Population pharmacokinetics of single-dose intravenous paracetamol in children.

BACKGROUND: To determine the pharmacokinetics (PK) of a new i.v. formulation of paracetamol (Perfalgan) in children ≤15 yr of age. METHODS: After obtaining written informed consent, children under 16 yr of age were recruited to this study. Blood samples were obtained at 0, 15, 30 min, 1, 2, 4, 6, and 8 h after administration of a weight-dependent dose of i.v. paracetamol. Paracetamol concentration was measured using a validated high-performance liquid chromatographic assay with ultraviolet detection method, with a lower limit of quantification (LLOQ) of 900 pg on column and an intra-day coefficient of variation of 14.3% at the LLOQ. Population PK analysis was performed by non-linear mixed-effect modelling using NONMEM. RESULTS: One hundred and fifty-nine blood samples from 33 children aged 1.8-15 yr, weight 13.7-56 kg, were analysed. Data were best described by a two-compartment model. Only body weight as a covariate significantly improved the goodness of fit of the model. The final population models for paracetamol clearance (CL), V(1) (central volume of distribution), Q (inter-compartmental clearance), and V(2) (peripheral volume of distribution) were: 16.51×(WT/70)(0.75), 28.4×(WT/70), 11.32×(WT/70)(0.75), and 13.26×(WT/70), respectively (CL, Q in litres per hour, WT in kilograms, and V(1) and V(2) in litres). CONCLUSIONS: In children aged 1.8-15 yr, the PK parameters for i.v. paracetamol were not influenced directly by age but were by total body weight and, using allometric size scaling, significantly affected the clearances (CL, Q) and volumes of distribution (V(1), V(2)).

Climate change and respiratory disease: European Respiratory Society position statement.

Climate change will affect individuals with pre-existing respiratory disease, but the extent of the effect remains unclear. The present position statement was developed on behalf of the European Respiratory Society in order to identify areas of concern arising from climate change for individuals with respiratory disease, healthcare workers in the respiratory sector and policy makers. The statement was developed following a 2-day workshop held in Leuven (Belgium) in March 2008. Key areas of concern for the respiratory community arising from climate change are discussed and recommendations made to address gaps in knowledge. The most important recommendation was the development of more accurate predictive models for predicting the impact of climate change on respiratory health. Respiratory healthcare workers also have an advocatory role in persuading governments and the European Union to maintain awareness and appropriate actions with respect to climate change, and these areas are also discussed in the position statement.

Changes in the prevalence of asthma, eczema and hay fever in pre-pubertal children: a 40-year perspective.

Surveys of primary schools children in Aberdeen carried out in 1964, 1989, 1994 and 1999 suggested a slowing of the increase in parent-reported wheeze between 1994 and 1999. To assess whether this pattern had continued, questionnaires were distributed to 5712 children aged 7-12 years in the same schools in 2004. A total of 3271 (57.3%) completed questionnaires were returned. As in earlier surveys the results were divided into those for younger children (school years 3-4; age 7-9 years) and older children (school years 5-7; age 9-12 years). Compared with 1999, the 2004 results showed a decrease in the proportion of children with wheeze in the last 3 years from 30.1% to 23.3% (P < 0.001) in the younger group and from 27.6% to 25.1% (P = 0.052) in the older group. There was no significant change in the lifetime prevalence of asthma in either the younger or the older group, but the lifetime prevalence of eczema and hay fever increased by around 10% in both the younger and older groups (all P < 0.001). The differences in the time trends for the different conditions suggest that the causal factors for wheeze and asthma differ from those for other allergic diseases of childhood.

Factor analysis in the Genetics of Asthma International Network family study identifies five major quantitative asthma phenotypes.

