Original Article
Is Time to Cooling Target Temperature Important? William Franklin Peacock, MD, FACEP, and Nathan Scott Deal, MD
W
hen cooling after cardiac arrest, the exact temperature of what the optimal target to aim for is undefined. Traditionally, one has aimed for 33°C, but some studies have suggested that a higher temperature might be better. The recent Target Temperature Management 33°C versus 36°C after Out-of-Hospital Cardiac Arrest (TTM) study1 attempted to address this conundrum. In this international multicenter trial of 939 unconscious adult survivors of a presumed out-of-hospital cardiac arrest, patients were randomized to a target temperature of either 33°C or 36°C, and subsequently evaluated for the primary outcome of all-cause mortality at the conclusion of the investigation. The authors reported that the target temperature of 33°C did not confer a benefit compared with 36°C, and there were no differences in several secondary outcome measures. In reviewing this new study, it is important to realize several limitations. We suggest that several important questions were not addressed in the original manuscript or published in the accompanying editorial. While the authors demonstrate a lack of benefit associated with the depth of postresuscitation cooling, an important consideration to understand this consequence is the relationship between the time required to reach the target temperature and outcomes. We suspect that, as is true in many pathologies, where delayed therapy is associated with worse outcomes, the actual time to the target temperature postresuscitation is also a critical determinant of outcomes. In the TTM study, a delay from resuscitation to enrollment of up to 4 hours was allowed per study protocol. Then, after enrollment, patients were randomized either to be cooled to 33°C or to be maintained at a temperature of 36°C (mean temperature at enrollment was 35.5°C). Examination of Figure 1 of the TTM study suggests that the 33°C temperature was not reached until a mean of 8 hours after randomization. If we include the up to 4-hour delay of randomization, then the goal temperature of 33°C was not reached for some patients until 12 hours after return of spontaneous circulation (ROSC). Would thrombolytics provide much benefit 12 hours after a myocardial infarction, or is the damage mostly irreparable at that juncture? By this reasoning, it is possible that the time delay built into the methodology of the TTM study potentially negated any benefit that could possibly be realized by the 33°C temperature and that an earlier and more aggressive cooling strategy may have produced a completely different result. That the time to target temperature is a critical event is supported by earlier studies. Bernard et al,2 by cooling patients with prehospital ice packs, and achieving 33°C within 2 hours of ROSC, found that patients were 88% more likely to recover with good outcomes when cooled. Conversely, the Hypothermia After Cardiac Arrest (HACA) trial,3 using a delayed cooling approach with inhospital surface cooling and reaching 32°C to 34°C 8 hours after ROSC, demonstrated an improvement of only 41% in the hypothermia cohort. This substantial difference of 47% in favorable outcome From Emergency Medicine, Ben Taub General Hospital, Houston, TX. Reprints: W. Frank Peacock, MD, Emergency Medicine, Ben Taub General Hospital, 1504 Taub Loop, Houston, Texas 77030. Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 1003-0117/14/1302-0082 DOI: 10.1097/HPC.0000000000000013
82 | www.critpathcardio.com
rates between the early and the delayed strategy of the 2 studies suggests that time to cooling may be a critical outcome determinant. Many laboratory and clinical studies support the principle that time to cooling target is critical for postresuscitation recovery.4–13 For example, animals cooled to 33°C within 4 hours have improved outcomes versus normothermic controls, while a cooling delay of 8 hours after resuscitation (similar to the 33°C target in the TTM study) abolishes these benefits.12 Further support for the importance of time to target temperature is found in a retrospective analysis of 172 postarrest patients. This study, with patients cooled to 32°C, reported that for every 5-minute delay in initiating hypothermia treatment, there was an 8% greater odds of