Exercise testing - Respiratory Medicine (2013)

Paolo Palange and Paolo Onorati The ability to exercise largely depends on the integrated physiological responses of the respiratory, cardiovascular and skeletal muscle systems. In healthy individuals, exercise tolerance is influenced by age, gender and level of fitness. In patients with lung diseases, exercise tolerance is typically reduced and limited by symptoms such as dyspnoea and leg fatigue.

Cardiopulmonary exercise testing (CPET), i.e. the study of ventilatory, cardiovascular and pulmonary gas exchange variables during symptom-limited incremental exercise, is considered the gold standard for evaluating the degree and causes of exercise intolerance in disease states (table 1).

Moreover, CPET has been extensively used in patients with COPD, CF, interstitial lung diseases (ILDs), pulmonary vascular disorders (PVDs) and CHF.

N

In COPD and CF, exercise tolerance is mainly limited by pulmonary mechanical

abnormalities (e.g. reduction in venti-latory capacity, dynamic hyperinflation)

N

In ILD, exercise tolerance is limited by ventilatory constraints and pulmonary gas exchange abnormalities (e.g. arterial oxygen desaturation).

N

In PVD and CHF, both circulatory (e.g.

reduced adaptation in cardiac output) and pulmonary gas exchange abnormalities contribute to exercise intolerance.

Exercise protocols

Maximal incremental test The symptom-limited maximal incremental exercise protocol is recommended as a first step in the evaluation of exercise tolerance.V9E, heart rate, oxygen uptake (V9O2), carbon dioxide production (V9CO2), and end-tidal oxygen and carbon dioxide tensions are the primary variables measured, typically on a breath-by-breath basis using computerised systems. Additional required measurements include ECG, blood pressure, dyspnoea, leg discomfort, exercise-related arterial oxygen desaturation and spirometry with flow–

volume loop recording. Careful selection of patients minimises the likelihood of serious complications during maximal incremental exercise testing. Myocardial infarction (within 3–5 days), unstable angina, severe arrhythmias, pulmonary embolism, dissecting aneurism and severe aortic stenosis represent absolute

contraindications to CPET. Resting lung function measurements and ECG are usually obtained before CPET. Cycle and treadmill exercise have been used interchangeably, although the former is largely used as the work rate for incremental and endurance tests is easier to quantify. As the exercise Key points

CPET is considered the gold standard for:

N

an objective measure of exercise capacity,

N

identifying the mechanisms limiting exercise intolerance,

N

establishing indices of the patient’s prognosis,

N

evaluating the effects of therapeutic interventions.

period should last 10–12 min, the work rate increment should be selected carefully. In patients with lung diseases, the usual rate of workload increase is 10 W?min^-1, although slower or faster rates are possible in the very sick and in fitter patients, respectively. The maximal incremental exercise test is also used to determine the appropriate work rate for an endurance protocol.

Constant work rate (CWR) tests, on a cycle ergometer or on a treadmill, are used for the measurement of exercise ‘endurance’

tolerance and ventilatory and pulmonary gas exchange kinetics. CWR exercise results in steady-state responses when work rate is of moderate intensity (i.e. below the lactate threshold (hL); conversely, high-intensity CWR exercise (i.e. above hL) results in steady states either being delayed or not attained at all.

Walking tests, such as the 6-min walking test, have been increasingly used for the assessment of exercise tolerance in chronic lung diseases. The object of this test is to walk as far as possible in 6 min. The test should be performed indoors along a 30-m flat, straight corridor; encouragement significantly increases the distance walked.

Measurements ofSpO2, heart rate and exertional symptoms are recommended during this test.

Indications for CPET

In patients with lung diseases, exercise testing is mainly used for functional and prognostic purposes. Other indications include: detection of exercise-induced bronchocontriction; selection of candidates

for surgery, including lung transplant; and evaluation of the effects of therapeutic intervention, including pulmonary rehabilitation.

Exercise variables and indexes Maximal V9O2 The classical criterion for defining exercise intolerance and classifying degrees of impairment is the maximal oxygen uptake (V9O₂max). With good subject effort on an incremental test,V9O2max reflects a subject’s maximal aerobic capacity. This index is taken to reflect the attainment of a limitation in the oxygen conductance pathway from the lungs to the mitochondria. Values ,80% predicted are considered abnormal while values ,40%

predicted indicate severe impairment.

