Nocturnal hypoxemic burden and micro- and macrovascular disease in patients with type 2 diabetes.

BACKGROUND: Micro- and macrovascular diseases are common in patients with type 2 diabetes mellitus (T2D) and may be partly caused by nocturnal hypoxemia. The study aimed to characterize the composition of nocturnal hypoxemic burden and to assess its association with micro- and macrovascular disease in patients with T2D. METHODS: This cross-sectional analysis includes overnight oximetry from 1247 patients with T2D enrolled in the DIACORE (DIAbetes COhoRtE) study. Night-time spent below a peripheral oxygen saturation of 90% (T90) as well as T90 associated with non-specific drifts in oxygen saturation (T90non - specific), T90 associated with acute oxygen desaturation (T90desaturation) and desaturation depths were assessed. Binary logistic regression analyses adjusted for known risk factors (age, sex, smoking status, waist-hip ratio, duration of T2D, HbA1c, pulse pressure, low-density lipoprotein, use of statins, and use of renin-angiotensin-aldosterone system inhibitors) were used to assess the associations of such parameters of hypoxemic burden with chronic kidney disease (CKD) as a manifestation of microvascular disease and a composite of cardiovascular diseases (CVD) reflecting macrovascular disease. RESULTS: Patients with long T90 were significantly more often affected by CKD and CVD than patients with a lower hypoxemic burden (CKD 38% vs. 28%, p < 0.001; CVD 30% vs. 21%, p < 0.001). Continuous T90desaturation and desaturation depth were associated with CKD (adjusted OR 1.01 per unit, 95% CI [1.00; 1.01], p = 0.008 and OR 1.30, 95% CI [1.06; 1.61], p = 0.013, respectively) independently of other known risk factors for CKD. For CVD there was a thresholdeffect, and only severly and very severly increased T90non-specific was associated with CVD ([Q3;Q4] versus [Q1;Q2], adjusted OR 1.51, 95% CI [1.12; 2.05], p = 0.008) independently of other known risk factors for CVD. CONCLUSION: While hypoxemic burden due to oxygen desaturations and the magnitude of desaturation depth were significantly associated with CKD, only severe hypoxemic burden due to non-specific drifts was associated with CVD. Specific types of hypoxemic burden may be related to micro- and macrovascular disease.

Predictors of Nocturnal Hypoxemic Burden in Patients Undergoing Elective Coronary Artery Bypass Grafting Surgery.

Background: Nocturnal hypoxemia has been linked to increased cardiovascular morbidity and mortality. Several common diseases, such as sleep-disordered breathing (SDB), heart failure (HF), obesity, and pulmonary disease, coincide with an elevated nocturnal hypoxemic burden with and without repetitive desaturations. Research question: This study aimed to evaluate the association of relevant common diseases with distinctive metrics of nocturnal hypoxemic burden with and without repetitive desaturations in patients undergoing coronary artery bypass grafting surgery. Study design and methods: In this subanalysis of the prospective observational study, CONSIDER-AF (NCT02877745) portable SDB monitoring was performed on 429 patients with severe coronary artery disease the night before cardiac surgery. Pulse oximetry was used to determine nocturnal hypoxemic burden, as defined by total recording time spent with oxygen saturation levels < 90% (T90). T90 was further characterized as T90 due to intermittent hypoxemia (T90desaturation) and T90 due to nonspecific and noncyclic SpO2-drifts (T90non-specific). Results: Multivariable linear regression analysis identified SDB (apnea-hypopnea-index ≥ 15/h; B [95% CI]: 6.5 [0.4; 12.5], p = 0.036), obesity (8.2 [2.5; 13.9], p = 0.005), and mild-to-moderate chronic obstructive pulmonary disease (COPD, 16.7 [8.5; 25.0], p < 0.001) as significant predictors of an increased nocturnal hypoxemic burden. Diseases such as SDB, obesity and HF were significantly associated with elevated T90desaturation. In contrast, obesity and mild-to-moderate COPD were significant modulators of T90non-specific. Interpretation: SDB and leading causes for SDB, such as obesity and HF, are associated with an increased nocturnal hypoxemic burden with repetitive desaturations. Potential causes for hypoventilation syndromes, such as obesity and mild-to-moderate COPD, are linked to an increased hypoxemic burden without repetitive desaturations. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT02877745.

