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Effect of Nebulized Magnesium vs Placebo Added to Albuterol on Hospitalization Among Children With Refractory Acute Asthma Treated in the Emergency Department: A Randomized Clinical Trial.
Schuh, S, Sweeney, J, Rumantir, M, Coates, AL, Willan, AR, Stephens, D, Atenafu, EG, Finkelstein, Y, Thompson, G, Zemek, R, et al
JAMA. 2020;(20):2038-2047
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Abstract
IMPORTANCE While intravenous magnesium decreases hospitalizations in refractory pediatric acute asthma, it is variably used because of invasiveness and safety concerns. The benefit of nebulized magnesium to prevent hospitalization is unknown. OBJECTIVE To evaluate the effectiveness of nebulized magnesium in children with acute asthma remaining in moderate or severe respiratory distress after initial therapy. DESIGN, SETTING, AND PARTICIPANTS A randomized double-blind parallel-group clinical trial from September 26, 2011, to November 19, 2019, in 7 tertiary-care pediatric emergency departments in Canada. The participants were otherwise healthy children aged 2 to 17 years with moderate to severe asthma defined by a Pediatric Respiratory Assessment Measure (PRAM) score of 5 or greater (on a 12-point scale) after a 1-hour treatment with an oral corticosteroid and 3 inhaled albuterol and ipratropium treatments. Of 5846 screened patients, 4332 were excluded for criteria, 273 declined participation, 423 otherwise excluded, 818 randomized, and 816 analyzed. INTERVENTIONS Participants were randomized to 3 nebulized albuterol treatments with either magnesium sulfate (n = 410) or 5.5% saline placebo (n = 408). MAIN OUTCOMES AND MEASURES The primary outcome was hospitalization for asthma within 24 hours. Secondary outcomes included PRAM score; respiratory rate; oxygen saturation at 60, 120, 180, and 240 minutes; blood pressure at 20, 40, 60, 120, 180, and 240 minutes; and albuterol treatments within 240 minutes. RESULTS Among 818 randomized patients (median age, 5 years; 63% males), 816 completed the trial (409 received magnesium; 407, placebo). A total of 178 of the 409 children who received magnesium (43.5%) were hospitalized vs 194 of the 407 who received placebo (47.7%) (difference, -4.2%; absolute risk difference 95% [exact] CI, -11% to 2.8%]; P = .26). There were no significant between-group differences in changes from baseline to 240 minutes in PRAM score (difference of changes, 0.14 points [95% CI, -0.23 to 0.50]; P = .46); respiratory rate (0.17 breaths/min [95% CI, -1.32 to 1.67]; P = .82); oxygen saturation (-0.04% [95% CI, -0.53% to 0.46%]; P = .88); systolic blood pressure (0.78 mm Hg [95% CI, -1.48 to 3.03]; P = .50); or mean number of additional albuterol treatments (magnesium: 1.49, placebo: 1.59; risk ratio, 0.94 [95% CI, 0.79 to 1.11]; P = .47). Nausea/vomiting or sore throat/nose occurred in 17 of the 409 children who received magnesium (4%) and 5 of the 407 who received placebo (1%). CONCLUSIONS AND RELEVANCE Among children with refractory acute asthma in the emergency department, nebulized magnesium with albuterol, compared with placebo with albuterol, did not significantly decrease the hospitalization rate for asthma within 24 hours. The findings do not support use of nebulized magnesium with albuterol among children with refractory acute asthma. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01429415.
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A multinational observational study identifying primary care patients at risk of overestimation of asthma control.
