Upper-Airway Collapsibility and Loop Gain Predict the Response to Oral Appliance Therapy in Patients with Obstructive Sleep Apnea

Abstract

Rationale: Oral appliances (OAs) are commonly used as an alternative treatment to continuous positive airway pressure for patients with obstructive sleep apnea (OSA). However, OAs have variable success at reducing the apnea-hypopnea index (AHI), and predicting responders is challenging. Understanding this variability may lie with the recognition that OSA is a multifactorial disorder and that OAs may affect more than just upper-airway anatomy/collapsibility.

Objectives: The objectives of this study were to determine how OA alters AHI and four phenotypic traits (upper-airway anatomy/collapsibility and muscle function, loop gain, and arousal threshold), and baseline predictors of which patients gain the greatest benefit from therapy.

Methods: In a randomized crossover study, 14 patients with OSA attended two sleep studies with and without their OA. Under each condition, AHI and the phenotypic traits were assessed. Multiple linear regression was used to determine independent predictors of the reduction in AHI.

Measurements and main results: OA therapy reduced the AHI (30 ± 5 vs. 11 ± 2 events/h; P < 0.05), which was driven by improvements in upper-airway anatomy/collapsibility under passive (1.9 ± 0.7 vs. 4.7 ± 0.6 L/min; P < 0.005) and active conditions (2.4 ± 0.9 vs. 6.2 ± 0.4 L/min; P < 0.001). No changes were seen in muscle function, loop gain, or the arousal threshold. Using multivariate analysis, baseline passive upper-airway collapsibility and loop gain were independent predictors of the reduction in AHI (r² = 0.70; P = 0.001).

Conclusions: Our findings suggest that OA therapy improves the upper-airway collapsibility under passive and active conditions. Importantly, a greater response to therapy occurred in those patients with a mild anatomic compromise and a lower loop gain.

Keywords: obstructive sleep apnea; upper-airway anatomy; ventilation.

Figure 1.

Technique for determining the physiologic traits using continuous positive airway pressure (CPAP) manipulations. The obstructive sleep apnea traits are measured by manipulating CPAP during supine non–REM sleep (A) and measuring the changes in ventilation (B). After determining ventilation on optimum CPAP (V_eupnea; i), a series of step-wise reductions (inset) in the CPAP from the therapeutic pressure was produced, and V_passive (ii) was taken as the y-intercept of the minute ventilation versus mask pressure regression (zero mask pressure). CPAP was then lowered until flow limitation started (iii) and arousals occurred intermittently. Ventilation just before arousal (iv) was defined as the “ventilation causing arousal” (V_arousal). During stable breathing between arousals, CPAP was dialed down or up to obtain V_active (v) and loop gain (vi), respectively. V_active is the ventilation at CPAP = 0 when pharyngeal muscles are maximally activated. Loop gain is the ventilatory response (overshoot in ventilation above V_eupnea) divided by the ventilatory disturbance (reduction in ventilation below V_eupnea). (C) Illustration of how these four ventilations can be used to calculate the arousal threshold and upper-airway (UA) response (or gain), and how all four traits interact to manifest the absence or presence of obstructive sleep apnea. Once the patient’s loop gain is known, the ventilation that causes arousal was translated into the ventilatory drive that causes the arousal, which is referred to as the arousal threshold (i.e., 9 L/min). Once the arousal threshold is known, starting at V_passive, as ventilatory drive is increased to a level near the arousal threshold, then the pharyngeal muscles activate and increase V_passive to the measured level V_active. The slope of this line is called the upper-airway gain and is a measure of the upper-airway muscle function. The steeper this slope, the better the upper-airway response to an increase in ventilatory drive, and the larger the distance between the V_active and V_passive. To not have obstructive sleep apnea (i.e., achieve stable breathing), V_active must be above V_arousal. CPAP_min = minimum tolerable level of continuous positive airway pressure; V_passive = passive anatomy/collapsibility.

Figure 2.

Integrative model of the obstructive sleep apnea (OSA) traits demonstrating how oral appliance therapy improves the physiology causing OSA. (A) The traits at baseline are consistent with OSA. Stable breathing is not possible because the achievable ventilation (V_active) is below the level needed to prevent arousal (V_arousal). (B) Oral appliance therapy restores stable breathing and abolishes OSA. This improvement is driven by the dramatic improvement in both V_passive and V_active. V_active = ventilation on zero continuous positive airway pressure when the upper-airway muscles are maximally active; V_arousal = ventilation that causes an arousal; V_eupnea = eupneic ventilation; V_passive = passive anatomy/collapsibility.

Figure 3.

Physiologic predictors of response to therapy. (A) The relationship between loop gain at baseline and percentage reduction in apnea–hypopnea index (AHI). Baseline loop gain (represented as the ratio of a ventilatory response/ventilatory disturbance) was the only significant predictor of the percent reduction in AHI (P = 0.001). A lower baseline loop gain (loop gains closer to zero) was associated with a greater percent reduction in AHI, indicating those with a low/normal loop gain were likely to have a greater improvement in their obstructive sleep apnea severity when treated with an oral appliance. (B) There was a near significant trend for the percent AHI reduction to be associated with passive anatomy/collapsibility (V_passive) at baseline. Negative values of V_passive indicate an airway that collapses despite positive airway pressure.

Figure 4.

Baseline physiologic characteristics of responders to therapy. Responders to therapy (using criterion 2) had (A) a lower loop gain and (B) a less collapsible airway under passive conditions (V_passive; expressed as a percentage of V_eupnea). Non-R = nonresponders; R = responders; V_eupnea = eupneic ventilation; V_passive = passive anatomy/collapsibility.

Figure 5.

Loop gain and passive upper-airway collapsibility (V_passive) combine to predict the response to oral appliance (OA) therapy. Responders have a significantly lower loop gain and less severe collapsibility (higher V_passive) than nonresponders (see multiple linear regression). Note that the patients with the two lowest loop gain values did not respond well to therapy; their poor responses are explained by the more severe collapsibility. The dashed line describes the multiple linear regression, shown here at a 67% reduction in apnea–hypopnea index (best approximating criterion 2, which is used to define responders and nonresponders here). The shaded region describes the region of predicted responders.