JSIMD Journal

Introduction

Cardiorespiratory fitness has been shown to be an independent predictor of morbidity and mortality and can be considered a vital sign [1]. Physical exercise requires the interaction of cellular, cardiovascular and ventilatory systems to support gas exchange between the exercising muscular cells (internal respiration) and the pulmonary environment (external respiration). Defects in the coupling of external to internal respiration result in the gas exchange abnormalities characteristic of the limiting organ systems that are amplified by exercise stress. Cardiopulmonary exercise testing (CPET) is a maximal progressive exercise test that combines gas exchange measurement with traditional exercise testing parameters (electrocardiogram [ECG], blood pressure, and blood gas analysis).

It provides comprehensive and reproducible data on the interaction between ventilation, gas exchange, and cardiovascular and musculoskeletal function, enables determination of deviations from normal and usually identifies which of multiple pathophysiological conditions (cardiocirculatory, pulmonary vascular or respiratory alone or in combination) is the leading cause of exercise intolerance.

Initially used in sports and exercise science to determine aerobic and anaerobic fitness thresholds in athletes, CPET is now being used in many clinical indications. The most common of these include [1-10]:

• determining the cause(s) and severity of exertional dyspnea, fatigue, exercise intolerance, reduced exercise performance or exercise-induced hypoxaemia;
• assessing peak exercise capacity and cardiorespiratory fitness; estimating prognosis in various disease states;
• assessing perisurgical and postsurgical complication risks;
• early detection and risk stratification of cardiovascular, pulmonary vascular and lung diseases, and musculoskeletal disorders;
• measuring the response to pharmacological and nonpharmacological treatment;
• designing personalised exercise training and cardiopulmonary rehabilitation programmes.

Current evidence suggests that CPET should be used more frequently in clinical practice, especially because the additional time required compared with less meaningful exercise tests is low in routine use [2-6]. A basic knowledge of exercise physiology and gas exchange is essential to analyse and interprete CPET findings. However, the physiological concepts required to understand CPET are typically complex to teach.

The objective of this mini review is to briefly describe the underlying principles of exercise physiology, including all the key parameters, that are relevant for the evaluation of CPET. For further information the reader is referred to the literature [2-8, 1013].

Exercise physiology

CPET aims at maximally stressing the oxygen transport and utilizations systems. The transport of oxygen to metabolically active body tissues depends largely on cardiac output, haemoglobin (Hb) concentration, Hb oxygen saturation, arterial vascular tone and the density of the capillary network. Figure 1 shows characteristic alterations in key physiological parameters that occur as the exercise work rate is increased.

Aerobic metabolism

The increasing energy requirements during exercise are mainly covered by aerobic glycolysis and lipolysis until the anaerobic threshold (AT) is reached.

As the work rate increases, oxygen uptake (V̇ O₂) and carbon dioxide production (V̇ CO₂) increase. The V̇ O₂ uptake usually exceeds the V̇ CO₂ increase during early exercise due to transient carbon dioxide (CO₂) uptake into body stores. As a result, the respiratory exchange rate (RER: ratio of V̇ CO₂ divided by V̇ O₂) declines during the first minutes of moderate exercise (before AT). RER increases further because the respiratory quotient (RQ) of the muscle substrate glycogen is higher than at rest. It should be noted that RER (calculated by comparing exhaled gases to room air) estimates RQ (calculated at cellular level) only during rest and light to moderate aerobic exercise that does not result in lactate accumulation (before AT). With increasing work rate, a linear rise in heart rate (HR), oxygen pulse (V̇ O₂/HR) and ventilation (V̇ E = minute ventilation) can be observed. Physiologically, V̇ E increases until tidal volume (V_T) is fully utilised (≈60% of vital capacity [VC]), thereafter V̇ E increases with a rise in breathing frequency (BF).

Figure 1: Principles of exercise physiology (modified from [11]); The characteristic changes in key variables of ventilation, cardiocirculation, pulmonary gas exchange and metabolism during progressive exercise work are shown; Anaerobic threshold (AT) documents the transition to mixed aerobic-anaerobic metabolism, respiratory compensation point (RCP) documents the transition to predominant anaerobic metabolism. Definition of abbreviations: EqCO₂, ventilatory equivalent of carbon dioxide; EqO₂, ventilatory equivalent of oxygen; HR: heart rate; O₂: oxygen; PETCO2: end-tidal pressure of carbon dioxide; PETO2: end-tidal pressure of oxygen; V̇ E: minute ventilation; V̇ CO₂: carbon dioxide output; V̇ O₂: oxygen uptake.

