Matthew Peak

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

BackgroundA 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.MethodA 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.ResultsThe 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.ConclusionManipulations 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.

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

BackgroundOff-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.MethodsA 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.ResultsA 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).ConclusionsOLUL 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.

Adverse Drug Reactions Causing Admission to a Paediatric Hospital

Objective(s) To obtain reliable information about the incidence of adverse drug reactions, and identify potential areas where intervention may reduce the burden of ill-health. Design Prospective observational study. Setting A large tertiary children’s hospital providing general and specialty care in the UK. Participants All acute paediatric admissions over a one year period. Main Exposure Any medication taken in the two weeks prior to admission. Outcome Measures Occurrence of adverse drug reaction. Results 240/8345 admissions in 178/6821 patients admitted acutely to a paediatric hospital were thought to be related to an adverse drug reaction, giving an estimated incidence of 2.9% (95% CI 2.5, 3.3), with the reaction directly causing, or contributing to the cause, of admission in 97.1% of cases. No deaths were attributable to an adverse drug reaction. 22.1% (95% CI 17%, 28%) of the reactions were either definitely or possibly avoidable. Prescriptions originating in the community accounted for 44/249 (17.7%) of adverse drug reactions, the remainder originating from hospital. 120/249 (48.2%) reactions resulted from treatment for malignancies. The drugs most commonly implicated in causing admissions were cytotoxic agents, corticosteroids, non-steroidal anti-inflammatory drugs, vaccines and immunosuppressants. The most common reactions were neutropenia, immunosuppression and thrombocytopenia. Conclusions Adverse drug reactions in children are an important public health problem. Most of those serious enough to require hospital admission are due to hospital-based prescribing, of which just over a fifth may be avoidable. Strategies to reduce the burden of ill-health from adverse drug reactions causing admission are needed.

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

BackgroundAdverse 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.MethodsWe 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.ResultsA 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).ConclusionsADRs 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.

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.

Adverse drug reactions causing admission to a paediatric hospital: a pilot study

What is known and Objective:  It is known that adverse drug reactions (ADRs) cause admission to hospital in adults and children. A recent adult study showed that ADRs are an important and frequent cause of hospital admission. The objective of this study is to develop methodology to ascertain the current burden of ADRs through a prospective analysis of all unplanned admissions to a paediatric hospital.

Estimating the requirement for manipulation of medicines to provide accurate doses for children

Objective To determine the type and frequency of manipulations of drug dosage forms required to administer smaller doses for children and the drugs involved. Methods An experienced paediatric clinical pharmacist estimated the requirement to manipulate a medicine to achieve accurate dose administration from prescription data in all neonatal and paediatric inpatients collected over 5-day periods and information on drug dosage form availability in a regional childrens hospital (RCH) and regional paediatric intensive care unit (RPICU), a regional neonatal intensive care unit (RNICU) and paediatric and neonatal wards of a district general hospital (DGH) using paper-based prescribing systems. Doses were expressed by weight. Ward stock supply with some intravenous drugs ready-to-administer was provided. The main outcome measures were the estimated requirement for dosage form manipulation, nature of the manipulation and drug name. Results Of 5375 evaluated drug administrations, 542 (10.1%) were judged to require manipulation or measurement of a small volume (<0.2 ml). The most frequent manipulation was measurement of oral dose in volumes of 0.1 to <0.2 ml in the DGH. Requirement to measure doses of <0.1 ml (oral and intravenous) accounted for 25.2% of all manipulations, with the need to measure intravenous doses of <0.1 ml being most frequent in the RNICU and RPICU (60.4% and 31.9% of manipulations, respectively). Hydrocortisone was the drug most frequently judged to require manipulation with both measurement of small volumes for intravenous injection (RPICU and RNICU) and segmentation of tablets (RCH). Conclusions Manipulation of medicines (including measurement of very small volumes) to provide accurate smaller doses for children is common in the hospital setting.

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

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.

Population Pharmacokinetics of Teicoplanin in Children

ABSTRACT Teicoplanin is frequently administered to treat Gram-positive infections in pediatric patients. However, not enough is known about the pharmacokinetics (PK) of teicoplanin in children to justify the optimal dosing regimen. The aim of this study was to determine the population PK of teicoplanin in children and evaluate the current dosage regimens. A PK hospital-based study was conducted. Current dosage recommendations were used for children up to 16 years of age. Thirty-nine children were recruited. Serum samples were collected at the first dose interval (1, 3, 6, and 24 h) and at steady state. A standard 2-compartment PK model was developed, followed by structural models that incorporated weight. Weight was allowed to affect clearance (CL) using linear and allometric scaling terms. The linear model best accounted for the observed data and was subsequently chosen for Monte Carlo simulations. The PK parameter medians/means (standard deviation [SD]) were as follows: CL, [0.019/0.023 (0.01)] × weight liters/h/kg of body weight; volume, 2.282/4.138 liters (4.14 liters); first-order rate constant from the central to peripheral compartment (Kcp), 0.474/3.876 h−1 (8.16 h−1); and first-order rate constant from peripheral to central compartment (Kpc), 0.292/3.994 h−1 (8.93 h−1). The percentage of patients with a minimum concentration of drug in serum (Cmin) of <10 mg/liter was 53.85%. The median/mean (SD) total population area under the concentration-time curve (AUC) was 619/527.05 mg · h/liter (166.03 mg · h/liter). Based on Monte Carlo simulations, only 30.04% (median AUC, 507.04 mg · h/liter), 44.88% (494.1 mg · h/liter), and 60.54% (452.03 mg · h/liter) of patients weighing 50, 25, and 10 kg, respectively, attained trough concentrations of >10 mg/liter by day 4 of treatment. The teicoplanin population PK is highly variable in children, with a wider AUC distribution spread than for adults. Therapeutic drug monitoring should be a routine requirement to minimize suboptimal concentrations. IMPORTANCE (This trial has been registered in the European Clinical Trials Database Registry [EudraCT] under registration number 2012-005738-12.)

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

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.