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VO2-HR relationship is determined by the stroke volume prematurity with its related structural and functional pul- and the arteriovenous oxygen content difference. This monary immaturity, the presence and severity of respira- slope is typically reduced when the stroke volume re- tory distress syndrome, the duration and intensity of oxy- sponse to exercise is impaired, such as in children with gen therapy, and positive pressure mechanical ventila- single-ventricle lesions corrected surgically by the Fontan tion. The vast majority of infants with BPD do not procedure [32]. Although left-ventricular dysfunction is require oxygen therapy by 2 years of age. However, a vari- not typically found in mild-to-moderate CF, stroke vol- ety of chronic impairments in lung function have been ume during exercise has been shown to be reduced in CF reported [61, 62]. Many will have hyperinflation as evi- adults with severe lung disease (FEV1 !55% predicted) denced by a large residual volume and a high ratio of [56]. ¢V˙ O2/¢HR may be useful in identifying early abnor- residual volume to total lung capacity. Evidence for air- malities in cardiac function in CF subjects. way obstruction and airway hyperreactivity is commonly found. Exercise-induced asthma may be present in as A much more substantial abnormality was the large many as 50% of BPD survivors. Many of these chronic increase in the slope of ¢V˙ E/¢V˙ CO2. The elevated slope respiratory symptoms may persist into adulthood [63]. As suggests excessive ventilation in CF subjects compared more premature infants are surviving, this is an ever- with controls as shown by the modified alveolar gas equa- increasing group of patients who will need chronic pulmo- tion: nary follow-up. V˙ E = [863 ! PaCO2–1 ! (1 – VD/VT)–1] ! V˙ CO2 Exercise testing is an important part of the follow-up and response to therapy. These children tend to lower val- where V˙ E is minute ventilation; V˙ CO2 is CO2 production, ues of VO2max and lactate threshold compared to con- PaCO2 is arterial CO2 tension, and VD/VT is dead space to trols. Values of minute ventilation and tidal volume tidal volume ratio. The two most likely explanations for tended to be lower during exercise, and these children excessive ventilation are increased VD/VT and changes in may have a limited ability to increase ventilation with chemoreceptor set point for PaCO2. In CF patients, pre- exercise. Arterial oxygen desaturation with exercise was vious investigators using other approaches have found not uncommon, occurring in as many as one-third of the exercise abnormalities both in chemoreceptor set point patients. As mentioned, exercise-induced asthma was [57] and increased ventilatory dead space [58, 59]. The common. As for cystic fibrosis, these exercise abnormali- measurement of ¢V˙ E/¢V˙ CO2 during exercise may prove ties are not predicted by resting pulmonary function tests. to be a noninvasive, relatively effort independent, and The effects of exercise training for these patients have not useful means to gauge dynamic respiratory function in been evaluated. these patients. Upper Airway Obstruction and Exercise A novel finding of recent studies was that the reduction Upper airway obstruction may also limit exercise per- in peak V˙ O2 in CF was observed even when normalized to formance in children. This is frequently overlooked as a muscle size (measured by MRI determined cross-section- cause of exercise-related dyspnea. The obstruction may al area). Thus, reduced muscle mass alone (resulting, per- occur above, at, or below the vocal cords. The airway may haps, from nutritional or ongoing inflammatory pro- be congenitally deformed, as in micrognathia associated cesses) could not account for all of the impairment of peak with the Pierre-Robin syndrome, or dysfunctional, as in V˙ O2 observed in CF. These observations indicate that the laryngomalacia and tracheomalacia [64–66]. The airway impaired exercise response in CF is related to altered oxy- may be secondarily obstructed. Granuloma formation gen delivery or intrinsic abnormality of muscle function either on or just below the vocal cords may be the result in CF subjects. of prolonged intubation and lead to exercise related stri- dor. Children who have had a tracheostomy frequently Bronchopulmonary Dysplasia and Exercise have residual subglottic narrowing following decannula- Premature infants who survive severe neonatal respi- tion. Vocal cord paralysis may follow chest surgery in ratory distress syndrome may develop a more chronic children, usually following tumor resection or repair of form of lung disease, termed bronchopulmonary dyspla- congenital cardiac malformations. Stridor may be func- sia (BPD) [60]. The condition is characterized by persis- tional as well, with no signs at rest, and only manifest dur- tence of respiratory distress, pulmonary radiographic ab- ing stress or exercise [67–69]. This is seen in vocal cord normalities, and the need for supplemental oxygen for at dysfunction were the vocal cords move paradoxically dur- least 4 weeks after birth. The etiology of BPD is multifac- torial. The principal risk factors appear to be the degree of Clinical Exercise Testing in Children 291

ing stress [70, 71]. Abnormal movement of the arytenoid complex (tetralogy of Fallot, Fontan operations for single region during extreme exertion may result in ‘exercise- ventricle [74]). The mechanism of such chronotropic induced laryngomalacia’, a syndrome associated with se- incompetence is unknown and probably multifactorial. vere dyspnea and stridor during intense exercise. This Damage to the SA nodal artery during cannulation for syndrome may only be diagnosed in the exercise laborato- heart-lung bypass, direct damage to the SA node or its ry and may require laryngoscopy during exercise to make artery during the surgical repair, and part of the natural the diagnosis. history of the disease have all been implicated. Maximal heart rates in the range of 140–160 beats/min are seen and The exercise laboratory is probably underutilized for can obviously contribute to or be responsible for exercise work-up and/or follow-up of children with the above or limitation [75–77]. As noted above, it is also possible to similar conditions. Any question of exercise-related utilize submaximal and novel approaches to exercise test- symptoms in this group should certainly be tested. ing in order to gain useful information regarding underly- ing pathophysiology in children with congenital heart dis- Pediatric Cardiology Referrals ease [32]. Children with congenital heart disease account for Blunted heart rate responses may also occur in some about 80–90% of pediatric cardiology patients. Current- forms of congenital heart disease even without surgery, ly, there are successful surgical or transcatheter options most notably congenitally corrected transposition (L- for repair or palliation of all forms of congenital heart transposition) of the great arteries. In addition, anti-ar- disease, and the mortality rate for infants with congenital rhythmic medications, especially beta-blockers, can also heart disease is less than 10%. Current estimates would blunt the heart rate response to exercise. Exercise testing is predict that soon there will be more adults with congeni- routinely performed to assess both the control of the tal heart disease than children with congenital heart dis- arrhythmia during exercise and to ensure that the heart rate ease. In addition, there are only a very few circumstances is not excessively inhibited. Children with complete heart that would require these patients, adults or children, to block, either congenital or surgically induced, obviously be restricted from athletics. Exercise testing is routinely have depressed heart rate responses both at rest and during recommended in these patients prior to sports participa- exercise. Determination of the heart rate response can help tion. It is beyond the scope of this chapter to review all decide if a pacemaker would be indicated. forms of congenital heart disease and their unique prob- lems, and only general functional problems will be dis- All children with pacemakers have exercise testing in cussed. order to adjust the pacemaker parameters to produce an adequate heart rate response during exercise [78, 79]. Acquired heart diseases are an important minority of Current pacemakers have maximal rates in the range of patients in pediatrics, and include patients with Kawasaki 180 beats/min. Dual chamber pacemakers (sensing and disease, cardiomyopathy and myocarditis, and rheumatic pacing in both the atria and the ventricles) may develop heart disease. With the exception of hypertrophic cardio- the equivalent of 2:1 heart block as the sinus node rate myopathy, these patients are also encouraged to be active, goes above 180 beats/min, and can produce severe symp- with few or no restrictions, and exercise testing is an toms with exercise. Careful adjustment of the upper rate important part of their work-up as well. limit behavior of dual chamber pacemakers during exer- cise testing is required to prevent this problem. Specific recommendations for exercise testing prior to sports participation have been published for both chil- Blood Pressure Response to Exercise dren and adults with congenital heart disease or acquired In the postoperative cardiac patient, it is important to heart disease. The ‘Bethesda Conference’ recommenda- determine if previous surgery may have involved either of tions are excellent guidelines, and deal with each form of the subclavian arteries. For coarctation of the aorta, the heart disease individually [72, 73]. left subclavian artery may have been used as part of the repair (subclavian patch aortoplasty), the left arm arterial Heart Rate Response to Exercise supply is via collaterals, and the blood pressure is not Blunting of the heart rate response during maximal accurate in the left arm. Similarly, if the patient has tetra- and submaximal exercise has been reported following sur- logy of Fallot, either subclavian artery may have been gical repair of all forms of congenital heart disease, from used for a Blalock-Taussig shunt, and the blood pressure the simple (atrial and ventricular septal defects) to the will not be accurate in that arm. If there is any doubt, the 292 Fahey/Nemet/Cooper

blood pressure should be taken in both arms prior to the monary artery [83]. These children will require periodic exercise test. exercise testing to assess for coronary insufficiency throughout their lives. The blood pressure response to exercise is exceedingly important for the follow-up and management of patients Children who have had Kawasaki disease comprise after repair of aortic coarctation. Although upper extremi- another major group of children at risk for coronary dis- ty blood pressure usually returns to normal after repair, in ease. Kawasaki disease is an inflammatory disease of as many as 30–65% of postcoarctectomy patients there is unknown etiology affecting only children, and may lead to an exaggerated systolic blood pressure response during coronary artery aneurysm formation. If untreated, 15– graded exercise [80, 81]. This is usually not associated 20% of children with Kawaski disease will develop coro- with symptoms or ECG changes. However, patients with nary artery aneursym; if treated early with gammaglobu- this response tend not to regress their left-ventricular lin, the incidence is reduced to 3–5%. Coronary aneu- hypertrophy following repair, and this may be an indica- rysms put the children at risk for coronary thrombosis, tion to institute anti-hypertensive therapy [82]. coronary stenosis, and myocardial infarction [84, 85]. Exercise testing, both with and without nuclear testing, It is never normal for the systolic blood pressure to will be necessary throughout the children’s lives [86]. decrease during a progressive exercise test and usually indicates an inability to increase cardiac output. This is Evaluation for Arrhythmias an indication to stop an exercise test. Classically, this was Open-heart surgery to repair congenital cardiac defects seen in severe aortic stenosis and pulmonary stenosis. leaves a surgical scar on either the right atrium or right However, patients are no longer left with severe aortic or ventricle, and may be a potential source of arrhythmias pulmonary stenosis and this should now be exceedingly for these patients [76, 77, 87, 88]. The arrhythmia poten- rare. However, such a response may be seen in hypertro- tial is increased if there is any residual hemodynamic bur- phic cardiomyopathy if there is subaortic obstruction due den on the myocardium. There may be a volume load on to asymmetric septal hypertrophy. Also, patients with the hearts due to valvar insufficiency or residual atrial or dilated cardiomyopathy may exhibit the same response. ventricular septal defects. There may be pressure loads if For both groups, this is an ominous sign and may be a risk there are residual stenoses at the valvar or supravalvar factor for sudden death. level. Some arrhythmias are precipitated by the increased myocardial oxygen demands associated with aerobic exer- Evaluation for Myocardial Ischemia cise. It is very common to perform maximal exercise tests Obviously, this is the most common indication for on postoperative cardiac patients, either to work-up exercise testing in adult cardiology due to the prevalence symptoms (palpitations, lightheadedness, syncope), to of atherosclerotic coronary artery disease in the adult pop- monitor the effectiveness of anti-arrhythmic therapy, or ulation. Significant atherosclerosis is rare in the pediatric for clearance prior to athletic participation [72]. age range. However, the coronary arteries may be abnor- Patients with extensive atrial surgery are at high risk mal in a variety of pediatric patients. Monitoring for ECG for atrial arrhythmias (atrial fibrillation, atrial flutter). changes of myocardial ischemia is the same in children as This includes patients with atrial switch operations (Mus- in adults. tard, Senning operations) for simple transposition of the The coronary arteries may be congenitally abnormal, great arteries [87, 89]. Moreover, patients with Fontan as in patients with anomalous left coronary artery from operation for single ventricle very commonly have atrial the pulmonary artery. There may be a single coronary arrhythmias. Patients with ventricular incisions are at artery system, with either the left coming off the right or risk for ventricular tachycardia. There is almost no cur- the right coming off the left and coursing aberrantly. rent operation for congenital heart disease that involves Alternatively, the coronary arteries may be manipulated an incision in the left ventricle. Patients with tetralogy of as part of surgical repair of a congenital heart defect. Dur- Fallot commonly have an incision along the right ventric- ing the arterial switch operation for simple transposition ular outflow tract in order to relieve sub-pulmonic ob- of the great arteries, both coronary arteries are removed, struction. Ventricular tachycardia is common in this mobilized and reimplanted in the new aortic root, and are group of patients, and there is a significant risk of sudden therefore at risk for stenosis. Similarly, the coronary arter- death in the group as a whole [90–92]. It is more common ies may be reimplanted during the Ross operation for if the right ventricle is dilated, as is seen in the group with repair of aortic valve disease. It is now routine to reim- significant pulmonary insufficiency. Most patients in this plant the left coronary in infants if it arises from the pul- Clinical Exercise Testing in Children 293

group have exercise tests every 2–3 years even if asymp- exercise test may be useful in showing the children and tomatic [73]. their parents that it is not dangerous to exercise. A careful exercise program can then be outlined. Pediatric patients may also have arrhythmias without congenital heart disease. Supraventricular tachycardia, Other Subspecialty Referrals with and without associated Wolf-Parkinson-White syn- drome is common. Patients are evaluated pre- and post- The Endocrinology and Metabolic Services may be a therapy with exercise testing. Patients with cardiomyopa- significant source of referrals. The recent increase in the thy, both hypertrophic and dilated, may have life-threat- incidence of type 2 diabetes in children and adolescents is ening ventricular arrhythmias. Hypertrophic cardiomyo- an alarming manifestation of the broader problem of pathy is a very high-risk group with a high risk (1–2% per physical inactivity, poor diet, and obesity afflicting young year) of sudden death. Although hypertrophic cardiomyo- people throughout the world [98]. The development of pathy used to be a contraindication to exercise stress test- frank diabetes in children and adolescents will be associ- ing, most patients today will have an exercise test for risk ated with intensive and costly medical therapy, and long- assessment and/or response to therapy. term chronic disease is almost certain. Determining the level of fitness in obese children and an accompanying Evaluation for Exercise Limitation, Sports realistic exercise and nutrition program is a major task of Participation the modern pediatric exercise physiology laboratory. The preparticipation physical has been a part of most pediatric sports activities for many years, but substantial Children with type 1 diabetes mellitus are encouraged controversy remains regarding its efficacy and cost effec- to be active and fit [99, 100]. Exercise-related symptoms tiveness [93–97]. Few, if any, prospective studies have are usually attributed to abnormal metabolism of exoge- been done to determine standards for preparticipation nous insulin, but, increasingly, new studies are leading to physicals. Finally, the use of stress exercise testing in the a more broad-based understanding of the effect of exer- preparticipation physical has not been adequately ad- cise on the hormonal response to stress [101, 102]. Similar dressed. to children with other chronic conditions, children with Nonspecific complaints of exercise limitation, easy type 1 diabetes are likely to benefit from exercise testing fatigability, or shortness of breath with exercise are com- with metabolic measurements to determine the optimal mon in children with congenital or acquired heart disease. role of exercise and physical activity for a particular child Obviously, the concern is for abnormalities due to the and his or her level of fitness. underlying heart disease. Pulmonary function testing and metabolic measurements during the exercise test should The Renal Service follows most patients with hyper- be performed whenever possible. Abnormalities in the tension. Essential hypertension is uncommon in the pe- heart rate or blood pressure response as noted above may diatric age range, accounting for less than 30% of children occur, and arrhythmias are a risk. Many of these children with hypertension. The majority of children with hyper- will have had multiple surgeries and/or prolonged periods tension have renal disease [103, 104]. As for aortic coarc- of intubation. It is not uncommon to find a restrictive pat- tation of the aorta, the blood pressure response to children tern on the baseline pulmonary function test due to pre- with hypertension may be exaggerated. Optimal blood vious thoracotomies and sternotomies, or pleural scleros- pressure control should include both resting and exercise ing procedures to treat chronic pleural effusions. Inspira- blood pressure. tory stridor may occur due to vocal cord granuloma of subglottic stenosis due to the previous intubations. Vocal Finally, there is growing understanding of the use of cord paralysis or paresis may have occurred during one of exercise testing in evaluating mitochondrial myopathies the surgeries. Exercise-induced asthma may also occur. [105]. In many of these disorders, a lifelong, nonspecific The exercise limitation may be ventilatory and not car- history of poor fitness or inability to ‘keep up with other diac in origin. children’ during exercise is often encountered. Using the Commonly, however, the exercise test may be normal, exercise laboratory to identify excessive acidosis with with the exception of a low VO2max. Deconditioning in exercise (which can be done with simultaneous blood this group of children is multifactorial. The children may sampling or by careful analysis of gas exchange) will be afraid to exercise. They may be encouraged not to exer- increasingly play an important role in this relatively new cise by anxious parents or medical caregivers. A normal area of clinical awareness. 294 Fahey/Nemet/Cooper

