Introduction
Sustained exercise requires tight integration of multiple physiologic systems including the cardiac, neuromuscular, and respiratory systems. Diseases affecting any of these systems can manifest as dyspnea or exercise limitation. In addition to other modalities commonly used in the assessment of patients with these complaints, cardiopulmonary exercise testing (CPET) provides a systematic means to assess exercise responses, unravel the different interacting components, and understand which system is contributing the most to the perceived limitation. Beyond this primary role, CPET has other important uses including (1) quantifying maximal exercise capacity and generating data that can be used to assess functional limitation, (2) prescribing appropriate rehabilitation and training regimens, and (3) guiding clinical decisions about fitness for planned procedures.
The goals of this chapter are to describe the application of CPET in clinical practice and assist the reader in understanding who would benefit from CPET and how it can be used to evaluate dyspnea and exercise limitation. Because CPET interpretation requires a solid understanding of the physiologic responses to exercise, the chapter begins with a review of exercise physiology that sets the foundation for the balance of the chapter. The review includes exercise responses in normal individuals and those with various forms of cardiopulmonary disease, including heart failure, chronic obstructive pulmonary disease (COPD), pulmonary vascular disease, interstitial lung diseases (ILDs), and adult congenital heart disease. The chapter then describes the primary indications and contraindications of CPET, reviews the various options for conducting exercise tests, and presents an approach to test interpretation. It concludes by describing alternative modalities for assessing exercise responses that are used in clinical practice.
Physiologic Responses to Exercise
Exercise as a Multisystem Process
The ability to perform vigorous aerobic exercise requires tight integration of multiple systems. The respiratory system serves as a ventilatory pump to move oxygen (O 2 ) from the atmosphere to the alveoli, where it efficiently moves across the alveolar walls to bind to hemoglobin. The heart must then pump the oxygenated blood to the exercising muscles, which extract oxygen to support adenosine triphosphate generation and muscle contraction. Muscle activity leads to production of carbon dioxide (CO 2 ), which must be delivered by the circulatory system to the lungs, where it diffuses across the alveolar walls and is eliminated via the ventilatory pump. The nervous system contributes at multiple stages in this process, providing important signals to increase ventilation and drive muscular contraction. All of these systems work in a highly coordinated manner to support exercise, and problems in one or more of these systems may manifest as dyspnea or exercise limitation.
Normal Individuals
To appreciate changes in exercise performance associated with cardiopulmonary diseases, it is helpful to examine the normal physiologic responses to progressive exercise in four major areas—metabolic activity, hemodynamic responses, ventilatory responses, and gas exchange.
Metabolic Activity
Oxygen Consumption.
Of all the parameters followed in clinical exercise testing, oxygen consumption, denoted as 
(a volume per time, e.g., mL/min), is perhaps the most useful for assessing overall exercise capacity. In essence, 
is the amount of fuel consumed in conducting work; the bigger or better the motor, the greater the maximum fuel consumption. To understand its utility in this regard, consider the determinants of 
using the Fick equation:
= cardiac output (mL/min), Ca o 2 = arterial oxygen content (mL/dL), and 
= mixed venous oxygen content (mL/dL). Rearranging the relationship as follows, 
provides useful information about many of the systems necessary to perform sustained high-level exercise.In addition to providing a sense of overall exercise capacity, the maximum oxygen consumption ( 
) achieved during progressive exercise is particularly useful for assessing cardiac function. Given that the arteriovenous oxygen content difference at maximum exercise is largely the same in normal individuals and those with cardiac disease, the wide variation in 
across individuals is primarily determined by the variation in cardiac output. The greater the 
, the greater an individual’s cardiac output and vice versa.
