Use of antimicrobials in pediatric wards of five Brazilian hospitals.

The use of antimicrobials (AMs) in pediatric infections is common practice and use may be inappropriate leading to antimicrobial resistance. Off-label AM use is also common in this group and can result in drug-related problems. There is lack of DUR data in Brazil and in Latin America, specially for AM pediatric use. The aim of this study was to describe the utilization of AMs in hospitalized children in five hospitals in Brazil. We conducted an observational study of the utilization of AMs in pediatric wards in hospitals in the states of Ceará (CE), Sergipe (SE), Rio de Janeiro (RJ), Rio Grande do Sul (RS) and the Federal District (DF). Data derived from patient medical records and prescriptions were collected over a six-month period in each hospital. The number of AMs used by each patient was recorded, and AM use was assessed using Days of therapy (DOT) and Length of therapy (LOT) per 1000 patient days according to different patient characteristics. Off-label (OL) use was described according to age. The study analyzed data from 1020 patients. The sex and age distributions were similar across the five hospitals. However, differences were found for comorbidities, history of ICU admission and length of hospital stay. The most common diseases were respiratory tract infections. There were wide variations in DOT/1000PD (278-517) and LOT/1000PD (265-390). AM utilization was highest in the hospital in SE. The consumption of second-generation penicillins and cephalosporins was high. The prevalence of OL use of AMs was higher for patients in the RJ hospital, in infants, in patients who underwent prolonged hospital stays, and in patients who used multiple AMs. The AM that showed the highest prevalence of OL use was azithromycin, in both oral and parenteral formulations. Overall AM use was high and showed differences in each setting, possibly influenced by local characteristics and by prescribing standards adopted by pediatricians.

Health professionals' initial experiences and perceptions of the acceptability of a whole-hospital, pro-active electronic paediatric early warning system (the DETECT study): a qualitative interview study.

BACKGROUND: Paediatric early warning systems (PEWS) alert health professionals to signs of a child's deterioration with the intention of triggering an urgent review and escalating care. They can reduce unplanned critical care transfer, cardiac arrest, and death. Electronic systems may be superior to paper-based systems. The objective of the study was to critically explore the initial experiences and perceptions of health professionals about the acceptability of DETECT e-PEWS, and what factors influence its acceptability. METHODS: A descriptive qualitative study (part of The DETECT study) was undertaken February 2020-2021. Single, semi-structured telephone interviews were used. The setting was a tertiary children's hospital, UK. The participants were health professionals working in study setting and using DETECT e-PEWS. Sampling was undertaken using a mix of convenience and snowballing techniques. Participants represented two user-groups: 'documenting vital signs' (D-VS) and 'responding to vital signs' (R-VS). Perceptions of clinical utility and acceptability of DETECT e-PEWS were derived from thematic analysis of transcripts. RESULTS: Fourteen HPs (12 nurses, 2 doctors) participated; seven in D-VS and seven in the R-VS group. Three main themes were identified: complying with DETECT e-PEWS, circumventing DETECT e-PEWS, and disregarding DETECT e-PEWS. Overall clinical utility and acceptability were deemed good for HPs in the D-VS group but there was diversity in perception in the R-VS group (nurses found it more acceptable than doctors). Compliance was better in the D-VS group where use of DETECT e-PEWS was mandated and used more consistently. Some health professionals circumvented DETECT e-PEWS and fell back into old habits. Doctors (R-VS) did not consistently engage with DETECT e-PEWS, which reduced the acceptability of the system, even in those who thought the system brought benefits. CONCLUSIONS: Speed and accuracy of real-time data, automation of triggering alerts and improved situational awareness were key factors that contributed to the acceptability of DETECT e-PEWS. Mandating use of both recording and responding aspects of DETECT e-PEWS is needed to ensure full implementation.

Translation, transcultural adaptation and validation to Brazilian Portuguese of tools for adverse drug reaction assessment in children.

