A new model of chronic intermittent hypoxia in humans: effect on ventilation, sleep, and blood pressure

Abstract

Obstructive sleep apnea is characterized by repetitive nocturnal upper airway obstructions that are associated with sleep disruption and cyclic intermittent hypoxia (CIH) The cyclic oscillations in O(2) saturation are thought to contribute to cardiovascular and other morbidity, but animal and patient studies of the pathogenic link between CIH and these diseases have been complicated by species differences and by the effects of confounding factors such as obesity, hypertension, and impaired glucose metabolism. To minimize these limitations, we set up a model of nocturnal CIH in healthy humans. We delivered O(2) for 15 s every 2 min during sleep while subjects breathed 13% O(2) in a hypoxic tent to create 30 cycles/h of cyclic desaturation-reoxygenation [saturation of peripheral O(2) (Sp(O(2))) range: 95-85%]. We exposed subjects overnight for 8-9 h/day for 2 wk (10 subjects) and 4 wk (8 subjects). CIH exposure induced respiratory disturbances (central apnea hypopnea index: 3.0 +/- 1.9 to 31.1 +/- 9.6 events/h of sleep at 2 wk). Exposure to CIH for 14 days induced an increase in slopes of hypoxic and hypercapnic ventilatory responses (1.5 +/- 0.6 to 3.1 +/- 1.2 l.min(-1).% drop in Sp(O(2)) and 2.2 +/- 1.0 to 3.3 +/- 0.9 l.min(-1).mmHg CO(2)(-1), respectively), consistent with hypoxic acclimatization. Waking normoxic arterial pressure increased significantly at 2 wk at systolic (114 +/- 2 to 122 +/- 2 mmHg) and for diastolic at 4 wk (71 +/- 1.3 to 74 +/- 1.7 mmHg). We propose this model as a new technique to study the cardiovascular and metabolic consequences of CIH in human volunteers.

Figures

Fig. 1.

Representation of the model. In a hospital room, a hypoxic tent was set on a standard bed. The tent was flushed with gas with a fraction of inspired O2 (FiO2) of 0.13 generated by an oxygen extractor (Hypoxico), bringing the subject's saturation of peripheral O2 SpO2 to ∼85%. Using a nasal cannula, an O2 bolus (1.5–2 l/min) was delivered for 15 s every 2 min, allowing the subject's SpO2 to rise to ∼95%.

Fig. 2.

Protocol timeline. PSG, polysomnogram; N, night.

Fig. 3.

SpO2 traces from a representative subject taken four times during the study: 1) at baseline during room air breathing, 2) with cyclic intermittent hypoxia (CIH) during adaptation with chamber FiO2 = 0.15, 3) with CIH during exposure on day 1 with chamber FiO2 = 0.13, and 4) with CIH during exposure on day 14 with chamber FiO2 = 0.13.

Fig. 4.

Representative tracings from an individual subject of transcutaneous CO2 pressure (Ptc CO2) levels from three time points during the study: 1) with CIH during adaptation on day −1 with chamber FiO2 = 0.15, 2) with CIH during exposure on day 1 with chamber FiO2 = 0.13, and 3) with CIH during exposure on day 14 with chamber FiO2 = 0.13.

Fig. 5.

Obstructive and central apnea-hypopnea indexes across the 14-day exposure. Note the predominance of central rather than obstructive events.

Fig. 6.

A: central events occurring synchronously with the return to normoxia in a representative tracing from an individual subject. B: the vast majority of central hypopneas were such synchronous events, occurring at the return to normoxia rather than occurring spontaneously at other points in the deoxygenation-reoxygenation cycle. Values represent means ± SD of the number of synchroneous and spontaneous central hypopneas during acclimatization on room air (day −1), during the first night of CIH (day 1 CIH), and during the 14th night of CIH (day 14 CIH). P values are represented with * when significant (P < 0.05).

Fig. 7.

Frequency of arousals across the 14-day exposure to CIH. Day −1 is the acclimatization night where subjects breathed room air, day 1 is the first night of CIH exposure, and day 14 is the 14th night of CIH exposure. Bars represent means ± SD of numbers of arousals per hour of sleep (11 subjects). Shaded bars indicates the number of arousals occurring in association with respiratory events; the remaining arousals (open bars) occurred spontaneously, without association with respiration. P values are represented with * when significant between respiratory microarousal from sleep (P < 0.05).

Fig. 8.

A: slopes of the ventilatory response to progressive isocapnic hypoxia increased across the CIH exposure (Friedman test: P < 0.01). This demonstrates a change in hypoxic chemosensitivity. *Significant difference by Wilcoxon test (P < 0.05). Values represent means ± SD of 6 subjects. B: slopes of the response to progressive hyperoxic hypercapnic increased across the CIH exposure (Friedman test: P < 0.05). This demonstrates a change in hypercapnic chemosensitivity. *Significant difference by Wilcoxon test (P < 0.05). Values represent means ± SD of 6 subjects.