Letters
Figure. Geometric Mean–Specific Gravity-Adjusted Urinary Bisphenol A (BPA) Concentration
Geometric Mean Specific Gravity-Adjusted Urinary BPA Concentration, μg/L
10.0 NHANES 2009-20106 95th Percentile
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
8.0
6.0
Funding/Support: This project was supported by grant 2 T42 OH008416-05 from the Harvard-NIOSH Education and Research Center. Role of the Sponsor: The Harvard-NIOSH Education and Research Center 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.
4.0 NHANES 2009-20106 Geometric Mean
2.0
0
Preexposurea
Postexposureb
Handling of Thermal Paper Receipts Without Gloves (n = 23)
Preexposurea
Postexposureb
Handling of Thermal Paper Receipts With Gloves (n = 12)
Error bars indicate 95% confidence intervals. NHANES indicates National Health and Nutrition Examination Survey. a
Adjusted BPA at 0 hours (baseline).
b
Adjusted BPA at 4 hours (handled receipts for 2 hours).
Discussion | In this pilot study, we observed an increase in urinary BPA concentrations after continuously handling receipts for 2 hours without gloves, but no significant increase when using gloves. The peak level (5.8 μg/L) was lower than that observed after canned soup consumption (20.8 μg/L).3 The clinical implications of the height of the peak level and the chronicity of exposure are unknown, but may be particularly relevant to occupationally exposed populations such as cashiers,5 who handle receipts 40 or more hours per week. Limitations include the small volunteer sample and loss of participants in the second simulation. However, urinary BPA concentrations at baseline were similar in the full and smaller groups and similar to the US population (1.83 μg/L).6 A larger study is needed to confirm our findings and evaluate the clinical implications. Shelley Ehrlich, MD, ScD, MPH Antonia M. Calafat, PhD Olivier Humblet, ScD Thomas Smith, PhD Russ Hauser, MD, ScD, MPH
Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention (CDC). The involvement of the CDC was determined not to constitute engagement in human subjects research. Additional Contributions: We thank Lori Torf (Harvard School of Public Health cafeteria) for providing us with access to the cafeteria cash registers for the simulations. We also thank the Hauser staff for assistance with storage of samples and supplies, Greg Wagner, MD (Harvard School of Public Health), for his advice and support at the start of the study, and Xiaoyun Ye, MS, Xiaoliu Zhou, MS, Tao Jia, MS, and Joshua Kramer (all 4 with the CDC) for technical assistance in measuring urinary bisphenol A. None of the individuals acknowledged were compensated for their contributions. 1. Ehrlich S, Williams PL, Missmer SA, et al. Urinary bisphenol A concentrations and early reproductive health outcomes among women undergoing IVF. Hum Reprod. 2012;27(12):3583-3592. 2. Braun JM, Kalkbrenner AE, Calafat AM, et al. Impact of early-life bisphenol A exposure on behavior and executive function in children. Pediatrics. 2011;128(5):873-882. 3. Carwile JL, Ye X, Zhou X, Calafat AM, Michels KB. Canned soup consumption and urinary bisphenol A: a randomized crossover trial. JAMA. 2011;306(20): 2218-2220. 4. Biedermann S, Tschudin P, Grob K. Transfer of bisphenol A from thermal printer paper to the skin. Anal Bioanal Chem. 2010;398(1):571-576. 5. Braun JM, Kalkbrenner AE, Calafat AM, et al. Variability and predictors of urinary bisphenol A concentrations during pregnancy. Environ Health Perspect. 2011;119(1):131-137. 6. Centers for Disease Control and Prevention, National Center for Environmental Health. Fourth national report on human exposure to environmental chemicals, updated tables, September 2013. http://www.cdc .gov/exposurereport/. Accessed January 25, 2014.
