[Exercise Testing in Respiratory Medicine - DGP Recommendations]. / Belastungsuntersuchungen in der Pneumologie ­ Empfehlungen der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin e. V.

This document replaces the DGP recommendations published in 1998 and 2013. Based on recent studies and a consensus conference, the indications, choice and performance of the adequate exercise testing method and its necessary technical and staffing setting are discussed. Detailed recommendations are provided: for blood gas analysis and right heart catheterization during exercise, walk tests, spiroergometry, and stress echocardiography. The correct use of different exercise tests is discussed for specific situations in respiratory medicine: exercise induced asthma, obesity, monitoring of rehabilitation or therapeutical interventions, preoperative risk stratification, and evaluation in occupational medicine.

[Exercise testing in respiratory medicine]. / Belastungsuntersuchungen in der Pneumologie.

This document replaces the DGP recommendations published in 1998. Based on recent studies and a consensus conference, the indications, choice and performance of the adequate exercise testing method in its necessary technical and staffing setting are discussed. Detailed recommendations are provided: for arterial blood gas analysis and right heart catherterization during exercise, 6-minute walk test, spiroergometry, and stress echocardiography. The correct use of different exercise tests is discussed for specific situations in respiratory medicine: exercise induced asthma, monitoring of physical training or therapeutical interventions, preoperative risk stratification, and evaluation in occupational medicine.

[Pulmonary hypertension: hemodynamic evaluation: hemodynamic evaluation ­ recommendations of the Cologne Consensus Conference 2010]. / Pulmonale Hypertonie: invasive Diagnostik: Empfehlungen der Kölner Konsensus-Konferenz 2010.

The 2009 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension (PH) have been adopted for Germany. Invasive hemodynamic data obtained by right heart catheterization are essential to confirm the diagnosis, test vasoreactivity, assess severity and guide therapy in PH patients. The definition of PH is resting on a mean pulmonary artery pressure ≥ 25 mm Hg obtained by right heart catheterization. Furthermore, a pulmonary capillary wedge pressure > 15 mm Hg excludes pre-capillary PH. Vasoreactivity testing is part of the diagnostic work-up in pulmonary arterial hypertension. Recent data on the use of inhaled iloprost update these guidelines and are of special importance due to the frequent diagnostic use of iloprost in Germany. Other aspects of invasive hemodynamic data in certain PH subgroups as well as their measurement and interpretation in children are discussed. Several aspects of right heart catheterization in PH justify a detailed commentary, and in some areas an update already appears necessary. In June 2010, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Paediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups were initiated, one of which was specifically addressing the invasive hemodynamic evaluation of patients with PH. This commentary summarizes the results and recommendations of this working group.

[Pulmonary hypertension and right ventricular failure in critical care medicine]. / Pulmonale Hypertonie und Rechtsherzversagen auf der Intensivstation.

The management of pulmonary hypertension and right ventricular failure in hemodynamically unstable patients is one of the most challenging situations in critical care medicine. Inadequate therapy, e.g. aggressive fluid resuscitation or invasive ventilation, may even harm patients with pulmonary hypertension. Identifying the underlying etiology therefore remains the primary focus for initiating successful management of patients with decompensated pulmonary hypertension and right ventricular failure. Pulmonary embolism requires immediate restoration of pulmonary vascular patency. The body of evidence from studies is scarce and favors dobutamine, NO inhalation, and intravenous prostacyclin. However, the use of other vasoactive substances, inotropes, and supportive measures has been successful in individual patients; it should be guided by the expected effects on the pulmonary vasculature or right ventricle, and should be adapted to the patient's concomitant diseases.

[A role for combination therapy in pulmonary arterial hypertension]. / Kombinationstherapie der Pulmonal-Arteriellen Hypertonie (PAH) -- Ergebnisse eines Experten-Workshops.

