Abstract Rationale Obstructive sleep apnea (OSA) is characterized by recurrent upper airway (UA) obstruction during sleep. Mechanical effects of increasing inspiratory effort on a collapsible UA cause airflow to plateau (inspiratory flow limitation, IFL) with further variable reductions in airflow as effort increases (negative effort dependence, NED). Airflow obstruction can elicit neuromuscular reflex responses that mitigate IFL and NED. Phrenic nerve stimulation (PNS) has traditionally been viewed as detrimental to airway stability, as it may worsen IFL and promote NED with additional diaphragmatic contraction. Alternatively, PNS can engage afferent pathways that enhance UA patency. We hypothesized that neural responses to PNS can overcome its mechanical effects by reducing airflow obstruction relative to unstimulated baseline breaths. Methods 19 patients (age 58±11yrs; 84% male; BMI 30.6±3.0 kg/m²; mean AHI 32±18events/hr) underwent drug induced sleep endoscopy (DISE). A pneumotachometer captured airflow while subtherapeutic CPAP was applied to produce flow-limited breathing for PNS testing. PNS was delivered via a transcutaneous neck electrode timed to the start of inspiration over 6-8 breaths bracketed by unstimulated control breaths. Changes in inspiratory flow (VI), tidal volume (TV), and minute ventilation (MV) were quantified between stimulation and control breaths. To assess whether PNS timing influenced response, isolated on/off stimulations were timed to three phases of respiration: end-expiration to inspiration (E→I), inspiration only (I→I), and inspiration to expiration (I→E). Changes in ventilatory metrics were compared with linear mixed-effects models. Results Sequential stimulation elicited sustained increases in VI (+171%), TV (+173%), and MV (+169%) (all p 0.01). (Figure) PNS also improved NED in patients when NED was observed. Our timing experiment revealed that E→I stimulation increased VI by 64% and TV by 71% (p 0.01), while I→I produced minor increases and I→E had no effect. A latency to airflow responses of ∼1.4 s was also observed between PNS onset and peak airflow response. Conclusions Our findings indicate that PNS counteracts, rather than promotes, dynamic airway collapse by reducing IFL and attenuating NED. PNS timing elicits the greatest improvements in VI, TV, and MV at end-expiration relative to other points in the respiratory cycle. Observed timing and latency of effects suggest activation of phrenic or airway afferent pathways that recruit UA dilator reflexes to maintain patency. These findings challenge the view that PNS worsens UA collapse. Instead, they suggest that phase-locked PNS activates neural responses that stabilize the UA and that these responses have potential therapeutic implications for OSA. This abstract is funded by: Research was supported by the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) under Award Numbers UL1TR002378 and KL2TR002381. Research was also supported by Lunair Medical, Inc.
Yu et al. (Fri,) studied this question.