A randomized crossover efficacy trial of oral CPAP (Oracle) compared with nasal CPAP in the management of obstructive sleep apnea

STUDY OBJECTIVES: To determine the therapeutic efficacy and viability of a novel oral interface for continuous positive airway pressure (CPAP) compared with conventional nasal interfaces. DESIGN: A randomized single-blind crossover study. SETTING: Hospital-based sleep laboratory. PATIENTS OR PARTICIPANTS: 21 CPAP-na?ve patients with obstructive sleep apnea (baseline apnea-hypopnea index, 85 +/- 36) Interventions: Nasal CPAP and oral CPAP MEASUREMENTS AND RESULTS: Patients were each treated for two 4-week periods using nasal CPAP and oral CPAP. The CPAP titrations were undertaken at the start of each treatment arm. Outcome measures were recorded at baseline and at the end of each treatment arm. These included polysomnography variables, CPAP compliance, subjective sleepiness, obstructive sleep apnea symptom ratings, and adverse effects. There were no significant differences between oral and nasal interfaces for the on-CPAP frequency of apneas and hypopneas (mean difference, nasal-oral [95%CI] = -4.6[-10.1-1.0]/h; P = 0.06) or arousals (-3.0 [-7.8-1.8]/h; P = 0.23). There were also no statistically significant differences between interfaces for scores on the Epworth Sleepiness Scale (-0.7 [-3.1-1.7]; P = 0.20), obstructive sleep apnea symptoms (-7.7 [-17.7-2.4]; P = 0.052), CPAP compliance (0.3 [-0.5-1.1] h/night; P = 0.50), CPAP pressure (0.05 [-0.66-0.76] cmH20; P = 0.73), CPAP side effects scores (-2.0 [-5.3-1.4]; P = 0.23), or mask preference (P = 0.407). In addition, both nasal and oral interfaces significantly improved polysomnographic variables, Epworth Sleepiness Scale scores, obstructive sleep apnea symptoms, and CPAP compliance from baseline (all P < 0.05). CONCLUSIONS: This preliminary study indicates that oral CPAP has similar efficacy to traditionally applied nasal CPAP in treating obstructive sleep apnea. Additional large studies are required to determine the range of clinical situations where oral CPAP is indicated.     

Nasal CPAP in obstructive sleep apnea: mechanisms of action

Sixteen patients with the obstructive sleep apnea syndrome (OSAS) were studied for 1-2 h while receiving continuous positive airway pressure (CPAP) delivered via a nasal mask. Obstructive apneas were obliterated in all. Eight patients had studies of genioglossal muscle activity (GG EMG) and one patient had computed tomograms (CT) of the upper airway while on nasal CPAP. The GG EMG studies showed two patterns: suppression and augmentation of GG EMG while on CPAP. The CT scan showed the airway to be narrowed while the patient was awake off CPAP. It returned to a normal caliber when CPAP was applied, despite sleep. These results are interpreted to suggest three potential mechanisms of action for nasal CPAP in OSAS: 1) reduced upper airway resistance due to prevention of sleep-induced collapse of the airway; 2) reduced upper airway resistance due to dilatation of the airway by nasal CPAP beyond its dimension in the awake state; and 3) possible stimulation of mechanoreceptors leading to an increase in airway tone while CPAP is applied.     

Protriptyline in obstructive sleep apnea: a double-blind trial

We evaluated protriptyline, a nonsedating tricyclic antidepressant, as a treatment for obstructive sleep apnea in a double-blind crossover study of five men. After two weeks of treatment, with no change in body weight, daytime somnolence was markedly reduced and nocturnal oxygenation was improved, although apnea duration and frequency were not significantly decreased. Rapid-eye-movement (REM) stage time as a fraction of the total sleep time was reduced during treatment from 0.231 +/- 0.031 to 0.107 +/- 0.013 (mean +/- S.E.M.) (P less than 0.05). REM apnea time as a fraction of total sleep time was reduced from 0.145 +/- 0.022 to 0.054 +/- 0.006 (P less than 0.05). REM reduction during treatment with protriptyline can account for decreased REM apnea time. Similar decreases in REM stage time and REM apnea duration and similar improvement in oxygenation continued after six months of treatment. In addition, body weight, apnea, and arousal frequency were decreased at this time. Although the obstructive sleep apnea was not resolved, it was reduced. Protriptyline can be effective in patients with sleep apnea when the disorder is not life-threatening.     

