Obstructive sleep apnoea and the progression of thoracic aortic aneurysm: a prospective cohort study.

BACKGROUND: Obstructive sleep apnoea (OSA) is associated with an increased prevalence of aortic aneurysms and it has also been suggested that severe OSA furthers aneurysm expansion in the abdomen. We evaluated whether OSA is a risk factor for the progression of ascending thoracic aortic aneurysm (TAA). METHODS: Patients with TAA underwent yearly standardised echocardiographic measurements of the ascending aorta over 3 years and two level III sleep studies. The primary outcome was the expansion rate of TAA in relation to the apnoea-hypopnoea index (AHI). Secondary outcomes included surveillance for aortic events (composite end-points of rupture/dissection, elective surgery or death). RESULTS: Between July 2014 and March 2020, 230 patients (median age 70 years, 83.5% male) participated in the cohort. At baseline, 34.8% of patients had AHI ≥15 events·h-1. There was no association between TAA diameter and AHI at baseline. After 3 years, mean±sd expansion rates were 0.55±1.25 mm at the aortic sinus and 0.60±1.12 mm at the ascending aorta. In the regression analysis, after controlling for baseline diameter and cardiovascular risk factors, there was strong evidence for a positive association of TAA expansion with AHI (aortic sinus estimate 0.025 mm, 95% CI 0.009-0.040 mm; p<0.001 and ascending aorta estimate 0.026 mm, 95% CI 0.011-0.041 mm; p=0.001). 20 participants (8%) experienced an aortic event; however, there was no association with OSA severity. CONCLUSION: OSA may be a modest but independent risk factor for faster TAA expansion and thus potentially contributes to life-threatening complications in aortic disease.

Continuous positive airway pressure effect on visual acuity in patients with type 2 diabetes and obstructive sleep apnoea: a multicentre randomised controlled trial.

We sought to establish whether continuous positive airway pressure (CPAP) for obstructive sleep apnoea (OSA) in people with type 2 diabetes and diabetic macular oedema (DMO) improved visual acuity.We randomly assigned 131 eligible patients aged 30-85 years from 23 UK centres with significant DMO causing visual impairment (LogMAR letters identified ≥39 and ≤78, score 0.92-0.14) plus severe OSA on screening to either usual ophthalmology care (n=67) or usual ophthalmology care plus CPAP (n=64) for 12 months.Mean age of participants was 64 years, 73% male, mean body mass index 35.0 kg·m- 2 Mean 4% oxygen desaturation index was 36 events·h-1 There was no significant difference in the visual acuity at 12 months between the CPAP group and the control group (mean LogMAR 0.33 (95% CI 0.29-0.37) versus 0.31 (95% CI 0.27-0.35); p=0.39), and no significant correlation between change in LogMAR and average CPAP use. The median±sd (range) daily CPAP use was 3.33±2.25 (0-7.93) h at 3 months, 3.19±2.54 (0-8.07) h at 6 months and 3.21±2.70 (0-7.98) h at 12 months.CPAP therapy for OSA did not improve visual acuity in people with type 2 diabetes and DMO compared with usual care alone over 12 months.

Effect of OSA on hypoxic and inflammatory markers during CPAP withdrawal: Further evidence from three randomized control trials.

