Agonists In Children Research Articles

Comparative Efficacy and Safety of Glucagon-like Peptide-1 Receptor Agonists in Children and Adolescents with Obesity or Overweight: A Systematic Review and Network Meta-Analysis.

Four glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been used in children and adolescents with obesity or overweight. This network meta-analysis was conducted to compare the efficacy and safety of these regimens. Embase, PubMed, and Scopus were searched on March 2023 and updated in June 2024 for eligible randomized controlled trials (RCTs). The primary efficacy outcomes were mean difference in actual body weight, BMI (body mass index), BMI z score, and waist circumference. Safety outcomes included nausea, vomiting, diarrhea, abdominal pain, injection-site reaction, and hypoglycemia. Eleven RCTs with 953 participants were eligible. Semaglutide exhibited greater effects in reducing weight, BMI, and BMI z score versus the placebo. Semaglutide was associated with greater weight loss and BMI z score reduction in comparison with exenatide, liraglutide, and dulaglutide. Semaglutide also significantly decreased BMI than exenatide. None of the four GLP-1 RAs were associated with higher risks of diarrhea, headache, and abdominal pain versus the placebo. Liraglutide was more likely to cause nausea, vomiting, hypoglycemia, and injection-site reactions than the placebo. Liraglutide also had higher odds of causing injection-site reactions than other GLP-1 RAs. Semaglutide appeared to be the most effective and safe option among four GLP-1 RAs in children and adolescents with obesity or overweight.

Alpha-2 Agonists in Children and Adolescents With Post-traumatic Stress Disorder: A Systematic Review.

Exposure to traumatic stress is common among children.Post-traumatic stress disorder (PTSD) is a debilitating chronic mental disorder that can develop following exposure to a traumatic event. Psychopharmacological research in pediatric PTSD is limited. There is some evidence supporting the use of alpha-2 (α2)agonists for symptoms associated with PTSD. This systematic review identified published studies evaluating the effectiveness of α2 agonists in treating PTSD symptoms in children and adolescents. We conducted an extensive literature search on PubMed, MEDLINE, EMBASE, Cochrane Collaboration, and PsycINFO databases for published articles that evaluated the use of α2agonists (clonidine and guanfacine) for treating symptoms of PTSD in children and adolescents. The study protocol was registered in Prospero (ID: CRD42021273692) and followed the PRISMA guidelines. A total of 10 published articles about clonidine or guanfacine use in PTSD in children and adolescents were identified. Studies found clonidine effective in reducing PTSD symptoms; however, the effects were variable. Clonidine and guanfacine showed effectiveness in treating nightmares, hyperarousal, aggression, and sleep disturbances and reducing re-experiencing, avoidant, and hyperarousal symptom clusters. No randomized, double-blind, placebo-controlled trials were found during the literature search. α2 agonists' effectiveness in treating symptoms associated with PTSD in children and adolescents is preliminary. Future placebo-controlled trials are needed to assess the efficacy and safety of α2 agonists.

Utilization of glucagon-like peptide-1 receptor agonists in children and adolescents in China: a real-world study.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been widely used in treating type 2 diabetes mellitus (T2DM) and obesity in adults, but scientific research about the indication in children and adolescents is scarce. The current study aims to explore the prescriptions of GLP-1RAs in children and adolescents in China and to evaluate its rationality. GLP-1RA prescriptions of children and adolescents were retrospectively obtained from the Hospital Prescription Analysis Cooperative Project. The study extracted information on patient's demographic characteristics, monotherapy and combination therapy of GLP-1RAs, and trends in GLP-1RA usage from 2016 to 2021. The rationality of GLP-1RA prescriptions was comprehensively assessed based on the indications approved by China National Medical Products Administration (NMPA), the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA), Pharmaceuticals and Medical Devices Agency (PMDA), and published randomized controlled trials (RCTs). A total of 234 prescriptions from 46 hospitals were included, with a median age of 17 years old. The majority of patients were diagnosed with overweight/obesity or prediabetes/diabetes, accounting for 43.59% and 46.15%, respectively. There were 88 patients on GLP-1RA monotherapy. GLP-1RAs plus metformin was the most common combination therapy (38.89%). 12.39% of patients were found a co-administration with orlistat. The share of overweight/obesity prescriptions increased from 27% in 2016 to 54% in 2021, whereas prediabetes/diabetes prescriptions declined from 55% to 42%. The prescriptions were divided into appropriate and questionable groups according to the diagnosis, and the potentially questionable prescription was related to age (p = 0.017), department visited (p = 0.002), and any hospitalization (p < 0.001). This study described the prescribing of GLP-1RAs in children and adolescents. Our findings indicated that the utilization of GLP-1RAs has increased from 2016 to 2021. There was a strong basis for administering GLP-1RAs in overweight/obesity and prediabetes/diabetes, whereas the evidence was insufficient in other conditions. It is crucial to demand robust and sustained efforts to enhance the awareness of the safety of utilization of GLP-1RAs in children and adolescents.