BACKGROUND: Asthma is a clinically heterogeneous disease caused by a complex interaction between genetic susceptibility and diverse environmental factors. In common with other complex diseases the lack of a standardized scheme to evaluate the phenotypic variability poses challenges in identifying the contribution of genes and environments to disease expression. OBJECTIVE: To determine the minimum number of sets of features required to characterize subjects with asthma which will be useful in identifying important genetic and environmental contributors. Methods Probands aged 7-35 years with physician diagnosed asthma and symptomatic siblings were identified in 1022 nuclear families from 11 centres in six countries forming the Genetics of Asthma International Network. Factor analysis was used to identify distinct phenotypes from questionnaire, clinical, and laboratory data, including baseline pulmonary function, allergen skin prick test (SPT). RESULTS: Five distinct factors were identified:(1) baseline pulmonary function measures [forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC)], (2) specific allergen sensitization by SPT, (3) self-reported allergies, (4) symptoms characteristic of rhinitis and (5) symptoms characteristic of asthma. Replication in symptomatic siblings was consistent with shared genetic and/or environmental effects, and was robust across age groups, gender, and centres. Cronbach's alpha ranged from 0.719 to 0.983 suggesting acceptable internal scale consistencies. Derived scales were correlated with serum IgE, methacholine PC(20), age and asthma severity (interrupted sleep). IgE correlated with all three atopy-related factors, the strongest with the SPT factor whereas severity only correlated with baseline lung function, and with symptoms characteristic of rhinitis and of asthma. CONCLUSION: In children and adolescents with established asthma, five distinct sets of correlated patient characteristics appear to represent important aspects of the disease. Factor scores as quantitative traits may be better phenotypes in epidemiological and genetic analyses than those categories derived from the presence or absence of combinations of +ve SPTs and/or elevated IgE.

Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report.

Asthma is the leading chronic disease among children in most industrialized countries. However, the evidence base on specific aspects of pediatric asthma, including therapeutic strategies, is limited and no recent international guidelines have focused exclusively on pediatric asthma. As a result, the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology nominated expert teams to find a consensus to serve as a guideline for clinical practice in Europe as well as in North America. This consensus report recommends strategies that include pharmacological treatment, allergen and trigger avoidance and asthma education. The report is part of the PRACTALL initiative, which is endorsed by both academies.

Linking NHS data for pediatric pharmacovigilance: Results of a Delphi survey.

BACKGROUND: Adverse drug events are a major cause of patient safety incidents. Current systems of pharmacovigilance under-report adverse drug reactions (ADRs), especially in children, leading to delays in their identification. This is of particular concern, as children especially have an increased vulnerability to ADRs. OBJECTIVES: The objective was to seek consensus among healthcare professionals (HCPs) about barriers and facilitators to the linkage of routinely collected health data for pediatric pharmacovigilance in Scotland. METHODS: A Delphi survey was conducted with a random sample of HCPs including nurses, pharmacists and doctors, working in primary or secondary care, in Scotland. Participants were identified from sampling frames of the target professionals such as an NHS workforce list for general practitioners and recruited by postal invitation. A total of 819 HCPs were invited to take part. Those agreeing to participate were given the option of completing the questionnaires online or as hard copy. Reminders were sent twice at a fortnightly interval. Questions content included description of professional role as well as testing for the willingness to support the proposed project and was informed by the Theoretical Domains Framework of Behavior Change (TDF) and earlier qualitative work. Three Delphi rounds were administered, including a first round for item generation. RESULTS: 121 of those invited agreed to take part (15%). The first round of the Delphi study included 21 open questions and generated over a 1000 individual statements from 61 participants that returned the questionnaires (50.4%). These were rationalized to 149 items for the second round in which participants rated their views on the importance (or not) of each item on a 9-point Likert scale (strongly disagree - strongly agree). After the third round, there was consensus on items that focused on professional standards, and practical requirements, overall there was support for data linkage and a multi-professional approach. CONCLUSIONS: It would be acceptable to stakeholders to introduce a data linkage system for pharmacovigilance as long as identified concerns are addressed. Concerns included adherence to current professional, legal and ethical standards, as well resolving practical issues.

Core requirements for successful data linkage: an example of a triangulation method.

OBJECTIVES: The aim was to explore the views of professional stakeholders and healthcare professionals (HCPs) on the linkage of UK National Health Service (NHS) data for paediatric pharmacovigilance purposes and to make recommendations for such a system. METHODS: A mixed methods approach including a literature review, interviews, focus groups and a three-round Delphi survey with HCPs in Scotland was followed by a triangulation process using a systematic protocol. The survey was structured using the Theoretical Domains Framework of behaviour change. Items retained after applying the matrix-based triangulation process were thematically coded. Ethical approval was granted by the North of Scotland Research Ethics Service. RESULTS: Results from 18 papers, 23 interviewees, 23 participants of focus groups and 61 completed questionnaires in the Delphi survey contributed to the triangulation process. A total of 25 key findings from all four studies were identified during triangulation. There was good convergence; 21 key findings were agreed and remained to inform recommendations. The items were coded as practical/technical (eg, decision about the unique patient identifier to use), mandatory (eg, governed by statute), essential (consistently mentioned in all studies and therefore needed to ensure professional support) or preferable. CONCLUSIONS: The development of a paediatric linked database has support from professional stakeholders and HCPs in Scotland. The triangulation identified three sets of core requirements for a new system of data linkage. An additional fourth set of 'preferable' requirements might increase engagement of HCPs and their support for the new system.

Corticosteroid-sparing options in the treatment of childhood asthma.

During the last 30 years, a significant rise in wheezing illness has occurred in the child population. Despite its high prevalence there is no clear definition of the disease, which includes a heterogeneous group of syndromes ranging from transient wheezing in infancy to atopic asthma with persistence into adult life. Molecular advances and further epidemiological information from well characterised individuals and their families are likely to clarify the different subtypes of wheezing illness and inform therapeutic options. With the recognition that chronic airway inflammation is a feature of persistent disease, at least in adults, there has been a trend towards the early introduction of anti-inflammatory treatment and particularly inhaled corticosteroids (ICS). However, the natural resolution of much wheezing illness, particularly in young children and in children with viral-induced episodes, suggests that newly presenting children should remain on symptomatic therapy alone while the severity of the disease is being assessed. Although ICS have become a cornerstone of management of chronic persistent disease, their ability to protect against exacerbations in young and mildly affected children is questionable. Alongside concerns about long term use of ICS and possible systemic adverse effects, there remains a need for alternative approaches to the control of the disease in children. Extrapolation of the findings of large multicentre adult studies into childhood, particularly for doubling the doses of ICS and long-acting beta2-agonists, may be unsound. Other approaches include the early introduction of inhaled cromones, use of second generation antihistamines, low dose theophyllines and, more recently, leukotriene modifiers. As the majority of preschool children will become asymptomatic by mid-childhood, there is an urgent need to identify those in whom chronic airway inflammation is developing, as it is in this group that early introduction of ICS may be of maximum benefit. In the remainder, other approaches, including use of corticosteroid-sparing longacting P2-agonists and leukotriene modifying drugs, may be more appropriate. Safe and effective oral preparations such as leukotriene modifying drugs are likely to establish a significant role in the management of symptoms in children of all ages and with all types of asthma and wheezing illness.

Early asthma prophylaxis, natural history, skeletal development and economy (EASE): a pilot randomised controlled trial.

OBJECTIVES: (1) To establish recruitment rates of newly presenting asthmatic children. (2) To establish acceptability of study protocols. (3) To pilot age-specific quality of life (QoL) assessment. (4) To assess short-term (6 months) outcomes of inhaled corticosteroids (ICS) treatment. (5) To refine sample size calculations for a definitive study. DESIGN: A randomised pragmatic longitudinal trial design was used, with no blinding or placebo, to examine early ICS introduction similar to its use in practice. Subjects were assessed at entry, 3 and 6 months. SETTING: Subjects were recruited from six general practices. Children under 6 years were assessed at the Craig Research and Investigation Unit, Royal Aberdeen Children's Hospital, or their family home, and subjects 6 years and over were assessed at their general practice. SUBJECTS: Children (aged 6 months-16 years) with symptoms suggestive of asthma/wheeze that had commenced no longer than 12 months before were identified retrospectively and prospectively from general practices. Subjects were also required to be naïve to prophylactic therapy with no other lung disease/concomitant illness. INTERVENTIONS: Subjects were randomised to ss2-agonist (ss2-only group) or ss2-agonist and ICS (ICS group) for 6 months. Physicians could later prescribe ICS in controls if needed. MAIN OUTCOME MEASURES: (1) Pulmonary function. (2) Asthma symptom diary. (3) Symptomatic health status questionnaire. (4) Caregiver's and child's QoL. (5) Growth. (6) Bone mass. (7) Bone turnover. (8) Economic issues. RESULTS: Of over 15,000 children yielded from general practice records, 11% had symptoms suggestive of asthma/wheeze, and two-thirds of these already used ICS. Of the remaining, 141 subjects met the criterion of early asthma, and 86 were randomised. Two-thirds of those randomised were < 6 years old, the males:females ratio was 2:1, and 67% had a family history of atopy. RESULTS - PHYSIOLOGICAL DEVELOPMENT: Pulmonary function did not significantly improve in the older children. Although tidal breathing measures in the pre-school children were significantly higher at 6 months in the ss2-only group, there was great variability. Incidence of wheeze and night-time cough reduced equally in both groups. Reduction of night-time symptom score and reliever use, and increase in symptom-free days were only significant in the ss2-only group. No significant differences were found in growth and bone mass between the two groups, but bone metabolism was significantly reduced at 6 months in the ICS group. RESULTS - PSYCHOLOGICAL DEVELOPMENT: The caregiver's QoL questionnaire was sensitive to child symptom changes over 3 months, but absolute impact of child symptoms on their QoL varied, whereas the child-centred questionnaire was not sensitive to change. RESULTS - ECONOMICS: There were no significant differences in medical consultation costs between the groups, but, as expected, prescription costs in the ICS group were higher over 6 months. Combined healthcare costs were significantly higher for patients assigned to ICS, but there were no significant differences in any effectiveness measures between the groups. CONCLUSIONS: Most (96%) of the proposed sample was recruited, and the low drop-out rate (8%) demonstrated acceptability of the study protocol. Most children first presenting with symptoms suggestive of asthma were < 6 years old and represented a group biased towards mild to moderate asthma, or virally induced wheeze. The caregiver's QoL questionnaire was found to better reflect a child's symptom changes than a child-centred instrument. In the short term, no adverse effects were seen on growth, but ICS treatment significantly reduced bone metabolism. Most of the young children with asthma/wheeze improved over time with ss2-agonist treatment alone, and clinical benefits of early ICS intervention amongst these children were not detected; however, there was inadequate power in this pilot study to establish this. (AB

Issues and unmet needs in pediatric asthma.

Asthma is common and becoming more so in childhood. Although mild asthma may incur low average annual costs per child, these estimates need to be viewed in the context of the very large numbers of affected individuals. Whereas asthma and wheezing illness in childhood had in the past been broadly subdivided into asthma (often associated with atopy) and wheezy bronchitis (wheeze only, with associated upper respiratory tract infection), this distinction was lost during the 1970s in view of the demonstrated underdiagnosis and undertreatment of symptomatic school-age children. The acceptance of asthma as a chronic inflammatory disease and evidence for airway remodeling and progressive deterioration in airway function in association with symptoms and atopy have led to earlier use of topical steroids at higher starting doses delivered by improved age-appropriate devices. Treating all children as if they were destined to become atopic asthmatics and at risk of airway remodeling may not be rational, particularly in those whose symptoms will subsequently resolve. However, there are as yet no screening tests which can clearly identify individuals at risk of long-term chronic airway inflammation and airway remodeling. The large number of infants and young children with current symptoms suggestive of asthma and in whom resolution is likely in the majority poses problems for the clinician in deciding the best initial therapy. There is an urgent need to develop simple and reliable measures that can identify the early manifestations of atopic airway sensitisation and to establish the place of early intervention with nonsteroidal drugs, including leukotriene antigonists.

Assessment of airway function in young children with asthma: comparison of spirometry, interrupter technique, and tidal flow by inductance plethsmography.

The assessment of airway function in young children requires adaptation of techniques designed for adults and/or application of techniques that do not require complex respiratory maneuvers. We sought to assess two methods of measuring airway function: time to peak expiratory flows as a ratio of expiratory time (T(PTEF)/T(E)), derived from respiratory inductance plethysmography, and total respiratory resistance by the interrupter technique (Rint), both obtained during quiet tidal breathing. Both techniques were referenced to FEV1 and flow at 50% expired volume (FEF50) from conventional spirometry in 30 children aged 4-8 years (median age, 6.9; range, 4.5-8.5 years) with a physician diagnosis of asthma and who were able to perform FEV1 with a repeatability of at least 8%. T(PTEF)/T(E) and Rint were performed in random order followed by spirometry, in order to reduce the possible effects of pulmonary stretch on tidal breathing measures. Coefficients of variation (CV) and mean absolute change/baseline standard deviation were derived for each measurement. Baseline FEV1 did not correlate significantly with T(PTEF)/T(E) (r = 0.025), but did correlate with Rint (r = 0.737, P < 0.001); respective relationships for change after bronchodilator were r = 0.09 (ns) and r = 0.64 (P < 0.001). FEF50 also correlated significantly with Rint (R = 0.769, P < 0.001) but not with T(PTEF)/T(E). FEV1 and FEF50 both increased postbronchodilator, with respective mean changes of 11.4% and 28% (P < 0.001), while Rint decreased by 24.3% (P < 0.001). No significant changes were noted for T(PTEF)/T(E). T(PTEF)/T(E) derived from inductance plethysmography does not detect mild airway obstruction or modest changes in airway caliber following bronchodilator in young children with asthma. The interrupter technique may have a role in assessing baseline airway function and response to therapy in children unable to perform reliable spirometry, and/or when the investigator wishes to avoid the possible influence of forced maneuvers on airway tone.

Total respiratory compliance in infants and young children with congenital heart disease.

The multiple occlusion technique was used to measure total respiratory system compliance (Crs) in 62 infants and young children with congenital heart disease (age range, 2 days to 2 years). Measurements were found to be reproducible in nine infants in whom repeat measurements were possible (maximum deviation between measurements less than 10%). The incidence of failure to obtain accurate results was no greater than when studying infants without cardiopulmonary disease. However, in the presence of severe growth retardation or alinearity of volume-pressure data, results may be difficult to interpret in individuals. Results of Crs were related to non-invasive assessments of cardiac disease severity using chest radiography and echocardiography. After the effects of growth had been taken into account, a significant negative relationship was found between Crs and the right pulmonary artery to aortic ratio, which reflects pulmonary vascular engorgement (P = 0.003, R2 = -0.40). However, no significant relationship was found between Crs and chest X-ray score (P = 0.27).

Issues in pediatric asthma.

Different wheezing syndromes can carry the diagnostic label of "asthma," especially in very young children, and an accurate differential diagnosis is essential for improving outcomes. Because presenting symptoms are similar, making a rapid, accurate differential diagnosis is often daunting. Asthma can, eventually, be distinguished from other wheezing disorders based on differences in symptomatology, pathophysiology, and disease evolution. Once diagnosed, inhaled corticosteroids (ICS) remain the cornerstone of treatment in persistent pediatric asthma. Compelling evidence supports the benefits of these agents in reducing asthma-related morbidity and mortality and in preventing airway remodeling. As a result, ICS use in young children with asthma has grown substantially in recent years. Questions are being raised about the appropriateness of early and long-term use of ICS in young children, and whether ICS are overused in this population. Because of the challenges faced by clinicians in differentiating asthma from the other childhood wheezing disorders often present in young children, it may be best to delay the use of regular ICS therapy until a definitive diagnosis can be established. Alternatives to ICS (such as the leukotriene receptor antagonists) should also be considered to avoid the growth-suppressing potential of steroids in the management of mild asthma.

Early environmental influences in the development of asthma and atopic disease.

Intrauterine and early life exposures are important contributors to allergic sensitisation and to the subsequent expression of allergic disease and asthma. The recent epidemic of asthma and atopy clearly underlines the strength of environmental factors such as respiratory and enteric infections, allergen exposure, diet and lifestyles including exposure to cigarette smoke. These and other as yet unidentified environmental contributors are also likely to interact with underlying genetic predisposition. Although recent research interest has focussed on host responses and priming of TH2 lymphocytes there are some paradoxes yet to be resolved. What are the determinants of "homing" of sensitisation to the airway and does persistent airway inflammation result in airway remodelling or are these features independent risk factors for persistence and disease? Evidence that environmental exposures in fetal life and infancy influence lifelong respiratory health remains controversial. However it is becoming apparent that a range of environmental exposures and conditions do influence the development of asthma and atopic disease and that whole population interventions aimed at primary prevention might soon become realistic.

Seasonality and the sudden infant death syndrome during 1987-9 and 1991-3 in Australia and Britain.

OBJECTIVE: To determine whether seasonality of the sudden infant death syndrome persists now that rates have fallen, mostly after widespread adoption of the "face upwards" sleeping position. DESIGN: Monthly data on the sudden infant death syndrome during 1987-9 were compared for seasonality with those of 1991-3; rates were studied as deaths per 1000 live births. SETTING: Australia and Britain (England, Wales, and Scotland). SUBJECTS: Infants under 1 year dying of the syndrome (2401 for Australia and 6630 for Britain). MAIN OUTCOME MEASURE: Extent of seasonal variation (amplitude) was established by cosinor analysis; amplitudes for the earlier and later years were compared. RESULTS: The rate fell in every month, and, though it did so relatively more in winter than summer, seasonality remained a distinctive feature. In the comparison of amplitudes the ratio between the earlier and later years was 1.4 in both Australia and Britain. Some differences between the hemispheres were noted. CONCLUSIONS: Seasonality of the sudden infant death syndrome remains to be explained and continues to be an important aetiological lead. Studies from other countries are needed.

Is the increase in asthma prevalence occurring in children without a family history of atopy?

We investigated the familial associations of asthma and atopic disease in a population in which the prevalence of asthma and atopy is increasing. Interviewer administered abbreviated family history questionnaires were applied in 416 families with a total of 1005 children ascertained through index children attending fracture and dressing clinics. The prevalence of reported asthma (22.5%), eczema (24%) and hayfever (20%) in the children was high but similar to previous studies in this population. Asthma was reported in 20.8% of children of parents without a history of asthma and 18% of children of parents without any history of atopic disease. Logistic regression analysis of outcomes in the index children showed increased risk of atopic disease associated with parental history of the same atopic disease. The presence of an affected sibling was associated with an increased risk of eczema (OR 3.04 CI 1.83-5.05) or hayfever (OR 1.79 CI 0.97-3.3) but not asthma (OR 1.18 CI 0.66-2.08). Increasing number of siblings was associated with reduced risk although this was significant only for hayfever (OR 0.62 CI 0.41-0.86). Although the presence of affected relatives is associated with an increased risk of atopic disease the high prevalence of reported atopic disease, particularly asthma. in children of parents without a family history of atopic disease suggests that much of the increase in asthma prevalence is occurring in children without a significant genetic predisposition. Childhood asthma developing in what would previously have been regarded as low risk families may differ in its aetiology from classical atopic asthma.

Seasonality of birth in sudden infant death syndrome.

The objective was to clarify the optimal birth month for avoidance of SIDS and the seasonal characteristic of each birth-month cohort. The statistical method was cosinor analysis, and this established seasonality of SIDS death and births, the extent of this seasonality (amplitude) and the position of the peak (acrophase). There is a lowering of risk, by one third, amongst babies born in February-May compared to those born in August-November. The seasonal variation of death was twice as great for birth in September as compared with those in April. Those born in May-June lived on average six weeks longer than those born in November-April. Advice on subsequent pregnancy delivery date should be given to families who have already experienced SIDS. For those born in autumn there may be two components-the first a genetic or intrauterine component independent of month of birth, and the second an independent effect of interaction with winter environment.

Views of healthcare professionals to linkage of routinely collected healthcare data: a systematic literature review.

OBJECTIVE: To review the literature on the views of healthcare professionals to the linkage of healthcare data and to identify any potential barriers and/or facilitators to participation in a data linkage system. METHODS: Published papers describing the views of healthcare professionals (HCPs) to data sharing and linkage were identified by searches of Medline, EMBASE, SCOPUS, CINAHL, and PsychINFO. The searches were limited to papers published in the English language from 2001 to 2011. RESULTS: A total of 2917 titles were screened. From these, 18 papers describing the views of HCPs about data linkage or data sharing of routinely collected healthcare data at an individual patient level were included. Views were generally positive, and potential benefits were reported. Facilitators included having trust in the system including data governance, reliability, and feedback. Some negative views, identified as barriers were also expressed including costs, data governance, technical issues, and privacy concerns. Effects on the physician-patient relationship, and workload were also identified as deterrent. DISCUSSION: From the published literature included in this review, the views of HCPs were in general positive towards data sharing for public health purposes. The identification of barriers to contributing to a data linkage system allows these to be addressed in a planned data linkage project for pharmacovigilance. The main barriers identified were concerns about costs, governance and interference with the prescriber-patient relationship. These would have to be addressed if healthcare professionals are to support a data linkage system to improve patient safety.

A retrospective observational study comparing rescue medication use in children on combined versus separate long-acting beta-agonists and corticosteroids.

BACKGROUND: Data on the efficacy and safety of long-acting ß2-agonists (LABA) in children are limited, and current guidelines recommend that LABA always be used with inhaled corticosteroids (ICS). OBJECTIVE: To compare asthma control, assessed by rescue medications use, in children prescribed LABA and ICS as a fixed-dose combination (LABA/ICS) or concurrently via separate inhalers (LABA+ICS). METHODS: Retrospective observational study of asthma medication prescribed to children aged 0-18 years registered with 40 primary care practices for the years 2002-6. Asthma control, reflected by requirement for oral corticosteroids (OCS) and/or six or more short-acting ß2-agonist (SABA) canisters per year, was assessed for children prescribed LABA/ICS or LABA+ICS. RESULTS: 10,454 (8%) of all registered children received at least one prescription for asthma medication over the study period. Prescribing of LABA/ICS increased significantly, with a concomitant decrease in prescribing of LABA+ICS. Use of OCS increased by 60%, with the lowest use in children prescribed only SABA and highest use in those prescribed LABA. Children prescribed LABA/ICS were significantly less likely than those prescribed LABA+ICS to require OCS rescue therapy and or >6 SABA inhalers a year (OR 1.6; 95% CI 1.1 to 2.2; p=0.04 and OR 1.7; 95% CI 1.1 to 2.5; p=0.005, respectively, for the years 2005-6). CONCLUSIONS: The results of this retrospective observational study suggest that children prescribed fixed-dose LABA-and-ICS combination devices achieve better asthma control, as reflected in reduced requirements for SABA and reduced courses of OCS than equivalent doses in separate devices.