Ioannis Stanopoulos

Exercise capacity in idiopathic pulmonary fibrosis: the effect of pulmonary hypertension.

Background and objective:  Increased pulmonary arterial pressure (PAP) usually coexists with impaired lung function in IPF. Data on the effect of pulmonary hypertension (PH) on cardiopulmonary responses during exercise in IPF patients is very limited. We sought to investigate the impact of PH on exercise capacity and the correlation between systolic PAP (sPAP) and pulmonary function testing, as well as cardiopulmonary exercise parameters, in patients with IPF and PH.

Anemia of Chronic Disease in Chronic Obstructive Pulmonary Disease: A Case-Control Study of Cardiopulmonary Exercise Responses

Background: Anemia may be present in patients with chronic obstructive pulmonary disease (COPD) and further impair their functional capacity. Objectives: This study investigated the prevalence of anemia of chronic disease (ACD) in COPD patients and its impact on dyspnea and exercise capacity, utilizing cardiopulmonary exercise testing (CPET). Methods: ACD prevalence was assessed in 283 consecutive patients with stable COPD (263 males, 60 females; age 60.31 ± 5.34 years; percent forced expiratory volume in 1 s 46.94 ± 6.12). ACD diagnosis was based on a combination of clinical and laboratory parameters [hemoglobin (Hb) <13 g/dl for males, <12 g/dl for females; ferritin >30 ng/ml; total iron-binding capacity <250 µg/dl, and transferrin saturation rate between 15 and 50%]. Twenty-seven patients who were identified with ACD (cases) and 27 matched nonanemic patients (controls) completed maximal CPET, and data were compared between the groups. Results: ACD was diagnosed in 29 patients, which represents a prevalence of 10.24%; the severity of anemia was generally mild (mean Hb: 12.19 ± 0.66 g/dl). Patients with ACD had a higher Medical Research Council dyspnea score compared to controls (2.78 ± 0.44 vs. 2.07 ± 0.55; p <0.001) and lower peak O2 uptake (VO2) (59.54 ± 17.17 vs. 71.26 ± 11.85% predicted; p <0.05), peak work rate (54.94 ± 21.42 vs. 68.72 ± 20.81% predicted; p <0.05) and peak VO2/heart rate (69.07 ± 17.26 vs. 82.04 ± 18.22% predicted; p <0.05). There was also a trend for a lower anaerobic threshold (48.48 ± 15.16 vs. 55.42 ± 9.99% predicted; p = 0.062). No exercise parameter indicative of respiratory limitation differed between the groups. Conclusions: ACD occurs in approximately 10% of stable COPD patients and has a negative impact on dyspnea and circulatory efficiency during exercise.

Sleep Apnea Syndrome and Diastolic Blood Pressure Elevation during Exercise

Background: Several studies assessing the role of obstructive sleep apnea syndrome (OSAS) as an independent risk factor for hypertension have produced conflictingresults. Although the sleep apnea syndrome is associated with hypertension, there are no references regarding the blood pressure response of normotensive OSAS patients during exercise. Study Objectives: The aim of this study was to investigate the relationship between diastolic blood pressure (DBP) response during exercise and the severity of OSAS. Methods: We performed exercise testing a day after polysomnography in 17 normotensive males who were admitted for the first time because of OSAS and in 10 normal subjects who were members of the same families. During maximal incremental exercise test (bicycle ergometry) oxygen consumption (VO2) and the DBP were estimated at rest and at peak exercise. VO2 was also measured when DBP were 100 and 110 mm Hg. Results: At peak exercise DBP was significantly higher in OSAS patients (115.3 ± 9.2 mm Hg) than in normal subjects (101 ± 8.4 mm Hg, p < 0.01). OSAS patients reached a DBP of 110 mm Hg with a significantly lower VO2 than normal subjects (1,881.5 ± 703.4 vs. 1,972.3 ± 108.6 ml/min, p = 0.045). VO2 was not different between the two groups at a DBP of 100 mm Hg (1,211.2 ± 371.7 vs. 1,536.6 ± 267.2 ml/min, p = 0.089) but OSAS patients had a significantly lower heart rate than normals (111.2 ± 13 vs. 118.6 ± 27.6, p = 0.009). None of the aspects of quality of life, according to the Nottingham Health Profile Questionnaire, Part 1, were significantly different between patients and normal subjects. Conclusions: Normotensive OSAS patients develop DBP elevation at an earlier stage during exercise compared to normal subjects. This hypertensive response was not correlated with the severity (apnea-hypopnea index, oxygen desaturation parameters) of OSAS. DBP elevation could be a limiting factor of physical performance in this group of patients.