COMMENT & RESPONSE
Next-Day Surgical Complications After Nighttime Procedures
Author Affiliations: Harvard School of Public Health, Boston, Massachusetts (Ehrlich, Smith, Hauser); Centers for Disease Control and Prevention, Atlanta, Georgia (Calafat); University of California, San Francisco (Humblet); Dr Ehrlich is now with the Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio (Ehrlich). Corresponding Author: Shelley Ehrlich, MD, ScD, MPH, University of Cincinnati College of Medicine, 3333 Burnet Ave, Cincinnati, OH 45229 (shelley.ehrlich @cchmc.org). Author Contributions: Dr Ehrlich 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: Ehrlich, Smith, Hauser. Acquisition of data: Ehrlich, Calafat. Analysis and interpretation of data: Ehrlich, Calafat, Humblet, Smith, Hauser. Drafting of the manuscript: Ehrlich, Humblet, Hauser. 860
Critical revision of the manuscript for important intellectual content: Ehrlich, Calafat, Humblet, Smith, Hauser. Statistical analysis: Ehrlich, Humblet, Hauser. Obtained funding: Ehrlich. Administrative, technical, and material support: Ehrlich, Calafat. Study supervision: Ehrlich, Calafat, Hauser.
To the Editor Interest in the effects of sleep deprivation on physician performance and patient safety has existed for a long time. A study by Dr Vinden and colleagues1 found that surgeons operating the night before did not perform next-day elective laparoscopic cholecystectomies with more complications, such as conversion to open cholecystectomy, iatrogenic complications, or death. Although these findings are interesting, some issues should be clarified. Sleep deprivation can lead to fatigue and impair performance in many situations. Owing to the limitation of a retrospective study, it is impossible for the researchers to ascertain how fatigued the surgeons were when performing the elective cases the next day. However, several factors may be related to fatigue, such as duration of sleep opportunity (hours
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between end of last overnight procedure and start of first morning procedure), operations on successive nights, and the age of the surgeon. Although several studies reported no overall association between physician sleep deprivation and patient outcomes, subgroup analyses in studies by Rothschild et al2 and Chu et al3 revealed associations between surgeon sleep hours and some adverse patient outcomes. The study by Vinden et al1 would be more convincing if the authors performed a post hoc analysis stratified by duration of sleep opportunity. Furthermore, general surgeons may be called to perform operations on successive nights, which can lead to cumulative fatigue. It would be interesting to know whether surgeons performing operations on successive nights performed elective operations with more complications. We are not aware of any evidence illustrating the interaction between sleep deprivation, the age of the surgeon, and postoperative outcomes. It would be important to investigate the contribution of age to surgeon performance when he or she experiences sleep deprivation. Lijun Hou, MD, PhD Xi Han, MD, PhD Yan Dong, MD, PhD Author Affiliations: Department of Neurosurgery, Changzheng Hospital, Shanghai, China (Hou, Dong); Department of Neurosurgery, Huashan Hospital, Shanghai, China (Han). Corresponding Author: Yan Dong, MD, PhD, Changzheng Hospital, 415 Fengyang Rd, Shanghai 200003, China ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Dong reported receiving research support from the Natural Science Foundation from Science and Technology Commission of Shanghai Municipality, Research Foundation for Returned Scholars from Ministry of Education of China. No other disclosures were reported. 1. Vinden C, Nash DM, Rangrej J, et al. Complications of daytime elective laparoscopic cholecystectomies performed by surgeons who operated the night before. JAMA. 2013;310(17):1837-1841. 2. Rothschild JM, Keohane CA, Rogers S, et al. Risks of complications by attending physicians after performing nighttime procedures. JAMA. 2009;302(14):1565-1572. 3. Chu MW, Stitt LW, Fox SA, et al. Prospective evaluation of consultant surgeon sleep deprivation and outcomes in more than 4000 consecutive cardiac surgical procedures. Arch Surg. 2011;146(9):1080-1085.
