Effect of Nitric Oxide via Cardiopulmonary Bypass on Ventilator-Free Days in Young Children Undergoing Congenital Heart Disease Surgery: The NITRIC Randomized Clinical Trial.

Importance: In children undergoing heart surgery, nitric oxide administered into the gas flow of the cardiopulmonary bypass oxygenator may reduce postoperative low cardiac output syndrome, leading to improved recovery and shorter duration of respiratory support. It remains uncertain whether nitric oxide administered into the cardiopulmonary bypass oxygenator improves ventilator-free days (days alive and free from mechanical ventilation). Objective: To determine the effect of nitric oxide applied into the cardiopulmonary bypass oxygenator vs standard care on ventilator-free days in children undergoing surgery for congenital heart disease. Design, Setting, and Participants: Double-blind, multicenter, randomized clinical trial in 6 pediatric cardiac surgical centers in Australia, New Zealand, and the Netherlands. A total of 1371 children younger than 2 years undergoing congenital heart surgery were randomized between July 2017 and April 2021, with 28-day follow-up of the last participant completed on May 24, 2021. Interventions: Patients were assigned to receive nitric oxide at 20 ppm delivered into the cardiopulmonary bypass oxygenator (n = 679) or standard care cardiopulmonary bypass without nitric oxide (n = 685). Main Outcomes and Measures: The primary end point was the number of ventilator-free days from commencement of bypass until day 28. There were 4 secondary end points including a composite of low cardiac output syndrome, extracorporeal life support, or death; length of stay in the intensive care unit; length of stay in the hospital; and postoperative troponin levels. Results: Among 1371 patients who were randomized (mean [SD] age, 21.2 [23.5] weeks; 587 girls [42.8%]), 1364 (99.5%) completed the trial. The number of ventilator-free days did not differ significantly between the nitric oxide and standard care groups, with a median of 26.6 days (IQR, 24.4 to 27.4) vs 26.4 days (IQR, 24.0 to 27.2), respectively, for an absolute difference of -0.01 days (95% CI, -0.25 to 0.22; P = .92). A total of 22.5% of the nitric oxide group and 20.9% of the standard care group developed low cardiac output syndrome within 48 hours, needed extracorporeal support within 48 hours, or died by day 28, for an adjusted odds ratio of 1.12 (95% CI, 0.85 to 1.47). Other secondary outcomes were not significantly different between the groups. Conclusions and Relevance: In children younger than 2 years undergoing cardiopulmonary bypass surgery for congenital heart disease, the use of nitric oxide via cardiopulmonary bypass did not significantly affect the number of ventilator-free days. These findings do not support the use of nitric oxide delivered into the cardiopulmonary bypass oxygenator during heart surgery. Trial Registration: anzctr.org.au Identifier: ACTRN12617000821392.

LPA1 antagonist BMS-986020 changes collagen dynamics and exerts antifibrotic effects in vitro and in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease with limited treatment options. A phase 2 trial (NCT01766817) showed that twice-daily treatment with BMS-986020, a lysophosphatidic acid receptor 1 (LPA1) antagonist, significantly decreased the slope of forced vital capacity (FVC) decline over 26 weeks compared with placebo in patients with IPF. This analysis aimed to better understand the impact of LPA1 antagonism on extracellular matrix (ECM)-neoepitope biomarkers and lung function through a post hoc analysis of the phase 2 study, along with an in vitro fibrogenesis model. METHODS: Serum levels of nine ECM-neoepitope biomarkers were measured in patients with IPF. The association of biomarkers with baseline and change from baseline FVC and quantitative lung fibrosis as measured with high-resolution computed tomography, and differences between treatment arms using linear mixed models, were assessed. The Scar-in-a-Jar in vitro fibrogenesis model was used to further elucidate the antifibrotic mechanism of BMS-986020. RESULTS: In 140 patients with IPF, baseline ECM-neoepitope biomarker levels did not predict FVC progression but was significantly correlated with baseline FVC and lung fibrosis measurements. Most serum ECM-neoepitope biomarker levels were significantly reduced following BMS-986020 treatment compared with placebo, and several of the reductions correlated with FVC and/or lung fibrosis improvement. In the Scar-in-a-Jar in vitro model, BMS-986020 potently inhibited LPA1-induced fibrogenesis. CONCLUSIONS: BMS-986020 reduced serum ECM-neoepitope biomarkers, which were previously associated with IPF prognosis. In vitro, LPA promoted fibrogenesis, which was LPA1 dependent and inhibited by BMS-986020. Together these data elucidate a novel antifibrotic mechanism of action for pharmacological LPA1 blockade. Trial registration ClinicalTrials.gov identifier: NCT01766817; First posted: January 11, 2013; https://clinicaltrials.gov/ct2/show/NCT01766817 .

Doxapram alleviates low SpO2 induced by the combination of propofol and fentanyl during painless gastrointestinal endoscopy.