General Pediatric Referrals may lead to underperfusion of the subendocardial layers of the heart and lead to myocardial ischemia and exertional There are three general pediatric problems that may be angina. Severe valvar stenosis is now a rare problem out of very difficult to sort out, and do not fall under any partic- the newborn period, and hypertrophic cardiomyopathy is ular subspecialty: (1) shortness of breath with exercise; now the leading cause of ventricular hypertrophy. (2) chest pain, and (3) syncope. They may eventually be referred to the exercise laboratory from a variety of Referral of children with chest pain for exercise testing sources. is common, especially if no clear etiology of the pain can be established by history or physical exam. Occasionally, Exercise-related dyspnea is common. Frequently, the the exercise test is diagnostic, i.e. if exercise-induced asth- children will already have had a trial of an inhaled beta- ma is found, chest wall pain is reproduced following exer- agonist with the assumption that the breathlessness is cise, or ECG changes develop. More commonly, the test is related to exercise-induced asthma. A maximal exercise normal but reassuring [106–109]. test with metabolic measurements and measurement of VO2max can usually sort out the problem and direct ther- Syncope is also common in the pediatric age group. apy. The test must be strenuous enough to reproduce the The vast majority is vasovagal in origin and unrelated to breathlessness. Exercise-induced asthma should be easily exercise. Syncope during exercise or in the immediate documented or ruled out. More rare problems like ar- postexercise period is more worrisome and deserves a rhythmia or exercise-induced stridor will be detected. complete work-up [110]. Syncope while exercising may be Deconditioning, documented by a low VO2max, can also due to a tachyarrhythmia, either atrial or ventricular. Syn- be diagnosed, and is probably more common than exer- cope while exercising may also signal an inability to cise-induced asthma. Recommendations for aerobic con- increase cardiac output adequately to meet the increased ditioning can be made at the same time. metabolic demands of exercise. Inability to increase stroke volume with exercise can be associated with valve Chest pain is a very common complaint in both chil- stenosis (aortic, pulmonary, mitral), hypertrophic cardio- dren and adolescents. It may occur at rest or with exercise. myopathy, dilated cardiomyopathy, primary pulmonary The media have been successful in associating chest pain hypertension, or excessive diuretic therapy. Inadequate and ‘heart attacks’ in the adult population. Both parents increases in heart rate may be associated with exercise- and children make the same association for the pediatric induced heart block. Blunting of the heart rate response age group. However, cardiac-related chest pain accounts with exercise has been discussed previously, and may be for less than 4% of all chest pain in children. associated with prior heart surgery and anti-arrhythmic therapy. Exercise syncope was a common presentation Musculoskeletal chest wall pain is the most common. for exercise-induced laryngomalacia. Sustaining exercise This pain may be worse with exercise due to the increased above the anaerobic threshold can lead to lightheadedness ventilation with exercise, and the association of the pain and syncope either during or immediately postexercise, with exercise does not make it more likely to be cardiac in and can be seen in athletes during training or competition. origin. Exercise-induced asthma may present with chest Therefore, a maximal exercise test with careful monitor- pain, due to the deep inspiratory ‘tightness’ that occurs ing of heart rate, ECG, blood pressure, ventilation and with bronchospasm. Obviously, the pain is usually postex- oxygen consumption should be performed as part of the ercise. Gastric reflux may present with low sternal or left work-up for exercise related syncope. Occasionally a rela- precordial chest pain. This may be aggravated by exercise, tively low VO2max in a competitive athlete is the only meals, or lying down. Cardiac pain usually occurs with abnormality found. two circumstances. Pericardial pain due to inflammation (pericarditis) usually causes acute severe, substernal chest Contraindications and Reasons to Terminate an pain. The pain is described as squeezing or tightening, Exercise Test and is worse with movement and breathing. It is highly unlikely that these children would be referred for an exer- There are both absolute and relative reasons to defer or cise study. Anginal chest pain is uncommon in pediatrics, cancel an exercise test. As for any test, the risks must be and as for adults, represents a mismatch between myocar- weighed against the importance of the information to be dial supply and demand. The coronary arteries may be gained [14]. Absolute contraindications usually involve congenitally abnormal (abnormal takeoff) or have ac- an acute and evolving process, frequently inflammatory, quired defects (Kawasaki disease) and these have been discussed previously. Marked ventricular hypertrophy Clinical Exercise Testing in Children 295

Table 2. Absolute contraindications to exercise testing should lead the examiner to terminate the test include: ST segment depression of greater than 3 mm indicating myo- 1 Acute myocarditis, pericarditis, or endocarditis cardial ischemia, a progressive decrease in systolic blood 2 Acute rheumatic fever pressure, or a rise in systolic blood pressure above 3 Acute phase of Kawasaki disease 250 mm Hg. The development of an arrhythmia, either 4 Acute myocardial infarction supraventricular or ventricular tachycardia, or the onset 5 Severe systemic hypertension of heart block should require exercise termination. An 6 Active pneumonia increase in ventricular ectopy with exercise is worrisome 7 Exacerbation of asthma but should be decided on an individual basis whether the 8 Active hepatitis exercise should continue. Table 3. Relative contraindications to exercise testing Safety Issues 1 Severe left-ventricular outflow tract obstruction, including Exercise testing can be performed in children at low hypertrophic cardiomyopathy risk, even in patients with significant cardiac or pulmo- nary disease [111]. Complications are rare but do occur, 2 Severe right-ventricular outflow tract obstruction and proper safety precautions are important to any pe- 3 Congestive heart failure diatric exercise laboratory. A pediatric ‘crash’ cart should 4 Ischemic coronary artery disease be available in the laboratory. A defibrillator with both 5 Advanced ventricular arrhythmias pediatric and adult paddles is mandatory. Oxygen and 6 Pacemakers with defibrillation capabilities suction should be available, as should equipment for bag- 7 Pulmonary vascular obstructive disease valve-mask ventilation. A nebulizer and asthma medica- 8 End-stage cystic fibrosis patients tions should be available. and exercise itself may potentially be harmful. Some of All staff members should be certified in cardiopulmo- these absolute contraindications are listed in table 2. nary resuscitation. It is optimal to have two staff members conduct each test. One should take blood pressure and Relative contraindications imply that the exercise test observe the ECG, while the other monitors the ergometer poses potential risks to the child. The physician in charge and observes the child. A staff member should stand of the exercise laboratory should be in contact with the behind the child during treadmill testing due to the risk of referring physician regarding the relative risks and bene- falling. If a test is deemed to be low risk for complications, fits for the particular patient, the exact question to be a physician does not need to be present for the test but answered, potential alternatives to or modifications of should be immediately available. The American Heart exercise to answer the question at lower risk, and specific Association has issued guidelines for groups of patients indications to end the test early. Examples or relative con- who are felt to be at low risk for exercise complications. traindications are included in table 3. Any such list should The medical director of the laboratory should review all be amended for each individual laboratory based on the referrals to the exercise laboratory prior to scheduling, capabilities of the technical personnel and the characteris- determine which studies have significant risk, and ensure tics of the referral population. that a qualified physician will be present for the test. Finally, all children and their parents or legal guardians There are four general reasons to terminate an exercise should sign an informed consent prior to the exercise test- test: ing procedures. (1) The patient requests to end the test. (2) Diagnostic findings have been established or a predetermined end point has been reached. (3) Failure of monitoring equipment which could com- promise patient safety. (4) Signs or symptoms occur that pose a significant risk for the patient if exercise continues. Worrisome symptoms would include dizziness, stridor or any excessive dyspnea, and headache. Signs which 296 Fahey/Nemet/Cooper

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Weisman IM, Zeballos RJ (eds): Clinical Exercise Testing. Prog Respir Res. Basel, Karger, 2002, vol 32, pp 300–322 OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO An Integrative Approach to the Interpretation of Cardiopulmonary Exercise Testing Idelle M. Weismana R. Jorge Zeballosb aHuman Performance Laboratory, Department of Clinical Investigation, Pulmonary-Critical Care Service, William Beaumont Army Medical Center, El Paso, Tex., and Department of Medicine, Pulmonary-Critical Care Division, University of Texas Health Science Center at San Antonio, San Antonio, Tex.; bHuman Performance Laboratory, Department of Clinical Investigation, William Beaumont Army Medical Center, and Department of Anesthesiology, Texas Tech University Health Sciences Center, El Paso, Tex., USA Summary Glossary Cardiopulmonary exercise testing (CPET) is currently being AT Anaerobic threshold used in a wide spectrum of clinical applications because of the BP Blood pressure valuable information that it provides in patient diagnosis and CPET Cardiopulmonary exercise test management. The goals of this article are to provide an over- ECG Electrocardiogram view of our CPET interpretative strategy and to demonstrate EELV End expiratory lung volume (TLC – IC = EELV) how the information obtained during cardiopulmonary exercise extFVL/MFVL Exercise tidal flow-volume loop referenced to resting testing can be appropriately presented, systematically ap- maximal flow-volume loop proached, and meaningfully applied in the clinical decision-mak- f Breathing frequency ing process. A case study format will highlight this approach. HCO3– Bicarbonate HR Heart rate Introduction HRR Heart rate reserve IC Inspiratory capacity Cardiopulmonary exercise testing (CPET) is currently IET Incremental exercise test being used in a wide spectrum of clinical applications LT Lactate threshold because of the valuable information that it provides in MVV Maximal voluntary ventilation patient diagnosis and management. Increasing use of O2 pulse Oxygen pulse CPET has been fueled by advances in technology, scien- PaO2 Arterial oxygen tension tific advances in exercise physiology, and growing aware- PaCO2 Arterial carbon dioxide tension ness of the importance of the integrative exercise response P(A-a)O2 Alveolar-arterial oxygen pressure difference in clinical assessment [1–4]. PETO2 End-tidal pressure of oxygen PETCO2 End-tidal pressure of carbon dioxide In order to achieve optimal use of this modality in clin- pH Hydrogen ion concentration ical practice, clarification of conceptual issues and stan- RER Respiratory exchange ratio SpO2 Pulse oximetry The opinions or assertions contained herein are the private views of SaO2 Arterial oxygen saturation the authors and are not to be construed as official or as reflecting the TI/TTOT Ratio of inspiratory time to breath total time (duty cycle) views of the Department of the Army or the Department of De- VD/VT Physiologic dead space to tidal volume ratio fense. V˙ E Minute ventilation V˙ E/V˙ O2 Ventilatory equivalent for oxygen V˙ E/V˙ CO2 Ventilatory equivalent for carbon dioxide V˙ E/MVV Ratio of indices of ventilatory demand to ventilatory capacity V˙ CO2 Carbon dioxide output VT Tidal volume V˙ O2 Oxygen uptake V˙ /Q˙ Ventilation-perfusion ratio VR Ventilatory reserve

dardization of CPET practices are necessary [5]. Progress quality, subject effort, and reason(s) for exercise cessa- in this direction has begun with the publication of ERS tion; (4) the identification of key measurements – initially guidelines [6] and the near completion of the joint ATS- V˙ O2, then HR, V˙ E, and SaO2 with other measurements ACCP statement on Cardiopulmonary Exercise Testing. evaluated subsequently based on the reasons for which CPET was obtained; (5) attention to trending phenomena The goals of this article are to provide an overview of (i.e. submaximal through maximal exercise results) using our CPET interpretative strategy and to demonstrate how both tabular and graphic display formats; (6) determina- the information obtained during cardiopulmonary exer- tion of whether the measurements are normal or abnor- cise testing can be appropriately presented, systematically mal compared to appropriate (normal) reference values; approached, and meaningfully applied in the clinical deci- (7) evaluation of limitations(s) to exercise including a sion-making process. A case study format will highlight determination of a physiologic vs. non-physiologic basis; this approach. Exercise interpretation will emphasize car- (8) evaluation of patterns of exercise responses; (9) con- diopulmonary results generated during maximal incre- sideration of conditions/clinical entities which maybe as- mental cycle ergometry, which is currently the most popu- sociated with these patterns, and (10) correlation of exer- lar approach. The complementary role of constant-work cise results with the patient’s clinical information includ- CPET in the interpretative and clinical decision-making ing results of other tests (i.e. PFTs, echocardiogram). processes will also be demonstrated. Additional salient comments for some of these consid- Interpretative Strategies erations appear below although all are discussed subse- quently. An interpretative strategy that is scientifically based and sufficiently flexible to be applied to a variety of clini- Reason(s) for CPET: Should always be noted and cal entities/pathophysiologic conditions is required for addressed in the final report. the optimal utilization of CPET in clinical practice. Sev- eral approaches should be considered since there is no Clinical Status Evaluation: Results of history, physical consensus on any one. Approaches that emphasize the examination, resting lab tests (i.e. PFTs, EKG), level of mechanism for exercise limitation (i.e. ventilatory limita- physical activity (most easily obtained using a health tion to exercise) are limited by their lack of ‘gold standard’ questionnaire), and medication history are all essential to definition and the realization that exercise limitation is accurate interpretation. A more meaningful physiologic- often multifactorial [7–9]. Algorithms based on key mea- clinical correlation and, in turn, accurate interpretation of surements and conceptual framework [4, 10, 11] are lim- CPET is possible when a thorough clinical subject profile ited by excessive reliance on single measurements. Inter- is available. pretative error may result if that one measurement at a key branch point is wrong for whatever reason (i.e. anaer- Assessment of Patient Effort: Knowledge of patient obic threshold). Standard algorithms are also inadequate effort and motivation are necessary for the accurate inter- for the evaluation of patients with early/mild disease, in pretation of CPET. Several studies have shown that V˙ O2 patients with combined disease (heart-lung [see case peak is the same or similar to V˙ O2max when at least one of study]), and when variable responses are borderline [3, the following requirements occurs: (1) patient looks ex- 12]. The greatest diagnostic potential and impact of hausted; (2) heart rate or V˙ E is close to predicted; CPET on the clinical decision making process is best (3) lactate is greater than 8 mEq/l, and/or (4) respiratory achieved by using an integrative approach to CPET inter- exchange ratio is greater than 1.15 [13–15]. A test may pretation, which emphasizes the interrelationships, trend- also be discontinued because of significant symptoms ing phenomena, and patterns of key variable responses in and/or serious ECG changes. a clinical setting framework [3, 6]. Reasons for Exercise Cessation: Should also be noted Integrative Approach and quantitated (i.e. Borg scale for dyspnea/leg fatigue/ An integrative approach to the interpretation of CPET chest pain) [16] (see chapter on Methodologic issues). results includes consideration of the following: (1) rea- Finally, as patients are often symptom rather than physio- son(s) for CPET; (2) attention to pertinent clinical and logically limited, a reduced V˙ O2peak may also reflect poor laboratory information; (3) assessment of overall test (or sub-maximal) effort with uncertainty persisting about exercise limitation and V˙ O2peak. The importance of as- sessing patient effort when V˙ O2peak is critical in clinical decision analysis has recently been underscored in a study involving patients for cardiac transplantation [17]. Interpretation of Cardiopulmonary Exercise 301 Testing

