Metered-dose inhaler ipratropium bromide for children with acute asthma exacerbation: A prospective, non-randomized, observational study.

BACKGROUND: Ipratropium bromide (IB), when administered with ß2-agonists, is effective in reducing hospital admissions of children presenting to the emergency department (ED) with severe asthma. While IB is commonly delivered in its nebulized form, using a metered-dose inhaler (MDI), can, reportedly, shorten patients' length of stay in the ED. However, the effectiveness and safety of IB administration using an MDI with a spacer have not been established. This study aimed to investigate the effectiveness and safety of MDI-delivered IB in pediatric patients with acute asthma exacerbation. METHODS: This prospective, non-randomized, observational study included patients aged ≥4 years with a history of severe asthma exacerbation. Patients received IB via MDI with a spacer three times at 20-min intervals. IB use was determined by the physicians' treatment policy. Propensity score matching was used to adjust the confounding factors related to IB administration. RESULTS: Of the 158 patients, 88 were treated with IB and 70 were treated without IB. A propensity score-matching analysis extracted 54 patients from each group. We found no statistical difference in the admission rate of the two groups (IB group: 25.9% vs non-IB group: 31.5%; P = 0.67). The post-treatment modified pulmonary index scores (mean ± SD) were also similar (IB: 6.6 ± 2.0 vs non-IB: 6.3 ± 2.5; P = 0.53). Only one patient (1.0%) treated with IB experienced vomiting, which resolved spontaneously. CONCLUSION: The metered-dose inhaler IB was ineffective in reducing the admission rate possibly because it was less effective than a nebulizer for IB inhalation.

The short-term bronchodilator effects of the dual phosphodiesterase 3 and 4 inhibitor RPL554 in COPD.

We investigated the short-term bronchodilator effects of RPL554 (an inhaled dual phosphodiesterase 3 and 4 inhibitor) combined with other bronchodilators in chronic obstructive pulmonary disease patients with reversibility (>150 mL to short-acting bronchodilators).Study 1 was a six-way, placebo-controlled crossover study (n=36) with single doses of RPL554 (6 mg), salbutamol (200 µg), ipratropium (40 µg), RPL554 (6 mg)+salbutamol (200 µg), RPL554 (6 mg)+ipratropium (40 µg) or placebo. Study 2 was a three-way crossover study (n=30) of tiotropium (18 µg) combined with RPL554 (1.5 or 6 mg) or placebo for 3 days. Forced expiratory volume in 1 s (FEV1), lung volumes and specific airway conductance (sG aw) were measured.In study 1, peak FEV1 change compared with placebo was similar with RPL554, ipratropium and salbutamol (mean 223, 199 and 187 mL, respectively). The peak FEV1 was higher for RPL554+ipratropium versus ipratropium (mean difference 94 mL; p<0.0001) and RPL554+salbutamol versus salbutamol (mean difference 108 mL; p<0.0001). In study 2 (day 3), both RPL554 doses caused greater peak FEV1 effects than placebo. The average FEV1 (0-12 h) increase was greater with RPL554 6 mg only versus placebo (mean difference 65 mL; p=0.0009). In both studies, lung volumes and sG aw showed greater RPL554 combination treatment effects versus monotherapy.RPL554 combined with standard bronchodilators caused additional bronchodilation and hyperinflation reduction.

Development of a novel digital breath-activated inhaler: Initial particle size characterization and clinical testing.

