A Model-Based Approach to Phenotyping Sleep-Related Breathing Disorders in Pediatric Obesity

Abstract

The prevalence of overweight and obesity in children has increased dramatically over the past two decades. A significant fraction of these obese children also have sleep-related breathing disorders. The ongoing study described in this talk combines overnight physiological measurements with a minimal closed-loop computational model of ventilatory control to investigate why this subject population exhibits large variations in sleep and clinical characteristics. The knowledge derived from this study may lead to a better understanding of the mechanisms through which the different phenotypes of sleep-related breathing disorders (SRBD) occur in obese children, and could be useful in providing better guidelines for customizing therapeutic strategies to individual patients. Obstructive sleep apnea (OSA) has been reported to occur at prevalence rates on the order of 50% in morbidly obese children, compared to only a few percent of the general pediatric population. This marked difference in prevalence rates becomes even larger if one were to include other forms of sleep-related breathing disorders (SRBD), such as hypoventilation and hypercapnia or hypoxemia without frank obstructions. Although 45% of obese children have adenotonsillar hypertrophy, adenotonsillectomy eliminates OSA in less than half of the obese subjects who elect to undergo this form of treatment. These data along with other recent findings suggest that, although upper airway anatomy is a key mediator in OSA, other factors that affect dynamic changes in upper airway patency, such as chemoreflex control and state dependence, also play important roles. Moreover, the pool of subjects with obesity-related SRDB display a large variation of polysomnographic and clinical characteristics. These may be classified broadly into the following 4 phenotypic categories: (a) primary snorers with no abnormalities of gas exchange, respiratory pattern or sleep disruption; (b) obstructive hypoventilation with hypercapnia or hypoxemia with near-normal respiratory or sleep patterns; (c) high arousal frequency without prominent gas exchange abnormality, obstructive apneas or hypopneas (includes upper airway resistance syndrome); (d) traditional OSA with recurrent episodes of obstructive hypopnea and apnea. We hypothesize that this diversity in phenotypic behavior results from the existence of different underlying physiological mechanisms, and that a quantitative dynamic model would allow us to better delineate the mechanistic differences.