Variability of the pharmacological response in children with different ADRB2 gene polymorphisms in recurrent bronchial obstruction and bronchial asthma

To date, methods of studying the effects of drugs at the molecular-genetic level are widely used in pediatric practice. The aim of our work was to evaluate the effectiveness of the effect of β2-agonists on the clinical course of recurrent bronchial obstruction (RBO) in children, depending on the variants of polymorphism of the ADRB2 gene. The effectiveness of salbutamol in children with RBO and bronchial asthma(BA) was evaluated depending on the distribution of alleles and genotypes of the ADRB2 Argl6Gly and Gln27Glu genes according to the degree of reversibility of bronchial obstruction. In the group of children with RBO carriers of the heterozygous A/G genotype of the Arg16Gly locus and the Gln27Glu locus of the ADRB2 gene, high efficacy of salbutamol therapy as a bronchodilator was noted. At the same time, in children with RBO representatives of the G/G genotype, the effectiveness of using the drug is low. In children with BA, the change in functional activity is associated with the polymorphism of the Gln27Glu gene locus and is associated with a low therapeutic response to β2–agonists in children with the G\G mutational genotype and a good effect in carriers of the homozygous variant with the A/A genotype. Knowledge of the genotype of polymorphic variants of the ADRB2 gene will make it possible to evaluate one of the factors of predisposition and effectiveness of therapy in the recurrent course of bronchial obstruction syndrome and bronchial asthma.

β3-Adrenoceptor Agonist for the Treatment of Bladder Dysfunction in Children: A Systematic Review and Meta-Analysis.

ß3-adrenergic receptor agonists (ß3 agonists) have been used in treatment of overactive bladder (OAB) and neurogenic detrusor overactivity (NDO) in adults. However, their use in children has only recently been approved by the U.S. Food and Drug Administration for patients with NDO. As in adults, the role of ß3 agonists in children may include conditions such as OAB. This systematic review and meta-analysis aims to understand the intended use, efficacy and safety of ß3 agonists in the pediatric population. A literature search was performed in February 2021 across MEDLINE®, Embase®, Scopus®, the Cochrane Library and ClinicalTrials.gov. No language restrictions were placed. All records describing the clinical use of ß3 agonists in pediatric patients (<18 years of age) were included, regardless of the methodological design or outcomes assessed. The identified records were screened by 2 independent authors. The reporting was compliant with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. Data extraction was performed by 2 independent reviewers, blinded to each other's extractions. The data were pooled using the fixed effects model. Of 367 records identified, 8 studies were included in the review (3 prospective and 5 retrospective). ß3 agonists led to improvements in both urodynamics parameters and self-reported outcomes such as incontinence. Commonly reported side effects were headaches (3%‒5.9%), constipation (3.5%‒5.7%), rhinitis/nasopharyngitis (1.7%‒5.8%) and blurred vision (1.7%‒2.9%). Clinically meaningful changes in safety outcomes (blood pressure, heart rate, electrocardiogram-related changes, liver function) were rare. Before and after ß3 agonist use, pooled effect estimates for maximum cystometric capacity for 171 patients were mean difference of +98.84 ml (95% CI 74.72, 122.96); for complete dryness, assessment of 235 patients showed a Peto odds ratio of 8.68 (95% CI 5.22, 14.45). ß3 agonists appear to be a promising, effective and safe alternative/adjunctive therapy in management of pediatric NDO or OAB, with improvements in both objective urodynamics parameters and subjective patient-reported outcomes following their use.

Electrocardiogram Changes Following the Treatment with Gonadotropin-Releasing Hormone Agonists in Patients with Precocious Puberty

Background: GnRH agonists are the standard treatment for precocious puberty. Studies on the side effects of these drugs in adults have shown that these drugs may cause changes in ECG and some cardiovascular effects; however, few studies have evaluated these effects in children. This study aims to investigate the effect of these drugs on ECG intervals in children with precocious puberty.Methods: In this study with a pre-post design 50 children with precocious puberty referred to the endocrinology clinic of Tabriz Children's Hospital in 2019 for receiving GnRH agonists were included. From all patients, ECGs were obtained before starting the treatment and then 6, 12, and 18 weeks later and PR, QRS, and QTc intervals were extracted from ECG records.Results: The mean age of the participants was 91±9 months including 48 (96%) girls and 2 (4%) boys. Triptorelin (GnRH agonist) was administered for all patients with the standard protocol. Comparison of pre- and post-treatment ECG intervals showed that the drug did not cause a significant change in PR (p = 0.535) and QTc (p = 0.250) intervals, whilst there was a significant increase in QRS interval after the treatment (p = 0.001).Conclusion: The use of GnRH agonists in children can lead to some changes in ECG records by increasing in QRS intervals; and ECG could be used as a tool to detect these changes. Further studies are also needed to identify ECG changes in larger sample sizes and longer intervals.

50.8 Alpha-2 Agonists in Children and Adolescents With PTSD: A Systematic Review

50.8 Alpha-2 Agonists in Children and Adolescents With PTSD: A Systematic Review

Intestinal Guanylate Cyclase-C mRNA Expression in Duodenum and Colon of Children.

Guanylate cyclase-C (GC-C) agonists, which increase intestinal secretion and accelerate transit, are used to treat chronic constipation and constipation-predominant irritable bowel syndrome and are being evaluated for pediatric use. Prior studies suggest GC-C receptor density may be higher in young children, potentially amplifying GC-C agonism with treatment implications. We aimed to quantitate duodenal and colonic GC-C mRNA expression in children. Mucosal biopsies were obtained from subjects aged 6 months to 18 years during clinically indicated upper, that is, esophago-gastro-duodenal, and/or colonic endoscopy. Tissue samples without histologic abnormalities were grouped by subject age (<24 months, 24 months to <6 years, 6 to <12 years, and 12 to <18 years) and analyzed for GC-C mRNA expression by qPCR. The relationship between GC-C mRNA levels and age was modeled using regression analyses. Ninety-nine subjects underwent upper endoscopy/colonoscopy; 93 had evaluable samples. Mean relative GC-C mRNA expression was 2.36 (range 2.21-2.46) for duodenal samples and 1.56 (range 1.22-1.91) for colonic samples. Predicted and observed normalized GC-C mRNA expression in each region were comparable among age groups. Pooled expression by region demonstrated lower expression in colonic versus duodenal samples. Uniform levels of GC-C mRNA expression were detected in children aged >6 months in the duodenum and >12 months in the colon. Higher expression was observed in all age groups in duodenal versus colonic samples, indicating regional variability in GC-C receptor density. These data are reassuring for further studies of GC-C agonists in children.

Safety and Efficacy of Glucagon-Like Peptide-1 Receptor Agonists in Children and Adolescents with Obesity: A Meta-Analysis

