Heart rate variability as a potential biomarker of pediatric obstructive sleep apnea resolution

Abstract

Study objectives: Pediatric obstructive sleep apnea (OSA) affects cardiac autonomic regulation, altering heart rate variability (HRV). Although changes in classical HRV parameters occur after OSA treatment, they have not been evaluated as reporters of OSA resolution. Specific frequency bands (named BW1, BW2, and BWRes) have been recently identified in OSA. We hypothesized that changes with treatment in these spectral bands can reliably identify changes in OSA severity and reflect OSA resolution.

Methods: Four hundred and four OSA children (5-9.9 years) from the prospective Childhood Adenotonsillectomy Trial were included; 206 underwent early adenotonsillectomy (eAT), while 198 underwent watchful waiting with supportive care (WWSC). HRV changes from baseline to follow-up were computed for classical and OSA-related frequency bands. Causal mediation analysis was conducted to evaluate how treatment influences HRV through mediators such as OSA resolution and changes in disease severity. Disease resolution was initially assessed by considering only obstructive events, and was followed by adding central apneas to the analyses.

Results: Treatment, regardless of eAT or WWSC, affects HRV activity, mainly in the specific frequency band BW2 (0.028-0.074 Hz). Furthermore, only changes in BW2 were specifically attributable to all OSA resolution mediators. HRV activity in BW2 also showed statistically significant differences between resolved and non-resolved OSA.

Conclusions: OSA treatment affects HRV activity in terms of change in severity and disease resolution, especially in OSA-related BW2 frequency band. This band allowed to differentiate HRV activity between children with and without resolution, so we propose BW2 as potential biomarker of pediatric OSA resolution.

Clinical trial registration: Childhood Adenotonsillectomy Trial, NCT00560859, https://sleepdata.org/datasets/chat.

Keywords: biomarker; causal mediation analysis; frequency domain analysis; heart rate variability; obstructive sleep apnea; resolution; treatment.

© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1.

Framework of the causal mediation analysis performed. (A) Typical estimation of the causal total effect measures the change in the outcome (ΔRPband) due to the intervention (regardless of eAT or WWSC). (B) Causal mediation analysis identifies the causal pathways (mediators) through which the intervention influences the change in the outcome. The average causal mediation effect (ACME) measures the change in the outcome due to the change in the mediator because of the treatment. The average direct effect (ADE) measures the change in the outcome unlinked to the mediator. In this study, these effects are averaged over both trial arms assuming no interaction between them. Both ACME and ADE jointly conform the total effect. (C) Representation for an outcome and a mediator of the effects estimated and the 95th percentile confidence intervals, where all of them are in the same direction. In this example, the estimations do not include the 0 value (no effect at all), so they are considered statistically significantly different from 0. (D) Representation for an outcome and a mediator of the effects estimated and the 95% of confidence intervals, with ACME showing an opposite direction to the ADE and Total Effect. In this case, the ACME does not include the 0 value, but ADE and total effect does, so only ACME is considered statistically significantly different from 0. eAT, early adenotonsillectomy; WWSC, watchful waiting with supportive care; RP, relative power; ΔRPband = RPband_follow-up − RPband_baseline; ΔAHI, change in the apnea-hypopnea index; ΔOAHI, change in the obstructive apnea-hypopnea index; ΔODI, change in the oxyhemoglobin desaturation index 3%; ΔMinsat, change in the minimum saturation level; ΔTAI, change in the total arousals index; OSA resol, obstructive sleep apnea resolution; OSAO+C resol, obstructive and central sleep apnea resolution.

Figure 2.

Differences at follow-up between children with and without resolution considering OSAO+C and OSA resolution approaches. Only parameters that showed statistically significant ACME with resolution mediators were evaluated. (A) Differences in RPBW2 considering OSAO+C resolution. (B) Differences in LF/HF ratio considering OSAO+C resolution. (C) Differences in RPBW2 considering OSA resolution.