For patients with pulmonary arterial hypertension (PAH) two first line therapies - iloprost inhalation (Ventavis) and bosentan (Tracleer) -- are available in Germany. A third substance, sildenafil, is already approved in the US and will be approved for this indication in the European Union soon. Patients with PAH can be stabilized or improved with a specific mono-therapy for a limited period of time only. Therefore, the question arises when and how to initiate treatment escalation. The available data from controlled clinical trials are insufficient to give a definite answer to these questions. Moreover, it is still unclear which combination of the above mentioned substances may be superior in the treatment of PAH. On the other hand, combination therapy is already reality in clinical practice. Based on this background experts from specialized centers dealing with PAH discussed the scientific basis of the role of combination therapy in PAH patients during a workshop held on April 22/23. 2005 in Wiesbaden. The goal of this workshop was to formulate a common position with regard to combination therapy of PAH on the basis of the available scientific data and clinical experience.

Respiratory muscle dysfunction in idiopathic pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (IPAH) is a pulmonary vasculopathy of unknown aetiology. Dyspnoea, peripheral airway obstruction and inefficient ventilation are common in IPAH. Data on respiratory muscle function are lacking. This prospective single-centre study included 26 female and 11 male patients with IPAH in World Health Organization functional classes II-IV. Mean+/-SD pulmonary artery pressure was 48.6+/-16.9 in females and 53.1+/-22.9 mmHg in males; cardiac output was 3.7+/-1.3 and 4.2+/-1.7 L x min(-1). Maximal inspiratory pressure (PI,max) was lower in the female patients than in 20 controls (5.3+/-2.0 versus 8.2+/-2.0 kPa). In the male patients, PI,max was lower than in 25 controls (6.8+/-2.2 versus 10.5+/-3.7 kPa). Maximal expiratory pressure (PE,max) was lower in the female patients than in controls (6.2+/-2.6 versus 9.5+/-2.1 kPa), and in male patients as compared to controls (7.1+/-1.6 versus 10.3+/-3.9 kPa). There was no correlation between PI,max or PE,max and parameters of pulmonary haemodynamics or exercise testing. The ratio of mouth occlusion pressure within the first 0.1 s of inspiration and PI,max was higher in IPAH than in controls (females 0.067+/-0.066 versus 0.021+/-0.008; males 0.047+/-0.061 versus 0.023+/-0.016). In conclusion, this study provides the first evidence of inspiratory and expiratory muscle weakness in idiopathic pulmonary arterial hypertension. The pathomechanisms and the prognostic significance should be further investigated.

Pathophysiological aspects of cardiopulmonary interaction.

The close interaction between heart and lungs has pathophysiological and clinical implications both in cardiac and pulmonary diseases. Some aspects of ventriculo-ventricular relations are illustrated using examples of left heart failure and right heart failure or cor pulmonale. This interaction is mediated either by pulmonary vasculature or directly through interventricular septum. Furthermore, effects of chronic congestive heart failure on pulmonary function and their clinical consequences are discussed.

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/cm(5). 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.

Respiratory muscle dysfunction in congestive heart failure: clinical correlation and prognostic significance.

BACKGROUND: In congestive heart failure (CHF), the prognostic significance of impaired respiratory muscle strength has not been established. METHODS AND RESULTS: Maximal inspiratory pressure (Pi(max)) was prospectively determined in 244 consecutive patients (207 men) with CHF (ischemic, n=75; idiopathic dilated cardiomyopathy, n=169; age, 54+/-11 years; left ventricular ejection fraction [LVEF], 22+/-10%). Pi(max) was lower in the 244 patients with CHF than in 25 control subjects (7.6+/-3.3 versus 10.5+/-3.7 kPa; P=0.001). The 57 patients (23%) who died during follow-up (23+/-16 months; range, 1 to 48 months) had an even more reduced Pi(max) (6.3+/-3.2 versus 8.1+/-3.2 kPa in survivors; P=0.001). Kaplan-Meier survival curves differentiated between patients subdivided according to quartiles for Pi(max) (P=0.014). Pi(max) was a strong risk predictor in both univariate (P=0.001) and multivariate Cox proportional hazard analyses (P=0.03); multivariate analyses also included NYHA functional class, LVEF, peak oxygen consumption (peak VO(2)), and norepinephrine plasma concentration. The areas under the receiver-operating characteristic curves for prediction of 1-year survival were comparable for Pi(max) and peak VO(2) (area under the curve [AUC], 0.68 versus 0.73; P=0.28), and they improved with the triple combination of Pi(max), peak VO(2), and LVEF (AUC, 0.82; P=0.004 compared with AUC of Pi(max)). CONCLUSIONS: In patients with CHF, inspiratory muscle strength is reduced and emerges as a novel, independent predictor of prognosis. Because testing for Pi(max) is simple in clinical practice, it might serve as an additional factor to improve risk stratification and patient selection for cardiac transplantation.

