The need for specificity in quantifying neurocirculatory vs. respiratory effects of eucapnic hypoxia and transient hyperoxia

Abstract

Key points The carotid chemoreceptor mediates the ventilatory and muscle sympathetic nerve activity (MSNA) responses to hypoxia and contributes to tonic sympathetic and respiratory drives. It is often presumed that both excitatory and inhibitory tests of chemoreflex function show congruence in the end‐organ responses. Ventilatory and neurocirculatory (MSNA, blood pressure and heart rate) responses to chemoreflex inhibition elicited by transient hyperoxia and to chemoreflex excitation produced by steady‐state eucapnic hypoxia were measured in a cohort of 82 middle‐aged individuals. Ventilatory and MSNA responsiveness to hyperoxia and hypoxia were not significantly correlated within individuals. It was concluded that ventilatory responses to hypoxia and hyperoxia do not predict MSNA responses and it is recommended that tests using the specific outcome of interest, i.e. MSNA or ventilation, are required. Transient hyperoxia is recommended as a sensitive and reliable means of quantifying tonic chemoreceptor‐driven levels of sympathetic nervous system activity and respiratory drive. Abstract Hypersensitivity of the carotid chemoreceptor leading to sympathetic nervous system activation and ventilatory instability has been implicated in the pathogenesis and consequences of several common clinical conditions. A variety of treatment approaches aimed at lessening chemoreceptor‐driven sympathetic overactivity are now under investigation; thus, the ability to quantify this outcome variable with specificity and precision is crucial. Accordingly, we measured ventilatory and neurocirculatory responses to chemoreflex inhibition elicited by transient hyperoxia and chemoreflex excitation produced by exposure to graded, steady‐state eucapnic hypoxia in middle‐aged men and women (n = 82) with continuous positive airway pressure‐treated obstructive sleep apnoea. Progressive, eucapnic hypoxia produced robust and highly variable increases in ventilation (+83 ± 59%) and muscle sympathetic nerve activity (MSNA) burst frequency (+55 ± 31%), whereas transient hyperoxia caused marked reductions in these variables (−35 ± 14% and −42 ± 16%, respectively). Coefficients of variation for ventilatory and MSNA burst frequency responses, indicating test–retest reproducibility, were respectively 9% and 24% for hyperoxia and 35% and 28% for hypoxia. Based on statistical measures of rank correlation or even comparisons across quartiles of corresponding ventilatory and MSNA responses, we found that the magnitudes of ventilatory inhibition with hyperoxia or excitation with eucapnic hypoxia were not correlated with corresponding MSNA responses within individuals. We conclude that, in conscious, behaving humans, ventilatory sensitivities to progressive, steady‐state, eucapnic hypoxia and transient hyperoxia do not predict MSNA responsiveness. Our findings also support the use of transient hyperoxia as a reliable, sensitive, measure of the carotid chemoreceptor contribution to tonic sympathetic nervous system activity and respiratory drive.

A sympathetic view of blood pressure control at high altitude: new insights from microneurographic studies

“…Nevertheless, it is evident that whilst the peripheral chemoreflex appears to be central in initiating sympathoexcitation during acute hypoxic exposures, the peripheral chemoreflex is not solely responsible for sustained sympathoexcitation during HA acclimatisation and adaptation. Importantly, there appears to be a dissociation between ventilatory and sympathetic responses during chronic hypoxia, a notion that is supported by recent studies of peripheral chemoreflex activation during acute hypoxia (Keir et al., 2019; Prasad et al., 2020). Nevertheless, the relative contribution of the peripheral chemoreflex mechanism to basal MSNA appears to vary between lowlanders, Andeans and Sherpa, which may be influenced by ancestral differences in peripheral chemoreceptor sensitivity to hypoxia (Beall et al., 1997; Severinghaus et al 1966).…”

Peripheral chemoresponsiveness during exercise in male athletes with exercise‐induced arterial hypoxaemia

“…Hyperoxia was used to determine the peripheral chemosensors’ tonic contribution to ventilation (Prasad et al., 2020). We elected not to use hypoxia because of the potential to hinder oxygen delivery and the greater variability of the response compared to hyperoxia (Prasad et al., 2020). For the hyperoxic trials, the gas mixture (100% O 2 ) was given through a similar four‐way valve.…”

Measuring Peripheral Chemoreflex Hypersensitivity in Heart Failure

“…This focus on the carotid body as a therapeutic target is largely based on a reportedly high prevalence and independent prognostic value of augmented peripheral chemoreflex HVR (i.e., sensitivity) in the HFrEF population measured from brief hypoxic exposures ( Chua et al, 1997 ; Ponikowski et al, 2001 ; Giannoni et al, 2009 ) rather than the sympathetic responsiveness per se . Importantly, this method of assessing peripheral chemoreflex sensitivity has known intrinsic limitations ( Duffin, 2007 , 2011 ; Powell, 2012 ), and the assumption of concordance between the ventilatory and sympathetic arms of the peripheral chemoreflex in HFrEF has been refuted in healthy individuals ( Keir et al, 2019 ) and in those with OSA ( Prasad et al, 2020 ). Investigations in HFrEF are underway ( Keir et al, 2020 ).…”

“…However, to our knowledge, no longitudinal studies thus far have associated peripheral chemoreceptor tone to survival in this population. Importantly, a recent publication, involving cohorts with hypertension and obstructive sleep apnea, subjected to steady-state hypoxia with PCO 2 maintained eucapnic also documented discordance between reflex ventilatory and sympathoneural response to this stimulus ( Prasad et al, 2020 ).…”