Can certain genotypes predispose to poor asthma control in children? A pharmacogenetic study of 9 candidate genes in children with difficult asthma

Objective - We tested the hypothesis that patients with difficult asthma have an increased frequency of certain genotypes that predispose them to asthma exacerbations and poor asthma control. Methods - A total of 180 Caucasian children with confirmed asthma diagnosis were selected from two phenotypic groups; difficult (n = 112) versus mild/moderate asthma (n = 68) groups. All patients were screened for 19 polymorphisms in 9 candidate genes to evaluate their association with difficult asthma. Key Results - The results indicated that LTA4H A-9188>G, TNFα G-308>A and IL-4Rα A1727>G polymorphisms were significantly associated with the development of difficult asthma in paediatric patients (p<0.001, p = 0.019 and p = 0.037, respectively). Haplotype analysis also revealed two haplotypes (ATA haplotype of IL-4Rα A1199>C, IL-4Rα T1570>C and IL-4Rα A1727>G and CA haplotype of TNFα C-863>A and TNFα G-308>A polymorphisms) which were significantly associated with difficult asthma in children (p = 0.04 and p = 0.018, respectively). Conclusions and Clinical Relevance - The study revealed multiple SNPs and haplotypes in LTA4H, TNFα and IL4-Rα genes which constitute risk factors for the development of difficult asthma in children. Of particular interest is the LTA4H A-9188>G polymorphism which has been reported, for the first time, to have strong association with severe asthma in children. Our results suggest that screening for patients with this genetic marker could help characterise the heterogeneity of responses to leukotriene-modifying medications and, hence, facilitate targeting these therapies to the subset of patients who are most likely to gain benefit.

Inappropriate oral formulations and information in paediatric trials

Previously, quality of formulations information provided for oral medications used in paediatric clinical trials published in 10 highly cited journals between 2002 and 2004 raised concerns. This short report explores if there was any subsequent improvement on how the formulations used in trials involving children

Medicines management across the primary-hospital healthcare interface: a study of paediatric patients

A comparison of medicines management documents in use by NHS organisations in the West Midlands confirms that there are important differences between the primary care and hospital sectors in respect to medicines management interface issues. Of these, two aspects important to paediatric patients have been studied. These are the transfer of information as a patient is admitted to hospital, and access to long-term medicines for home-patients. National guidance provided by NICE requires medication reconciliation to be undertaken on admission to hospital for adults. A study of paediatric admissions, reported in this thesis, demonstrates that the clinical importance of this process is at least as important for children as for adults, and challenges current UK guidance. The transfer of essential medication information on hospital admission is central to the medication reconciliation process. Two surveys of PCTs in 2007 and again in 2009 demonstrate that very few PCTs provide guidance to GPs to support this process. Provision of guidance is increasing slowly but remains the exception. The provision of long-term medicines for children at home is hindered by this patient population often needing unlicensed drugs. Further studies demonstrate that primary care processes regularly fail to maintain access to essential drugs and patients and their carers frequently turn to hospitals for help. Surveys of hospital medical staff (single site) and hospital nurses (six UK sites) demonstrates the activity these healthcare workers perform to help children get the medicines they need. A similar survey of why carers turn to a hospital pharmacy department for urgent supplies (usually termed rescue-medicines) adds to the understanding of these problems and supports identifying service changes. A large survey of community pharmacies demonstrates the difficulties they have when dispensing hospital prescriptions and identifies practical solutions. This programme concludes by recommending service changes to support medication management for children.