Utilisation of machine learning to predict surgical candidates for the treatment of childhood upper airway obstruction.

OBJECTIVE: To investigate the effect of adenotonsillectomy on OSAS symptoms based on a data-driven approach and thereby identify criteria that may help avoid unnecessary surgery in children with OSAS. METHODS: In 323 children enrolled in the Childhood Adenotonsillectomy Trial, randomised to undergo either early adenotonsillectomy (eAT; N = 165) or a strategy of watchful waiting with supportive care (WWSC; N = 158), the apnea-hypopnea index, heart period pattern dynamics, and thoraco-abdominal asynchrony measurements from overnight polysomnography (PSG) were measured. Using machine learning, all children were classified into one of two different clusters based on those features. The cluster transitions between follow-up and baseline PSG were investigated for each to predict those children who recovered spontaneously, following surgery and those who did not benefit from surgery. RESULTS: The two clusters showed significant differences in OSAS symptoms, where children assigned in cluster A had fewer physiological and neurophysiological symptoms than cluster B. Whilst the majority of children were assigned to cluster A, those children who underwent surgery were more likely to stay in cluster A after seven months. Those children who were in cluster B at baseline PSG were more likely to have their symptoms reversed via surgery. Children who were assigned to cluster B at both baseline and 7 months after surgery had significantly higher end-tidal carbon dioxide at baseline. Children who spontaneously changed from cluster B to A presented highly problematic ratings in behaviour and emotional regulation at baseline. CONCLUSIONS: Data-driven analysis demonstrated that AT helps to reverse and to prevent the worsening of the pathophysiological symptoms in children with OSAS. Multiple pathophysiological markers used with machine learning can capture more comprehensive information on childhood OSAS. Children with mild physiological and neurophysiological symptoms could avoid AT, and children who have UAO symptoms post AT may have sleep-related hypoventilation disease which requires further investigation. Furthermore, the findings may help surgeons more accurately predict children on whom they should perform AT.

Cyclic alternating pattern in children with obstructive sleep apnea and its relationship with adenotonsillectomy, behavior, cognition, and quality of life.

STUDY OBJECTIVES: To determine in children with obstructive sleep apnea (OSA) the effect of adenotonsillectomy (AT) on the cyclic alternating pattern (CAP) and the relationship between CAP and behavioral, cognitive, and quality-of-life measures. METHODS: CAP parameters were analyzed in 365 overnight polysomnographic recordings of children with mild-to-moderate OSA enrolled in the Childhood Adenotonsillectomy Trial (CHAT), randomized to either early AT (eAT) or watchful waiting with supportive care (WWSC). We also analyzed CAP in a subgroup of 72 children with moderate OSA (apnea-hypopnea index > 10) that were part of the CHAT sample. Causal mediation analysis was performed to determine the independent effect of changes in CAP on selected outcome measures. RESULTS: At baseline, a higher number of A1 phases per hour of sleep was significantly associated with worse behavioral functioning (caregiver Behavior Rating Inventory of Executive Function (BRIEF) Global Executive Composite (GEC): ρ = 0.24, p = 0.042; caregiver Conners' Rating Scale Global Index: ρ = 0.25, p = 0.036) and lower quality of life (OSA-18: ρ = 0.27, p = 0.022; PedsQL: ρ = -0.29, p = 0.015) in the subgroup of children with moderate OSA, but not across the entire sample. At 7-months follow-up, changes in CAP parameters were comparable between the eAT and WWSC arms. CAP changes did not account for significant proportions of variations in behavioral, cognitive, and quality-of-life performance measures at follow-up. CONCLUSIONS: We show a significant association between the frequency of slow, high-amplitude waves with behavioral functioning, as well as the quality of life in children with moderate OSA. Early AT in children with mild-to-moderate OSA does not alter the microstructure of nonrapid eye movement sleep compared with watchful waiting after an approximately 7-month period of follow-up. CLINICAL TRIAL: The study "A Randomized Controlled Study of Adenotonsillectomy for Children With Obstructive Sleep Apnea Syndrome" was registered at Clinicaltrials.gov (#NCT00560859).

Effect of adenotonsillectomy for childhood obstructive sleep apnea on nocturnal heart rate patterns.

