Diagnosis of paediatric airway foreign body: is it easy?

Foreign-body aspiration in children results in diagnostic problems, mainly because of nonspecific signs. Therefore, in this study, we placed particular stress on false-positive and -negative predictors. Charts of 139 consecutive paediatric patients aged 6.0 months to 15.5 years who underwent bronchoscopy for a suspected foreign body aspiration were analysed retrospectively. A foreign body was found in 95 cases (68%). The anamnesis was positive in 91%. Cough was the most common clinical symptom (91%) with a sensitivity and specificity of 94% and 23%, respectively. There were no significant correlations between clinical symptoms and the locations of foreign bodies. The majority of focal hyperinflation (24%) and atelectasis (15%) were seen in chest radiographs, with a sensitivity and specificity of 33% and 89% (hyperinflation) and 15% and 82% (atelectasis), respectively. Chest X-rays were normal in 46 cases; however, an object was removed in 25. Persistent infiltrates were present in 14 X-rays, and a foreign body was extracted during bronchoscopy in 4. A highly significant correlation between the type of foreign body and radiological signs was noted (p = 0.00001). Anamnesis, clinical symptoms, and radiological findings are helpful in confirming aspiration, but can be misleading. Chronic or recurrent pneumonia should prompt further bronchoscopic diagnosis.     

Leukotriene receptor antagonists – risks and benefits for use in paediatric asthma

Leukotrienes (LTs) are important mediators of the pathophysiology of asthma, specifically, bronchoconstriction, airway inflammation and oedema and mucus hypersecretion. The LT receptor antagonists (LTRAs) inhibit these potent effects by selectively blocking the cysteinyl LT₁ receptor. These are the first novel therapies for asthma since the introduction of inhaled corticosteroids (ICS) in 1972. Unlike generalised inhibition of airway inflammation by ICS, the LTRAs target inhibition of specific mediators. In general, paediatric data concerning these agents remain quite limited. However, they have demonstrated efficacy against allergen- and exercise-induced bronchospasm in both adults and children. Recently, their potential role for the treatment of viral-induced wheeze in young children has been explored. In multiple, placebo-controlled trials, the LTRAs have demonstrated efficacy for the treatment of mild persistent asthma, additive benefit in the management of symptomatic moderate asthmatics on maintenance ICS and evidence of significant steroid-sparing. Findings from these clinical trials and real-world experience support the use of the LTRAs as controller agents for persistent asthma. Based on their excellent safety profiles, tolerance and ease of administration (including once daily dosing with montelukast), this drug class may offer several important features for use as controller therapy, particularly in asthmatic children as young as 1 year of age, however, this must continue to be reviewed as new paediatric data become available.     

Treatment of paediatric visceral leishmaniasis: amphotericin B or pentavalent antimony compounds?

Pentavalent antimony compounds and amphotericin B lipid formulations have been found highly active for the treatment of visceral leishmaniasis. This study focuses on which treatment is preferable in the best interests of the child. Records were reviewed of children in our hospital aged 0-14 years, diagnosed with visceral leishmaniasis, during the last 4 years. Twenty-nine children were identified. Ten were treated with meglumine antimonate (20 mg/kg/day for 21 days) and remained in hospital for 11-28 days (median 19 days), while 19 patients received liposomal amphotericin B at four different dosage schemes and were in hospital for 6-11 days (median 7 days). All of the patients were cured regardless of the treatment regime they followed. No relapses were noted. Liposomal amphotericin B would be preferable to meglumine antimonate if the reduction in hospital stay and hence the convenience of the patient balance the cost of medication. The optimal duration of treatment with liposomal amphotericin B remains to be determined.     

