title: The Combination of Supplemental Oxygen and a Hypnotic Markedly Improves Obstructive Sleep Apnea in Patients with a Mild to Moderate Upper Airway Collapsibility.
abstract: Obstructive sleep apnea (OSA) results from the interaction of several physiological traits; specifically a compromised upper airway anatomy and muscle function, and two key non-anatomical deficits: elevated loop gain and a low arousal threshold. Although continuous positive airway pressure (CPAP) is an efficacious treatment, it is often poorly tolerated. An alternative approach could involve administering therapies targeting the non-anatomic causes. However, therapies (oxygen or hypnotics) targeting these traits in isolation typically improve, but rarely resolve OSA. Therefore, our aim was to determine how the combination of oxygen and eszopiclone alters the phenotypic traits and OSA severity and to assess the baseline phenotypic characteristics of responders/nonresponders to combination therapy.
  
  
  
  In a single-blinded randomized crossover study, 20 OSA patients received combination therapy (3 mg eszopiclone and 40% oxygen) versus placebo/sham air, with 1 w between conditions. Under each condition, we assessed the effects on OSA severity (clinical polysomnography) and the phenotypic traits causing OSA using CPAP manipulations (research polysomnography).
  
  
  
  Combination therapy reduced the apnea-hypopnea index (51.9 ± 6.2 vs. 29.5 ± 5.3 events/h; P < 0.001), lowered both the ventilation associated with arousal (5.7 ± 0.3 vs. 5.2 ± 0.3 L/min; P = 0.05) and loop gain (3.3 ± 0.5 vs. 2.2 ± 0.3; P = 0.025). Responders to therapy (apnea-hypopnea index reduced by > 50% to below 15 events/h; n = 9/20) had less severe OSA (P = 0.001), a less collapsible upper airway (P = 0.01) and greater upper airway muscle effectiveness (P = 0.002).
  
  
  
  The combination of lowering loop gain and raising the arousal threshold is an effective therapy in patients whose anatomy is not severely compromised. Our work demonstrates that combining therapies that target multiple traits can resolve OSA in selected individuals.
  
  
  
  ClinicalTrials.gov, ID: NCT01633827.
authors.affiliation: Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women's Hospital & Harvard Medical School, Boston, MA.|Sleep and Circadian Medicine Laboratory, Department of Physiology Monash University, Melbourne, VIC, Australia.|School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, VIC, Australia.
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Edwards
authors.affiliation: Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women's Hospital & Harvard Medical School, Boston, MA.|Department of Allergy, Immunology and Respiratory Medicine and Central Clinical School, The Alfred and Monash University, Melbourne, VIC, Australia.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Sands
authors.affiliation: Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women's Hospital & Harvard Medical School, Boston, MA.|Division of Pulmonary and Critical Care Medicine, University of California San Diego, CA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Owens
authors.affiliation: Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women's Hospital & Harvard Medical School, Boston, MA.|Neuroscience Research Australia (NeuRA) and the University of New South Wales, Randwick, Sydney, NSW, Australia.
authors.forename: Danny J
authors.initials: DJ
authors.lastname: Eckert
authors.affiliation: Sleep and Circadian Medicine Laboratory, Department of Physiology Monash University, Melbourne, VIC, Australia.|School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, VIC, Australia.
authors.forename: Shane
authors.initials: S
authors.lastname: Landry
authors.affiliation: Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women's Hospital & Harvard Medical School, Boston, MA.
authors.forename: David P
authors.initials: DP
authors.lastname: White
authors.affiliation: Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women's Hospital & Harvard Medical School, Boston, MA.|Division of Pulmonary and Critical Care Medicine, University of California San Diego, CA.
authors.forename: Atul
authors.initials: A
authors.lastname: Malhotra
authors.affiliation: Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women's Hospital & Harvard Medical School, Boston, MA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wellman
mesh_terms: D000328:Adult; D000368:Aged; D003131:Combined Modality Therapy; D045422:Continuous Positive Airway Pressure; D018592:Cross-Over Studies; D000069582:Eszopiclone / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006993:Hypnotics and Sedatives / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010102:Oxygen Inhalation Therapy; D017286:Polysomnography; D012720:Severity of Illness Index; D016037:Single-Blind Method; D020181:Sleep Apnea, Obstructive / Q000175:diagnosis / Q000503:physiopathology / Q000628:therapy*; D016896:Treatment Outcome
chemical_list: D006993:Hypnotics and Sedatives; D000069582:Eszopiclone
keywords: arousal threshold; loop gain; phenotyping; sleep apnea