Central sleep apnoea (CSA) - the temporary absence or diminution of ventilatory effort during sleep - is seen in a variety of forms including periodic breathing in infancy and healthy adults at altitude and Cheyne-Stokes respiration in heart failure. In most circumstances, the cyclic absence of effort is paradoxically a consequence of hypersensitive ventilatory chemoreflex responses to oppose changes in airflow, that is elevated loop gain, leading to overshoot/undershoot ventilatory oscillations. Considerable evidence illustrates overlap between CSA and obstructive sleep apnoea (OSA), including elevated loop gain in patients with OSA and the presence of pharyngeal narrowing during central apnoeas. Indeed, treatment of OSA, whether via continuous positive airway pressure (CPAP), tracheostomy or oral appliances, can reveal CSA, an occurrence referred to as complex sleep apnoea. Factors influencing loop gain include increased chemosensitivity (increased controller gain), reduced damping of blood gas levels (increased plant gain) and increased lung to chemoreceptor circulatory delay. Sleep-wake transitions and pharyngeal dilator muscle responses effectively raise the controller gain and therefore also contribute to total loop gain and overall instability. In some circumstances, for example apnoea of infancy and central congenital hypoventilation syndrome, central apnoeas are the consequence of ventilatory depression and defective ventilatory responses, that is low loop gain. The efficacy of available treatments for CSA can be explained in terms of their effects on loop gain, for example CPAP improves lung volume (plant gain), stimulants reduce the alveolar-inspired PCO₂ difference and supplemental oxygen lowers chemosensitivity. Understanding the magnitude of loop gain and the mechanisms contributing to instability may facilitate personalized interventions for CSA.

Novel concepts and technological advances have the potential to change the landscape on which clinical sleep medicine is practiced. Screening for sleep apnea will take advantage of readily available mobile telephone technology (sound, accelerometers) to enable widespread recognition of sleep-disordered breathing. Advanced computer-assisted scoring algorithms will improve efficiency and reliability of sleep apnea diagnoses. As the field adopts a personalized approach to therapies, methods to determine the mechanisms of sleep apnea in individuals will be developed-utilizing simplified tests and available recordings-with the promise of predicting outcomes of novel therapies.

Rationale

Measures of unstable ventilatory control (loop gain) can be obtained directly from the periodic breathing duty ratio on polysomnography in patients with Cheyne-Stokes respiration/central sleep apnea and can predict the efficacy of continuous positive airway pressure (CPAP) therapy.

Objectives

In this pilot study, we aimed to determine if this measure could also be applied to patients with complex sleep apnea (predominant obstructive sleep apnea, with worsening or emergent central apneas on CPAP). We hypothesized that loop gain was higher in patients whose central events persisted 1 month later despite CPAP treatment versus those whose events resolved over time.

Methods

We calculated the duty ratio of the periodic central apneas remaining on the CPAP titration (or second half of the split night) while patients were on optimal CPAP with the airway open (obstructive apnea index < 1/h). Loop gain was calculated by the formula: LG = 2π/[(2πDR - sin(2πDR)]. Patients were followed on CPAP for 1 month. Post-treatment apnea-hypopnea index and compliance data were recorded from smart cards.

Measurements and main results

Thirty-two patients with complex sleep apnea were identified, and 17 patients had full data sets. Eight patients continued to have a total of more than five events per hour (11.8 ± 0.5/h) (nonresponders). The remaining nine patients had an apnea-hypopnea index less than 5/h (2.2 ± 0.4/h) (responders). Loop gain was higher in the nonresponders versus responders (2.0 ± 0.1 vs. 1.7 ± 0.2, P = 0.026). Loop gain and the residual apnea-hypopnea index 1 month after CPAP were associated (r = 0.48, P = 0.02). CPAP compliance was similar between groups.

Conclusions

In this pilot study, loop gain was higher for patients with complex sleep apnea in whom central apneas persisted after 1 month of CPAP therapy (nonresponders). Loop gain measurement may enable an a priori determination of those who need alternative modes of positive airway pressure.