Is spinal manipulation effective for paediatric conditions? An overview of systematic reviews

The aim of this overview was to critically evaluate the evidence of effectiveness for spinal manipulation in any paediatric condition. Four electronic databases were searched from their inception to July 2011 to identify all relevant systematic reviews of spinal manipulation for any paediatric condition. Reviews were defined as systematic if they included explicit and repeatable inclusion and exclusion criteria. Five systematic reviews were included, which covered the following conditions: infant colic (n=2), kinetic imbalance due to suboccipital strain (n=1), nocturnal enuresis (n=1) and otitis media (n=1). None of the systematic reviews generated conclusive evidence to suggest that spinal manipulation is an effective treatment for any paediatric condition. Collectively these data failed to demonstrate that spinal manipulation is a useful therapy for paediatric complaints. The safety of spinal manipulation in paediatrics is also less than clear.     

Are computerised monitoring systems of value to improve pharmacovigilance in paediatric patients?

Objective The aim of the present study was to evaluate a computerised monitoring system (CMS) based on laboratory test results for the detection of adverse drug reactions (ADRs) on a paediatric ward.Methods A prospective, 6-month pharmacoepidemiological survey was performed on a 22-bed paediatric isolation ward. ADRs were identified by intensive chart review. In addition to spontaneous reporting by the treating physician, automatic laboratory signals generated by a CMS were evaluated for their association with ADRs. ADRs were classified by the affected target organs according to the WHO–ART system organ classes.Results A total of 73 ADRs were identified in 439 admissions (396 patients) by chart review. The CMS alerted 31 (42.4%) ADRs while 23 (31.5%) ADRs were found solely by treating physicians. Eight ADRs were detected by both approaches resulting in a total detection rate of 74% (compared with intensive pharmacovigilance). Out of a total of 27,434 laboratory tests performed routinely, 1,563 were classified as abnormal by the predefined CMS and used as the basis of alerts. The sensitivity of the system with respect to patients alerted was 90.3% and the specificity only 19.6%.Conclusion This study demonstrates that, using CMS, a different kind of mild adverse events were detected compared to the observation by the treating physician. The system presented appears to be sufficiently sensitive, but the specificity is too low to make it acceptable for physicians in daily practice. In children, clinically important ADRs can be detected best by intensified surveillance.     

Pragmatic measures in paediatric psychopharmacology — Are we getting it right?

Recent changes in legislation have stimulated a new wave of interest and activity in paediatric psychopharmacology. This increased activity has coincided with a recognition that pragmatic measures of outcome such as those that tap into impairment and health related quality of life (HRQOL) have the potential to add considerably to the traditional symptom based measures of outcome. There are however considerable methodological issues associated with these types of measure, and these are made more complex when they are applied in mental health and paediatric settings. There is a clear need for the continued development of valid and reliable measures of HRQOL and impairment that are fit for purpose for use in clinical trials. Other more specific issues that need to be considered, and which all require further investigation include those relating to; age, self versus proxy ratings, contextual issues, generic versus disorder specific measures and definitions of clinically meaningful change. Most of the child and adolescent mental health trials that have included pragmatic measures have been conducted in ADHD samples, have been industry sponsored, use only parent ratings and focus on one drug (atomoxetine). Taken together they do however suggest that pharmacological treatments can impact positively on impairment and HRQOL, although with smaller effect sizes than is seen for symptom reduction. Further studies, across a wider range of disorders and treatments with multiple measures and multiple raters, are to be encouraged. In addition to reporting the basic outcomes from these studies researchers should use these data to improve the measurement models and refine both the measures and the trial designs.     

Challenges in health state valuation in paediatric economic evaluation: are QALYs contraindicated?

