Letters

Funding/Support: This study was supported by Pierre Fabre Dermatologie pharmaceutical company and the French Health Products Agency. The pharmaceutical company developed and provided the oral pediatric specific formulation of propranolol chlorhydrate. Role of the Funder/Sponsor: Pierre Fabre Dermatologie pharmaceutical company and the French Health Products Agency had a 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. Additional Contributions: We thank Valérie Ortis, MD (Laboratoire Pierre Fabre Dermatologie, Lavaur, France), for coordinating the French Compassionate Use Program, in particular checking inclusion criteria and collection of vigilance data, and Sarah Tilly, MS (Scinopsis, Frejus, France), for reviewing the manuscript. Both were compensated. 1. Léauté-Labrèze C, Prey S, Ezzedine K. Infantile haemangioma, part I: pathophysiology, epidemiology, clinical features, life cycle and associated structural abnormalities. J Eur Acad Dermatol Venereol. 2011;25(11):1245-1253. 2. Drolet BA, Frommelt PC, Chamlin SL, et al. Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Pediatrics. 2013;131 (1):128-140. 3. Hermans DJJ, Bauland CG, Zweegers J, van Beynum IM, van der Vleuten CJM. Propranolol in a case series of 174 patients with complicated infantile haemangioma: indications, safety and future directions. Br J Dermatol. 2013;168 (4):837-843. 4. Agence nationale de sécurité du médicament et des produits de santé. Autorisations temporaires d’utilisation. http://ansm.sante.fr/Activites /Autorisations-temporaires-d-utilisation-ATU/Qu-est-ce-qu-une-autorisation -temporaire-d-utilisation/%28offset%29/0. Accessed June 25, 2013. 5. Bégaud B, Evreux JC, Jouglard J, Lagier G. Imputation of the unexpected or toxic effects of drugs: actualization of the method used in France [in French]. Therapie. 1985;40(2):111-118. 6. Léauté-Labrèze C, Hoeger P, Mazereeuw-Hautier J, et al. A randomized, controlled trial of oral propranolol in infantile hemangioma. N Engl J Med. 2015; 372(8):735-746.

COMMENT & RESPONSE

Physical Activity vs Health Education for Cognition in Sedentary Older Adults To the Editor Dr Sink and colleagues1 reported that a 24-month moderate-intensity physical activity program did not improve global or domain-specific cognitive function compared with a health education program in sedentary adults. We have concerns about their working definition of moderateintensity physical activity, the implementation and monitoring of the intervention, and the intensity of the physical activity intervention. The latest guidelines for older adults from the American College of Sports Medicine2 define moderate-intensity aerobic exercise training as 60% or greater maximal oxygen up˙ O2max or exercise intensity was not ˙ O2max). Because V take (V measured in this study, it is unknown whether the intervention met these latest guidelines. Cardiorespiratory stress testing would have allowed ˙ O2max and therefore to set approthe authors to determine V priate aerobic exercise training intensity. Stress testing provides important baseline information and is the criterion standard for assessing changes in cardiorespiratory fitness. Studies, such as the one by Tyndall et al,3 provide the necessary control measurements to determine whether improvements in cardiorespiratory fitness confer benefits on cognitive performance in older, healthy, sedentary jama.com