Kritikos, V, Price, D, Papi, A, Infantino, A, Ställberg, B, Ryan, D, Lavorini, F, Chrystyn, H, Haughney, J, Lisspers, K, et al
NPJ primary care respiratory medicine. 2019;(1):43
Abstract
Factors related to the discrepancy between patient-perceived and actual disease control remain unclear. Identifying patients at risk of overestimation of asthma control remains elusive. This study aimed to (i) investigate the relationship between patient-reported and actual level of asthma control (ii), compare the characteristics between patients who believe their asthma is well controlled that accurately report 'well-controlled' asthma with those that do not, and (iii) identify factors associated with inaccurately reported 'well-controlled' asthma. A historical, multinational, cross-sectional study using data from the iHARP (initiative Helping Asthma in Real-life Patients) review service for adults with asthma prescribed fixed-dose combination therapy. Data from 4274 patients were analysed. A major discrepancy between patient-reported and Global Initiative for Asthma defined asthma control was detected; 71.1% of patients who reported 'well-controlled' asthma were inaccurate in their perception despite receiving regular maintenance therapy. Significant differences were noted in age, gender, body mass index, education level, medication use, side effects, attitudes to preventer inhaler use, inhaler technique review and respiratory specialist review between patients who accurately reported 'well-controlled' asthma and those who did not. Independent risk factors associated with inaccurately reported 'well-controlled' asthma were: having taken a maximum of 5-12 puffs or more of reliever inhaler on at least one day within the previous 4 weeks; being female; having seen a respiratory specialist more than a year ago (rather than in the previous year); and having required oral corticosteroids for worsening asthma in the previous year. The study highlighted the significant hidden burden associated with under-recognition of poor asthma control, on the part of the patient and the need for targeted interventions designed to address the continuing discrepancy between perceived and actual disease control.
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COPD patients' self-reported adherence, psychosocial factors and mild cognitive impairment in pulmonary rehabilitation.
Pierobon, A, Sini Bottelli, E, Ranzini, L, Bruschi, C, Maestri, R, Bertolotti, G, Sommaruga, M, Torlaschi, V, Callegari, S, Giardini, A
International journal of chronic obstructive pulmonary disease. 2017;:2059-2067
Abstract
In addition to clinical comorbidities, psychological and neuropsychological problems are frequent in COPD and may affect pulmonary rehabilitation delivery and outcome. The aims of the study were to describe a COPD population in a rehabilitative setting as regards the patients depressive symptoms, anxiety, mild cognitive impairment (MCI) and self-reported adherence and to analyze their relationships; to compare the COPD sample MCI scores with normative data; and to investigate which factors might predict adherence to prescribed physical exercise. This was a multicenter observational cross-sectional study. Of the 117 eligible stable COPD inpatients, 84 were enrolled according to Global initiative for chronic Obstructive Lung Disease (GOLD) criteria (mainly in Stage III-IV). The assessment included Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), anxiety, depression and self-reported pharmacological and nonpharmacological adherence. From the MMSE, 3.6% of patients were found to be impaired, whereas from the MoCA 9.5% had a likely MCI. Patients referred had mild-severe depression (46.7%), anxiety (40.5%), good pharmacological adherence (80.3%) and difficulties in following prescribed diet (24.1%) and exercise (51.8%); they struggled with disease acceptance (30.9%) and disease limitations acceptance (28.6%). Most of them received good family (89%) or social (53%) support. Nonpharmacological adherence, depression, anxiety and MCI showed significant relations with 6-minute walking test, body mass index (BMI) and GOLD. Depression was related to autonomous long-term oxygen therapy modifications, disease perception, family support and MCI. In the multivariate logistic regression analysis, higher BMI, higher depression and lower anxiety predicted lower adherence to exercise prescriptions (P=0.0004, odds ratio =0.796, 95% CI =0.701, 0.903; P=0.009, odds ratio =0.356, 95% CI =0.165, 0.770; and P=0.05, odds ratio =2.361, 95% CI =0.995, 5.627 respectively). In COPD patients, focusing on pharmacological and nonpharmacological adherence enhance the possibility of tailored pulmonary rehabilitation programs.
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Fluctuation Analysis of Peak Expiratory Flow and Its Association with Treatment Failure in Asthma.