poor outcome, and for every 30-minute delay in reaching target temperature, there was a 17% greater probability of poor outcome.13 It is true that not all studies find a benefit to earlier cooling. Two relatively large randomized trials14,15 failed to show that prehospital cooling with cold intravenous infusions improved outcomes. Both showed a trend toward worsened outcomes. It has been suggested that the lack of a time/outcome relationship may have been because of increased venous loading and the resultant complications associated with the specific cooling method of cold intravenous infusion, which included recurrent cardiac arrests and pulmonary edema.15 We therefore suggest that all future authors reporting the results of hypothermia trials address and report the following questions: a. What is the average delay from resuscitation to the start of cooling? b. Was there any association between the timing of cooling and outcome? Such an analysis should adjust for patient variables and look at both the time of start of cooling and the time at which target temperatures were reached. c. What proportion of patients received intravenous cold infusions? DISCLOSURES W.F.P. received research grants from Abbott, Alere, Brahms,Novartis, Roche, The Medicine’s Company; is a consultant of Abbott, Alere, BG Medicine, Cardiorentis, GE, Jannsen, Lily, The Medicine’sCompany, Singulex, Verathon; has ownership interest for Comprehensive Research Associates LLC, Vital Sensors,Emergencies in Medicine LLC. S.D.S. received research grantsfrom Cardiorentis, Alere, Novartis, and is a consultant of Alere, BGMedicine, GE, and Thermo Fisher. REFERENCES 1. 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. 2. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557–563. 3. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549–556. 4. Busto R, Dietrich WD, Globus MY, Ginsberg MD. Postischemic moderate hypothermia inhibits CA1 hippocampal ischemic neuronal injury. Neurosci Lett. 1989;101:299–304. 5. Kuboyama K, Safar P, Radovsky A, Tisherman SA, Stezoski SW, Alexander H. Delay in cooling negates the beneficial effect of mild resuscitative cerebral
Critical Pathways in Cardiology • Volume 13, Number 2, June 2014
Critical Pathways in Cardiology • Volume 13, Number 2, June 2014
hypothermia after cardiac arrest in dogs: a prospective, randomized study. Crit Care Med. 1993;21:1348–1358. 6. Carroll M, Beek O. Protection against hippocampal CA1 cell loss by postischemic hypothermia is dependent on delay of initiation and duration. Metab Brain Dis. 1992;7:45–50. 7. Markgraf CG, Clifton GL, Moody MR. Treatment window for hypothermia in brain injury. J Neurosurg. 2001;95:979–983. 8. Alam HB, Chen Z, Honma K, et al. The rate of induction of hypothermic arrest determines the outcome in a Swine model of lethal hemorrhage. J Trauma. 2004;57:961–969. 9. Shao ZH, Chang WT, Chan KC, et al. Hypothermia-induced cardioprotection using extended ischemia and early reperfusion cooling. Am J Physiol Heart Circ Physiol. 2007;292:H1995–H2003. 10. Janata A, Weihs W, Bayegan K, et al. Therapeutic hypothermia with a novel surface cooling device improves neurologic outcome after prolonged cardiac arrest in swine. Crit Care Med. 2008;36:895–902.
© 2014 Lippincott Williams & Wilkins
Time to Cool
11. Zhao H, Steinberg G. Limited therapeutic time windows of mild-to-moderate hypothermia in a focal ischemia model in rat. Stroke Res Treat. 2011;2011:131834. 12. Che D, Li L, Kopil CM, Liu Z, Guo W, Neumar RW. Impact of therapeutic hypothermia onset and duration on survival, neurologic function, and neurodegeneration after cardiac arrest. Crit Care Med. 2011;39:1423–1430. 13. Sendelbach S, Hearst MO, Johnson PJ, Unger BT, Mooney MR. Effects of variation in temperature management on cerebral performance category scores in patients who received therapeutic hypothermia post cardiac arrest. Resuscitation. 2012;83:829–834. 14. Bernard SA, Smith K, Cameron P, et al; Rapid Infusion of Cold Hartmanns (RICH) Investigators. Induction of therapeutic hypothermia by paramedics after resuscitation from out-of-hospital ventricular fibrillation cardiac arrest: a randomized controlled trial. Circulation. 2010;122:737–742. 15. Kim F, Nichol G, Maynard C, et al. Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest—a randomized trial. JAMA. 2014;311:45–52.