BACKGROUND: Delivery of inhaled respiratory medications have been associated with variable delivery of drug due to errors in device operations and have not been designed to monitor true delivery of medication. A fully digital breath-activated inhaled (DBAI) delivery platform has been developed with integrated firmware and software to address these limitations. METHODS: the device was designed to produce similar aerosol particle output to a marketed albuterol MDI and to the albuterol/ipratropium combination in a soft mist inhaler (SMI). Cascade impactor studies were conducted to demonstrate comparable aerodynamic particle size distribution (APSD) metrics. Efficacy was evaluated by pharmacodynamic studies involving spirometry in two separate protocols with adult subjects having COPD (albuterol DBAI vs. albuterol MDI - Study A, albuterol/ipratropium DBAI single arm - Study B). RESULTS: The total emitted doses (TED) were 81.9 ±â€¯10.3, 109.3 ±â€¯15.0 and 121.9 ±â€¯7.0 µg/actuation for the DBAI, SMI and MDI respectively, and the fine (respirable) particle doses (FPD) were 56.2 ±â€¯6.0, 61.7 ±â€¯5.5 and 79.4 ±â€¯2.7 µg/actuation. MMADs for albuterol sulfate were 1.93 ±â€¯0.11, 1.75 ±â€¯0.19, and 2.65 ±â€¯0.05 µm for the DBAI, Respimat soft mist inhaler (SMI) and MDI respectively. The corresponding GSDs were 1.96 ±â€¯0.16, 2.79 ±â€¯0.25, and 1.48 ±â€¯0.02 µm. The corresponding respirable fractions were 68.7 ±â€¯3.2%, 57.3 ±â€¯10.5%, and 65.2 ±â€¯2.4%. Spirometric study A enrolled 23 subjects (age 64 ±â€¯7.3 years, 39% male, FEV1 45 ±â€¯14% predicted). Study B enrolled 23 subjects (age 65 ±â€¯8.6 years, 43% male, FEV1 47 ±â€¯10% predicted). For Study A, FEV1 at 20 min post-dose improved by 120 (167) mL (p = 0.002) for the DBAI device and 109 (183) mL (p = 0.008) for the MDI device (p = 0.86 for between group differences). For Study B, FEV1 (20 min post-dose) improved by 216 (126) mL (p < 0.001). CONCLUSION: The DBAI generated highly respirable aerosols containing albuterol sulfate that were similar to the MDI and SMI in respirable fraction but lower in dose. Subsequent pharmacodynamic studies delivering albuterol sulfate alone and in combination with ipratropium bromide confirmed similar responses for the DBAI compared with the other inhalers, which could possibly be related to a response ceiling. The DBAI breath-activated capability combined with the ability to monitor actual delivery of medication may improve effectiveness by overcoming patient miscoordination.

Comparison of the in vitro pharmacological profiles of long-acting muscarinic antagonists in human bronchus.

BACKGROUND AND PURPOSE: Long-acting muscarinic antagonists (LAMAs) have been recommended for the treatment of chronic obstructive pulmonary disease and (more recently) asthma. However, the in vitro pharmacological profiles of the four LAMAs currently marketed (tiotropium, umeclidinium, aclidinium and glycopyrronium) have not yet been compared (relative to ipratropium) by using the same experimental approach. EXPERIMENTAL APPROACH: With a total of 560 human bronchial rings, we investigated the antagonists' potency, onset and duration of action for inhibition of the contractile response evoked by electrical field stimulation. We also evaluated the antagonists' potency for inhibiting cumulative concentration-contraction curves for acetylcholine and carbachol. KEY RESULTS: The onset and duration of action were concentration-dependent. At submaximal, equipotent concentrations, the antagonists' onsets of action were within the same order of magnitude. However, the durations of action differed markedly. After washout, ipratropium's inhibitory activity decreased rapidly (within 30-90 min) but those of tiotropium and umeclidinium remained stable (at above 70%) for at least 9 h. Aclidinium and glycopyrronium displayed less stable inhibitory effects, with a progressive loss of inhibition at submaximal concentrations. In contrast to ipratropium, all the LAMAs behaved as insurmountable antagonists by decreasing the maximum responses to both acetylcholine and carbachol. CONCLUSIONS AND IMPLICATIONS: The observed differences in the LAMAs' in vitro pharmacological profiles in the human bronchus provide a compelling pharmacological rationale for the differences in the drugs' respective recommended daily doses and frequencies of administration.

A Controlled Trial of Inhaled Bronchodilators in Familial Dysautonomia.

BACKGROUND: Chronic lung disease is a leading cause of premature death in patients with familial dysautonomia (FD). A significant number of patients have obstructive airway disease, yet it is not known whether this is pharmacologically reversible. METHODS: We conducted a double-blind, placebo-controlled, randomized clinical trial comparing the beta 2 agonist albuterol with the muscarinic blocker ipratropium bromide in patients homozygous for the IKBKAP founder mutation. Albuterol, ipratropium bromide, and placebo were administered on 3 separate days via nebulizer in the seated position. Airway responsiveness was evaluated using spirometry and impulse oscillometry 30 min post dose. Cardiovascular effects were evaluated by continuous monitoring of blood pressure, RR intervals, cardiac output, and systemic vascular resistance. RESULTS: A total of 14 patients completed the trial. Neither active agent had significant detrimental effects on heart rate or rhythm or blood pressure. Albuterol and ipratropium were similar in their bronchodilator effectiveness causing significant improvement in forced expiratory volume in 1-s (FEV1, p = 0.002 and p = 0.030). Impulse oscillometry measures were consistent with a reduction in total airway resistance post nebulization (resistance at 5 Hz p < 0.006). CONCLUSION: Airway obstruction is pharmacologically reversible in a number of patients with FD. In the short term, both albuterol and ipratropium were well tolerated and not associated with major cardiovascular adverse events.

Bilateral acute angle closure developing due to use of ipratropium bromide and salbutamol.