BACKGROUND: Children are more vulnerable to adverse drug reactions (ADRs) due to complex changes in the body during the growth process and lack specific pharmacoepidemiologic studies. Causality and Avoidability assessment of ADRs are relevant to clinical guidelines development and pharmacovigilance. This study aimed to translate and transcultural adapt two new tools-Liverpool Causality Assessment Tool (LCAT) and the Liverpool Avoidability Assessment Tool (LAAT)-to Brazilian-Portuguese and evaluate the psychometric properties of these tools to analyse ADRs in Brazilian children. METHODS: The validation of the cross-cultural adaptation of tools was obtained by the functional (conceptual, semantic, operational, and measurement) equivalence between the original and translated versions of each instrument. The translated version of LCAT and LAAT was applied to assessing the twenty-six case reports of suspected adverse drug reactions in a Brazilian teaching paediatric hospital. The inter-rater reliability (a pharmacist and a physician) was evaluated using Cronbach's alpha. The exact agreement percentages (%EA) and extreme disagreement (%ED) were computed. Overall Kappa index was calculated with a 95% confidence interval. RESULTS: There was a need to modify some terms translated into Portuguese for semantic and conceptual equivalence. The Cronbach's alpha coefficient values obtained were 0.95 and 0.85, and the weighted Kappa (95% confidence interval) were 0.82 (0.67-0.97) and 0.68 (0.45-0.91) for LCAT and LAAT, respectively. The Brazilian-Portuguese versions of the LCAT and LAAT showed reliable and valid tools for the diagnosis and follow-up of ADRs in children. CONCLUSION: The methodological approach allowed the translation, transcultural adaptation, and validation to Brazilian-Portuguese of two easy and quick to perform tools for causality and avoidability of ADRs in children by a multidisciplinary expert specialist committee, including the authors of original tools. We believe these versions may be applied by professionals (patient safety teams) and researchers in Brazil in groups or by a single reviewer. TRIAL REGISTRATION: This study was evaluated and approved by the Research Ethics Committee (Instituto de Pediatria e Puericultura Martagão Gesteira - Federal University of Rio de Janeiro - Number: 3.264.238.

Salivary cortisol, cortisone and serum cortisol concentrations are related to age and body mass index in healthy children and young people.

BACKGROUND: Saliva is an ideal medium in which to measure cortisol in children. However, there are very few data reporting salivary cortisol or cortisone concentrations in healthy children since the introduction of liquid chromatography-mass spectrometry (LC-MS/MS) to routine laboratory practice. DESIGN: Early morning serum cortisol, salivary cortisol and cortisone were measured on fasting samples, and salivary hormones were measured in samples collected every 2 hours during waking hours, and 30 minutes after waking the following morning. PARTICIPANTS: 43 healthy paediatric volunteers (19 female), median age 11.5 years, range 6.2-18.7, participated. RESULTS: Early morning serum cortisol (265 nmol/L, 156-516) correlated strongly with salivary cortisol (4.7 nmol/L, 1.1-14.6) and cortisone (28.8 nmol/L, 11.7-56.6), P < .0001 for both. Serum cortisol, salivary cortisol and salivary cortisone correlated directly with age (P < .0001, P = .002 and P = .015, respectively), and salivary cortisone/cortisol ratio correlated indirectly with age (P = .007). Between 08.00 and 21.00, area under the curve for salivary cortisol (mean ± 1 SD) was 41.8 ± 19.1 and for cortisone 213.0 ± 61.2. Salivary cortisol was undetectable in 25/130 (19%) of samples collected after 13.00, while cortisone was always detectable. DISCUSSION: Salivary cortisol and cortisone concentrations are strongly related to serum cortisol concentrations; however, cortisone may be a preferable measure as cortisol is often undetectable. Age may be an important factor in the interpretation of early morning cortisol measurements made in serum and saliva.

Novel FOXA2 mutation causes Hyperinsulinism, Hypopituitarism with Craniofacial and Endoderm-derived organ abnormalities.

Congenital hypopituitarism (CH) is characterized by the deficiency of one or more pituitary hormones and can present alone or in association with complex disorders. Congenital hyperinsulinism (CHI) is a disorder of unregulated insulin secretion despite hypoglycaemia that can occur in isolation or as part of a wider syndrome. Molecular diagnosis is unknown in many cases of CH and CHI. The underlying genetic etiology causing the complex phenotype of CH and CHI is unknown. In this study, we identified a de novo heterozygous mutation in the developmental transcription factor, forkhead box A2, FOXA2 (c.505T>C, p.S169P) in a child with CHI and CH with craniofacial dysmorphic features, choroidal coloboma and endoderm-derived organ malformations in liver, lung and gastrointestinal tract by whole exome sequencing. The mutation is at a highly conserved residue within the DNA binding domain. We demonstrated strong expression of Foxa2 mRNA in the developing hypothalamus, pituitary, pancreas, lungs and oesophagus of mouse embryos using in situ hybridization. Expression profiling on human embryos by immunohistochemistry showed strong expression of hFOXA2 in the neural tube, third ventricle, diencephalon and pancreas. Transient transfection of HEK293T cells with Wt (Wild type) hFOXA2 or mutant hFOXA2 showed an impairment in transcriptional reporter activity by the mutant hFOXA2. Further analyses using western blot assays showed that the FOXA2 p.(S169P) variant is pathogenic resulting in lower expression levels when compared with Wt hFOXA2. Our results show, for the first time, the causative role of FOXA2 in a complex congenital syndrome with hypopituitarism, hyperinsulinism and endoderm-derived organ abnormalities.

Dynamic Electronic Tracking and Escalation to reduce Critical care Transfers (DETECT): the protocol for a stepped wedge mixed method study to explore the clinical effectiveness, clinical utility and cost-effectiveness of an electronic physiological surveillance system for use in children.

BACKGROUND: Active monitoring of hospitalised adults, using handheld electronic physiological surveillance systems, is associated with reduced in-patient mortality in the UK. Potential also exists to improve the recognition and response to deterioration in hospitalised children. However, the clinical effectiveness, the clinical utility, and the cost-effectiveness of this technology to reduce paediatric critical deterioration, have not been evaluated in an NHS environment. METHOD: This is a non-randomised stepped-wedge prospective mixed methods study. Participants will be in-patients under the age of 18 years, at a tertiary children's hospital. Day-case, neonatal surgery and Paediatric Intensive Care Unit (PICU) patients will be excluded. The intervention is the implementation of Careflow Vitals and Connect (System C) to document vital signs and sepsis screening. The underpinning age-specific Paediatric Early Warning Score (PEWS) risk model calculates PEWS and provides associated clinical decision support. Real-time data of deterioration risk are immediately visible to the entire clinical team to optimise situation awareness, the chronology of the escalation and response are captured with automated reporting of the organisational safety profile. Baseline data will be collected prospectively for 1 year preceding the intervention. Following a 3 month implementation period, 1 year of post-intervention data will be collected. The primary outcome is unplanned transfers to critical care (HDU and/or PICU). The secondary outcomes are critical deterioration events (CDE), the timeliness of critical care transfer, the critical care interventions required, critical care length of stay and outcome. The clinical effectiveness will be measured by prevalence of CDE per 1000 hospital admissions and per 1000 non-PICU bed days. Observation, field notes, e-surveys and focused interviews will be used to establish the clinical utility of the technology to healthcare professionals and the acceptability to in-patient families. The cost-effectiveness will be analysed using Health Related Group costs per day for the critical care and hospital stay for up to 90 days post CDE. DISCUSSION: If the technology is effective at reducing CDE in hospitalised children it could be deployed widely, to reduce morbidity and mortality, and associated costs. TRIAL REGISTRATION: Current Controlled Trials ISRCTN61279068 , date of registration 03.06.19, retrospectively registered.

Adrenal responses to a low-dose short synacthen test in children with asthma.

OBJECTIVES: Corticosteroids are known to cause adrenal suppression. The aim of this study was to assess clinical factors affecting responses to a low dose short synacthen test (LDSST) in asthmatic children using corticosteroids. DESIGN: Patients were recruited from secondary care paediatric asthma populations within the UK. PATIENTS: Asthmatic children (5-18 years), receiving corticosteroids, underwent a LDSST (n = 525). MEASUREMENTS: Demographics and corticosteroid doses were tested for association with baseline and peak (stimulated) cortisol concentrations. RESULTS: Baseline cortisol was significantly associated with age (log baseline increased 0·04 nm per year of age, P < 0·0001), but not with gender or corticosteroid dose. Peak cortisol was significantly associated with total corticosteroid cumulative dose (decreased 0·73 nm per 200 mcg/day, P < 0·001) but not with age, gender inhaled/intranasal corticosteroid cumulative dose or number of courses of rescue corticosteroids. Biochemically impaired response (peak cortisol ≤500 nm) occurred in 37·0% (161/435) overall, including children using GINA low (200-500 mcg/day beclomethasone-CFC equivalent 32%, n = 60), medium (501-1000 mcg/day (33%, n = 57) and high (>1000 mcg/day 40%, n = 13) doses of inhaled corticosteroid (ICS) similarly, and 36·6% of those using fluticasone ICS ≥500 mcg/day (71/194). Impaired response was more frequent in patients on regular oral corticosteroids (66%, n = 27, P < 0·001). CONCLUSION: Children with asthma can develop biochemical adrenal suppression at similar frequencies for all ICS preparations and doses. The clinical consequence of biochemical suppression needs further study.

Early morning salivary cortisol and cortisone, and adrenal responses to a simplified low-dose short Synacthen test in children with asthma.

OBJECTIVE: To examine serum cortisol responses to a simplified low-dose short Synacthen test (LDSST) in children treated with inhaled corticosteroids (ICS) for asthma and to compare these to early morning salivary cortisol (EMSC) and cortisone (EMSCn) levels. DESIGN: Early morning salivary cortisol and EMSCn samples were collected for three consecutive days. On day three, Synacthen 500 ng/1·73 m(2) was administered intravenously. Samples were collected at 0, 15, 25, 35 min. RESULTS: A total of 269 subjects (160 M: 109 F), median (range) age 10·0 (5·1-15·2) years were studied. Peak cortisol in the LDSST was <500 nmol/l in 101 subjects (37·5%) and <350 nmol/l in 12 subjects (4·5%). Basal cortisol correlated with peak cortisol: r = 0·55, (95% CI: 0·46, 0·63, P < 0·0001). Time at which peak cortisol concentration was achieved was significantly related to the value of peak cortisol (P < 0·0001), with higher cortisol peaks occurring later in the test and lower cortisol peaks occurring earlier. EMSC and EMSCn had no predictive value for the identification of patients with a peak cortisol <500 nmol/l. EMSCn was superior to EMSC in identifying patients with a peak cortisol <350 nmol/l: a minimum EMSCn cut-off value of 12·5 nmol/l gave a negative predictive value of 99·2% and positive predictive value of 30·1%. CONCLUSION: Our data illustrate that basal measures of cortisol are likely to be of value in screening populations for patients at greatest risk of adrenal crisis. EMSCn shows promise as a screening tool for the identification of patients with severe adrenal insufficiency.

Adverse drug reactions and off-label and unlicensed medicines in children: a nested case-control study of inpatients in a pediatric hospital.

BACKGROUND: Off-label and unlicensed (OLUL) prescribing has been prevalent in pediatric practice. Using data from a prospective cohort study of adverse drug reactions (ADRs) among pediatric inpatients, we aimed to test the hypothesis that OLUL status is a risk factor for ADRs. METHODS: A nested case?control study was conducted within a prospective cohort study. Details of all medicines administered were recorded, including information about OLUL status. The odds ratio for OLUL medicines being implicated in a probable or definite ADR was calculated. A multivariate Cox proportional hazards regression model was fitted to the data to assess the influence that OLUL medicine use had on the hazard of an ADR occurring. RESULTS: A total of 10,699 medicine courses were administered to 1,388 patients. The odds ratio (OR) of an OLUL medicine being implicated in an ADR compared with an authorized medicine was 2.25 (95% confidence interval (CI) 1.95 to 2.59). Medicines licensed in children but given to a child below the minimum age or weight had the greatest odds of being implicated in an ADR (19% of courses in this category were implicated, OR 3.54 (95% CI 2.82 to 4.44). Each additional OLUL medicine given significantly increased the hazard of an ADR (hazard ratio (HR) 1.3 95% CI 1.2 to 1.3, P <0.001). Each additional authorized medicine given also significantly increased the hazard (HR 1.2 95% CI 1.2 to 1.3, P <0.001). CONCLUSIONS: OLUL medicines are more likely to be implicated in an ADR than authorized medicines. The number of medicines administered is a risk factor for ADRs highlighting the need to use the lowest number of medicines, at the lowest dose for the shortest period, with continual vigilance by prescribers, in order to reduce the risk of ADRs.

Incidence, characteristics and risk factors of adverse drug reactions in hospitalized children - a prospective observational cohort study of 6,601 admissions.

BACKGROUND: Adverse drug reactions (ADRs) are an important cause of harm in children. Current data are incomplete due to methodological differences between studies: only half of all studies provide drug data, incidence rates vary (0.6% to 16.8%) and very few studies provide data on causality, severity and risk factors of pediatric ADRs. We aimed to determine the incidence of ADRs in hospitalized children, to characterize these ADRs in terms of type, drug etiology, causality and severity and to identify risk factors. METHODS: We undertook a year-long, prospective observational cohort study of admissions to a single UK pediatric medical and surgical secondary and tertiary referral center (Alder Hey, Liverpool, UK). Children between 0 and 16 years 11 months old and admitted for more than 48 hours were included. Observed outcomes were occurrence of ADR and time to first ADR for the risk factor analysis. RESULTS: A total of 5,118 children (6,601 admissions) were included, 17.7% of whom experienced at least one ADR. Opiate analgesics and drugs used in general anesthesia (GA) accounted for more than 50% of all drugs implicated in ADRs. Of these ADRs, 0.9% caused permanent harm or required admission to a higher level of care. Children who underwent GA were at more than six times the risk of developing an ADR than children without a GA (hazard ratio (HR) 6.40; 95% confidence interval (CI) 5.30 to 7.70). Other factors increasing the risk of an ADR were increasing age (HR 1.06 for each year; 95% CI 1.04 to 1.07), increasing number of drugs (HR 1.25 for each additional drug; 95% CI 1.22 to 1.28) and oncological treatment (HR 1.90; 95% CI 1.40 to 2.60). CONCLUSIONS: ADRs are common in hospitalized children and children who had undergone a GA had more than six times the risk of developing an ADR. GA agents and opiate analgesics are a significant cause of ADRs and have been underrepresented in previous studies. This is a concern in view of the increasing number of pediatric short-stay surgeries.

What can we learn from parents about enhancing participation in pharmacovigilance?

AIMS: To investigate parents' views and experiences of direct reporting of a suspected ADR in their child. METHODS: We audio-recorded semi-structured qualitative interviews with parents of children with suspected ADRs. Our sample included parents with (n = 17) and without (n = 27) previous experience of submitting a Yellow Card. RESULTS: Parents in both groups described poor awareness of the Yellow Card Scheme. Parents who had participated in the Yellow Card Scheme were generally happy to report their child's ADR via the Scheme and valued the opportunity to report concerns independently of health practitioners. They expressed motivations for reporting that have not previously been described linked to the parental role, including how registering a concern about a medicine helped to resolve uncomfortable feelings about their child's ADR. Parents who had not previously submitted a Yellow Card expressed uncertainty about the legitimacy of their involvement in reporting and doubts about the value of the information that they could provide. CONCLUSION: Promoting wider participation in pharmacovigilance schemes will depend on raising public awareness. Additionally, our findings point to the need to empower lay people to submitting reports and to reassure them about the value of their reports.

Manipulation of drugs to achieve the required dose is intrinsic to paediatric practice but is not supported by guidelines or evidence.

BACKGROUND: A lack of age-appropriate formulations can make it difficult to administer medicines to children. A manipulation of the dosage form may be required to achieve the required dose. This study aimed to describe medicines that are manipulated to achieve the required dose in paediatric practice. METHOD: A structured, undisguised observational study and postal survey. The observational study investigated drug manipulations occurring in clinical practice across three sites. The questionnaire, administered to a sample of paediatric nurses throughout the UK, surveyed manipulations conducted and nurses' experiences and views. RESULTS: The observational study identified 310 manipulations, of which 62% involved tablets, 21% were intravenous drugs and 10% were sachets. Of the 54 observed manipulations 40 involved tablets with 65% of the tablets being cut and 30% dispersed to obtain a smaller dose. 188 manipulations were reported by questionnaire respondents, of these 46% involved tablets, 12% were intravenous drugs, and 12% were nebuliser solutions. Manipulations were predominantly, but not exclusively, identified in specialist clinical areas with more highly dependent patients. Questionnaire respondents were concerned about the accuracy of the dose achieved following manipulations and the lack of practice guidance. CONCLUSION: Manipulations to achieve the required dose occur throughout paediatric in-patient settings. The impact of manipulations on the efficacy of the drugs, the accuracy of the dose and any adverse effects on patients is not known. There is a need to develop evidence-based guidance for manipulations of medicines in children.

Stuck in transit: A qualitative study of the transitional care needs of young people with epilepsy and juvenile idiopathic arthritis.

Transition services for young people with long-term conditions often fall short. This qualitative study explored perspectives on service features that enable effective transition in epilepsy and juvenile idiopathic arthritis. Patients, parents, clinicians and service commissioners took part in semi-structured interviews (n = 18). Thematic analysis was used to identify key features, barriers and facilitators of effective transition across participant groups. Analysis led to the development of nine sub-themes which mapped to overarching domains of communication, capability, continuity and capacity. Findings include the need for age appropriate communication, the link between parental dependence, self-care and patient knowledge, the value of service integration for continuity and the impact of capacity on flexible and age appropriate transition services.

The use of Special-Order products in England between 2012 and 2020: An insight into the need for Point-of-Care manufacturing.

Point-of-care manufacturing such as 3D printing has recently received significant attention from regulatory bodies and the pharmaceutical industry. However, little information is available on the quantity of the most prescribed patient-specific items, their dosage form, and why they were required to be dispensed. In England, 'Specials' are unlicensed medicines formulated to meet the requirements of a specific prescription, prescribed if no suitable licensed alternative exists. This work aims to quantify and examine trends in the prescribing of 'Specials' in England during 2012-2020, using the NHS Business Services Authority (NHSBSA) database. Quarterly prescription data from NHSBSA for the top 500 'Specials' by quantity from 2012 to 2020 were compiled yearly. The changes in net ingredient cost, the number of items, British National Formulary (BNF) drug category, dosage form, and a potential reason for requiring a 'Special' were identified. In addition, the cost-per-unit was calculated for each category. The total spending on 'Specials' decreased by 62 % from £109.2 M in 2012 to £41.4 M in 2020, primarily due to a 55.1 % reduction in the number of 'Specials' items issued. The most frequently prescribed dosage form type of 'Special' was oral dosage forms (59.6 % of all items in 2020) particularly oral liquids. The most common reason for prescribing a 'Special' was an inappropriate dosage form (74 % of all 'Specials' in 2020). The total number of items dropped over the 8 years as commonly prescribed 'Specials' such as melatonin and cholecalciferol became licensed. In conclusion, the total spending on 'Specials' dropped from 2012 to 2020 primarily due to a reduction in the number of 'Specials' items issued and pricing changes in the Drug tariff. Based on the current demand for 'special order' products, these findings are instrumental for formulation scientists to identify 'Special' formulations to design the next generation of extemporaneous medicine to be produced at the point of care.

Towards point-of-care manufacturing and analysis of immediate-release 3D printed hydrocortisone tablets for the treatment of congenital adrenal hyperplasia.

