5. Redberg RF, Jacoby AF, Sharfstein JM. Power morcellators, postmarketing surveillance, and the US Food and Drug Administration. JAMA. doi:10.1001/jama.2017.7704 6. Rosenbaum L. N-of-1 policymaking: tragedy, trade-offs, and the demise of morcellation. N Engl J Med. 2016;374(10):986-990. 7. Ibrahim AM, Dimick JB. Monitoring medical devices: missed warning signs within existing data. JAMA. doi:10.1001/jama.2017.6584 8. Wimmer NJ, Secemsky EA, Mauri L, et al. Effectiveness of arterial closure devices for preventing complications with percutaneous coronary intervention: an instrumental variable analysis. Circ Cardiovasc Interv. 2016;9(4):e003464. 9. Farooq V, Goedhart D, Ludman P, de Belder MA, Harcombe A, El-Omar M; British Cardiovascular Intervention Society and the National Institute for Cardiovascular Outcomes Research. Relationship between femoral vascular closure devices and short-term mortality from 271 845 percutaneous coronary intervention procedures performed in the United Kingdom between 2006 and 2011: a propensity score-corrected analysis from the British Cardiovascular Intervention Society. Circ Cardiovasc Interv. 2016;9(6):e003560. 10. Resnic FS, Majithia A, Marinac-Dabic D, et al. Registry-based prospective, active surveillance of medical-device safety. N Engl J Med. 2017;376(6): 526-535. 11. Yeh RW, Kennedy K, Spertus JA, et al. Do postmarketing surveillance studies represent real-world populations? A comparison of patient characteristics and outcomes after carotid artery stenting. Circulation. 2011;123(13):1384-1390. 12. Rathi VK, Krumholz HM, Masoudi FA, Ross JS. Characteristics of clinical studies conducted over the total product life cycle of high-risk therapeutic medical devices receiving FDA premarket approval in 2010 and 2011. JAMA. 2015;314(6):604-612. 13. Reynolds IS, Rising JP, Coukell AJ, Paulson KH, Redberg RF. Assessing the safety and effectiveness of devices after US Food and Drug Administration approval: FDA-mandated postapproval studies. JAMA Intern Med. 2014;174(11):1773-1779. 14. Kramer DB, Tan YT, Sato C, Kesselheim AS. Postmarket surveillance of medical devices: a comparison of strategies in the US, EU, Japan, and China. PLoS Med. 2013;10(9):e1001519. Targeted Temperature Management After Cardiac Arrest Finding the Right Dose for Critical Care Interventions Clifton W. Callaway, MD, PhD Many clinical trials in critically ill patients do not detect im- portant differences in outcomes between groups receiving dif- ferent treatments. The trial by Kirkegaard et al 1 in this issue of JAMA compared 24 hours vs 48 hours of targeted tem- perature management (TTM) with cooling to 33°C among 355 patients who were comatose after out-of-hospital cardiac arrest. The investigators found no significant difference in fa- vorable functional neurologic outcome (defined as Cerebral Performance Categories score of 1 or 2) at 6 months for pa- tients treated for 24 hours (n = 176; 64% with favorable out- come) vs 48 hours (n = 175; 69% with favorable outcome) (difference, 5%; 95% CI, −5% to 14.8%). This absence of a dose-effect relationship could cast doubt on the efficacy of TTM, but it also should prompt examination of the core as- sumptions of dose-finding trials in resuscitation. Targeted temperature management changed post- cardiac arrest care. For decades, survival of patients with res- toration of pulses after cardiac arrest did not change. In 2002, 2 trials randomized 352 patients after out-of-hospital cardiac arrest and reported improved survival and functional recov- ery with a package of care that included mild hypothermia (32°C-34°C for 12 or 24 hours) compared with care with no hypothermia. 2,3 Implementation of therapeutic hypother- mia, which came to be known as TTM, improved outcomes in many locales, 4 but outcomes worsened with lower adher- ence to TTM. 5 Most institutions adopted the temperatures (32°C-34°C) and duration (usually 24 hours) used in these early trials. 6 However, no clinical data existed on the optimal depth, timing, or duration of hypothermia. In other words, what was the optimum dose of TTM? No particular depth of hypothermia is clearly superior for TTM. In a recent systematic review, no superiority was iden- tified for various temperatures from 32°C to 36°C. 7 The larg- est trial reported similar excellent outcomes for 939 patients after out-of-hospital cardiac arrest who were randomized to TTM at 33°C or at 36°C. 8 More rapid initiation of TTM is not clearly superior. Six trials found no difference in outcomes for 2379 patients after out-of-hospital cardiac arrest who were randomized to very early, prehospital initiation of hypothermia (<1 hour after arrest) vs later, in-hospital initiation of hypothermia (1-4 hours after arrest). 9 Observational studies of hundreds of nonrandomized patients who received TTM have found no consistent relationship between time-to-target temperature and outcome with early (<4-6 hours) initiation. 10 Preclinical data suggest that TTM initiated after 4 hours is no different from non-TTM treatment. 11 In the trial by Kirkegaard et al, 1 patients had prompt initiation of TTM (<2 hours) and reached target temperature at around 5 hours. The investigators also found no differential effect of TTM duration among patients who reached target temperature within 4 hours after arrest. Is any duration of hypothermia superior? A systematic review found no interventional clinical data to answer this question. 7 Yet in one preclinical study, 48 hours of hypo- thermia was superior to 24 hours of hypothermia for reduc- ing neuronal degeneration. 11 It is thus biologically plausible that longer periods of hypothermia may be clinically benefi- cial. The clinical trial by Kirkegaard et al 1 is the first to explore whether longer durations of TTM improve patient outcomes. This pragmatic trial also made a reasonable assumption that doubling the usual duration of hypother- mia to 48 hours was a sufficient dose escalation to detect any signal of benefit while minimizing adverse effects from very prolonged hypothermia. This trial has many excellent features in its design and conduct. 1,12 Participating centers enrolled more than 98% of Related article page 341 Opinion Editorial 334 JAMA July 25, 2017 Volume 318, Number 4 (Reprinted) jama.com © 2017 American Medical Association. All rights reserved. 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