Comparing the effect of hypercapnia and hypoxia on the electroencephalogram during wakefulness
Introduction
Sleep-disordered breathing (SDB) is a common cause of increased daytime sleepiness and neurocognitive impairment which may lead to a 2–3 times increased risk of motor vehicle and occupational accidents (Teran-Santos et al., 1999, Lindberg et al., 2001, Malhotra and White, 2002). Patients with SDB usually have a slower waking electroencephalogram (EEG) which correlates with increased daytime sleepiness and may be corrected by continuous positive airway pressure (CPAP) therapy (Morisson et al., 1998, Morisson et al., 2001, D’Rozario et al., 2013). The underlying mechanism of SDB-related daytime drowsiness is unclear. It has been postulated that neurobiological impairments in obstructive sleep apnea (OSA) are a result of a combination of sleep fragmentation and hypoxia. However, the correlation between sleep disruptions measured by apnea and arousal frequency and daytime sleepiness is not robust (Cheshire et al., 1992, Kingshott et al., 1998). SDB is actually characterized by recurrent episodes of both hypoxia and hypercapnia (Dempsey et al., 2010). It has been claimed that it is the intermittent hypoxia that causes daytime sleepiness (Mediano et al., 2007, Dempsey et al., 2010, Canessa et al., 2011, Quan et al., 2011). However, supplemental O2 therapy does not improve hypersomnolence in OSA patients despite improving oxygenation (Gold et al., 1986, Phillips et al., 1990, Lim et al., 2007). Similarly, there has been a lack of convincing evidence demonstrating that hypoxia alone significantly affects EEG leading to neurocognitive impairment (Kraaier et al., 1988, Van der Worp et al., 1991, Jernajczyk et al., 2006). Hypoxia protocols in previous studies usually lead to concomitant hyperventilation and hypocapnia which can independently affect EEG activity (Burykh, 2008). The potential importance of hypercapnia in sleep-disordered breathing has been neglected partially due to the lack of clinical equipment to reliably measure continuous changes in the arterial CO2 pressure (pCO2) during overnight sleep study.
We recently reported increased Slow Wave Sleep (SWS) in 97 patients with respiratory failure with associated high awake arterial CO2 measurements. Awake pCO2 measured from arterial blood gas (ABG) sampling in those patients was the best predictor for the increased SWS, while hypoxia related parameters were not related (Wang et al., 2011). Some uncontrolled studies suggest that hypercapnia may cause slowing of the EEG in a dose-dependent manner (Woodbury and Karler, 1960, Matakas et al., 1978, Forslid et al., 1986, Kalkman et al., 1991, Bloch-Salisbury et al., 2000, Halpern et al., 2003, Thesen et al., 2012) and impaired mental and psychomotor function (Hesser et al., 1978, Sayers et al., 1987, Henning et al., 1990, Fothergill et al., 1991). Our recent intervention study demonstrated a significant cross-correlation between a reduced wake pCO2, a faster sleep EEG (reduced Delta/Alpha ratio) and reduced daytime sleepiness during positive airway pressure treatment in hypercapnic SDB patients (Wang et al., in press). Multiple regression analyses showed that the degree of change in hypercapnia but not hypoxia was the only significant predictor of both the Delta/Alpha ratio and daytime sleepiness (Wang et al., in press). In order to directly compare the generic effect of hypoxia and hypercapnia on EEG, the present study used an experimental design that carefully controlled for the mix of inspired oxygen and carbon dioxide while monitoring EEG activity during wakefulness. Delta/Alpha ratio was the primary outcome of interest.
Section snippets
Methods
This experiment was conducted at the clinical sleep laboratory of the Royal Prince Alfred Hospital (RPAH), a major teaching hospital of the University of Sydney. The study protocol was approved by Sydney South West Area Health Service (SSWAHS) Ethics Review Committee (Protocol Number: X11-0325). All participants provided written informed consent. The Australian & New Zealand Clinical Trial Registry number is ACTRN12612000454875.
Results
From the 20 healthy volunteers tested, we obtained technically satisfactory data in 19 (9M, 10F) with an average age of 29.7 ± 9.8 years and BMI of 23.2 ± 4.3 kg/m2.
In Protocol 1, compared to the baseline values, the hypercapnia produced by rebreathing during iso-hyperoxia (150 mmHg) led to a lower Alpha% and higher D/A ratio in the EEG spectra (Table 1). Similarly, in Protocol 2, the hypercapnia produced by rebreathing during iso-hypoxia (50 mmHg) induced a higher Delta%, a lower Alpha% and higher D/A
Discussion
Our controlled experimental data demonstrate that hypercapnia but not hypoxia causes EEG slowing (increased Delta/Alpha ratio). This findings support our latest clinical data showing that hypercapnia might be a key mechanism for EEG slowing and subsequent impairments in waking function, such as daytime sleepiness, in patients with SDB (Wang et al., in press). Certainly our experimental data question the view that hypoxia is the dominant mechanism causing EEG slowing in SDB (Mediano et al., 2007
Acknowledgments
We would like to thank Dr. Nathaniel Marshall for proof-reading the manuscript. Dr. David Wang is supported by NHMRC Health Professional Research Fellowship (#571165), NHMRC Project Grant (#1043633) and Sydney Medical School Early Career Researcher/New Staff Award. Prof Ronald Grunstein is supported by NHMRC Practitioner Fellowship. Dr. Jong-Won Kim is supported by NHMRC CRE in Sleep Medicine. No conflict of interest is reported by the authors.
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