Dejan Radovanovic

Assessment of acute bronchodilator effects from specific airway resistance changes in stable COPD patients

BACKGROUND In COPD patients, reversibility is currently evaluated from the changes of forced expiratory volume at 1s (ΔFEV1) and forced vital capacity (ΔFVC). By lowering peripheral airway smooth muscle tone, bronchodilators should decrease dynamic hyperinflation, gas trapping, and possibly dyspnea at rest. Hence, we hypothesize that specific airway resistance changes (ΔsRAW) should better characterize the acute response to bronchodilators. METHODS On two days, 60 COPD patients underwent dyspnea evaluation (VAS score) and pulmonary function testing at baseline and one hour after placebo or 300μg indacaterol administration. RESULTS Spirographic and ΔsRAW-based criteria identified as responders 24 and 45 patients, respectively. ΔsRAW correlated with changes of intrathoracic gas volume (ΔITGV) (r=0.61; p<0.001), residual volume (ΔRV) (r=0.60; p<0.001), ΔFVC (r=0.44; p=0.001), and ΔVAS (r=0.73; p<0.001), while ΔFEV1 correlated only with ΔFVC (r=0.34; p=0.008). Significant differences in terms of ΔITGV (p=0.002), ΔRV (p=0.023), and ΔVAS (p<0.001) occurred only if patients were stratified according to ΔsRAW. CONCLUSIONS In assessing the acute functional effect of bronchodilators, ΔsRAW-based criterion is preferable to FEV1-FVC-based criteria, being more closely related to bronchodilator-induced improvements of lung mechanics and dyspnea at rest.

A systematic review on tracheostomy decannulation: A proposal of a quantitative semiquantitative clinical score

BackgroundTracheostomy is one of the most common surgical procedures performed in critical care patient management; more specifically, ventilation through tracheal cannula allows removal of the endotracheal tube (ETT). Available literature about tracheostomy care and decannulation is mainly represented by expert opinions and no certain knowledge arises from it.MethodsIn lack of statistical requirements, a systematic and critical review of literature regarding tracheostomy tube removal was performed in order to assess predictor factors of successful decannulation and to propose a predictive score. We combined 3 terms and a literature search has been performed using the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE via Ovid SP; EMBASE via Ovid SP; EBSCO. Abstracts were independently reviewed: for those studies fitting the inclusion criteria on the basis of the title and abstract, full-text was achieved. We included studies published from January 1, 1995 until March 31, 2014; any sort of review and expert opinion has been excluded by our survey. English language restriction was applied. Ten studies have been considered eligible for inclusion in the review and were analysed further.ResultsCough effectiveness and ability to tolerate tracheostomy tube capping are the most considered parameters in clinical practice; other parameters are taken into different consideration by many authors in order to proceed to decannulation. Among them, we distinguished between objective quantitative parameters and semi-quantitative parameters more dependent from clinician’s opinion. We then built a score (the Quantitative semi Quantitative score: QsQ score) based on selected parameters coming from literature.ConclusionsOn our knowledge, this review provides the first proposal of decannulation score system based on current literature that is hypothetical and requires to be validated in daily practice. The key point of our proposal is to give a higher value to the objective parameters coming from literature compared to less quantifiable clinical ones.

Effect of indacaterol on lung deflation improves cardiac performance in hyperinflated COPD patients: an interventional, randomized, double-blind clinical trial

