Hans-Jürgen Seyfarth

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.

Bosentan therapy for portopulmonary hypertension

The dual endothelin receptor antagonist bosentan has been approved in several countries for pulmonary arterial hypertension, and patients with portopulmonary hypertension (PPHTN) have not specifically been excluded. However, no data have been published on the efficacy and safety of bosentan in this patient population. Here, the first clinical experiences with bosentan in patients with Child A cirrhosis and severe PPHTN are reported. In total, 11 consecutive patients with cirrhosis and severe PPHTN in New York Heart Association Functional Classes III and IV were treated for >1 yr with bosentan. After 1 yr of treatment with bosentan, all patients showed improved symptoms and exercise capacity. The 6-min walking distance increased from 310±102 m at baseline to 388±81 m at 1 yr. Cardiopulmonary exercise testing disclosed a significant increase in peak oxygen uptake, from 12.6±3.5 to 16.6±2.8 mL·min−1·kg−1. Pulmonary vascular resistance fell from 944±519 to 635±321 dynes·s·L−1. The medication was well tolerated by all patients, and there was no evidence of drug-related liver injury. In conclusion, bosentan proved to be efficacious and safe in a small number of patients with portopulmonary hypertension.

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.

Exhaled breath condensate acidification in acute lung injury

Lung injury in ventilated lungs may occur due to local or systemic disease and is usually caused by or accompanied by inflammatory processes. Recently, acidification of exhaled breath condensate pH (EBC-pH) has been suggested as marker of inflammation in airway disease. We investigated pH, ammonia, Lactate, pCO2, HCO3-, IL-6 and IL-8 in EBC of 35 ventilated patients (AECC-classification: ARDS: 15, ALI: 12, no lung injury: 8). EBC-pH was decreased in ventilated patients compared to volunteers (5.85 +/- 0.32 vs. 7.46 +/- 0.48; P < 0.0001). NH4+, lactate, HCO3-, pCO2, IL-6 and IL-8 were analyzed in EBC and correlated with EBC-pH. We observed correlations of EBC-pH with markers of local (EBC IL-6: r = -0.71, P < 0.0001, EBC IL-8: r = -0.68, P < 0.0001) but not of systemic inflammation (serum IL-6, serum IL-8) and with indices of severity of lung injury (Murrays Lung Injury Severity Score; r = -0.73, P < 0.0001, paO2/FiO2; r = 0.54, P < 0.001). Among factors potentially contributing to pH of EBC, EBC-lactate and EBC-NH4+ were found to correlate with EBC-pH. Inflammation-induced disturbances of regulatory mechanisms, such as glutaminase systems may result in EBC acidification. EBC-pH is suggested to represent a marker of acute lung injury caused by or accompanied by pulmonary inflammation.

Assessment and Prognostic Relevance of Right Ventricular Contractile Reserve in Patients With Severe Pulmonary Hypertension

Background— This study sought to analyze a new approach to assess exercise-induced pulmonary artery systolic pressure (PASP) increase by means of stress Doppler echocardiography as a possible measure of right ventricular contractile reserve in patients with severe pulmonary hypertension and right heart failure. Methods and Results— In this prospective study, patients with invasively diagnosed pulmonary arterial hypertension or inoperable chronic thromboembolic pulmonary hypertension and impaired right ventricular pump function despite a stable targeted pulmonary arterial hypertension medication underwent a broad panel of noninvasive assessments, including stress echocardiography and cardiopulmonary exercise testing. On the basis of the assumption that exercise-induced PASP is a measure of right ventricular contractile reserve, patients were classified into 2 groups according to an exercise-induced PASP increase above or below the median. Patients were followed up for 3.0±1.8 years. Univariate and multivariate analyses were used for factors predicting survival. Of 124 patients, 66 were below the median exercise-induced PASP increase of 30 mm Hg (low PASP), and 58 patients were above the median (high PASP). These groups were not significantly different in terms of medication and resting hemodynamics. Low PASP was associated with a significantly lower 6-minute walking distance, peak O2 per kilogram, and 1-, 3-, and 4-year survival rates (92%, 69%, and 48%, respectively, versus 96%, 92%, and 89%). In the multivariate Cox model analysis adjusted for age and sex, PASP increase during exercise and peak O2 per kilogram remained independent prognostic markers (hazard ratio, 2.56 for peak O2 per kilogram and 2.84 for PASP increase). Conclusions— Exercise-induced PASP increase is of high clinical and prognostic relevance in pulmonary hypertension patients and may indicate right ventricular contractile reserve. Stress Doppler echocardiography may be a useful tool for prognostic assessment in pulmonary hypertension patients.

