Identifying an acceptable number of ambulatory blood pressure measurements for accuracy of average blood pressure and nocturnal dipping status.

We aimed to identify the minimum number of ambulatory blood pressure (ABP) measures to accurately determine daytime and nighttime systolic blood pressure (BP) averages and nocturnal dipping status (i.e., relative daytime:nighttime change). A total of 43 midlife participants wore an ABP monitor for 24 h with measurements every 20/30 min during the daytime/nighttime, as identified by a sleep diary. We calculated daytime/nighttime systolic BP average and dipping status from all available measurements per participant (i.e., normative data). We then calculated daytime and nighttime BP per participant based on a random selection of 8-20 and 4-10 measurements and replicated random selections 1,000 times. We calculated accuracy by checking the proportion from 1,000 different randomly selected samples for a particular number of measurements that systolic BP was ±5 mmHg of normative data, and dipping status remained unchanged for each participant compared with the normative value. The best fit for the regression model estimated the minimal number of measurements for an accuracy of 95% in BP averages. For a 95% accuracy in estimating daytime and nighttime systolic BP, 11 daytime and 8 nighttime measurements were required. The highest accuracy for dipping status was 91.6 ± 13.4% using 20 daytime and 10 nighttime measures, while the lowest was (83.4 ± 15.1%) using 8 daytime and 4 nighttime measures. In midlife adults, 11 daytime and 8 nighttime measurements are likely enough to calculate average systolic BPs accurately. However, no minimum number is suggested to accurately calculate dipping status.NEW & NOTEWORTHY We found that a minimum of 11 blood pressure (BP) measures are necessary to calculate an accurate average daytime BP, and 8 nighttime measures are necessary to calculate an accurate nighttime average if 95% accuracy is acceptable. Regarding BP dipping status, the current recommendations (20 daytime/7 nighttime) inaccurately classified the dipping status 10.5% of the time, suggesting that guidelines may need to be updated to classify patients as nocturnal dippers or nondippers correctly.

Obesity alters the circadian profiles of energy metabolism and glucose regulation in humans.

OBJECTIVE: Given the complex interaction among the circadian system, energy metabolism, and obesity, the authors tested whether having obesity impacts the circadian variation in energy and glucose metabolism in humans. METHODS: Participants with BMI either in the healthy weight or obesity ranges were studied in a 5-day, in-laboratory protocol that equally distributed behaviors (i.e., sleep, eating, exercise) across 24 h. Energy metabolism was measured at rest and during a standardized exercise bout and blood was sampled before and after each identical study meal to assess glucose and insulin levels. RESULTS: In those with a healthy weight, the circadian nadir of energy expenditure, during both rest and exercise, occurred when participants would normally be asleep. However, in those with obesity, this nadir appears to occur during the habitual wake period. Differences in glucose regulation also depended on the circadian phase, such that individuals with obesity appeared to have relatively greater glucose intolerance during the circadian day and produced less insulin during the circadian night. CONCLUSIONS: Obesity is associated with altered circadian energy and glucose metabolism. Understanding and addressing these associations could lead to strategies that improve body weight and metabolic health in people with obesity.

Mood correlates with circadian alignment in healthy individuals.

OBJECTIVE: To determine whether there is a correlation between mood and the alignment between the timing of the circadian pacemaker (circadian phase) and the timing of sleep in healthy, euthymic individuals. METHODS: Participants were 25 first-year medical students (25.9 ± 3.3years, 16 females). Mood (Profile of Mood States, brief form) and circadian phase (salivary dim light melatonin onset) were assessed 4 times over 7weeks. Circadian alignment was determined using the dim light melatonin onset to average midsleep interval (phase angle difference). RESULTS: Profile of Mood States, brief form score and phase angle difference were correlated: later dim light melatonin onset relative to midsleep (shorter phase angle differences) was associated with worse mood (F1,75 =10.953, p = .001). There was no difference in Profile of Mood States, brief form score between female and male participants and no interaction between gender and phase angle difference. CONCLUSIONS: There is a correlation between circadian alignment and mood among healthy individuals as has been found in individuals with seasonal and nonseasonal depression. This finding has implications for the development, prevention and treatment of mood disorders.

