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Invasive cardiopulmonary exercise testing in the evaluation of unexplained dyspnea: Insights from a multidisciplinary dyspnea center

Invasive cardiopulmonary exercise testing in the evaluation of unexplained dyspnea: Insights from... Abstract Background Unexplained dyspnea is a common diagnosis that often results in repeated diagnostic testing and even delayed treatments while a determination of the cause is being investigated. Through a retrospective study, we evaluated the diagnostic efficacy of a multidisciplinary dyspnea evaluation center (MDEC) using invasive cardiopulmonary exercise test to diagnose potential causes of unexplained dyspnea. Methods We reviewed the medical records of all patients referred with unexplained dyspnea to the MDEC between March 2011 and October 2014. We assessed the diagnostic efficacy before and after presentation to the MDEC. Results During the study period a total of 864 patients were referred to the MDEC and, of those, 530 patients underwent further investigation with invasive cardiopulmonary exercise test and constituted the study sample. The median age was 57 (44–68) years, 67.2% were women, and median body mass index was 26.22 (22.78–31.01). A diagnosis was made in 530 patients including: exercise pulmonary arterial hypertension of 88 (16.6%), heart failure with preserved ejection fraction of 94 (17.7%), dysautonomia 112 (21.1%), oxidative myopathy of 130 (24.5%), primary hyperventilation of 43 (8.1%), and other 58 (10.9%). The time from initial presentation to referral was significantly longer than time to diagnosis after referral for non-standardized conventional methods versus diagnosis through MDEC using invasive cardiopulmonary exercise test (511 days (292–1095 days) vs. 27 days (13–53 days), p < 0.0001). In a subgroup analysis, we reviewed that patients referred from cardiovascular clinics were more likely to have a greater number of diagnostic tests performed and, conversely, patients referred from pulmonary clinics were more likely to have a greater number of treatments prescribed before referral to MDEC. Conclusions As a result of this retrospective study, we have evaluated that a multidisciplinary approach that includes invasive cardiopulmonary exercise test dramatically reduces the time to diagnosis compared with traditional treatment and testing methods. Dyspnea, exertional intolerance, invasive CPET, evaluation, exercise testing Introduction Dyspnea is a common but nonspecific symptom in patients presenting to both primary care and subspecialty practices, with a peak incidence in patients who are 55 to 69 years of age.1,2 It is considered chronic when lasting more than one month.3 Dyspnea during exertion, sometimes characterized as “exercise intolerance”, is usually associated with a cardiac or pulmonary cause. Other etiologies such as deconditioning, obesity, malignancy, anemia, and sleep apnea are recognized less frequently.4 Patients with neuromuscular diseases, mitochondrial myopathies, and metabolic disorders may also present with a primary complaint of dyspnea. Many patients will have an obvious cause of dyspnea, such as an exacerbation of known asthma, chronic obstructive pulmonary disease (COPD), or heart failure; however, many patients will require a thorough diagnostic evaluation to establish the underlying cause and provide effective therapy. All too often the cause of dyspnea remains elusive even after an aggressive evaluation,5 and despite prior testing at rest or with exercise.6 Such cases of unexplained dyspnea account for about 15% of patients who present with chronic dyspnea.3,7 Additionally, population based studies suggest a prevalence of unexplained exertional intolerance of 9–35%,8–12 and becoming more prevalent with increased age. The dyspneic patient without an obvious primary etiology may be referred to a number of different specialists for evaluation. The initial evaluation may include extensive blood work, pulmonary function testing, echocardiography, cardiac catheterization, radiographic and nuclear imaging modalities, and cardiac stress and cardiopulmonary exercise testing (CPET). Clinicians in different disciplines may approach the evaluation of dyspnea with contrasting methods, often without timely communication or collaboration. As a result, inefficient evaluation of dyspnea involving multiple referrals can be costly and very frustrating for the patient. Noninvasive cardiopulmonary exercise testing (niCPET) is often used to assess the physiologic contributions to a patient’s symptoms of dyspnea and exercise intolerance. The test provides a breath-by-breath analysis of ventilation, pulmonary gas exchange and cardiac function at rest and during incremental exercise. The niCPET primarily determines whether patients have normal or reduced maximal exercise capacity (VO2max) and, if so, suggests possible causes. The exercise-based test is much more sensitive in detecting early or subclinical disease than tests done at rest. Invasive CPET (iCPET) is a variant of the test that adds pulmonary and radial artery catheter-derived pressure and blood gas sampling to the niCPET. This approach allows for direct systemic blood pressure measurement, dead space to tidal volume ratios, alveolar/arterial oxygen gradient, measurement of pulmonary hemodynamic parameters, and direct Fick cardiac output assessment, allowing for the derivation of systemic and pulmonary vascular resistance.13 (See Maron et al.13 for a detailed description of approach and diagnostic criteria.) (Figure 1). Figure 1. Open in new tabDownload slide Flow diagram of diagnostic approach and diagnostic criteria. MDEC: Multidisciplinary Dyspnea/Exercise Intolerance Center; niCPET: noninvasive cardiopulmonary exercise testing; iCPET: invasive cardiopulmonary exercise testing; PAP: pulmonary artery pressure; Max.: maximum; PVR: pulmonary vascular resistance; PAH: pulmonary arterial hypertension; PCWP: pulmonary capillary wedge pressure; HFpEF: exercise-heart failure preserved ejection fraction; EF: ejection fraction; COPD: chronic obstructive pulmonary disease; RAP: Right atrial pressure; mPAP: mean pulmonary artery pressure. Brigham and Women’s Hospital recently established the Multidisciplinary Dyspnea/Exercise Intolerance Center (MDEC) to evaluate patients with unexplained dyspnea. MDEC brought together a core group of clinical experts from pulmonary medicine, cardiovascular medicine, and radiology along with input from neurology, rheumatology, and psychiatry to collaboratively develop a high quality, cost effective, and streamlined approach to assessing and treating the patient with unexplained exertional dyspnea. In the current study, we sought to evaluate the diagnostic efficacy of a MDEC that uses iCPET to diagnose potential causes of unexplained dyspnea. We hypothesized that a stepwise approach leveraging iCPET when a multidisciplinary review of a parsimonious set of investigations is inconclusive would substantially reduce the time associated with obtaining a final diagnosis. Methods Protected health information The Partners Healthcare Institutional Review Board approved the protocol for the use of human subject data at Brigham and Women’s Hospital for this retrospective analysis. Subjects and study design We reviewed the medical records of all patients referred to the Brigham and Women’s Hospital MDEC between 1 March 2011 and 30 October 2014. Patients were referred to the MDEC for unexplained exertional symptoms. (For description of the MDEC approach to the evaluation please see the online supplement). Additional indications for referral included: 1) symptoms out of proportion to resting abnormalities on echocardiography, pulmonary function testing, and/or other imaging modalities; 2) lack of expected improvement with “standard therapy” for a suspected diagnosis such as asthma, COPD, or heart failure; or 3) the presence of multiple diagnoses potentially contributing to dyspnea for determination of appropriate treatment. All patients had normal or inconclusive prior testing including blood laboratory testing, electrocardiograms, echocardiograms (both resting and stress), complete pulmonary function testing, and radiographic imaging. The number and type of tests and the time course of patient assessment in the evaluation of dyspnea prior to referral to MDEC were compared with testing patterns and time to diagnosis by MDEC physicians. Additionally, we quantified the following available analyses for each patient: 1) pulmonary function testing; 2) echocardiography; 3) cardiac catheterization; 4) radiographic and nuclear imaging modalities; 5) cardiac stress and CPET; 6) empiric treatments; and 7) assessment of functional status and subjective quality of life measures, before and after referral to MDEC. Diagnostic efficiency evaluation We compared assessments made after the patient was first seen in MDEC with the patient’s experience with conventional dyspnea evaluations prior to referral to MDEC. In particular, based on the medical records, we estimated the duration patients had been living with unexplained dyspnea prior to referral to MDEC. When analyzing the patients’ experience prior to MDEC referral, we truncated the look-back period at four years; however, 89 (16.8%) patients had complaints of dyspnea exceeding four years. The primary outcomes included the identification of a final diagnosis along with time to diagnosis. By design, all patients referred to MDEC during the time period of the study had a prior complaint of chronic dyspnea and had undergone prior evaluation that had failed to reach an accurate diagnosis of the underlying condition. We measured the percentage of MDEC patients for whom an accurate diagnosis of underlying conditions was reached through the MDEC evaluation protocol and compared that with the frequency of different categories of conditions observed. We divided the patient’s total time to diagnosis into two periods. These two time periods included number of days from initial dyspnea complaint to first referral to MDEC compared with the number of days after referral to MDEC to the final diagnosis of the underlying cause of dyspnea. Statistical analysis The statistical analyses were performed with SPSS version 23.0 (SPSS Inc., Chicago, IL, USA). All numeric values are reported as median (first and third quartile) because the majority of the parameters were not normally distributed. Mann–Whitney U tests or a Chi-Square test were used to assess group differences. Multiple comparisons were performed using analysis of variance with Bonferroni correction. Spearman correlation coefficients were calculated. A p value <0.05 was considered statistically significant. Results Characteristics of MDEC referral patients There were 864 patients referred to MDEC between 1 March 2011 and 30 October 2014. Of those total patients evaluated, a diagnosis of the underlying cause of dyspnea was provided to 310 patients (36%) based on the initial MDEC evaluation, which included a thorough history and physical examination, full pulmonary function testing, chest imaging, an echocardiogram, and a review of data from patient testing which occurred prior to MDEC referral. These patients required no further evaluation and were excluded from the study group. In the remaining 554 patients (64%), a diagnosis of the underlying cause could not be reached based on the initial MDEC evaluation. These patients with unexplained dyspnea then underwent iCPET at MDEC. There were 24 patients who had iCPET who were excluded from the analysis because of incomplete medical records, leaving a total evaluable study group of 530 patients. The unexplained dyspnea cohort (n = 530) had a median age of 57 years (44–68 years), 356 (67.2%) were women, and median body mass index for the cohort was 26.22 (22.78–31.01). They were referred from various specialty clinics including: pulmonary clinics (n = 174), cardiovascular clinics (n = 165), general medicine practices (n = 103), neurology (n = 28), rheumatology (n = 13), family medicine (n = 6), lung transplant list (n = 6), gastroenterology (n = 6), infectious disease (n = 6), thoracic surgery (n = 5), general pediatric medicine (n = 4), nephrology (n = 3), allergy/immunology (n = 3), hematology (n = 3), oncology (n = 3), and two patients were self-referred. In the study group cohort, we found that there were 80 different laboratory tests and 63 different types of non-laboratory tests (including imaging, noninvasive and invasive stress tests) used in the assessment of unexplained dyspnea. Prior to referral to MDEC, patients had undergone a median of 15 (range 5–41) laboratory based tests as part of the evaluation of dyspnea, and a median of 6 (range 4–10) non-laboratory based diagnostic tests (including imaging noninvasive and invasive stress tests) per patient before they were referred to MDEC. Four hundred patients (75.5%) had repeated testing before referral to MDEC. In contrast, there were no repeat tests after MDEC. Through our analysis, we found that patients referred from cardiovascular specialty clinics had a greater number of diagnostic tests performed prior to MDEC referral than patients referred from pulmonary, general medicine, or other practices (Table 1). After MDEC, patients received a median of 2 (range 1–5) laboratory tests, and a median of 0 (range 0–1) non-laboratory tests (excluding iCPET)—significantly fewer tests per patient compared with the period before referral to MDEC (p < 0.0001). For thoroughness of evaluation by MDEC, some patients required complete pulmonary function tests, chest radiography, and an echocardiogram after referral to MDEC if not previously performed and were felt to be clinically indicated. This included 50 patients who had either a chest radiograph or chest computed tomography scan, and 88 patients who had an echocardiogram after referral to MDEC. Table 1. Diagnostic tests, treatment, and time referred from different clinics before Multidisciplinary Dyspnea/Exercise Intolerance Center. . Cardiology (n = 165) . Pulmonology (n = 174) . General medicine (n = 103) . Others (n = 88) . p value . Age 65 (50–72) 52 (37–62)a 59 (48–71)b 58 (48–68)b <0.001 Women, n(%) 101 (61.21) 122 (70.11) 74 (71.84) 59 (67.05) NS BMI 29.83 (24.76–33.60) 29.63 (24.77–33.98) 27.61 (23.92–32.57) 29.35 (24.97–34.63) NS Lab tests 13 (6.0–46.0) 8 (2.0–25.0)a 14 (7.0–39.0)b 19 (6.0–36.0)b 0.011 Other tests 7 (5.0–13.0) 6 (4.0–9.0)a 6 (4.0-10.0)a 5 (3.0–7.0)a 0.025 Treatment, n (%) 71 (43.03) 102 (58.62)a 64 (62.14)a 50 (56.82)a 0.006 Diagnostic time, days 383 (285–747) 730 (329–1095)a 365 (292–730) 511 (228–748) NS . Cardiology (n = 165) . Pulmonology (n = 174) . General medicine (n = 103) . Others (n = 88) . p value . Age 65 (50–72) 52 (37–62)a 59 (48–71)b 58 (48–68)b <0.001 Women, n(%) 101 (61.21) 122 (70.11) 74 (71.84) 59 (67.05) NS BMI 29.83 (24.76–33.60) 29.63 (24.77–33.98) 27.61 (23.92–32.57) 29.35 (24.97–34.63) NS Lab tests 13 (6.0–46.0) 8 (2.0–25.0)a 14 (7.0–39.0)b 19 (6.0–36.0)b 0.011 Other tests 7 (5.0–13.0) 6 (4.0–9.0)a 6 (4.0-10.0)a 5 (3.0–7.0)a 0.025 Treatment, n (%) 71 (43.03) 102 (58.62)a 64 (62.14)a 50 (56.82)a 0.006 Diagnostic time, days 383 (285–747) 730 (329–1095)a 365 (292–730) 511 (228–748) NS a Compared with patients referred from cardiology specialty practices, p < 0.05. b Compared with the patients referred from pulmonology specialty practices, p < 0.05. BMI: body mass index. Open in new tab Table 1. Diagnostic tests, treatment, and time referred from different clinics before Multidisciplinary Dyspnea/Exercise Intolerance Center. . Cardiology (n = 165) . Pulmonology (n = 174) . General medicine (n = 103) . Others (n = 88) . p value . Age 65 (50–72) 52 (37–62)a 59 (48–71)b 58 (48–68)b <0.001 Women, n(%) 101 (61.21) 122 (70.11) 74 (71.84) 59 (67.05) NS BMI 29.83 (24.76–33.60) 29.63 (24.77–33.98) 27.61 (23.92–32.57) 29.35 (24.97–34.63) NS Lab tests 13 (6.0–46.0) 8 (2.0–25.0)a 14 (7.0–39.0)b 19 (6.0–36.0)b 0.011 Other tests 7 (5.0–13.0) 6 (4.0–9.0)a 6 (4.0-10.0)a 5 (3.0–7.0)a 0.025 Treatment, n (%) 71 (43.03) 102 (58.62)a 64 (62.14)a 50 (56.82)a 0.006 Diagnostic time, days 383 (285–747) 730 (329–1095)a 365 (292–730) 511 (228–748) NS . Cardiology (n = 165) . Pulmonology (n = 174) . General medicine (n = 103) . Others (n = 88) . p value . Age 65 (50–72) 52 (37–62)a 59 (48–71)b 58 (48–68)b <0.001 Women, n(%) 101 (61.21) 122 (70.11) 74 (71.84) 59 (67.05) NS BMI 29.83 (24.76–33.60) 29.63 (24.77–33.98) 27.61 (23.92–32.57) 29.35 (24.97–34.63) NS Lab tests 13 (6.0–46.0) 8 (2.0–25.0)a 14 (7.0–39.0)b 19 (6.0–36.0)b 0.011 Other tests 7 (5.0–13.0) 6 (4.0–9.0)a 6 (4.0-10.0)a 5 (3.0–7.0)a 0.025 Treatment, n (%) 71 (43.03) 102 (58.62)a 64 (62.14)a 50 (56.82)a 0.006 Diagnostic time, days 383 (285–747) 730 (329–1095)a 365 (292–730) 511 (228–748) NS a Compared with patients referred from cardiology specialty practices, p < 0.05. b Compared with the patients referred from pulmonology specialty practices, p < 0.05. BMI: body mass index. Open in new tab Before referral to MDEC, 54% of the study cohort patients had specific therapies prescribed based on the findings of prior testing. Two hundred and ten (90.6%) patients were prescribed two or more treatments. Most patients received an assortment of treatments including 2–3 inhalers, diuretics, and anti-depressant treatments. Diagnosis after iCPET The underlying cause of dyspnea was determined in all patients who underwent iCPET (Table 2). Diagnoses included pulmonary arterial hypertension apparent only with exercise, 88 (EPAH, 16.6%); heart failure with preserved ejection fraction apparent only with exercise, 94 (HFpEF, 17.7%); dysautonomia or preload failure, 112 (21.1%); oxidative myopathy, 130 (24.5%) and primary hyperventilation, 43 (8.1%). Fifty-eight (10.9%) patients were dyspneic because of various other conditions including left to right shunting, patent foramen ovale, severe mitral valve regurgitation found only with exercise (no volume retention, normal resting echocardiogram, normal pulmonary capillary wedge pressure at peak exercise), chronotropic incompetence including drug effects or cardiac pacemaker heart rate limitation, hypoventilation, and deconditioning. Five out of the 530 iCPET patients (0.9%) had known heart failure with reduced ejection fraction. These patients were referred because they had improvement in left ventricular ejection fraction and no evidence of volume retention, but continued to complain of limiting dyspnea. In all five cases, a diagnosis of exercise HFpEF was made. Table 2. Diagnostic tests, treatment, and time of diagnosis subgroup before Multidisciplinary Dyspnea/Exercise Intolerance Center. . HFpEF (n = 99) . EPAH (n = 88) . Dysautonomia (n = 112) . Oxidative myopathy (n = 130) . Hyperventilation (n = 43) . Others (n = 58) . p value . Age 68 (60–74) 61 (54–72)a 45 (28–62)a,b 47 (30–58)a,b 62 (53–71)c,+ 56 (46–68)a,c,d,e <0.0001 Women, n (%) 44 (44.44) 55 (62.5)a 75 (66.96)a 107 (82.30)a 36 (83.72)a 39 (67.05)a,d <0.0001 BMI 32.0 (27.60–37.12) 31.43 (27.72–37.09) 24.58 (21.79–27.86)a,b 26.77 (23.36–31.27)a,b 28.96 (25.68–31.52)a,b,c 30.57 (25.26–35.86)b,c <0.0001 Lab tests 17.0 (5.0–55.0) 14.0 (5.0–47.0) 13.0 (4.0–33.0) 14.0 (5.0–32.0) 14.0 (5.0–35.0) 17.0 (6.0–40.0) NS Other tests 8.0 (5.0–18.0) 8.0 (4.0–14.0) 6.0 (4.0–8.0)a,b 5.0 (4.0–8.0)a,b 7.0 (4.0–11.0) 7.0 (4.0–12.0)c,d NS Treatment, (%) n46 (46.46) 50 (56.82) 60 (53.57) 76 (58.46) 22 (51.16) 33 (56.90) NS Diagnostic time, days 397 (329–733) 362 (183–729) 548 (292–1079) 363 (179–731) 380 (292–1095) 365 (146–734) NS . HFpEF (n = 99) . EPAH (n = 88) . Dysautonomia (n = 112) . Oxidative myopathy (n = 130) . Hyperventilation (n = 43) . Others (n = 58) . p value . Age 68 (60–74) 61 (54–72)a 45 (28–62)a,b 47 (30–58)a,b 62 (53–71)c,+ 56 (46–68)a,c,d,e <0.0001 Women, n (%) 44 (44.44) 55 (62.5)a 75 (66.96)a 107 (82.30)a 36 (83.72)a 39 (67.05)a,d <0.0001 BMI 32.0 (27.60–37.12) 31.43 (27.72–37.09) 24.58 (21.79–27.86)a,b 26.77 (23.36–31.27)a,b 28.96 (25.68–31.52)a,b,c 30.57 (25.26–35.86)b,c <0.0001 Lab tests 17.0 (5.0–55.0) 14.0 (5.0–47.0) 13.0 (4.0–33.0) 14.0 (5.0–32.0) 14.0 (5.0–35.0) 17.0 (6.0–40.0) NS Other tests 8.0 (5.0–18.0) 8.0 (4.0–14.0) 6.0 (4.0–8.0)a,b 5.0 (4.0–8.0)a,b 7.0 (4.0–11.0) 7.0 (4.0–12.0)c,d NS Treatment, (%) n46 (46.46) 50 (56.82) 60 (53.57) 76 (58.46) 22 (51.16) 33 (56.90) NS Diagnostic time, days 397 (329–733) 362 (183–729) 548 (292–1079) 363 (179–731) 380 (292–1095) 365 (146–734) NS a Compared with heart failure, p < 0.05. b Compared with EPAH, p < 0.05. c Compared with dysautonomia, p < 0.05. d Compared with oxidative myopathy, p < 0.05. e Compared with hyperventilation, p < 0.05. HFpEF: exercise heart failure preserved ejection fraction; EPAH: exercise-pulmonary hypertension; BMI: body mass index. Open in new tab Table 2. Diagnostic tests, treatment, and time of diagnosis subgroup before Multidisciplinary Dyspnea/Exercise Intolerance Center. . HFpEF (n = 99) . EPAH (n = 88) . Dysautonomia (n = 112) . Oxidative myopathy (n = 130) . Hyperventilation (n = 43) . Others (n = 58) . p value . Age 68 (60–74) 61 (54–72)a 45 (28–62)a,b 47 (30–58)a,b 62 (53–71)c,+ 56 (46–68)a,c,d,e <0.0001 Women, n (%) 44 (44.44) 55 (62.5)a 75 (66.96)a 107 (82.30)a 36 (83.72)a 39 (67.05)a,d <0.0001 BMI 32.0 (27.60–37.12) 31.43 (27.72–37.09) 24.58 (21.79–27.86)a,b 26.77 (23.36–31.27)a,b 28.96 (25.68–31.52)a,b,c 30.57 (25.26–35.86)b,c <0.0001 Lab tests 17.0 (5.0–55.0) 14.0 (5.0–47.0) 13.0 (4.0–33.0) 14.0 (5.0–32.0) 14.0 (5.0–35.0) 17.0 (6.0–40.0) NS Other tests 8.0 (5.0–18.0) 8.0 (4.0–14.0) 6.0 (4.0–8.0)a,b 5.0 (4.0–8.0)a,b 7.0 (4.0–11.0) 7.0 (4.0–12.0)c,d NS Treatment, (%) n46 (46.46) 50 (56.82) 60 (53.57) 76 (58.46) 22 (51.16) 33 (56.90) NS Diagnostic time, days 397 (329–733) 362 (183–729) 548 (292–1079) 363 (179–731) 380 (292–1095) 365 (146–734) NS . HFpEF (n = 99) . EPAH (n = 88) . Dysautonomia (n = 112) . Oxidative myopathy (n = 130) . Hyperventilation (n = 43) . Others (n = 58) . p value . Age 68 (60–74) 61 (54–72)a 45 (28–62)a,b 47 (30–58)a,b 62 (53–71)c,+ 56 (46–68)a,c,d,e <0.0001 Women, n (%) 44 (44.44) 55 (62.5)a 75 (66.96)a 107 (82.30)a 36 (83.72)a 39 (67.05)a,d <0.0001 BMI 32.0 (27.60–37.12) 31.43 (27.72–37.09) 24.58 (21.79–27.86)a,b 26.77 (23.36–31.27)a,b 28.96 (25.68–31.52)a,b,c 30.57 (25.26–35.86)b,c <0.0001 Lab tests 17.0 (5.0–55.0) 14.0 (5.0–47.0) 13.0 (4.0–33.0) 14.0 (5.0–32.0) 14.0 (5.0–35.0) 17.0 (6.0–40.0) NS Other tests 8.0 (5.0–18.0) 8.0 (4.0–14.0) 6.0 (4.0–8.0)a,b 5.0 (4.0–8.0)a,b 7.0 (4.0–11.0) 7.0 (4.0–12.0)c,d NS Treatment, (%) n46 (46.46) 50 (56.82) 60 (53.57) 76 (58.46) 22 (51.16) 33 (56.90) NS Diagnostic time, days 397 (329–733) 362 (183–729) 548 (292–1079) 363 (179–731) 380 (292–1095) 365 (146–734) NS a Compared with heart failure, p < 0.05. b Compared with EPAH, p < 0.05. c Compared with dysautonomia, p < 0.05. d Compared with oxidative myopathy, p < 0.05. e Compared with hyperventilation, p < 0.05. HFpEF: exercise heart failure preserved ejection fraction; EPAH: exercise-pulmonary hypertension; BMI: body mass index. Open in new tab Diagnostic time The median time patients had lived with unexplained dyspnea prior to referral to MDEC was 511 days (range 292–1095 days). The median time between the first visit to MDEC and obtaining a diagnosis for the cause of their dyspnea was 27 days (13–53 days) (Figure 2). The difference in the time to diagnosis before referral to MDEC and after presentation to MDEC was 642 days (Figure 2). Between 2011 and 2014, the time to referral to MDEC increased each year while the time to diagnosis after referral to MDEC decreased each year (Figure 2). Figure 2. Open in new tabDownload slide Median time patients had lived with unexplained dyspnea prior to referral to Multidisciplinary Dyspnea/Exercise Intolerance Center (MDEC). ⋄f Time to diagnosis prior to establishment of the MDEC; ▪ time to diagnosis after establishment of the MDEC; ▴ difference in time to diagnosis between before and after the establishment of the MDEC. Patients referred from cardiology (43.03%) were less likely to be given empiric treatment intended to treat dyspnea than those patients referred from non-cardiology clinics (Table 1). The time to referral to MDEC from the pulmonary clinic subgroup was longer than that of the cardiology clinic subgroup (Table 1). The diagnostic time before referral to MDEC was significantly longer in patients <50 years old (Table 3). Additionally, diagnostic time before referral to MDEC was significantly longer in men compared with women (Table 4). We also found that women (57.87%) were more likely to be treated empirically (Table 4). There were no differences by age, sex, or referring specialty in the time to diagnosis after referral to MDEC. As expected, there were differences in the distribution of final diagnosis depending on what clinic the patient was referred from (Table 5). Patients referred from a cardiology clinic were more likely to have HFpEF, and less likely to have EPAH or oxidative myopathy than referrals from other clinics. Table 3. Diagnostic tests, treatment, and time of age subgroup before Multidisciplinary Dyspnea/Exercise Intolerance Center. . Age < 50 (n = 180) . Age ≥ 50 (n = 350) . p value . Age 37 (25–44) 65 (57–72)a <0.0001 Women, n (%) 135 (75.0) 221 (63.14)a 0.006 BMI 26.25 (22.83–31.14) 30.07 (25.50–34.73)a <0.0001 Lab tests 12.0 (5.0–31.0) 16.0 (5.0–48.0) NS Other tests 5.0 (3.0–8.0) 7.0 (5.0–13.0)a 0.001 Treatment, n (%) 105 (58.33) 182 (52.0) NS Diagnostic time, days 584 (292–1090) 402 (292–858)a 0.014 . Age < 50 (n = 180) . Age ≥ 50 (n = 350) . p value . Age 37 (25–44) 65 (57–72)a <0.0001 Women, n (%) 135 (75.0) 221 (63.14)a 0.006 BMI 26.25 (22.83–31.14) 30.07 (25.50–34.73)a <0.0001 Lab tests 12.0 (5.0–31.0) 16.0 (5.0–48.0) NS Other tests 5.0 (3.0–8.0) 7.0 (5.0–13.0)a 0.001 Treatment, n (%) 105 (58.33) 182 (52.0) NS Diagnostic time, days 584 (292–1090) 402 (292–858)a 0.014 a Compared with age < 50, p < 0.05. BMI: body mass index. Open in new tab Table 3. Diagnostic tests, treatment, and time of age subgroup before Multidisciplinary Dyspnea/Exercise Intolerance Center. . Age < 50 (n = 180) . Age ≥ 50 (n = 350) . p value . Age 37 (25–44) 65 (57–72)a <0.0001 Women, n (%) 135 (75.0) 221 (63.14)a 0.006 BMI 26.25 (22.83–31.14) 30.07 (25.50–34.73)a <0.0001 Lab tests 12.0 (5.0–31.0) 16.0 (5.0–48.0) NS Other tests 5.0 (3.0–8.0) 7.0 (5.0–13.0)a 0.001 Treatment, n (%) 105 (58.33) 182 (52.0) NS Diagnostic time, days 584 (292–1090) 402 (292–858)a 0.014 . Age < 50 (n = 180) . Age ≥ 50 (n = 350) . p value . Age 37 (25–44) 65 (57–72)a <0.0001 Women, n (%) 135 (75.0) 221 (63.14)a 0.006 BMI 26.25 (22.83–31.14) 30.07 (25.50–34.73)a <0.0001 Lab tests 12.0 (5.0–31.0) 16.0 (5.0–48.0) NS Other tests 5.0 (3.0–8.0) 7.0 (5.0–13.0)a 0.001 Treatment, n (%) 105 (58.33) 182 (52.0) NS Diagnostic time, days 584 (292–1090) 402 (292–858)a 0.014 a Compared with age < 50, p < 0.05. BMI: body mass index. Open in new tab Table 4. Diagnostic tests, treatment, and time of sex subgroup before Multidisciplinary Dyspnea/Exercise Intolerance Center. . Women (n = 356) . Men (n = 174) . p value . Age 55 (41–68) 60 (49–69)a 0.0131 BMI 28.22 (23.90–34.10) 29.80 (25.61–33.66) NS Lab tests 15.0 (6.0–39.0) 12.0 (2.0–45.0) NS Other tests 6.0 (4.0–10.0) 7.0 (4.0–13.0) NS Treatment, n (%) 206 (57.87) 81 (46.55)a 0.014 Diagnostic time, days 438 (256–1095) 548 (292–1059)a 0.022 . Women (n = 356) . Men (n = 174) . p value . Age 55 (41–68) 60 (49–69)a 0.0131 BMI 28.22 (23.90–34.10) 29.80 (25.61–33.66) NS Lab tests 15.0 (6.0–39.0) 12.0 (2.0–45.0) NS Other tests 6.0 (4.0–10.0) 7.0 (4.0–13.0) NS Treatment, n (%) 206 (57.87) 81 (46.55)a 0.014 Diagnostic time, days 438 (256–1095) 548 (292–1059)a 0.022 a Compared with women, p < 0.05. BMI: body mass index. Open in new tab Table 4. Diagnostic tests, treatment, and time of sex subgroup before Multidisciplinary Dyspnea/Exercise Intolerance Center. . Women (n = 356) . Men (n = 174) . p value . Age 55 (41–68) 60 (49–69)a 0.0131 BMI 28.22 (23.90–34.10) 29.80 (25.61–33.66) NS Lab tests 15.0 (6.0–39.0) 12.0 (2.0–45.0) NS Other tests 6.0 (4.0–10.0) 7.0 (4.0–13.0) NS Treatment, n (%) 206 (57.87) 81 (46.55)a 0.014 Diagnostic time, days 438 (256–1095) 548 (292–1059)a 0.022 . Women (n = 356) . Men (n = 174) . p value . Age 55 (41–68) 60 (49–69)a 0.0131 BMI 28.22 (23.90–34.10) 29.80 (25.61–33.66) NS Lab tests 15.0 (6.0–39.0) 12.0 (2.0–45.0) NS Other tests 6.0 (4.0–10.0) 7.0 (4.0–13.0) NS Treatment, n (%) 206 (57.87) 81 (46.55)a 0.014 Diagnostic time, days 438 (256–1095) 548 (292–1059)a 0.022 a Compared with women, p < 0.05. BMI: body mass index. Open in new tab Table 5. Comparison of the distribution of final diagnosis based on referral from different clinics. . Cardiology (n = 165) . Pulmonology (n = 174) . General medicine (n = 103) . Others (n = 88) . p value . EPAH (n = 88) 18 (10.91%) 36 (20.69%)a 21 (20.39%)a 13 (14.77%)a NS Heart failure (n = 99) 51 (30.91%) 21 (12.07%)a 18 (17.48%)a 9 (10.23%)a <0.001 Dysautonomia (n = 112) 29 (17.58%) 38 (21.84%) 26 (25.24%) 19 (21.59%) NS Oxidative myopathy (n = 130) 26 (15.76%) 48 (27.59%)a 30 (29.13%)a 26 (29.55%)a 0.018 Hyperventilation (n = 43) 14 (8.48%) 13 (7.47%) 5 (4.85%) 11 (12.5%) NS Others (n = 58) 27 (16.36%) 18 (10.34%) 3 (2.91%)a,b 10 (11.36%)c 0.008 . Cardiology (n = 165) . Pulmonology (n = 174) . General medicine (n = 103) . Others (n = 88) . p value . EPAH (n = 88) 18 (10.91%) 36 (20.69%)a 21 (20.39%)a 13 (14.77%)a NS Heart failure (n = 99) 51 (30.91%) 21 (12.07%)a 18 (17.48%)a 9 (10.23%)a <0.001 Dysautonomia (n = 112) 29 (17.58%) 38 (21.84%) 26 (25.24%) 19 (21.59%) NS Oxidative myopathy (n = 130) 26 (15.76%) 48 (27.59%)a 30 (29.13%)a 26 (29.55%)a 0.018 Hyperventilation (n = 43) 14 (8.48%) 13 (7.47%) 5 (4.85%) 11 (12.5%) NS Others (n = 58) 27 (16.36%) 18 (10.34%) 3 (2.91%)a,b 10 (11.36%)c 0.008 a Compared with cardiology, p < 0.05. b Compared with pulmonology, p < 0.05. c Compared with general medicine, p < 0.05. EPAH: exercise-pulmonary hypertension. Open in new tab Table 5. Comparison of the distribution of final diagnosis based on referral from different clinics. . Cardiology (n = 165) . Pulmonology (n = 174) . General medicine (n = 103) . Others (n = 88) . p value . EPAH (n = 88) 18 (10.91%) 36 (20.69%)a 21 (20.39%)a 13 (14.77%)a NS Heart failure (n = 99) 51 (30.91%) 21 (12.07%)a 18 (17.48%)a 9 (10.23%)a <0.001 Dysautonomia (n = 112) 29 (17.58%) 38 (21.84%) 26 (25.24%) 19 (21.59%) NS Oxidative myopathy (n = 130) 26 (15.76%) 48 (27.59%)a 30 (29.13%)a 26 (29.55%)a 0.018 Hyperventilation (n = 43) 14 (8.48%) 13 (7.47%) 5 (4.85%) 11 (12.5%) NS Others (n = 58) 27 (16.36%) 18 (10.34%) 3 (2.91%)a,b 10 (11.36%)c 0.008 . Cardiology (n = 165) . Pulmonology (n = 174) . General medicine (n = 103) . Others (n = 88) . p value . EPAH (n = 88) 18 (10.91%) 36 (20.69%)a 21 (20.39%)a 13 (14.77%)a NS Heart failure (n = 99) 51 (30.91%) 21 (12.07%)a 18 (17.48%)a 9 (10.23%)a <0.001 Dysautonomia (n = 112) 29 (17.58%) 38 (21.84%) 26 (25.24%) 19 (21.59%) NS Oxidative myopathy (n = 130) 26 (15.76%) 48 (27.59%)a 30 (29.13%)a 26 (29.55%)a 0.018 Hyperventilation (n = 43) 14 (8.48%) 13 (7.47%) 5 (4.85%) 11 (12.5%) NS Others (n = 58) 27 (16.36%) 18 (10.34%) 3 (2.91%)a,b 10 (11.36%)c 0.008 a Compared with cardiology, p < 0.05. b Compared with pulmonology, p < 0.05. c Compared with general medicine, p < 0.05. EPAH: exercise-pulmonary hypertension. Open in new tab Discussion This study provides evidence that a multidisciplinary approach to the evaluation of unexplained dyspnea employing iCPET delivered in a specialized MDEC provides significant value in reducing the time associated with the assessment of unexplained dyspnea and the achievement of a final diagnosis. Finding the cause(s) of unexplained dyspnea is best achieved using a protocol based approach14 centered on objective findings and verification, rather than clinical impression alone, which will more consistently lead to an accurate diagnosis and an improved therapeutic outcome.15 In our study, in one-third of the cases, diagnosis was made based on the initial MDEC evaluation based on prior appropriate testing. In the remaining two-thirds of cases, iCPET was performed and generated information sufficient to reach a final diagnosis, thus leading to the conclusion that using a multidisciplinary approach and, if needed, in combination with iCPET can provide definitive diagnostic results in a shorter timeframe as compared with traditional methods. Many of the patients seen in MDEC had experienced extensive testing prior to referral. Most patients had been repeatedly referred to subspecialists for lack of a diagnosis. More than 75% of patients had undergone repeated testing. The lack of a standard dyspnea evaluation protocol and the concern for missing potentially life threatening causes of dyspnea frequently lead to multiple diagnostic tests being ordered to rule out different causes of dyspnea. As part of the initial MDEC protocol, all new patient referrals underwent an agreed upon panel of laboratory testing to screen for occult causes of dyspnea. We have since learned that the majority of the laboratory tests ordered provided no additional diagnostic power. We have since eliminated prespecified laboratory testing. An additional goal of our program was to provide a simplified referral process for primary care physicians, subspecialty colleagues, and surgical specialties. The referring clinician no longer had to decide to which specialist a patient should be sent. Most importantly, the MDEC program provided a simplified process for our patients. The clinical analysis should begin with a thorough clinic evaluation including a detailed history and physical examination and an assessment of the character and severity of the patient’s shortness of breath. Our findings strongly suggest that if a cause of dyspnea is not determined based on a thorough history, physical examination, full pulmonary function testing, chest imaging, an echocardiogram, and evaluation for coronary artery disease in appropriate patients it