Reference Values: The selection of an appropriate set Measurements and Graphic Interrelationships of reference values is a function of the patient population, age, height, weight, sex, and physical activity and may Computerized exercise systems permit an impressive vary from lab to lab [4, 18, 19]. Knowledge of physical number of variables to be measured during CPET (ta- activity is important in accurately interpreting CPET ble 2). The number of variables to be measured will results. For example, very fit individuals and athletes may depend on the reasons for which CPET was requested. experience significant reductions in their peak V˙ O2 as a The graphic inter-relationships between these variables result of pulmonary, cardiac or (peripheral) muscle illness are discussed in the case studies. Also, in table 2, the mea- and still be within the normal confidence interval for sed- surements are represented as noninvasive or invasive (i.e. entary subjects. Different sets of maximal (or peak) refer- arterial sampling intervention). A listing of selected peak ence values may have significant impact on the interpre- CPET measurements, including caveats and suggested tation of CPET results as demonstrated in table 1. There- normal guidelines for interpretation gleaned from the lit- fore, for the future, standardization of normal reference erature, appear in table 3. values processes/practices for CPET is necessary to facili- tate interpretation and optimize clinical application V˙O2max or V˙O2peak [3, 6]. The measurement of V˙ O2max or V˙ O2peak remains the best index for the assessment of exercise capacity. Table1. Impact of different reference values on interpretation of car- V˙ O2peak should be directly measured since its estimation diopulmonary exercise testing results from resting indices, work rate, or exercise protocols is unreliable [20]. V˙ O2peak should be expressed in absolute 59-year-old white female, nonsmoker, 160 cm, 83 kg values (liters/min) and as percent predicted. The optimal FVC = 100%; FEV1 = 115%; FEV1/FVC = 86%; TLC = 104%; normalization for body mass remains controversial. The DLCO = 84% normalization could be done for body weight (ml/kg/ Protocol: maximal, symptom-limited 10 W/min incremental exer- min), body mass index (kg/m2), or ideally for fat-free mass cise test (ml/kg/min) [21]. Some prefer normalization by height (V˙ O2/ht) as it may prove to be a better correlate of lean Variables Peak Hansen Jones Blackie body mass [4]. V˙ O2/kg is most commonly used (i.e. Amer- [80] [96] [97, 98] ican Heart Association, American College of Sports Medi- cine) and is the easiest to calculate, but may produce Work rate, W 70 95% 60% 50% deceptively low values in obese subjects [22]. V˙ O2max V˙ O2, liters/min 1.23 88% 79% 65% values have been regarded as most reliable when V˙ O2 V˙ E, liters/min 61 74% 105% 102% does not increase (plateau) despite further increase in HR, beats/min 155 90% 97% work rate [23, 24]. Such a plateau however, especially in 8 100% 73% patients is not often observed and the maximum V˙ O2 O2 pulse, ml/beat Table 2. Cardiopulmonary variables Variables Noninvasive Invasive (ABGs) measured during cardiopulmonary exercise testing Work WR lactate Metabolic V˙ O2, V˙ CO2, R, AT Cardiovascular HR, ECG, BP, O2 pulse SaO2, PaO2, P(A-a)O2, Ventilatory V˙ E, VT, f VD/VT Pulmonary gas SpO2, V˙ E/V˙ CO2, V˙ E/V˙ O2 PETO2, pH, PaCO2, HCO3– PETCO2 exchange Acid, base Dyspnea, leg fatigue, chest pain Symptoms Abnormality of a variable does not necessarily define exercise limitation in that category. Modified from Zeballos and Weisman [19], with permission. 302 Weisman/Zeballos

Table 3. Selected peak cardiopulmonary exercise testing measurements Variables Measurement caveats Comments Suggested guidelines [3, 4, 80, 87, 91] V˙ O2max or max: When plateau is achieved global assessment of respiratory, cardiovascular, 1 84 % predicted V˙ O2peak peak: V˙ O2 at max exercise, but no plateau blood and muscle function Anaerobic direct: lactate in arterial blood; indirect: modified threshold V-Slope (V˙ CO2 vs. V˙ O2) and conventional estimator of the onset of metabolic acidosis during 1 40% V˙ O2max predicted; (a.k.a. lactate (V˙ E/V˙ O2, V˙ E/V˙ CO2, PETO2, PETCO2); no one wide range of normal: 35–80%; threshold) noninvasive method is consistently superior exercise (AT); not an effective discriminator among clinical validation is required Heart rate (HR) predicted maximum HR: 210 – (age !0.65) different clinical entities; appears nonessential for Reserve (HRR) HRR: Age Predicted max HR – max HR achieved exercise Rx in COPD; 50–60% V˙ O2max in average O2 pulse persons; higher in fit persons (V˙ O2/HR) determined at plateau, when max O2 extraction ¢V˙ O2/¢WR and stroke volume have been reached age-related variability in max HR predicted; max HR 1 90% age predicted measured during IET (V˙ O2peak – V˙ O2 min 3 normals usually no HRR HRR ! 15 bpm Ventilatory unloading)/(W/min ! duration test – 0.75) reserve (VR) reflects stroke volume assuming that O2 extraction is 1 80% MVV – V˙ Emax or V˙ E/MVV ! 100 (widely used). normal; its use in COPD/CHF remains unvalidated Breathing MVV can be measured directly or calculated frequency (f) (FEV1 ! 40); extFVL/MFVL to visualize ‘limi- used as index of O2 delivery/utilization by the 1 8.3 ml/min/W tation’; quantitate: IC = TLC-EELV; EILV/TLC muscle; could be abnormal in patients with cardio- V˙ E/V˙ CO2 vascular/pulm vascular disease; normal in patient MVV – V˙ Emax: 1 11 liters; (at AT) different breathing strategies in COPD and ILD; with pulmonary disease V˙ E/MVV ! 100: ! 75% wide erratic in malingers; high in psychogenic disorders normal range: 72 B15% VD/VT potential ventilation in L that could be increased; measured throughout but reported at AT (near percentage of the max breathing capacity used; PaO2 nadir) when PaCO2 is steady, to avoid the effect of no gold standard for its determination hyperventilation acidosis, etc. P(A-a)O2 reflects abnormalities in the mechanics of breathing, ! 60 brpm PaCO2 should be used in its determination; control of breathing, and/or hypoxemia or psycho- PETCO2 produces unreliable results logical disorders careful anaerobic collection at near maximal and noninvasive measurement of efficiency of ventila- ! 34 peak exercise for consistency in the results tion (L of V˙ E to eliminate 1 liter of V˙ CO2); reflects increase in VD/VT and or hyperventilation. arterial blood should be collected slowly in the middle of the respective interval reflects efficiency of CO2 exchange or lung units ! 0.28 with proportionally higher V˙ A than Q˙ (increased VD); normally decreases with increased exercise intensity ability to exchange O2 is best assessed by measure- 1 80 mm Hg ment of PaO2 and not by pulse oximetry evaluates gas transfer; abnormal high values may ! 35 mm Hg reflect V˙ /Q˙ mismatching (shunt type), diffusion limitation, shunt and/or reduced PvO2 Modified from Weisman and Zeballos [25], with permission. achieved is called V˙ O2peak [13–14]. For practical pur- Anaerobic Threshold (AT) poses V˙ O2max and V˙ O2peak are used interchangeably. Also known as lactate threshold (LT), is an estimator of the onset of metabolic acidosis caused predominantly by A reduced V˙ O2peak response to exercise reflects prob- increases in lactic acid during exercise. After 30 years, the lems with O2 transport and/or peripheral abnormalities physiologic significance, clinical significance, and the [1, 7–9]. A reduced V˙ O2peak may also reflect poor effort. methodology for the determination of the AT remain con- V˙ O2peak is modulated by physical activity, and, conse- troversial [26–28]. Current knowledge would suggest that quently, is considered the gold standard for the evaluation the AT may be considered to be affected by factors that of level of fitness. A normal V˙ O2peak reflects a normal impact both O2 transport and O2 utilization processes, aerobic power and exercise capacity and provides reassu- pattern of muscle fiber recruitment, and possibly others [29]. The AT is usually 50–60% V˙ O2max in sedentary rance that no significant functional abnormality exists. individuals and higher in fit individuals [4]. There is a Even though the V˙ O2peak is normal, CPET may reveal wide range of normal predicted values (35–70%) [6]. other abnormalities (i.e. abnormal breathing patterns [see case studies]) that may be of diagnostic value [25]. Interpretation of Cardiopulmonary Exercise 303 Testing

The AT can be determined invasively by measurement Ventilatory Reserve (VR) of arterial lactate (gold standard) or, more often, noninva- This concept is used to denote if ventilatory limitation sively using ventilatory or gas exchange variables. Al- occurs during exercise. It expresses the relationship be- though there are several ways to determine the AT nonin- tween the maximal ventilation achieved during exercise vasively, none appears consistently superior [30]. Cur- (V˙ Emax) as an index of the ventilatory demand and the rently, the modified V-slope method (change in the slope MVV as an estimator of the maximal ventilatory capacity. of the plot of V˙ CO2 vs. V˙ O2) is most popular [31]. The AT, This relationship can be expressed as V˙ E/MVV [4]. VR is using the ventilatory equivalents method, is defined as the dependent on many factors responsible for ventilatory lowest (nadir) for V˙ E/V˙ O2 and PETO2 before beginning to demand including metabolic demand, body weight, mode consistently increase, while V˙ E/V˙ CO2 and PETCO2 remain of testing, dead space ventilation as well as neuroregulato- unchanged [4]. A ‘dual methods’ approach, which com- ry and behavioral considerations. Mechanical factors, bines the modified V-slope and the ventilatory equiva- ventilatory muscle function, genetic endowment, aging, lents method, is recommended [19] (see case studies). and disease impact maximal ventilatory capacity [33]. RER \" 1 is also useful [4]. False-positive noninvasive AT Ventilatory capacity may also vary during exercise de- determinations have been reported in COPD and can be pending on bronchodilation or bronchoconstriction and avoided by obtaining blood samples for standard bicar- operational lung volume [34]. bonate or lactates [26]. The AT determination is helpful A high V˙ E/MVV is one of the criteria often used to as an indicator of level of fitness and to monitor the effect indicate encroachment on the ventilatory reserve and pos- of physical training [32]. The AT is reduced in a wide sible ventilatory limitation to exercise. Although widely spectrum of clinical entities – i.e. heart disease, lung dis- used and practical, MVV may not be a reliable indicator ease, deconditioning, post lung and heart transplantation, of maximal ventilatory capacity nor provide insight into skeletal muscle abnormalities (metabolic myopathy, mus- breathing strategy (see chapter on methodology) [34]. cle dysfunction in chronic disease), etc., and, therefore, Controversy has surrounded the assessment of VR and may be of limited discriminatory value in interpretative V˙ E/MVV. Emerging methodologies compare aligned exer- schemes [3]. cise tidal flow-volume loops to resting maximal flow-vol- ume loops (extFVL/MFVL). The volume and the expira- Heart Rate tory flow rate differences between the exercise tidal flow The best index for the evaluation of cardiac function volume loops and MFVL curve maybe useful for the during exercise would be the measurement of cardiac out- determination of ventilatory limitation and calculation of put. However, this is not routinely performed in the clini- the theoretical maximal ventilatory capacity (V˙ Ecap [see cal exercise laboratory. Since it is well established that chapter on Methodology]) [34]. Exercise tidal flow-vol- increase in cardiac output are initially accomplished by ume loop analysis has been applied in several clinical set- increases in stroke volume and HR, and then at higher tings [34–38]. Alternatively, the negative expiratory pres- work rates almost exclusively by increase in HR [24], the sure (NEP) technique has been suggested as a means to evaluation of HR yields an estimate of the level of cardiac determine expiratory flow limitation by applying negative output achieved during exercise. pressure (5 cm) at the mouth during expiration and deter- It is important to remember that there is considerable mining whether ventilation is able to increase [39]. How- variability (10–15 beats per minute) within an age group ever, unless NEP technique is combined with an assess- when these estimates of maximal HR are used. The differ- ment of exercise tidal flow volume loops, flow limitation ence between the age-predicted maximal HR and the max- is defined as ‘all or none’ without any quantitation of con- imum HR achieved during exercise is referred to as the straint. HR reserve (HRR). Normally, at maximal exercise, there is little or no heart rate reserve. Peak heart rate achieved Pulmonary Gas Exchange during exercise in patient populations, however, may vary The ventilatory equivalent for V˙ CO2 (V˙ E/V˙ CO2) is a good considerably due to the disease itself or due to medications noninvasive estimator of inefficient ventilation. This used in treatment. Finally, heart rate recovery has recently variable should be reported at the AT (near its nadir) been reported to be important as an independent predictor when PaCO2 is steady to avoid the effect of the lactic aci- of mortality in a cohort of patients referred for exercise dosis and other stimuli (anxiety) on ventilation. Higher electrocardiography [32a], see chapter Methods for Car- values reflect hyperventilation and/or increased dead diopulmonary Exercise Testing, pp 43–59. space (wasted) ventilation. Determination of PETCO2, or 304 Weisman/Zeballos

