Influence of the incremental step size in work rate on exercise response and gas exchange in patients with pulmonary hypertension.

BACKGROUND: Cardiopulmonary exercise testing (CPET) has become increasingly important as a routine procedure in daily clinical work. So far, it is generally accepted that an individualized exercise protocol with exercise duration of 6 to 12 minutes is preferable to assess maximal exercise performance. The aim of this study was to compare an individualized NYHA adapted exercise protocol with a fixed standard protocol in patients with severe pulmonary arterial hypertension. METHODS: Twenty-two patients (17 female, 5 male; mean age 49 +/- 14 yrs) underwent symptom limited CPET on a bicycle. On two consecutive days each subject performed a stepwise CPET according to a modified Jones protocol (16 Watt per minute stages) as well as an individualized NYHA adapted protocol with 5 or 10 Watt/min stages in a randomized order. Oxygen uptake at peak exercise (peakVO2) and anaerobic threshold (VO2AT), maximal ventilation (VE), breathing reserve (VE/MVV), ventilatory efficiency (VE vs. VCO2 slope), exercise time, maximal power and work rate were assessed and compared between both protocols. RESULTS: Comparing both, adapted NYHA protocol and standardized Jones protocol, we found significant differences in maximal power (56.7 +/- 19 W vs. 74 +/- 18 W; p < 0.001) and exercise time (332 +/- 107 sec. vs. 248 +/- 72 sec.; p < 0.001). In contrast, no significant differences were obvious comparing both protocols concerning work rate, VE, VE/MVV, peakVO2, VO2AT and VE vs. VCO2 slope. CONCLUSION: Variations of incremental step size during CPET significantly affect exercise time and maximal power, whereas relevant parameters for clinical judgement and prognosis such as oxygen uptake, ventilation and ventilatory efficiency remain unchanged. These findings have practical implications for the exercise evaluation of patients with pulmonary hypertension. To reach maximal results for ventilation, oxygen uptake and gas exchange an individualization of incremental step size appears not to be mandatory.

Impaired peripheral endothelial function in severe idiopathic pulmonary hypertension correlates with the pulmonary vascular response to inhaled iloprost.

BACKGROUND: Pulmonary endothelial function is known to be impaired in subjects with idiopathic pulmonary arterial hypertension (IPAH), but peripheral endothelial dysfunction and its predictive value for pulmonary vasoreactivity have not been previously investigated. METHODS: Measurements of peripheral endothelium-dependent and endothelium-independent vasoreactivity using flow-mediated dilation (FMD) and nitroglycerin-mediated dilation of the brachial artery were performed in 18 patients with severe IPAH (15 women; mean age 50 years [95% confidence interval 46-55 years], mean pulmonary artery pressure [PAP] 51 mm Hg [43-59 mm Hg], pulmonary vascular resistance [PVR] 1239 dyn s cm(-5) [861-1618 dyn s cm(-5)] at baseline) and in 36 age- and sex-matched controls. In patients with IPAH, acute pulmonary vasoreactivity was measured as pulmonary vascular response to inhaled iloprost (PVRII) during pulmonary catheterization. RESULTS: Compared to controls, patients with IPAH demonstrated impaired peripheral endothelial function (FMD, 0.19 [0.07-0.31] vs 0.38 [0.30-0.44] mm among controls; P =.002). No such impairment was observed for nitroglycerin-mediated dilation (0.34 [0.23-0.46] vs 0.36 [0.20-0.51] mm among controls; P = .679). Among patients with IPAH, iloprost lowered mean PAP by 8.2 mm Hg (2.0-14.5 mm Hg) (P = .001) and PVR by 395 dyn s cm(-5) (109-680 dyn s cm(-5)) (P < .001). Subsequent analysis of the association between peripheral endothelial function and PVRII disclosed a correlation of FMD with the percent decrease in mean PAP (r = .65, P = .003) and PVR (r = 0.67, P = .002), in which patients with IPAH with the greatest PVRII also exhibited the highest FMD values. CONCLUSIONS: Idiopathic pulmonary arterial hypertension is associated with peripheral endothelial dysfunction. Peripheral endothelium-dependent vasoreactivity correlates with the PVRII. It remains to be established if FMD has the potential as a clinical tool for noninvasive estimation of pulmonary vasoreactivity in IPAH.

