Publications by authors named "Clete A Kushida"

120 Publications

Estimation of Apnea-Hypopnea Index using Deep Learning on 3D Craniofacial Scans.

IEEE J Biomed Health Inform 2021 May 7;PP. Epub 2021 May 7.

Obstructive sleep apnea (OSA) is characterized by decreased breathing events that occur through the night, with severity reported as the apnea-hypopnea index (AHI), which is associated with certain craniofacial features. In this study, we used data from 1366 patients collected as part of Stanford Technology Analytics and Genomics in Sleep (STAGES) across 11 US and Canadian sleep clinics and analyzed 3D craniofacial scans with the goal of predicting AHI, as measured using gold standard nocturnal polysomnography (PSG). First, the algorithm detects pre-specified landmarks on mesh objects and aligns scans in 3D space. Subsequently, 2D images and depth maps are generated by rendering and rotating scans by 45-degree increments. Resulting images were stacked as channels and used as input to multi-view convolutional neural networks, which were trained and validated in a supervised manner to predict AHI values derived from PSGs. The proposed model achieved a mean absolute error of 11.38 events/hour, a Pearson correlation coefficient of 0.4, and accuracy for predicting OSA of 67% using 10-fold cross-validation. The model improved further by adding patient demographics and variables from questionnaires. We also show that the model performed at the level of three sleep medicine specialists, who used clinical experience to predict AHI based on 3D scan displays. Finally, we created topographic displays of the most important facial features used by the model to predict AHI, showing importance of the neck and chin area. The proposed algorithm has potential to serve as an inexpensive and efficient screening tool for individuals with suspected OSA.
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http://dx.doi.org/10.1109/JBHI.2021.3078127DOI Listing
May 2021

Objective adherence to dental device versus positive airway pressure treatment in adults with obstructive sleep apnea.

J Sleep Res 2020 Nov 30:e13240. Epub 2020 Nov 30.

Division of Sleep Medicine, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.

Although mandibular advancement device (MAD) treatment of adults with obstructive sleep apnea (OSA) is generally less efficacious than positive airway pressure (PAP), the two treatments are associated, with similar clinical outcomes. As a sub-analysis of a randomized trial comparing the effect of MAD versus PAP on blood pressure, this study compared objectively measured adherence to MAD versus PAP treatment in adults with OSA. Adults with OSA (age 54.1 ± 11.2 [standard deviation] years, 71.1% male, apnea-hypopnea index 31.6 ± 22.7 events/h) were randomized to MAD (n = 89) or PAP (n = 91) treatment for 3-6 months. Objective adherence was assessed with a thermal sensor embedded in the MAD and a pressure sensor in the PAP unit. In a per protocol analysis, no difference was observed in average daily hours of use over all days in participants on MAD (n = 35, 4.4 ± 2.9 h) versus PAP (n = 51, 4.7 ± 1.6 h, p = .597) treatment when days with missing adherence data were included as no use. MAD was used on a lower percentage of days (62.5 ± 36.4% versus 79.9 ± 19.8%, p = .047), but with greater average daily hours of use on days used (6.4 ± 1.9 h versus 5.7 ± 1.2 h, p = .013). Average daily hours of use in the first week were associated with long-term adherence to MAD (p < .0001) and PAP (p = .0009) treatment. Similar results were obtained when excluding days with missing adherence data. In conclusion, no significant difference was observed in objectively measured average daily hours of MAD and PAP adherence in adults with OSA, despite differences in the patterns of use. MAD adherence in the first week predicted long-term use.
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http://dx.doi.org/10.1111/jsr.13240DOI Listing
November 2020

The sodium in sodium oxybate: is there cause for concern?

Sleep Med 2020 11 21;75:497-501. Epub 2020 Sep 21.

Stanford University Medical Center, 450 Broadway Street, MC 5704, Pavilion C, 2nd Floor, Redwood City, CA, USA. Electronic address:

Sodium oxybate (SO), the sodium salt of γ-hydroxybutyric acid, is one of the primary pharmacologic agents used to treat excessive sleepiness, disturbed nighttime sleep, and cataplexy in narcolepsy. The sodium content of SO ranges from 550 to 1640 mg at 3-9 g, given in two equal nightly doses. Clinicians are advised to consider daily sodium intake in patients with narcolepsy who are treated with SO and have comorbid disorders associated with increased cardiovascular (CV) risk, in whom sodium intake may be a concern. It remains unclear whether all patients with narcolepsy treated with SO should modify or restrict their sodium intake. No data are currently available specific to the sodium content or threshold of SO at which patients might experience increased CV risk. To appraise attributable risk, critical evaluation of the literature was conducted to examine the relationship between CV risk and sodium intake, narcolepsy, and SO exposure. The findings suggest that increased CV risk is associated with extremes of daily sodium intake, and that narcolepsy is associated with comorbidities that may increase CV risk in some patients. However, data from studies regarding SO use in patients with narcolepsy have shown a very low frequency of CV side effects (eg, hypertension) and no overall association with CV risk. In the absence of data that specifically address CV risk with SO based on its sodium content, the clinical evidence to date suggests that SO treatment does not confer additional CV risk in patients with narcolepsy.
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http://dx.doi.org/10.1016/j.sleep.2020.09.017DOI Listing
November 2020

How Support of Early Career Researchers Can Reset Science in the Post-COVID19 World.

Cell 2020 06 12;181(7):1445-1449. Epub 2020 Jun 12.

Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA 94305, USA.

The COVID19 crisis has magnified the issues plaguing academic science, but it has also provided the scientific establishment with an unprecedented opportunity to reset. Shoring up the foundation of academic science will require a concerted effort between funding agencies, universities, and the public to rethink how we support scientists, with a special emphasis on early career researchers.
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http://dx.doi.org/10.1016/j.cell.2020.05.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291965PMC
June 2020

A randomized controlled trial of CBT-I and PAP for obstructive sleep apnea and comorbid insomnia: main outcomes from the MATRICS study.