preferably PaCO2, is useful in distinguishing between Table 4. Mechanisms of exercise limitation these possibilities [3, 4, 18]. Pulmonary In clinical settings requiring accurate pulmonary gas Ventilatory (mechanical) Respiratory muscle dysfunction (dynamic hyperinflation) exchange determinations, direct arterial blood gas (ABG) Gas exchange sampling during exercise should be considered for calcu- Cardiovascular Reduced stroke volume lation of alveolar-arterial oxygen pressure difference Abnormal heart rate response Abnormal systemic and pulmonary circulation (PAO2 – PaO2) and physiologic dead space to tidal vol- Hemodynamic consequences of dynamic hyperinflation ume ratio (VD/VT) [40]. VD/VT determined noninvasively Abnormal blood (anemia, COHb) using PETCO2 yields unreliable results [41]. PaO2 and SaO2 should be directly measured since pulse oximetry is only Peripheral Inactivity (disuse), loss of muscle mass (atrophy), an estimator of SaO2 [19]. Corroboration of incremental neuromuscular dysfunction results may be achieved with ABG measurement during a Peripheral circulatory abnormalities Reduced skeletal muscle oxidative capacity 6-min constant work (CW) exercise test at 70% of the (metabolic myopathy, COPD) maximum work achieved, which is \" 90% V˙ O2peak (see Malnutrition case studies). Recently, validation of pulmonary gas ex- Perceptual change measurements during IET with CW testing above Motivational Environmental the AT has been reported [42]. Abnormal widening of Exercise limitation is often multifactorial P(A-a)O2 with exercise usually reflects V˙ /Q˙ mismatching, but also can be due to diffusion abnormalities, anatomical itation resulting in reduced V˙ O2max. These include car- diovascular limitation (O2 transport), ventilatory limita- shunt and/or reduced O2 saturation in mixed venous tion, and peripheral limitation; the latter involves a broad blood worsening the V˙ /Q˙ mismatching (shunt effect) [43]. spectrum of abnormalities that could impact tissue O2 conductance, O2 utilization and mechanisms of contrac- Normally, VD/VT decreases as exercise intensity increases tion [50–51]. [3, 4, 18, 43]. Failure of VD/VT to decrease normally with exercise is indicative of V˙ /Q˙ abnormalities caused by increases in physiologic dead space (wasted ventilation) [3, 4, 18, 43]. VD/VT measurements can be impacted by exercise breathing patterns resulting in abnormally high values [44, 45]; both false-positive [46] and false-negative [47] results have been reported. Clinical Signs and Symptoms Evaluation of Cardiopulmonary Exercise Testing Ratings of perceived exertional symptoms (breathless- Results ness, fatigue, chest pain) using the Borg Scale (0–10) [16] A reduced V˙ O2peak is the starting point in the evalua- or other rating scores including visual analogue scales tion of reduced exercise capacity. Typical CPET response [48–49] should be noted with the physiologic measure- patterns for several clinical conditions including chronic ments (table 2). heart failure, COPD, ILD, pulmonary vascular disease, obesity, and deconditioning appear in table 5. This table Exercise Limitation is admittedly oversimplified and does not permit the wide range of responses that may be seen within a full spectrum Clinically, it is increasingly appreciated that exercise (mild to severe) of patients with, for instance, COPD or limitation or low V˙ O2max achieved is multifactorial and, heart disease. It must be clearly appreciated that signifi- as such, is not limited by any single component of the O2 cant overlap exists in the response patterns of patients transport/utilization process, but rather by their collective with different cardiopulmonary diseases to exercise. Fur- quantitative interaction [7–9]. Although several factors thermore, coexisting conditions (obesity, deconditioning, may be involved, one factor often predominates with etc.), often contribute to exercise intolerance and may variable contributions to exercise intolerance from the confound CPET interpretation. other factors. Exercise in normal subjects is mainly lim- ited by the cardiovascular system. Table 4 lists the most Cardiovascular Disease important categories and factors involved in exercise lim- Many factors contribute to exercise intolerance in pa- tients with cardiovascular disease including inadequate Interpretation of Cardiopulmonary Exercise 305 Testing

Table 5. Usual cardiopulmonary exercise response patterns Measurements Heart failure COPD ILD Pulmonary Obesity Deconditioned decreased vascular disease V˙ O2max or peak decreased decreased normal or decreased decreased decreased for actual, decreased normal for ideal weight decreased decreased Anaerobic threshold decreased normal/decreased/ normal normal or indeterminate normal or decreased normal/slightly decreased normal or increased decreased Peak HR variable, decreased, increased decreased normal/slightly normal/slightly usually normal normal in mild increased normal decreased decreased O2 pulse decreased decreased increased (Peak V˙ E/MVV) ! 100 normal or decreased normal or decreased increased increased normal decreased V˙ E/V˙ CO2 (at AT) normal or increased decreased VD/VT increased increased increased normal or increased normal PaO2 normal PAO2 – PaO2 normal increased normal normal increased normal normal variable normal/may increase normal variable, may decrease normal usually increased Decreased, normal, increased with respect to normal response. Modified from multiple sources [4, 25, 67]. O2 transport, abnormalities in the distribution of the reserve but with an abnormal breathing strategy consist- peripheral circulation, skeletal muscle abnormalities (i.e. ing of rapid respiratory frequency and low tidal volumes. O2 utilization, atrophy, etc.), deconditioning, and pulmo- A spectrum of pulmonary gas exchange abnormalities nary abnormalities [52–55]. Consequently, these patients including evidence of inefficient ventilation (increased stop exercise prematurely with attainment of a lower V˙ O2. V˙ E/V˙ CO2) increased dead space ventilation (abnormal Early onset metabolic acidosis is manifested by a reduced VD/VT responses), hypoxemia (↓ PaO2), and arterial desa- AT. O2 pulse, as an indirect measure of reduced stroke turation with abnormal widening of the P(A-a)O2 are seen volume (assuming normal CaO2-CvO2), is reduced and [4, 18, 56, 59, 60]. cardiac output is maintained almost exclusively by in- creases in heart rate [56]. Usually, there is little or no heart Deconditioning rate reserve; however, this may be highly variable and is a Physical inactivity, for a variety of reasons. is the main function of the type and severity of the heart disease [56]. cause of deconditioning or unfitness [61–63]. In decondi- Patients with heart failure manifest an abnormal heart tioning, early cessation of exercise is associated with low/ rate response with the likelihood of chronotropic dysfunc- low normal V˙ O2peak, normal or early onset of metabolic tion increasing as disease severity increases [56, 57]. The acidosis (normal/low AT), a reduced O2 pulse, and little/ early exercise cessation is usually associated with a re- no HRR but with increased HR at submaximal levels of duced V˙ Emax, a considerable ventilatory reserve and no V˙ O2. There is significant ventilatory reserve and no abnor- arterial desaturation. Increases in VD/VT and V˙ E/V˙ CO2 due mal pulmonary gas exchange. Deconditioning is often dif- to reduced pulmonary perfusion consequent to reduced ficult to distinguish form early or mild heart disease [3, 4, cardiac output are also observed [58]. The presence of a 18, 56]. Although occurring much less frequently, recent reduced ventilatory reserve (high V˙ E/MVV) in these pa- work has suggested that mitochondrial myopathy also be tients may signal the presence of combined cardiovascu- included within the differential diagnosis [64]. Decondi- lar and respiratory limitation [12] (see case study 4). tioning commonly co-exists in patients with chronic ill- ness including those with heart and lung disease and in Pulmonary Vascular Disease patients with mitochondrial myopathy. Response to an Patients with pulmonary vascular disease are likewise aerobic training regimen with monitoring of responses usually cardiovascular limited, with a normal ventilatory (V˙ O2, O2 pulse, AT, HR) may help to distinguish between 306 Weisman/Zeballos

heart disease and deconditioning, but not necessarily interstitial pulmonary fibrosis has suggested that the ven- between deconditioning and mitochondrial myopathy tilatory reserve is normal and that cardiovascular/pulmo- (see chapter on Mitochondrial Myopathy) [64]. nary circulatory limitation to exercise occurs [72]. The AT is usually normal, but pulmonary circulatory involvement Chronic Obstructive Pulmonary Disease may be suspected if the AT is low. A combined cardiovas- Depending on the stage of disease, a spectrum of exer- cular and respiratory limitation may exist [3]. Rapid, cise response patterns can be seen in patients with COPD. shallow breathing (high respiratory rate, low tidal volume) Whereas, patients with mild COPD have an essentially occurs commonly as does evidence of inefficient ventila- normal exercise response pattern with normal/near nor- tion (↑ V˙ E/V˙ CO2) in response to increases in VD/VT. mal exercise capacity, patients with moderate-to-severe Impressive arterial desaturation with abnormal widening COPD will usually have reduced V˙ O2peak and work rate of PAO2 – PaO2 is usually seen [73–76]. (see chapter on COPD) [65–67]. One of the distinguishing features of many patients with COPD is a reduced ven- Obesity tilatory reserve (V˙ E/MVV approaching or exceeding V˙ O2 as percent of predicted can be normal or low in 100%) suggesting ventilatory limitation to exercise [4]. obese patients; however, when expressed as V˙ O2 per kg There is usually significant heart rate reserve, a reflection body weight is low and with increasing obesity; dispro- that the cardiovascular system has been relatively un- portionately lower. There is an excessive metabolic re- stressed. In a retrospective study of patients with COPD quirement manifested by an upwardly displaced V˙ O2- categorized as mild, moderate, or severe, as disease sever- work rate relationship with a normal slope [77]. The V˙ E at ity progressed, V˙ O2max and VR decreased and HRR a given external WR is higher as a reflection of increased increased [68]. Exercise limitation in COPD, however, is mechanical work, but the ventilatory reserve (V˙ E/MVV) usually multifactorial [7–9]. can be normal or increased. A trend towards abnormally In patients with COPD, the AT response may be nor- increased respiratory rate and reduced tidal volume is mal, low or indeterminate. Early onset metabolic acidosis often seen [78]. Recent exercise tidal flow-volume loop (low AT) usually reflects deconditioning due to physical analysis suggests that there is ventilatory constraint (flow inactivity and/or skeletal muscle dysfunction including limitation) during exercise as obese subjects breathe at alterations in exercise related substrate levels, especially low lung volumes [33–35]. HR is increased at submaxi- glutamate [63, 69]. The O2 pulse is usually (but not invari- mal work with attainment of normal or near normal peak ably) proportionately reduced to V˙ O2max due to ventilato- HR with little or no heart rate reserve [79]. Resting PaO2 ry limitation, deconditioning and possibly hypoxemia. and P(A-a)O2 may improve with exercise, reflecting im- Reduction in O2 pulse, as has been suggested, may also proved V˙ /Q˙ relationships. Obesity is often associated reflect the hemodynamic consequences of dynamic hyper- with other conditions in negatively impacting exercise inflation [70]. Other respiratory abnormalities include capacity. increasing dynamic hyperinflation (IC decreases with ex- ercise), inefficiency of ventilation (V˙ E/V˙ CO2) due to in- Conclusions creased dead space ventilation with abnormal VD/VT responses, alveolar hypoventilation with PaCO2 not The integrative approach to the interpretation of changing or increasing compared to normals, and hypox- CPET results is evolving and requires attention to funda- emia [3, 4, 18, 66, 67, 71]. PaO2 may be variable but is mental principles including a systematic analysis of fac- more often reduced in patients with moderate-severe tors discussed previously (see section on Integrative Ap- COPD; PAO2 – PaO2 usually increases abnormally, espe- proach, fig. 1, and tables 1–5). Inherent in this approach cially when PaO2 decreases. are ‘operational’ assumptions (precepts) that, although reasonable, require additional study. For instance, al- Interstitial Lung Disease (ILD) though a ‘patterns based’ approach is flexible and theoret- V˙ O2peak and peak work rate are usually reduced. A ically attractive, relatively few studies have evaluated the spectrum of ventilatory and pulmonary gas exchange sensitivity, specificity, and positive predictive value of abnormalities are seen (see chapter on ILD). A reduced patterns of exercise responses in diagnosing and distin- ventilatory reserve (high V˙ E/MVV) and ventilatory limi- guishing different clinical entities. Moreover, the impact tation to exercise are often seen in patients with ILD. of this approach on clinical decision-making in well-estab- However, a recent retrospective analysis of patients with Interpretation of Cardiopulmonary Exercise 307 Testing

Fig.1. Overview of a step approach to the interpretation of cardiopul- plished by analysis of ventilatory reserve (V˙ E/MVV) and heart rate reserve (HRR). The AT may be helpful at this point in establishing monary exercise testing results. Initial consideration of patient infor- generic diagnostic categories. Additional CPET measurements and patterns of response are established and (likely) associated clinical mation, reason(s) for testing, and analysis of overall quality of the test entities are considered resulting in more specific diagnostic pathways are followed by determination of normality of V˙ O2max/V˙ O2peak. [99] (reprinted with permission). Subsequently, simultaneous assessment of three basic variables – HR, V˙ E and SaO2. Determination of physiologic limitation is accom- lished clinical entities remains incompletely character- situations. In addition to the exercise response data, ized. Fortunately, an increasing number of well-designed appropriate baseline clinical and laboratory data will be and executed clinical studies that fulfill evidence-based presented to enhance the physiologic-clinical correlation. criteria are providing an expanded database of CPET The contribution of the exercise results in the clinical results for systematic review that hopefully will provide decision-making process is emphasized. For practical pur- answers to clinically relevant questions not immediately poses, interpretation of these case studies was accom- available. plished using information provided in tables 2–5 and fig- ure 1. Case Studies The data are formatted for both tabular and graphic The integrative approach to the interpretation of analysis. Maximal predicted values from Hansen et al. CPET results is highlighted in the following case studies. [80] were used. Multiple sources were used to provide the The 4 cases that will be presented reflect common clinical comparative normal responses for the graphic representa- tion of the submaximal exercise [80–82]. Suggested crite- ria for normal maximal values for interpretation of CPET 308 Weisman/Zeballos

Table 6. Maximal cardiopulmonary incremental exercise test with pre and post spirometry in a patient with exertional dyspnea (case 1) 20-year-old male, Hispanic, height: 173 cm, weight: 69 kg; clinical Dx: asthma Medications: none Reason for testing: unexplained exertional dyspnea a Cardiopulmonary exercise test1 Variable Peak % pred Work rate, W 200 83 V˙ O2, liters/min 2.92 98 V˙ O2, ml/kg/min 42.3 98 AT, liters/min 1.60 N (1 1.19) ¢V˙ O2/¢WR 12.3 N (1 8.3) HR, bpm 181 91 108 O2 pulse, ml/beat 16.1 63 BP, mm Hg H N V˙ E, liters/min 106 f, br/min 96 V˙ E/V˙ CO2, at AT 25 Stop: volitional exhaustion/fatigue 10/10. b Spirometery before and after CPET (exercise-induced bronchoconstriction test) Baseline 5 min %2 15 min %2 30 min %2 Post %3 post post post BD FVC 5.06 (96%) 5.14 +2 4.51 –11 4.47 –12 4.58 +2 4.34 (97%) 4.25 –2 3.63 –16 3.34 –23 3.76 +13 FEV1 86% 83% 80% 75% 82% FEV1/FVC 5.09 (104%) 5.45 +7 3.82 –25 2.26 –49 4.60 +103 FEF25–75 1 Protocol: maximal, symptom-limited incremental cycle ergometry, 25 W/min. 2 Percent change from baseline values. 3 Percent change post bronchodilator from 30-min values. results obtained from several sources appears in table 3. Case Study 1: Maximal CPET in a Subject with These suggested guideline values are (at least for some Exertional Dyspnea variables) approximations of normality; evidence based criteria are necessary. Some of the data have been modi- Clinical History fied to enhance/focus the case relevant didactic message. A 20-year-old soldier, lifelong nonsmoker with a past medical history remarkable only for some poorly charac- Exercise interpretation is limited to CPET results gen- terized childhood allergies was referred for evaluation of a erated during maximal incremental cycle ergometry. In 2 1-month history of exertional shortness of breath associat- cases, arterial blood gases were obtained at rest and then ed with chest tightness and inability to pass a required during minute 5 of constant work exercise testing which 2-mile run that he had successfully completed 3 months was used for an approximation of peak values for pulmo- earlier. Physical examination, chest roentgenography, nary gas exchange. Finally, the reader is reminded that for ECG, and screening laboratory tests, including pulmo- the interpretation of pulmonary gas exchange, our labora- nary function tests, were all within normal limits. A tory is at 1,270 m, mean barometric pressure 656 mm Hg methacholine challenge test was positive (PC20 = 4.2 mg/ (PIO2 = 128 mm Hg). ml) and a diagnosis of exercise-induced bronchospasm (EIB) was established. After 6 weeks of an aggressive asth- Interpretation of Cardiopulmonary Exercise 309 Testing