is very unlikely that a diagnosis will be found with additional standard testing. At that point, a better course of action is referral to an MDEC and consideration of iCPET. The strength of the MDEC evaluation protocol is the focus on understanding the physiologic basis of dyspnea through the use of exercise testing to reproduce the patient’s symptoms. niCPET provides an objective measure of exercise capacity and permits evaluation of patterns of response of V·O2 and V·CO2 to describe the exercise limitation based on physiologic parameters. niCPET is most useful for distinguishing between normal and abnormal. Abnormal findings are not necessarily specific to a single disease state.16 While niCPET may be considered in the evaluation of unexplained exertional dyspnea and aid in developing a differential diagnosis, niCPET is generally used to direct further testing rather than to make a specific diagnosis.17 For patients with unexplained exercise intolerance for which initial test results (e.g. pulmonary function testing with diffusing capacity for carbon monoxide (DLCO), radiographic imaging, and echocardiography) did not lead to a definitive diagnosis, niCPET can suggest whether exertional dyspnea is due to abnormalities of oxygen transport, deconditioning, or pulmonary mechanical limitations.18 In our study, 30% of our patients had niCPET and, among those, 10 patients had a repeat niCPET prior to referral to MDEC. iCPET refers to niCPET performed with pulmonary artery and radial artery catheters, and breath-by-breath analysis of respiratory gas exchange at rest and during a period of incremental exercise to exhaustion. iCPET provides an assessment of exercise capacity, and quantifies the relative contributions of any respiratory, cardiovascular, and metabolic dysfunction. By adding invasive hemodynamic monitoring during exercise, iCPET provides a unique opportunity to identify early stages of pulmonary vascular disease and low left ventricular diastolic reserve. In early stages of disease, non-invasive measurements such as VE/VCO2 slope are insensitive,19 suggesting limitations of non-invasive exercise screening for early disease. In our experience, ventilatory inefficiency also lacks specificity as it is also present in patients with early stage left heart disease,20 dysautonomia, and even skeletal muscle mitochondrial dysfunction. Additionally, another commonly used non-invasive measurement, peak end-tidal carbon dioxide tension, which correlates with pulmonary arterial hypertension severity, also performs poorly in detecting exercise pulmonary hypertension in our experience. Finally, in many cases, a decreased peak VO2 is detected by a niCPET. However, due to the lack of specificity of peak VO2, the underlying cause might remain elusive and multiple mechanisms such as impaired cardiac output augmentation, peripheral O2 extraction, or dysautonomia (in isolation or in combination) remain as part of the differential diagnosis for patients’ symptoms; an iCPET will elucidate and differentiate these conditions.13 Regarding the possible advantages of iCPET compared with niCPET combined with echocardiography, pulmonary pressure assessed by echocardiography has a good correlation with invasive hemodynamics measures during exercise only in those patients where a high-quality TR spectral Doppler envelope is obtained.21 However, less than 35% of patients have high quality echo measurements. niCPET has clear limitations and can serve as an initial screening tool, but often a clear diagnosis requires invasive testing. Combining cardiopulmonary exercise testing with exercise hemodynamic measurements as with iCPET permits evaluation of different pulmonary vascular responses in combination with objective measures of health and fitness. The use of upright cycle ergometry and iCPET to accurately characterize the measurement of pulmonary arterial and cardiac filling pressures during exercise reproduces what subjects actually go through during exertion and exercise. This approach provides an assessment of exercise capacity, and defines the detailed contributions of any cardiac, pulmonary, metabolic, or vascular limitations. We do not suggest every patient presenting with unexplained dyspnea go directly to iCPET. A key value of the multidisciplinary approach is that it may make better use of existing test data than an uncoordinated assortment of clinicians. For the subset of patients referred to MDEC where an iCPET was not pursued, the information to make a correct diagnosis was available before referral, but an uncoordinated effort failed to make the final diagnosis. Based on our results and those of earlier studies,14,15 an algorithmic approach utilizing basic conventional tests including imaging of the chest with either a chest radiograph or chest computed tomogram, echocardiogram, and full pulmonary function testing with DLCO may define the cause of dyspnea in a large subset of patients (Figure 1). For those patients where there is no definitive answer, combining these initial tests with iCPET potentially reduces the overall diagnostic time and likely saves medical resources. There are a number of limitations to the current study. This study design was entirely retrospective and only allowed for the review of an available historical dataset. Ultimately, a prospective evaluation would provide for a more precise comparison of time for diagnosis and testing requirements. Additionally, we only tracked patients who were referred to our MDEC and used their past history as a comparator. Therefore, we could not observe the frequency of successful diagnosis among patients with unexplained dyspnea diagnosed outside our MDEC. Nonetheless, the fact that one-third of patients referred to MDEC could be diagnosed without invasive testing using a standardized multidisciplinary approach suggests that prompt referral to MDEC is likely the most efficient path to accurate diagnosis. Our results likely underestimate the benefits of MDEC’s approach due to the truncation of the look-back period at four years prior to referral to MDEC. About 16% of patients had been seeking diagnosis of the underlying cause of their dyspnea for longer than four years. This was especially true in those patients with dysautonomia and mitochondrial myopathies. These patients typically had a very slowly progressive course, and often had been dismissed as having an anxiety disorder. On average, the patients referred to MDEC required an average of 2.2 visits to provide an underlying diagnosis. In conclusion, this study provides evidence that a multidisciplinary approach to the evaluation of unexplained dyspnea employing iCPET delivered in a specialized MDEC provides significant value in reducing the time associated with the assessment of unexplained dyspnea and the achievement of a final diagnosis. Therefore, we recommend a multidisciplinary approach to the patient with unexplained dyspnea with the establishment of a dyspnea center through which a single clinic referral would include evaluation by clinical experts with a specific interest in unexplained dyspnea. This is also an opportunity to compile the data from previous testing and review that data with a fresh set of eyes. In several cases, simply reviewing the cumulative data can provide an explanation for the patient’s dyspnea. In other cases, additional iCPET testing might be required. Author contribution WH and ABW together conceived the original study design, performed the primary data analysis and interpretation, and writing of the manuscript. SR, DMS, and BAC contributed substantially to the study design, data analysis and interpretation, and writing of the manuscript. RKFO contributed to study design and critically reviewed the manuscript. ABW and WH had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Declaration of conflicting interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Wei Huang received funding from the National Natural Science Foundation of China (81170188and 30971212), the Natural Science Foundation of Chongqing (CSCT2009BB5069). RKFO received funds from the São Paulo Research Foundation (FAPESP, grant #2014/12212-5) and from the Brazilian National Council for Scientific and Technological Development (CNPq, grant #232643/2014-8). Aaron B Waxman and David M Systrom received funding from NIH/NHLBI HL06023412A1 and U01 HL125215. References 1 Sarkar S , Amelung PJ. Evaluation of the dyspneic patient in the office . Prim Care 2006 ; 33 : 643 – 657 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Shiber JR , Santana J. Dyspnea . Med Clin North Am 2006 ; 90 : 453 – 479 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Karnani NG , Reisfield GM, Wilson GR. Evaluation of chronic dyspnea . Am Fam Physician 2005 ; 71 : 1529 – 1537 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 4 DePaso WJ , Winterbauer RH, Lusk JAet al. . Chronic dyspnea unexplained by history, physical examination, chest roentgenogram, and spirometry. Analysis of a seven-year experience . Chest 1991 ; 100 : 1293 – 1299 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Martinez FJ , Stanopoulos I, Acero Ret al. . Graded comprehensive cardiopulmonary exercise testing in the evaluation of dyspnea unexplained by routine evaluation . Chest 1994 ; 105 : 168 – 174 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Gillespie DJ , Staats BA. Unexplained dyspnea . Mayo Clin Proc 1994 ; 69 : 657 – 663 . Google Scholar Crossref Search ADS PubMed WorldCat 7 Han JN , Zhu YJ, Li SW. [Diagnosis and treatment of medically unexplained dyspnea] . Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2004 ; 26 : 76 – 78 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 8 Currow DC , Plummer JL, Crockett Aet al. . A community population survey of prevalence and severity of dyspnea in adults . J Pain Symptom Manage 2009 ; 38 : 533 – 545 . Google Scholar Crossref Search ADS PubMed WorldCat 9 Cuyler Hammond E . Some preliminary findings on physical complaints from a prospective study of 1,064,004 men and women . Am J Public Health Nations Health 1964 ; 54 : 11 – 23 . Google Scholar Crossref Search ADS PubMed WorldCat 10 Ho SF , O’Mahony MS, Steward JAet al. . Dyspnoea and quality of life in older people at home . Age Ageing 2001 ; 30 : 155 – 159 . Google Scholar Crossref Search ADS PubMed WorldCat 11 Kroenke K , Arrington ME, Mangelsdorff AD. The prevalence of symptoms in medical outpatients and the adequacy of therapy . Arch Intern Med 1990 ; 150 : 1685 – 1689 . Google Scholar Crossref Search ADS PubMed WorldCat 12 Parshall MB , Schwartzstein RM, Adams Let al. . An official American Thoracic Society statement: Update on the mechanisms, assessment, and management of dyspnea . Am J Respir Crit Care Med 2012 ; 185 : 435 – 452 . Google Scholar Crossref Search ADS PubMed WorldCat 13 Maron BA , Cockrill BA, Waxman ABet al. . The invasive cardiopulmonary exercise test . Circulation 2013 ; 127 : 1157 – 1164 . Google Scholar Crossref Search ADS PubMed WorldCat 14 Pratter MR , Abouzgheib W, Akers Set al. . An algorithmic approach to chronic dyspnea . Respir Med 2011 ; 105 : 1014 – 1021 . Google Scholar Crossref Search ADS PubMed WorldCat 15 Pratter MR , Curley FJ, Dubois Jet al. . Cause and evaluation of chronic dyspnea in a pulmonary disease clinic . Arch Intern Med 1989 ; 149 : 2277 – 2282 . Google Scholar Crossref Search ADS PubMed WorldCat 16 Hansen JE , Ulubay G, Chow BFet al. . Mixed-expired and end-tidal CO2 distinguish between ventilation and perfusion defects during exercise testing in patients with lung and heart diseases . Chest 2007 ; 132 : 977 – 983 . Google Scholar Crossref Search ADS PubMed WorldCat 17 Palange P , Ward SA, Carlsen KHet al. . Recommendations on the use of exercise testing in clinical practice . Eur Respir J 2007 ; 29 : 185 – 209 . Google Scholar Crossref Search ADS PubMed WorldCat 18 Wasserman K . Principles of exercise testing and interpretation: Including pathophysiology and clinical applications , 5th ed. Philadelphia : Wolters Kluwer Health/Lippincott Williams & Wilkins , 2012 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 19 Tolle JJ , Waxman AB, Van Horn TLet al. . Exercise-induced pulmonary arterial hypertension . Circulation 2008 ; 118 : 2183 – 2189 . Google Scholar Crossref Search ADS PubMed WorldCat 20 Oliveira RK , Waxman AB, Agarwal Met al. . Pulmonary haemodynamics during recovery from maximum incremental cycling exercise . Eur Respir J 2016 ; 48 : 158 – 167 . Google Scholar Crossref Search ADS PubMed WorldCat 21 Van Riel AC , Opotowsky AR, Santos Met al. . Accuracy of echocardiography to estimate pulmonary artery pressures with exercise: A simultaneous invasive-noninvasive comparison . Circ Cardiovasc Imaging 2017 ; 10 : e005711 – e005711 . Google Scholar Crossref Search ADS PubMed WorldCat © The European Society of Cardiology 2017 This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © The European Society of Cardiology 2017 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Preventive Cardiology Oxford University Press