Acute angle closure can be seen as a side effect of some medications that can be used systemically. In this article, clinical characteristics of 54-year-old female patient who applied to our clinic with bilateral acute angle closure and has been received nebulized form of salbutamol and ipratropium bromide due to asthma for 4 days was evaluated. Right and left eye IOP were measured as 50 and 48 mmHg. IOP was reduced with anti-glaucomatous treatment. and peripheral iridectomy was done, and then the patient was discharged. It is necessary to be careful to prevent contact with the eye of nebulized form of these drugs which may result in angle closure glaucoma when used systemically.

Experimental Substantiation of Inhalation Administration of Pathogenic Therapy of Toxic Convulsive Disorder for Correction of External Respiration Disorders.

We studied the dynamics of respiratory function in rats during intratracheal poisoning with diisopropyl fluorophosphate and pentylenetetrazole in doses corresponding to the LD50 in humans. The maximum of external respiration impairment was recorded in 30 min after poisoning. Administration of diazepam and atropine both separately and in combination during the development of the first signs of poisoning did not significantly affect the respiration parameters, but reduced the incidence of seizures and contributed to a decrease in the rate of animal death. Intratracheal administration of cholinolytic, ß2-adrenomimetic, or glutamate receptors antagonist promoted correction of the respiratory function. It was found that the maximum therapeutic effect in case of diisopropyl fluorophosphates poisoning was achieved after intratracheal administration of ipratropium bromide (0.086 mg/kg), salbutamol (0.086 mg/kg), and MK-801 (0.1 mg/kg), while in case of pentylenetetrazole poisoning, intratracheal administration of ipratropium bromide (0.086 mg/kg) was most effective.

Inhaled magnesium sulfate in the treatment of acute asthma.

BACKGROUND: Asthma exacerbations can be frequent and range in severity from mild to life-threatening. The use of magnesium sulfate (MgSO4) is one of numerous treatment options available during acute exacerbations. While the efficacy of intravenous MgSO4 has been demonstrated, the role of inhaled MgSO4 is less clear. OBJECTIVES: To determine the efficacy and safety of inhaled MgSO4 administered in acute asthma. SPECIFIC AIMS: to quantify the effects of inhaled MgSO4 I) in addition to combination treatment with inhaled ß2-agonist and ipratropium bromide; ii) in addition to inhaled ß2-agonist; and iii) in comparison to inhaled ß2-agonist. SEARCH METHODS: We identified randomised controlled trials (RCTs) from the Cochrane Airways Group register of trials and online trials registries in September 2017. We supplemented these with searches of the reference lists of published studies and by contact with trialists. SELECTION CRITERIA: RCTs including adults or children with acute asthma were eligible for inclusion in the review. We included studies if patients were treated with nebulised MgSO4 alone or in combination with ß2-agonist or ipratropium bromide or both, and were compared with the same co-intervention alone or inactive control. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial selection, data extraction and risk of bias. We made efforts to collect missing data from authors. We present results, with their 95% confidence intervals (CIs), as mean differences (MDs) or standardised mean differences (SMDs) for pulmonary function, clinical severity scores and vital signs; and risk ratios (RRs) for hospital admission. We used risk differences (RDs) to analyse adverse events because events were rare. MAIN RESULTS: Twenty-five trials (43 references) of varying methodological quality were eligible; they included 2907 randomised patients (2777 patients completed). Nine of the 25 included studies involved adults; four included adult and paediatric patients; eight studies enrolled paediatric patients; and in the remaining four studies the age of participants was not stated. The design, definitions, intervention and outcomes were different in all 25 studies; this heterogeneity made direct comparisons difficult. The quality of the evidence presented ranged from high to very low, with most outcomes graded as low or very low. This was largely due to concerns about the methodological quality of the included studies and imprecision in the pooled effect estimates. Inhaled magnesium sulfate in addition to inhaled ß2-agonist and ipratropiumWe included seven studies in this comparison. Although some individual studies reported improvement in lung function indices favouring the intervention group, results were inconsistent overall and the largest study reporting this outcome found no between-group difference at 60 minutes (MD -0.3 % predicted peak expiratory flow rate (PEFR), 95% CI -2.71% to 2.11%). Admissions to hospital at initial presentation may be reduced by the addition of inhaled magnesium sulfate (RR 0.95, 95% CI 0.91 to 1.00; participants = 1308; studies = 4; I² = 52%) but no difference was detected for re-admissions or escalation of care to ITU/HDU. Serious adverse events during admission were rare. There was no difference between groups for all adverse events during admission (RD 0.01, 95% CI -0.03 to 0.05; participants = 1197; studies = 2). Inhaled magnesium sulfate in addition to inhaled ß2-agonistWe included 13 studies in this comparison. Although some individual studies reported improvement in lung function indices favouring the intervention group, none of the pooled results showed a conclusive benefit as measured by FEV1 or PEFR. Pooled results for hospital admission showed a point estimate that favoured the combination of MgSO4 and ß2-agonist, but the confidence interval includes the possibility of admissions increasing in the intervention group (RR 0.78, 95% CI 0.52 to 1.15; participants = 375; studies = 6; I² = 0%). There were no serious adverse events reported by any of the included studies and no between-group difference for all adverse events (RD -0.01, 95% CI -0.05 to 0.03; participants = 694; studies = 5). Inhaled magnesium sulfate versus inhaled ß2-agonistWe included four studies in this comparison. The evidence for the efficacy of ß2-agonists in acute asthma is well-established and therefore this could be considered a historical comparison. Two studies reported a benefit of ß2-agonist over MgSO4 alone for PEFR and two studies reported no difference; we did not pool these results. Admissions to hospital were only reported by one small study and events were rare, leading to an uncertain result. No serious adverse events were reported in any of the studies in this comparison; one small study reported mild to moderate adverse events but the result is imprecise. AUTHORS' CONCLUSIONS: Treatment with nebulised MgSO4 may result in modest additional benefits for lung function and hospital admission when added to inhaled ß2-agonists and ipratropium bromide, but our confidence in the evidence is low and there remains substantial uncertainty. The recent large, well-designed trials have generally not demonstrated clinically important benefits. Nebulised MgSO4 does not appear to be associated with an increase in serious adverse events. Individual studies suggest that those with more severe attacks and attacks of shorter duration may experience a greater benefit but further research into subgroups is warranted.Despite including 24 trials in this review update we were unable to pool data for all outcomes of interest and this has limited the strength of the conclusions reached. A core outcomes set for studies in acute asthma is needed. This is particularly important in paediatric studies where measuring lung function at the time of an exacerbation may not be possible. Placebo-controlled trials in patients not responding to standard maximal treatment, including inhaled ß2-agonists and ipratropium bromide and systemic steroids, may help establish if nebulised MgSO4 has a role in acute asthma. However, the accumulating evidence suggests that a substantial benefit may be unlikely.