Fig. 2. Graphic representation of a maximal, incremental, cardiopul- D minute ventilation (V˙ E) vs. carbon dioxide output (V˙ CO2). E Tidal volume (VT) and respiratory frequency (f) vs. V˙ O2. F Ventilatory monary exercise test in a subject with unexplained exertional dys- equivalent for O2 (V˙ E/V˙ O2), ventilatory equivalent for CO2 (V˙ E/ V˙ CO2) vs. V˙ O2. G Minute ventilation (V˙ E) vs. V˙ O2. H End-tidal pres- pnea. These graphic data are 1-min interval averaged. The results are sure for O2 (PETO2) and end-tidal pressure for CO2 (PETCO2) vs. V˙ O2. Graphs F and H are also used for the determination of the AT using compared with calculated reference values obtained from several sources (dashed line). A Oxygen uptake (V˙ O2) vs. work rate. B Heart the ventilatory equivalents method. rate (HR) and O2 pulse vs. V˙ O2. C Indirect determination of the anaerobic threshold (AT) using the modified V slope method in which the carbon dioxide production (V˙ CO2) is plotted vs. V˙ O2. ma treatment regimen, there was significant abatement of Interpretation of Exercise exertional chest tightness symptoms but shortness of breath persisted. While awaiting discharge from the Army Excellent effort was evidenced by near maximal pre- for asthma, a CPET was performed to exclude the possi- dicted value for V˙ O2 (98%), greater than normal pre- bility of an additional etiology for his exertional shortness dicted O2 Pulse (108% predicted), predicted HR = 91%, of breath. Anthropomorphic data, PFTs, and peak CPET and the patient appearing exhausted. Exercise stopped results appear in table 6 and graphically in figure 2. because of leg fatigue (7/10). The aerobic capacity (V˙ O2 peak) was normal as was the V˙ O2-work rate relationship 310 Weisman/Zeballos

(A). There was a normal cardiovascular response to exer- Table 7. Maximal cardiopulmonary incremental exercise test in a cise with a normal HR-V˙ O2 relationship (B) and O2 pulse patient with non-ischemic, dilated, cardiomyopathy (case 2) response (B). The AT was indeterminate using the V-slope method due to an abnormal breathing pattern (C [see 31-year-old female, Caucasian, height: 175 cm, weight: 94 kg; clinical below]). However, the AT was identified and within nor- Dx: cardiomyopathy mal limits using the ventilatory equivalents method (F, H) thereby providing practical evidence that the ‘dual a Resting pulmonary function tests methods’ approach is preferable to using only 1 noninva- sive methodology for AT determination [19]. There was Variable Actual % pred [100] plenty of ventilatory reserve at peak exercise (D, G) with a normal V˙ O2 vs. V˙ E relationship (G). An abnormal, atypical FVC, liters 4.23 96 breathing pattern was noted with f dramatically increas- FEV1, liters 3.62 99 ing from 29 breaths per minute to 70 within 1 min and in FEV1/FVC 86% the next minute achieving f = 96 at peak exercise (E)! This TLC, liters 5.81 100 was associated with an increased but flattened VT re- RV, liters 1.43 99 sponse, which actually decreased as f dramatically in- DCO, ml/min/mm Hg 20.7 77 creased (E). Alveolar hypoventilation was noted as PETCO2 increased to 50 mm Hg during low-to-moderate intensity b Cardiopulmonary exercise test1 exercise and which decreased to only 42 mm Hg at peak exercise (H). Variable Peak % pred Spirometry performed before and after cycle exercise Work rate, W 135 76 revealed a normal baseline study and significant reduc- V˙ O2, liters/min 1.51 76 tions in FEV1 at 15 and 30 min postexercise with signifi- V˙ O2, ml/kg/min 16.1 57 cant improvement after inhaled bronchodilator (table 6). AT, liters /min 0.80 L (1 1.24) This is consistent with the diagnosis of EIB that was ini- ¢V˙ O2/¢WR 7.60 L (1 8.3) tially suggested by methacholine challenge [6, 83–85] (see HR, bpm 170 90 chapters on Asthma and Exercise and Modalities of Clini- 84 cal Exercise Testing – EIB). O2 Pulse, ml/beat 8.9 57 BP, mm Hg 125/75 N N V˙ E, liters /min 66 f, br/min 51 V˙ E/V˙ CO2, at AT 32 SpO2,% (rest 94%) 94% Stop: Leg fatigue 10/10; ideal weight = 71 kg. Conclusion 1 Protocol: maximal, symptom-limited, incremental cycle ergome- Abnormal CPET with spirometry despite an aerobic try, 15 W/min. capacity that was WNL. CPET was useful in establishing 2 coexisting diagnoses – EIB and psychogenic dysfunc- Postscript tion. The patient was referred for psychological evaluation and the diagnosis of separation anxiety (from family) was Comment confirmed. The patient was discharged from the armed This case underscores the value of noting both maximal services. and submaximal CPET responses especially in estab- lishing a psychogenic etiology of unexplained exertional Case Study 2: Maximal CPET in a Patient with dyspnea [25]. The magnitude of the abnormal breathing Nonischemic Dilated Cardiomyopathy response pattern is noteworthy and atypical for asthma. Furthermore, typically in asthma, the bronchoconstriction Clinical History occurs postexercise [6, 84]. As 10% of patients with unex- A 31-year-old Caucasian female, lifelong nonsmoker plained exertional dyspnea have 2 etiologies (see chapter with nonischemic dilated cardiomyopathy, with LVEF on Unexplained Dyspnea), it is important to monitor !30–35%, normal coronaries, increased filling pressures response to treatment [25, 46]. A second CPET performed (LVEDP = 20 mm Hg, RV (systolic/diastolic) = 50/18 on another day while the patient was on an optimized asth- mm Hg, RA = 12 mm Hg), moderate pulmonary hyper- ma regimen elicited the same magnitude of abnormal breathing pattern but without significant changes in post- exercise spirometry (negative test for EIB). Interpretation of Cardiopulmonary Exercise 311 Testing

Fig. 3. Graphic representation of a maximal, incremental, cardiopul- D Minute ventilation (V˙ E) vs. carbon dioxide output (V˙ CO2). E Tidal volume (VT) and respiratory frequency (f) vs. V˙ O2. F Ventilatory monary exercise test in a patient with non-ischemic dilated cardio- equivalent for O2 (V˙ E/V˙ O2), ventilatory equivalent for CO2 (V˙ E/V˙ CO2) vs. V˙ O2. G Minute ventilation (V˙ E) vs. V˙ O2. H SpO2 vs. V˙ O2. I End- myopathy. These graphic data are 1-min interval averaged. The tidal pressure for O2 (PETO2) and end-tidal pressure for CO2 (PETCO2) vs. V˙ O2. Graphs F and I are used for the determination of the AT results are compared with calculated reference values obtained from using the ventilatory equivalents method. several sources (dashed line). A Oxygen uptake (V˙ O2) vs. work rate. B Heart rate (HR) and O2 pulse vs. V˙ O2. C Indirect determination of the anaerobic threshold (AT) using the modified V slope method in which the carbon dioxide production (V˙ CO2) is plotted vs. V˙ O2. tension PA (systolic/diastolic/ mean) = 45/20/28 mm Hg), illness, she was physically active running 3 ! weekly. and global hypokinesis was referred for CPET as part of a Current medications included carvedilol, lisinopril, furo- cardiac transplantation evaluation. Resting ECG revealed semide, and paroxitene. Anthropomorphic data, PFTs, a left bundle branch pattern (LBBB). In the preceding 1 and peak incremental CPET results appear in table 7 and year she had progressive exertional dyspnea, generalized graphically in figure 3. fatigue and had gained 12 kg. Prior to the onset of her 312 Weisman/Zeballos

Fig. 4. Constant work cycle ergometry in a patient with nonischemic fested by an abnormal slope of the V˙ E vs. V˙ CO2 relation- dilated cardiomyopathy. V˙ O2 (solid circle; green), V˙ CO2 (square; red), ship (slope = 39, upper limit 95% CI !34) (D), which has and V˙ E (triangle; blue) vs. time (min). An arterial blood sample been previously reported in heart failure patients [87] (D). (ABG) is obtained at minute 5 constant work exercise and referenced There was a rapid, shallow breathing pattern (E); there to the appropriate metabolic measurement interval for determina- were normal values for V˙ E/V˙ CO2 and V˙ E/V˙ O2 at near AT, tion of P(A-a)O2 and VD/VT (case 2). which were slightly increased at peak exercise (F) with reduced values for PETCO2 at near peak exercise (I) likely Interpretation reflecting mild alveolar hyperventilation. There was no Spirometry and lung volumes are WNL. DLCO is bor- desaturation with pulse oximetry (H). derline reduced most probably reflecting reduced cardiac output and resultant V˙ /Q˙ derangement and probable To better characterize the abnormal ventilatory re- alveolar capillary loss. sponses and to exclude a significant pulmonary gas ex- Exercise: Maximal effort was evidenced by achieving a change abnormality, a constant work rate exercise test peak HR = 90% while on Carvedilol and clinically looking approximating 75% of peak incremental WR was per- truly exhausted. Exercise stopped because of leg fatigue formed 1 h after the incremental CPET. An ABG ob- (10/10). There was a mild reduction in peak WR and peak tained at minute 5 from a single radial arterial puncture V˙ O2 (A) that was associated with a low ¢V˙ O2/¢WR, and a approximates near maximal incremental exercise test val- reduced O2 pulse (B). When V˙ O2 is expressed per kg body ues and may provide a clinically useful alternative to a weight, it is disproportionately reduced reflecting signifi- radial arterial line (fig. 4) [42]. Resting and constant work cant obesity (BMI = 33.2). The HR-V˙ O2 relationship was ABG data appear in table 8 (note that at this level of CW, normal (A). The BP did not increase appropriately with the patient achieved a V˙ O2 equal to the peak incremental exercise; there were no additional abnormal ECG changes CPET). The resting ABG revealed no hypoxemia and (known LBBB pattern at rest noted). Exercise was cardio- likely mixed metabolic and respiratory alkalosis at this vascular limited as there was no heart rate reserve altitude. There was no arterial desaturation during exer- (15 bpm) at peak exercise (B). The AT was low using the cise. PaO2 increased with exercise due to alveolar hyper- ‘dual methods’ approach (C, F) [19]. This pattern of ventilation (decreased PaCO2) and the PAO2 – PaO2 abnormalities is consistent with cardiovascular disease. increased appropriately and was well within normal lim- Early onset metabolic acidosis (low AT) in this patient is its. VD/VT response decreased normally. Although not consistent with cardiovascular disease but could also seen in this patient, abnormal VD/VT responses are often reflect deconditioning and/or skeletal muscle dysfunc- observed in patients with heart failure due to reduced car- tion. diac output and resultant V˙ /Q˙ derangement [58]. The CW There was plenty of ventilatory reserve at peak exercise exercise ABG revealed a combined metabolic acidosis (V˙ E/MVV = 47%) (D, G). Abnormal ventilatory responses and respiratory alkalosis with ↑ in arterial lactate and were observed including excessive ventilation for the met- appropriate reciprocal ↓ in serum HCO3–. abolic rate requirement throughout exercise as mani- Conclusion Abnormal exercise test. There was a mild reduction in aerobic capacity (V˙ O2peak) with an abnormal exercise response pattern consistent with cardiovascular disease and a predominantly O2 transport limitation to exercise. The abnormal ventilatory responses do not appear exer- cise limiting; this is consistent with the heart failure litera- ture as is the normal SaO2, PaO2, and PAO2 – PaO2 obtained during CW exercise. As exercise limitation is usually multifactorial, the variable contribution of decon- ditioning, skeletal muscle dysfunction, and obesity to this patient’s exercise intolerance should be considered. Comments A V˙ O2peak = 76% on a cycle ergometer (\" 80–84% on a treadmill) is well above the 50% level of V˙ O2max associ- Interpretation of Cardiopulmonary Exercise 313 Testing

ated with poor survival in patients with chronic heart fail- Table 8. Constant work cycle ergometry in a patient with non- ischemic, dilated cardiomyopathy (case 2) ure [54, 88]. Consequently, emergent cardiac transplanta- CW (%)1 Rest CW tion was not necessary and the patient continued to (5 min)2 receive optimized medical management. Importantly, Time, min 5:00 SaO2, % 97 97 this patient had only a mildly reduced V˙ O2peak when ref- 100 (75) PaO2 84 95 erence values for sedentary subjects were used demon- Power, watts 1.50 (99) PaCO2 36.1 31.3 V˙ O2, liters/min 16.0 (99) pH 7.453 7.422 strating that physically fit individuals such as this patient V˙ O2, ml/kg/min 168 (99) HCO3– 24.9 20.1 may experience significant reductions in their peak V˙ O2 as HR, bpm 8.9 (100) P(A-a)O2 1 3 a result of illness and still either be within the normal con- VD/VT 0.34 0.23 O2 pulse, ml/beat 61 (92) Lactate 0.75 5.01 fidence interval for sedentary subjects, borderline, or only BP, mm Hg 46 V˙ E, liters/min 1.09 mildly abnormal. f, br/min The addition of CW exercise testing permitted the RER evaluation of pulmonary gas exchange at (near) maximal 1 % max incremental CPET. V˙ O2 (tables 7, 8) [42]. Increasingly, CW exercise testing is 2 Single stick ABG. being utilized in clinical decision-making [89, 90]. Final- ly, the patient’s CPET results provided the basis for an individualized cardiac rehabilitation prescription and an objective measure of interval evaluation. Postscript Table 9. Maximal cardiopulmonary incremental exercise test in a After 1 year of an optimized medical regimen and car- patient with COPD (case 3) diac rehabilitation, repeat CPET revealed significant im- provement in aerobic capacity – V˙ O2peak (↑ 10%), O2 63-year old male, Caucasian, height: 180 cm, weight: 88.9 kg; clinical pulse, AT, and exertional symptoms while ventilatory Dx: COPD. abnormalities were reduced. This was consistent with improvements in cardiac echocardiography and quality of a Resting pulmonary function tests life. Although improving, the etiology of the non-ischemic dilated cardiomyopathy remains uncertain. Variable Actual % pred [100] Case Study 3: Maximal CPET in a Patient with FVC, liters 4.28 89 COPD FEV1, liters 1.80 48 FEV1/FVC, % 42% TLC, liters 8.83 123 DCO, ml/min/mm Hg 17.9 52 Clinical History b Cardiopulmonary exercise test1 A 63-year-old Caucasian male with moderate-severe COPD was referred for CPET because of increasing exer- Variable Peak % pred tional dyspnea over the last 1 year with stable PFTs and ECG. He was considering relocating to a New Mexico ski Work rate, W 120 78 resort (altitude \" 3,000 m). The patient had a 150 pack V˙ O2, liters/min 1.43 64 year smoking history but had stopped when the diagnosis V˙ O2, ml/kg/min 16.0 59 of COPD was established 10 years earlier. His present AT, liters/min 0.87 L (1 0.89) medications included ipratropium bromide, triamcina- 90 lone acetate, and albuterol metered dose inhalers. His HR, bpm 152 71 weight had been stable for the past 5 years. He had 115 become a self-declared ‘couch potatoe’ as a result of his O2 pulse, ml/beat 9.4 N increasing exertional dyspnea. His chest radiograph H showed hyperinflation and routine labs were within nor- V˙ E, liters/min 82 mal limits. Anthropomorphic data, PFTs, and peak CPET responses appear in table 9 and graphically in fig- f, br/min 42 ure 5. V˙ E/V˙ CO2, at AT 48 Stop: dyspnea 9/10. Ideal weight = 82 kg. 1 Protocol: maximal, symptom-limited, incremental cycle ergome- try, 20 W/min. 314 Weisman/Zeballos

