Effect of oxygen in obstructive sleep apnea: Role of loop gain

Abstract

We compared the effect of oxygen on the apnea–hypopnea index (AHI) in six obstructive sleep apnea patients with a relatively high loop gain (LG) and six with a low LG. LG is a measure of ventilatory control stability. In the high LG group (unstable ventilatory control system), oxygen reduced the LG from 0.69 ± 0.18 to 0.34 ± 0.04 (p < 0.001) and lowered the AHI by 53 ± 33% (p = 0.04 compared to the percent reduction in the low LG group). In the low LG group (stable ventilatory control system), oxygen had no effect on LG (0.24 ± 0.04 on room air, 0.29 ± 0.07 on oxygen, p = 0.73) and very little effect on AHI (8 ± 27% reduction with oxygen). These data suggest that ventilatory instability is an important mechanism causing obstructive sleep apnea in some patients (those with a relatively high LG), since lowering LG with oxygen in these patients significantly reduces AHI.

Introduction

Recurrent upper airway collapse is the cardinal feature of obstructive sleep apnea (OSA). While a small (narrow lumen) upper airway increases the risk of collapse, other mechanisms, such as ventilatory control instability, might further increase the risk. This is because the upper airway muscles, like the diaphragm, are linked to ventilatory control. An increase in ventilatory drive activates the upper airway muscles and promotes patency (Badr et al., 1991, Badr et al., 1994), whereas a decrease in ventilatory drive relaxes the upper airway muscles and facilitates closure (Kuna et al., 1993, Badr et al., 1995). Consequently, fluctuations in ventilatory drive (due to ventilatory control instability) can lead to upper airway instability and potentially collapse at the nadir of ventilatory drive (Onal et al., 1986, Hudgel et al., 1987, Warner et al., 1987). This suggests that stabilizing the ventilatory control system might be one way to reduce the risk of upper airway collapse in patients with OSA.

Since oxygen has well described ventilatory stabilizing properties (primarily a reduction in peripheral chemoresponsiveness (Nielsen and Smith, 1952, Reite et al., 1975, Severinghaus and Crawford, 1978, Cunningham et al., 1986, Bisgard and Neubauer, 1996, Mohan and Duffin, 1997, Duffin et al., 2000, Simakajornboon et al., 2002)) and is easy to administer, investigators have tested its effectiveness in patients with OSA. The results have been quite variable. Of 37 subjects studied in four prior experiments (Martin et al., 1982, Smith et al., 1984, Gold et al., 1985, Gold et al., 1986), 14 exhibited a 50% or greater reduction in apnea–hypopnea index (AHI) with oxygen. The rest, however, demonstrated little or no improvement. We believe that this is the result of varying levels of ventilatory instability in different patients. In these studies, however, subjects were not categorized using a measurement of instability. We speculate that the subjects who responded well to oxygen in these studies had an unstable ventilatory control system, and that this instability significantly contributed to their disordered breathing.

To test this, we administered oxygen to two groups of OSA patients: those with a stable ventilatory control system (control group) and those with a relatively unstable ventilatory control system (treatment group). Ventilatory instability was quantified by determining each patient's loop gain (LG). LG is an engineering term that describes the gain of the negative feedback loop that regulates ventilation. Mathematically, it is the ratio of the ventilatory response to a ventilatory disturbance. If the magnitude of the response (e.g., hyperpnea) is greater than or equal to the magnitude of the disturbance (e.g., hypopnea), then the LG ratio will be ≥1 and ventilation will fluctuate between hyperpnea and hypopnea/apnea (i.e., the system is highly unstable). If the LG ratio is less than 1, or near 0, then ventilation will remain stable (little to no fluctuations in breathing) in response to a disturbance (see Fig. 1).

In this study, we hypothesized that OSA patients with a high LG (unstable ventilatory control system) would exhibit a significant reduction in AHI during supplemental oxygen breathing. On the contrary, OSA patients with a low LG (stable control system) would have little or no change in AHI during oxygen administration.