Hypothermia After Cardiac Arrest - Effects on Myocardial Function and Inflammatory Response. (IH3)

The on-going randomized clinical trial TTM2 (Target Hypothermia Versus Targeted Normothermia After Out-of-hospital Cardiac Arrest, NCT02908308) investigates if there is a difference in mortality, neurological function or quality of life in comatose survivors after out-of-hospital cardiac arrest if treated (Group A) at target temperature of 33 oC or (Group B) by avoiding fever during the first 24 h.

In this sub study, the effect of different target temperatures on cardiac and circulatory physiology is evaluated by echocardiography and pulmonary artery catheter. Tissue damage after cardiac arrest in part is caused by an activation of different parts of the inflammatory system (reperfusion injury). This study investigates the effect of temperature management on inflammation and the link to the circulatory effects.

Study Overview

• Status: Completed
• Conditions: Inflammatory Response; Hypothermia; Ischemia Reperfusion Injury; Out of Hospital Cardiac Arrest
• Intervention / Treatment: Procedure: Targeted temperature management; Procedure: Standard care, early treatment of fever

Detailed Description

Hypothermia (HT) is used as an adjunctive treatment to improve outcome in comatose survivors of out-of-hospital cardiac arrest (OHCA). Optimal temperature is debated and in the TTM-trial (Target Temperature Management study), which randomized to management at either 33 degrees C or 36 degrees C for 24h after return of spontaneous circulation (ROSC), no difference in mortality or neurological outcome was shown. The TTM-2-trial (Target Hypothermia Versus Targeted Normothermia After Out-of-hospital Cardiac Arrest, NCT02908308) was initiated to investigate if there is a difference in mortality, neurological function or quality of life between target temperature of 33 degrees C or avoiding fever in comatose patients after out-of-hospital cardiac arrest and meet some of the critique that was raised against the TTM-trial regarding the speed of induction of hypothermia, that both groups were treated at different degrees of hypothermia and that both groups could have benefitted from this intervention.

This study is a prospective sub-study to the TTM-2 trial investigating the cardiac and hemodynamic effects of different target temperatures using echocardiography and pulmonary artery catheter (PAC). Data will be harvested and echocardiographic registration will be made during the target temperature phase, upon rewarming and after 48-72 hours. There will be a follow-up echocardiographic examination at 6 months from randomization.

Ischemia/reperfusion (I/R) injury is a key challenge in myocardial infarction and cardiac arrest. In this study most patients will experience myocardial infarction affecting the heart only, while all patients will experience cardiac arrest affecting the whole body. A major determinant of long-term outcome is the degree of cell death due to stop of blood supply during ischemia and aggravation of organ damage during reperfusion caused by innate immune activation. In this study we will address the importance of the innate immune system in determining outcome and the interplay and dependency with cardiac function.

Blood samples will be collected at the same time points as echocardiography registrations and collection of hemodynamic data and analyzed post study cessation.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Norway
  • Oslo, Norway, 0424
    • Oslo University Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Included in the TTM2-trial and treated at the Intensive Care Unit at Rikshospitalet, Oslo
• Out-of-hospital cardiac arrest of a presumed cardiac or unknown cause
• Sustained ROSC - defined as 20 minutes with signs of circulation without the need for chest compressions.
• Unconsciousness defined as not being able to obey verbal commands (FOUR-score motor response of <4) and no verbal response to pain after sustained ROSC.
• Eligible for intensive care without restrictions or limitations
• Inclusion within 180 minutes of ROSC

Exclusion Criteria:

• Not included in the TTM2-trial
• Unwitnessed cardiac arrest with an initial rhythm of asystole
• Temperature on admission <30°C.
• On ECMO prior to ROSC
• Obvious or suspected pregnancy
• Intracranial bleeding
• Severe chronic obstructive pulmonary disorder (COPD) with long-term home oxygen therapy"

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Targeted temperature management at 33°C; Cooling and temperature control at 33°C, according to the study protocol of the TTM2-trial	Procedure: Targeted temperature management; Target temperature management at 33°C
ACTIVE_COMPARATOR: Standard care, early treatment of fever; Standard of care and normothermia. If temperature 37,8 °C or above use of device for temperature control.	Procedure: Standard care, early treatment of fever; Standard of care with early treatment of fever

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in wall motion score	Cardiac output	48 hours , 72 hours, 6 months
Plasma concentration of inflammatory markers	inflammatory markers to be specified (e.g. Complement system activation, pro-inflammatory cytokines like IL-6 expressed as nanogram/milliliter)	48 hours , 72 hours, 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Association between inflammatory response and cardiac function	Association of plasma concentration of inflammatory markers (nanogram/milliliter) and Cardiac output (liter/minute)	48 hours , 72 hours, 6 months

Collaborators and Investigators

• Sponsor: Oslo University Hospital
• Investigators: Principal Investigator: Søren Pischke, MD, PhD, Oslo University Hospital, Oslo, Norway

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 8, 2018
• Primary Completion (ACTUAL): July 20, 2020
• Study Completion (ACTUAL): July 20, 2020

Study Registration Dates

• First Submitted: November 6, 2018
• First Submitted That Met QC Criteria: November 13, 2018
• First Posted (ACTUAL): November 16, 2018

Study Record Updates

• Last Update Posted (ACTUAL): September 20, 2021
• Last Update Submitted That Met QC Criteria: September 17, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: cardiac arrest; ischemia reperfusion injury; hypothermia, therapeutic; Innate Immune system
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Postoperative Complications; Body Temperature Changes; Ischemia; Heart Arrest; Reperfusion Injury; Hypothermia; Out-of-Hospital Cardiac Arrest
• Other Study ID Numbers: 2018/1057 C

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No