Oxygen consumption can also be used to estimate stroke volume at maximum exercise. To understand this, equation (2) can be rewritten:
, referred to as the oxygen pulse or O 2 pulse, can be used as a surrogate marker for stroke volume. The expected changes in normal individuals for this parameter, as well as cardiac output, are described as follows.During progressive exercise to a symptom-limited maximum, 
increases linearly from resting values near 250 mL/min for an average-sized person until a plateau is reached at 
. If a plateau is not identified, the term 
is often applied instead to denote that it may not represent the individual’s potential maximum. In average sedentary individuals, 
is roughly 30 to 40 mL/kg/min at end-exercise, whereas fit athletes can attain values as high as 80 to 90 mL/kg/min. An individual’s 
is influenced by a variety of factors including age and gender, which are discussed further later. With intensive training, unfit subjects can increase 
by 15% to 25%, but it is not possible to raise 
from an average level to an elite level. What tends to improve with training is the efficiency of work and ability to sustain high levels of power output. Genetic factors also play an important role in determining an individual’s 
in the sedentary state, as well as in their response to training regimens. In clinical exercise testing, an individual’s 
is typically expressed in reference to what would be predicted for their age and gender on the basis of data from large population studies. Numerous reference values have been published, but methodologic issues limit the wide applicability of many of them. As with all reference values, the normal range is dependent on the population studied. For example, Hansen and colleagues used studies from ex-shipyard workers who tended to be primarily older men while Neder and colleagues randomly selected their subjects to include equal numbers of men and women uniformly drawn across ages 20 to 80.
Carbon Dioxide Output.
With increasing work, carbon dioxide output ( 
) increases linearly from resting values, which are near 200 mL/min for an average-size person, at about the same rate as oxygen consumption. Above the ventilatory threshold, an important exercise time point described further later, the rate of CO 2 output steepens as bicarbonate buffering of increasing lactate production leads to CO 2 production beyond that generated by aerobic metabolism.
Respiratory Exchange Ratio.
Defined as CO 2 production divided by oxygen uptake ( 
), the respiratory exchange ratio (R) remains largely stable between 0.8 and 0.9 in early to mid-exercise, with slight variation between individuals depending on the balance of dietary fats and carbohydrates. Just before and in the early stages of exercise, R can transiently increase due to anticipatory hyperventilation. Above the ventilatory threshold, 
increases markedly and R increases above 1.0. With cessation of exercise, 
decreases abruptly while 
remains elevated as tissue CO 2 stores continue to be eliminated. R can subsequently increase over 1 to 2 minutes to values as high as 1.3 to 1.5 before returning to baseline levels.
Ventilatory Thresholds.
Normal individuals demonstrate a phenomenon termed the ventilatory threshold at about 50% to 60% of the 
, although there is considerable interindividual variability in the timing of this phenomenon. This threshold marks a critical point in progressive exercise where blood flow to the exercising muscle is no longer sufficient to meet metabolic demands and the individual is transitioning from light-moderate to moderate-high-intensity exercise. Alternatively referred to as the lactate threshold, gas exchange threshold, or anaerobic threshold, the phenomenon is temporally related to an increase in lactic acid production and a decrease in pH, with considerable debate regarding the mechanisms for the increased lactate production and whether it happens suddenly or in a more continuous manner throughout exercise. As lactic acid dissociates, hydrogen ions are buffered by intracellular bicarbonate leading to further CO 2 generation beyond that associated with aerobic metabolism. This leads to a steep rise in the 
versus work relationship, as well as the 
versus 
relationship ( Fig. 26-1 ). Identifying the change in slope of the latter relationship is referred to as the V-slope method and is a key step in CPET interpretation described later in this chapter.
) and carbon dioxide production ( 
) rise at the same rate. A best-fit line through these points is labeled L1 and is denoted in brown. After the threshold, 
rises faster than 
. A best-fit line through these points is labeled L2 and is denoted in blue. The point at which the two lines intersect denotes the 
at which the ventilatory threshold is reached. With further increases in work beyond the ventilatory threshold, many individuals demonstrate a second ventilatory threshold, sometimes referred to as the respiratory compensation point, at which rising lactate concentrations cannot be buffered by intracellular bicarbonate, and minute ventilation ( 
) increases beyond that expected for the increase in 
, thereby leading to a respiratory alkalosis. This point, which may not be visible in all individuals due to interindividual variation in ventilatory responses to metabolic acidosis, can be identified by finding threshold responses in several ventilatory parameters described further later.
Further information on how to identify various thresholds is provided in “Interpreting Cardiopulmonary Exercise Tests” later.
Hemodynamic Responses
Cardiac Output.
Cardiac output (mL/min), which can be either estimated from oxygen uptake using the Fick principle, measured invasively with a pulmonary artery catheter, or estimated noninvasively using inert gas rebreathing techniques, increases linearly with workload before reaching a plateau near peak exercise. The initial increase is a function of increasing stroke volume and heart rate, whereas the changes seen near peak exercise are driven primarily by increases in heart rate.
Heart Rate.