Inhalable Ipratropium Bromide Particle Engineering with Multicriteria Optimization.

Spray-dried ipratropium bromide (IPB) microspheres for oral inhalation were engineered using Quality by Design. The interrogation of material properties, process parameters, and critical product quality attributes interplay enabled rational product design. A 27-3 screening design exhibited the Maillard reaction between L-leucine (LL) and lactose at studied outlet temperatures (OT) >130°C. A response surface custom design was used in conjunction with multicriteria optimization to determine the operating design space to achieve inhalable microparticles. Statistically significant predictive models were developed for volume median diameter (p = 0.0001, adjusted R 2 = 0.9938), span (p = 0.0278, adjusted R 2 = 0.7912), yield (p = 0.0020, adjusted R 2 = 0.9320), and OT (p = 0.0082, adjusted R 2 = 0.8768). An independent verification batch confirmed the model's predictive capability. The prediction and actual values were in good agreement. Particle size and span were 3.32 ± 0.09 µm and 1.71 ± 0.18, which were 4.7 and 5.3% higher than the predicted values. The process yield was 50.3%, compared to the predicted value of 65.3%. The OT was 100°C versus the predicted value of 105°C. The label strength of IPB microparticles was 99.0 to 105.9% w/w suggesting that enrichment occurred during the spray-drying process. The present study can be utilized to initiate the design of the first commercial IPB dry powder inhaler.

IPRATROPIUM BROMIDE FOR ACUTE ASTHMA IN CHILDREN: A RETROSPECTIVE TRIAL.

BACKGROUND: Inhaled anticholinergics such as ipratropium bromide (IB), when administered with ß2-agonists, are effective in reducing hospital admissions of children presenting to the emergency department with moderate to severe asthma. However, treatment of acute asthma with IB is still uncommon in Japan. The aim of this study was to investigate the effectiveness and safety of IB for the treatment of pediatric acute asthma. METHODS: We conducted a retrospective study to compare the admission rate of patients who received IB with those who did not. Patients aged 4 years or older with a history of moderate to severe attacks were included. For analysis, propensity score matching was used to adjust the confounding factors related to IB use. Patients received IB by metered-dose inhaler (40µg per dose) with a spacer three times at 20-min intervals. RESULTS: Among 175 patients included in the analysis, 102 patients were treated with IB (IB group) and 73 patients were treated without IB (Non-IB group). A propensity score matching analysis extracted 63 patients from each group. There was no statistical difference between the two groups in terms of admission rate (IB group 12.7% vs Non-IB group 9.5%; p=0.78). One patient (1.0%) treated with IB experienced dryness of the mouth, which resolved spontaneously. CONCLUSIONS: The admission rate did not decline with IB use. Several confounding factors could have influenced and limited our results. A prospective study is needed to investigate the effectiveness of IB in Japan.