BACKGROUND AND OBJECTIVE: Obstructive sleep apnoea (OSA) is associated with cardiovascular disease. Intermittent hypoxia, endothelial dysfunction and adipose tissue-mediated inflammation have all been linked to cardiovascular disease in OSA. We therefore explored the effect of OSA on relevant associated blood markers: adrenomedullin (ADM), endocan, endothelin-1 (ET-1), resistin and vascular endothelial growth factor (VEGF). METHODS: Patients with OSA, established on and compliant with continuous positive airways pressure (CPAP) therapy for >1 year were included from three randomized controlled trials, conducted at two centres. Patients were randomized to either continued therapeutic CPAP or sham CPAP (CPAP withdrawal) for 2 weeks. Blood markers were measured at baseline and at 14 days and the treatment effect between sham CPAP and therapeutic CPAP was analysed. RESULTS: A total of 109 patients were studied (therapeutic CPAP n = 54, sham CPAP n = 55). Sham CPAP was associated with a return of OSA (between-group difference in oxygen desaturation index (ODI) 36.0/h, 95% CI 29.9-42.2, P < 0.001). Sham CPAP was associated with a reduction in ADM levels at 14 days (-26.0 pg/mL, 95% CI -47.8 to -4.3, P = 0.02), compared to therapeutic CPAP. Return of OSA was not associated with changes in endocan, ET-1, resistin or VEGF. CONCLUSION: Whilst CPAP withdrawal was associated with return of OSA, it was associated with an unexpected significant reduction in the vasodilator ADM and not with expected increases in hypoxia-induced markers, markers of endothelial function or resistin. We propose that the vascular effects occurring in OSA may be brought about by other mechanisms, perhaps partly through a reduction in ADM.

Effect of CPAP Withdrawal on BP in OSA: Data from Three Randomized Controlled Trials.

BACKGROUND: Based on meta-analyses, the BP-lowering effect of CPAP therapy in patients with OSA is reported to be approximately 2 to 3 mm Hg. This figure is derived from heterogeneous trials, which are often limited by poor CPAP adherence, and thus the treatment effect may possibly be underestimated. We analyzed morning BP data from three randomized controlled CPAP withdrawal trials, which included only patients with optimal CPAP compliance. METHODS: Within the three trials, 149 patients with OSA who were receiving CPAP were randomized to continue therapeutic CPAP (n = 65) or to withdraw CPAP (n = 84) for 2 weeks. Morning BP was measured at home before and after sleep studies in the hospital. RESULTS: CPAP withdrawal was associated with a return of OSA (apnea-hypopnea index [AHI] at a baseline of 2.8/h and at follow-up of 33.2/h). Office systolic BP (SBP) increased in the CPAP withdrawal group compared with the CPAP continuation group by +5.4 mm Hg (95% CI, 1.8-8.9 mm Hg; P = .003) and in the home SBP group by +9.0 mm Hg (95% CI, 5.7-12.3 mm Hg; P < .001). Office diastolic BP (DBP) increased by +5.0 mm Hg (95% CI, 2.7-7.3 mm Hg; P < .001), and home DBP increased by +7.8 mm Hg (95% CI, 5.6-10.4 mm Hg; P < .001). AHI, baseline home SBP, use of statin drugs, sex, and the number of antihypertensive drugs prescribed were all independently associated with SBP change in multivariate analysis, controlling for age, BMI, smoking status, diabetes, and sleepiness. CONCLUSIONS: CPAP withdrawal results in a clinically relevant increase in BP, which is considerably higher than in conventional CPAP trials; it is also underestimated when office BP is used. Greater OSA severity is associated with a higher BP rise in response to CPAP withdrawal. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01332175 and NCT01797653) URL: www.clinicaltrials.gov and ISRCTN registry (ISRCTN 93153804) URL: http://www.isrctn.com/.

Effect of CPAP Withdrawal on myocardial perfusion in OSA: A randomized controlled trial.

BACKGROUND AND OBJECTIVE: Obstructive sleep apnoea (OSA) is highly prevalent and associated with an increased incidence of cardiovascular events. Endothelial dysfunction is the proposed causative mechanism. Continuous positive airway pressure (CPAP) is presumed to improve cardiovascular outcome in OSA. CPAP withdrawal was recently shown to lead to peripheral endothelial dysfunction. However, it is not known whether short-term CPAP withdrawal reduces myocardial perfusion in OSA. METHODS: In this double-blind randomized controlled study, 45 patients with moderate to severe OSA previously adherent to CPAP were assigned to either subtherapeutic or continuing therapeutic CPAP for 2 weeks. The primary outcome was adenosine-induced myocardial blood flow (MBF) as a measure of endothelial function, assessed by (13) N-ammonia positron emission tomography. Secondary outcomes were measures of dermal and renal microvascular function, morning blood pressure (BP) and heart rate. RESULTS: Despite return of OSA associated with significant increases in BP (+9.1 mm Hg, 95% CI +4.9 to +13.4 mm Hg, P < 0.001) and heart rate (+9.6 bpm, 95% confidence interval (CI) +4.6 to +14.6 bpm, P < 0.001), CPAP withdrawal had no significant effect on maximal myocardial perfusion capacity (hyperaemic MBF -0.01 ml/min/g, 95% CI -0.33 to +0.24 ml/min/g, P = 0.91), nor renal and dermal microvascular function. CONCLUSION: In patients with OSA, a short-term CPAP withdrawal does not lead to detectable impairment of coronary endothelial function, as has been demonstrated in the brachial artery, despite a clinically relevant increase in BP of nearly 10 mm Hg. There was also no evidence of an impairment of renal or dermal microvascular function.

