Ingrid Jullian-Desayes

Impact of obstructive sleep apnea treatment by continuous positive airway pressure on cardiometabolic biomarkers: a systematic review from sham CPAP randomized controlled trials.

Reducing cardiometabolic risk may represent an important target for effective obstructive sleep apnea (OSA) treatment. The impact of continuous positive airway pressure (CPAP), the first line therapy of OSA, on metabolic or inflammatory markers is still debated. A systematic literature search using several databases was performed. We provide a systematic analysis of randomized studies comparing therapeutic versus sham CPAP intervention and also include studies using a CPAP withdrawal design. We addressed the impact of CPAP on the following cardiometabolic biomarkers: 1) plasma and urine catecholamines and their metabolites that reflect sympathetic activity; 2) insulin resistance and lipid metabolism biomarkers; 3) oxidative stress, systemic and vascular inflammation biomarkers; 4) liver enzymes highlighting the association between OSA and nonalcoholic fatty liver disease (NAFLD); 5) coagulation biomarkers. The impact of CPAP on sympathetic activity is robust across studies and occurs rapidly. In contrast to sympathetic activity, the well-designed studies included in this review failed to demonstrate that CPAP alters metabolic or inflammatory markers in OSA. CPAP did not change glucose, lipids, insulin resistance levels or the ratio of patients with metabolic syndrome. In unselected OSA patients, it is not realistic to expect a clinically relevant decrease in cardiometabolic biomarkers with CPAP therapy.

Impact of effective versus sham continuous positive airway pressure on liver injury in obstructive sleep apnoea: Data from randomized trials.

Obstructive sleep apnoea (OSA) could be an independent risk factor for non‐alcoholic fatty liver disease (NAFLD) occurrence and progression. The impact of continuous positive airway pressure (CPAP) treatment on non‐invasive markers of NAFLD has not been studied. The aim of this study was to evaluate the effect of 6–12 weeks of effective CPAP on the FibroMax test (comprising components including the SteatoTest, NashTest and FibroTest) through three randomized sham controlled studies.

Impact of concomitant medications on obstructive sleep apnoea

Obstructive sleep apnoea (OSA) is characterized by repeated episodes of apnoea and hypopnoea during sleep. Little is known about the potential impact of therapy drugs on the underlying respiratory disorder. Any influence should be taken into account and appropriate action taken, including drug withdrawal if necessary. Here, we review drugs in terms of their possible impact on OSA; drugs which (1) may worsen OSA; (2) are unlikely to have an impact on OSA; (3) those for which data are scarce or contradictory; and (4) drugs with a potentially improving effect. The level of evidence is ranked according to three grades: A – randomized controlled trials (RCTs) with high statistical power; B – RCTs with lower power, non‐randomized comparative studies and observational studies; C – retrospective studies and case reports. Our review enabled us to propose clinical recommendations. Briefly, agents worsening OSA or inducing weight gain, that must be avoided, are clearly identified. Drugs such as ‘Z drugs’ and sodium oxybate should be used with caution as the literature contains conflicting results. Finally, larger trials are needed to clarify the potential positive impact of certain drugs on OSA. In the meantime, some, such as diuretics or other antihypertensive medications, are helpful in reducing OSA‐associated cardiovascular morbidity.

Nonalcoholic fatty liver disease in chronic obstructive pulmonary disease

Nonalcoholic fatty liver disease (NAFLD) is independently linked to cardiometabolic morbidity and mortality. Low-grade inflammation, oxidative stress and ectopic fat, common features of chronic obstructive pulmonary disease (COPD), might contribute to the development of NAFLD. We aimed to investigate the prevalence of NAFLD and to evaluate the relationship between various types of liver damage and COPD severity, comorbidities and circulating inflammatory cytokines. Validated noninvasive tests (FibroMax: SteatoTest, NashTest and FibroTest) were used to assess steatosis, nonalcoholic steatohepatitis (NASH) and liver fibrosis. Patients underwent an objective assessment of COPD comorbidities, including sleep studies. Biological parameters included a complete lipid profile and inflammatory markers. In COPD patients the prevalence of steatosis, NASH and fibrosis were 41.4%, 36.9% and 61.3%, respectively. In multivariate analysis, SteatoTest and FibroTest were significantly associated with sex, body mass index (BMI), untreated sleep apnoea and insulin resistance, and, in addition, COPD Global Initiative for Chronic Obstructive Lung Disease stage for SteatoTest. Patients with steatosis had higher tumour necrosis factor-α levels and those with NASH or a combination of liver damage types had raised leptin levels after adjustment for age, sex and BMI. We concluded that NAFLD is highly prevalent in COPD and might contribute to cardiometabolic comorbidities. Nonalcoholic fatty liver disease is highly prevalent in COPD patients and may contribute to comorbidities http://ow.ly/cH2h309yOlM