In Reply We agree with Dr Hou and colleagues that it would be informative to determine the degree of sleep deprivation among physicians in our study; however, our databases do not allow us to identify the actual duration of sleep opportunity. The subgroup analysis by Rothschild et al1 (Table 6) is interesting in that those surgeons who operated at night but had more than 6 hours of sleep opportunity had a lower complication rate (3.1%) than the surgeons in the control group from the primary analysis who did not operate at all the night before (7.1%). Whether this result reached statistical significance when adjusted for age, sex, and comorbidities was not published; however, a simple 2-by-2 contingency table analysis suggests that it did. Thus, it may not be accurate to con-
clude that this study showed that sleep opportunity has a significant association with complication rates. In the analysis by Chu et al,2 which focused on hours of sleep, only 2 of the 14 patient outcomes assessed (septicemia and length of stay) were statistically significantly higher with less sleep by physicians. The statistical significance of these outcomes may have been spurious based on multiple testing. Furthermore, Chu et al2 concluded that their study showed no evidence of the sleep hours of surgeons affecting patient complications. Even though we agree that prospective data are better than retrospective data, we think it is unlikely that such an endeavor is feasible for a study as large as ours. Our study captured data on 331 surgeons and 94 183 procedures over 7 years, and we think it unlikely that regular self-reporting on sleep could be done on this scale. We would also question the validity of self-reported sleep quality. Furthermore, it is difficult to determine how such a study would affect practice because we would envision difficulty in enacting any policies wherein a surgery would be cancelled based on self-reported insomnia or disturbed sleep patterns. We did not analyze complications on the basis of surgeon age in our study, but studies have shown that older adults need less sleep than younger adults.3 However, many other common risk factors, including obesity and depression, can affect the quality of sleep and may be more important than age.4 In addition, we did not look at the association of complications with procedures performed on successive nights. Our study used one of the world’s largest population-based health care databases, which enabled the study to be adequately powered for our primary outcome. Given the relatively low complication rates in our study, subgroup analyses focusing on procedures performed on successive nights or surgeon age would likely be underpowered to detect any significant associations despite the size of our databases. Christopher Vinden, MD Danielle Nash, MSc Author Affiliations: Division of General Surgery, Western University, London, Ontario, Canada (Vinden); Institute for Clinical Evaluative Sciences, London, Ontario, Canada (Nash). Corresponding Author: Christopher Vinden, MD, Western University, 800 Commissioners Rd E, London, ON N6A 5W9, Canada ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Vinden reported receiving an institutional grant from the Division of General Surgery, University of Western Ontario; board membership and receipt of travel and accommodation expenses from the Ontario Association of General Surgeons; board membership and receipt of per diem honorarium and travel expenses from the Ontario Medical Association, Section of General Surgery; providing expert testimony for the Canadian Medical Protective Association; and receiving travel accommodations and/or meeting expenses from Cancer Care Ontario. No other disclosures were reported. 1. Rothschild JM, Keohane CA, Rogers S, et al. Risks of complications by attending physicians after performing nighttime procedures. JAMA. 2009;302(14):1565-1572. 2. Chu MW, Stitt LW, Fox SA, et al. Prospective evaluation of consultant surgeon sleep deprivation and outcomes in more than 4000 consecutive cardiac surgical procedures. Arch Surg. 2011;146(9):1080-1085.
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3. Duffy JF, Willson HJ, Wang W, Czeisler CA. Healthy older adults better tolerate sleep deprivation than young adults. J Am Geriatr Soc. 2009;57(7):1245-1251. 4. Bixler EO, Vgontzas AN, Lin HM, Calhoun SL, Vela-Bueno A, Kales A. Excessive daytime sleepiness in a general population sample: the role of sleep apnea, age, obesity, diabetes, and depression. J Clin Endocrinol Metab. 2005;90(8):4510-4515.