Effects of short-term CPAP withdrawal on neurobehavioral performance in patients with obstructive sleep apnea

STUDY OBJECTIVE: Changes in sleep parameters and neurobehavioral functioning were systematically investigated after an acute (1 night) and short-term (7 nights) period of withdrawal from continuous positive airway pressure (CPAP) treatment and 1 subsequent night of CPAP reintroduction in patients with obstructive sleep apnea. DESIGN: Repeated-measurement within-subject design. SETTING: Sleep laboratory, university teaching hospital. PARTICIPANTS: Twenty participants receiving optimal CPAP therapy for > or = 12 months. INTERVENTIONS: CPAP withdrawal. MEASUREMENTS AND RESULTS: Polysomnograms were performed on Night 0 (with CPAP), Night 1 and Night 7 (without CPAP) and Night 8_R (with CPAP). Acute CPAP withdrawal resulted in the recurrence of sleep-disordered breathing with sleep disruption, hypoxemia, and increased subjective sleepiness. Short-term CPAP withdrawal exacerbated hypoxemia, increased subjective and objective sleepiness and poor mood ratings. Neurobehavioral functioning assessed using the Psychomotor Vigilance Task was impaired following Night 7 and associated with hypoxemia and changes in morning levels of tumor necrosis factor-alpha. However, other neurobehavioral measures were not affected. Autonomic arousals measured via respiratory-related reductions in finger blood volume by peripheral arterial tonometry decreased from Night 1 to Night 7. On Night 8_R, reintroduction of CPAP treatment eliminated most airway obstruction, maintained oxygenation, and reversed daytime sleepiness and some vigilance decrements. CONCLUSION: Despite recurrence of sleep-disordered breathing with increased sleepiness and impaired vigilance, most neurobehavioral variables were unaffected by CPAP withdrawal. The reduction in vigilance appeared to be associated with worsened hypoxemia and changed levels of tumor necrosis factor-alpha. Resumption of CPAP treatment had immediate benefits on sleep consolidation and subjective sleepiness.     

Oral appliance therapy reduces blood pressure in obstructive sleep apnea: a randomized, controlled trial

STUDY OBJECTIVE: To investigate the short-term effect (4 weeks) of oral appliance therapy for obstructive sleep apnea on blood pressure. DESIGN: Randomized, controlled, crossover trial. SETTING: Multidisciplinary sleep disorders clinic in a university teaching hospital. PATIENTS: Sixty-one patients diagnosed with obstructive sleep apnea on polysomnography (apnea hypopnea index > or = 10 per hour and at least 2 of the following symptoms--daytime sleepiness, snoring, witnessed apneas, fragmented sleep; age > 20 years; and minimum mandibular protrusion of 3 mm). INTERVENTION: A mandibular advancement splint (MAS) and control oral appliance for 4 weeks each. MEASUREMENTS AND RESULTS: Polysomnography and 24-hour ambulatory blood pressure monitoring were carried out at baseline and following each 4-week intervention period. Patients showed a 50% reduction in mean apnea hypopnea index with MAS compared with the control and a significant improvement in both minimum oxygen saturation and arousal index. There was a significant reduction with the MAS in mean (+/- SEM) 24-hour diastolic blood pressure (1.8 +/- 0.5 mmHg) compared with the control (P = .001) but not in 24-hour systolic blood pressure. Awake blood-pressure variables were reduced with the MAS by an estimated mean (+/- SEM) of 3.3 +/- 1.1 mmHg for systolic blood pressure (P = .003) and 3.4 +/- 0.9 mmHg for diastolic blood pressure (P < .0001). There was no significant difference in blood pressure measured asleep. CONCLUSION: Oral appliance therapy for obstructive sleep apnea over 4 weeks results in a reduction in blood pressure, similar to that reported with continuous positive airway pressure therapy.     