Lactate threshold hLis the highestV9O2at which the arterial lactate concentration is not systematically increased, and is estimated using an incremental test. It is considered an important functional demarcator of exercise intensity. Sub-hL work rates can normally be sustained for prolonged periods. hLis dependent on age, sex, body mass and fitness. Noninvasive estimation of hLrequires the demonstration of an augmentedV9CO2in excess of that produced by aerobic metabolism, and its associated ventilatory sequelae.

Oxygen pulse The oxygen pulse is the product of the stroke volume and the difference between the arterial oxygen content (CaO2) and the mixed venous oxygen content (CvO2). Given the Fick equation

V9O25cardiac output6(CaO2-CvO2) the oxygen pulse can be calculated as:

Oxygen pulse5V9O2/heart rate In patients with ILD, the oxygen pulse at peak exercise is lower and its rate of increase with increasing work rate is usually reduced because of the reductions in stroke volume andCaO2. In PVD, the oxygen pulse is characteristically low at peak exercise and may not increase during incremental exercise, reflecting the abnormal cardiac output adaptation.

Table 1. Some causes of exercise intolerance in lung diseases

Ventilatory limitation to exercise Dynamic hyperinflation Increased work of breathing

Pulmonary gas exchange abnormalities Excessive perception of symptoms Impaired cardiovascular response to

exercise and reduced oxygen delivery Peripheral muscle weakness/dysfunction

Heart rate reserve (HRR) The peak heart rate (HRpeak) achieved in a symptom-limited exercise test decreases with age. The most commonly used equation to predict HRpeakis

HRpeak,pred5200-age HRR is defined as the difference between HRpeak,predand HRpeak. In healthy individuals, HHR is virtually zero; a high HRR is usually observed in patients with COPD, CF and ILD.

V9E–V9^CO2slope and ventilatory equivalent for carbon dioxide It is conventional to express the ventilatory response to exercise relative toV9CO2. It can be measured as the slope of theV9E–V9CO2relationship (DV9E/DV9CO2) over its linear region,i.e. typically extending from ‘unloaded pedalling’ to the respiratory compensation point. In normal individuals, DV9^E/DV9CO₂values of around 23–25 have been reported.

The adequacy of the ventilatory response to exercise is also expressed by the ratio V9E/V9CO2that represents the litres of ventilation necessary to clear 1 L of carbon dioxide. Up to the respiratory

compensation point,V9E/V9CO2declines curvilinearly as work rate increases. It is common practice to record the value at hL(V9E/V9CO2@hL) or the minimum value.

These have each been proposed to provide noninvasive indices of ventilatory inefficiency. In normal individuals, V9E/V9CO2@hLvalues of 25–28 have been reported. Several factors may increase DV9E/DV9CO2andV9E/V9CO2@hL, such as hypoxaemia, acidosis, increased levels of wasted ventilation and pulmonary hypertension.

Breathing reserve (BR) provides an index of the proximity of the ventilation at the limit of tolerance (V9Emax) to the maximal voluntary ventilation (MVV):

MVV5resting FEV1640

BR can be defined asV9Emaxas a percentage of MVV:

BR51-V9Emax/MVV

In COPD, CF and ILD, BR is usually reduced or absent at peak CPET exercise (fig. 1).

Analysis of flow–volume loops is also emerging as an important tool to assess the degree of airflow and ventilatory limitation during exercise in patients with COPD.

Dynamic hyperinflation In normal subjects, end-expiratory lung volume (EELV) decreases with increasing work rate by as much as 0.5–1.0 L below functional residual capacity. Changes in EELV during exercise can be estimated by asking the subject to perform an inspiratory capacity manoeuvre at a selected point in the exercise test. In COPD, particularly in the advanced phases of the disease, EELV increases during exercise (i.e. dynamic hyperinflation) in spite of expiratory muscle activity.

Arterial oxygen desaturation During exercise, S^pO2is normally maintained in the region of around 97–98%. However, arterial oxygen desaturation can be observed in patients with moderate–severe ILD and in patients with primary pulmonary hypertension.

Tolerable limit of exercise and ‘isotime’

measurements Tlimis the tolerable limit of exercise, expressed as function of time measured during CWR protocols. In clinical practice, high-intensity (around 70–80% of maximal work rate) CWR protocols are used for the evaluation of interventions. In

V'E

Figure 1. Ventilatory response and limitation to exercise. Ventilatory limitation to exercise is typically observed in patients with COPD compared with normal subjects. In COPD, but also in CF and ILD, ventilatory reserve is reduced at peak exercise. See the main text for further comments.

addition to Tlim, measurement of pertinent physiological variables (e.g. V9E, inspiratory capacity and dyspnoea) at a standardised time (isotime) are obtained.