To determine the weight, body mass index (BMI), cardiometabolic, and gastrointestinal effects of glucagon-like peptide-1 (GLP-1) receptor agonists in children with obesity. Web of Science, PubMed/MEDLINE, and Scopus databases from 01/01/1994-01/01/2021 for randomized control trials examining the weight, BMI, cardiometabolic, or gastrointestinal effects of GLP-1 receptor agonists in children and adolescents with obesity. Data were extracted by 2 independent surveyors and a random effects model was applied to meta-analyze generic inverse variance outcomes. Primary outcomes were related to weight and cardiometabolic profile, and secondary outcomes of interest were gastrointestinal-related treatment-emergent adverse events. Nine studies involving 574 participants were identified, of which 3 involved exenatide and 6 involved liraglutide. GLP-1 receptor agonists use caused a modest reduction in body weight (mean difference [MD] -1.50 [-2.50,-0.50] kg, I2 64%), BMI (MD -1.24 [-1.71,-0.77] kg/m2, I2 0%), and BMI z score (MD -0.14 [-0.23,-0.06], I2 43%). Glycemic control was improved in children with proven insulin resistance (glycated hemoglobin A1c MD -1.05 [-1.93,-0.18] %, I2 76%). Although no lipid profile improvements were noted, a modest decrease in systolic blood pressure was detected (MD -2.30 [-4.11,-0.49] mm Hg; I2 0%). Finally, analysis of gastrointestinal-related treatment-emergent adverse events revealed an increased risk of nausea (risk ratio 2.11 [1.44, 3.09]; I2 0%), without significant increases in other gastrointestinal symptoms. This meta-analysis indicates that GLP-1 receptor agonists are safe and effective in modestly reducing weight, BMI, glycated hemoglobin A1c, and systolic blood pressure in children and adolescents with obesity in a clinical setting, albeit with increased rates of nausea. CRD42020195869.

Discordant use of short‐acting β2 agonists in children and adults with severe, uncontrolled asthma from the U‐BIOPRED cohort

Discordant use of short‐acting β₂ agonists in children and adults with severe, uncontrolled asthma from the U‐BIOPRED cohort

Relation between Substitution of Threonine for Isoleucine at Β2 Adrenergic Receptor on Bronchial Asthma in Children

Introduction: Pediatric asthma is a complex disorder involving immunologic, genetic, environmental and other factors. Objective: To evaluate the role of substitution of threonine for isoleucine at codon 164 on bronchial asthma susceptibility, severity and response to short- and long- term acting β2-adrenergic receptor agonists in children. Patients and Methods: This study was a prospective case control study, which was done in Pediatric Department of Zagazig University Hospital from Pulmonology Clinic in the period from February 2016 to February 2018. 100 children were included, 50 of them had asthma with bronchodilator and their ages ranged from 5 to 12 years (25 males and 25 females) with the mean age of 6.8 ± 2.5 years. In addition, 50 healthy age and sex matched worked as control children. All studied groups were subjected to full history taking, clinical examination, pulmonary function tests, total serum IgE and identification of adrenergic β2 receptor (ADRβ2) substitution of threonine for isoleucine at codon 164 polymorphism. Results: In this study, there was a significant association between homozygous isoleucine and increase incidence of asthma, this mean that the gene gives harmful effect when it is in a homozygous form. However, there was no statistically significant difference between asthma severity and gene polymorphism (CC, CT and TT). Conclusion: In the present study ADRβ Thr164Ile polymorphism is reported as an important variant at salbutamol refractoriness in sever asthmatics. In addition, the polymorphism form is susceptible variant to develop asthma risk.

Thrombopoietin Receptor Agonists in Children with Immune Thrombocytopenia: A New Therapeutic Era.

Immune thrombocytopenia (ITP) is a common bleeding disorder in childhood. The management of ITP in children is controversial, requiring personalized assessment of patients and therapeutic choices. Thrombopoietin receptor agonists (TPO-RAs), eltrombopag and romiplostim, have been shown to be safe and effective for the treatment of pediatric ITP. The aim of our research is to define the role of thrombopoietin receptor agonists in the management of pediatric ITP. This review focuses on the use of TPO-RAs in pediatric ITP, in randomized trials and in clinical routine, highlighting their key role in the management of the disease. Eltrombopag and romiplostim appear effective treatment options for children with ITP. Several clinical studies have assessed that the use of TPO-RAs increases platelet count, decreases bleeding symptoms and improves health-related quality of life. Moreover, TPO-RAs are well tolerated with minor side effects. Although long term efficacy and safety of TPO-RAs still require further investigations, their use is gradually expanding in the clinical practice of children with ITP.

Do Beta –2 Agonists Reduce Admission Rate in Children With Bronchiolitis?

Introduction: Bronchiolitis is a very common disease in children less than 2 years of age. RSV virus is the major cause of this illness and its admissions represent 18 % of all pediatric hospitalization in infant less than 1 year of age. Globally, RSV infections in children less than 5 years of age account for 3.4 million hospitalizations and the admission rate has relatively increased during the last 15 years, despite the routine use of Beta-2 agonists in children with bronchiolitis in emergency departments. Methods: The aim is to determine from the medical literature whether the use of Albuterol in children (less than 2 years of age) with bronchiolitis, reduce admission rate or not? PubMed, Scopus, web of science and OneFile gale were searched, 1591 articles identified. Randomized controlled trials that comparing Albuterol group recipients with placebo recipients in children (less than 2 years of age) were only included in this study. Results: 7 (RCT)s representing 670 patients with bronchiolitis published between 1990 to 2011, Risk of bias generally low and quality of evidence are high, (100%) of included studies have concluded that Beta-2 agonists did not reduce Admission rate in children with bronchiolitis (16.5% in Albuterol group vs 20% in placebo group [ odd ratio 0.74 , P = 0.20, confidence interval (CI) = (0.47 - 1.16) ]. Conclusion: Use of Beta-2 Agonists in children (less than 2 years of age) with bronchiolitis do not reduce the admission rate.

Efficacy and safety of thrombopoietin receptor agonists in children with chronic immune thrombocytopenic purpura: meta-analysis

Immune thrombocytopenic purpura (ITP) is an autoimmune disorder presenting with low platelet count <100 × 109/L. The condition affects both adults and children. Thrombopoietin receptor agonists (TPO-RAs) are second-line of therapy that includes Romiplostim and Eltrombopag, which stimulate the production of normally functioning platelets. Although the biological effect of these drugs is well established, there has not been a meta-analysis in children. To estimate the efficacy and safety of Romiplostim and Eltrombopag, we performed a systematic review and meta-analysis in children with chronic ITP. Systematic literature search was conducted in the following database: PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL). Review Manager 5.3 for Windows was used to analyze the data. Five randomized controlled trials with total of 261 pediatric patients from 1–17 years of age were included. The efficacy and safety analysis showed TPO-RA groups were superior over placebo, and there was no difference in adverse event occurrence between TPO-RA (Romiplostim and Eltrombopag) and placebo groups. The efficacy and safety of Eltrombopag did not differ significantly from those of Romiplostim. Both drugs were effective in treatment of children with chronic ITP. Our findings extend the currently available data on ITP treatment and is helpful for pediatric health providers and for the design of future clinical trials.

Trends in the "Off-Label" Use of GnRH Agonists Among Pediatric Patients in the United States.

Gonadotropin-releasing hormone (GnRH) agonists are FDA approved for the treatment of precocious puberty. The therapy consists of histrelin acetate (Supprelin), a surgically implanted device, or Lupron injections. In recent years, the use of these agents has been extended to include the off-label treatment of children with normally timed puberty. Trends in the off-label use of GnRH agonists in children across the U.S. have not been previously described in the literature. We analyzed data on the use of Supprelin and Lupron reported to the Pediatric Health Information System (PHIS) from 2013 to 2016 to determine the trends in both the FDA-approved and off-label uses of these medications. We identified a stable cohort of 39 children's hospitals administering GnRH agonist therapies from 2013 to 2016. During this period, the annual number of children treated with these medications for precocious puberty increased modestly, from 283 to 303; meanwhile, the fraction of children receiving therapy for an off-label indication more than doubled, from 12% (39 of 322 total patients) to 29% (125 of 428 total patients). Privately insured patients were more likely to be treated for an off-label indication (13%; 119 out of 883 patients) than Medicaid patients (8%; 58 out of 706 patients; χ2[1] = 10.97, P = .00093). From 2013 to 2016, the proportion of children treated with GnRH agonists for an off-label indication notably increased. The number of children treated for precocious puberty modestly increased. Private insurance coverage was associated with higher rates of off-label use.

Efficacy and safety of thrombopoietin receptor agonists in children with chronic immune thrombocytopenia: a meta-analysis.

Background and AimThrombopoietin receptor agonists (TPO-RAs) have been shown to be safe and effective for adults with chronic immune thrombocytopenia (ITP). The aim of this meta-analysis is to assess the efficacy and safety of thrombopoietin receptor agonists for children with chronic ITP.Materials and MethodsClinical randomized controlled trials (RCTs) evaluating the efficacy and safety of TPO-RAs in pediatric ITP patients published up to June 2017 were retrieved from PubMed, Cochrane Library, and Embase databases. Relevant data were extracted, and the Physiotherapy Evidence Database scale was used to assess the methodological quality. Stata/SE 12.0 was used to perform a meta-analysis.ResultsSeven RCTs were included, with 238 patients and 107 patients in the TPO-RA group and the control group, respectively. Assessing efficacy, better results were found in the TPO-RA group for the rate of overall platelet response, durable response, and rescue medication needed. Furthermore, the TPO-RA group yielded superior results in the incidence of clinically significant bleeding events but had a comparable result in the incidence of any bleeding events and severe bleeding events. No significant difference was found between the two groups in health-related quality of life and parental burden. Assessing safety, no significant difference was found between the two groups in the incidence of any adverse events and severe adverse events.ConclusionsTPO-RAs are effective and safe agents for the treatment of chronic ITP in pediatric patients. Eltrombopag appears to be better than romiplostim in terms of the rate of rescue medication needed and clinically significant bleeding events.

Thrombopoietin-receptor agonists in children with immune thrombocytopenia

Thrombopoietin-receptor agonists in children with immune thrombocytopenia

Addition of intravenous beta(2)-agonists to inhaled beta(2)-agonists for acute asthma.

Inhaled beta-agonist therapy is central to the management of acute asthma. This review evaluates the benefit of an additional use of intravenous beta(2)-agonist agents. To determine the benefit of adding intravenous (IV) beta(2)-agonists to inhaled beta(2)-agonist therapy for acute asthma treated in the emergency department. Randomised controlled trials (RCTs) were identified using the Cochrane Airways Group Register which is a compilation of systematic searches of MEDLINE, EMBASE, CINAHL, and CENTRAL as well as handsearching of 20 respiratory journals. Bibliographies from included studies and known reviews were also searched. Primary authors and content experts were contacted to identify eligible studies. The search was performed in September 2012. Only RCTs were considered for inclusion. Studies were included if patients presented to the emergency department with acute asthma and were treated with IV beta(2)-agonists with inhaled beta(2)-agonist therapy and existing standard treatments versus inhaled beta(2)-agonists and existing standard treatments. Two review authors independently extracted data and confirmed their findings with corresponding authors of trials. We obtained missing data from authors or calculated from data present in the papers. We used fixed-effect model for odds ratios (OR) and for mean differences (MD) we used both fixed-effect and random-effects models and reported 95% confidence intervals (CI). From 109 potentially relevant studies only three (104 patients) met our inclusion criteria: Bogie 2007 (46 children), Browne 1997 (29 children) and Nowak 2010 (29 adults). Bogie 2007 investigated the addition of intravenous terbutaline to high dose nebulised albuterol in children with acute severe asthma, requiring intensive care unit (ICU) admission. Browne 1997 investigated the benefit of adding intravenous salbutamol to inhaled salbutamol in children with acute severe asthma in the emergency department. Nowak 2010 investigated addition of IV bedoradrine to standard care (nebulised albuterol, ipratropium and oral corticosteroids) among adults, and was reported as a conference abstract only.There was no significant advantage (OR 0.29; 95%CI 0.06 to 1.38, one trial, 29 adults) for adding IV bedoradrine to standard care (nebulised albuterol, ipratropium and oral corticosteroids) with regard to hospitalisation rates.Various outcome indicators for the length of stay were reported among the trials. Browne 1997 reported a significantly shorter recovery time (in terms of cessation of 30 minute salbutamol) for children in the IV salbutamol with inhaled salbutamol group (four hours) versus the 11.1 hours for the inhaled salbutamol group (P = 0.03). Time to cessation of hourly nebuliser was also significantly shorter (P = 0.02) for the IV plus inhaled salbutamol group (11.5 hours versus 21.2 hours), and they were ready for emergency patient discharge on average 9.7 hours earlier than the inhaled salbutamol group (P < 0.05). In a paediatric ICU study Bogie 2007 reported no significant advantage in length of paediatric ICU admission (hours) for adding IV terbutaline to nebulised albuterol (MD -12.95, 95% CI: -38.74, 12.84).Browne 1997 reported there were only six out of 14 children with a pulmonary index score above six in the IV plus inhaled salbutamol group at two hours compared with 14 of the 15 in the inhaled salbutamol group (P = 0.02)In Browne 1997 there was a higher proportion of tremor in the IV plus inhaled salbutamol group than in the inhaled salbutamol group (P < 0.02). Nowak 2010 did not report any statistically significant adverse effects associated with adding IV bedoradrine to standard care (nebulised albuterol, ipratropium and oral corticosteroids). Troponin levels were elevated in three children in the IV terbutaline + nebulised albuterol group at 12 and 24 hours in Bogie 2007 There is very limited evidence from one study (Browne 1997) to support the use of IV beta(2)-agonists in children with severe acute asthma with respect to shorter recovery time, and similarly there is limited evidence (again from one study Browne 1997) suggesting benefit with regard to pulmonary index scores; however this advantage needs to be considered carefully in relation to the increased side effects associated with IV beta(2)-agonists. We identified no significant benefits for adults with severe acute asthma. Until more, adequately powered, high quality clinical trials in this area are conducted it is not possible to form a robust evaluation of the addition of IV beta(2)-agonists in children or adults with severe acute asthma.

The Cochrane Library and safety of regular long‐acting beta2‐ agonists in children with asthma: an overview of reviews

AbstractBackground: Two large randomized trials of regular salmeterol monotherapy in adults with asthma found an increased risk of asthma‐related mortality for salmeterol versus placebo or regular salbutamol. There are no similar large trials in children, and the safety of monotherapy with salmeterol or other long‐acting beta2‐agonists in children with asthma is unclear. Current guidelines recommend that regular long‐acting beta2‐agonist therapy should be given only in combination with regular inhaled corticosteroids. However, the safety of combination therapy in children with asthma is also unclear.Objectives: We used the paediatric trial results from Cochrane systematic reviews to assess the safety of regular long‐acting beta2‐agonist therapy, either as monotherapy or as combination therapy with inhaled corticosteroids, in children with asthma.Methods: We searched the Cochrane Database of Systematic Reviews in May 2012 for Cochrane reviews relating to the safety of regular formoterol and salmeterol, and ran updated searches for trials for each of the Cochrane reviews. We used odds ratios (ORs) to summarize the direct randomized evidence on safety from trials comparing regular formoterol or regular salmeterol as monotherapy versus placebo and then as combination therapy with inhaled corticosteroids versus the same dose of inhaled corticosteroids. We indirectly compared the safety of monotherapy and combination therapy by testing for differences between the pooled ORs for monotherapy and for combination therapy. We used ORs to summarize the direct randomized evidence on safety from trials comparing regular formoterol with regular salmeterol. We also compared the safety of regular formoterol and regular salmeterol indirectly by calculating an OR for the pooled results of trials assessing formoterol and the pooled results of trials assessing salmeterol, and then combined the direct and indirect evidence by calculating an overall OR for this comparison.Results: We identified four Cochrane reviews examining the safety of regular formoterol or salmeterol as either monotherapy or combination therapy. The reviews included 19 trials in children and we found two additional studies on salmeterol combination therapy, for a total of 21 trials in 7318 children. We identified two Cochrane reviews comparing the safety of formoterol with salmeterol, which included a single trial in 156 children. We found a statistically significant increase in the odds of suffering a nonfatal serious adverse event in children on formoterol monotherapy [OR = 2.48; 95% confidence interval (CI) = 1.27–4.83, I2 = 0%, five trials, N = 1335] and smaller nonsignificant increases in odds for salmeterol monotherapy (OR = 1.30; 95% CI = 0.82–2.05, I2 = 17%, five trials, N = 1333), formoterol combination therapy (OR = 1.60; 95% CI = 0.80–3.28, I2 = 32%, seven trials, N = 2788) and salmeterol combination therapy (OR = 1.20; 95% CI = 0.37–2.91, I2 = 0%, five trials, N = 1862). There was no significant difference between the pooled ORs of a serious adverse event on monotherapy (OR = 1.60; 95% CI = 1.10–2.33, 10 trials, N = 2668) and combination therapy (OR = 1.50; 95% CI = 0.82–2.75, 12 trials, N = 4650). However, there was an absolute increase of 21 children (95% CI = 4–45) suffering a severe adverse event of any cause for every thousand children treated over six months on monotherapy, compared with an absolute increase of three (95% CI = 1 fewer to 12 more) per 1000 children over three months on combination therapy. The evidence comparing the safety of regular salmeterol to regular formoterol was limited, and even when direct and indirect evidence were combined, the CI around the effect on serious adverse events was too wide to tell whether there was a difference in the comparative safety of formoterol and salmeterol (OR = 1.26; 95% CI = 0.37–4.32). Only one child died across all the trials, so the impact on mortality could not be assessed.Authors' conclusions: Although regular combination therapy is likely to be safer than monotherapy in children with asthma, the safety of regular combination therapy with formoterol or salmeterol in children remains uncertain, particularly in terms of mortality. The relative safety of formoterol and salmeterol is also unclear. There are currently large ongoing surveillance studies that may clarify the risks of combination therapy in children and adolescents with asthma. Copyright © 2012 The Cochrane Collaboration. Published by John Wiley &amp; Sons, Ltd. The Cochrane Collaboration