Study Objectives: To assess the effect of adenotonsillectomy for relieving obstructive sleep apnea syndrome (OSAS) symptoms in children on cardiac autonomic modulation. Methods: In 354 children enrolled in the Childhood Adenotonsillectomy Trial, randomized to undergo either early adenotonsillectomy (eAT; N = 181) or a strategy of watchful waiting with supportive care (WWSC; N = 173), nocturnal heart rate control was analyzed during quiet, event-free sleep at baseline and at 7 months using overnight polysomnography (PSG). The relative frequency of patterns indicating monotonous changes in heart rate was quantified. Results: Children who underwent eAT demonstrated a significantly greater reduction in heart rate patterns postsurgery than the WWSC group. On assessing those heart rate patterns regarding normalization of clinical PSG, heart patterns were reduced to a similar level in both groups. In children whose AHI normalized spontaneously, heart rate patterns were already significantly less frequent at baseline, suggesting that upper airway obstruction was milder in this group at the outset. Conclusions: Adenotonsillectomy reduces monotonous heart rate patterns throughout quiet event-free sleep, reflecting a reduction in cardiac autonomic modulation. Heart rate pattern analysis may help quantifying the effect of OSAS on autonomic nervous system activity in children. Clinical Trial Registration: The study was registered at Clinicaltrials.gov (#NCT00560859).

Ascending aortic blood flow velocity is increased in children with primary snoring/mild sleep-disordered breathing and associated with an increase in CD8 + T cells expressing TNFα and IFNγ.

Sleep-disordered breathing (SDB) is associated with cardiovascular disease and systemic inflammation in adults but this remains to be explored in children, especially in children with the most common form of SDB, i.e. primary snoring/mild SDB. This pilot study investigated the relationship between the cardiovascular function and inflammation in children with mild SDB. Nineteen participants aged 5-14 years underwent overnight polysomnography, cardiac magnetic resonance imaging (aortic blood flow velocity and left and right ventricular systolic function) and assessment for inflammatory markers (intracellular cytokine analysis of T cells by flow cytometry). Parents also completed the Sleep Disturbances Scale for Children (SDSC). Children with mild SDB exhibited increased ascending aortic peak systolic velocity compared to controls (SDB 119.95 m/s vs. control 101.49 m/s, p < 0.05). No significant group differences were observed for left and right ventricular ejection fraction or mean aortic blood flow velocity from either the ascending aorta or pulmonary artery. Children with mild SDB had increased inflammatory markers as demonstrated by elevated T cell interferon gamma (IFNγ) (SDB 52 ± 4% vs. control 25 ± 3% positive cells, p < 0.005) and tumour necrosis factor alpha (TNFα) (SDB 39 ± 4% vs. control 20 ± 2% positive cells, p < 0.005) expression from CD8+ cells. A strong positive correlation was observed between ascending aorta peak blood flow velocity and both TNFα and IFNγ (TNFα, r = 0.54, p < 0.03; IFNγ, r = 0.63, p < 0.005, respectively). Polysomnography revealed that oxygen saturation (SaO2) nadir was significantly lower in children with mild SDB compared to controls (SDB 92.3 ± 2.7% vs. control 94.4 ± 1.6%, p < 0.05). A lower SaO2 nadir was associated with an increased ascending aorta peak systolic velocity (r = - 0.48, p < 0.05). As well, both a lower SaO2 nadir and an increased ascending aorta peak systolic velocity were associated with higher SDSC Sleep-Disordered Breathing and Disorder of Initiating and Maintaining Sleep subscale scores but not the polysomnographic-derived Obstructive Apnea-Hypopnea Index. The finding of elevated ascending aortic peak systolic blood flow velocity and its association with increased inflammatory markers suggests that the profile of cardiovascular changes noted in adult SDB may also occur in children with mild SDB.

Altered Nocturnal Cardiovascular Control in Children With Sleep-Disordered Breathing.

