Chronic obstructive pulmonary disease (COPD) is an extremely prevalent disease that presents with airway or alveolar abnormalities, causing persistent respiratory symptoms and airflow limitations.1 According to the World Health Organization, COPD is projected to rank fifth in terms of disease burden globally.2 Pulmonary hypertension (PH) is a well-known complication of COPD, with a reported prevalence of 20% to 90%.3–6
Pulmonary hypertension in COPD is mainly caused by acute and long-term alveolar hypoxia that leads to pulmonary vasoconstriction and pulmonary vascular remodeling, respectively.7 Moreover, arterial oxygen saturation (SpO2) is shown to be directly associated with mean pulmonary artery pressure (mPAP)3 and chronic inflammatory state in COPD due to vascular inflammatory effect is one of the potential contributors of PH.8 An increase in mPAP by as much as 20 mm Hg may occur in patients with acute exacerbation of COPD and return to its baseline after recovery.9 Pulmonary hypertension due to COPD is correlated with a reduced survival rate in relation to pulmonary arterial pressure (PAP),10 even in patients on long-term O2 therapy.6
Right-sided heart catheterization is considered as the gold standard test to diagnose PH; however, it is an invasive method and is not suitable for patients who do not show signs and symptoms associated with PH.11 Two-dimensional transthoracic Doppler echocardiography can be securely used in COPD patients. It is considered an excellent tool for the identification of PH in such patients. It is recommended that all patients with severe to very severe COPD and mild to moderate COPD with abnormal dyspnea should be routinely screened by echocardiography for PH.12
Exercise causes noticeable increase in the PAP of COPD patients.13 Therefore, exercise testing has been recommended as it is helpful in early identification of PH.14 Cardiopulmonary exercise testing (CPX) is an assessment tool that aids in the evaluation of dynamic responses to exercise by various body systems such as cardiovascular, pulmonary, hematopoietic, and neuropsychological. It is a noninvasive physiological evaluation of both peak and submaximal exercise responses.15 CPX may help in the evaluation of PH in patients with either ventilatory or circulatory inefficiency. A recent investigation16 has clearly indicated the role of CPX combined with arterial blood gas analysis in the evaluation of PH. The present study aimed to examine the hypothesis that CPX would be a valid tool to diagnose PH in patients with COPD and there would be a significant correlation between CPX variables and indices of PH.
The present study was conducted after obtaining ethical clearance from the Institutional Ethics Committee of Jamia Millia Islamia (a central university), New Delhi, India, and from the Metro Ethics Review Board, Metro Hospital, Noida, India. A written informed consent was obtained from all participants, and research procedures were conducted in accordance with the Declaration of Helsinki, 1964. Patients with moderate to very severe COPD, between 40 and 80 yr of age, were recruited from the Pulmonary Outpatient Department of Metro Hospital. Sample size was estimated using a formula (n = 10 k/p) utilized by a previous study,17 where p is the smallest of the proportions of positive or negative cases in the sample and k is the number of covariates. According to Thabut et al,5 PH is prevalent in almost half of the COPD patients and there are 4 covariates in the present study. Using these estimates, a sample size of 48 patients was found to be necessary to test the hypothesis.
Moderate (50% ≤ forced expiratory volume in 1 sec [FEV1] <80% predicted) to severe (FEV1<30% predicted) COPD patients >40 yr of age, having stable illness without exacerbation for 4 wk, and able to perform incremental CPX were recruited from Metro Hospital. COPD patients with a history of acute myocardial infarction within 3 to 5 d of the study, unstable angina, acute viral myocarditis, pulmonary embolism, uncontrolled heart failure, systemic hypertension (≥160/90 mm Hg), and with room air oxygen saturation at rest (<85%) were excluded.
PROTOCOL FOR DATA COLLECTION
Before enrollment, COPD diagnosis was confirmed by spirometry18 before and after bronchodilation. Thereafter, testing was performed over a period of 3 d. On day 1, after demographic and clinical assessments, patients underwent pulmonary function testing (PFT) and a 6-min walk test (6MWT), with adequate rest periods between the tests. On day 2, PH was diagnosed by 2-dimensional transthoracic Doppler echocardiography, using Vivid Ultrasound (GE Healthcare), which was performed by a cardiologist who was unaware of the purpose of the study. On day 3, CPX was conducted using a symptom-limited incremental test by a different investigator who was not aware of patient diagnosis based on echocardiography.
Patients underwent PFT using Jaeger (CareFusion) as per the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines.19 The ratio of FEV1 and forced vital capacity (FVC) (FEV1/FVC), FVC, FEV1, diffusion capacity of carbon monoxide (DLCO), and the ratio of residual volume and total lung capacity were measured.
