Bradley A Edwards1,2,3, Scott A Sands1,4, Robert L Owens1,5, Danny J Eckert1,6, Shane Landry2,3, David P White1, Atul Malhotra1,5, Andrew Wellman1. 1. Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women's Hospital & Harvard Medical School, Boston, MA. 2. Sleep and Circadian Medicine Laboratory, Department of Physiology Monash University, Melbourne, VIC, Australia. 3. School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, VIC, Australia. 4. Department of Allergy, Immunology and Respiratory Medicine and Central Clinical School, The Alfred and Monash University, Melbourne, VIC, Australia. 5. Division of Pulmonary and Critical Care Medicine, University of California San Diego, CA. 6. Neuroscience Research Australia (NeuRA) and the University of New South Wales, Randwick, Sydney, NSW, Australia.
Abstract
STUDY OBJECTIVES: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. METHODS: In a single-blinded randomized crossover study, 20 OSA patients receivedcombination 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). RESULTS: 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). CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT01633827.
RCT Entities:
STUDY OBJECTIVES: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT01633827.
Authors: Bradley A Edwards; Andrew Wellman; Scott A Sands; Robert L Owens; Danny J Eckert; David P White; Atul Malhotra Journal: Sleep Date: 2014-07-01 Impact factor: 5.849
Authors: Simon A Joosten; Bradley A Edwards; Andrew Wellman; Anthony Turton; Elizabeth M Skuza; Philip J Berger; Garun S Hamilton Journal: Sleep Date: 2015-09-01 Impact factor: 5.849
Authors: Bradley A Edwards; James G Connolly; Lisa M Campana; Scott A Sands; John A Trinder; David P White; Andrew Wellman; Atul Malhotra Journal: Sleep Date: 2013-02-01 Impact factor: 5.849
Authors: Danny J Eckert; David P White; Amy S Jordan; Atul Malhotra; Andrew Wellman Journal: Am J Respir Crit Care Med Date: 2013-10-15 Impact factor: 21.405
Authors: Marijke Dieltjens; Anneclaire V Vroegop; Annelies E Verbruggen; Kristien Wouters; Marc Willemen; Wilfried A De Backer; Johan A Verbraecken; Paul H Van de Heyning; Marc J Braem; Nico de Vries; Olivier M Vanderveken Journal: Sleep Breath Date: 2014-10-22 Impact factor: 2.816
Authors: Shane A Landry; Simon A Joosten; Scott A Sands; David P White; Atul Malhotra; Andrew Wellman; Garun S Hamilton; Bradley A Edwards Journal: Respirology Date: 2017-04-13 Impact factor: 6.424
Authors: Ludovico Messineo; Luigi Taranto-Montemurro; Ali Azarbarzin; Melania D Oliveira Marques; Nicole Calianese; David P White; Andrew Wellman; Scott A Sands Journal: J Physiol Date: 2018-07-06 Impact factor: 5.182
Authors: Scott A Sands; Bradley A Edwards; Philip I Terrill; James P Butler; Robert L Owens; Luigi Taranto-Montemurro; Ali Azarbarzin; Melania Marques; Lauren B Hess; Erik T Smales; Camila M de Melo; David P White; Atul Malhotra; Andrew Wellman Journal: Eur Respir J Date: 2018-09-27 Impact factor: 16.671
Authors: Luigi Taranto-Montemurro; Ludovico Messineo; Ali Azarbarzin; Daniel Vena; Lauren B Hess; Nicole A Calianese; David P White; Andrew Wellman; Scott A Sands Journal: Chest Date: 2020-01-30 Impact factor: 9.410
Authors: Bradley A Edwards; Leonardo Nava-Guerra; James S Kemp; John L Carroll; Michael C Khoo; Scott A Sands; Philip I Terrill; Shane A Landry; Raouf S Amin Journal: Sleep Date: 2018-11-01 Impact factor: 5.849
Authors: Pedro R Genta; Fabiola Schorr; Bradley A Edwards; Andrew Wellman; Geraldo Lorenzi-Filho Journal: J Clin Sleep Med Date: 2020-09-15 Impact factor: 4.062
Authors: Scott A Sands; Philip I Terrill; Bradley A Edwards; Luigi Taranto Montemurro; Ali Azarbarzin; Melania Marques; Camila M de Melo; Stephen H Loring; James P Butler; David P White; Andrew Wellman Journal: Sleep Date: 2018-01-01 Impact factor: 5.849