rolmanejo

The Role of Exercise Testing in the Management of Pulmonary Arterial Hypertension Ronald J. Oudiz, M.D., F.A.C.P., F.A.C.C.1

ABSTRACT

The assessment of exercise capacity is of critical importance in the evaluation and management of patients with moderate to severe pulmonary arterial hypertension (PAH).

The practicing clinician uses various exercise modalities in evaluating and managing patients with PAH. These include the 6-minute walk test (6MW), cardiopulmonary exercise testing, and exercise echocardiography. The change in exercise capacity appears to parallel other clinical indicators of disease severity, such as survival, hemodynamics, and time to clinical worsening. Exercise testing can aid the clinician in outlining the nature of a patient’s exercise limitation, noninvasively assessing disease severity, establishing prognosis, and evaluating the response to therapy. Additional work must be done to validate the utility of measuring exercise capacity in patients with less severe PAH. KEYWORDS: Exercise testing, 6-minute walk test, cardiopulmonary exercise test

Objectives: Upon completion of this article, the reader should be able to: (1) be familiar with the various modalities of exercise testing used in PAH; (2) know how to interpret the results of exercise tests in the context of prognosis and response to therapy; and (3) understand the physiological basis for cardiopulmonary exercise testing in PAH. Accreditation: The University of Michigan is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians.

Credits: The University of Michigan designates this educational activity for a maximum of 1 category 1 credit toward the AMA Physician’s Recognition Award.

T

he abnormalities of lung perfusion that lead to the symptoms experienced by most patients with pulmonary arterial hypertension (PAH) are related to the inability of the right ventricle to provide the necessary increase in pulmonary blood flow, and therefore cardiac output, during exercise. Thus measuring the physiological response to exercise in patients with PAH is of critical importance and is useful for the following purposes: (1) to assess the degree of impairment in aerobic

function to quantitate disease severity and estimate prognosis; (2) to establish a baseline for noninvasive comparison of future assessments of disease severity; and (3) to measure the response to therapy. The 6-minute walk test (6MWT), treadmill testing, and cycle ergometry are the main modalities utilized in measuring these parameters. In clinical trials of PAH therapies, significant responses to therapy using these measures have paralleled improvements in survival,

Pulmonary Arterial Hypertension; Editor in Chief, Joseph P. Lynch, III, M.D.; Guest Editor, Victor F. Tapson, M.D. Seminars in Respiratory and Critical Care Medicine, volume 26, number 4, 2005. Address for correspondence and reprint requests: Ronald J. Oudiz, M.D., Division of Cardiology, Harbor–UCLA Medical Center, 1124 W. Carson St. #405, Torrance, CA 90502. E-mail: oudiz@humc.edu. 1David Geffen School of Medicine at UCLA, Los Angeles, California; Liu Center for Pulmonary Hypertension, Los Angeles Biomedical Research Institute at Harbor– UCLA, Division of Cardiology, Harbor–UCLA Medical Center, Torrance, California. Copyright # 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. 1069-3424,p;2005,26,04,379,384,ftx,en;srm00389x.

379

380

SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 26, NUMBER 4

hemodynamics, functional class, quality of life,1 and time to clinical worsening.2 A placebo-corrected increase in 6MWT distance of 47 m with epoprostenol therapy paralleled an 20% survival advantage at 12 weeks, as well as a hemodynamic improvement, with an 28% decrease in pulmonary vascular resistance.1 Rubin et al demonstrated an improvement in 6MWT distance of 44 m with bosentan therapy that paralleled a delay in time to clinical worsening by 25%.2 Using cardiopulmonary exercise testing (CPET), absolute differences in peak oxygen consump_ 2) in the range of 12 to 15 mL/kg/min tion (peak VO separated pediatric PAH patients with and without adverse clinical outcomes.3 In adult PAH patients, long-term clinical improvement with epoprostenol was _ 2 of 10% marked by an absolute increase in peak VO predicted.4 Thus clinically meaningful improvements in exercise capacity translate into significant improvements in several markers of disease severity.

