsen N, Morten Grejs A, Wise MP, Hangghi M, Smid O, Patroniti N, Robba C; TTM2 trial investigators. Association between early airway intervention in the pre-hospital setting and outcomes in out of hospital cardiac arrest patients: A post-hoc analysis of the Target Temperature Management-2 (TTM2) trial. Resuscitation. 2024 Oct;203:110390. doi: 10.1016/j.resuscitation.2024.110390. Epub 2024 Sep 5.
Lang M, Kenda M, Scheel M, Martola J, Wheeler M, Owen S, Johnsson M, Annborn M, Dankiewicz J, Deye N, During J, Friberg H, Halliday T, Jakobsen JC, Lascarrou JB, Levin H, Lilja G, Lybeck A, McGuigan P, Rylander C, Sem V, Thomas M, Ullen S, Unden J, Wise MP, Cronberg T, Wasselius J, Nielsen N, Leithner C, Moseby-Knappe M. Standardised and automated assessment of head computed tomography reliably predicts poor functional outcome after cardiac arrest: a prospective multicentre study. Intensive Care Med. 2024 Jul;50(7):1096-1107. doi: 10.1007/s00134-024-07497-2. Epub 2024 Jun 20.
Holgersson J, Meyer MAS, Dankiewicz J, Lilja G, Ullen S, Hassager C, Cronberg T, Wise MP, Belohlavek J, Hovdenes J, Pelosi P, Erlinge D, Schrag C, Smid O, Brunetti I, Rylander C, Young PJ, Saxena M, Aneman A, Cariou A, Callaway C, Eastwood GM, Haenggi M, Joannidis M, Keeble TR, Kirkegaard H, Leithner C, Levin H, Nichol AD, Morgan MPG, Nordberg P, Oddo M, Storm C, Taccone FS, Thomas M, Bro-Jeppesen J, Horn J, Kjaergaard J, Kuiper M, Pellis T, Stammet P, Wanscher MJ, Friberg H, Nielsen N, Jakobsen JC. Hypothermic versus Normothermic Temperature Control after Cardiac Arrest. NEJM Evid. 2022 Nov;1(11):EVIDoa2200137. doi: 10.1056/EVIDoa2200137. Epub 2022 Jun 15.
Lilja G, Ullen S, Dankiewicz J, Friberg H, Levin H, Nordstrom EB, Heimburg K, Jakobsen JC, Ahlqvist M, Bass F, Belohlavek J, Olsen RB, Cariou A, Eastwood G, Fanebust HR, Grejs AM, Grimmer L, Hammond NE, Hovdenes J, Hrecko J, Iten M, Johansen H, Keeble TR, Kirkegaard H, Lascarrou JB, Leithner C, Lesona ME, Levis A, Mion M, Moseby-Knappe M, Navarra L, Nordberg P, Pelosi P, Quayle R, Rylander C, Sandberg H, Saxena M, Schrag C, Siranec M, Tiziano C, Vignon P, Wendel-Garcia PD, Wise MP, Wright K, Nielsen N, Cronberg T. Effects of Hypothermia vs Normothermia on Societal Participation and Cognitive Function at 6 Months in Survivors After Out-of-Hospital Cardiac Arrest: A Predefined Analysis of the TTM2 Randomized Clinical Trial. JAMA Neurol. 2023 Oct 1;80(10):1070-1079. doi: 10.1001/jamaneurol.2023.2536.
Robba C, Badenes R, Battaglini D, Ball L, Sanfilippo F, Brunetti I, Jakobsen JC, Lilja G, Friberg H, Wendel-Garcia PD, Young PJ, Eastwood G, Chew MS, Unden J, Thomas M, Joannidis M, Nichol A, Lundin A, Hollenberg J, Hammond N, Saxena M, Martin A, Solar M, Taccone FS, Dankiewicz J, Nielsen N, Grejs AM, Ebner F, Pelosi P; TTM2 Trial collaborators. Oxygen targets and 6-month outcome after out of hospital cardiac arrest: a pre-planned sub-analysis of the targeted hypothermia versus targeted normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial. Crit Care. 2022 Oct 21;26(1):323. doi: 10.1186/s13054-022-04186-8.