Sleep 2020 09;43(9)

Center for Circadian and Sleep Medicine, Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL.

Study Objectives: To investigate treatment models using cognitive behavioral therapy for insomnia (CBT-I) and positive airway pressure (PAP) for people with obstructive sleep apnea (OSA) and comorbid insomnia.

Methods: 121 adults with OSA and comorbid insomnia were randomized to receive CBT-I followed by PAP, CBT-I concurrent with PAP, or PAP only. PAP was delivered following standard clinical procedures for in-lab titration and home setup and CBT-I was delivered in four individual sessions. The primary outcome measure was PAP adherence across the first 90 days, with regular PAP use (≥4 h on ≥70% of nights during a 30-day period) serving as the clinical endpoint. The secondary outcome measures were the Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI) with good sleeper (PSQI <5), remission (ISI <8), and response (ISI reduction from baseline >7) serving as the clinical endpoints.

Results: No significant differences were found between the concomitant treatment arms and PAP only on PAP adherence measures, including the percentage of participants who met the clinical endpoint. Compared to PAP alone, the concomitant treatment arms reported a significantly greater reduction from baseline on the ISI (p = .0009) and had a greater percentage of participants who were good sleepers (p = .044) and remitters (p = .008). No significant differences were found between the sequential and concurrent treatment models on any outcome measure.

Conclusions: The findings from this study indicate that combining CBT-I with PAP is superior to PAP alone on insomnia outcomes but does not significantly improve adherence to PAP.
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http://dx.doi.org/10.1093/sleep/zsaa041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487869PMC
September 2020

A Multidisciplinary Perioperative Intervention to Improve Positive Airway Pressure Adherence in Patients With Obstructive Sleep Apnea: A Case Series.

A A Pract 2020 Feb;14(4):119-122

From the Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California.

Positive airway pressure (PAP) adherence in patients with obstructive sleep apnea (OSA) remains low despite known benefits. The postoperative inpatient period may represent a unique opportunity to address technical issues and promote self-efficacy, 2 important factors determining adherence, which may result in patients' seeking outpatient sleep medicine follow-up. We report our experience in developing a perioperative multidisciplinary intervention of reintroducing PAP therapy to nonadherent OSA patients with the intent of motivating patients to return to their outpatient sleep medicine clinics.
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http://dx.doi.org/10.1213/XAA.0000000000001165DOI Listing
February 2020

Corrigendum to "Adherence to continuous positive airway pressure improves attention/psychomotor function and sleepiness: a bias-reduction method with further assessment of APPLES" [Sleep Medicine 37 (2017) 130-134].

Sleep Med 2019 May 8;57:162. Epub 2019 Apr 8.

Stanford Sleep Medicine Center, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 450 Broadway Street, MC 5704, Pavilion C, 2nd Floor, Redwood City, CA, 94063-5704, USA. Electronic address:

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http://dx.doi.org/10.1016/j.sleep.2019.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511451PMC
May 2019

Positive Airway Pressure and Survival in Patients With Obstructive Sleep Apnea.

Authors:
Clete A Kushida

JAMA Otolaryngol Head Neck Surg 2019 06;145(6):515

Division of Sleep Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California.

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http://dx.doi.org/10.1001/jamaoto.2019.0345DOI Listing
June 2019

Epidemiological and pathophysiological evidence supporting links between obstructive sleep apnoea and Type 2 diabetes mellitus.

Singapore Med J 2019 Feb;60(2):54-56

Department of Respiratory and Critical Care Medicine, Tan Tock Seng Hospital, Singapore.

Obstructive sleep apnoea (OSA) and Type 2 diabetes mellitus (T2DM) are common diseases. The global prevalence of OSA is between 2% and 7% in general population cohorts. The worldwide prevalence of T2DM among adults (aged 20-79 years) was estimated to be 6.4%. The concurrent presence of OSA and T2DM can be expected in the same patient, given their high prevalence and similar predisposition. We reviewed the overlapping pathophysiology of OSA and T2DM in this article.
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http://dx.doi.org/10.11622/smedj.2019015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395837PMC
February 2019

Associations Between Sleep Quality, Sleep Architecture and Sleep Disordered Breathing and Memory After Continuous Positive Airway Pressure in Patients with Obstructive Sleep Apnea in the Apnea Positive Pressure Long-term Efficacy Study (APPLES).

Sleep Sci 2018 Jul-Aug;11(4):231-238

Stanford University, Sleep Clinic and Center for Human Sleep Research - Redwood City - CA - United States.

Objective: The role of sleep architecture in consolidation of memory has not been extensively investigated. In this study, the association of continuous positive airway pressure (CPAP) and sleep architecture and quality, and sleep disordered breathing on changes in memory are explored during the course of a 6 month clinical trial of CPAP or sham CPAP (APPLES).

Methods: 848 participants had polysomnographic and memory assessments (Buschke Selective Reminding Test [Buschke] and Digit Symbol Substitution Test [DSST]) at baseline, CPAP/Sham CPAP titration, and the 2 and 6 month time points. Half were assigned to the CPAP and Sham CPAP groups respectively. Changes in performance on the Buschke and the DSST were analyzed over the course of the study between CPAP and Sham CPAP as well as in relationship to changes in sleep architecture, sleep quality and sleep disordered breathing (SDB).