Levels of inflammatory mediators in chronic obstructive pulmonary disease patients with anemia of chronic disease: a case–control study

BACKGROUND Although a subset of patients with chronic obstructive pulmonary disease (COPD) display anemia, the role of elevated pro-inflammatory cytokines in COPD-related anemia of chronic disease (ACD) has not been fully investigated. AIM To examine the levels of interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor-alpha (TNFα), interferon-gamma (IFNγ), C-reactive protein (CRP) and erythropoietin in stable COPD outpatients with and without ACD. DESIGN A case-control design was followed. METHODS Fifty-four patients with stable COPD were studied. Among them, 27 had ACD according to strict clinical and laboratory criteria (group of cases), while another 27 nonanemic COPD patients, carefully matched to cases for age, gender, height, lung function and smoking status represented the controls. Serum levels of IL-1β, IL-6, IL-10, TNFα, IFNγ, CRP and erythropoietin were measured in both groups. RESULTS Patients with ACD had significantly higher levels of IL-10 [25.6 (1.9-95.2) vs. 4.1 (1.9-31.9) pg/ml, P = 0.049] and IFNγ [15.2 (2.2-106.9) vs. 2 (1.2-18.3) pg/ml, P = 0.026] and had more frequently elevated CRP than controls. Levels of IL-1β [26.2 (9.8-96.4) vs. 7.9 (2.1-28.4) pg/ml, P = 0.073], IL-6 [20.3 (2.1-125.4) vs. 6.2 (1.2-33.8) pg/ml, P = 0.688] and TNFα [30.1 (3.2-107.5) vs. 10.1 (3.2-50.4) pg/ml, P = 0.131] were also higher in cases, but the differences did not reach statistical significance. Patients with ACD also displayed significantly higher erythropoietin levels than controls [(21.9 (8.4-101.7) vs. 9.7 (6.3-21.7) mIU/ml, P = 0.010], indicating erythropoietin resistance. CONCLUSION This study shows that in stable COPD outpatients with strictly defined ACD, levels of inflammatory mediators and erythropoietin are elevated compared to nonanemic controls.

Pharmacokinetics of Ciprofloxacin and Its Penetration into Bronchial Secretions of Mechanically Ventilated Patients with Chronic Obstructive Pulmonary Disease

ABSTRACT We evaluated the pharmacokinetic profile of ciprofloxacin and its penetration into bronchial secretions of critically ill patients with chronic obstructive pulmonary disease (COPD). Twenty-five mechanically ventilated patients with severe COPD who were suffering from an acute, infectious exacerbation were included in this prospective, open-label study. All subjects received a 1-hour intravenous infusion of 400 mg ciprofloxacin every 8 h. Serial blood and bronchial secretion samples were obtained at steady state, and concentrations were determined using high-performance liquid chromatography. The pharmacodynamic parameters that are associated with the efficacy of fluoroquinolones against Gram-negative pathogens were also calculated. The mean peak (maximum) concentration (Cmax) and trough (minimum) concentration in plasma were 5.37 ± 1.57 and 1 ± 0.53 mg/liter, respectively. Mean values for volume of distribution, clearance, half-life, and area under the curve from 0 to 24 h (AUC0–24) were 169.87 ± 84.11 liters, 26.96 ± 8.86 liters/h, 5.35 ± 2.21 h, and 47.41 ± 17.02 mg · h/liter, respectively. In bronchial secretions, a mean Cmax of 3.08 ± 1.21 mg/liter was achieved in 3.12 ± 1.01 h, and the penetration ratio was 1.16 ± 0.59. The target of AUC0–24/MIC of ≥125 was attained in all patients, in the majority of them (76%), and in none at MICs of 0.125, 0.25, and 1 μg/ml, respectively. Slightly better results were obtained for the ratio Cmax/MIC of ≥10. In conclusion, ciprofloxacin demonstrates excellent penetration into bronchial secretions. There is wide interindividual variability in its pharmacokinetic parameters in critically ill COPD patients and inadequate pharmacodynamic exposure against bacteria with MICs of ≥0.5 μg/ml.