Combination Therapy Salmeterol/Fluticasone Versus Doubling Dose of Fluticasone in Children With Asthma

To determine if the addition of a long-acting bronchodilator is noninferior to doubling the dose of inhaled corticosteroids in children whose asthma is not controlled with use of low-to-moderate doses of inhaled corticosteroids alone.Children aged 6 to 16 years who were using fluticasone propionate (100 μg twice daily) to treat their asthma were enrolled in this study (N = 257). A 4-week run-in period was used to monitor these children. Those who were still symptomatic despite regular use of fluticasone propionate were included in the randomization of study groups (n = 158). The study was conducted at multiple pediatric medical centers throughout Europe.Symptomatic children were randomly assigned to 1 of 2 treatment groups: fluticasone propionate (200 μg twice per day) or salmeterol/fluticasone propionate (50/100 μg twice per day), used for a 26-week treatment period. Lung-function measurements were recorded at the start of the run-in period, at time of randomization, and at all visits during the treatment period. The provocative dose of methacholine that causes a 20% decrease (PD20) in the forced expiratory volume in 1 second (FEV1) and exhaled nitric-oxide levels were measured at the start and end of the treatment period. The number of symptom-free days and asthma exacerbations were logged at each clinic visit. Exacerbations were classified as mild, moderate, or severe on the basis of the medical interventions needed.There was no significant difference between the treatment groups in the percentage of symptom-free days. Each treatment group had an increase in symptom-free days by ∼25% while on treatment compared to baseline (P < .001). Furthermore, no significant difference was seen in the percentage of days in which rescue salbutamol was used; both groups had a gradual decline in use of the salbutamol. A combined ranked assessment of all exacerbations among the treatment groups revealed no statistically significant difference between the 2 groups. Lung-function parameters did not differ between groups other than a slightly greater effect on maximal expiratory flow seen in the salmeterol/fluticasone group during the first week of treatment. The 2 groups did not differ in statural growth or number of adverse events.The results of this study indicate that the combination of a long-acting bronchodilator with inhaled corticosteroid has equal efficacy in controlling symptoms and preserving lung function when compared with doubling the dose of inhaled corticosteroids in children who were symptomatic on a moderate dose of inhaled corticosteroids. Therefore, combination of a long-acting bronchodilator is likely an appropriate alternative in step-up therapy.This study provides us with an adequate alternative step 3 treatment option. The results of this study are in line with those of previous work. Further study is now needed to evaluate whether there might be specific asthma phenotypes that respond more favorably to 1 treatment option versus another. The fear of increased severe asthma exacerbations and asthma-related deaths associated with use of long-acting β2 agonists in children is still present. Further data from large numbers of children are needed to make a more definite conclusion about this possible risk.