P.N.R. Dekhuijzen

Levosimendan Enhances Force Generation of Diaphragm Muscle from Patients with Chronic Obstructive Pulmonary Disease

RATIONALEnLevosimendan is clinically used to improve myocardial contractility by enhancing calcium sensitivity of force generation. The effects of levosimendan on skeletal muscle contractility are unknown. Patients with chronic obstructive pulmonary disease (COPD) suffer from diaphragm weakness, which is associated with decreased calcium sensitivity.nnnOBJECTIVESnTo investigate the effects of levosimendan on contractility of diaphragm fibers from patients with COPD.nnnMETHODSnMuscle fibers were isolated from diaphragm biopsies obtained from thoracotomized patients with and without COPD (both groups n = 5, 10 fibers per patient). Diaphragm fibers were skinned and activated with solutions containing incremental calcium concentrations and 10 microM levosimendan or vehicle (0.02% dimethyl sulfoxide). Developed force was measured at each step and force versus calcium concentration relationships were derived. Results were grouped per myosin heavy chain isoform, which was determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE).nnnMEASUREMENTS AND MAIN RESULTSnAt sub-maximal activation levosimendan improved force generation of COPD and non-COPD diaphragm fibers by approximately 25%, both in slow and fast fibers. Levosimendan increased calcium sensitivity of force generation (P < 0.01) in both slow and fast diaphragm fibers from patients with and without COPD, without affecting maximal force generation.nnnCONCLUSIONSnLevosimendan enhances force generating capacity of diaphragm fibers from patients with and without COPD patients by increasing calcium sensitivity of force generation. These results provide a strong rationale for testing the effect of calcium sensitizers on respiratory muscle dysfunction in patients with COPD.

Systemic Immunological Response to Exercise in Patients with Chronic Obstructive Pulmonary Disease: What Does It Mean?

Chronic obstructive pulmonary disease (COPD) is no longer seen as a pulmonary disease, but is increasingly associated with systemic effects with important clinical relevance. Systemic immunological changes in COPD patients are characterized by an increased number of circulating inflammatory cells, functional changes of the inflammatory cells, elevated plasma levels of cytokines, and oxidative stress. Physical exercise induces an abnormal systemic inflammatory and oxidative response in COPD patients, which is seen in both the circulation and the peripheral muscles. Although mechanisms and consequences of these effects are not yet fully understood, they could be harmful in COPD patients by inducing damage or functional changes in, for example, skeletal muscles. Whether these changes of the immune system can also affect the susceptibility to infections in these patients is unknown. The concept of COPD as a systemic rather than only a pulmonary disease also opens new perspectives on the development for new therapeutic interventions. The effects of new antioxidative and anti-inflammatory agents are investigated. A better understanding of the complexity of the systemic effects will aid the development of new therapies and management strategies for patients with COPD.

Pursed-Lips Breathing Improves Inspiratory Capacity in Chronic Obstructive Pulmonary Disease

Background: In patients with severe chronic obstructive pulmonary disease (COPD), pursed-lips breathing (PLB) improves the pulmonary gas exchange and hyperinflation measured by electro-optic coupling. The response to PLB in inspiratory lung function tests is not known. Objectives: The purpose of this study was to measure the effect of PLB on inspiratory parameters. Methods: Thirty-five subjects with stable COPD and a forced expiratory volume in first second (FEV1) <50% of the predicted value were tested for the following primary parameters before and immediately after PLB, and 5 min later: forced inspiratory vital capacity, inspiratory capacity (IC), forced inspiratory volume in first second, maximal inspiratory flow at 50% of vital capacity, and peak inspiratory flow. Patients were also tested for the following secondary parameters: vital capacity, FEV1, breathing frequency, end-tidal CO2 tension, and oxygen saturation. Results: Of all the primary parameters only IC (p = 0.006) improved significantly; with regard to the secondary parameters, the mean oxygen saturation was improved by 1% (p = 0.005) and the mean end-tidal CO2 tension and breathing frequency decreased significantly (p < 0.0001 for both) to 3.2 mm Hg and 3.1 breaths/min, respectively. After 5 min the effects diminished. Conclusion: Improved IC after PLB indicates less hyperinflation in patients with severe COPD; there was no effect on parameters of flow.

Recommendations for the measurement of FIV(1) values in chronic obstructive pulmonary disease.

Background: In contrast to static inspiratory parameters such as vital capacity and inspiratory capacity, information on forced inspiratory volume in 1 s (FIV₁) in patients with chronic obstructive pulmonary disease (COPD) is limited. Objectives: It was the aim of this study to investigate the influence of the preceding expiratory manoeuvre and the optimal number of manoeuvres on FIV₁ values. Methods: In 169 patients with COPD, FIV₁ manoeuvres were performed after a forced (FIV₁-Fe) and a slow (FIV₁-Se) expiration. To investigate the optimal number of the FIV₁-Se manoeuvres, 8 attempts were performed. Results: The variability of FIV₁-Fe was greater than that of FIV₁-Se. The mean difference between FIV₁-Se and FIV₁-Fe was 0.21 litres (p < 0.01) and dependent on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage. The higher the GOLD stage, the greater the difference between the 2 techniques. The correlation coefficient between FIV₁-Se and FIV₁-Fe was high (r = 0.89, p = 0.01), but there was a poor agreement between these parameters (limits of agreement –0.52 to 0.94 litres). Five manoeuvres were needed to obtain an optimal FIV₁-Se. There was no association with the GOLD stage. Conclusions: In COPD patients, FIV₁-Se are less variable than FIV₁-Fe, the agreement between the 2 manoeuvres is poor, and at least 5 FIV₁-Se manoeuvres are needed to get an acceptable FIV₁. This holds for all GOLD stages.

