A comprehensive review of respiratory, autonomic and cardiovascular responses to intermittent hypoxia in humans

Abstract

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.

Testosterone Supplementation Induces Age-Dependent Augmentation of the Hypoxic Ventilatory Response in Male Rats With Contributions From the Carotid Bodies

“…Abnormal carotid body function also contributes to hypertension, an important comorbidity of SDB (Paton et al, 2013;Del Rio et al, 2016;Narkiewicz et al, 2016;Iturriaga et al, 2021). Animal models of SDB reproducing the recurrent drops in arterial O 2 show that chronic intermittent hypoxia augments the CB's chemosensitivity and reproduce key cardiorespiratory comorbidities observed in SDB patients (Dempsey et al, 2010;Puri et al, 2021). However, chronic intermittent hypoxia is a consequence of SDB and the periodic total or partial obstruction of the upper airway is not reached in this model.…”

Divergent Ventilatory and Blood Pressure Responses are Evident Following Repeated Daily Exposure to Mild Intermittent Hypoxia in Males with OSA and Hypertension

“…Uncoupling of muscle sympathetic nervous system activity and blood pressure following exposure to hypoxia has been reported previously (Cutler et al, 2004a;Cutler et al, 2004b;Lusina et al, 2006;Querido et al, 2010). Local vasodilatory effects of systemic hypoxia could override vasoconstrictor influences from the increased sympathetic outflow resulting in changes in vascular resistance that are unexpected based on sympathetic nervous system activity (Puri et al, 2021). Indeed, Xie et al (2001) reported sustained increases in muscle sympathetic nerve activity following hypoxia without significant modifications in blood pressure or leg blood flow, suggesting that the amount of sympathetic activation was insufficient to raise total peripheral resistance or that the short exposures to hypoxia may not elicit pro-hypertensive mechanisms.…”

“…Mild intermittent hypoxia (MIH) is defined by exposure to a few episodes of hypoxia (i.e., no greater than 15 episodes) that are short (i.e., no greater than 4 min) and accompanied by a decrease in oxygen saturation of no less than 85% (Puri et al, 2021). Acute exposure to MIH may result in the initiation of two forms of respiratory plasticity in humans.…”

“…Acute exposure to MIH may result in the initiation of two forms of respiratory plasticity in humans. Progressive augmentation of the hypoxic ventilatory response (PA) and long-term facilitation (LTF) of ventilation (Puri et al, 2021). Progressive augmentation is characterized by a progressive increase in the ventilatory response to hypoxia from the initial to the final hypoxic episode of an MIH protocol.…”

APOE4, Age & Sex Regulate Respiratory Plasticity Elicited By Acute Intermittent Hypercapnic-Hypoxia

“…In a published companion article, we reported that intermittent exposure to concurrent hypoxia and hypercapnia (AIHH: acute intermittent hypercapnic-hypoxia; ~9.5% inspired O 2 ; ~4.5% inspired CO 2 ) elicited robust facilitation of diaphragm motor-evoked potential, MEP, reflection volitional pathways to phrenic motor neurons, and mouth occlusion pressure in 100 msec (P 0.1 ), reflecting automatic ventilatory control, in healthy adults [3]. Combined hypoxia and hypercapnia are more effective at triggering respiratory motor plasticity in humans [4, 5], possibly because greater carotid chemoreceptor activation augments serotonergic raphe neuron activity more than hypoxia alone [6, 7], and/or direct activation of raphe neurons by hypercapnia [8], thereby enhancing cell signaling cascades that strengthen synapses onto phrenic motor neurons. Consistent with published human AIH trials [2], ~40% of participants respond minimally to AIHH (defined as <25% increase in diaphragm MEP amplitudes).…”