Hypothermia Versus Normothermia After Extracorporeal Cardiopulmonary Resuscitation for Out-of-hospital Cardiac Arrest (J-NEURO)

Hypothermia Versus Normothermia After Extracorporeal Cardiopulmonary Resuscitation for Out-of-hospital Cardiac Arrest: A Cluster Randomized Trial (SAVE-J NEUROTHERM Trial)

The SAVE-J NEUROTHERM trial is a cluster randomized trial that evaluated and compared the mortality risk, neurological outcomes, and adverse events between patients who underwent hypothermia and those who underwent normothermia after extracorporeal cardiopulmonary resuscitation for out-of-hospital cardiac arrest.

Study Overview

• Status: Recruiting
• Conditions: Temperature; ECMO Treatment; Out-of-hospital Cardiac Arrest (OHCA); Post Cardiac Arrest Syndrome
• Intervention / Treatment: Procedure: Temperature control; Procedure: Temperature control

Detailed Description

Temperature control is a key neurointensive care for post-cardiac arrest patients. Although therapeutic hypothermia has been shown to be effective in the past, recent large randomized controlled trials have failed to demonstrate its efficacy. The international guidelines recommend temperature control under 37.7°C. However, the optimal temperature control, i.e., hypothermia versus normothermia, remains controversial. Additionally, randomized controlled trials that examined temperature control after extracorporeal cardiopulmonary resuscitation (ECPR) are lacking.

ECPR is a resuscitation technique using extracorporeal membrane oxygenation (ECMO) for refractory cardiac arrest. In ECPR patients, ECMO using a heat exchanger can more rapidly achieve the targeted temperature as compared to other temperature control devices. Early cooling to achieve hypothermia after resuscitation is expected to be more effective for neuroprotection in the injured brain. Thus, the investigators hypothesized that hypothermia would be effective in ECPR patients.

Furthermore, ECMO can stabilize the respiratory and circulatory status. Therefore, hypothermia, which may have side effects such as electrolyte abnormalities and arrhythmias, may be safely performed by ECMO. However, ECMO requires the administration of anticoagulants; therefore, it has the risk of hemorrhagic complications. Among patients receiving ECPR, bleeding is a common complication due to its relatively difficult procedure, considering the fact that emergent cannulation is performed under resuscitation. Additionally, CPR-related complications can also result in bleeding. These complications may be enhanced by hypothermia. Therefore, hypothermia after ECPR could contribute to a favorable outcome, but it could also cause bleeding.

The SAVE-J NEUROTHERM trial is a cluster randomized trial that evaluated and compared the mortality risk, neurological outcomes, and adverse events between out-of-hospital cardiac arrest (OHCA) patients who underwent hypothermia and normothermia after ECPR.

• Study Type: Interventional
• Enrollment (Estimated): 468
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Akihiko Inoue; Phone Number: 81-87-981-2392; Email: j-neuro@googlegroups.com

