“It is likely that no test in medicine is as informative and cost-effective as cardiopulmonary exercise testing for distinguishing among the broad spectrum of disorders causing symptoms of exercise intolerance. Without it, the evaluation of patients with exercise intolerance may be too narrowly focused by the physician’s particular subspecialty.” (Preface Wasserman & Whipp’s Principles of Exercise Testing and Interpretation, 6th. edn. [1]).
Cardiopulmonary exercise testing (CPET) is a maximal exercise test with concomitant gas exchange analysis that provides an integrative and comprehensive assessment of physiologic responses to exercise and cardiorespiratory fitness. In contrast to exercise ECG, the direct noninvasive determination of minute ventilation, heart rate and expired gases analysis (oxygen uptake and carbon dioxide output) at rest and during exercise provides accurate and reproducible data on the interaction of ventilation, gas exchange, and cardiovascular and musculoskeletal function, and enables determination of deviations from normal.
Use of CPET detects abnormalities in the functional capacity of these organ systems that are amplified or are only present during exercise (e.g., coronary arterial disease [CAD], right-to-left shunt [R-L shunt]) and helps to define the pathophysiology of exercise limitation. It is important to note that patient report of symptoms or stated levels of exercise intolerance correlate only modestly with resting functional and imaging tests [1,2,3]. As a result, CPET can be particularly valuable in identifying the source of exercise intolerance, monitoring disease progression, evaluating treatment responsiveness and providing information about prognosis.
There are many indications for CPET. The most common of these include [1, 4,5,6,7,8,9,10,11,12]:
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determining the cause(s) and severity of exertional dyspnoea, exercise intolerance or exercise-induced hypoxaemia;
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assessing exercise capacity and estimating prognosis in various disease states (including chronic heart failure);
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assessing perisurgical and postsurgical complication risk (e.g., for thoracic, heart and visceral surgery; surgical and bronchoscopic lung volume reduction);
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early detection and risk stratification of cardiovascular, pulmonary vascular and lung diseases, and musculoskeletal disorders;
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measuring the response to treatment (e.g., drugs, rehabilitation);
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guiding and monitoring individual physical training in rehabilitation (e.g., cardiac, pulmonary), and in preventive and sports medicine;
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evaluating the limitations/impairments of individual maximum and continuous exercise capacity in occupational medicine.
The absolute contraindications to CPET are consistent with those of exercise ECG [1, 3, 5, 8]. Recommendations for CPET during endemic, epidemic and pandemic health conditions such as COVID-19 have recently been issued [13, 14].
The objective of this practical introduction is to describe the basic principles of exercise physiology and provide an easy-to-follow approach for those primarily interested in learning how to conduct, analyse and interpret CPET in their clinical practice. For further information, reference is given to the literature [3, 5,6,7, 10, 11, 15,16,17,18,19,20] and the updated reference work [1].
Understanding exercise physiology
The transport of oxygen to body tissues depends largely on cardiac output, haemoglobin (Hb) concentration, Hb oxygen saturation, arterial vascular tone and the density of the capillary network.
A basic working knowledge of exercise (patho)physiology and gas exchange is fundamental to understanding the pathophysiology of exercise intolerance and to the proper analysis and interpretation of CPET. Figure1 illustrates characteristic alterations of key physiological parameters as exercise work rate is increased.
Ventilation/perfusion mismatching
The ratio of ventilation (V) to perfusion (Q) is decisive for the quality of the gas exchange in the lungs. Pronounced ventilation/perfusion mismatch (V/Q) occurs in pulmonary disease, pulmonary vascular disorders and heart failure [21, 22]. Therefore, gas exchange measurements are central to the understanding of the pathophysiology of exercise limitation.
