A method for measuring and modeling the physiological traits causing obstructive sleep apnea

Abstract

There is not a clinically available technique for measuring the physiological traits causing obstructive sleep apnea (OSA). Therefore, it is often difficult to determine why an individual has OSA or to what extent the various traits contribute to the development of OSA. In this study, we present a noninvasive method for measuring four important physiological traits causing OSA: 1) pharyngeal anatomy/collapsibility, 2) ventilatory control system gain (loop gain), 3) the ability of the upper airway to dilate/stiffen in response to an increase in ventilatory drive, and 4) arousal threshold. These variables are measured using a single maneuver in which continuous positive airway pressure (CPAP) is dropped from an optimum to various suboptimum pressures for 3- to 5-min intervals during sleep. Each individual's set of traits is entered into a physiological model of OSA that graphically illustrates the relative importance of each trait in that individual. Results from 14 subjects (10 with OSA) are described. Repeatability measurements from separate nights are also presented for four subjects. The measurements and model illustrate the multifactorial nature of OSA pathogenesis and how, in some individuals, small adjustments of one or another trait (which might be achievable with non-CPAP agents) could potentially treat OSA. This technique could conceivably be used clinically to define a patient's physiology and guide therapy based on the traits.

Fig. 1.

Measurement of loop gain from a continuous positive airway pressure (CPAP) drop. Top tracing is mask pressure (P_MASK), and bottom tracing is breath-to-breath ventilation. See text for details.

Fig. 2.

Plot of loop gain. A: ventilation is on the x-axis and ventilatory drive is on the y-axis. Starting at the eupneic ventilation on optimum CPAP, the disturbance (a reduction in ventilation of −2.3 l/min, obtained from Fig. 1) is added, followed by the response (an increase in ventilation of 4.2 l/min). The slope of the line connecting the vectors is the loop gain. B: axes are flipped and the reciprocal of loop gain is plotted. Other traits will subsequently be added to B.

Fig. 3.

A: determination of V̇₀. Ventilation at several levels of mask pressure is plotted (□) and fit with a straight line. The anatomy trait is the ventilation at zero mask pressure (■), which is 0.7 l/min in this example. B: model with the upper airway anatomy and loop gain plotted. To plot V̇₀ in the model, the eupneic level of ventilatory drive is found on the x-axis (5.1 l/min) and a closed square is placed at a ventilation of 0.7 l/min.

Fig. 4.

A: measurement of the upper airway gain from a CPAP drop. As in Fig. 1, a single 3-min drop is shown. The increase in ventilation across the drop (ΔV̇e) is divided by the increase in ventilatory drive (ΔVentilatory Drive) to get the upper airway gain. In this example, the upper airway gain is 1.3 l/min ÷ 4.2 l/min, which equals 0.31. The OSA model, with the addition of the upper airway gain, is shown in B. Starting at the anatomy point (■), the upper airway gain (dashed line) is plotted by drawing vectors for the increase in ventilatory drive and the resulting increase in ventilation (justification for plotting the upper airway gain starting at the anatomy point, V̇₀, is given in the online Supplement Section III.A.). The intersection of the solid (1/Loop gain) and dashed (upper airway gain) lines is the predicted steady-state ventilation off CPAP (this intersection is termed the “steady-state point”). The model indicates that, in the absence of CPAP, ventilation will increase as a function of increasing ventilatory drive until it reaches a steady-state level at 2.2 l/min.

Fig. 5.

Determination of the arousal threshold from a CPAP drop. A: same CPAP drop as that shown in Figs. 1 and 4A. As described in Fig. 1, the steady-state loop gain is calculated by dividing the response by the disturbance. The dynamics of the ventilatory control system (Delay and time constant) are estimated from the time course of the decline in ventilation after the overshoot. The dotted line is the calculated increase in ventilatory drive determined from a dynamic model of the ventilatory control system (described later in the text and in detail in the online Supplement Section I.B.). B: CPAP drop that produces an arousal. The solid line is the ventilation, and the dotted line is the calculated ventilatory drive. At 70 s, an arousal occurs. Ventilatory drive at arousal, which defines the arousal threshold, is 9 l/min.

Fig. 6.

A: OSA model with all 4 traits plotted. Arousal threshold (dashed line) is added by moving along the x-axis and placing a vertical line at 9 l/min. The model indicates that, off CPAP, an arousal will occur before stable breathing can be achieved, i.e., the subject will have OSA. Diagram B illustrates the potential clinical usefulness of the model and suggests that slight adjustments in the anatomy point (moving the square vertically upwards from 0.7 to 1.7 l/min, as might occur with weight loss or pharyngeal surgery) and the arousal threshold (shifting the dotted line to the right by 1 l/min, as might be achievable with a sedative) may move the intersection of the solid and dashed lines from the right (unstable region) to the left (stable region) of the arousal threshold line and eliminate or substantially reduce apnea.

Fig. 7.

Back extrapolation from the peak of the overshoot is used to construct the ventilatory drive signal (dotted line) during the last 60 s of the CPAP drop (from 150 to 210 s). After the CPAP drop, from 210 s onwards, the ventilation matches the ventilatory drive (because the airway is open and there is no longer any impediment to ventilation) and the dotted and solid lines equal one another. There are now 2 signals: the solid line, which is the pneumotach-measured ventilation signal that is the input to the transfer function model, ΔV̇e(s); and the dotted line which is the derived ventilatory drive signal that is the output of the model, ΔV̇_drive(s). Online Supplement Section I.A. describes in detail the justification for this “back extrapolation” procedure.

Fig. 8.

A: example of a survival analysis plot used for determining the arousal threshold. Arousal threshold is defined as the ventilatory drive at which there is a 50% probability of arousal (marked by the dot). The 90% confidence intervals (calculated using Greenwood's formula; Ref. 8) are indicated by the dotted lines. In this patient, the estimated arousal threshold is 12.2 l/min. B: ventilation signals used for estimating loop gain in one subject. The last portion of each drop (breaths 1–12) and the subsequent 3 min (breaths 13–49) are plotted. Change in ventilation, rather than absolute ventilation, is plotted on the y-axis. Disturbance magnitudes have been normalized to 1 l/min. C: representative graph used for determining V̇₀. The open squares at 6 cm H₂O are the mean ventilations at the holding pressure (eupneic ventilation). The other open squares are the ventilations at various levels of mask pressure. Data are fit with a straight line and 90% confidence intervals. V̇₀ is the ventilation at zero mask pressure (■). D: plot showing the change in ventilation from the beginning of the drop (leftmost dots) to the end of the drop (rightmost dots) as a function of increasing ventilatory drive for one subject. Each pair of dots is connected with a straight line. In this patient, ventilation increases as ventilatory drive increases, i.e., the slope of the upper airway gain is positive. Eupneic ventilation is marked by the single dot at 6.9 l/min.

Fig. 9.

Model results and AHI for subjects 1–10 (subjects 11–14 are shown in Fig. 10). As in the previous diagrams, eupneic ventilation is marked by the dot, V̇₀ by the square, the reciprocal of loop gain by the solid line, the upper airway gain by the dashed line, and the arousal threshold by the vertical dotted line. Values for each trait are listed in the top left of each graph. V_E, ventilation on optimum CPAP; G_L, loop gain; V₀, ventilation at zero nasal pressure and eupneic ventilatory drive; T_A, arousal threshold in l/min; G_ua, upper airway gain. The 90% confidence intervals are marked by shading.

Fig. 10.

Repeatability data in subjects 11–14 (labeled A–D). Night 1 is on the left and Night 2 is on the right. See text for details.