Acetazolamide improves loop gain but not the other physiological traits causing obstructive sleep apnoea

Abstract

There is some evidence to suggest that acetazolamide may improve obstructive sleep apnoea (OSA).However, how acetazolamide affects the key traits causing OSA remains uncertain. We aimed to investigate the effect of acetazolamide on the traits contributing to OSA and its severity. Acetazolamide (500 mg twice daily) was administered for 1 week to 13 OSA subjects. Pharyngeal anatomy/collapsibility, loop gain (LG), upper-airway muscle responsiveness (gain) and the arousal threshold were determined using multiple 3 min 'CPAP pressure drops': pharyngeal anatomy/collapsibility was quantified as the ventilation at CPAP=0. LG was defined as the ratio of the ventilatory overshoot to the preceding reduction in ventilation. Upper-airway gain was taken as the ratio of the increase in ventilation to the increase in ventilatory drive across the drop. Arousal threshold was quantified as the level of ventilatory drive associated with arousal. The apnoea-hypopnoea index (AHI)was assessed on separate nights using standard polysomnography. Acetazolamide reduced the median [interquartile range] LG (3.4 [2.4-5.4] versus 2.0 [1.4-3.5]; P <0.05) and NREM AHI (50 [36-57] versus 24 [13-42] events h-1; P <0.05), but did not significantly alter pharyngeal anatomy/collapsibility, upper-airway gain, or arousal threshold. There was a modest correlation between the percentage reduction in LG and the percentage reduction in AHI (r =0.660, P =0.05). Our findings suggest that acetazolamide can improve OSA, probably due to reductions in the sensitivity of the ventilatory control system. Identification of patients who may benefit from reductions in LG alone or in combination with other therapies to alter the remaining traits may facilitate pharmacological resolution of OSA in the future.

Figure 1. Technique for determining and modelling the physiological traits using CPAP drops

To determine the four physiological traits, CPAP is dropped to a subtherapeutic level (A) which causes partial airway obstruction and a reduction in ventilation (B). Using the time course in ventilation, we calculate the pharyngeal anatomy/collapsibility (), upper airway gain (z/x), loop gain (x/y) and arousal threshold (if an arousal occurs); see text for details. C depicts how these four traits can be incorporated into a model to predict the susceptibility towards OSA. In this example, the new steady state (the intersection of the diagonal lines) occurs in the unstable region (i.e. right of the arousal threshold) and thus OSA is predicted to be present.

Figure 2. An example of a CPAP drop

A representative example of a CPAP drop taken from one subject. The top panel shows the CPAP level being dropped from 9 to 3.5 cmH₂O. The middle panel shows the reduction in ventilatory flow associated with the CPAP drop. The bottom panel shows the minute ventilation. When CPAP is dropped, minute ventilation falls from 8.9 to 3.5 l min⁻¹. To estimate the pharyngeal anatomy or , minute ventilation immediately after the drop is plotted on a graph against mask pressure. To estimate LG, the overshoot in ventilation (x) is divided by the amount ventilation was reduced (y). In this example, LG (x/y) is 3.3 and the upper airway gain (z/x) is +0.2 (inset panel). A delay and time constant is also calculated from the ventilatory overshoot which is used for the calculation of ventilatory drive and dynamic LG (see Supplemental Material). In this example, there was no EEG arousal, such that this drop could not be used to determine arousal threshold.

Figure 3. Overall effect of acetazolamide on the physiological traits

Median data of resting ventilation and the four physiological traits at baseline (A) and during acetazolamide treatment (B) from all 12 subjects. Administration of acetazolamide significantly increased resting ventilation (P < 0.001) during stable NREM sleep and reduced LG (P < 0.05). However, administration of acetazolamide did not significantly alter the remaining traits. Note that the reduction in LG decreases the distance between the steady-state intersection and the arousal threshold from 3.6 l min⁻¹ to 1.2 l min⁻¹ (i.e. the steady-state intersection is closer to the stable region). However, the intersection has not crossed over into the stable region, which may explain the ability of acetazolamide to reduce, but not eliminate, OSA.

Figure 4. Individual effects of acetazolamide on loop gain and the severity of sleep-disordered breathing

A, individual data comparing steady-state LG during baseline and acetazolamide conditions. Note that the steady-state LG was reduced in all but one subject. B, acetazolamide significantly reduced the median apnoea-hypopnoea index (AHI) from 49.6 [35.5–56.6] to 24.1 [12.9–42.3] events per hour, during supine NREM sleep. Median values for each condition are indicated by the solid white bars. Note that the one patient whose LG doubled with acetazolamide also exhibited a similar rise in AHI (asterisk).

Figure 5. Potential effects of manipulating other traits in addition to loop gain on OSA severity

If, in addition to reducing LG by 41% with acetazolamide (taken from Fig. 3A), the arousal threshold was also increased by a small amount (e.g. 30%) with a sedative (A), or if the can be improved by approximately 2.5 l min⁻¹ with weight loss (B), then the model predicts that this would move the steady-state intersection to the left of the arousal threshold and into the stable region (i.e. stable breathing is now possible). Therefore, our model allows us to speculate that such combination therapy could achieve a complete resolution of OSA.