Hydrocortisone (HC) is the preferred drug in children with congenital adrenal hyperplasia due to its lower potency as well as fewer reports of side effects. Fused deposition modelling (FDM) 3D printing holds the potential to produce low-cost personalised doses for children at the point of care. However, the compatibility of the thermal process to produce immediate-release bespoke tablets for this thermally labile active is yet to be established. This work aims to develop immediate-release HC tablets using FDM 3D printing and assess drug contents as a critical quality attribute (CQA) using a compact, low-cost near-infrared (NIR) spectroscopy as a process analytical technology (PAT). The FDM 3D printing temperature (140 °C) and drug concentration in the filament (10%-15% w/w) were critical parameters to meet the compendial criteria for drug contents and impurities. Using a compact low-cost NIR spectral device over a wavelength of 900-1700 nm, the drug contents of 3D printed tablets were assessed. Partial least squares (PLS) regression was used to develop individual calibration models to detect HC content in 3D printed tablets of lower drug contents, small caplet design, and relatively complex formula. The models demonstrated the ability to predict HC concentrations over a wide concentration range (0-15% w/w), which was confirmed by HPLC as a reference method. Ultimately, the capability of the NIR model had preceding dose verification performance on HC tablets, with linearity (R2 = 0.981) and accuracy (RMSECV = 0.46%). In the future, the integration of 3DP technology with non-destructive PAT techniques will accelerate the adoption of on-demand, individualised dosing in a clinical setting.

Adverse Drug Reactions to Anti-infectives in Hospitalized Children: A Multicenter Study in Brazil.

INTRODUCTION: Adverse drug reactions (ADRs) to anti-infectives affect especially hospitalized children and contribute to increased morbidity, mortality, length of stay, and costs in healthcare systems. OBJECTIVE: To assess ADRs associated with anti-infective use in Brazilian hospitalized children. METHODS: A prospective cohort study was conducted in 5 public hospitals over 6 months. Children aged 0-11 years and 11 months who were hospitalized for more than 48 h and prescribed anti-infectives for over 24 h were included. RESULTS: A total of 1020 patients met the inclusion criteria. Of these, 152 patients experienced 183 suspected ADRs. Most reactions were related to the gastrointestinal system (65.6%), followed by skin reactions (18.6%). Most reactions were classified as probable causality (58.5%), moderate severity (61.1%), and unavoidable (56.2%). Our findings showed that ADRs were associated with increased length of stay (P < .001), increased length of therapy (P < .015), increased days of therapy (P = .038), and increased number of anti-infectives prescribed per patient (P < .001). CONCLUSION: Almost 15% of hospitalized children exposed to anti-infectives presented suspected ADRs. Their occurrence was classified as probable, of moderate severity, and unavoidable. ADRs were significantly influenced by the length of hospital stay and the number of anti-infectives prescribed per patient.

The manipulation of drugs to obtain the required dose: systematic review.

AIM: To describe the development of a systematic review protocol that maps the evidence relating to drug manipulations conducted to obtain the required dose. This process included defining a search strategy and methods to assess the quality and to synthesize the evidence retrieved. BACKGROUND: Economic constraints mean that marketed formulations may not meet the needs of all patients. Consequently, it is sometimes necessary to manipulate marketed products with the aim of obtaining the required dose. Most clinical practice appears to be guided by ad hoc approaches and informal literature reviews. METHODS: This systematic review protocol has been designed to identify the evidence available on drug manipulation. The review aims to identify what evidence is available and where the gaps appear in the current evidence. This report describes the challenges of developing a systematic review in an area that potentially involves many drugs and considers outcomes other than effectiveness. In particular, searches required the use of non-specific terms and the iterative development of a complex search strategy. The development of quality assessment criteria is also described. Funding commenced in April 2009. DISCUSSION: The systematic review described here will capture a broad selection of research about drug manipulations and may also be of interest to those conducting reviews in broad remit subject areas that are not easy to define using accepted terminology.

Humidified and standard oxygen therapy in acute severe asthma in children (HUMOX): A pilot randomised controlled trial.