Background COPD is often associated with cardiovascular comorbidity. Treatment guidelines recommend therapy with bronchodilators as first choice. We investigated the acute effect of single-dose indacaterol on lung hyperinflation in COPD subjects, for the first time evaluating the potential effects on right heart performance. Methods In this Phase IV, randomized, interventional, double-blind, crossover clinical study, we recruited 40 patients (50–85 years of age) with stable COPD. Patients were treated with 150 μg indacaterol or placebo and after 60 minutes (T60) and 180 minutes (T180) the following tests were performed: trans-thoracic echocardiography (TTE), plethysmography, diffusing capacity of the lung for carbon monoxide, saturation of peripheral oxygen, and visual analog scale dyspnea score. Patients underwent a crossover re-challenge after a further 72 hours of pharmacological washout. All TTE measurements were conducted blindly by the same operator and further interpreted by two different blinded operators. Consensus decisions were taken on every value and parameter. The primary outcome was the effect of the reduction of residual volume and functional residual capacity on right heart systolic and diastolic function indexes evaluated by TTE in patients treated with indacaterol, as compared to placebo. Results Vital capacity, inspiratory capacity, and forced expiratory volume in 1 second were significantly increased by indacaterol, when compared with placebo, while residual volume, intrathoracic gas volume, and specific airway resistance were significantly reduced in patients treated with indacaterol. Tricuspid annular plane systolic excursion was significantly increased versus placebo, paralleled by an increase of tricuspid E-wave deceleration time. The cardiac frequency was also significantly reduced in indacaterol-treated patients. Conclusion Indacaterol significantly reduces lung hyperinflation in acute conditions, with a clinically relevant improvement of dyspnea. These modifications are associated with a significant increase of the right ventricular compliance indexes and may have a role in improving left ventricular preload leading to a reduction in cardiac frequency.

Doctor–patient relationship: A resource to improve respiratory diseases management ☆

BACKGROUND Many respiratory diseases are chronic conditions that are strongly linked with the patient-physician relationship, disease perception and therapy adherence. The aim of the present study was to evaluate patients viewpoint about the different aspects involved in their respiratory diseases. METHODS This is a prospective observational survey. 46 Italian medical centres were involved and equally distributed. The interviews were carried out and were performed by means of a questionnaire which consisted of 32 questions regarding lung disease, modality of access to medical facilities, therapy and level of medical assistance. RESULTS 1116 patients were enrolled and the most important respiratory symptoms referred were: dyspnoea (69%), chronic phlegm (28%), cough (13%). During programmed visits 98.3% and 98.8% of interviewed patients knew were aware of asthma and COPD respectively, percentage that dropped, during emergency accesses, to 1.7% and 1.1% knew to have asthma and COPD respectively. Primarily were prescribed 1.67 spirometry/patient/year while only the 2% of patients referred to have performed a blood gas analysis. The 18% of patients spontaneously discontinued the therapy, considering it too complex. The average time that patients identified as being used by the doctor to perform the visit was of 22 minutes, with an high mean medical assistance satisfaction score. DISCUSSION There has been little research examining what factors may influence patient acceptance and participation of chronic respiratory diseases. Our national survey demonstrated that a good patient-physician relationship represents one of the first points in the successful management of respiratory diseases.

Prostaglandin D2 receptor antagonists in early development as potential therapeutic options for asthma

ABSTRACT Introduction: Asthma is a chronic inflammatory disease characterized by bronchial hyper-reactivity. Although many currently available treatment regimens are effective, poor symptom control and refractory severe disease still represent major unmet needs. In the last years, numerous molecular therapeutic targets that interfere with the innate inflammatory response in asthma have been identified. Promising preliminary results concern the signaling cascade promoted by prostaglandin D2 (PGD2) and its receptor antagonists. Areas covered: The aim of this review is to provide the most recent clinical and preclinical data on the efficacy and safety of newly developed compounds for the treatment of allergic asthma. The authors will present an overview of the pathogenetic molecular mechanisms sustaining the chronic inflammatory response in asthma; the focus will be then directed on the mediators of the PGD2 pathway, the chemoattractant receptor-homologous molecule expressed on TH2 cells, and their latest antagonists developed. Expert opinion: Bronchodilators and corticosteroids are not sufficient to achieve a satisfactory management of all asthmatic patients; the development of new specific treatments appears therefore essential. The good results in terms of cellular, functional and clinical outcomes, together with an acceptable safety of the CRTh2 antagonists represent a promising start for a tailored management of allergic asthma.