The 6MWT was performed in accordance with the ATS/ERS guidelines,19 and parameters such as dyspnea, SpO2, blood pressure, and pulse rate were measured at the beginning and end of the test. Each patient was asked to walk at a comfortable pace for as much distance as possible in the allotted time. The distance covered was recorded and reported in meters and percentage. A predicted 6MWT distance was calculated using the equation given by Enright and Sherrill,20 and the results were as follows: (7.57 × Height [cm]) − (5.02 × Age) − (1.76 × Weight [kg]) − 309 m for men and (2.11 × Height [cm]) − (2.29 × Weight [kg]) − (5.78 × Age) + 667 m for women. The percentage predicted 6MWT distance was then calculated by dividing the observed value with the predicted value multiplied by 100 for each patient.
Two-dimensional transthoracic Doppler echocardiography with Vivid Ultrasound (GE Healthcare) was used to detect PH in COPD patients. Parameters of PH—systolic pulmonary artery pressure (sPAP) and right atrial pressure—were measured, and patients were classified as positive or negative for PH. Positive cases were classified into mild, moderate, and severe PH categories depending on the results obtained: sPAP ≥30 mm Hg was defined as PH; PH was classified into mild (sPAP = 30-50 mm Hg), moderate (sPAP = 50-70 mm Hg), and severe (sPAP >70 mm Hg) categories. These values were chosen according to the formula of Chemla et al,21 mPAP = 0.61 sPAP + 2 mm Hg, by taking the value of mPAP for mild, moderate, and severe PH as 25 to 35, 35 to 45, and >45 mm Hg, respectively.22
Symptom-limited CPX was performed as per the guidelines15 on an electronically braked cycle ergometer Ergoselect200P/200K (COSMED). Data for
O2 (L/min), and minute
E (L/min) were collected using a gas analyzer Quark PFT ergo (COSMED) during the test, which provided data on the gases consumed by the patient every 10 sec. The equipment was calibrated at the beginning of every test. Incremental exercise protocol was initiated after a rest period of 3 min, followed by a 3-min warm-up phase at 0 W. The intensity of exercise was increased gradually by increasing 5 or 10 W according to work rate selection every 60 sec until the test termination criterion was obtained. The incremental load was calculated using the equation developed by Pretto et al23 [Increments (W) = 3.05 FEV1 − 0.09 Age + 2.44 Gender + 6.18]. The exercise test was followed by a 3-min recovery phase. Heart rate and blood pressure were monitored by a pulse oximeter and a 12-lead electrocardiogram (ECG), respectively. The test was terminated if the patient felt any discomfort such as chest pain, unsustainable dyspnea, or leg fatigue or if there was ECG ST-segment depression, systolic blood pressure >260 mm Hg and/or systolic blood pressure drop >20 mm Hg or diastolic blood pressure >140 mm Hg.
O2peak was defined as
O2 that increased <1 mL/kg/min for ≥30 sec despite increments in workload.24 Anaerobic threshold (AT) was marked at the point by COSMED quark software when ventilatory response was obtained because of metabolic acidosis.15 Cardiac, ventilatory, and gas exchange parameters in CPX, such as peak oxygen uptake (
O2 at anaerobic threshold (
O2 @ AT), peak work rate (peak WR), oxygen pulse (
O2/HR), peak respiratory exchange ratio (peak RER), heart rate reserve (HRR), dead space ventilation (
T), end-tidal volume partial pressure of carbon dioxide (PETCO2), ventilatory equivalents for O2 and CO2 (
CO2), and desaturation (%), were obtained.
Statistical analysis was performed using SPSS software version 23 (IBM Corporation) and MedCalc version 18.2.1 (MedCalc Software bvba). Normality of distribution scores was tested using the Shapiro-Wilk test, and nonnormal variables were log transformed for further analysis. Clinical and CPX parameters were compared between COPD patients with and without PH using an independent-samples t test. Pearson correlation coefficients were calculated to investigate the association between CPX variables and mPAP. Diagnostic ability of CPX parameters for PH in COPD patients was determined using receiver operating characteristic (ROC) curve analysis. Area under the ROC curve (AUC), sensitivity, specificity, positive and negative predicted values (PPV and NPV), and positive and negative likelihood ratios (LR+ and LR−) were calculated. In addition, univariate and multivariate logistic regression analyses were performed. CPX variables, which significantly correlated with indices of PH, were dichotomized for PH based on their respective cutoff values obtained in ROC curve analysis. First, OR with 95% CI were calculated for
O2peak [% predicted (% pred)],
O2peak (mL/min), oxygen pulse (mL/beat), oxygen pulse (% pred),
O2/kg, and desaturation using univariate logistic regression. Afterward, multivariate logistic regression was employed controlling for relevant lung function variables (FEV1 [% pred], FVC [L], and DLCO) and age to estimate OR for the continuous (model 1) and dichotomous (model 2) CPX parameters for independent prediction of PH in COPD patients. A P value <.05 was considered statistically significant.