Exercise significantly improves ventilation/perfusion distribution (through increased pulmonary blood flow and deep breathing (increased V_T) resulting in an enlarged gas exchange area. This improved efficiency is reflected by a decrease in the ventilatory equivalents EqO₂ (≈V̇ E/V̇ O₂) and EqCO₂ (≈V̇ E/V̇ CO₂) because more oxygen (O₂; V̇ O₂ ↑) is taken in and more carbon dioxide (CO₂; V̇ CO₂↑) is eliminated relative to ventilation. The lowest point (nadir) of the ventilatory equivalents is where the lungs are working most effectively (e.g, only a small volume must be ventilated to breath in one litre of O₂ or breath out one litre of CO₂).

The partial pressures of O₂ (P_ETO₂) and CO₂ (P_ETCO₂) measured at the end of exhalation (end-tidal [ET]) correspond to the alveolar pressures, PAO₂ and PACO₂, in a healthy individual. P_ETCO₂ increases slightly and peaks during early exercise, reflecting the elevated CO₂ production in exercising muscles, while increased peripheral O₂ extraction (V̇ O₂ ↑) means that less O₂ is exhaled (P_ETO₂ ↓).

Aerobic-anaerobic transition zone

As the exercise work rate continues to increase, ventilation increases (PAO₂↑ and PACO₂↓) without any more oxygen being taken up by the blood (no further increase in PaO₂ or arterial O₂ content) because haemoglobin is already fully saturated with oxygen. As a result of the maximally utilised aerobic metabolism, additional adenosine triphosphate (ATP) is generated via anaerobic glycolysis (advantage: rapid oxygen-independent energy supply; disadvantage: low energy yield: [2 mol of ATP for each 1 mol of glucose]). The acidic end product of anaerobic glycolysis is lactate. The resulting hydrogen ions (H+) are buffered by sodium bicarbonate (HCO₃^–) to maintain a neutral pH: H⁺ + HCO₃^– → H₂O and CO₂. The resulting excess CO₂ production stimulates a very strong ventilatory drive.

Due to this CO₂-induced increase in ventilation, significantly more CO₂ is exhaled (V̇ CO₂ ↑), while the increase in oxygen uptake (V̇ O₂↑) continues to rise only in parallel with the work rate. Accordingly, the increase in V̇ CO₂ is now significantly steeper than V̇ O₂ (AT) which is associated with a rise in RER. Since V̇ E and V̇ CO₂ increase almost proportionally, the ratio V̇ E/V̇ CO₂ ≈ EqCO₂ remains relatively constant. Consequently, P_ETCO₂ (≈ PACO₂) also transitions into a plateau (or drops off slightly). In contrast, the ratio of V̇ E/V̇ O₂ ≈ EqO₂ increases due to the relatively higher increase in V̇ E versus V̇ O₂. The end-expiratory or alveolar O₂ (P_ETO₂ [≈PAO₂]) also increases as a result of CO₂-mediated hyperventilation. The elevated O₂ pulse tends to tail off during later exercise when the stroke volume cannot be further enhanced but the HR continues to rise linearly with increasing work.

Note: any pathophysiology that increases respiratory drive (e.g, dysfunctional breathing, PaCO₂↑, pH↓) can cause or exacerbate dyspnea. In hyperventilation, CO₂ elimination exceeds CO₂ production (washout of body CO₂ stores), with the opposite occurring in hypoventilation. The determination of both gas exchange thresholds (AT and respiratory compensation point [RCP]) - is summarized in Table 1.

Table 1: Threshold criteria for aerobic threshold and respiratory compensation point [2, 9, 14].

Definition of abbreviations: AT, anaerobic threshold; CO2 , carbon dioxide; ET, end-tidal; HR, heart rate; O2 , oxygen; P, pressure; RCP, respiratory compensation point; VE, minute ventilation; V̇ E/V̇ CO2 , ventilatory equivalent for carbon dioxide; V̇ E/V̇ O2 , ventilatory equivalent for oxygen; V̇ CO2 , carbon dioxide output; V̇ O2 , oxygen uptake. *Full details of the V-slope methode can be found elsewhere [2, 9, 13, 14]. By combining several methods (3 - panel view) AT and RCP can be determined in most cases.