BACKGROUND: Painless gastrointestinal endoscopy under intravenous propofol anesthesia is widely applied in the clinical scenario. Despite the good sedation and elimination of anxiety that propofol provides, low SpO2 may also result. Doxapram is a respiratory stimulant with a short half-life. The primary aim of this study was to investigate the effects of doxapram on alleviating low SpO2 induced by the combination of propofol and fentanyl during painless gastrointestinal endoscopy. METHODS: In this prospective study, patients scheduled for painless gastrointestinal endoscopy were randomly assigned to group D or S with 55 patients per group. Initially, both groups received a combination of propofol and fentanyl. Patients in group D received 50 mg doxapram after propofol injection, while patients in group S received an equal volume of saline. Vital signs of the patients, propofol dose, examination duration, and incidences of low SpO2 were recorded. RESULTS: There were no statistical differences in propofol consumption and examination duration between the two groups. Twenty-six patients in group S experienced low SpO2 versus 10 in group D (P = 0.001). Nineteen patients in group S underwent oxygenation with a face mask in contrast to 8 in group D (P = 0.015). Eighteen patients in group S were treated with jaw lifting compared to 5 in group D (P = 0.002). Four patients in group S underwent assisted respiration compared to 2 in group D (without statistical difference). The average oxygen saturation in group S was significantly lower than that in group D at 1, 2 and 3 min after propofol injection (P < 0.001, P = 0.001 and P = 0.020, respectively). There were no statistical differences in oxygen saturation at other time points. There were no statistical differences in MAP and HR (except for the time point of 1 min after the induction) between the two groups. CONCLUSIONS: Low dose of doxapram can effectively alleviate low SpO2 in painless gastrointestinal endoscopy with intravenous propofol, without affecting propofol consumption, examination duration, MAP, or HR. TRAIL REGISTRATION: The study was approved by the Institutional Ethics Committee of Clinical and New Technology of Wuxi People's Hospital on 20th July, 2018 (KYLLH2018029) and registered in the Chinese Clinical Trial Register on 16th August, 2018 (ChiCTR1800017832).

Effects of Eucalyptol in respiratory system mechanics on acute lung injury after exposure to short-term cigarette smoke.

Eucalyptol is a compound that has demonstrated antioxidant, anti-inflammatory and bronchodilator effects, but there are no investigations about the effects of this constituent on the respiratory system mechanics in relation to acute lung injury caused by short-term cigarette smoke (CS) exposure. In view of the above, this work investigated the effects of Eucalyptol on the mechanics of the respiratory system of mice in short-term CS exposure. For this, we used data from respiratory mechanics in vivo, and histopathology and lung parenchymal morphometry analysis in vitro. The experiments were performed on C57black/6 mice divided into 5 groups. One group exposed to ambient air (AA + T), and another to cigarette smoke (CS + T) for 5 consecutive days and treated with 1% Tween 80 solution. The other groups were exposed to cigarette smoke for 5 consecutive days, and treated with Eucalyptol at doses of 30 mg/kg (CS + E30), 100 mg/kg (CS + E100), 300 mg/kg (CS + E300). Our results demonstrated significant changes in all variables of respiratory mechanics and lung parenchyma morphometry analyzed for the AA + T group compared to the CS + T group, confirming the establishment of the lesion induced by exposure to cigarette smoke. We also observed that mice treated with Eucalyptol orally at a dose of 300 mg/kg (CS + E300) showed improvement in all variables compared to the group exposed to cigarette smoke and treated with 1% Tween 80 (CS + T) demonstrating the effectiveness of Eucalyptol in preventing lung injury induced by exposure to CS. In conclusion, our results demonstrated that the Eucalyptol was able to prevent the acute lung injury in mice submitted to short-term cigarette smoke exposure.

Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled trial.