β-Blocker Therapy for Patients With Hypertension To the Editor Meta-analyses of β-blocker efficacy in reducing allcause death and cardiovascular events in patients with hypertension that do not take age into account are liable to miss the essential strengths and weaknesses of β-blockade.1 The Framingham Heart Study2 has shown that the development of diastolic hypertension occurs in younger patients and is closely linked to obesity, in contrast to isolated systolic hypertension that occurs in older patients and is associated with aging and stiffening of the arteries. Appropriate treatment for these 2 types of hypertension will require different approaches, particularly because central obesity is linked to high levels of sympathetic nerve activity in younger individuals.3 Meta-analyses that take age into account4 reveal that in younger patients with hypertension, β-blockade is significantly superior to placebo in reducing the risk of death, stroke, or myocardial infarction. In contrast, in patients older than 60 years, β-blockers (mainly atenolol) are significantly inferior to other drugs in reducing the risk of death, stroke, or myocardial infarction. If smoking status is taken into account in younger patients, the risk of myocardial infarction in nonsmokers is reduced with β-blockers vs placebo or diuretics. This benefit is not observed in smokers. For example, in the Metoprolol Atherosclerosis Prevention in Hypertensives study,5 compared with diuretic therapy, metoprolol was associated with a significant 40% reduction in coronary events in nonsmokers only. Smoking induces an increase in epinephrine secretion, which in the presence of β-1 and β-2 blockade, results in uninhibited α vasoconstriction and an increase in blood pressure. This potentially harmful interaction can be avoided by using drugs with high β-1 selectivity (eg, bisoprolol, which permits β-2–induced vasodilatation). Thus, in my opinion, traditional β-blockade should not be the first-line therapy for elderly patients with hypertension, unless coronary artery disease is also present. For younger patients with hypertension, β-1 blockade should be the firstline treatment. Agents that increase sympathetic nerve activity in younger patients (ie, diuretics, dihydropyridine calcium antagonists, and angiotensin receptor blockers) should not be administered as first-line therapy. John Cruickshank, BM, BCH, MA Author Affiliation: Dr Cruickshank is retired. Corresponding Author: John Cruickshank, BM, BCH, MA, 42 Harefield, Sudbury CO10 9DE, England ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Cruickshank reported receiving honoraria for giving lectures for AstraZeneca and Merck (Germany). 862
1. Wiysonge CS, Opie LH. β-Blockers as initial therapy for hypertension. JAMA. 2013;310(17):1851-1852. 2. Franklin SS, Pio JR, Wong ND, et al. Predictors of new-onset diastolic and systolic hypertension: the Framingham Heart Study. Circulation. 2005;111(9):1121-1127. 3. Grassi G, Dell’Oro R, Facchini A, et al. Effect of central and peripheral body fat distribution on sympathetic and baroreflex function in obese normotensives. J Hypertens. 2004;22(12):2363-2369. 4. Khan N, McAlister FA. Re-examining the efficacy of beta-blockers for the treatment of hypertension: a meta-analysis. CMAJ. 2006;174(12):1737-1742. 5. Wikstrand J, Warnold I, Tuomilehto J, et al. Metoprolol versus thiazide diuretics in hypertension: morbidity results from the MAPHY Study. Hypertension. 1991;17(4):579-588.
In Reply Dr Cruikshank stresses the role of sympathetic activity, which transmits both α- and β-mediated stimuli, in the optimal control of blood pressure; however, he mainly focuses on studies of β-blockers, thereby ignoring the important role of countering both divisions of the autonomic nervous system. That overall sympathetic activity is involved in severe hypertension has been known since the time of Smithwick1 who showed the efficacy of total sympathectomy in 1949. Recent studies of renal artery denervation for severe hypertension also show that the ideal for sympathetic blockade is total (ie, α and β) and not specific ally β. Yet large-sc ale outcome studies with α- and β-blockers are still lacking. Recent studies led to the downgrading of β-blockade from initial therapy. The Anglo-Scandinavian Cardiac Outcomes Trial 2 showed better outcomes with a regimen of amlodipine with or without perindopril than with atenolol with or without bendroflumethiazide. This finding has played a key part in the debate on guidelines for the management of hypertension. The ABCD approach (A, angiotensin inhibition; B, β-blocker; C, calcium channel blocker; D, diuretic) was recently updated to ACD and adopted in the UK National Institute of Clinical Excellence guidelines.3 Of note is the omission of β-blockade among the first-line agents. However, this is not only a UK point of view but one also supported by the recent omission of β-blockers among first-line therapy combinations by the task force of the European Society of Hypertension and European Society of Cardiology4 and by the Eighth Joint National Committee5 in the United States. Overall, β-blockade has demonstrated clear benefit in stroke reduction vs placebo, yet without significant effects on total mortality or coronary heart disease,6 and thus being inferior to calcium channel blockers and renin-angiotensinsystem inhibitors. Referring to the meta-analyses by Khan and McAlister, Cruikshank claims that β-blockade should remain first-line therapy in patients younger than 60 years. The 60-year cutoff age used by Khan and McAlister is arbitrary because there are currently no trials of blood pressure control stratified by age to support age-related divergent pathological mechanisms. The assumption that β-blocker deficiencies are limited to elderly patients relies heavily on the Medical Research Council trial in elderly patients in which one-quarter of study participants were lost to followup. In addition, Khan and McAlister classified trials that
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Figure. Geometric Mean–Specific Gravity-Adjusted Urinary Bisphenol A (BPA) Concentration
Geometric Mean Specific Gravity-Adjusted Urinary BPA Concentration, μg/L
10.0 NHANES 2009-20106 95th Percentile
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
8.0
6.0
Funding/Support: This project was supported by grant 2 T42 OH008416-05 from the Harvard-NIOSH Education and Research Center. Role of the Sponsor: The Harvard-NIOSH Education and Research Center 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.