Chronological distribution of readings in ambulatory blood pressure monitoring exams affects the nighttime average and the magnitude of blood pressure dipping.

STUDY OBJECTIVES: Averaged nighttime blood pressure (BP) is superior to daytime BP for cardiovascular risk stratification, and the relative change between daytime/nighttime BP (dipping%) significantly predicts cardiovascular risk. Newer reports suggest that 4 measurements at night may be enough for cardiovascular risk stratification. Since BP oscillates across the night, the temporal distribution of measurements across the night may impact nighttime BP and dipping%. Therefore, we compared average nighttime BP and dipping% when using measurements in the first half (1st-half), second (2nd-half), and a combination of both (combined). METHODS: Forty-three (17 females and twenty-six males) midlife adults aged 50±10 years old wore an ambulatory BP monitor for 24 hours at home, programmed to measure BP every 20 minutes when scheduled for daytime and every 30 minutes during a self-selected 8-hour nighttime for time-in-bed. We compared the nighttime BP averages and dipping% when using either the first four measurements from the 1st-half or 2nd-half of the nighttime and combined. RESULTS: Nighttime Systolic BP was significantly different across 1st-half, 2nd-half, and combined (111±9 vs.107±11 vs. 109±9 mmHg, p<0.01), respectively, with significant pairwise differences across all categories (p<0.01 for each). Systolic BP dipping% was significantly different across 1st-half, 2nd-half, and combined (9.9±5.5 vs.13.5±6.4 vs. 11.7±5.0 %, p<0.01), respectively, with significant pairwise differences across all categories (p<0.01 for each. Diastolic BP and diastolic dipping% were similar across the three different bins. CONCLUSION: In midlife adults, systolic nighttime BP and dipping% may depend upon when BP measurements are taken during the night.

The circadian system modulates the cortisol awakening response in humans.

Background: In humans, circulating cortisol usually peaks 30-60 min after awakening from nocturnal sleep, this is commonly referred to as the cortisol awakening response (CAR). We examined the extent to which the CAR is influenced by the circadian system, independent of behaviors including sleep. Materials and methods: We examined the CAR in 34 adults (20 female) using two complementary multiday in-laboratory circadian protocols performed in dim light, throughout which behavioral factors were uniformly distributed across the 24-hour circadian cycle. Protocol 1 consisted of 10 identical consecutive 5-hour 20-minute sleep/wake cycles, and protocol 2 consisted of 5 identical consecutive 18-hour sleep/wake cycles. Salivary melatonin was used as the circadian phase marker (0° = dim light melatonin onset). During each sleep/wake cycle, salivary cortisol was measured upon scheduled awakening and 50-minutes later, with the change in cortisol defined as the CAR. Cosinor analyses were used to detect any significant circadian rhythmicity in the CAR. In secondary analyses, we adjusted the models for time awake before lights on, total sleep time, percent of rapid eye movement (REM) sleep, and percent of non-rapid eye movement (NREM) sleep. Results: Both protocols revealed a similar circadian rhythm in the CAR, with peaks occurring at a circadian phase corresponding to 3:40-3:45 a.m., with no detectable CAR during the circadian phases corresponding to the afternoon. In addition to the sinusoidal component of the circadian rhythm, total sleep time was also associated with the CAR for protocol 1. The percent of sleep spent in REM or NREM sleep were not associated with the CAR in either protocol. Conclusion: Our results show that the CAR exhibits a robust circadian rhythm that persists even after adjusting for prior sleep. Presuming that the CAR optimizes physiological responses to the anticipated stressors related to awakening, these findings may have implications for shift workers who wake up at unusual circadian phases. A blunted CAR in shift workers upon awakening in the evening may result in diminished responses to stressors.

Drugs Used in Circadian Sleep-Wake Rhythm Disturbances.

