Early Atherosclerotic Inflammatory Pathways in Children with Obstructive Sleep Apnea.

OBJECTIVE: To evaluate structural and functional carotid changes and inflammatory profiles in children with obstructive sleep apnea (OSA) and healthy controls. STUDY DESIGN: Patients with OSA and matched controls (ages 5-13 years) were recruited. Proinflammatory cytokines and acute phase reactants were measured at 6:00 p.m. Common carotid artery measures were determined using ultrasound. Confirmatory factor analysis was used to determine subgroups of cytokines and their effects on carotid measures. RESULTS: Ninety-six patients participated (53 healthy controls, 43 patients with OSA). OSA was associated with increased proinflammatory cytokines (cluster of differentiation-40 ligand [CD40-L], interleukin [IL]-6, and IL-8) and high sensitivity C-reactive protein (P < .05 for all). One cytokine subgroup (IL-6 and IL-8) was negatively associated with markers of carotid function, indicating reduced arterial distensibility and increased stiffness (P < .05 for 3 ultrasound measures); and tumor necrosis factor-α had an opposing effect on carotid function compared with this cytokine subgroup (P < .05 for 2 ultrasound measures). Linear regression demonstrated significant associations between and tumor necrosis factor- α and 2 measures of carotid function (P < .05 for each). Children with OSA did not have functional or structural carotid changes compared with controls. CONCLUSION: OSA was not directly associated with structural and functional carotid changes but was associated with upregulation of key proinflammatory cytokines (sCD40-L, IL-6, and IL-8). Together, IL-6 and IL-8 were associated with changes in carotid function. Longitudinal studies are needed to demonstrate that the inflammatory milieu observed in our population is a precursor of atherosclerosis in children.

Cardioventilatory Control in Preterm-born Children and the Risk of Obstructive Sleep Apnea.

RATIONALE: The contribution of ventilatory control to the pathogenesis of obstructive sleep apnea (OSA) in preterm-born children is unknown. OBJECTIVES: To characterize phenotypes of ventilatory control that are associated with the presence of OSA in preterm-born children during early childhood. METHODS: Preterm- and term-born children without comorbid conditions were enrolled. They were categorized into an OSA group and a non-OSA group on the basis of polysomnography. MEASUREMENTS AND MAIN RESULTS: Loop gain, controller gain, and plant gain, reflecting ventilatory instability, chemoreceptor sensitivity, and blood gas response to a change in ventilation, respectively, were estimated from spontaneous sighs identified during polysomnography. Cardiorespiratory coupling, a measure of brainstem maturation, was estimated by measuring the interval between inspiration and the preceding electrocardiogram R-wave. Cluster analysis was performed to develop phenotypes based on controller gain, plant gain, cardiorespiratory coupling, and gestational age. The study included 92 children, 63 of whom were born preterm (41% OSA) and 29 of whom were born at term (48% OSA). Three phenotypes of ventilatory control were derived with risks for OSA being 8%, 47%, and 77% in clusters 1, 2, and 3, respectively. There was a stepwise decrease in controller gain and an increase in plant gain from clusters 1 to 3. Children in cluster 1 had significantly higher cardiorespiratory coupling and gestational age than clusters 2 and 3. No difference in loop gain was found between clusters. CONCLUSIONS: The risk for OSA could be stratified according to controller gain, plant gain, cardiorespiratory coupling, and gestational age. These findings could guide personalized care for children at risk for OSA.

Age-related changes in baroreflex sensitivity and cardiac autonomic tone in children mirrored by regional brain gray matter volume trajectories.

BackgroundThe baroreflex and central autonomic brain regions together control the cardiovascular system. Baroreflex sensitivity (BRS) decreases with age in adults. Age-related changes in brain regions for cardiovascular control in children are unknown. We studied age-related changes in BRS, cardiac autonomic tone, and gray matter volume (GMV) of brain regions associated with cardiovascular control.MethodsBeat-to-beat blood pressure and heart rate (HR) were recorded in 49 children (6-14 years old). Spontaneous BRS was calculated by the sequence method. Cardiac autonomic tone was measured by spectral analysis of HR variability. GMV was measured using voxel-based morphometryin 112 healthy children (5-18 years old).ResultsAge-related changes in BRS were significantly different in children <10 years and ≥10 years. Age-related changes in GMV in regions of interest (ROI) were also significantly different between children <10 and ≥10 years and between children <11 and ≥11 years. However, age-related changes in cardiac autonomic tone were progressive.ConclusionsSignificant changes in BRS trajectories between <10 and ≥10 years may be associated with similar age-related changes of GMV in brain ROI. This new knowledge will guide future studies examining whether childhood cardiovascular disruption manifests as deviated maturation trajectories of specific brain regions.

The effect of including dynamic imaging derived airway wall motion in CFD simulations of respiratory airflow in patients with OSA.