Study objectives: To assess cardiovascular control during sleep in children with sleep-disordered breathing (SDB) and the effect of adenotonsillectomy in comparison to healthy nonsnoring children. Methods: Cardiorespiratory signals obtained from overnight polysomnographic recordings of 28 children with SDB and 34 healthy nonsnoring children were analyzed. We employed an autoregressive closed-loop model with heart period (RR) and pulse transit time (PTT) as outputs and respiration as an external input to obtain estimates of respiratory gain and baroreflex gain. Results: Mean and variability of PTT were increased in children with SDB across all stages of sleep. Low frequency power of RR and PTT were attenuated during non-rapid eye movement (REM) sleep. Baroreflex sensitivity was reduced in children with SDB in stage 2 sleep, while respiratory gain was increased in slow wave sleep. After adenotonsillectomy, these indices normalized in the SDB group attaining values comparable to those of healthy children. Conclusions: In children with mild-to-moderate SDB, vasomotor activity is increased and baroreflex sensitivity decreased during quiet, event-free non-REM sleep. Adenotonsillectomy appears to reverse this effect.

Relationship between Vascular Resistance and Sympathetic Nerve Fiber Density in Arterial Vessels in Children With Sleep Disordered Breathing.

BACKGROUND: Sleep disordered breathing in children is associated with increased blood flow velocity and sympathetic overactivity. Sympathetic overactivity results in peripheral vasoconstriction and reduced systemic vascular compliance, which increases blood flow velocity during systole. Augmented blood flow velocity is recognized to promote vascular remodeling. Importantly, increased vascular sympathetic nerve fiber density and innervation in early life plays a key role in the development of early-onset hypertension in animal models. Examination of sympathetic nerve fiber density of the tonsillar arteries in children undergoing adenotonsillectomy for Sleep disordered breathing will address this question in humans. METHODS AND RESULTS: Thirteen children scheduled for adenotonsillectomy to treat sleep disordered breathing underwent pupillometry, polysomnography, flow-mediated dilation, resting brachial artery blood flow velocity (velocity time integral), and platelet aggregation. The dorsal lingual artery (tonsil) was stained and immunofluorescence techniques used to determine sympathetic nerve fiber density. Sympathetic nerve fiber density was correlated with increased resting velocity time integral (r=0.63; P<0.05) and a lower Neuronal Pupillary Index (r=-0.71, P<0.01), as well as a slower mean pupillary constriction velocity (mean, r=-0.64; P<0.05). A faster resting velocity time integral was associated with a slower peak pupillary constriction velocity (r=-0.77; P<0.01) and higher platelet aggregation to collagen antigen (r=0.64; P<0.05). Slower mean and peak pupillary constriction velocity were associated with higher platelet aggregation scores (P<0.05; P<0.01, respectively). CONCLUSIONS: These results indicate that sympathetic activity is associated with change in both the function and structure of systemic vasculature in children with sleep disordered breathing.

Adenotonsillectomy for childhood obstructive sleep apnoea reduces thoraco-abdominal asynchrony but spontaneous apnoea-hypopnoea index normalisation does not.

The efficacy of adenotonsillectomy for treating obstructive sleep apnoea syndrome (OSAS) in children has been established, but its precise effects on inspiratory effort are not well documented.In 353 children enrolled in the Childhood Adenotonsillectomy Trial, randomised to undergo either early adenotonsillectomy (n=182) or a strategy of watchful waiting with supportive care (WWSC) (n=171), thoraco-abdominal asynchrony (TAA) was analysed during quiet, non-apnoeic and non-hypopnoeic breathing during sleep at baseline and at 7 months using overnight polysomnography.Children who underwent early adenotonsillectomy demonstrated a reduction in TAA post-surgery while the WWSC arm showed no change. On assessing TAA with regard to normalisation of clinical polysomnography findings at follow-up, TAA was reduced in children who had surgical resolution of OSAS (based on apnoea-hypopnoea index), but not in children who displayed spontaneous normalisation of apnoea-hypopnoea index. In the latter group, TAA was inversely correlated with quality of life.We conclude that adenotonsillectomy reduces TAA during quiet sleep. Monitoring of instantaneous TAA may yield additional insight in the dynamic changes of inspiratory effort. In combination with traditional indices of obstruction, TAA may more accurately characterise the degree of sleep-disordered breathing in children.

The effect of adenotonsillectomy for childhood sleep apnoea on cardiorespiratory control.