EXERCISE TESTING MODALITIES The 6MWT distance5 has been the most commonly used primary end point for demonstrating efficacy in most randomized, controlled trials of PAH therapies.1,2,6–11 The use of the 6MWT has been adapted for PAH patients because of its success in congestive heart failure (CHF) patients. Because it is simple and noninvasive, the 6MWT is most commonly used in clinical practice in PAH centers as a means to longitudinally follow patients over time. The 6MWT can be performed at any institution and requires only a test administrator with a stopwatch, and a flat surface (preferably indoors) marked with 30 m intervals. Patients perform the walk at their own pace, with the option of stopping and sitting at strategically placed chairs as needed. The total distance walked in 6 minutes is recorded by the administrator. It is common practice to record the level of dyspnea and fatigue at the end of the test using the Borg dyspnea scale,12 Mahler dyspnea index,13 or an equivalent rating scale. In addition, it is not uncommon to measure pulse oximetry during the 6MWT (see later discussion). In most clinical trials of PAH therapies, the 6MWTs have been unencouraged, with minimal interaction between the administrator and the patient.

The 6MWT distance has been shown to correlate _ 2 in patients with PAH.4 And in with peak VO large groups of PAH patients with advanced disease (New York Heart Association [NYHA] class III and IV), 6MWT distance correlates with survival.14–16 In two separate studies, Miyamoto et al15 and Sitbon et al14 have shown that, for patients who walk above a threshold of 332 m at baseline or 380 m after 3 months of therapy, respectively, survival is significantly improved compared with those patients who walked shorter distances. It

2005

should be noted that, although the survival advantage above these 6MWT distances is significant, these threshold distances still represent moderate to severely impaired exercise capacity. It is not yet known whether the 6MWT can be of similar prognostic value in patients with less severe impairment.

Exercise oximetry is useful for measuring the degree of hypoxemia in PAH patients during exercise and is commonly performed with the use of a pulse oximeter during the performance of the 6MWT. Paciocco et al demonstrated that a > 10% fall in arterial O2 saturation during the 6MWT predicted a higher mortality than patients with less or no desaturation.17 In 2004, the American College of Chest Physicians (ACCP) guidelines for PAH management recommended that serial determinations of exercise capacity be made in patients with PAH using the 6MWT to provide benchmarks for disease severity, response to therapy, and progression.18 Although useful as a crude measure of aerobic capacity, the 6MWT distance does not aid the clinician in confirming the diagnosis of suspected PAH because it does not differentiate the nature of a patient’s exercise limitation (i.e., cardiac, respiratory, pulmonary vascular, or musculoskeletal). Furthermore, factors such as stride length, body weight, and walking skills may be more important determinants of 6MWT distance than aerobic capacity.5 CPET is a noninvasive diagnostic tool with relevance to numerous cardiovascular and respiratory disorders. CPET can help to confirm the diagnosis of suspected PAH and differentiate the nature of a patient’s exercise limitation.19 CPET has also been adapted for PAH patients because of its success in patients with _ 2 measured during CPET is the gold CHF. Peak VO standard for which the 6MWT was developed as a surrogate.

Fig. 1 illustrates the basis for CPET in PAH. Fig. 2 shows the devices, primary measurements, and derived variables obtained from CPET. While seated on a stationary cycle ergometer, the patient breathes through a mouthpiece with a nose clip in place. Breath_ _ 2, by-breath measurements of respiratory rate, VE, VO _VCO2, end-tidal PO2 and pCO2, O2 pulse, VE/ _ VO _ 2, _ _ and VE/VCO2 are made at rest and during incremental, symptom-limited exercise. Measurements are usually obtained during 3 minutes of rest, during 3 minutes of unloaded pedaling at 60 rpm, and during a progressive increase in work rate (WR). Using cycle ergometry, a WR of 5 to 15 W (watts) per minute is most commonly chosen for patients with PAH, based on clinical appraisal, in an attempt to prevent excessively short or long test durations (target total test time 10–12 min). Patients are told to exercise until they become sufficiently symptomatic to cause them to stop. Measurements are made continuously throughout rest, exercise, and early

EXERCISE IN THE MANAGEMENT OF PAH/OUDIZ

Figure 1 Schematic showing the basis for cardiopulmonary exercise testing (CPET) in pulmonary arterial hypertension. Solid arrows represent the sequence of events leading from the effects of increased PVR to the symptoms of dyspnea and fatigue. Plain UP arrow represents the abnormal increase in lactate and CO2 production during exercise. Crossed DOWN arrows represent the blunting of the increases in cardiac output, O2 delivery to tissues, and adenosine triphosphate (ATP) regeneration during exercise. Dashed arrows represent the CPET measurements relevant to each pathophysiological process (see text). PVR, pulmonary vascular resistance; RV, right ventricular; DOE, dyspnea on exertion.

