Heinrike Wilkens

Exercise and Respiratory Training Improve Exercise Capacity and Quality of Life in Patients With Severe Chronic Pulmonary Hypertension

Background— Pulmonary hypertension (PH) is associated with restricted physical capacity, limited quality of life, and a poor prognosis because of right heart failure. The present study is the first prospective randomized study to evaluate the effects of exercise and respiratory training in patients with severe symptomatic PH. Methods and Results— Thirty patients with PH (21 women; mean age, 50±13 years; mean pulmonary artery pressure, 50±15 mm Hg; mean World Health Organization [WHO] class, 2.9±0.5; pulmonary arterial hypertension, n=23; chronic thromboembolic PH, n=7) on stable disease-targeted medication were randomly assigned to a control (n=15) and a primary training (n=15) group. Medication remained unchanged during the study period. Primary end points were the changes from baseline to week 15 in the distance walked in 6 minutes and in scores of the Short Form Health Survey quality-of-life questionnaire. Changes in WHO functional class, Borg scale, and parameters of echocardiography and gas exchange also were assessed. At week 15, patients in the primary and secondary training groups had an improved 6-minute walking distance; the mean difference between the control and the primary training group was 111 m (95% confidence interval, 65 to 139 m; P<0.001). Exercise training was well tolerated and improved scores of quality of life, WHO functional class, peak oxygen consumption, oxygen consumption at the anaerobic threshold, and achieved workload. Systolic pulmonary artery pressure values at rest did not change significantly after 15 weeks of exercise and respiratory training (from 61±18 to 54±18 mm Hg) within the training group. Conclusions— This study indicates that respiratory and physical training could be a promising adjunct to medical treatment in severe PH. The effects add to the beneficial results of modern medical treatment.

A comparison of the acute hemodynamic effects of inhaled nitric oxide and aerosolized iloprost in primary pulmonary hypertension

OBJECTIVE We sought to compare the acute hemodynamic effects of inhaled nitric oxide (NO) and aerosolized iloprost in primary pulmonary hypertension (PPH). BACKGROUND Inhalation of the stable prostacyclin analogue iloprost has recently been described as a novel therapeutic strategy for PPH and may offer an alternative to continuous intravenous infusion of prostacyclin or inhalation of NO. METHODS During right heart catheterization, 35 patients with PPH sequentially inhaled 40 ppm of NO and 14 to 17 microg of iloprost, and the effects on hemodynamics and blood gases were monitored. RESULTS Both NO and iloprost caused significant increases in cardiac output, mixed-venous oxygen saturation and stroke volume as well as significant decreases in pulmonary artery pressure and pulmonary vascular resistance, whereas only inhaled iloprost significantly increased the arterial PO2 (p = 0.01). Compared with inhaled NO, aerosolized iloprost was more effective in reducing pulmonary artery pressure (-8.3 +/- 7.5 mm Hg vs. -4.3 +/- 8.8 mm Hg; p = 0.0001) and the pulmonary vascular resistance (-447 +/- 340 dynes x s x cm(-5) vs. -183 +/- 305 dyne x s x cm(-5); p < 0.0001). Furthermore, aerosolized iloprost caused a significantly greater increase of the cardiac output compared with NO (+0.7 +/- 0.6 liter/min vs. +0.3 +/- 0.4 liter/min; p = 0.0002) and had a more pronounced effect on the mixed-venous oxygen saturation (p = 0.003). CONCLUSIONS During acute drug testing, aerosolized iloprost was more potent than inhaled NO as a pulmonary vasodilator in PPH at the doses used in this study.