The neuronal norepinephrine transporter in experimental heart failure: evidence for a posttranscriptional downregulation.

An impairment of norepinephrine (NE) re-uptake by the neuronal NE transporter (NET) has been shown to contribute to the increased cardiac net-release of NE in congestive heart failure (CHF). The present study investigated which mechanisms are involved in the impairment of NET. Rats with supracoronary aortic banding characterized by myocardial hypertrophy, elevated left ventricular end diastolic pressures and severe pulmonary congestion were used as an experimental model for CHF. Compared to sham-operated controls, aortic-banded rats had enhanced plasma NE concentrations and decreased cardiac NE stores. In isolated perfused hearts of aortic-banded rats, functional impairment of NET was indicated by a 37% reduction in [(3)H]-NE-uptake. In addition, pharmacological blockade of NET with desipramine led to a markedly attenuated increase in the overflow of endogenous NE from hearts of aortic-banded rats. Determination of cardiac NET protein and of NET mRNA in the left stellate ganglion by [(3)H]-desipramine binding and competitive RT-PCR, respectively, revealed a 41% reduction of binding sites but no difference in gene expression. The density of sympathetic nerve fibers within the heart was unchanged, as shown by glyoxylic acid-induced histofluorescence. In conclusion, as impairment of intracardiac NE re-uptake by a reduction of NET binding sites is neither mediated by a decreased NET gene expression nor by a loss of noradrenergic nerve terminals, a posttranscriptional downregulation of NET per neuron is suggested in CHF.

Inefficient ventilation and reduced respiratory muscle capacity in congestive heart failure.

The extent and time-course of changes in lung volumes, ventilatory efficiency at rest and during exercise, and respiratory muscle function and their influence on exercise limitation in congestive heart failure (CHF) are unclear. It is unknown whether respiratory muscle function may predict changes in exercise limitation or may be impaired in patients with poor outcome. 145 male patients (54 +/- 1 years) suffering from CHF (NYHA class I-III, mean 2.3 +/- 0.1), with a LVEF of 23 +/- 1%, and a mean peak O2 uptake (VO2peak) 15.0 +/- 0.5 mL X min(-1) X kg(-1), were studied. They were grouped in Weber functional classes A to D according to their VO2peak. Significant increases in ventilatory equivalents for O2 and CO2 (VE/VCO2peak) and in dead space ventilation at rest and during exercise were found with increasing exercise limitation. Moreover, there was a correlation of static and dynamic lung volumes (inspiratory vital capacity, IVC, r = 0.43, P < 0.01), as well as of maximal inspiratory pressure (MIP; r = 0.46, P < 0.01) with VO2peak. Patients who died (n = 26) or were heart transplanted (n = 20) during a follow-up (mean 800 +/- 10 days) had a reduced MIP (6.4 +/- 0.4 kPa) as compared with survivors (n = 82; 9.3 +/- 0.7 kPa, P < 0.01). In a subgroup of 33 patients re-evaluated after six months, individual changes in IVC and VE/CO2peak, but not in MIP, correlated to changes in VO2peak (r = 0.69 and r = 0.72 respectively; P < 0.01). In CHF, exercise limitation is associated with reversible lung restriction and inefficient ventilation at rest and during exercise. Patients with severe CHF have a significant reduction in MIP, a finding that is associated with poor outcome.