Fig. 5. Graphic representation of a maximal, incremental, cardiopul- dioxide output (V˙ CO2). E Tidal volume (VT) and respiratory frequen- cy (f) vs. V˙ O2. F Ventilatory equivalent for O2 (V˙ E/V˙ O2), ventilatory monary exercise test in a patient with COPD. These graphic data are equivalent for CO2 (V˙ E/V˙ CO2) vs. V˙ O2. G Minute ventilation (V˙ E) vs. V˙ O2. H Illustrates end-tidal pressure for O2 (PETO2) and end- 1-min interval averaged. The results are compared with calculated tidal pressure for CO2 (PETCO2) vs. V˙ O2. Graphs F and H are also used for the determination of the AT using the ventilatory equivalents reference values obtained from several sources (dashed line). A Oxy- gen uptake (V˙ O2) vs. work rate. B Heart rate (HR) and O2 pulse vs. method. V˙ O2. C Indirect determination of the anaerobic threshold (AT) using the modified V slope method in which the carbon dioxide production (V˙ CO2) is plotted vs. V˙ O2. D Minute ventilation (V˙ E) vs. carbon Interpretation predicted, RER = 1.16, and patient appearing truly ex- PFTs: Moderate-to-severe obstructive ventilatory im- pairment. Lung volumes are consistent with air trapping. hausted; exercise stopped due to dyspnea (9/10). Moder- A moderate-severe reduction in DLCO is observed. ate reduction in V˙ O2peak was noted (A). There was a mild Exercise: Outstanding effort as reflected by patient reduction in peak WR with the V˙ O2-WR relationship achieving physiologic (ventilatory) limitation, HR = 90% appearing somewhat right-shifted (A). The HR-V˙ O2 rela- tionship was left-shifted (↑ HR at submaximal V˙ O2) with Interpretation of Cardiopulmonary Exercise 315 Testing

Table10. Constant work cycle ergomerty in CW (%)1 Rest CW (5 min)2 a patient with COPD 5:00 93 76 Time, min 85 (70) SaO2, % 63 42 1.22 (85) PaO2, mm Hg 34 33 Power, W 13.6 (85) PaCO2, mm Hg 7.445 7.362 V˙ O2, liters/min 148 (97) pH 23 58 V˙ O2, ml/kg/min 8.3 (88) 0.44 0.39 HR, bpm 79 (96) P(A-a)O2, mm Hg 44 VD/VT O2 Pulse ml/beat 1.18 V˙ E, liters/min f, br/min RER 1 % max incremental CPET. 2 ABG from single stick. suggestion of an abnormal slope at higher work intensi- \"85% incremental V˙ O2peak) was performed 1 h after the incremental CPET. Resting and minute 5 CW ABG ties. There was mild heart rate reserve at peak exercise results appear in table 10. Resting ABG revealed mild resting hypoxemia (for this altitude) with borderline wi- (17 bpm), although peak HR = 90% predicted (B); the O2 dened PAO2 – PaO2, an abnormal VD/VT, and acute pulse was reduced with suggestion of an early ‘plateau’ respiratory alkalosis. Pulmonary gas exchange abnormali- ties during exercise included impressive arterial desatura- effect (B). There were normal exercise BP and nonspecific tion (93→76 mm Hg, including a greater magnitude drop than demonstrated by pulse oximetry), hypoxemia with a ST-T changes on ECG. The AT is low (C, F). This pattern ↓ PaO2 (63→42 mm Hg), an abnormally widened PAO2 – PaO2 (23→58 mm Hg), a minimally changed (abnormal) of cardiovascular and AT responses may be seen in VD/VT response (44→39). The essentially unchanged PaCO2 response (34→33 mm Hg) reflects a reduced level patients with COPD who are ventilatory limited, decon- of alveolar ventilation due to increased dead space venti- lation, possibly blunted ventilatory responses to metabol- ditioned, and who may also have some additional cardio- ic acidosis, and perhaps ventilatory limitation. The drop in PaO2 was mostly due to V˙ /Q˙ mismatching and also to vascular stressor to increase the peak HR response (see alveolar hypoventilation. The acid-base status at near peak exercise is consistent with a metabolic (lactic) acido- below), and/or have a concurrent cardiovascular abnor- sis. mality. Conclusion Abnormal exercise test. Moderate reduction in aerobic A plethora of abnormal respiratory responses both capacity. Abnormal respiratory factors were exercise lim- iting. Ventilatory limitation due to mechanical derange- mechanical and pulmonary gas exchange were observed. ment was associated with a spectrum of pulmonary gas V˙ E peak was reduced but when referenced to MVV, peak exchange abnormalities including inefficient ventilation V˙ E/MVV = 115% indicating no ventilatory reserve (D, (↑ V˙ E/V˙ CO2), increased dead space ventilation (VD/VT), G), defining ventilatory limitation to exercise. The arterial desaturation (↓ SaO2), hypoxemia (↓ PaO2), and a possible blunted ventilatory response to metabolic acido- breathing strategy reflected that the increase in VT was sis. These factors contributed to this patient’s ventilatory limited (possibly related to dynamic hyperinflation) with demand exceeding capacity and consequent ventilatory increases in V˙ E achieved mostly through increases in f (E). limitation and overall exercise intolerance. The HR re- Other abnormal ventilatory responses included excessive sponse most probably reflects the additional cardiovascu- ventilation for the metabolic requirement throughout ex- ercise as manifested by an abnormal slope of the V˙ E vs. V˙ CO2 relationship (slope = 44 using linear regression) (D), an abnormal V˙ E vs. V˙ O2 relationship (G), and increased values for V˙ E/V˙ CO2 and V˙ E/V˙ O2 throughout exercise (F). PETCO2 did not change significantly with exercise (H). There was a significant decrease in exercise SpO2 (93% →85%), but with poor correlation to arterial pul- sation. To better characterize the abnormal pulmonary gas exchange responses and in view of DLCO = 51%, a con- stant work rate exercise test approximating 70% of peak incremental WR (achieving during min 5 CW exercise 316 Weisman/Zeballos

Table11. Maximal cardiopulmonary incremental exercise test in a patient with non-ischemic dilated cardiomyopathy and COPD (case 4) 56-year-old, male, black, height: 180 cm, weight: 71 kg, Hb 9.6; clinical Dx: dilated cardio- myopathy. a Resting pulmonary function tests Variable Actual % pred [100] FVC, liters 2.80 66 FEV1, liters 1.33 40 FEV1/FVC 48% MVV, liters/min 54 104 TLC, liters 3.73 138 RV, liters 2.60 DCO, ml/min/mm Hg 12.1 43 b Cardiopulmonary exercise test1 Variable Peak % pred Variable Rest Peak Work Rate, W 80 52 SaO2, % 89% 78% V˙ O2, liters/min 1.13 53 SpO2, % 90% 86% V˙ O2, ml/kg/min 16.0 53 PaO2, mm Hg 65 54 AT, liters/min 0.75 L (1 0.85) PaCO2, mm Hg 40 39 7.39 7.31 HR, bpm 168 97 pH 24 20 7.0 55 HCO3–, mEq/l 19 39 O2 Pulse, ml/beat 7.2 L (1 8.3) 0.48 0.42 ¢V˙ O2/¢WR 61 112 P(A-a)O2, mm Hg 1.0 5.3 V˙ E, liters/min VD/VT f, br/min 44 N Lactate, mEq/l V˙ E/V˙ CO2, at AT 50 H RER 1.12 H Stop: dyspnea and fatigue 10/10. Ideal weight = 81 kg. 1 Protocol: maximal, symptom limited, incremental cycle ergometry, 10 W/min. lar stress of severe hypoxemia. The O2 pulse could have Case Study 4: Maximal CPET in a Patient with been reduced due to the early termination of exercise Combined Heart and Lung Disease (ventilatory limitation), hypoxemia, deconditioning and/ or skeletal muscle dysfunction, and theoretically, also to Clinical History the hemodynamic consequences of dynamic hyperinfla- A 56-year-old black man with a 5-year history of non- tion. The multifactorial etiology of exercise limitation is ischemic dilated cardiomyopathy (NIDCM) (class 111- nicely demonstrated in this patient. NYHA) and COPD with a greater than 60 pack years smoking history (recently stopped) was referred for CPET Postscript because of progressive increase in dyspnea on exertion The patient was started on supplemental O2 for activi- and fatigue associated with reduced exercise tolerance ties requiring exertion. It was recommended that he not over the preceding 12 months. He had noted a decrease in relocate to 3,000 m. Maximal CPET and subsequent CW muscle mass/strength in the last 1–2 years. The patient exercise testing were valuable in establishing the need for was referred for CPET for cardiac transplantation evalua- and titration of supplemental O2 during exercise. CPET tion and determination of exercise limitation in this results were also used to exclude clinically significant cor- patient with both heart and lung disease. A recent cardiac onary artery disease and for writing an individualized echocardiogram revealed global chamber enlargement, exercise prescription for pulmonary rehabilitation. depressed left ventricular function (LVEF \" 15%), apical Interpretation of Cardiopulmonary Exercise 317 Testing

Fig. 6. Graphic representation of a maximal, incremental, cardiopul- F Ventilatory equivalent for O2 (V˙ E/V˙ O2), ventilatory equivalent for CO2 (V˙ E/V˙ CO2), end-tidal pressure for O2 (PETO2) and end-tidal pres- monary exercise test in a patient with nonischemic dilated cardio- sure for CO2 (PETCO2) vs. V˙ O2. This graph is also used for the determi- nation of the AT using the ventilatory equivalents method. myopathy and COPD. These graphic data are 1-min interval aver- G Alveolar O2 pressure (PAO2), arterial O2 tension (PaO2), alveolar- aged. The results are compared with calculated reference values obtained from several sources (dashed line). A Oxygen uptake (V˙ O2) arterial O2 pressure difference (PAO2 – PaO2), and arterial O2 satura- vs. work rate. B Heart rate (HR) and O2 pulse vs. V˙ O2. C Indirect tion (SaO2) vs. V˙ O2. H Physiologic dead space to tidal volume ratio determination of the anaerobic threshold (AT) using the modified (VD/VT) and arterial CO2 tension vs. V˙ O2. I Determination of AT V slope method in which the carbon dioxide production (V˙ CO2) using the plot of arterial lactate vs. V˙ O2. is plotted vs. V˙ O2. D Minute ventilation (V˙ E) vs. oxygen uptake (V˙ O2). E Tidal volume (VT) and respiratory frequency (f) vs. V˙ O2. LV thrombus, intact valves and moderate pulmonary goxin, lisinopril, furosemide, and Coumadin. Labs: he- hypertension (PA systolic/diastolic = 49/20 mm Hg). moglobin/hematocrit = 9.6/34.8. Anthropomorphic data, Resting ECG revealed nonspecific ST-T changes, occa- PFTs, and peak CPET results appear in table 11 and sional PVCS, and an abnormal P wave axis in AVL. Med- graphically in figure 6, respectively. ications included: ipratropium MDI, albuterol MDI, di- 318 Weisman/Zeballos

