Cardiopulmonary Exercise Testing with Right-heart Catheterization in Patients with Systemic Sclerosis

Patients

A retrospective chart review of test results for all SSc patients who underwent CPET/RHC evaluation at our institution over the 5-year period February 2003 to February 2008 is the basis for this report. The Institutional Review Board approved all data collection procedures for this study and waived informed consent for this retrospective review.

Patients with SSc were referred to the Boston Medical Center Pulmonary Hypertension Center for evaluation of unexplained dyspnea on exertion. Subjects were subsequently scheduled for CPET/RHC testing based on preliminary evaluation that failed to define a most probable explanation for their symptoms, and raised the possibility of pulmonary vascular disease (Table 1). The majority of patients underwent chest radiography, high resolution chest tomography, echocardiogram, and pulmonary function testing prior to CPET/RHC testing. The diagnosis of SSc per American College of Rheumatology criteria was confirmed by clinical evaluation of a board-certified rheumatologist. Documentation of serologic testing was available for 8/19 subjects and therefore was not included in this analysis.

CPET protocol

Study personnel for CPET/RHC included a pulmonary Attending and Fellow, a registered nurse, and a registered respiratory therapist. All patients provided informed consent for the CPET/RHC procedure. Patients were escorted to the pulmonary function test laboratory where a radial arterial blood gas was drawn. Patients underwent pulmonary function testing (Viasys Encore; Cardinal Health, Dublin, OH, USA) including spirometry, maximal voluntary ventilation, and DLCO testing. Patients were then escorted to a designated catheterization suite, where a RHC was placed through an 8.5 French jugular venous introducer under sterile conditions; RHC placement was confirmed by chest radiograph prior to CPET. Baseline supine RHC hemodynamic values were obtained [central venous pressure (CVP), right ventricular pressure (RVP), pulmonary arterial pressure (PA_mean), pulmonary capillary wedge pressure (PCWP), cardiac output and cardiac index via thermodilution (CO and CI), pulmonary vascular resistance (PVR), systemic vascular resistance (SVR)]. Patients returned to the pulmonary function laboratory, where baseline blood pressure, heart rate, oxygen saturation, EKG, and identical right-heart catheter hemodynamic values were repeated after the patient had been properly positioned on an upright bicycle ergometer. All measurements were obtained using the Viasys Encore system with integrated continuous EKG monitoring (Max-1 EKG; Marquette Medical, Milwaukee, WI, USA). Patients were fitted with headgear to support a flow sensor and an oximeter to measure continuous oxygen saturation. After a 1-min warm-up phase at 60 rpm and no resistance, the subject began a graded exercise program with a work increase of 5–10 w/min, depending on baseline conditioning status, with a goal rate of 60 rpm. Manual blood pressure measurements and RHC hemodynamic values were obtained every 2 min during exercise, with PCWP measured at end exhalation via analysis of the RHC pressure tracings. 12-lead EKG monitoring was continuous. Patients exercised until they were unable to maintain 60 rpm or until experiencing symptoms and/or abnormal vital signs that necessitated discontinuation of the procedure. Criteria for terminating CPET prior to patient request were based on institutional policy and included ischemic chest pain or EKG changes, complex ectopy, second or third degree heart block, fall in systolic blood pressure (SBP) > 20 mm Hg, systolic blood pressure ≥ 250, diastolic blood pressure ≥ 120 mm Hg, oxygen saturation < 85%, sudden pallor, loss of coordination, mental status changes, presyncope, or signs of respiratory failure. Patients whose studies were not terminated for any of these complications continued into recovery mode, cycling at no resistance for 2 min. At this time, a second radial arterial blood gas sample was obtained. Anaerobic threshold was determined by the V-slope method¹⁵. If no clear change in slope was seen, the R value or ventilatory equivalent methods were utilized.