With the growth in the use of health economic evaluation to inform healthcare resource allocation decisions, the challenges in applying standard methods to child health have become apparent. A unique limitation is the paucity of child-specific preference-based measures. A single, valid, preference-based measure of utility that can be used in children of all ages does not exist. Thus, the ability to derive a QALY for use in cost-utility analysis (CUA) is compromised. This paper presents and discusses existing and novel options for deriving utilities for paediatric health states for use in CUAs. While a direct elicitation may be preferred, a child's ability to complete a standard gamble or time trade-off task is hampered by cognitive and age limitations. The abstract notions contained in indirect instruments such as the EQ-5D and Health Utilities Index may also pose challenges for young children. Novel approaches to overcome these challenges include the development of age-appropriate instruments such as the EQ-5D-Y, the development of new child-specific utility instruments such as the Child Health Utility-9D and the re-calibration of existing adult instruments to derive preference weights for health states from children themselves. For children aged <6 years, researchers have little choice but to use a proxy reporter such as parents. While parents may be reliable reporters for physical activity limitations and externally manifest symptoms, their ability to accurately report on subjective outcomes such as emotion is questionable. Catalogues of utility weights for a range of conditions are increasingly becoming available but retain many of the same limitations as valuing health states from children or from proxies. Given the dynamic relationship in quality of life (QOL) between family members when a child is ill, it seems appropriate to consider a 'family perspective' rather than an individual perspective in child health state valuation. In a collective approach, health state utilities derived from multiple family members may be combined mathematically. Alternatively, in a unitary approach, a single utility estimate may be determined to represent the family's perspective. This may include deriving utilities through parent-child dyad estimation or by using a household model that combines the utility weights of the patient and family members, incorporating reciprocal QOL effects. While these various approaches to child health state valuation represent novel research developments, the measurement challenges and threats to validity persist. Given the importance of non-health benefits to child health, especially in the domains of education and public policy, it may be worthwhile to consider an approach that allows incorporation of externalities to produce a cost-benefit analysis. The use of discrete-choice methods to assess willingness to pay for novel child health interventions holds promise as a means to produce meaningful economic evidence. Regardless of the approach taken, the highest degree of methodological rigour is essential. The increasing attention being paid by health economic researchers to the measurement challenges of paediatric health state valuation can only increase the value of child health economic evidence for decision making.     

Paediatric drug development: are population models predictive of pharmacokinetics across paediatric populations?

AIMS

To assess the predictive value of a model-based approach for dose selection across paediatric populations in early clinical drug development.

METHODS

Abacavir was selected as a paradigm compound using data across a wide age range. Abacavir pharmacokinetics (PK) in children were analysed separately from infants and toddlers. Two independent models were obtained, and systemic exposure (AUC) was then simulated across populations based on the estimates from each model. Drug exposures in infants and toddlers were predicted using pharmacokinetic parameter distributions obtained from children, and the other way around.

RESULTS

The pharmacokinetic models (a two-compartment PK model for infants and toddlers and a one compartment PK model for children) accurately described the exposure in the population from which they were built. However, neither model predicted exposure in a different population: in infants, the median AUC (95%^-CI) was estimated at 7.03 (6.72, 7.48) µg ml⁻¹ h, whilst it was predicted at 5.75 (4.82, 6.26) µg ml⁻¹ h; in children, the estimated median AUC was 6.96 (5.85, 7.91) µg ml⁻¹ h, whilst the predicted value was 6.45 (5.80, 7.01) µg ml⁻¹ h.

CONCLUSIONS

These findings suggest that the assumption of an identical (linear or nonlinear) correlation between pharmacokinetic parameters and demographic factors may not hold true across age groups. Whilst the use of modelling enables accurate characterization of pharmacokinetic properties, extrapolations based on such parameter estimates may have limited value due to differences in the impact of developmental growth across populations.     

Off-label use of medicines in children: can available evidence avoid useless paediatric trials?

Purpose  In some cases of drug therapy, the available evidence might be sufficient to extend the indications to children without further clinical studies. Methods  We reviewed the available evidence for one of the categories of drugs most frequently used off-label in children: proton pump inhibitors (PPIs) used for the treatment of gastroesophageal reflux disease (GERD). A classification of the appropriateness of off-label use of PPIs in children with GERD was also performed. Results  Of the five PPIs evaluated, only omeprazole has a paediatric indication in Europe. Overall, 19 clinical trials were retrieved and evaluated on the basis of pharmacokinetics, efficacy and safety data. The off-label use of omeprazole, esomeprazole and lansoprazole in children was evaluated as appropriate given the consistent available evidence retrieved in literature. Conclusion  This study demonstrates the existence of a large body of clinical evidence on the use of PPIs in children. Regulatory agencies and ethical committees should cope with this issue for ethical reasons to avoid unnecessary trial replication.     