[Assessment of cardiopulmonary function at rest and during exercise in patients with pulmonary hypertension]. / Beurteilung der kardiopulmonalen Funktion und Belastungstests bei Patienten mit pulmonaler Hypertonie.

Pulmonary hypertension is diagnosed by various investigations that are essential for making the diagnosis. Following a careful history and physical examination, an electrocardiogram, a chest X-ray, lung function studies, blood tests and an echocardiogram form the basis of the diagnostic algorithm. Following these studies, a right and sometimes additional left heart catheterization are carried out to establish the diagnosis and to perform acute vasodilator testing. Most of these studies are performed at rest. However, exercise studies are an important part of the functional assessment in this group of patients. Exercise capacity can be estimated by functional class, measured with the 6-min walk test or comprehensively assessed by cardiopulmonary exercise testing with gas exchange analysis. Once the diagnosis and etiology of pulmonary hypertension have been established, several parameters can predict outcome in these patients: functional class, right ventricular function, pulmonary hemodynamics, and certain laboratory parameters (uric acid, brain natriuretic peptide, troponin, endothelin-1). In addition, exercise parameters such as walking distance, peak oxygen uptake or peak systolic blood pressure can reliably predict prognosis in these patients.

Treatment of malignant pleural effusion with the trifunctional antibody catumaxomab (Removab) (anti-EpCAM x Anti-CD3): results of a phase 1/2 study.

Catumaxomab is a trifunctional monoclonal antibody consisting of a mouse immunoglobulin G2a part and a rat immunoglobulin G2b part with 2 different antigen binding sites binding the epithelial cell adhesion molecule antigen on tumor cells and CD3 on T lymphocytes. The intact Fc region provides a third functional binding site, binding and activating selectively Fcgamma receptor I, IIa, and III-positive accessory cells. These binding properties lead to specific tumor cell killing. As catumaxomab demonstrated efficacy in patients with malignant ascites, we performed this phase 1/2 trial in patients with malignant pleural effusion (MPE). We investigated a series of 3 escalating doses of 5 to 200 microg catumaxomab administered intrapleurally to patients with MPE containing epithelial cell adhesion molecule -positive cells. Primary objectives were determination of dose-limiting toxicity, safety, and tolerability. Secondary objectives were efficacy and pharmacodynamics. Twenty-four patients were treated with catumaxomab. Most frequent adverse events were pyrexia, elevated liver enzymes, nausea, and decreased lymphocytes. Dose-limiting toxicities were observed in 2 patients: One had pleural empyema and fatal sepsis and 1 had grade 3 erythema and hepatobiliary disorder. Five patients with breast cancer out of 7 evaluable patients had a response to treatment. Intrapleural administration of catumaxomab is feasible although the substantial number of drop-outs and deaths in short proximity to study treatment raise questions whether MPE is the right indication for catumaxomab or whether the patient population should be defined different. Safety profile was as expected reflecting catumaxomab's mode of action. Preliminary efficacy showed a suggestion of improvement in some patients.

Effect of inhaled iloprost during off-medication time in patients with pulmonary arterial hypertension.

BACKGROUND: Iloprost is a stable prostacyclin analogue that is associated with a longer duration of vasodilatation and has been approved for inhalative use with 6 or 9 inhalations during the daytime and a night pause. It is not known if during the night pause rebound pulmonary hypertension occurs. The aim of this study was to assess the hemodynamics in iloprost-treated patients during the daytime and at night. METHODS: We enrolled 5 adult patients (aged 45 +/- 10 years) with idiopathic pulmonary arterial hypertension (IPAH) and chronic inhaled iloprost therapy for at least 12 months. Further medication remained unchanged during the study period. Hemodynamics were monitored by right heart catheterization. RESULTS: After 30-60 min of nebulized iloprost, mean pulmonary arterial pressures (PAP) decreased from 68 +/- 15 to 51 +/- 18 mm Hg (p = 0.004). After 6 h off-medication sleeping time, mean PAP initially increased until 2 a.m. and decreased subsequently until wake-up time at 6 a.m. Mean PAP, cardiac index and pulmonary vascular resistance at night were not significantly different from the values during the day. CONCLUSIONS: In this study, patients with IPAH and chronic nebulized iloprost therapy did not reveal a rebound pulmonary hypertension during off-medication sleeping time.