Invasive cardiopulmonary exercise testing in the evaluation of unexplained dyspnea: Insights from a multidisciplinary dyspnea center

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Oxford University Press
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Copyright © 2022 European Society of Cardiology
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2047-4873
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2047-4881
DOI
10.1177/2047487317709605
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Abstract

Abstract Background Unexplained dyspnea is a common diagnosis that often results in repeated diagnostic testing and even delayed treatments while a determination of the cause is being investigated. Through a retrospective study, we evaluated the diagnostic efficacy of a multidisciplinary dyspnea evaluation center (MDEC) using invasive cardiopulmonary exercise test to diagnose potential causes of unexplained dyspnea. Methods We reviewed the medical records of all patients referred with unexplained dyspnea to the MDEC between March 2011 and October 2014. We assessed the diagnostic efficacy before and after presentation to the MDEC. Results During the study period a total of 864 patients were referred to the MDEC and, of those, 530 patients underwent further investigation with invasive cardiopulmonary exercise test and constituted the study sample. The median age was 57 (44–68) years, 67.2% were women, and median body mass index was 26.22 (22.78–31.01). A diagnosis was made in 530 patients including: exercise pulmonary arterial hypertension of 88 (16.6%), heart failure with preserved ejection fraction of 94 (17.7%), dysautonomia 112 (21.1%), oxidative myopathy of 130 (24.5%), primary hyperventilation of 43 (8.1%), and other 58 (10.9%). The time from initial presentation to referral was significantly longer than time to diagnosis after referral for non-standardized conventional methods versus diagnosis through MDEC using invasive cardiopulmonary exercise test (511 days (292–1095 days) vs. 27 days (13–53 days), p < 0.0001). In a subgroup analysis, we reviewed that patients referred from cardiovascular clinics were more likely to have a greater number of diagnostic tests performed and, conversely, patients referred from pulmonary clinics were more likely to have a greater number of treatments prescribed before referral to MDEC. Conclusions As a result of this retrospective study, we have evaluated that a multidisciplinary approach that includes invasive cardiopulmonary exercise test dramatically reduces the time to diagnosis compared with traditional treatment and testing methods. Dyspnea, exertional intolerance, invasive CPET, evaluation, exercise testing Introduction Dyspnea is a common but nonspecific symptom in patients presenting to both primary care and subspecialty practices, with a peak incidence in patients who are 55 to 69 years of age.1,2 It is considered chronic when lasting more than one month.3 Dyspnea during exertion, sometimes characterized as “exercise intolerance”, is usually associated with a cardiac or pulmonary cause. Other etiologies such as deconditioning, obesity, malignancy, anemia, and sleep apnea are recognized less frequently.4 Patients with neuromuscular diseases, mitochondrial myopathies, and metabolic disorders may also present with a primary complaint of dyspnea. Many patients will have an obvious cause of dyspnea, such as an exacerbation of known asthma, chronic obstructive pulmonary disease (COPD), or heart failure; however, many patients will require a thorough diagnostic evaluation to establish the underlying cause and provide effective therapy. All too often the cause of dyspnea remains elusive even after an aggressive evaluation,5 and despite prior testing at rest or with exercise.6 Such cases of unexplained dyspnea account for about 15% of patients who present with chronic dyspnea.3,7 Additionally, population based studies suggest a prevalence of unexplained exertional intolerance of 9–35%,8–12 and becoming more prevalent with increased age. The dyspneic patient without an obvious primary etiology may be referred to a number of different specialists for evaluation. The initial evaluation may include extensive blood work, pulmonary function testing, echocardiography, cardiac catheterization, radiographic and nuclear imaging modalities, and cardiac stress and cardiopulmonary exercise testing (CPET). Clinicians in different disciplines may approach the evaluation of dyspnea with contrasting methods, often without timely communication or collaboration. As a result, inefficient evaluation of dyspnea involving multiple referrals can be costly and very frustrating for the patient. Noninvasive cardiopulmonary exercise testing (niCPET) is often used to assess the physiologic contributions to a patient’s symptoms of dyspnea and exercise intolerance. The test provides a breath-by-breath analysis of ventilation, pulmonary gas exchange and cardiac function at rest and during incremental exercise. The niCPET primarily determines whether patients have normal or reduced maximal exercise capacity (VO2max) and, if so, suggests possible causes. The exercise-based test is much more sensitive in detecting early or subclinical disease than tests done at rest. Invasive CPET (iCPET) is a variant of the test that adds pulmonary and radial artery catheter-derived pressure and blood gas sampling to the niCPET. This approach allows for direct systemic blood pressure measurement, dead space to tidal volume ratios, alveolar/arterial oxygen gradient, measurement of pulmonary hemodynamic parameters, and direct Fick cardiac output assessment, allowing for the derivation of systemic and pulmonary vascular resistance.13 (See Maron et al.13 for a detailed description of approach and diagnostic criteria.) (Figure 1). Figure 1. Open in new tabDownload slide Flow diagram of diagnostic approach and diagnostic criteria. MDEC: Multidisciplinary Dyspnea/Exercise Intolerance Center; niCPET: noninvasive cardiopulmonary exercise testing; iCPET: invasive cardiopulmonary exercise testing; PAP: pulmonary artery pressure; Max.: maximum; PVR: pulmonary vascular resistance; PAH: pulmonary arterial hypertension; PCWP: pulmonary capillary wedge pressure; HFpEF: exercise-heart failure preserved ejection fraction; EF: ejection fraction; COPD: chronic obstructive pulmonary disease; RAP: Right atrial pressure; mPAP: mean pulmonary artery pressure. Brigham and Women’s Hospital recently established the Multidisciplinary Dyspnea/Exercise Intolerance Center (MDEC) to evaluate patients with unexplained dyspnea. MDEC brought together a core group of clinical experts from pulmonary medicine, cardiovascular medicine, and radiology along with input from neurology, rheumatology, and psychiatry to collaboratively develop a high quality, cost effective, and streamlined approach to assessing and treating the patient with unexplained exertional dyspnea. In the current study, we sought to evaluate the diagnostic efficacy of a MDEC that uses iCPET to diagnose potential causes of unexplained dyspnea. We hypothesized that a stepwise approach leveraging iCPET when a multidisciplinary review of a parsimonious set of investigations is inconclusive would substantially reduce the time associated with obtaining a final diagnosis. Methods Protected health information The Partners Healthcare Institutional Review Board approved the protocol for the use of human subject data at Brigham and Women’s Hospital for this retrospective analysis. Subjects and study design We reviewed the medical records of all patients referred to the Brigham and Women’s Hospital MDEC between 1 March 2011 and 30 October 2014. Patients were referred to the MDEC for unexplained exertional symptoms. (For description of the MDEC approach to the evaluation please see the online supplement). Additional indications for referral included: 1) symptoms out of proportion to resting abnormalities on echocardiography, pulmonary function testing, and/or other imaging modalities; 2) lack of expected improvement with “standard therapy” for a suspected diagnosis such as asthma, COPD, or heart failure; or 3) the presence of multiple diagnoses potentially contributing to dyspnea for determination of appropriate treatment. All patients had normal or inconclusive prior testing including blood laboratory testing, electrocardiograms, echocardiograms (both resting and stress), complete pulmonary function testing, and radiographic imaging. The number and type of tests and the time course of patient assessment in the evaluation of dyspnea prior to referral to MDEC were compared with testing patterns and time to diagnosis by MDEC physicians. Additionally, we quantified the following available analyses for each patient: 1) pulmonary function testing; 2) echocardiography; 3) cardiac catheterization; 4) radiographic and nuclear imaging modalities; 5) cardiac stress and CPET; 6) empiric treatments; and 7) assessment of functional status and subjective quality of life measures, before and after referral to MDEC. Diagnostic efficiency evaluation We compared assessments made after the patient was first seen in MDEC with the patient’s experience with conventional dyspnea evaluations prior to referral to MDEC. In particular, based on the medical records, we estimated the duration patients had been living with unexplained dyspnea prior to referral to MDEC. When analyzing the patients’ experience prior to MDEC referral, we truncated the look-back period at four years; however, 89 (16.8%) patients had complaints of dyspnea exceeding four years. The primary outcomes included the identification of