BACKGROUND: Inhaled corticosteroids have been used in patients with chronic obstructive pulmonary disease (COPD), but the potential benefits of their use in triple therapy are not well known. We aimed to compare the efficacy of a triple therapy with corresponding dual therapies in symptomatic patients with moderate to very severe COPD, without a requirement for a history of exacerbations. METHODS: In this double-blind, parallel-group, multicentre phase 3 randomised controlled trial, we recruited patients from hospitals and care centres in Canada, China, Japan, and the USA. Eligible patients were 40-80 years of age, were current or former smokers (with a smoking history of ≥10 pack-years), had an established clinical history of COPD, and were symptomatic for COPD, despite receiving two or more inhaled maintenance therapies for at least 6 weeks before screening. We randomly assigned patients (2:2:1:1) using an interactive web response system to receive budesonide/glycopyrrolate/formoterol fumarate metered-dose inhaler 320/18/9·6 µg (BGF MDI), glycopyrrolate/ formoterol fumarate metered-dose inhaler 18/9·6 µg (GFF MDI), budesonide/formoterol fumarate metered-dose inhaler 320/9·6 µg (BFF MDI), or open-label budesonide/formoterol fumarate dry-powder inhaler 400/12 µg (BUD/ FORM DPI). Primary endpoints for the Europe/Canada statistical analysis approach were FEV1 area under the curve from 0-4 h (AUC0-4) for BGF MDI versus BFF MDI and BGF MDI versus BUD/FORM DPI over 24 weeks; and change from baseline in morning pre-dose trough FEV1 for BGF MDI versus GFF MDI and non-inferiority of BFF MDI versus BUD/FORM DPI (margin of -50 mL from lower bound of 95% CI) over 24 weeks. Comparisons with BUD/FORM DPI were made for the Europe/Canada statistical analysis approach only. This study is registered with ClinicalTrials.gov, number NCT02497001. FINDINGS: Between Aug 20, 2015, and Jan 5, 2018, 3047 patients were screened from 215 sites, and 1902 were randomly assigned to receive BGF MDI (n=640), GFF MDI (n=627), BFF MDI (n=316), or BUD/FORM DPI (n=319). Over 24 weeks, BGF MDI significantly improved FEV1 AUC0-4 versus BFF MDI (least squares mean difference 104 mL, 95% CI 77 to 131; p<0·0001) and BUD/FORM DPI (91 mL, 64 to 117; p<0·0001). BGF MDI also significantly improved pre-dose trough FEV1 versus GFF MDI (22 mL, 4 to 39; p=0·0139) and was non-inferior to BUD/FORM DPI (-10 mL, -36 to 16; p=0·4390). At week 24, patients in the BGF MDI group had a significantly improved FEV1 AUC0-4 compared with patients receiving BFF MDI (116 mL, 95% CI 80 to 152; p<0·0001); there was a non-significant improvement in the change from baseline in morning pre-dose trough FEV1 at week 24 versus GFF MDI (13 mL, -9 to 36 mL; p=0·2375). The most common treatment-emergent adverse events were nasopharyngitis (n=49 [8%] in the BGF MDI group; n=41 [7%] in the GFF MDI group; n=26 [8%] in the BFF MDI group; and n=30 [9%] in the BUD/FORM DPI group) and upper respiratory tract infection (n=65 [10%]; n=38 [6%]; n=18 [6%]; and n=22 [7%]). Pneumonia incidence was low (<2%) and similar across treatments. There were two treatment-related deaths, both in the GFF MDI group. INTERPRETATION: BGF MDI was efficacious, well tolerated, and could be a more appropriate treatment than the corresponding dual therapies for symptomatic patients with moderate to very severe COPD, irrespective of exacerbation history. FUNDING: Pearl-a member of the AstraZeneca Group.

Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial of BMS-986020, a Lysophosphatidic Acid Receptor Antagonist for the Treatment of Idiopathic Pulmonary Fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) causes irreversible loss of lung function. The lysophosphatidic acid receptor 1 (LPA1) pathway is implicated in IPF etiology. Safety and efficacy of BMS-986020, a high-affinity LPA1 antagonist, was assessed vs placebo in a phase 2 study in patients with IPF. METHODS: IM136003 was a phase 2, parallel-arm, multicenter, randomized, double-blind, placebo-controlled trial. Adults with IPF (FVC, 45%-90%; diffusing capacity for carbon monoxide, 30%-80%) were randomized to receive placebo or 600 mg BMS-986020 (once daily [qd] or bid) for 26 weeks. The primary end point was rate of change in FVC from baseline to week 26. RESULTS: Of 143 randomized patients, 108 completed the 26-week dosing phase. Thirty-five patients discontinued prematurely. Patient baseline characteristics were similar between treatment groups (placebo: n = 47; 600 mg qd: n = 48; 600 mg bid: n = 48). Patients treated with BMS-986020 bid experienced a significantly slower rate of decline in FVC vs placebo (-0.042 L; 95% CI, -0.106 to -0.022 vs -0.134 L; 95% CI, -0.201 to -0.068, respectively; P = .049). Dose-related elevations in hepatic enzymes were observed in both BMS-986020 treatment groups. The study was terminated early because of three cases of cholecystitis that were determined to be related to BMS-986020 after unblinding. CONCLUSIONS: BMS-986020 600 mg bid treatment for 26 weeks vs placebo significantly slowed the rate of FVC decline. Both regimens of BMS-986020 were associated with elevations in hepatic enzymes. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01766817; URL: www.clinicaltrials.gov.

Preventing Clinically Important Deterioration of COPD with Addition of Umeclidinium to Inhaled Corticosteroid/Long-Acting ß2-Agonist Therapy: An Integrated Post Hoc Analysis.