Results: Sleep architecture, sleep quality and SDB improved in the CPAP group at 6 months; performance on the Buschke and DSST improved equally in both CPAP and Sham CPAP groups. There also were no significant correlations between changes in the amount or percentage of sleep stages between baseline and the 6 months, and corresponding changes in either the Buschke or the DSST. However, when stratified by the upper quartile and lower 3 quartiles, greater changes in the Buschke occurred over 6 months in the top quartile of total sleep time (5.7±7.3 vs. 4.0±6.8, ≤0.01) and amount of N3 sleep (55.9±7.7 vs. 53.6±8.9 min, ≤0.01). Those with more %N3 at 6 months scored better on the Buschke as well (55.9±7.8 vs. 53.6±8.9, ≤0.01). Borderline improvement in the DSST over 6 months was observed in the top quartiles of amount of N3 and %N3. Those in the top quartile of the amount of REM and %REM also showed greater improvement in the Buschke after 6 months. No differences were observed for the AHI, but those in the top quartile of oxygen desaturation had worse scores on the Buschke at 6 months. CPAP/Sham CPAP adherence did not impact 6 month Buschke or DSST performance.

Conclusions: CPAP improved long-term sleep duration, quality and architecture, but did not memory. However, large changes in REM and N3 sleep as well as moderate amounts of nocturnal hypoxemia are associated with changes in assessments of memory.
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http://dx.doi.org/10.5935/1984-0063.20180037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361302PMC
February 2019

Non-steady State Modeling of the Ventilatory Depressant Effect of Remifentanil in Awake Patients Experiencing Moderate-to-severe Obstructive Sleep Apnea.

Anesthesiology 2019 02;130(2):213-226

From the Department of Anesthesiology, Perioperative and Pain Medicine (A.G.D., S.L.S.) the Department of Psychiatry and Behavioral Sciences, and Stanford Center for Sleep Sciences and Medicine (C.A.K.) the Department of Otolaryngology Head & Neck Surgery (R.C.), Stanford University School of Medicine, Stanford, California the Outcomes Research Consortium, Cleveland, Ohio (A.G.D.) the Department of Otorhinolaryngology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia (N.H.A.R.).

Background: Evidence suggests that obstructive sleep apnea promotes postoperative pulmonary complications by enhancing vulnerability to opioid-induced ventilatory depression. We hypothesized that patients with moderate-to-severe obstructive sleep apnea are more sensitive to remifentanil-induced ventilatory depression than controls.

Methods: After institutional approval and written informed consent, patients received a brief remifentanil infusion during continuous monitoring of ventilation. We compared minute ventilation in 30 patients with moderate-to-severe obstructive sleep apnea diagnosed by polysomnography and 20 controls with no to mild obstructive sleep apnea per polysomnography. Effect site concentrations were estimated by a published pharmacologic model. We modeled minute ventilation as a function of effect site concentration and the estimated carbon dioxide. Obstructive sleep apnea status, body mass index, sex, age, use of continuous positive airway pressure, apnea/hypopnea events per hour of sleep, and minimum nocturnal oxygen saturation measured by pulse oximetry in polysomnography were tested as covariates for remifentanil effect site concentration at half-maximal depression of minute ventilation (Ce50) and included in the model if a threshold of 6.63 (P < 0.01) in the reduction of objective function was reached and improved model fit.

Results: Our model described the observed minute ventilation with reasonable accuracy (22% median absolute error). We estimated a remifentanil Ce50 of 2.20 ng · ml (95% CI, 2.09 to 2.33). The estimated value for Ce50 was 2.1 ng · ml (95% CI, 1.9 to 2.3) in patients without obstructive sleep apnea and 2.3 ng · ml (95% CI, 2.2 to 2.5) in patients with obstructive sleep apnea, a statistically nonsignificant difference (P = 0.081). None of the tested covariates demonstrated a significant effect on Ce50. Likelihood profiling with the model including obstructive sleep apnea suggested that the effect of obstructive sleep apnea on remifentanil Ce50 was less than 5%.

Conclusions: Obstructive sleep apnea status, apnea/hypopnea events per hour of sleep, or minimum nocturnal oxygen saturation measured by pulse oximetry did not influence the sensitivity to remifentanil-induced ventilatory depression in awake patients receiving a remifentanil infusion of 0.2 μg · kg of ideal body weight per minute.
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http://dx.doi.org/10.1097/ALN.0000000000002430DOI Listing
February 2019

Thirty-five alternatives to positive airway pressure therapy for obstructive sleep apnea: an overview of meta-analyses.

Expert Rev Respir Med 2018 11 3;12(11):919-929. Epub 2018 Oct 3.

f Department of Psychiatry, Division of Sleep Medicine , Stanford Hospital and Clinics , Redwood City , CA , USA.

Introduction: Positive airway pressure (PAP) devices are generally considered to be the first-line treatment of choice for most adults with obstructive sleep apnea (OSA). However, there are several alternatives. It is important for patients and their sleep providers to be aware of the most up-to-date information regarding the current international literature. Areas covered: The objective is to provide an overview of the meta-analyses evaluating non-PAP treatments for OSA. Four authors searched four databases, including PubMed/MEDLINE through 30 November 2017, for meta-analyses evaluating non-PAP therapies as treatment for OSA. Thirty-five non-PAP treatments were identified and were categorized based on the following anatomical subsites: (1) nose, (2) palate and oropharynx, (3) tongue, (4) skeletal surgery and jaw repositioning, and (5) other surgical and medical interventions. Treatments identified included surgeries, drugs, behavior modifications, nonsurgical weight loss, medical devices, body positioning, and oxygen treatment. Expert commentary: The 35 treatments described vary in their effectiveness in treating OSA in adults. In general, isolated nasal treatments are the least effective, whereas treatments that bypass the upper airway, significantly open the upper airway, and/or address multiple levels of the upper airway are more effective in improving apnea-hypopnea index and lowest oxygen saturation.
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http://dx.doi.org/10.1080/17476348.2018.1522253DOI Listing
November 2018

Deception in clinical trials and its impact on recruitment and adherence of study participants.

