Obstructive sleep apnea: personalizing CPAP alternative therapies to individual physiology

References

• Benjafield AV, Ayas NT, Eastwood PR, et al. Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis. Lancet Respir Med. 2019;7(8):687–698.
   PubMed Web of Science ®Google Scholar
• Patil SP, Ayappa IA, Caples SM, et al. Treatment of adult obstructive sleep apnea with positive airway pressure: an American academy of sleep medicine clinical practice guideline. J Clin Sleep Med. 2019;15(2):335–343.
   PubMed Web of Science ®Google Scholar
• Jacobowitz O, Afifi L, Penzel T, et al. Endorsement of: “treatment of adult obstructive sleep apnea with positive airway pressure: an American academy of sleep medicine clinical practice guideline” by world sleep society. Sleep Med. 2022;89:19–22.
   PubMed Web of Science ®Google Scholar
• Owens RL, Wilson KC, Gurubhagavatula I, et al. Philips respironics recall of positive airway pressure and noninvasive ventilation devices: a brief statement to inform response efforts and identify key steps forward. Am J Respir Crit Care Med. 2021;204(8):887–890.
   PubMed Web of Science ®Google Scholar
• Weaver TE, Kribbs NB, Pack AI, et al. Night-to-night variability in CPAP use over the first three months of treatment. Sleep. 1997;20(4):278–283.
   PubMed Web of Science ®Google Scholar
• Sullivan CE, Issa FG, Berthon-Jones M, et al. Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares. Lancet. 1981;1(8225):862–865.
   PubMed Web of Science ®Google Scholar
• Nokes B, Lin E, McGuire WC, et al. Recommended reading from University of California, San Diego Fellows. Am J Respir Crit Care Med. 2021;204(8):986–988.
   PubMedGoogle Scholar
• Edwards BA, Redline S, Sands SA, et al. More than the sum of the respiratory events: personalized medicine approaches for obstructive sleep apnea. Am J Respir Crit Care Med. 2019;200(6):691–703.
   PubMed Web of Science ®Google Scholar
• Strohl KP, Butler JP, Malhotra A. Mechanical properties of the upper airway. Compr Physiol. 2012;2(3):1853–1872.
   PubMed Web of Science ®Google Scholar
• Malhotra A, Fogel RB, Edwards JK, et al. Local mechanisms drive genioglossus activation in obstructive sleep apnea. Am J Respir Crit Care Med. 2000;161(5):1746–1749.
   PubMed Web of Science ®Google Scholar
• Genta PR, Edwards BA, Sands SA, et al. Tube law of the pharyngeal airway in sleeping patients with obstructive sleep apnea. Sleep. 2016;39(2):337–343.
   PubMed Web of Science ®Google Scholar
• Malhotra A, Pillar G, Fogel RB, et al. Pharyngeal pressure and flow effects on genioglossus activation in normal subjects. Am J Respir Crit Care Med. 2002;165(1):71–77.
   PubMed Web of Science ®Google Scholar
• Malhotra A, Trinder J, Fogel R, et al. Postural effects on pharyngeal protective reflex mechanisms. Sleep. 2004;27(6):1105–1112.
   PubMed Web of Science ®Google Scholar
• Malhotra A, Huang Y, Fogel R, et al. Aging influences on pharyngeal anatomy and physiology: the predisposition to pharyngeal collapse. Am J Med. 2006;119(1):72 e79–14.
   Google Scholar
• Malhotra A, Mesarwi O, Pepin JL, et al. Endotypes and phenotypes in obstructive sleep apnea. Curr Opin Pulm Med. 2020;26(6):609–614.
   PubMed Web of Science ®Google Scholar
• Mann DL, Terrill PI, Azarbarzin A, et al. Quantifying the magnitude of pharyngeal obstruction during sleep using airflow shape. Eur Respir J. 2019;54(1):1802262.
   PubMed Web of Science ®Google Scholar
• Sands SA, Edwards BA, Terrill PI, et al. Phenotyping pharyngeal pathophysiology using polysomnography in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 2018;197(9):1187–1197.