adults. Such testing is normally conducted in exercise studies in which cognition is a main outcome and is essential to provide new insights on dose intensity and exercise duration for brain health.4 In the study by Sink and colleagues,1 exercise sessions were unsupervised and adherence to the exercise program was measured by self-report along with 1 week of accelerometry data every 6 months. The authors claimed that the physical activity levels were maintained or increased during the 24-month period, but only difference scores were presented, making it unclear if the weekly dose of exercise recorded by the physical activity group actually met the study’s goal of 150 minutes/week. The dose intensity was low and training sessions (30 minutes) were short. The fact that those older than 80 years and those with the lowest physical activity levels benefited suggests that exercise dose was important. Physiological studies suggest that dose intensity much higher than that achieved is required to produce benefit.3,5 Exercise studies should address dose intensity. Marc J. Poulin, PhD, DPhil Gail A. Eskes, PhD Michael D. Hill, MD Author Affiliations: Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada (Poulin); Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada (Eskes); Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada (Hill). Corresponding Author: Marc J. Poulin, PhD, DPhil, Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, HMRB-210, 3330 Hospital Dr NW, Calgary, Alberta T2N 4N1, Canada ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Hill reported receiving grants from the Canadian Institutes of Health Research, HoffmannLaRoche Canada, and Covidien; being a board member for the Heart and Stroke Foundation of Alberta, Institute for Circulatory and Respiratory Health of the Canadian Institutes of Health Research, and Canadian Federation of Neurological Sciences; being a consultant to Merck; receiving payment for lectures from Hoffmann-LaRoche Canada, Servier Canada, and BMS Canada; owning stock in Calgary Scientific; and receiving salary awards from the Heart and Stroke Foundation of Alberta and Alberta Innovates Health Solutions. No other disclosures were reported. 1. Sink KM, Espeland MA, Castro CM, et al; LIFE Study Investigators. Effect of a 24-month physical activity intervention vs health education on cognitive outcomes in sedentary older adults: the LIFE randomized trial. JAMA. 2015;314 (8):781-790. 2. Chodzko-Zajko WJ, Proctor DN, Fiatarone Singh MA, et al; American College of Sports Medicine. American College of Sports Medicine position stand: exercise and physical activity for older adults. Med Sci Sports Exerc. 2009;41(7): 1510-1530. 3. Tyndall AV, Davenport MH, Wilson BJ, et al. The brain-in-motion study: effect of a 6-month aerobic exercise intervention on cerebrovascular regulation and cognitive function in older adults. BMC Geriatr. 2013;13:21. 4. Prakash RS, Voss MW, Erickson KI, Kramer AF. Physical activity and cognitive vitality. Annu Rev Psychol. 2015;66:769-797. 5. Vidoni ED, Johnson DK, Morris JK, et al. Dose-response of aerobic exercise on cognition: a community-based, pilot randomized controlled trial. PLoS One. 2015;10(7):e0131647.

In Reply The purpose of the Lifestyle Interventions and Independence for Elders (LIFE) study was to test whether a (Reprinted) JAMA January 26, 2016 Volume 315, Number 4

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Letters

long-term structured physical activity program reduced the risk of major mobility disability in individuals with compromised lower extremity functioning. 1 Our recent article reported prespecified secondary cognitive outcomes. The trial was not designed to test the effect of changes in cardiorespiratory fitness on cognition, as implied by ˙ O2 was not included in Dr Poulin and colleagues. Testing of V the LIFE study because in our pilot study, we found that maximal exercise testing was not well tolerated and the data were of little value for exercise prescription.2 We disagree with Poulin and colleagues’ assertions about our definition of moderate-intensity physical activity. The LIFE study defined moderate-intensity exercise in terms of ratings of perceived exertion with a prescribed target of 13 (somewhat hard) and using accelerometry (>760 counts/min). Ratings of perceived exertion have been used in numerous randomized clinical trials of physical activity in older adults and use of these ratings is generally accepted as a valid indicator of exercise intensity.3 The American College of Sports Medicine and the American Heart Association have acknowledged that defining aerobic exercise intensity in absolute terms (eg, target ˙ O2max) with older adults can be heart rate derived from V problematic due to high levels of heterogeneity (ie, low levels of fitness, compromised functioning).4 Recent evidence suggests that moderate-intensity activity for a population aged 70 to 77 years corresponds to 669 to 4048 counts/min depending on sex and fitness level, highlighting the importance of tailoring thresholds for older adults.5 Thus, our definition of moderate-intensity physical activity based on accelerometer counts is consistent with published data, especially because our sample was older (mean age, 78.9 years), sedentary, and had physical function limitations. Poulin and colleagues state that the exercise sessions were unsupervised and adherence was self-reported. The intervention involved 2 center-based sessions/week and 3 days/week of home-based physical activity. The centerbased sessions were supervised and adherence was closely monitored. Each center-based session included an average of 36 minutes of walking as well as strength, balance, and flexibility training for a total of 60 minutes. Based on accelerometry data in a subsample of LIFE participants, we found that the mean counts/minute were 1555 for men and 1237 for women each session and the ratings of perceived exertion were within target.6 In addition, averaged across follow-up, accelerometry data indicated that the physical activity group engaged in 213 minutes/week of moderateintensity activity.1 Although it is possible that participants did not engage in a sufficient dose of physical activity to generate changes in cognitive functioning, the precise dose-response relationship between physical activity and cognition is not well understood, despite Poulin and colleagues’ suggestion that the intensity was too light and sessions too short. Interventionists used a variety of techniques to motivate participants to exercise at the prescribed intensity, and higher 416