Contemp Clin Trials 2018 09 21;72:146-157. Epub 2018 Aug 21.

Stanford Sleep Medicine Center, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 450 Broadway Street, MC 5704, Pavilion C, 2nd Floor, Redwood City, CA 94063-5704, United States.

Deceptive practices by participants in clinical research are prevalent. It has been shown that as high as 75% of participants withheld information to avoid exclusion from studies. Self-reported adherence has been found to be largely inaccurate. Overcoming deception is a critical issue, since the safety of study participants, the integrity of research data and research resources are at risk. In this review article, we examine deception from the perspective of investigators conducting clinical trials; we describe the types (concealment, fabrication, drug holidays and collusion), prevalence, risks, and predictors of deception, and propose an approach to reduce the impact of deception, especially on adherence, in clinical trials.
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http://dx.doi.org/10.1016/j.cct.2018.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203693PMC
September 2018

Vitamin D and obstructive sleep apnea: a systematic review and meta-analysis.

Sleep Med 2018 03 14;43:100-108. Epub 2017 Dec 14.

Otolaryngology-Head and Neck Surgery, Tripler Army Medical Center, HI, USA. Electronic address:

Objective/background: Several studies have reported an association between 25-hydroxyvitamin D (25(OH)D) levels and obstructive sleep apnea (OSA) patients. The objective of the current study was to perform a systematic review and meta-analysis of these studies and report the findings.

Patients/methods: Authors searched for studies (through January 1, 2017) reporting 25(OH)D serum levels in OSA patients. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was followed.

Results: Fourteen studies with 4937 subjects met inclusion criteria. There were 1513 controls and 3424 OSA patients. The 25(OH)D serum levels for controls and mild OSA patients were 28.16 ± 9.39 ng/mL (95% CI 27.64, 28.68) and 27.41 ± 9.42 ng/mL (95% CI 26.87, 27.95), respectively. The 25(OH)D serum levels for controls and moderate OSA patients were 28.21 ± 9.38 ng/mL (95% CI 27.70, 28.72) and 25.48 ± 10.34 ng/mL (95% CI 24.68, 26.28), respectively. The 25(OH)D serum levels for controls and severe OSA patients were 28.32 ± 9.65 ng/mL (95% CI 27.80, 28.84) and 21.88 ± 10.24 ng/mL (95% CI 21.08, 22.68), respectively. Using random effects modeling, the 25(OH)D serum levels were decreased for patients with OSA when compared to control groups (mean differences were -2.7% for mild OSA, -10.1% for moderate OSA and -17.4% for severe OSA).

Conclusions: There was a relative insufficiency in serum 25(OH)D levels among OSA patients compared to control patients, which was incrementally exacerbated with increasing severity of sleep apnea. It was unclear whether a low 25(OH)D was a risk factor for OSA or if OSA was a risk factor for 25(OH)D. It was also possible that the association between 25(OH)D and OSA was due to body mass index (BMI).
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http://dx.doi.org/10.1016/j.sleep.2017.10.016DOI Listing
March 2018

Reliability of the American Academy of Sleep Medicine Rules for Assessing Sleep Depth in Clinical Practice.

J Clin Sleep Med 2018 02 15;14(2):205-213. Epub 2018 Feb 15.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Study Objectives: The American Academy of Sleep Medicine has published manuals for scoring polysomnograms that recommend time spent in non-rapid eye movement sleep stages (stage N1, N2, and N3 sleep) be reported. Given the well-established large interrater variability in scoring stage N1 and N3 sleep, we determined the range of time in stage N1 and N3 sleep scored by a large number of technologists when compared to reasonably estimated true values.

Methods: Polysomnograms of 70 females were scored by 10 highly trained sleep technologists, two each from five different academic sleep laboratories. Range and confidence interval (CI = difference between the 5th and 95th percentiles) of the 10 times spent in stage N1 and N3 sleep assigned in each polysomnogram were determined. Average values of times spent in stage N1 and N3 sleep generated by the 10 technologists in each polysomnogram were considered representative of the true values for the individual polysomnogram. Accuracy of different technologists in estimating delta wave duration was determined by comparing their scores to digitally determined durations.

Results: The CI range of the ten N1 scores was 4 to 39 percent of total sleep time (% TST) in different polysomnograms (mean CI ± standard deviation = 11.1 ± 7.1 % TST). Corresponding range for N3 was 1 to 28 % TST (14.4 ± 6.1 % TST). For stage N1 and N3 sleep, very low or very high values were reported for virtually all polysomnograms by different technologists. Technologists varied widely in their assignment of stage N3 sleep, scoring that stage when the digitally determined time of delta waves ranged from 3 to 17 seconds.

Conclusions: Manual scoring of non-rapid eye movement sleep stages is highly unreliable among highly trained, experienced technologists. Measures of sleep continuity and depth that are reliable and clinically relevant should be a focus of clinical research.
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http://dx.doi.org/10.5664/jcsm.6934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786839PMC
February 2018

Predictors of sleepiness in obstructive sleep apnoea at baseline and after 6 months of continuous positive airway pressure therapy.

Eur Respir J 2017 11 30;50(5). Epub 2017 Nov 30.

Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

We evaluated factors associated with subjective and objective sleepiness at baseline and after 6 months of continuous positive airway pressure (CPAP) therapy in patients with obstructive sleep apnoea (OSA).We analysed data from the Apnoea Positive Pressure Long-term Efficacy Study (APPLES), a prospective 6-month multicentre randomised controlled trial with 1105 subjects with OSA, 558 of who were randomised to active CPAP. Epworth sleepiness scale (ESS) scores and the mean sleep latency (MSL) on the maintenance of wakefulness test at baseline and after 6 months of CPAP therapy were recorded.Excessive sleepiness (ESS score >10) was present in 543 (49.1%) participants. Younger age, presence of depression and higher apnoea-hypopnoea index were all associated with higher ESS scores and lower MSL. Randomisation to the CPAP group was associated with lower odds of sleepiness at 6 months. The prevalence of sleepiness was significantly lower in those using CPAP >4 h·night using CPAP ≤4 h·night Among those with good CPAP adherence, those with ESS >10 at baseline had significantly higher odds (OR 8.2, p<0.001) of persistent subjective sleepiness.Lower average nightly CPAP use and presence of sleepiness at baseline were independently associated with excessive subjective and objective sleepiness after 6 months of CPAP therapy.
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http://dx.doi.org/10.1183/13993003.00348-2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435030PMC
November 2017

Adjustment for Variable Adherence Under Hierarchical Structure: Instrumental Variable Modeling Through Compound Residual Inclusion.

Med Care 2017 12 13;55(12):e120-e130. Epub 2016 Jan 13.

*Stanford University Human Immune Monitoring Center, Institute for Immunity Transplantation and Infection, Stanford University School of Medicine, Stanford †Center for Innovation to Implementation, VA Palo Alto Health Care System, Menlo Park ‡Department of Medicine, Division of General Medical Disciplines §Stanford Sleep Medicine Center and Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA.

Background: Variable adherence to assigned conditions is common in randomized clinical trials.

Objectives: A generalized modeling framework under longitudinal data structures is proposed for regression estimation of the causal effect of variable adherence on outcome, with emphasis upon adjustment for unobserved confounders.

Research Design: A nonlinear, nonparametric random-coefficients modeling approach is described. Estimates of local average treatment effects among compliers can be obtained simultaneously for all assigned conditions to which participants are randomly assigned within the trial. Two techniques are combined to address time-varying and time-invariant unobserved confounding-residual inclusion and nonparametric random-coefficients modeling. Together these yield a compound, 2-stage residual inclusion, instrumental variables model.

Subjects: The proposed method is illustrated through a set of simulation studies to examine small-sample bias and in application to neurocognitive outcome data from a large, multicenter, randomized clinical trial in sleep medicine for continuous positive airway pressure treatment of obstructive sleep apnea.

Results: Results of simulation studies indicate that, relative to a standard comparator, the proposed estimator reduces bias in estimates of the causal effect of variable adherence. Bias reductions were greatest at higher levels of residual variance and when confounders were time varying.

Conclusions: The proposed modeling framework is flexible in the distributions of outcomes that can be modeled, applicable to repeated measures longitudinal structures, and provides effective reduction of bias due to unobserved confounders.
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http://dx.doi.org/10.1097/MLR.0000000000000464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942413PMC
December 2017

Adherence to continuous positive airway pressure improves attention/psychomotor function and sleepiness: a bias-reduction method with further assessment of APPLES.

Sleep Med 2017 Sep 14;37:130-134. Epub 2017 Jul 14.

Stanford Sleep Medicine Center, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 450 Broadway Street, MC 5704, Pavilion C, 2nd Floor, Redwood City, CA 94063-5704, USA. Electronic address:

Objective/background: Variable adherence to prescribed therapies for sleep disorders is commonplace. This study was designed to integrate three available statistical technologies (instrumental variables, residual inclusion, and shrinkage) to allow sleep investigators to employ data on variable adherence in the estimation of the causal effect of treatment as received on clinical outcomes.

Patients/methods: Using data from the Apnea Positive Pressure Long-term Efficacy Study (APPLES), regression adjustment for observed and unobserved confounders was applied to two primary neurocognitive outcomes, plus two measures of sleepiness. We demonstrate how to obtain estimates of reduced uncertainty for the causal effect of treatment as received for continuous positive airway pressure (CPAP) within clinical subpopulations (defined by baseline disease severity) of sleep apnea patients.

Results And Conclusions: Following six months of treatment, statistically significant improvements caused by device adherence were detected for subjective sleepiness in mild, moderate, and severe disease, objective sleepiness in severe disease, and attention and psychomotor function in moderate disease. Some evidence for worsening of learning and memory due to increased adherence in moderate disease was also detected. Application to APPLES illustrates that this method can yield bias corrections for unobserved confounders that are substantial-revealing new clinical findings. Use of this fully general method throughout sleep research could sharpen understanding of the true efficacy of pharmacotherapies, medical devices, and behavioral interventions. Extensive technical appendices are provided to facilitate application of this general method. Clinicaltrials.gov identifier NCT00051363.
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http://dx.doi.org/10.1016/j.sleep.2017.06.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609486PMC
September 2017

History and strategic initiatives of the new World Sleep Society.

Authors:
Clete A Kushida

Sleep Med Rev 2018 12 25;42:229-230. Epub 2017 Jul 25.

Stanford University, Stanford, CA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.smrv.2017.07.003DOI Listing
December 2018

Short Sleep Duration Is Associated With Abnormal Serum Aminotransferase Activities and Nonalcoholic Fatty Liver Disease.

Clin Gastroenterol Hepatol 2018 04 4;16(4):588-590. Epub 2017 Sep 4.

Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California. Electronic address:

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http://dx.doi.org/10.1016/j.cgh.2017.08.049DOI Listing
April 2018

Tongue retaining devices for obstructive sleep apnea: A systematic review and meta-analysis.

Am J Otolaryngol 2017 May - Jun;38(3):272-278. Epub 2017 Jan 18.

Department of Otolaryngology, Division of Sleep Surgery and Medicine, Tripler Army Medical Center, HI, USA; Department of Psychiatry and Behavioral Sciences, Division of Sleep Medicine,Stanford Hospital and Clinics, 450 Broadway St. 2nd Floor, Redwood City, CA 94063, USA. Electronic address:

Objective: Tongue Retaining Devices (TRD) anteriorly displace the tongue with suction forces while patients sleep. TRD provide a non-surgical treatment option for patients with Obstructive Sleep Apnea (OSA). Our objective was to conduct a systematic review of the international literature for TRD outcomes as treatment for OSA.