Pulmonary Rehabilitation in COPD: A Reappraisal (2008–2012)

Chronic Obstructive Pulmonary Disease (COPD) is a complex pathological condition associated with an important reduction in physical activity and psychological problems that contribute to the patients disability and poor health-related quality of life. Pulmonary rehabilitation is aimed to eliminate or at least attenuate these difficulties, mainly by promoting muscular reconditioning. The scope of this paper has been the analysis of the literature on pulmonary rehabilitation in COPD patients has appeared in the last five years, focusing on the principal outcomes obtained. The results demonstrate that pulmonary rehabilitation has a beneficial effect on dyspnoea relief, improving muscle strength and endurance. Moreover, pulmonary rehabilitation appears to be a highly effective and safe treatment for reducing hospital admissions mortality and improving health-related quality of life in COPD patients. It represents, therefore, a very important therapeutic option that, along with standard pharmachological therapy, can be used to obtain the best patient management. The favourable results obtained with pulmonary rehabilitation programs should stimulate researchers to improve our understanding of the mechanisms that form the basis of the beneficial effects of this therapeutic intervention. This would in turn increase the effectiveness of pulmonary rehabilitation in COPD patients.

Airway occlusion assessed by single breath N2 test and lung P-V curve in healthy subjects and COPD patients.

PURPOSE To determine whether the analysis of the slow expiratory transpulmonary pressure-volume (PL-V) curve provides an alternative to the single-breath nitrogen test (SBN) for the assessment of the closing volume (CV). METHODS SBN test and slow deflation PL-V curve were simultaneously recorded in 40 healthy subjects and 43 COPD patients. Onset of phase IV identified CV in SBN test (CVSBN), whereas in the PL-V curve CV was identified by: a) deviation from the exponential fit (CVexp), and b) inflection point of the interpolating sigmoid function (CVsig). RESULTS In the absence of phase IV, COPD patients exhibited a clearly discernible inflection in the PL-V curve. In the presence of phase IV, CVSBN and CVexp coincided (CVSBN/CVexp=1.04±0.04 SD), whereas CVsig was systematically larger (CVsig/CVexp=2.1±0.86). CONCLUSION The coincidence between CVSBN and CVexp, and the presence of the inflection in the absence of phase IV indicate that the deviation of the PL-V curve from the exponential fit reliably assesses CV.

Improvements in Lung Diffusion Capacity following Pulmonary Rehabilitation in COPD with and without Ventilation Inhomogeneity

Background: Lung diffusing capacity (D<smlcap>LCO</smlcap>) and lung volume distribution predict exercise performance and are altered in COPD patients. If pulmonary rehabilitation (PR) can modify D<smlcap>LCO</smlcap> parameters is unknown. Objectives: To investigate changes in D<smlcap>LCO</smlcap> and ventilation inhomogeneity following a PR program and their relation with functional outcomes in patients with COPD. Methods: This was a prospective, observational, multicentric study. Patients were evaluated before and after a standardized 3-week PR program. Functional assessment included body plethysmography, D<smlcap>LCO</smlcap>, transfer factor (KCO) and alveolar volume (V<smlcap>A</smlcap>), gas exchange, the 6-min walking test (6MWT) and exercise-related dyspnea. Patients were categorized according to the severity of airflow limitation and presence of ventilation inhomogeneity, identified by a V<smlcap>A</smlcap>/TLC <0.8. Results: Two hundred and fifty patients completed the study. Baseline forced expiratory volume in 1 s (FEV₁) % predicted (mean ± SD) was 50.5 ± 20.1 (76% males); 137 patients had a severe disease. General study population showed improvements in 6MWT (38 ± 55 m; p < 0.01), D<smlcap>LCO</smlcap> (0.12 ± 0.63 mmol × min^-1 kPa^-1; p < 0.01), lung function and dyspnea. Comparable improvements in D<smlcap>LCO</smlcap> were observed regardless of the severity of disease and the presence of ventilation inhomogeneity. While patients with V<smlcap>A</smlcap>/TLC <0.8 improved the D<smlcap>LCO</smlcap> increasing their V<smlcap>A</smlcap> (177 ± 69 ml; p < 0.01), patients with V<smlcap>A</smlcap>/TLC >0.8 improved their KCO (8.1 ± 2.8%; p = 0.019). The latter had also better baseline lung function and higher improvements in 6MWT (14.6 ± 6.7 vs. 9.0 ± 1.8%; p = 0.015). Lower D<smlcap>LCO</smlcap> at baseline was associated with lower improvements in 6MWT, the greatest difference being between subjects with very severe and mild D<smlcap>LCO</smlcap> impairment (2.7 ± 7.4 vs. 14 ± 2%; p = 0.049). Conclusions: In COPD patients undergoing a PR program, different pathophysiological mechanisms may drive improvements in D<smlcap>LCO</smlcap>, while ventilation inhomogeneity may limit improvements in exercise tolerance.

