INNOVATION FUND The Future of Academic Medicine Quality Improvement & Outcomes SHOWCASE 2023

Improving neuromuscular fatigue with supplemental oxygen to enhance exercise tolerance in pulmonary fibrosis: a randomized, placebo-controlled trial

Quality Improvement & Outcomes

Alberto Nader
613-549-6666 ext 4664


Kingston Health Sciences Centre
Queen’s University


Matthew James
613-549-6666 ext. 4910


Kingston Health Sciences Centre
Respiratory Investigation Unit, Queen’s University


Pulmonary fibrosis (PF) is a devastating disease in which the lungs lose the ability to transfer oxygen (O2) to the blood. Lack of O2 causes shortness of breath but also leads to a sensation of leg weakness. It was, however, unknown whether giving extra-O2 to patients would improve this sensation and muscle functioning, contributing to increasing tolerance to exertion.
This project showed, for the first time, that low O2 levels impair the efficiency at which the leg muscles contract during exercise in persons with PF. When O2 was given, this was reversed; as such, they were able to do more with less leg fatigue and enhanced stamina.
Our results will be translated into the care of persons with PF: since we now know that O2 improves leg muscle resistance, it should be given to those feeling excessive muscle fatigability on daily life and during rehabilitation sessions targeted to improve muscle functioning.


Pulmonary fibrosis (PF) regroups >200 restrictive ventilatory disorders that share close similarities as they progress to diffuse collagen deposition and architectural distortion. The hallmarks of PF include a profound decrease in arterial O2 levels (hypoxemia), dyspnea on exertion, and poor exercise tolerance. Exertional O2 supplementation is, however, a costly intervention whose efficacy on dyspnea and exercise tolerance remains highly controversial in PF. Thus, it is urgent to improve our understanding of the reasons behind the lack of a consistent ergogenic effect of O2 in PF.
Clinically, many patients report “leg tiredness” as a key symptom to limit their exercise tolerance. Of note, there is sound evidence that the lack of O2 is the main mechanism that renders skeletal muscles poorly responsive to neural stimulation, precipitating contractile fatigue. Thus, our project aimed at exploring the link between hypoxemia and muscle symptoms suggestive of underlying neuromuscular fatigue in PF. We postulated that hypoxemia triggers neuromuscular fatigue in patients who end up being more responsive to supplemental O2. As a corollary, reversion of hypoxemia with supplemental O2 would improve locomotor muscle fatigue in PF.
Following a total of 118 experimental visits, we found that:
a) hypoxemic patients with PF had faster and greater muscle deoxygenation, which strongly correlated with their tolerance to exercise and their symptoms of leg discomfort;
b) severe hypoxemia was not only responsible for poorer muscle oxygenation but also for ~50% greater quadriceps muscle fatigability;
c) quadriceps fatigability was strongly linked to patients’ heightened perceived sense of fatigability during exercise;
d) under O2 to correct hypoxemia, we demonstrated that it offsets impairments in muscle deoxygenation and fatigability and, importantly,
e) these improvements were associated with a clinically-relevant decrease in leg discomfort (>1 Borg unit).
This project is the first to demonstrate that exertional hypoxemia, a cardinal feature of PF, is associated with poor muscle oxygenation, exacerbated skeletal muscle fatigability, and increased leg discomfort. It is also the first to show that supplemental O2 can be beneficial for exercise tolerance and patients’ symptoms beyond the respiratory system, i.e., not only due to less dyspnea due to lowered ventilatory requirements. Thus, it provides a strong rationale for this intervention as an ergogenic aid to the leg muscles to improve patients’ mobility in daily life while potentiating the beneficial effect of pulmonary rehabilitation in PF.


The project led to 6 publications [Marillier M – Neder JA (Project Lead): 1st – senior author)] + 8 presentations in national or international meetings. The main paper was published in THORAX, the 5th top medical journal in respiratory science.
P1 DOI: 10.1016/j.resp.2020.103601
P2 DOI: 10.1136/thoraxjnl-2020-215135
P3 DOI: 10.3389/fnhum.2021.789053
P4 DOI: 10.1111/cpf.12809
P5 DOI: 10.1183/23120541.00726-2022
P6 Med Sci Sports Exerc (currently under revision – R1)

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