Influence of exertional hypoxemia on cerebral oxygenation in fibrotic interstitial lung disease

Highlights

• Exertional hypoxemia impairs cerebral oxygenation in a dose-dependent fashion in interstitial lung disease.

• Impaired cerebral oxygenation independently predicts a poor tolerance to physical exertion in this patient population.

• The contributory role of cerebral hypoxia in limiting exercise tolerance in these patients remains, however, to be spelled out.

Abstract

It is unknown whether hypoxemia, a hallmark of fibrotic interstitial lung disease (f-ILD), may impair cerebral oxygenation during exercise in these patients.

Twenty-seven patients [23 males, 72 ± 8 years, lung diffusing capacity for carbon monoxide (DL_CO) = 44 ± 11 % predicted] and 12 controls performed an incremental bicycle test. Prefrontal oxygenation [tissue saturation index (TSI)] was assessed by near-infrared spectroscopy.

Patients showed lower arterial O₂ saturation (SpO₂) and larger fall in cerebral TSI during exercise vs controls (p < 0.05). However, changes (Δ) from rest to peak-exercise in SpO₂ (-2.2 % to -26.9 %) and TSI (1.4 % to -16.6 %) varied substantially among patients. In the 16 patients showing significant cerebral deoxygenation (Δ TSI ≥ 4% based on controls), SpO₂ decreased more (-12.6 ± 6.7 % vs -5.7 ± 2.8 %, p = 0.001) and peak O₂ uptake was lower (68.3 ± 19.2 % vs 87.8 ± 24.8 % predicted, p = 0.03) vs their 11 counterparts. In association with DL_CO and forced vital capacity, Δ cerebral TSI independently predicted peak O₂ uptake on multivariable regression analysis (R² = 0.54).

Exertional hypoxemia impairs cerebral oxygenation in a dose-dependent fashion in f-ILD. Future studies are warranted to investigate whether this potentially reversible abnormality play a contributory role in limiting exercise tolerance in these patients.

Introduction

Adequate oxygen (O₂) delivery to the brain during exercise is critically dependent on cerebral blood flow (CBF) and arterial O₂ content (CaO₂). (Smith and Ainslie, 2017) In healthy humans, impaired cerebral O₂ delivery has been related to the development of central fatigue i.e. a reduction in central motor output to the peripheral muscles. (Amann et al., 2007; Verges et al., 2012) The inhibition of the descending central drive is particularly relevant in the presence of severe hypoxemia (Amann et al., 2007) and may translate into increased perception of effort/fatigue upon exertion. (Amann et al., 2007; Millet et al., 2012) It follows that impaired cerebral oxygenation might contribute to poor exercise tolerance in chronic respiratory diseases associated with low CaO₂. (Goodall et al., 2014a)

In this context, fibrotic interstitial lung disease (f-ILD) constitutes a group of disorders in which profound exercise-related hypoxemia is a cardinal feature. (Du Plessis et al., 2018) Although exercise intolerance in f-ILD is characteristically multi-factorial [e.g. impaired pulmonary gas exchange, abnormalities in respiratory mechanics, cardio-circulatory abnormalities (Agusti et al., 1991; Faisal et al., 2016; Hansen and Wasserman, 1996)], the influence of severe hypoxemia on cerebral oxygenation during exercise in these patients is currently unknown. Several investigations previously showed that an impairment in cerebral oxygenation may contribute to a reduction in exercise tolerance in diverse chronic cardiorespiratory diseases. (Marillier et al., 2018b; Oliveira et al., 2016, 2012) Patients with f-ILD may also present with limited ability of increasing cardiac output to compensate for a severely reduced CaO₂. Pulmonary micro-vasculopathy, hypoxia-induced pulmonary vasoconstriction and, as observed in some patients, overt pulmonary hypertension (Han et al., 2013; Patel et al., 2007) may hinder these compensatory haemodynamic adjustments aiming at preserving O₂ delivery under these conditions. Additionally, recent findings suggest a role for exertional hypoxemia towards reduced brain perfusion and atrophy in patients with idiopathic pulmonary fibrosis. (Hett, 2019) Collectively, these premises suggest a hitherto unexplored contributory role for cerebral hypoxia in decreasing f-ILD patients’ tolerance to dynamic exercise.

We therefore aimed to: (i) investigate the effect of exercise-related hypoxemia on cerebral oxygenation in patients with f-ILD and, (ii) determine whether impairment in cerebral oxygenation, when present, is associated with poorer exercise tolerance in these patients. We hypothesized that (i) increased severity of exertional hypoxemia would be associated with poorer cerebral oxygenation in patients with f-ILD and, (ii) impaired cerebral oxygenation would be associated with poorer exercise tolerance in this patient population.