Effect of 12 weeks continuous positive airway pressure on day and night arterial stiffness and blood pressure in patients with type 2 diabetes and obstructive sleep apnea: A randomized controlled trial

The objective of this study was to evaluate the effect of continuous positive airway pressure treatment on pulse wave velocity and blood pressure in patients with type 2 diabetes and obstructive sleep apnea. A randomized controlled study was performed, including 72 patients with type 2 diabetes and newly diagnosed obstructive sleep apnea recruited from outpatient clinics at three Danish hospitals. The patients were randomized to continuous positive airway pressure for 12 weeks or no continuous positive airway pressure. Office measurements were performed at baseline, 4 weeks and 12 weeks. At baseline and 12 weeks, a 24‐hr measurement of pulse wave velocity and blood pressure was performed. No significant change was observed in the primary outcome variable of carotid‐femoral pulse wave velocity measured with SphygmoCor. With the Mobil‐O‐Graph, changes in office pulse wave velocity between the groups were significant: 0.3 m/s; 95% confidence interval, 0.1–0.6; p = .02. The group receiving continuous positive airway pressure had a larger decrease in pulse wave velocity than controls but none of the changes within the groups were significant. No significant change in ambulatory blood pressure was observed in any of the two groups after 12 weeks. In conclusion, continuous positive airway pressure treatment for 12 weeks does not significantly reduce pulse wave velocity or blood pressure in patients with type 2 diabetes and obstructive sleep apnea.     

Effect of CPAP therapy on daytime cardiovascular regulations in patients with obstructive sleep apnea

Obstructive sleep apnea (OSA) is a sleep disorder with a high prevalence that causes pathological changes in cardiovascular regulation during the night and also during daytime. We investigated whether the treatment of OSA at night by means of continuous positive airway pressure (CPAP) improves the daytime consequences. Twenty-eight patients with OSA, 18 with arterial hypertension, 10 with normal blood pressure, were investigated at baseline and with three months of CPAP treatment. Ten age and sex matched healthy control subjects were investigated for comparisons. We recorded a resting period with 20min quiet breathing and an exercise stress test during daytime with ECG and blood pressure (Portapres). The bicycle ergometry showed a significant reduction of the diastolic blood pressure at a work load of 50W and 100W (p<0.05 and p<0.01, respectively) and a decrease of the heart rate recovery time after the stress test (p<0.05). These results indicate a reduction of vascular resistance and sympathetic activity during daytime. The coupling analysis of the resting periods by means of symbolic coupling traces approach indicated an effect of the CPAP therapy on the baroreflex reaction in hypertensive patients where influences of the systolic blood pressure on the heart rate changed from pathological patterns to adaptive mechanisms of the normotensive patients (p<0.05).     

Changes of vitamin D levels and bone turnover markers after CPAP therapy: a randomized sham‐controlled trial

