Keith McConnell

Activity-Adjusted 24-Hour Ambulatory Blood Pressure and Cardiac Remodeling in Children with Sleep Disordered Breathing

Questions remain as to whether pediatric sleep disordered breathing increases the risk for elevated blood pressure and blood pressure–dependent cardiac remodeling. We tested the hypothesis that activity-adjusted morning blood pressure surge, blood pressure load, and diurnal and nocturnal blood pressure are significantly higher in children with sleep disordered breathing than in healthy controls and that these blood pressure parameters relate to left ventricular remodeling. 24-hour ambulatory blood pressure parameters were compared between groups. The associations between blood pressure and left ventricular relative wall thickness and mass were measured. 140 children met the inclusion criteria. In children with apnea hypopnea index <5 per hour, a significant difference from controls was the morning blood surge. Significant increases in blood pressure surge, blood pressure load, and in 24-hour ambulatory blood pressure were evident in those whom the apnea hypopnea index exceeded 5 per hour. Sleep disordered breathing and body mass index had similar effect on blood pressure parameters except for nocturnal diastolic blood pressure, where sleep disordered breathing had a significantly greater effect than body mass index. Diurnal and nocturnal systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure predicted the changes in left ventricular relative wall thickness. Therefore, sleep disordered breathing in children who are otherwise healthy is independently associated with an increase in morning blood pressure surge, blood pressure load, and 24-hour ambulatory blood pressure. The association between left ventricular remodeling and 24-hour blood pressure highlights the role of sleep disordered breathing in increasing cardiovascular morbidity.

Growth Velocity Predicts Recurrence of Sleep-disordered Breathing 1 Year after Adenotonsillectomy

RATIONALE Adenotonsillectomy, the first line of treatment of sleep-disordered breathing (SDB), is the most commonly performed pediatric surgery. Predictors of the recurrence of SDB after adenotonsillectomy and its impact on cardiovascular risk factors have not been identified. OBJECTIVES Demonstrate that gain velocity in body mass index (BMI) defined as unit increase in BMI/year confers an independent risk for the recurrence of SDB 1 year after adenotonsillectomy. METHODS Children with SDB and hypertrophy of the tonsils and a comparison group of healthy children were followed prospectively for 1 year. MEASUREMENTS AND MAIN RESULTS Serial polysomnographies, BMI, and blood pressure were obtained before adenotonsillectomy and 6 weeks, 6 months, and 1 year postoperatively. Gain velocity in BMI, BMI and being African American (odds ratios, 4-6/unit change/yr; 1.4/unit and 15, respectively) provided equal amounts of predictive power to the risk of recurrence of SDB. In the group that experienced recurrence, systolic blood pressure at 1 year was higher than at baseline and higher than in children who did not experience recurrence. CONCLUSIONS Three clinical parameters confer independent increased risk for high recurrence of SDB after adenotonsillectomy: gain velocity in BMI, obesity, and being African American. A long-term follow-up of children with SDB and monitoring of gain velocity in BMI are essential to identifying children at risk for recurrence of SDB and in turn at risk for hypertension.

Pulmonary dysfunction in neonatal SP-B-deficient mice

Pulmonary function was assessed in newborn wild-type and homozygous and heterozygous surfactant protein B (SP-B)-deficient mice after birth. SP-B +/+ and SP-B+/- mice became well oxygenated and survived postnatally. Although lung compliance was decreased slightly in the SP-B+/- mice, lung volumes and compliances were decreased markedly in homozygous SP-B-/- mice. They died rapidly after birth, failing to inflate their lungs or oxygenate. SP-B proprotein was absent in the SP-B-/- mice and was reduced in the SP-B+/- mice, as assessed by Western analysis. Surfactant protein A, surfactant proprotein C, surfactant protein D, and surfactant phospholipid content in lungs from SP-B+/- and SP-B-/- mice were not altered. Lung saturated phosphatidylcholine and precursor incorporation into saturated phosphatidylcholine were not influenced by SP-B genotype. Intratracheal administration of perfluorocarbon resulted in lung expansion, oxygenation, and prolonged survival of SP-B-/- mice and in reduced lung compliance in SP-B+/+ and SP-B+/- mice. Lack of SP-B caused respiratory failure at birth, and decreased SP-B protein was associated with reduced lung compliance. These findings demonstrate the critical role of SP-B in perinatal adaptation to air breathing.Pulmonary function was assessed in newborn wild-type and homozygous and heterozygous surfactant protein B (SP-B)-deficient mice after birth. SP-B+/+ and SP-B+/- mice became well oxygenated and survived postnatally. Although lung compliance was decreased slightly in the SP-B+/- mice, lung volumes and compliances were decreased markedly in homozygous SP-B-/- mice. They died rapidly after birth, failing to inflate their lungs or oxygenate. SP-B proprotein was absent in the SP-B-/- mice and was reduced in the SP-B+/- mice, as assessed by Western analysis. Surfactant protein A, surfactant proprotein C, surfactant protein D, and surfactant phospholipid content in lungs from SP-B+/- and SP-B-/- mice were not altered. Lung saturated phosphatidylcholine and precursor incorporation into saturated phosphatidylcholine were not influenced by SP-B genotype. Intratracheal administration of perfluorocarbon resulted in lung expansion, oxygenation, and prolonged survival of SP-B-/- mice and in reduced lung compliance in SP-B+/+ and SP-B+/- mice. Lack of SP-B caused respiratory failure at birth, and decreased SP-B protein was associated with reduced lung compliance. These findings demonstrate the critical role of SP-B in perinatal adaptation to air breathing.