Baclofen and sleep apnoea syndrome: analysis of VigiBase, the WHO pharmacovigilance database

Baclofen is a centrally acting gamma aminobutyric acid (GABA)-B agonist, widely used for chronic spasticity in neurological disorders, available in oral and intrathecal formulations. Depending on the severity of spasticity and tolerance, standard treatment includes daily oral administration of 40–80 mg [1]. The main adverse effects reported with baclofen are sedation, sleepiness, weakness, dizziness and psychological disturbances [2]. According to the depressant effects of GABA on the central nervous system, baclofen might also induce or aggravate sleep-disordered breathing by depressing central ventilatory drive and/or increasing upper airway obstruction. A single oral low dose of baclofen did not significantly impair the apnoea–hypopnoea index (AHI) in a population with moderate obstructive sleep apnoea [3], but bolus intrathecal administration of the drug increased central sleep apnoea (CSA) in patients with severe spasticity [4]. Baclofen is associated with sleep apnoea syndrome especially the high oral doses prescribed for alcohol addiction http://ow.ly/J5H730h4znW

Prevalence of obesity hypoventilation syndrome in ambulatory obese patients attending pathology laboratories

The prevalence of obesity hypoventilation syndrome (OHS) in the unselected obese is unknown. Our objectives were: (i) to determine the prevalence of OHS in ambulatory obese patients not previously referred to a pulmonologist for suspicion of sleep breathing disorders and (ii) to assess whether venous bicarbonate concentration [HCO3 − v] can be used to detect OHS.

Ticagrelor and Central Sleep Apnea

Ticagrelor is a P2Y12 receptor antagonist used in first-line dual-antiplatelet therapy in coronary artery disease [(1)][1]. Cheyne-Stokes respiration with central sleep apnea was reported in 4 patients after ticagrelor therapy was initiated and disappeared after ticagrelor withdrawal and switch to

What is the best treatment strategy for obstructive sleep apnoea-related hypertension?

Obstructive sleep apnoea (OSA) is characterized by the repetitive occurrence of complete (apnoea) and incomplete (hypopnea) pharyngeal collapse inducing chronic intermittent hypoxia (CIH) and sleep fragmentation. The prevalence of hypertension in OSA patients reaches 50% [1] with a high rate of uncontrolled and resistant hypertension [1, 2], both leading to cardiovascular diseases [3]. CIH leads to intermediary mechanisms such as increased sympathetic activity [4] and/or dysregulation of the renin–angiotensin aldosterone system [1], which can be targeted by specific classes of antihypertensive agents. Additional data suggest that fluid accumulated in the legs during the day is shifted during sleep from the legs to the upper body, reducing upper airway size, increasing upper airway collapsibility and aggravating OSA [5]. This suggests that diuretics could play a critical role in reducing OSA severity and treating OSA-related hypertension. For primary hypertension, the main classes recommended for treatment initiation in monotherapy are thiazide diuretics, beta-blockers (BB), long-acting calcium channel blockers (CCB) and renin–angiotensin blockers (angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB, also known as sartans)). In the general population, these drug classes have been shown to be equally effective. Owing to the specific underlying mechanisms of OSArelated hypertension some of these classes might be anticipated to be better candidates, but a head-to-head comparison between BB, CCB, ACE and ARB is still lacking in the sleep apnoea literature. To address this question, we exploited the baseline data of the OPTISAS2 multicentre randomized controlled trial (NCT: 01505959), in which 213 OSA patients at high cardiovascular risk had measured self-home blood pressure (BP) (three measurements each morning and evening for 3 days). Our aim was to identify individual classes or combinations of anti-hypertensive medications associated with the best blood pressure control in this OSA population. The method of inverse probability of treatment weight (IPTW) estimator is well adapted to address this question using observational data. Briefly, this causal inference method balances patients according to their baseline characteristics by creating pseudo-populations in which each patient is weighted by the inverse of the probability of receiving his/her treatment. In the final pseudo-population, treatment exposure is independent of the measured confounders. In this way, the average treatment effect of each antihypertensive strategy could be assessed with a validity and strength of demonstration close to that of a randomized controlled trial [6, 7]. We used two approaches: (1) a multinomial IPTW estimator to assess the respective impact of different antihypertensive monotherapies on BP control; (2) a standard IPTW estimator to assess the impact of different dual therapies, including diuretics, on BP control. For both methods, we used stabilized weight and a robust estimator of the variance. A weight truncation at the 95th percentile was performed to reduce the risk of violation of the positivity assumption. All statistical analyses were performed by using SAS v9.4 (SAS Institute Inc., Cary, These authors contributed equally: Bruno Revol, Ingrid JullianDesayes

POLLAR: Impact of air POLLution on Asthma and Rhinitis; a European Institute of Innovation and Technology Health (EIT Health) project