The aim was to investigate whether continuous positive airway pressure treatment could modulate serum vitamin D (25‐hydroxyvitamin D) and bone turnover markers (collagen‐type 1 cross‐linked C‐telopeptide, osteocalcin and N‐terminal propeptide of type 1 collagen) in secondary analysis from a randomized controlled trial. Sixty‐five continuous positive airway pressure‐naïve male patients with obstructive sleep apnea (age = 49 ± 12 years, apnea–hypopnea index = 39.9 ± 17.7 events h^?1, body mass index = 31.3 ± 5.2 kg m^?2) were randomized to receive either real (n  = 34) or sham (n  = 31) continuous positive airway pressure for 12 weeks. At 12 weeks, all participants received real continuous positive airway pressure for an additional 12 weeks. After 12 weeks of continuous positive airway pressure (real versus sham), there were no between‐group differences for any of the main outcomes [Δ25‐hydroxyvitamin D: ?0.80 ± 5.28 ng mL ^?1 (mean ± SE ) versus 3.08 ± 3.66 ng mL ^?1, P  = 0.42; Δcollagen‐type 1 cross‐linked C‐telopeptide: 0.011 ± 0.014 ng mL ^?1 versus ?0.004 ± 0.009 ng mL ^?1, P  = 0.48; Δosteocalcin: 1.13 ± 1.12 ng mL ^?1 versus 0.46 ± 0.75 ng mL ^?1, P  = 0.80; ΔN‐terminal propeptide of type 1 collagen: 2.07 ± 3.05 μ g L^?1 versus ?1.05 ± 2.13 μ g L^?1, P  = 0.48]. There were no further differences in subgroup analyses (continuous positive airway pressure‐compliant patients, patients with severe obstructive sleep apnea or sleepy patients). However, after 24 weeks irrespective of initial randomization, vitamin D increased in patients with severe obstructive sleep apnea (9.56 ± 5.51 ng mL ^?1, P  = 0.045) and in sleepy patients (14.0 ± 4.69 ng mL ^?1, P  = 0.007). Also, there was a significant increase in osteocalcin at 24 weeks (3.27 ± 1.06 ng mL ^?1, P  = 0.01) in compliant patients. We conclude that 12 weeks of continuous positive airway pressure did not modulate vitamin D or modulate any of the bone turnover markers compared with sham. However, it is plausible that continuous positive airway pressure may have late beneficial effects on vitamin D levels and bone turnover markers in selected groups of patients with obstructive sleep apnea.     

Night‐to‐night variability of obstructive sleep apnea

One night of a sleep study is the standard for diagnosis and exclusion of obstructive sleep apnea. Single testing requires high sensitivity of the test method and a stable disease of interest to warrant a low rate of false‐negative tests. Obstructive sleep apnea is diagnosed and graded by conventional thresholds of apneas and hypopneas per hour of sleep, and treatment is usually initiated in the presence of symptoms. The aim of this study was to assess night‐to‐night variability of obstructive sleep apnea to reassess the current practice. Seventy‐seven patients previously diagnosed with obstructive sleep apnea, randomised to continuous positive airway pressure withdrawal within four trials, performed nightly pulse‐oximetry over 2 weeks while off continuous positive airway pressure. The main outcome of interest was the coefficient of variation of the oxygen desaturation index marking night‐to‐night variability in obstructive sleep apnea. Obstructive sleep apnea was categorised according to conventional thresholds using oxygen desaturation index (no obstructive sleep apnea: <5 per h; mild: 5–15 per h; moderate: 15–30 per h; and severe: >30 per h). High night‐to‐night variability of obstructive sleep apnea was evidenced by a coefficient of variation of oxygen desaturation index of 31.1% (SD 16.5). Differences in oxygen desaturation index of >10 per h between nights were found in 84.4% and shifts in obstructive sleep apnea severity category in 77.9% of patients. The probability of missing moderate obstructive sleep apnea was up to 60%. Variability was higher in less severe obstructive sleep apnea. Obstructive sleep apnea shows a considerable night‐to‐night variability. Single‐night diagnostic sleep studies are prone to miscategorise obstructive sleep apnea if arbitrary thresholds are used. Thus, treatment decisions should be based less on the conventional derivatives from sleep studies, especially in patients with less severe obstructive sleep apnea. Clinical trial registration: www.controlled-trials.com (ISRCTN 93153804, ISRCTN 73047833) and www.clinicaltrials.gov (NCT01332175 & NCT02050425).     

Effects of nasal pathologies on obstructive sleep apnea

Increased airway resistance can induce snoring and sleep apnea, and nasal obstruction is a common problem in snoring and obstructive sleep apnea (OSA) patients. Many snoring and OSA patients breathe via the mouth during sleep. Mouth breathing may contribute to increased collapsibility of the upper airways due to decreased contractile efficiency of the upper airway muscles as a result of mouth opening. Increased nasal airway resistance produces turbulent flow in the nasal cavity, induces oral breathing, promotes oscillation of the pharyngeal airway and can cause snoring.     