This article focuses on melatonin and other melatonin receptor agonists and summarizes their circadian phase shifting and sleep-enhancing properties, along with their associated possible safety concerns. The circadian system and circadian rhythm sleep-wake disorders are described, along with the latest American Academy of Sleep Medicine recommendations for the use of exogenous melatonin in treating them. In addition, the practical aspects of using exogenous melatonin obtainable over the counter in the United States, consideration of the effects of concomitant light exposure, and assessing treatment response are discussed.

Behaviorally and environmentally induced non-24-hour sleep-wake rhythm disorder in sighted patients.

STUDY OBJECTIVES: To determine whether there was evidence of circadian or sleep-regulatory dysfunction in sighted individuals with non-24-hour sleep-wake rhythm disorder. METHODS: Three sighted individuals with signs and/or symptoms of non-24-hour sleep-wake rhythm disorder were studied. Thirty-five- to 332-day laboratory and home-based assessments of sleep-wake and circadian timing, endogenous circadian period, photic input to the circadian pacemaker, and/or circadian and sleep-wake-dependent regulation of sleep were conducted. RESULTS: No evidence of circadian dysfunction was found in these individuals. Instead, sleep-wake timing appeared to dissociate from the circadian timing system, and/or self-selected sleep-wake and associated light/dark timing shifted the circadian pacemaker later, rather than the circadian pacemaker determining sleep-wake timing. CONCLUSIONS: These findings suggest that the etiology of this disorder may be light- and/or behaviorally induced in some sighted people, which has implications for the successful treatment of this disorder. CITATION: Emens JS, St Hilaire MA, Klerman EB, et al. Behaviorally and environmentally induced non-24-hour sleep-wake rhythm disorder in sighted patients. J Clin Sleep Med. 2022;18(2):453-459.

Sleep Efficiency is Inversely Associated with Brachial Artery Diameter and Morning Blood Pressure in Midlife Adults, with a Potential Sex-Effect.

PURPOSE: Sleep efficiency is inversely associated with cardiovascular risk. Brachial artery diameter and flow-mediated dilation (FMD) are noninvasive cardiovascular disease markers. We assessed the associations between sleep efficiency and these vascular markers in midlife adults, including people with sleep apnea. PATIENTS AND METHODS: Thirty (18 males) participants completed an in-laboratory 8-hour sleep opportunity beginning at their habitual bedtimes. Polysomnography was used to assess sleep patterns and sleep efficiency (time asleep/time in bed). We measured systolic and diastolic blood pressure, heart rate, and baseline diameter, and FMD immediately upon awakening in the morning. Mixed model analyses, adjusting for apnea-hypopnea and body mass indices, were used to assess the relationship between overnight sleep efficiency and cardiovascular markers. We also explored sex differences. RESULTS: Sleep efficiency was negatively associated with baseline brachial artery diameter (p = 0.005), systolic BP (p = 0.01), and diastolic BP (p = 0.02), but not flow-mediated dilation or heart rate (p > 0.05). These relationships were confirmed with correlations between sleep efficiency and baseline diameter (r = -0.52, p = 0.004), systolic BP (r = -0.43, p = 0.017), and diastolic BP (r = -0.43, p = 0.019). There was a sex-specific interaction trend for sleep efficiency and arterial diameter (p = 0.07) and a significant sex-specific interaction (p < 0.05) for BP, such that the relationships between sleep efficiency and cardiovascular markers were significant in women but not in men. CONCLUSION: In midlife adults, poor sleep efficiency is associated with increased brachial artery diameter and blood pressure, effects that were primarily driven by significant associations in women. These associations could underlie the observed increase in cardiovascular risk in adults with poor sleep and cardiovascular disease.

Workshop report. Circadian rhythm sleep-wake disorders: gaps and opportunities.

