Unstable ventilatory chemoreflex control, quantified as loop gain, is recognized as one of four key pathophysiological traits that contribute to cause obstructive sleep apnea (OSA). Novel treatments aimed at reducing loop gain are being investigated, with the intention that future OSA treatment may be tailored to the individual's specific cause of apnea. However, few studies have evaluated loop gain in OSA and non-OSA controls and those that have provide little evidence to support an inherent abnormality in either overall chemical loop gain in OSA patients vs. non-OSA controls, or its components (controller and plant gain). However, intermittent hypoxia may induce high controller gain through neuroplastic changes to chemoreflex control, and may also decrease plant gain via oxidative stress induced inflammation and reduced lung function. The inherent difficulties and limitations with loop gain measurements are discussed and areas where further research are required are highlighted, as only by understanding the mechanisms underlying OSA are new therapeutic approaches likely to emerge in OSA.

Study Objectives: Controversy exists as to whether elevated loop gain is a cause or consequence of obstructive sleep apnea (OSA). Upper airway surgery is commonly performed in Asian patients with OSA who have failed positive airway pressure therapy and who are thought to have anatomical predisposition to OSA. We hypothesized that high loop gain would decrease following surgical treatment of OSA due to reduced sleep apnea severity. Methods: Polysomnography was performed preoperatively and postoperatively to assess OSA severity in 30 Chinese participants who underwent upper airway surgery. Loop gain was calculated using a validated clinically-applicable method by fitting a feedback control model to airflow. Results: Patients were followed up for a median (interquartile range) of 130 (62, 224) days after surgery. Apnea-hypopnea index (AHI) changed from 60.8 (33.7, 71.7) to 18.4 (9.9, 42.5) events/h (P < .001). Preoperative and postoperative loop gain was 0.70 (0.58, 0.80) and 0.53 (0.46, 0.63) respectively (P < .001). There was a positive association between the decrease in loop gain and the improvement of AHI (P = .025). Conclusions: High loop gain was reduced by surgical treatment of OSA in our cohort. These data suggest that elevated loop gain may be acquired in OSA and may provide mechanistic insight into improvement in OSA with upper airway surgery.

Reduced ventilatory control stability (elevated loop gain) is a key non-anatomical pathological trait contributing to obstructive sleep apnea (OSA), yet the mechanisms responsible remain unclear. We sought to identify the key factors contributing to elevated loop gain in OSA (controller versus plant contributions) and to examine if abnormalities in these factors persist after OSA treatment. In 15 males (8 OSA, 7 height, weight- and age-matched controls) we measured loop gain, controller gain and plant gain using a pseudorandom binary CO stimulation method during wakefulness. Factors potentially influencing plant gain were also assessed (supine lung volume via helium dilution and spirometry). Measures were repeated 2 and 6 weeks after initiating CPAP. Loop gain was higher in OSA versus controls (LG at 1 cycle/min 0.28 ± 0.04 versus 0.16 ± 0.04, p = 0.046) and the controller exhibited a greater peak response to CO2 and faster roll-off in OSA. OSA patients also exhibited reduced FEV1 and FVC compared to controls (92.2 ± 1.7 versus 102.9 ± 3.5% predicted, p = 0.021; 93.4 ± 3.1 versus 106.6 ± 3.6% predicted, p = 0.015, respectively). There was no effect of treatment on any variable. These findings confirm loop gain is higher in untreated OSA patients than in matched controls, however this was not affected by treatment.