The effects of testosterone on ventilatory responses in men with obstructive sleep apnea: a randomised,placebo‐controlled trial

We recently showed that testosterone therapy worsens sleep‐disordered breathing at 6–7 weeks, but not after 18 weeks, in men with obstructive sleep apnea. Changes in ventilatory chemoreflexes may be responsible. The effect of testosterone on ventilatory chemoreflexes in men with obstructive sleep apnea has not been systematically studied before. Twenty‐one obese men with obstructive sleep apnea, a subgroup of our recent report, were randomised in an 18‐week, randomised, double‐blind, placebo‐controlled, parallel group trial to three intramuscular injections (0, 6, 12 weeks) of either 1000 mg testosterone undecanoate (n = 10) or placebo (n = 11). Awake ventilatory chemoreflex testing was performed before (week 0), during (week 6) and at the end of treatment (week 18) to determine the ventilatory carbon dioxide recruitment threshold and chemosensitivity. Sleep and breathing was assessed by overnight polysomnography at 0, 7 and 18 weeks. Serum hormones levels were measured at every visit. A significant increase in blood testosterone levels (5.65 nmol L^?1, 0.51–10.8 nmol L^?1, P = 0.03) and lean muscle mass (2.36 kg, 0.8–3.9 kg, P = 0.007) between the two groups was observed as expected. No significant differences were seen in ventilatory chemoreflexes between the two groups at 6 weeks or at 18 weeks. However, positive correlations were observed between changes in serum testosterone and hyperoxic ventilatory recruitment threshold (r = 0.55, P = 0.03), and between changes in hyperoxic ventilatory recruitment threshold and time spent with oxygen saturations during sleep <90% (r = 0.57, P = 0.03) at 6–7 weeks, but not at 18 weeks. Time‐dependent alterations in ventilatory recruitment threshold may therefore mediate the time‐dependent changes in sleep breathing observed with testosterone.     

Maintenance diets following rapid weight loss in obstructive sleep apnea: a pilot 1‐year clinical trial

Very low energy diets (VLED ) appear to be the most efficacious dietary‐based obesity reduction treatments in obstructive sleep apnea (OSA ); however, effective weight loss maintenance strategies remain untested in this condition. Our study aimed to assess the feasibility, tolerability and efficacy of two common maintenance diets during a 10‐month follow‐up period after rapid weight loss using a 2‐month VLED . In this two‐arm, single‐centre, open‐label pilot trial, obese adult OSA patients received a 2‐month VLED before being allocated to either the Australian Guide to Healthy Eating diet (AGHE ) or a low glycaemic index high‐protein diet (LGHP ). Outcomes were measured at 0, 2 and 12 months. We recruited 44 patients [113.1 ± 19.5 kg, body mass index (BMI ): 37.2 ± 5.6 kg m^?2, 49.3 ± 9.2 years, 12 females]. Twenty‐four patients were on continuous positive airway pressure (CPAP ) or mandibular advancement splint (MAS ) therapy for OSA . Forty‐two patients completed the VLED . The primary outcome of waist circumference was reduced by 10.6 cm at 2 months [95% confidence interval (CI ): 9.2–12.1], and patients lost 12.9 kg in total weight (95% CI : 11.2–14.6). There were small but statistically significant regains in waist circumference between 2 and 12 months [AGHE  = 3.5 cm (1.3–5.6) and LGHP  = 2.8 cm (0.6–5.0]. Other outcomes followed a similar pattern of change. After weight loss with a 2‐month VLED in obese patients with OSA , a structured weight loss maintenance programme incorporating commonly used diets was feasible, tolerable and efficacious for 10 months. This programme may be deployed easily within sleep clinics; however, future research should first test its translation within general clinical practice.     