13-cis retinoic acid and isomerisation in paediatric oncology--is changing shape the key to success?

Retinoic acid isomers have been used with some success as chemotherapeutic agents, most recently with 13-cis retinoic acid showing impressive clinical efficacy in the paediatric malignancy neuroblastoma. The aim of this commentary is to review the evidence that 13-cis retinoic acid is a pro-drug, and consider the implications of retinoid metabolism and isomerisation for the further development of retinoic acid for cancer therapy. The low binding affinity of 13-cis retinoic acid for retinoic acid receptors, low activity in gene expression assays and the accumulation of the all-trans isomer in cells treated with 13-cis retinoic acid, coupled with the more-favourable pharmacokinetic profile of 13-cis retinoic acid compared to other isomers, suggest that intracellular isomerisation to all-trans retinoic acid is the key process underlying the biological activity of 13-cis retinoic acid. Intracellular metabolism of all-trans retinoic acid by a positive auto-regulatory loop may result in clinical resistance to retinoic acid. Agents that block or reduce the metabolism of all-trans retinoic acid are therefore attractive targets for drug development. Devising strategies to deliver 13-cis retinoic acid to tumour cells and facilitate the intracellular isomerisation of 13-cis retinoic acid, while limiting metabolism of all-trans retinoic acid, may have a major impact on the efficacy of 13-cis retinoic acid in paediatric oncology.     

Pharmacokinetics of lamotrigine in paediatric and young adult epileptic patients—nonlinear mixed effects modelling approach

Purpose

The purpose of the study was to examine and describe adjunctive lamotrigine (LTG) pharmacokinetics in paediatric and young adult patients using a nonlinear mixed effects modelling (NONMEM) approach.

Methods

The study included 53 patients (age range 3–35 years) who were concomitantly treated with carbamazepine (CBZ) and/or valproic acid (VPA). A total of 70 blood samples corresponding to trough levels were available for analysis. Data were modelled, and the final model was evaluated using NONMEM and auxiliary software tools.

Results

The final LTG population model included the effects of concomitant drugs and patient’s weight (WT) which stratified the population into three groups: ≤25 kg, >25 to <60 kg and ≥60 kg. Based on the final model, the estimated LTG oral clearance (CL/F) for a typical patient weighing ≤25 kg, >25 to <60 kg or ≥60 kg who was concomitantly treated with CBZ was estimated to be 3.28, 4.23, or 7.15 l/h, respectively. If a patient was concomitantly treated with CBZ + VPA, the CL/F decreased on average by 69.5 % relative to LTG + CBZ co-therapy. VPA was found to decrease the LTG CL/F by 87.6 % compared to co-therapy with only CBZ.

Conclusion

The LTG population pharmacokinetic model developed in this study may be a reliable method for individualising the LTG dosing regimen in paediatric and young adult patients on combination therapy during therapeutic drug monitoring.     

Supporting the recommended paediatric dosing regimen for rufinamide in Lennox–Gastaut syndrome using clinical trial simulation

Rufinamide was approved for the treatment of seizures associated with Lennox–Gastaut syndrome (LGS) as adjunctive therapy in patients aged 4 years and older. Rufinamide pharmacokinetics (PK) has been established on pooled data from several clinical studies in epilepsy, including one in LGS patients. Demographic covariates and drug–drug interactions with several antiepileptic drugs have been explored using population PK modelling. Two types of drug–drug interactions models were developed and compared. The PK analysis demonstrated that the co-administration of valproate decreases rufinamide clearance, requiring potential dose adjustment. To explore rufinamide exposure under different dosing regimens in LGS patients, clinical trial simulations were performed. The objective of the simulations was to select the doses giving an exposure shown to be safe and efficacious in larger populations. The concentrations simulated in a subgroup of patients with body weight less than 30 kg presented a larger inter-individual variability than in other patients. Additional simulations demonstrated that this increased variability was due partly to greater valproate concentrations in some of the children treated with rufinamide. Simulations of the rufinamide exposure under different maximum daily dose in presence and in absence of valproate co-administration were used to establish the dosing recommendation. The simulations support the proposal of a lower maximum daily rufinamide dose for patients under 30 kg receiving both drugs: the dose of 600 mg/day was proposed as a maximum daily dose in children also receiving valproate concomitantly, whereas in absence of valproate, the maximum daily dose is 1000 mg/day.     

