BACKGROUND: Delayed hypothermia, initiated after hospital arrival, several hours after cardiac arrest with 8-10 hours to reach the target temperature, is likely to have limited impact on overall survival. However, the effect of ultrafast hypothermia, i.e., delivered intra-arrest or immediately after return of spontaneous circulation (ROSC), on functional neurologic outcome after out-of-hospital cardiac arrest (OHCA) is unclear. In two prior trials, prehospital trans-nasal evaporative intra-arrest cooling was safe, feasible and reduced time to target temperature compared to delayed cooling. Both studies showed trends towards improved neurologic recovery in patients with shockable rhythms. The aim of the PRINCESS2-study is to assess whether cooling, initiated either intra-arrest or immediately after ROSC, followed by in-hospital hypothermia, significantly increases survival with complete neurologic recovery as compared to standard normothermia care, in OHCA patients with shockable rhythms. METHODS/DESIGN: In this investigator-initiated, randomized, controlled trial, the emergency medical services (EMS) will randomize patients at the scene of cardiac arrest to either trans-nasal cooling within 20 minutes from EMS arrival with subsequent hypothermia at 33°C for 24 hours after hospital admission (intervention), or to standard of care with no prehospital or in-hospital cooling (control). Fever (>37,7°C) will be avoided for the first 72 hours in both groups. All patients will receive post resuscitation care and withdrawal of life support procedures according to current guidelines. Primary outcome is survival with complete neurologic recovery at 90 days, defined as modified Rankin scale (mRS) 0-1. Key secondary outcomes include survival to hospital discharge, survival at 90 days and mRS 0-3 at 90 days. In total, 1022 patients are required to detect an absolute difference of 9% (from 45 to 54%) in survival with neurologic recovery (80% power and one-sided α=0,025, β=0,2) and assuming 2,5% lost to follow-up. Recruitment starts in Q1 2024 and we expect maximum enrolment to be achieved during Q4 2024 at 20-25 European and US sites. DISCUSSION: This trial will assess the impact of ultrafast hypothermia applied on the scene of cardiac arrest, as compared to normothermia, on 90-day survival with complete neurologic recovery in OHCA patients with initial shockable rhythm. TRIAL REGISTRATION: NCT06025123.

2nd Department of Medicine Department of Cardiovascular Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague Liberec Czech Republic

Cardiovascular Research Division CARDIO ELA Madrid Spain

Center for Intensive Internal Medicine University Medical Center Ljubljana Slovenia

Department of Anesthesiology Intensive Care and Emergency Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico University of Milan Milan Italy

Department of Biomedical and Clinical Sciences Linköping University Linköping Sweden

Department of Clinical Science and Education Center for Resuscitation Science Södersjukhuset Karolinska Institutet Stockholm Sweden

Department of Clinical Science and Education Center for Resuscitation Science Södersjukhuset Karolinska Institutet Stockholm Sweden; Function Perioperative Medicine and Intensive Care Karolinska University Hospital Stockholm Sweden

Department of Emergency Medicine Medical University of Vienna Vienna Austria

Department of Emergency Medicine University Hospital of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

Department of Intensive Care Erasme University Hospital Université Libre de Bruxelles Brussels Belgium

Department of Medicine Karolinska Institutet Solna Sweden

Rapid Response Car Capio Stockholm Sweden; Function Perioperative Medicine and Intensive Care Karolinska University Hospital Stockholm Sweden; Section for Anaesthesiology and Intensive Care Medicine Department of Physiology and Pharmacology Karolinska Institutet Stockholm Sweden

SAMUR Protección Civil Madrid Spain

Servicio de Emergencias 061 de La Rioja Centro de Investigación Biomédica de La Rioja La Rioja Spain

University of Washington Harborview Center for Prehospital Emergency Care University of Washington Seattle WA

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Hypothermia after Cardiac Arrest in Large Animals (HACA-LA): a randomized controlled experimental study

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ClinicalTrials.gov
NCT06025123