Quote:The physiological mechanism that leads to the occurrence of TECSA in OSA patients exposed to CPAP or other therapies is not well established. To date, several possible mechanisms including ventilatory control instability (high loop gain), low arousal threshold, activation of lung stretch receptors, and prolonged circulation time, have been suggested.

Quote:Medications could be selected to improve ventilatory control stability or elevate the arousal threshold for TECSA patients, which may be a supplement to PAP therapy. For example, acetazolamide, a carbonic anhydrase inhibitor, can modulate loop gain. Glidewell et al described a case of successful control of CompSAS with CPAP and acetazolamide in a 41-year-old white woman on long-term opioid therapy. This case suggested that acetazolamide may be an effective adjunct to PAP therapy for the treatment of TECSA in patients on long-term opioid therapy. Similarly, some studies reported that both trazodone and eszopiclone increased the respiratory arousal threshold of OSA patients with a low arousal threshold. Hence, these medications could possibly be a new method for the treatment of TECSA. It is necessary to conduct large sample clinical trials to confirm the effectiveness and safety of such therapeutic options.

Quote:The typical course of TECSA appears variable. The majority of patients with TECSA show resolution of central apneas over a few weeks to months. Although most cases of TECSA resolve over time, about one-third of such patients convert to TPCSA related to PAP therapy. Our systematic review noted that 0.9%-3.2% of all patients treated with PAP therapy for OSA will exhibit TPCSA on a long-term basis. They represent 14.3%-46.2% of TECSA patients, who continue to experience PAP therapy-related central sleep apnea over a protracted period after they were first diagnosed with TECSA. Javaheri et al, noted that the daily CPAP adherence tends to be lower in patients who eventually declare themselves as TPCSA on PAP-2 compared to patients who experience resolution of their TECSA.

The prevalence of TPCSA at 0.9%-3% in all patients with treated OSA may be an underrepresentation given some patients in the discussed studies were lost to follow-up after the first titration study. Cassel et al . reported a TPCSA prevalence of 3.2%, which was the highest of the five studies evaluating this phenomenon. Even this TPCSA prevalence figure could be an underestimation, as 28 out of the 82 patients with TECSA at PAP-1 were lost to follow-up and hence unavailable to undergo a PAP-2 study. Similarly, in the study by Dernaika et al, which reported the TPCSA prevalence at 1.7%, it was noted that seven out of 21 patients with TECSA at PAP-1 were lost to follow-up and also unavailable for a PAP-2 study. Selective exclusion of patients with preexisting central sleep apnea from the titration study can also lead to underestimation of overall prevalence.

Quote:Results: Fifteen trials with a total of 256 patients were pooled in our systematic review. Acetazolamide reduced the overall AHI in CSA, but not in OSA. Acetazolamide reduced the respiratory related arousal index, improved partial arterial of oxygen, mean oxygen saturation, total sleep time, N2 sleep and sleep efficiency.

Conclusions: Acetazolamide improves the AHI and several sleep metrics in CSA. The drug may be of clinical benefit in patients with high loop gain apnea of various etiologies and patterns. The existence of high heterogeneity is an important limitation in applicability of our analysis.

Quote:Acetazolamide can reduce loop gain by approximately 40% in individuals with OSA. Due to a diuretic effect, it could facilitate the fluid clearance from the neck area/lung and improve ventilation/perfusion ratios. Moreover, the hypoxic ventilatory response can be reduced possibly by inhibiting the carotid bodies and the interaction of O2–H+.

Renal/metabolic acidosis effects or even speculatively neuroplasticity of carotid body function may exist and contributes to long term effects of acetazolamide.

In conclusion, chronic acetazolamide treatment could be a useful adjunct to CPAP therapy when high loop gain is present in patients with OSA.

Quote:These complex algorithms also interact with numerous other factors to generate a pressure cycling response—including arousals from other etiologies, mask leak, sleep–wake transitions, and phasic REM sleep. Thus, not all what is noted as pressure cycling is harmful or generated solely by the ASV device. Patients with periodic breathing or central sleep apnea have a high propensity for arousals and sleep fragmentation, which likely contributed to some of the pressure cycling seen.

Quote:Improvements in AHI and normalization of airflow have commonly been accepted as surrogate markers of improvement in sleep quality, but if those improvements come at the cost of inducing patient-device desynchrony, with associated microarousals and surges in autonomic activity, the trade-off is suboptimal.

Quote:The ASV algorithm may in some instances contribute to disruption of sleep, but numerous reasons for persistent and excessive pressure cycling exist.

Quote:The subset of patients found to have severe pressure cycling and desynchrony can then undergo further titration or evaluation of adjunctive therapies such as acetazolamide, oxygen, sedatives, or hypocapnia minimization, to attempt to identify pressure settings that allow improvements in sleep quality and hemodynamics.

Quote:The following potential mechanisms of patient-ventilator desynchrony and persistent pressure cycling are speculative, but biologically plausible. Loop gain may be too high for the device algorithm to compensate or correct. Variable obstructive features may add to variability of tidal or flow volumes sensed by these devices and trigger or sustain pressure cycling. Induction of hypocapnia can worsen respiratory  control  instability. Arousals associated with pressure cycling can amplify loop gain and desynchrony effects. Analogous to pacemaker-loop arrhythmias, it is possible that the ventilator’s oscillatory output algorithm loops with circulation time and controller gain to cause a perpetual cycle during periods of unstable NREM sleep. Some patients find the sensation of ASV-related pressure oscillations uncomfortable, which may prolong sleep–wake transitional instability and enhance pressure cycling. Some of these challenges, though unlikely all, can be addressed in principle with improved machine algorithms. Reduced pressure cycling in users of acetazolamide (itself started likely for excessive pressure cycling) suggests that persistent and unresolved high loop gain effects drive at least some of the pressure cycling.