Association between rewarming duration and neurological outcome in out-of-hospital cardiac arrest patients receiving therapeutic hypothermia



      The European Resuscitation Council guidelines recommend a slow rate of rewarming of 0.25 °C/h–0.5 °C/h for out-of-hospital cardiac arrest (OHCA) patients receiving therapeutic hypothermia (TH). Conversely, a very slow rewarming of 1 °C/day is generally applied in Japan. The rewarming duration ranged from less than 24 h up to more than 50 h. No randomized control trials have examined the optimal rewarming speed for TH in OHCA patients. Therefore, we examined the association between the rewarming duration and neurological outcomes in OHCA patients who received TH.


      This study was a secondary analysis of the Japanese Population-based Utstein-style study with defibrillation and basic/advanced Life Support Education and implementation-Hypothermia (J-PULSE-HYPO) study registry, a multicenter prospective cohort study. Patients suffering from OHCA who received TH (target temperature, 34 °C) after the return of spontaneous circulation from 2005 to 2011 in 14 hospitals throughout Japan were enrolled. The rewarming duration was defined as the time from the beginning of rewarming at a target temperature of 34 °C until reaching 36 °C. The primary outcome was an unfavorable neurological outcome at hospital discharge, i.e., a cerebral performance category of 3–5.


      The J-PULSE-HYPO study enrolled 452 OHCA patients. Of these, 328 were analyzed; 79.9% survived to hospital discharge, of which 56.4% had a favorable neurological outcome. Multivariable logistic regression analysis revealed that the rewarming duration was independently associated with unfavorable neurological outcomes [odds ratio (per 5 h), 0.89; 95% confidence interval, 0.79–0.99; p =  0.032].