Inhaled iloprost To treat severe pulmonary hypertension : An uncontrolled trial

Progressive right-heart failure is the ultimate cause of death for most patients with primary pulmonary hypertension. The prognosis is particularly poor for patients with New York Heart Association functional class IV disease and severely increased central venous pressure (1). Prostacyclin was the first drug shown to be life-saving in a controlled study of primary pulmonary hypertension (2). However, the lack of pulmonary selectivity of the vasodilatory effect and consequent systemic side effects limit the usefulness of prostacyclin (3). Patients with severe arterial hypotension and preexistent shunt areas in the lung often cannot tolerate intravenous prostacyclin (4-6). Inhaled nitric oxide has pulmonary selectivity, but its vasodilatory potency in the pulmonary vasculature is lower than that of prostacyclin (7, 8). Because nitric oxide has a short half-life, interruption of nitric oxide inhalation may provoke an immediate rebound hypertensive crisis (9, 10). In patients with severe primary or secondary pulmonary hypertension, we recently demonstrated that inhalation of aerosolized iloprost, the stable analogue of prostacyclin, substantially decreases pulmonary artery pressure and resistance and increases cardiac output without a significant decrease in systemic artery pressure and ventilation-perfusion mismatch (11, 12). This observation was consistent with previous findings in mechanically ventilated patients with acute respiratory failure, in whom aerosolized vasodilatory prostanoids effected selective pulmonary vasodilatation and preferential distribution of the nebulized vasodilator to the best-ventilated lung areas, with improvement of ventilation-perfusion matching (5, 12-18). We also reported on a patient with circulatory shock and right ventricular decompensation due to severe primary pulmonary hypertension (4) and a patient with decompensating right-heart failure due to collagen vascular disease-induced lung fibrosis (5). Both conditions were refractory to maximum conventional therapy; inhaled iloprost, however, seemed to improve hemodynamics and long-term survival. We extended these findings in an open, uncontrolled trial of 19 patients with primary or secondary pulmonary hypertension, all of whom presented with life-threatening pulmonary hypertension and progressive right-heart failure. Methods Patients Between May 1995 and May 1998, we enrolled 19 patients with severe pulmonary hypertension from six university hospitals in Germany. Eighty-seven patients were eligible for therapy with inhaled iloprost, but we enrolled only patients who met criteria for clinical instability. Clinical instability was defined as the occurrence of at least one of the following: 1) rapid deterioration of exercise tolerance, as indicated by a decrease of more than 30% in the distance walked in 6 minutes in the past 1 to 2 months; 2) central venous pressure of 17 mm Hg or higher during physical rest with adequate diuretic therapy; 3) cardiogenic edema that was refractory to intravenous diuretic therapy; 4) cardiogenic ascites or pleural effusion that was refractory to diuretic therapy; 5) hepatic failure, indicated by an increase in bilirubin level above 86 mol/L [5 mg/dL] or aminotransferase levels more than three times the upper limit of normal; 6) renal failure, as indicated by a creatinine concentration greater than 159 mol/L [1.8 mg/dL] or oligoanuria; or 7) cardiogenic somnolence. Severe pulmonary hypertension was diagnosed in all patients before study entry. Diagnostic procedures included transthoracic and, in most cases, transesophageal echocardiography; chest radiography; high-resolution computed tomography of the lung; spirometry; measurement of carbon monoxide diffusion capacity; electrocardiography; and laboratory measurements, including thyroid hormones, antinuclear antibodies, and extractable nuclear antigens. Ventilation and perfusion scanning of the lung and spiral computed tomography or pulmonary angiography were done if pulmonary embolism was suspected. We excluded patients with fresh lung embolism or chronic lung embolism of central or segmental vessels and patients with active interstitial lung disease requiring high-dose steroids or immunosuppressant therapy. Patients with disorders of the left ventricle, mitral or aortic valve disease, severe liver disease, or hemorrhagic diathesis were not eligible. All patients gave written informed consent. The study was approved by the local ethics committees of all participating centers. Intervention Iloprost (Ilomedin, Schering AG, Berlin, Germany) was diluted in 0.9% saline (10 g/mL), jet-nebulized with room air at a pressure of 80 kPa (fluid flux, 0.07 mL/min; mass median aerodynamic diameter of particles, 3.2 m; geometric SD, 1.8 as determined by impactor technique) and delivered to a spacer connected to the afferent limb of a Y-valve mouthpiece for 12 to 15 minutes (total nebulized dose, 8.4 to 10.5 