Sedation in paediatric intensive care

Paediatric intensive care is an expanding specialty that has been shown to improve the quality of care provided to critically ill children. An important aspect of the management of critically ill children includes the provision of effective sedation to reduce stress and anxiety during their stay in intensive care. However, to achieve effective and safe sedation in these children, is recognised as a challenge that is not without risk. Often children receive too much or too little sedation resulting in over sedation or under sedation respectively. These problems have arisen owing to a lack of information regarding altered pharmacokinetics and pharmacodynamics of medicines administered to critically ill children. In addition there are few validated sedation scoring systems in practice with which to monitor level of sedation and titrate medication appropriately. This study consisted of two stages. Stage 1 investigated the reproducibility and practicality of two observational sedation assessment scales for use in critically ill children. The two scales were different in design, the first being simple in design requiring a single assessment of the patient. The second was more complex in design requiring assessment of five patient parameters to obtain an overall sedation score. Both scales were found to achieve good reproducibility (kappa values 0.50 and 0.62 respectively). Practicality of each sedation scale was undertaken by obtaining nursing staff opinion about both scales using questionnaire and interview technique. It was established that nursing staff preferred the second, more complex sedation scale mainly because it was perceived to give a more accurate assessment of level of sedation and anxiety rather than merely level of sedation. Stage 2 investigated the pharmacokinetics and pharmacodynamics of midazolam in critically ill children. 52 children, aged between 0 and 18 years were recruited to the study and 303 blood samples taken to analyse midazolam and its metabolites, I-hydroxyrnidazolam (I-OR) and 4-hydroxymidazolam (4-0H). Analysis of plasma was undertaken using high performance liquid chromatography. A significant correlation was found between midazolam plasma concentration and sedative effect (r=0.598, p=O.OI). It was found that a midazolam plasma concentration of 223ng/ml (±31.9) achieved a satisfactory level of sedation. Only a poor correlation was found between dose of midazolam and plasma concentration of midazolam. Similarly only a poor correlation was found between sedative effect and dose of midazolam. Clearance of midazolam was found to be 6.3mllkglmin (±0.36), which is lower than that reported in healthy children (9.Il-13.3mllkg/min). Age related differences in midazolam clearance were observed in the study. Neonates produced the lowest clearance values (l.63mllkg/min), compared to children aged 1 to 12 months (8.52mllkg/min) who achieved the highest clearance values. Clearance was found to decrease after the age of 12 months to values of 5.34mllkglmin in children aged 7 years and above. Patients with renal (n=5) and liver impairment (n~4) were found to have reduced midazolam clearance (1.37 and 0.74ml/kg/min respectively). Plasma concentrations of I-OH and 4-0H ranged from 0-5 1 89nglml and 0-27 Inglml respectively. All children were found to be capable of producing both metabolites irrespective of age, although no trend was established between age and extent of production of either metabolite. Disease state was found to affect production of l-OH. Patients with renal impairment (n=5) produced the lowest I-OH midazolam plasma ratio (0.059) compared to patients with head injury (0.858). Patients with severe liver impairment were found to be capable of manufacturing both metabolites despite having a severely damaged liver.

A tree-based decision model to support prediction of the severity of asthma exacerbations in children

This paper describes the development of a tree-based decision model to predict the severity of pediatric asthma exacerbations in the emergency department (ED) at 2 h following triage. The model was constructed from retrospective patient data abstracted from the ED charts. The original data was preprocessed to eliminate questionable patient records and to normalize values of age-dependent clinical attributes. The model uses attributes routinely collected in the ED and provides predictions even for incomplete observations. Its performance was verified on independent validating data (split-sample validation) where it demonstrated AUC (area under ROC curve) of 0.83, sensitivity of 84%, specificity of 71% and the Brier score of 0.18. The model is intended to supplement an asthma clinical practice guideline, however, it can be also used as a stand-alone decision tool.

Paediatric 'care closer to home':stake-holder views and barriers to implementation

In this study we explore the views of NHS stakeholders on providing paediatric ‘care closer to home’ (CCTH), in community-based outpatient clinics delivered by consultants. Design: Semi-structured interviews and thematic framework analysis. Setting: UK specialist children's hospital and surrounding primary care trusts. Participants: 37 NHS stakeholders including healthcare professionals, managers, commissioners and executive team members. Results: Participants acknowledged that outreach clinics would involve a change in traditional ways of working and that the physical setting of the clinic would influence aspects of professional practice. Different models of CCTH were discussed, as were alternatives for improving access to specialist care. Participants supported CCTH as a good principle for paediatric outpatient services; however the challenges of setting up and maintaining community clinics meant they questioned how far it could be achieved in practice. Conclusions: The place of service delivery is both an issue of physical location and professional identity. Policy initiatives which ignore assumptions about place, power and identity are likely to meet with limited success.

Intern pharmacists as change agents to improve the practice of nonprescription medication supply: provision of salbutamol to patients with asthma

BACKGROUND: Earlier work established an evidence practice gap during provision of nonprescription salbutamol (albuterol). Pharmacist interns are hypothesized to be in a position to improve professional practice in the community pharmacy setting. OBJECTIVE: To explore the potential of intern pharmacists to improve the professional practice of community pharmacy staff in the provision of nonprescription salbutamol. METHODS: Intern pharmacists (n = 157) delivered an asthma intervention in 136 pharmacies consisting of an educational activity to pharmacy staff and a health promotion campaign to consumers. Post-intervention, simulated patients presented to 100 intervention and 100 control community pharmacies with a request for salbutamol. The appropriate outcome was medical referral for poor asthma control and correction of poor inhaler technique. Incidence and quantity of patient assessment and counseling provided during the visit were also assessed. Logistic regression was used to determine the predictors of medical referral. RESULTS: A doubling in the rate of medical referral was seen in the intervention group (19% vs 40%; p = 0.001). Assessment of reliever use frequency was the main predictor of medical referral (OR = 22.7; 95% CI 9.06 to 56.9). Correction of poor inhaler technique did not improve; however, a reduction in salbutamol supplied without patient assessment (23% vs 8%; p = 0.009) or counseling (75% vs 48%; p < 0.001) was noted. CONCLUSIONS: A doubling in the rate of medical referral showed a clear improvement in professional practice during the provision of nonprescription salbutamol. The improved patient outcome in the intervention group was due to increased assessment of reliever use frequency. Identification of poor inhaler technique remained near zero in both groups, which suggests that intern pharmacists were able to improve the current practice of community pharmacies yet were unable to establish a new practice behavior. This study provides evidence that intern pharmacists can act as change agents to improve pharmacy practice.

