Mild intermittent hypoxia initiates progressive augmentation (PA) and ventilatory long-term facilitation (vLTF) in humans. The magnitude of these forms of plasticity might be influenced by anthropometric and physiological variables, as well as protocol elements. However, the impact of many of these variables on the magnitude of respiratory plasticity has not been established in humans. A meta-analysis was completed using anthropometric and physiological variables obtained from 124 participants that completed one of three intermittent hypoxia protocols. Simple correlations between the aggregate variables and the magnitude of PA and vLTF standardized to baseline was completed. Thereafter, the variables correlated to PA or vLTF were input into a multilinear regression equation. Baseline measures of the hypoxic ventilatory response was the sole predictor of PA (R = 0.370, P = 0.012). Similarly, this variable along with the hypoxic burden predicted the magnitude of vLTF (R = 0.546, P < 0.006 for both variables). In addition, the magnitude of PA was strongly correlated to vLTF (R = 0.617, P < 0.001). Anthropometric measures do not predict the magnitude of PA and vLTF in humans. Alternatively, the hypoxic ventilatory response was the sole predictor of PA, and in combination with the hypoxic burden, predicted the magnitude of vLTF. These influences should be considered in the design of mild intermittent hypoxia protocol studies in humans. Moreover, the strong correlation between PA and vLTF suggests that a common mechanistic pathway may have a role in the initiation of these forms of plasticity. KEY POINTS: Mild intermittent hypoxia initiates progressive augmentation (PA) and ventilatory long-term facilitation (vLTF) in humans. Many of the anthropometric and physiological variables that could impact the magnitude of these forms of plasticity are unknown. Anthropometric and physiological variables were measured from a total of 124 participants that completed one of three distinct intermittent hypoxia protocols. The variables correlated to PA or vLTF were input into a multilinear regression analysis. The hypoxic ventilatory response was the sole predictor of PA, while this variable in addition to the average hypoxic burden predicted the magnitude of vLTF. A strong correlation between PA and vLTF was also revealed. These influences should be considered in the design of mild intermittent hypoxia protocol studies in humans. Moreover, the strong correlation between PA and vLTF suggests that a common mechanistic pathway may have a role in the initiation of these forms of plasticity.

Introduction: Resting minute ventilation and ventilation during and following hypoxia may be enhanced following daily exposure to mild intermittent hypoxia (MIH). In contrast, resting systolic blood pressure (SBP) is reduced following daily exposure to MIH. However, it is presently unknown if the reduction in resting SBP following daily exposure, is coupled with reduced SBP responses during and after acute exposure to MIH. Methods: Participants with obstructive sleep apnea (OSA) and hypertension (n = 10) were exposed to twelve 2-min bouts of MIH (oxygen saturation-87%)/day for 15 days. A control group (n = 6) was exposed to a sham protocol during which compressed air (i.e., FIO2 = 0.21) was inspired in place of MIH. Results: The hypoxic ventilatory response (HVR) and hypoxic systolic blood pressure response (HSBP) increased from the first to the last hypoxic episode on the initial (HVR: 0.08 ± 0.02 vs. 0.13 ± 0.02 L/min/mmHg, p = 0.03; HSBP: 0.13 ± 0.04 vs. 0.37 ± 0.06 mmHg/mmHg, p < 0.001) and final (HVR: 0.10 ± 0.01 vs. 0.15 ± 0.03 L/min/mmHg, p = 0.03; HSBP: 0.16 ± 0.03 vs. 0.41 ± 0.34 mmHg/mmHg, p < 0.001) day. The magnitude of the increase was not different between days (p ≥ 0.83). Following exposure to MIH, minute ventilation and SBP was elevated compared to baseline on the initial (MV: 16.70 ± 1.10 vs. 14.20 ± 0.28 L/min, p = 0.01; SBP: 167.26 ± 4.43 vs. 151.13 ± 4.56 mmHg, p < 0.001) and final (MV: 17.90 ± 1.25 vs. 15.40 ± 0.77 L/min, p = 0.01; SBP: 156.24 ± 3.42 vs. 137.18 ± 4.17 mmHg, p < 0.001) day. The magnitude of the increases was similar on both days (MV: 3.68 ± 1.69 vs. 3.22 ± 1.27 L/min, SBP: 14.83 ± 2.64 vs. 14.28 ± 1.66 mmHg, p ≥ 0.414). Despite these similarities, blood pressure at baseline and at other time points during the MIH protocol was reduced on the final compared to the initial day (p ≤ 0.005). Conclusion: The ventilatory and blood pressure responses during and following acute MIH were similar on the initial and final day of exposure. Alternatively, blood pressure was down regulated, while ventilation was similar at all time points (i.e., baseline, during and following MIH) after daily exposure to MIH.

This review explores forms of respiratory and autonomic plasticity, and associated outcome measures, that are initiated by exposure to intermittent hypoxia. The review focuses primarily on studies that have been completed in humans and primarily explores the impact of mild intermittent hypoxia on outcome measures. Studies that have explored two forms of respiratory plasticity, progressive augmentation of the hypoxic ventilatory response and long-term facilitation of ventilation and upper airway muscle activity, are initially reviewed. The role these forms of plasticity might have in sleep disordered breathing are also explored. Thereafter, the role of intermittent hypoxia in the initiation of autonomic plasticity is reviewed and the role this form of plasticity has in cardiovascular and hemodynamic responses during and following intermittent hypoxia is addressed. The role of these responses in individuals with sleep disordered breathing and spinal cord injury are subsequently addressed. Ultimately an integrated picture of the respiratory, autonomic and cardiovascular responses to intermittent hypoxia is presented. The goal of the integrated picture is to address the types of responses that one might expect in humans exposed to one-time and repeated daily exposure to mild intermittent hypoxia. This form of intermittent hypoxia is highlighted because of its potential therapeutic impact in promoting functional improvement and recovery in several physiological systems.

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.