The efficacy of adenotonsillectomy for relieving obstructive sleep apnoea symptoms in children has been firmly established, but its precise effects on cardiorespiratory control are poorly understood. In 375 children enrolled in the Childhood Adenotonsillectomy Trial, randomised to undergo either adenotonsillectomy (n=194) or a strategy of watching waiting (n=181), respiratory rate, respiratory sinus arrhythmia and heart rate were analysed during quiet, non-apnoeic and non-hypopnoeic breathing throughout sleep at baseline and at 7 months using overnight polysomnography. Children who underwent early adenotonsillectomy demonstrated an increase in respiratory rate post-surgery while the watchful waiting group showed no change. Heart rate and respiratory sinus arrhythmia were comparable between both arms. On assessing cardiorespiratory variables with regard to normalisation of clinical polysomnography findings during follow-up, heart rate was reduced in children who had resolution of obstructive sleep apnoea syndrome, while no differences in their respiratory rate or respiratory sinus arrhythmia were observed. Adenotonsillectomy for obstructive sleep apnoea increases baseline respiratory rate during sleep. Normalisation of apnoea-hypopnoea index, spontaneously or via surgery, lowers heart rate. Considering the small average effect size, the clinical significance is uncertain.

Delayed brachial artery dilation response and increased resting blood flow velocity in young children with mild sleep-disordered breathing.

AIM: This study aimed to evaluate whether the vascular dysfunction perceived in adults with sleep-disordered breathing (SDB) was also evident in children with snoring referred for evaluation of clinically suspected SDB. OBJECTIVES: This study compared flow-mediated dilatation (FMD), measured at the brachial artery, at rest and during hyperaemic stress between children who snore [n = 23; mean standard deviation (SD) age = 7.51 (1.3) years] and healthy, non-snoring children [n = 11; age = 8.0 (1.3) years]. METHODS: Children with suspected obstructive sleep apnoea (OSA) and healthy non-snoring controls underwent overnight polysomnography (PSG). Using standard techniques, non-invasive FMD and brachial arterial blood flow velocity during rest and hyperaemia were subsequently measured by ultrasound imaging MEASUREMENTS: Resting and hyperaemic velocity time integral (area under the curve of mean systolic velocity × ejection time), maximal dilation response (highest percentage difference from baseline diameter) and the time taken to reach maximal dilation were calculated. RESULTS: Children awaiting adenotonsillectomy compared to healthy non-snoring control children had higher velocity time integrals at rest (14 ± 3 m vs. 20 ± 8 m, p < 0.01) and during hyperaemic stress (56 ± 6m vs. 63 ± 13m, p < 0.01) despite having only mild SDB on polysomnographic assessment. Lower nadir oxygen saturation values during non-rapid eye movement sleep were negatively associated with higher resting (r = -0.58, p <0.001) and hyperaemic (r = -0.36, p < 0.05) velocity time integrals. Maximal FMD dilatation response was not significantly different between snoring and non-snoring groups, but the estimated time to reach maximal dilation was significantly delayed in children who snored (60.7 ± 28.4 vs. 39.2 ± 13.2 s, p < 0.05). CONCLUSIONS: Children with mild SDB showed increased blood flow velocity at rest and during hyperaemic stress suggesting altered cardiovascular and haemodynamic function. The delay in time to maximal vessel dilatation in children who snored also suggests possible reduced vascular compliance in response to hyperaemic sheer stress. Mild SDB appears to alter the peripheral vascular response in young children. The long-term vascular implications of these changes in the growing child are unknown and warrant further investigation.

Effect of respiration on heartbeat-evoked potentials during sleep in children with sleep-disordered breathing.

OBJECTIVE: Heartbeat-evoked potentials (HEPs) in electroencephalogram (EEG) provide a quantitative measure of cardiac interoception during sleep. We previously reported reduced HEPs in children with sleep-disordered breathing (SDB), indicative of attenuated cardiac information processing. The objective of this study was to investigate the link between HEP and respiration. PATIENTS/METHODS: From the overnight polysomnograms of 40 healthy children and 40 children with SDB, we measured HEPs during epochs of stage 2, slow-wave and rapid eye movement (REM) sleep free of abnormal respiratory events. HEPs were analysed with respect to respiratory phase. RESULTS: We observed a marked association between respiratory phase and HEP in children with SDB during REM sleep, but not in normal children. In children with SDB, HEP waveforms were attenuated during expiration compared to inspiration. Following adenotonsillectomy, expiratory HEP peak amplitude increased in the SDB children and was no longer different from those of normal children. CONCLUSIONS: The expiratory phase of respiration is primarily associated with attenuated cardiac information processing in children with SDB, establishing a pathophysiological link between breathing and HEP attenuation.