Due initially to decreased vagal tone and later to increases in sympathetic activity, heart rate (beats/min) increases linearly with increasing oxygen consumption. The heart rate reserve, defined as the difference between the maximum predicted heart rate and the heart rate achieved at peak exercise, is typically small or nonexistent in normal individuals (<20 beats/min), but this parameter is difficult to use in exercise test interpretation due to significant variability in maximum heart rates in normal age-matched individuals. Another measure of heart rate response, also termed the heart rate reserve, is the difference between the resting and maximal heart rate. This review uses the former definition.
Pulmonary Artery Pressure.
Pulmonary artery pressure rises only modestly with progressive exercise in normal individuals, due to recruitment and distention of the pulmonary vasculature and the subsequent decrease in pulmonary vascular resistance. There is interindividual variability in observed responses, with greater variability seen in older individuals. (For physiologic implications of pulmonary vascular recruitment see Chapter 4 ).
Stroke Volume.
Characterized during CPET by the O 2 pulse (described earlier), stroke volume increases in early exercise before leveling off and possibly decreasing slightly at high levels of exercise. The initial increases are driven largely by mobilization of blood from lower extremity venous capacitance vessels, whereas later, smaller increases result from increased inotropic activity.
Systemic Blood Pressure.
Due to increases in cardiac output and vascular resistance in the skin and renal and splanchnic circulations, systemic blood pressure (mm Hg) increases with progressive exercise. Although vasodilation in exercising muscle beds limits the rise in diastolic pressure, systolic pressure rises significantly, particularly following the ventilatory threshold, and may reach values over 200 mm Hg at peak exercise.
Ventilatory Responses
Minute Ventilation.
Due to an increase in both the respiratory rate and tidal volume, minute ventilation ( 
, mL/min) rises throughout exercise with large increases seen following the ventilatory threshold. The tidal volume plateaus at about 50% to 60% of vital capacity, after which further increases in 
are driven solely by increases in respiratory rate. At peak exercise, 
is typically less than 80% of the predicted maximum, as estimated by the maximum voluntary ventilation (MVV) or forced expiratory volume in 1 second (FEV 1 ) × 40.
Ventilatory Equivalents for Oxygen and Carbon Dioxide.
The ventilatory response can be expressed as a function of the amount of ventilation per liter of oxygen consumed ( 
, unitless) or per liter of exhaled carbon dioxide ( 
, unitless). Both ratios remain relatively steady (~24 to 30) through early exercise as ventilation rises proportionately with 
and 
. Due to the large increases in 
noted earlier, both parameters rise following the ventilatory threshold, peaking at around 35 to 40, with slightly greater increases seen in the 
. Both parameters may be elevated in early exercise in highly fit or anxious individuals but typically return to the normal range as exercise progresses and reach their nadir just before the ventilatory threshold. The range of ventilatory equivalents seen across normal individuals reflects the variability in respiratory drives in the population.
Dead Space Fraction.
Because of increased tidal volumes and recruitment of the pulmonary vasculature resulting from increased pulmonary blood flow, the dead space fraction (V d /V t , unitless) normally decreases from 0.3 to 0.4 at rest to less than 0.2 at peak exercise, with the lowest values seen in younger individuals.
Gas Exchange
Arterial and End-Tidal Partial Pressures of Carbon Dioxide.
Despite increasing 
, the arterial (Pa co 2 , mm Hg) and end-tidal partial pressure (P etco 2 , mm Hg) of carbon dioxide remain near normal through early exercise due to the fact that alveolar ventilation rises proportionally with increasing 
. Low values may be seen in normal individuals who hyperventilate at the start of exercise, but these values typically normalize over the first few minutes of work. Following the ventilatory threshold, minute and alveolar ventilation rise out of proportion to the increase in 
and, as a result, both arterial P co 2 and P etco 2 decrease so that both values are nearly always less than 40 mm Hg at 
.
Arterial and End-Tidal Partial Pressures of Oxygen and the Alveolar-Arterial Oxygen Difference.
Below the ventilatory threshold, both the end-tidal partial pressure of oxygen (P eto 2 , mm Hg), which is used as a surrogate measure of alveolar oxygen tensions, and the arterial (P o 2 , mm Hg) remain in the normal range, as do both the arterial oxygen saturation (Sa o 2 , %) and the alveolar-arterial oxygen difference ((A-a)P o 2 , mm Hg). As normal individuals pass their ventilatory threshold and approach maximum exercise, P eto 2 increases due to alveolar ventilation that increases out of proportion to 
.