4.0 NHANES 2009-20106 Geometric Mean
2.0
0
Preexposurea
Postexposureb
Handling of Thermal Paper Receipts Without Gloves (n = 23)
Preexposurea
Postexposureb
Handling of Thermal Paper Receipts With Gloves (n = 12)
Error bars indicate 95% confidence intervals. NHANES indicates National Health and Nutrition Examination Survey. a
Adjusted BPA at 0 hours (baseline).
b
Adjusted BPA at 4 hours (handled receipts for 2 hours).
Discussion | In this pilot study, we observed an increase in urinary BPA concentrations after continuously handling receipts for 2 hours without gloves, but no significant increase when using gloves. The peak level (5.8 μg/L) was lower than that observed after canned soup consumption (20.8 μg/L).3 The clinical implications of the height of the peak level and the chronicity of exposure are unknown, but may be particularly relevant to occupationally exposed populations such as cashiers,5 who handle receipts 40 or more hours per week. Limitations include the small volunteer sample and loss of participants in the second simulation. However, urinary BPA concentrations at baseline were similar in the full and smaller groups and similar to the US population (1.83 μg/L).6 A larger study is needed to confirm our findings and evaluate the clinical implications. Shelley Ehrlich, MD, ScD, MPH Antonia M. Calafat, PhD Olivier Humblet, ScD Thomas Smith, PhD Russ Hauser, MD, ScD, MPH
Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention (CDC). The involvement of the CDC was determined not to constitute engagement in human subjects research. Additional Contributions: We thank Lori Torf (Harvard School of Public Health cafeteria) for providing us with access to the cafeteria cash registers for the simulations. We also thank the Hauser staff for assistance with storage of samples and supplies, Greg Wagner, MD (Harvard School of Public Health), for his advice and support at the start of the study, and Xiaoyun Ye, MS, Xiaoliu Zhou, MS, Tao Jia, MS, and Joshua Kramer (all 4 with the CDC) for technical assistance in measuring urinary bisphenol A. None of the individuals acknowledged were compensated for their contributions. 1. Ehrlich S, Williams PL, Missmer SA, et al. Urinary bisphenol A concentrations and early reproductive health outcomes among women undergoing IVF. Hum Reprod. 2012;27(12):3583-3592. 2. Braun JM, Kalkbrenner AE, Calafat AM, et al. Impact of early-life bisphenol A exposure on behavior and executive function in children. Pediatrics. 2011;128(5):873-882. 3. Carwile JL, Ye X, Zhou X, Calafat AM, Michels KB. Canned soup consumption and urinary bisphenol A: a randomized crossover trial. JAMA. 2011;306(20): 2218-2220. 4. Biedermann S, Tschudin P, Grob K. Transfer of bisphenol A from thermal printer paper to the skin. Anal Bioanal Chem. 2010;398(1):571-576. 5. Braun JM, Kalkbrenner AE, Calafat AM, et al. Variability and predictors of urinary bisphenol A concentrations during pregnancy. Environ Health Perspect. 2011;119(1):131-137. 6. Centers for Disease Control and Prevention, National Center for Environmental Health. Fourth national report on human exposure to environmental chemicals, updated tables, September 2013. http://www.cdc .gov/exposurereport/. Accessed January 25, 2014.