Chronic thromboembolic pulmonary hypertension (CTEPH): Updated Recommendations of the Cologne Consensus Conference 2011 ✩

In the 2009 European Guidelines on the diagnosis and treatment of pulmonary hypertension (PH), one section covers aspects of pathophysiology, diagnosis and treatment of chronic thromboembolic pulmonary hypertension (CTEPH). The practical implementation of the guidelines for this disease is of crucial importance, because CTEPH is a subset of PH which can potentially be cured by pulmonary endarterectomy (PEA). Nowadays, CTEPH is commonly underdiagnosed and not properly managed. Any patient with unexplained PH should be evaluated for the presence of CTEPH, and a ventilation/perfusion (V/Q) lung scan is recommended as screening method of choice. If the V/Q scan or CT angiography reveals signs of CTEPH, the patient should be referred to a specialized center with expertise in the medical and surgical management of this disease. Every case has to be reviewed by an experienced PEA surgeon for the assessment of operability. In this updated recommendation, important contents of the European guidelines were commented, and more recent information regarding diagnosis and treatment was added.

Long-term outcome with intravenous iloprost in pulmonary arterial hypertension

There is limited data on the long-term efficacy of intravenous iloprost in patients with pulmonary arterial hypertension (PAH). This retrospective multicentre analysis evaluated the clinical course of patients with PAH treated with i.v. iloprost, in most cases after having received inhaled iloprost as first-line therapy. Between 1997 and 2001, 79 PAH patients were treated with i.v. iloprost and followed until 2007. These patients had advanced and progressive disease as indicated by a mean pulmonary vascular resistance of 1,533 dyn·s·cm−5 at the time of diagnosis and of 1,858 dyn·s·cm−5 at the onset of i.v. iloprost therapy. Introduction of i.v. iloprost therapy resulted in initial haemodynamic and clinical improvement. At the end of the observation period, however, 50 (61%) patients had died and 21 (26%) required lung transplantation. Transplantation-free survival rates at 1, 3, and 5 yrs were 86%, 59% and 45%, respectively, after the diagnosis of PAH, and 54%, 31% and 15%, respectively, after the introduction of i.v. iloprost therapy. Predictors of an adverse outcome at baseline were a low 6-min walk distance and a low mixed venous oxygen saturation. In conclusion, despite initial haemodynamic and clinical improvement, overall long-term survival with i.v. iloprost therapy was limited.

Effects of nasal high flow on ventilation in volunteers, COPD and idiopathic pulmonary fibrosis patients.

Background: A high flow of air applied by large bore nasal cannulae has been suggested to improve symptoms of chronic respiratory insufficiency. In pediatric patients, nasal high-flow (nHF) ventilation was similarly effective compared to noninvasive ventilation with a face mask. Objectives: The aim of this study was to describe changes in respiratory parameters. Methods: We measured pressure amplitudes during the respiratory cycle and mean pressures in patients with idiopathic pulmonary fibrosis (IPF) and COPD. In order to achieve tidal volume and minute volume measurements, we used a polysomnography device. Capillary blood was taken for blood gas analysis before and after nHF breathing (8 h). Results: nHF led to an increase in pressure amplitude and mean pressure in healthy volunteers and in patients with COPD and IPF in comparison with spontaneous breathing. In COPD, nHF increased tidal volume, while no difference in tidal volume was observed in patients with IPF. Interestingly, tidal volume decreased in healthy volunteers. Breathing rates and minute volumes were reduced in all groups. Capillary pCO2 decreased in patients with IPF and COPD. Conclusions: nHF resulted in significant effects on respiratory parameters in patients with obstructive and restrictive pulmonary diseases. The rise in pressure amplitude and mean pressure and the decrease in breathing rate and minute volume will support inspiratory efforts, helps to increase effectiveness of ventilation and will contribute to a reduction in the work of breathing. A CO2 wash-out effect in the upper airway part of the anatomical dead space may contribute to the beneficial effects of the nHF instrument.

