A crossover randomised controlled trial of oral mandibular advancement devices for obstructive sleep apnoea-hypopnoea (TOMADO).

RATIONALE: Mandibular advancement devices (MADs) are used to treat obstructive sleep apnoea-hypopnoea syndrome (OSAHS) but evidence is lacking regarding their clinical and cost-effectiveness in less severe disease. OBJECTIVES: To compare clinical- and cost-effectiveness of a range of MADs against no treatment in mild to moderate OSAHS. MEASUREMENTS AND METHODS: This open-label, randomised, controlled, crossover trial was undertaken at a UK sleep centre. Adults with Apnoea-Hypopnoea Index (AHI) 5-<30/h and Epworth Sleepiness Scale (ESS) score ≥9 underwent 6 weeks of treatment with three non-adjustable MADs: self-moulded (SleepPro 1; SP1); semi-bespoke (SleepPro 2; SP2); fully-bespoke MAD (bMAD); and 4 weeks no treatment. Primary outcome was AHI scored by a polysomnographer blinded to treatment. Secondary outcomes included ESS, quality of life, resource use and cost. MAIN RESULTS: 90 patients were randomised and 83 were analysed. All devices reduced AHI compared with no treatment by 26% (95% CI 11% to 38%, p=0.001) for SP1, 33% (95% CI 24% to 41%) for SP2 and 36% (95% CI 24% to 45%, p<0.001) for bMAD. ESS was 1.51 (95% CI 0.73 to 2.29, p<0.001, SP1) to 2.37 (95% CI 1.53 to 3.22, p<0.001, bMAD) lower than no treatment (p<0.001 for all). Compliance was lower for SP1, which was the least preferred treatment at trial exit. All devices were cost-effective compared with no treatment at a £20,000/quality-adjusted life year (QALY) threshold. SP2 was the most cost-effective up to £39,800/QALY. CONCLUSIONS: Non-adjustable MADs achieve clinically important improvements in mild to moderate OSAHS and are cost-effective. Of those trialled, the semi-bespoke MAD is an appropriate first choice. TRIAL REGISTRATION NUMBER: ISRCTN02309506.

Alternatives to continuous positive airway pressure 2: mandibular advancement devices compared.

PURPOSE OF REVIEW: Although mandibular advancement devices (MADs) provide an alternative to continuous positive airway pressure (CPAP) therapy in obstructive sleep apnea (OSA), their effectiveness and role remain unclear. Several recent studies and an updated meta-analysis have attempted to address these uncertainties. This review examines their contribution to the existing evidence and discusses the future priorities for MAD research. RECENT FINDINGS: Recent work has examined the impact of MAD design on clinical and cost-effectiveness in milder disease. A robust comparison of CPAP and MADs in more severe OSA has reported equivalent improvements in several important health outcomes. Other notable contributions have examined compliance, definitions of treatment success and longer term outcomes of MAD therapy. SUMMARY: There is now a growing body of evidence suggesting that MADs are a clinically and cost-effective treatment for OSA; and in some cases, patient preference may make them a better option than CPAP. Further work needs to continue to refine MAD therapy in order to optimize treatment response and compliance, whilst retaining a pragmatic and cost-effective approach that is relevant to clinical practice and sustainable in the longer term.

Positive role of continuous positive airway pressure for intensive care unit patients with severe hypoxaemic respiratory failure due to COVID-19 pneumonia: A single centre experience.