Defining the minimal important difference for the visual analogue scale assessing dyspnea in patients with malignant pleural effusions.

BACKGROUND: The minimal important difference (MID) is essential for interpreting the results of randomised controlled trials (RCTs). Despite a number of RCTs in patients with malignant pleural effusions (MPEs) which use the visual analogue scale for dyspnea (VASD) as an outcome measure, the MID has not been established. METHODS: Patients with suspected MPE undergoing a pleural procedure recorded their baseline VASD and their post-procedure VASD (24 hours after the pleural drainage), and in parallel assessed their breathlessness on a 7 point Likert scale. FINDINGS: The mean decrease in VASD in patients with a MPE reporting a 'small but just worthwhile decrease' in their dyspnea (i.e. equivalent to the MID) was 19mm (95% CI 14-24mm). The mean drainage volume required to produce a change in VASD of 19mm was 760ml. INTERPRETATION: The mean MID for the VASD in patients with a MPE undergoing a pleural procedure is 19mm (95% CI 14-24mm). Thus choosing an improvement of 19mm in the VASD would be justifiable in the design and analysis of future MPE studies.

SleepAp: an automated obstructive sleep apnoea screening application for smartphones.

Obstructive sleep apnoea (OSA) is a sleep disorder with long-term consequences. Long-term effects include sleep-related issues and cardiovascular diseases. OSA is often diagnosed with an overnight sleep test called a polysomnogram. Monitoring can be costly with long wait times for diagnosis. In this paper, a novel OSA screening framework and prototype phone application are introduced. A database of 856 patients that underwent at-home polygraphy was collected. Features were derived from audio, actigraphy, photoplethysmography (PPG), and demographics, and used as the inputs of a support vector machine (SVM) classifier. The SVM was trained on 735 patients and tested on 121 patients. Classification on the test set had an accuracy of up to 92.2% when classifying subjects as having moderate or severe OSA versus being healthy or a snorer based on the clinicians' diagnoses. The signal processing and machine learning algorithms were ported to Java and integrated into the phone application-SleepAp. SleepAp records the body position, audio, actigraphy and PPG signals, and implements the clinically validated STOP-BANG questionnaire. It derives features from the signals and classifies the user as having OSA or not using the SVM trained on the clinical database. The resulting software could provide a new, easy-to-use, low-cost, and widely available modality for OSA screening.

Is continuous positive airway pressure necessarily an everyday therapy in patients with obstructive sleep apnoea?

There are limited data on the evolution of obstructive sleep apnoea (OSA) during continuous positive airway pressure (CPAP) therapy and whether this treatment is required every night. 125 OSA patients with an original oxygen desaturation index (ODI) >10 events per hour, established on CPAP, were asked to withdraw CPAP for four nights and performed ambulatory nocturnal pulse oximetry on the fourth night of CPAP withdrawal. An ODI >10 events per hour during pulse oximetry was considered to indicate persistent OSA. Patients not experiencing recurrence of OSA underwent repeat ambulatory pulse oximetry after a further 2-week period off CPAP. In 71% of the patients, OSA recurred after four nights of CPAP withdrawal (group 1); thus, OSA did not recur in 29% (group 2). 55% of group 2 had an ODI >10 events per hour after 2 weeks off CPAP; thus, 45% remained without a recurrence. In multivariate analysis, higher original ODI, longer duration of CPAP therapy, current smoking status and larger neck circumference were independently associated with a higher ODI after four nights of CPAP withdrawal (all p<0.05). Following CPAP withdrawal, a third of CPAP-treated patients do not experience significant recurrence of oxygen desaturations after 4 days and ∼10% do not after 2 weeks. Thus, a significant proportion of patients may be able to stop CPAP for short periods.