Exercise training in pulmonary arterial hypertension associated with connective tissue diseases

IntroductionThe objective of this prospective study was to assess short- and long-term efficacy of exercise training (ET) as add-on to medical therapy in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-APAH).MethodsPatients with invasively confirmed CTD-APAH received ET in-hospital for 3 weeks and continued at home for 12 weeks. Efficacy parameters have been evaluated at baseline and after 15 weeks by blinded-observers. Survival rate has been evaluated in a follow-up period of 2.9 ± 1.9 years.ResultsTwenty-one consecutive patients were included and assessed at baseline, and after 3 weeks, 14 after 15 weeks. Patients significantly improved the mean distance walked in 6 minutes compared to baseline by 67 ± 52 meters after 3 weeks (p < 0.001) and by 71 ± 35 meters after 15 weeks (p = 0.003), scores of quality of life (p < 0.05), heart rate at rest, peak oxygen consumption, oxygen saturation and maximal workload. Systolic pulmonary artery pressure and diastolic systemic blood pressure improved significantly after 3 weeks of ET. The 1- and 2-year overall-survival rates were 100%, the 3-year survival 73%. In one patient lung transplantation was performed 6 months after ET.ConclusionET as add-on to medical therapy is highly effective in patients with CTD-APAH to improve work capacity, quality of life and further prognostic relevant parameters and possibly improves the 1-, 2- and 3-year survival rate. Further randomized controlled studies are needed to confirm these results.Trial registrationClinicalTrials.gov: NCT00491309.

Exercise training improves peak oxygen consumption and haemodynamics in patients with severe pulmonary arterial hypertension and inoperable chronic thrombo-embolic pulmonary hypertension: a prospective, randomized, controlled trial.

Abstract Aims The impact of exercise training on the right heart and pulmonary circulation has not yet been invasively assessed in patients with pulmonary hypertension (PH) and right heart failure. This prospective randomized controlled study investigates the effects of exercise training on peak VO2/kg, haemodynamics, and further clinically relevant parameters in PH patients. Methods and results Eighty-seven patients with pulmonary arterial hypertension and inoperable chronic thrombo-embolic PH (54% female, 56 ± 15 years, 84% World Health Organization functional class III/IV, 53% combination therapy) on stable disease-targeted medication were randomly assigned to a control and training group. Medication remained unchanged during the study period. Non-invasive assessments and right heart catheterization at rest and during exercise were performed at baseline and after 15 weeks. Primary endpoint was the change in peak VO2/kg. Secondary endpoints included changes in haemodynamics. For missing data, multiple imputation and responder analyses were performed. The study results showed a significant improvement of peak VO2/kg in the training group (difference from baseline to 15 weeks: training +3.1 ± 2.7 mL/min/kg equals +24.3% vs. control −0.2 ± 2.3 mL/min/kg equals +0.9%, P < 0.001). Cardiac index (CI) at rest and during exercise, mean pulmonary arterial pressure, pulmonary vascular resistance, 6 min walking distance, quality of life, and exercise capacity significantly improved by exercise training. Conclusion Low-dose exercise training at 4–7 days/week significantly improved peak VO2/kg, haemodynamics, and further clinically relevant parameters. The improvements of CI at rest and during exercise indicate that exercise training may improve the right ventricular function. Further, large multicentre trials are necessary to confirm these results.