Insights into Spray Development from Metered-Dose Inhalers Through Quantitative X-ray Radiography.

PURPOSE: Typical methods to study pMDI sprays employ particle sizing or visible light diagnostics, which suffer in regions of high spray density. X-ray techniques can be applied to pharmaceutical sprays to obtain information unattainable by conventional particle sizing and light-based techniques. METHODS: We present a technique for obtaining quantitative measurements of spray density in pMDI sprays. A monochromatic focused X-ray beam was used to perform quantitative radiography measurements in the near-nozzle region and plume of HFA-propelled sprays. RESULTS: Measurements were obtained with a temporal resolution of 0.184 ms and spatial resolution of 5 µm. Steady flow conditions were reached after around 30 ms for the formulations examined with the spray device used. Spray evolution was affected by the inclusion of ethanol in the formulation and unaffected by the inclusion of 0.1% drug by weight. Estimation of the nozzle exit density showed that vapour is likely to dominate the flow leaving the inhaler nozzle during steady flow. CONCLUSIONS: Quantitative measurements in pMDI sprays allow the determination of nozzle exit conditions that are difficult to obtain experimentally by other means. Measurements of these nozzle exit conditions can improve understanding of the atomization mechanisms responsible for pMDI spray droplet and particle formation.

Efficacy and safety of ipratropium bromide/albuterol compared with albuterol in patients with moderate-to-severe asthma: a randomized controlled trial.

BACKGROUND: Many patients with asthma require frequent rescue medication for acute symptoms despite appropriate controller therapies. Thus, determining the most effective relief regimen is important in the management of more severe asthma. This study's objective was to evaluate whether ipratropium bromide/albuterol metered-dose inhaler (CVT-MDI) provides more effective acute relief of bronchospasm in moderate-to-severe asthma than albuterol hydrofluoroalkaline (ALB-HFA) alone after 4 weeks. METHODS: In this double-blind, crossover study, patients who had been diagnosed with asthma for ≥1 year were randomized to two sequences of study medication "as needed" for symptom relief (1-7 day washout before second 4-week treatment period): CVT-MDI/ALB-HFA or ALB-HFA/CVT-MDI. On days 1 and 29 of each sequence, 6-hour serial spirometry was performed after administration of the study drug. Co-primary endpoints were FEV1 area under the curve (AUC0-6) and peak (post-dose) forced expiratory volume in 1 s (FEV1) response (change from test day baseline) after 4 weeks. The effects of "as needed" treatment with ALB-HFA/CVT-MDI were analyzed using mixed effect model repeated measures (MMRM). RESULTS: A total of 226 patients, ≥18 years old, with inadequately controlled, moderate-to-severe asthma were randomized. The study met both co-primary endpoints demonstrating a statistically significant treatment benefit of CVT-MDI versus ALB-HFA. FEV1 AUC0-6h response was 167 ml for ALB-HFA, 252 ml for CVT-MDI (p <0.0001); peak FEV1 response was 357 ml for ALB-HFA, 434 ml for CVT-MDI (p <0.0001). Adverse events were comparable across groups. CONCLUSIONS: CVT-MDI significantly improved acute bronchodilation over ALB-HFA alone after 4 weeks of "as-needed" use for symptom relief, with a similar safety profile. This suggests additive bronchodilator effects of ß2-agonist and anticholinergic treatment in moderate-to-severe, symptomatic asthma. TRIAL REGISTRATION: ClinicalTrials.gov No.: NCT00818454 ; Registered November 16, 2009.

Daily variation in lung function in COPD patients with combined albuterol and ipratropium: results from a 4-week, randomized, crossover study.