Anaerobic metabolism

As exercise intensity continues to increase, more and more lactate accumulates in the muscles because the buffer base capacity for lactate-associated H⁺ is exhausted. The resulting metabolic lactic acidosis (pH↓) stimulates an additional strong central ventilatory drive (partial respiratory compensation of metabolic acidosis) beyond CO₂-induced hyperventilation. As a result of the excessively increased ventilation, even more CO₂ is exhaled (V̇ CO₂↑), while V̇ O₂ continues to increase only in parallel with the increasing work rate. Beyond the RCP, V̇ E increases at a greater rate than V̇ CO2 (V̇ E/V̇ CO2↑), causing PETCO2 to decrease (increased ventilatory elimination of CO₂). In addition, there is a disproportional increase in RER (V̇ CO₂/V̇ O₂) . The excessive increase in ventilation is associated with elevations of P_ETO₂ and of the two ventilatory equivalents EqO₂ and EqCO₂. In the anaerobic range, V̇ O₂ continues to tail off relative to HR, resulting in a flattened O₂ pulse. Reaching the anaerobic range signals the impending termination of exercise.

Note: even though there is no standard for defining a maximal effort, maximal performance can be defined by the V̇ O₂ reached at maximal effort (pending attainment of a respiratory exchange ratio; e.g., RER ≥ 1.15, lactate > 8 mmol/L) beyond which no further increases in V̇ O₂ occur (plateau concept). Measuring peak V̇ O₂ is the gold clinical standard to objectively determine exercise capacity in individuals who cannot attain a maximal response. Of course, normal values of key CPET parameters vary because there will be expected differences in exercise physiology between trained athletes and the general population (Table 2) [2, 8, 15, 16, 17].

Recovery period (without figure)

V̇ E remains elevated for a short time (usually 2–3 min, but this depends on exercise intensity) due to respiratory compensation of lactic acidosis with increased ventilatory elimination of CO₂ (P_ETCO₂ ↓). At the same time, the ventilatory equivalents for O₂ and CO₂, RER (faster recovery of V̇ O₂ [↓] vs. V̇ CO₂ to baseline) and P_ETO₂ also increase before they rapidly return to normal.

Table 2: Key physiological parameters and their response to exercise [2, 15, 16].

Definition of abbreviations: AT, anaerobic threshold; BR, breathing reserve; CO2 , carbon dioxide; ET, end-tidal; HR, heart rate; O2 , oxygen; P, pres- sure; V̇ E/V̇ CO2 , ventilatory equivalent for carbon dioxide; V̇ O2 , oxygen uptake; V/Q, ventilation perfusion. 1Refers to endurance athletes with a high aerobic/oxidative metabolism. 2 Athletes reach their AT at a later stage, meaning that aerobic metabolism can be maintained over an extended period of time. 3 Indirect estimate of stroke volume. 4 Maximal HR in athletes is significantly lower than in the normal population emphasizing the role of an increased stroke volume. 5 Physiologically, V̇ E increases until VT is fully utilised (60% of vital capacity [VC]), then V̇ E increases with a rise in BF. 6 BR indicates the actual percentage of the maximum ventilatory capacity (not shown in this article). A low BR indicates reduced ventilatory capacity due to impaired lung mechanics or increased ventilatory demands during exercise. Exercise is normally not limited by breathing and athletes may have breathing reserves (MVV-V̇ E divided by MVV x 100) close to zero. The maximum voluntary ventilation (MVV) is usually calculated indirectly as forced expiratory volume in 1 second (FEV1 ) × 40 before the exercise test. 7 Elite athletes demonstrate (highly efficient) low values for V̇ E/V̇ O2 and V̇ E/ V̇ CO2 (relative hypoventilation) with consecutive PETCO2 increases during exercise.

Conclusion

The benefit of performing CPET is that it provides a thorough assessment of the integrative global physiological response to exercise. CPET requires a sound understanding and knowledge of exercise physiology and pulmonary gas exchange. Assessments of pulmonary gas exchange, in particular, are fundamental to the understanding of the pathophysiology of exercise limitation and go far beyond simple measurements of V̇ O₂ peak or V̇ O₂ max. This is because they also provide a physiological link with ventilation-perfusion matching (e.g, ventilatory efficiency as determined by V̇ E/V̇ CO₂). Considering that the first gas exchange threshold (=AT) and the prognostic V̇ E/V̇ CO₂ relationship are determined at submaximal levels of exercise increases, CPET can also be applied in elderly or unfit individuals who may be unable to provide maximal effort. It is important to ensure that CPET findings are not interpreted in isolation and instead take the individual clinical and (patho)physiological context into account.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

TG was responsible for the conception of the manuscript including figure and tables and wrote the initial draft manuscript. CT contributed to write and review the draft manuscript. Both authors were responsible for the decision to publish the manuscript.

