Nonnutritive sweeteners, such as aspartame, sucralose and stevioside, are widely consumed, yet their long-term health impact is uncertain. We synthesized evidence from prospective studies to ...determine whether routine consumption of non-nutritive sweeteners was associated with long-term adverse cardiometabolic effects.
We searched MEDLINE, Embase and Cochrane Library (inception to January 2016) for randomized controlled trials (RCTs) that evaluated interventions for nonnutritive sweeteners and prospective cohort studies that reported on consumption of non-nutritive sweeteners among adults and adolescents. The primary outcome was body mass index (BMI). Secondary outcomes included weight, obesity and other cardiometabolic end points.
From 11 774 citations, we included 7 trials (1003 participants; median follow-up 6 mo) and 30 cohort studies (405 907 participants; median follow-up 10 yr). In the included RCTs, nonnutritive sweeteners had no significant effect on BMI (mean difference -0.37 kg/m
; 95% confidence interval CI -1.10 to 0.36;
9%; 242 participants). In the included cohort studies, consumption of nonnutritive sweeteners was associated with a modest increase in BMI (mean correlation 0.05, 95% CI 0.03 to 0.06;
0%; 21 256 participants). Data from RCTs showed no consistent effects of nonnutritive sweeteners on other measures of body composition and reported no further secondary outcomes. In the cohort studies, consumption of nonnutritive sweeteners was associated with increases in weight and waist circumference, and higher incidence of obesity, hypertension, metabolic syndrome, type 2 diabetes and cardiovascular events. Publication bias was indicated for studies with diabetes as an outcome.
Evidence from RCTs does not clearly support the intended benefits of nonnutritive sweeteners for weight management, and observational data suggest that routine intake of nonnutritive sweeteners may be associated with increased BMI and cardiometabolic risk. Further research is needed to fully characterize the long-term risks and benefits of nonnutritive sweeteners.
PROSPERO-CRD42015019749.
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To compare the efficacy and safety of LTRAs versus placebo in the management of children (≥ 5 years) and adults ...with mild asthma.
Background
Anti‐leukotrienes (5‐lipoxygenase inhibitors and leukotriene receptors antagonists) serve as alternative monotherapy to inhaled corticosteroids (ICS) in the management of recurrent and/or ...chronic asthma in adults and children.
Objectives
To determine the safety and efficacy of anti‐leukotrienes compared to inhaled corticosteroids as monotherapy in adults and children with asthma and to provide better insight into the influence of patient and treatment characteristics on the magnitude of effects.
Search methods
We searched MEDLINE (1966 to Dec 2010), EMBASE (1980 to Dec 2010), CINAHL (1982 to Dec 2010), the Cochrane Airways Group trials register, and the Cochrane Central Register of Controlled Trials (Dec 2010), books, and reference lists of review articles and trials. We contacted colleagues and the international headquarters of anti‐leukotrienes producers.
Selection criteria
We included randomised trials that compared anti‐leukotrienes with inhaled corticosteroids as monotherapy for a minimum period of four weeks in patients with asthma aged two years and older.
Data collection and analysis
Two review authors independently assessed the methodological quality of trials and extracted data. The primary outcome was the number of patients with at least one exacerbation requiring systemic corticosteroids. Secondary outcomes included patients with at least one exacerbation requiring hospital admission, lung function tests, indices of chronic asthma control, adverse effects, withdrawal rates and biological inflammatory markers.
