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Is It Still Cool to Cool? Interpreting the Latest Hypothermia for Cardiac Arrest Trial
ANNALS OF EMERGENCY MEDICINE JOURNAL CLUB
Is It Still Cool to Cool? Interpreting the Latest Hypothermia for Cardiac Arrest Trial March 2014 Annals of Emergency Medicine Journal Club Guest Contributors Daniel M. Rolston, MD, MS; Jarone Lee, MD, MPH 0196-0644/$-see front matter Copyright © 2014 by the American College of Emergency Physicians. http://dx.doi.org/10.1016/j.annemergmed.2014.01.001
Editor’s Note: You are reading the 38th installment of Annals of Emergency Medicine Journal Club. This Journal Club refers to the Nielsen et al1 article titled “Targeted Temperature Management at 33 C Versus 36 C After Cardiac Arrest” that was published in the New England Journal of Medicine.1 This bimonthly feature seeks to improve the critical appraisal skills of emergency physicians and other interested readers through a guided critique of actual Annals of Emergency Medicine articles. Each Journal Club will pose questions that encourage readers—be they clinicians, academics, residents, or medical students—to critically appraise the literature. During a 2- to 3-year cycle, we plan to ask questions that cover the main topics in research methodology and critical appraisal of the literature. To do this, we will select articles that use a variety of study designs and analytic techniques. These may or may not be the most clinically important articles in a specific issue, but they are articles that serve the mission of covering the clinical epidemiology curriculum. Journal Club entries are published in 2 phases. In the first phase, a list of questions about the article is published in the issue in which the article appears. Questions are rated “novice” ( ), “intermediate” ( ), and “advanced” ( ) so that individuals planning a journal club can assign the right question to the right student. The answers to this journal club will be published in the August 2014 issue. US residency directors will have immediate access to the answers through the Council of Emergency Medicine Residency Directors Share Point Web site. International residency directors can gain access to the questions by going to http://www. emergencymedicine.ucla.edu/annalsjc/ and following the directions. Thus, if a program conducts its journal club within 5 months of the publication of the questions, no one will have access to the published answers except the residency director. The purpose of delaying the publication of the answers is to promote discussion and critical review of the literature by residents and medical students and discourage regurgitation of the published answers. It is our hope that the Journal Club will broaden Annals of Emergency Medicine’s appeal to residents and medical students. We are interested in receiving feedback about this feature. Please e-mail [email protected] with your comments.
DISCUSSION POINTS
1. The authors reference 2 previous trials2,3 that compared therapeutic hypothermia (32 C to 34 C [89.6F to 93.2F] for 12 to 24 hours) with standard treatment and “showed
368 Annals of Emergency Medicine
a significant improvement in neurologic function and survival with therapeutic hypothermia.”1 A What was the treatment effect in the previous 2 studies? What percentage of patients had neurologically intact survival? How many patients would one need to treat with hypothermia to produce 1 additional neurologically intact patient? B There is good evidence that the presence of an initial shockable rhythm greatly enhances the probability of survival from cardiac arrest. Have any randomized trials demonstrated an improvement in neurologic outcomes in patients whose initial rhythm was pulseless electrical activity or asystole? 2. Previous studies have reported deleterious effects when patients recovering from an out-of-hospital cardiac arrest develop fever,1,4,5 leading authors to question whether reported benefits are due to hypothermia or prevention of hyperthermia.1 The authors conducted a multicenter, international trial that randomized unconscious adults, who had return of spontaneous circulation after out-of-hospital cardiac arrest, to either 33 C or 36 C (91.4F or 96.8F) temperature target. A The current recommendation by many expert consensus groups is to cool out-of-hospital cardiac arrest victims to 32 C to 34 C (89.6F to 93.2F) after ventricular fibrillation and possibly other rhythms. The authors did not follow this recommendation for one of the arms of the study. Do you believe there was equipoise? Discuss the importance of equipoise in clinical research. B Could this trial have been performed in the United States? What additional requirements would the investigators have to complete to receive institutional review board approval for exception from informed consent? C The authors note the inability to blind the critical care practitioners; however, they were able to blind the assessors providing follow-up neurologic examination. Were the methods used to eliminate the risk of critical care provider bias sufficient? 3. The authors examined the primary outcome of survival time and followed patients up to the end of the trial
Volume 63, no. 3 : March 2014
Rolston & Lee
Journal Club
