Letters

Author Affiliations: Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois (Rogalski, Wieneke, Bigio, Weintraub, Mesulam); Department of Preventative Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois (Rademaker); Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (Bigio); Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois (Weintraub); Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (Mesulam). Corresponding Author: Emily J. Rogalski, PhD, Northwestern University, Cognitive Neurology and Alzheimer’s Disease Center (CNADC), 320 E Superior St, Searle Bldg, 11th Floor, Chicago, IL 60611 ([email protected]). Author Contributions: Dr Rogalski had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Rogalski, Weintraub, Mesulam. Acquisition, analysis, or interpretation of data: Rogalski, Rademaker, Wieneke, Bigio, Mesulam. Drafting of the manuscript: Rogalski, Rademaker, Mesulam. Critical revision of the manuscript for important intellectual content: Rogalski, Wieneke, Bigio, Weintraub, Mesulam. Statistical analysis: Rogalski, Rademaker, Mesulam. Obtained funding: Mesulam. Administrative, technical, or material support: Rogalski, Wieneke. Study supervision: Weintraub. Conflict of Interest Disclosures: None reported. Funding/Support: This project was supported by grant DC008552 from the National Institute on Deafness and Communication Disorders; grant AG13854 (Alzheimer Disease Core Center) from the National Institute on Aging; and grant NS075075 from the National Institute of Neurological Disorders and Stroke. Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. 1. Mesulam MM, Weintraub S, Rogalski EJ, Wieneke C, Geula C, Bigio EH. Asymmetry and heterogeneity of Alzheimer’s and frontotemporal pathology in primary progressive aphasia. Brain. 2014;137(pt 4):1176-1192. 2. Rogalski E, Johnson N, Weintraub S, Mesulam M. Increased frequency of learning disability in patients with primary progressive aphasia and their first-degree relatives. Arch Neurol. 2008;65(2):244-248. 3. Miller ZA, Mandelli ML, Rankin KP, et al. Handedness and language learning disability differentially distribute in progressive aphasia variants. Brain. 2013;136 (pt 11):3461-3473. 4. Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology. 2011;76(11):1006-1014. 5. Mackenzie IR, Neumann M, Bigio EH, et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol. 2010;119(1):1-4. 6. Montine TJ, Phelps CH, Beach TG, et al; National Institute on Aging; Alzheimer’s Association. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol. 2012;123(1):1-11.

COMMENT & RESPONSE

Therapeutic Hypothermia and Targeted Temperature Management After Cardiac Arrest To the Editor We read with great interest the Viewpoint by Little and Feldman titled “Therapeutic Hypothermia After Cardiac Arrest Without Return of Consciousness: Skating on Thin Ice.”1 The authors argued that literature has shed doubt on hypothermia for comatose cardiac arrest survivors, namely, research by Nielsen et al and the Targeted Temperature Management Trial investigators.2 The authors commented at the end of their article: “How can we ensure in the future that we commit resources to rigorous establishment of the value of a

