Duration of Therapeutic Hypothermia After Out-of-Hospital Cardiac Arrest
William J. Meurer, Sharon D. Yeatts, Romergryko G. Geocadin, Akash Roy, Clifton W. Callaway, Viswanathan Ramakrishnan, Scott M. Berry, Angela F. Caveney, Sara Meyer, Nia Bozeman, Deneil M. Harney, Mickie Speers, Valerie Lynn Willis Stevenson, Cemal B. Sozener, Mohamud R. Daya, David G. Beiser, Jonathan Elmer, Imad R. Khan, Karen G. Hirsch, J. Hope Kilgannon, Michelle Nassal, Nicholas J. Johnson, Rachel Beekman, Teresa L. May, Jeremy Brown, Robert Silbergleit, , Sara Difiore-Sprouse, Joseph Darby, Ankur Doshi, Byron Drumheller, Laura Faiver, Katharyn Flickinger, Francis Guyette, Ata Kaynar, Bradley Molyneaux, Cecelia Ratay, Alexis Steinberg, Jonathan Tam, Alexandra Weissman, Patrick Coppler, Nicholas Case, Maja Strusinska-Thayer, Nancy Le, Jeffrey Smith, Jennifer Cook, Joshua Lupton, William Spurlock, Joy Kim, Marwan Mouammar, Matthew Neth, Keeley Mcconnell, Sara Roy, Mazin Sabeh, Alaa Kassir, Jonathan Paul, Karli Molignoni, Lars-Kristofer Peterson, Nitin Puri, Lauren Remboski, Christopher Jones, Dylan Kurowsky, Daryl Mchugh, Reanna Stewart, Benjamin George, Caledonia Banker, Daniyal Kamal, Nancy Wood, Ashley Proctor, David Adler, Joshua Acidera, Megan Fuentes, Katherine Elkort, Sarah Katsandres, Vasisht Srinivasan, Kathryn Thompson, Peter Kudenchuk, Michael Kampp, Emily Gilmore, Charles Wira, Sara Jasak, Kathryn Kisken, Eva Kitlen, Sarah Perman, Gail D'Onofrio, Kathryn Meehl, Nina Gentile, Hannah Reimer, Derek Isenberg, Mohammad T Abboud, Michael Gezalian, Shouri Lahiri, Shahed Toosi, Sung Min Na, Jeena Cha, Gloria Obialisi, Maranatha Ayodele, Sam Torbati, John Wilburn, Lauren Buck, Thomas Mazzocco, Valerie Mika, Arun Sherma, Rahul Nene, Arthur Davis, Gabriel Wardi, Alexandrea Cronin, Alyssa Henning, Bryce Duchman, Rebecca Sell, Matthew Greer, Abhijeet Gorhe, Manoj Kesarwani, Daniel Nishijima, Christian Sebat, Jeffrey Vitt, Lori Kennedy, Lara Zimmermann, Donovan S. Nielsen, Cindy Hsu, Jennifer Fowler, Florian Schmitzberger, Michael P. Thomas, Justin Benoit, Alexandra Ramirez, William Knight, Natalie Kreitzer, Gregory Fermann, Cora Reinhart, Abigail Vollmer, Benton Hunter, Patti Hogan, Nicholas Montelauro, Henry Ludwig, Huma Siddiqui, Timothy Ellender, Sarah Maghraoui, Alexander Limkakeng, Tammy Hawley, Anjni Joiner, Tedra Porter, Bria Johnston, Mary Motta, Joseph Miller, Tiffany Gomez, Margaret Beyer, Jimmy Nehme, Kathleen Wilson, Yasin Almri, Gillian Grafton, Namita Jayaprakash, Howard Klausner, Christopher Lewandowski, Jason Muir, Mohammed Rehman, Douglas Kupas, Susan Kilbride, Paul Berry, Kay Reiner, Eric Melnychuk, Claude Hemphill, Katherine Peterson, Dominica Randazzo, Debbie Madhok, Michael Baumann, Henry Selker, Christine Lord, Richard Riker, Robert Swor, Heather Grace, Carol Clark, Steven Timmis, David Berger, Brian Driver, Audrey Hendrickson, Matthew Prekker, Kowsar Hurreh, Ellen Maruggi, Sung-Min Cho, Aba Osei-Frimpong, Michelle Parish, Crystal LaBozzetta, Liam Pauli, Richard Rothman, Daniel Swedien, Lauren Zimmerman, John Greenwood, Dena Torrente, Olivia Doran, Komal Khan, Benjamin Abella, William Paolo, Lauren Pacelli, Devin Burke, Anne Ellison, Anna Prince, Ivy Philogene, Julius Gene Latorre, Birendra