Obstructive sleep apnea (OSA) is an airway disease caused by periodic collapse of the airway during sleep. Imaging-based subject-specific computational fluid dynamics (CFD) simulations allow non-invasive assessment of clinically relevant metrics such as total pressure loss (TPL) in patients with OSA. However, most of such studies use static airway geometries, which neglect physiological airway motion. This study aims to quantify how much the airway moves during the respiratory cycle, and to determine how much this motion affects CFD pressure loss predictions. Motion of the airway wall was quantified using cine MRI data captured over a single respiratory cycle in three subjects with OSA. Synchronously-measured respiratory airflow was used as the flow boundary condition for all simulations. Simulations were performed for full respiratory cycles with 5 different wall boundary conditions: (1) a moving airway wall, and static airway walls at (2) peak inhalation, (3) end inhalation, (4) peak exhalation, and (5) end exhalation. Geometric analysis exposed significant local airway cross-sectional area (CSA) variability, with local CSA varying as much as 300%. The comparative CFD simulations revealed the discrepancies between dynamic and static wall simulations are subject-specific, with TPL differing by up to 400% between static and dynamic simulations. There is no consistent pattern to which static wall CFD simulations overestimate or underestimate the airway TPL. This variability underscores the complexity of accurately modeling airway physiology and the importance of considering dynamic anatomical factors to predict realistic respiratory airflow dynamics in patients with OSA.

The interaction between neuromuscular forces, aerodynamic forces, and anatomical motion in the upper airway predicts the severity of pediatric OSA.

Upper airway neuromuscular response to air pressure during inhalation is an important factor in assessing pediatric subjects with obstructive sleep apnea (OSA). The neuromuscular response's strength, timing, and duration all contribute to the potential for airway collapses and the severity of OSA. This study quantifies these factors at the soft palate, tongue, and epiglottis to assess the relationship between neuromuscular control and OSA severity in 20 pediatric subjects with and without trisomy 21, under dexmedetomidine-induced sedation. The interaction between neuromuscular force and airflow pressure force was assessed based on power transferred between the airway wall and airflow calculated from airway wall motion (from cine magnetic resonance images) and air pressure acting on the airway wall (from computational fluid dynamics simulations). Airway wall motion could be asynchronous with pressure forces due to neuromuscular activation, or synchronous with pressure forces, indicating a passive response to airflow. The obstructive apnea-hypopnea index (oAHI) quantified OSA severity. During inhalation, the normalized work done through asynchronous dilation of the airway at the soft palate, tongue, and epiglottis correlated significantly with oAHI (Spearman's ρ = 0.54, 0.50, 0.64; P = 0.03, 0.03, 0.003). Synchronous collapse at the epiglottis correlated significantly with oAHI (ρ = 0.52; P = 0.02). Temporal order of synchronous and asynchronous epiglottis motion during inhalation predicted the severity of OSA (moderate vs. severe) with 100% sensitivity and 70% specificity. Subjects with severe OSA and/or trisomy 21 have insufficient neuromuscular activation during inhalation, leading to collapse and increased neuromuscular activation. Airflow-driven airway wall motion during late inhalation likely is the main determinant of OSA severity.NEW & NOTEWORTHY This is the first study that combines cine MRI and computational fluid dynamics with in vivo synchronous respiratory flow measurement to quantify the interaction between airway neuromuscular forces, aerodynamic forces, and airway anatomy noninvasively in pediatric patients with obstructive sleep apnea (OSA). The results indicate power transfer predicts OSA severity.

Computational assessment of upper airway muscular activity in obstructive sleep apnea - In vitro validation.

Neuromuscular control of the upper airway contributes to obstructive sleep apnea (OSA). An accurate, non-invasive method to assess neuromuscular function is needed to improve surgical treatment outcomes. Currently, surgical approaches for OSA are based on airway anatomy and are often not curative. When the airway surface moves, the power transferred between air in the airway lumen and the structures of the upper airway may be a measure of airway neuromuscular activity. The aim of this study was to validate power transfer as a measure of externally applied forces, representing neuromuscular activity, through cine computed tomography (CT) imaging and computational fluid dynamics (CFD) analysis in a 3D-printed airway model. A hollow elastic airway model was manufactured. An insufflation/exsufflation device generated airflow within the model lumen. The model was contained in an airtight chamber that could be positively or negatively pressurized to represent muscular forces. These forces were systematically applied to dilate and collapse the model. Cine CT imaging captured airway wall movement during respiratory cycles with and without externally applied forces. Power transfer was calculated from the product of wall movement and internal aerodynamic pressure forces using CFD simulations. Cross-correlation peaks between power transfer and changes in externally applied pressure during exhalation and inhalation were -0.79 and 0.95, respectively. Power transfer calculated via cine CT imaging and CFD was an accurate surrogate measure of externally applied forces representing airway muscular activity. In the future, power transfer may be used in clinical practice to phenotype patients with OSA and select personalized therapies.

Predicting critical closing pressure in children with obstructive sleep apnea using fluid-structure interaction.