      A longer rewarming duration was significantly associated with and was an independent predictor of favorable neurological outcomes in OHCA patients who received TH.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Resuscitation
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Fukuda T.
        Targeted temperature management for adult out-of-hospital cardiac arrest: current concepts and clinical applications.
        J Intensive Care. 2016; 4: 30
        • Polderman K.H.
        Mechanisms of action, physiological effects, and complications of hypothermia.
        Crit Care Med. 2009; 37: S186-S202
        • Kirkegaard H.
        • Soreide E.
        • de Haas I.
        • et al.
        Targeted temperature management for 48 vs 24 hours and neurologic outcome after out-of-hospital cardiac arrest: a randomized clinical trial.
        JAMA. 2017; 318: 341-350
        • Nielsen N.
        • Wetterslev J.
        • Cronberg T.
        • et al.
        Targeted temperature management at 33 °C versus 36 °C after cardiac arrest.
        N Engl J Med. 2013; 369: 2197-2206
        • Hypothermia after Cardiac Arrest Study G
        Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest.
        N Engl J Med. 2002; 346: 549-556
        • Bernard S.A.
        • Gray T.W.
        • Buist M.D.
        • et al.
        Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia.
        N Engl J Med. 2002; 346: 557-563
        • Arrich J.
        • European Resuscitation Council Hypothermia After Cardiac Arrest Registry Study G
        Clinical application of mild therapeutic hypothermia after cardiac arrest.
        Crit Care Med. 2007; 35: 1041-1047
        • Nolan J.P.
        • Soar J.
        • Cariou A.
        • et al.
        European Resuscitation Council and European Society of Intensive Care Medicine Guidelines for Post-resuscitation Care 2015: Section 5 of the European Resuscitation Council Guidelines for Resuscitation 2015.
        Resuscitation. 2015; 95: 202-222
        • Inoue A.
        • Hifumi T.
        • Yonemoto N.
        • et al.
        The impact of heart rate response during 48-hour rewarming phase of therapeutic hypothermia on neurologic outcomes in out-of-hospital cardiac arrest patients.
        Crit Care Med. 2018; 46: e881-e888
        • Suehiro E.
        • Singleton R.H.
        • Stone J.R.
        • Povlishock J.T.
        The immunophilin ligand FK506 attenuates the axonal damage associated with rapid rewarming following posttraumatic hypothermia.
        Exp Neurol. 2001; 172: 199-210
        • Suehiro E.
        • Ueda Y.
        • Wei E.P.
        • Kontos H.A.
        • Povlishock J.T.
        Posttraumatic hypothermia followed by slow rewarming protects the cerebral microcirculation.
        J Neurotrauma. 2003; 20: 381-390
        • Polderman K.H.
        • Callaghan J.
        Equipment review: cooling catheters to induce therapeutic hypothermia?.
        Crit Care. 2006; 10: 234
        • Yokoyama H.
        • Nagao K.
        • Hase M.
        • et al.
        Impact of therapeutic hypothermia in the treatment of patients with out-of-hospital cardiac arrest from the J-PULSE-HYPO study registry.
        Circ J. 2011; 75: 1063-1070
        • Soga T.
        • Nagao K.
        • Sawano H.
        • et al.
        Neurological benefit of therapeutic hypothermia following return of spontaneous circulation for out-of-hospital non-shockable cardiac arrest.
        Circ J. 2012; 76: 2579-2585
        • Abbas S.
        Resection and primary anastomosis in acute complicated diverticulitis, a systematic review of the literature.
        Int J Colorectal Dis. 2007; 22: 351-357
        • Guehne U.
        • Riedel-Heller S.
        • Angermeyer M.C.
        Mortality in dementia.
        Neuroepidemiology. 2005; 25: 153-162
        • Greenland P.
        • Alpert J.S.
        • Beller G.A.
        • et al.
        2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
        Circulation. 2010; 122: 2748-2764
        • Cummins R.O.
        • Chamberlain D.A.
        • Abramson N.S.
        • et al.
        Recommended guidelines for uniform reporting of data from out-of-hospital cardiac arrest: the Utstein Style. A statement for health professionals from a task force of the American Heart Association, the European Resuscitation Council, the Heart and Stroke Foundation of Canada, and the Australian Resuscitation Council.
        Circulation. 1991; 84: 960-975
        • Gando S.
        • Saitoh D.
        • Ogura H.
        • et al.
        Disseminated intravascular coagulation (DIC) diagnosed based on the Japanese Association for Acute Medicine criteria is a dependent continuum to overt DIC in patients with sepsis.
        Thromb Res. 2009; 123: 715-718
        • Singh R.K.
        • Baronia A.K.
        • Sahoo J.N.
        • et al.
        Prospective comparison of new Japanese Association for Acute Medicine (JAAM) DIC and International Society of Thrombosis and Hemostasis (ISTH) DIC score in critically ill septic patients.
        Thromb Res. 2012; 129: e119-e125
        • Smith P.
        • Perrin S.
        • Yule W.
        • Hacam B.
        • Stuvland R.
        War exposure among children from Bosnia–Hercegovina: psychological adjustment in a community sample.
        J Trauma Stress. 2002; 15: 147-156
        • Bouwes A.
        • Robillard L.B.
        • Binnekade J.M.
        • et al.
        The influence of rewarming after therapeutic hypothermia on outcome after cardiac arrest.
        Resuscitation. 2012; 83: 996-1000
        • Kim K.
        • Jo Y.H.
        • Rhee J.E.
        • et al.
        Effect of speed of rewarming and administration of anti-inflammatory or anti-oxidant agents on acute lung injury in an intestinal ischemia model treated with therapeutic hypothermia.
        Resuscitation. 2010; 81: 100-105
        • Nielsen N.
        • Sunde K.
        • Hovdenes J.
        • et al.
        Adverse events and their relation to mortality in out-of-hospital cardiac arrest patients treated with therapeutic hypothermia.
        Crit Care Med. 2011; 39: 57-64
        • Bro-Jeppesen J.
        • Hassager C.
        • Wanscher M.
        • et al.
        Post-hypothermia fever is associated with increased mortality after out-of-hospital cardiac arrest.
        Resuscitation. 2013; 84: 1734-1740
        • Thomsen J.H.
        • Nielsen N.
        • Hassager C.
        • et al.
        Bradycardia during targeted temperature management: an early marker of lower mortality and favorable neurologic outcome in comatose out-of-hospital cardiac arrest patients.
        Crit Care Med. 2016; 44: 308-318
        • Thomsen J.H.
        • Hassager C.
        • Bro-Jeppesen J.
        • et al.
        Sinus bradycardia during hypothermia in comatose survivors of out-of-hospital cardiac arrest — a new early marker of favorable outcome?.
        Resuscitation. 2015; 89: 36-42