Sah, Jason Hack, Nirali Patel, Jennifer Stahl, Douglas Schiller, Miriam Wood, Shayla Vickers, Amer Ardati, Marina Del Rios, Pavitra Kotini-Shah, Sara Heinert, Janey Kottler, Terry Vanden Hoek, Shaveta Khosla, Michael Kurz, Laura Laupus, Nivedita Patkar, James Paxton, Nicholas Wesner, Farhan Ayaz, Brian O'neil, Wazim Mohamed, Michael Hill, Jennifer Smith, Henry Wang, Richard Gumina, Matthew Exline, Carson Reider, James Quinn, Elizabeth Osborn, Anita Visweswaran, Angie Murkins, Arely Campos-Melendez, Elizabeth Pernicka, Joseph Tonna, Margaret Carlson, Alyssa Messina, Scott Youngquist, Lisa Merck, Emilia Byrne, Joseph Ornato, Mary Ann Peberdy, Walter Cooper, Natalie Nerobeieva, Stephanie DeMasi, Megan Donohue, Michelle Gossip, Noah Hillerbrand, J. Michael Joyce, Kabir Yadav, Santos Vazquez, Elizabeth Hernandez, Janine Lapage, Yuria Ushitani, Kassi Kronfeld, Charles Lanks, Juliana Tolles, Cameron Hypes, Elizabeth Salvagio Campbell, Jarrod Mosier, Mary Labus, Firas Kaddouh, Amber Rice, Bailey Bowles, Sachin Agarwal, Edward Suh, Angela Velazquez, Jan Claassen, Soojin Park, Shivani Ghoshal , David Roh, You Lim Song, Jerima Carmona, Adam Singer, Ethan Brandler, Merry Taylor, Felix Zamora, Kealy Ham, Nell Adams, Elizabeth Butler, Yeng Moua, Alan Denney, Matthew Koenig, Hangyul Chung-Esaki, Tracy Stern, Kim Nguyen, Kelly Diedrich, Peter Pruitt, Phillip Bragg, Thomas Bleck, Kayla Muschong, Katherine Piserchia, Zachary Taylor, John Bruno, Ralisa Pop, Nicole Bostick, Amy Holland, Nastasia James, Magali Jorand-Fletcher, Carolina Maciel, Torben Becker, Alex Parker, Anum Khaliq, Tom Aufderheide, Anna Curtis, Sarah Abdallah, Devin Gillespie, Jamie Jasti, Jacob Labinski, Linda Mattrisch, Rahul Nanchal, Christopher Roberts, Evan Robinsin, David Gaieski, Kristin Rising, Nicole Renzi, Aaron Barksdale, Brooklin Zimmerman, Benjamin Miller, Jessica Staloch, Joshua Goldstein, Blair Perry, Michael Silverman, Brenna McKaig, Olivia Nelson, Renee Hua, Eleonore Kugener, Chun Mei Su, Kayleigh Fischer, Elizabeth Jones, Misha Bhatti, Joseph Boyle, Misha Granado, Benjamin Karfunkle, Misty Ottman, Jon Rittenberger, Brent Bloomquist, Adam Breslin, Christopher Berry, Kimberly Stermer, Donna Tyburczy, Imgard Lewis, Flavia Lee, Betty Davis, Aarti Sarwal, Lauren Koehler, Ivor Douglas, Jason Haukoos, Terra Hiller, Alicia Cupelo, Stephanie Gravitz, Carolynn Lyle, Adrienne Malik, Lucas Lemar, Robert O'Connor, Ashley Simpson, Vedant Gupta, Terren Trott, Aaron Tyagi, Theresa Mimms, Ronda Petrey, Joann Short, Roger Humphries, Ryan Huebinger, Amisha Choudhary, Masoom Desai, Richelle Cooper, Julia Vargas, Rebecca Beutler, Oscar De La Rosa, Steven Chang, Erik Kochert, Gretchen Meise, Scott Leroux, Kiran Faryar, Andie Moore, Colin McCloskey, Christine Bartle, Nidhi Garg, Ana Centeno Rahbani, Neil Hakimi, Bryan Klein, Kenneth Dodd, Ryan Mckillip, Nicole Hannigan, Kathleen Hesse, Erik Kulstad, Valerie Griffeth, Sam Parnia, Joseph Offenbacher, Catherine Swarts, Natalia Leontovich, David Ledrick, Randall King, Evan Hollar, Dee Tilley, Drew Toth, Betty Yang, Diana Hamza, Paula Arellano-Cruz, Lauren Kerich, Tori Broadbent, Katherine Martin, Trang Pham, Ava Pierce, Avi Ruderman, Michael Donnino, Franklin Li, Jacob Boise, Adit Ginde, Katherine