Kaminsky, DA, Wang, LL, Bates, JH, Thamrin, C, Shade, DM, Dixon, AE, Wise, RA, Peters, S, Irvin, CG
American journal of respiratory and critical care medicine. 2017;(8):993-999
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Abstract
RATIONALE Temporal fluctuations have been demonstrated in lung function and asthma control, but the effect of controller therapy on these fluctuations is unknown. OBJECTIVES To determine if fluctuations in peak expiratory flow (PEF) are predictive of subsequent treatment failure and may be modified by controller therapy. METHODS We applied detrended fluctuation analysis to once-daily PEF data from 493 participants in the LOCCS (Leukotriene Modifier Corticosteroid or Corticosteroid-Salmeterol) trial of the American Lung Association Airways Clinical Research Centers. We evaluated the coefficient of variation of PEF (CVpef) and the scaling exponent α, reflecting self-similarity of PEF, in relation to treatment failure from the run-in period of open-label inhaled fluticasone, and the treatment periods for subjects randomized to (1) continued twice daily fluticasone (F), (2) once daily fluticasone plus salmeterol (F + S), or (3) once daily oral montelukast (M). MEASUREMENTS AND MAIN RESULTS The CVpef was higher in those with treatment failure in the F and F + S groups in the run-in phase, and all three groups in the treatment phase. α was similar between those with and without treatment failure in all three groups during the run-in phase but was higher among those with treatment failure in the F and F + S groups during the treatment phase. Participants in all three groups showed variable patterns of change in α leading up to treatment failure. CONCLUSIONS We conclude that increased temporal self-similarity (α) of more variable lung function (CVpef) is associated with treatment failure, but the pattern of change in self-similarity leading up to treatment failure is variable across individuals.
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Pharmacokinetics, Pharmacodynamics, Efficacy, and Safety of Albuterol (Salbuterol) Multi-dose Dry-Powder Inhaler and ProAir(®) Hydrofluoroalkane for the Treatment of Persistent Asthma: Results of Two Randomized Double-Blind Studies.
Kerwin, EM, Taveras, H, Iverson, H, Wayne, D, Shah, T, Lepore, MS, Miller, DS
Clinical drug investigation. 2016;(1):55-65
Abstract
BACKGROUND AND OBJECTIVE Metered-dose inhalers require patients to coordinate inhalation with actuation. The present albuterol multi-dose dry-powder inhaler (mDPI) does not require patients to coordinate inspiration with actuation, thereby simplifying delivery of albuterol to the lungs. The aim of the present study was to compare the efficacy, pharmacokinetics, pharmacodynamics, extrapulmonary pharmacodynamics, and safety of albuterol (salbuterol) delivered via a ProAir® hydrofluoroalkane (HFA) metered-dose inhaler and an mDPI. METHODS Two double-blind, randomized, double-dummy, crossover, multicenter, placebo-controlled studies in persistent asthma patients were conducted. Study 1: 47 adult patients were treated with cumulative doses of albuterol mDPI or ProAir HFA (90 µg/inhalation; 1 + 1 + 2 + 4 + 8 inhalations) or placebo. Study 2: 71 patients aged ≥12 years were randomly assigned to receive 90 or 180 μg of albuterol mDPI or ProAir HFA, or placebo. Primary efficacy endpoints were baseline-adjusted forced expiratory volume in 1 s (FEV1) at 30 min (30-min FEV1) after each cumulative dose (Study 1) and FEV1 area under the effect curve over 6 h (FEV1 AUEC0-6) after dosing (Study 2). RESULTS Study 1: differences, with corresponding 90% confidence intervals, between albuterol mDPI and ProAir HFA in FEV1 after each cumulative dose and in FEV1 AUEC0-6 after the final dose were within pre-established equivalence limits. The difference in FEV1 at high vs. low doses was significant for both active treatments (p < 0.0001). Active treatments were similar in systemic exposure, extrapulmonary pharmacodynamics, and safety. Study 2: mean FEV1 AUEC0-6 was significantly greater than for placebo for both doses of albuterol mDPI and ProAir HFA (p < 0.0001). Albuterol mDPI was comparable to ProAir HFA at 90 and 180 µg. Both study treatments were generally well tolerated. CONCLUSION The bronchodilatory efficacy and pharmacokinetic/pharmacodynamic profiles of albuterol mDPI and ProAir HFA are comparable, with a safety profile consistent with that of inhaled albuterol.
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A genome-wide analysis of the response to inhaled β2-agonists in chronic obstructive pulmonary disease.
Hardin, M, Cho, MH, McDonald, ML, Wan, E, Lomas, DA, Coxson, HO, MacNee, W, Vestbo, J, Yates, JC, Agusti, A, et al
The pharmacogenomics journal. 2016;(4):326-35
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Abstract
Short-acting β2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled β2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 × 10(-7)) and KCNJ2 (P=1.79 × 10(-7)) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 × 10(-9)). A nominal association with CDH13 was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.65.
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Which intravenous bronchodilators are being administered to children presenting with acute severe wheeze in the UK and Ireland?
Morris, I, Lyttle, MD, O'Sullivan, R, Sargant, N, Doull, IJ, Powell, CV, ,
Thorax. 2015;(1):88-91
Abstract
During a prospective 10-week assessment period, 3238 children aged 1-16 years presented with acute wheeze to Paediatric Emergency Research in the UK and Ireland centres. 110 (3.3%) received intravenous bronchodilators. Intravenous magnesium sulfate (MgSO4) was used in 67 (60.9%), salbutamol in 61 (55.5%) and aminophylline in 52 (47.3%) of cases. In 35 cases (31.8%), two drugs were used together, and in 18 cases (16.4%), all three drugs were administered. When used sequentially the most common order was salbutamol, then MgSO4, then aminophylline. Overall, 30 different intravenous treatment regimens were used varying in drugs, dose, rate and duration.
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Nebulized hypertonic saline for bronchiolitis: a randomized clinical trial.
Wu, S, Baker, C, Lang, ME, Schrager, SM, Liley, FF, Papa, C, Mira, V, Balkian, A, Mason, WH
JAMA pediatrics. 2014;(7):657-63
Abstract
IMPORTANCE Bronchiolitis is one of the most common and costly respiratory diseases in infants and young children. Previous studies have shown a potential benefit of nebulized hypertonic saline; however, its effect in the emergency department (ED) setting is unclear. OBJECTIVE To compare the effect of nebulized 3% hypertonic saline vs 0.9% normal saline on admission rate and length of stay in infants with bronchiolitis. DESIGN, SETTING, AND PARTICIPANTS We conducted a double-blind, randomized clinical trial during 3 consecutive bronchiolitis seasons from March 1, 2008, through April 30, 2011. We recruited a convenience sample of patients younger than 24 months with a primary diagnosis of viral bronchiolitis presenting to the ED of 2 urban free-standing tertiary children's hospitals. We excluded patients who were premature (gestational age, <34 weeks) or who had chronic pulmonary disease, immune deficiency, cardiac disease, or previous episodes of wheezing or inhaled bronchodilator use. Of eligible patients who were approached, 161 (26.6%) declined to participate. INTERVENTIONS Patients received 4 mL of 3% sodium chloride (hypertonic saline [HS group]) or 0.9% sodium chloride (normal saline [NS group]) inhaled as many as 3 times in the ED. Those admitted received the assigned medication every 8 hours until discharge. All treatment solutions were premedicated with albuterol sulfate. MAIN OUTCOMES AND MEASURES Hospital admission rate, length of stay for admitted patients, and Respiratory Distress Assessment Instrument score. RESULTS A total of 197 patients were enrolled in the NS group and 211 in the HS group. Admission rate in the 3% HS group was 28.9% compared with 42.6% in the NS group (adjusted odds ratio from logistic regression, 0.49 [95% CI, 0.28-0.86]). Mean (SD) length of stay for hospitalized patients was 3.92 (5.24) days for the NS group and 3.16 (2.11) days for the HS group (P = .24). The Respiratory Distress Assessment Instrument score decreased after treatment in both groups; however, we found no significant difference between groups (P = .35). CONCLUSIONS AND RELEVANCE Hypertonic saline given to children with bronchiolitis in the ED decreases hospital admissions. We can detect no significant difference in Respiratory Distress Assessment Instrument score or length of stay between the HS and NS groups. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00619918.