Increased thoracoabdominal asynchrony during breathing periods free of discretely scored obstructive events in children with upper airway obstruction.

OBJECTIVE: This study aims to investigate the impact of upper airway obstruction (UAO) in children by measuring thoracoabdominal asynchrony (TAA) during periods of sleep apnea/hypopnea and during scored-event-free (SEF) breathing periods. METHODS: Respiratory inductive plethysmographic signals were extracted from polysomnographic data, recorded before and after adenotonsillectomy in 40 children with UAO and 40 healthy, matched children at equivalent time points. Thoracoabdominal asynchrony was computed using a Hilbert transform-based phase difference estimation method in SEF periods during stage 2, stage 4 non-rapid eye movement (NREM), and rapid eye movement (REM) sleep and compared between the groups. RESULTS: At baseline, in the UAO group, TAA during obstructions were significantly higher than TAA during SEF periods in both stage 2 and REM sleep. Compared to controls, children with UAO had a significantly higher TAA during SEF periods in stage 2, stage 4 sleep, and REM sleep. This between-group difference was not significant post adenotonsillectomy. UAO group showed a significant decrease in TAA compared to their baseline during SEF stage 2 and 4 NREM, but not in REM. CONCLUSION: Upper airway obstruction in children is associated with increased TAA during SEF periods, indicative of continuous partial obstruction of the upper airway. Adenotonsillectomy decreased this effect significantly in non-REM sleep as evidenced by reduced asynchrony levels post-surgery. TAA assessment during sleep may therefore provide additional diagnostic information.

Movement distribution: a new measure of sleep fragmentation in children with upper airway obstruction.

STUDY OBJECTIVES: To develop a measure of sleep fragmentation in children with upper airway obstruction based on survival curve analysis of sleep continuity. DESIGN: Prospective repeated measures. SETTING: Hospital sleep laboratory. PARTICIPANTS: 92 children aged 3.0 to 12.9 years undergoing 2 overnight polysomnographic (PSG) sleep studies, 6 months apart. Subjects were divided into 3 groups based on their obstructive apnea and hypopnea index (OAHI) and other upper airway obstruction (UAO) symptoms: primary snorers (PS; n = 24, OAHI <1), those with obstructive sleep apnea syndrome (OSAS; n = 20, OAHI ≥1) and non-snoring controls (C; n = 48, OAHI <1). INTERVENTIONS: Subjects in the PS and OSAS groups underwent tonsillectomy and adenoidectomy between PSG assessments. MEASUREMENTS AND RESULTS: Post hoc measures of movement and contiguous sleep epochs were exported and analyzed using Kaplan-Meier estimates of survival to generate survival curves for the 3 groups. Statistically significant differences were found between these group curves for sleep continuity (P < 0.05) when using movement events as the sleep fragmenting event, but not if stage 1 NREM sleep or awakenings were used. CONCLUSION: Using conventional indices of sleep fragmentation in survival curve analysis of sleep continuity does not provide a useful measure of sleep fragmentation in children with upper airway obstruction. However, when sleep continuity is defined as the time between gross body movements, a potentially useful clinical measure is produced.

Heartbeat evoked potentials during sleep and daytime behavior in children with sleep-disordered breathing.

RATIONALE: Event-related brain potentials allow probing of cortical information processing, but when evoked with externally induced stimuli may disrupt sleep homeostasis and do not provide insight into intrinsic cortical information processing. To investigate if cortical processing of intrinsic information in children with sleep-disordered breathing (SDB) is different from healthy children and, if so, whether it resolves with treatment, we used heartbeat as a source of interoceptive event-related brain potentials. OBJECTIVES: To investigate heartbeat evoked potentials (HEP) during sleep in healthy children and in children with SDB before and after treatment and to explore if there are any associations between HEP and daytime behavioral deficits in children with SDB. METHODS: Heartbeat-aligned EEG was assessed for presence of HEP within stage 2, slow-wave sleep, and REM sleep in 40 children with primarily mild to moderate SDB before and after adenotonsillectomy and in 40 matched control subjects at similar time points. MEASUREMENTS AND MAIN RESULTS: In both groups, nonrandom HEP were present in all sleep stages analyzed; however, amplitude of HEP were significantly lower in children with SDB during non-REM sleep (stage 2: P = 0.03; slow-wave sleep: P = 0.001). This between-group difference was not significant post adenotonsillectomy. Significant negative associations between HEP and daytime behavioral scores were observed at baseline. CONCLUSIONS: Children with SDB displayed reduced HEP amplitude during sleep, which might be indicative of changes in afferent sensory inputs to the brain and/or signify differences in sensory gating of cardiac-related information in the insular cortex. Adenotonsillectomy appears to reverse this effect.