novel therapy before committing resources to its premature adoption with such a thin evidence base?”1 We find this last comment interesting given 2 randomized clinical trials in 2002 by Bernard et al3 and the Hypothermia after Cardiac Arrest Study Group,4 as well as the International Liaison Committee on Resuscitation/American Heart Association guidelines,5 which recommend the use of hypothermia. There is physiologic evidence that decreasing brain temperature reduces cerebral blood flow and cerebral oxygen consumption. While there are inherent complexities to cardiac arrest research, there are few randomized clinical trials that address the evidence base, and the literature has evolved over time. The Nielsen et al2 trial was methodically different than the 2002 randomized clinical trials in which only ventricular tachycardia/ventricular fibrillation patients with coma were included. Also, in the Nielsen et al2 trial, they included pulseless electrical activity and asystolic patients who generally have poorer outcomes compared with ventricular tachycardia/ ventricular fibrillation patients. The Nielsen et al2 trial also seemed to be structured as a noninferiority trial because it had 2 active treatment arms. The authors reported no superiority between temperatures 33°C and 36°C. However, 36°C is not technically normothermia because 37°C (98.6°F) is considered normothermia in most textbooks. Therefore, the 36°C arm might be considered a super mild hypothermia or forced normothermia therapeutic arm. The 36°C arm of the Nielsen et al2 study may in fact support Safar’s first 1964 description of the ABCs of cardiac arrest, with the H in the alphabet being for hypothermia if there is “no neuro recovery.”6 It is perhaps part of Safar’s wisdom that bundling intensive care unit interventions helps hospitals and teams to focus on details of critically ill cardiac arrest patients that lead to better outcomes rather than single intervention alone. Such bundles have been shown to improve care with ventilator-associated pneumonia and central catheter placement, for example. Finally, we think national efforts to improve postcardiac arrest care by including hypothermia training or targeted temperature management (current term) to prevent and control fever should continue. The Nielsen et al2 study perhaps did not show a difference between the 2 groups because of overwhelming evidence that fever is detrimental to virtually all human brain-injury models including cardiac arrest.7 Perhaps it is not the depth of the hypothermia or targeted temperature management literature that should be questioned per se, but the optimal temperature range (33°C or 36°C) for cardiac arrest patients that is treading on “thin ice”? William D. Freeman, MD Lioudmila V. Karnatovskaia, MD Tyler F. Vadeboncoeur, MD Author Affiliations: Department of Neurology, Mayo Clinic, Jacksonville, Florida (Freeman); Department of Neurosurgery, Mayo Clinic, Jacksonville, Florida (Freeman); Department of Critical Care, Mayo Clinic, Jacksonville, Florida (Freeman); Department of Critical Care at Mayo Clinic, Rochester, Minnesota (Karnatovskaia); Department of Emergency Medicine, Mayo Clinic, Jacksonville, Florida (Vadeboncoeur). Corresponding Author: William D. Freeman, MD, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224 ([email protected]).

jamaneurology.com

JAMA Neurology December 2014 Volume 71, Number 12

Copyright 2014 American Medical Association. All rights reserved.

Downloaded From: http://archneur.jamanetwork.com/ by a University of Georgia User on 08/10/2015

1577

Letters

Conflict of Interest Disclosures: None reported. 1. Little NE, Feldman EL. Therapeutic hypothermia after cardiac arrest without return of consciousness: skating on thin ice. JAMA Neurol. 2014;71(7):823-824. 2. Nielsen N, Wetterslev J, Cronberg T, et al; TTM Trial Investigators. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369(23):2197-2206. 3. 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(8):557-563. 4. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549-556. 5. Committee ECC; ECC Committee, Subcommittees and Task Forces of the American Heart Association. 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2005;112(24)(suppl):IV1-IV203. 6. Safar P. Community-wide cardiopulmonary resuscitation. J Iowa Med Soc. 1964; 54:629-635. 7. Marion DW. Controlled normothermia in neurologic intensive care. Crit Care Med. 2004;32(2)(suppl):s43-s45.