recovery. Values for the anaerobic threshold (AT) are usually obtained using the v-slope method.20 Blood pressure is usually measured with an automated pressure cuff. Twelve-lead electrocardiographic (EKG) recordings are obtained at rest for monitoring heart rate (HR) and rhythm during each minute of exercise and during recovery. _ 2 increases with the inIn normal subjects, VO creased demands of cellular respiration in response to exercise. In patients with PAH, the blunting of the expected increase in pulmonary blood flow (and therefore cardiac output) with exercise is reflected in the _ 2 (Fig. 1), which fails to meet blunted increase in VO the increased demands of cellular respiration in response to exercise.21,22 The pulmonary vasculopathy in PAH also results in an increase in the resting ventilatory dead space fraction of the tidal volume (VD/VT) and its failure to

decrease with exercise because the regions of ventilated lung that are underperfused at rest remain underperfused during exercise despite an increased pulmonary artery pressure. This ‘‘ventilatory inefficiency’’ increases the ventilatory requirement of PAH patients during exercise and further contributes to the symptoms of dyspnea.

During CPET, the ventilatory inefficiency is measured _ as an abnormally high ratio of VE (L/min) to VCO 2 (L/ _ min) at the AT. The magnitude of the elevation in VE/ _ VCO at AT is unique to patients with pulmonary 2 vascular disease, with a sensitive and accurate cut point of 34, above which a pulmonary vascular limit to exercise can be determined.23 In the presence of inadequate O2 delivery during exercise, anaerobic glycolysis is required to provide high energy phosphate for the exercising muscles; thus lactic acidosis ensues. This increases CO2 production relative to O2 consumption due to release of CO2 from

Figure 2 The devices, primary measurements, and derived variables obtained from cardiopulmonary exercise testing.

381

382

SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 26, NUMBER 4

bicarbonate as it buffers lactic acid. This additional CO2 production and the metabolic acidosis add to the ventilatory drive. Eventually, the source of adenosine triphosphate (ATP) regeneration from anaerobic glycolysis is inadequate. Consequently, muscular contraction cannot be maintained, and the muscles fatigue. Using CPET, the early lactic acidosis, causing increased CO2 output and ventilatory drive, is measured as a decrease in the AT. _ 2, AT, VE/ _ VCO _ Peak VO 2 at AT, peak VO2/HR (O2 pulse), and peak WR achieved during CPET correlate with PAH disease severity21 in a pattern that reflects the blunting of the expected increase in cardiac output and perfusion of the pulmonary vascular bed during exercise, the pathophysiological hallmark of the disease. This pattern shares common cardiopulmonary _ 2, AT, gas exchange aberrations with CHF (low peak VO _ 2/D WR, and O2 pulse); however, the VE/ _ VCO _ DVO 2 is distinctively higher at rest in PAH and continues to rise during exercise, rather than falling,24 despite similar 6MWT distance and functional class. Furthermore, peak O2 pulse is lower in PAH, and the AT occurs at a _ 2 as compared with CHF, higher percentage of peak VO again despite similar 6MWT distance and functional class.

Wensel et al demonstrated the importance of CPET in PAH for prognostication.25 In a multivariate _ 2 analysis, peak exercise blood pressure and peak VO during CPET predicted survival. Survival was significantly better for patients able to achieve a peak _ 2 > 10.4 mL/kg/min.

VO Although CPET variability is higher in patients with heart failure than in less-disabled subjects,26 Hansen et al have shown that CPET in PAH patients is highly reproducible, with little test to test variability.27 Importantly, in their study of paired CPET studies performed in 42 PAH patients, they showed that the coefficient of variation for AT, although slightly higher than for other CPET parameters, was only 6%. This provides validation for the use of submaximal CPET (using AT as the surrogate for exercise capacity) for those clinicians reluctant to perform maximal exercise tests in their disabled PAH patients.

BICYCLE VERSUS TREADMILL EXERCISE The O2 uptake response to exercise can vary between patients; this effect can be minimized with cycle ergometry. With a treadmill, the O2 uptake response is variable from one subject to the other and less precise from time to time. With the cycle ergometer, the response is uniform in most subjects, and oxygen uptake _ 2/ increases at a constant rate of 10.3 mL/min/W (VO 28 WR) in normal subjects. Porszasz et al recently demonstrated a new treadmill protocol that results in more uniform O2 uptake. This protocol requires a computer-

2005

controlled, continuously variable system to adjust belt speed and level of incline and has not yet been validated in patients with cardiopulmonary disease. Cycle ergometry exercise may be superior to treadmill exercise in patients with PAH because patients can stop cycling when they decide to, whereas patients cannot stop walking on the treadmill until the technician decides to turn off the treadmill and the belt stops moving.

