Restoration of Autonomic Dysfunction in Children with Obstructive Sleep Apnea after Adenotonsillectomy

The authors have indicated no financial conflicts of interest. Obstructive sleep apnea syndrome (OSAS) is associated with significant adverse neurobehavioural, cardiovascular, and metabolic outcomes. In recent years, studies of autonomic nervous system (ANS) function have demonstrated autonomic dysregulation in both children1–3 and adults with OSAS.4–7 Studies on ANS function and OSAS are important because they can potentially provide mechanistic pathways to explain some of the important morbidities associated with OSAS, such as hypertension, cardiovascular disease and insulin resistance,8,9 and provide a better understanding of how treatment modalities can mediate outcomes of OSAS via the ANS. Several methods have been used to study ANS responses in children with OSAS. Pulse arterial tonometry is a noninvasive technique for detecting sympathetic vasomotor tone in peripheral vessels using a finger plethysmograph. Increased sympathetic activity resulting in vasoconstriction corresponds to attenuation of the tonometry signal on the plethysmograph.2 Heart rate variability estimates sympathetic to parasympathetic balance by calculating the ratio of low-frequency to high-frequency band power extracted from electrocardiographic recordings.10 In general, the above methods have demonstrated sympathetic predominance in children with OSAS.1,2,11 This sympathetic predominance may be mediated by the stimulation of peripheral arterial chemoreceptors by hypoxemia that results in increased sympathetic efferent traffic during hypoxemic episodes. In addition, respiratory events during sleep such as apnea/hypopnea may interrupt physiologic sympathetic inhibition during inhalation by vagal circuits.12,13 Finally, arousals resulting from OSAS may also induce increased sympathetic output.14 Baroreflex sensitivity (BRS), in contrast, evaluates the baroreflex function of the ANS. Baroreceptors in the carotid sinus and aortic arch relay changes in arterial wall stretch to control centers in the brainstem from where autonomic outflow is modulated, producing changes in cardiovascular variables—heart rate (HR), heart contractility and vasoconstriction. The change in HR in response to changes in arterial blood pressure (ABP) provides a measure of BRS. It can be assessed in the time domain for ascending and descending sequences by the slope of regression of HR interval versus ABP and in the frequency domain by calculating the α index from spectral analysis of variability in HR interval and ABP. The α index is the square root of the integration of the ABP and HR interval power spectra where the coherence (a measure of correlation) between the HR and ABP changes is greater than 0.5. The α index is estimated at the low frequency band (0.04 to 0.15 Hz) and also the high-frequency band (0.15 to 0.5 Hz), which corresponds to the respiratory frequency. Changes in BRS are associated with an increased risk of developing hypertension and cardiovascular disease.15,16 In this issue of SLEEP, Crisalli and colleagues report on the extent of restoration of BRS changes in children with OSAS after adenotonsillectomy.17 Their study follows a cross-sectional study by the authors3 demonstrating altered BRS in young children with severe OSAS (obstructive apnea-hypopnea index > 5/hour) in the form of absence of the normal monotonic overnight increase in BRS in the ascending and descending sequences and high-frequency α index. Severe OSAS was also associated with lower temporal and spectral BRS indices compared to children with mild OSAS and matched controls who were healthy non-snoring children. Also, children with mild OSA had lower high-frequency α than control children. In the current study Crisalli and colleagues used an interventional model to test if ANS changes associated with OSAS are reversible by tracking BRS in these children with OSAS six months after tonsillectomy along with their matched controls. This is a convenient model since adenotonsillectomy usually resolves or significantly mitigates OSAS in children, as was the case in this cohort. The authors report increases in all BRS parameters in children with severe OSAS following adenotonsillectomy except the low-frequency α index, in addition to a restoration of the normal pattern of rising baroreflex gain during the night. BRS remained mostly unchanged in controls for the duration of the study. Of note, the magnitude of improvement in baroreflex gain correlated with the change in the apnea-hypopnea index and change in arousal index, but not the oxygen desaturation index. Thus BRS impairment correlated with severity of OSAS, but the data did not have sufficient resolution to discriminate between the effects of oxygen desaturation and arousals. Significantly, the temporal indices of BRS and the high-frequency (respiratory frequency associated) α index in children with severe OSAS remained lower than that of control subjects even after 6 months; this may be related to residual mild OSAS or a slow restoration of autonomic function. The low-frequency α index was not different in the children with severe OSAS from controls at six months, but this may be due to power issues from loss of some subjects to follow-up. The authors speculate that baroreflex suppression with OSAS leads to reduction in the direct inhibition of sympathetic discharge by the baroreceptor stimulation, in turn leading to sympathetic predominance, particularly at the respiratory frequency from disruption of the coordination of the respiratory drive, baroreflex sensitivity and sympathetic discharge. Overall, this study demonstrates that OSAS in children alters BRS and that BRS impairments are reversible to a large extent, but may persist for prolonged periods after resolution of OSAS. These findings are in concordance with other studies that note improvement in ANS function using HRV measure in children with OSAS after adenotonsillectomy,11,18 but the current study has the advantages of a prospective design, larger numbers and a comparison group of healthy children who were followed for an equivalent interval. One of the important issues in sleep medicine is establishing the thresholds of sleep indices that are associated with pathophysiologic changes. While normative data have been established for polysomnography indices in children,19,20 the diverse morbidities of OSAS may be associated with disparate levels of various polysomnography indices. This study suggests that autonomic dysfunction is likely to be present with an obstructive apnea hypopnea index ≥ 5/hour. Overall, this study provides compelling evidence of autonomic dysfunction caused by OSAS in children that is at least partially reversible with appropriate treatment. However, several additional questions are raised by these findings. How strongly is the biological effect of altered ANS function associated with clinical outcomes such as hypertension? Do children with significant persistent OSAS have a greater likelihood of complications in adult life because of prolonged exposure to OSAS? How effective are available treatments in preventing complications related to autonomic dysfunction? The answers to these interrelated questions will require carefully planned longitudinal studies and treatment trials powered by large numbers of subjects.