Due to gravity, at rest there is a small gradient in ventilation and a much more pronounced gradient in perfusion from the apex to the bottom of the lung in the upright position (e.g., V/Q drops from the apex [high V/Q] to the bottom) and renders gas exchange ineffective. During exercise, these V/Q heterogeneities diminish, because the upper lung segments are now well ventilated and perfused through deep inhalation, vascular dilation and recruitment of previously closed capillaries. The result is an enlarged gas exchange area. In principle, two kinds of ventilation/perfusion disturbances reflecting true ventilatory inefficiency can be distinguished, and these often overlap:
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low V/Q regions (incomplete ventilation disorder; shunt effect). The ventilation to perfusion ratio decreases in subventilated but normally perfused alveoli (relative hypoventilation). Examples include chronic obstructive lung diseases (COPD) and restrictive lung diseases (pulmonary fibrosis). As a net effect, hypoxaemia occurs as a result of venous admixture, which cannot be compensated for by hyperventilation, resulting in an increase of P(A-a) O2. Elevated PaCO2 is usually prevented by hyperventilation in other lung areas. The different effects on PaO2 and PaCO2 are attributable to the different dissociation curves of O2 (sigmoidal form of the O2 dissociation curve) and CO2 (linear form of the CO2 dissociation curve). Hypoxic pulmonary vasoconstriction is one mechanism to redistribute perfusion to better oxygenated regions and thus limit the extent of hypoxaemia.
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high V/Q regions (incomplete distribution disorder; increased dead-space ventilation [VD/VT↑]). In normally ventilated but poorly perfused alveoli (relative hyperventilation), the V/Q ratio increases (dead-space effect). Examples include pulmonary emphysema (compression effects due to hyperinflation, reduced capillary bed), chronic heart failure, primary or secondary pulmonary vascular disease, and restrictive lung disease (e.g., interstitial lung disease [ILD] with reduced capillary bed). Overall, high V/Q mismatch usually has only a minor effect on arterial blood gases (more on CO2 than on O2 due to impaired release of CO2 to the alveoli), resulting in increased P(a-ET)CO2, because other lung areas are overventilated in a compensatory manner.
The two extreme variants (V/Q = 0 [complete ventilation disorder; e.g., atelectasis, pneumonia] and V/Q = ∞ [complete perfusion disorder, e.g., acute pulmonary embolism]) do not play a practical role in CPET, because the clinical situation usually precludes exercise testing. Note: V/Q mismatch primarily affects PaO2 because changes in PaCO2 are usually well compensated by hyperventilation in patients with maintained breathing reserve.
Performing CPET
CPETis typically performed using acycle ergometer or treadmill [1, 3, 5, 11]. The cycle ergometer is generally safer, is more appropriate for a wide range of patients (e.g., deconditioning, obesity, joint issues), enables more convenient intra-test procedures (monitoring of ECG and blood pressure, blood sampling) and provides an accurate measurement of external work rate. Treadmill ergometry allows subjects to walk or run at measured speeds and grades of incline. The treadmill activates more muscle groups, elicits greater oxygen desaturation and produces higher levels of peak oxygen uptake. In most clinical circ*mstances, cycle ergometry is the preferable mode of exercise; however, depending on the reason for which CPET is requested, treadmill ergometry may be a suitable alternative [1–3]. Prior to CPET, a precise medical history (pre-existing and concomitant diseases, pacemaker/defibrillator, medications, stimulants, patient activity), clinical examination, basic cardiopulmonary diagnostics (chest X-ray, ECG, blood pressure, body temperature, lung function, TLCO) and laboratory results (e.g., blood count, glucose, creatinine, thyroid-stimulating hormone, blood gas analysis [BGA]) should be available. This facilitates subsequent interpretation and individual risk assessment. Although CPET is considered a safe examination, cardiac emergencies, hypoxaemia and vasovagal/orthostatic syncope can occur. Therefore, qualified staff must be regularly trained for emergency management. A trained physician should be present during testing, at least when at-risk patients are being assessed [23].
CPET is usually performed as symptom-limited cycle ergometry in a sitting position. A continuously incrementing ramp protocol (increase of work rate, e.g., every 2–15s) or minute-by-minute increments in 5–30W/min steps to symptom-limited maximum of exercise is used as standard. This offers the advantage of a short protocol with low initial work rate and a brief duration of high-intensity cardiopulmonary exercise.
According to current recommendations [1, 6, 10, 11, 24], the CPET procedure is divided into four parts:
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Resting phase (2–3min): adaptation of respiration to the mask or mouthpiece including measurements of capillary BGA, ECG and blood pressure.
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Unloaded phase (“active baseline”; 2–3min): unloaded cycling with no added resistance (internal work rate depending on equipment: 0–15 watts), cadence 55–70 revolutions per min (rpm). \({\dot{\text{V}}\text{O}}_{2}\) normally doubles during this warm-up phase.
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Incremental exercise phase (10 ± 2min): cadence 55–70rpm.
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Recovery phase (cool down period; 3–5min): unloaded pedalling.