Measuring the assessment and counselling provided with the supply of non-prescription asthma reliever medication: a simulated patient study

BACKGROUND: Over one quarter of asthma reliever medications are provided without prescription by community pharmacies in Australia. Evidence that community pharmacies provide these medications with sufficient patient assessment and medication counseling to ensure compliance with the government's Quality Use of Medicines principles is currently lacking. OBJECTIVE: To assess current practice when asthma reliever medication is provided in the community pharmacy setting and to identify factors that correlate with assessment of asthma control. METHODS: Researchers posing as patients visited a sample of Perth metropolitan community pharmacies in May 2007. During the visit, the simulated patient enacted a standardized scenario of someone with moderately controlled asthma who wished to purchase a salbutamol (albuterol) inhaler without prescription. Results of the encounter were recorded immediately after the visit. Regression analysis was performed, with medication use frequency (a marker of asthma control) as the dependent variable. RESULTS: One hundred sixty community pharmacies in the Perth metropolitan area were visited in May 2007. Pharmacists and/or pharmacy assistants provided some form of assessment in 84% of the visits. Counseling was provided to the simulated patients in 24% of the visits. Only 4 pharmacy staff members asked whether the simulated patient knew how to use the inhaler. Significant correlation was found between assessment and/or counseling of reliever use frequency and 3 independent variables: visit length (p < 0.001), number of assessment questions asked (p < 0.001), and the simulated patient who conducted the visit (p < 0.02). CONCLUSIONS: Both patient assessment and medication counseling were suboptimal compared with recommended practice when nonprescription asthma reliever medication was supplied in the community pharmacy setting. Pharmacy and pharmacist demographic variables do not appear to affect assessment of asthma control. This research indicates the need for substantial improvements in practice in order to provide reliever medication in line with Quality Use of Medication principles of ensuring safe and effective use of medication.

Asthma management : implementation of short-acting beta agonist guidelines in Western Australia:a unique collaboration

Background: The Respiratory Health Network in Western Australia developed the Asthma Model of Care in 2010 which incorporates best practice guidelines. At the same time short-acting beta agonist guidelines (SABA) were developed by stakeholder consensus at University of Western Australia (UWA) and incorporated the use of an Asthma Action Plan Card. Objective: To report on the implementation of a key component of the WA Asthma Model of Care, the SABA guidelines that incorporate the Asthma Action Plan card. Methods: Implementation strategies included lectures, direct pharmacy detailing, media releases, and information packs (postal and electronic). Groups targeted included pharmacists, consumers and medical practitioners. Results: State-based (n=18) and national (n=6) professional organisations were informed about the launch of the guidelines into practice in WA. In the four-month implementation period more than 47,000 Asthma Action Plan Cards were distributed, primarily to community pharmacies. More than 500 pharmacies were provided with information packs or individual detailing. More than 10,000 consumers were provided with information about the guidelines. Conclusions and implications: The collaboration of stakeholders in this project allowed for widespread access to various portals which, in turn, resulted in a multifaceted approach in disseminating information. Ongoing maintenance programs are required to sustain and build on the momentum of the implementation program and to ultimately address patient outcomes and practice change, which would be the longer-term goals of such a project. Future research will seek to ascertain the impact of the card on patient outcomes in WA.

Validation of the Paediatric food allergy quality of life questionnaire (PFA-QL)

Objective - The aim of the current study was to validate child (PFA-QL) and parent–proxy (PFA-QL-PF) versions of the scale in a specialist allergy clinic and in parents of children with food allergy. Methods - For the clinic sample, a generic QoL scale (PedsQL) and the PFA-QL were completed by 103 children (age 6–16 yrs) with peanut or tree nut allergy; test–retest reliability of the PFA-QL was tested in 50 stable patients. For the non-clinical sample, 756 parents of food allergic children completed the PFA-QL-PF, the Child Health Questionnaire (CHQ-PF50), Food Allergy Quality of Life Parental Burden Scale (FAQL-PB) and a Food Allergy Impact Measure. Results - The PFA-QL and PFA-QL-PF had good internal consistency (a's of 0.77–0.82), and there was moderate-to-good agreement between the generic- and disease-specific questionnaires. The PFA-QL was stable over time in the clinic sample, and in both samples, girls were reported to have poorer QoL than boys. Conclusions - The PFA-QL and PFA-QL-PF are reliable and valid scales for use in both clinical and non-clinical populations. Unlike other available tools, they were developed and validated in the UK and thus provide a culture-specific choice for research, clinical trials and clinical practice in the UK. Validation in other countries is now needed.