Twenty-nine COPD patients had raised PAP at rest with an mPAP >25 mm Hg and were classified as positive for PH; of whom, 18 were classified as mild, 7 as moderate, and 4 as severe PH. Correlation analysis revealed that mPAP was inversely correlated with CPX measures such as
O2peak (% pred) (r = −0.82),
O2peak (mL/min) (r = −0.79),
O2/kg (r = −0.66), oxygen pulse (% pred) (r = −0.81), oxygen pulse (mL/beat) (r = −0.076), and peak
E (L/min) (r = −0.29). Positive relationship was observed between mPAP and desaturation (r = 0.674) and mPAP and peak
CO2 (r = 0.30) parameters (Figure 1).
Compared with patients without PH, those with PH showed low exercise capacity, low oxygen pulse, low heart rate, and lower oxygen saturation during exercise testing. They also showed significantly reduced SpO2 and 6MWT distance during the functional capacity test. In lung function parameters, patients with PH had reduced DLCO and FVC compared to patients without PH (Table 1).
ROC curve analysis showed good diagnostic ability of
O2peak (% pred),
O2peak (mL/min), oxygen pulse (% pred),
O2/kg, and desaturation for PH.
O2peak (mL/min) demonstrated an AUC of 0.92 (P < .001) with 79% sensitivity and 95% specificity at the cutoff value of ≤962 mL/min.
O2peak (% pred) exhibited an AUC of 0.84 (P < .0001) with 90% sensitivity and 95% specificity at the cutoff value of ≤67%. Predictive accuracy with 93% sensitivity and 89% specificity was demonstrated by oxygen pulse (% pred) with an AUC of 0.96 (P < .001) at the cutoff value of ≤74%. Our findings suggested that
O2/kg can identify PH with 97% sensitivity and 47% specificity with an AUC of 0.76 (P < .001) at the cutoff value of ≤21.34. Desaturation revealed an AUC of 0.83 (P < .001) with 55% sensitivity and 100% specificity at the cutoff value of >4 for detecting PH.
O2peak and oxygen pulse were found to be superior diagnostic indicators of PH (Figure 2).
Univariate logistic regression models demonstrated that diminished
O2peak (% pred), oxygen pulse (mL/beat), oxygen pulse (% pred), desaturation (%) during exercise, and FVC and DLCO were found to be significant predictors of PH in COPD patients (Table 2). Multivariate logistic regression was used to calculate the OR adjusted for age and relevant lung function data (FEV1 %, FVC, and DLCO).
O2peak (%), oxygen pulse (mL/beat), and desaturation (%) demonstrated independent prediction of PH even after adjustment of relevant demographic and clinical measures (Table 3).
The present study examined the diagnostic validity of CPX parameters for diagnosing PH in patients with COPD. We found that
O2peak (% pred),
O2peak (mL/min), oxygen pulse (% pred),
O2/kg, and desaturation (%) were accurate diagnostic indicators of PH in COPD patients.
In the present study, an inverse association could be seen between mPAP and CPX measures such as
O2peak (% pred),
O2/kg, oxygen pulse (%), and oxygen pulse (mL/beat), whereas positive relationship was observed between mPAP and peak
CO2 and desaturation. Although cause and effect relationship cannot be established by measuring associations, it could be assumed that increased PH might lead to low
O2peak and oxygen pulse. Findings of a previous study18 stated that pulmonary vascular resistance (PVR) induced by PH in COPD patients is inversely related to oxygen uptake and higher PVR and, in turn, is associated with higher
CO2. Our outcomes are in accordance with the study of Thirapatarapong et al,25 which demonstrated inverse correlation between mPAP and
O2peak and oxygen pulse in COPD patients.