The Impact of Pulmonary Arterial Pressure on Exercise Capacity in Mild-to-Moderate Cystic Fibrosis: A Case Control Study

Background. Pulmonary hypertension (PH) is an often complication of severe cystic fibrosis (CF); however, data on the presence and impact of pulmonary vasculopathy in adult CF patients with milder disease, is very limited. Aim. To investigate, for the first time, the impact of systolic pulmonary arterial pressure (PASP) on maximal exercise capacity in adults with mild-to-moderate cystic fibrosis, without PH at rest. Methods. This is a Case Control study. Seventeen adults with mild-to-moderate CF, without PH at rest (cases) and 10 healthy, nonsmoking, age, and height matched controls were studied. All subjects underwent maximal cardiopulmonary exercise testing and echocardiography before and within 1 minute after stopping exercise. Results. Exercise ventilation parameters were similar in the two groups; however, cases, compared to controls, had higher postexercise PASP and decreased exercise capacity, established with lower peak work rate, peak O2 uptake, anaerobic threshold, and peak O2 pulse. Furthermore, the change in PASP values before and after exercise was strongly correlated to the parameters of exercise capacity among cases but not among controls. Conclusions. CF adults with mild-to-moderate disease should be screened for the presence of pulmonary vasculopathy, since the elevation of PASP during exercise might contribute to impaired exercise capacity.

Should we routinely screen patients with idiopathic pulmonary fibrosis for nocturnal hypoxemia

Dear Editor, An increased incidence of sleep-disordered breathing in patients with idiopathic pulmonary fibrosis (IPF) has been reported in recently published studies [1–3]. Sleep-related oxygen desaturation seems to represent a common, usually undertreated disorder in these patients [4]. Nocturnal hypoxemia theoretically might aggravate vasoconstriction and vascular remodeling in pulmonary circulation. Pulmonary hypertension (PH) is a common complication of IPF with a reported incidence ranging from 32 to 85 % [5]. The development of PH during the course of the disease has a negative impact on functional status and quality of life of IPF patients and is associated with a poor survival [6, 7]. Currently, there is no specific therapy for PH associated with IPF, and the published experience with specific PH drug therapy is disappointing. The pathogenesis of PH in IPF is incompletely understood. Hypoxic pulmonary vasoconstriction leading to permanent medial hypertrophy is a wellrecognized mechanism of PH in chronic lung disease. Patients with IPF often demonstrate hypoxemia, commonly with minimal exercise and even at rest at advanced stages of the disease. However, the role of nocturnal hypoxemia in the development of PH in IPF patients has not been studied thoroughly. Given this background, we sought to determine the potential correlation between nocturnal hypoxemia and PH in a cohort of IPF patients. Thirty-three consecutive IPF patients (26 male), mean age 69±8.7 years, referred for evaluation in the respiratory failure unit, were prospectively studied. Diagnosis of IPF was established according to the American Thoracic Society/European Respiratory Society criteria [8]. All patients underwent pulmonary function tests (PFTs), arterial blood gases measurement at room air, 6-min walk test with recording of O2 saturation (SpO2) by noninvasive pulse oximetry, and a limited sleep study with recording of finger pulse oximetry using a portable diagnostic system (Embletta; Medcare Flaga, Reykjavik, Iceland). During the sleep study, none of the patients was under supplemental oxygen therapy. Pulmonary function assessment was performed by spirometry (MasterScreen PFT; Jaeger, Höchberg, Germany). Forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), total lung capacity (TLC), DLCO, and carbon monoxide transfer coefficient (KCO, in percent) were measured. A transthoracic echocardiographic study was performed within 1 week of the initial evaluation of the patients. Resting systolic pulmonary arterial pressure (sPAP) was estimated by calculating the maximal velocity of the tricuspid regurgitant jet, applying the Bernoulli equation and then adding to this value an estimated right atrial pressure, based on both the size of the inferior vena cava and the change in diameter of this vessel during respiration. PH was defined as sPAP of >36 mmHg. The patients were clinically stable and continued to receive the same medical treatment throughout the study. All data are presented as means±1 SD. The Pearson’s G. Pitsiou (*) :V. Bagalas :A. Boutou : I. Stanopoulos : P. Argyropoulou-Pataka Respiratory Failure Unit, Gen. Hospital “G. Papanikolaou”, Aristotle University of Thessaloniki, Exohi, Thessaloniki 57010, Greece e-mail: gpitsiou@yahoo.gr