Diagnostic classifications and definitions

Diagnostic classifications derived from the CPET/RHC analysis by the attending pulmonary physician of record at the time of testing were utilized as the primary outcome for this study. The original CPET/RHC-diagnosed etiologies for exercise limitation were classified for study purposes as “pulmonary vascular limitation” (PVL), “left ventricular diastolic dysfunction” (LVDD), “ventilatory limitation” (restrictive lung disease), or “deconditioning/cardiovascular limitation.” CPET/RHC diagnoses at our institution were determined by combining guidance from algorithms proposed by Wasserman, et al¹⁵ with the hemodynamic results from the RHC. For example, these algorithms suggest a diagnosis of PVL in subjects with decreased maximal VO₂ and anaerobic threshold with elevated ventilatory equivalent for CO₂ (VE/VCO₂); additionally, these subjects should have no evidence of pulmonary venous hypertension (PCWP < 18) on RHC. LVDD was considered for similar CPET findings, except with echocardiographic evidence of normal ejection fraction (≥ 50%) and RHC showing peak exercise-PCWP ≥ 18 mm Hg and a pulmonary artery-diastolic pressure to-PCWP gradient ≤ 5 mm Hg. Ventilatory limitations were considered for patients with low VO₂ and a low breathing reserve. Deconditioning was defined as a low maximum VO₂ without evidence for ventilatory, pulmonary vascular, or left ventricular abnormalities seen with CPET or RHC. A cardiovascular limitation was diagnosed for subjects with a low maximum VO₂ without evidence for ventilatory, pulmonary vascular, or hemodynamic abnormalities seen with CPET or RHC, but with an abnormal resting echocardiogram. Given similar CPET and RHC findings, subjects with deconditioning and cardiovascular limitation diagnoses were combined for purposes of analysis. Three attending physicians trained in pulmonary and critical care medicine were responsible for CPET readings during the study. For the purposes of the study, these CPET were then reread by an independent reviewer (MI) blinded to the initial readings — these readings agreed with the initial diagnostic assessment with a kappa statistic of 0.93 (95% CI 0.79–1.0).

SSc was subclassified into limited, diffuse, and scleroderma overlap syndromes. EKG was defined as normal or abnormal (any abnormality with the exception of nonspecific T wave changes). Chest radiographs were classified as normal, abnormal lung parenchyma, or abnormal cardiac silhouette. Chest computed tomography (CT) scans were classified as normal or parenchymal abnormalities (a radiologist report of fibrosis, ground glass, pneumonitis, reticulo-nodular). Echocardiography results were classified from the cardiologist’s final echocardiogram report as normal (≥ 50%) or abnormal (< 50%) left ventricular ejection fraction (EF), normal or abnormal diastolic function based on Doppler interrogation of the mitral inflow pattern (E/A ratio), and normal [estimated pulmonary artery systolic pressure (PASP) < 40 mm Hg] or abnormal (PASP ≥ 40 mm Hg) PASP calculated from the tricuspid regurgitant jet.

Statistics

SAS v 9.1 (SAS Inc., Cary, NC, USA) was utilized for all data analysis. Continuous variables were expressed as mean ± standard deviations for normally distributed variables and median (interquartile range, IQR) for nonparametric variables. Due to the limited sample size and multiple nonparametric variables, Wilcoxon rank sum and Kruskal-Wallis testing were used for comparisons of continuous variables. Categorical variables were analyzed with chi-square or Fisher’s exact testing, where appropriate. An alpha level less than 0.05 indicated statistical significance.

Baseline data

Twenty patients with SSc underwent CPET/RHC testing during the study timeframe. One patient was excluded from analysis due to unreliable CPET data resulting from secretions occluding the mouthpiece. Thus, 19 SSc patients were included in this analysis, including 10 patients with limited SSc, 5 with diffuse SSc, one with lupus/SSc overlap syndrome, and 2 without SSc subtype specified in the medical record. All subjects were referred for CPET/RHC for unexplained dyspnea on exertion and suspicion of PVL to exertion. Additional reasons for CPET/RHC referral and baseline subject data are listed in Table 1. Subjects with limited SSc were on average older than subjects with diffuse SSc (58.7 ± 14 vs 38.6 ± 4.7 yrs, respectively; p = 0.04). Otherwise, no baseline differences were observed between SSc subtypes. No complications occurred during CPET/RHC.