Surgical treatment of obstructive sleep apnea (OSA) in children requires knowledge of upper airway dynamics, including the closing pressure (Pcrit), a measure of airway collapsibility. We applied a flow-structure interaction (FSI) computational model to estimate Pcrit in patient-specific upper airway models obtained from magnetic resonance imaging (MRI) scans. We sought to examine the agreement between measured and estimated Pcrit from FSI models in children with Down syndrome. We hypothesized that the estimated Pcrit would accurately reflect measured Pcrit during sleep and therefore reflect the severity of OSA as measured by the obstructive apnea-hypopnea index (AHI). All participants (n = 41) underwent polysomnography and sedated sleep MRI scans. We used Bland-Altman plots to examine the agreement between measured and estimated Pcrit. We determined associations between estimated Pcrit and OSA severity, as measured by AHI, using regression models. The agreement between passive and estimated Pcrit showed a fixed bias of -1.31 [confidence interval (CI) = -2.78, 0.15] and a nonsignificant proportional bias. A weaker agreement with active Pcrit was observed. A model including AHI, gender, an interaction term for AHI, and gender and neck circumference explained the largest variation (R2 = 0.61) in the relationship between AHI and estimated Pcrit (P < 0.0001). Overlap between the areas of the airway with the lowest stiffness, and areas of collapse on dynamic MRI, was 77.4 ± 30% for the nasopharyngeal region and 78.6 ± 33% for the retroglossal region. The agreement between measured and estimated Pcrit and the significant association with AHI supports the validity of Pcrit estimates from the FSI model.NEW & NOTEWORTHY We present a noninvasive method for estimating critical closing pressure (Pcrit) using fluid-structure interaction (FSI) simulations and magnetic resonance imaging (MRI) scans in patients with obstructive sleep apnea (OSA). We used patient-specific stiffness measures in our FSI model to account for any individual variability in the elasticity of soft tissues surrounding the upper airway. We validated this model by measuring the degree of agreement between measured and estimated Pcrit.

Baroreflex gain in children with obstructive sleep apnea.

RATIONALE: We previously demonstrated that children with obstructive sleep apnea have increased blood pressure associated with changes in left ventricular mass index. Others have shown in adults that blood pressure variability is an important predictor of changes in left ventricular mass. The baroreflex system buffers blood pressure changes by varying heart rate. We have thus hypothesized that (1) baroreflex system gain is increased during sleep, improving blood pressure buffering; (2) children with obstructive sleep apnea lack this baroreflex gain increase; and (3) reduced blood pressure buffering results in exaggerated blood pressure variability that is associated with end-organ damage. OBJECTIVES: Compare measures of left ventricular mass index and nighttime baroreflex gain of healthy children to those of children with obstructive sleep apnea. METHODS: A total of 169 children (50 control subjects, 63 with mild obstructive sleep apnea, and 56 with severe obstructive sleep apnea) with a mean age of 9.9 years (+/-2.2) underwent echocardiography followed by polysomnography with continuous blood pressure measurement. Baroreflex gain was calculated in time and frequency domains. MEASUREMENTS AND MAIN RESULTS: Healthy children demonstrated a nighttime pattern of increasing baroreflex gain. Children with obstructive sleep apnea had decreased nighttime baroreflex gain compared with control subjects. Nighttime blood pressure and blood pressure variability were significantly correlated with left ventricular mass index. CONCLUSIONS: Obstructive sleep apnea is associated with a decrease in nighttime baroreflex gain and an increase in blood pressure variability. This increase is correlated with changes in left ventricular mass index.

Randomized trial of lung hyperinflation therapy in children with congenital muscular dystrophy.

OBJECTIVE: Respiratory compromise in congenital muscular dystrophy (CMD) occurs, in part, from chest wall contractures. Passive stretch with hyperinsufflation therapy could reduce related costo-vertebral joint contractures. We sought to examine the impact of hyperinsufflation use on lung function and quality of life in children with CMD. STUDY DESIGN: We conducted a randomized controlled trial on hyperinsufflation therapy in children with CMD at two centers. An individualized hyperinsufflation regimen of 15 minutes twice daily using a cough assist device over a 12 months period was prescribed. We measured lung function, quality of life, and adherence. To demonstrate reproducibility, pulmonary function was measured twice on the same day. A mixed-effects regression model adjusting for confounders was used to assess the effects of hyperinsufflation. RESULTS: We enrolled 34 participants in the study; 31 completed the trial (n = 17 treatment group and n = 14 controls). Participants in the treatment group demonstrated a relative gain in lung volume measured at 4 and 8 months, but not at 12 months. The control group required increases in the maximum insufflation pressures to achieve maximum lung volumes while the treatment group did not. Adherence was best early in the study, peaking at the first visit and decreasing at subsequent visits. Caregiver-reported quality of life was higher in the treatment group. CONCLUSION: Hyperinsufflation therapy is effective in increasing and sustaining lung volume over time. Adherence, however, was inconsistent and difficult to maintain. Further research should determine if improved adherence leads to sustained benefits of hyperinsufflation.