This White Paper presents the results from a workshop cosponsored by the Sleep Research Society (SRS) and the Society for Research on Biological Rhythms (SRBR) whose goals were to bring together sleep clinicians and sleep and circadian rhythm researchers to identify existing gaps in diagnosis and treatment and areas of high-priority research in circadian rhythm sleep-wake disorders (CRSWD). CRSWD are a distinct class of sleep disorders caused by alterations of the circadian time-keeping system, its entrainment mechanisms, or a misalignment of the endogenous circadian rhythm and the external environment. In these disorders, the timing of the primary sleep episode is either earlier or later than desired, irregular from day-to-day, and/or sleep occurs at the wrong circadian time. While there are incomplete and insufficient prevalence data, CRSWD likely affect at least 800,000 and perhaps as many as 3 million individuals in the United States, and if Shift Work Disorder and Jet Lag are included, then many millions more are impacted. The SRS Advocacy Taskforce has identified CRSWD as a class of sleep disorders for which additional high-quality research could have a significant impact to improve patient care. Participants were selected for their expertise and were assigned to one of three working groups: Phase Disorders, Entrainment Disorders, and Other. Each working group presented a summary of the current state of the science for their specific CRSWD area, followed by discussion from all participants. The outcome of those presentations and discussions are presented here.

Circadian rhythm in negative affect: Implications for mood disorders.

In humans, there is an endogenous, near 24-h (i.e., circadian) variation in mood with the best mood occurring during the circadian day and the worst mood occurring during the circadian night. Only positive affect, and not negative affect, has been shown to contribute to this circadian rhythm. We discovered a sharp circadian peak in negative affect during the circadian night coincident with a circadian trough in positive affect. These findings may help explain the association of depression with insomnia, the increased risk of suicide with nocturnal wakefulness, and the correlation between circadian misalignment and symptom severity in Major Depressive Disorder.

Drugs Used in Circadian Sleep-Wake Rhythm Disturbances.

This article focuses on melatonin and other melatonin receptor agonists, and specifically their circadian phase shifting and sleep-enhancing properties. The circadian system and circadian rhythm sleep-wake disorders are briefly reviewed, followed by a summary of the circadian phase shifting, sleep-enhancing properties, and possible safety concerns associated with melatonin and other melatonin receptor agonists. The recommended use of melatonin, including dose and timing, in the latest American Academy of Sleep Medicine Clinical Practice Guidelines for the treatment of intrinsic circadian rhythm disorders is also reviewed. Lastly, the practical aspects of treatment and consideration of clinical treatment outcomes are discussed.

Circadian Rhythm of Vascular Function in Midlife Adults.

Objective- Adverse cardiovascular events occur more frequently in the morning than at other times of the day. Vascular endothelial function (VEF)-a robust cardiovascular risk marker-is impaired during this morning period. We recently discovered that this morning impairment in VEF is not caused by either overnight sleep or the inactivity that accompanies sleep. We determined whether the endogenous circadian system is responsible for this morning impairment in VEF. We also assessed whether the circadian system affects mechanistic biomarkers, that is, oxidative stress (malondialdehyde adducts), endothelin-1, blood pressure, and heart rate. Approach and Results- Twenty-one (11 women) middle-aged healthy participants completed a 5-day laboratory protocol in dim light where all behaviors, including sleep and activity, and all physiological measurements were evenly distributed across the 24-hour period. After baseline testing, participants underwent 10 recurring 5-hour 20-minute behavioral cycles of 2-hour 40-minute sleep opportunities and 2 hours and 40 minutes of standardized waking episodes. VEF, blood pressure, and heart rate were measured, and venous blood was sampled immediately after awakening during each wake episode. Independent of behaviors, VEF was significantly attenuated during the subjective night and across the morning ( P=0.04). Malondialdehyde adducts and endothelin-1 exhibited circadian rhythms with increases across the morning vulnerable period and peaks around noon ( P≤0.01). Both systolic ( P=0.005) and diastolic blood pressure ( P=0.04) were rhythmic with peaks in the late afternoon. Conclusions- The endogenous circadian system impairs VEF and increases malondialdehyde adducts and endothelin-1 in the morning vulnerable hours and may increase the risk of morning adverse cardiovascular events in susceptible individuals. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT02202811.

Separate and interacting effects of the endogenous circadian system and behaviors on plasma aldosterone in humans.