The effect of CPAP treatment on excessive daytime somnolence in patients with obstructive sleep apnea

The study was undertaken to investigate whether a CPAP therapy improves symptoms of excessive daytime sleepiness (EDS) in patients with obstructive sleep apnoea (OSA). In seventy six patients (66 M and 10 F) with AHI = 50 +/- 3.3, BMI = 34 +/- 0.9 kg/m2 and mean age = 50.4 +/- 1 years OSA was diagnosed using standard polysomnography. EDS was assessed using Epworth Sleepiness Scale (ESS). Each patient was examined two or three times, before, after 1 and/or 2-15 months of CPAP treatment. Significant reduction of EDS within 1 month of CPAP therapy was found. Mean ESS was reduced from 14.3 +/- 0.9 to 7.0 +/- 0.7 after 1 month therapy (p < 0.001). Continuation of treatment had no further effect on decrease of symptoms of daytime sleepiness. There was a correlation between percent of sleep spent with CPAP and improvement in ESS.     

Efficacy of continuous positive airway pressure treatment on 5‐year survival in patients with ischaemic stroke and obstructive sleep apnea: a randomized controlled trial

The main purpose of the present analysis is to assess the influence of introducing early nasal continuous positive airway pressure (nCPAP) treatment on cardiovascular recurrences and mortality in patients with a first‐ever ischaemic stroke and moderate–severe obstructive sleep apnea (OSA) with an apnea–hypopnea index (AHI) ≥20 events h^?1 during a 5‐year follow‐up. Patients received conventional treatment for stroke and were assigned randomly to the nCPAP group (n = 71) or the control group (n = 69). Cardiovascular events and mortality were registered for all patients. Survival and cardiovascular event‐free survival analysis were performed after 5‐year follow‐up using the Kaplan–Meier test. Patients in the nCPAP group had significantly higher cardiovascular survival than the control group (100 versus 89.9%, log‐rank test 5.887; P = 0.015) However, and also despite a positive tendency, there were no significant differences in the cardiovascular event‐free survival at 68 months between the nCPAP and control groups (89.5 versus 75.4%, log‐rank test 3.565; P = 0.059). Early nCPAP therapy has a positive effect on long‐term survival in ischaemic stroke patients and moderate–severe OSA.     

Association between proteomics and obstructive sleep apnea phenotypes in a community‐based cohort of women

Proteomic‐based technologies offer new opportunities to identify proteins that might reflect the cardiometabolic stress caused by different aspects of sleep‐disordered breathing. We aimed to investigate whether severe obstructive sleep apnea and severe obstructive sleep apnea during rapid eye movement sleep are associated with changed levels of inflammatory and cardiac disease‐related proteins in a population‐based cohort of women. In the community‐based “Sleep and Health in Women” (SHE) cohort study, 400 women underwent polysomnography, anthropometric measurements and blood sampling. Two proteomic assays (Olink Proseek^® Inflammation panel and Olink Proseek^® Cardiovascular II panel), each measuring 92 proteins, were analysed in a subsample of 253 women. p‐Values were adjusted for multiple testing, with false discovery rate set at 10%. In unadjusted models, 57 proteins were associated with apnea?hypopnea index, 56 proteins with oxygen desaturation index and 64 proteins with rapid eye movement?apnea?hypopnea index. After adjustment for age, body mass index and plate, there were no significant associations between apnea?hypopnea index or oxygen desaturation index and any of the proteins. Severe obstructive sleep apnea during rapid eye movement sleep (rapid eye movement?apnea?hypopnea index ≥ 30) was associated with decreased levels of two anti‐inflammatory proteins; Sirt2 (q‐value .016) and LAP‐TGF‐β₁ (q‐value .016). There was also a negative association between rapid eye movement?apnea?hypopnea index of ≥ 30 and Axin1 (q‐value .095), a protein thought to facilitate TGF‐β‐signalling. We conclude that severe obstructive sleep apnea during rapid eye movement sleep is associated with low levels of Sirt2, LAP‐TGF‐β₁ and Axin1, anti‐inflammatory proteins involved in metabolic regulation and in the atherosclerotic process. For obstructive sleep apnea based on a whole night, the associations with cardiac and inflammatory proteins are weaker, and explained to a large extent by age and body mass index.