BACKGROUND: Oxygen (O2) is a mainstay of treatment in acute severe asthma but how it is administered varies widely. The objectives were to examine whether a trial comparing humidified O2 to standard O2 in children is feasible, and specifically to obtain data on recruitment, tolerability and outcome measure stability. METHODS: Heated humidified, cold humidified and standard O2 treatments were compared for children (2-16 years) with acute severe asthma in a multi-centre, open, parallel, pilot randomised controlled trial (RCT). Multiple outcomes were assessed. RESULTS: Of 258 children screened, 66 were randomised (heated humidified O2 n = 25; cold humidified O2 n = 21; standard O2 n = 20). Median (IQR) length of stay (hours) in hospital was 37.9 (29.1), 52 (35.4) and 49.1 (29.7) for standard, heated humidified and cold humidified respectively and time (hours) on O2 was 15.9 (9.4), 13.6 (14.9) and 13.1 (14.9) for the three groups respectively. The mean (standard deviation) time (hours) taken to step down nebulised to inhaled treatment was 5.6 (14.3), 35.1 (28.2) and 32.7 (20.1). Asthma Severity Score decreased in all three groups similarly, although missing data prevented complete analysis. Humidified O2 was least well tolerated with eight participants discontinuing their randomised treatment early. An important barrier to recruitment was research nurse availability. CONCLUSION: Although, the results of this pilot study should not be extrapolated beyond the study sample and inferential conclusions should not be drawn from the results, this is the first RCT to compare humidified and standard O2 therapy in acute severe asthmatics of any age. These findings and accompanying screening data show that a large RCT of O2 therapy is feasible. However, challenges associated with randomisation and data collection should be addressed in any future trial design.

Development and evaluation of an assessment of the age-appropriateness/inappropriateness of formulations used in children.

BACKGROUND: Medicines designed for adults may be inappropriate for use in children in terms of strength, dosage form and/or excipient content. There is currently no standardised method of assessing the age-appropriateness of a medicine for paediatric use. AIM: To develop and test a tool to assess whether a dosage form (formulation) is appropriate for children and estimate the proportion of formulations considered 'inappropriate' in a cohort of hospitalised paediatric patients with a chronic illness. METHOD: A multi-phase study: patient data collection, tool development, case assessments and tool validation. Inpatients aged 0-17 years at two UK paediatric/neonatal hospitals during data collection periods between January 2015 and March 2016. Written informed consent/assent was obtained. Medicines assessed were new or regularly prescribed to inpatients as part of their routine clinical care. All medicine administration episodes recorded were assessed using the Age-appropriate Formulation tool. The tool was developed by a consensus approach, as a one-page flowchart. Independent case assessments were evaluated in 2019. RESULTS: In 427 eligible children; 2,199 medicine administration episodes were recorded. Two assessors reviewed 220 episodes in parallel: percentage exact agreement was found to be 91.7% (99/108) and 93.1% (95/102). In total, 259/2,199 (11.8%) medicine administration episodes involved a dosage form categorised as 'age-inappropriate'. CONCLUSION: A novel tool has been developed and internally validated. The tool can identify which medicines would benefit from development of an improved paediatric formulation. It has shown high inter-rater reliability between users. External validation is needed to further assess the tool's utility in different settings.

Pharmacogenomics and asthma treatment: acceptability to children, families and healthcare professionals.

BACKGROUND: Evidence supporting personalised treatment for asthma based on an individual's genetics is mounting. The views of children and young people (CYP), parents and healthcare professionals (HCPs) about this evolution of clinical care are not known. METHODS: A pilot prospective questionnaire-based study was undertaken of CYP with asthma, their parents and HCPs at a secondary/tertiary children's hospital in the UK. RESULTS: Fifty-nine questionnaires were distributed and 50 returned (response rate 84.7%), comprising 26 CYP (10 were 5-11 years, 11 were 12-15 years and 5 were 16-18 years old), 13 parents and 11 HCPs. For all types of data, personal information was ranked as the 'most important' (n=19, 47.5%) and 'most private' (n=16, 40%), but with considerable variation across groups. Within health data, allergies were rated as 'most important' (n=12, 30.8%), and mental health records the 'most private' (n=21, 53.8%), again with variation across groups. A 'personalised genetic asthma plan' was acceptable to the majority overall (n=40, 80.0%). With regard to sharing CYP's genetic data, 23 (46%) of participants were happy for unconditional sharing between HCPs, and 23 (46%) agreed to sharing solely in relation to the CYP's asthma management. Forty-two (84.0%) of participants felt CYP should be informed about genetic data being shared, and the majority felt this should commence by 12 years of age. CONCLUSION: The use of genetic information to guide management of asthma in CYP is largely acceptable to CYP, parents/guardians and HCPs. However, there are key differences between the opinions of CYP, parents and HCPs.