Aminophylline Dosage In Asthma Exacerbations in Children: A Systematic Review

<div><p>Background</p><p>Adequate asthma treatment of childhood exacerbations with IV aminophylline depends on appropriate dosage. Recommendations to aim for a target therapeutic range may be inappropriate as serum concentrations correlate poorly with clinical improvement. This review aims to evaluate the evidence for the optimum dosage strategy of intravenous aminophylline in children suffering an exacerbation of asthma.</p><p>Methods</p><p>A systematic review comparing dosage regimens of intravenous aminophylline in children suffering an exacerbation of asthma. Primary outcomes were time until resolution of symptoms, mortality and need for mechanical ventilation. Secondary outcomes were date until discharge criteria are met, actual discharge and adverse effects.</p><p>Data sources</p><p>CENTRAL, CINAHL, MEDLINE and Web of Science. Search performed in March 2016</p><p>Eligibility criteria</p><p>Studies using intravenous aminophylline in children with an acute exacerbation of asthma which reported the dosage and clinical outcomes.</p><p>Findings</p><p>14 RCTs were included. There is a poor relationship between the dosage administered to children and symptom resolution, length of stay or need for mechanical ventilation. This study is limited due to its use of indirect evidence.</p><p>Conclusion</p><p>The currently recommended dosage regimens may not represent the optimum safety and efficacy of intravenous aminophylline. There is a need to develop the evidence base correlating dosage with patient centered clinical outcomes, to improve prescribing practices.</p></div

The Evidence for Intravenous Theophylline Levels between 10-20mg/L in Children Suffering an Acute Exacerbation of Asthma: A Systematic Review

<div><p>Background</p><p>Intravenous theophyllines are a second line treatment for children suffering an acute exacerbation of asthma. Various guidelines and formularies recommend aiming for serum theophylline levels between 10-20mg/l. This review aims to assess the evidence underpinning this recommendation.</p><p>Methods</p><p>A systematic review comparing outcomes of children who achieved serum theophylline concentrations between 10-20mg/l with those who did not. Primary outcomes were time until resolution of symptoms, mortality and need for mechanical ventilation. Secondary outcomes were date until discharge criteria are met, actual discharge, adverse effects and FEV1.</p><p>Data sources</p><p>MEDLINE, CINAHL, CENTRAL and Web of Science. Search performed in October 2015.</p><p>Eligibility criteria</p><p>Interventional or observational studies utilizing intravenous theophyllines for an acute exacerbation of asthma in children where serum theophylline levels and clinical outcomes were measured.</p><p>Findings</p><p>10 RCTs and 2 observational studies were included. Children with serum levels between 10-20mg/l did not have a reduction in duration of symptoms, length of hospital stay or need for mechanical ventilation or better spirometric results compared with levels <10mg/l. Levels above 20mg/l are not associated with higher rates of adverse effects. This study is limited due to heterogeneity in the way theophylline levels were reported and poor surveillance of adverse effects across studies.</p><p>Conclusion</p><p>Dosing strategies aiming for levels between 10-20mg/l are not associated with better outcomes. Clinicians should rely on clinical outcomes and not serum levels when using intravenous theophyllines in children suffering an acute exacerbation of asthma.</p></div

Using the Delphi Technique to Determine Which Outcomes to Measure in Clinical Trials: Recommendations for the Future Based on a Systematic Review of Existing Studies

Ian Sinha and colleagues advise that when using the Delphi process to develop core outcome sets for clinical trials, patients and clinicians be involved, researchers and facilitators avoid imposing their views on participants, and attrition of participants be minimized

Outcomes in clinical trials in children with asthma

The selection of outcomes is a critically important decision when designing randomised controlled trials (RCTs). Informed clinical decisions can only be based on the results of RCTs that have measured outcomes of importance to both clinicians and patients. It can be difficult to know which outcomes should be measured in RCTs. Some groups advocate core outcome sets, which are a minimum set of outcomes that should be measured, and reported, in all clinical trials in a given condition. These increase the likelihood that important outcomes are measured, reduce nonuniformity between studies, and reduce the risk of outcome reporting bias. We systematically reviewed studies that determined which outcomes to measure in clinical trials in children, and found that such work had been conducted in only few conditions, and the quality of existing work was variable. Few studies used structured consensus techniques to reach agreement about which outcomes to measure in trials, and parents were seldom involved. No studies included children. One condition in which there were no robust recommendations about which outcomes to measurein RCTs was childhood asthma, which is a condition of considerable global importance. We subsequently aimed to assess whether the absence of a core outcome set for RCTs of children with asthma meant that certain outcome domains were measured less frequently than others, and whether there was nonuniformity between studies in terms of outcomes selected. We conducted a systematic review of RCTs of children with asthma, published between January 1988 and December 2007, and found that the included studies focussed on short-term disease activity, but quality of life, functional status, and long-term outcomes were infrequently measured. Certain outcomes were measured and reported in various ways. We recommended that a core outcome set should be developed for childhood asthma, using structured consensus techniques, such as the Delphi process. In order to aid the development of such a core set, we first systematically reviewed studies that used the Delphi process to determine which outcomes to measure in clinical trials. We observed variations in the methodology used, identified potential sources of bias, and provided recommendations about how such studies could be conducted and reported. In order to develop a core outcome set for childhood asthma, we used a Delphi process to ascertain the views of 46 clinicians, and around 100 parents and young people, about which outcomes are most important and relevant from their perspective, when making shared decisions about regular therapies which control asthma. The most important outcomes were symptoms, exacerbations, and quality of life. Although consensus still needs to be reached amongst other groups of individuals involved in clinical trials, we conclude that these outcomes should be measured, and reported, in all RCTs that aim to evaluate the effectiveness of regular therapies for children and young people with asthma

The Role of Systematic Reviews in Pharmacovigilance Planning and Clinical Trials Authorisation Application: Example from the SLEEPS Trial

BACKGROUND: Adequate sedation is crucial to the management of children requiring assisted ventilation on Paediatric Intensive Care Units (PICU). The evidence-base of randomised controlled trials (RCTs) in this area is small and a trial was planned to compare midazolam and clonidine, two sedatives widely used within PICUs neither of which being licensed for that use. The application to obtain a Clinical Trials Authorisation from the Medicines and Healthcare products Regulatory Agency (MHRA) required a dossier summarising the safety profiles of each drug and the pharmacovigilance plan for the trial needed to be determined by this information. A systematic review was undertaken to identify reports relating to the safety of each drug. METHODOLOGY/PRINCIPAL FINDINGS: The Summary of Product Characteristics (SmPC) were obtained for each sedative. The MHRA were requested to provide reports relating to the use of each drug as a sedative in children under the age of 16. Medline was searched to identify RCTs, controlled clinical trials, observational studies, case reports and series. 288 abstracts were identified for midazolam and 16 for clonidine with full texts obtained for 80 and 6 articles respectively. Thirty-three studies provided data for midazolam and two for clonidine. The majority of data has come from observational studies and case reports. The MHRA provided details of 10 and 3 reports of suspected adverse drug reactions. CONCLUSIONS/SIGNIFICANCE: No adverse reactions were identified in addition to those specified within the SmPC for the licensed use of the drugs. Based on this information and the wide spread use of both sedatives in routine practice the pharmacovigilance plan was restricted to adverse reactions. The Clinical Trials Authorisation was granted based on the data presented in the SmPC and the pharmacovigilance plan within the clinical trial protocol restricting collection and reporting to adverse reactions

Improving the quality of written information available at weekends in a paediatric hospital: the TRANSMIT sheet.

The clinical outcomes at weekends are worse than during the week in a hospital setting. There are many potential factors which influence this. High quality communication between the weekday teams and the on call weekend staff could help improve clinical outcomes at weekends, but there are no validated forms of communication that have been established in a paediatric hospital setting. The casenotes of all medical patients (n=119) were prospectively evaluated across all medical wards in a large paediatric hospital over three weekends, to establish the quality of information available to on call teams. Following introduction of structured documentation, known as a TRANSMIT (including Tasks, Respiratory, Anticipated problems, Nutrition, Sepsis, Medication, Intravenous access, Transfer/discharge) sheet, the audit was repeated (n=111). A qualitative survey of junior doctors using TRANSMIT was carried out after introduction. Prior to the introduction of the structured documentation (TRANSMIT sheet) an accurate problem list was present in 56% (67/119), and an adequate written management plan in 63% (75/119). Following introduction, an improvement in the notes was seen, with accurate problem lists in 82% (91/111) and an adequate plan in 76% (84/111). Improvements in the quantity and quality of information available to weekend on call medical staff were noted. The use of a structured documentation (TRANSMIT sheet) can improve the quality of written information available to on-call teams in a paediatric hospital setting. A retrospective qualitative assessment of junior doctors using TRANSMIT sheets showed an improvement in both the quantity and quality of information available to on call staff at weekends

Doubly robust confidence sequences for sequential causal inference

This paper derives time-uniform confidence sequences (CS) for causal effects in experimental and observational settings. A confidence sequence for a target parameter $\psi$ is a sequence of confidence intervals $(C_t)_{t=1}^\infty$ such that every one of these intervals simultaneously captures $\psi$ with high probability. Such CSs provide valid statistical inference for $\psi$ at arbitrary stopping times, unlike classical fixed-time confidence intervals which require the sample size to be fixed in advance. Existing methods for constructing CSs focus on the nonasymptotic regime where certain assumptions (such as known bounds on the random variables) are imposed, while doubly robust estimators of causal effects rely on (asymptotic) semiparametric theory. We use sequential versions of central limit theorem arguments to construct large-sample CSs for causal estimands, with a particular focus on the average treatment effect (ATE) under nonparametric conditions. These CSs allow analysts to update inferences about the ATE in lieu of new data, and experiments can be continuously monitored, stopped, or continued for any data-dependent reason, all while controlling the type-I error. Finally, we describe how these CSs readily extend to other causal estimands and estimators, providing a new framework for sequential causal inference in a wide array of problems

MEF2C regulates outflow tract alignment and transcriptional control of Tdgf1

Congenital heart defects are the most common birth defects in humans, and those that affect the proper alignment of the outflow tracts and septation of the ventricles are a highly significant cause of morbidity and mortality in infants. A late differentiating population of cardiac progenitors, referred to as the anterior second heart field (AHF), gives rise to the outflow tract and the majority of the right ventricle and provides an embryological context for understanding cardiac outflow tract alignment and membranous ventricular septal defects. However, the transcriptional pathways controlling AHF development and their roles in congenital heart defects remain incompletely elucidated. Here, we inactivated the gene encoding the transcription factor MEF2C in the AHF in mice. Loss of Mef2c function in the AHF results in a spectrum of outflow tract alignment defects ranging from overriding aorta to double-outlet right ventricle and dextro-transposition of the great arteries. We identify Tdgf1, which encodes a Nodal co-receptor (also known as Cripto), as a direct transcriptional target of MEF2C in the outflow tract via an AHFrestricted Tdgf1 enhancer. Importantly, both the MEF2C and TDGF1 genes are associated with congenital heart defects in humans. Thus, these studies establish a direct transcriptional pathway between the core cardiac transcription factor MEF2C and the human congenital heart disease gene TDGF1. Moreover, we found a range of outflow tract alignment defects resulting from a single genetic lesion, supporting the idea that AHF-derived outflow tract alignment defects may constitute an embryological spectrum rather than distinct anomalies

DEPRESCRIBING LONG ACTING BETA2 AGONISTS IN CHILDREN AND ADOLESCENTS WITH STABLE ASTHMA: A SYSTEMATIC REVIEW

IntroductionCurrent guidelines recommend step-down of asthma drugs once stable asthma has been achieved but there is no guidance regarding deprescribing long acting beta2 agonists (LABAs) in the paediatric population.AimTo systematically review evidence regarding deprescribing methods of LABAs in the paediatric population.MethodsSearches were undertaken in the following databases: EMBASE, Medline, PubMed and CINAHL regarding reports of deprescription or discontinuation of LABAs in children and adolescents with persistent asthma.ResultsThe search returned 168 papers following deduplication. 4 papers met the eligibility criteria including 3 randomised control trials and 1 retrospective study. Overall, LABA step down was attempted in 365 children and young people (5–18 years old). The studies had variable follow up durations once deprescribing was undertaken, from 2 to 12 weeks. Effects of withdrawal were measured using parameters such as airway hyperresponsiveness tests (3 studies), asthma control test scores (3 studies), use of rescue medication (3 studies) and lung function tests (FeNO, FEV1, FEF25–75%, peak expiratory flow rate (PEFR),% forced expiratory flow at 50% of vital capacity (%V50)) (all studies). Airway responsiveness was unchanged 2 weeks following LABA withdrawal, however decreases in%PEFR and%V50, FEV1 and asthma control test scores were observed. 2 studies assessed changes in LABA related adverse effects after deprescribing.ConclusionThere is limited and short-term evidence regarding stepping down LABAs in paediatrics. To fully implement national and international guidelines, prospective studies in this area are required.</jats:sec