Funding

The authors declare that they have received non-financial support from Chiesi GmbH, Hamburg, Germany, for the graphic implementation of figure 1 by an expert agency. The funding source was not involved in the writing of the manuscript or in the decision to submit the article for publication. The authors have not been paid to write this article by a pharmaceutical company or other agency.

Acknowledgment

We would like to thank Chiesi GmbH, Hamburg, Germany, for their support of graphic implementation of figure 1 provided by the agency “gemeinsam werben”, Hamburg, Germany. We also thank Nicola Ryan for linguistic review of the manuscript.

References

1. Ross R, Blair SN, Arena R, Church TS, Després JP, et al. (2016)Importance of assessing cardiorespiratory fitness in clinical practice: Acase for fitness as a clinical vital sign. A scientific statement from the American Heart Association. Circulation 134: e653-e699.
2. Sietsema KE, Sue DY, Stringer WW, Ward SA (2021) Wasserman & Whipp’s principles of exercise testing and interpretation. 6th ed.Philadelphia: Wolters Kluwer.
3. Guazzi M, Adams V, Conraads V, Halle M, Mezzani A, et al. (2012) EACPR/AHA Scientific Statement. Clinical recommendations forcardiopulmonary exercise testing data assessment in specific patient Circulation 126: 2261–2274.
4. Guazzi M, Arena R, Halle M, Piepoli MF, Myers J, et al. (2016) 2016 Focused update: Clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations. Circulation 133: e694-771.
5. Datta D, Normandin E, Zuwallack R (2015) Cardiopulmonary exercise testing in the assessment of exertional dyspnea. Ann Thoracic Med 10: 77-86.
6. Laveneziana P, Di Paolo M, Palange P (2021) The clinical value of cardiopulmonary exercise testing in the modern era. Eur Respir Rev 30: 200187.
7. Radtke T, Crook S, Kaltsakas G, Louvaris Z, Berton D, et al. (2019) ERS statement on standardization of cardiopulmonary exercise testing in chronic lung diseases. Eur Respir Rev 28: 180101.
8. Löllgen H, Leyk D Exercise Testing in Sports Medicine (2018) Dtsch Arztebl Int 115: 409-416.
9. Older PO, Levett DZH (2017) Cardiopulmonary exercise testing and Ann Am Thorac Soc 14(Suppl. 01): S74-S83.
10. Phillips DB, Collins SÉ, Stickland MK (2020) Measurement and Interpretation of Exercise Ventilatory Efficiency. Front Physiol 11: 659.
11. Glaab T, Taube C (2022) Practical guide to cardiopulmonary exercise testing in adults. Respir Res 23: 9.
12. Pritchard A, Burns P, Correia J, Jamieson P, Moxon P, et al. (2021) ARTP statement on cardiopulmonary exercise testing 2021. BMJOpen Respir Res 8: e001121.
13. Chambers DJ, Wisely NA (2019) Cardiopulmonary exercise testing - a beginner’s guide to the nine-panel plot. BJA Educ 19: 158-164.
14. Westhoff M, Rühle KH, Greiwing A, Schomaker R, Eschenbacher H, et al. (2013) [Positional paper of the German working group “cardiopulmonary exercise testing” to ventilatory and metabolic (lactate) thresholds]. Dtsch Med Wochenschr 138: 275-80.
15. Mazaheri, R, Schmied C, Niederseer D, Guazzi M (2021) Cardiopulmonary exercise test parameters in athletic population: A J Clin Med 10: 5073.
16. Petek BJ, Gustus SK, Wasfy MM (2021) Cardiopulmonary exercise testing in athletes: Expect the unexpected. Curr Treat Options Cardiovasc Med 23: 49.
17. Wells GD, Norris SR (2009) Assessment of physiological capacities of elite athletes & respiratory limitations to exercise performance. Paediatr Respir Rev 10: 91-8. »