CPET test data

Subjects with limited SSc had a higher predicted FVC (82.4 ± 16% vs 52 ± 13%), higher predicted FEV1 (85 ± 15% vs 57 ± 15.7%) and lower FEV1/FVC ratio (0.76 ± 0.05 vs 0.85 ± 0.05) than subjects with diffuse SSc. No differences in diffusion capacity were observed between SSc subgroups. Supplementary Appendix Table 1 gives baseline pulmonary function test (PFT) data for all subjects.

Complete CPET and arterial blood gas measurements for all SSc subjects are listed in Supplementary Appendix Table 2. No significant differences were observed between limited and diffuse SSc subtypes for these tests. RHC data resting supine, resting upright, and while upright during peak exercise are shown in Table 2. No differences in cardiopulmonary hemodynamics were found between SSc subtypes.

Etiology of exercise limitation

The distributions of etiologies for exercise intolerance as determined by CPET/RHC testing were ventilatory limitation (n = 6), deconditioning/cardiovascular limitation (n = 6), LVDD (n = 4), and PVL (n = 3). All subjects with PVL to exercise were of the limited SSc subtype. Eight subjects (42%) had results showing additional, significant pathology on either CPET or RHC analysis that was not felt to be exercise-limiting, including severe ventilatory abnormalities in 6 subjects, elevated PCWP in 2 subjects, and elevated PA_mean in 2 subjects. Thus, 4 subjects had exercise-induced elevations in PA pressures that were not felt to be the primary etiology of exercise limitation as determined by combined analysis of CPET and RHC testing.

At baseline, no clinical information acquired prior to CPET/RHC was predictive of the CPET/RHC-derived etiology of exercise intolerance or dyspnea (Table 3 shows data for individual subjects, Table 4 shows data for the study population). This included the indication for CPET/RHC referral, New York Heart Association (NYHA) class, resting echocardiographic values (PASP, diastolic function, left ventricular ejection fraction), pulmonary function test results, and imaging data (chest radiograph, CT). Specifically, exertional hypoxemia detected by outpatient transcutaneous oximetry prior to CPET testing was not an accurate predictor of exercise-induced hypoxemia. The correlation between pulse oximetry in clinic and during the CPET was poor (Pearson r = 0.28, p = 0.28), with only 5/10 instances of abnormal desaturation seen with clinic oximetry associated with an abnormal A-a gradient during exercise. Resting echocardiography results also did not coincide with CPET/RHC data: 4/6 (66%) subjects with a ventilatory limit to exertion were found to have a resting echocardiogram demonstrating elevated PA pressures, although only one of these patients was found to have elevated PA_mean during CPET/RHC. In contrast, only 50% of patients meeting the study criteria for a pulmonary vascular limitation showed elevated PASP on resting echocardiography. Also, despite 5 subjects with elevated PCWP during CPET/RHC, no subject was found to have abnormal diastolic function by resting echocardiography. Imaging and pulmonary function testing were similarly unrevealing: all but one subject had evidence of interstitial lung disease on CT scan and there were no significant differences in baseline PFT measurements — including DLCO — according to final diagnosis of exertional limitation by CPET/RHC.

Table 4 demonstrates that significant differences between CPET/RHC diagnostic categories were seen for breathing reserve [median breathing reserve for deconditioning/cardiovascular limit: 28 (IQR 25, 32) vs pulmonary vascular: 31 (IQR 21, 33) vs exercise-LVDD: 24 (IQR 15, 48) vs ventilatory limitation: 5 (IQR 2, 7); p = 0.01] and P(A-a)O₂ at peak exercise [in mm Hg: deconditioning/cardiovascular limit: 12 (IQR 4, 16) vs ventilatory limit: 29.1 (IQR 3.5, 36.0) vs pulmonary vascular limit: 48.0 (IQR 45, 62) vs exercise-LVDD: 26.0 (IQR 10.6, 36.0); p = 0.04].

Major treatment changes occurred in 11/19 (58%) patients after CPET/RHC, including 5 who started or changed dosing of immunosuppressive therapy for interstitial lung disease, 2 who started pulmonary vasodilator therapy, 2 who started treatment for left ventricular dysfunction, and 2 subjects with deconditioning who were prescribed a conditioning regimen.