   PubMed Web of Science ®Google Scholar
• Alex RM, Sofer T, Azarbarzin A, et al. Within-night repeatability and long-term consistency of sleep apnea endotypes: the multi-ethnic study of atherosclerosis and osteoporotic fractures in men study. Sleep. 2022. DOI:10.1093/sleep/zsac129.
   PubMed Web of Science ®Google Scholar
• Isono S, Feroah TR, Hajduk EA, et al. Interaction of cross-al area, driving pressure, and airflow of passive velopharynx. J Appl Physiol (1985). 1997;83(3):851–859.
   PubMed Web of Science ®Google Scholar
• Lambeth C, Kolevski B, Amis T, et al. Feedback modulation of surrounding pressure determines the onset of negative effort dependence in a collapsible tube bench model of the pharyngeal airway. J Appl Physiol (1985). 2017;123(5):1118–1125.
   PubMed Web of Science ®Google Scholar
• Eckert DJ, White DP, Jordan AS, et al. Defining phenotypic causes of obstructive sleep apnea. Identification of novel therapeutic targets. Am J Respir Crit Care Med. 2013;188(8):996–1004.
   PubMed Web of Science ®Google Scholar
• Schwartz AR, Smith PL. CrossTalk proposal: the human upper airway does behave like a Starling resistor during sleep. J Physiol. 2013;591(9):2229–2232.
   PubMed Web of Science ®Google Scholar
• Smith PL, Wise RA, Gold AR, et al. Upper airway pressure-flow relationships in obstructive sleep apnea. J Appl Physiol (1985). 1988;64(2):789–795.
   PubMed Web of Science ®Google Scholar
• Younes M. Role of respiratory control mechanisms in the pathogenesis of obstructive sleep disorders. J Appl Physiol (1985). 2008;105(5):1389–1405.
   PubMed Web of Science ®Google Scholar
• Owens RL, Edwards BA, Sands SA, et al. The classical Starling resistor model often does not predict inspiratory airflow patterns in the human upper airway. J Appl Physiol (1985). 2014;116(8):1105–1112.
   PubMed Web of Science ®Google Scholar
• Suratt PM, Wilhoit SC, Cooper K. Induction of airway collapse with subatmospheric pressure in awake patients with sleep apnea. J Appl Physiol Respir Environ Exerc Physiol. 1984;57(1):140–146.
   PubMed Web of Science ®Google Scholar
• Issa FG, Sullivan CE. Upper airway closing pressures in obstructive sleep apnea. J Appl Physiol Respir Environ Exerc Physiol. 1984;57(2):520–527.
   PubMed Web of Science ®Google Scholar
• Owens RL, Edwards BA, Sands SA, et al. Upper airway collapsibility and patterns of flow limitation at constant end-expiratory lung volume. J Appl Physiol (1985). 2012;113(5):691–699.
   PubMed Web of Science ®Google Scholar
• Wellman A, Edwards BA, Sands SA, et al. A simplified method for determining phenotypic traits in patients with obstructive sleep apnea. J Appl Physiol (1985). 2013;114(7):911–922.
   PubMed Web of Science ®Google Scholar
• Terrill PI, Edwards BA, Nemati S, et al. Quantifying the ventilatory control contribution to sleep apnoea using polysomnography. Eur Respir J. 2015;45(2):408–418.
   PubMed Web of Science ®Google Scholar
• Gell LK, Vena D, Alex RM, et al. Neural ventilatory drive decline as a predominant mechanism of obstructive sleep apnoea events. Thorax. 2022;77(7):707–716.
   PubMed Web of Science ®Google Scholar
• Messineo L, Eckert DJ, Taranto-Montemurro L, et al. Ventilatory drive withdrawal rather than reduced genioglossus compensation as a mechanism of obstructive sleep apnea in REM sleep. Am J Respir Crit Care Med. 2022;205(2):219–232.
   PubMed Web of Science ®Google Scholar
• Turnbull CD, Wang SH, Manuel AR, et al. Relationships between MRI fat distributions and sleep apnea and obesity hypoventilation syndrome in very obese patients. Sleep Breath. 2018;22(3):673–681.
   PubMed Web of Science ®Google Scholar
• Arnardottir ES, Maislin G, Jackson N, et al. The role of obesity, different fat compartments and sleep apnea severity in circulating leptin levels: the icelandic sleep apnea cohort study. Int J Obes (Lond). 2013;37(6):835–842.
   PubMed Web of Science ®Google Scholar
• Jordan AS, White DP, Owens RL, et al. The effect of increased genioglossus activity and end-expiratory lung volume on pharyngeal collapse. J Appl Physiol (1985). 2010;109(2):469–475.
   PubMed Web of Science ®Google Scholar
• Wang SH, Keenan BT, Wiemken A, et al. Effect of weight loss on upper airway anatomy and the apnea-hypopnea index. the importance of tongue fat. Am J Respir Crit Care Med. 2020;201(6):718–727.
   PubMed Web of Science ®Google Scholar
• Cai Y, Goldberg AN, Chang JL. The nose and nasal breathing in sleep apnea. Otolaryngol Clin North Am. 2020;53(3):385–395.
   PubMed Web of Science ®Google Scholar
• Lofaso F, Coste A, d’Ortho MP, et al. Nasal obstruction as a risk factor for sleep apnoea syndrome. Eur Respir J. 2000;16(4):639–643.
   PubMed Web of Science ®Google Scholar
• Lee SH, Choi JH, Shin C, et al. How does open-mouth breathing influence upper airway anatomy? Laryngoscope. 2007;117(6):1102–1106.
   PubMed Web of Science ®Google Scholar
• Sss N, Tam WWS, Lee RWW, et al. Effect of weight loss and continuous positive airway pressure on obstructive sleep apnea and metabolic profile stratified by craniofacial phenotype: a randomized clinical trial. Am J Respir Crit Care Med. 2022;205(6):711–720.
   PubMed Web of Science ®Google Scholar
• Kairaitis K, Amatoury J, Jordan A. Muscling up pharyngeal airflow. Chest. 2021;159(3):912–914.
   PubMed Web of Science ®Google Scholar
• Tsai M, Khayat R. Sleep apnea in heart failure. Curr Treat Options Cardiovasc Med. 2018;20(4):33.
   PubMedGoogle Scholar
• Khayat RN, Javaheri S, Porter K, et al. In-hospital management of sleep apnea during heart failure hospitalization: a randomized controlled trial. J Card Fail. 2020;26(8):705–712.
   PubMed Web of Science ®Google Scholar
• Stanchina ML, Malhotra A, Fogel RB, et al. Genioglossus muscle responsiveness to chemical and mechanical stimuli during non-rapid eye movement sleep. Am J Respir Crit Care Med. 2002;165(7):945–949.
   PubMed Web of Science ®Google Scholar
• Berry RB, White DP, Roper J, et al. Awake negative pressure reflex response of the genioglossus in OSA patients and normal subjects. J Appl Physiol (1985). 2003;94(5):1875–1882.
   PubMed Web of Science ®Google Scholar
• Stanchina ML, Malhotra A, Fogel RB, et al. The influence of lung volume on pharyngeal mechanics, collapsibility, and genioglossus muscle activation during sleep. Sleep. 2003;26(7):851–856.
   PubMed Web of Science ®Google Scholar
• Gastaut H, Duron B, Tassinari CA, et al. Mechanism of the respiratory pauses accompanying slumber in the Pickwickian syndrome. Act Nerv Super (Praha). 1969;11(3):2095.
   PubMedGoogle Scholar
• Remmers JE, deGroot WJ, Sauerland EK, et al. Pathogenesis of upper airway occlusion during sleep. J Appl Physiol Respir Environ Exerc Physiol. 1978;44(6):931–938.
   PubMed Web of Science ®Google Scholar
• Sands SA, Eckert DJ, Jordan AS, et al. Enhanced upper-airway muscle responsiveness is a distinct feature of overweight/obese individuals without sleep apnea. Am J Respir Crit Care Med. 2014;190(8):930–937.
   PubMed Web of Science ®Google Scholar
• Taranto-Montemurro L, Messineo L, Azarbarzin A, et al., Effects of the combination of atomoxetine and oxybutynin on OSA endotypic traits. Chest. 2020;157(6):1626–1636.
   PubMed Web of Science ®Google Scholar
• Maghsoudipour M, Nokes B, Bosompra NO, et al., A pilot randomized controlled trial of effect of genioglossus muscle strengthening on obstructive sleep apnea outcomes. J Clin Med. 2021;10(19):4554.
   PubMed Web of Science ®Google Scholar
• Dempsey JA. Central sleep apnea: misunderstood and mistreated! F1000Res. 2019;8:981.
   Google Scholar
• Dempsey JA, Smith CA. Update on chemoreception: influence on cardiorespiratory regulation and pathophysiology. Clin Chest Med. 2019;40(2):269–283.
   PubMed Web of Science ®Google Scholar
• Smith JC, Ellenberger HH, Ballanyi K, et al. Pre-Botzinger complex: a brainstem region that may generate respiratory rhythm in mammals. Science. 1991;254(5032):726–729.
   PubMed Web of Science ®Google Scholar
• Dempsey JA, Powell FL, Bisgard GE, et al. Role of chemoreception in cardiorespiratory acclimatization to, and deacclimatization from, hypoxia. J Appl Physiol (1985). 2014;116(7):858–866.
   PubMed Web of Science ®Google Scholar
• Zera T, Moraes DJA, da Silva MP, et al. The logic of carotid body connectivity to the brain. Physiology (Bethesda). 2019;34(4):264–282.
   PubMed Web of Science ®Google Scholar
• Barbara Morgan JD. Chemoreception: pathways, plasticity, and pathophysiology. Control of Breathing During Sleep: From Bench to Bedside 1st ed. Boca Raton, FL: Taylor Francis. 2022. ISBN: 9780367430115 (In press)
   Google Scholar
• Edwards BA, Sands SA, Skuza EM, et al. Increased peripheral chemosensitivity via dopaminergic manipulation promotes respiratory instability in lambs. Respir Physiol Neurobiol. 2008;164(3):419–428.
   PubMed Web of Science ®Google Scholar
• Giannoni A, Emdin M, Passino C. Cheyne-stokes respiration, chemoreflex, and ticagrelor-related dyspnea. N Engl J Med. 2016;375(10):1004–1006.
   PubMed Web of Science ®Google Scholar
• Bochorishvili G, Stornetta RL, Coates MB, et al. Pre-Botzinger complex receives glutamatergic innervation from galaninergic and other retrotrapezoid nucleus neurons. J Comp Neurol. 2012;520(5):1047–1061.
   PubMed Web of Science ®Google Scholar
• Guyenet PG, Mulkey DK, Stornetta RL, et al. Regulation of ventral surface chemoreceptors by the central respiratory pattern generator. J Neurosci. 2005;25(39):8938–8947.
   PubMed Web of Science ®Google Scholar
• Burke PG, Kanbar R, Basting TM, et al. State-dependent control of breathing by the retrotrapezoid nucleus. J Physiol. 2015;593(13):2909–2926.
   PubMed Web of Science ®Google Scholar
• Li P, Janczewski WA, Yackle K, et al. The peptidergic control circuit for sighing. Nature. 2016;530(7590):293–297.
   PubMed Web of Science ®Google Scholar
• Guyenet PG, Stornetta RL, Bayliss DA. Central respiratory chemoreception. J Comp Neurol. 2010;518(19):3883–3906.
   PubMed Web of Science ®Google Scholar
• Guyenet PG, Stornetta RL, Bayliss DA. Retrotrapezoid nucleus and central chemoreception. J Physiol. 2008;586(8):2043–2048.
   PubMed Web of Science ®Google Scholar
• Smith CA, Forster HV, Blain GM, et al. An interdependent model of central/peripheral chemoreception: evidence and implications for ventilatory control. Respir Physiol Neurobiol. 2010;173(3):288–297.
   PubMed Web of Science ®Google Scholar
• Smith CA, Blain GM, Henderson KS, et al. Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO2: role of carotid body CO2. J Physiol. 2015;593(18):4225–4243.
   PubMed Web of Science ®Google Scholar
• Guyenet PG. Regulation of breathing and autonomic outflows by chemoreceptors. Compr Physiol. 2014;4(4):1511–1562.
   PubMed Web of Science ®Google Scholar
• Malhotra A, Orr JE, Owens RL. On the cutting edge of obstructive sleep apnoea: where next? Lancet Respir Med. 2015;3(5):397–403.
   PubMed Web of Science ®Google Scholar
• Dempsey JA, Smith CA, Przybylowski T, et al. The ventilatory responsiveness to CO(2) below eupnoea as a determinant of ventilatory stability in sleep. J Physiol. 2004;560(Pt 1):1–11.
   PubMed Web of Science ®Google Scholar
• Schmickl CN, Landry S, Orr JE, et al. Effects of Acetazolamide on control of breathing in sleep apnea patients: mechanistic insights using meta-analyses and physiological model simulations. Physiol Rep. 2021;9(20):e15071.
   PubMed Web of Science ®Google Scholar
• Deacon-Diaz N, Malhotra A. Inherent vs. induced loop gain abnormalities in obstructive sleep apnea. Front Neurol. 2018;9:896.
   PubMed Web of Science ®Google Scholar
• Messineo L, Taranto-Montemurro L, Azarbarzin A, et al. Loop gain in REM versus non-REM sleep using CPAP manipulation: a pilot study. Respirology. 2019;24(8):805–808.
   PubMed Web of Science ®Google Scholar
• Landry SA, Andara C, Terrill PI, et al. Ventilatory control sensitivity in patients with obstructive sleep apnea is sleep stage dependent. Sleep. 2018;41(5). DOI:10.1093/sleep/zsy040.
   Web of Science ®Google Scholar
• Eckert DJ, Younes MK. Arousal from sleep: implications for obstructive sleep apnea pathogenesis and treatment. J Appl Physiol (1985). 2014;116(3):302–313.
   PubMed Web of Science ®Google Scholar
• Loewen A, Ostrowski M, Laprairie J, et al. Determinants of ventilatory instability in obstructive sleep apnea: inherent or acquired? Sleep. 2009;32(10):1355–1365.
   PubMed Web of Science ®Google Scholar
• Kaur S, Saper CB. Neural circuitry underlying waking up to hypercapnia. Front Neurosci. 2019;13:401.
   PubMed Web of Science ®Google Scholar
• Gleeson K, Zwillich CW, White DP. The influence of increasing ventilatory effort on arousal from sleep. Am Rev Respir Dis. 1990;142(2):295–300.
   PubMed Web of Science ®Google Scholar
• Younes M. Role of arousals in the pathogenesis of obstructive sleep apnea. Am J Respir Crit Care Med. 2004;169(5):623–633.
   PubMed Web of Science ®Google Scholar
• Douglas NJ, Jan MA, Yildirim N, et al. Effect of posture and breathing route on genioglossal electromyogram activity in normal subjects and in patients with the sleep apnea/hypopnea syndrome. Am Rev Respir Dis. 1993;148(5):1341–1345.
   PubMedGoogle Scholar
• Omobomi O, Quan SF. Positional therapy in the management of positional obstructive sleep apnea-a review of the current literature. Sleep Breath. 2018;22(2):297–304.
   PubMed Web of Science ®Google Scholar
• Mickelson SA. Oral appliances for snoring and obstructive sleep apnea. Otolaryngol Clin North Am. 2020;53(3):397–407.
   PubMed Web of Science ®Google Scholar
• Ramar K, Dort LC, Katz SG, et al. Clinical practice guideline for the treatment of obstructive sleep apnea and snoring with oral appliance therapy: an update for 2015. J Clin Sleep Med. 2015;11(7):773–827.
   PubMed Web of Science ®Google Scholar
• Chan AS, Sutherland K, Schwab RJ, et al. The effect of mandibular advancement on upper airway structure in obstructive sleep apnoea. Thorax. 2010;65(8):726–732.
   PubMed Web of Science ®Google Scholar
• Petri N, Svanholt P, Solow B, et al. Mandibular advancement appliance for obstructive sleep apnoea: results of a randomised placebo controlled trial using parallel group design. J Sleep Res. 2008;17(2):221–229.
   PubMed Web of Science ®Google Scholar
• Vena D, Azarbarzin A, Marques M, et al. Predicting sleep apnea responses to oral appliance therapy using polysomnographic airflow. Sleep. 2020; 43(7). DOI: 10.1093/sleep/zsaa004
   PubMed Web of Science ®Google Scholar
• Camacho M, Certal V, Capasso R. Comprehensive review of surgeries for obstructive sleep apnea syndrome. Braz J Otorhinolaryngol. 2013;79(6):780–788.
   PubMed Web of Science ®Google Scholar
• Liu SY, Awad M, Riley R, et al. The role of the revised stanford protocol in today’s precision medicine. Sleep Med Clin. 2019;14(1):99–107.
   PubMed Web of Science ®Google Scholar
• MacKay S, Carney AS, Catcheside PG, et al., Effect of multilevel upper airway surgery vs medical management on the apnea-hypopnea index and patient-reported daytime sleepiness among patients with moderate or severe obstructive sleep apnea: the sams randomized clinical trial. JAMA. 2020;324(12):1168.
   PubMed Web of Science ®Google Scholar
• Mansukhani MP, Olson EJ, Caples SM. Upper airway surgery for obstructive sleep apnea. JAMA. 2020;324(12):1161–1162.
   PubMed Web of Science ®Google Scholar
• Awad M, Capasso R. Skeletal surgery for obstructive sleep apnea. Otolaryngol Clin North Am. 2020;53(3):459–468.
   PubMed Web of Science ®Google Scholar
• Zaghi S, Holty JE, Certal V, et al. Maxillomandibular advancement for treatment of obstructive sleep apnea: a meta-analysis. JAMA Otolaryngol Head Neck Surg. 2016;142(1):58–66.
   PubMed Web of Science ®Google Scholar
• Riley R, Guilleminault C, Powell N, et al. Mandibular osteotomy and hyoid bone advancement for obstructive sleep apnea: a case report. Sleep. 1984;7(1):79–82.
   PubMed Web of Science ®Google Scholar
• Puccia R, Woodson BT. Palatopharyngoplasty and palatal anatomy and phenotypes for treatment of sleep apnea in the twenty-first century. Otolaryngol Clin North Am. 2020;53(3):421–429.
   PubMed Web of Science ®Google Scholar
• Choi JH, Cho SH, Kim SN, et al. Predicting outcomes after uvulopalatopharyngoplasty for adult obstructive sleep apnea: a meta-analysis. Otolaryngol Head Neck Surg. 2016;155(6):904–913.
   PubMed Web of Science ®Google Scholar
• Khan A, Ramar K, Maddirala S, et al. Uvulopalatopharyngoplasty in the management of obstructive sleep apnea: the mayo clinic experience. Mayo Clin Proc. 2009;84(9):795–800.
   PubMed Web of Science ®Google Scholar
• Varendh M, Berg S, Andersson M. Long-term follow-up of patients operated with Uvulopalatopharyngoplasty from 1985 to 1991. Respir Med. 2012;106(12):1788–1793.
   PubMed Web of Science ®Google Scholar
• Strollo PJ SRJ Jr., Maurer JT, Maurer JT, et al., Upper-airway stimulation for obstructive sleep apnea. N Engl J Med. 2014;370(2):139–149.
   PubMed Web of Science ®Google Scholar
• Eastwood PR, Barnes M, MacKay SG, et al. Bilateral hypoglossal nerve stimulation for treatment of adult obstructive sleep apnoea. Eur Respir J. 2020;55(1):1901320.
   PubMed Web of Science ®Google Scholar
• Withrow K, Evans S, Harwick J, et al. Upper airway stimulation response in older adults with moderate to severe obstructive sleep apnea. Otolaryngol Head Neck Surg. 2019;161(4):714–719.
   PubMed Web of Science ®Google Scholar
• Thaler E, Schwab R, Maurer J, et al. Results of the ADHERE upper airway stimulation registry and predictors of therapy efficacy. Laryngoscope. 2020;130(5):1333–1338.
   PubMed Web of Science ®Google Scholar
• Lewis R, Petelle B, Campbell MC, et al. Implantation of the nyxoah bilateral hypoglossal nerve stimulator for obstructive sleep apnea. Laryngoscope Investig Otolaryngol. 2019;4(6):703–707.
   PubMed Web of Science ®Google Scholar
• Sommer JU, Hormann K. Innovative surgery for obstructive sleep apnea: nerve stimulator. Adv Otorhinolaryngol. 2017;80:116–124.
   PubMedGoogle Scholar
• de Beeck S O, Wellman A, Dieltjens M, et al. Endotypic mechanisms of successful hypoglossal nerve stimulation for obstructive sleep apnea. Am J Respir Crit Care Med. 2021;203(6):746–755.
   PubMed Web of Science ®Google Scholar
• Heiser C, Steffen A, Boon M, et al. Post-approval upper airway stimulation predictors of treatment effectiveness in the ADHERE registry. Eur Respir J. 2019;53(1):1801405.
   PubMed Web of Science ®Google Scholar
• Li Y, Ye J, Han D, et al. The effect of upper airway surgery on loop gain in obstructive sleep apnea. J Clin Sleep Med. 2019;15(6):907–913.
   PubMed Web of Science ®Google Scholar
• Joosten SA, Tan M, Wong AM, et al. A randomized controlled trial of oxygen therapy for patients who do not respond to upper airway surgery for obstructive sleep apnea. J Clin Sleep Med. 2021;17(3):445–452.
   PubMed Web of Science ®Google Scholar
• Puhan MA, Suarez A, Lo Cascio C, et al. Didgeridoo playing as alternative treatment for obstructive sleep apnoea syndrome: randomised controlled trial. BMJ. 2006;332(7536):266–270.
   PubMed Web of Science ®Google Scholar
• Baptista P, Martínez Ruiz de Apodaca P, Marina C, et al. Daytime neuromuscular electrical therapy of tongue muscles in improving snoring in individuals with primary snoring and mild obstructive sleep apnea. J Clin Med. 2021;10(9):1883.
   PubMed Web of Science ®Google Scholar
• Kent DT, Zealear D, Schwartz AR. Ansa cervicalis stimulation: a new direction in neurostimulation for OSA. Chest. 2021;159(3):1212–1221.
   PubMed Web of Science ®Google Scholar
• Taranto-Montemurro L, Messineo L, Wellman A. Targeting endotypic traits with medications for the pharmacological treatment of obstructive sleep apnea. A review of the current literature. J Clin Med. 2019;8(11):1846.
   Web of Science ®Google Scholar
• Schmickl CN, Li Y, Orr JE, et al. Effect of venlafaxine on apnea-hypopnea index in patients with sleep apnea: a randomized, double-blind crossover study. Chest. 2020;158(2):765–775.
   PubMed Web of Science ®Google Scholar
• Taranto-Montemurro L, Messineo L, Sands SA, et al. The combination of atomoxetine and oxybutynin greatly reduces obstructive sleep apnea severity. A randomized, placebo-controlled, double-blind crossover trial. Am J Respir Crit Care Med. 2019;199(10):1267–1276.
   PubMed Web of Science ®Google Scholar
• Horner RL, Grace KP, Wellman A. A resource of potential drug targets and strategic decision-making for obstructive sleep apnoea pharmacotherapy. Respirology. 2017;22(5):861–873.
   PubMed Web of Science ®Google Scholar
• Gaisl T, Turnbull CD, Weimann G, et al. BAY 2253651 for the treatment of obstructive sleep apnoea: a multicentre, double-blind, randomised controlled trial (SANDMAN). Eur Respir J. 2021;58(5):2101937.
   PubMed Web of Science ®Google Scholar
• Wellman A, Jordan AS, Malhotra A, et al. Ventilatory control and airway anatomy in obstructive sleep apnea. Am J Respir Crit Care Med. 2004;170(11):1225–1232.
   PubMed Web of Science ®Google Scholar
• Orr JE, Sands SA, Edwards BA, et al. Measuring loop gain via home sleep testing in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 2018;197(10):1353–1355.
   PubMed Web of Science ®Google Scholar
• Schmickl CN, Landry SA, Orr JE, et al. Acetazolamide for OSA and central sleep apnea: a comprehensive systematic review and meta-analysis. Chest. 2020;158(6):2632–2645.
   PubMed Web of Science ®Google Scholar
• Eckert DJ, Owens RL, Kehlmann GB, et al. Eszopiclone increases the respiratory arousal threshold and lowers the apnoea/hypopnoea index in obstructive sleep apnoea patients with a low arousal threshold. Clin Sci (Lond). 2011;120(12):505–514.
   PubMed Web of Science ®Google Scholar
• Amatoury J, Azarbarzin A, Younes M, et al. Arousal intensity is a distinct pathophysiological trait in obstructive sleep apnea. Sleep. 2016;39(12):2091–2100.
   PubMed Web of Science ®Google Scholar
• Saboisky J, Eckert D, Malhotra A. Stable breathing through deeper sleeping. Thorax. 2010;65(2):95–96.
   PubMed Web of Science ®Google Scholar
• Messineo L, Eckert DJ, Lim R, et al. Zolpidem increases sleep efficiency and the respiratory arousal threshold without changing sleep apnoea severity and pharyngeal muscle activity. J Physiol. 2020;598(20):4681–4692.
   PubMed Web of Science ®Google Scholar
• Messineo L, Carter SG, Taranto-Montemurro L, et al. Addition of zolpidem to combination therapy with atomoxetine-oxybutynin increases sleep efficiency and the respiratory arousal threshold in obstructive sleep apnoea: a randomized trial. Respirology. 2021;26(9):878–886.
   PubMed Web of Science ®Google Scholar
• Schmickl CN, Lettieri CJ, Orr JE, et al. The arousal threshold as a drug target to improve continuous positive airway pressure adherence: secondary analysis of a randomized trial. Am J Respir Crit Care Med. 2020;202(11):1592–1595.
   PubMed Web of Science ®Google Scholar
• Edwards BA, Sands SA, Owens RL, et al. The combination of supplemental oxygen and a hypnotic markedly improves obstructive sleep apnea in patients with a mild to moderate upper airway collapsibility. Sleep. 2016;39(11):1973–1983.
   PubMed Web of Science ®Google Scholar
• Messineo L, Magri R, Corda L, et al. Phenotyping-based treatment improves obstructive sleep apnea symptoms and severity: a pilot study. Sleep Breath. 2017;21(4):861–868.
   PubMed Web of Science ®Google Scholar
• Malhotra A, Ayappa I, Ayas N, et al. Metrics of sleep apnea severity: beyond the apnea-hypopnea index. Sleep. 2021;44(7). DOI:10.1093/sleep/zsab030.
   Web of Science ®Google Scholar
• Kribbs NB, Pack AI, Kline LR, et al. Objective measurement of patterns of nasal CPAP use by patients with obstructive sleep apnea. Am Rev Respir Dis. 1993;147(4):887–895.
   PubMed Web of Science ®Google Scholar
• Malhotra A, Butler J, Wellman A. The pharyngeal airway is bigger really better? Chest. 2012;141(6):1372–1375.
   PubMed Web of Science ®Google Scholar
• Penner CG, Gerardy B, Ryan R, et al. The odds ratio product (an objective sleep depth measure): normal values, repeatability, and change with CPAP in patients with OSA. J Clin Sleep Med. 2019;15(8):1155–1163.
   PubMed Web of Science ®Google Scholar
• Azarbarzin A, Sands SA, Stone KL, et al. The hypoxic burden of sleep apnoea predicts cardiovascular disease-related mortality: the osteoporotic fractures in men study and the sleep heart health study. Eur Heart J. 2019;40(14):1149–1157.
   PubMed Web of Science ®Google Scholar
• Azarbarzin A, Sands SA, Taranto-Montemurro L, et al. The sleep apnea-specific hypoxic burden predicts incident heart failure. Chest. 2020;158(2):739–750.
   PubMed Web of Science ®Google Scholar