COMMENT & RESPONSE
Next-Day Surgical Complications After Nighttime Procedures
Author Affiliations: Harvard School of Public Health, Boston, Massachusetts (Ehrlich, Smith, Hauser); Centers for Disease Control and Prevention, Atlanta, Georgia (Calafat); University of California, San Francisco (Humblet); Dr Ehrlich is now with the Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio (Ehrlich). Corresponding Author: Shelley Ehrlich, MD, ScD, MPH, University of Cincinnati College of Medicine, 3333 Burnet Ave, Cincinnati, OH 45229 (shelley.ehrlich @cchmc.org). Author Contributions: Dr Ehrlich 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: Ehrlich, Smith, Hauser. Acquisition of data: Ehrlich, Calafat. Analysis and interpretation of data: Ehrlich, Calafat, Humblet, Smith, Hauser. Drafting of the manuscript: Ehrlich, Humblet, Hauser. 860
Critical revision of the manuscript for important intellectual content: Ehrlich, Calafat, Humblet, Smith, Hauser. Statistical analysis: Ehrlich, Humblet, Hauser. Obtained funding: Ehrlich. Administrative, technical, and material support: Ehrlich, Calafat. Study supervision: Ehrlich, Calafat, Hauser.
To the Editor Interest in the effects of sleep deprivation on physician performance and patient safety has existed for a long time. A study by Dr Vinden and colleagues1 found that surgeons operating the night before did not perform next-day elective laparoscopic cholecystectomies with more complications, such as conversion to open cholecystectomy, iatrogenic complications, or death. Although these findings are interesting, some issues should be clarified. Sleep deprivation can lead to fatigue and impair performance in many situations. Owing to the limitation of a retrospective study, it is impossible for the researchers to ascertain how fatigued the surgeons were when performing the elective cases the next day. However, several factors may be related to fatigue, such as duration of sleep opportunity (hours
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between end of last overnight procedure and start of first morning procedure), operations on successive nights, and the age of the surgeon. Although several studies reported no overall association between physician sleep deprivation and patient outcomes, subgroup analyses in studies by Rothschild et al2 and Chu et al3 revealed associations between surgeon sleep hours and some adverse patient outcomes. The study by Vinden et al1 would be more convincing if the authors performed a post hoc analysis stratified by duration of sleep opportunity. Furthermore, general surgeons may be called to perform operations on successive nights, which can lead to cumulative fatigue. It would be interesting to know whether surgeons performing operations on successive nights performed elective operations with more complications. We are not aware of any evidence illustrating the interaction between sleep deprivation, the age of the surgeon, and postoperative outcomes. It would be important to investigate the contribution of age to surgeon performance when he or she experiences sleep deprivation. Lijun Hou, MD, PhD Xi Han, MD, PhD Yan Dong, MD, PhD Author Affiliations: Department of Neurosurgery, Changzheng Hospital, Shanghai, China (Hou, Dong); Department of Neurosurgery, Huashan Hospital, Shanghai, China (Han). Corresponding Author: Yan Dong, MD, PhD, Changzheng Hospital, 415 Fengyang Rd, Shanghai 200003, China ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Dong reported receiving research support from the Natural Science Foundation from Science and Technology Commission of Shanghai Municipality, Research Foundation for Returned Scholars from Ministry of Education of China. No other disclosures were reported. 1. Vinden C, Nash DM, Rangrej J, et al. Complications of daytime elective laparoscopic cholecystectomies performed by surgeons who operated the night before. JAMA. 2013;310(17):1837-1841. 2. Rothschild JM, Keohane CA, Rogers S, et al. Risks of complications by attending physicians after performing nighttime procedures. JAMA. 2009;302(14):1565-1572. 3. Chu MW, Stitt LW, Fox SA, et al. Prospective evaluation of consultant surgeon sleep deprivation and outcomes in more than 4000 consecutive cardiac surgical procedures. Arch Surg. 2011;146(9):1080-1085.