a final diagnosis along with time to diagnosis. By design, all patients referred to MDEC during the time period of the study had a prior complaint of chronic dyspnea and had undergone prior evaluation that had failed to reach an accurate diagnosis of the underlying condition. We measured the percentage of MDEC patients for whom an accurate diagnosis of underlying conditions was reached through the MDEC evaluation protocol and compared that with the frequency of different categories of conditions observed. We divided the patient’s total time to diagnosis into two periods. These two time periods included number of days from initial dyspnea complaint to first referral to MDEC compared with the number of days after referral to MDEC to the final diagnosis of the underlying cause of dyspnea. Statistical analysis The statistical analyses were performed with SPSS version 23.0 (SPSS Inc., Chicago, IL, USA). All numeric values are reported as median (first and third quartile) because the majority of the parameters were not normally distributed. Mann–Whitney U tests or a Chi-Square test were used to assess group differences. Multiple comparisons were performed using analysis of variance with Bonferroni correction. Spearman correlation coefficients were calculated. A p value <0.05 was considered statistically significant. Results Characteristics of MDEC referral patients There were 864 patients referred to MDEC between 1 March 2011 and 30 October 2014. Of those total patients evaluated, a diagnosis of the underlying cause of dyspnea was provided to 310 patients (36%) based on the initial MDEC evaluation, which included a thorough history and physical examination, full pulmonary function testing, chest imaging, an echocardiogram, and a review of data from patient testing which occurred prior to MDEC referral. These patients required no further evaluation and were excluded from the study group. In the remaining 554 patients (64%), a diagnosis of the underlying cause could not be reached based on the initial MDEC evaluation. These patients with unexplained dyspnea then underwent iCPET at MDEC. There were 24 patients who had iCPET who were excluded from the analysis because of incomplete medical records, leaving a total evaluable study group of 530 patients. The unexplained dyspnea cohort (n = 530) had a median age of 57 years (44–68 years), 356 (67.2%) were women, and median body mass index for the cohort was 26.22 (22.78–31.01). They were referred from various specialty clinics including: pulmonary clinics (n = 174), cardiovascular clinics (n = 165), general medicine practices (n = 103), neurology (n = 28), rheumatology (n = 13), family medicine (n = 6), lung transplant list (n = 6), gastroenterology (n = 6), infectious disease (n = 6), thoracic surgery (n = 5), general pediatric medicine (n = 4), nephrology (n = 3), allergy/immunology (n = 3), hematology (n = 3), oncology (n = 3), and two patients were self-referred. In the study group cohort, we found that there were 80 different laboratory tests and 63 different types of non-laboratory tests (including imaging, noninvasive and invasive stress tests) used in the assessment of unexplained dyspnea. Prior to referral to MDEC, patients had undergone a median of 15 (range 5–41) laboratory based tests as part of the evaluation of dyspnea, and a median of 6 (range 4–10) non-laboratory based diagnostic tests (including imaging noninvasive and invasive stress tests) per patient before they were referred to MDEC. Four hundred patients (75.5%) had repeated testing before referral to MDEC. In contrast, there were no repeat tests after MDEC. Through our analysis, we found that patients referred from cardiovascular specialty clinics had a greater number of diagnostic tests performed prior to MDEC referral than patients referred from pulmonary, general medicine, or other practices (Table 1). After MDEC, patients received a median of 2 (range 1–5) laboratory tests, and a median of 0 (range 0–1) non-laboratory tests (excluding iCPET)—significantly fewer tests per patient compared with the period before referral to MDEC (p < 0.0001). For thoroughness of evaluation by MDEC, some patients required complete pulmonary function tests, chest radiography, and an echocardiogram after referral to MDEC if not previously performed and were felt to be clinically indicated. This included 50 patients who had either a chest radiograph or chest computed tomography scan, and 88 patients who had an echocardiogram after referral to MDEC. Table 1. Diagnostic tests, treatment, and time referred from different clinics before Multidisciplinary Dyspnea/Exercise Intolerance Center. . Cardiology (n = 165) . Pulmonology (n = 174) . General medicine (n = 103) . Others (n = 88) . p value . Age 65 (50–72) 52 (37–62)a 59 (48–71)b 58 (48–68)b <0.001 Women, n(%) 101 (61.21) 122 (70.11) 74 (71.84) 59 (67.05) NS BMI 29.83 (24.76–33.60) 29.63 (24.77–33.98) 27.61 (23.92–32.57) 29.35 (24.97–34.63) NS Lab tests 13 (6.0–46.0) 8 (2.0–25.0)a 14 (7.0–39.0)b 19 (6.0–36.0)b 0.011 Other tests 7 (5.0–13.0) 6 (4.0–9.0)a 6 (4.0-10.0)a 5 (3.0–7.0)a 0.025 Treatment, n (%) 71 (43.03) 102 (58.62)a 64 (62.14)a 50 (56.82)a 0.006 Diagnostic time, days 383 (285–747) 730 (329–1095)a 365 (292–730) 511 (228–748) NS . Cardiology (n = 165) . Pulmonology (n = 174) . General medicine (n = 103) . Others (n = 88) . p value . Age 65 (50–72) 52 (37–62)a 59 (48–71)b 58 (48–68)b <0.001 Women, n(%) 101 (61.21) 122 (70.11) 74 (71.84) 59 (67.05) NS BMI 29.83 (24.76–33.60) 29.63 (24.77–33.98) 27.61 (23.92–32.57) 29.35 (24.97–34.63) NS Lab tests 13 (6.0–46.0) 8 (2.0–25.0)a 14 (7.0–39.0)b 19 (6.0–36.0)b 0.011 Other tests 7 (5.0–13.0) 6 (4.0–9.0)a 6 (4.0-10.0)a 5 (3.0–7.0)a 0.025 Treatment, n (%) 71 (43.03) 102 (58.62)a 64 (62.14)a 50 (56.82)a 0.006 Diagnostic time, days 383 (285–747) 730 (329–1095)a 365 (292–730) 511 (228–748) NS a Compared with patients referred from cardiology specialty practices, p < 0.05. b Compared with the patients referred from pulmonology specialty practices, p < 0.05. BMI: body mass index. Open in new tab Table 1. Diagnostic tests, treatment, and time referred from different clinics before Multidisciplinary Dyspnea/Exercise Intolerance Center. . Cardiology (n = 165) . Pulmonology (n = 174) . General medicine (n = 103) . Others (n = 88) . p value . Age 65 (50–72) 52 (37–62)a 59 (48–71)b 58 (48–68)b <0.001 Women, n(%) 101 (61.21) 122 (70.11) 74 (71.84) 59 (67.05) NS BMI 29.83 (24.76–33.60) 29.63 (24.77–33.98) 27.61 (23.92–32.57) 29.35 (24.97–34.63) NS Lab tests 13 (6.0–46.0) 8 (2.0–25.0)a 14 (7.0–39.0)b 19 (6.0–36.0)b 0.011 Other tests 7 (5.0–13.0) 6 (4.0–9.0)a 6 (4.0-10.0)a 5 (3.0–7.0)a 0.025 Treatment, n (%) 71 (43.03) 102 (58.62)a 64 (62.14)a 50 (56.82)a 0.006 Diagnostic time, days 383 (285–747) 730 (329–1095)a 365 (292–730) 511 (228–748) NS . Cardiology (n = 165) . Pulmonology (n = 174) . General medicine (n = 103) . Others (n = 88) . p value . Age 65 (50–72) 52 (37–62)a 59 (48–71)b 58 (48–68)b <0.001 Women, n(%) 101 (61.21) 122 (70.11) 74 (71.84) 59 (67.05) NS BMI 29.83 (24.76–33.60) 29.63 (24.77–33.98) 27.61 (23.92–32.57) 29.35 (24.97–34.63) NS Lab tests 13 (6.0–46.0) 8 (2.0–25.0)a 14 (7.0–39.0)b 19 (6.0–36.0)b 0.011 Other tests 7 (5.0–13.0) 6 (4.0–9.0)a 6 (4.0-10.0)a 5 (3.0–7.0)a 0.025 Treatment, n (%) 71 (43.03) 102 (58.62)a 64 (62.14)a 50 (56.82)a 0.006 Diagnostic time, days 383 (285–747) 730 (329–1095)a 365 (292–730) 511 (228–748) NS a Compared with patients referred from cardiology specialty practices, p < 0.05. b Compared with the patients referred from pulmonology specialty practices, p < 0.05. BMI: body mass index. Open in new tab Before referral to MDEC, 54% of the study cohort patients had specific therapies prescribed based on the findings of prior testing. Two hundred and ten (90.6%) patients were prescribed two or more treatments. Most patients received an assortment of treatments including 2–3 inhalers, diuretics, and anti-depressant treatments. Diagnosis after iCPET The underlying cause of dyspnea was determined in all patients who underwent iCPET (Table 2). Diagnoses included pulmonary arterial hypertension apparent only with exercise, 88 (EPAH, 16.6%); heart failure with preserved ejection fraction apparent only with exercise, 94 (HFpEF, 17.7%); dysautonomia or preload failure, 112 (21.1%); oxidative myopathy, 130 (24.5%) and primary hyperventilation, 43 (8.1%). Fifty-eight (10.9%) patients were dyspneic because of various other conditions including left to right shunting, patent foramen ovale, severe mitral valve regurgitation found only with exercise (no volume retention, normal resting echocardiogram, normal pulmonary capillary wedge pressure at peak exercise), chronotropic incompetence including drug effects or cardiac pacemaker heart rate limitation, hypoventilation, and deconditioning. Five out of the 530 iCPET patients (0.9%) had known heart failure with reduced ejection fraction. These patients were referred because they had improvement in left ventricular ejection fraction and no evidence of volume retention, but continued to complain of limiting dyspnea. In all five cases, a diagnosis of exercise HFpEF was made. Table 2. Diagnostic tests, treatment, and time of diagnosis subgroup before Multidisciplinary Dyspnea/Exercise Intolerance Center. . HFpEF (n = 99) . EPAH (n = 88) . Dysautonomia (n = 112) . Oxidative myopathy (n = 130) . Hyperventilation (n = 43) . Others (n = 58) . p value . Age 68 (60–74) 61 (54–72)a 45 (28–62)a,b 47 (30–58)a,b 62 (53–71)c,+ 56 (46–68)a,c,d,e <0.0001 Women, n (%) 44 (44.44) 55 (62.5)a 75 (66.96)a 107 (82.30)a 36 (83.72)a 39 (67.05)a,d <0.0001 BMI 32.0 (27.60–37.12) 31.43 (27.72–37.09) 24.58 (21.79–27.86)a,b 26.77 (23.36–31.27)a,b 28.96 (25.68–31.52)a,b,c 30.57 (25.26–35.86)b,c <0.0001 Lab tests 17.0 (5.0–55.0) 14.0 (5.0–47.0) 13.0 (4.0–33.0) 14.0 (5.0–32.0) 14.0 (5.0–35.0) 17.0 (6.0–40.0) NS Other tests 8.0 (5.0–18.0) 8.0 (4.0–14.0) 6.0 (4.0–8.0)a,b 5.0 (4.0–8.0)a,b 7.0 (4.0–11.0) 7.0 (4.0–12.0)c,d NS Treatment, (%) n46 (46.46) 50 (56.82) 60 (53.57) 76 (58.46) 22 (51.16) 33 (56.90) NS Diagnostic time, days 397 (329–733) 362 (183–729) 548 (292–1079) 363 (179–731) 380 (292–1095) 365 (146–734) NS . HFpEF (n = 99) . EPAH (n = 88) . Dysautonomia (n = 112) . Oxidative myopathy (n = 130) . Hyperventilation (n = 43) . Others (n = 58) . p value . Age 68 (60–74) 61 (54–72)a 45 (28–62)a,b 47 (30–58)a,b 62 (53–71)c,+ 56 (46–68)a,c,d,e <0.0001 Women, n (%) 44 (44.44) 55 (62.5)a 75 (66.96)a 107 (82.30)a 36 (83.72)a 39 (67.05)a,d <0.0001 BMI 32.0 (27.60–37.12) 31.43 (27.72–37.09) 24.58 (21.79–27.86)a,b 26.77 (23.36–31.27)a,b 28.96 (25.68–31.52)a,b,c 30.57 (25.26–35.86)b,c <0.0001 Lab tests 17.0 (5.0–55.0) 14.0 (5.0–47.0) 13.0 (4.0–33.0) 14.0 (5.0–32.0) 14.0 (5.0–35.0) 17.0 (6.0–40.0) NS Other tests 8.0 (5.0–18.0) 8.0 (4.0–14.0) 6.0 (4.0–8.0)a,b 5.0 (4.0–8.0)a,b 7.0 (4.0–11.0) 7.0 (4.0–12.0)c,d NS Treatment, (%) n46 (46.46) 50 (56.82) 60 (53.57) 76 (58.46) 22 (51.16) 33 (56.90) NS Diagnostic time, days 397 (329–733) 362 (183–729) 548 (292–1079) 363 (179–731) 380 (292–1095) 365 (146–734) NS a Compared with heart failure, p < 0.05. b Compared with EPAH, p < 0.05. c Compared with dysautonomia, p < 0.05. d Compared with oxidative myopathy, p < 0.05. e Compared with hyperventilation, p < 0.05. HFpEF: exercise heart failure preserved ejection fraction; EPAH: exercise-pulmonary hypertension; BMI: body mass index. Open in new tab Table 2. Diagnostic tests, treatment, and time of diagnosis subgroup before Multidisciplinary Dyspnea/Exercise Intolerance Center. . HFpEF (n = 99) . EPAH (n = 88) . Dysautonomia (n = 112) . Oxidative myopathy (n = 130) . Hyperventilation (n = 43) . Others (n = 58) . p value . Age 68 (60–74) 61 (54–72)a 45 (28–62)a,b 47 (30–58)a,b 62 (53–71)c,+ 56 (46–68)a,c,d,e <0.0001 Women, n (%) 44 (44.44) 55 (62.5)a 75 (66.96)a 107 (82.30)a 36 (83.72)a 39 (67.05)a,d <0.0001 BMI 32.0 (27.60–37.12) 31.43 (27.72–37.09) 24.58 (21.79–27.86)a,b 26.77 (23.36–31.27)a,b 28.96 (25.68–31.52)a,b,c 30.57 (25.26–35.86)b,c <0.0001 Lab tests 17.0 (5.0–55.0) 14.0 (5.0–47.0) 13.0 (4.0–33.0) 14.0 (5.0–32.0) 14.0 (5.0–35.0) 17.0 (6.0–40.0) NS Other tests 8.0 (5.0–18.0) 8.0 (4.0–14.0) 6.0 (4.0–8.0)a,b 5.0 (4.0–8.0)a,b 7.0 (4.0–11.0) 7.0 (4.0–12.0)c,d NS Treatment, (%) n46 (46.46) 50 (56.82) 60 (53.57) 76 (58.46) 22 (51.16) 33 (56.90) NS Diagnostic time, days 397 (329–733) 362 (183–729) 548 (292–1079) 363 (179–731) 380 (292–1095) 365 (146–734) NS . HFpEF (n = 99) . EPAH (n = 88) . Dysautonomia (n = 112) . Oxidative myopathy (n = 130) . Hyperventilation (n = 43) . Others (n = 58) . p value . Age 68 (60–74) 61 (54–72)a 45 (28–62)a,b 47 (30–58)a,b 62 (53–71)c,+ 56 (46–68)a,c,d,e <0.0001 Women, n (%) 44 (44.44) 55 (62.5)a 75 (66.96)a 107 (82.30)a 36 (83.72)a 39 (67.05)a,d <0.0001 BMI 32.0 (27.60–37.12) 31.43 (27.72–37.09) 24.58 (21.79–27.86)a,b 26.77 (23.36–31.27)a,b 28.96 (25.68–31.52)a,b,c 30.57 (25.26–35.86)b,c <0.0001 Lab tests 17.0 (5.0–55.0) 14.0 (5.0–47.0) 13.0 (4.0–33.0) 14.0 (5.0–32.0) 14.0 (5.0–35.0) 17.0 (6.0–40.0) NS Other tests 8.0 (5.0–18.0) 8.0 (4.0–14.0) 6.0 (4.0–8.0)a,b 5.0 (4.0–8.0)a,b 7.0 (4.0–11.0) 7.0 (4.0–12.0)c,d NS Treatment, (%) n46 (46.46) 50 (56.82) 60 (53.57) 76 (58.46) 22 (51.16) 33 (56.90) NS Diagnostic time, days 397 (329–733) 362 (183–729) 548 (292–1079) 363 (179–731) 380 (292–1095) 365 (146–734) NS a Compared with heart failure, p < 0.05. b Compared with EPAH, p < 0.05. c Compared with dysautonomia, p < 0.05. d Compared with oxidative myopathy, p < 0.05. e Compared with hyperventilation, p < 0.05. HFpEF: exercise heart failure preserved ejection fraction; EPAH: exercise-pulmonary hypertension; BMI: body mass index. Open in new tab Diagnostic time The median time patients had lived with unexplained dyspnea prior to referral to MDEC was 511 days (range 292–1095 days). The median time between the first visit to MDEC and obtaining a diagnosis for the cause of their dyspnea was 27 days (13–53 days) (Figure 2). The difference in the time to diagnosis before referral to MDEC and after presentation to MDEC was 642 days (Figure 2). Between 2011 and 2014, the time to referral to MDEC increased each year while the time to diagnosis after referral to MDEC decreased each year (Figure 2). Figure 2. Open in new tabDownload slide Median time patients had lived with unexplained dyspnea prior to referral to Multidisciplinary Dyspnea/Exercise Intolerance Center (MDEC). ⋄f Time to diagnosis prior to establishment of the MDEC; ▪ time to diagnosis after establishment of the MDEC; ▴ difference in time to diagnosis between before and after the establishment of the MDEC. Patients referred from cardiology (43.03%) were less likely to be given empiric treatment intended to treat dyspnea than those patients referred from non-cardiology clinics (Table 1). The time to referral to MDEC from the pulmonary clinic subgroup was longer than that of the cardiology clinic subgroup (Table 1). The diagnostic time before referral to MDEC was significantly longer in patients <50 years old (Table 3). Additionally, diagnostic time before referral to MDEC was significantly longer in men compared with women (Table 4). We also found that women (57.87%) were more likely to be treated empirically (Table 4). There were no differences by age, sex, or referring specialty in the time to diagnosis after referral to MDEC. As expected, there were differences in the distribution of final diagnosis depending on what clinic the patient was referred from (Table 5). Patients referred from a cardiology clinic were more likely to have HFpEF, and less likely to have EPAH or oxidative myopathy than referrals from other clinics. Table 3. Diagnostic tests, treatment, and time of age subgroup before Multidisciplinary Dyspnea/Exercise Intolerance Center. . Age < 50 (n = 180) . Age ≥ 50 (n = 350) . p value . Age 37 (25–44) 65 (57–72)a <0.0001 Women, n (%) 135 (75.0) 221 (63.14)a 0.006 BMI 26.25 (22.83–31.14) 30.07 (25.50–34.73)a <0.0001 Lab tests 12.0 (5.0–31.0) 16.0 (5.0–48.0) NS Other tests 5.0 (3.0–8.0) 7.0 (5.0–13.0)a 0.001 Treatment, n (%) 105 (58.33) 182 (52.0) NS Diagnostic time, days 584 (292–1090) 402 (292–858)a 0.014 . Age < 50 (n = 180) . Age ≥ 50 (n = 350) . p value . Age 37 (25–44) 65 (57–72)a <0.0001 Women, n (%) 135 (75.0) 221 (63.14)a 0.006 BMI 26.25 (22.83–31.14) 30.07 (25.50–34.73)a <0.0001 Lab tests 12.0 (5.0–31.0) 16.0 (5.0–48.0) NS Other tests 5.0 (3.0–8.0) 7.0 (5.0–13.0)a 0.001 Treatment, n (%) 105 (58.33) 182 (52.0) NS Diagnostic time, days 584 (292–1090) 402 (292–858)a 0.014 a Compared with age < 50, p < 0.05. BMI: body mass index. Open in new tab Table 3. Diagnostic tests, treatment, and time of age subgroup before Multidisciplinary Dyspnea/Exercise Intolerance Center. . Age < 50 (n = 180) . Age ≥ 50 (n = 350) . p value . Age 37 (25–44) 65 (57–72)a <0.0001 Women, n (%) 135 (75.0) 221 (63.14)a 0.006 BMI 26.25 (22.83–31.14) 30.07 (25.50–34.73)a <0.0001 Lab tests 12.0 (5.0–31.0) 16.0 (5.0–48.0) NS Other tests 5.0 (3.0–8.0) 7.0 (5.0–13.0)a 0.001 Treatment, n (%) 105 (58.33) 182 (52.0) NS Diagnostic time, days 584 (292–1090) 402 (292–858)a 0.014 . Age < 50 (n = 180) . Age ≥ 50 (n = 350) . p value . Age 37 (25–44) 65 (57–72)a <0.0001 Women, n (%) 135 (75.0) 221 (63.14)a 0.006 BMI 26.25 (22.83–31.14) 30.07 (25.50–34.73)a <0.0001 Lab tests 12.0 (5.0–31.0) 16.0 (5.0–48.0) NS Other tests 5.0 (3.0–8.0) 7.0 (5.0–13.0)a 0.001 Treatment, n (%) 105 (58.33) 182 (52.0) NS Diagnostic time, days 584 (292–1090) 402 (292–858)a 0.014 a Compared with age < 50, p < 0.05. BMI: body mass index. Open in new tab Table 4. Diagnostic tests, treatment, and time of sex subgroup before Multidisciplinary Dyspnea/Exercise Intolerance Center. . Women (n = 356) . Men (n = 174) . p value . Age 55 (41–68) 60 (49–69)a 0.0131 BMI 28.22 (23.90–34.10) 29.80 (25.61–33.66) NS Lab tests 15.0 (6.0–39.0) 12.0 (2.0–45.0) NS Other tests 6.0 (4.0–10.0) 7.0 (4.0–13.0) NS Treatment, n (%) 206 (57.87) 81 (46.55)a 0.014 Diagnostic time, days 438 (256–1095) 548 (292–1059)a 0.022 . Women (n = 356) . Men (n = 174) . p value . Age 55 (41–68) 60 (49–69)a 0.0131 BMI 28.22 (23.90–34.10) 29.80 (25.61–33.66) NS Lab tests 15.0 (6.0–39.0) 12.0 (2.0–45.0) NS Other tests 6.0 (4.0–10.0) 7.0 (4.0–13.0) NS Treatment, n (%) 206 (57.87) 81 (46.55)a 0.014 Diagnostic time, days 438 (256–1095) 548 (292–1059)a 0.022 a Compared with women, p < 0.05. BMI: body mass index. Open in new tab Table 4. Diagnostic tests, treatment, and time of sex subgroup before Multidisciplinary Dyspnea/Exercise Intolerance Center. . Women (n = 356) . Men (n = 174) . p value . Age 55 (41–68) 60 (49–69)a 0.0131 BMI 28.22 (23.90–34.10) 29.80 (25.61–33.66) NS Lab tests 15.0 (6.0–39.0) 12.0 (2.0–45.0) NS Other tests 6.0 (4.0–10.0) 7.0 (4.0–13.0) NS Treatment, n (%) 206 (57.87) 81 (46.55)a 0.014 Diagnostic time, days 438 (256–1095) 548 (292–1059)a 0.022 . Women (n = 356) . Men (n = 174) . p value . Age 55 (41–68) 60 (49–69)a 0.0131 BMI 28.22 (23.90–34.10) 29.80 (25.61–33.66) NS Lab tests 15.0 (6.0–39.0) 12.0 (2.0–45.0) NS Other tests 6.0 (4.0–10.0) 7.0 (4.0–13.0) NS Treatment, n (%) 206 (57.87) 81 (46.55)a 0.014 Diagnostic time, days 438 (256–1095) 548 (292–1059)a 0.022 a Compared with women, p < 0.05. BMI: body mass index. Open in new tab Table 5. Comparison of the distribution of final diagnosis based on referral from different clinics. . Cardiology (n = 165) . Pulmonology (n = 174) . General medicine (n = 103) . Others (n = 88) . p value . EPAH (n = 88) 18 (10.91%) 36 (20.69%)a 21 (20.39%)a 13 (14.77%)a NS Heart failure (n = 99) 51 (30.91%) 21 (12.07%)a 18 (17.48%)a 9 (10.23%)a <0.001 Dysautonomia (n = 112) 29 (17.58%) 38 (21.84%) 26 (25.24%) 19 (21.59%) NS Oxidative myopathy (n = 130) 26 (15.76%) 48 (27.59%)a 30 (29.13%)a 26 (29.55%)a 0.018 Hyperventilation (n = 43) 14 (8.48%) 13 (7.47%) 5 (4.85%) 11 (12.5%) NS Others (n = 58) 27 (16.36%) 18 (10.34%) 3 (2.91%)a,b 10 (11.36%)c 0.008 . Cardiology (n = 165) . Pulmonology (n = 174) . General medicine (n = 103) . Others (n = 88) . p value . EPAH (n = 88) 18 (10.91%) 36 (20.69%)a 21 (20.39%)a 13 (14.77%)a NS Heart failure (n = 99) 51 (30.91%) 21 (12.07%)a 18 (17.48%)a 9 (10.23%)a <0.001 Dysautonomia (n = 112) 29 (17.58%) 38 (21.84%) 26 (25.24%) 19 (21.59%) NS Oxidative myopathy (n = 130) 26 (15.76%) 48 (27.59%)a 30 (29.13%)a 26 (29.55%)a 0.018 Hyperventilation (n = 43) 14 (8.48%) 13 (7.47%) 5 (4.85%) 11 (12.5%) NS Others (n = 58) 27 (16.36%) 18 (10.34%) 3 (2.91%)a,b 10 (11.36%)c 0.008 a Compared with cardiology, p < 0.05. b Compared with pulmonology, p < 0.05. c Compared with general medicine, p < 0.05. EPAH: exercise-pulmonary hypertension. Open in new tab Table 5. Comparison of the distribution of final diagnosis based on referral from different clinics. . Cardiology (n = 165) . Pulmonology (n = 174) . General medicine (n = 103) . Others (n = 88) . p value . EPAH (n = 88) 18 (10.91%) 36 (20.69%)a 21 (20.39%)a 13 (14.77%)a NS Heart failure (n = 99) 51 (30.91%) 21 (12.07%)a 18 (17.48%)a 9 (10.23%)a <0.001 Dysautonomia (n = 112) 29 (17.58%) 38 (21.84%) 26 (25.24%) 19 (21.59%) NS Oxidative myopathy (n = 130) 26 (15.76%) 48 (27.59%)a 30 (29.13%)a 26 (29.55%)a 0.018 Hyperventilation (n = 43) 14 (8.48%) 13 (7.47%) 5 (4.85%) 11 (12.5%) NS Others (n = 58) 27 (16.36%) 18 (10.34%) 3 (2.91%)a,b 10 (11.36%)c 0.008 . Cardiology (n = 165) . Pulmonology (n = 174) . General medicine (n = 103) . Others (n = 88) . p value . EPAH (n = 88) 18 (10.91%) 36 (20.69%)a 21 (20.39%)a 13 (14.77%)a NS Heart failure (n = 99) 51 (30.91%) 21 (12.07%)a 18 (17.48%)a 9 (10.23%)a <0.001 Dysautonomia (n = 112) 29 (17.58%) 38 (21.84%) 26 (25.24%) 19 (21.59%) NS Oxidative myopathy (n = 130) 26 (15.76%) 48 (27.59%)a 30 (29.13%)a 26 (29.55%)a 0.018 Hyperventilation (n = 43) 14 (8.48%) 13 (7.47%) 5 (4.85%) 11 (12.5%) NS Others (n = 58) 27 (16.36%) 18 (10.34%) 3 (2.91%)a,b 10 (11.36%)c 0.008 a Compared with cardiology, p < 0.05. b Compared with pulmonology, p < 0.05. c Compared with general medicine, p < 0.05. EPAH: exercise-pulmonary hypertension. Open in new tab Discussion This study provides evidence that a multidisciplinary approach to the evaluation of unexplained dyspnea employing iCPET delivered in a specialized MDEC provides significant value in reducing the time associated with the assessment of unexplained dyspnea and the achievement of a final diagnosis. Finding the cause(s) of unexplained dyspnea is best achieved using a protocol based approach14 centered on objective findings and verification, rather than clinical impression alone, which will more consistently lead to an accurate diagnosis and an improved therapeutic outcome.15 In our study, in one-third of the cases, diagnosis was made based on the initial MDEC evaluation based on prior