Methods: Three authors independently and systematically searched four databases (including PubMed/MEDLINE) through June 26, 2016. We followed guidelines set within the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Results: Sixteen studies with 242 patients met criteria. The overall means±standard deviations (M±SD) for apnea-hypopnea index (AHI) decreased from 33.6±21.1/h to 15.8±16.0/h (53% reduction). Seven studies (81 patients) reported lowest oxygen saturation (LSAT), which improved from 79.8±17.5% to 83.9±8.6%. Four studies (93 patients) reported Epworth sleepiness scale (ESS), which decreased from 10.8±4.8 to 8.2±4.5, p <0.0001. Four studies (31 patients) reported Oxygen Desaturation Index (ODI) which decreased from 29.6±32.1 to 12.9±8.7, a 56.4% reduction.

Conclusion: Current international literature demonstrates that tongue retaining devices reduce apnea-hypopnea index by 53%, increase lowest oxygen saturation by 4.1 oxygen saturation points, decrease oxygen desaturation index by 56% and decrease Epworth sleepiness scale scores by 2.8 points. Tongue retaining devices provide a statistically effective alternative treatment option for obstructive sleep apnea.
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http://dx.doi.org/10.1016/j.amjoto.2017.01.006DOI Listing
April 2018

Effect of Pioglitazone on Cardiometabolic Risk in Patients With Obstructive Sleep Apnea.

Am J Cardiol 2017 04 25;119(8):1205-1210. Epub 2017 Jan 25.

Department of Medicine, Stanford University School of Medicine, Stanford, California.

Prevalence of insulin resistance is increased in patients with obstructive sleep apnea (OSA). Because insulin resistance is an independent predictor of cardiovascular disease (CVD), this study was initiated to see if pioglitazone administration would improve insulin sensitivity and thereby decrease risk of CVD in overweight/obese, nondiabetic, insulin-resistant patients with untreated OSA. Patients (n = 30) were administered pioglitazone (45 mg/day) for 8 weeks, and measurements were made before and after intervention of insulin action (insulin-mediated glucose uptake by the insulin suppression test), C-reactive protein, lipid/lipoprotein profile, and gene expression profile of periumbilical subcutaneous fat tissue. Insulin sensitivity increased 31% (p <0.001) among pioglitazone-treated subjects, associated with a decrease in C-reactive protein concentration (p ≤0.001), a decrease in plasma triglyceride, and increase in high-density lipoprotein cholesterol concentrations (p ≤0.001), accompanied by significant changes in apolipoprotein A1 and B concentrations and lipoprotein subclasses known to decrease CVD risk. In addition, subcutaneous adipose tissue gene expression profile showed a 1.6-fold (p <0.01) increase in GLUT4 expression and decreased expression in 5 of 9 inflammatory genes (p <0.05). In conclusion, enhanced insulin sensitivity can significantly decrease multiple cardiometabolic risk factors in patients with untreated OSA, consistent with the view that coexisting insulin resistance plays an important role in the association between OSA and increased risk of CVD.
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http://dx.doi.org/10.1016/j.amjcard.2016.12.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386603PMC
April 2017

Laser-Assisted Uvulopalatoplasty for Obstructive Sleep Apnea: A Systematic Review and Meta-Analysis.

Sleep 2017 03;40(3)

Department of Otolaryngology-Head and Neck Surgery, Division of Sleep Surgery, Stanford Hospital and Clinics, Stanford, CA.

Study Objectives: Laser-assisted uvulopalatoplasty (LAUP) has been used as treatment for obstructive sleep apnea (OSA). The objective of this study was to perform a systematic review and meta-analysis for LAUP alone as treatment for OSA in adults.

Methods: Three authors searched five databases (including PubMed/MEDLINE) from inception through October 30, 2016 for peer-reviewed studies, with any design/language. A study quality assessment tool was used. The PRISMA statement was followed. A meta-analysis was performed.

Results: Twenty-three adult studies (717 patients) reported outcomes (age: 50 ± 9 years, body mass index: 29 ± 4 kg/m2). The pre- and post-LAUP means (M) ± standard deviations (SDs) for apnea-hypopnea index (AHI) were 28 ± 13 and 19 ± 12 events/h (32% reduction). Random effects modeling for 519 patients demonstrated an AHI mean difference (MD) of -6.56 [95% CI -10.14, -2.97] events/h. Individual patient data analyses demonstrate a 23% success rate (≥50% reduction in AHI and <20 events/h) and an 8% cure rate. Additionally, 44% of patients had worsening of their AHI after LAUP. Lowest oxygen saturation (LSAT) improved from a M ± SD of 80 ± 8% to 82 ± 7%. A limitation is that most studies were case series studies and only two were randomized controlled trials.

Conclusions: In this meta-analysis, LAUP reduced AHI by 32% among all patients; while the LSAT only changed minimally. Individual data demonstrated a success rate of 23%, cure rate of 8%, and worsening of the AHI among 44% of patients. We recommend that LAUP be performed with caution or not performed at all given the unfavorable results of currently published studies.
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http://dx.doi.org/10.1093/sleep/zsx004DOI Listing
March 2017

Preoperative Treatment of Obstructive Sleep Apnea With Positive Airway Pressure is Associated With Decreased Incidence of Atrial Fibrillation After Cardiac Surgery.

J Cardiothorac Vasc Anesth 2017 Aug 14;31(4):1250-1256. Epub 2016 Nov 14.

Department of Psychiatry & Behavioral Science-Stanford Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Stanford, CA.