(ie, 180 days after the enrollment of the last patient) and powered the study to this outcome. A The trial was designed as a superiority trial to detect a 20% reduction in the hazard ratio for death with hypothermia at 33 C (91.4F) versus a control group at 36 C (96.8F). Was the study appropriately powered for this outcome? B How would the power calculations change if the study design were a noninferiority trial of relative normothermia at 36 C (96.8F) versus hypothermia at 33 C (91.4F)? C What were the secondary outcomes? Discuss the advantages and disadvantages of using composite outcomes in medical research. D Therapeutic hypothermia causes many physiologic changes and potential dangers to the patient. Therefore, the authors also collected the incidence of predefined serious adverse events up to day 7 in the ICU. Which specific adverse events did they collect? Do you think these adverse events and 7-day interval were sufficient? If not, what other events or intervals might you have chosen? E To evaluate neurologic outcomes, the authors used the Cerebral Performance Category (CPC) and the modified Rankin score (mRS). For scores to be effective, they should be already validated. Have these 2 scores been previously validated? Are there other scores that the authors could have used? 4. For analysis of their results, hazard ratios were used for the analysis of the primary outcome (end-of-trial mortality), but risk ratios were used to analyze the secondary outcomes (CPC score, mRS). What are the differences
between hazard ratios and risk ratios? Why did the authors use different tests to analyze their primary and secondary outcomes? 5. If you were creating a cardiac arrest protocol in your hospital, what would you set for the target temperature? Do you think the temperature or the protocol is more important for survival? Section editors: Tyler W. Barrett, MD, MSCI; David L. Schriger, MD, MPH Author affiliations: From the University of California, Los Angeles, CA (Rolston); and the Harvard School of Medicine, Boston, MA (Lee).
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. 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. 5. Leary M, Grossestreuer AV, Iannacone S, et al. Pyrexia and neurologic outcomes after therapeutic hypothermia for cardiac arrest. Resuscitation. 2013;84:1056-1061.
Did you know? Podcasts are available for almost every article in Annals.
Visit http://www.annemergmed.com/content/podcast to find out more.
Volume 63, no. 3 : March 2014
Annals of Emergency Medicine 369
Is It Still Cool to Cool? Interpreting the Latest Hypothermia for Cardiac Arrest Trial March 2014 Annals of Emergency Medicine Journal Club Guest Contributors Daniel M. Rolston, MD, MS; Jarone Lee, MD, MPH 0196-0644/$-see front matter Copyright © 2014 by the American College of Emergency Physicians. http://dx.doi.org/10.1016/j.annemergmed.2014.01.001
Editor’s Note: You are reading the 38th installment of Annals of Emergency Medicine Journal Club. This Journal Club refers to the Nielsen et al1 article titled “Targeted Temperature Management at 33 C Versus 36 C After Cardiac Arrest” that was published in the New England Journal of Medicine.1 This bimonthly feature seeks to improve the critical appraisal skills of emergency physicians and other interested readers through a guided critique of actual Annals of Emergency Medicine articles. Each Journal Club will pose questions that encourage readers—be they clinicians, academics, residents, or medical students—to critically appraise the literature. During a 2- to 3-year cycle, we plan to ask questions that cover the main topics in research methodology and critical appraisal of the literature. To do this, we will select articles that use a variety of study designs and analytic techniques. These may or may not be the most clinically important articles in a specific issue, but they are articles that serve the mission of covering the clinical epidemiology curriculum. Journal Club entries are published in 2 phases. In the first phase, a list of questions about the article is published in the issue in which the article appears. Questions are rated “novice” ( ), “intermediate” ( ), and “advanced” ( ) so that individuals planning a journal club can assign the right question to the right student. The answers to this journal club will be published in the August 2014 issue. US residency directors will have immediate access to the answers through the Council of Emergency Medicine Residency Directors Share Point Web site. International residency directors can gain access to the questions by going to http://www. emergencymedicine.ucla.edu/annalsjc/ and following the directions. Thus, if a program conducts its journal club within 5 months of the publication of the questions, no one will have access to the published answers except the residency director. The purpose of delaying the publication of the answers is to promote discussion and critical review of the literature by residents and medical students and discourage regurgitation of the published answers. It is our hope that the Journal Club will broaden Annals of Emergency Medicine’s appeal to residents and medical students. We are interested in receiving feedback about this feature. Please e-mail [email protected] with your comments.