In Reply We agree with Dr Hou and colleagues that it would be informative to determine the degree of sleep deprivation among physicians in our study; however, our databases do not allow us to identify the actual duration of sleep opportunity. The subgroup analysis by Rothschild et al1 (Table 6) is interesting in that those surgeons who operated at night but had more than 6 hours of sleep opportunity had a lower complication rate (3.1%) than the surgeons in the control group from the primary analysis who did not operate at all the night before (7.1%). Whether this result reached statistical significance when adjusted for age, sex, and comorbidities was not published; however, a simple 2-by-2 contingency table analysis suggests that it did. Thus, it may not be accurate to con-
clude that this study showed that sleep opportunity has a significant association with complication rates. In the analysis by Chu et al,2 which focused on hours of sleep, only 2 of the 14 patient outcomes assessed (septicemia and length of stay) were statistically significantly higher with less sleep by physicians. The statistical significance of these outcomes may have been spurious based on multiple testing. Furthermore, Chu et al2 concluded that their study showed no evidence of the sleep hours of surgeons affecting patient complications. Even though we agree that prospective data are better than retrospective data, we think it is unlikely that such an endeavor is feasible for a study as large as ours. Our study captured data on 331 surgeons and 94 183 procedures over 7 years, and we think it unlikely that regular self-reporting on sleep could be done on this scale. We would also question the validity of self-reported sleep quality. Furthermore, it is difficult to determine how such a study would affect practice because we would envision difficulty in enacting any policies wherein a surgery would be cancelled based on self-reported insomnia or disturbed sleep patterns. We did not analyze complications on the basis of surgeon age in our study, but studies have shown that older adults need less sleep than younger adults.3 However, many other common risk factors, including obesity and depression, can affect the quality of sleep and may be more important than age.4 In addition, we did not look at the association of complications with procedures performed on successive nights. Our study used one of the world’s largest population-based health care databases, which enabled the study to be adequately powered for our primary outcome. Given the relatively low complication rates in our study, subgroup analyses focusing on procedures performed on successive nights or surgeon age would likely be underpowered to detect any significant associations despite the size of our databases. Christopher Vinden, MD Danielle Nash, MSc Author Affiliations: Division of General Surgery, Western University, London, Ontario, Canada (Vinden); Institute for Clinical Evaluative Sciences, London, Ontario, Canada (Nash). Corresponding Author: Christopher Vinden, MD, Western University, 800 Commissioners Rd E, London, ON N6A 5W9, Canada ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Vinden reported receiving an institutional grant from the Division of General Surgery, University of Western Ontario; board membership and receipt of travel and accommodation expenses from the Ontario Association of General Surgeons; board membership and receipt of per diem honorarium and travel expenses from the Ontario Medical Association, Section of General Surgery; providing expert testimony for the Canadian Medical Protective Association; and receiving travel accommodations and/or meeting expenses from Cancer Care Ontario. No other disclosures were reported. 1. Rothschild JM, Keohane CA, Rogers S, et al. Risks of complications by attending physicians after performing nighttime procedures. JAMA. 2009;302(14):1565-1572. 2. Chu MW, Stitt LW, Fox SA, et al. Prospective evaluation of consultant surgeon sleep deprivation and outcomes in more than 4000 consecutive cardiac surgical procedures. Arch Surg. 2011;146(9):1080-1085.
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3. Duffy JF, Willson HJ, Wang W, Czeisler CA. Healthy older adults better tolerate sleep deprivation than young adults. J Am Geriatr Soc. 2009;57(7):1245-1251. 4. Bixler EO, Vgontzas AN, Lin HM, Calhoun SL, Vela-Bueno A, Kales A. Excessive daytime sleepiness in a general population sample: the role of sleep apnea, age, obesity, diabetes, and depression. J Clin Endocrinol Metab. 2005;90(8):4510-4515.
