Intermittent hypoxia, respiratory plasticity and sleep apnea in humans: present knowledge and future investigations

Abstract

This review examines the role that respiratory plasticity has in the maintenance of breathing stability during sleep in individuals with sleep apnea. The initial portion of the review considers the manner in which repetitive breathing events may be initiated in individuals with sleep apnea. Thereafter, the role that two forms of respiratory plasticity, progressive augmentation of the hypoxic ventilatory response and long-term facilitation of upper airway and respiratory muscle activity, might have in modifying breathing events in humans is examined. In this context, present knowledge regarding the initiation of respiratory plasticity in humans during wakefulness and sleep is addressed. Also, published findings which reveal that exposure to intermittent hypoxia promotes breathing instability, at least in part, because of progressive augmentation of the hypoxic ventilatory response and the absence of long-term facilitation, are considered. Next, future directions are presented and are focused on the manner in which forms of plasticity that stabilize breathing might be promoted while diminishing destabilizing forms, concurrently. These future directions will consider the potential role of circadian rhythms in the promotion of respiratory plasticity and the role of respiratory plasticity in enhancing established treatments for sleep apnea.

Keywords: Circadian rhythms; Intermittent hypoxia; Long-term facilitation; Progressive augmentation; Upper airway muscles.

Published by Elsevier B.V.

Figures

Figure 1

Breath-by-breath minute ventilation values recorded from a human participant before, during and following exposure to 12 episodes of hypoxia. Each hypoxic episode and subsequent recovery period was 4 min in duration with the exception of the last recovery period, which was 30 min in duration. Note that during exposure to intermittent hypoxia the ventilatory response to hypoxia gradually increased from the initial hypoxic episode to the final hypoxic episode. This phenomenon is referred to as progressive augmentation. Also note that during exposure to intermittent hypoxia minute ventilation gradually increased during the normoxic recovery periods so that it was substantially higher during the final recovery period compared with baseline. This phenomenon is referred to as long-term facilitation. Republished from Mateika and Narwani (2009), Exp. Physiol. 91, 89–102.

Figure 2

Schematic diagram showing the sequence of events leading to the development of a central and/or obstructive apnea, and subsequent events that ultimately results in re-establishing patency of the upper airway. In addition, various points along the pathway (see Points A–D) are highlighted. These points highlight outcomes that might occur in response to the manifestation of progressive augmentation of the hypoxic ventilatory response or long term facilitation of minute ventilation or upper airway muscle activity.

Figure 3

A schematic diagram showing that initiation of long-term facilitation of upper airway muscle activity and minute ventilation may serve to maintain upper airway patency and respiratory muscle activity. Ultimately, this integrated response promotes breathing and potentially mitigates the severity of apnea. In order for this scenario to occur long-term facilitation must persist despite reductions in carbon dioxide levels (i.e. hypocapnia) (see dotted red boxes). If long-term facilitation cannot persist in the presence of hypocapnia, as suggested by published findings, then alterations in chemoreflex properties must be minimized or eliminated (indicated by dashed line and diagonal red lines) to ensure the maintenance of desired carbon dioxide levels. Adapted from Mateika and Narwani (2009), Exp. Physiol. 91, 89–102.

Figure 4

A diagram outlining a scenario in which long-term facilitation is induced in upper airway muscles following exposure to intermittent hypoxia but ultimately is ineffective in mitigating apnea because decreases in carbon dioxide reserve and increases in chemoreflex sensitivity increase the propensity for developing hypocapnia. The induced hypocapnia restrains long-term facilitation of upper airway muscle activity and respiratory muscle activity, ultimately resulting in the promotion of apnea. Adapted from Mateika and Narwani (2009), Exp. Physiol. 91, 89–102.

Figure 5

A schematic diagram outlining the potential impact of an endogenous circadian rhythm on breathing stability during nighttime (red arrows) and daytime sleep (blue arrows) as a consequence of oscillations in (i) chemoreflex properties and neuromuscular control of the upper airway and (ii) the magnitude of respiratory plasticity. The diagram also shows the role that an endogenous circadian rhythm, either alone or in combination with the initiation of respiratory plasticity, may have in determining the magnitude of continuous positive airway pressure. The overlying theme of the diagram is that an endogenous circadian rhythm may promote mechanisms (e.g. neuromuscular control of upper airway muscle activity) and forms of plasticity that stabilize breathing, while simultaneously minimizing mechanisms that destabilize breathing (i.e. increases in the ventilatory response to hypoxia or hypercapnia and decreases in the carbon dioxide reserve) during daytime compared to nighttime sleep. The increases (+, ++) and decreases (−, − −) shown are meant to reflect changes that might occur during nighttime compared to daytime sleep as a consequence of an endogenous circadian rhythm. For example, it is hypothesized that the apneic threshold will decrease (−) (i.e. move further away from resting levels of carbon dioxide) and chemoreflex sensitivity will decrease (−) leading to an increase in the carbon dioxide reserve (+) and ultimately breathing stability (+) during daytime compared to nighttime sleep. + = increase; − = decrease; ++ = a greater increase; − − = a greater decrease.

Figure 6

A diagram summarizing a situation in which exposure to intermittent hypoxia leads to fatigue of the upper airway muscles which results in the promotion of apnea, despite alterations in chemoreflex properties that could potentially mitigate apnea. Adapted from Mateika and Narwani (2009), Exp. Physiol. 91, 89–102.