INTRODUCTION: Assessing clinically important measures of disease progression is essential for evaluating therapeutic effects on disease stability in chronic obstructive pulmonary disease (COPD). This analysis assessed whether providing additional bronchodilation with the long-acting muscarinic antagonist umeclidinium (UMEC) to patients treated with inhaled corticosteroid (ICS)/long-acting ß2-agonist (LABA) therapy would improve disease stability compared with ICS/LABA therapy alone. METHODS: This integrated post hoc analysis of four 12-week, randomized, double-blind trials (NCT01772134, NCT01772147, NCT01957163, NCT02119286) compared UMEC 62.5 µg with placebo added to open-label ICS/LABA in symptomatic patients with COPD (modified Medical Research Council dyspnea scale score ≥ 2). A clinically important deterioration (CID) was defined as: a decrease from baseline of ≥ 100 mL in trough forced expiratory volume in 1 s (FEV1), an increase from baseline of ≥ 4 units in St George's Respiratory Questionnaire (SGRQ) total score, or a moderate/severe exacerbation. Risk of a first CID was evaluated in the intent-to-treat (ITT) population and in patients stratified by Global initiative for chronic Obstructive Lung Disease (GOLD) classification, exacerbation history and type of ICS/LABA therapy. Adverse events (AEs) were also assessed. RESULTS: Overall, 1637 patients included in the ITT population received UMEC + ICS/LABA (n = 819) or placebo + ICS/LABA (n = 818). Additional bronchodilation with UMEC reduced the risk of a first CID by 45-58% in the ITT population and all subgroups analyzed compared with placebo (all p < 0.001). Improvements were observed in reducing FEV1 (69% risk reduction; p < 0.001) and exacerbation (47% risk reduction; p = 0.004) events in the ITT population. No significant reduction in risk of a SGRQ CID was observed. AE incidence was similar between treatment groups. CONCLUSION: Symptomatic patients with COPD receiving ICS/LABA experience frequent deteriorations. Additional bronchodilation with UMEC significantly reduced the risk of CID and provided greater short-term stability versus continued ICS/LABA therapy in these patients. FUNDING: GlaxoSmithKline (study number: 202067). Plain language summary available for this article.

The utility of drug reaction assessment trials for inhaled therapies in patients with chronic lung diseases.

BACKGROUND: Current guidelines recommend a Drug Reaction Assessment (DRA) before beginning inhaled therapies to assess for bronchoconstriction and tolerability. There is limited evidence to support this recommendation. METHODS: In this study we aimed to establish the predictors of successful DRAs in different patient groups using a cohort of all DRAs performed in adults between 2011 and 2016 at the Royal Brompton Hospital. Spirometry, age, gender, height, and underlying lung disease were recorded. A multivariable logistic regression model was constructed to ascertain variables associated with successful DRAs. RESULTS: There were 1492 DRA trials using hypertonic saline (32%), antimicrobials (63%), or rhDNase (5%). The majority of patients (94%, n = 1408) passed the DRA. Mean FEV1% predicted was 58.03 (SD 23.36). Female sex, type of inhaled product, and FEV1% predicted were established as significant predictors for DRA success. An FEV1% predicted > 55% was associated with greater probability of DRA success (Odds Ratio [OR]: 2.96 (1.80,4.86) p < 0.0001). Those receiving dry powder, inhaled antibiotics were more likely to pass the DRA compared to nebulised antibiotics (OR: 3.99 (1.38,11.51) p = 0.01)). CONCLUSION: This study classifies distinct patient groups with varying baseline risks which can be used to predict tolerability when adding an inhaled product to their management plan. Some "low risk" patients may in future be able to self-assess their tolerability for inhaled therapies at home to avoid unneeded hospital monitoring.

Missed diagnosis and overtreatment of COPD among smoking primary care population in Central Greece: old problems persist.

Background: The diagnosis of COPD is not always consistent with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy in daily clinical practice, especially in primary care. This study aimed to estimate the overall COPD prevalence and severity, to identify differences between newly and previously diagnosed patients, and to evaluate the potential COPD overtreatment in a smoking population attending a primary care spirometry surveillance program. Methods: A study was conducted in 10 primary health care centers of Central Greece during a 7-month period. Eligible participants were aged ≥40 years and were either current smokers or exsmokers. Results: A total of 186 subjects were included (68% males, mean age 62.3±12.6 years, mean life-time tobacco exposure 50 pack-years). COPD prevalence was 17.8%, identified to be higher in elderly males. Forty-two percent of the COPD group were newly diagnosed patients, who were of younger age, current smokers, presented with less dyspnea and better health status, and mainly appeared with mild-to-moderate disease. Interestingly, 61.4% of non-COPD and 85.7% of newly diagnosed COPD individuals had been using inhaled medication under primary care provider's prescription without ever undergoing spirometry or further evaluation by a pulmonologist; thus, the phenomena of COPD overdiagnosis and missed diagnosis came into the spotlight. Moreover, only 26.3% of known COPD patients were properly medicated according to GOLD guidelines, while half of them were inappropriately treated with triple inhaled therapy. Conclusion: We reported a significant prevalence of COPD in smoking population attending this spirometry program. A remarkable proportion of COPD patients were undiagnosed and made case finding worthwhile. Underutilization of spirometry in the diagnosis and management of COPD as well as general practitioners' nonadherence to the GOLD treatment guidelines was confirmed by our data. These findings highlight the need for a major overhaul and culture change in primary care settings of Central Greece.

Homemade Hypertonic Saline: Essential Treatment Can Be Available and Affordable.