Note: unloaded cycling (warm-up) before exercise represents the real cardiopulmonary and metabolic baseline, and should be viewed as an obligatory part of CPET for all patients. Adherence to these guideline recommendations will clearly facilitate standardisation and comparability of CPET results.
Standards of CPET measurement
Standardised examination procedures as outlined in the recent European Respiratory Society statement on standardisation of CPET in chronic lung diseases contribute very significantly to the data quality and the comparability of measurement results [24]. In that context, quality control, specific training and experience of the qualified staff is essential [23].
To obtain conclusive data, patients must be informed about the procedure (including communication by hand signals during the exercise) and encouraged to apply their full effort [25]. On the day of testing, the patient should take his/her usual medications, wear comfortable sportswear/athletic footwear and have eaten their last light meal at least 2–3h before the investigation. In addition, the patient should be clinically stable, free of infection and avoid smoking or vaping, intensive sports, and alcohol for 24h before the examination.
After ensuring the equipment is calibrated and working correctly, the mask (or mouthpiece) and cycle ergometer is attached to the subject, who is then connected to the monitoring equipment. A representative spirometry provides the foundation for determining the maximum voluntary ventilation. After selecting the appropriate incremental ramp protocol, the patient should pedal with a constant cadence (approximately 55–70rpm). Stopping rules are consistent with those of exercise ECG. At the end of the exercise test, assessment of dyspnoea and leg effort is recorded using a modified Borg CR 10® scale, and the cause(s) of termination are documented.
During CPET, the O2 and CO2 concentrations of exhaled air and minute ventilation (\({\dot{\text{V}}\text{E}}\)) (tidal volume × breathing frequency) are continuously measured via the face-mask (or mouthpiece) with connected gas and flow (or volume) sensors. From these measurements and exercise test monitoring (heart rate and work rate), several key variables can be derived (Figs.1, 2, 3 and 4).
The data are collected for each individual breath (single breath analysis), averaged over 8–10 breaths (rolling averages) or averaged over a fixed period of 10–30s and graphically displayed as a tabular summary and a 9-panel graphical array. The graphical display, parameter selection and scaling are preconfigured and can be adapted to investigator requirements with the support of the manufacturer. A number of formatting conventions regarding the 9-panel plots have been proposed to improve the clarity, reproducibility, interpretation and comparability of CPET results [28]. For reference values [29], we prefer to use the equations from the SHIP cohort [30] or, alternatively, the similar values from Hansen/Wasserman [31].
In addition, capillary BGA [time points: at rest, sub-maximum exercise (in the range of AT), peak exercise, end of recovery (e.g., 2min post-exercise)] from a hyperaemic earlobe by trained staff is recommended to quantify the amount of potential V/Q mismatch [determination of P(A-a) O2 and of P(a-ET) CO2]. This is in line with current practice and recent recommendations de-emphasising the need for arterial BGA samples for CPET in non-hypoxaemic patients [1, 32]. However, differences between capillary and arterial PO2 (usually in the range of 5–10mm Hg) in patients with oxygen saturation (SpO2) > 90% should be kept in mind.
Selection of the individual work rate
Incremental exercise should ideally last for 10 ± 2min, or for at least 5min in severely restricted patients. The selection of a work rate increment that is too rapid (ramp too steep) should be avoided because this is often associated with marked hyperventilation, an inability to determine AT and premature termination of exercise due to lactate acidosis. Thus, selecting a work rate increase of 5 watts/min in significantly impaired patients might be worth considering.
There are several options when selecting the total workload (watts) and rate of work rate increase (watts/min). Basically, a simple orientation on exercise capacity in everyday life has proven to be useful and pragmatic: the staircase question (e.g., how many floors can you walk up quickly without stopping? [11, 33]. Responses can inform CPET ramp modifications as follows:
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One floor is equivalent to approximately 50 watts (≈5W/min for a 10-min test) and corresponds to easy hiking, playing golf, etc. For patients with severe cardiac and/or lung disease, 50 watts may represent their maximum exercise capacity, therefore, assign a work rate increment of 5W/min to achieve a 10-min test.
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Two floors is equivalent to approximately 100 watts, corresponding to “Nordic Walking”, cycling on a flat track, gardening etc. Suggested work rate increment is 10W/min.
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Three floors is equivalent to approximately 125–150 watts, corresponding to swimming, mountain hiking, etc. Suggested work rate increment is 15W/min.