Respiratory cycle-related electroencephalographic changes during sleep in healthy children and in children with sleep disordered breathing.

STUDY OBJECTIVE: To investigate respiratory cycle-related electroencephalographic changes (RCREC) in healthy children and in children with sleep disordered breathing (SDB) during scored event-free (SEF) breathing periods of sleep. DESIGN: Interventional case-control repeated measurements design. SETTING: Paediatric sleep laboratory in a hospital setting. PARTICIPANTS: Forty children with SDB and 40 healthy, age- and sex-matched children. INTERVENTIONS: Adenotonsillectomy in children with SDB and no intervention in controls. MEASUREMENTS AND RESULTS: Overnight polysomnography; electroencephalography (EEG) power variations within SEF respiratory cycles in the overall and frequency band-specific EEG within stage 2 nonrapid eye movement (NREM) sleep, slow wave sleep (SWS), and rapid eye movement (REM) sleep. Within both groups there was a decrease in EEG power during inspiration compared to expiration across all sleep stages. Compared to controls, RCREC in children with SDB in the overall EEG were significantly higher during REM and frequency band specific RCRECs were higher in the theta band of stage 2 and REM sleep, alpha band of SWS and REM sleep, and sigma band of REM sleep. This between-group difference was not significant postadenotonsillectomy. CONCLUSION: The presence of nonrandom respiratory cycle-related electroencephalographic changes (RCREC) in both healthy children and in children with sleep disordered breathing (SDB) during NREM and REM sleep has been demonstrated. The RCREC values were higher in children with SDB, predominantly in REM sleep and this difference reduced after adenotonsillectomy. CITATION: Immanuel SA, Pamula Y, Kohler M, Martin J, Kennedy D, Saint DA, Baumert M. Respiratory cycle-related electroencephalographic changes during sleep in healthy children and in children with sleep disordered breathing.

Respiratory timing and variability during sleep in children with sleep-disordered breathing.

Sleep-disordered breathing (SDB) in children is assessed by quantification of hypopnea and apnea events. Little is known, however, about respiratory timing and breath-to-breath variability during sleep. The aim of this study was to investigate respiratory parameters across sleep stages in children with SDB before and after treatment compared with healthy children. Overnight polysomnography (PSG) was conducted in 40 children with SDB prior to and 6 mo following adenotonsillectomy. For comparison, a control group of 40 healthy sex- and age-matched children underwent two PSGs at equivalent time points but without intervention. The following variables were measured breath by breath during obstruction-free periods in stage 2 nonrapid eye movement (NREM), stage 4 NREM, and REM sleep: inspiratory time (Ti), expiratory time (Te), total time (Ttotal), inspiratory duty cycle (DC; =Ti/Ttotal), respiratory frequency (fR), and SD of the parameters Ti, Te, fR, and DC. Variability in waveform morphology was also computed using the residue of respiratory patterns. The severity of SDB was relatively mild in the study cohort (obstructive apnea hypopnea index: baseline, 5.1 ± 9.4 vs. 0.1 ± 0.2, P < 0.001; follow-up, 0.3 ± 0.3 vs. 0.8 ± 1.0, P < 0.01). Compared with healthy controls, children with SDB showed significantly longer Ti and Te and a lower fR at the baseline study. These differences were not significant after adenotonsillectomy. Sleep stages were associated with significant differences in all of the respiratory measures in both groups of children. In conclusion, children with relatively mild SDB showed prolonged inspiration and expiration indicative of chronic narrowing of the upper airway. Treatment of SDB normalizes respiratory timing. Documentation of these parameters may aid in both understanding and management of children with SDB.