Continuous positive airway pressure improves sleepiness but not calculated vascular risk in patients with minimally symptomatic obstructive sleep apnoea: the MOSAIC randomised controlled trial.

BACKGROUND: Continuous positive airway pressure (CPAP) for symptomatic obstructive sleep apnoea (OSA) improves sleepiness and reduces vascular risk, but such treatment for the more prevalent, minimally symptomatic disease is contentious. METHODS: This multicentre, randomised controlled, parallel, hospital-based trial across the UK and Canada, recruited 391 patients with confirmed OSA (oxygen desaturation index >7.5/h) but insufficient symptoms to warrant CPAP therapy. Patients were randomised to 6 months of auto-adjusting CPAP therapy, or standard care. Coprimary endpoints were change in Epworth Sleepiness Score (ESS) and predicted 5-year mortality using a cardiovascular risk score (components: age, sex, height, systolic blood pressure, smoking, diabetes, cholesterol, creatinine, left ventricular hypertrophy, previous myocardial infarction or stroke). Secondary endpoints included some of the individual components of the vascular risk score, objectively measured sleepiness and self-assessed health status. RESULTS: Of 391 patients randomised, 14 withdrew, 347 attended for their follow-up visit at 6 months within the predefined time window, of which 341 had complete ESS data (baseline mean 8.0, SD 4.3) and 310 had complete risk score data. 22% of patients in the CPAP group reported stopping treatment and overall median CPAP use was 2 : 39 h per night. CPAP significantly improved subjective daytime sleepiness (adjusted treatment effect on ESS -2.0 (95% CI -2.6 to -1.4), p<0.0001), objectively measured sleepiness and self-assessed health status. CPAP did not improve the 5-year calculated vascular risk or any of its components. CONCLUSIONS: In patients with minimally symptomatic OSA, CPAP can reduce subjective and objective daytime sleepiness, and improve self-assessed health status, but does not appear to improve calculated vascular risk.

Protocol for diaphragm pacing in patients with respiratory muscle weakness due to motor neurone disease (DiPALS): a randomised controlled trial.

BACKGROUND: Motor neurone disease (MND) is a devastating illness which leads to muscle weakness and death, usually within 2-3 years of symptom onset. Respiratory insufficiency is a common cause of morbidity, particularly in later stages of MND and respiratory complications are the leading cause of mortality in MND patients. Non Invasive Ventilation (NIV) is the current standard therapy to manage respiratory insufficiency. Some MND patients however do not tolerate NIV due to a number of issues including mask interface problems and claustrophobia. In those that do tolerate NIV, eventually respiratory muscle weakness will progress to a point at which intermittent/overnight NIV is ineffective. The NeuRx RA/4 Diaphragm Pacing System was originally developed for patients with respiratory insufficiency and diaphragm paralysis secondary to stable high spinal cord injuries. The DiPALS study will assess the effect of diaphragm pacing (DP) when used to treat patients with MND and respiratory insufficiency. METHOD/DESIGN: 108 patients will be recruited to the study at 5 sites in the UK. Patients will be randomised to either receive NIV (current standard care) or receive DP in addition to NIV. Study participants will be required to complete outcome measures at 5 follow up time points (2, 3, 6, 9 and 12 months) plus an additional surgery and 1 week post operative visit for those in the DP group. 12 patients (and their carers) from the DP group will also be asked to complete 2 qualitative interviews. DISCUSSION: The primary objective of this trial will be to evaluate the effect of Diaphragm Pacing (DP) on survival over the study duration in patients with MND with respiratory muscle weakness. The project is funded by the National Institute for Health Research, Health Technology Assessment (HTA) Programme (project number 09/55/33) and the Motor Neurone Disease Association and the Henry Smith Charity. TRIAL REGISTRATION: Current controlled trials ISRCTN53817913. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or the Department of Health.