Non-invasive ventilation abolishes the IL-6 response to exercise in muscle-wasted COPD patients: A pilot study

Systemic inflammation in patients with chronic obstructive pulmonary disease (COPD) has been related to the development of comorbidities. The level of systemic inflammatory mediators is aggravated as a response to exercise in these patients. The aim of this study was to investigate whether unloading of the respiratory muscles attenuates the inflammatory response to exercise in COPD patients. In a cross‐over design, eight muscle‐wasted stable COPD patients performed 40u2009W constant work‐rate cycle exercise with and without non‐invasive ventilation support (NIV vs control). Patients exercised until symptom limitation for maximally 20u2009min. Blood samples were taken at rest and at isotime or immediately after exercise. Duration of control and NIV‐supported exercise was similar, both 12.9u2009±u20092.8u2009min. Interleukin‐ 6 (IL‐6) plasma levels increased significantly by 25u2009±u20099% in response to control exercise, but not in response to NIV‐supported exercise. Leukocyte concentrations increased similarly after control and NIV‐supported exercise by ∼15%. Plasma concentrations of C‐reactive protein, carbonylated proteins, and production of reactive oxygen species by blood cells were not affected by both exercise modes. This study demonstrates that NIV abolishes the IL‐6 response to exercise in muscle‐wasted patients with COPD. These data suggest that the respiratory muscles contribute to exercise‐induced IL‐6 release in these patients.

Maximal Exercise Capacity in Chronic Obstructive Pulmonary Disease: A Limited Indicator of the Health Status

Background: Dyspnoea and diminished functional status are pivotal features of the health status (HS) in chronic obstructive pulmonary disease (COPD). However, it is still not fully understood how pulmonary function tests and cardiopulmonary exercise testing relate to these aspects. This may be due to incomplete assessment and/or deficient definitions of HS. Especially regarding peak oxygen consumption, inconsistent results have been reported. Objectives: To determine the value of maximal cycle ergometry in relation to a broad spectrum of HS aspects. Methods: 129 patients with COPD, stage II and III according to the GOLD classification, performed a cardiopulmonary exercise test. Sixteen independent sub-domains of HS were assessed according to the Nijmegen Integral Assessment Framework, covering physiological functioning, complaints, functional impairments and quality of life as main domains. v̇O2max and HS sub-domains were correlated by bivariate analysis. Results: Weak correlations of v̇O2max with most sub-domains were found, except for exercise capacity; the other 5 sub-domains of physiological functioning did not correlate. Between different types of exercise limitation (5 types were differentiated), no significant differences were noted in the scores of 13/16 HS sub-domains. Conclusions: v̇O2max is indeed correlated with most aspects of HS, except for physiological variables, but associations are weak. No single exercise limitation type is associated with specific HS problems. Thus separate assessment of all HS sub-domains is advocated to ensure adequate planning of therapeutic interventions.

Reversibility of inspiratory lung function parameters after short-term bronchodilators in COPD

BACKGROUNDnThe responsiveness of short-term bronchodilator use on inspiratory lung function parameters (ILPs), including Forced Inspiratory Volume in one second (FIV(1)), Inspiratory Capacity (IC), Forced Inspiratory Flow at 50% of the vital capacity (FIF(50)), Peak Inspiratory Flow (PIF) and on the relationship between these values and dyspnea in COPD subjects has been examined only sparsely in past studies. The aim of this study was to assess the effects of inhaled salbutamol 400 mcg, ipratropium 80 mcg and a placebo on ILP and FEV(1) and their relationship to dyspnea, as measured with a Visual Analogue Scale (VAS).nnnMETHODSnA total of 85 subjects with stable COPD participated in a crossover, randomized, double-blind, placebo-controlled study. Spirometry was performed before and after inhalation of salbutamol, ipratropium or a placebo. The primary analysis was performed using 63 participants with absent reversibility.nnnRESULTSnAll ILP and FEV(1) values improved significantly after bronchodilator administration except for FIF(50) after ipratropium administration. After administration of both bronchodilators, the mean percent changes from initial values did not significantly differ between the various ILPs and FEV(1). The mean VAS score showed significant improvements after bronchodilator and placebo inhalation but did not significantly correlate with changes in lung function parameters. For each lung function parameter, patients were further classified as responders if the amount of change was greater than the coefficient of repeatability of the test. Response rates did not differ significantly between the various ILPs. Moreover, no significant differences were found between responders and non-responders with respect to dyspnea after bronchodilator inhalation. This finding applied to all ILP and FEV(1) values.nnnCONCLUSIONSnIn subjects with COPD, all ILP, FEV(1) values and VAS scores showed significant improvements after bronchodilator use as well as with placebo. However, ILPs were not more sensitive than FEV(1) for detecting responders after bronchodilator use or changes in the VAS score.