BACKGROUND: Nebulized hypertonic saline (HS) treatment is unavailable to large populations worldwide. OBJECTIVES: To determine the bacterial contamination and electrolyte concentrations in homemade (HM-HS) vs. pharmacy made (PM-HS). METHODS: We conducted three double-blind consecutive trials: 50 boiled-water homemade 3%-HS (B-HM-HS) bottles and 50 PM-HS. The bottles were cultured after 48 hours. Electrolyte concentrations were measured in 10 bottles (5 per group). Forty bottles (20 per group) were distributed to volunteers for simulation of realistic treatment by drawing 4 ml HS three times daily. From each bottle, 4 ml samples were cultured after 1, 5, and 7 days. Volunteers prepared 108 bottles containing 3%-HS, sterilizing them using a microwave oven (1100-1850W). These bottles were cultured 24 hours, 48 hours, and 1 month after preparation. RESULTS: Contamination rates of B-HM-HS and PM-HS after 48 hours were 56% and 14%, respectively (P = 0.008). Electrolyte concentrations were similar: 3.7% ± 0.4 and 3.5% ± 0.3, respectively (P = NS). Following a single day of simulation B-HM-HS bottles were significantly more contaminated than PM-HS bottles: 75% vs. 20%, respectively (P < 0.01). By day 7, 85% of PM-HS bottles and 100% of B-HM-HS bottles were contaminated (P = 0.23). All 108 microwave-oven prepared bottles (MICRO-HS) were sterile, which was significantly better than the contamination rate of B-HM-HS and PM-HS (P < 0.001). Calculated risk for a consecutive MICRO-HS to be infected was negligible. CONCLUSIONS: Microwave preparation provides sterile HS with adequate electrolyte concentrations, and is a cheap, fast, and widely available method to prepare HS.

When to start and when to stop antifibrotic therapies.

Idiopathic pulmonary fibrosis (IPF) is characterised by progressive changes of the lung architecture causing cough and dyspnoea and ultimately leading to lung failure and death. Today, for the first time, two drugs that may reduce the inexorable progression of the disease are available, suggesting that treatment with specific drugs for IPF should be started as soon as diagnosis is made. This applies to any disease and particularly to IPF, which is marked by a 5-year survival comparable or even worse than many cancers. However, despite common sense and even worse, in spite of scientific data coming from clinical trials, post hoc analysis, long-term safety studies and real-life experiences, the question of when to start and when to stop treatment with antifibrotics is still debated. In IPF, particularly when the disease is diagnosed at an early stage, "wait and watch" behaviour is not rare to observe. This is largely due to the lack of awareness of both patients and clinicians regarding the progression of the disease and its prognosis. Another important issue is when treatment should be stopped. In general, there are two main reasons to stop a therapy: unbearable side-effects and/or lack of efficacy. According to current (although preliminary) evidence, antifibrotic drugs should not be discontinued except for safety issues.

Inhaled versus systemic corticosteroids for the treatment of bronchopulmonary dysplasia in ventilated very low birth weight preterm infants.

BACKGROUND: This is an update of a review published in 2012. A related review "Inhaled versus systemic corticosteroids for preventing bronchopulmonary dysplasia in ventilated very low birth weight preterm neonates" has been updated as well. Bronchopulmonary dysplasia (BPD) is a serious and common problem among very low birth weight infants, despite the use of antenatal steroids and postnatal surfactant therapy to decrease the incidence and severity of respiratory distress syndrome. Due to their anti-inflammatory properties, corticosteroids have been widely used to treat or prevent BPD. However, the use of systemic steroids has been associated with serious short- and long-term adverse effects. Administration of corticosteroids topically through the respiratory tract may result in beneficial effects on the pulmonary system with fewer undesirable systemic side effects. OBJECTIVES: To compare the effectiveness of inhaled versus systemic corticosteroids administered to ventilator-dependent preterm neonates with birth weight ≤ 1500 g or gestational age ≤ 32 weeks after 7 days of life on the incidence of death or BPD at 36 weeks' postmenstrual age. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 1), MEDLINE via PubMed (1966 to 23 February 2017), Embase (1980 to 23 February 2017), and CINAHL (1982 to 23 February 2017). We also searched clinical trials registers, conference proceedings and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing inhaled versus systemic corticosteroid therapy (irrespective of dose and duration) starting after the first week of life in ventilator-dependent very low birth weight infants. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by the Cochrane Collaboration. MAIN RESULTS: We included three trials that involved a total of 431 participants which compared inhaled versus systemic corticosteroids to treat BPD. No new trials were included for the 2017 update.Although one study randomised infants at < 72 hours (N = 292), treatment started when infants were aged > 15 days. In this larger study, deaths were included from the point of randomisation and before treatment started. Two studies (N = 139) randomised and started treatment at 12 to 21 days.Two trials reported non-significant differences between groups for the primary outcome: incidence of death or BPD at 36 weeks' postmenstrual age among all randomised infants. Estimates for the largest trial were Relative risk (RR) 1.04 (95% Confidence interval (CI) 0.86 to 1.26), Risk difference (RD) 0.03 (95% CI -0.09 to 0.15); (moderate-quality evidence). Estimates for the other trial reporting the primary outcome were RR 0.94 (95% CI 0.83 to 1.05), RD -0.06 (95% CI -0.17 to 0.05); (low-quality evidence).Secondary outcomes that included data from all three trials showed no significant differences in the duration of mechanical ventilation or supplemental oxygen, length of hospital stay, or the incidence of hyperglycaemia, hypertension, necrotising enterocolitis, gastrointestinal bleed, retinopathy of prematurity or culture-proven sepsis moderate- to low-quality evidence).In a subset of 75 surviving infants who were enrolled from the United Kingdom and Ireland, there were no significant differences in developmental outcomes at seven years of age between groups (moderate-quality evidence). One study received grant support and the industry provided aerochambers and metered dose inhalers of budesonide and placebo for the same study. No conflict of interest was identified. AUTHORS' CONCLUSIONS: We found no evidence that inhaled corticosteroids confer net advantages over systemic corticosteroids in the management of ventilator-dependent preterm infants. There was no evidence of difference in effectiveness or adverse event profiles for inhaled versus systemic steroids.A better delivery system guaranteeing selective delivery of inhaled steroids to the alveoli might result in beneficial clinical effects without increasing adverse events.To resolve this issue, studies are needed to identify the risk/benefit ratio of different delivery techniques and dosing schedules for administration of these medications. The long-term effects of inhaled steroids, with particular attention to neurodevelopmental outcomes, should be addressed in future studies.

