Melania Marques

Desipramine improves upper airway collapsibility and reduces OSA severity in patients with minimal muscle compensation.

We recently demonstrated that desipramine reduces the sleep-related loss of upper airway dilator muscle activity and reduces pharyngeal collapsibility in healthy humans without obstructive sleep apnoea (OSA). The aim of the present physiological study was to determine the effects of desipramine on upper airway collapsibility and apnoea–hypopnea index (AHI) in OSA patients. A placebo-controlled, double-blind, randomised crossover trial in 14 OSA patients was performed. Participants received treatment or placebo in randomised order before sleep. Pharyngeal collapsibility (critical collapsing pressure of the upper airway (Pcrit)) and ventilation under both passive (V′0,passive) and active (V′0,active) upper airway muscle conditions were evaluated with continuous positive airway pressure (CPAP) manipulation. AHI was quantified off CPAP. Desipramine reduced active Pcrit (median (interquartile range) −5.2 (4.3) cmH2O on desipramine versus −1.9 (2.7) cmH2O on placebo; p=0.049) but not passive Pcrit (−2.2 (3.4) versus −0.7 (2.1) cmH2O; p=0.135). A greater reduction in AHI occurred in those with minimal muscle compensation (defined as V′0,active−V′0,passive) on placebo (r=0.71, p=0.009). The reduction in AHI was driven by the improvement in muscle compensation (r=0.72, p=0.009). In OSA patients, noradrenergic stimulation with desipramine improves pharyngeal collapsibility and may be an effective treatment in patients with minimal upper airway muscle compensation. Desipramine administered before sleep reduces pharyngeal collapsibility in patients with obstructive sleep apnoea http://ow.ly/1auA302CL8F

Estimation of pharyngeal collapsibility during sleep by peak inspiratory airflow.

Objectives Pharyngeal critical closing pressure (Pcrit) or collapsibility is a major determinant of obstructive sleep apnea (OSA) and may be used to predict the success/failure of non-continuous positive airway pressure (CPAP) therapies. Since its assessment involves overnight manipulation of CPAP, we sought to validate the peak inspiratory flow during natural sleep (without CPAP) as a simple surrogate measurement of collapsibility. Methods Fourteen patients with OSA attended overnight polysomnography with pneumotachograph airflow. The middle third of the night (non-rapid eye movement sleep [NREM]) was dedicated to assessing Pcrit in passive and active states via abrupt and gradual CPAP pressure drops, respectively. Pcrit is the extrapolated CPAP pressure at which flow is zero. Peak and mid-inspiratory flow off CPAP was obtained from all breaths during sleep (excluding arousal) and compared with Pcrit. Results Active Pcrit, measured during NREM sleep, was strongly correlated with both peak and mid-inspiratory flow during NREM sleep (r = -0.71, p < .005 and r = -0.64, p < .05, respectively), indicating that active pharyngeal collapsibility can be reliably estimated from simple airflow measurements during polysomnography. However, there was no significant relationship between passive Pcrit, measured during NREM sleep, and peak or mid-inspiratory flow obtained from NREM sleep. Flow measurements during REM sleep were not significantly associated with active or passive Pcrit. Conclusions Our study demonstrates the feasibility of estimating active Pcrit using flow measurements in patients with OSA. This method may enable clinicians to estimate pharyngeal collapsibility without sophisticated equipment and potentially aid in the selection of patients for non- positive airway pressure therapies.