While the alveolar P o 2 increases, the arterial P o 2 remains unchanged due to a lower 
and normal physiologic shunting. As a result, the (A-a)P o 2 increases slightly with heavy exercise. In a minority of highly fit individuals with high 
, arterial P o 2 and arterial S o 2 can decline in late exercise, a phenomenon referred to as exercise-induced arterial hypoxemia.
In CPET, the changes in many of the parameters described earlier can be identified from tabular data but are often best appreciated graphically using an approach developed by Wasserman and colleagues in which nine separate graphs are displayed in a standardized format. The exercise responses in normal individuals described earlier are depicted in this manner in Figure 26-2 .
) versus watts; B, heart rate and oxygen pulse ( 
) versus watts; C, oxygen consumption ( 
) and carbon dioxide production ( 
) versus watts; D, 
versus 
; E, 
versus 
; F, ventilatory equivalents for oxygen ( 
) and ventilatory equivalents for carbon dioxide ( 
) versus watts; G, tidal volume (V t ) versus 
; H, respiratory exchange ratio (R) versus watts; I, end-tidal partial pressure of oxygen (P eto 2 ) and end-tidal partial pressure of carbon dioxide (P etco 2 ) versus watts. Labels for the y-axis variables are presented on the top of each graph. Note that for the variables on the x- and y-axes the lowest values are in the lower left-hand corner of each plot. Changes with Age
Perhaps the most important change in exercise responses with aging is the decrease in maximum exercise capacity, which has been consistently reported in both cross-sectional and longitudinal studies. The expected rate of decline in 
is unclear because documented rates vary from as low as 0.28 mL/kg/min/yr to as high as 1.04 mL/kg/min/yr, with much of the variation attributable to differences in study design such as participant age, activity levels at the time of enrollment, and time intervals over which the study took place. Although some studies demonstrate a slower rate of decline in active individuals compared with sedentary individuals, others have reported no effect of activity level on age-related declines in 
. Training programs in older sedentary individuals may be able to reverse much of the age-related decline in 
, which accelerates in the later stages of life.
The etiology of the decrease in 
varies depending on the time period examined. Between 20 and 50 years of age the decline in 
is largely attributable to impaired peripheral oxygen extraction, whereas later changes relate to impaired peripheral extraction and decrements in maximum cardiac output due to an inability to raise stroke volume at maximum exercise. Impairment in peripheral extraction may be due to decreases in lean body mass, age-related changes in skeletal muscle, or blood flow distribution at peak-exercise ; the decline in cardiac output may represent the increasing incidence of comorbid conditions affecting cardiac performance.
Gender Differences
Comparisons of exercise responses in men and women are difficult because the majority of studies of physiologic responses to exercise have been performed in men. The available evidence shows that women have the same qualitative responses to exercise as men but have lower 
, even after accounting for differences in lean body mass and training status. The mechanism for the observed differences remains unclear but may relate to differences in blood volume, heart size, hormonal and metabolic status, as well as autonomic nervous system regulation of the heart and vascular system. Although some studies report slower age-related rates of decline in 
in women compared with men, a recent large, cross-sectional study found no differences in this regard.
Ventilatory responses and gas exchange may also differ by gender, with some studies noting higher 
and 
in women and others reporting higher (A-a)P o 2 in fit women at high levels of oxygen consumption. At high exercise intensities, women may also rely more heavily than men on fat oxidation as a fuel source and, as a result, may have a lower respiratory exchange ratio.
Obesity
Obese individuals lacking underlying cardiac or pulmonary disease display 
lower than predicted for age and gender when expressed per kilogram of actual body weight but normal values when adjusted for ideal body weight. Because of the increased metabolic requirements resulting from their increased weight, however, several important differences are observed relative to nonobese individuals. 
for any given level of work is higher than in the nonobese, although the rate of change in oxygen consumption per given change in work rate ( 
) remains the same. Obese individuals also have markedly increased 
when pedaling without resistance (unloaded pedaling) due to the energy demands of moving heavier legs against gravity that is not reflected in the work rate reported on the cycle ergometer.
Another consequence of the increased metabolic requirements is an increase in 
for a given work rate compared with the nonobese due to the added CO 2 production from the additional tissues. This is typically achieved by increasing respiratory rate rather than tidal volume, which some data suggest is decreased during exercise relative to normal individuals, possibly due to the increased inspiratory load associated with extra chest wall soft tissue. Obese individuals also have difficulty decreasing end-expiratory lung volume during exercise, likely as a result of expiratory flow limitation and air trapping.
