Chapter 10 Exercise Testing
Clinical exercise testing is widely accepted as an important component of the clinical assessment of patients with chronic respiratory illness, because impaired exercise capacity in these patients shows significant associations with health-related quality of life and with relevant clinical outcomes such as hospitalization rates and survival.
Impaired exercise capacity can be defined by the inability of the subject to sustain a required work rate long enough for the successful completion of a given task that could be achieved by a healthy person. Limitation of oxygen transport from the atmosphere to the cell is the most common cause of exercise limitation in chronic respiratory disease, but altered oxygen utilization due to abnormally low mitochondrial oxidative potential also can be a contributing factor in patients with advanced disease (Figure 10-1).
Figure 10-1 Major elements of the O2 transport–O2 utilization pathway. Integrated effects of all steps involved to move oxygen from air to mitochondria are essential to determine maximum capacity of the system. In disease, nonuniformity of ventilation-perfusion ratios in the lung, altered response of the cardiovascular system to exercise, and/or mismatching of metabolism-perfusion ratios in the peripheral tissues may be of considerable importance in determining cell oxygenation. Moreover, in patients with advanced chronic obstructive pulmonary disease (COPD), impaired oxygen utilization due to altered mitochondrial oxidative capacity has been demonstrated.
Clinical manifestations of limited exercise capacity are breathlessness, perception of limb fatigue, or even, in some conditions, frank pain. Abnormally low exercise capacity is the hallmark of a range of cardiovascular, respiratory, and other systemic diseases, of which congestive heart failure and chronic obstructive pulmonary disease (COPD) are the most prominent. However, the causes of a reduced exercise capacity are many, ranging from physical unfitness and obesity to muscle and neurologic diseases, anemia, and locomotor disorders.
Several studies have shown that the functional reserve (i.e., aerobic capacity) of patients with COPD and interstitial lung disease is not accurately predicted from resting lung function indices. In this scenario, cardiopulmonary exercise testing (CPET) constitutes a proper tool to assess both magnitude and mechanisms of impaired exercise capacity. CPET also can provide indices of the functional reserve of the different systems (pulmonary, cardiovascular, skeletal muscle) involved in the exercise response, with implications for factors contributing to the limitation of oxygen uptake at peak exercise. Moreover, CPET also is useful for establishing the profiles and adequacy of the system responses at submaximal exercise.
The chapter describes the laboratory exercise protocols more commonly used for clinical purposes, but it also covers simple exercise tests of increasing clinical usefulness that are extensively used outside the laboratory with well-defined purposes.
The various clinical indications for CPET can be divided into three principal groups: assessment of functional reserve (aerobic capacity), identification of predominant factors limiting exercise capacity, and, last but not least, diagnostic purposes. Of note, adequate identification of the clinical problem requiring exercise testing should be considered a necessary prelude to CPET, as should an appropriate preassessment of the patient by (1) medical history, (2) physical examination, (3) chest radiograph, (4) resting pulmonary function testing, and (5) electrocardiogram (ECG). The clinical problem that prompts CPET and the specific aims of such testing (e.g., assessment of aerobic capacity, analysis of pulmonary gas exchange during exercise) determine both the type of exercise protocol to be used and the variables to be considered in the interpretation of the findings.
Assessment of aerobic capacity and identification of potential limiting factors constitute the most important indications for CPET. These goals are particularly important in evaluating dyspnea but also for assessing the degree of functional impairment in patients with chronic diseases. Appropriate use of CPET allows the investigator (1) to quantify the degree of functional limitation and to discriminate among causes of impairment of exercise capacity, (2) to differentiate between dyspnea of cardiac or pulmonary origin when respiratory and cardiac diseases coexist, and (3) to analyze unexplained dyspnea when initial pulmonary function testing does not provide conclusive results. CPET also is useful to assess the effects of pharmacologic interventions.
An important area for CPET is preoperative assessment in certain conditions—for example, for planned major abdominal surgery in elderly patients. Also, CPET is indicated before lung cancer resection and lung volume reduction surgery, either to confirm the patient’s fitness to survive the procedure, if this is in question, or to ensure that postoperative respiratory function will be adequate. Information on predicted postoperative lung function can help to modulate the amount of lung parenchyma to be removed and determines the type of perioperative strategy needed to prevent complications. Pulmonary function tests performed in the resting state are considered adequate to evaluate low-risk patients (FEV1 greater than 2 L and DLCO within the reference limits), but CPET plays a pivotal role in the evaluation of patients at high risk.
Assessment of impairment-disability also constitutes a major indication for CPET. It is now well accepted that CPET provides different and relevant information, compared with resting cardiopulmonary measurements, in impairment-disability evaluation and therefore constitutes a key tool in this area.