In Reply We are pleased to respond to Freeman et al in the letter concerning our Viewpoint1 titled “Therapeutic Hypothermia After Cardiac Arrest Without Return of Consciousness: Skating on Thin Ice.” We concluded our Viewpoint with a call to commit resources to rigorously establishing the value of a novel therapy before its premature adoption. The 2 randomized clinical trials referenced by Freeman et al and analyzed by us in the Viewpoint had major shortcomings yet serve as the basis for the widespread use of therapeutic hypothermia (TH). As detailed in the Viewpoint, the International Liaison Committee on Resuscitation had only a thin evidence base for its recommendation. Widespread adoption of treatment strategies where the patient has no possibility of input, such as TH, demand more rigorous evidence than those where shared decision making can take place. In the absence of patient autonomy, we believe clinicians must continue to advocate for solid evidence of effectiveness. Physiologic plausibility, while part of a sound basis for a well-executed clinical trial, is hardly sufficient in itself to justify widespread adoption for novel therapies in clinical medicine. Every clinical trial that has failed had a sound physiological base. We agree with the comment by Freeman et al that “there are few randomized clinical trials that address the evidence base” for cardiac arrest research. However, we do not believe that historical shortcomings justify the continued adoption of less than methodologically rigorous evidence. An isolated quote from 1964 from a prominent researcher hardly qualifies as evidence, especially in the face of the well-done trial by Nielsen et al.2 We need to move beyond eminencebased medicine to evidenced-based medicine. We laud Nielsen et al2 for such a large, rigorous trial in the setting of unquestioned acceptance of the value of TH. The Nielsen et al2 trial did include patients with cardiac arrest of all causes, not just ventricular tachycardia/ventricular fibrillation, which mimics clinical conditions, and we believe adds to its value. The fact that TH benefited only the ventricular tachycardia/ventricular fibrillation subgroup of patients in the small Hypothermia after Cardiac Arrest Study Group3 and Bernard et al4 trials should make one suspicious that the ben1578

eficial effect of TH was a random effect. The inclusion of patients who did not become hypothermic in the hypothermia arms of these trials was adequately discussed in our Viewpoint, and, as noted, could account for the reported benefit of TH. If the beneficial effect of TH is on the brain, as postulated, the manner or final rhythm of the heart should not influence its effects. While the higher targeted temperature in the study by Nielsen et al,2 36°C, may not meet an arbitrary textbook definition of hypothermia, it was in fact higher than presenting patients’ temperatures (35.2°C-35.3°C). While the study by Nielsen et al2 did not report statistically significant superiority for the higher temperature target, all point estimates were in favor of the higher not lower temperature. We continue to believe that clinicians and researchers must advocate for robust evidence for novel therapies, especially where patient autonomy is lacking, before their widespread adoption. Therapeutic hypothermia remains on thin ice. Neal E. Little, MD Eva L. Feldman, MD, PhD Author Affiliations: Emergency Physicians Medical Group PC, Ann Arbor, Michigan (Little); Department of Neurology, University of Michigan, Ann Arbor (Feldman). Corresponding Author: Eva L. Feldman, MD, PhD, Department of Neurology, University of Michigan, 109 Zina Pitcher Pl, 5017 BSRB, Ann Arbor, MI 48109 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Little NE, Feldman EL. Therapeutic hypothermia after cardiac arrest without return of consciousness: skating on thin ice. JAMA Neurol. 2014;71(7):823-824. 2. Nielsen N, Wetterslev J, Cronberg T, et al; TTM Trial Investigators. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369(23):2197-2206. 3. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549-556. 4. 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(8):557-563.

Congenital Absence of Apolipoprotein E and Neurological Function To the Editor We read with interest the article by Mak et al,1 which reported a lack of obvious neurological or retinal abnormalities in a 40-year-old patient with severe dysbetalipoproteinemia associated with the absence of functional apolipoprotein E (apoE). Although these observations would appear to contradict the compelling clinical and preclinical evidence implicating an isoform-specific role for apoE in the development of neurodegenerative disease and response to central nervous system (CNS) injury, perhaps we should not be surprised. A substantial body of work has demonstrated the absence of phenotype in genetically modified animals in which genes of interest have been selectively deleted. This is likely owing to the development of compensatory mechanisms and functional redundancy of other proteins necessary to maintain homeostasis. For example, previous studies have demonstrated that APOE−/− mice display only a mild phenotype,

JAMA Neurology December 2014 Volume 71, Number 12

Copyright 2014 American Medical Association. All rights reserved.

Downloaded From: http://archneur.jamanetwork.com/ by a University of Georgia User on 08/10/2015

jamaneurology.com

Therapeutic hypothermia and targeted temperature management after cardiac arrest.

Therapeutic hypothermia and targeted temperature management after cardiac arrest. - PDF Download Free
60KB Sizes 0 Downloads 16 Views