Objective: Based on clinical studies in the nonsurgical population that positive airway pressure (PAP) therapy for patients with obstructive sleep apnea (OSA) provides benefits for those with atrial fibrillation, the authors tested the hypothesis that PAP in patients with OSA reduces the incidence of postoperative atrial fibrillation (POAF) after cardiac surgery.

Design: Retrospective analysis.

Setting: Single-center university hospital.

Participants: The study comprised 192 patients in sinus rhythm preoperatively who were undergoing nontransplantation or ventricular assist device implantation cardiac surgery requiring cardiopulmonary bypass but not requiring systemic circulatory arrest, with documented PAP adherence from January 2008 to October 2015.

Interventions: Retrospective review of medical records.

Measurements And Main Results: POAF was defined as atrial fibrillation requiring therapeutic intervention. Of the 192 patients with OSA, 104 (54%) were documented to be PAP-adherent and 88 (46%) were reported to be PAP-nonadherent. Among PAP users, 49 (47%) developed POAF; among PAP nonusers, 59 (66%) developed POAF. The adjusted hazard ratio was 0.59 (95% confidence interval 0.40-0.86, p<0.01). No differences were observed in intensive care unit length of stay (4.0±3.4 days for PAP-adherent group v 5.0±6.2 days for PAP-nonadherent group; p = 0.22) or hospital length of stay (10.7±6.6 days for PAP-adherent group v 10.9±7.3 days for PAP nonadherent group; p = 0.56). A lower median postoperative creatinine rise was observed in PAP-adherent patients (18.2% [8.3%-37.5%) v 31.3% [13.3%-50%]; p< 0.01).

Conclusion: Preoperative PAP use in patients with OSA was associated with a decreased rate of POAF after cardiac surgery.
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http://dx.doi.org/10.1053/j.jvca.2016.11.016DOI Listing
August 2017

Nasal Dilators (Breathe Right Strips and NoZovent) for Snoring and OSA: A Systematic Review and Meta-Analysis.

Pulm Med 2016 13;2016:4841310. Epub 2016 Dec 13.

Department of Psychiatry and Behavioral Sciences, Sleep Medicine Division, Stanford Hospital and Clinics, Redwood City, CA 94063, USA.

. To systematically review the international literature for studies evaluating internal (NoZovent) and external (Breathe Right Strips) nasal dilators as treatment for obstructive sleep apnea (OSA). . Systematic review with meta-analysis. . Four databases, including PubMed/MEDLINE, were searched through September 29, 2016. . One-hundred twelve studies were screened, fifty-eight studies were reviewed, and fourteen studies met criteria. In 147 patients, the apnea-hypopnea index (AHI) was reported, and there was an improvement from a mean ± standard deviation (M ± SD) of 28.7 ± 24.0 to 27.4 ± 23.3 events/hr, value 0.64. There was no significant change in AHI, lowest oxygen saturation, or snoring index in OSA patients when using nasal dilators. However, a subanalysis demonstrated a slight reduction in apnea index (AI) with internal nasal dilators (decrease by 4.87 events/hr) versus minimal change for external nasal dilators (increase by 0.64 events/hr). . Although nasal dilators have demonstrated improved nasal breathing, they have not shown improvement in obstructive sleep apnea outcomes, with the exception of mild improvement in apnea index when internal nasal dilators were used.
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http://dx.doi.org/10.1155/2016/4841310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5187471PMC
March 2017

Understanding Phenotypes of Obstructive Sleep Apnea: Applications in Anesthesia, Surgery, and Perioperative Medicine.

Anesth Analg 2017 01;124(1):179-191

From the *Department of Anesthesiology, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; †Toronto Sleep and Pulmonary Centre, Toronto, Ontario, Canada; ‡Department of Psychiatry and Behavioral Sciences, Stanford Center for Sleep Sciences and Medicine, University of California, Palo Alto, California; §Division of Pulmonary and Critical Care Medicine, University of California, San Diego, San Diego, California.

Obstructive sleep apnea (OSA) is a prevalent sleep-disordered breathing with potential long-term major neurocognitive and cardiovascular sequelae. The pathophysiology of OSA varies between individuals and is composed of different underlying mechanisms. Several components including the upper airway anatomy, effectiveness of the upper airway dilator muscles such as the genioglossus, arousal threshold of the individual, and inherent stability of the respiratory control system determine the pathogenesis of OSA. Their recognition may have implications for the perioperative health care team. For example, OSA patients with a high arousal threshold are likely to be sensitive to sedatives and narcotics with a higher risk of respiratory arrest in the perioperative period. Supplemental oxygen therapy can help to stabilize breathing in OSA patients with inherent respiratory instability. Avoidance of supine position can minimize airway obstruction in patients with a predisposition to upper airway collapse in this posture. In this review, the clinically relevant endotypes and phenotypes of OSA are described. Continuous positive airway pressure (CPAP) therapy is the treatment of choice for most patients with OSA but tolerance and adherence can be a problem. Patient-centered individualized approaches to OSA management will be the focus of future research into developing potential treatment options that will help decrease the disease burden and improve treatment effectiveness.
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http://dx.doi.org/10.1213/ANE.0000000000001546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429962PMC
January 2017

Does enhanced insulin sensitivity improve sleep measures in patients with obstructive sleep apnea: a randomized, placebo-controlled pilot study.

Sleep Med 2016 06 21;22:57-60. Epub 2016 Jun 21.

Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.

Background: High fasting insulin levels have been reported to predict development of observed apneas, suggesting that insulin resistance may contribute to the pathogenesis of obstructive sleep apnea (OSA). The aim of this study was to determine whether enhancing insulin sensitivity in individuals with OSA would improve sleep measures.

Patients/methods: Insulin-resistant, nondiabetic individuals with untreated OSA were randomized (2:1) to pioglitazone (45 mg/day) or placebo for eight weeks in this single-blind study. All individuals had repeat measurements pertaining to sleep (overnight polysomnography and functional outcomes of sleep questionnaire) and insulin action (insulin suppression test).