appropriate testing. In the remaining two-thirds of cases, iCPET was performed and generated information sufficient to reach a final diagnosis, thus leading to the conclusion that using a multidisciplinary approach and, if needed, in combination with iCPET can provide definitive diagnostic results in a shorter timeframe as compared with traditional methods. Many of the patients seen in MDEC had experienced extensive testing prior to referral. Most patients had been repeatedly referred to subspecialists for lack of a diagnosis. More than 75% of patients had undergone repeated testing. The lack of a standard dyspnea evaluation protocol and the concern for missing potentially life threatening causes of dyspnea frequently lead to multiple diagnostic tests being ordered to rule out different causes of dyspnea. As part of the initial MDEC protocol, all new patient referrals underwent an agreed upon panel of laboratory testing to screen for occult causes of dyspnea. We have since learned that the majority of the laboratory tests ordered provided no additional diagnostic power. We have since eliminated prespecified laboratory testing. An additional goal of our program was to provide a simplified referral process for primary care physicians, subspecialty colleagues, and surgical specialties. The referring clinician no longer had to decide to which specialist a patient should be sent. Most importantly, the MDEC program provided a simplified process for our patients. The clinical analysis should begin with a thorough clinic evaluation including a detailed history and physical examination and an assessment of the character and severity of the patient’s shortness of breath. Our findings strongly suggest that if a cause of dyspnea is not determined based on a thorough history, physical examination, full pulmonary function testing, chest imaging, an echocardiogram, and evaluation for coronary artery disease in appropriate patients it is very unlikely that a diagnosis will be found with additional standard testing. At that point, a better course of action is referral to an MDEC and consideration of iCPET. The strength of the MDEC evaluation protocol is the focus on understanding the physiologic basis of dyspnea through the use of exercise testing to reproduce the patient’s symptoms. niCPET provides an objective measure of exercise capacity and permits evaluation of patterns of response of V·O2 and V·CO2 to describe the exercise limitation based on physiologic parameters. niCPET is most useful for distinguishing between normal and abnormal. Abnormal findings are not necessarily specific to a single disease state.16 While niCPET may be considered in the evaluation of unexplained exertional dyspnea and aid in developing a differential diagnosis, niCPET is generally used to direct further testing rather than to make a specific diagnosis.17 For patients with unexplained exercise intolerance for which initial test results (e.g. pulmonary function testing with diffusing capacity for carbon monoxide (DLCO), radiographic imaging, and echocardiography) did not lead to a definitive diagnosis, niCPET can suggest whether exertional dyspnea is due to abnormalities of oxygen transport, deconditioning, or pulmonary mechanical limitations.18 In our study, 30% of our patients had niCPET and, among those, 10 patients had a repeat niCPET prior to referral to MDEC. iCPET refers to niCPET performed with pulmonary artery and radial artery catheters, and breath-by-breath analysis of respiratory gas exchange at rest and during a period of incremental exercise to exhaustion. iCPET provides an assessment of exercise capacity, and quantifies the relative contributions of any respiratory, cardiovascular, and metabolic dysfunction. By adding invasive hemodynamic monitoring during exercise, iCPET provides a unique opportunity to identify early stages of pulmonary vascular disease and low left ventricular diastolic reserve. In early stages of disease, non-invasive measurements such as VE/VCO2 slope are insensitive,19 suggesting limitations of non-invasive exercise screening for early disease. In our experience, ventilatory inefficiency also lacks specificity as it is also present in patients with early stage left heart disease,20 dysautonomia, and even skeletal muscle mitochondrial dysfunction. Additionally, another commonly used non-invasive measurement, peak end-tidal carbon dioxide tension, which correlates with pulmonary arterial hypertension severity, also performs poorly in detecting exercise pulmonary hypertension in our experience. Finally, in many cases, a decreased peak VO2 is detected by a niCPET. However, due to the lack of specificity of peak VO2, the underlying cause might remain elusive and multiple mechanisms such as impaired cardiac output augmentation, peripheral O2 extraction, or dysautonomia (in isolation or in combination) remain as part of the differential diagnosis for patients’ symptoms; an iCPET will elucidate and differentiate these conditions.13 Regarding the possible advantages of iCPET compared with niCPET combined with echocardiography, pulmonary pressure assessed by echocardiography has a good correlation with invasive hemodynamics measures during exercise only in those patients where a high-quality TR spectral Doppler envelope is obtained.21 However, less than 35% of patients have high quality echo measurements. niCPET has clear limitations and can serve as an initial screening tool, but often a clear diagnosis requires invasive testing. Combining cardiopulmonary exercise testing with exercise hemodynamic measurements as with iCPET permits evaluation of different pulmonary vascular responses in combination with objective measures of health and fitness. The use of upright cycle ergometry and iCPET to accurately characterize the measurement of pulmonary arterial and cardiac filling pressures during exercise reproduces what subjects actually go through during exertion and exercise. This approach provides an assessment of exercise capacity, and defines the detailed contributions of any cardiac, pulmonary, metabolic, or vascular limitations. We do not suggest every patient presenting with unexplained dyspnea go directly to iCPET. A key value of the multidisciplinary approach is that it may make better use of existing test data than an uncoordinated assortment of clinicians. For the subset of patients referred to MDEC where an iCPET was not pursued, the information to make a correct diagnosis was available before referral, but an uncoordinated effort failed to make the final diagnosis. Based on our results and those of earlier studies,14,15 an algorithmic approach utilizing basic conventional tests including imaging of the chest with either a chest radiograph or chest computed tomogram, echocardiogram, and full pulmonary function testing with DLCO may define the cause of dyspnea in a large subset of patients (Figure 1). For those patients where there is no definitive answer, combining these initial tests with iCPET potentially reduces the overall diagnostic time and likely saves medical resources. There are a number of limitations to the current study. This study design was entirely retrospective and only allowed for the review of an available historical dataset. Ultimately, a prospective evaluation would provide for a more precise comparison of time for diagnosis and testing requirements. Additionally, we only tracked patients who were referred to our MDEC and used their past history as a comparator. Therefore, we could not observe the frequency of successful diagnosis among patients with unexplained dyspnea diagnosed outside our MDEC. Nonetheless, the fact that one-third of patients referred to MDEC could be diagnosed without invasive testing using a standardized multidisciplinary approach suggests that prompt referral to MDEC is likely the most efficient path to accurate diagnosis. Our results likely underestimate the benefits of MDEC’s approach due to the truncation of the look-back period at four years prior to referral to MDEC. About 16% of patients had been seeking diagnosis of the underlying cause of their dyspnea for longer than four years. This was especially true in those patients with dysautonomia and mitochondrial myopathies. These patients typically had a very slowly progressive course, and often had been dismissed as having an anxiety disorder. On average, the patients referred to MDEC required an average of 2.2 visits to provide an underlying diagnosis. In conclusion, this study provides evidence that a multidisciplinary approach to the evaluation of unexplained dyspnea employing iCPET delivered in a specialized MDEC provides significant value in reducing the time associated with the assessment of unexplained dyspnea and the achievement of a final diagnosis. Therefore, we recommend a multidisciplinary approach to the patient with unexplained dyspnea with the establishment of a dyspnea center through which a single clinic referral would include evaluation by clinical experts with a specific interest in unexplained dyspnea. This is also an opportunity to compile the data from previous testing and review that data with a fresh set of eyes. In several cases, simply reviewing the cumulative data can provide an explanation for the patient’s dyspnea. In other cases, additional iCPET testing might be required. Author contribution WH and ABW together conceived the original study design, performed the primary data analysis and interpretation, and writing of the manuscript. SR, DMS, and BAC contributed substantially to the study design, data analysis and interpretation, and writing of the manuscript. RKFO contributed to study design and critically reviewed the manuscript. ABW and WH had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Declaration of conflicting interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Wei Huang received funding from the National Natural Science Foundation of China (81170188and 30971212), the Natural Science Foundation of Chongqing (CSCT2009BB5069). RKFO received funds from the São Paulo Research Foundation (FAPESP, grant #2014/12212-5) and from the Brazilian National Council for Scientific and Technological Development (CNPq, grant #232643/2014-8). Aaron B Waxman and David M Systrom received funding from NIH/NHLBI HL06023412A1 and U01 HL125215. References 1 Sarkar S , Amelung PJ. Evaluation of the dyspneic patient in the office . Prim Care 2006 ; 33 : 643 – 657 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Shiber JR , Santana J. Dyspnea . Med Clin North Am 2006 ; 90 : 453 – 479 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Karnani NG , Reisfield GM, Wilson GR. Evaluation of chronic dyspnea . 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Accuracy of echocardiography to estimate pulmonary artery pressures with exercise: A simultaneous invasive-noninvasive comparison . Circ Cardiovasc Imaging 2017 ; 10 : e005711 – e005711 . Google Scholar Crossref Search ADS PubMed WorldCat © The European Society of Cardiology 2017 This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © The European Society of Cardiology 2017

Journal

European Journal of Preventive Cardiology – Oxford University Press

Published: Jul 1, 2017

Keywords: patient referral; dyspnea; exercise stress test; diagnosis; lung

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