β-Blocker Therapy for Patients With Hypertension To the Editor Meta-analyses of β-blocker efficacy in reducing allcause death and cardiovascular events in patients with hypertension that do not take age into account are liable to miss the essential strengths and weaknesses of β-blockade.1 The Framingham Heart Study2 has shown that the development of diastolic hypertension occurs in younger patients and is closely linked to obesity, in contrast to isolated systolic hypertension that occurs in older patients and is associated with aging and stiffening of the arteries. Appropriate treatment for these 2 types of hypertension will require different approaches, particularly because central obesity is linked to high levels of sympathetic nerve activity in younger individuals.3 Meta-analyses that take age into account4 reveal that in younger patients with hypertension, β-blockade is significantly superior to placebo in reducing the risk of death, stroke, or myocardial infarction. In contrast, in patients older than 60 years, β-blockers (mainly atenolol) are significantly inferior to other drugs in reducing the risk of death, stroke, or myocardial infarction. If smoking status is taken into account in younger patients, the risk of myocardial infarction in nonsmokers is reduced with β-blockers vs placebo or diuretics. This benefit is not observed in smokers. For example, in the Metoprolol Atherosclerosis Prevention in Hypertensives study,5 compared with diuretic therapy, metoprolol was associated with a significant 40% reduction in coronary events in nonsmokers only. Smoking induces an increase in epinephrine secretion, which in the presence of β-1 and β-2 blockade, results in uninhibited α vasoconstriction and an increase in blood pressure. This potentially harmful interaction can be avoided by using drugs with high β-1 selectivity (eg, bisoprolol, which permits β-2–induced vasodilatation). Thus, in my opinion, traditional β-blockade should not be the first-line therapy for elderly patients with hypertension, unless coronary artery disease is also present. For younger patients with hypertension, β-1 blockade should be the firstline treatment. Agents that increase sympathetic nerve activity in younger patients (ie, diuretics, dihydropyridine calcium antagonists, and angiotensin receptor blockers) should not be administered as first-line therapy. John Cruickshank, BM, BCH, MA Author Affiliation: Dr Cruickshank is retired. Corresponding Author: John Cruickshank, BM, BCH, MA, 42 Harefield, Sudbury CO10 9DE, England ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Cruickshank reported receiving honoraria for giving lectures for AstraZeneca and Merck (Germany). 862
1. Wiysonge CS, Opie LH. β-Blockers as initial therapy for hypertension. JAMA. 2013;310(17):1851-1852. 2. Franklin SS, Pio JR, Wong ND, et al. Predictors of new-onset diastolic and systolic hypertension: the Framingham Heart Study. Circulation. 2005;111(9):1121-1127. 3. Grassi G, Dell’Oro R, Facchini A, et al. Effect of central and peripheral body fat distribution on sympathetic and baroreflex function in obese normotensives. J Hypertens. 2004;22(12):2363-2369. 4. Khan N, McAlister FA. Re-examining the efficacy of beta-blockers for the treatment of hypertension: a meta-analysis. CMAJ. 2006;174(12):1737-1742. 5. Wikstrand J, Warnold I, Tuomilehto J, et al. Metoprolol versus thiazide diuretics in hypertension: morbidity results from the MAPHY Study. Hypertension. 1991;17(4):579-588.
In Reply Dr Cruikshank stresses the role of sympathetic activity, which transmits both α- and β-mediated stimuli, in the optimal control of blood pressure; however, he mainly focuses on studies of β-blockers, thereby ignoring the important role of countering both divisions of the autonomic nervous system. That overall sympathetic activity is involved in severe hypertension has been known since the time of Smithwick1 who showed the efficacy of total sympathectomy in 1949. Recent studies of renal artery denervation for severe hypertension also show that the ideal for sympathetic blockade is total (ie, α and β) and not specific ally β. Yet large-sc ale outcome studies with α- and β-blockers are still lacking. Recent studies led to the downgrading of β-blockade from initial therapy. The Anglo-Scandinavian Cardiac Outcomes Trial 2 showed better outcomes with a regimen of amlodipine with or without perindopril than with atenolol with or without bendroflumethiazide. This finding has played a key part in the debate on guidelines for the management of hypertension. The ABCD approach (A, angiotensin inhibition; B, β-blocker; C, calcium channel blocker; D, diuretic) was recently updated to ACD and adopted in the UK National Institute of Clinical Excellence guidelines.3 Of note is the omission of β-blockade among the first-line agents. However, this is not only a UK point of view but one also supported by the recent omission of β-blockers among first-line therapy combinations by the task force of the European Society of Hypertension and European Society of Cardiology4 and by the Eighth Joint National Committee5 in the United States. Overall, β-blockade has demonstrated clear benefit in stroke reduction vs placebo, yet without significant effects on total mortality or coronary heart disease,6 and thus being inferior to calcium channel blockers and renin-angiotensinsystem inhibitors. Referring to the meta-analyses by Khan and McAlister, Cruikshank claims that β-blockade should remain first-line therapy in patients younger than 60 years. The 60-year cutoff age used by Khan and McAlister is arbitrary because there are currently no trials of blood pressure control stratified by age to support age-related divergent pathological mechanisms. The assumption that β-blocker deficiencies are limited to elderly patients relies heavily on the Medical Research Council trial in elderly patients in which one-quarter of study participants were lost to followup. In addition, Khan and McAlister classified trials that
JAMA February 26, 2014 Volume 311, Number 8
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