Finally, CPET plays a role in the diagnosis of a range of disease conditions, namely: exercise-induced asthma, cardiac ischemia, foramen ovale patency with development of right-to-left shunt during exercise, and McArdle syndrome.
Availability of oxygen to all body tissues and cells is essential for survival. During steady-state conditions, oxygen consumption () matches the turnover of adenosine triphosphate (ATP), the high-energy phosphate needed to fulfill the bioenergetic requirements of the cells. ATP is efficiently generated by oxidative phosphorylation into the mitochondria. Within the inner mitochondrial matrix, pyruvate is converted to acetyl coenzyme A (CoA) and metabolized aerobically by way of the tricarboxylic acid cycle to yield water and carbon dioxide (CO2) as residual products to be subsequently eliminated.
Alternative pathways of energy production not requiring oxygen constitute rapid but only transient solutions to fulfill the bioenergetic requirements. That is, anaerobic reduction of pyruvate to lactic acid in the cytosol is inefficient in terms of ATP production. Moreover, increased lactate levels provoke a marked fall in intracellular pH that may alter mitochondrial function. Likewise, skeletal muscle contains high levels of phosphocreatine (PCr) compared to other tissues, but the breakdown of muscle PCr stores can supply cellular needs of ATP for only a few seconds of strenuous contractions. Compared with glycolysis, aerobic metabolism requires longer to become activated. Energy utilization during exercise may require higher ATP turnover than the synthesis from aerobic pathways in the muscles allows. This phenomenon causes an “oxygen debt” that must be repaid after exercise. Aerobic metabolism, in turn, is more efficient in terms of ATP production and it enables the cell to utilize stored lipid as fuel via fatty acid metabolism. Consequently, the integrity of the different pathways governing cellular O2 transport–O2 utilization is a pivotal determinant of exercise capacity in both health and disease (see Figure 10-1).
Lactate threshold (LT), or anaerobic threshold, is the threshold for arterial lactate concentration increase. The LT should be considered to partition moderate from heavy-intensity exercise, and it corresponds to a transitional exercise intensity that triggers a series of physiologic responses associated with increased lactate production that stress ventilation, pulmonary gas exchange, and acid-base regulation. Of note, the LT is highly task-specific. It occurs at an appreciably lower for arm exercise than for leg exercise and typically is lower for cycle ergometry than for treadmill exercise, reflecting the magnitude of muscle mass over which the work is distributed. A wide range of techniques have been advocated for estimation of LT, including both direct measurements and indirect estimation, as described next.
Critical power is the highest sustainable level of and usually is at an intensity below the maximal for an individual subject and at an intensity of exercise that can still generate a plateau in (Figure 10-2). Heavier exercise intensities, well beyond LT, are not sustainable and may peak at max (see Figure 10-2). During moderate intensity submaximal exercise, the components of the O2 transport pathway can provide adequate O2 flux between the air and the mitochondria. Mitochondrial oxidative capacity will not have been reached, symptoms usually are tolerable, and muscle fatigue has not occurred, or at least may be insufficient to impair performance appreciably. Although the concept of critical power is relevant for understanding the exercise response, it is not assessed in clinical exercise testing, because no normal ranges for submaximal exercise comparable between laboratories or diseases have been established.
Maximal exercise (max) corresponds to maximal aerobic capacity, as displayed in Figure 10-2. At this point, maximal oxygen transport capacity and/or maximal mitochondrial oxidative potential have been reached. The subject cannot increase when work rate is increased or the highest tolerated work rate is sustained for a period of time. Often, max can only be clearly identified in fit subjects that can sustain high levels of exercise for a few minutes. Extreme motivation is needed to reach true max, and it is, in general, an unsuitable and unsafe test for patient populations.
Peak exercise (peak) occurs when maximal work rate has been limited by severe symptoms at a level that does not require maximal O2 transport or maximal oxidative capacity. Under these conditions, a plateau in O2 (max) has not been reached, and the appropriate designation is peak rather than maximal . Symptom-limited exercise testing is common in the clinical setting, and this approach does not preclude adequate interpretation of the test results.
Figure 10-2 Response of oxygen uptake to four different constant-work-rate exercise tests carried out using a cycle ergometer in a healthy subject. From moderate to heavy exercise: Green, 55 watts, corresponding to a work rate moderately above the lactate threshold (LT), approximately 58% of max, indicates the transition from moderate to intense exercise; dark blue, 85 watts, indicates the critical power (approximately 88% max) corresponding to the highest level of sustainable exercise; red, 100 watts, indicates nonsustainable exercise above the critical power; and light blue, 120 watts, supramaximal nonsustainable exercise intensity. Of note, the two last exercise intensities, 100 and 120 watts, generate identical oxygen uptake that, by definition, corresponds to maximal O2 uptake, max.