Inhaled versus systemic corticosteroids for preventing bronchopulmonary dysplasia in ventilated very low birth weight preterm neonates.

BACKGROUND: Bronchopulmonary dysplasia (BPD) remains an important cause of mortality and morbidity in preterm infants and inflammation plays a significant role in its pathogenesis. The use of inhaled corticosteroids may modulate the inflammatory process without concomitant high systemic steroid concentrations and less risk of adverse effects. This is an update of a review published in 2012 (Shah 2012). We recently updated the related review on "Inhaled versus systemic corticosteroids for treating bronchopulmonary dysplasia in ventilated very low birth weight preterm neonates". OBJECTIVES: To determine the effect of inhaled versus systemic corticosteroids started within the first 7 days of life on preventing death or BPD in ventilated very low birth weight infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 1), MEDLINE via PubMed (1966 to 23 February 2017), Embase (1980 to 23 February 2017), and CINAHL (1982 to 23 February 2017). We searched clinical trials registers, conference proceedings and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-randomised trials. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing inhaled versus systemic corticosteroid therapy (irrespective of dose and duration) starting in the first seven days of life in very low birth weight preterm infants receiving assisted ventilation. DATA COLLECTION AND ANALYSIS: Clinical outcomes data were extracted and analysed using Review Manager. When appropriate, meta-analysis was performed using typical relative risk (RR), typical risk difference (RD) and weighted mean difference (WMD). Meta-analyses were performed using typical relative risk, typical risk difference (RD), and weighted mean difference with their 95% confidence intervals (CI). If RD was statistically significant, the number needed to benefit or the number needed to harm was calculated. We assessed the quality of evidence was evaluated using GRADE principles. MAIN RESULTS: We included two trials that involved 294 infants. No new studies were included for the 2017 update. The incidence of death or BPD at 36 weeks' postmenstrual age was not statistically significantly different between infants who received inhaled or systemic steroids (RR 1.09, 95% CI 0.88 to 1.35; RD 0.05, 95% CI -0.07 to 0.16; 1 trial, N = 278). The incidence of BPD at 36 weeks' postmenstrual age among survivors was not statistically significant between groups (RR 1.34, 95% CI 0.94 to 1.90; RD 0.11, 95% CI -0.02 to 0.24; 1 trial, N = 206). There was no statistically significant difference in the outcomes of BPD at 28 days, death at 28 days or 36 weeks' postmenstrual age and the combined outcome of death or BPD by 28 days between groups (2 trials, N = 294). The duration of mechanical ventilation was significantly longer in the inhaled steroid group compared with the systemic steroid group (typical MD 4 days, 95% CI 0.2 to 8; 2 trials, N = 294; I² = 0%) as was the duration of supplemental oxygen (typical MD 11 days, 95% CI 2 to 20; 2 trials, N = 294; I² = 33%).The incidence of hyperglycaemia was significantly lower with inhaled steroids (RR 0.52, 95% CI 0.39 to 0.71; RD -0.25, 95% CI -0.37 to -0.14; 1 trial, N = 278; NNTB 4, 95% CI 3 to 7 to avoid 1 infant experiencing hyperglycaemia). The rate of patent ductus arteriosus increased in the group receiving inhaled steroids (RR 1.64, 95% CI 1.23 to 2.17; RD 0.21, 95% CI 0.10 to 0.33; 1 trial, N = 278; NNTH 5, 95% CI 3 to 10). In a subset of surviving infants in the United Kingdom and Ireland there were no significant differences in developmental outcomes at 7 years of age. However, there was a reduced risk of having ever been diagnosed as asthmatic by 7 years of age in the inhaled steroid group compared with the systemic steroid group (N = 48) (RR 0.42, 95% CI 0.19 to 0.94; RD -0.31, 95% CI -0.58 to -0.05; NNTB 3, 95% CI 2 to 20).According to GRADE the quality of the evidence was moderate to low. Evidence was downgraded on the basis of design (risk of bias), consistency (heterogeneity) and precision of the estimates.Both studies received grant support and the industry provided aero chambers and metered dose inhalers of budesonide and placebo for the larger study. No conflict of interest was identified. AUTHORS' CONCLUSIONS: We found no evidence that early inhaled steroids confer important advantages over systemic steroids in the management of ventilator-dependent preterm infants. Based on this review inhaled steroids cannot be recommended over systemic steroids as a part of standard practice for ventilated preterm infants. Because they might have fewer adverse effects than systemic steroids, further randomised controlled trials of inhaled steroids are needed that address risk/benefit ratio of different delivery techniques, dosing schedules and long-term effects, with particular attention to neurodevelopmental outcome.

