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Association of Extended Work Shifts, Vascular Function, and Inflammatory Markers in Internal Medicine Residents: A Randomized Crossover Trial
To the Editor: Sleep loss during extended work shifts is common in medical training.1 Pathophysiological consequences of sleep loss include increased daytime blood levels of proinflammatory cytokines, which may contribute to daytime sleepiness and decline in neurobehavioral function.1-3 Increased proinflammatory cytokines in response to sleep loss may also affect cardiovascular health as inflammation within the vascular wall is thought to play an important role in the pathogenesis of atherosclerosis.4 We tested the hypothesis that sleep loss during extended work shifts is associated with evidence of vascular inflammation and dysfunction.
Methods
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We studied 22 healthy Internal Medicine residents (15 men and 7 women; mean age, 29 years) in a prospective, single-blind, crossover design during an intensive care unit rotation (extended overnight work shifts every fourth night). Of 48 potential participants, 24 declined, most often due to the protocol requirement to abstain from caffeine, and 2 were ineligible due to medication use. No information is available on nonparticipants. The Yale School of Medicine Human Investigation Committee approved the study, and all participants provided written informed consent.
Participants were assigned to 2 study sessions in random order. One session was conducted at 1 PM after completion of a 30-hour extended work shift (from 7 AM until 1 PM the following day) and the other session was conducted at 1 PM after completion of a 6-hour nonextended work shift (from 7 AM until 1 PM on the same day). Participants fasted from 7 AM to 1 PM on each study day to mitigate potential confounding effects of food ingestion on study measurements. At each session, sleep hours from the past night were recorded with a written diary adapted from a previously validated procedure5; brachial artery flow-mediated dilation, a physiological marker of vascular endothelial function, was determined noninvasively with high-resolution ultrasound imaging6; and 15 mL of blood were obtained from an indwelling intravenous catheter. Blood was assayed for sleep-related cytokines (interleukin-6 [IL-6] and tumor necrosis factor  [TNF-]; R&D Systems, Minneapolis, Minn), markers of vascular inflammation (high-sensitivity C-reactive protein [CRP]; Alfa Wasserman high-sensitivity CRP reagent, Caldwell, NJ), soluble intercellular adhesion molecule-1 (ICAM-1) and soluble vascular cell adhesion molecule-1 (VCAM-1; R&D Systems), and plasma norepinephrine (ESA Inc, Chelmsford, Mass).
The distributions of the primary outcome variable, brachial artery flow-mediated dilation, and other outcome variables were compared after extended and nonextended work shifts with Wilcoxon signed rank tests (sign rank command, Stata software version 8.0, College Park, Tex). No significant period or treatment-order effects were detected. Based on expected flow-mediated dilation after nonextended work shift of 6.7% (SD, 2.0%), 22 participants provided at least 90% power to detect a clinically meaningful 25% difference in flow-mediated dilation after extended vs nonextended work shifts, using 2-tailed = .05. The study sample provided 74% to 99% power to detect 25% changes in other laboratory variables.
Results
Compared with nonextended work shifts, extended work shifts were associated with significantly decreased sleep hours, significantly lower brachial artery flow-mediated dilation, and significantly higher blood levels of IL-6, high-sensitivity CRP, and norepinephrine (Table). Serum levels of TNF-, soluble ICAM-1, and soluble VCAM-1 did not differ after extended vs nonextended work shifts.
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Table. Sleep Duration, Brachial Artery Flow-Mediated Dilation, Sleep-Related Cytokines, and Markers of Vascular Inflammation After Extended and Nonextended Work Shifts
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Comment
Extended work shifts during an intensive care unit rotation are associated with increased blood levels of IL-6, high-sensitivity CRP, and norepinephrine, and decreased flow-mediated vasodilation. To our knowledge, this is the first study to concurrently determine the effects of sleep loss in medical residents on sleep-related cytokines, biochemical markers of vascular inflammation, and physiological measures of vascular endothelial function.
Our findings are in agreement with previous investigations that reported increased CRP levels in response to acute total and short-term partial sleep deprivation in healthy adults7 and impaired flow-mediated dilation in physicians working night shifts.8 The magnitude and duration of the changes observed in our sample of healthy medical trainees are less than that previously reported in populations with cardiovascular disease.4, 9 Accordingly, the prognostic implications of the observed changes are uncertain but may merit concern because repeated episodes of transient vascular injury and inflammation could contribute to increased long-term atherosclerosis risk.4, 9
These findings must be interpreted with caution, because the study sample was small and we did not characterize potential confounders, such as long-term sleep history, work-related stress and physical activity, and other neurobehavioral and cognitive effects of sleep loss. Nonetheless, our findings provide evidence of a potential mechanistic link between work-related sleep disturbance and cardiovascular risk that warrants further investigation in health care professionals and other populations exposed to work-related sleep loss.
Author Contributions: Dr Katz 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: Zheng, Hryniewicz, Katz.
Acquisition of data: Zheng, Patel, Katz.
Analysis and interpretation of data: Zheng, Katz.
Drafting of the manuscript: Katz.
Critical revision of the manuscript for important intellectual content: Zheng, Patel, Hryniewicz.
Statistical analysis: Zheng, Patel, Katz.
Obtained funding: Katz.
Study supervision: Katz.
Financial Disclosures: None reported.
Funding/Support: This work was supported by grant MO1 RR00645 from the Division of Research Resources, General Clinical Research Centers Program, National Institutes of Health, and grants K24 HL0404 and R01 HL51433 from the National Institutes of Health, National Heart, Lung, and Blood Institute.
Role of the Sponsors: The funding sources had no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.
Acknowledgment: We thank James Dziura, PhD, MPH, biostatistician for the Yale General Clinical Research Center, who provided invaluable expert guidance for the statistical analysis in this article.
Haoyi Zheng, MD, PhD;
Milan Patel, MD;
Katarzyna Hryniewicz, MD;
Stuart D. Katz, MD
stuart.katz{at}yale.edu
Yale University School of Medicine
New Haven, Conn
1. Philibert I. Sleep loss and performance in residents and nonphysicians: a meta-analytic examination. Sleep. 2005;28:1392-1402.
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2. Vgontzas AN, Zoumakis E, Bixler EO, et al. Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines. J Clin Endocrinol Metab. 2004;89:2119-2126.
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3. Arnedt JT, Owens J, Crouch M, Stahl J, Carskadon MA. Neurobehavioral performance of residents after heavy night call vs after alcohol ingestion. JAMA. 2005;294:1025-1033.
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4. Libby P, Ridker PM. Inflammation and atherosclerosis: role of C-reactive protein in risk assessment. Am J Med. 2004;116(suppl 6A):9S-16S.5. Lockley SW, Cronin JW, Evans EE, et al. Effect of reducing interns' weekly work hours on sleep and attentional failures. N Engl J Med. 2004;351:1829-1837.
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6. Katz SD, Balidemaj K, Homma S, Wu H, Wang J, Maybaum S. Acute type 5 phosphodiesterase inhibition with sildenafil enhances flow-mediated vasodilation in patients with chronic heart failure. J Am Coll Cardiol. 2000;36:845-851.
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7. Meier-Ewert HK, Ridker PM, Rifai N, et al. Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. J Am Coll Cardiol. 2004;43:678-683.
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8. Amir O, Alroy S, Schliamser JE, et al. Brachial artery endothelial function in residents and fellows working night shifts. Am J Cardiol. 2004;93:947-949.
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9. Mancini GB. Vascular structure versus function: is endothelial dysfunction of independent prognostic importance or not? J Am Coll Cardiol. 2004;43:624-628.
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JAMA. 2006;296:1049-1050.
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