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.

Determinants of Regional Cerebral Oxygenation in Children with Sleep-disordered Breathing

RATIONALE An association between neurocognitive deficits and pediatric sleep-disordered breathing has been suggested; however, weak correlations between disease severity and functional outcomes underscore the lack of knowledge regarding factors modulating cognitive morbidity of sleep-disordered breathing. OBJECTIVES To identify the parameters affected by sleep-disordered breathing that modulate cerebral oxygenation, an important determinant of cognition. A further objective was to use these parameters with demographic data to develop a predictive statistical model of pediatric cerebral oxygenation. METHODS Ninety-two children (14 control subjects, 32 with primary snoring, and 46 with obstructive sleep apnea) underwent polysomnography with continuous monitoring of cerebral oxygenation and blood pressure. Analysis of covariance was used to relate the blood pressure, sleep diagnostic parameters, and demographic characteristics to regional cerebral oxygenation. MEASUREMENTS AND MAIN RESULTS To account for anatomic variability, an index of cerebral oxygenation during sleep was derived by referencing the measurement obtained during sleep to that obtained during wakefulness. In a repeated measures model predicting the index of cerebral oxygenation, mean arterial pressure, rapid eye movement (REM) sleep, female sex, age, and oxygen saturation had a positive effect on cerebral oxygenation levels, whereas arousal index and non-REM (NREM) sleep had a negative effect. CONCLUSIONS Increasing mean arterial pressure, age, oxygen saturation, and REM sleep augment cerebral oxygenation, while sleep-disordered breathing, male sex, arousal index, and NREM sleep diminish it. The proposed model may explain the sources of variability in cognitive function of children with sleep-disordered breathing.

An Adverse Effect of Positive Airway Pressure on the Upper Airway Documented With Magnetic Resonance Imaging

IMPORTANCE Positive pressure air is used during basic life support to provide respirations and applied as continuous positive airway pressure to maintain a patent airway during sleep or anesthesia. These functions are more critical in children with obstructive sleep apnea, who often have smaller airway dimensions and increased airway collapsibility. OBSERVATIONS We report 2 cases of boys with Down syndrome and a history of obstructive sleep apnea in whom adverse narrowing of the retroglossal airway is caused by continuous positive airway pressure applied via face mask as documented with magnetic resonance imaging. CONCLUSIONS AND RELEVANCE Administration of continuous positive airway pressure by means of face mask to patients can result in adverse effects on the airway patency by pushing the tongue posteriorly. Awareness of this effect on patients with open mouths and large tongues, as present in Down syndrome, is important for sleep apnea treatment, anesthesia, and emergency respiratory support. Generalization of our observation is not possible at this time. Additional prospective studies of the effects of continuous positive airway pressure on airway patency in sedated and/or anesthetized children are required to confirm our anecdotal observations.

Determination of respiratory phase during acquisition of airway cine MR images.

Subjects were imaged on a 1.5-T Signa MRI system using the head-neck vascular coil. An axial fast gradient echo cine, at the base of the second cervical vertebra, was obtained. A total of 128 images were acquired with a rapid image acquisition (one per second) over several respiratory cycles. The analog signal from the MR scanner (RF unblank) was utilized to determine the duration of the cine MR sequence. The phase of respiration was determined by analyzing the nasal air flow connected via pressure tubing to a pressure transducer outside the MR scanner room. We were thus able to determine the phase of respiration during acquisition of individual airway cine MR images. There was a wide range of airway volume measurements over the respiratory cycle with the lowest volume at end expiration and the highest at peak inspiration.

