Effects of controlled carbon dioxide delivery by a novel device on sleep in healthy subjects

Low-dose carbon dioxide (CO₂) can stabilize ventilatory drive, reduce sleep-disordered breathing, and improve sleep quality. However, the existing delivery systems introduce dead space and resistance that limit tolerability. We developed a novel mask with low resistance and minimal dead space to deliver CO₂ and evaluated its overnight effects on neural respiratory drive, sleep architecture, and potential CO₂ accumulation in healthy individuals. Sixteen healthy volunteers [age 42 ± 15 yr; body mass index (BMI) 22.0 ± 2.3 kg/m²] first underwent polysomnography with diaphragmatic electromyography (EMG) recorded via esophageal electrodes under inhalation of different concentrations of CO₂. Participants then completed four consecutive overnight polysomnography sessions, with each night involving inhalation of a different CO₂ concentration (0.0%, 2.5%, 3.5%, or 5.0%) in randomized order. Arterial blood gases were sampled in the evening before inhalation and the following morning during CO₂ exposure. Overnight urinary catecholamines were also measured. Neural respiratory drive increased dose-dependently. Sleep efficiency was highest at 2.5% CO₂ (91.7 ± 5.7%) and lowest at 5.0% (78.5 ± 10.1%, P < 0.001); 3.5% CO₂ showed sleep efficiency similar to room air, whereas 5.0% reduced rapid eye movement (REM) sleep and increased arousals. Blood gases, blood pressure, heart rate, and catecholamines remained normal at ≤3.5%. Baseline blood gases remained normal after multiple consecutive nights of CO₂ inhalation. Overnight inhalation of 2.5% CO₂ delivered via the special mask enhances sleep efficiency without adverse physiological effects. Concentrations ≤3.5% appear safe, and no cumulative effect was observed after multiple consecutive nights of CO₂ inhalation in healthy subjects.NEW & NOTEWORTHY A novel low-resistance open-mask system enables safe delivery of low-dose CO₂ during sleep. Inhaling 2.5% CO₂ improves sleep efficiency and increases N3 sleep in healthy adults, without CO₂ retention or physiological stress. CO₂ up to 3.5% was safe and well tolerated and showed no cumulative effects. These findings demonstrate the physiological safety of low-dose CO₂ during sleep and support its potential for treating hypocapnia-related central sleep apnea.