www.critpathcardio.com | 83
Is Time to Cooling Target Temperature Important? William Franklin Peacock, MD, FACEP, and Nathan Scott Deal, MD
W
hen cooling after cardiac arrest, the exact temperature of what the optimal target to aim for is undefined. Traditionally, one has aimed for 33°C, but some studies have suggested that a higher temperature might be better. The recent Target Temperature Management 33°C versus 36°C after Out-of-Hospital Cardiac Arrest (TTM) study1 attempted to address this conundrum. In this international multicenter trial of 939 unconscious adult survivors of a presumed out-of-hospital cardiac arrest, patients were randomized to a target temperature of either 33°C or 36°C, and subsequently evaluated for the primary outcome of all-cause mortality at the conclusion of the investigation. The authors reported that the target temperature of 33°C did not confer a benefit compared with 36°C, and there were no differences in several secondary outcome measures. In reviewing this new study, it is important to realize several limitations. We suggest that several important questions were not addressed in the original manuscript or published in the accompanying editorial. While the authors demonstrate a lack of benefit associated with the depth of postresuscitation cooling, an important consideration to understand this consequence is the relationship between the time required to reach the target temperature and outcomes. We suspect that, as is true in many pathologies, where delayed therapy is associated with worse outcomes, the actual time to the target temperature postresuscitation is also a critical determinant of outcomes. In the TTM study, a delay from resuscitation to enrollment of up to 4 hours was allowed per study protocol. Then, after enrollment, patients were randomized either to be cooled to 33°C or to be maintained at a temperature of 36°C (mean temperature at enrollment was 35.5°C). Examination of Figure 1 of the TTM study suggests that the 33°C temperature was not reached until a mean of 8 hours after randomization. If we include the up to 4-hour delay of randomization, then the goal temperature of 33°C was not reached for some patients until 12 hours after return of spontaneous circulation (ROSC). Would thrombolytics provide much benefit 12 hours after a myocardial infarction, or is the damage mostly irreparable at that juncture? By this reasoning, it is possible that the time delay built into the methodology of the TTM study potentially negated any benefit that could possibly be realized by the 33°C temperature and that an earlier and more aggressive cooling strategy may have produced a completely different result. That the time to target temperature is a critical event is supported by earlier studies. Bernard et al,2 by cooling patients with prehospital ice packs, and achieving 33°C within 2 hours of ROSC, found that patients were 88% more likely to recover with good outcomes when cooled. Conversely, the Hypothermia After Cardiac Arrest (HACA) trial,3 using a delayed cooling approach with inhospital surface cooling and reaching 32°C to 34°C 8 hours after ROSC, demonstrated an improvement of only 41% in the hypothermia cohort. This substantial difference of 47% in favorable outcome From Emergency Medicine, Ben Taub General Hospital, Houston, TX. Reprints: W. Frank Peacock, MD, Emergency Medicine, Ben Taub General Hospital, 1504 Taub Loop, Houston, Texas 77030. Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 1003-0117/14/1302-0082 DOI: 10.1097/HPC.0000000000000013
82 | www.critpathcardio.com
rates between the early and the delayed strategy of the 2 studies suggests that time to cooling may be a critical outcome determinant. Many laboratory and clinical studies support the principle that time to cooling target is critical for postresuscitation recovery.4–13 For example, animals cooled to 33°C within 4 hours have improved outcomes versus normothermic controls, while a cooling delay of 8 hours after resuscitation (similar to the 33°C target in the TTM study) abolishes these benefits.12 Further support for the importance of time to target temperature is found in a retrospective analysis of 172 postarrest patients. This study, with patients cooled to 32°C, reported that for every 5-minute delay in initiating hypothermia treatment, there was an 8% greater odds of poor