Phenotyping Pharyngeal Pathophysiology using Polysomnography in Patients with Obstructive Sleep Apnea

Rationale: Therapies for obstructive sleep apnea (OSA) could be administered on the basis of a patients own phenotypic causes (“traits”) if a clinically applicable approach were available. Objectives: Here we aimed to provide a means to quantify two key contributors to OSA—pharyngeal collapsibility and compensatory muscle responsiveness—that is applicable to diagnostic polysomnography. Methods: Based on physiological definitions, pharyngeal collapsibility determines the ventilation at normal (eupneic) ventilatory drive during sleep, and pharyngeal compensation determines the rise in ventilation accompanying a rising ventilatory drive. Thus, measuring ventilation and ventilatory drive (e.g., during spontaneous cyclic events) should reveal a patients phenotypic traits without specialized intervention. We demonstrate this concept in patients with OSA (N = 29), using a novel automated noninvasive method to estimate ventilatory drive (polysomnographic method) and using “gold standard” ventilatory drive (intraesophageal diaphragm EMG) for comparison. Specialized physiological measurements using continuous positive airway pressure manipulation were employed for further comparison. The validity of nasal pressure as a ventilation surrogate was also tested (N = 11). Measurements and Main Results: Polysomnography‐derived collapsibility and compensation estimates correlated favorably with those quantified using gold standard ventilatory drive (R = 0.83, P < 0.0001; and R = 0.76, P < 0.0001; respectively) and using continuous positive airway pressure manipulation (R = 0.67, P < 0.0001; and R = 0.64, P < 0.001; respectively). Polysomnographic estimates effectively stratified patients into high versus low subgroups (accuracy, 69‐86% vs. ventilatory drive measures; P < 0.05). Traits were near‐identical using nasal pressure versus pneumotach (N = 11, R ≥ 0.98, both traits; P < 0.001). Conclusions: Phenotypes of pharyngeal dysfunction in OSA are evident from spontaneous changes in ventilation and ventilatory drive during sleep, enabling noninvasive phenotyping in the clinic. Our approach may facilitate precision therapeutic interventions for OSA.

Effect of Sleeping Position on Upper Airway Patency in Obstructive Sleep Apnea Is Determined by the Pharyngeal Structure Causing Collapse

Objectives In some patients, obstructive sleep apnea (OSA) can be resolved with improvement in pharyngeal patency by sleeping lateral rather than supine, possibly as gravitational effects on the tongue are relieved. Here we tested the hypothesis that the improvement in pharyngeal patency depends on the anatomical structure causing collapse, with patients with tongue-related obstruction and epiglottic collapse exhibiting preferential improvements. Methods Twenty-four OSA patients underwent upper airway endoscopy during natural sleep to determine the pharyngeal structure associated with obstruction, with simultaneous recordings of airflow and pharyngeal pressure. Patients were grouped into three categories based on supine endoscopy: Tongue-related obstruction (posteriorly located tongue, N = 10), non-tongue related obstruction (collapse due to the palate or lateral walls, N = 8), and epiglottic collapse (N = 6). Improvement in pharyngeal obstruction was quantified using the change in peak inspiratory airflow and minute ventilation lateral versus supine. Results Contrary to our hypothesis, patients with tongue-related obstruction showed no improvement in airflow, and the tongue remained posteriorly located while lateral. Patients without tongue involvement showed modest improvement in airflow (peak flow increased 0.07 L/s and ventilation increased 1.5 L/min). Epiglottic collapse was virtually abolished with lateral positioning and ventilation increased by 45% compared to supine position. Conclusions Improvement in pharyngeal patency with sleeping position is structure specific, with profound improvements seen in patients with epiglottic collapse, modest effects in those without tongue involvement and-unexpectedly-no effect in those with tongue-related obstruction. Our data refute the notion that the tongue falls back into the airway during sleep via gravitational influences.

