[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.

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.

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."

S-adenosylhomocysteine hydrolase activity in human myocardium.

OBJECTIVE: Measurement of S-adenosylhomocysteine (SAH) accumulation in the heart reflects the concentration of free cytosolic adenosine and is thus a sensitive indicator of regional myocardial ischaemia. To evaluate the possibility of applying this method in combination with 11C-SAH positron emission tomography (PET) to patients with ischaemic heart disease the activity of SAH hydrolase in human heart muscle and its regional distribution were studied. METHODS: Myocardium from patients with dilated cardiomyopathy (n = 4), hypertrophic obstructive cardiomyopathy (HOCM, n = 6), and mitral stenosis (n = 3) was analysed. Additional studies were performed in myocardium, isolated cardiomyocytes, and endothelial cells from dog and guinea pig hearts. Enzyme activity in synthetic and hydrolytic direction including kinetic data (Vmax, KM values, pH dependency) was measured in the cytosolic fraction of myocardial tissue and cell extracts, using high performance liquid chromatography and photometric methods, respectively. RESULTS: Rates of SAH synthesis (Vmax) in the left ventricle in dilated cardiomyopathy, mitral stenosis, and HOCM were 0.8 (SEM 0.1), 1.0(0.2), and 1.7(0.1) nmol.min-1.mg-1 protein respectively. KM values for DL-homocysteine, adenosine, and SAH in HOCM were 187, 2.2, and 3.4 microM, respectively. Enzyme activity was homogeneously distributed among right and left atria, right and left ventricles, and septum. Additional studies in homogenated muscle and isolated cardiomyocytes of guinea pig and canine hearts showed activities similar to man. CONCLUSIONS: (1) SAH hydrolase activity in the human heart is quantitatively comparable to that found in other mammals but certain myocardial diseases may go along with changes in SAH hydrolase activity; (2) the kinetic properties, absolute amounts, and homogeneous distribution of the enzyme may permit the non-invasive determination of free adenosine in the human heart by PET.

Transregulation of adenylyl-cyclase-coupled inhibitory receptors in heart failure enhances anti-adrenergic effects on adult rat cardiomyocytes.

OBJECTIVE: In congestive heart failure (CHF), a desensitisation of stimulatory beta-receptors and of adenylyl cyclase in the heart is associated with an increase in inhibitory Gi proteins. To investigate whether the regulation of the Gi-mediated inhibitory side of the adenylyl cyclase system may be of functional importance in the failing myocardium, the contractile response of isolated adult cardiomyocytes to stimulation of inhibitory muscarinic M2 and A1 adenosine receptors was analysed. METHODS: CHF was induced in rats by banding of the ascending aorta and was verified by doubling of lung wet weight. After four weeks, contraction amplitude (delta L) and the velocity (dL/dtmax) of isolated ventricular cardiomyocytes during electrical field stimulation in the presence of 1 mM Ca2+ were measured using video micrometry. RESULTS: Contractile responses of failing cardiomyocytes to 5 mM Ca2+ were unchanged. The response to increasing concentrations of the beta-adrenergic agonist, isoproterenol (0.1-30 nM), and to forskolin (0.1 nM-1 microM) were significantly blunted. When A1 receptors were activated with N6-(R-phenyl-isopropyl)-adenosine (PIA; 0.01-1 microM) in the presence of 3 nM isoproterenol, contractility was unchanged in cells compared with those from sham-operated rats, but delta L was reduced by up to 23% and dL/dtmax by 35% in failing cardiomyocytes (P < 0.01), demonstrating an enhanced inhibitory effect of A1 receptors. The response to the M2 receptor agonist, carbachol (0.01-3 microM), was augmented to a comparable extent (delta L, -22%, dL/dtmax, -39%; P < 0.01). CONCLUSIONS: In CHF, the inotropic responses to beta-receptor-stimulation and to direct stimulation of adenylyl cyclase, but not to Ca2+, are diminished due to desensitisation of the stimulatory side of the adenylyl cyclase signal transduction system. In parallel, the responses to inhibitory receptors are augmented, leading to a pronounced Gi-mediated negative inotropic effect on failing heart muscle cells. Those anti-adrenergic effects could contribute to the contractile dysfunction of the failing heart. Reversal of the sensitisation to inhibitory stimuli might be one of the desirable mechanisms of medical therapy in CHF.

Noninvasive assessment of regional cardiac adenosine using positron emission tomography.

One of the early metabolic changes associated with myocardial ischemia is the breakdown of adenine nucleotides resulting in the enhanced production of adenosine. In order to image regional cardiac adenosine by positron emission tomography (PET) the enzymatic conversion of adenosine into [11C]-S-adenosylhomocysteine ([11C]SAH) was used in the presence of 11C-labeled homocysteine thiolactone (adenosine + [11C] - homocysteine-->[11C] - SAH + H2O). Following production of an experimental coronary constriction in anesthetized dogs carrier added 1-[11C]-D,L-homocysteine thiolactone (5-27 mCi, 30 mg/kg) was infused over 1 min. This intervention, while hemodynamically ineffective, increased the plasma homocysteine concentration from 2.5 to 306 microM, which thereafter declined with a T1/2 of 28 min to 97 microM after 60 min. During the first minutes following infusion of [11C] homocysteine, the radioactivity concentration in the blood pool, the nonischemic and the ischemic myocardium were similar. Between 20 and 60 min, however, the regional radioactivity concentration was highest in the perfusion area of the stenosed vessel: 6.6% compared to 5.2 and 5.2% of the injected dose per 1 I tissue. The elevated radioactivity concentration was strictly confined to the perfusion area of the occluded artery. Using [35S]-L-homocysteine (20 microCi; 30 mg/kg) chromatographic separation of SAH in tissue extracts confirmed that the radioactivity accumulation was due to trapping of adenosine in the cellular SAH-pool. These experiments provide first evidence that 1-[11C]homocysteine thiolactone can be successfully used to assess regional adenosine formation in the heart with PET via measurement of [11C] SAH accumulation.

