Drug-Induced Sleep Endoscopy Differences by Age in Surgically Naive Children With Sleep-Disordered Breathing.

Importance: Drug-induced sleep endoscopy (DISE) is increasingly used to guide treatment decisions in children with sleep-disordered breathing (SDB). Previous reports of DISE findings in children have typically included a broad age range, but it is unclear how these patterns of obstruction vary with age. Objective: To compare patterns of airway obstruction observed during DISE in 3 age groups of surgically naive children with SDB. Design, Setting, and Participants: This cross-sectional analysis of a prospective cohort of surgically naive nonsyndromic children with SDB or obstructive sleep apnea [OSA] at risk for residual disease after adenotonsillectomy (defined as having at least 1 of these criteria: severe OSA, older than 7 years, obesity, or Black race) who were recruited between May 1, 2015, and February 28, 2020, was conducted at a tertiary children's hospital. Data analysis was conducted from September 2021 to February 2022. Exposures: DISE. Main Outcomes and Measures: DISE findings were rated at 6 anatomic sites using the Sleep Endoscopy Rating Scale (SERS). The association between age and severity of obstruction at each anatomic site and overall were compared using correlation (Kendall τ) and ordinal logistic regression analysis. Results: Data from 288 children (144 girls [50%]; 20 American Indian/Alaska Native [7%], 4 Asian [1%], 19 Black [7%], 93 Hispanic [33%], 2 Middle Eastern [1%], 6 Native Hawaiian/Pacific Islander [2%], and 203 White [70%] individuals; median [IQR] age, 9.2 [7.0-11.7] years) were stratified by participant age into preschool (age 2-5 years; 27 [9%]), younger school-aged (age 5-10 years; 146 [51%]), and older school-aged (age 10-18 years; 115 [40%]). Among these subgroups, the prevalence of multilevel obstruction was 59%, 51%, and 30%, respectively. Increasing age was inversely correlated with obstruction of the nasal airway (τb, -0.19; 95% CI, -0.29 to -0.09), nasopharynx (τb, -0.20; 95% CI, -0.31 to -0.10), velopharynx (τb, -0.16; 95% CI, -0.26 to -0.06), and overall obstruction (SERS total score: τb, -0.24; 95% CI, -0.33 to -0.14). An adjusted analysis demonstrated an inverse association between age and nasopharyngeal obstruction (odds ratio [OR], 0.84; 95% CI, 0.76 to 0.92), SERS total score (OR, 0.83; 95% CI, 0.76 to 0.90), and the number of sites of complete obstruction (OR, 0.87; 95% CI, 0.87 to 0.95). Conclusions and Relevance: This cross-sectional analysis of data from a prospective cohort study of surgically naive children with SDB found that preschool-aged children had more frequent multilevel obstruction, more severe overall obstruction, and nasopharyngeal obstruction compared with older children. Understanding the most common sites of obstruction and expected changes with age could inform personalized treatment for children with SDB.

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.

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.

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.

Morning impairment in vascular function is unrelated to overnight sleep or the inactivity that accompanies sleep.

Adverse cardiovascular events, such as myocardial infarction and sudden cardiac death, occur more frequently in the morning. Prior studies have shown that vascular endothelial function (VEF), a marker of cardiovascular disease, is attenuated during physical inactivity and declines across the night. We sought to determine whether a morning attenuation in VEF is a result of prior sleep or the inactivity that inevitably accompanies sleep. After 1 wk of a rigorously controlled sleep-wake schedule and behaviors, 10 healthy participants completed a randomized crossover protocol in dim light and constant conditions, incorporating a night of 6 h of sleep opportunity and a night of immobility while they were supine and awake. VEF was measured in the dominant brachial artery as flow mediated dilation (FMD) before and after each 6-h trial. To avoid disturbing sleep and posture of the participants, blood was drawn using a 12-ft catheter from an adjoining laboratory room before, during, and after each 6-h trial, and plasma was analyzed for markers of oxidative stress [malondialdehyde adducts (MDA)], and endothelin-1. Contrary to expectation, both nocturnal sleep and nocturnal inactivity significantly increased FMD ( P < 0.05). There was no significant change in MDA or endothelin-1 within and between trials. Contrary to expectations based on prior studies, we found that overnight sleep or the inactivity that accompanies sleep did not result in attenuation in VEF in the morning hours in healthy people. Thus, it is plausible that the endogenous circadian system, a remaining factor not studied here, is responsible for the commonly observed decline in VEF across the night.