outcome, and for every 30-minute delay in reaching target temperature, there was a 17% greater probability of poor outcome.13 It is true that not all studies find a benefit to earlier cooling. Two relatively large randomized trials14,15 failed to show that prehospital cooling with cold intravenous infusions improved outcomes. Both showed a trend toward worsened outcomes. It has been suggested that the lack of a time/outcome relationship may have been because of increased venous loading and the resultant complications associated with the specific cooling method of cold intravenous infusion, which included recurrent cardiac arrests and pulmonary edema.15 We therefore suggest that all future authors reporting the results of hypothermia trials address and report the following questions: a. What is the average delay from resuscitation to the start of cooling? b. Was there any association between the timing of cooling and outcome? Such an analysis should adjust for patient variables and look at both the time of start of cooling and the time at which target temperatures were reached. c. What proportion of patients received intravenous cold infusions? DISCLOSURES W.F.P. received research grants from Abbott, Alere, Brahms,Novartis, Roche, The Medicine’s Company; is a consultant of Abbott, Alere, BG Medicine, Cardiorentis, GE, Jannsen, Lily, The Medicine’sCompany, Singulex, Verathon; has ownership interest for Comprehensive Research Associates LLC, Vital Sensors,Emergencies in Medicine LLC. S.D.S. received research grantsfrom Cardiorentis, Alere, Novartis, and is a consultant of Alere, BGMedicine, GE, and Thermo Fisher. REFERENCES 1. 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. 2. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557–563. 3. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549–556. 4. Busto R, Dietrich WD, Globus MY, Ginsberg MD. Postischemic moderate hypothermia inhibits CA1 hippocampal ischemic neuronal injury. Neurosci Lett. 1989;101:299–304. 5. Kuboyama K, Safar P, Radovsky A, Tisherman SA, Stezoski SW, Alexander H. Delay in cooling negates the beneficial effect of mild resuscitative cerebral
Critical Pathways in Cardiology • Volume 13, Number 2, June 2014
Critical Pathways in Cardiology • Volume 13, Number 2, June 2014
hypothermia after cardiac arrest in dogs: a prospective, randomized study. Crit Care Med. 1993;21:1348–1358. 6. Carroll M, Beek O. Protection against hippocampal CA1 cell loss by postischemic hypothermia is dependent on delay of initiation and duration. Metab Brain Dis. 1992;7:45–50. 7. Markgraf CG, Clifton GL, Moody MR. Treatment window for hypothermia in brain injury. J Neurosurg. 2001;95:979–983. 8. Alam HB, Chen Z, Honma K, et al. The rate of induction of hypothermic arrest determines the outcome in a Swine model of lethal hemorrhage. J Trauma. 2004;57:961–969. 9. Shao ZH, Chang WT, Chan KC, et al. Hypothermia-induced cardioprotection using extended ischemia and early reperfusion cooling. Am J Physiol Heart Circ Physiol. 2007;292:H1995–H2003. 10. Janata A, Weihs W, Bayegan K, et al. Therapeutic hypothermia with a novel surface cooling device improves neurologic outcome after prolonged cardiac arrest in swine. Crit Care Med. 2008;36:895–902.
© 2014 Lippincott Williams & Wilkins
Time to Cool
11. Zhao H, Steinberg G. Limited therapeutic time windows of mild-to-moderate hypothermia in a focal ischemia model in rat. Stroke Res Treat. 2011;2011:131834. 12. Che D, Li L, Kopil CM, Liu Z, Guo W, Neumar RW. Impact of therapeutic hypothermia onset and duration on survival, neurologic function, and neurodegeneration after cardiac arrest. Crit Care Med. 2011;39:1423–1430. 13. Sendelbach S, Hearst MO, Johnson PJ, Unger BT, Mooney MR. Effects of variation in temperature management on cerebral performance category scores in patients who received therapeutic hypothermia post cardiac arrest. Resuscitation. 2012;83:829–834. 14. Bernard SA, Smith K, Cameron P, et al; Rapid Infusion of Cold Hartmanns (RICH) Investigators. Induction of therapeutic hypothermia by paramedics after resuscitation from out-of-hospital ventricular fibrillation cardiac arrest: a randomized controlled trial. Circulation. 2010;122:737–742. 15. Kim F, Nichol G, Maynard C, et al. Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest—a randomized trial. JAMA. 2014;311:45–52.
www.critpathcardio.com | 83