Contrast-enhanced doppler ultrasound for noninvasive assessment of pulmonary artery pressure during exercise in patients with chronic congestive heart failure.

Pulmonary artery pressure response to exercise was assessed using contrast enhancement of tricuspid regurgitation peak velocities in 19 patients with chronic congestive heart failure. Estimated systolic pulmonary artery pressures correlated closely with invasively measured pressures at rest (r=0.82, p <0.001) and during peak exercise (r=0.86, p <0.001) at a good level of agreement (mean difference 7.3 +/- 12 mm Hg), indicating that this method provides a reliable, noninvasive approach to evaluating functional reserve in patients with chronic congestive heart failure.

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.

[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.

Adenine nucleotide release from isolated perfused guinea pig hearts and extracellular formation of adenosine.

The quantification of adenine nucleotides released from the heart is hampered by their rapid dephosphorylation to adenosine in the extracellular space catalyzed by highly active ectonucleotidases. To determine the total release of adenine nucleotides from isolated Langendorff-perfused guinea pig hearts, ecto 5'-nucleotidase was effectively blocked by infusion of alpha, beta-methylene-ADP (AOPCP, 50 microM). Adenine nucleotides were measured in the coronary venous effluent by the luciferin-luciferase method after enzymatic rephosphorylation to ATP. In hearts perfused at a constant flow rate (10 ml/min) with normoxic buffer (95% O2, 5% CO2) the release +/- SEM of adenine nucleotides and adenosine was 0.06 +/- 0.01 (n = 11) and 0.04 +/- 0.01 (n = 13) nmol/min. In the presence of AOPCP, the release of adenine nucleotides increased to 0.43 +/- 0.04 nmol/min (n = 9; p less than 0.05), whereas adenosine remained unchanged. Hypoxic perfusion (10% O2, 85% N2, 5% CO2) caused a threefold increase in adenine nucleotide release but a 40-fold increase in adenosine. In contrast, global ischemia (30 seconds) caused adenine nucleotide and adenosine release to rise to similar values of 1.06 +/- 0.10 and 0.80 +/- 0.14 nmol/min (n = 9). Stimulation of hearts with isoproterenol (4 nM) likewise increased the release of adenine nucleotides (0.50 +/- 0.04 nmol/min) and adenosine (0.87 +/- 0.21 nmol/min) (n = 6). To determine the cellular source of adenine nucleotides released from the heart, the coronary endothelial adenine nucleotide pool was selectively prelabeled by [3H]adenosine. Global ischemia increased the specific radioactivity of released adenine nucleotides by 57%. The findings indicate that 1) adenine nucleotides and adenosine are released at the same order of magnitude from the well-oxygenated heart; 2) beta-adrenergic stimulation and ischemia stimulate the release of adenine nucleotides and adenosine, both purines reaching vasoactive concentrations in the effluent perfusate; 3) during hypoxic perfusion only the release of adenosine is greatly enhanced; and 4) the coronary endothelium preferentially contributes to the ischemia-induced adenine nucleotide release.

Repetitive hemodilution in chronic obstructive pulmonary disease and pulmonary hypertension: effects on pulmonary hemodynamics, gas exchange, and exercise capacity.

BACKGROUND: In cor pulmonale associated with severe chronic obstructive pulmonary disease (COPD), disturbances of pulmonary microcirculation may contribute significantly to hypoxemia, pulmonary hypertension, and exercise intolerance. OBJECTIVE: It was tested whether reduction of blood viscosity induced by repetitive hemodilution might improve pulmonary hemodynamics and oxygen uptake. METHODS: Seven patients with stable COPD (forced expiratory volume in 1 s 33 +/- 3 % of predicted, means +/- SE) and pulmonary hypertension were phlebotomized 5-6 times over a period of 3 months with substitution of 6% hydroxyethyl starch (molecular weight 40, 000). This resulted in a stepwise reduction of the hematocrit from 53.3 +/- 2.6 to 45.8 +/- 3.1% and a reduction of whole blood viscosity from 9.8 +/- 0.6 to 8.8 +/- 0.7 mPa x s at a shear rate of 2.0 s-1. Before and after the treatment period, patients underwent cardiopulmonary exercise testing and right heart catheterization. RESULTS: Mean pulmonary artery pressure (PAm) decreased from 30 +/- 3 to 22 +/- 2 mm Hg and arterial oxygen partial pressure (PaO2) increased from 63.2 +/- 2.2 to 71.8 +/- 3.7 mm Hg at rest. During peak exercise, PAm decreased from 59 +/- 7 to 53 +/- 7 mm Hg and PaO2 increased from 54.0 +/- 5.7 to 63.2 +/- 2.4 mm Hg after hemodilution. Peak oxygen consumption rose from 573 +/- 84 to 750 +/- 59 ml x min-1, corresponding to an increase in cardiac index from 4.25 +/- 0.5 to 5.88 +/- 0.76 liters x min-1 x m-2. Pulmonary vascular resistance fell from 345 +/- 53 to 194 +/- 32 dyn x s x cm-5. The patients' peak exercise capacity increased from 9.2 +/- 2. 0 before to 13.5 +/- 3.2 kJ at the end of the study (p < 0.05 for all differences, paired t test). CONCLUSION: The findings suggest that a prolonged improvement of pulmonary microcirculation by reducing blood viscosity may improve pulmonary gas exchange, central hemodynamics, and exercise tolerance in patients with severe COPD and pulmonary hypertension.