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Four floors is equivalent to approximately 200 watts (similar to running at ≥ 10km/h). Suggested work rate increment is 20W/min.
Alternatively, other work rate increment estimates have been proposed in the literature [1, 24].
Validity check
A validity check is mandatory to detect and correct equipment malfunctions before and during CPET (e.g., mask leakage, defect or drift of the gas analysers). A simple validity check can be limited to the following considerations [11]:
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Adequate minute ventilation? Implausible if the increase of \({\dot{\text{V}}\text{E}}\) does not follow an increase in work rate (mask leakage, anxiety, poor effort?). For rapid estimation of an adequate \({\dot{\text{V}}\text{E}}\) relative to work rate we suggest using the 9-point rule described by Rühle [11]: each 25W increase in work rate requires 9 L of \({\dot{\text{V}}\text{E}}\) plus 9 L of \({\dot{\text{V}}\text{E}}\) at rest. Example: a total work rate of 100W (4 × 25) requires a \({\dot{\text{V}}\text{E}}\) of 4 × 9 L + 9 L (at rest) = 45 L/min.
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Adequate \({\dot{\text{V}}\text{O}}_{2}\) increase for a given work rate (\({\dot{\text{V}}\text{O}}_{2}\) increase/WR)? Implausible if the increase during early exercise (first 1–2min) is too low (e.g., mask leakage). The actual value can be read online on the screen. Rule of thumb: \({\dot{\text{V}}\text{O}}_{2}\) increase/WR ≥ 10mL/min/watt. A value of 5–6mL/min/kg is suitable as a plausibility check at rest for \({\dot{\text{V}}\text{O}}_{2}\) (rule of thumb).
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Adequate respiratory exchange rate (RER)? Implausible if RER at rest is < 0.7 or RER at early exercise is > 1 (volitional or anticipatory hyperventilation, gas analyser malfunction, clogged sample tube, mask leakage).
Possible solutions: follow the manufacturer’s instructions for the warm-up period of the measuring equipment, repeat calibration, check gas cartridge, exchange (mask, measuring sensors, sample tube). Relevant artefacts also occur if the marked termination of the incremental exercise period in the software does not match the actual end of active exercise on the ergometer. Another common error is a faulty capillary BGA sample (erroneous blood sample extraction or analysis, missing or incorrect marking or incorrect order of the BGA entries in the software program).
Adequate patient effort
Parameters such as end-exercise values of RER ≥ 1.05 (ill person) or ≥ 1.1 (healthy people), exceeding the \({\dot{\text{V}}\text{O}}_{2}\) at anaerobic threshold (AT) and coming close to the maximal predicted values of \({\dot{\text{V}}\text{O}}_{2}\) peak, heart rate and \({\dot{\text{V}}\text{E}}\) (and/or \({\dot{\text{V}}\text{E}}\)/\({\dot{\text{V}}\text{O}}_{2}\) > 30–35) suggest sufficient patient effort. Importantly, CPET should not be stopped when these criteria are met.
Analysing the 9-panel plot array
The analysis and interpretation of CPET results requires the basic knowledge of exercise physiology along with a structured approach. Regarding exercise capacity/performance, the maximum achieved exercise performance (\({\dot{\text{V}}\text{O}}_{2}\) peak = highest oxygen uptake upon discontinuation of exercise) is more relevant than the maximum attainable exercise capacity (\({\dot{\text{V}}\text{O}}_{2}\) max), which is the domain of sports medicine.
Key variables and their interrelationships are systematically summarised in the 9-panel display of Wasserman et al. [26]. The plot enables a reliable, structured interpretation and a feasible distribution of test results. In 2012, Wasserman et al. rearranged the original 9-panel display, with identical content, for didactic reasons [34]. However, the updated display has not yet become generally established, so we will refer to both versions.
The primary objective of the interpretation is to determine whether and to what extent there is impaired exercise capacity and what cause(s) of cardiovascular, pulmonary vascular or pulmonary origin may be primary.
It has proven useful to analyse the 9-panel display in a systematic order across the entire period of testing (at rest, exercise and recovery) [1, 3, 11, 19, 20]. Information on the cardiovascular response and oxygen transport is reflected in panels 1 → 2 → 3 (original version: panels 3 → 2 → 5).
Information on pulmonary gas exchange and V/Q mismatch can be found in panels 4 → 6 → 7 (original version: panels 6 → 4 → 9). A possible limitation of ventilatory capacity is shown in panels 5 → 8 → 9 (original version: panels 1 → 8 → 7).