Abnormal pulmonary artery pressure response in asymptomatic carriers of primary pulmonary hypertension gene.

BACKGROUND: Familial primary pulmonary hypertension (PPH) is an autosomal-dominant inherited disease with incomplete penetrance and poor prognosis. This study was performed to examine whether asymptomatic carriers of a mutated PPH gene can be identified at an early stage by their pulmonary artery systolic pressure (PASP) response to exercise. METHODS AND RESULTS: Stress Doppler echocardiography during supine bicycle exercise and genetic linkage analysis were performed on 52 members of 2 families with PPH. In 4 PPH patients, the mean PASP was increased at rest (73+/-16 mm Hg). Fourteen additional family members with normal PASP at rest revealed an abnormal PASP response to exercise (from 23+/-4 to 56+/-11 mm Hg) without secondary cause (abnormal response [AR] group). Twenty-seven other members (NR group) revealed a normal PASP response (maximal pressure <40 mm Hg) to exercise (from 24+/-4 to 37+/-3 mm Hg, P<0. 0001). All 14 AR but only 2 NR members shared the risk haplotype with the PPH patients. The molecular genetic analysis supported linkage to chromosome 2q31-32 with a logarithm of the odds score of 4.4 when the 4 patients and the 14 AR members were classified as affected. CONCLUSIONS: We conclude that the pathological rise of PASP in asymptomatic family members is linked to chromosome 2q31-32 and is probably an early sign of PPH. Therefore, stress Doppler echocardiography may be a useful tool to identify persons at risk for PPH even before pulmonary artery pressures at rest are elevated.

A comparison of the acute hemodynamic effects of inhaled nitric oxide and aerosolized iloprost in primary pulmonary hypertension. German PPH study group.

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.

Desensitization of the pulmonary adenylyl cyclase system: a cause of airway hyperresponsiveness in congestive heart failure?

OBJECTIVES: This study was designed to investigate whether the adrenergic signal transduction in the lung and the responsiveness of airway smooth muscle to adrenergic stimulation are modulated in congestive heart failure. BACKGROUND: Wheezing and airway hyperresponsiveness are often present in heart failure. In the failing heart, chronic adrenergic stimulation down-regulates beta-adrenergic receptors and adenylyl cyclase. We hypothesized that airway dysfunction in heart failure could be due to a similar modulation of pulmonary adrenergic signal transduction. METHODS: Heart failure was induced in rats by aortic banding, resulting in increases in plasma norepinephrine, lung wet weight indicating congestion and left ventricular end diastolic pressure after four weeks. Beta-receptor densities in pulmonary plasma membranes were measured by radioligand binding using [125I]iodocyanopindolol. The G protein levels were determined by Western blot. Adenylyl cyclase activities in lung membranes were quantified as [32P]cAMP (cyclic adenosine-5'-monophosphate) synthesis rate. To functionally assess airway smooth muscle relaxation, carbachol-precontracted isolated tracheal strips were used. RESULTS: Beta-receptor density was significantly decreased in heart failure from 771 +/- 89 to 539 +/- 44 fmol/mg protein without changes in receptor affinities. The beta1-/beta2-subtype ratio, however, remained constant. The G(i and alpha) and G(s alpha) protein expression was unchanged. Adenylyl cyclase activity stimulated directly with forskolin was decreased by 28%. Relaxation of tracheal strips in response to isoproterenol and forskolin, but not to papaverin, was diminished by 30%. CONCLUSIONS: In heart failure, the down-regulation of pulmonary beta-receptors and concomitant decrease in adenylyl cyclase activity result in a significant attenuation of cAMP-mediated airway relaxation. These mechanisms may play a pivotal role in the pathogenesis of"cardiac asthma."