Clinical effect of montelukast sodium combined with inhaled corticosteroids in the treatment of OSAS children.

This study was designed to investigate the clinical effect of montelukast sodium combined with inhaled corticosteroids in the treatment of children with obstructive sleep apnea syndrome (OSAS).One hundred ninety-five children were enrolled and divided into 3 groups: groups A, B, and C; the group A (oral use of montelukast sodium), group B (nasal spray of mometasone furoate), and group C (oral use of montelukast sodium + nasal spray of mometasone furoate). Telephone questionnaire surveys were carried out. Polysomnography monitoring was performed and lateral x-ray radiographs of the cervical spine were taken before treatment and at 12 weeks after treatment. The improvement of clinical symptoms after treatment and its effective rate were analyzed. The difference in clinical characteristics between groups C1 and C2 was analyzed.In the 3 groups, clinical symptoms improved at 12 weeks after treatment compared with before (P < .05 or P < .01). Apnea-hypopnea index value decreased (P < .05) and minimal SaO2 increased (P < .05), while adenoidal/nasopharyngeal ratio was reduced (P < .05). Compared with groups A and B, group C had a shortened response duration of snoring, apnea, and restless sleep (P < .05). Differences in the response duration of buccal respiration and hyperhidrosis were not statistically significant (P > .05). The total effective rate was higher in group C than in A and B (P < .05), while the differences in all indices between groups A and B were not statistically significant (P > .05). The difference in the grade of the size of the tonsil between groups C1 and C2 was statistically significant (P < .05).The total effective rate of the combined treatment was higher than that of the single use of any of the 2 drugs, which allowed the rapid relief of symptoms. Drug treatment may have a poor curative effect in the treatment of OSAS patients with ≥ grade 3 tonsil hypertrophy.

[Anti-fibrotics as novel therapy for idiopathic pulmonary fibrosis]. / Anti-Fibrotika als neue Therapie der idiopathischen Lungenfibrose.

Recent studies have shown efficacy to slow the decrease of forced vital capacity in patients with idiopathic pulmonary fibrosis. This summary refers to recent anti-fibrotic medications and describes current studies, indication for treatment and side effects, as well as discusses open questions of treatment.

The Influence of Nebulized Drugs on Nasal Ciliary Activity.

INTRODUCTION: Nebulized drugs are used in the treatment of cystic fibrosis (CF) lung disease, asthma, and COPD, and increasingly also in other chronic lung diseases. Their use in CF is reasonably evidence based, but this is not so for use in other orphan diseases. Potential side effects often have not been studied. Therefore, we evaluated the influence of nebulized drugs on ciliary activity in an in vitro model. METHODS: We constructed an in vitro nebulization model to examine the effect of drugs on ciliary activity. The model was validated by testing solutions with known neutral, positive, or negative effect on ciliary beat frequency (CBF). Next, the influence on CBF of other inhaled drugs was tested. RESULTS: Nebulization of NaCl 0.9% had no influence on CBF, and was used as paired neutral control in further experiments. Salbutamol (Ventolin(®)) had a ciliostimulatory effect (CBF +18%, CBF at t0-t10-t60 7.1-8.5-8.6 Hz, p = 0.002), while hypertonic saline (CBF - 11%, CBF at t0-t10-t60 6.5-5.1-5.9 Hz, p = 0.018) and dry air (CBF -10%, CBF at t0-t10-t60 6.8-5.8-6.1 Hz, p = 0.008) had a cilioinhibitory effect. Nebulization of tobramycin inhaled solution (TOBI(®)) (p = 0.662), colistimethate (Colistineb(®)) (p = 0.369), rhDNAse (Pulmozyme(®)) (p = 0.069), ceftazidim (Glazidim(®)) (p = 0.875), and aztreonam (Cayston(®)) (p = 0.435) did not affect CBF. Obracin(®), a tobramycin containing solution manufactured for intravenous use, had a negative effect on CBF (CBF - 21%, CBF at t0-t10-t60 6.9-5.2-4.5 Hz, p = 0.004). CONCLUSION: Inhaled drugs that are used off-label might have an influence on ciliary activity. This must be taken into account when prescribing these drugs for non-CF indications.

Inhibitory respiratory responses to progesterone and allopregnanolone in newborn rats chronically treated with caffeine.