CPX parameters were significantly altered in COPD patients with PH in the present study. Exercise testing showed that COPD patients with PH had diminished
O2peak and oxygen pulse, excessive desaturation, and impaired exercise capacity compared with those without PH. These findings clearly indicate that exercise capacity is impaired in COPD patients with PH due to hampered oxygen pulse and
O2peak. Our findings are in agreement with the study by Boerrigter et al26 and Vonbank et al,18 which showed that
O2peak and WR were significantly reduced in COPD patients with PH compared with those without PH. Alteration in exercise capacity in patients with PH may be explained by the abnormal rise in PAP during physical exercise due to the fact that PVR does not decrease but may increase during exercise, limiting the increase in cardiac output.27 Zhao et al28 demonstrated lower
O2peak, oxygen pulse, and WR in COPD patients with PH. They also found that combined
CO2 slope and AT score provides high specificity and may be used for screening PH in echocardiography-suspected patients. However, because most of the patients did not achieve
O2 @ AT, we were unable to analyze the influence of PH on AT in our study. Similar to the findings of Vonbank et al18 and Pynnaert et al,29 we found that there was no significant difference in RER and ventilatory reserve between COPD patients with and without PH. No significant difference was observed in peak
CO2 and PETCO2 in COPD patients with and without PH, which is in accordance with the findings of Pynnaert et al.29 It might have been caused by reduced response to metabolic acidosis and severely decreased alveolar ventilation.30,31 Such insignificant differences may also be attributed to the fact that a majority of patients in this study were suffering from mild to moderate PH (86.2%) and that mild or moderate PH does not add to ventilatory limitation to limit
CO2 and PETCO2.29 The insignificant differences may also be due to the fact that, in our study, exercise testing was terminated before the attainment of metabolic acidosis. Our findings revealed high diagnostic ability of
O2peak (% pred),
O2peak, oxygen pulse (% pred),
O2/kg, and desaturation to diagnose PH in COPD patients.
O2peak (%) and
O2peak (mL/min) can identify PH with 90% sensitivity and 95% specificity and 79% sensitivity and 95% specificity, respectively (Figure 2). A similar study for diagnosing PH in patients with dilated cardiomyopathy32 reported that
O2peak (% pred) and
O2peak (mL/min) could diagnose PH with 83% sensitivity and 86% specificity and 91% sensitivity and 71% specificity, respectively. However, our diagnostic analysis showed greater predictive accuracy and high specificity of
O2peak (% pred) for PH. Similarly,
CO2 slope and Δ
O2/ΔWR demonstrated greater diagnostic performance in our study for diagnosing PH than in the study by Hirashiki et al,32 where oxygen pulse (%),
O2/kg, and desaturation demonstrated lesser diagnostic accuracy than the previously discussed variables for diagnosing PH. These findings indicate that CPX parameters may be used to assess PH associated with COPD, with even better accuracy than for detecting PH associated with cardiomyopathy. A recent investigation16 was conducted on COPD patients and the results demonstrated that low exercise performance and PaO2 strongly indicated the presence of PH in COPD patients with a sensitivity of 86% and specificity of 78% at the cutoff value of <61 mm Hg for PaO2. However, in that study, CPX alone could not predict PH in COPD patients. Another study33 on patients with heart failure also claimed significant diagnostic ability of CPX for PH. CPX parameters have even been shown to improve the diagnostic specificity in patients with echocardiography-suspected PH.28
In the present investigation, univariate logistic regression models demonstrated that diminished
O2peak, oxygen pulse, and desaturation during exercise are significant predictors of PH in COPD patients.
O2peak (mL/min) and oxygen pulse (mL/beat) were independent predictors of PH in COPD patients, while age, FEV1, and FVC were additional predictors of PH in model 1 and model 2. A recent study demonstrated that
CO2 slope and AT are independent predictors of PH.28 These findings reflect that probably different CPX parameters are affected in PH due to COPD versus PH associated with other diseases and thus there should be a holistic evaluation of all CPX parameters for PH of different origins. Some of the CPX parameters thus prove to be independent indicators of PH in COPD patients and may be used as an adjunct tool to diagnose and monitor PH.
The present study has some limitations. First, patients were diagnosed for PH by echocardiographic assessment rather than the standard method of right-sided heart catheterization.34 Second, hemodynamic measurements such as pulmonary vasoreactivity were not used during the exercise test. Third, this study did not constitute a follow-up and, in future research, it would be interesting to longitudinally follow patients with impaired CPX parameters and examine the occurrence of PH in them.
CPX is a diagnostic tool employed to investigate serialized changes in exercise capacity. Our findings contribute in establishing
O2peak (mL/min) and oxygen pulse as relevant diagnostic tools for correctly identifying PH in COPD patients. The results validate the use of CPX for diagnosing PH in COPD patients as an adjunct to echocardiographic measurement of PH.
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