In view of the large number of CPET variables (approximately 150), the reduction to a few clinically meaningful key variables is truly remarkable and also enables non-specialists to perform a structured analysis and interpretation using the 9-panel display.
In Figs.2, 3 and 4, we describe the individual panels in the above-mentioned sequential order using the example of a normal finding in a healthy 44-year-old man who performed cycle ergometry with an incremental ramp protocol. The panels thus reflect the physiological changes during exercise as summarised in Fig.1. The individual panels contain additionalinformation on the key variables, suggestions for structured analysis and embedded examples of possible abnormal reaction patterns.
Determination of the anaerobic threshold (AT)
Measurement of the AT allows the objective assessment of aerobic metabolism at submaximal exercise levels. It can be automatically calculated by computer programme but needs to be cross-checked. A low AT indicates impaired cardiovascular transport of oxygen or poor muscular oxygen utilisation. By combining several methods (so-called 3- panel view (panels 3, 4, 7 [original version: panels 5, 6, 9]), AT can be determined in most cases and excludes non-physiologic hyperventilation as the origin of the V-slope inflection point [12]. Valid determination of AT is not always possible, as has been shown for very severe respiratory limitations (COPD, ILD) or significant heart failure when ventilation and/or perfusion can no longer be adequately increased in response to increasing exercise. Other reasons include an excessively steep/mild incremental ramp protocol or performance-reducing factors such as arthrosis, peripheral arterial disease or poor effort. We have not considered the second gas exchange threshold [respiratory compensation point (RCP)] due to its relatively low clinical worth.
Table 1 summarises normal and abnormal values of some central CPET parameters, knowledge of which can be useful for data interpretation. The values are meant for orientation only, because no generally accepted target values have been yet established.
Interpretation of CPET results
Exercise capacity in healthy subjects is normally limited by the heart or the musculoskeletal system. In patients complaining of exercise intolerance, a CPET can often reveal the primary source of exercise limitation that, together with the results from clinical history (including neurological disorders [autonomic dysfunction]) and resting functional diagnostics can narrow down a broad differential diagnosis and diagnostic options.
Table 2 shows an example of a CPET interpretation worksheet that can guide structured interpretation of the data and determine the primary pattern of exercise limitation (e.g., cardiocirculatory, pulmonary vascular, pulmonary, deconditioning).
The worksheet approach is certainly not the only primer for a physiologically-based interpretation of exercise intolerance (e.g., see structured flowchart approach [1]), but offers the advantage that in most cases it can help clarify which is/are the primary pattern(s) of exercise limitation [20]. As illustrated in Table 2, a statement can be made from the sum of individual findings for each category. In addition, overlaps can occur between the categories, but usually a clear distinction can be made as to which of the categories—cardiac, pulmonary vascular or pulmonary—is dominant and whether there is evidence of secondary effects (e.g., pulmonary hypertension) or coexistent disease that may affect outcomes. Consequently, this analysis might lead to unexpected previously unknown causes of exercise intolerance that cannot be determined without CPET. Finally, CPET may also be useful in confirming normal findings that make significant disease unlikely.
It is also important to note that an individual with normal peak \({\dot{\text{V}}\text{O}}_{2}\) may still have exercise limitation caused by deconditioning, obesity, anxiety or early/mild cardiopulmonary disease. Other confounding factors such as anaemia, thyroid function or acid–base disorders should be investigated before the examination.
Exercise ECG and blood pressure
During the entire examination, attention must be paid to abnormalities in blood pressure and ECG (ST changes, arrhythmias, ectopic beats and block patterns).
CPET reporting
Suggestions for a CPET report have been described in the literature [1, 5,6,7, 24]. The possibilities of computer-assisted report generation are often underutilised, but this would be likely to improve the necessary timeframe, the interpretation and quality of the test report.
Intrabreath curves (IC manoeuvre)
The non-standardised registration of intrabreath or inspiratory capacity (IC) manoeuvres during exercise (times of measurement: at rest, at moderate exercise (before AT), at peak exercise) can provide additional information about respiratory mechanics (dynamic hyperinflation, expiratory flow limitation) in condition-specific cases (e.g., obstructive lung disease, pulmonary vascular disorders) [2, 7, 11, 35].The IC manoeuvre should not be confused with that of exercise-induced bronchoconstriction [36].