KEY POINTS: In premature newborns, recurrent apnoea is systematically treated with caffeine to prevent long-term neurocognitive disorders, but a substantial percentage of apnoea persists particularly in neonates born before 28 weeks of gestation. Progesterone has been proposed as a respiratory stimulant potentially suitable for the treatment of newborn apnoea persistent to caffeine. Accordingly we asked whether acute progesterone administration reduces apnoea frequency in newborn rats treated with caffeine. Surprisingly our results show that in newborn rats treated with caffeine, administration of progesterone inhibits breathing and increases apnoea frequency. Additional experiments showed an enhanced GABAergic inhibitory drive on breathing after caffeine treatment, and that progesterone is converted to allopregnanolone (an allosteric modulator of GABAA receptors) to inhibit breathing. We conclude that combining progesterone and chronic caffeine is not an option in preterm neonates, unless the effects of allopregnanolone can be counteracted. ABSTRACT: Caffeine is the main treatment for apnoea in preterm neonates, but its interactions with other respiratory stimulants like progesterone are unknown. We tested the hypothesis that the addition of progesterone to caffeine treatments further stimulates ventilation. Newborn rats were treated with water (control) or caffeine (15 mg kg(-1)) by daily gavage between postnatal day (P)3 and P12. At P4 and P12, we measured apnoea frequency, ventilatory responses and metabolic parameters under both normoxia and hypoxia (12% O2, 20 min) following an acute administration of either saline or progesterone (4 mg kg(-1); i.p.). Progesterone injection increased the serum levels of both progesterone and its neuroactive metabolite allopregnanolone. Progesterone had no effect on ventilation in control rats under normoxia. Progesterone depressed ventilation in P12 caffeine-treated rats under normoxia and hypoxia and increased apnoea frequency in both P4 and P12 rats. Because allopregnanolone is an allosteric modulator of GABAA receptors and caffeine may enhance GABAergic inhibition in newborns, we studied the effects of the GABAA receptor antagonist bicuculline at 0, 1, 2 and 3 mg kg(-1) doses and allopregnanolone (10 mg kg(-1) dose) in P12 rats. In caffeine-treated rats, bicuculline enhanced ventilation, while allopregnanolone decreased ventilation and increased total apnoea time. Progesterone had no effect on ventilation and apnoea frequency in caffeine-treated rats injected with finasteride, which blocks the conversion of progesterone to allopregnanolone. We conclude that combining progesterone and chronic caffeine therapy is not an option for the treatment of persistent apnoea in preterm neonates, unless the effects of allopregnanolone can be counteracted.

Efficiency of controlled halotherapy in rehabilitation of patients with occupational lung diseases.

The study was aimed at features and efficiency of controlled halotherapy method in patients with occupational chronic obstructive lung disease (COLD). Examination covered 73 patients with occupational mild and moderate stages of COLD, aged 45 to 64. All the patients were randomized to 2 comparable groups - main and reference (37 and 36 examinees respectively). The main group in addition to conventional medical therapy received courses of controlled halotherapy (10 procedures with certain concentration of sodium chloride dry aerosol in accordance to methodic recommendations). Based on complex evaluation of clinical, functional and laboratory methods, the authors assessed efficiency of controlled halotherapy in patients with occupational COLD. Considerable improvement was seen: for mild COLD-- in 40% of cases, for moderate COLD - in 30%, with general efficiency for these patients of 90 and 85% respectively. Analysis of the results obtained enables to evaluate controlled halotherapy as an effective method of rehabilitation and prevention in occupational COLD patients.

Empowering family physicians to impart proper inhaler teaching to patients with chronic obstructive pulmonary disease and asthma.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) and asthma depend on inhalers for management, but critical errors committed during inhaler use can limit drug effectiveness. Outpatient education in inhaler technique remains inconsistent due to limited resources and inadequate provider knowledge. OBJECTIVE: To determine whether a simple, two-session inhaler education program can improve physician attitudes toward inhaler teaching in primary care practice. METHODS: An inhaler education program with small-group hands-on device training was instituted for family physicians (FP) in British Columbia and Alberta. Sessions were spaced one to three months apart. All critical errors were corrected in the first session. Questionnaires surveying current inhaler teaching practices and attitudes toward inhaler teaching were distributed to physicians before and after the program. RESULTS: Forty-one (60%) of a total 68 participating FPs completed both before and after program questionnaires. Before the program, only 20 (49%) reported providing some form of inhaler teaching in their practices, and only four (10%) felt fully competent to teach patients inhaler technique. After the program, 40 (98%) rated their inhaler teaching as good to excellent. Thirty-four (83%) reported providing inhaler teaching in their practices, either by themselves or by an allied health care professional they had personally trained. All stated they could teach inhaler technique within 5 min. Observation of FPs during the second session by certified respiratory educators found that none made critical errors and all had excellent technique. CONCLUSION: A physician inhaler education program can improve attitudes toward inhaler teaching and facilitate implementation in clinical practices.

[Idiopathic Pulmonary Fibrosis]. / Die idiopathische Lungenfibrose.

Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia and a disease of the elderly. Cigarette smoking and longterm exposure to substances harming alveolar epithelial cells are risk factors for the development of IPF. There is also evidence for a genetic susceptibility. IPF is defined as the idiopathic variant of Usual Interstitial Pneumonitis (UIP). Diagnosis of IPF is complex and based on the exclusion of other diseases associated with an UIP pattern. The only cure is lung transplantation. In the last years there was a breakthrough in the treatment of IPF. With pirfenidone and nintedanib there are now two compounds approved for the treatment of IPF.