The presence and magnitude of observed differences in these parameters may be a function of the degree of obesity, with greater differences seen in heavier individuals. The presence or absence of comorbid conditions may also be important, as demonstrated by Vanhecke and colleagues, who showed that obese individuals (average body mass index 49 ± 9 kg/m 2 ) with obstructive sleep apnea (OSA) have lower 
, increased systolic and diastolic blood pressure, and impaired heart rate recovery compared with obese patients lacking OSA.
Individuals with Underlying Cardiopulmonary Disease
The physiologic responses to exercise described earlier are altered by the presence of underlying cardiopulmonary disease with different responses seen depending on the particular disease process.
Heart Failure
As in normal individuals, maximum exercise in patients with heart failure is limited by the amount of blood that can be delivered to exercising muscle (i.e., they have a cardiac limitation to exercise). As a result, patients with heart failure demonstrate the same patterns of physiologic responses during progressive exercise to a symptom-limited maximum, albeit with significant differences in the magnitude of many of the observed responses.
The most important difference is the decrease in 
and peak work rate relative to normal individuals. The decrease in 
, which does not vary in magnitude between patients with systolic or diastolic dysfunction, results from an inability to raise cardiac output adequately due to impaired stroke volume responses with progressive exercise, denoted by the decreased 
. The ventilatory threshold is still usually reached at 50% to 60% of 
, but because 
is decreased, the threshold is at a lower 
compared with normal individuals.
Many patients with heart failure compensate for the decreased stroke volume with an increase in heart rate for any given level of work. As a result, the heart rate reserve at peak exercise is usually small (<20 beats/min). There is considerable variability in these responses, however, with some patients manifesting an inability to raise heart rate with progressive exercise, a phenomenon referred to as chronotropic incompetence, that persists even following discontinuation of β-blockers. Patients with heart failure also may demonstrate an abnormal decline in heart rate on stopping exercise. In particular, heart rate recovery, which takes place as a result of reactivation of vagal tone and is defined as the difference between peak heart rate and heart rate 1 minute into the recovery period, is decreased compared with normal individuals.
Altered ventilatory responses have also been described in patients with heart failure including increased airway resistance, expiratory flow limitation at low work rates, and an increased ventilatory reserve due to the fact that they are not able to do as much work and therefore do not require a high 
. Perhaps the most important difference, however, is the increased ventilatory inefficiency in patients with moderate to severe systolic or diastolic dysfunction, as indicated by an increased 
at the ventilatory threshold or an increased slope of the relationship between these parameters ( 
). The most likely cause of this phenomenon is an increase in physiologic dead space due to impaired lung perfusion. Studies have shown, for example, that ventilatory inefficiency is related to abnormal pulmonary vascular tone or right ventricular dysfunction and actually improves following treatment with phosphodiesterase inhibitors and improvements in right ventricular function even when left ventricular function is unchanged. Abnormal peripheral and central chemoreceptor sensitivity may also play a role in augmenting ventilation above that necessary for a given level of CO 2 production.
Between 13% and 50% of patients with heart failure demonstrate another abnormal ventilatory response, referred to as exercise oscillatory ventilation, in which exercise ventilation is marked by periodicity similar to that seen in central sleep apnea. The mechanism for this is not clear but may relate to increased circulatory times, increased peripheral chemoreceptor sensitivity, increased ventilatory responses related to pulmonary congestion, and increased ergoreflex signaling (a peripheral reflex originating in skeletal muscle) related to muscle metabolic abnormalities. Exercise oscillatory ventilation may be a marker of reduced cardiac index both at rest and during exercise and may also improve following therapeutic interventions directed at the underlying heart failure such as treatment with sildenafil or an exercise training program. Despite these altered ventilatory responses, patients with heart failure have a normal (A-a)P o 2 and do not develop hypoxemia during exercise even though pulmonary artery occlusion pressure is elevated.
The pattern of exercise responses seen in patients with heart failure is displayed graphically in Figure 26-3 .