Main results
Sixty‐five trials met the inclusion criteria for this review. Fifty‐six trials (19 paediatric trials) contributed data (representing total of 10,005 adults and 3,333 children); 21 trials were of high methodological quality; 44 were published in full‐text. All trials pertained to patients with mild or moderate persistent asthma. Trial durations varied from four to 52 weeks. The median dose of inhaled corticosteroids was quite homogeneous at 200 µg/day of microfine hydrofluoroalkane‐propelled beclomethasone or equivalent (HFA‐BDP eq). Patients treated with anti‐leukotrienes were more likely to suffer an exacerbation requiring systemic corticosteroids (N = 6077 participants; risk ratio (RR) 1.51, 95% confidence interval (CI) 1.17, 1.96). For every 28 (95% CI 15 to 82) patients treated with anti‐leukotrienes instead of inhaled corticosteroids, there was one additional patient with an exacerbation requiring rescue systemic corticosteroids. The magnitude of effect was significantly greater in patients with moderate compared with those with mild airway obstruction (RR 2.03, 95% CI 1.41, 2.91 versus RR 1.25, 95% CI 0.97, 1.61), but was not significantly influenced by age group (children representing 23% of the weight versus adults), anti‐leukotriene used, duration of intervention, methodological quality, and funding source. Significant group differences favouring inhaled corticosteroids were noted in most secondary outcomes including patients with at least one exacerbation requiring hospital admission (N = 2715 participants; RR 3.33; 95% CI 1.02 to 10.94), the change from baseline FEV1 (N = 7128 participants; mean group difference (MD) 110 mL, 95% CI 140 to 80) as well as other lung function parameters, asthma symptoms, nocturnal awakenings, rescue medication use, symptom‐free days, the quality of life, parents' and physicians' satisfaction. Anti‐leukotriene therapy was associated with increased risk of withdrawals due to poor asthma control (N = 7669 participants; RR 2.56; 95% CI 2.01 to 3.27). For every thirty one (95% CI 22 to 47) patients treated with anti‐leukotrienes instead of inhaled corticosteroids, there was one additional withdrawal due to poor control. Risk of side effects was not significantly different between both groups.
Authors' conclusions
As monotherapy, inhaled corticosteroids display superior efficacy to anti‐leukotrienes in adults and children with persistent asthma; the superiority is particularly marked in patients with moderate airway obstruction. On the basis of efficacy, the results support the current guidelines' recommendation that inhaled corticosteroids remain the preferred monotherapy.
Background
Long‐acting beta2‐agonists (LABA) in combination with inhaled corticosteroids (ICS) are increasingly prescribed for children with asthma.
Objectives
To assess the safety and efficacy of ...adding a LABA to an ICS in children and adolescents with asthma. To determine whether the benefit of LABA was influenced by baseline severity of airway obstruction, the dose of ICS to which it was added or with which it was compared, the type of LABA used, the number of devices used to deliver combination therapy and trial duration.
Search methods
We searched the Cochrane Airways Group Asthma Trials Register until January 2015.
Selection criteria
We included randomised controlled trials testing the combination of LABA and ICS versus the same, or an increased, dose of ICS for at least four weeks in children and adolescents with asthma. The main outcome was the rate of exacerbations requiring rescue oral steroids. Secondary outcomes included markers of exacerbation, pulmonary function, symptoms, quality of life, adverse events and withdrawals.
Data collection and analysis
Two review authors assessed studies independently for methodological quality and extracted data. We obtained confirmation from trialists when possible.
Main results
We included in this review a total of 33 trials representing 39 control‐intervention comparisons and randomly assigning 6381 children. Most participants were inadequately controlled on their current ICS dose. We assessed the addition of LABA to ICS (1) versus the same dose of ICS, and (2) versus an increased dose of ICS.
LABA added to ICS was compared with the same dose of ICS in 28 studies. Mean age of participants was 11 years, and males accounted for 59% of the study population. Mean forced expiratory volume in one second (FEV1) at baseline was ≥ 80% of predicted in 18 studies, 61% to 79% of predicted in six studies and unreported in the remaining studies. Participants were inadequately controlled before randomisation in all but four studies.
There was no significant group difference in exacerbations requiring oral steroids (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.70 to 1.28, 12 studies, 1669 children; moderate‐quality evidence) with addition of LABA to ICS compared with ICS alone. There was no statistically significant group difference in hospital admissions (RR 1.74, 95% CI 0.90 to 3.36, seven studies, 1292 children; moderate‐quality evidence)nor in serious adverse events (RR 1.17, 95% CI 0.75 to 1.85, 17 studies, N = 4021; moderate‐quality evidence). Withdrawals occurred significantly less frequently with the addition of LABA (23 studies, 471 children, RR 0.80, 95% CI 0.67 to 0.94; low‐quality evidence). Compared with ICS alone, addition of LABA led to significantly greater improvement in FEV1 (nine studies, 1942 children, inverse variance (IV) 0.08 L, 95% CI 0.06 to 0.10; mean difference (MD) 2.99%, 95% CI 0.86 to 5.11, seven studies, 534 children; low‐quality evidence), morning peak expiratory flow (PEF) (16 studies, 3934 children, IV 10.20 L/min, 95% CI 8.14 to 12.26), reduction in use of daytime rescue inhalations (MD ‐0.07 puffs/d, 95% CI ‐0.11 to ‐0.02, seven studies; 1798 children) and reduction in use of nighttime rescue inhalations (MD ‐0.08 puffs/d, 95% CI ‐0.13 to ‐0.03, three studies, 672 children). No significant group difference was noted in exercise‐induced % fall in FEV1, symptom‐free days, asthma symptom score, quality of life, use of reliever medication and adverse events.
A total of 11 studies assessed the addition of LABA to ICS therapy versus an increased dose of ICS with random assignment of 1628 children. Mean age of participants was 10 years, and 64% were male. Baseline mean FEV1 was ≥ 80% of predicted. All trials enrolled participants who were inadequately controlled on a baseline inhaled steroid dose equivalent to 400 µg/d of beclomethasone equivalent or less.
There was no significant group differences in risk of exacerbation requiring oral steroids with the combination of LABA and ICS versus a double dose of ICS (RR 1.69, 95% CI 0.85 to 3.32, three studies, 581 children; moderate‐quality evidence) nor in risk of hospital admission (RR 1.90, 95% CI 0.65 to 5.54, four studies, 1008 children; moderate‐quality evidence).
No statistical significant group difference was noted in serious adverse events (RR 1.54, 95% CI 0.81 to 2.94, seven studies, N = 1343; moderate‐quality evidence) and no statistically significant differences in overall risk of all‐cause withdrawals (RR 0.96, 95% CI 0.67 to 1.37, eight studies, 1491 children; moderate‐quality evidence). Compared with double the dose of ICS, use of LABA was associated with significantly greater improvement in morning PEF (MD 8.73 L/min, 95% CI 5.15 to 12.31, five studies, 1283 children; moderate‐quality evidence), but data were insufficient to aggregate on other markers of asthma symptoms, rescue medication use and nighttime awakening. There was no group difference in risk of overall adverse effects, A significant group difference was observed in linear growth over 12 months, clearly indicating lower growth velocity in the higher ICS dose group (two studies: MD 1.21 cm/y, 95% CI 0.72 to 1.70).
Authors' conclusions
In children with persistent asthma, the addition of LABA to ICS was not associated with a significant reduction in the rate of exacerbations requiring systemic steroids, but it was superior for improving lung function compared with the same or higher doses of ICS. No differences in adverse effects were apparent, with the exception of greater growth with the use of ICS and LABA compared with a higher ICS dose. The trend towards increased risk of hospital admission with LABA, irrespective of the dose of ICS, is a matter of concern and requires further monitoring.
There is a plethora of interventions and policies aimed at changing practice habits of primary healthcare professionals, but it is unclear which are the most appropriate, sustainable, and effective. ...We aimed to evaluate the evidence on behavior change interventions and policies directed at healthcare professionals working in primary healthcare centers.
Study design: overview of reviews.
MEDLINE (Ovid), Embase (Ovid), The Cochrane Library (Wiley), CINAHL (EbscoHost), and grey literature (January 2005 to July 2015).
two reviewers independently, and in duplicate, identified systematic reviews, overviews of reviews, scoping reviews, rapid reviews, and relevant health technology reports published in full-text in the English language.
two reviewers extracted data pertaining to the types of reviews, study designs, number of studies, demographics of the professionals enrolled, interventions, outcomes, and authors' conclusions for the included studies. We evaluated the methodological quality of the included studies using the AMSTAR scale. For the comparative evaluation, we classified interventions according to the behavior change wheel (Michie et al.).
Of 2771 citations retrieved, we included 138 reviews representing 3502 individual studies. The majority of systematic reviews (91%) investigated behavior and practice changes among family physicians. Interactive and multifaceted continuous medical education programs, training with audit and feedback, and clinical decision support systems were found to be beneficial in improving knowledge, optimizing screening rate and prescriptions, enhancing patient outcomes, and reducing adverse events. Collaborative team-based policies involving primarily family physicians, nurses, and pharmacists were found to be most effective. Available evidence on environmental restructuring and modeling was found to be effective in improving collaboration and adherence to treatment guidelines. Limited evidence on nurse-led care approaches were found to be as effective as general practitioners in patient satisfaction in settings like asthma, cardiovascular, and diabetes clinics, although this needs further evaluation. Evidence does not support the use of financial incentives to family physicians, especially for long-term behavior change.
Behavior change interventions including education, training, and enablement in the context of collaborative team-based approaches are effective to change practice of primary healthcare professionals. Environmental restructuring approaches including nurse-led care and modeling need further evaluation. Financial incentives to family physicians do not influence long-term practice change.
Background
Inhaled anticholinergics given in addition to β2‐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 β2‐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 s. The search is current to November 2013.
Selection criteria
Randomised trials comparing the combination of inhaled or nebulised anticholinergics and short‐acting β2‐agonists versus short‐acting β2‐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 β2‐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 β2‐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 β2‐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 β2‐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.
Background
Daily inhaled corticosteroids (ICS) are the recommended mainstay of treatment in children and adults with persistent asthma. However, often, ICS are used intermittently by patients or ...recommended by physicians to be used only at the onset of exacerbations.
Objectives
The aim of this review was to compare the efficacy and safety of intermittent versus daily ICS in the management of children and adults with persistent asthma and preschool‐aged children suspected of persistent asthma.
Search methods
We searched the Cochrane Airways Group Specialised Register of trials (CAGR) and the ClinicalTrials.gov web site up to October 2012.
Selection criteria
We included randomised controlled trials (RCTs) that compared intermittent ICS versus daily ICS in children and adults with persistent asthma. No co‐interventions were permitted other than rescue relievers and oral corticosteroids used during exacerbations.
Data collection and analysis
Two review authors independently assessed trials for inclusion, methodological quality and extracted data. The primary efficacy outcome was the number of patients with one or more exacerbations requiring oral corticosteroids and the primary safety outcome was the number of patients with serious adverse health events. Secondary outcomes included exacerbations, lung function tests, asthma control, adverse effects, withdrawal rates and inflammatory markers. Equivalence was assumed if the risk ratio (RR) estimate and its 95% confidence interval (CI) were between 0.9 and 1.1. Quality of the evidence was assessed using GRADE.
Main results
Six trials (including one trial testing two relevant protocols) met the inclusion criteria for a total of seven group comparisons. The four paediatric trials (two involving preschool children and two school‐aged children) and two adult parallel‐group trials, lasting 12 to 52 weeks, were of high methodological quality. A total of 1211 patients with confirmed, or suspected, persistent asthma contributed to the meta‐analyses. There was no statistically significant group difference in the risk of patients experiencing one or more exacerbations requiring oral corticosteroids (1204 patients; RR 1.07; 95% CI 0.87 to 1.32; the large confidence interval translates into a risk of exacerbations in the intermittent ICS group varying between 17% and 25%, assuming a 19% risk with daily ICS). Age, severity of airway obstruction, step‐up protocol used during exacerbations and trial duration did not significantly influence the primary efficacy outcome. No group difference was observed in the risk of patients with serious adverse health events (1055 patients; RR 0.82; 95% CI 0.33 to 2.03). Compared to the daily ICS group, the intermittent ICS group displayed a smaller improvement in change from baseline peak expiratory flow rate (PEFR) by 2.56% (95% CI ‐4.49% to ‐0.63%), fewer symptom‐free days (standardised mean difference (SMD) ‐0.15 (95% CI ‐0.28 to ‐0.03), fewer asthma control days ‐9% (95% CI ‐14% to ‐4%), more use of rescue β2‐agonists by 0.12 puffs/day (95% CI 0 to 0.23) and a greater increase from baseline in exhaled nitric oxide of 16.80 parts per billion (95% CI 11.95 to 21.64). There was no significant group difference in forced expiratory volume in one second (FEV1), quality of life, airway hyper‐reactivity, adverse effects, hospitalisations, emergency department visits or withdrawals. In paediatric trials, intermittent ICS (budesonide and beclomethasone) were associated with greater growth by 0.41 cm change from baseline (532 children; 95% CI 0.13 to 0.69) compared to daily treatment.
Authors' conclusions
In children and adults with persistent asthma and in preschool children suspected of persistent asthma, there was low quality evidence that intermittent and daily ICS strategies were similarly effective in the use of rescue oral corticosteroids and the rate of severe adverse health events. The strength of the evidence means that we cannot currently assume equivalence between the two options.. Daily ICS was superior to intermittent ICS in several indicators of lung function, airway inflammation, asthma control and reliever use. Both treatments appeared safe, but a modest growth suppression was associated with daily, compared to intermittent, inhaled budesonide and beclomethasone. Clinicians should carefully weigh the potential benefits and harm of each treatment option, taking into account the unknown long‐term (> one year) impact of intermittent therapy on lung growth and lung function decline.
Background
International guidelines advocate using daily inhaled corticosteroids (ICS) in the management of children and adults with persistent asthma. However, in real world clinical settings, these ...medicines are often used at irregular intervals by patients. Recent evidence suggests that the use of intermittent ICS, with treatment initiated at the time of early symptoms, may still have benefits for reducing the severity of an asthma exacerbation.
Objectives
To compare the efficacy and safety of intermittent ICS versus placebo in the management of children and adults diagnosed with, or suspected to have, symptoms of mild persistent asthma.
Search methods
We searched the Cochrane Airways Group Specialised Register of trials (CAGR), the ClinicalTrials.gov website and the World Health Organization (WHO) trials portal in March 2015.
Selection criteria
We included randomised controlled trials (RCTs) that compared intermittent ICS versus placebo in children and adults with symptoms of persistent asthma. No co‐interventions were permitted other than rescue relievers and oral corticosteroids used during exacerbations.
Data collection and analysis
Two review authors independently assessed trials for inclusion, methodological quality and extracted data. The primary efficacy outcome was the risk of asthma exacerbations requiring oral corticosteroids and the primary safety outcome was serious adverse health events. Secondary outcomes included exacerbations, lung function tests, asthma control, adverse effects, and withdrawal rates. Quality of the evidence was assessed using the GRADE criteria.
Main results
Six trials (representing 490 preschool children, 145 school‐aged children and 240 adults) met the inclusion criteria. Study durations were 12 to 52 weeks. Results for preschool children were presented in a separate analysis as this represents a distinct clinical condition, not necessarily related to the development of long term asthma.
There was a reduction in the risk of patients experiencing one or more exacerbations requiring oral corticosteroids in older children (145 participants, odds ratio (OR) 0.57; 95% confidence interval (CI) 0.29 to 1.12, low quality evidence) and adults with asthma (240 participants, OR 0.10; 95% CI 0.01 to 1.95, low quality evidence). These analyses were each based on the findings of a single study. No group difference was observed in the risk of serious adverse health events (385 participants; OR 1.00; 95% CI 0.14 to 7.25, moderate quality evidence). Compared to the placebo group, there was an insufficient number of participants to make firm conclusions whether the intermittent ICS group displayed any reduction in the rate of hospitalisations, day time and night time symptoms scores, or adverse events. Lung function tests reported by a single study favoured the use of ICS. There was no significant group difference in growth rate of children, or overall withdrawals.
In preschool children with frequent wheezing episodes, the use of intermittent ICS at the onset of early symptoms reduced the likelihood of requiring rescue oral corticosteroids by half (490 participants; OR: 0.48; 95% CI 0.31 to 0.73, moderate quality evidence with minimal heterogeneity). Intermittent therapy was associated with fewer serious adverse events (439 participants; OR 0.42; 95% CI 0.17 to 1.02, low quality evidence). There was no significant difference in hospitalisations or in a single study measuring parent perceived quality of life. However, intermittent therapy was associated with improvements in both day time and night time symptoms. There was no increase in the rates of withdrawals, and overall and treatment‐specific adverse events.
Authors' conclusions
In children and adults with mild persistent asthma, two studies have shown that the use of intermittent ICS at the time of exacerbation reduced the chances of needing oral corticosteroids by half. This result is statistically significant if we assume that the effect size is the same for each study population (fixed effects model), but is not statistically significant when using a random effects model. However, the paucity of published evidence limits our conclusions towards the 'as‐needed' use of this medication. The small number of studies and participants were the major reasons for downgrading the overall quality of the findings. A corresponding result was found in preschool children with wheeze. In this age group, an improvement in day time and night time asthma symptoms score and parental perceived quality of life of children similarly favoured the ICS group. However, there was no statistical difference in hospitalisation rates in any group. This treatment was not associated with any significant increase in adverse events. There was no growth suppression noted with the use of intermittent ICS in either preschool or school‐aged children. Considering the limited number of available studies, we emphasise the need for more randomised controlled studies in order to confirm these findings.