Study Locations

• Japan
  • Kyoto, Japan, 6028026
    • Not yet recruiting
    • Kyoto Second Red Cross Hospital
    • Principal Investigator: Hiromichi Narumiya
  • Okayama, Japan, 7008558
    • Recruiting
    • Okayama University Hospital
    • Principal Investigator: Hiromichi Naito
  • Saitama, Japan, 3308553
    • Recruiting
    • Saitama Red Cross Hospital
    • Principal Investigator: Syunichi Kato
  • Tokyo, Japan, 1608582
    • Recruiting
    • Keio University Hospital
    • Principal Investigator: Ryo Yamamoto
  • Tokyo, Japan, 1048560
    • Recruiting
    • St. Luke's International Hospital
    • Principal Investigator: Shutaro Isokawa
    • Sub-Investigator: Kasumi Shirasaki
  • Tokyo, Japan, 1138519
    • Recruiting
    • Institute of Science Tokyo Hospital
    • Principal Investigator: Wataru Takayama
  • Tokyo, Japan, 1138603
    • Recruiting
    • Nippon Medical School Hospital
    • Principal Investigator: Toru Takiguchi
    • Sub-Investigator: Takuro Hamaguchi
  • Tokyo, Japan, 1308575
    • Recruiting
    • Tokyo Metropolitan Bokutoh Hospital
    • Principal Investigator: Kazuhiro Sugiyama
    • Sub-Investigator: Taichi Kato
  • Tokyo, Japan, 1838524
    • Recruiting
    • Tokyo Metropolitan Tama Medical Center
    • Principal Investigator: Yuichi Horikoshi
  • Tokyo, Japan, 1900014
    • Recruiting
    • National Hospital Organization Disaster Medical Center
    • Principal Investigator: Kazushige Inoue
  • Tokyo, Japan, 1808610
    • Recruiting
    • Japanese Red Cross Musashino Hospital
    • Principal Investigator: Manato Watanabe
  • Tottori, Japan, 6800901
    • Recruiting
    • Tottori Prefectural Central Hospital
    • Principal Investigator: Makoto Kobayashi
  • Fukuoka
    • Kurume, Fukuoka, Japan, 8300011
      • Recruiting
      • Kurume University Hospital
      • Principal Investigator: Maki Otsuka
  • Hokkaido
    • Asahikawa, Hokkaido, Japan, 0788510
      • Not yet recruiting
      • Asahikawa Medical University Hospital
      • Principal Investigator: Akihito Tampo
    • Sapporo, Hokkaido, Japan, 0608648
      • Recruiting
      • Hokkaido University Hospital
      • Principal Investigator: Takeshi Wada
    • Sapporo, Hokkaido, Japan, 0608556
      • Recruiting
      • Sapporo Medical University Hospital
      • Principal Investigator: Naofumi Bunya
  • Hyogo
    • Kakogawa, Hyogo, Japan, 6758555
      • Recruiting
      • Hyogo Prefectural Kakogawa Medical Center
      • Principal Investigator: Atushi Tanaka
    • Kobe, Hyogo, Japan, 6510073
      • Recruiting
      • Hyogo Emergency Medical Center
      • Principal Investigator: Akihiko Inoue
      • Sub-Investigator: Takeshi Nishimura
    • Toyooka, Hyogo, Japan, 6688501
      • Recruiting
      • Toyooka Public Hospital
      • Principal Investigator: Futoshi Nagashima
  • Kagawa
    • Kita-gun, Kagawa, Japan, 7610793
      • Recruiting
      • Kagawa University Hospital
      • Principal Investigator: Kenya Kawakita
      • Sub-Investigator: Takuya Taira
  • Kagoshima
    • Amami, Kagoshima, Japan, 8940015
      • Recruiting
      • Oshima Prefectural Hospital
      • Principal Investigator: Kentaro Nakamura
  • Kanagawa
    • Ebina, Kanagawa, Japan, 2430432
      • Recruiting
      • Ebina General Hospital
      • Principal Investigator: Takahiro Yukawa
    • Yokohama, Kanagawa, Japan, 2308765
      • Recruiting
      • Saiseikai Yokohamashi Tobu Hospital
      • Principal Investigator: Kosei Omasa
  • Miyagi
    • Sendai, Miyagi, Japan, 9808574
      • Recruiting
      • Tohoku University Hospital
      • Principal Investigator: Shigeki Kushimoto
    • Sendai, Miyagi, Japan, 9838520
      • Recruiting
      • Sendai Medical Center
      • Principal Investigator: Yu Kawazoe
  • Okayama
    • Tsuyama, Okayama, Japan, 7080841
      • Recruiting
      • Tsuyama Chuo Hospital
      • Principal Investigator: Hiroki Maeyama
  • Okinawa
    • Shimajiri-gun, Okinawa, Japan, 9011193
      • Recruiting
      • Okinawa Prefectural Nanbu Medical Center & Children's Medical Center
      • Principal Investigator: Kota Hoshino
  • Osaka
    • Suita, Osaka, Japan, 5650862
      • Recruiting
      • Osaka Saiseikai Senri Hospital
      • Principal Investigator: Hirotaka Sawano

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• OHCA
• Age of 18-75 years, known or estimated
• An initial cardiac arrest rhythm of ventricular fibrillation/pulseless ventricular tachycardia or pulseless electrical activity

Exclusion Criteria:

• ECMO initiated after sustained return of spontaneous circulation (ROSC) and patients with sustained ROSC before ECMO initiation
• OHCA of presumed non-cardiac etiology
• Time from emergency call or witnessed arrest to hospital arrival of >60 min
• Time from hospital arrival to ECMO initiation of >60 min
• Pre-hospital ECPR
• Unavailability of the ECMO heat exchanger for temperature control
• Glasgow Coma Scale score before temperature control of >8
• Core body temperature upon hospital arrival of ≤32ºC
• Surgical intervention before temperature control (e.g., surgical intervention for the primary disease or complications related to resuscitation/ECMO procedures)
• Do Not Attempt Resuscitation) order confirmed prior to temperature control
• Limitations in intensive care before temperature control
• Known cerebral performance category (CPC) of 3-4 before cardiac arrest
• Known chronic obstructive pulmonary disease with home oxygen therapy
• Known or suspected pregnancy
• Concomitant illness, such as malignancy, shortens life expectancy (180-day survival unlikely)
• Consent not obtained or withdrawn by the participant or surrogate
• Other reasons, physician's decision not to enroll the patient

