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Original research
Neural ventilatory drive decline as a predominant mechanism of obstructive sleep apnoea events
  1. Laura K Gell,
  2. Daniel Vena,
  3. Raichel M Alex,
  4. Ali Azarbarzin,
  5. Nicole Calianese,
  6. Lauren B Hess,
  7. Luigi Taranto-Montemurro,
  8. David P White,
  9. Andrew Wellman,
  10. Scott A Sands
  1. Division of Sleep and Circadian Disorders, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to Dr Laura K Gell, Brigham and Women's Hospital, Boston, Massachusetts, USA; lgell{at}bwh.harvard.edu

Abstract

Background In the classic model of obstructive sleep apnoea (OSA), respiratory events occur with sleep-related dilator muscle hypotonia, precipitating increased neural ventilatory ‘drive’. By contrast, a drive-dependent model has been proposed, whereby falling drive promotes dilator muscle hypotonia to precipitate respiratory events. Here we determine the extent to which the classic versus drive-dependent models of OSA are best supported by direct physiological measurements.

Methods In 50 OSA patients (5–91 events/hour), we recorded ventilation (‘flow’, oronasal mask and pneumotach) and ventilatory drive (calibrated intraoesophageal diaphragm electromyography, EMG) overnight. Flow and drive during events were ensemble averaged; patients were classified as drive dependent if flow fell/rose simultaneously with drive. Overnight effects of lower drive on flow, genioglossus muscle activity (EMGgg) and event risk were quantified (mixed models).

Results On average, ventilatory drive fell (rather than rose) during events (−20 (−42 to 3)%baseline, median (IQR)) and was strongly correlated with flow (R=0.78 (0.24 to 0.94)). Most patients (30/50, 60%) were classified as exhibiting drive-dependent event pathophysiology. Lower drive during sleep was associated with lower flow (−17 (−20 to –14)%/drive) and EMGgg (−3.5 (−3.8 to –3.3)%max/drive) and greater event risk (OR: 2.2 (1.8 to 2.5) per drive reduction of 100%eupnoea); associations were concentrated in patients with drive-dependent OSA (ie, flow: −37 (−40 to –34)%/drive, OR: 6.8 (5.3 to 8.7)). Oesophageal pressure—without tidal volume correction—falsely suggested rising drive during events (classic model).

Conclusions In contrast to the prevailing view, patients with OSA predominantly exhibit drive-dependent event pathophysiology, whereby flow is lowest at nadir drive, and lower drive raises event risk. Preventing ventilatory drive decline is therefore considered a target for OSA intervention.

  • sleep apnoea
  • respiratory muscles

Data availability statement

Data are available on reasonable request. A summary table of individual participant data can be made available on request for the purposes of data review. Deidentified (pseudonymised) raw signals data may be made available to qualified scientists pending a data use agreement with the Brigham and Women’s Hospital.

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Data availability statement

Data are available on reasonable request. A summary table of individual participant data can be made available on request for the purposes of data review. Deidentified (pseudonymised) raw signals data may be made available to qualified scientists pending a data use agreement with the Brigham and Women’s Hospital.

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Footnotes

  • Contributors Conception: LG, AW and SS. Study design: LG, AW and SS. Data collection and analysis: LG, DV, RMA, NC, LBH, LT-M and SS. All authors interpreted data, edited the manuscript for important intellectual content and approved the final draft. LG acts as the guarantor of the manuscript and accepts full responsibility for its content.

  • Funding This work was supported financially by the American Heart Association (15SDG25890059) and the National Institute of Health National Heart, Lung and Blood Institute (R01HL146697 and R01HL102321). The authors are grateful to Maquet Getinge Group for the loan of the Servo-i ventilator to measure intraoesophageal diaphragm EMG. AA was supported by the National Institutes of Health (R01HL153874), American Heart Association (19CDA34660137) and the American Academy of Sleep Medicine Foundation (188-SR-17).

  • Competing interests SS received grant support from Apnimed, Prosomnus and Dynaflex and has served as a consultant for Apnimed, Nox Medical and Merck. DPW is a distinguished scientist with Apnimed and a consultant for RBNC Therateutics, Philips Respironics, Cryosa and Cerebra Health. AA serves as consultant for Somnifix and Apnimed and receives grant support from Somnifix. AW works as a consultant for Apnimed, Nox, Inspire and Somnifix and has received grants from Sanofi and Somnifix. LT-M works as medical director at Apnimed. AW and LT-M have a financial interest in Apnimed Inc, a company developing pharmacological therapies for sleep apnoea; their interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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