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Use of nebulised magnesium sulphate as an adjuvant in the treatment of acute exacerbations of COPD in adults: a randomised double-blind placebo-controlled trial.
Edwards, L, Shirtcliffe, P, Wadsworth, K, Healy, B, Jefferies, S, Weatherall, M, Beasley, R, ,
Thorax. 2013;(4):338-43
Abstract
BACKGROUND Intravenous magnesium has been shown to cause bronchodilation in acute severe asthma and in small trials in acute exacerbations of chronic obstructive pulmonary disease (AECOPD). There is also some evidence of benefit from nebulised magnesium in acute severe asthma. Our hypothesis was that adjuvant magnesium treatment administered via repeated nebulisation was effective in the management of AECOPD. METHODS In this randomised double-blind placebo-controlled trial, we approached 161 patients with AECOPD presenting to the emergency departments at two New Zealand hospitals with a forced expiratory volume in 1 s (FEV1) <50% predicted 20 min after initial administration of salbutamol 2.5 mg and ipratropium 500 µg via nebulisation. Patients received 2.5 mg salbutamol mixed with either 2.5 ml isotonic magnesium sulphate (151 mg per dose) or 2.5 ml isotonic saline (placebo) on three occasions at 30 min intervals via nebuliser. The primary outcome measure was FEV1 at 90 min. RESULTS 116 patients were randomised, 52 of whom were randomly allocated to the magnesium adjuvant group. At 90 min the mean (SD) FEV1 in the magnesium group (N=47) was 0.78 (0.33) l compared with 0.81 (0.30) l in the saline group (N=61) (difference -0.026 l (95% CI -0.15 to 0.095, p=0.67). No patients required non-invasive ventilation. There were 43/48 admissions to hospital in the magnesium group and 56/61 in the saline group (RR 0.98, 95% CI 0.86 to 1.10, p=0.69). CONCLUSIONS Nebulised magnesium as an adjuvant to salbutamol treatment in the setting of AECOPD has no effect on FEV1. Australian New Zealand Clinical Trials Registry ACTRN12608000167369.
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Effects of fluticasone propionate and salmeterol hydrofluoroalkane inhalation aerosol on asthma-related quality of life.
Edin, HM, Andersen, LB, Schoaf, L, Scott-Wilson, CA, Ho, SY, Ortega, HG
Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2009;(4):323-7
Abstract
BACKGROUND Current asthma guidelines emphasize domains of impairment and risk for assessing severity and control, noting the need to consider separately the effects of asthma on asthma quality of life and functional capacity. Proper treatment to control asthma should result in improvements in patient well-being and functional status. OBJECTIVE To assess asthma-related quality of life after treatment with combination fluticasone propionate and salmeterol delivered via hydrofluoroalkane 134a metered-dose inhaler compared with the individual components alone. METHODS Asthma-related quality of life was assessed as part of two 12-week, randomized, double-blind, placebo-controlled clinical trials comparing the fluticasone propionate-salmeterol combination administered via a single metered-dose inhaler with salmeterol, fluticasone propionate, and placebo administered via traditional chlorofluorocarbon metered-dose inhaler. The Asthma Quality of Life Questionnaire was completed at baseline and end point. Score changes, overall and for the 4 separate domains, were compared within and among the treatment groups. RESULTS A total of 720 of 725 patients completed a baseline Asthma Quality of Life Questionnaire and were included in the analyses. In both studies, all mean scores improved significantly from baseline with the fluticasone propionate-salmeterol combination, with significantly greater improvement in the overall score compared with salmeterol alone, fluticasone propionate alone, and placebo groups. Improvements with the combination were also clinically meaningful compared with changes with salmeterol and placebo in both studies and with fluticasone propionate in study 1. CONCLUSIONS Treatment with combination fluticasone propionate and salmeterol delivered via hydrofluoroalkane metered-dose inhaler resulted in significantly greater improvements in asthma-related quality of life compared with individual components and placebo administered via traditional chlorofluorocarbon metered-dose inhaler.