Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: The Apnea Positive Pressure Long-term Efficacy Study (APPLES)

Abstract

Study objective: To determine the neurocognitive effects of continuous positive airway pressure (CPAP) therapy on patients with obstructive sleep apnea (OSA).

Design, setting, and participants: The Apnea Positive Pressure Long-term Efficacy Study (APPLES) was a 6-month, randomized, double-blind, 2-arm, sham-controlled, multicenter trial conducted at 5 U.S. university, hospital, or private practices. Of 1,516 participants enrolled, 1,105 were randomized, and 1,098 participants diagnosed with OSA contributed to the analysis of the primary outcome measures.

Intervention: Active or sham CPAP MEASUREMENTS: THREE NEUROCOGNITIVE VARIABLES, EACH REPRESENTING A NEUROCOGNITIVE DOMAIN: Pathfinder Number Test-Total Time (attention and psychomotor function [A/P]), Buschke Selective Reminding Test-Sum Recall (learning and memory [L/M]), and Sustained Working Memory Test-Overall Mid-Day Score (executive and frontal-lobe function [E/F])

Results: The primary neurocognitive analyses showed a difference between groups for only the E/F variable at the 2 month CPAP visit, but no difference at the 6 month CPAP visit or for the A/P or L/M variables at either the 2 or 6 month visits. When stratified by measures of OSA severity (AHI or oxygen saturation parameters), the primary E/F variable and one secondary E/F neurocognitive variable revealed transient differences between study arms for those with the most severe OSA. Participants in the active CPAP group had a significantly greater ability to remain awake whether measured subjectively by the Epworth Sleepiness Scale or objectively by the maintenance of wakefulness test.

Conclusions: CPAP treatment improved both subjectively and objectively measured sleepiness, especially in individuals with severe OSA (AHI > 30). CPAP use resulted in mild, transient improvement in the most sensitive measures of executive and frontal-lobe function for those with severe disease, which suggests the existence of a complex OSA-neurocognitive relationship.

Clinical trial information: Registered at clinicaltrials.gov. Identifier: NCT00051363.

Citation: Kushida CA; Nichols DA; Holmes TH; Quan SF; Walsh JK; Gottlieb DJ; Simon RD; Guilleminault C; White DP; Goodwin JL; Schweitzer PK; Leary EB; Hyde PR; Hirshkowitz M; Green S; McEvoy LK; Chan C; Gevins A; Kay GG; Bloch DA; Crabtree T; Demen WC. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: the Apnea Positive Pressure Long-term Efficacy Study (APPLES). SLEEP 2012;35(12):1593-1602.

Figure 1

Participant flow diagram. Study visits included: (1) Clinical Evaluation (CE) included informed consent, baseline testing and screening, and a medical examination by a study physician; (2) Training Sessions 1 and 2 (TS) consisted of neurocognitive test training, screening, and administration of psychological tests; (3) Diagnostic Polysomnography (PSG) Visit (DX PSG Visit) involved an overnight diagnostic sleep study, questionnaires, maintenance of wakefulness test (MWT), and the neurocognitive test battery; (4) CPAP Titration Visit (CT) included administration of questionnaires and an overnight CPAP titration PSG study conducted for both active and sham CPAP group participants to determine the optimal CPAP pressure for those in the active CPAP group; (5) CPAP Set-up Visit provided the participant with the active or sham CPAP device following the CPAP titration visit; (6) Two Month Post-CPAP Follow-Up Visit (2M CPAP Visit) represented a follow-up overnight CPAP titration PSG study, with questionnaires, psychological tests, MWT, and neurocognitive test battery; (7) Four Month Post-CPAP Follow-Up Visit (4M CPAP Visit) consisted of questionnaires and a follow-up appointment with a study physician that included a physical examination and discussion of CPAP adherence, protocol compliance, safety issues, and medication changes; (8) Six Month Post-CPAP Follow-Up Visit (6M CPAP Visit) used the same protocol as the 2M-CPAP Visit; (9) Additional Follow-Up Visit allowed the participant to discuss any issues or problems; (10) Exit Interview gave the participant an opportunity to initiate other OSA treatment options. ^‡Excluded: participant removed from study “pre-randomization” due to exclusion criteria (e.g., taking exclusionary medication); Withdrawn: participant quit study “pre-randomization” due to participant's choice (e.g., too busy); Dropped: participant quit study “post-randomization” due to a participant-initiated decision (e.g., did not wish to continue with protocol); Disqualified: participant removed from study “post-randomization” due to a physician-initiated decision based on medical/safety reasons (e.g., following SAE based on opinion of Physician-Observer). All participants who dropped post-randomization were asked to continue with participant visits, even if they had discontinued therapy, based on our intention-to-treat study design. Participants who were disqualified for a medical/safety reason were asked to continue participant visits only after approval by the Site Director. On-Treatment: participant completed visits on originally assigned treatment condition; On-Study: participant completed visits, but may or may not be on originally assigned treatment condition.