g). Patients inhaled 6 to 12 times daily after the baseline examination was performed. The frequency of inhalations was adjusted as necessary according to decreasing physical capacity or anginal symptoms between doses. The single dose was reduced if adverse effects (such as nausea) occurred during inhalation of the full dose. Patients were taught how to prepare the inhalation device and administer the drug by hospital staff. Study Protocol Before therapy with inhaled iloprost was started, a fiberoptic thermodilution pulmonary artery catheter was used to measure central venous pressure, pulmonary artery pressure, pulmonary artery wedge pressure, cardiac output, and central venous oxygen saturation (Svo2); a femoral artery catheter was used to measure systemic arterial pressure and systemic arterial oxygen saturation (Sao 2). The test trial included inhaled nitric oxide, 20 to 40 parts per million, and aerosolized iloprost as described above. Catheter studies were repeated after 3 months of therapy with inhaled iloprost. One patient (patient 17) entered the study 48 hours after start of therapy with intravenous prostacyclin for decompensating right-heart failure. On initiation of therapy with inhaled iloprost, the dose of intravenous prostacyclin was reduced in a stepwise manner from 20 ng/kg of body weight per minute to 0 within 1 week. In this patient, no baseline test with inhaled iloprost and nitric oxide was performed. The time from the diagnosis of clinical instability to the start of therapy was no more than 2 weeks. After hospital discharge, the investigators who performed the baseline measurements saw the patients every 4 weeks. At these visits, lung function tests and blood gas analysis were performed and patients were asked about adverse effects. Between study visits, patients were managed by their own physicians but could call the investigator if any problems occurred. The primary outcome of the study was the change in physical capacity in 3 months, assessed by the distance walked in 6 minutes. In addition, we monitored hemodynamic changes during short-term and long-term therapy with inhaled iloprost and followed patients until death, transplantation, or any other cause of cessation of therapy. Statistical Analysis Data are presented as the mean (SD) unless otherwise noted. The exact Wilcoxon matched-pair signed-rank test was used to assess the acute effects of inhaled iloprost (comparison of mean values before and after inhaled iloprost application) and the changes during 3 months of therapy (comparison of mean values at baseline and at 3 months) in the 12 patients for whom complete hemodynamic measurements at baseline and 3 months were available. Changes were assessed by using the Hodges-Lehmann point estimate, and the corresponding exact 95% CIs were calculated. For the 6-minute walk test, we assigned a value of 0 m to patients who had died in the 3 months from the start of iloprost therapy instead of doing a last-observation-carried-forward analysis. To calculate the Hodges-Lehmann point estimate and the 95% CIs, only the valid pairs were used: that is, patients who could not walk at baseline or at 3 months were excluded from analysis. A P value less than 0.05 was considered statistically significant. Role of the Funding Source The preparation and evaluation of data in this multicenter study was supported by PPH e.V., a German nonprofit patient self-care organization, and by the Deutsche Forschungsgemeinschaft. The conduct and reporting of the trial were not influenced by these organizations. Results Patient Characteristics All patients had clinical instability (Table 1). Seventeen patients had rapid deterioration; 12 had refractory edema, ascites, or pleural effusion; and 4 had commencing organ failure. Underlying disease was primary pulmonary hypertension in 12 patients, pulmonary hypertension associated with the CREST syndrome (calcinosis cutis, the Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia) without pulmonary fibrosis (isolated pulmonary hypertension) in 3 patients, chronic peripheral lung embolism in 2 patients, and lung fibrosis in 2 patients. No patient had taken anorexigens, and none had liver cirrhosis or HIV infection. Table 1. Patient Characteristics at Baseline and 3 Months Concomitant therapy included diuretics and anticoagulant agents in every patient. Seven patients were receiving long-term therapy with calcium antagonists before catheterization and continued to take these agents during therapy with inhaled iloprost. No patient began taking a calcium antagonist along with inhaled iloprost. Only one patient (patient 17) previously received intravenous prostanoids; this patient had received intravenous prostacyclin 48 hours before therapy with inhaled iloprost was started. The mean age of the patients was 39 14 years (Table 1). Patients with the CREST syndrome were, on average, older than those with primary pulmonary hypertension (58 12 years compared with 34 11 years). The physical capacity of the

Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension

Addition of inhaled iloprost to bosentan may have beneficial effects in patients with idiopathic pulmonary arterial hypertension (IPAH). A multicentre, open, randomised, controlled trial was performed to assess the safety and efficacy of inhaled iloprost in patients with IPAH who had already been treated with bosentan. The trial was terminated early after a futility analysis predicted failure with respect to the predetermined sample size. At that time, 40 patients were randomised to receive either bosentan alone (control group) or bosentan plus inhaled iloprost (combination group) for a 12-week period. The primary end-point, change in 6-min walking distance, was not met (mean changes +1 m and -9 m in the control and combination group, respectively). These results may have been skewed by three outliers in the iloprost group who presented with severe clinical worsening. None of the secondary end-points including functional class, peak oxygen uptake, and time to clinical worsening differed significantly between groups. The current study failed to show a positive effect of adding inhaled iloprost to bosentan in idiopathic pulmonary arterial hypertension patients. Further studies involving larger sample sizes and long-term follow-up are needed to determine the efficacy of adding inhaled iloprost to bosentan in patients with idiopathic pulmonary arterial hypertension.

Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: results from the COMPERA registry.

BACKGROUND Originally reported to occur predominantly in younger women, idiopathic pulmonary arterial hypertension (IPAH) is increasingly diagnosed in elderly patients. We aimed to describe the characteristics of such patients and their survival under clinical practice conditions. METHODS Prospective registry in 28 centers in 6 European countries. Demographics, clinical characteristics, hemodynamics, treatment patterns and outcomes of younger (18-65 years) and elderly (>65 years) patients with newly diagnosed IPAH (incident cases only) were compared. RESULTS A total of 587 patients were eligible for analysis. The median (interquartile, [IQR]) age at diagnosis was 71 (16) years. Younger patients (n=209; median age, 54 [16] years) showed a female-to-male ratio of 2.3:1 whereas the gender ratio in elderly patients (n=378; median age, 75 [8] years) was almost even (1.2:1). Combinations of PAH drugs were widely used in both populations, albeit less frequently in older patients. Elderly patients were less likely to reach current treatment targets (6 min walking distance>400 m, functional class I or II). The survival rates 1, 2, and 3 years after the diagnosis of IPAH were lower in elderly patients, even when adjusted for age- and gender-matched survival tables of the general population (p=0.006 by log-rank analysis). CONCLUSIONS In countries with an aging population, IPAH is now frequently diagnosed in elderly patients. Compared to younger patients, elderly patients present with a balanced gender ratio and different clinical features, respond less well to medical therapy and have a higher age-adjusted mortality. Further characterization of these patients is required. CLINICAL TRIALS REGISTRATION NCT01347216.

Safety and efficacy of exercise training in various forms of pulmonary hypertension

The objective of this prospective study was to assess safety and efficacy of exercise training in a large cohort of patients with different forms and World Health Organization (WHO) functional classes of chronic pulmonary hypertension (PH). 183 patients with PH (pulmonary arterial hypertension (PAH), chronic thromboembolic PH and PH due to respiratory or left heart diseases received exercise training in hospital for 3 weeks and continued at home. Adverse events have been monitored during the in-hospital training programme. Efficacy parameters were evaluated at baseline, and after 3 and 15 weeks. After 3 and 15 weeks, patients significantly improved the distance walked in 6 min (6MWD) compared to baseline, scores of quality of life, WHO functional class, peak oxygen consumption, oxygen pulse, heart rate and systolic pulmonary artery pressure at rest and maximal workload. The improvement in 6MWD was similar in patients with different PH forms and functional classes. Even in severely affected patients (WHO functional class IV), exercise training was highly effective. Adverse events, such as respiratory infections, syncope or presyncope, occurred in 13% of patients. Exercise training in PH is an effective but not a completely harmless add-on therapy, even in severely diseased patients, and should be closely monitored.

Differences in CMV-Specific T-Cell Levels and Long-Term Susceptibility to CMV Infection after Kidney, Heart and Lung Transplantation

Patients after kidney, heart and lung transplantation differ in their immunosuppressive drug regimens and in susceptibility to infectious complications with cytomegalovirus (CMV). In this study, CMV‐specific T‐cell responses were characterized in long‐term transplant recipients and associated with the frequency of infectious complications. CMV‐reactive CD4 T cells from 50 healthy controls, 68 renal, 14 heart and 24 lung transplant recipients were flow cytometrically quantified by the induction of cytokines after specific stimulation. Moreover, the immunosuppressive effect of calcineurin inhibitors on specific T‐cell reactivity was quantified in vitro and compared with responses in vivo. Median CMV‐specific T‐cell frequencies in long‐term renal (1.48%; range 0.06–17.26%) and heart transplant recipients (0.90%; 0.13–12.49%) did not differ from controls (1.82%; 0.26–21.00%). In contrast, CMV‐specific T‐cell levels were significantly lower in lung transplant recipients (0.50%; <0.05–4.98%) and showed a significant correlation with the frequency of infectious episodes (r =−0.57, p = 0.005). The differences within the groups were associated with increasing dosages of immunosuppressive drugs, as exemplified for calcineurin inhibitors that dose dependently reduced specific T‐cell reactivity in vitro. In conclusion, monitoring CMV‐specific CD4 T cells may serve as a measure for long‐term disease susceptibility and may contribute to an improved management of CMV complications after lung transplantation.