BACKGROUND: The bronchodilator response to short-acting ß2-agonist and short-acting muscarinic antagonist monotherapies varies on a day-to-day basis within individual patients. The objective of this study was to compare daily variation in bronchodilator response to the combined use of albuterol and ipratropium with monotherapies in patients with chronic obstructive pulmonary disease (COPD). METHODS: This was a 4-week, randomized, open-label, two-period crossover study in patients with COPD. Patients were randomized 1:1 to receive albuterol via metered dose inhaler followed by ipratropium or vice versa during treatment Period 1 (10-14 days). The order of treatments was then reversed during treatment Period 2 (10-14 days). Pre-defined efficacy endpoints were: forced expiratory volume in 1 s (FEV1), derived FEV1, inspiratory capacity (IC) and daily variability of FEV1 and IC as measured by coefficient of variation (CV). RESULTS: Albuterol and ipratropium improved FEV1 when administered as the first bronchodilator, compared with pre-dose values (0.269 and 0.243 L, respectively). Administration of the second bronchodilator provided further improvements in lung function, but to a lesser magnitude than the first bronchodilator (0.094 L for both treatments). A statistically significant reduction in daily variability in FEV1 was observed for dual bronchodilator therapy compared with monotherapy (difference in CV = 0.007; p = 0.019) and pre-dose values (no treatment; difference in CV = 0.022; p < 0.001). CONCLUSIONS: The free combination of albuterol and ipratropium resulted in greater improvements and lower day-to-day variability in FEV1 compared with either monotherapy or no bronchodilator therapy. The reduced daily variability may be an important therapeutic advantage of using different classes of bronchodilators in COPD. TRIAL REGISTRATION: NCT01691482.

Metered-dose inhaler ipratropium bromide in moderate acute asthma in children: A single-blinded randomised controlled trial.

AIM: To determine if the addition of ipratropium bromide (IB) by metered-dose inhaler in moderate acute asthma in children affects hospital admission rates when compared with inhaled salbutamol and oral prednisolone alone. METHODS: A prospective, single-blinded, randomised, controlled, equivalence trial in a tertiary paediatric emergency department. Patients aged 2-15 years with acute, moderate asthma were randomised to two groups, one receiving salbutamol, prednisolone and IB, the other receiving only salbutamol and prednisolone. The managing doctor was blinded to treatment. Admission rates were compared, and less than 15% difference was accepted as statistically equivalent. RESULTS: Recruitment ran from June 2007 until January 2011. Three hundred forty-seven subjects were analysed. The admission rate in the IB group was 70.1% (122/174) compared with 64.2% (111/173) in the non-IB group. The absolute difference of +5.9% (95% confidence interval -4.0% to 15.8%) is not statistically equivalent but does not show a statistically significant decrease in admission rates when IB was given. Adverse effects were more prevalent in the IB group, at 13.2% (23/174), compared with 4.6% (8/173) in the non-IB group, a relative risk of 2.86 (95% confidence interval 1.31-6.21). CONCLUSION: In children with acute asthma of moderate severity who are treated with adequate doses of salbutamol and prednisolone, the addition of IB is not significantly associated with a reduction in admission rates. There is a significantly higher rate of adverse effects if IB is given. IB should be reserved for children with severe asthma exacerbations.

A randomized, placebo-controlled, double-blind trial on the management of post-infective cough by inhaled ipratropium and salbutamol administered in combination.

Post-viral cough is a type of cough originating from upper respiratory tract infections that persists after the infection is resolved. Although it was hypothesized that bronchodilators might have a role in the management of post-viral cough, a clear demonstration of their efficacy is missing. Therefore, we tested the efficacy of a combination of a ß-agonist and an anticholinergic agent in reducing post-viral cough with a randomized, double blind, placebo controlled clinical trial. Patients were treated for 10 days with either a nebulized combination of salbutamol 1.875 mg/0.5 mL and ipratropium bromide 0.375 mg/0.5 mL, or a placebo, and followed up for another 10 days. Daytime and nighttime cough severity and spirometry testing were assessed before starting treatment, after 10 and 20 days. Ninety-two patients were randomized to receive placebo (n = 46) or the active treatment (n = 46); nine of them (4 in the placebo group, 5 in the active treatment group) dropped out from the study. Daytime and nighttime cough severity were significantly reduced in both groups during the study period, but the reduction was more prominent in the active treatment group vs. placebo after 10 days of treatment (P = 0.003 for day cough; P = 0.061 for night cough), whereas at the end of follow-up period cough severity was comparable between the two groups. Small but significant increases in spirometric parameters were observed in the active treatment vs. placebo group, although at the end of follow-up these values returned to be comparable to placebo. The frequency of adverse events was not significantly different between the two groups of patients. We concluded that a combination of a ß-agonist and an anticholinergic agent can effectively reduce post-viral cough, and can thus represent a valid option for this type of cough.

Magnesium sulfate versus ipratropium bromide in chronic obstructive pulmonary disease exacerbation: a randomized trial.