Altered cardio-respiratory response to spontaneous cortical arousals in children with upper airway obstruction.

OBJECTIVE: Upper airway obstruction (UAO) during childhood is associated with cardiovascular morbidity. The aim of this study was to investigate the cardio-respiratory response to cortical arousal during sleep in children with UAO. METHODS: Standard paediatric overnight polysomnography (PSG) was conducted in 40 children with UAO (25M, 7.5±2.7yrs) prior to and 6 months following adenotonsillectomy. For comparison a control group of 40 normal, sex and age matched children (21M, 7.5±2.6yrs) underwent two PSGs without intervention at the same time points. RESULTS: Heart rate and respiratory rate were measured during spontaneous and respiratory arousals in stage 2 and REM sleep 15s prior to and 15s immediately following cortical arousal onset. Cortical arousal was associated with a significant increase in heart and respiratory rate in both groups of children. UAO children, however, showed a significantly higher heart rate response in stage 2 sleep (-17.5±6.0 vs. -14.4±4.8%; p<0.05), a lower pre-arousal baseline respiratory rate (stage 2: 17.1±1.4 vs. 18.2±1.7 BPM; p<0.01) and a prolonged increase in respiratory rate compared to control children. Cardiac and respiratory arousal responses were not significantly different from controls following adenotonsillectomy in the UAO children. CONCLUSIONS: UAO in children is associated with an altered cardiorespiratory response to spontaneous arousal from sleep, which may indicate early signs of autonomic dysfunction. Surgical treatment of UAO appears to reverse these outcomes.

Relation between QT interval variability and cardiac sympathetic activity in hypertension.

Elevated QT interval variability is a predictor of malignant ventricular arrhythmia, but the underlying mechanisms are incompletely understood. A recent study in dogs with pacing-induced heart failure suggests that QT variability is linked to cardiac sympathetic nerve activity. The aim of this study was to determine whether increased cardiac sympathetic activity is associated with increased beat-to-beat QT interval variability in patients with essential hypertension. We recorded resting norepinephrine (NE) spillover into the coronary sinus and single-lead, short-term, high-resolution, body-surface ECG in 23 patients with essential hypertension and 9 normotensive control subjects. To assess beat-to-beat QT interval variability, we calculated the overall QT variability (QTVN) as well as the QT variability index (QTVi). Cardiac NE spillover (12.2 ± 6.5 vs. 20.7 ± 14.7, P = 0.03) and QTVi (-1.75 ± 0.36 vs. -1.42 ± 0.50, P = 0.05) were significantly increased in hypertensive patients compared with normotensive subjects. QTVN was significantly correlated with cardiac NE spillover (r(2) = 0.31, P = 0.001), with RR variability (r(2) = 0.20, P = 0.008), and with systolic blood pressure (r(2) = 0.16, P = 0.02). Linear regression analysis identified the former two as independent predictors of QTVN. In conclusion, elevated repolarization lability is directly associated with sympathetic cardiac activation in patients with essential hypertension.

Short-term heart rate complexity is reduced in patients with type 1 diabetes mellitus.

OBJECTIVE: The aim of this study was to test whether new heart rate variability (HRV) complexity measures provide diagnostic information regarding early subclinical autonomic dysfunction in diabetes mellitus (DM). METHODS: HRV in DM type 1 patients (n=17, 10f, 7m) aged 12.9-31.5 years (duration of DM 12.4+/-1.2 years) was compared to a control group of 17 healthy matched probands. The length of R-R intervals was measured over 1h using a telemetric ECG system. In addition to linear measures, we assessed HRV complexity measures, including multiscale entropy (MSE), compression entropy and various symbolic dynamic measures (Shannon and Renyi entropies, normalized complexity index (NCI), and pattern classification). RESULTS: HRV magnitude was significantly reduced in patients with DM. Several HRV complexity parameters (MSE at scales 2-4, Renyi entropy, NCI) were also significantly reduced in diabetics. MSE indices and compression entropy did not correlate with linear measures. CONCLUSIONS: The magnitude and complexity of HRV are reduced in young patients with DM, indicating vagal dysfunction. SIGNIFICANCE: The quantification of HRV complexity in combination with its magnitude may provide an improved diagnostic tool for cardiovascular autonomic neuropathy in DM.