Time-differentiated Therapeutic Hypothermia (TTH48)

Time-differentiated Treatment With Mild Therapeutic Hypothermia Following Cardiac Arrest, a Multi Center Study.

The purpose of this study is to determine if 48 hours of mild therapeutic hypothermia following out of hospital cardiac arrest gives a better cerebral outcome compared to 24 hours therapeutic hypothermia.

Study Overview

• Status: Completed
• Conditions: Out of Hospital Cardiac Arrest
• Intervention / Treatment: Other: Therapeutic hypothermia

Detailed Description

Sudden out-of-hospital cardiac arrest (OOH-CA) remains a significant cause of death. However, in 2002 it was in two clinical trials demonstrated that mild therapeutic hypothermia in comatose OOH-CA victims yields a better cerebral outcome measured by Cerebral Performance Category Score (CPC) after 6 month. The optimal mild hypothermia treatment time is however not known. The two trials from 2002 apply the treatment for 12 and 24 hours respectively. In newborns with cerebral hypoxic damage the standard treatment time is 72 hours. It is therefore relevant to investigate the influence of the treatment time on the cerebral outcome in OOH-CA victims. In the present study cerebral outcome after mild therapeutic hypothermia (target temperature 33 degrees centigrade) in OOH-CA patients for 24 is compared to outcome after 48 hours of mild hypothermia. The main outcome parameter is mortality and CPC score measured 6 month after the treatment.

• Study Type: Interventional
• Enrollment (Actual): 355
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1070
    • Department of Intensive Care, Erasme Hospital
• Denmark
  • Aalborg, Denmark, 9000
    • Department of Anesthesiology and Intensive Care Medicine, Aarhus University Hospital, Aalborg
  • Aarhus, Denmark, 8200
    • Department og Anesthesiologi and Intensive Care Medicine,
  • Copenhagen, Denmark, 2100
    • Department of Cardiology, Copenhagen University Hospital, Rigshospitalet
  • Odense, Denmark, 5000
    • Department of Anaesthesiology and Intensive Care Medicine, Odense University Hospital
• Estonia
  • Tallinn, Estonia, 13419
    • Anaesthesiology Clinic, North Estonia Medical Centre
• Finland
  • Helsinki, Finland, 00029-HUS
    • Division of Anaesthesiology and Intensive Care Medicine, Department of Surgery, Helsinki University Central Hospital
  • Turku, Finland
    • Hospital District of Southwest Finland), Kiinamyllynkatu
• Germany
  • Berlin, Germany
    • Department of Internal Medicine, Nephrology and Intensive Care; Charité-Universitätsmedizin Berlin
• Norway
  • Stavanger, Norway, 4068
    • Anesthesiology and Critical Care, Stavanger University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Out of hospital cardiac arrest of suspected cardiac origin
2. Return of spontaneous circulation (ROSC)
3. Glasgow Coma Score < 8
4. Estimated time interval from cardiac arrest to ROSC ≤ 60 min

Exclusion Criteria:

1. OOH-CA of suspected origin other than cardiac
2. In hospital Cardiac arrest
3. Terminal disease
4. Coagulation disorders
5. Unwitnessed asystolia
6. Time from cardiac arrest to start of hypothermia treatment > 240 min
7. GCS ≥ 8
8. Pregnancy
9. Persistent cardiogenic shock (Systolic blood pressure < 80 mmHg despite inotropic treatment and aortic balloon pump).
10. CPC 3-4 before cardiac arrest
11. Acute intra cerebral bleeding
12. Acute stroke
13. Acute coronary artery bypass grafting

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: 24 hours hypothermia	Other: Therapeutic hypothermia; Mild therapeutic hypothermia with a target temperature of 33 degrees Centigrade for 24 or 48 hours
EXPERIMENTAL: 48 hours hypothermoa; 48 hours hypothermia	Other: Therapeutic hypothermia; Mild therapeutic hypothermia with a target temperature of 33 degrees Centigrade for 24 or 48 hours

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CPC	CPC = Cerebral Performance Category Score. The primary outcome of the study is analyzed as the proportion of patients with good neurological outcome in the two groups, (CPC 1-2) at 6 months after CA.	6 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	Adverse events are registered during the treatment and until discharge from primary hospital unit	10 days
CPC at discharge	CPC at discharge from primary hospital unit and after 28 days plus after 3 month	3 month
Mortality	CPC 5 at 6 month	6 month

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
GCS	Glasgow Coma Score at day 4 and at discharge from primary hospital unit	28 days
GCS progression	Glasgow Coma Score throughout the observation period	25 weeks