The evidence on tiotropium bromide in asthma: From the rationale to the bedside

Severe and poorly controlled asthma still accounts for a great portion of the patients affected. Disease control and future risk management have been identified by international guidelines as the main goals in patients with asthma. The need for new treatment approaches has led to reconsider anticholinergic drugs as an option for asthma treatment. Tiotropium is the first anticholinergic drug that has been approved for children and adults with poorly controlled asthma and is currently considered as an option for steps 4 and 5 of the Global Initiative for Asthma. In large randomized clinical trials enrolling patients with moderate to severe asthma, add-on therapy with tiotropium has demonstrated to be efficacious in improving lung function, decreasing risk of exacerbation and slowing the worsening of disease; accordingly, tiotropium demonstrated to be non inferior compared to long acting beta-agonists in the maintenance treatment along with medium to high inhaled corticosteroids. In view of the numerous ancillary effects acting on inflammation, airway remodeling, mucus production and cough reflex, along with the good safety profile and the broad spectrum of efficacy demonstrated in different disease phenotypes, tiotropium can represent a beneficial alternative in the therapeutic management of poorly controlled asthma. The present extensive narrative review presents the pharmacological and pathophysiological basis that guided the rationale for the introduction of tiotropium in asthma treatment algorithm, with a particular focus on its conventional and unconventional effects; finally, data on tiotropium efficacy and safety. from recent randomized clinical trials performed in all age categories will be extensively discussed.

Acute effects of long-acting bronchodilators on small airways detected in COPD patients by single-breath N2 test and lung P-V curve

Small airways represent the key factor of chronic obstructive pulmonary disease (COPD) pathophysiology. The effect of different classes of bronchodilators on small airways is still poorly understood and difficult to assess. Hence the acute effects of tiotropium (18 µg) and indacaterol (150 µg) on closing volume (CV) and ventilation inhomogeneity were investigated and compared in 51 stable patients (aged 70 ± 7 yr, mean ± SD; 82% men) with moderate to very severe COPD. Patients underwent body plethysmography, arterial blood gas analysis, tidal expiratory flow limitation (EFL), dyspnea assessment, and simultaneous recording of single-breath N2 test and transpulmonary pressure-volume curve (PL-V), before and 1 h after drug administration. The effects produced by indacaterol on each variable did not differ from those caused by tiotropium, independent of the severity of disease, assessed according to the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) scale and the presence of EFL. Bronchodilators significantly decreased the slope of phase III and CV (-5 ± 4 and -2.5 ± 2.1%, respectively, both P < 0.001), with an increase in both slope and height of phase IV and of the anatomical dead space. Arterial oxygen pressure and saturation significantly improved (3 ± 3 mmHg and 2 ± 2%, respectively, both P < 0.001); their changes negatively correlated with those of phase III slope (r = -0.659 and r = -0.454, respectively, both P < 0.01). The vital capacity (VC) increased substantially, but the PL-V/VC curve above CV was unaffected. In conclusion, bronchodilators reduce the heterogeneity of peripheral airway mechanical properties and the extent of their closure, with minor effects on critical closing pressure. This should lessen the risk of small-airway damage and positively affect gas exchange.NEW & NOTEWORTHY This is the first study investigating in stable chronic obstructive pulmonary disease patients the acute effects of two long-acting bronchodilators, a β-agonist and a muscarinic antagonist, on peripheral airways using simultaneous lung pressure-volume curve and single-breath N2 test. By lessening airway mechanical property heterogeneity, both drugs similarly reduced ventilation inhomogeneity and extent of small-airway closure, as indicated by the decrease of phase III slope, increased oxygen saturation, and fall of closing volume, often below expiratory reserve volume.