Effect of induced acute metabolic alkalosis on the V̇E/V̇CO2 response to exercise in healthy adults

https://doi.org/10.1016/j.resp.2021.103740Get rights and content

Highlights

  • Ingestion of sodium bicarbonate (0.3 g/kg) induced a metabolic alkalosis.

  • Acute induced metabolic alkalosis decreased the V̇E/V̇CO2 response to exercise.

Abstract

We tested the hypothesis that increasing the respiratory control systems’ arterial PCO2 equilibrium point via induced acute metabolic alkalosis by ingestion of sodium bicarbonate (NaHCO3, 0.3 g/kg) would decrease the ventilatory equivalent for CO2 (V̇E/V̇CO2) at its lowest point (“nadir”) during constant-load cycle exercise testing performed at 80 % of peak power output in 18 healthy young adults. Compared to the sodium chloride (4 g) control condition, ingestion of NaHCO3: increased arterialized venous pH, HCO3- and PCO2 at rest by 0.05 ± 0.01 units (mean ± SE), 6.4 ± 0.4 mEq/L and 4.3 ± 0.7 mmHg, respectively (all p < 0.0001); and decreased the V̇E/V̇CO2 nadir during exercise by 9.4 % (p < 0.0001) secondary to a 4.7 ± 1.8 L/min decrease in V̇E (p = 0.019). In conclusion, induced acute metabolic alkalosis by ingestion of NaHCO3 decreased the V̇E/V̇CO2 response to strenuous exercise in healthy adults.

Introduction

The ventilatory response (V̇E) to exercise-induced increases in the rate of CO2 production (V̇CO2) depends on the arterial PCO2 (PaCO2) equilibrium point and the dead space to tidal volume ratio (VD/VT), as described by the modified alveolar ventilation equation: V̇E/V̇CO2 = 863/(PaCO2 x [1-VD/VT]) (Wasserman, 1976; Whipp et al., 1984).

An abnormally high V̇E/V̇CO2 response to exercise, consequent to a high VD/VT and/or low PaCO2 equilibrium point (Wasserman, 1976; Whipp et al., 1984), is a key pathophysiological feature of patients with chronic cardiopulmonary disease (Phillips et al., 2020), including heart failure (Arena et al., 2008b; Sue, 2011), pulmonary arterial hypertension (Sun et al., 2001), interstitial lung disease (Faisal et al., 2016; Vainshelboim et al., 2016), and chronic obstructive pulmonary disease (Neder et al., 2015; Jones et al., 2017; Neder et al., 2017a, b; Phillips et al., 2021b, c). In these patient groups, the abnormally high V̇E/V̇CO2 response to exercise is associated with: disease severity and progression (Sun et al., 2001; Arena et al., 2004; Thirapatarapong et al., 2013; Neder et al., 2015; Faisal et al., 2016); exercise intolerance (Sun et al., 2001; Arena and Humphrey, 2002; Ingle et al., 2007; Poggio et al., 2010; Neder et al., 2015; Shen et al., 2015; Faisal et al., 2016; Vainshelboim et al., 2016; Neder et al., 2017a, b); exertional breathlessness (Elbehairy et al., 2015; Neder et al., 2015; Faisal et al., 2016; Neder et al., 2017a, b; Neder et al., 2019); and increased risk of hospitalization (Arena and Humphrey, 2002; Arena et al., 2008a), major cardiac events (Tabet et al., 2003; Arena et al., 2010; Poggio et al., 2010) and premature death (Poggio et al., 2010; Sue, 2011; Schwaiblmair et al., 2012; Neder et al., 2016; Vainshelboim et al., 2016; Barratt et al., 2020; Maiorana et al., 2020; Rosato et al., 2020). It follows that any intervention capable of decreasing the V̇E/V̇CO2 response to exercise has the potential to improve clinical and/or patient-reported outcomes. Unfortunately, our ability to decrease the V̇E/V̇CO2 response to exercise is limited by the fact that, with the possible exception of lung volume reduction surgery in chronic obstructive pulmonary disease (Criner et al., 1999; Geddes et al., 2000; Stirling et al., 2001; Armstrong et al., 2015) and pulmonary vasodilator therapy in pulmonary arterial hypertension (Oudiz et al., 2007), heart failure (Kim et al., 2015) or chronic obstructive pulmonary disease (Phillips et al., 2021a), ventilation-perfusion abnormalities reflecting a high VD/VT are often irreversible (e.g., (Elbehairy et al., 2018; Stringer et al., 2021)).

A largely unexplored approach to decreasing the V̇E/V̇CO2 response to exercise is increasing the respiratory control systems’ PaCO2 equilibrium point by inducing a metabolic alkalosis via administration of an alkalizing agent such as sodium bicarbonate (NaHCO3). Oren et al. (1981) examined the effect of induced chronic metabolic alkalosis by three consecutive days of NaHCO3 administered orally (0.7 g/kg/day) on V̇E/V̇CO2 responses to exercise in seven healthy men. Compared to the calcium carbonate control condition (CaCO3, 0.1 g/kg/day), NaHCO3 increased PaCO2 by ∼3.5 mmHg at rest and decreased V̇E/V̇CO2 responses to (i) symptom-limited incremental cycle exercise testing and (ii) constant-load cycle exercise testing at a power output below the anaerobic threshold; however, none of these differences were statistically significant. A study of six healthy men by Iwaoka et al. (1989) reported that, compared to the starch control condition, single-dose ingestion of NaHCO3 (0.2 g/kg) significantly decreased V̇E/V̇CO2 ratios during cycle exercise above but not below the respiratory compensation point coincident with small non-significant increases in PaCO2 at rest and during exercise. A study of six healthy men by Light et al. (1999) found that, compared to the sodium chloride control condition (NaCl, 1 mEq/kg/day), ingestion of NaHCO3 (3 mEq/kg/day) once a day for five consecutive days significantly increased PaCO2 at rest by 5.2 mmHg, but otherwise had no effect on the V̇E/V̇CO2 response to symptom-limited incremental cycle exercise testing performed with or without added dead space. Based on the results of these small studies, it remains unclear whether inducing a metabolic alkalosis via administration of NaHCO3 has the potential to decrease the V̇E/V̇CO2 response to exercise in human subjects by increasing the respiratory control systems’ PaCO2 equilibrium point.

The primary objective of this randomized, double blind, placebo controlled, crossover study was to test the hypothesis that increasing the respiratory control systems PaCO2 equilibrium point via induced acute metabolic alkalosis by single-dose oral administration of NaHCO3 would decrease the V̇E/V̇CO2 response to high-intensity constant-load cycle exercise testing in healthy adults.

Section snippets

Participants

Participants included healthy, non-smoking, non-obese men and women aged 18–40 years with normal spirometry: forced expiratory volume in 1-sec (FEV1) ≥80 % predicted and a FEV1-to-forced vital capacity ratio (FEV1/FVC) >70 %. Participants were excluded if they were taking doctor prescribed medications other than oral contraceptives and/or had a history of gastrointestinal, cardiovascular, respiratory, kidney, liver, musculoskeletal, endocrine, neuromuscular and/or metabolic disease/disorder.

Participant characteristics

Participants included 18 young (22.2 ± 0.5 years), non-obese (body mass index, 24.2 ± 0.7 kg/m2) men and women (n = 12 and 6, respectively) with normal spirometry (FEV1, 104 ± 3 % predicted (Hankinson et al., 1999); FEV1/FVC, 82.1 ± 1.8 %), and a PPO of 219.4 ± 13.9 W (108 ± 6 % predicted) and a V̇O2peak of 51.8 ± 2.6 ml/kg/min (129 ± 6 % predicted).

Blood biochemistry

As illustrated in Fig. 1, single-dose oral administration of NaHCO3 induced a partially compensated metabolic alkalosis with decreases in [H+] by

Discussion

The primary finding of this randomized, double blind, placebo-controlled, crossover study is that increasing the respiratory control systems’ resting PaCO2 equilibrium point via induced acute metabolic alkalosis by ingestion of NaHCO3 decreased the V̇E/V̇CO2 response to high-intensity constant-load cycle exercise testing in healthy adults.

The modified alveolar ventilation equation (V̇E/V̇CO2 = 863/[PaCO2 x (1-VD/VT)]) predicts that the V̇E response to any given increment in V̇CO2 during

Conclusion

This study provided new evidence to support the hypothesis that increasing the respiratory control systems’ resting PaCO2 equilibrium point via induced acute metabolic alkalosis by ingestion of NaHCO3 can decrease the V̇E/V̇CO2 response to exercise, at least in healthy young adults during high-intensity constant-load cycle exercise testing. The clinical relevance/implications of these findings should be the focus of future research.

Funding

Financial support was provided to DJ by the Natural Sciences and Engineering Research Council of Canada (RGPIN 402598-2011 and RGPIN 04918-2016). DJ was supported by a Chercheurs-Boursiers Junior 1 salary awardfrom the Fonds de Recherche du Québec-Santé (FRQS) and by a William Dawson Research Scholars Award (McGill University). DJ holds a Canada Research Chair in Clinical Exercise and Respiratory Physiology (Tier 2) from the Canadian Institutes of Health Research.

Author contributions

Concept and design: JB, DJ. Acquisition and assembly of data: JB. Analysis and interpretation of data: JB, DJ. Drafting of the manuscript and/or revising it critically for important intellectual content: JB, DJ. Both JB and DJ approved the final version of the manuscript, while DJ is accountable for all aspects of the work. Experiments were performed in the Clinical Exercise and Respiratory Physiology Laboratory (CERPL) at McGill University, Montreal, Quebec, Canada.

Declaration of Competing Interest

No conflicts of interest, financial or otherwise, are declared by the authors.

Acknowledgements

The authors would like to thank the participants for their time and cooperation; and Daniel Gornitsky, Marcus Waskiw-Ford and Courtney Wilkinson-Maitland for their help with data acquisition and analysis.

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