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RATIONALE Mandibular advancement device (MAD) treatment efficacy varies among obstructive sleep apnea (OSA) patients. OBJECTIVES The current study aims to explain underlying individual differences in efficacy using OSA endotypic traits calculated from baseline clinical polysomnography: collapsibility (airflow at normal ventilatory drive, Vpassive), loop gain (drive response to reduced airflow), arousal threshold (drive preceding arousal), compensation (increase in airflow as drive increases) and the ventilatory response to arousal (VRA, increase in drive explained by arousal). Based on previous research, we hypothesized that responders to MAD treatment have a lower loop gain and milder collapsibility. METHODS Thirty-six patients (apnea-hypopnea index [AHI] 23.5[IQR:19.7-29.8]/h) underwent baseline and 3-month follow-up full polysomnography, with MAD fixed at 75% of maximal protrusion. Traits were estimated using baseline polysomnography according to Sands et al. (AJRCCM 2018). Response was defined as AHI reduction ≥ 50%. RESULTS MAD treatment significantly reduced AHI (49.7%[23.9-63.6] of baseline, median[IQR]). Responders exhibited lower loop gain (mean[95%CI], 0.53[0.48-0.58] vs. 0.65[0.57-0.73]; p=0.020) at baseline compared to non-responders, a difference that persisted after adjustment for baseline AHI and BMI. Elevated loop gain remained associated with non-response after adjustment for collapsibility (OR: 3.03 [1.16 - 7.88] per 1 SD increase in loop gain [SD=0.15]; p=0.023). CONCLUSIONS MAD non-responders exhibit greater ventilatory instability, expressed as higher loop gain. Assessment of the baseline degree of ventilatory instability using this approach may improve upfront MAD treatment patient selection. CLINICAL TRIAL REGISTRATION The current study is a secondary analysis of the parent clinical trial NCT01532050 (Clinicaltrial.gov).