Interpretation often due to increased dead space ventilation. In turn, PFTs: Severe obstructive ventilatory impairment with patients with heart failure can also have abnormal V˙ E/ V˙ CO2 responses, especially patients with more severe dis- air trapping. Severe reduction in DLCO. ease. Recent work has suggested that the slope of V˙ E vs. Exercise: Because of this patient’s severe COPD and V˙ CO2 relationship is a valuable supplemental prognostic indicator for survival (V˙ O2max was still better) in patients likelihood for desaturation and the fact that pulse oxime- with chronic heart failure [87]. However, in this patient with co-existing severe heart and lung disease, V˙ E/V˙ CO2 try may potentially be unreliable in patients with heart has limited discriminatory value and is most probably, primarily abnormal due to severe COPD. failure [92] and in black subjects [19, 93], CPET with Importantly, there was no ventilatory reserve as radial arterial line was performed. Outstanding effort V˙ E/MVV = 112% predicted (D). V˙ E/MVV is usually was evidenced by patient achieving V˙ E/MVV = 112% !75% in patients with heart failure. In patients with predicted, HR = 97% predicted, R = 1.12, and patient severe COPD, the V˙ E/MVV often approaches or exceeds the ventilatory ceiling (V˙ E/MVV 6100%). appearing exhausted. Exercise stopped because of dys- Abnormal pulmonary gas exchange responses in this pnea (10/10) and fatigue (9/10). There was a moderate patient including significant arterial desaturation (↓ ¢ reduction in aerobic capacity (V˙ O2peak) and peak WR 11%) (G), hypoxemia (↓ PaO2) with widened PAO2 – achieved (A). The V˙ O2-WR relationship appears to reach PaO2 (normal !35) (G), and abnormal (essentially un- an early plateau with a low¢V˙ O2/¢WR (A), reflecting changed) VD/VT responses (H) with no real change in reduced O2 transport and/or O2 utilization. The V˙ O2-HR PaCO2 (40→ 39) (H) were observed. The lack of change in relationship was left-shifted (↑ HR at submaximal levels PaCO2 reflects a reduced level of alveolar ventilation due of V˙ O2 with an abnormal slope) (B). Also, noteworthy is to a mechanical limitation and a blunted ventilatory the achieved peak HR = 97% predicted in a patient who response to metabolic acidosis. These pulmonary gas exchange abnormalities are most likely due to COPD. is ventilatory limited and who has moderate-to-severe VD/VT abnormalities occurring in patients with heart fail- ure are explained by the same pathophysiology noted NIDCM and more likely to manifest chronotropic dys- above for abnormal V˙ E/V˙ CO2 responses [58, 87]. function (see section on Cardiovascular Disease) [56]. Importantly, patients with heart failure usually do not develop arterial desaturation and maintain relatively nor- Hypoxemia and anemia [94, 95] provided additional mal PaO2 during exercise. Therefore, a primary respirato- ry etiology of these pulmonary gas exchange abnormali- cardiovascular stresses responsible for achieving that ties due to COPD is more likely in this patient. The ↓ in PaO2 and in SaO2 are consistent with DLCO = 39% pre- peak HR. dicted. Pulmonary hypertension may also have contrib- uted to these pulmonary gas exchange abnormalities. The The O2 pulse was markedly reduced (B). This patient acid-base status at peak exercise is consistent with a meta- possessed a number of factors known to impact O2 pulse bolic acidosis without the appropriate respiratory com- including reduced stroke volume due to systolic dysfunc- pensation due to COPD. The increase in serum lactate with exercise was paralleled by a reciprocal decrease in tion, hypoxemia with progressive arterial desaturation serum bicarbonate. during exercise, anemia, deconditioning, ventilatory limi- Conclusion Abnormal exercise test, moderate-to-severe reduction tation to exercise and possibly even dynamic hyperinfla- in aerobic capacity but above the 50% level associated with poor outcome in patients being evaluated for cardiac tion and its potential for hemodynamic consequences. transplantation [54, 88]. Exercise limitation in this pa- tient is multifactorial: (1) ventilatory (mechanical) and There were no abnormal BP or ECG responses. Interest- pulmonary gas exchange derangements (hypoxemia, ar- terial desaturation, ↑ dead space ventilation) due to ingly, ventricular premature contractions decreased dur- ing exercise despite ↓SaO2 and ↓PaO2. The AT was low using the noninvasive ‘dual methods’ approach (C, F) [19] and confirmed through direct lactate measurements (I). Clearly, a cardiovascular (O2 transport) abnormality is evidenced. Respiratory Responses: Abnormal ventilatory re- sponses were observed including excessive ventilation for the metabolic requirement throughout exercise as mani- fested by an abnormal V˙ E vs. V˙ O2 relationship (D), an abnormal slope of the V˙ E vs. V˙ CO2 relationship (slope = 45, 95% CI !34 [not shown]), and increased values for V˙ E/V˙ CO2 and V˙ E/V˙ O2 throughout exercise (F). A rapid shallow breathing pattern was observed (E). V˙ E/V˙ CO2, a noninvasive estimator of ventilation effi- ciency is often abnormal in patients with lung disease due to increased contribution of high V˙ /Q˙ regions or more Interpretation of Cardiopulmonary Exercise 319 Testing

COPD appear to be the predominant cause (s) of exercise mendations were made: (1) supplemental O2 especially limitation; (2) O2 transport abnormalities due to cardio- during exercise; (2) aggressive treatment to optimize re- vascular dysfunction and compensated nonischemic di- spiratory function; (3) consider adding carvedilol to car- lated cardiomyopathy certainly contributed, as did pul- diac regimen; (4) anemia work-up, including GI evalua- monary hypertension; (3) deconditioning with skeletal tion; (5) cardiopulmonary rehabilitation with an individ- muscle dysfunction and attendant O2 utilization abnor- ualized exercise program based on CPET results, and malities were also likely, and (4) anemia may also have (6) interval evaluation after above recommendations. contributed to reduction in O2 carrying capacity [94, 95]. Postscript Comment A GI work-up revealed a guiac-positive stool; subse- Standard algorithms are inadequate in interpreting quent colonoscopy revealed 2 polyps, which were re- CPET results in patients with both heart and lung disease. moved. Iron supplementation was initiated with im- V˙ E/MVV exceeding 100% predicted in patients with heart provement in hemogram. Exertional oxygen supplemen- failure may signal the presence of combined heart and tation was prescribed, respiratory, and cardiac medica- lung disease. Currently, the exercise variables most help- tions were optimized, and cardiopulmonary rehabilita- ful in distinguishing between heart failure and COPD tion was begun. include V˙ E/MVV, SaO2 and PaO2 responses, and BP and ECG responses. CPET was able to identify, prioritize, and Acknowledgements (relatively) quantitate exercise-limiting factors contribut- ing to this patient’s exercise intolerance so that an effec- The authors wish to acknowledge Mr. Raul Hernandez, Ms. Luz tive clinical management scheme could be initiated. B. Torres and Mr. Sean Connery for their diligence in preparation of Based on the results of the CPET, the following recom- the manuscript. References 1 Hamilton AL, Killian KJ, Summers E, Jones 9 Wagner PD: Determinants of maximal oxygen 17 Ramos-Barbon D, Fitchett D, Gibbons WJ, NL: Muscle strength, symptom intensity, and transport and utilization. Annu Rev Physiol Latter DA, Levy RD: Maximal exercise testing exercise capacity in patients with cardiorespi- 1996;58:21–50. for the selection of heart transplantation candi- ratory disorders. 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OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO Author Index Agostoni, P. 99 Gay, S.E. 81 Schols, A.M.W.J. 18 Artal, R. 273 Gordon, S.M. 1 Sciurba, F.C. 173 Bach, D.S. 109 Gosker, H.R. 18 Sietsema, K.E. 264 Baird, J.C. 72 Gosselink, R. 60 Slater, W.R. 254 Beck, K.C. 43 Guazzi, M. 99 Spector, S.L. 205 Bolliger, C.T. 231 Hales, C.A. 200 Strelich, K. 109 Braith, R.W. 120 Haverkamp, H.C. 1 Sue, D.Y. 217 Celli, B.R. 159 Johnson, B.D. 89 Systrom, D.M. 200 Cockrill, B.A. 200 Krishnan, B.S. 186 Tan, R.A. 205 Cooper, D.M. 282 Mahler, D.A. 72 Troosters, T. 60 Decramer, M. 60 Marciniuk, D.D. 186 Uszko-Lencer, N.H.M.K. 18 Dempsey, J.A. 1 Martinez, F.J. 81, 242 Vusse, G.J. van der 18 Diacon, A.H. 231 Nemet, D. 282 Weisman, I.M. 30, 43, 81, 242, 300 Edwards, D.G. 120 O’Donnell, D.E. 138 Williams, T.J. 254 Fahey, J. 282 O’Toole, M.L. 273 Wouters, E.F.M. 18 Fierro-Carrion, G. 72 Patel, S.A. 173 Zeballos, R.J. 30, 242, 300 Flaherty, K.R. 81, 242 Rodman, J.R. 1 323

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO Subject Index ACE inhibitors, see Angiotensin-converting exercise testing Bronchodilator therapy enzyme inhibitors bronchial provocation challenge chronic obstructive pulmonary disease comparison 211, 212 exercise performance effects 152 Aging cycle ergometer 211 exercise-induced asthma 213, 214 muscle effects 63 exercise protocol 208, 209 exertional dyspnea effects 78 respiratory system changes hyperventilation 211 advanced age effects 97 precautions 208 Bronchopulmonary dysplasia, pediatric breathing pattern 91 treadmill testing 209–211 exercise testing 291 demand scaling to capacity 97 end expiratory lung volume regula- metacholine challenge testing 207, Bullectomy, exertional dyspnea studies 79 tion 91, 92 208 expiratory flow and pressure devel- Cardiac output opment 92, 93 epidemiology 205 exercise response 9 inspiratory flow and pressure devel- pathophysiology 205, 206 heart transplant recipients 128–130 opment 93 pediatric exercise testing 289 pregnancy 274 overview 89, 90 prevention 214 pulmonary gas exchange treatment Cardiac rehabilitation, see Congestive heart alveolar to arterial gas exchange failure, Heart transplant 95 antileukotrienes 214 dead space and alveolar ventila- athletes 212, 213 Cardiac stress test tion 94 bronchodilators 213, 214 exercise treadmill test, see Exercise lung diffusion 94, 95 cromolyn 213, 214 treadmill test pulmonary vasculature 95, 97 inhaled heparin 214 stages of Bruce protocol 38 ventilatory demand 90 nonpharmacologic therapy 212 stress echocardiography, see Stress echo- work and cost of breathing during AT1 receptor blockers, cardiopulmonary cardiography exercise 93 exercise test evaluation of congestive stress myocardial perfusion imaging, heart failure patients 105 see Stress myocardial perfusion Alveolar ventilation equation 1 imaging Angiotensin-converting enzyme inhibitors, ß-agonists, see Bronchodilator therapy test selection factors 117 ß-blockers, cardiopulmonary exercise test cardiopulmonary exercise test evalua- Cardiopulmonary exercise test tion of congestive heart failure patients evaluation of congestive heart failure applications 30, 31, 39 104, 105 patients 105 children, see Pediatric exercise testing Antileukotrienes, exercise-induced asthma Blood pressure chronic fatigue syndrome 269, 270 management 214 cardiopulmonary exercise test measure- contraindications 53, 54 Arrhythmia, pediatric evaluation 293, 294 diabetes 267 Asbestosis, pulmonary dysfunction 225 ment 51, 52 dyspnea evaluation, see Dyspnea Asthma, exercise-induced pediatric response to exercise 292, equipment 43 bronchospasm features and testing 38 exercise protocol clinical features 206, 214 293 cycle ergometer vs treadmill 43, 44, diagnosis Breathing retraining 49 cycle ergometry bronchodilator response 206 biofeedback 170 constant work protocols 50, 51 differential diagnosis 207 overview 169 incremental or ramp protocols postural changes 170 49, 50 pursed lip breathing 170, 171 yoga 170

treadmill protocols 51 pregnancy, see Pregnancy exercise performance prediction from heart failure assessment, see Congestive preliminary requirements 53, 54 resting pulmonary function 224, 225 protocol overview 53–55 heart failure pulmonary arterial hypertension, muscular alterations impairment and disability assessment, energy metabolism 20–22 see Pulmonary arterial hypertension fiber type distribution 20 see Impairment and disability quality control and validation mechanisms interpretation, integrative approach disuse 24 ergometer validation 48 hypoxia 22, 23 case studies metabolic measurement quality oxidative stress 23, 24 chronic obstructive pulmonary weight loss and altered substrate disease 314–317 control 48, 49 metabolism 24, 25 dilated cardiomyopathy 311–314 reproducibility of measurements 47, morphology 19 with chronic obstructive overview 18 pulmonary disease 48 performance 18, 19 317–320 rationale 38, 39 exertional dyspnea 309–311 safety 55 oxygen therapy effects on exercise thyroid disorders 268, 269 performance 152, 153 clinical status evaluation 301 ventilatory limitation evaluation exercise cessation reasons 301 pulmonary rehabilitation, see Pulmo- exercise limitation analysis 55–57 nary rehabilitation Carnitine deficiency, clinical features 246, cardiovascular disease 305, 306 Congestive heart failure chronic obstructive pulmonary 247 cardiopulmonary exercise test evalua- Carnitine palmitoyltransferase deficiency, tion disease 307 cardiac surgery patients 105 deconditioning 306, 307 clinical features 247 exercise modalities 99, 100 interstitial lung disease 307 Chest pain, pediatric exercise testing 295 heart transplant patient selection and mechanisms 305 Children, see Pediatric exercise testing follow-up 101, 102 obesity 307 Chronic fatigue syndrome integrative approach in interpreta- pulmonary vascular disease 306 tion 311–314 test result evaluation 305 cardiopulmonary exercise testing measurements 100, 101 measurements and graphic interrela- findings 270 overview 99 tionships physiological effects 269 pacemaker patients 106 clinical signs and symptoms 305 pharmacotherapy evaluation gas exchange 304, 305 definition 269 angiotensin-converting enzyme heart rate 304 Chronic obstructive pulmonary disease inhibitors 104, 105 lactic acid threshold 303, 304 AT1 receptor blockers 105 ventilatory reserve 304 bronchodilator therapy effects on exer- ß-blockers 105 VO2max 302, 303 cise performance 152 hormones 105 overview 307, 308 vasodilators 104 patient effort assessment 301 cardiopulmonary exercise testing, inte- protocols 100 rationale 301 grative approach in interpretation typical response 104 reasons for testing 301 307, 314–317 ultrafiltration patients 105, 106 reference values 302 dilated cardiomyopathy with chronic interstitial lung disease, see Interstitial deconditioning 63, 68 obstructive pulmonary disease lung disease dilated cardiomyopathy with chronic 317–320 lung resection candidates, see Lung exercise intolerance mechanisms resection obstructive pulmonary disease baroreflex desensitization and lung transplant patients, see Lung trans- 317–320 sympathetic activation 121, 122 plant exercise intolerance left ventricular function impairment measurements 38, 219, 220 cardiopulmonary exercise test find- 121 blood pressure 51, 52 neurohormonal activation 122 electrocardiography 51, 54 ings 139, 141, 142 pulmonary abnormalities 122, 123 expiratory flow and volume 44, 45 cardiovascular factors 151 skeletal muscle abnormalities 103, gas concentration dynamic hyperinflation 122 arterial blood gas 52, 63 vasodilation impairment 122 expiration 45, 46 dyspnea 146 exercise-limiting factors invasive vs noninvasive testing 51 inspiratory muscle function 144, circulation 103 metabolic measurement heart 102, 103 comparison of techniques 46, 47 145 lungs 103, 104 concepts 45, 46 inspiratory muscle muscle fibers 103 power output 43, 44 sympathetic neuroendocrine system pulse oximetry 52 fatigue 149 103 muscle disorders, see Muscle weakness 148, 149 obesity 265, 266 management 153, 154 overview 138 peripheral muscle dysfunction 150, 151 tidal volume restriction 143, 144 ventilatory constraints 142 ventilatory demand 148 ventilatory limitation and gas exchange abnormalities 146–148 ventilatory mechanics 143 ventilatory-locomotor muscle competition during exercise 151 Subject Index 325