Lang M, Leithner C, Scheel M, Kenda M, Cronberg T, During J, Rylander C, Annborn M, Dankiewicz J, Deye N, Halliday T, Lascarrou JB, Matthew T, McGuigan P, Morgan M, Thomas M, Ullen S, Unden J, Nielsen N, Moseby-Knappe M. Prognostic accuracy of head computed tomography for prediction of functional outcome after out-of-hospital cardiac arrest: Rationale and design of the prospective TTM2-CT-substudy. Resusc Plus. 2022 Oct 12;12:100316. doi: 10.1016/j.resplu.2022.100316. eCollection 2022 Dec.
During J, Annborn M, Cariou A, Chew MS, Dankiewicz J, Friberg H, Haenggi M, Haxhija Z, Jakobsen JC, Langeland H, Taccone FS, Thomas M, Ullen S, Wise MP, Nielsen N. Influence of temperature management at 33 degrees C versus normothermia on survival in patients with vasopressor support after out-of-hospital cardiac arrest: a post hoc analysis of the TTM-2 trial. Crit Care. 2022 Jul 31;26(1):231. doi: 10.1186/s13054-022-04107-9.
Robba C, Badenes R, Battaglini D, Ball L, Brunetti I, Jakobsen JC, Lilja G, Friberg H, Wendel-Garcia PD, Young PJ, Eastwood G, Chew MS, Unden J, Thomas M, Joannidis M, Nichol A, Lundin A, Hollenberg J, Hammond N, Saxena M, Annborn M, Solar M, Taccone FS, Dankiewicz J, Nielsen N, Pelosi P; TTM2 Trial Collaborators. Ventilatory settings in the initial 72 h and their association with outcome in out-of-hospital cardiac arrest patients: a preplanned secondary analysis of the targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest (TTM2) trial. Intensive Care Med. 2022 Aug;48(8):1024-1038. doi: 10.1007/s00134-022-06756-4. Epub 2022 Jul 2.
Robba C, Nielsen N, Dankiewicz J, Badenes R, Battaglini D, Ball L, Brunetti I, Pedro David WG, Young P, Eastwood G, Chew MS, Jakobsen J, Unden J, Thomas M, Joannidis M, Nichol A, Lundin A, Hollenberg J, Lilja G, Hammond NE, Saxena M, Martin A, Solar M, Taccone FS, Friberg HA, Pelosi P. Ventilation management and outcomes in out-of-hospital cardiac arrest: a protocol for a preplanned secondary analysis of the TTM2 trial. BMJ Open. 2022 Mar 3;12(3):e058001. doi: 10.1136/bmjopen-2021-058001.
Dankiewicz J, Cronberg T, Lilja G, Jakobsen JC, Levin H, Ullen S, Rylander C, Wise MP, Oddo M, Cariou A, Belohlavek J, Hovdenes J, Saxena M, Kirkegaard H, Young PJ, Pelosi P, Storm C, Taccone FS, Joannidis M, Callaway C, Eastwood GM, Morgan MPG, Nordberg P, Erlinge D, Nichol AD, Chew MS, Hollenberg J, Thomas M, Bewley J, Sweet K, Grejs AM, Christensen S, Haenggi M, Levis A, Lundin A, During J, Schmidbauer S, Keeble TR, Karamasis GV, Schrag C, Faessler E, Smid O, Otahal M, Maggiorini M, Wendel Garcia PD, Jaubert P, Cole JM, Solar M, Borgquist O, Leithner C, Abed-Maillard S, Navarra L, Annborn M, Unden J, Brunetti I, Awad A, McGuigan P, Bjorkholt Olsen R, Cassina T, Vignon P, Langeland H, Lange T, Friberg H, Nielsen N; TTM2 Trial Investigators. Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest. N Engl J Med. 2021 Jun 17;384(24):2283-2294. doi: 10.1056/NEJMoa2100591.
Dankiewicz J, Cronberg T, Lilja G, Jakobsen JC, Belohlavek J, Callaway C, Cariou A, Eastwood G, Erlinge D, Hovdenes J, Joannidis M, Kirkegaard H, Kuiper M, Levin H, Morgan MPG, Nichol AD, Nordberg P, Oddo M, Pelosi P, Rylander C, Saxena M, Storm C, Taccone F, Ullen S, Wise MP, Young P, Friberg H, Nielsen N. Targeted hypothermia versus targeted Normothermia after out-of-hospital cardiac arrest (TTM2): A randomized clinical trial-Rationale and design. Am Heart J. 2019 Nov;217:23-31. doi: 10.1016/j.ahj.2019.06.012. Epub 2019 Jun 26.
Related Links
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Trial official webpage
Other Identifiers
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TTM-2
Identifier Type: -
Identifier Source: org_study_id
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