BACKGROUND: One of the key mechanisms underlying OSA is reduced pharyngeal muscle tone during sleep. Data suggest that pharmacologic augmentation of central serotonergic/adrenergic tone increases pharyngeal muscle tone. RESEARCH QUESTION: We hypothesized that venlafaxine, a serotonin-norepinephrine reuptake inhibitor, would improve OSA severity. STUDY DESIGN AND METHODS: In this mechanistic, randomized, double-blind, placebo-controlled crossover trial, 20 patients with OSA underwent two overnight polysomnograms ≥ 4 days apart, receiving either 50 mg of immediate-release venlafaxine or placebo before bedtime. Primary outcomes were the apnea-hypopnea index (AHI) and peripheral oxygen saturation (Spo2) nadir, and secondary outcomes included sleep parameters and pathophysiologic traits with a view toward understanding the impact of venlafaxine on mechanisms underlying OSA. RESULTS: Overall, there was no significant difference between venlafaxine and placebo regarding AHI (mean reduction, -5.6 events/h [95% CI, -12.0 to 0.9]; P = .09) or Spo2 nadir (median increase, +1.0% [-0.5 to 5]; P = .11). Venlafaxine reduced total sleep time, sleep efficiency, and rapid eye movement (REM) sleep, while increasing non-REM stage 1 sleep (Pall < .05). On the basis of exploratory post hoc analyses venlafaxine decreased (improved) the ventilatory response to arousal (-30%; P = .049) and lowered (worsened) the predicted arousal threshold (-13%; [P = .02]; ie, more arousable), with no effects on other pathophysiologic traits (Pall ≥ .3). Post hoc analyses further suggested effect modification by arousal threshold (P = .002): AHI improved by 19% in patients with a high arousal threshold (-10.9 events/h [-3.9 to -17.9]) but tended to increase in patients with a low arousal threshold (+7 events/h [-2.0 to 16]). Other predictors of response were elevated AHI and less collapsible upper airway anatomy at baseline (|r| > 0.5, P ≤ .02). INTERPRETATION: In unselected patients, venlafaxine simultaneously worsened and improved various pathophysiologic traits, resulting in a zero net effect. Careful patient selection based on pathophysiologic traits, or combination therapy with drugs countering its alerting effects, may produce a more robust response. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02714400; URL: www.clinicaltrials.gov.

Oxygen therapy is known to reduce loop gain (LG) in patients with obstructive sleep apnoea (OSA), yet its effects on the other traits responsible for OSA remain unknown. Therefore, we assessed how hyperoxia and hypoxia alter four physiological traits in OSA patients. Eleven OSA subjects underwent a night of polysomnography during which the physiological traits were measured using multiple 3-min 'drops' from therapeutic continuous positive airway pressure (CPAP) levels. LG was defined as the ratio of the ventilatory overshoot to the preceding reduction in ventilation. Pharyngeal collapsibility was quantified as the ventilation at CPAP of 0 cmH2O. Upper airway responsiveness was defined as the ratio of the increase in ventilation to the increase in ventilatory drive across the drop. Arousal threshold was estimated as the level of ventilatory drive associated with arousal. On separate nights, subjects were submitted to hyperoxia (n = 9; FiO2 ∼0.5) or hypoxia (n = 10; FiO2 ∼0.15) and the four traits were reassessed. Hyperoxia lowered LG from a median of 3.4 [interquartile range (IQR): 2.6-4.1] to 2.1 (IQR: 1.3-2.5) (P < 0.01), but did not alter the remaining traits. By contrast, hypoxia increased LG [median: 3.3 (IQR: 2.3-4.0) vs. 6.4 (IQR: 4.5-9.7); P < 0.005]. Hypoxia additionally increased the arousal threshold (mean ± s.d. 10.9 ± 2.1 l min(-1) vs. 13.3 ± 4.3 l min(-1); P < 0.05) and improved pharyngeal collapsibility (mean ± s.d. 3.4 ± 1.4 l min(-1) vs. 4.9 ± 1.3 l min(-1); P < 0.05), but did not alter upper airway responsiveness (P = 0.7). This study demonstrates that the beneficial effect of hyperoxia on the severity of OSA is primarily based on its ability to reduce LG. The effects of hypoxia described above may explain the disappearance of OSA and the emergence of central sleep apnoea in conditions such as high altitude.

Rationale

Obstructive sleep apnea (OSA) has multiple pathophysiological causes. A low respiratory arousal threshold (ArTh) and a high loop gain (unstable ventilatory control) can contribute to recurrent respiratory events in patients with OSA. Prior studies have shown that donepezil, an acetylcholinesterase inhibitor, might improve OSA, but the mechanism is unknown.

Objectives

To determine whether a single dose of donepezil lowers the apnea-hypopnea index by modulating the ArTh or loop gain.

Methods

In this randomized, double-blind, crossover trial, 41 subjects with OSA underwent two polysomnograms with ArTh and loop gain evaluated, during which 10 mg of donepezil or placebo was administered.

Measurements and main results

Compared with placebo, sleep efficiency (77.2 vs. 71.9%; P = 0.015) and total sleep time decreased with donepezil (372 vs. 351 min; P = 0.004). No differences were found in apnea-hypopnea index (51.8 vs. 50.0 events/h; P = 0.576) or nadir oxygen saturation as determined by pulse oximetry (80.3 vs. 81.1%; P = 0.241) between placebo and donepezil, respectively. ArTh was not significantly changed (-18.9 vs. -18.0 cm H₂O; P = 0.394) with donepezil. As a whole group, loop gain (ventilatory response to a 1-cycle/min disturbance) did not change significantly (P = 0.089).

Conclusions

A single dose of donepezil did not appear to affect the overall severity of OSA in this patient group, and no consistent effects on ArTh or loop gain were observed. Donepezil may have minor effects on sleep architecture. Clinical trial registered with www.clinicaltrials.gov (NCT02264353).