Pulmonary Vascular Disease (for discussion of clinical aspects of pulmonary vascular disease, see Chapter 58 )
In many respects, patients with pulmonary vascular diseases such as pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension demonstrate physiologic responses to progressive exercise similar to those seen in patients with heart failure. Relative to normal individuals, 
, peak work rate and 
are decreased while the ventilatory threshold is reached at a lower 
. Similar to patients with heart failure, the observed decline in 
, which correlates inversely with mean pulmonary arterial pressure, is due to an inability to raise cardiac output in response to exercise. The decreased cardiac output in patients with pulmonary hypertension exists because the right ventricle is unable to adequately preload the left ventricle due to high pulmonary vascular resistance. The fact that treatment with a pulmonary vasodilator such as sildenafil over a several-month period leads to improvements in both 
and 
provides support for this concept.
These patients also demonstrate abnormal ventilatory responses including increases in 
and 
of greater magnitude than those seen in patients with heart failure of similar New York Heart Association (NYHA) functional class. This ventilatory inefficiency can be attributed to increased physiologic dead space, as well as increased peripheral chemoreceptor stimulation from exercise-induced hypoxemia, and improves following several months of treatment with sildenafil. Depending on the extent of vascular occlusion and subsequent differences in physiologic dead space, the degree of ventilatory inefficiency, as measured by 
, may vary in magnitude between classes of pulmonary vascular disease patients, with higher values seen in patients with chronic thromboembolic pulmonary hypertension compared with PAH.
Aside from these similarities, an important difference between heart failure and pulmonary vascular disease is seen in the pulmonary artery pressure responses. Unlike in normal individuals or patients with heart failure where pulmonary artery pressure rises only modestly with increasing exercise, pulmonary vascular disease patients experience large rises in their pulmonary artery pressure with increasing blood flow due to impaired recruitment and distention of the pulmonary vasculature.
Physiologic dead space also changes in a different manner. Whereas V d /V t decreases from 0.3 to 0.4 at rest to less than 0.2 at peak exercise in normal individuals and patients with heart failure, it decreases only mildly and may even increase in patients with pulmonary vascular disease. For example, Zhai and colleagues reported V d /V t of 0.42 ± 0.13 and 0.53 ± 0.08 at peak exercise in patients with PAH and chronic thromboembolic pulmonary hypertension, respectively. This response is abnormal because perfusion of many lung units does not increase proportionately with alveolar ventilation due to impaired recruitment and distention. In addition, if patients develop right-to-left shunt by opening a patent foramen ovale during exercise, mean expired CO 2 decreases, leading to higher calculated V d /V t . As a result of the abnormal physiologic dead space, P etco 2 is decreased relative to normal individuals at all stages of exercise in proportion to the patient’s functional limitation.
A final important difference is the fact that patients with pulmonary vascular disease develop hypoxemia with progressive exercise even in the absence of resting hypoxemia. For example, Deboeck and colleagues reported an oxygen saturation by pulse oximetry of 86 ± 2% at peak exercise in PAH patients compared with 96 ± 3% in patients with heart failure with similar NYHA functional class and D’Alonzo and colleagues reported a mean (A-a)P o 2 of 45 ± 17 mm Hg at peak exercise in idiopathic PAH patients, a higher value than typically seen in normal individuals. In some patients, hypoxemia develops due to right-to-left shunting through an existing right-to-left communication or through a foramen ovale that opens during exercise due to the rise in pulmonary artery pressure, a finding that is predictive of death or need for transplant. In other cases, hypoxemia may be due to diffusion limitation; red blood cell capillary transit time decreases with increasing pulmonary blood flow and may no longer be sufficient to ensure full equilibration between the capillary and alveolar P o 2 in the setting of the decreased functional capillary bed. This latter phenomenon is further accentuated by the low 
that exists due to the low cardiac output in this patient population. (For clinical discussion of mechanisms of hypoxemia, see Chapter 4 .)
The findings noted earlier pertain to patients with PAH at rest. Recent work suggests that measurement of hemodynamic variables during exercise may identify an intermediary phenotype between healthy individuals and overt PAH in which individuals develop mean pulmonary artery pressure greater than 30 mm Hg during exercise. This group may represent an early form of PAH. Standardized protocols to guide clinical practice regarding these patients are lacking at this time.
The pattern of exercise responses seen in patients with pulmonary vascular disease is displayed graphically in Figure 26-4 .
