Phenotyping interindividual variability in obstructive sleep apnoea response to temazepam using ventilatory chemoreflexes during wakefulness

Abstract

SUMMARY Centrally active agents have a variable impact in patients with obstructive sleep apnoea (OSA) that is unexplained. How to phenotype the individual OSA response is clinically important, as it may help to identify who will be at risk of respiratory depression and who will benefit from a centrally active agent. Based on loop gain theory, we hypothesized that OSA patients with higher central chemosensitivity have higher breathing instability following the use of a hypnosedative, temazepam. In 20 men with OSA in a double-blind, placebo-controlled cross-over trial we tested the polysomnographically (PSG) measured effects of temazepam 10 mg versus placebo on sleep apnoea. Treatment nights were at least 1 week apart. Ventilatory chemoreflexes were also measured during wakefulness in each subject. The patients (mean ± standard deviation; 44 ± 12 years) had predominantly mild-to-moderate OSA [baseline apnoea-hypopnoea index (AHI) = 16.8 ± 14.1]. PatientsÕ baseline awake central chemosensitivity correlated significantly with both the change of SpO 2 nadir between temazepam and placebo (r = )0.468, P = 0.038) and oxygen desaturation index (ODI; r = 0.485, P = 0.03), but not with the change of AHI (r = 0.18, P = 0.44). Peripheral chemosensitivity and ventilatory recruitment threshold were not correlated with the change of SpO 2 nadir, ODI or AHI (all P > 0.05). Mild-moderate OSA patients with higher awake central chemosensitivity had greater respiratory impairment during sleep with temazepam. Relatively simple daytime tests of respiratory control may provide a method of determining the effect of sedativehypnotic medication on breathing during sleep in OSA patients.k e y w o r d s chemosensitivity, phenotype, sleep apnoea, ventilatory chemoreflex

Trazodone Increases the Respiratory Arousal Threshold in Patients with Obstructive Sleep Apnea and a Low Arousal Threshold

“…[41][42][43][44][45][46][47] In preselecting patients with OSA with low respiratory arousal thresholds, we anticipated that trazodone would reduce apnea severity similar to recent findings with eszopiclone whereby eight patients with OSA and a low arousal threshold had invariable reductions in their AHI. 9 There are several possibilities that may account for the apparent disparity between studies, outlined in the next paragraphs.…”

The effects of a single mild dose of morphine on chemoreflexes and breathing in obstructive sleep apnea

“…We (Wang et al, 2011) and others (Eckert et al, 2011;Edwards et al, 2012) have identified certain respiratory phenotypes that may characterise sub-groups of OSA patients that will improve sleep apnea following use of CNS depressants. In these patients, the use of safe doses of a respiratory depressant may modulate the chemoreflexes by alteration of the VRT or/and chemical drives/loop gain.…”

“…OSA has been characterized with high loop gain/chemical drive/chemosensitivity which can cause ventilatory over-shoot, and the repetitive pattern is crucial in precipitating a cyclic sleep-disordered breathing pattern (White, 2005;Dempsey et al, 2010). In our OSA patients, the mild dose of morphine may reduce ventilatory chemosensitivity, and therefore the controller gain and the chance of cyclic ventilatory overshoot, thus improve OSA (Edwards et al, 2012;Wang et al, 2011). On the other hand, the increased VRT in our OSA patients may indicate an increased RRT and a widened CO 2 reserve, and a greater breathing stability during sleep.…”

“…Furthermore, we could ideally include peripheral chemoreflex test as part of the awake chemoreflex test which could better explain the potential mechanisms (Wang et al, 2011). We did not test this as we have very limited window of time after the slow-release morphine taking effect (9 pm) and before sleep time (10 pm).…”

Clinical Predictors of the Respiratory Arousal Threshold in Patients with Obstructive Sleep Apnea

“…To date, the effects of sedatives on either the ArTH, OSA severity, or both have been assessed in a few studies involving relatively small numbers of participants (12,14,(31)(32)(33)(34). The ArTH consistently increases (becomes more negative) with sedatives, although the effects on AHI have been inconsistent.…”