Treatment with short-acting ß2-agonists for exacerbations of chronic obstructive pulmonary disease (COPD) results in clinical improvement. It has not been established whether combining short-acting ß2-agonists to other bronchodilators is more effective than ß2-agonists alone. We conducted a study in patients presenting to the emergency department with exacerbation of COPD. They were randomized to receive nebulized ipratropium bromide (IB group; n = 62) or combined nebulized and intravenous bolus of magnesium sulfate (MgSO4 group; n = 62). All nebulized drugs were administered at 30-minute intervals for 2 hours. Primary outcome included hospital admission, endotracheal intubation, and hospital death rates. Secondary outcome measures were improvement in peak expiratory flow, dyspnea score, and arterial blood gas changes within the first 3 hours. There were no significant differences in primary outcome between MgSO4 and IB groups. Patients given IB average 32 L greater improvement in peak expiratory flow rate compared with magnesium sulfate (95% confidence interval, 19-43 L) at 180 minutes. Simultaneously, there was a significant reduction in PaCO2 compared with baseline values in IB group but not in MgSO4 group. There was a statistically nonsignificant trend toward a decrease in dyspnea score in both groups although adverse events were similar. Although the improvement in peak expiratory flow rate and arterial blood gas favored nebulized IB over magnesium sulfate, there was a nonsignificant difference between both drugs with regard to hospital admission, intubation, and hospital death rates in patients with COPD treated in the emergency department for acute exacerbation.

Inhaled anticholinergics and short-acting beta(2)-agonists versus short-acting beta2-agonists alone for children with acute asthma in hospital.

BACKGROUND: Inhaled anticholinergics given in addition to ß2-agonists are effective in reducing hospital admissions in children presenting to the emergency department with a moderate to severe asthma exacerbation. It seems logical to assume a similar beneficial effect in children hospitalised for an acute asthma exacerbation. OBJECTIVES: To assess the efficacy and safety of anticholinergics added to ß2-agonists as inhaled or nebulised therapy in children hospitalised for an acute asthma exacerbation. To investigate the characteristics of patients or therapy, if any, that would influence the magnitude of response attributable to the addition of anticholinergics. SEARCH METHODS: We identified trials from the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived through systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED and PsycINFO and through handsearching of respiratory journals and meeting abstracts. The search is current to November 2013. SELECTION CRITERIA: Randomised trials comparing the combination of inhaled or nebulised anticholinergics and short-acting ß2-agonists versus short-acting ß2-agonists alone in children one to 18 years of age hospitalised for an acute asthma exacerbation were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the methodological quality of trials and extracted data; disagreement was resolved by consensus or with the input of a third review author, when needed. Primary outcomes were duration of hospital stay and serious adverse events. Secondary outcomes included admission and duration of stay in the intensive care unit (ICU), ventilation assistance, time to short-acting ß2-agonists spaced at four hours or longer, supplemental asthma therapy, duration of supplemental oxygen, change from baseline in asthma severity, relapse after discharge, adverse health effects and withdrawals. MAIN RESULTS: Seven randomised trials were included, four of which reported usable data on 472 children with asthma one to 18 years of age who were admitted to paediatric wards. No trials included patients admitted to the ICU. The anticholinergic used, ipratropium bromide 250 µg, was given every one to eight hours over a period from four hours to the entire length of the hospital stay. Two of four trials (50%) contributing data were deemed of high methodological quality. The addition of anticholinergics to ß2-agonists showed no evidence of effect on the duration of hospital admission (mean difference (MD) -0.28 hours, 95% confidence interval (CI) -5.07 to 4.52, 3 studies, 327 participants, moderate quality evidence) and no serious or non-serious adverse events were reported in any included trials. As a result of the similarity of trials, we could not explore the influence of age, admission site, intensity of anticholinergic treatment and co-interventions on primary outcomes. No statistically significant group difference was noted in other secondary outcomes, including the need for supplemental asthma therapy, time to short-acting ß2-agonists spaced at four hours or longer, asthma clinical scores, lung function and overall withdrawals for any reason. AUTHORS' CONCLUSIONS: In children hospitalised for an acute asthma exacerbation, no evidence of benefit for length of hospital stay and other markers of response to therapy was noted when nebulised anticholinergics were added to short-acting ß2-agonists. No adverse health effects were reported, yet the small number of trials combined with inadequate reporting prevent firm reassurance regarding the safety of anticholinergics. In the absence of trials conducted in ICUs, no conclusion can be drawn regarding children with impending respiratory failure. These findings support current national and international recommendations indicating that healthcare practitioners should refrain from using anticholinergics in children hospitalised for acute asthma.

Republished: pro-arrhythmic and pro-ischaemic effects of inhaled anticholinergic medications.

