The hypoxic ventilatory response and ventilatory long-term facilitation are altered by time of day and repeated daily exposure to intermittent hypoxia

Abstract

This study examined whether time of day and repeated exposure to intermittent hypoxia have an impact on the hypoxic ventilatory response (HVR) and ventilatory long-term facilitation (vLTF). Thirteen participants with sleep apnea were exposed to twelve 4-min episodes of isocapnic hypoxia followed by a 30-min recovery period each day for 10 days. On days 1 (initial day) and 10 (final day) participants completed the protocol in the evening (PM); on the remaining days the protocol was completed in the morning (AM). The HVR was increased in the morning compared with evening on the initial (AM 0.83 ± 0.08 vs. PM 0.64 ± 0.11 l·min⁻¹·%SaO₂⁻¹; P ≤ 0.01) and final days (AM 1.0 ± 0.08 vs. PM 0.81 ± 0.09 l·min⁻¹·%SaO₂⁻¹; P ≤ 0.01, where %SaO₂ refers to percent arterial oxygen saturation). Moreover, the magnitude of the HVR was enhanced following daily exposure to intermittent hypoxia in the morning (initial day 0.83 ± 0.08 vs. final day 1.0 ± 0.08 l·min⁻¹·%SaO₂⁻¹; P ≤ 0.03) and evening (initial day 0.64 ± 0.11 vs. final day 0.81 ± 0.09 l·min⁻¹·%SaO₂⁻¹; P ≤ 0.03). vLTF was reduced in the morning compared with the evening on the initial (AM 19.03 ± 0.35 vs. PM 22.30 ± 0.49 l/min; P ≤ 0.001) and final (AM 20.54 ± 0.32 vs. PM 23.11 ± 0.54 l/min; P ≤ 0.01) days. Following daily exposure to intermittent hypoxia, vLTF was enhanced in the morning (initial day 19.03 ± 0.35 vs. final day 20.54 ± 0.32 l/min; P ≤ 0.01). We conclude that the HVR is increased while vLTF is decreased in the morning compared with the evening in individuals with sleep apnea and that the magnitudes of these phenomena are enhanced following daily exposure to intermittent hypoxia.

Human intermittent hypoxia-induced respiratory plasticity is not caused by inflammation

“…The increased AHVR (via an increase in breathing frequency) within the placebo condition is similar to previous reports [7][8][9][10][11][12]. Although the mechanism is incompletely understood, oxidative stress has been proposed to be a primary mediator, as antioxidant treatment before [20] and during [18] IH exposure prevents carotid body sensory long-term facilitation and the enhanced chemosensory response to hypoxia [20] as well as augmentation of the AHVR [3,18].…”

“…Greater ventilatory instability is associated with increasing OSA severity [5] and occurs in humans following IH exposure via enhanced ventilatory responses to hypoxia [7][8][9][10][11][12] and hypercapnia [11][12][13][14]. Animal models implicate increased inflammation in promoting the IH-induced AHVR augmentation, suggesting that anti-inflammatory medications may offer a therapeutic pathway to decrease ventilatory instability and, therefore, OSA severity [18,25].…”

“…IH exposure is thought to contribute to increased ventilatory instability in OSA as both acute (minutes to hours) and chronic (days to years) exposure increase the AHVR [7][8][9][10][11] and the AHCVR [11][12][13][14], although these are not consistent findings [8,15]. The progressive increase in the AHVR and AHCVR following IH may be considered as forms of respiratory plasticity (defined as a continuing alteration in the neural system controlling breathing based on prior experience [16]).…”

Short-term modulation of the ventilatory response to exercise is preserved in obstructive sleep apnea

“…Obesity and CIH associated with OSA may impact STM in multiple ways. First, since CIH preconditioning enhances the ability to express serotonin-dependent respiratory motor plasticity (Gerst et al, 2011; Ling et al, 2001), including CIH accompanied by other attributes of OSA (Lee et al, 2009), serotonin-dependent STM may be enhanced in OSA patients. On the other hand, the capacity for STM is limited in both animal models (Mitchell, 1990) and normal humans (Wood et al, 2008a, 2010, 2011), suggesting that mechanical impairment associated with obesity and increased upper airway resistance may overload the system, diminishing the ability to express further STM with the addition of respiratory dead space.…”

The effect of intermittent hypoxia on obstructive sleep apnea: beneficial or detrimental?

“…A strength of the study is that it was conducted on patients with mild-tomoderate OSA, the very group most likely to benefit from treatment. The study of Gerst et al (7) has some limitations. The experimental conditions were different from those during spontaneous UA obstructions.…”