Effect of Exercise and Respiratory Training on Clinical Progression and Survival in Patients with Severe Chronic Pulmonary Hypertension

Background: Even though specific agents for the treatment of patients with pulmonary hypertension (PH) are available, in PH patients, physical capacity and quality of life (QoL) are often restricted and survival is reduced. Objectives: This study prospectively investigated the long-term effects of respiratory and exercise training in patients with severe chronic PH regarding safety, time to clinical worsening and survival. Methods: Fifty-eight consecutive patients with severe PH on stable disease-targeted medication received exercise and respiratory training in hospital for 3 weeks and continued at home. They were prospectively followed for 24 ± 12 months. Primary endpoints were time to clinical worsening and survival. Adverse events and changes in the 6-min walking test, QoL, WHO functional class and gas exchange were secondary endpoints and were evaluated at baseline and at weeks 3 and 15. Results: All patients tolerated the exercise training well without severe adverse events. In week 15, 6-min walking test results were significantly improved compared to baseline (by 84 ± 49 m, p < 0.001), as well as QoL scores, WHO functional class (from 2.9 ± 0.5 to 2.6 ± 0.6, p < 0.01), peak oxygen consumption (from 12.5 ± 3.0 to 14.6 ± 3.9 ml/min/kg, p < 0.001), heart rate at rest (from 75 ± 12 to 61 ± 18 beats/min, p < 0.001) and maximal workload (from 65 ± 21 to 80 ± 25 W, p < 0.001). Survival at 1 and 2 years was 100 and 95%, respectively. Fifteen events occurred during the follow-up. Conclusion: This study indicates that exercise and respiratory training as add-on to medical treatment may improve exercise capacity and QoL, and that they have a good long-term safety in the described setting.

Riociguat for interstitial lung disease and pulmonary hypertension: a pilot trial

We assessed the safety, tolerability and preliminary efficacy of riociguat, a soluble guanylate cyclase stimulator, in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD). In this open-label, uncontrolled pilot trial, patients received oral riociguat (1.0–2.5 mg three times daily) for 12 weeks (n=22), followed by an ongoing long-term extension (interim analysis at 12 months) in those eligible (n=15). Primary end-points were safety and tolerability. Secondary end-points included haemodynamic changes and 6-min walk distance (6MWD). Overall, 104 adverse events were reported, of which 25 were serious; eight of the latter were considered drug-related. After 12 weeks of therapy, mean cardiac output increased (4.4±1.5 L·min−1 to 5.5±1.8 L·min−1), pulmonary vascular resistance (PVR) decreased (648±207 dyn·s−1·cm−5 to 528±181 dyn·s−1·cm−5) and mean pulmonary artery pressure (mPAP) remained unchanged compared with baseline. Arterial oxygen saturation decreased but mixed-venous oxygen saturation slightly increased. The 6MWD increased from 325±96 m at baseline to 351±111 m after 12 weeks. Riociguat was well tolerated by most patients and improved cardiac output and PVR, but not mPAP. Further studies are necessary to evaluate the safety and efficacy of riociguat in patients with PH-ILD.

Peripheral airway obstruction in primary pulmonary hypertension

Background: As there is controversy about changes in lung function in primary pulmonary hypertension (PPH), lung mechanics were assessed with a focus on expiratory airflow in relation to pulmonary haemodynamics. Methods: A cross sectional study was performed in 64 controls and 171 patients with PPH (117 women) of mean (SD) age 45 (13) years, pulmonary artery pressure (PAPmean) 57 (15) mm Hg, and pulmonary vascular resistance 1371 (644) dyne.s/cm5. Results: Mean (SD) total lung capacity was similar in patients with PPH and controls (98 (12)% predicted v 102 (17)% predicted, mean difference –4 (95% confidence interval (CI) –7.89 to –0.11); residual volume (RV) was increased (118 (24)% predicted v 109 (27)% predicted, mean difference 9 (95% CI 1.86 to 16.14); and vital capacity (VC) was decreased (91 (16)% predicted v 102 (10)% predicted, mean difference –11 (95% CI 15.19 to –6.80). RV/TLC was increased (117 (27)% predicted v 97 (29)% predicted, mean difference 20 (95% CI 12.3 to 27.8)) and correlated with PAPmean (r=0.31, p<0.001). In patients with PAPmean above the median of 56 mm Hg, RV/TLC was further increased (125 (32)% predicted v 111 (22)% predicted, mean difference –14 (95% CI –22.2 to –5.8)). Expiratory flow-volume curves were reduced and curvilinear in patients with PPH. Conclusions: Peripheral airway obstruction is common in PPH and is more pronounced in severe disease. This may contribute to symptoms. Reversibility of bronchodilation and relation to exercise capacity need further evaluation.