OBJECTIVES: Continuous positive airway pressure (CPAP) may be a useful treatment strategy for patients with severe COVID-19 pneumonia but its effectiveness in preventing mechanical ventilation is unknown. We aimed to evaluate the outcomes of COVID-19 patients treated with CPAP and determine predictors of CPAP response. DESIGN: This was a retrospective observational cohort study. SETTING: The study took place in the intensive care unit (ICU) at Royal Papworth Hospital (RPH) in Cambridge, UK. PATIENTS: We included all consecutive patients with confirmed COVID-19 pneumonia who were transferred from neighbouring hospitals between 14th March and 6th May, 2020 for consideration of ventilatory support. INTERVENTION: We instituted the use of CPAP for all patients who arrived in RPH not intubated and were not making satisfactory progress on supplemental oxygen alone. MEASUREMENTS AND MAIN RESULTS: Of 33 self-ventilating patients included in this study, 22 (66.7%) were male and the mean age was 54 ± 13.23 patients received CPAP. They were more hypoxaemic than those treated with oxygen alone (PaO2/FiO2 ratio; 84.3 ± 19.0 vs 170.0 ± 46.0 mmHg, p = 0.001). There was a significant improvement in PaO2/FiO2 ratio 1-2 hours after CPAP initiation (167.4 ± 49.0 from 84.3 ± 19.0 mmHg, p = 0.001). 14 (61%) patients responded to CPAP and 9 required intubation. There was no difference between these two groups in terms of the severity of baseline hypoxaemia (PaO2/FiO2 ratio; 84.5 ± 16.0 vs 83.9 ± 23.0 mmHg, p = 0.94) but CPAP responders had significantly lower C-reactive protein (CRP) (176 ± 83 vs 274 ± 63 mg/L, p = 0.007), interleukin-6 (IL-6) (30 ± 47 vs 139 ± 148 pg/mL, p = 0.037), and D-dimer (321 ± 267 vs 941 + 1990 ng/mL, p = 0.003). CT pulmonary angiogram was performed in 6 out of 9 intubated patients and demonstrated pulmonary emboli in 5 of them. All patients were discharged from ICU and there were no fatalities. CONCLUSIONS: In this cohort, CPAP was an effective treatment modality to improve hypoxaemia and prevent invasive ventilation in a substantial proportion of patients with severe respiratory failure. Accepting the small sample size, we also found raised biomarkers of inflammation (CRP and IL-6) and coagulopathy (D-Dimer) to be more useful predictors of CPAP responsiveness than the severity of hypoxaemia, and could help to guide intubation decisions in this clinical setting.

Rare PSAP Variants and Possible Interaction with GBA in REM Sleep Behavior Disorder.

BACKGROUND: PSAP encodes saposin C, the co-activator of glucocerebrosidase, encoded by GBA. GBA mutations are associated with idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of synucleinopathy. OBJECTIVE: To examine the role of PSAP mutations in iRBD. METHODS: We fully sequenced PSAP and performed Optimized Sequence Kernel Association Test in 1,113 iRBD patients and 2,324 controls. We identified loss-of-function (LoF) mutations, which are very rare in PSAP, in three iRBD patients and none in controls (uncorrected p = 0.018). RESULTS: Two variants were stop mutations, p.Gln260Ter and p.Glu166Ter, and one was an in-frame deletion, p.332_333del. All three mutations have a deleterious effect on saposin C, based on in silico analysis. In addition, the two carriers of p.Glu166Ter and p.332_333del mutations also carried a GBA variant, p.Arg349Ter and p.Glu326Lys, respectively. The co-occurrence of these extremely rare PSAP LoF mutations in two (0.2%) GBA variant carriers in the iRBD cohort, is unlikely to occur by chance (estimated co-occurrence in the general population based on gnomAD data is 0.00035%). Although none of the three iRBD patients with PSAP LoF mutations have phenoconverted to an overt synucleinopathy at their last follow-up, all manifested initial signs suggestive of motor dysfunction, two were diagnosed with mild cognitive impairment and all showed prodromal clinical markers other than RBD. Their probability of prodromal PD, according to the Movement Disorder Society research criteria, was 98% or more. CONCLUSION: These results suggest a possible role of PSAP variants in iRBD and potential genetic interaction with GBA, which requires additional studies.

Long-term non-invasive ventilation to manage persistent ventilatory failure after COPD exacerbation.

BACKGROUND AND OBJECTIVE: Patients with ventilatory failure at discharge from hospital following an exacerbation of COPD (ECOPD) have increased work of breathing and reduced inspiratory muscle strength compared with those with a normal arterial carbon dioxide tension (PaCO(2)). They also have a significantly worse prognosis. Long-term non-invasive positive pressure ventilation (NIPPV) may offer a treatment strategy but benefits have not been established. METHODS: We examined the outcomes of 35 patients, with a PaCO(2) >7.5 kPa and normal pH, following hospital admission with an ECOPD. Patients were initiated on long-term NIPPV. Our aims were to establish if NIPPV was tolerated and to describe the effects on ventilatory parameters. RESULTS: Daytime arterial blood gases and nocturnal ventilatory parameters improved significantly on NIPPV. Diurnal PaO(2), self-ventilating, rose from (mean (SD)) 7.3 (1.8) to 8.1 (0.9) kPa (P = 0.005) and PaCO(2) fell from 8.8 (1.3) to 7.3 (0.8) kPa (P

Screening the human prepro-orexin gene in a single-centre narcolepsy cohort.