Results: A total of 45 overweight/obese men and women with moderate/severe OSA were randomized to pioglitazone (n = 30) or placebo (n = 15). Although insulin sensitivity increased 31% among pioglitazone-treated compared with no change among individuals receiving placebo (p <0.001 for between-group difference), no improvement in quantitative or qualitative sleep measurements was observed.

Conclusions: Pioglitazone administration increased insulin sensitivity in otherwise untreated individuals with OSA, without any change in polysomnographic sleep measures over an eight-week period. These findings do not support a causal role for insulin resistance in the pathogenesis of OSA.
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http://dx.doi.org/10.1016/j.sleep.2016.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996352PMC
June 2016

A review of neurocognitive function and obstructive sleep apnea with or without daytime sleepiness.

Sleep Med 2016 07 2;23:99-108. Epub 2016 Mar 2.

Department of Psychiatry and Behavioral Sciences, Division of Sleep Medicine, Stanford Hospital and Clinics, Redwood City, CA, USA. Electronic address:

Excessive daytime sleepiness (EDS) and neurocognitive dysfunction are commonly observed in patients with obstructive sleep apnea (OSA), and these daytime functional deficits can be reversed partly or completely with treatment such as continuous positive airway pressure (CPAP). Although daytime sleepiness is a possible etiology for neurocognitive dysfunction in OSA patients, EDS is not universally present in all patients with OSA. The objective of this review is to summarize the relationship between neurocognitive function and EDS in OSA, as well as the difference in cognitive domains, improvement, and application of CPAP therapy between patients with and without EDS. Two authors independently searched PubMED/Medline, The Cochrane Library and Scopus through May 27, 2015. Sixty-five articles were included in this review. The literature demonstrated a wide range of neurocognitive deficits in OSA patients with EDS, but no more extensive and complex cognitive domains (eg, executive function) in patients without EDS. However, the current literature had very few studies with large sample sizes and extended follow-up that evaluated the effect of CPAP for OSA in patients with and without sleepiness. CPAP failed to improve cognitive dysfunction in OSA patients without EDS after short-term therapy. The evidence suggests that daytime sleepiness possibly relates to the domain and extent of cognitive impairments in OSA, and CPAP therapy has little effect on the improvement of cognitive deficits in OSA patients without EDS. We recommend that additional prospective studies be performed to further quantify the relationship between neurocognitive function in OSA patients with and without EDS.
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http://dx.doi.org/10.1016/j.sleep.2016.02.008DOI Listing
July 2016

Impact of continuous positive airway pressure (CPAP) on quality of life in patients with obstructive sleep apnea (OSA).

J Sleep Res 2016 12 30;25(6):731-738. Epub 2016 May 30.

Division of Sleep and Circadian Disorders Medicine, Brigham and Women's Hospital and Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.

Obstructive sleep apnea is a chronic illness with increasing prevalence. In addition to associated cardiovascular comorbidities, obstructive sleep apnea syndrome has been linked to poor quality of life, occupational accidents, and motor vehicle crashes secondary to excessive daytime sleepiness. Although continuous positive airway pressure is the gold standard for sleep apnea treatment, its effects on quality of life are not well defined. In the current study we investigated the effects of treatment on quality of life using the data from the Apnea Positive Pressure Long-term Efficacy Study (APPLES), a randomized controlled trial of continuous positive airway pressure (CPAP) versus sham CPAP. The Calgary Sleep Apnea Quality of Life Index (SAQLI) was used to assess quality of life. Overall we found no significant improvement in quality of life among sleep apnea patients after CPAP treatment. However, after stratifying by OSA severity, it was found that long-term improvement in quality of life might occur with the use of CPAP in people with severe and possibly moderate sleep apnea, and no demonstrable improvement in quality of life was noted among participants with mild obstructive sleep apnea.
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http://dx.doi.org/10.1111/jsr.12430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436801PMC
December 2016

Five-Minute Awake Snoring Test for Determining CPAP Pressures (Five-Minute CPAP Test): A Pilot Study.

Sleep Disord 2016 11;2016:7380874. Epub 2016 Jan 11.

Department of Psychiatry and Behavioral Sciences, Division of Sleep Medicine, Stanford Hospital and Clinics, Redwood City, CA 94063, USA.

Objective. To develop a quick, simple, bedside test for determining continuous positive airway pressures (CPAP) for obstructive sleep apnea (OSA) patients. Study Design. Prospective case series at a tertiary medical center. Methods. The Five-Minute Awake Snoring Test for Determining CPAP (Five-Minute CPAP Test) was developed and tested. Patients wear a soft-gel nasal triangle mask while holding a tongue depressor with the wide section (1.75 cm) between the teeth. Fixed pressure nasal CPAP is applied while the patient simulates snoring at 4 centimeters of water pressure. The pressure is incrementally titrated up and then down to determine the lowest pressure at which the patient cannot snore (Quiet Pressure). Results. Overall, thirty-eight patients participated. All could simulate snoring. Correlation coefficients were statistically significant between Quiet Pressures and body mass index (r s = 0.60 [strong positive relationship], p = 0.0088), apnea-hypopnea index (r s = 0.49 [moderate positive relationship], p = 0.039), lowest oxygen saturation (r s = -0.47 [moderate negative relationship], p = 0.048), and oxygen desaturation index (r s = 0.62 [strong positive relationship], p = 0.0057). Conclusion. This pilot study introduces a new concept, which is the final product of over one year of exploration, development, and testing. Five-Minute CPAP Test is a quick, inexpensive, and safe bedside test based on supine awake simulated snoring with nasal CPAP.
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http://dx.doi.org/10.1155/2016/7380874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737054PMC
February 2016