title: Time-differentiated target temperature management after out-of-hospital cardiac arrest: a multicentre, randomised, parallel-group, assessor-blinded clinical trial (the TTH48 trial): study protocol for a randomised controlled trial.
abstract: BACKGROUND
  The application of therapeutic hypothermia (TH) for 12 to 24 hours following out-of-hospital cardiac arrest (OHCA) has been associated with decreased mortality and improved neurological function. However, the optimal duration of cooling is not known. We aimed to investigate whether targeted temperature management (TTM) at 33 ± 1 °C for 48 hours compared to 24 hours results in a better long-term neurological outcome.
  
  
  METHODS
  The TTH48 trial is an investigator-initiated pragmatic international trial in which patients resuscitated from OHCA are randomised to TTM at 33 ± 1 °C for either 24 or 48 hours. Inclusion criteria are: age older than 17 and below 80 years; presumed cardiac origin of arrest; and Glasgow Coma Score (GCS) <8, on admission. The primary outcome is neurological outcome at 6 months using the Cerebral Performance Category score (CPC) by an assessor blinded to treatment allocation and dichotomised to good (CPC 1-2) or poor (CPC 3-5) outcome. Secondary outcomes are: 6-month mortality, incidence of infection, bleeding and organ failure and CPC at hospital discharge, at day 28 and at day 90 following OHCA. Assuming that 50 % of the patients treated for 24 hours will have a poor outcome at 6 months, a study including 350 patients (175/arm) will have 80 % power (with a significance level of 5 %) to detect an absolute 15 % difference in primary outcome between treatment groups. A safety interim analysis was performed after the inclusion of 175 patients.
  
  
  CONCLUSIONS
  This is the first randomised trial to investigate the effect of the duration of TTM at 33 ± 1 °C in adult OHCA patients. We anticipate that the results of this trial will add significant knowledge regarding the management of cooling procedures in OHCA patients.
  
  
  BACKGROUND
  NCT01689077.
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Aarhus University Hospital and Aarhus University, Aarhus, Denmark. hanskirkegaard@dadlnet.dk.
authors.forename: Hans
authors.initials: H
authors.lastname: Kirkegaard
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Bodil S
authors.initials: BS
authors.lastname: Rasmussen
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Inge
authors.initials: I
authors.lastname: de Haas
authors.affiliation: Hammel Neurorehabilitation Centre and University Research Clinic, Aarhus University, Hammel, Denmark.
authors.forename: Jørgen Feldbæk
authors.initials: JF
authors.lastname: Nielsen
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Susanne
authors.initials: S
authors.lastname: Ilkjær
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Kaltoft
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Aarhus University Hospital and Aarhus University, Aarhus, Denmark.
authors.forename: Anni Nørregaard
authors.initials: AN
authors.lastname: Jeppesen
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Aarhus University Hospital and Aarhus University, Aarhus, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Grejs
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Aarhus University Hospital and Aarhus University, Aarhus, Denmark.
authors.forename: Christophe Henri Valdemar
authors.initials: CH
authors.lastname: Duez
authors.affiliation: Department of Cardiology, Stavanger University Hospital, Stavanger, Norway.|Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Alf Inge
authors.initials: AI
authors.lastname: Larsen
authors.affiliation: Division of Intensive Care, Department of Anesthesiology and Intensive Care Medicine, Helsinki University Hospital and Helsinki University, Helsinki, Finland.|Intensive Care, Inselspital, Bern University Hospital, Bern, Switzerland.
authors.forename: Ville
authors.initials: V
authors.lastname: Pettilä
authors.affiliation: Department of Anesthesiology, Intensive Care and Emergency Medicine, North Estonia Medical Centre, Tallinn, Estonia.
authors.forename: Valdo
authors.initials: V
authors.lastname: Toome
authors.affiliation: Department of Intensive Cardiac Care, North Estonia Medical Centre, Tallinn, Estonia.
authors.forename: Urmet
authors.initials: U
authors.lastname: Arus
authors.affiliation: Department of Intensive Care, Hôpital Erasme, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Fabio Silvio
authors.initials: FS
authors.lastname: Taccone
authors.affiliation: Department of Internal Medicine, Nephrology and Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Storm
authors.affiliation: Division of Intensive Care, Department of Anesthesiology and Intensive Care Medicine, Helsinki University Hospital and Helsinki University, Helsinki, Finland.
authors.forename: Markus B
authors.initials: MB
authors.lastname: Skrifvars
authors.affiliation: Department of Anaesthesiology and Intensive Care, Stavanger University Hospital, Stavanger, Norway.|Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors.forename: Eldar
authors.initials: E
authors.lastname: Søreide
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001833:Body Temperature Regulation; D002985:Clinical Protocols; D005060:Europe; D005260:Female; D015600:Glasgow Coma Scale; D006801:Humans; D007036:Hypothermia, Induced / Q000009:adverse effects; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D058687:Out-of-Hospital Cardiac Arrest / Q000175:diagnosis / Q000401:mortality / Q000503:physiopathology / Q000628:therapy*; D010351:Patient Discharge; D012107:Research Design; D012151:Resuscitation / Q000009:adverse effects; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
keywords: Mild therapeutic hypothermia; Out-of-hospital cardiac arrest; Prolonged target temperature management; Target temperature management