CPET response patterns

Ventilatory Response In normal individuals during incremental exercise,V9Eincreases linearly relative to work rate orV9O₂. At some point,V9Ebegins to increase more steeply in response to the development of lactic acidosis, to maintain acid–base homeostasis (normal individual in fig. 1).

The ventilatory response to exercise in patients with lung disorders is increased (COPD patient in fig. 1). Conventionally, the ratio ofV9Eat peak exercise to the estimated MVV represents the assessment of the ventilatory limitation or of the prevailing ventilatory constraints. Ventilatory limitation is commonly judged to occur whenV9E/MVV exceeds 85%. In lung diseases, the increase inV9^E/MVV may reflect a reduction in MVV or an increase inV9^E. The ventilatory response during exercise is influenced by metabolic rate (V9CO₂),PaCO₂and the physiological dead space fraction of the tidal volume (VD/VT). The relationship between these variables is described as:

V9E5(8636V9CO2)/(PaCO26(1-VD/VT)) wherePaCO2is expressed in Torr. In lung diseases, for a givenV9CO2andPaCO2,V9Eis usually increased because of a higherVD/VT. DV9E/DV9CO2orV9E/V9CO2@hLis often used in the functional assessment of patients with lung diseases (e.g. COPD, ILD and PVD) and cardiovascular disorders (e.g. CHF). V9E/ V9CO2is usually increased, particularly in patients with PVD (fig. 2). Another particular behaviour of theV9Eresponse during exercise is the cyclic fluctuation ofV9Eand expired gas kinetics, also defined as exertional oscillatory ventilation, which can occur in approximately one-third of patients with CHF. While the origin of such a ventilatory abnormality is still controversial, its clinical relevance in terms of a negative prognosis is well established.

Pulmonary gas exchange The efficiency of pulmonary gas exchange can be assessed by studying the magnitude of alveolar–arterial oxygen tension difference (PA–aO2) at rest

and during exercise. Normally,P^aO2does not decrease during exercise andPA–aO2at peak exercise usually remains below 20–30 Torr. In most patients with ILD and PVD, pulmonary gas exchange efficiency is impaired, as indicated by an abnormally largePA–aO2(.30 Torr) at peak exercise accompanied by arterial oxygen

desaturation. These changes reflect regional ventilation–perfusion ratio dispersion and alterations in pulmonary capillary transit time resulting from the recruited pulmonary capillary volume becoming inadequate for the high levels of pulmonary blood flow.

Cardiovascular response CPET has proved very useful in the detection and quantification of cardiovascular abnormalities during exercise. The characteristic findings are a reduced V9O2max, reduced hL, steeper heart rate–V9O2

relationship (with a reduced heart rate reserve at peak exercise) and a shallower profile (or even flattening) of the oxygen pulse increase with increasingV9O2. An abnormal cardiovascular response to exercise is observed in PVD and, in particular, in patients with idiopathic pulmonary arterial hypertension.

Exercise testing in prognostic evaluation Exercise tolerance is well recognised as a valuable predictor of mortality in healthy subjects. This also appears to be the case in chronic pulmonary diseases. Exercise testing has become an essential component

V'E

Normal PVD CHF, COPD

V'CO2

Figure 2. DV9E/DV9^CO2during exercise. Different DV9^E/DV9^CO2slopes are seen in normal subjects and in patients with PVD, COPD and CHF.

in the prognostic evaluation of patients with lung diseases (table 2).

Several studies have confirmed thatV9O2max is superior to other indexes in the risk stratification of patients with end-stage lung diseases; many centres, however, use field tests for prognostic purposes.

Evaluating the effects of therapeutic interventions

High-intensity (75–80% of peak work rate) endurance CWR protocols performed on a cycle ergometer or treadmill to Tlimhave been successfully used in COPD patients for the evaluation of the effects of therapeutic interventions (e.g.

bronchodilators, oxygen, heliox and rehabilitation). These types of protocols have a greater power to discriminate therapy-induced changes in COPD patients, with a higher fractional improvement in exercise tolerance compared with incremental CPET.

However, it should be recognised that the hyperbolic profile of the relationship between the power output and exercise duration (Tlim) (the ‘power–duration curve’) during CWR tests is responsible for a considerable proportion of variability in the improvement magnitude of Tlim. That is, Tlimis influenced by the pre-intervention work rate and exercise duration and their relative positioning on the power–duration profile. Without knowledge of these aspects, any change in Tlimto a single CWR bout must be cautiously interpreted in terms of realistic physiological benefits obtained from the intervention.