Health care professionals' views of paediatric outpatient non-attendance:implications for general practice

Background. Non-attendance at paediatric hospital outpatient appointments poses potential risks to children's health and welfare. Prevention and management of missed appointments depends on the perceptions of clinicians and decision makers from both primary and secondary care, including general practitioners (GPs) who are integral to non-attendance follow-up. Objectives. To examine the views of clinical, managerial and executive health care staff regarding occurrence and management of non-attendance at general paediatric outpatient clinics. Methods. A qualitative study using individual semi-structured interviews was carried out at three English Primary Care Trusts and a nearby children's hospital. Interviews were conducted with 37 staff, including GPs, hospital doctors, other health care professionals, managers, executives and commissioners. Participants were recruited through purposive and 'snowball' sampling methods. Data were analysed following a thematic framework approach. Results. GPs focused on situational difficulties for families, while hospital-based staff emphasized the influence of parents' beliefs on attendance. Managers, executives and commissioners presented a broad overview of both factors, but with less detailed views. All groups discussed sociodemographic factors, with non-attendance thought to be more likely in 'chaotic families'. Hospital interviewees emphasized child protection issues and the need for thorough follow-up of missed appointments. However, GPs were reluctant to interfere with parental responsibilities. Conclusion. Parental motivation and practical and social barriers should be considered. Responsibilities regarding missed appointments are not clear across health care sectors, but GPs are uniquely placed to address non-attendance issues and are central to child safeguarding. Primary care policies and strategies could be introduced to reduce non-attendance and ensure children receive the care they require. © The Author 2013.

The cost of paediatric obesity

There has been a great deal of media attention given to the rising levels of obesity and overweight in children and adolescents, but what is the real cost of pediatric obesity? This article reviews information about the recent rise in pediatric obesity and discusses the cost of this condition from medical, financial and psychological perspectives.

Ethanol intake of paediatric intensive care patients

Background - Limiting the amount of alcohol in children's medicines is advisable but as alcohol is the second most common solvent used in liquid preparations, paediatric patients with increased medication intake may be exposed to a considerable alcohol intake. Few medicines are specifically designed for children in Paediatric Intensive Care (PICU), and therefore adult formulations are frequently administered, with high medication use further exposing a PICU patient to undesired alcohol intake. Aims - This small pilot study aimed to examiine the intake of a sample of PICU patients, highlight common medicines used on PICU containing alcohol, provide alternatives where possible and where alternatives are not possible, provide the prescriber with a list of the higher alcohol containing medicines. Method - A retrospective medication chart review was undertaken as a two point snap shot. Data collected included age, weight, medications prescribed and the formulations used at time of the study. The patients' sedation score was recorded. The electronic medicine compendium (EMC) was consulted for any ethanol content for the commercially available products. The manufacturer was contacted for ethanol content of all ‘specials’ and any commercial products found to contain ethanol from the EMC. The PICU patient's daily intake of ethanol was calculated. The calculation was converted to an adult equivalent alcohol unit intake and although this method of conversion is crude and does not take physiological differences of adult and children into account, it was done in order to provide the clinician with commonly used terminology in deciding the risk to the patient. Results - Twenty-eight patients were prescribed a range of 69 different medications. Of the 69 medicines, 12 products were found to contain ethanol. Patient ages ranged from a 26 week premature infant to 15 years old, weights ranges from 0.7 kg to 45 kg. Only 2 out of the 28 patients did not receive ethanol containing medications, and most patients were prescribed at least two medicines containing ethanol. Daily ethanol intake uncorrected for weight ranged from 0.006 ml to 2.18 ml (median 0.26 ml). Converting this to adult units per week, alcohol intake ranged from 0.07 to 15.2 units (median 1.4 units). The two patients receiving above 15 units/week adult equivalent were prescribed an oral morphine weaning regimen, therefore the high alcohol exposure was short term. The most common drugs prescribed containing alcohol were found to be nystatin, ranitidine, furosemide and morphine. No commercially available alcohol-free oral liquid preparations were found for ranitidine, furosemide or morphine at the time of the study. Correlation of the sedation score against ethanol intake was difficult to analyse as most patients were actively sedated. Conclusions - Polypharmacy in PICU patients increases the exposure to alcohol. Some commercially available medicines provide excessive ethanol intake, providing the clinician with ethical, potentially economical dilemmas of prescribing an unlicensed medicine to minimise ethanol exposure. Further research is required to evaluate the scope of the problem, effects of exposure and provision of alcohol free formulations.

Patient education in the treatment of asthma:a controlled evaluation of providing information for "new" asthmatics

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