Congestive heart failure (continued) sensitivity and specificity 116 definition 82 exercise training special cases 117 dynamic hyperinflation in chronic adaptations stress myocardial perfusion imaging baroreflex and sympathetic acti- dobutamine infusion 114 obstructive pulmonary disease 146 vation 123 exercise protocol 114 exercise induction, see Exertional clinical outcomes 125 imaging techniques 114 myocardial remodeling 123 interpretation 114 dyspnea neurohormonal systems 123, prognostic assessment 115 interstitial lung disease 188 124 radiotracers 113, 114 pediatric exercise testing 295 overview 125 sensitivity and specificity 115 skeletal muscle metabolism 124, special cases 115 Echocardiography, see Stress echocardiog- 125 vasodilation 114 raphy vasodilatory capacity 124 Cromolyn, exercise-induced asthma VO2peak 123 management 213, 214 Electrocardiography initial intensity 126 Cystic fibrosis cardiopulmonary exercise test 51, 54 progression of program 126, 127 cardiopulmonary exercise test and lung exercise treadmill test 110, 111, 113 prospects 135 transplantation 260, 261 risk stratification and patient pediatric exercise testing 289–291 End expiratory lung volume screening 125, 126 chronic obstructive pulmonary disease heart transplant outcomes 120, 121 Deconditioning 139, 141, 143 muscular alterations cardiopulmonary exercise testing, inte- regulation 91, 92 energy metabolism 20–22, 122 grative approach in interpretation fiber type distribution 20 306, 307 Endurance training, respiratory system mechanisms chronic obstructive pulmonary disease effects 14, 15 disuse 24 impact 63, 68 hypoxia 22, 23 definition 60, 61 Exercise oxidative stress 23, 24 lung volume reduction surgery patients aging effects on capacity, see Aging weight loss and altered substrate 178 cardiorespiratory interactions 10, 11 metabolism 24, 25 prevention 68 cardiovascular system response 9, 10 morphology 19 skeletal muscle abnormalities pulmonary gas exchange 6–9 overview 18 atrophy mechanisms 62, 63 respiratory limitations to performance performance 18, 19 bed rest studies 61, 62 11–14 socioeconomic impact 120 treatment with exercise training aerobic exercise 64–66 Exercise hyperpnea Coronary artery disease endurance training breathing mechanics during exercise cardiopulmonary exercise testing, inte- implementation 66 4–6 grative approach in interpretation muscle impact 66 neurochemical control 1–4 305, 306 principles 64 exercise treadmill test rationale 63, 64 Exercise-induced arterial hypoxemia electrocardiography 110, 111, 113 resistance/strength training causes 11 indications 110 implementation 67 performance limitations 12–14 interpretation 111, 112 modalities 67 limitations 113 muscle impact 67, 68 Exercise-induced asthma, see Asthma, exer- popularity 110 cise-induced premature ventricular complexes Diabetes 111, 112 cardiopulmonary exercise testing 267 Exercise-induced bronchospasm, prognostic assessment 112, 113 pediatric exercise testing 294 see also Asthma, exercise-induced protocol 110, 111 features 38 safety 110 Disability, see Impairment and disability testing methodology 38 sensitivity and specificity 112 Dyspnea special cases 113 Exercise intolerance, see specific conditions termination indications 111 cardiopulmonary exercise testing of Exercise treadmill test pediatric myocardial ischemia evalua- unexplained dyspnea tion 293 differential diagnosis 85–87 electrocardiography 110, 111, 113 risk stratification 109 popularity of use 85 indications 110 stress echocardiography specificity 87 interpretation 111, 112 dobutamine echocardiography 115, limitations 113 116 causes 81, 82 popularity 110 exercise echocardiography 115 chronic dyspnea evaluation premature ventricular complexes 111, interpretation 116 prognostic assessment 117 chest film 84 112 medical history 82 prognostic assessment 112, 113 physical examination 82–84 protocol 110, 111 pulmonary function testing 84, 85 safety 110 routine laboratory testing 84 sensitivity and specificity 112 special cases 113 termination indications 111 Exertional dyspnea bronchodilator therapy effects 78 bullectomy studies 79 cardiopulmonary exercise testing, inte- grative approach in interpretation 309–311 326 Subject Index

central mechanisms 6, 72 Heart failure, see Congestive heart failure Interstitial lung disease definition 72 Heart rate cardiopulmonary exercise testing lung volume reduction surgery studies indications 190 cardiopulmonary exercise testing 304 integrative approach in interpreta- 79 heart transplant recipients 127, 128 tion 307 measurement pediatric response to exercise 292 interpretation 192 reserve and exercise capacity 221 measurements 191, 192 continuous computerized measure- Heart transplant normal subject comparisons 192, ment 76–78 cardiopulmonary exercise testing for 193, 195 patient management impact 197 continuum of ratings 76 patient selection and follow-up 101, protocol 190, 191 CR-10 74, 75 102 disease-specific differences in exercise global vs local psychophysical congestive heart failure outcomes 120, responses 189 121 etiology 186 methods 74 exercise intolerance factors in recipients exercise intolerance factors peak values 75, 76 cardiac output 128–130 cardiovascular dysfunction 189 VAS 74 glucocorticoid-induced osteoporosis dynamic ventilatory mechanics 188 oxygen therapy effects 79 dyspnea 188 pulmonary rehabilitation studies 79 and resistance exercise therapy gas exchange impairment 187, 188 receptors in sensation 133, 134 overview 187 chemoreceptors 73 heart rate 127, 128 pulmonary hypertension 189 lung receptors 73, 74 hemodynamics 130 respiratory muscle function 188, mechanoreceptors 73 peripheral circulation 133 189 stimuli 74 pulmonary diffusion 130 exercise performance prediction from Expiratory flow limitation, chronic obstruc- pulmonary spirometry 130 resting pulmonary function 225 tive pulmonary disease 141, 142 skeletal muscle tidal flow-volume relationships 193, metabolism 130, 131 195, 197 FEV1 resistance exercise therapy 132, ventilatory mechanics and lung volumes lung resection candidates 234 during exercise 197 respiratory impairment 222, 223 133 strength 132 Ischemia, see Coronary artery disease Fick’s law exercise program oxygen diffusion in lung 7 design 134 Lactic acid VO2max 11 initial intensity and progression exercise hyperpnea feedback 3 135 threshold Gas analysis prospects 135 cardiopulmonary exercise testing breath-by-breath method 46 safety precautions 135 303, 304 cardiopulmonary exercise test Hypoxia sustained exercise capacity 220, arterial blood gas 52, 63 high altitude hypoxia exercise limita- 221 expiration 45, 46 tions 14 comparison of techniques 46, 47 muscle alterations in chronic obstructive Lung resection mixing chamber technique 46 pulmonary disease or congestive complications standard temperature and pressure heart failure 22, 23 cardiac 233 conversion 46 pulmonary 233 water vapor effects 46 Impairment and disability indications 231 American Thoracic Society Recommen- preoperative evaluation Gas exchange dations for Respiratory Impairment algorithm 236–238 aging effects 222 cardiopulmonary exercise test alveolar to arterial gas exchange 95 cardiopulmonary exercise testing maximal tests 235, 236 dead space and alveolar ventilation decision making on impairment minimal achievement tests 235 94 226, 227 rationale 232, 234 lung diffusion 94, 95 principles 219, 220 submaximal tests 235 cardiopulmonary exercise testing 304, quantification of impairment 227, cardiopulmonary risk index 238, 305 228 239 chronic obstructive pulmonary disease rationale 218, 219, 221 computed tomography 238 abnormalities 146–148 recommendations 228, 229 exercise-limited patients 238 exercise dynamics 6–9 definitions 219 ideal parameter for evaluation 231, interstitial lung disease impairment exercise performance prediction from 232 187, 188 resting pulmonary function pulmonary function testing 234 lung volume reduction surgery response 223–225 smokers 233 176, 178 nonventilatory limitation during exer- split function studies 234, 239 measurement 221 cise 225, 226 tumor type and staging 232 ventilatory requirement relationship occupational disease 217, 218 222 ventilatory capacity 222, 223 Subject Index 327

Lung transplant Mitochondrial myopathy Negative expiratory pressure exercise response and limitations post- clinical features 247, 248 chronic obstructive pulmonary disease transplantation diagnosis 248 testing 142 cardiac response 257 exercise testing 248–251 ventilatory limitation analysis 56, 57, exercise-induced hypoxemia 257 pediatric exercise testing 294 304 skeletal muscle dysfunction 257, pulmonary function testing 248 258 respiratory muscle function 248 Nitric oxide synthase, endothelial enzyme ventilation 257 response to endurance training 15 historical perspective 254, 255 Mitral valve repair, cardiopulmonary exer- outcome measurements cise test evaluation of congestive heart Obesity cardiopulmonary exercise test failure patients 105 cardiopulmonary exercise testing cystic fibrosis 260, 261 findings 265, 266 idiopathic pulmonary fibrosis Multiple inter gas elimination technique, integrative approach in interpreta- 258–260 PO2 alveolar to arterial difference in tion 307 incremental testing 256, 257 exercise 8, 9 physiological effects of obesity 265 obstructive lung disease 260 definition 264, 265 pulmonary hypertension 261 Muscle, see also Deconditioning rationale 258 aging effects 63 Osteoporosis, heart transplant recipient functional class 255, 256 chronic obstructive pulmonary disease glucocorticoid-induced osteoporosis and lung function 255 or congestive heart failure alterations resistance exercise therapy 133, 134 six-minute walk test 256 energy metabolism 20–22 survival 255 fiber type distribution 20 Oxidative stress, muscle alterations in mechanisms chronic obstructive pulmonary disease Lung volume reduction surgery disuse 24 or congestive heart failure 23, 24 controversies 173, 174 hypoxia 22, 23 exercise testing oxidative stress 23, 24 Oxygen therapy cardiopulmonary exercise test weight loss and altered substrate chronic obstructive pulmonary disease parameters 180–182 metabolism 24, 25 exercise performance effects 152, preoperative assessment and prog- morphology 19 153 nosis 182, 183 overview 18 interstitial lung disease 197 rationale 174 performance 18, 19 trials 178, 179 training adaptations 124, 125 Pacemaker, cardiopulmonary exercise test walk distance improvement 179, congestive heart failure effects 103, 122 evaluation of congestive heart failure 180 disorders patients 106 exertional dyspnea studies 79 carnitine deficiency 246, 247 indications 239 carnitine palmitoyltransferase defi- Pediatric exercise testing physiological responses ciency 247 approaches 283 gas exchange 176, 178 metabolic pathways 243 bronchopulmonary dysplasia 291 lung and chest wall mechanics mitochondrial myopathy cardiology referrals 174–176 clinical features 247, 248 arrhythmia evaluation 293, 294 peripheral muscle conditioning 178 diagnosis 248 blood pressure response to exercise pulmonary vascular function 178 exercise testing 248–251 292, 293 pediatric exercise testing 294 exercise limitation and sports evalu- McArdle disease, clinical features 245, 246 pulmonary function testing 248 ation 294 Master two-step test respiratory muscle function 248 heart diseases 292 muscle bulk disorders and exercise heart rate response to exercise 292 applications 32 testing 251, 252 myocardial ischemia evaluation 293 methodology 33 overview 242, 243 chest pain 295 Maximum flow volume loop, ventilatory phosphofructokinase deficiency 246 contraindications and test termination limitation analysis 56, 57 phosphorylase deficiency 245, 246 295, 296 Maximum ventilatory capacity endurance training effects 66 cystic fibrosis 289–291 chronic obstructive pulmonary disease fatiguing of respiratory muscle in perfor- diabetes 294 mance limitation 12–14 dyspnea 295 142 heart transplant recipients exercise-induced asthma 289 interstitial lung disease 195 metabolism 130, 131 healthy child responses to exercise 282, Maximum voluntary ventilation resistance exercise therapy 132, 133 283 chronic dyspnea evaluation 84 strength 132 indications 288, 289 estimation 56, 304 lung transplant recipient dysfunction maturation of physiological responses to interstitial lung disease 188, 195, 197 257, 258 exercise 284, 285 Methacholine challenge test resistance/strength training effects 67, measurements 285 chronic dyspnea evaluation 84 68 mitochondrial myopathy 294 exercise-indued asthma diagnosis 207, sympathetic nervous system flow during protocols exercise 10 Balke protocol 288 208 brief constant work rate tests 286 Bruce protocol 287, 288 328 Subject Index

cycles vs treadmills 286, 287 intensive care patient training 169 interpretation 114 maximum exercise testing 285, 286 strength training 167 prognostic assessment 115 stress tests 286 ventilatory isocapneic hyperpnea radiotracers 113, 114 renal hypertension 294 sensitivity and specificity 115 safety 296 168, 169 special cases 115 syncope 295 Pulse oximetry, cardiopulmonary exercise vasodilation 114 upper airway obstruction 291, 292 Syncope, pediatric exercise testing 295 Phosphofructokinase deficiency, clinical test 52 features 246 Thyroid disorders, cardiopulmonary exer- PO2 Reconditioning, see Cardiac rehabilitation, cise testing 268, 269 aging effects 95 Pulmonary rehabilitation alveolar to arterial difference in exercise Tidal volume 6–9, 11, 12, 95 Renal hypertension, pediatric exercise chronic obstructive pulmonary disease Pregnancy testing 294 restrictions 143, 144 anatomic and physiological changes 274 interstitial lung disease 188 exercise testing Shuttle-walking test tidal flow-volume relationships in inter- cardiopulmonary exercise testing comparison with other tests 37 stitial lung disease 193, 195, 197 constant work shuttle-walking test 37 indications 273 Upper airway obstruction, pediatric exer- contraindications 274, 275 Single photon emission computed tomog- cise testing 291, 292 maximum exercise tests raphy, see Stress myocardial perfusion imaging Vasodilation expected responses 278, 279 congestive heart failure impairment 122 protocol selection 276, 277 Six-minute walk test exercise response 9, 10 safety 277 comparison with other functional postpartum testing 280 capacity tests 36, 37 Vasodilators rationale 275, 276 development 33 cardiopulmonary exercise test evalua- submaximum exercise tests indications 31, 33 tion of congestive heart failure expected responses 279, 280 lung transplant recipients 256 patients 104 protocol selection 279 methodology stress myocardial perfusion imaging weight-bearing exercise 276 measurements 35 114 weight-supported exercise 276 monitor 35 postpartum exercise prescription 280 patient preparation 34 VCO2, cardiopulmonary exercise test Primary pulmonary hypertension, practice test 35 measurement 45, 46, 101 see Pulmonary arterial hypertension protocol 35 Pulmonary arterial hypertension standardization 34 Ventilatory muscle threshold training cardiopulmonary exercise testing track 34 intensive care patients 169 diagnosis 202, 203 outcome factors pulmonary rehabilitation 167, 168 grading 203 course length and shape 33, 34 therapeutic response assessment 203 encouragement 34 VO2 definition 200 medications 34 cardiopulmonary exercise test measure- primary pulmonary hypertension 201 supplemental oxygen 34 ment 45, 46, 100, 101 pulmonary circulatory response to exercise training effect 34 obesity 265, 266 abnormal response 202 reference values and clinical signifi- PaCO2 relationship 193 normal response 201, 202 cance 36 submaximal exercise changes 220 secondary precapillary hypertension reproducibility 36 thyroid disorders 269 200, 201 safety 35, 36 Pulmonary rehabilitation treadmill test 37 VO2max breathing retraining cardiopulmonary exercise testing 302, biofeedback 170 Skeletal muscle, see Muscle 303 overview 169 Stair climbing test congestive heart failure patients 100, postural changes 170 101 pursed lip breathing 170, 171 applications 31, 32 Fick equation 11 yoga 170 methodology 31, 32 respiratory limitations to exercise lower extremity exercise 161–164 Standard temperature and pressure, conver- performance 11–13 reconditioning principles 159, 160 sions for gas analysis 46 training adaptation 160, 161 Stress echocardiography VO2peak upper extremity exercise 164–166 dobutamine echocardiography 115, 116 cardiopulmonary exercise testing 220, ventilatory muscle strength exercise echocardiography 115 302, 303 endurance training 167 interpretation 116 diabetes 267 flow resistive and threshold loading prognostic assessment 117 exercise adaptation in congestive heart 167, 168 sensitivity and specificity 116 failure 123 special cases 117 Stress myocardial perfusion imaging Water vapor, effects on gas measurement dobutamine infusion 114 46 exercise protocol 114 chronic fatigue syndrome 270 imaging techniques 114 thyroid disorders 268, 269 Subject Index 329