Allergic rhinitis (AR) is impacted by allergens and air pollution but interactions between air pollution, sleep and allergic diseases are insufficiently understood. POLLAR (Impact of air POLLution on sleep, Asthma and Rhinitis) is a project of the European Institute of Innovation and Technology (EIT Health). It will use a freely-existing application for AR monitoring that has been tested in 23 countries (the Allergy Diary, iOS and Android, 17,000 users, TLR8). The Allergy Diary will be combined with a new tool allowing queries on allergen, pollen (TLR2), sleep quality and disorders (TRL2) as well as existing longitudinal and geolocalized pollution data. Machine learning will be used to assess the relationship between air pollution, sleep and AR comparing polluted and non-polluted areas in 6 EU countries. Data generated in 2018 will be confirmed in 2019 and extended by the individual prospective assessment of pollution (portable sensor, TLR7) in AR. Sleep apnea patients will be used as a demonstrator of sleep disorder that can be modulated in terms of symptoms and severity by air pollution and AR. The geographic information system GIS will map the results. Consequences on quality of life (EQ-5D), asthma, school, work and sleep will be monitored and disseminated towards the population. The impacts of POLLAR will be (1) to propose novel care pathways integrating pollution, sleep and patients’ literacy, (2) to study sleep consequences of pollution and its impact on frequent chronic diseases, (3) to improve work productivity, (4) to propose the basis for a sentinel network at the EU level for pollution and allergy, (5) to assess the societal implications of the interaction. MASK paper N°32.

Drugs and obstructive sleep apnoea

We greatly appreciated the Letter to the Editor from Montastruc and colleagues [1] in response to our review dealing with the impact of concomitant medications on obstructive sleep apnoea (OSA) [2]. As little is known about the putative role of drugs on OSA, we reviewed drugs in terms of their possible impact on OSA – i.e. drugs: (i) whichmay worsen OSA; (ii) which are unlikely to have an impact on OSA; (iii) for which data are scarce or contradictory; and (iv) with a potentially beneficial effect. The level of evidence was ranked according to three different grades: randomized controlled trials (RCTs) with a large sample size and sufficient power; RCTs with a small sample size, nonrandomized comparative studies and observational studies; retrospective studies or case reports. Our work has enabled us to propose expert clinical recommendations: drugs exacerbating OSA that should be avoided were identified (i.e. opiates, benzodiazepines, baclofen or drugs associated with weight gain), based on robust RCTs. The two pharmacovigilance studies investigating drugs associated with OSA from Linselle and colleagues [3, 4] offer very important additional data from original databases in real-life situations. These two studies use the French Pharmacovigilance Database (based on six spontaneously registered reports [3]) and VigiBase®, the World Health Organization Global Individual Case Safety Report (ICSR) database (covering 3325 adverse drug reactions [4]). The authors concluded that the main drugs associated with OSA were psychotropic agents (benzodiazepines, neuroleptic drugs), coxibs and opioids, reinforcing the results of randomized trials. Other pharmacovigilance signals have been described for drugs for which the underlying mechanism linking the drug to OSA was difficult to elucidate – concerning individual drugs (alendronic acid, digoxin and esomeprazole) and also classes of drugs (bisphosphonates, interferons, proton pump inhibitors and thiazolidinediones). The causal relationship with OSA remains to be demonstrated as these drugs might be markers of OSA-related symptoms or comorbidities rather than drugs favouring OSA or increasing its severity. For example, oesophageal reflux is clearly linked to huge variations in intrathoracic pressure during apnoeas and hypopnoeas, and it is plausible that proton pump inhibitors were used in this indication. Accordingly, a recent systematic review and meta-analysis concluded that proton pump inhibitors might improve the quality of sleep in OSA patients with concomitant gastroesophageal reflux disease, without any effect on apnoea–hypopnoea indices [5]. Along the same lines, OSA is highly prevalent in patients with multiple sclerosis [6] and this might explain the pharmacovigilance signal observed for interferons. As an example of a contradictory result between the literature and the case– noncase study from Linselle and colleagues [4], the Cochrane Collaboration has proposed sodium oxybate as a potential therapeutic option for a subgroup of patients with OSA [7]. We agree with the authors that quetiapine, clozapine, benzodiazepines, opium alkaloids and thiazolidinediones could worsenOSA. Theweight gain induced byneuroleptic agents unequivocally worsens OSA [8]. Finally, new pharmacovigilance signals have been provided by Linselle and colleagues for drugs previously unexplored in OSA – digoxin and bisphosphonates [4] – that need to be further investigated. It is important to note that our results were based mainly on patients, in whom there was well-documented sleep studies and a distinction between obstructive and central sleep apnoea. Information about polysomnographic testing is not systematically available in pharmacovigilance databases. Moreover, in most British Journal of Clinical Pharmacology Br J Clin Pharmacol (2017) 83 2317–2318 2317