Development and evaluation of age-appropriate film-coated tablets of levamisole for paediatric use (2 – 18 years)

Objectives: To develop an oral solid dosage form of levamisole suitable for the paediatric population in terms of dose accuracy, palatability, stability and ease of administration.

Methods: Small undividable tablets (Ø5 – 8 mm) in four different strengths were manufactured to allow for flexible and accurate dosing. In vitro dissolution testing was used to determine drug release in different media. The bitter taste of levamisole was masked using a film-coat and assessed in healthy volunteers. Suitability and acceptability of the tablets were evaluated in 100 patients with nephrotic syndrome aged 2 – 18 years participating in a double blind, placebo-controlled, randomised trial.

Results: All tablet strengths showed good taste-masking characteristics and similar, pH independent, dissolution profiles. Successful taste masking was achieved without affecting the dissolution rate. In a total of 100 paediatric patients, more than 20,000 levamisole tablets were swallowed without any difficulties, choking or aspiration.

Conclusion: The formulated tablets were found to be suitable for children aged 2 – 18 years and to provide good dose accuracy.     

Categorising paediatric prescribing errors by junior doctors through prescribing competency assessment: does assessment reflect actual practice?

Purpose

It is recognised that paediatric prescribing errors are prevalent, and that most are made by junior doctors; however, detecting errors in order to demonstrate actual error rates can be difficult. There is evidence to suggest that dosing errors are the most common type of prescribing error in practice, but there has been little research on whether prescribing assessments are an effective reflection of actual practice.This article aims to determine if prescribing error types in a paediatric prescribing competency assessment reflects error types seen in actual practice.

Methods

This study was conducted in Royal Manchester Children’s Hospital (RMCH) and the participants were junior doctors working at RMCH in 2010-2011. The intervention was a prescribing competency assessment package at RMCH.The main outcome measurement was the category and rate of prescribing errors. Results were taken from the junior doctors’ prescribing competency assessment. The assessment papers were analysed for errors and the errors were then broken down into pre-defined categories.

Results

Rates of prescribing errors in the competency assessment are higher than published results shown in practice (23.1 %). The most common type of prescribing error (incorrect calculation of dose) reflects results seen in actual practice.

Conclusion

The types of prescribing errors made in the competency assessment are reflective of errors made in actual practice. Prescribing teaching can be tailored according to the types of errors noted; and the prescribing competency package as a whole can be used to educate junior doctors on good prescribing practice and reduce prescribing errors.     

Assessing the viability of long-acting β2-agonists in paediatric asthma patients: a pharmacokinetic/pharmacodynamic perspective

Introduction: Long-acting β₂-agonists (LABAs) combined with inhaled corticosteroids (ICSs) are still commonly prescribed to asthmatic children. Unfortunately, pediatric LABA use is based primarily on data from adults, despite the fact that children are not simply small adults and the magnitude of changes in dose exposure and/or exposure response may not be solely reflected by differences in body weight.

Areas covered: The differences in pharmacokinetics (PK) and pharmacodynamics (PD) of LABAs are described and discussed with reference children and adults.

Expert opinion: Data on the PK behavior of LABAs is very limited and there is almost no data on once-daily LABAs available in the pediatric population. We do not believe that this is due to a fundamental lack of information because therapeutic response and adverse effects are more useful for the optimization of β₂-agonist treatment than measurement of plasma drug concentrations per se. Nevertheless, population PK-PD studies in children are needed according to the European rules in order to define rational, patient-tailored dosing schemes. Population PK-PD modeling and simulation using non-linear mixed effect modeling should be considered as the preferred tool to develop effective and safe dosing regimens for children because they present an opportunity to analyze sparse and unbalanced datasets, thereby minimizing the burden for each child.