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Opinion statement: Complex sleep apnea currently refers to the emergence and persistence of central apneas and hypopneas following the application of positive airway pressure therapy in patients with obstructive sleep apnea. However, this narrow definition is an “outcome” and does not capture the spectrum of pathological activation of the respiratory chemoreflex in sleep apnea. The International Classification of Sleep Disorders – 3rd edition recognizes the phenomenon of Treatment-Related Central Sleep Apnea, but the phenotype is usually evident prior to onset of therapy. The key polysomnographic characteristics of chemoreflex modulated and mediated sleep apnea are nonrapid eye movement (NREM) dominance of respiratory events, short (<30 seconds) or long (>60 seconds) cycle time with a self-similar metronomic timing, and spontaneous improvement during rapid eye movement (REM) sleep. Thus, the majority of chemoreflex effects go unrecognized due to the bias toward obstructive sleep apnea’s current scoring criteria. Any treatment of apparently obstructive sleep apnea, including surgery and oral appliances, can expose chemoreflex-driven instabilities. As both sleep fragmentation and a narrow CO 2 reserve or increased loop gain drive the disease, sedatives (to induce longer periods of stable NREM sleep and reduce the destabilizing effects of arousals in NREM sleep) and CO 2-based stabilization approaches are logical. Adaptive ventilation reduces mean hyperventilation yet can induce ventilator-patient desynchrony, while enhanced expiratory rebreathing space (EERS, dead space during positive pressure therapy) and CO 2 manipulation directly stabilize respiratory control by moving CO 2 above the apnea threshold. Carbonic anhydrase inhibition can provide further adjunctive benefits. Novel pharmacological approaches may target mediators of carotid body hypoxic sensitization, such as the balance between gas neurotransmitters. In complex apnea patients, single mode therapy is unlikely to be successful, and the power of multi-modality therapy should be harnessed for optimal outcomes. [ABSTRACT FROM AUTHOR]