Predicting epiglottic collapse in patients with obstructive sleep apnoea

Obstructive sleep apnoea (OSA) is characterised by pharyngeal obstruction occurring at different sites. Endoscopic studies reveal that epiglottic collapse renders patients at higher risk of failed oral appliance therapy or accentuated collapse on continuous positive airway pressure. Diagnosing epiglottic collapse currently requires invasive studies (imaging and endoscopy). As an alternative, we propose that epiglottic collapse can be detected from the distinct airflow patterns it produces during sleep. 23 OSA patients underwent natural sleep endoscopy. 1232 breaths were scored as epiglottic/nonepiglottic collapse. Several flow characteristics were determined from the flow signal (recorded simultaneously with endoscopy) and used to build a predictive model to distinguish epiglottic from nonepiglottic collapse. Additionally, 10 OSA patients were studied to validate the pneumotachograph flow features using nasal pressure signals. Epiglottic collapse was characterised by a rapid fall(s) in the inspiratory flow, more variable inspiratory and expiratory flow and reduced tidal volume. The cross-validated accuracy was 84%. Predictive features obtained from pneumotachograph flow and nasal pressure were strongly correlated. This study demonstrates that epiglottic collapse can be identified from the airflow signal measured during a sleep study. This method may enable clinicians to use clinically collected data to characterise underlying physiology and improve treatment decisions. Epiglottic collapse can be identified from airflow characteristics during sleep http://ow.ly/IafB30dbD60

Effect of 4-Aminopyridine on Genioglossus Muscle Activity during Sleep in Healthy Adults

Rationale: The reduction in upper airway muscle activity from wakefulness to sleep plays a key role in the development of obstructive sleep apnea. Potassium (K+) channels have been recently identified as the downstream mechanisms through which hypoglossal motoneuron membrane excitability is reduced both in non‐rapid eye movement (NREM) sleep and REM sleep. In animal models, the administration of 4‐aminopyridine (4‐AP), a voltage‐gated K+ channel blocker, increased genioglossus activity during wakefulness and across all sleep stages. Objectives: We tested the hypothesis that administration of a single dose of 4‐AP 10 mg extended release would increase genioglossus activity (electromyography of the genioglossus muscle [EMGGG]) during wakefulness and sleep, and thereby decrease pharyngeal collapsibility. Methods: We performed a randomized controlled crossover proof‐of‐concept trial in 10 healthy participants. Participants received active treatment or placebo in randomized order 3 hours before bedtime in the physiology laboratory. Results: EMGGG during wakefulness and NREM sleep and upper airway collapsibility measured during NREM sleep were unchanged between placebo and 4‐AP nights. Tonic but not phasic EMGGG during REM sleep was higher on the 4‐AP night when measured as a percentage of maximal voluntary activation (median [interquartile range] 0.3 [0.5] on placebo vs. 0.8 [1.9] %max on 4 AP; P = 0.04), but not when measured in &mgr;V or as a percentage of wakefulness value. Conclusions: A single dose of 4‐AP 10 mg extended release showed only a small increase in tonic EMGGG during REM sleep in this group of healthy subjects. We speculate that a higher dose of 4‐AP may further increase EMGGG. However, given the potentially severe, dose‐related adverse effects of this drug, including seizures, the administration of 4‐AP does not appear to be an effective strategy to increase genioglossus activity during sleep in humans. Clinical Trial registered with clinicaltrials.gov (NCT02656160).

Breath‐holding as a means to estimate the loop gain contribution to obstructive sleep apnoea

A hypersensitive ventilatory control system or elevated “loop gain” during sleep is a primary phenotypic trait causing obstructive sleep apnoea (OSA). Despite the multitude of methods available to assess the anatomical contributions to OSA during wakefulness in the clinical setting (e.g. neck circumference, pharyngometry, Mallampati score), it is currently not possible to recognize elevated loop gain in patients in this context. Loop gain during sleep can now be recognized using simplified testing during wakefulness, specifically in the form of a reduced maximal breath‐hold duration, or a larger ventilatory response to voluntary 20‐second breath‐holds. We consider that easy breath‐holding manoeuvres will enable daytime recognition of a high loop gain in OSA for more personalized intervention.