Measurements of aldosterone for diagnosis of primary aldosteronism are usually made from blood sampled in the morning when aldosterone typically peaks. We tested the relative contributions and interacting influences of the circadian system, ongoing behaviors, and prior sleep to this morning peak in aldosterone. To determine circadian rhythmicity and separate effects of behaviors on aldosterone, 16 healthy participants completed a 5-day protocol in dim light while all behaviors ranging from sleep to exercise were standardized and scheduled evenly across the 24-h circadian period. In another experiment, to test the separate effects of prior nocturnal sleep or the inactivity that accompanies sleep on aldosterone, 10 healthy participants were studied across 2 nights: 1 with sleep and 1 with maintained wakefulness (randomized order). Plasma aldosterone was measured repeatedly in each experiment. Aldosterone had a significant endogenous rhythm ( P < 0.001), rising across the circadian night and peaking in the morning (~8 AM). Activity, including exercise, increased aldosterone, and different behaviors modulated aldosterone differently across the circadian cycle (circadian phase × behavior interaction; P < 0.001). In the second experiment, prior nocturnal sleep and prior rested wakefulness both increased plasma aldosterone ( P < 0.001) in the morning, to the same extent as the change in circadian phases between evening and morning. The morning increase in aldosterone is due to effects of the circadian system plus increased morning activities and not prior sleep or the inactivity accompanying sleep. These findings have implications for the time of and behaviors preceding measurement of aldosterone, especially under conditions of shift work and jet lag.

Drugs Used in Circadian Sleep-Wake Rhythm Disturbances.

This article focuses on melatonin and other melatonin receptor agonists, and specifically their circadian phase shifting and sleep-enhancing properties. The circadian system and circadian rhythm sleep-wake disorders are briefly reviewed, followed by a summary of the circadian phase shifting, sleep-enhancing properties, and possible safety concerns associated with melatonin and other melatonin receptor agonists. The recommended use of melatonin, including dose and timing, in the latest American Academy of Sleep Medicine Clinical Practice Guidelines for the treatment of intrinsic circadian rhythm disorders is also reviewed. Lastly, the practical aspects of treatment and consideration of clinical treatment outcomes are discussed.

Restoration of resident sleep and wellness with block scheduling.

CONTEXT: Block scheduling during residency is an innovative model in which in-patient and ambulatory rotations are separated. We hypothesised that this format may have a positive impact on resident sleep and wellness in comparison with a traditional format. METHODS: We performed a single-centre, cross-sectional, observational study of residents rotating in the medical intensive care unit (MICU). Residents were observed for 4 weeks at a time: internal medicine (IM) residents were observed for 3 weeks in the MICU followed by 1 week in an ambulatory context, and non-IM residents were observed for 4 weeks in the MICU. We monitored daily total sleep time (TST) utilising actigraphy, and wellness measures with weekly Epworth Sleepiness Scale (ESS) and Perceived Stress Scale (PSS) questionnaires. RESULTS: A total of 64 of 110 (58%) eligible residents participated; data for 49 of 110 (45%) were included in the final analysis. Mean ± standard deviation (SD) daily TST in the entire cohort was 6.53 ± 0.78 hours. Residents slept significantly longer during the ambulatory block than during the MICU block (mean ± SD TST 6.97 ± 1.00 hours and 6.43 ± 0.78 hours, respectively; p < 0.0005). Sleep duration during night call was significantly shorter than during day shift (mean ± SD TST 6.07 ± 1.16 hours and 6.50 ± 0.73 hours, respectively; p < 0.0005). A total of 390 of 490 (80%) ESS and PSS questionnaires were completed; scores significantly declined during rotations in the MICU. Internal medicine residents showed significant improvements in TST, and in ESS and PSS scores (p < 0.05) at the end of the ambulatory week. Non-IM residents, who remained in the MICU for a fourth week, continued a trend that showed a decline in perceived wellness. CONCLUSIONS: Despite duty hour restrictions, residents obtain inadequate sleep. As MICU days accumulate, measures of resident wellness decline. Residents in a block schedule experienced improvements in all measured parameters during the ambulatory week, whereas residents in a traditional schedule continued a downward trend. Block scheduling may have the previously unrecognised benefits of repaying sleep debt, correcting circadian misalignment and improving wellness.