DISCUSSION POINTS
1. The authors reference 2 previous trials2,3 that compared therapeutic hypothermia (32 C to 34 C [89.6F to 93.2F] for 12 to 24 hours) with standard treatment and “showed
368 Annals of Emergency Medicine
a significant improvement in neurologic function and survival with therapeutic hypothermia.”1 A What was the treatment effect in the previous 2 studies? What percentage of patients had neurologically intact survival? How many patients would one need to treat with hypothermia to produce 1 additional neurologically intact patient? B There is good evidence that the presence of an initial shockable rhythm greatly enhances the probability of survival from cardiac arrest. Have any randomized trials demonstrated an improvement in neurologic outcomes in patients whose initial rhythm was pulseless electrical activity or asystole? 2. Previous studies have reported deleterious effects when patients recovering from an out-of-hospital cardiac arrest develop fever,1,4,5 leading authors to question whether reported benefits are due to hypothermia or prevention of hyperthermia.1 The authors conducted a multicenter, international trial that randomized unconscious adults, who had return of spontaneous circulation after out-of-hospital cardiac arrest, to either 33 C or 36 C (91.4F or 96.8F) temperature target. A The current recommendation by many expert consensus groups is to cool out-of-hospital cardiac arrest victims to 32 C to 34 C (89.6F to 93.2F) after ventricular fibrillation and possibly other rhythms. The authors did not follow this recommendation for one of the arms of the study. Do you believe there was equipoise? Discuss the importance of equipoise in clinical research. B Could this trial have been performed in the United States? What additional requirements would the investigators have to complete to receive institutional review board approval for exception from informed consent? C The authors note the inability to blind the critical care practitioners; however, they were able to blind the assessors providing follow-up neurologic examination. Were the methods used to eliminate the risk of critical care provider bias sufficient? 3. The authors examined the primary outcome of survival time and followed patients up to the end of the trial
Volume 63, no. 3 : March 2014
Rolston & Lee
Journal Club
(ie, 180 days after the enrollment of the last patient) and powered the study to this outcome. A The trial was designed as a superiority trial to detect a 20% reduction in the hazard ratio for death with hypothermia at 33 C (91.4F) versus a control group at 36 C (96.8F). Was the study appropriately powered for this outcome? B How would the power calculations change if the study design were a noninferiority trial of relative normothermia at 36 C (96.8F) versus hypothermia at 33 C (91.4F)? C What were the secondary outcomes? Discuss the advantages and disadvantages of using composite outcomes in medical research. D Therapeutic hypothermia causes many physiologic changes and potential dangers to the patient. Therefore, the authors also collected the incidence of predefined serious adverse events up to day 7 in the ICU. Which specific adverse events did they collect? Do you think these adverse events and 7-day interval were sufficient? If not, what other events or intervals might you have chosen? E To evaluate neurologic outcomes, the authors used the Cerebral Performance Category (CPC) and the modified Rankin score (mRS). For scores to be effective, they should be already validated. Have these 2 scores been previously validated? Are there other scores that the authors could have used? 4. For analysis of their results, hazard ratios were used for the analysis of the primary outcome (end-of-trial mortality), but risk ratios were used to analyze the secondary outcomes (CPC score, mRS). What are the differences
between hazard ratios and risk ratios? Why did the authors use different tests to analyze their primary and secondary outcomes? 5. If you were creating a cardiac arrest protocol in your hospital, what would you set for the target temperature? Do you think the temperature or the protocol is more important for survival? Section editors: Tyler W. Barrett, MD, MSCI; David L. Schriger, MD, MPH Author affiliations: From the University of California, Los Angeles, CA (Rolston); and the Harvard School of Medicine, Boston, MA (Lee).
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. 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. 5. Leary M, Grossestreuer AV, Iannacone S, et al. Pyrexia and neurologic outcomes after therapeutic hypothermia for cardiac arrest. Resuscitation. 2013;84:1056-1061.
Did you know? Podcasts are available for almost every article in Annals.
Visit http://www.annemergmed.com/content/podcast to find out more.
Volume 63, no. 3 : March 2014
Annals of Emergency Medicine 369