Variability of vigilance and ventilation: studies on the control of respiration during sleep

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Abstract

Ventilation is under metabolic as well as under behavioural control. This causes a complex interaction between states of ‘vigilance’ and respiration. This paper briefly summarizes sleep-related changes of respiration and presents an experimental study on the course of respiratory CO2-sensitivity during a whole night’s sleep in ten healthy volunteers. The feedback control of breathing was challenged by continuous step changes of inspired CO2 every 7 min, resulting in 60, 3-step steady-state hypercapnic ventilatory responses (HCVR) per night in each subject. We analysed the variability of baseline ventilation and the effects of hypercapnia on ventilation with respect to sleep stages. There were only small differences in baseline PCO2 and ventilation between sleep stages, but a high variability of the slope of the CO2–response curves in the course of the night, ranging from 0.5 to 3.0 L min−1 Torr−1. The HCVR was significantly lower during REM sleep than during all stages of NREM sleep. Due to a compensatory left shift of the flattened CO2–response curves, however, ventilation at baseline CO2 as well as during slight hypercapnia varied much less than would be expected from the high variability of slopes. We conclude that the characteristics of the CO2-sensitive feedback control system of respiration, are highly variable during sleep, but due to offsetting effects, PCO2 and ventilation remain quite stable in the physiological range.

Introduction

With sleep onset the functional organisation of respiration changes considerably: The so-called ‘wakefulness drives’ lose their influence (Orem et al., 1985). Ventilation is more directly controlled by metabolic needs at least during NREM sleep (White et al., 1985). Nevertheless, the slopes of the hypoxic (HVR) (Douglas et al., 1982b) and hypercapnic ventilatory responses (HCVR) (Douglas et al., 1982c) are reduced. The airway resistance increases (Hudgel et al., 1984). Periodic breathing patterns occur during sleep onset (Dempsey et al., 1996, Dunai et al., 1996). The hypoxic and hypercapnic arousal thresholds are elevated (Berthon-Jones and Sullivan, 1982), resistive loads are incompletely compensated (Issa and Sullivan, 1983). For details the reader is referred to comprehensive review articles that summarize these multiple sleep-related interactions in the respiratory system (Phillipson and Bowes, 1986White, 1990Douglas, 1994).

This paper focuses on an aspect of chemical control of breathing during sleep. Since the work of Douglas et al. (1982c) we know that the slopes of the HCVR were significantly reduced in all stages of sleep compared with those during wakefulness (1.60±0.19 SEM L min−1 Torr−1 CO2), falling to less than half the waking HCVR during NREM sleep (0.75±0.08 L min−1 Torr−1 CO2), with a further significant marked drop during REM sleep (0.45±0.10 L min−1 Torr−1 CO2). This was the first quantitative study of the HCVR during REM sleep in adults; systematic observations of respiration (Magnussen, 1944) and reduced CO2 sensitivity during sleep date back to the forties and fifties of our century (Ostergaard, 1944Reed and Kellogg, 1958Robin et al., 1958Bellville et al., 1959).

Another important aspect was addressed by Raschke and Möller (1989), who found a circadian rhythm of the HCVR in awake subjects. They performed CO2 rebreathing tests in intervals of 2 h under constant-routine conditions and described a peak of the slope of the HCVR in the afternoon and a nadir at 03:00 h in the morning. The amplitude of this circadian variability of the HCVR during wakefulness was almost two-fold that observed between different sleep stages. They concluded that a superposition of these two rhythms, the slow circadian and the faster sleep-related ultradian, should result in serious reductions of the respiratory CO2-sensitivity during sleep in the early morning hours. This reduction could be responsible for sleep-related breathing disorders such as hypoventilation, hypercapnia and hypoxia with potentially dangerous sequelae.

Coming from this hypothesis the present study examined the course of the HCVR in healthy volunteers using a new paradigm of repeated stepwise changes of the inspiratory CO2 concentration throughout the whole night’s sleep. This resulted in data of approximately 60 steady-state CO2–response curves and a time-resolution of 7 min. Indeed, the data supported the hypothesis showing high variability (up to factor 8) of the slopes and the position of the HCVR resulting in a very low CO2 sensitivity between 03:00 and 05:00 h. Nevertheless we will show that ventilation at baseline PCO2, baseline PCO2 itself, and even CO2-stimulated ventilation calculated for isocapnic conditions varied much less than it would be expected from the variability of the slopes of the CO2–response curves alone.

Section snippets

Subjects

Ten healthy men with a mean age of 25±2.6 SD years (range 23–32 years) volunteered in this study. They were non-obese (mean body weight 72±8 kg, mean heigth 182±5 cm) without a history of cardiac, pulmonary or neurological disorders. None of the subjects took any medications or had sleep complaints or was sleep-deprived. Each subject was a regular nocturnal sleeper and had refrained from stimulants like caffeine since the early morning of the study day. Every subject gave informed consent to

Step changes in PETCO2

In the ten subjects a mean number of 18.5±2.6 SD complete cycles (range 15–23) with three levels of PetCO2, lasting 6–7 min each, were achieved. A representative example is shown in Fig. 1. The mean baseline PetCO2 of 41.7±2.8 Torr was increased to 44.4±2.6 Torr by inhalation of CO2-enriched air (PiCO2 14.7±2.8 Torr), and further to 47.0±2.4 Torr (PiCO2 24.5±2.9 Torr). The corresponding inspiratory and expiratory oxygen partial pressures were 154±1, 152±1, 150±1 and 110±4, 119±5 and 126±5 Torr,

Discussion

In this study we continuously challenged the CO2-sensitive feedback control of respiration during the whole night’s sleep by regular step changes of FiCO2. As main results we found a reduced steady-state hypercapnic ventilatory response (HCVR) during REM-sleep compared with NREM-sleep, with an offsetting shift of the CO2–response curve to the left, a reduction of the HCVR during deep sleep from the first half of the night to the second half, a significant decline of baseline PCO2 within the

Acknowledgements

The author thanks Cornelia Bombosch and Marcus Altmeier for their help in performing the measurements.

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