High prevalence of sleep disordered breathing in patients with diabetic macular edema.

BACKGROUND: Diabetic retinopathy is more common and severe in patients with sleep disordered breathing (SDB). This study aimed to establish whether this is also true for patients with diabetic clinically significant macular edema (CSME). It is hypothesized that SDB, through intermittent hypoxia and blood pressure oscillations, might provoke worsening of CSME. METHODS: Patients with CSME had a home sleep study (ApneaLink; ResMed) to identify SDB. These results were compared with relevant control populations. Macular thickness was measured using optical coherence tomography, and retinal photographs were graded to assess the severity of retinopathy. RESULTS: Eighty of 195 patients (40 men) consented, with average age of 64.7 (11.7) years, neck circumference of 40.4 (5.4) cm, body mass index of 30.2 (6.2) kg/m2, glycosylated hemoglobin (HbA1c) 7.8% (1.4%) [62 (8.0) mmol/mol], and Epworth sleepiness scale of 7.4 (4.8). Overall, 54% had an oxygen desaturation index ≥ 10, and 31% had an apnea-hypopnea index ≥ 15. This SDB prevalence is probably higher than would be expected from the available matched control data. Those with SDB were not sleepier, but they were older and more obese. No significant relationship was identified between the degree of macular thickness and the severity of SDB. CONCLUSION: Individuals with CSME have a high prevalence of SDB. Sleep disordered breathing may contribute to the pathophysiology of CSME, but the mechanism remains unclear. Given the high prevalence, retinal specialists should perhaps consider a diagnosis of SDB in patients with CSME.

Visual improvement following continuous positive airway pressure therapy in diabetic subjects with clinically significant macular oedema and obstructive sleep apnoea: proof of principle study.

BACKGROUND: Diabetic retinopathy and diabetic macular oedema are more prevalent in patients with coexistent obstructive sleep apnoea (OSA). OBJECTIVES: We assessed if treatment of OSA with continuous positive airway pressure (CPAP) might improve visual acuity (VA). METHODS: A total of 35 patients with clinically significant macular oedema (CSMO) and OSA [oxygen desaturation index (ODI) ≥10 or apnoea-hypopnoea index (AHI) ≥15] were identified and agreed to be studied. VA (expressed as the logarithm of the minimum angle of resolution, logMAR), macular thickness, fundal photographs, glycosylated haemoglobin (HbA1c) and rhodopsin mRNA were measured twice at baseline and at 3 and 6 months post-CPAP. Fluorescein angiography and the Epworth Sleepiness Scale (ESS) were obtained once at baseline and at 6 months. RESULTS: Three patients withdrew before the first trial visit. Thus, a total of 32 patients (17 males) entered the study, and 4 subsequently withdrew; thus 28 completed 6 months of follow-up. Baseline characteristics of the subjects were as follows [mean (SD or inter-quartile range)]: age 66.2 (7.1) years, body mass index 31.7 (6.3), HbA1c 7.4% (1.44) [57.1 (15.7) mmol/mol], AHI 16.5 (11-25), ODI 16.0 (12-25), ESS 6.5 (4.0-12.0) and duration of diabetes 9.5 years (5.0-16.5). Participants were divided into 13 high and 15 low CPAP compliers (≥ and <2.5 h/night over the 6 months, respectively). At 6 months, the adjusted treatment effect on VA of high compliance versus low compliance was 0.11 (95% confidence interval 0.21 to -0.002; p = 0.047), equivalent to a one-line improvement on the logMAR chart. There was no significant improvement in macular oedema or fundal photographs. CONCLUSIONS: This hypothesis-generating, uncontrolled study suggests that ≥2.5 h/night CPAP usage over 6 months in individuals with CSMO and OSA may be associated with improvement in VA. This provides justification for a randomised controlled trial of CPAP therapy in such patients.