Restrictive pulmonary dysfunction and its predictors in young patients with β-thalassaemia major.

Pulmonary dysfunction represents one of the most undervalued and less recognized complications in patients with β‐thalassaemia.

Phenotyping Exercise Limitation in Systemic Sclerosis: The Use of Cardiopulmonary Exercise Testing

Background: Exercise impairment is a common symptom of systemic sclerosis (SSc), a disorder which is frequently complicated by cardiopulmonary involvement. Objectives: This studys aims were: (a) to define the prevalence and the potential causes of limited exercise capacity and (b) to study potential differences in clinical, radiological and functional characteristics and blood serology among SSc patients with exercise limitation of different etiology. Methods: Prospectively collected data on SSc patients who had conducted full lung function testing, blood serology, thorax high-resolution computed tomography, Doppler echocardiogram and a maximal cardiopulmonary exercise testing (CPET) were retrospectively analyzed. Using a CPET algorithm, patients were characterized as having normal or subnormal exercise capacity (N), respiratory limitation (RL), left ventricular dysfunction (LVD) or pulmonary vasculopathy (PV). Group comparisons were conducted using either one-way ANOVA or the Kruskal-Wallis test. A p value <0.05 was considered significant. Results: The study population consisted of 78 patients (53.7 ± 13.7 years old; 10.3% male). PV was present in 32.1%, LVD in 25.6% and RL in 10.2%, while 32.1% of the patients constituted the N group. The presence of antisclero-70 antibodies, low anaerobic threshold and low peak exercise capacity measures could discriminate LVD from the other groups. Low end-tidal carbon dioxide pressure and its change from rest to anaerobic threshold could discriminate between the PV, LVD and N groups, while respiratory restriction along with ventilatory inefficiency indices could differentiate the RL group from the rest. Conclusions: The combined evaluation of CPET gas exchange patterns with baseline measurements could discriminate the causes of exercise limitation among SSc patients.

Sarcoidosis-associated pulmonary hypertension: a role for endothelin receptor antagonists?

Data on the treatment of sarcoidosis-associated pulmonary hypertension are scarce, while the variety of underlying pathophysiologic mechanisms are a major limitation in the implementation of a universal therapy. We report a 47-year-old male patient who presented with stage II sarcoidosis and associated severe pulmonary hypertension. Corticosteroid treatment resolved parenchymal lesions of the lung while vascular involvement did not respond, with the patient remaining in poor functional status. Addition of bosentan, a dual endothelin receptor antagonist, resulted in marked improvement in functional class and exercise capacity of the patient, allowing gradual tapering of steroids.