The upper airway is often modeled as a classical Starling resistor, featuring a constant inspiratory airflow, or plateau, over a range of downstream pressures. However, airflow tracings from clinical sleep studies often show an initial peak before the plateau. To conform to the Starling model, the initial peak must be of small magnitude or dismissed as a transient. We developed a method to simulate fast or slow inspirations through the human upper airway, to test the hypothesis that this initial peak is a transient. Eight subjects [4 obstructive sleep apnea (OSA), 4 controls] slept in an "iron lung" and wore a nasal mask connected to a continuous/bilevel positive airway pressure machine. Downstream pressure was measured using an epiglottic catheter. During non-rapid eye movement (NREM) sleep, subjects were hyperventilated to produce a central apnea, then extrathoracic pressure was decreased slowly (∼2-4 s) or abruptly (<0.5 s) to lower downstream pressure and create inspiratory airflow. Pressure-flow curves were constructed for flow-limited breaths, and slow vs. fast reductions in downstream pressure were compared. All subjects exhibited an initial peak and then a decrease in flow with more negative pressures, demonstrating negative effort dependence (NED). The rate of change in downstream pressure did not affect the peak to plateau airflow ratio: %NED 22 ± 13% (slow) vs. 20 ± 5% (fast), P = not significant. We conclude that the initial peak in inspiratory airflow is not a transient but rather a distinct mechanical property of the upper airway. In contrast to the classical Starling resistor model, the upper airway exhibits marked NED in some subjects.

Background and objective

Upper airway collapsibility predicts the response to several non-continuous positive airway pressure (CPAP) interventions for obstructive sleep apnoea (OSA). Measures of upper airway collapsibility cannot be easily performed in a clinical context; however, a patient's therapeutic CPAP requirement may serve as a surrogate measure of collapsibility. The present work aimed to compare the predictive use of CPAP level with detailed physiological measures of collapsibility.

Methods

Therapeutic CPAP levels and gold-standard pharyngeal collapsibility measures (passive pharyngeal critical closing pressure (P_crit ) and ventilation at CPAP level of 0 cmH₂ O (V_passive )) were retrospectively analysed from a randomized controlled trial (n = 20) comparing the combination of oxygen and eszopiclone (treatment) versus placebo/air control. Responders (9/20) to treatment were defined as those who exhibited a 50% reduction in apnoea/hypopnoea index (AHI) plus an AHI<15 events/h on-therapy.

Results

Responders to treatment had a lower therapeutic CPAP requirement compared with non-responders (6.6 (5.4-8.1)  cmH₂ O vs 8.9 (8.4-10.4) cmH₂ O, P = 0.007), consistent with their reduced collapsibility (lower P_crit , P = 0.017, higher V_passive P = 0.025). Therapeutic CPAP level provided the highest predictive accuracy for differentiating responders from non-responders (area under the curve (AUC) = 0.86 ± 0.9, 95% CI: 0.68-1.00, P = 0.007). However, both P_crit (AUC = 0.83 ± 0.11, 95% CI: 0.62-1.00, P = 0.017) and V_passive (AUC = 0.77 ± 0.12, 95% CI: 0.53-1.00, P = 0.44) performed well, and the difference in AUC for these three metrics was not statistically different. A therapeutic CPAP level ≤8 cmH₂ O provided 78% sensitivity and 82% specificity (positive predictive value = 78%, negative predictive value = 82%) for predicting a response to these therapies.

Conclusion

Therapeutic CPAP requirement, as a surrogate measure of pharyngeal collapsibility, predicts the response to non-anatomical therapy (oxygen and eszopiclone) for OSA.

Study objectives

The current gold-standard method of diagnosing obstructive sleep apnea (OSA) is polysomnography, which can be inefficient. We therefore sought to determine a method to triage patients at risk of OSA, without using subjective data, which are prone to mis-reporting. We hypothesized that acoustic pharyngometry in combination with age, gender, and neck circumference would predict the presence of moderate-to-severe OSA.

Methods

Untreated subjects with suspected OSA were recruited from a local sleep clinic and underwent polysomnography. We also included a control group to verify differences. While seated in an upright position and breathing through the mouth, an acoustic pharyngometer was used to measure the minimal cross-sectional area (MCA) of the upper airway at end-exhalation.

Results

Sixty subjects were recruited (35 males, mean age 42 years, range 21-81 years; apnea-hypopnea index (AHI) 33 ± 30 events/h (mean ± standard deviation), Epworth Sleepiness Scale score 11 ± 6, body mass index 34 ± 8 kg/m(2)). In univariate logistic regression, MCA was a significant predictor of mild-no OSA (AHI < 15). A multivariate logistic regression model including MCA, age, gender, and neck circumference significantly predicted AHI < 15, explaining approximately one-third of the total variance (χ(2)(4) = 37, p < 0.01), with only MCA being a significant independent predictor (adjusted odds ratio 54, standard error 130; p < 0.01).

Conclusions

These data suggest that independent of age, gender, and neck size, objective anatomical assessment can significantly differentiate those with mild versus moderate-to-severe OSA in a clinical setting, and may have utility as a component in stratifying risk of OSA.