The role of the nose in the pathogenesis of obstructive sleep apnea.

PURPOSE OF REVIEW: To define the relationship between obstructive sleep apnea (OSA) and nasal obstruction, we have reviewed the literature on epidemiological, physiological, and randomized controlled studies in which the relationship between nasal obstruction and OSA was investigated. RECENT FINDINGS: Data from observational studies suggest that nasal obstruction contributes to the pathogenesis of OSA. Recently, studies have mainly focused on the effects of therapeutic interventions on the nose and OSA. Eleven trials with randomized controlled designs were found; external nasal dilators were used in five studies, topically applied steroids in one, nasal decongestants in three, and surgical treatment in two studies. Data from these studies showed only minor improvement in the symptoms and severity of OSA. SUMMARY: The current evidence suggests that the nose may not play a significant role in the pathogenesis of OSA. The impact of treating nasal obstruction in patients with OSA on long-term outcome remains to be defined more accurately through randomized controlled trials of medical and surgical therapies with large numbers of patients.

Road ahead to respiratory health: experts chart future research directions.

Respiratory illnesses are a huge and rising burden to health-care systems and societies worldwide. Research is crucial to tackle the enormous problem of chest diseases. However the vast number of research questions and available research approaches often creates confusion and risks dilution of resources by spreading them too diffusely. Clear research directions will help to use research funds efficiently to provide treatment advances that benefit patient care. This paper presents the visions of leading experts on future research directions, focusing on what should rather than what is going to be done. These opinions provide a guide for new investigators and a platform for intellectual debates through which coordinated research efforts can help progress towards respiratory health.

Cost-effectiveness of oral appliances in the treatment of obstructive sleep apnoea-hypopnoea.

PURPOSE: Oral appliances (OA) are commonly prescribed for the treatment of obstructive sleep apnoea-hypopnoea (OSAH), but there is limited evidence on their cost-effectiveness. MATERIALS AND METHODS: A model was designed to simulate the costs and benefits of treatment of OSAH with OA or continuous positive airway pressure (CPAP) based on their effects on quality of life, motor vehicle crashes, and cardiovascular effects. The primary outcome was the incremental cost-effectiveness ratio (ICER) in terms of costs per one quality-adjusted life year (QALY) gained 5 years after treatment. RESULTS: Compared with no treatment, OA results in $268 higher costs and an incremental QALY of 0.0899 per patient (ICER = $2,984/QALY). Compared with OA, CPAP resulted in $1,917 more costs and 0.0696 additional QALYs (ICER = $27,540/QALY). For the most part in the sensitivity analyses, CPAP remained cost-effective compared to OA, and OA remained cost-effective with respect to no treatment in almost all scenarios. CONCLUSIONS: OAs are less economically attractive than CPAP but remain a cost-effective treatment for patients who are unwilling or unable to adhere to CPAP therapy.

Exhaled nitric oxide as a screening tool for asthma in school children.

It is now widely accepted that augmented levels of fractional exhaled nitric oxide (FeNO) reflect airway inflammation and the methodology has been optimised for potential clinical use. We were interested in investigating whether this measurement can be used as a tool to screen and identify school children with asthma. To do this, FeNO was measured using an on-line single exhalation analyser in 368 children aged 8-10 years in six Oxfordshire primary schools, by two investigators blinded to the disease status of the children. The children were then categorised into 'normal', 'atopic asthma', 'non-atopic asthma' and 'atopy only' groups, according to their responses to the ISAAC questionnaire and perusal of the children's medical records kept by their family practitioners. Increased levels of FeNO were found in 'atopic asthmatic', 'non-atopic asthmatics' and 'atopic only' groups (median values of 24.4, 7.8 and 15.3 ppb, respectively, compared to normal controls' of 6.9 ppb). Levels were increased in atopic children regardless of whether they had asthma and were significantly higher than non-atopic asthmatics. We conclude that FeNO measurement is not a useful tool for identifying children with asthma in the community, as increased levels did not discriminate between those with asthmatic and atopic symptoms.