intensity exercise would not have been feasible without jeopardizing participant safety and adherence. The LIFE study realistically tested the effect of a longterm, multimodal physical activity program on cognitive outcomes in older adults who were sedentary, deconditioned, and had physical limitations. Jeffrey A. Katula, PhD, MA Timothy Church, MD, PhD, MPH Kaycee M. Sink, MD, MAS Author Affiliations: Department of Health and Exercise Science, Wake Forest University, Winston Salem, North Carolina (Katula); Pennington Biomedical Research Center, Baton Rouge, Louisiana (Church); Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston Salem, North Carolina (Sink). Corresponding Author: Kaycee M. Sink, MD, MAS, Sticht Center on Aging, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, One Medical Center Boulevard, Winston Salem, NC 27157 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Sink reported receiving grants from the National Institute on Aging and Navidea. No other disclosures were reported. 1. Pahor M, Guralnik JM, Ambrosius WT, et al; LIFE study investigators. Effect of structured physical activity on prevention of major mobility disability in older adults: the LIFE study randomized clinical trial. JAMA. 2014;311(23): 2387-2396. 2. Church TS, Gill TM, Newman AB, Blair SN, Earnest CP, Pahor M. Maximal fitness testing in sedentary elderly at substantial risk of disability: LIFE-P study experience. J Aging Phys Act. 2008;16(4):408-415. 3. Chodzko-Zajko WJ, Proctor DN, Fiatarone Singh MA, et al; American College of Sports Medicine. American College of Sports Medicine position stand: exercise and physical activity for older adults. Med Sci Sports Exerc. 2009;41(7): 1510-1530. 4. Nelson ME, Rejeski WJ, Blair SN, et al. Physical activity and public health in older adults: recommendation from the American College of Sports Medicine and the American Heart Association. Med Sci Sports Exerc. 2007;39(8): 1435-1445. 5. Zisko N, Carlsen T, Salvesen Ø, et al. New relative intensity ambulatory accelerometer thresholds for elderly men and women: the Generation 100 study. BMC Geriatr. 2015;15(1):97. 6. Rejeski WJ, Axtell R, Fielding R, et al; LIFE Study Investigator Group. Promoting physical activity for elders with compromised function: the Lifestyle Interventions and Independence for Elders (LIFE) study physical activity intervention. Clin Interv Aging. 2013;8:1119-1131.

Epinephrine Administration and Pediatric In-Hospital Cardiac Arrest To the Editor The study by Dr Andersen and colleagues1 found an association between delayed administration of epinephrine and poorer survival rates after in-hospital pediatric cardiac arrest. There are at least 3 possible scenarios for delivering epinephrine: the patient might already have a functioning c annula or central line, venous access might be attempted during resuscitation, or epinephrine might be delivered by intraosseous injection. Epinephrine can be given quickly and reliably by intraosseous injection, but clinicians could preferentially attempt intravenous administration first. We wonder whether the reason for delay in epinephrine administration was related to unsuccessful attempts at ve-

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