), the solid blue line ( Line 1 ) represents the expected response for a patient with pulmonary vascular disease while the dashed blue line ( Line 2 ) represents the expected response for a patient with interstitial lung disease. Interstitial Lung Diseases (for discussion of clinical aspects of interstitial lung diseases, see Chapter 63 , Chapter 64 , Chapter 65 , Chapter 66 )
Patients with interstitial lung disease (ILD) manifest physiologic responses during progressive exercise similar to those seen in patients with pulmonary vascular disease. In particular, they demonstrate reduced 
and maximum work rate (W max ), increased 
and 
, reduced tidal volumes and increased respiratory rates, stable or increased V d /V t at end-exercise, and hypoxemia with reduced arterial P o 2 and increased (A-a)P o 2 . Although patients with ILD may not have a decreased 
and the ventilatory threshold may not be decreased relative to their 
, these differences are usually not sufficient to distinguish between these two classes of patients on the basis of CPET alone and further studies such as pulmonary function tests (PFTs) and computed tomography (CT) imaging are necessary. Of note, when ILD develops in the setting of a collagen vascular disease, some of these responses can be observed before pulmonary involvement is evident on PFTs.
Debate exists regarding the underlying mechanism for the reduction in maximum exercise capacity. Hansen and Wasserman, for example, demonstrated that abnormal cardiac function due to pulmonary vascular pathology was more important than respiratory system factors in limiting exercise while Marciniuk and colleagues used dead space loading during exercise to show that abnormal respiratory mechanics were the more important factor. Ventilatory equivalents are increased due to the increased dead space and the hypoxic ventilatory response, whereas exercise-induced hypoxemia, for which risk is increased in patients with a low diffusion capacity for carbon monoxide (D l CO ) on PFTs, is due to a combination of ventilation-perfusion ( 
) inequality and diffusion limitation.
Because the term interstitial lung disease represents a heterogeneous group of disorders, the physiologic responses to exercise vary on the basis of the specific disease process. Wells and colleagues, for example, found increased dyspnea and hypoxemia in idiopathic pulmonary fibrosis compared with systemic sclerosis with ILD, while other studies have also shown worse hypoxemia, as well as increased pulmonary artery pressure responses in patients with idiopathic pulmonary fibrosis compared with sarcoidosis and other forms of ILD. The onset of pulmonary hypertension as a complication of ILD or an underlying systemic illness is associated with worse exercise tolerance, hypoxemia, and ventilatory inefficiency compared with otherwise similar patients with normal pulmonary artery pressures.
The pattern of exercise responses seen in patients with interstitial lung disease is displayed graphically in Figure 26-4 .
Adult Congenital Heart Disease
With improvements in medical care, many patients with congenital heart disease are living into adulthood and the increasing use of CPET in disease management has enhanced the understanding of their physiologic responses to exercise. Similar to that seen in patients with heart failure, patients with congenital heart disease demonstrate reductions in 
, peak work rate, and maximum heart rate and increases in 
compared with normal individuals. In contrast, however, many congenital heart disease patients develop hypoxemia at end-exercise. Given that many have coexisting pulmonary hypertension, one might also expect stable or increased V d /V t at end-exercise in many patients but this variable has not been reported in major series.
Owing to the diversity in the type and severity of congenital lesions, there is significant variability in the magnitude of observed changes in 
and 
with the most serious abnormalities seen in those patients with Eisenmenger syndrome and complex lesions such as double-outlet ventricle or univentricular physiology. Patients with cyanosis and/or pulmonary hypertension also demonstrate greater reductions in these parameters when compared with patients lacking these problems. Importantly, functional impairment is not limited to those with significant lesions because even patients who are reportedly asymptomatic or those with mild lesions such as repaired coarctation of the aorta demonstrate decreased 
and increased 
compared with normal individuals. Surgical repair is associated with improvements in exercise capacity, with the degree of improvement related in some cases to whether the abnormality is repaired when the patient is a child or an adult.
Although much of the decrement in exercise capacity in these patients is attributable to cardiac and pulmonary vascular dysfunction related to the underlying defect or its repair, some patients are also limited by abnormal respiratory mechanics. Up to 50% of patients who have undergone surgical repairs have findings suggestive of restriction on spirometry, perhaps due to their often multiple thoracotomies and sternotomies. Those with abnormal spirometry show worse exercise capacity and NYHA functional class compared with those with normal spirometry.
Chronic Obstructive Pulmonary Disease (for clinical discussion, see Chapters 43 and 44 )
Patients with mild COPD may actually have normal exercise capacity while patients with moderate to severe COPD demonstrate decrements in 
and peak work rate proportional to the severity of their disease as measured by Global Initiative for Obstructive Lung Disease (GOLD) stage. Beyond this decrease in exercise capacity, the pattern of physiologic responses to progressive exercise in COPD is different from that seen in patients with heart failure. Whereas exercise is limited in heart failure by an inability to deliver oxygen-rich blood to exercising muscles, patients with moderate-severe COPD are limited by altered respiratory mechanics; their ventilatory pump fails before the heart does.