BACKGROUND AND PURPOSE: Although the orexin system has an established role in narcolepsy, the mechanism of orexin deficiency in human cases is unknown. The strong association with human leukocyte antigen (HLA) DQB1*0602 suggests an autoimmune basis, but supporting evidence is lacking. Although data indicate that HLA status is not the sole genetic factor, only a single case of a functional orexin system mutation has been discovered, in a study with a selection bias designed to increase yield. In this study, we examined the prepro-orexin gene for mutations in a cohort of unrelated patients with narcolepsy from a national UK referral centre. PATIENTS AND METHODS: Subjects with a diagnosis of narcolepsy were recruited from a patient database. DNA samples were obtained using buccal smear kits. The prepro-orexin gene was amplified using polymerase chain reactions and screened for polymorphisms and mutations. RESULTS: Eighty-one patients were recruited, of whom 69 provided DNA samples. A previously described intronic single nucleotide polymorphism, of unlikely significance, was identified in one subject who had typical clinical and electrophysiological features of narcolepsy. It was located 16 base pairs downstream from exon 1. No other mutations were found. CONCLUSION: This result supports existing evidence which indicates that mutations of the prepro-orexin gene are rare and that the genetic contribution to the aetiology of human narcolepsy is likely to be complex.

Prolonged invasive ventilation following acute ventilatory failure in COPD: weaning results, survival, and the role of noninvasive ventilation.

BACKGROUND: Invasive ventilation for COPD has significant mortality, and weaning can be difficult. At Papworth Hospital, we provide a specialist weaning service using noninvasive ventilation (NIV) for patients requiring prolonged invasive ventilation after recovery from acute illness. We analyzed our results for patients with COPD to identify factors associated with weaning outcome and survival. METHODS: A retrospective analysis was conducted of COPD patients admitted for weaning from invasive ventilation, from 1992 to 2003. Weaning success and survival were assessed. Associations were sought between these outcomes and age, sex, spirometry, arterial blood gas levels, APACHE (acute physiology and chronic health evaluation) II score, length of stay (LOS), and the use of NIV and long-term oxygen therapy. RESULTS: Sixty-seven patients were identified, all of whom were receiving tracheostomy ventilation on transfer to the Respiratory Support and Sleep Centre (RSSC). Sixty-four patients (95.5%) were weaned, and 62 patients survived to hospital discharge. NIV was used in weaning 40 patients and in the long term in 25 patients. Median survival was 2.5 years (interquartile range, 0.7 to 4.6 years). One-year, 2-year, and 5-year survival rates were 68%, 54%, and 25%, respectively. Long-term survival was inversely associated with age and LOS in the ICU and the RSSC. The provision of maintenance NIV after weaning was associated with better long-term survival, independent of age and LOS (hazard rate, 0.48; p = 0.03). CONCLUSIONS: These results demonstrate that a specialist multidisciplinary approach, including the use of NIV, can be successful in weaning most COPD patients from prolonged invasive ventilation. The data also suggest that long-term NIV may improve survival in selected patients.

Meta-analysis of randomised controlled trials of oral mandibular advancement devices and continuous positive airway pressure for obstructive sleep apnoea-hypopnoea.

Obstructive sleep apnoea-hypopnoea (OSAH) causes excessive daytime sleepiness, impairs quality-of-life, and increases cardiovascular disease and road traffic accident risks. Continuous positive airway pressure (CPAP) treatment and mandibular advancement devices (MAD) have been shown to be effective in individual trials but their effectiveness particularly relative to disease severity is unclear. A MEDLINE, Embase and Science Citation Index search updating two systematic reviews to August 2013 identified 77 RCTs in adult OSAH patients comparing: MAD with conservative management (CM); MAD with CPAP; or CPAP with CM. Overall MAD and CPAP significantly improved apnoea-hypopnoea index (AHI) (MAD -9.3/hr (p < 0.001), CPAP -25.4 (p < 0.001)). In direct comparisons mean AHI and Epworth sleepiness scale score were lower (7.0/hr (p < 0.001) and 0.67 (p = 0.093) respectively) for CPAP. There were no CPAP vs. MAD trials in mild OSAH but in comparisons with CM, MAD and CPAP reduced ESS similarly (MAD 2.01 (p < 0.001); CPAP 1.23 (p = 0.012). Both MAD and CPAP are clinically effective in the treatment of OSAH. Although CPAP has a greater treatment effect, MAD is an appropriate treatment for patients who are intolerant of CPAP and may be comparable to CPAP in mild disease.

Unmet needs of patients with narcolepsy: perspectives on emerging treatment options.

The treatment options currently available for narcolepsy are often unsatisfactory due to suboptimal efficacy, troublesome side effects, development of drug tolerance, and inconvenience. Our understanding of the neurobiology of narcolepsy has greatly improved over the last decade. This knowledge has not yet translated into additional therapeutic options for patients, but progress is being made. Some compounds, such as histaminergic H3 receptor antagonists, may prove useful in symptom control of narcolepsy. The prospect of finding a cure still seems distant, but hypocretin replacement therapy offers some promise. In this narrative review, we describe these developments and others which may yield more effective narcolepsy treatments in the future.