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Normothermia; Temperature control at 36 °C	Procedure: Temperature control; Procedure: Temperature control at 33-34 °C In the hypothermia group, patients receiving ECPR will be immediately cooled to 33ºC-34ºC with ECMO using a heat exchanger. After reaching this targeted temperature, the maintenance phase will start, and the target temperature will be kept at 33ºC-34°C. The maintenance phase will end 24 h after reaching this targeted temperature. Subsequently, rewarming to 36ºC-37ºC will be conducted in 24 h. After the rewarming, the temperature will be kept in the range of 36ºC-37.5ºC for 24 h after rewarming or until the end of ECMO, and should not exceed 37.5ºC. Other interventions, such as sedation, administration of neuromuscular blocking agents, antipyretics, and catecholamines, as well as mechanical circulatory support, are optional and performed at the patient's discretion.; Procedure: Temperature control; Procedure: Temperature control at 36 °C In the normothermia group receiving ECPR, the temperature of 36ºC will be immediately reached with ECMO using a heat exchanger. After reaching this targeted temperature, the maintenance phase will start, and the target temperature will be maintained at 36ºC. The maintenance phase will end 24 h after reaching this targeted temperature. Then, rewarming to 36ºC-37ºC will be conducted in 24 h. After the rewarming, the temperature will be kept in the range of 36ºC-37.5ºC for 24 h after rewarming or until the end of ECMO, and should not exceed 37.5ºC. Other interventions, such as sedation, administration of neuromuscular blocking agents, antipyretics, and catecholamines, as well as mechanical circulatory support, are optional and performed at the patient's discretion.
Experimental: Hypothermia; Temperature control at 33-34 °C	Procedure: Temperature control; Procedure: Temperature control at 33-34 °C In the hypothermia group, patients receiving ECPR will be immediately cooled to 33ºC-34ºC with ECMO using a heat exchanger. After reaching this targeted temperature, the maintenance phase will start, and the target temperature will be kept at 33ºC-34°C. The maintenance phase will end 24 h after reaching this targeted temperature. Subsequently, rewarming to 36ºC-37ºC will be conducted in 24 h. After the rewarming, the temperature will be kept in the range of 36ºC-37.5ºC for 24 h after rewarming or until the end of ECMO, and should not exceed 37.5ºC. Other interventions, such as sedation, administration of neuromuscular blocking agents, antipyretics, and catecholamines, as well as mechanical circulatory support, are optional and performed at the patient's discretion.; Procedure: Temperature control; Procedure: Temperature control at 36 °C In the normothermia group receiving ECPR, the temperature of 36ºC will be immediately reached with ECMO using a heat exchanger. After reaching this targeted temperature, the maintenance phase will start, and the target temperature will be maintained at 36ºC. The maintenance phase will end 24 h after reaching this targeted temperature. Then, rewarming to 36ºC-37ºC will be conducted in 24 h. After the rewarming, the temperature will be kept in the range of 36ºC-37.5ºC for 24 h after rewarming or until the end of ECMO, and should not exceed 37.5ºC. Other interventions, such as sedation, administration of neuromuscular blocking agents, antipyretics, and catecholamines, as well as mechanical circulatory support, are optional and performed at the patient's discretion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Survival	At discharge (approximately 25 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival		At 30 days, 90 days, and 1 year after admission
Neurological function: Cerebral performance categories (CPC)	The range of cerebral performance category (CPC) score is from 1 (normal/good cerebral function) to 5 (brain death or death). The higher the score, the worse the outcome. A favorable neurological outcome was defined as a CPC of 1-2, whereas an unfavorable outcome was defined as a CPC of 3-5	At discharge (approximately 25 days), 30 days, 90 days, and 1 year after admission
Adverse events	Adverse events during intensive care unit stay (arrhythmia, bleeding, pneumonia, and bacteremia)	During the intensive care unit stay, an average of 2 weeks

Collaborators and Investigators

• Sponsor: Kagawa University
• Investigators: Principal Investigator: Akihiko Inoue, Hyogo Emergency Medical Center; Study Chair: Yasuhiro Kuroda, Kagawa University; Study Director: Tetsuya Sakamoto, Teikyo University; Study Director: Naoaki Ichihara, Osaka University; Study Chair: Toru Hifumi, Kyorin University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): January 6, 2025
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: January 3, 2025
• First Submitted That Met QC Criteria: January 14, 2025
• First Posted (Actual): January 15, 2025

Study Record Updates

• Last Update Posted (Actual): June 27, 2025
• Last Update Submitted That Met QC Criteria: June 26, 2025
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Cardiac arrest; Out-of-hospital cardiac arrest (OHCA); Extracorporeal cardiopulmonary resuscitation (ECPR); Temperature control; Post cardiac arrest syndrome (PCAS)
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Postoperative Complications; Pathologic Processes; Heart Diseases; Body Temperature Changes; Brain Injuries; Reperfusion Injury; Post-Cardiac Arrest Syndrome; Heart Arrest; Hypothermia; Out-of-Hospital Cardiac Arrest
• Other Study ID Numbers: j-neuro

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No