Retropalatal and retroglossal airway compliance in patients with obstructive sleep apnea

OBJECTIVES We hypothesized that preferential retropalatal as compared to retroglossal collapse in patients with obstructive sleep apnea was due to a narrower retropalatal area and a higher retropalatal compliance. Patients with a greater retropalatal compliance would exhibit a recognizable increase in negative effort dependence (NED). METHODS Fourteen patients underwent upper airway endoscopy with simultaneous recordings of airflow and pharyngeal pressure during natural sleep. Airway areas were obtained by manually outlining the lumen. Compliance was calculated by the change of airway area from end-expiration to a pressure swing of -5 cm H2O. NED was quantified for each breath as [peak inspiratory flow minus flow at -5 cm H2O]/[peak flow] × 100. RESULTS Compared to the retroglossal airway, the retropalatal airway was smaller at end-expiration (p < 0.001), and had greater absolute and relative compliances (p < 0.001). NED was positively associated with retropalatal relative area change (r = 0.47; p < 0.001). CONCLUSIONS Retropalatal airway is narrower and more collapsible than retroglossal airway. Retropalatal compliance is reflected in the clinically-available NED value.

Palatal prolapse as a signature of expiratory flow limitation and inspiratory palatal collapse in patients with obstructive sleep apnoea

In some individuals with obstructive sleep apnoea (OSA), the palate prolapses into the velopharynx during expiration, limiting airflow through the nose or shunting it out of the mouth. We hypothesised that this phenomenon causes expiratory flow limitation (EFL) and is associated with inspiratory “isolated” palatal collapse. We also wanted to provide a robust noninvasive means to identify this mechanism of obstruction. Using natural sleep endoscopy, 1211 breaths from 22 OSA patients were scored as having or not having palatal prolapse. The patient-level site of collapse (tongue-related, isolated palate, pharyngeal lateral walls and epiglottis) was also characterised. EFL was quantified using expiratory resistance at maximal epiglottic pressure. A noninvasive EFL index (EFLI) was developed to detect the presence of palatal prolapse and EFL using the flow signal alone. In addition, the validity of using nasal pressure was assessed. A cut-off value of EFLI >0.8 detected the presence of palatal prolapse and EFL with an accuracy of >95% and 82%, respectively. The proportion of breaths with palatal prolapse predicted isolated inspiratory palatal collapse with 90% accuracy. This study demonstrates that expiratory palatal prolapse can be quantified noninvasively, is associated with EFL and predicts the presence of inspiratory isolated palatal collapse. Expiratory palatal prolapse can be quantified noninvasively and predicts inspiratory isolated palatal collapse http://ow.ly/vm6c30hB839

Identifying obstructive sleep apnoea patients responsive to supplemental oxygen therapy

A possible precision-medicine approach to treating obstructive sleep apnoea (OSA) involves targeting ventilatory instability (elevated loop gain) using supplemental inspired oxygen in selected patients. Here we test whether elevated loop gain and three key endophenotypic traits (collapsibility, compensation and arousability), quantified using clinical polysomnography, can predict the effect of supplemental oxygen on OSA severity. 36 patients (apnoea–hypopnoea index (AHI) >20 events·h−1) completed two overnight polysomnographic studies (single-blinded randomised-controlled crossover) on supplemental oxygen (40% inspired) versus sham (air). OSA traits were quantified from the air-night polysomnography. Responders were defined by a ≥50% reduction in AHI (supine non-rapid eye movement). Secondary outcomes included blood pressure and self-reported sleep quality. Nine of 36 patients (25%) responded to supplemental oxygen (ΔAHI=72±5%). Elevated loop gain was not a significant univariate predictor of responder/non-responder status (primary analysis). In post hoc analysis, a logistic regression model based on elevated loop gain and other traits (better collapsibility and compensation; cross-validated) had 83% accuracy (89% before cross-validation); predicted responders exhibited an improvement in OSA severity (ΔAHI 59±6% versus 12±7% in predicted non-responders, p=0.0001) plus lowered morning blood pressure and “better” self-reported sleep. Patients whose OSA responds to supplemental oxygen can be identified by measuring their endophenotypic traits using diagnostic polysomnography. A subgroup of patients with obstructive sleep apnoea who benefit from stabilising ventilatory control with supplemental oxygen therapy can be recognised by estimating pathophysiological mechanisms from a routine diagnostic sleep study http://ow.ly/yeVp30lewG4