The hallmark of ventilatory limitation in moderate to severe COPD is the fact that both arterial P co 2 and P etco 2 remain stable or increase at end-exercise due to an inability to raise minute and alveolar ventilation in response to increasing 
and, when present, a metabolic acidosis. This phenomenon, which is present to a greater extent at higher GOLD stages of disease, results from mechanical constraints due to dynamic hyperinflation during exercise (discussed further later) and altered ventilation-perfusion relationships.
In addition, 
at peak exercise will be at or close to the maximum predicted ventilation as measured by the MVV or FEV 1 × 40, a marked contrast from normal sedentary individuals and those with heart failure in whom 
is normally less than 75% to 80%. Ventilation is typically higher for any given work rate and is usually marked by a high respiratory rate, low tidal volume, higher end-expiratory volume, and lower inspiratory capacity compared with normal individuals. Still another manifestation of ventilatory limitation is the absence of a ventilatory threshold in most patients with severe disease. Although patients with mild disease may still develop a metabolic acidosis and even manifest a ventilatory threshold at lower levels of 
than normal individuals, patients with severe disease will not manifest such changes. Along with the fact that peak heart rate is typically well below the maximum predicted heart rate in severe disease, the absence of the ventilatory threshold is strongly indicative of the fact that the ventilatory pump is failing before the circulatory pump.
Perhaps the most important reason for these manifestations of ventilatory limitation is a phenomenon referred to as dynamic hyperinflation. Due to expiratory flow limitation that develops even at low-moderate levels of exercise, patients with COPD must increase end-expiratory lung volumes and encroach on their inspiratory reserve volume in order to raise 
as metabolic activity increases ( Fig. 26-5 ). The hyperinflation that results causes flattening of the diaphragm, which limits contractile strength, increases respiratory muscle fatigue, and causes increased dyspnea for any given level of ventilation. Interestingly, patients with dynamic hyperinflation have less locomotor muscle fatigue with exercise because the ventilatory pump fails before the nonrespiratory muscle groups face significant loads.
Dynamic hyperinflation also has significant hemodynamic effects, including alterations in cardiac preload and afterload that subsequently impair cardiac function and manifest as a decrease in 
. The magnitude of this problem inversely correlates with the increase in end-expiratory lung volumes, and improvement can be seen following interventions that decrease dynamic hyperinflation such as lung volume reduction surgery (LVRS). Impaired right ventricular function may also result from increased pulmonary vascular resistance due to hypoxic pulmonary vasoconstriction and structural changes in the pulmonary circulation. In fact, in patients whose COPD is complicated by pulmonary hypertension (mean PAP ≥ 40 mm Hg), impaired circulatory function is the primary factor limiting exercise rather than the ventilatory constraints. Some patients with COPD also manifest chronotropic incompetence, which may limit the cardiac response to exercise. The increased work of breathing may also contribute to exercise limitation by limiting blood flow to locomotor muscles.
Another important feature of progressive exercise in patients with COPD is the onset of hypoxemia with a widened (A-a)P o 2 . This problem correlates with reductions in diffusing capacity, is more common when the COPD is due to emphysema rather than to chronic bronchitis, is more severe in patients with pulmonary hypertension, and is more prominent with walking as opposed to cycling. The predominant mechanism is 
inequality, the effects of which are magnified by reductions in 
during exercise. Depending on the distribution of blood flow and ventilation, however, 
inequality may actually improve during exercise, which accounts for the observation that some patients with COPD actually see improvement in arterial P o 2 during exercise testing.
The pattern of exercise responses seen in patients with ventilatory limitation due to COPD is displayed in Figure 26-6 .
Cardiopulmonary Exercise Testing
Indications and Contraindications
The indications for CPET sort into five general areas: determining the etiology of exercise limitation, assessing functional status, stratifying risk for surgery, prognosticating outcomes related to specific diseases, and creating individualized exercise prescriptions for rehabilitation programs. The list of indications for CPET ( Table 26-1 ) is largely compiled from expert opinions, and the evidence for the utility of CPET varies by indication, each of which is reviewed later.
| Indications | Contraindications |
|---|---|
|
|
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