The addition of cardiac imaging to standard exercise testing, such as in exercise echocardiography, offers certain advantages and disadvantages in the diagnosis and management of patients with PAH. The main advantage of this modality is to determine estimates of rest and exercise right ventricular systolic pressure (RVSP).29 This may be of particular importance in patients with normal resting RVSP who develop abnormally high RVSP with exercise, implying the presence of exercise-induced pulmonary hypertension, which may not be associated with significant symptoms and may not be evident by subjective assessments of exercise capacity (i.e., NYHA or World Health Organization functional class).30 However, the clinical impact of exerciseinduced PAH is not yet fully understood. Moreover, noninvasive estimates of RVSP may not accurately reflect the actual hemodynamics in all patients, and thus RVSP may be over- or underestimated.31 Finally, echocardiography cannot accurately differentiate non-PAH forms of pulmonary hypertension, such as pulmonary venous hypertension, from PAH, without confirmatory cardiac catheterization. These issues are of significant importance because they ultimately have therapeutic implications.

Most studies of exercise capacity in PAH have reported outcomes in patients with advanced PAH (mostly NYHA functional class III). In many of these trials, the incremental benefit of therapy has been shown to be greatest in patients with the lowest baseline exercise capacity. The value of exercise capacity measurements in patients with less severe disease has not yet been evaluated. A promising and possibly more discriminating exercise modality in this subset may be to measure exercise duration (at constant WR), as was done in a small clinical crossover study of sildenafil versus placebo in PAH,32 perhaps combined with a simple measure of ventilatory inefficiency using endtidal PCO2 (PET CO2) at end exercise, as shown by Yasunobu et al.33 The current practice for patients with severe left ventricular failure utilizes measurements obtained from CPET as the major factor in determining the need for heart transplantation.34,35 Because exercise capacity correlates with survival in PAH, it is likely that future studies examining exercise capacity in patients with PAH and right ventricular failure may play a role in determining the need for lung transplantation, possibly using selected CPET parameters that indicate the

EXERCISE IN THE MANAGEMENT OF PAH/OUDIZ

severity of the pulmonary vascular pathophysiology.21 This aspect of PAH outcome has not yet been studied.

In summary, exercise testing is a valuable noninvasive modality in the diagnosis and management of PAH. Measures of exercise capacity predict survival and clinical outcome in patients with moderate to severe PAH and play an integral role in determining disease severity and response to therapy in patients with PAH. Additional work must be done to validate exercise capacity as an end point in patients with less severe PAH.

REFERENCES 1. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension.

The Primary Pulmonary Hypertension Study Group. N Engl J Med 1996;334:296–302 2. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346: 896–903 3. Yetman AT, Taylor AL, Doran A, Ivy DD. Utility of cardiopulmonary stress testing in assessing disease severity in children with pulmonary arterial hypertension. Am J Cardiol 2005;95:697–699 4. Wax D, Garofano R, Barst RJ. Effects of long-term infusion of prostacyclin on exercise performance in patients with primary pulmonary hypertension. Chest 1999;116:914–920 5. Guyatt GH, Sullivan MJ, Thompson PJ, et al. The 6-minute walk: a new measure of exercise capacity in patients with chronic heart failure. Can Med Assoc J 1985;132:919–923 6. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001;358:1119–1123 7. Galie` N, Humbert M, Vachiery JL, et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol 2002;39:1496– 1502 8. Langleben D, Christman BW, Barst RJ, et al. Effects of the thromboxane synthetase inhibitor and receptor antagonist terbogrel in patients with primary pulmonary hypertension.

