An Integrative Model of Physiological Traits Can be Used to Predict Obstructive Sleep Apnea and Response to Non Positive Airway Pressure Therapy

Abstract

Study objectives: Both anatomical and nonanatomical traits are important in obstructive sleep apnea (OSA) pathogenesis. We have previously described a model combining these traits, but have not determined its diagnostic accuracy to predict OSA. A valid model, and knowledge of the published effect sizes of trait manipulation, would also allow us to predict the number of patients with OSA who might be effectively treated without using positive airway pressure (PAP).

Design, participants and intervention: Fifty-seven subjects with and without OSA underwent standard clinical and research sleep studies to measure OSA severity and the physiological traits important for OSA pathogenesis, respectively. The traits were incorporated into a physiological model to predict OSA. The model validity was determined by comparing the model prediction of OSA to the clinical diagnosis of OSA. The effect of various trait manipulations was then simulated to predict the proportion of patients treated by each intervention.

Measurements and results: The model had good sensitivity (80%) and specificity (100%) for predicting OSA. A single intervention on one trait would be predicted to treat OSA in approximately one quarter of all patients. Combination therapy with two interventions was predicted to treat OSA in ∼50% of patients.

Conclusions: An integrative model of physiological traits can be used to predict population-wide and individual responses to non-PAP therapy. Many patients with OSA would be expected to be treated based on known trait manipulations, making a strong case for the importance of non-anatomical traits in OSA pathogenesis and the effectiveness of non-PAP therapies.

Keywords: arousal threshold; non PAP therapy; obstructive sleep apnea; upper airway anatomy.

Figure 1

The obstructive sleep apnea traits are measured using repeated continuous positive airway pressure (CPAP) drops from the holding pressure, which defines eupneic ventilation. With abrupt decrease in CPAP, ventilation decreases to a level determined by the passive upper airway anatomy. (The passive upper airway ventilation at different PAP levels allows extrapolation to ventilation off of PAP.) Allowing time for delay, the decrease in ventilation causes an increase in pCO₂ and ventilatory drive, which will recruit upper airway muscles and improve ventilation. After 3 min, the therapeutic CPAP level is restored, and the ventilatory drive in response to hypoventilation is revealed–the loop gain. With knowledge of the loop gain, the ventilatory drive that leads to arousal (the arousal threshold) can be determined.

Figure 2

Using the traits to model obstructive sleep apnea (OSA). Achievable ventilation is described by the line that begins at the passive upper airway (UA) anatomy ventilation (i.e., ventilation off of positive airway pressure (PAP) at the eupneic ventilatory drive), and which increases according to the ability of the upper airway muscles to augment ventilation in response to the increased ventilatory drive. Desired ventilation begins at the eupneic ventilation (where ventilation = ventilatory demand), and ventilatory demand increases as ventilation falls according to 1/loop gain. The intersection of the two lines represents a new steady state off continuous positive airway pressure (CPAP), which is achieved if the steady state point occurs to the left of the arousal threshold (no OSA). Otherwise, an arousal (scored as hypopnea) will occur (OSA).

Figure 3

Examples of single-trait manipulation. All of the manipulations shown here move the equilibrium point to the left of the arousal threshold, suggesting that stable flow-limited hypoventilation will occur, rather than arousals. OSA, obstructive sleep apnea.

Figure 4

Examples of the traits in eight different individuals. In each example, the obstructive sleep apnea (OSA) severity is listed (AHI, events/h), and a brief description of the salient model features that predispose to or protect against OSA. AHI, apnea-hypopnea index

Figure 5

The relationship between anatomy and obstructive sleep apnea (OSA) is straightforward with very favorable (no OSA) or very poor anatomy (inevitable OSA). However, the relationship with intermediate, or vulnerable, anatomy and OSA is modified by the other traits to lead to or protect against OSA. These other traits are effect modifiers: they modify the effect of the exposure (anatomy) on the outcome (OSA status).

Figure 6

Difference between eupneic and passive upper airway ventilation, representing the deficit in ventilation that must be overcome by recruitment of upper airway muscles. As expected, subjects with NREM AHI > 10 events/h have a significantly greater deficit than those with AHI < 10 events/h. However, there is substantial overlap between the two groups when the deficit in ventilation is between 1–5 L/min. In this range, other non-anatomical traits are likely to protect or promote obstructive sleep apnea. Greater anatomical deficits in ventilation may be impossible to overcome despite other very favorable traits. AHI, apnea-hypopnea index; NREM, nonrapid eye movement.

Figure 7

Effect modification. In all subjects, there is no significant difference in upper airway gain between subjects with an AHI < 10 events/h and those with an AHI > 10 events per hour during NREM sleep. However, among subjects with a similar ventilation deficit, those with an AHI < 10 events per hour have a substantially higher upper airway gain than those with an AHI > 10 events/h. AHI, apnea-hypopnea index; NREM, nonrapid eye movement.

Figure 8

Although patients may have defects in one trait, therapy toward another trait may still help. This subject with severe obstructive sleep apnea and a very poor loop gain would still be expected to improve with therapy that increased the arousal threshold.