The majority of deaths in COPD are from cardiovascular causes. Several large randomized controlled trials demonstrate that inhaled anticholinergic agents ipratropium and tiotropium increase the risk of serious cardiovascular events, including cardiovascular mortality. Tiotropium Respimat is associated with a statistically significant increased risk of mortality (RR 1.52; 95% CI 1.06 to 2.16) and cardiovascular death (RR 2.05; 95% CI 1.06 to 3.99) compared with placebo in a meta-analysis of clinical trials. In the largest study, the subgroup of patients with COPD in the Respimat group with known rhythm and cardiac disorders at baseline had an especially high risk for cardiac death (RR 8.6; 95% CI 1.1 to 67.2). Although there was no significantly increased risk of mortality (HR 0.89; 95% CI 0.79 to 1.02) or myocardial infarction (MI) (RR 0.73; 95% CI 0.53 to 1.00) with tiotropium handihaler in the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial, the reported excess of angina (RR 1.44; 95% CI 0.91 to 2.26), imbalance in strokes related to ischaemia and rates of supraventricular tachyarrhythmias are consistent with the pro-ischemic and pro-arrhythmic effects. The subjects at greatest risk of cardiovascular death, such as those with a recent history of MI, unstable or life-threatening cardiac arrhythmias or hospitalisation with heart failure, were excluded from the UPLIFT trial. The Prevention of Exacerbations with Tiotropium in COPD trial showed an excess of serious coronary ischaemic events of angina, myocardial ischaemia and MI with the tiotropium Handihaler compared with salmeterol. The authors urge caution in prescribing inhaled anticholinergics for patients with pre-existing arrhythmias or cardiac disorders.

The Use of Ipratropium Bromide for the Treatment of Pediatric Sialorrhea: A Retrospective Clinical Case Series.

OBJECTIVE: This retrospective review documents the experience of ipratropium bromide use among pediatric patients with sialorrhea at our multidisciplinary sialorrhea clinic at Children's Hospital at London Health Sciences Centre (LHSC). METHODS: A retrospective chart review of patients diagnosed with sialorrhea at our multidisciplinary clinic between January 2015 and June 2021 was completed. Data on patient demographics, comorbidities, clinical presentation, previous interventions, quality of life, and medication adverse side effects was collected. Drooling Frequency and Severity Scale (DFSS) scores were reviewed to compare sialorrhea management pre- and post-treatment with topical 0.03% ipratropium bromide nasal solution. A descriptive analysis and Wilcoxon signed rank tests were conducted to compare pre- versus post-treatment DFSS scores. RESULTS: A total of 12 patients presented for follow-up and were included in the final analysis. At the pre-treatment visit, the median DFSS score was 4 for frequency and 5 for severity. Post-treatment, median DFSS score was 3 for frequency and 4.5 for severity, (P = .020 and .129, respectively). Minimal adverse effects were encountered. CONCLUSIONS: Ipratropium bromide provided a statistically significant benefit for drooling frequency in the patients studied and may present an additional topical medical option for pediatric sialorrhea with limited adverse effects.

Intelligent spectrophotometric resolution platforms for the challenging spectra of ipratropium and fenoterol in their combination inhaler with ecological friendliness assessment.

Asthma and chronic obstructive pulmonary disease (COPD) are the most common diagnoses for adults and children with respiratory tract inflammation. Recently, a novel fixed dose combination consisting of Ipratropium and Fenoterol has been released for the management and control of the symptoms of such disorders. The current research has newly developed and optimized three smart, accurate, simple, cost-effective, and eco-friendly spectrophotometric methods that enabled the simultaneous determination of the drugs under study in their combined inhaler dosage form, without the need for any previous separation steps, using water as a green solvent. The strategy employed was based on calculating one or two factors as a numerical spectrum or constant, which provided the complete removal of any component in the mixture that might overlap and the mathematical filtration of the targeted analyte. The methods developed could be classified into two types of spectrophotometric windows. Window I; involved absorption spectrum in their original zero-order forms (°D), which included recently designed methods named induced concentration subtraction (ICS) and induced dual wavelength (IDW). While window III focused on the ratio spectrum as the induced amplitude modulation (IAM) method. The extremely low absorptivity and lack of distinct absorption maximum in the zero-order absorption spectrum of Ipratropium were two intrinsic challenges that were better overcome by the proposed spectrophotometric methods than by the conventionally used ones. According to ICH guidelines, the proposed methods were validated using unified regression over range 2.0-40.0 µg/mL in the ICS method, while the linearity ranges for the IDW and IAM methods were 5.0-40.0 µg/mL of Ipratropium and 2.0-40.0 µg/mL of Fenoterol. Moreover, the three proposed methods were effectively used to assay the co-formulated marketed inhaler and further expanded to confirm the delivered dose uniformity in compliance with the USP guidelines. Finally, the established methods were evaluated for their greenness and blueness, in comparison to the official and reported analysis methods, using advanced cutting edge software metrics. Furthermore, the suggested techniques adhered well to the white analytical chemistry postulates that were recently published.