Because the catabolic capacity of the myosin ATPase is such that it outstrips by far the capacity of the respiratory system to deliver energy aerobically, exercise tolerance (max) is determined by the capacity of the O2 transport–O2 utilization system, rather than by the muscle’s contractile machinery (see Figure 10-1).
Two physiologic muscle properties—muscle strength and muscle fatigability—may modulate functional performance of the patient in daily life activities as well as during clinical exercise testing. Muscle strength is defined as the force generated by a muscle. It is determined by the number and type of motor units recruited. Muscle fatigue has been defined as a loss of contractile functions (force, velocity, power, or work) that is caused by prolonged exercise and is reversible by rest. Factors involved in muscle fatigue are complex, consisting mainly of contractile machinery, muscle respiratory capacity, and redox status of the muscle.
As the patient with lung disease exercises harder, O2 consumption, CO2 production, ventilation, and cardiac output all increase to fulfill increased muscle bioenergetic requirements, as they do in the normal subject, but submaximal exercise response is abnormal and peak levels attained are lower, and increasingly so with increasing severity of the disease.
Ventilation and cardiac output markedly increase during exercise to match O2 transport with augmented cellular O2 requirements. Because ventilation increases to a relatively higher extent than pulmonary blood flow, the ratio of total alveolar ventilation to blood flow (overall ratio) rises rather substantially. At moderate levels of exercise, the dispersion of the distributions does not change, but the ratios as the mean of both ventilation and perfusion distributions increase markedly owing to the higher overall ratio. Consequently, the efficiency of the lung as an O2 and CO2 exchanger improves at these exercise levels. Mixed venous PO2 falls dramatically during exercise because the relative increase in is considerably greater than that of cardiac output, and mixed venous PCO2 levels rise equally remarkably. Arterial PO2 levels generally remain unchanged until extremely high levels of exercise are undertaken. Arterial PCO2 levels also are relatively stable until the appearance of high blood lactate levels generates acidosis with even more ventilation and a corresponding fall in PCO2 levels. The alveolar-arterial O2 gradient, PO2(A−a), progressively increases with the level of exercise, reaching values of 20 mm Hg close to maximal exercise (peak) in average subjects and even greater—up to 40 mm Hg or more—in some elite athletes. Such an increase in PO2(A−a) indicates inefficiency of pulmonary gas exchange during heavy exercise that is even more apparent in other animal species. It has been shown that the increase in the PO2(A−a) during exercise is due in part to ventilation-perfusion mismatching, but it is mostly explained by alveolar–end-capillary O2 diffusion limitation. Experimental studies suggest that development of subclinical pulmonary edema may explain the deterioration of pulmonary gas exchange during heavy exercise in elite athletes.
In patients with COPD, resting levels of minute ventilation () are abnormally high but, during exercise, the slope between and work rate is normal. For a given level of during exercise, tidal volume (VT) tends to be lower and respiratory rate (f) higher in patients than in healthy subjects. Moreover, the O2 cost of breathing per unit ventilation is higher in persons with COPD than in healthy subjects. Impaired respiratory mechanics requires more effort to move a given volume of air. Peak exercise VT is strongly related to vital capacity in these patients, in whom two strategies are adopted during exercise to increase : First, end-expiratory lung volume (EELV) increases, allowing higher maximum expiratory flow rates. This dynamic hyperinflation does not occur in normal persons, who show a fall in EELV during exercise (Figure 10-3). Second, inspiratory flow rate increases, so that inspiratory time decreases and more time is available for expiration.
Figure 10-3 The resting maximal flow-volume curve from a patient with chronic obstructive pulmonary disease is represented by the blue solid line. The solid smallest green loop corresponds to tidal volume at rest, and the dashed red curve indicates tidal volume at maximal exercise. During exercise, end-inspiratory and end-expiratory lung volumes are increased (dynamic hyperinflation), and expiratory flow limitation is seen over most of expiration.
(From Roca J, Rabinovich R: Clinical exercise testing. In Gosselink R, Stam H, editors: Lung function testing, Eur Resp Mon 31:146–165, 2005.)
Impaired respiratory mechanics (i.e., dynamic hyperinflation) seems to play a major role limiting exercise tolerance in these patients. During exercise in COPD, a balance is struck between the need for ventilation and the high cost of the work of breathing. The most common end result is a small rise in arterial PCO2 and similar fall in PaO2. However, unless pulmonary CO transfer capacity (DLCO) is severely impaired (less than 50% predicted value), PaO2