Collaborators and Investigators

• Sponsor: University of Aarhus
• Investigators: Principal Investigator: Hans Kirkegaard, Professor, Department of Anaesthesia and Intensive care medicine, Aarhus University Hosptal, Brendstrupgaardsvej 8200 Aarhus, Denmark

Publications and helpful links

General Publications

• Larsen AI, Grejs AM, Vistisen ST, Strand K, Skadberg O, Jeppesen AN, Duez CHV, Kirkegaard H, Soreide E. Kinetics of 2 different high-sensitive troponins during targeted temperature management in out-of-hospital cardiac arrest patients with acute myocardial infarction: a post hoc sub-study of a randomised clinical trial. BMC Cardiovasc Disord. 2022 Jul 30;22(1):342. doi: 10.1186/s12872-022-02778-4.
• Bach HM, Duez CHV, Jeppesen AN, Strand K, Soreide E, Kirkegaard H, Grejs AM. MR-proANP and NT-proBNP During Targeted Temperature Management Following Out-of-Hospital Cardiac Arrest: A Post hoc Analysis of the TTH48 Trial. Ther Hypothermia Temp Manag. 2022 Jun;12(2):82-89. doi: 10.1089/ther.2021.0012. Epub 2021 Aug 10.
• Hastbacka J, Kirkegaard H, Soreide E, Taccone FS, Rasmussen BS, Storm C, Kjaergaard J, Laitio T, Duez CHV, Jeppesen AN, Grejs AM, Skrifvars MB. Severe or critical hypotension during post cardiac arrest care is associated with factors available on admission - a post hoc analysis of the TTH48 trial. J Crit Care. 2021 Feb;61:186-190. doi: 10.1016/j.jcrc.2020.10.026. Epub 2020 Nov 2.
• Skrifvars MB, Soreide E, Sawyer KN, Taccone FS, Toome V, Storm C, Jeppesen A, Grejs A, Duez CHV, Tiainen M, Rasmussen BS, Laitio T, Hassager C, Kirkegaard H. Hypothermic to ischemic ratio and mortality in post-cardiac arrest patients. Acta Anaesthesiol Scand. 2020 Apr;64(4):546-555. doi: 10.1111/aas.13528. Epub 2019 Dec 26.
• Evald L, Bronnick K, Duez CHV, Grejs AM, Jeppesen AN, Soreide E, Kirkegaard H, Nielsen JF. Prolonged targeted temperature management reduces memory retrieval deficits six months post-cardiac arrest: A randomised controlled trial. Resuscitation. 2019 Jan;134:1-9. doi: 10.1016/j.resuscitation.2018.12.002. Epub 2018 Dec 17.
• Kirkegaard H, Soreide E, de Haas I, Pettila V, Taccone FS, Arus U, Storm C, Hassager C, Nielsen JF, Sorensen CA, Ilkjaer S, Jeppesen AN, Grejs AM, Duez CHV, Hjort J, Larsen AI, Toome V, Tiainen M, Hastbacka J, Laitio T, Skrifvars MB. Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial. JAMA. 2017 Jul 25;318(4):341-350. doi: 10.1001/jama.2017.8978.
• Kirkegaard H, Pedersen AR, Pettila V, Hjort J, Rasmussen BS, de Haas I, Nielsen JF, Ilkjaer S, Kaltoft A, Jeppesen AN, Grejs AM, Duez CH, Larsen AI, Toome V, Arus U, Taccone FS, Storm C, Laitio T, Skrifvars MB, Soreide E. A statistical analysis protocol for the time-differentiated target temperature management after out-of-hospital cardiac arrest (TTH48) clinical trial. Scand J Trauma Resusc Emerg Med. 2016 Nov 28;24(1):138. doi: 10.1186/s13049-016-0334-0.
• Kirkegaard H, Rasmussen BS, de Haas I, Nielsen JF, Ilkjaer S, Kaltoft A, Jeppesen AN, Grejs A, Duez CH, Larsen AI, Pettila V, Toome V, Arus U, Taccone FS, Storm C, Skrifvars MB, Soreide E. 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. Trials. 2016 May 4;17(1):228. doi: 10.1186/s13063-016-1338-9.

Study record dates

Study Major Dates

• Study Start: January 1, 2013
• Primary Completion (ACTUAL): January 1, 2017
• Study Completion (ACTUAL): January 1, 2017

Study Registration Dates

• First Submitted: September 17, 2012
• First Submitted That Met QC Criteria: September 17, 2012
• First Posted (ESTIMATE): September 20, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): January 18, 2017
• Last Update Submitted That Met QC Criteria: January 17, 2017
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Body Temperature Changes; Heart Arrest; Hypothermia; Out-of-Hospital Cardiac Arrest
• Other Study ID Numbers: TTH48