Dynamic Volume Computed Tomography Imaging of the Upper Airway in Obstructive Sleep Apnea

STUDY OBJECTIVES To describe a dynamic three-dimensional (3D) computed tomography (CT) technique for the upper airway and compare the required radiation dose to that used for common clinical studies of a similar anatomical area, such as for subjects undergoing routine clinical facial CT. METHODS Dynamic upper-airway CT was performed on eight subjects with persistent obstructive sleep apnea, four of whom were undergoing magnetic resonance imaging and an additional four subjects who had a contraindication to magnetic resonance imaging. This Health Insurance Portability and Accountability Act-compliant study was approved by our institutional review board, and informed consent was obtained. The control subjects (n = 41) for comparison of radiation dose were obtained from a retrospective review of the clinical picture-archiving computer system to identify 10 age-matched patients per age-based control group undergoing facial CT. RESULTS Dynamic 3D CT can be performed with an effective radiation dose of less than 0.38 mSv, a dose that is less than or comparable to that used for clinical facial CT. The resulting data- set is a uniquely complete, dynamic 3D volume of the upper airway through a full respiratory cycle that can be processed for clinical and modeling analyses. CONCLUSIONS A dynamic 3D CT technique of the upper airway is described that can be performed with a clinically reasonable radiation dose and sets a benchmark for future use.

Assessing the relationship between movement and airflow in the upper airway using computational fluid dynamics with motion determined from magnetic resonance imaging

BACKGROUND Computational fluid dynamics simulations of respiratory airflow in the upper airway reveal clinically relevant information, including sites of local resistance, inhaled particle deposition, and the effect of pathological constrictions. Unlike previous simulations, which have been performed on rigid anatomical models from static medical imaging, this work utilises ciné imaging during respiration to create dynamic models and more closely represent airway physiology. METHODS Airway movement maps were obtained from non-rigid image registration of fast-cine MRI and applied to high-spatial-resolution airway surface models. Breathing flowrates were recorded simultaneously with imaging. These data formed the boundary conditions for large eddy simulation computations of the airflow from exterior mask to bronchi. Simulations with rigid geometries were performed to demonstrate the resulting airflow differences between airflow simulations in rigid and dynamic airways. FINDINGS In the analysed rapid breathing manoeuvre, incorporating airway movement significantly changed the findings of the CFD simulations. Peak resistance increased by 19.8% and occurred earlier in the breath. Overall pressure loss decreased by 19.2%, and the proportion of flow in the mouth increased by 13.0%. Airway wall motion was out-of-phase with the air pressure force, demonstrating the presence of neuromuscular motion. In total, the anatomy did 25.2% more work on the air than vice versa. INTERPRETATIONS Realistic movement of the airway is incorporated into CFD simulations of airflow in the upper airway for the first time. This motion is vital to producing clinically relevant computational models of respiratory airflow and will allow novel analysis of dynamic conditions, such as sleep apnoea.

Upper Airway Elasticity Estimation in Pediatric Down Syndrome Sleep Apnea Patients Using Collapsible Tube Theory

Elasticity of the soft tissues surrounding the upper airway lumen is one of the important factors contributing to upper airway disorders such as snoring and obstructive sleep apnea. The objective of this study is to calculate patient specific elasticity of the pharynx from magnetic resonance (MR) images using a ‘tube law’, i.e., the relationship between airway cross-sectional area and transmural pressure difference. MR imaging was performed under anesthesia in children with Down syndrome (DS) and obstructive sleep apnea (OSA). An airway segmentation algorithm was employed to evaluate changes in airway cross-sectional area dilated by continuous positive airway pressure (CPAP). A pressure-area relation was used to make localized estimates of airway wall stiffness for each patient. Optimized values of patient specific Young’s modulus for tissue in the velopharynx and oropharynx, were estimated from finite element simulations of airway collapse. Patient specific deformation of the airway wall under CPAP was found to exhibit either a non-linear ‘hardening’ or ‘softening’ behavior. The localized airway and tissue elasticity were found to increase with increasing severity of OSA. Elasticity based patient phenotyping can potentially assist clinicians in decision making on CPAP and airway or tissue elasticity can supplement well-known clinical measures of OSA severity.