Pharmacotherapies for obstructive sleep apnoea: where are we now?

Obstructive sleep apnoea (OSA) is common, causes considerable morbidity and probably contributes to mortality particularly through associated cardiovascular disease. The physical therapy of continuous positive airway pressure (CPAP) is extremely effective in the majority of patients but most patients would prefer an alternative. Intuitively, OSA should be amenable to pharmacotherapy. The upper airway of affected individuals can be narrowed but is patent during wakefulness. Collapse of the airway during sleep occurs when negative intra-luminal pressure generated by inspiratory effort exceeds the tone of the upper airway dilators. This mismatch may be in part due to respiratory drive instability but the state-dependent fall in drive to the airway dilator muscles is the biggest factor in most patients. Various drugs have been investigated as treatment for OSA. Acetazolamide, theophylline, nicotine, opioid antagonists and medroxyprogesterone have been used to increase respiratory drive. Clonidine has been tested with the aim of reducing rapid eye movement sleep when OSA is often most severe. Various antidepressants have been used to suppress rapid eye movement sleep and to preferentially activate the upper airway dilators. The drug trials have often been of poor design and none has included more than a few patients. Most of the drugs have been found to be ineffective and those that have worked for some patients (acetazolamide and protriptyline) have produced intolerable adverse effects. There have been recent advances in the understanding of the neurotransmitters involved in the control of sleep and the upper airway motor neurones, offering the possibility of novel approaches to the drug treatment of OSA for those patients who cannot tolerate or do not benefit from CPAP. It seems likely that a better understanding of the mechanisms of OSA in individual patients and tailoring of drug therapy will be the way forward.

Obstructive sleep apnoea in the elderly: recognition and management considerations.

Obstructive sleep apnoea is characterised by repetitive interruptions of breathing during sleep due to upper airway collapse. It affects sleep quality, daytime alertness and quality of life. It is associated with increased cardiovascular morbidity and mortality and an increased risk of road traffic accidents. Sleep apnoea is common among older people and its effects can be more severe than in younger people. The added impact is because of a physiological decline in sleep quality with age in most people and the increasing frequency of other comorbidities with increasing years that affect both sleep and daytime function. It is important to be alert to the diagnosis, bearing in mind these other influences on sleep quality. The diagnosis is generally straightforward once appropriate tests are performed. Treatment is aimed at minimising upper airway obstruction during sleep and the most effective therapy is continuous positive airway pressure. Weight loss can also be effective. Other management options, including surgery, mandibular advancement devices and drug treatment, are less effective, but there are interesting advances in the understanding of the pharmacology of the upper airway. Specific serotonergic agonists hold the greatest potential for a useful drug treatment for this widespread and debilitating condition.

Volume assured versus pressure preset non-invasive ventilation for compensated ventilatory failure in COPD.

BACKGROUND: The addition of domiciliary non-invasive ventilation (NIV) to standard therapy in chronic obstructive pulmonary disease (COPD) patients with compensated ventilatory failure (CVF) is reported to have beneficial effects. Compliance with NIV is an important factor. Volume assured NIV (va-NIV) may improve compliance and ventilation during sleep by automatically titrating ventilatory pressures. METHODS: A prospective single centre, randomised, parallel group trial comparing va-NIV and pressure preset NIV (pp-NIV) in COPD patients with CVF naïve to domiciliary NIV was performed (ISCRTN91892415). The primary outcomes were arterial blood gases, mean overnight oximetry (mSpO2) and compliance after three months. Secondary outcomes included pulmonary function, exercise capacity and health-related quality of life assessment. RESULTS: Forty patients were randomised in a 1:1 ratio. The va-NIV median target minute ventilation was 8.4 L/min and pp-NIV median inspiratory pressure was 28 cmH2O. There were no significant differences between groups in primary or secondary outcomes after three months. Mean (SD) PaO2 8.7 (1.7) versus 7.9 (1.7) kPa (p = 0.19), PaCO2 6.7 (0.5) versus 7.3 (1.1) kPa (p = 0.1), mSpO2 89.7 (4.2) versus 89.8 (3.9) % (p = 0.95), compliance 5.0 (3.1) versus 4.7 (3.2) hours (p = 0.8) in va-NIV versus pp-NIV respectively. Patients allocated va-NIV spent fewer days in hospital initiating therapy 3.3 (1.6) versus 5.2 (2.8) (p = 0.02). Both groups showed significant improvements in PaCO2 and mSpO2 after three months treatment. CONCLUSIONS: Domiciliary va-NIV and pp-NIV have similar effects on physiological outcomes in COPD patients with CVF and both are well tolerated.