Inhaled anticholinergics given in addition to β2-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.
To assess the efficacy and safety of anticholinergics added to β2-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.
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.
Randomised trials comparing the combination of inhaled or nebulised anticholinergics and short-acting β2-agonists versus short-acting β2-agonists alone in children one to 18 years of age hospitalised for an acute asthma exacerbation were eligible.
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 β2-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.
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 β2-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 β2-agonists spaced at four hours or longer, asthma clinical scores, lung function and overall withdrawals for any reason.
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 β2-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.
Background
In the treatment of children with mild persistent asthma, low‐dose inhaled corticosteroids (ICS) are recommended as the preferred monotherapy (referred to as step 2 of therapy). In ...children with inadequate asthma control on low doses of ICS (step 2), asthma management guidelines recommend adding an anti‐leukotriene agent to existing ICS as one of three therapeutic options to intensify therapy (step 3).
Objectives
To compare the efficacy and safety of the combination of anti‐leukotriene agents and ICS to the use of the same, an increased, or a tapering dose of ICS in children and adolescents with persistent asthma who remain symptomatic despite the use of maintenance ICS. In addition, we wished to determine the characteristics of people or treatments, if any, that influenced the magnitude of response attributable to the addition of anti‐leukotrienes.
Search methods
We identified trials from the Cochrane Airways Group Specialised Register of Trials (CAGR), which were derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, AMED, and CINAHL; and the handsearching of respiratory journals and meeting s, as well as the www.clinicaltrials.gov website. The search was conducted until January 2013.
Selection criteria
We considered for inclusion randomised controlled trials (RCTs) conducted in children and adolescents, aged one to 18 years, with asthma, who remained symptomatic despite the use of a stable maintenance dose of ICS and in whom anti‐leukotrienes were added to the ICS if they were compared to the same, an increased, or a tapering dose of ICS for at least four weeks.
Data collection and analysis
We used standard methods expected by The Cochrane Collaboration.
Main results
Five paediatric (parallel group or cross‐over) trials met the inclusion criteria. We considered two (40%) trials to be at a low risk of bias. Four published trials, representing 559 children (aged ≥ six years) and adolescents with mild to moderate asthma, contributed data to the review. No trial enrolled preschoolers. All trials used montelukast as the anti‐leukotriene agent administered for between four and 16 weeks. Three trials evaluated the combination of anti‐leukotrienes and ICS compared to the same dose of ICS alone (step 3 versus step 2). No statistically significant group difference was observed in the only trial reporting participants with exacerbations requiring oral corticosteroids over four weeks (N = 268 participants; risk ratio (RR) 0.80, 95% confidence interval (CI) 0.34 to 1.91). There was also no statistically significant difference in percentage change in FEV₁ (forced expiratory volume in 1 second) with mean difference (MD) 1.3 (95% CI ‐0.09 to 2.69) in this trial, but a significant group difference was observed in the morning (AM) and evening (PM) peak expiratory flow rates (PEFR): N = 218 participants; MD 9.70 L/min (95% CI 1.27 to 18.13) and MD 10.70 (95% CI 2.41 to 18.99), respectively. One trial compared the combination of anti‐leukotrienes and ICS to a higher‐dose of ICS (step 3 versus step 3). No significant group difference was observed in this trial for participants with exacerbations requiring rescue oral corticosteroids over 16 weeks (N = 182 participants; RR 0.82, 95% CI 0.54 to 1.25), nor was there any significant difference in exacerbations requiring hospitalisation. There was no statistically significant group difference in withdrawals overall or because of any cause with either protocol. No trial explored the impact of adding anti‐leukotrienes as a means to taper the dose of ICS.
Authors' conclusions
The addition of anti‐leukotrienes to ICS is not associated with a statistically significant reduction in the need for rescue oral corticosteroids or hospital admission compared to the same or an increased dose of ICS in children and adolescents with mild to moderate asthma. Although anti‐leukotrienes have been licensed for use in children for over 10 years, the paucity of paediatric trials, the absence of data on preschoolers, and the variability in the reporting of relevant clinical outcomes considerably limit firm conclusions. At present, there is no firm evidence to support the efficacy and safety of anti‐leukotrienes as add‐on therapy to ICS as a step‐3 option in the therapeutic arsenal for children with uncontrolled asthma symptoms on low‐dose ICS.
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