Mayer, Amanda Martinez, Jennifer Peers, Shelby Shelton, Jong Lee, Janet Orozco, Mallika Purandare, Damarcus Baymon, Benjamin M. Scirica, Rafael Wabl, Rebecca Watson, Benjamin Friedman, Dennis Ortiz, Carlo Lutz, Ari Maskowitz, Joseph Piktel, Julie Nichols, Vaishnavi Ragavapuram, Harris Skaramagas, Firas Anaya, Aisha Siraj, Vidya Krishnan, Lance Wilson, Andre Holder, Nick Stanley, Lovie Negrin, Alaina Williams, David Wright, Alex Hall, Stephan Mayer, Kelly Sawyer, Jean-Christophe Arnaud, Keith Pauls, Sarah Wells, Wenle Zhao, Theodore Iwashyna, Frank Moler, Peyton Kline, Jennifer Conley, Amy Schroeder, Kimberly Brown, Courtney Miller, Aimee Spiteri , Noelle Carlozzi, Anna Kratz, Joy Black, Sofia Perez, Josephine Karas, Kristine Broglio, Mark Fitzgerald, Joe MarionImportance
Therapeutic hypothermia is widely used for neuroprotection following cardiac arrest, but clinical trials have not consistently demonstrated improved neurological outcomes, and the optimal duration of cooling remains uncertain.
Objective
To determine the duration of therapeutic hypothermia that maximizes neurological recovery in comatose survivors of out-of-hospital cardiac arrest.
Design, Setting, and Participants
Multicenter, randomized, adaptive-allocation clinical trial conducted at 71 hospitals in the US. Adults with out-of-hospital cardiac arrest who remained unconscious, achieved a target temperature less than 34 °C within 4 hours of cardiac arrest, and had a definitive temperature control device started were eligible. Patients were enrolled between June 2020 and June 2025.
Interventions
Therapeutic hypothermia at 33 °C with adaptive randomized allocation to cooling durations of 6, 12, 18, 24, 30, 36, 42, 48, 60, and 72 hours. The first 200 patients were randomized to 12-, 24-, and 48-hour durations in a 1:1:1 ratio. Subsequently, a response-adaptive randomization algorithm allocated preferentially to the groups most likely to be optimal and to best inform the duration-response curve separately within each rhythm type.
Main Outcomes and Measures
The primary outcome was neurological function at 90 days, measured using a weighted modified Rankin Scale score, analyzed using a bayesian duration-response model. The primary analysis estimated the posterior probability that each duration was optimal, wherein optimal indicates the shortest duration consistent with the best outcome observed at any duration.
Results
A total of 1158 patients were randomized (883 with nonshockable rhythms and 275 with shockable rhythms). Participants had a median age of 61 (IQR, 50-70) years and 39.6% were female. The trial met a prespecified stopping rule at the interim analysis. For the nonshockable rhythm cohort, the posterior probability that 6 hours was the shortest duration achieving the maximal mean weighted modified Rankin Scale score was 0.51. Results were similar in the shockable rhythm cohort. No differences were observed in secondary outcomes or mortality across cooling durations.
Conclusions and Relevance
Among comatose survivors of out-of-hospital cardiac arrest treated with therapeutic hypothermia at 33 °C, increasing cooling duration did not improve neurological outcomes.
Trial Registration
ClinicalTrials.gov Identifier: