Dr. Michelle Cao is board certified in pulmonary medicine, critical care medicine, and sleep medicine. Dr. Cao's clinical expertise are in the subspecialties of home mechanical ventilation, noninvasive ventilation, and complex pulmonary and sleep related respiratory disorders including obstructive and central sleep apnea syndromes.

Clinical Focus

  • Home Mechanical Ventilation
  • Pulmonology and Sleep Disorders
  • Pulmonary and sleep related breathing disorders in neuromuscular disease
  • Sleep Apnea Syndromes
  • Critical Care Medicine

Academic Appointments

Boards, Advisory Committees, Professional Organizations

  • Chair, American Academy of Sleep Medicine; Sleep Technologist & Respiratory Therapist Education Committee (2022 - Present)
  • Vice Chair, American College of Chest Physicians - Scientific Presentations and Awards Committee (2021 - Present)
  • President, California Thoracic Society (2022 - 2023)
  • Chair, American College of Chest Physicians - Home Mechanical Ventilation and Neuromuscular Disease NetWork (2019 - 2021)
  • Member, American Thoracic Society (2008 - Present)
  • Fellow, American Academy of Sleep Medicine (2007 - Present)
  • Fellow, American College of Chest Physicians (2004 - Present)

Professional Education

  • Residency: Loma Linda University School of Medicine (2003) CA
  • Fellowship: Stanford University CAPS Postdoctoral Fellowship (2008) CA
  • Fellowship: Harbor UCLA Medical Center (2007) CA
  • Medical Education: Western University of Health Sciences College of Osteopathic Medicine of the Pacific (2000) CA
  • Board Certification: American Board of Internal Medicine, Pulmonary Disease (2006)
  • Board Certification: American Board of Internal Medicine, Critical Care Medicine (2007)
  • Board Certification: American Board of Internal Medicine, Sleep Medicine (2009)

Current Research and Scholarly Interests

Positive Airway Pressure devices for central sleep apnea

Graduate and Fellowship Programs

  • Sleep Medicine (Fellowship Program)

All Publications

  • Roadmap for Advancing a New Subspecialty in Pulmonary Medicine Devoted to Chronic Respiratory Failure. Annals of the American Thoracic Society Cao, M., Katz, S. L., Hansen-Flaschen, J. H. 2024

    View details for DOI 10.1513/AnnalsATS.202309-810IP

    View details for PubMedID 38445980

  • International consensus statement on obstructive sleep apnea. International forum of allergy & rhinology Chang, J. L., Goldberg, A. N., Alt, J. A., Ashbrook, L., Auckley, D., Ayappa, I., Bakhtiar, H., Barrera, J. E., Bartley, B. L., Billings, M. E., Boon, M. S., Bosschieter, P., Braverman, I., Brodie, K., Cabrera-Muffly, C., Caesar, R., Cahali, M. B., Cai, Y., Cao, M., Capasso, R., Caples, S. M., Chahine, L. M., Chang, C. P., Chang, K. W., Chaudhary, N., Cheong, C. S., Chowdhuri, S., Cistulli, P. A., Claman, D., Collen, J., Coughlin, K., Creamer, J., Davis, E. M., Dupuy-McCauley, K. L., Durr, M. L., Dutt, M., Ali, M. E., Elkassabany, N. M., Epstein, L. J., Fiala, J. A., Freedman, N., Gill, K., Gillespie, M. B., Golisch, L., Gooneratne, N., Gottlieb, D. J., Green, K. K., Gulati, A., Gurubhagavatula, I., Hayward, N., Hoff, P. T., Hoffmann, O. M., Holfinger, S. J., Hsia, J., Huntley, C., Huoh, K. C., Huyett, P., Inala, S., Ishman, S., Jella, T. K., Jobanputra, A. M., Johnson, A. P., Junna, M. R., Kado, J. T., Kaffenberger, T. M., Kapur, V. K., Kezirian, E. J., Khan, M., Kirsch, D. B., Kominsky, A., Kryger, M., Krystal, A. D., Kushida, C. A., Kuzniar, T. J., Lam, D. J., Lettieri, C. J., Lim, D. C., Lin, H., Liu, S. Y., MacKay, S. G., Magalang, U. J., Malhotra, A., Maurer, J. T., May, A. M., Mitchell, R. B., Mokhlesi, B., Mullins, A. E., Nada, E. M., Naik, S., Nokes, B., Olson, M. D., Pack, A. I., Pang, E. B., Pang, K. P., Patil, S. P., de Perck, E. V., Piccirillo, J. F., Pien, G. W., Piper, A. J., Plawecki, A., Quigg, M., Ravesloot, M. J., Redline, S., Rotenberg, B. W., Ryden, A., Sarmiento, K. F., Sbeih, F., Schell, A. E., Schmickl, C. N., Schotland, H. M., Schwab, R. J., Seo, J., Shah, N., Shelgikar, A. V., Shochat, I., Soose, R. J., Steele, T. O., Stephens, E., Stepnowsky, C., Strohl, K. P., Sutherland, K., Suurna, M. V., Thaler, E., Thapa, S., Vanderveken, O. M., de Vries, N., Weaver, E. M., Weir, I. D., Wolfe, L. F., Woodson, B. T., Won, C. H., Xu, J., Yalamanchi, P., Yaremchuk, K., Yeghiazarians, Y., Yu, J. L., Zeidler, M., Rosen, I. M. 2022


    BACKGROUND: Evaluation and interpretation of the literature on obstructive sleep apnea is needed to consolidate and summarize key factors important for clinical management of the OSA adult patient. Toward this goal, an international collaborative of multidisciplinary experts in sleep apnea evaluation and treatment have produced the International Consensus statement on Obstructive Sleep Apnea (ICS:OSA).METHODS: Using previously defined methodology, focal topics in OSA were assigned as literature review (LR), evidence-based review (EBR), or evidence-based review with recommendations (EBR-R) formats. Each topic incorporated the available and relevant evidence which was summarized and graded on study quality. Each topic and section underwent iterative review and the ICS:OSA was created and reviewed by all authors for consensus.RESULTS: The ICS:OSA addresses OSA syndrome definitions, pathophysiology, epidemiology, risk factors for disease, screening methods, diagnostic testing types, multiple treatment modalities, and effects of OSA and treatment on the multiple comorbidities. Specific focus on outcomes with positive airway pressure (PAP) and surgical treatments were evaluated.CONCLUSION: This review of the literature in OSA consolidates the available knowledge and identifies the limitations of the current evidence. This effort aims to highlight the basis of OSA evidence-based practice and identify future research needs. Knowledge gaps and opportunities for improvement include improving the metrics of OSA disease, determining the optimal OSA screening paradigms, developing strategies for PAP adherence and longitudinal care, enhancing selection of PAP alternatives and surgery, understanding health risk outcomes, and translating evidence into individualized approaches to therapy. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/alr.23079

    View details for PubMedID 36068685

  • Chronic Opioid Use and Sleep Disorders. Sleep medicine clinics Javaheri, S., Cao, M. 2022; 17 (3): 433-444


    Opioid medications are considered a significant component in the multidisciplinary management of chronic pain. In the past twodecades, the use of opioid medications has dramatically risen in part because of an increased awareness by health care providers to treat chronic pain more effectively. In addition, patients are encouraged to seek treatment. The release of a sentinel joint statement in 1997 by the American Academy of Pain Medicine and the American Pain Society in a national effort to increase awareness and support the treatment of chronic pain has undoubtedly contributed to the opioid crisis.

    View details for DOI 10.1016/j.jsmc.2022.06.008

    View details for PubMedID 36150805

  • Obstructive sleep apnea: personalizing CPAP alternative therapies to individual physiology. Expert review of respiratory medicine Nokes, B., Cooper, J., Cao, M. 2022


    Introduction The recent continuous positive airway pressure (CPAP) crisis has highlighted the need for alternative obstructive sleep apnea (OSA) therapies. This article serves to review OSA pathophysiology and how sleep apnea mechanisms may be utilized to individualize alternative treatment options.Areas covered: The research highlighted below focuses on 1) mechanisms of OSA pathogenesis and 2) CPAP alternative therapies based on mechanism of disease. We reviewed PubMed from inception to July 2022 for relevant articles pertaining to OSA pathogenesis, sleep apnea surgery, as well as sleep apnea alternative therapies.Expert opinion: Although the field of individualized OSA treatment is still in its infancy, much has been learned about OSA traits and how they may be targeted based on a patient's physiology and preferences. While CPAP remains the gold-standard for OSA management, several novel alternatives are emerging. CPAP is a universal treatment approach for all severities of OSA. We believe that a personalized approach to OSA treatment beyond CPAP lies ahead. Additional research is needed with respect to implementation and combination of therapies longitudinally, but we are enthusiastic about the future of OSA treatment based on the data presented here.

    View details for DOI 10.1080/17476348.2022.2112669

    View details for PubMedID 35949101

  • The Effect of Obstructive Sleep Apnea Treatment and Severity on Choroidal Thickness in Patients With Central Serous Chorioretinopathy. Journal of vitreoretinal diseases Azad, A. D., Davila, J. R., Rayess, N., Cao, M., Mruthyunjaya, P., Pan, C. K. 2022; 6 (1): 22-30


    This work aimed to analyze the association of obstructive sleep apnea (OSA) with choroidal thickness (CT) in patients with central serous chorioretinopathy (CSC).We identified patients in the Stanford Research Repository with a diagnosis of CSC and OSA. Age- and sex-matched controls with either CSC or OSA only were also identified. CT was measured at 5 points (subfoveal, and 1500 and 3000 µm nasal and temporal) by 2 graders. In addition to OSA treatment and severity, we also investigated the association of Oxygen Desaturation Index and nocturnal oxygen saturation nadir with subfoveal CT (SFCT).A total of 57 patients and 72 eyes met the study inclusion criteria. The mean SFCT was significantly different across the 3 groups: OSA-only was the thinnest, followed by CSC with OSA, and CSC-only was the thickest (194.2 μm, 295.1 μm, and 357.8 μm, respectively, P < .001). SFCT was thicker in CSC with OSA compared with those with only OSA (P < .05). OSA treatment status and OSA severity did not show a significant difference in SFCT in multivariable modeling. Nocturnal oxygen saturation nadir was positively associated with SFCT, but this did not reach significance..SFCT is significantly different in patients with OSA alone, CSC with OSA, and CSC alone. While OSA treatment status did not demonstrate a significant difference in SFCT in this study, future studies should evaluate patients for OSA in patients known to have CSC and atypically thin CT to further investigate the novel metrics leveraged in this study.

    View details for DOI 10.1177/24741264211009677

    View details for PubMedID 37007726

    View details for PubMedCentralID PMC9976222

  • A deep learning-based system for survival benefit prediction of tyrosine kinase inhibitors and immune checkpoint inhibitors in stage IV non-small cell lung cancer patients: A multicenter, prognostic study eClinicalMedicine Deng, K., Wang, L., Liu, Y., Li, X., Hou, Q., Cao, M., Ng, N. N., Wang, H., Chen, H., Yeom, K. W., Zhao, M., Wu, N., Gao, P., Shi, J., Liu, Z., Li, W., Tian, J., Song, J. 2022; 51: 1-14
  • The Effect of Obstructive Sleep Apnea Treatment and Severity on Choroidal Thickness in Patients With Central Serous Chorioretinopathy JOURNAL OF VITREORETINAL DISEASES Azad, A. D., Davila, J. R., Rayess, N., Cao, M., Mruthyunjaya, P., Pan, C. K. 2022; 6 (1): 22-30
  • Obstructive sleep apnea and severe COVID-19 infection: is there a plausible link? Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine Sahni, A., Cao, M. 2021

    View details for DOI 10.5664/jcsm.9644

    View details for PubMedID 34473047

  • Acute on Chronic Neuromuscular Respiratory Failure in the Intensive Care Unit: Optimization of Triage, Ventilation Modes, and Extubation CUREUS Murray, N. M., Reimer, R. J., Cao, M. 2021; 13 (7)
  • Acute on Chronic Neuromuscular Respiratory Failure in the Intensive Care Unit: Optimization of Triage, Ventilation Modes, and Extubation. Cureus Murray, N. M., Reimer, R. J., Cao, M. 2021; 13 (7): e16297


    Critical care management of acute respiratory failure in patients with neuromuscular disease (NMD) such as amyotrophic lateral sclerosis (ALS) is not standardized and is challenging for many critical care specialists. Progressive hypercapnic respiratory failure and ineffective airway clearance are key issues in this patient population. Often at the time of hospital presentation, patients are already supported by home mechanical ventilatory support with noninvasive ventilation (NIV) and an airway clearance regimen. Prognosis is poor once a patient develops acute respiratory failure requiring intubation and invasive mechanical ventilatory support, commonly leading to tracheostomy or palliative-focused care.  We focus on this understudied group of patients with ALS without tracheostomy and incorporate existing data to propose a technical approach to the triage and management of acute respiratory failure, primarily for those who require intubation and mechanical ventilatory support for reversible causes, and also for progression of end-stage disease. Optimizing management in this setting improves both quality and quantity of life. Neuromuscular patients with acute respiratory failure require protocolized and personalized triage and treatment. Here, we describe the technical methods used at our single institution. The triage phase incorporates comprehensive evaluation for new etiologies of hypoxia and hypercapnia, which are not initially presumed to be secondary to progression or end-stage neuromuscular respiratory failure. In select patients, this may involve intubation or advanced adjustments of NIV machines. Next, once the acute etiology(s) is identified and treated, the focus shifts: training and use of mechanical airway clearance to optimize pulmonary function, facilitation of NIV wean or successful extubation to NIV, and transition to a stable regimen for home ventilation. The comprehensive protocol described here incorporates multi-institutional approaches and effectively optimizes acute respiratory failure in patients with neuromuscular pulmonary disease.

    View details for DOI 10.7759/cureus.16297

    View details for PubMedID 34381654

    View details for PubMedCentralID PMC8351614

  • Reply to Comment on: The Effect of Obstructive Sleep Apnea on Absolute Risk of Central Serous Chorioretinopathy AMERICAN JOURNAL OF OPHTHALMOLOGY Pan, C. K., Vail, D., Bhattacharya, J., Cao, M., Mruthyunjaya, P. 2021; 226: 271-272
  • Reply to Comment on: The Effect of Obstructive Sleep Apnea on Absolute Risk of Central Serous Chorioretinopathy. American journal of ophthalmology Pan, C. K., Vail, D., Bhattacharya, J., Cao, M., Mruthyunjaya, P. 2021

    View details for DOI 10.1016/j.ajo.2021.01.016

    View details for PubMedID 33567302

  • Noninvasive Ventilator Devices and Modes. Sleep medicine clinics Singh, G., Cao, M. 2020; 15 (4): 545–55


    Noninvasive ventilation has become an increasingly common treatment strategy for patients with diverse conditions involving chronic respiratory failure. An intimate understanding of various advanced respiratory devices and modes is essential in the management of these patients. Pressure-limited modes of ventilation are more commonly used than volume modes for noninvasive ventilation owing to enhanced patient comfort and synchrony with the ventilator, as well as improved leak compensation. Common pressure modes include spontaneous/timed and pressure control, with volume-assured pressure support being an additive feature available on certain devices. Evidence guiding the optimal mode of ventilation for specific diseases is limited.

    View details for DOI 10.1016/j.jsmc.2020.08.005

    View details for PubMedID 33131664

  • Consensus-Based Care Recommendations for Pulmonologists Treating Adults with Myotonic Dystrophy Type 1. Respiration; international review of thoracic diseases Boentert, M. n., Cao, M. n., Mass, D. n., De Mattia, E. n., Falcier, E. n., Goncalves, M. n., Holland, V. n., Katz, S. L., Orlikowski, D. n., Sannicolò, G. n., Wijkstra, P. n., Hellerstein, L. n., Sansone, V. A. 2020: 1–9


    Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects approximately 1 in 2,500 individuals globally [Ashizawa et al.: Neurol Clin Pract 2018;8(6):507-20]. In patients with DM1, respiratory muscle weakness frequently evolves, leading to respiratory failure as the main cause of death in this patient population, followed by cardiac complications [de Die-Smulders et al.: Brain 1998;121(Pt 8):1557-63], [Mathieu et al.: Neurology 1999;52(8):1658-62], [Groh et al.: Muscle Nerve 2011;43(5):648-51]. This paper provides a more detailed outline on the diagnostic and management protocols, which can guide pulmonologists who may not have experience with DM1 or who are not part of a neuromuscular multidisciplinary clinic. A group of neuromuscular experts in DM1 including pulmonologists, respiratory physiotherapists and sleep specialists discussed respiratory testing and management at baseline and during follow-up visits, based on their clinical experience with patients with DM1. The details are presented in this report.Myotonic recruited 66 international clinicians experienced in the treatment of people living with DM1 to develop and publish consensus-based care recommendations targeting all body systems affected by this disease [Ashizawa et al.: Neurol Clin Pract. 2018;8(6):507-20]. Myotonic then worked with 12 international respiratory therapists, pulmonologists and neurologists with long-standing experience in DM respiratory care to develop consensus-based care recommendations for pulmonologists using a methodology called the Single Text Procedure. This process generated a 7-page document that provides detailed respiratory care recommendations for the management of patients living with DM1. This consensus is completely based on expert opinion and not backed up by empirical evidence due to limited clinical care data available for respiratory care management in DM patients. Nevertheless, we believe it is of relevance for professionals treating adults with myotonic dystrophy because it addresses practical issues related to respiratory management and care, which have been adapted to meet the specific issues in patients with DM1.The resulting recommendations are intended to improve respiratory care for the most vulnerable of DM1 patients and lower the risk of untoward respiratory complications and mortality by providing pulmonologist who are less experienced with DM1 with practical indications on which tests and when to perform them, adapting the general respiratory knowledge to specific issues related to this multiorgan disease.

    View details for DOI 10.1159/000505634

    View details for PubMedID 32299079

  • Sleep medicine exposure offered by United States residency training programs. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine Sullivan, S. S., Cao, M. T. 2020


    To understand the sleep medicine (SM) educational exposure among parent specialties of sleep medicine fellowships, we conducted an online survey among ACGME-approved training programs.Target respondents were program directors of family medicine, otolaryngology, psychiatry, neurology, pediatrics, and pulmonary and critical care (PCCM) training programs in the United States. The survey was based on the Sleep Education Survey (SES), a peer-reviewed, published survey created by the American Academy of Neurology Sleep Section. The modified 18-question survey was emailed via Survey Monkey per published methods totaling 3 requests approximately one week apart in January 2017.A total of 1,228 programs were contacted, and 479 responses were received for an overall response rate of 39%. Some programs in every specialty group offered a SM elective or a required rotation to trainees. PCCM and neurology reported the highest percentages of SM rotation as an option for housestaff (85.7% and 90.8%, respectively), and PCCM had the highest portion of programs indicating a rotation requirement (75.4%). Teaching format was a mixture of didactic lectures, sleep center/lab exposure, and case reports; with lectures being the most common format. Didactics averaged 4.75 hours per year. Few programs reported trainees subsequently pursuing SM fellowship (< 10% produced a fellow over five years), and even fewer reported having a trainee who pursued grant funding for sleep-related research over five years.There is wide variability and overall low exposure to sleep medicine education among United States "parent" ACGME training programs whose medical boards offer sleep medicine certification.

    View details for DOI 10.5664/jcsm.9062

    View details for PubMedID 33382031

  • The Effect of Obstructive Sleep Apnea on Absolute Risk of Central Serous Chorioretinopathy. American journal of ophthalmology Pan, C. K., Vail, D. n., Bhattacharya, J. n., Cao, M. n., Mruthyunjaya, P. n. 2020


    To determine the incidence of central serous chorioretinopathy (CSC) stratified by age, sex, and diagnosis with obstructive sleep apnea (OSA), and to determine whether some patients with newly diagnosed CSC may be candidates for OSA evaluation.Retrospective cohort study.We used the IBM Marketscan database to select 59,016,145 commercially-insured patients in the United States between 2007 and 2016. We identified patients' first diagnosis with CSC, and defined patients as having OSA if they had a diagnosis following a sleep study. We specified Cox proportional hazard models with interactions between age, sex, and OSA status to determine patients' risk of developing CSC. We estimated the positive predictive value (PPV) that a new diagnosis of CSC would have in predicting a subsequent diagnosis of OSA.Risk of CSC increased with age in years (HR=1.030, p<.001) and OSA diagnosis (HR=1.081, p=.033), and was lower in women (HR=0.284, p<.001). We estimated the annual incidence of CSC was 9.6 and 23.4 per 100,000 women and men, respectively. Incidence was higher in women and men with OSA (17.2 and 40.8 per 100,000). The PPV of CSC diagnosis as a predictor of OSA was highest in the fifth decade of life.The incidence of CSC in our patient sample is higher than previously reported. Risk of CSC is higher in men than in women, and OSA increases risk of CSC in both men and women. Some patients, particularly older males, may be good candidates for OSA evaluation following a CSC diagnosis.

    View details for DOI 10.1016/j.ajo.2020.05.040

    View details for PubMedID 32574769

  • Chronic opioid use on sleep and respiration: scratching the surface. Sleep medicine Cao, M. n. 2019

    View details for DOI 10.1016/j.sleep.2019.12.003

    View details for PubMedID 32029365

  • Effects of Chronic Opioid Use on Sleep and Wake SLEEP MEDICINE CLINICS Cao, M., Javaheri, S. 2018; 13 (2): 271-+


    Chronic use of opioids negatively affects sleep on 2 levels: sleep architecture and breathing. Patients suffer from a variety of daytime sequelae. There may be a bidirectional relationship between poor sleep quality, sleep-disordered breathing, and daytime function. Opioids are a potential cause of incident depression. The best therapeutic option is withdrawal of opioids, which proves difficult. Positive airway pressure devices are considered first-line treatment for sleep-related breathing disorders. New generation positive pressure servo ventilators are increasingly popular as a treatment option for opioid-induced sleep-disordered breathing. Treatments to improve sleep quality, sleep-related breathing disorders, and quality of life in patients who use opioids chronically are discussed.

    View details for PubMedID 29759277

  • Survey of Sleep Education Offered by US Pulmonary and Critical Care Fellowship Training Programs Sullivan, S., Cao, M. ELSEVIER SCIENCE BV. 2017: 554A
  • Sleep and Health: Medical Students' Perspectives and Lessons Learned ACADEMIC PSYCHIATRY Sullivan, S. S., Cao, M. T. 2017; 41 (5): 679–81

    View details for PubMedID 28929351

  • Factors Influencing Noninvasive Ventilation Initiation in Amyotrophic Lateral Sclerosis Doddamreddy, P., Singh, G., Schultz, B., Cao, M. ELSEVIER SCIENCE BV. 2017: 187A
  • Continuous positive airway pressure therapy in obstuctive sleep apnea: benefits and alternatives EXPERT REVIEW OF RESPIRATORY MEDICINE Cao, M. T., Sternbach, J. M., Guilleminault, C. 2017; 11 (4): 259-272


    Obstructive sleep apnea (OSA) is a highly prevalent condition affecting persons of all age with an increasing public health burden. It is implicated in cardiovascular disease, metabolic syndrome, neurocognitive impairment, reductions in quality of life, and increased motor vehicle accidents. The goals of OSA treatment are to improve sleep and daytime symptoms, and minimize cardiovascular risks.Areas covered: Continuous positive airway pressure (CPAP) is considered the gold standard therapy that delivers pressurized air into the upper airway to relieve obstruction during sleep. Although CPAP is an effective modality of treatment for OSA, adherence to therapy is highly variable. This article highlights the benefits of CPAP therapy, along with alternative treatment options including oral appliance, implantable and wearable devices, and surgery. Expert commentary: CPAP therapy is the gold standard treatment option and should continue to be offered to those who suffer from OSA. Alternative options are available for those who are unable to adhere to CPAP or choose an alternative treatment modality. The most interesting advances have been incorporating orthodontic procedures in conjunction with myofunctional therapy in prepubertal children, raising the possibility of OSA prevention by initiating treatment early in life.

    View details for DOI 10.1080/17476348.2017.1305893

    View details for PubMedID 28287009

  • The hypocretin/orexin system in sleep disorders: preclinical insights and clinical progress. Nature and science of sleep Chow, M., Cao, M. 2016; 8: 81-86


    Much of the understanding of the hypocretin/orexin (HCRT/OX) system in sleep-wake regulation came from narcolepsy-cataplexy research. The neuropeptides hypocretin-1 and -2/orexin-A and -B (HCRT-1 and -2/OX-A and -B, respectively), as we know, are intimately involved in the regulation wakefulness. The HCRT/OX system regulates sleep-wake control through complex interactions between monoaminergic/cholinergic (wake-promoting) and gamma-aminobutyric acid-ergic (sleep-promoting) neuronal systems. Deficiency of HCRT/OX results in loss of sleep-wake control or stability with consequent unstable transitions between wakefulness to nonrapid eye movement and rapid eye movement sleep. This manifests clinically as abnormal daytime sleepiness with sleep attacks and cataplexy. Research on the development of HCRT/OX agonists and antagonists for the treatment of sleep disorders has dramatically increased with the US Food and Drug Administration approval of the first-in-class dual HCRT/OX receptor antagonist for the treatment of insomnia. This review focuses on the origin, mechanisms of HCRT/OX receptors, clinical progress, and applications for the treatment of sleep disorders.

    View details for DOI 10.2147/NSS.S76711

    View details for PubMedID 27051324

    View details for PubMedCentralID PMC4803263

  • Opioids, Sedatives, and Sleep Hypoventilation SLEEP MEDICINE CLINICS Arora, N., Cao, M., Javaheri, S. 2014; 9 (3): 391-+
  • A Novel Adaptive Servoventilation (ASVAuto) for the Treatment of Central Sleep Apnea Associated with Chronic Use of Opioids. Journal of clinical sleep medicine Cao, M., Cardell, C., Willes, L., Mendoza, J., Benjafield, A., Kushida, C. 2014; 10 (8): 855-861


    To compare the efficacy and patient comfort of a new mode of minute ventilation-targeted adaptive servoventilation (ASVAuto) with auto-titrating expiratory positive airway pressure (EPAP) versus bilevel with back-up respiratory rate (bilevel-ST) in patients with central sleep apnea (CSA) associated with chronic use of opioid medications.Prospective, randomized, crossover polysomnography (PSG) study. Eighteen consecutive patients (age ≥ 18 years) who had been receiving opioid therapy (≥ 6 months), and had sleep disordered breathing with CSA (central apnea index [CAI] ≥ 5) diagnosed during an overnight sleep study or positive airway pressure (PAP) titration were enrolled to undergo 2 PSG studies-one with ASVAuto and one with bilevel-ST. Patients completed 2 questionnaires after each PSG; Morning After Patient Satisfaction Questionnaire and PAP Comfort Questionnaire.Patients had a mean age of 52.9 ± 15.3 years. PSG prior to randomization showed an apnea hypopnea index (AHI) of 50.3 ± 22.2 and CAI of 13.0 ± 18.7. Titration with ASVAuto versus bilevel-ST showed that there were significant differences with respect to AHI and CAI. The AHI and CAI were significantly lower on ASVAuto than bilevel-ST (2.5 ± 3.5 versus 16.3 ± 20.9 [p = 0.0005], and 0.4 ± 0.8 versus 9.4 ± 18.8 [p = 0.0002], respectively). Respiratory parameters were normalized in 83.3% of patients on ASVAuto versus 33.3% on bilevel-ST. Patients felt more awake and alert on ASVAuto than bilevel-ST based on scores from Morning After Patient Satisfaction Questionnaire (p = 0.0337).The ASVAuto was significantly more effective than bilevel-ST for the treatment of CSA associated with chronic opioid use.Cao M, Cardell CY, Willes L, Mendoza J, Benjafield A, Kushida C. A novel adaptive servoventilation (ASVAuto) for the treatment of central sleep apnea associated with chronic use of opioids. J Clin Sleep Med 2014;10(8):855-861.

    View details for DOI 10.5664/jcsm.3954

    View details for PubMedID 25126031

    View details for PubMedCentralID PMC4106939

  • Central Sleep Apnea: Effects on Stroke Volume in Heart Failure AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Cao, M., Guilleminault, C., Lin, C. 2013; 187 (4): 340-341

    View details for DOI 10.1164/rccm.201212-2250ED

    View details for Web of Science ID 000315075800004

    View details for PubMedID 23418326

  • Sleep-Disordered Breathing, Heart Failure, and Phrenic Nerve Stimulation CHEST Cao, M., Guilleminault, C. 2012; 142 (4): 821-823

    View details for DOI 10.1378/chest.12-0591

    View details for PubMedID 23032447

  • Acute and Chronic Sleep Loss: Implications on Age-Related Neurocognitive Impairment SLEEP Cao, M., Guilleminault, C. 2012; 35 (7): 901-902

    View details for DOI 10.5665/sleep.1944

    View details for PubMedID 22754034



    Mutual interactions between neurohormones, sleep, and the circadian system have been extensively studied. Hormonal secretion is either influenced by sleep and is independent of circadian timing or is closely coupled with the light-dark cycle, although both processes ultimately interact with each other. Sleep has a strong effect on the levels of some hormones (e.g., growth hormone) but little effect on others that are primarily regulated by the circadian system (e.g., melatonin). The exact mechanisms through which sleep affects circulating hormonal levels are not well understood. Much more is known about how the circadian system influences the secretion of hormones. Under normal circumstances, behaviors and the circadian system are synchronized with an optimal phase relationship, and consequently, hormonal systems are exquisitely regulated. Every bit of information constitutes but one small component of a broader, more global neurohormonal picture. In this review, we attempt to divide this analysis into sections including the pineal gland, adenohypophysis, neurohypophysis, describing the reciprocal influence regarding sleep and various neurohormones.

    View details for DOI 10.1016/B978-0-12-394623-2.00001-9

    View details for Web of Science ID 000306815900001

    View details for PubMedID 22640605

  • Hypocretin Antagonists in Insomnia Treatment and Beyond CURRENT PHARMACEUTICAL DESIGN Ruoff, C., Cao, M., Guilleminault, C. 2011; 17 (15): 1476-1482


    Hypocretin neuropeptides have been shown to regulate transitions between wakefulness and sleep through stabilization of sleep promoting GABAergic and wake promoting cholinergic/monoaminergic neural pathways. Hypocretin also influences other physiologic processes such as metabolism, appetite, learning and memory, reward and addiction, and ventilatory drive. The discovery of hypocretin and its effect upon the sleep-wake cycle has led to the development of a new class of pharmacologic agents that antagonize the physiologic effects of hypocretin (i.e. hypocretin antagonists). Further investigation of these agents may lead to novel therapies for insomnia without the side-effect profile of currently available hypnotics (e.g. impaired cognition, confusional arousals, and motor balance difficulties). However, antagonizing a system that regulates the sleep-wake cycle while also influencing non-sleep physiologic processes may create an entirely different but equally concerning side-effect profile such as transient loss of muscle tone (i.e. cataplexy) and a dampened respiratory drive. In this review, we will discuss the discovery of hypocretin and its receptors, hypocretin and the sleep-wake cycle, hypocretin antagonists in the treatment of insomnia, and other implicated functions of the hypocretin system.

    View details for PubMedID 21476951

  • Hypocretin and Its Emerging Role as a Target for Treatment of Sleep Disorders CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS Cao, M., Guilleminault, C. 2011; 11 (2): 227-234


    The neuropeptides hypocretin-1 and -2 (orexin A and B) are critical in the regulation of arousal and maintenance of wakefulness. Understanding the role of the hypocretin system in sleep/wake regulation has come from narcolepsy-cataplexy research. Deficiency of hypocretin results in loss of sleep/wake control with consequent unstable transitions from wakefulness into non-rapid eye movement (REM) and REM sleep, and clinical manifestations including daytime hypersomnolence, sleep attacks, and cataplexy. The hypocretin system regulates sleep/wake control through complex interactions between monoaminergic/cholinergic wake-promoting and GABAergic sleep-promoting neuronal systems. Research for the hypocretin agonist and the hypocretin antagonist for the treatment of sleep disorders has vigorously increased over the past 10 years. This review will focus on the origin, functions, and mechanisms in which the hypocretin system regulates sleep and wakefulness, and discuss its emerging role as a target for the treatment of sleep disorders.

    View details for DOI 10.1007/s11910-010-0172-9

    View details for PubMedID 21170610

  • Advances in the pharmacological approach to sleep disorders. Current pharmaceutical design Cao, M. 2011; 17 (15): 1416-1417

    View details for PubMedID 21476950

  • Obstructive Sleep Apnea and Chronic Opioid Use LUNG Guilleminault, C., Cao, M., Yue, H. J., Chawla, P. 2010; 188 (6): 459-468


    The use of opioids has been associated with development of sleep-disordered breathing, including central apneas, nocturnal oxygen desaturations, and abnormal breathing patterns. We describe sleep-disordered breathing and its subsequent treatment in a group of obstructive sleep apneic patients on chronic opioid therapy. Clinical evaluation followed by diagnostic overnight polysomnogram was performed in subjects on chronic opioid therapy who met the study criteria. All subjects had an initial CPAP titration followed by a repeat clinical evaluation. Subjects with an apnea-hypopnea index (AHI) ≥ 5 continued to report symptoms and had follow-up titration with bilevel positive therapy; then bilevel positive-pressure therapy with a back-up rate was then performed. Age-, sex-, and disease-severity-matched obstructive sleep apnea patients served as controls. Forty-four study participants, including a large group of women (50%), and 44 controls were enrolled in the study. Opioid subjects had AHI = 43.86 ± 1.19, with a central apnea index of 0.64 ± 1.36. Two abnormal breathing patterns were seen, including decreased inspiratory effort during an obstructive event and longer than expected pauses in breathing. Despite adequate titration with CPAP and bilevel positive-pressure therapy, nocturnal awakenings and central apnea awakenings persisted (AHI and central apnea indices of 13.81 ± 2.77 and 11.52 ± 2.12, respectively). Treatment with bilevel positive-pressure therapy with a back-up rate controlled the problem. Nonobese OSA patients with opioid intake have obstructive breathing with a different pattern. In this study, bilevel positive-pressure therapy with a back-up rate was the most effective treatment.

    View details for DOI 10.1007/s00408-010-9254-3

    View details for PubMedID 20658143

  • Families with sleepwalking SLEEP MEDICINE Cao, M., Guilleminault, C. 2010; 11 (7): 726-734


    Studies on families with sleepwalking are uncommonly published but can give further information on the phenotype of patients with chronic sleepwalking.Out of 51 individuals referred for chronic sleepwalking during a 5-year period, we obtained sufficient information on 7 families with direct relatives who reported sleepwalking with or without sleep terrors. Among 70 living direct family members, we obtained questionnaire responses from 50 subjects and identified 34 cases with a history of sleepwalking. Of the 50 subjects, 16 completed only questionnaires, while all the others also completed a clinical evaluation and nocturnal sleep recordings.There was a positive history of sleepwalking on either the paternal or maternal side of the family over several generations in our 7 families. Thirty-three clinically evaluated subjects had evidence of sleep-disordered breathing (SDB), with associated craniofacial risk factors for SDB (particularly maxillary and/or mandibular deficiencies). There was a complete overlap with the report of parasomnias and the presence of SDB. In cases with current sleepwalking, treatment of SDB coincided with clear improvement of the parasomnia.All of our subjects with parasomnias presented with familial traits considered as risk factors for SDB. These anatomical risk factors are present at birth and even subtle SDB can lead to sleep disruption and instability of NREM sleep. The question raised is: are factors leading to chronic sleep disruption the familial traits responsible for familial sleepwalking?

    View details for DOI 10.1016/j.sleep.2010.01.011

    View details for PubMedID 20598633

  • Advances in Narcolepsy MEDICAL CLINICS OF NORTH AMERICA Cao, M. 2010; 94 (3): 541-?


    Narcolepsy with cataplexy is a rare but life-long and challenging disorder. Current insight into the pathophysiology of this condition seems to be autoimmune-mediated postnatal cell death of hypocretin neurons occurring by organ-specific autoimmune targeting with HLA-T-cell receptor interactions. The hypocretin system seems to have an influence on multiple organ systems beyond its wake-promoting mechanisms. The recent availability of cerebrospinal fluid hypocretin-1 analysis has led to definitive diagnostic criteria for narcolepsy with cataplexy. Pharmacologic first-line treatments for excessive daytime sleepiness and cataplexy is sodium oxybate, with modafinil for daytime sleepiness, in adults and children. Other investigative agents and treatment modalities hold promise in future directions for narcolepsy.

    View details for DOI 10.1016/j.mcna.2010.02.008

    View details for Web of Science ID 000278853600008

    View details for PubMedID 20451031

  • Pediatric sleep disorders: How can sleep-medicine make a difference? SLEEP MEDICINE REVIEWS Cao, M., Guilleminault, C. 2009; 13 (2): 107-110

    View details for DOI 10.1016/j.smrv.2008.11.002

    View details for Web of Science ID 000264943400001

    View details for PubMedID 19233696

  • Sleep and breathing: The impact of mechanical ventilation on the quality of sleep CRITICAL CARE MEDICINE Cao, M., Sarinas, P. S. 2008; 36 (6): 1960-1962

    View details for DOI 10.1097/CCM.0b013e3181761260

    View details for Web of Science ID 000256513000042

    View details for PubMedID 18520652

  • Sleep difficulties and behavioral outcomes in children ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE Cao, M., Guilleminault, C. 2008; 162 (4): 385-389

    View details for Web of Science ID 000254752200014

    View details for PubMedID 18391149

  • Maxillomandibular advancement surgery for obstructive sleep apnea Minerva Pneumologica Cao M, Li KK, Guilleminault C 2008; 47: 203-12
  • The dual-wave bolus feature in continuous subcutaneous insulin infusion pumps controls prolonged post-prandial hyperglycaemia better than standard bolus in Type 1 diabetes DIABETES NUTRITION & METABOLISM Lee, S. W., Cao, M., Sajid, S., Hayes, M., Choi, L., Rother, C., de Leon, R. 2004; 17 (4): 211-216


    The dual-wave bolus delivers a combination of an immediate normal pre-meal insulin bolus (approximately 3 min) followed by an extended (or square-wave) bolus that is evenly delivered over several hr as programmed by the patient. The purpose of this study was to compare post-prandial glycaemic excursions following a high-fat meal after administration of insulin by normal vs dual-wave bolus. During this prospective, cross-over, repeated measures study, subjects with diabetes and treated with insulin pump therapy were evaluated using the continuous glucose monitoring system (CGMS) following three combinations of meal and bolus type. A control meal or a high-fat meal was given in place of the evening meal on three separate occasions and comparisons were made between: a) the control meal with normal insulin bolus delivery, b) the high-fat meal with normal insulin bolus delivery, and c) the high-fat meal with dual-wave insulin bolus delivery. Although mean baseline CGMS values were similar in each of the three combinations of meal and bolus type (p=0.54) and in the three hr immediately following the meal (p=0.64, p=0.83, p=1.0), when compared to the control meal/normal bolus and high-fat meal/dual-wave bolus combinations, CGMS profiles disclosed significantly elevated post-prandial glucose in hr 5 through 14 (p<0.05) following the high-fat/normal bolus combination. Prolonged post-prandial glycaemic excursions are identified using the CGMS. Treating post-prandial hyperglycaemia with dual-wave insulin delivery may help manage chronic hyperglycaemia in patients with diabetes.

    View details for Web of Science ID 000224974200002

    View details for PubMedID 15575341