Am Heart J 2002;143:E4 9. Olschewski H, Simonneau G, Galie` N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002;347: 322–329 10. Simonneau G, Barst RJ, Galie` N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a doubleblind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002;165:800–804 11. Barst RJ, McGoon M, McLaughlin V, et al. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2003;41:2119–2125 12. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982;14:377–381 13. Mahler DA, Weinberg DH, Wells CK, Feinstein AR. The measurement of dyspnea: contents, interobserver agreement,

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

and physiologic correlates of two new clinical indexes. Chest 1984;85:751–758 Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002;40:780–788 Miyamoto S, Nagaya N, Satoh T, et al. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension: comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med 2000;161:487–492 Paciocco G, Martinez FJ, Bossone E, Pielsticker E, Gillespie B, Rubenfire M. Oxygen desaturation on the six-minute walk test and mortality in untreated primary pulmonary hypertension. Eur Respir J 2001;17:647–652 Paciocco G, Martinez FJ, Bossone E, et al. Oxygen desaturation on the six-minute walk test and mortality in untreated primary pulmonary hypertension. Eur Respir J 2001;17:647–652 McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004;126(suppl 1):14S–34S Oudiz RJ, Sun XG. Abnormalities in exercise gas exchange in primary pulmonary hypertension. In: Wasserman K, ed.

Cardiopulmonary Exercise Testing and Cardiovascular Health. Armonk, NY: Futura; 2002:179–190 Beaver WL, Wasserman K, Whipp BJ. A new method for detecting anaerobic threshold by gas exchange. J Appl Physiol 1986;60:2020–2027 Sun X-G, Oudiz RJ, Hansen JE, Wasserman K. Exercise pathophysiology in primary pulmonary hypertension. Circulation 2001;104:429–435 Wasserman K, Hansen JE, Sue DY, Casaburi R, Whipp BJ, eds. Principles of Exercise Testing and Interpretation. 4th ed.

Philadelphia: Lippincott Williams & Wilkins; 2004 Markowitz DH, Systrom DM. Diagnosis of pulmonary vascular limit to exercise by cardiopulmonary exercise testing.

J Heart Lung Transplant 2004;23:88–95 Deboeck G, Niset G, Lamotte M, Vachiery J-L, Naeije R. Exercise testing in pulmonary arterial hypertension and in chronic heart failure. Eur Respir J 2004;23:747–751 Wensel R, Opitz CF, Anker SD, et al. Assessment of survival in patients with primary pulmonary hypertension: importance of cardiopulmonary exercise testing. Circulation 2002;106: 319–324 Janicki JS, Gupta S, Ferris ST, et al. Long-term reproducibility of respiratory gas exchange measurements during exercise in patients with stable cardiac failure. Chest 1990; 97:12–17 Hansen JE, Sun XG, Yasunobu Y, et al. Reproducibility of cardiopulmonary exercise measurements in patients with pulmonary arterial hypertension. Chest 2004;126:816– 824 Porszasz J, Casaburi R, Somfay A, Woodhouse LJ, Whipp BJ. A treadmill ramp protocol using simultaneous changes in speed and grade. Med Sci Sports Exerc 2003;35:1596–1603 Himelman RB, Stulbarg M, Kircher B, et al. Noninvasive evaluation of pulmonary artery pressure during exercise by saline-enhanced Doppler echocardiography in chronic pulmonary disease. Circulation 1989;79:863–871 Oelberg DA, Marcotte F, Kreisman H, Wolkove N, Langleben D, Small D. Evaluation of right ventricular systolic

383

384

SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 26, NUMBER 4

pressure during incremental exercise by Doppler echocardiography in adults with atrial septal defect. Chest 1998;113: 1459–1465 31. Vachiery JL, Brimioulle S, Crasset V, Naeije R. False-positive diagnosis of pulmonary hypertension by Doppler echocardiography. Eur Respir J 1998;12:1476–1478 32. Sastry BK, Narasimhan C, Reddy NK, Raju BS. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol 2004;43:1149–1153 33. Yasunobu Y, Oudiz RJ, Sun X, Hansen J, Wasserman K. End-tidal PCO2 as a measure of ventilatory efficiency and

2005

exercise limitation in patients with primary pulmonary hypertension. Chest 2005;127:1637–1646 34. Costanzo MR, Augustine S, Bourge R, et al. Selection and treatment of candidates for heart transplantation: a statement for health professionals from the Committee on Heart Failure and Cardiac Transplantation of the Council on Clinical Cardiology, American Heart Association. Circulation 1995;92:3593–3612 35. Stevenson LW. Role of exercise testing in the evaluation of candidates for cardiac transplantation. In: Wasserman K, ed.

Exercise Gas Exchange in Heart Disease. Armonk, NY: Futura; 1996:271