Noel Cranswick

Antibiotic Prophylaxis and Recurrent Urinary Tract Infection in Children

BACKGROUND Antibiotics are widely administered to children with the intention of preventing urinary tract infection, but adequately powered, placebo-controlled trials regarding efficacy are lacking. This study from four Australian centers examined whether low-dose, continuous oral antibiotic therapy prevents urinary tract infection in predisposed children. METHODS We randomly assigned children under the age of 18 years who had had one or more microbiologically proven urinary tract infections to receive either daily trimethoprim-sulfamethoxazole suspension (as 2 mg of trimethoprim plus 10 mg of sulfamethoxazole per kilogram of body weight) or placebo for 12 months. The primary outcome was microbiologically confirmed symptomatic urinary tract infection. Intention-to-treat analyses were performed with the use of time-to-event data. RESULTS From December 1998 to March 2007, a total of 576 children (of 780 planned) underwent randomization. The median age at entry was 14 months; 64% of the patients were girls, 42% had known vesicoureteral reflux (at least grade III in 53% of these patients), and 71% were enrolled after the first diagnosis of urinary tract infection. During the study, urinary tract infection developed in 36 of 288 patients (13%) in the group receiving trimethoprim-sulfamethoxazole (antibiotic group) and in 55 of 288 patients (19%) in the placebo group (hazard ratio in the antibiotic group, 0.61; 95% confidence interval, 0.40 to 0.93; P = 0.02 by the log-rank test). In the antibiotic group, the reduction in the absolute risk of urinary tract infection (6 percentage points) appeared to be consistent across all subgroups of patients (P > or = 0.20 for all interactions). CONCLUSIONS Long-term, low-dose trimethoprim-sulfamethoxazole was associated with a decreased number of urinary tract infections in predisposed children. The treatment effect appeared to be consistent but modest across subgroups. (Australian New Zealand Clinical Trials Registry number, ACTRN12608000470392.)

Mortality associated with attention-deficit hyperactivity disorder (ADHD) drug treatment: a retrospective cohort study of children, adolescents and young adults using the general practice research database

AbstractBackground: Following reports of sudden death in patients taking medication to treat attention-deficit hyperactivity disorder (ADHD), this study aimed to identify cases of death in patients prescribed stimulants and atomoxetine and to determine any association between these and sudden death. Method: The UK General Practice Research Database (GPRD) was used to identify patients aged 2–21 years from 1 January 1993 to 30 June 2006 with a prescription for methylphenidate, dexamfetamine or atomoxetine. Patients were followed from the date of first prescription until whichever came first: date of death, transferred-out date, age >21 years or end of the study period. Results: From a cohort of 18 637 patient-years, seven patients died. Cause of death was obtained for six of the patients. None were deemed to be cases of sudden death. Compared with a general population rate of sudden death in the literature, the worst-case scenario of one case of sudden death gave an incident rate ratio of 1.63 (95% CI 0.04, 9.71). Although it was not the primary outcome of the study, following reports of suicide in the cohort the standardized mortality ratio (SMR) of suicide was calculated. Due to differences in the definition of suicide used for children and adults, patients were categorized into two age groups: 11–14 years and 15–21 years. The SMR for suicide for patients aged 11–14 years was 161.91 (95% CI 19.61, 584.88). The SMR for suicide for patients aged 15–21 years was 1.84 (95% CI 0.05, 10.25). Conclusion: This study demonstrated no increase in the risk of sudden death associated with stimulants or atomoxetine. However, an increased risk of suicide was seen. Although we cannot exclude that the medications may contribute to the increased risk of suicide, there are other factors such as depression and antisocial behaviour that frequently co-exist with ADHD, which can also predispose to teenage suicide. Clinicians should identify patients at increased risk of cardiovascular events and identify those patients at increased risk of suicide, particularly males with co-morbid conditions, and monitor them appropriately.

Minimising medication errors in children

Medical errors are a major problem in the UK and other countries. Apart from the direct expense to the healthcare system, there are great personal costs to those involved including patients, their families and staff, and public confidence is undermined. Therefore, policy initiatives have been implemented to reduce such mistakes. Medication errors are thought to be the most common type of medical errors, with the majority of studies being conducted in adults. However, recent evidence highlights the fact that medication errors are also a significant problem in the paediatric population. This paper reviews the factors contributing to paediatric medication errors, including lack of appropriate paediatric formulations, communication issues between health professionals, dose calculation mistakes and inadequate clinical practice. This review will also discuss risk reduction strategies such as electronic prescribing and computerised physician order entry (CPOE) systems which can significantly reduce paediatric medication errors in conjunction with pharmacist monitoring, improved communication and environments which promote best practice.

Survey of complementary and alternative medicine use at a tertiary children's hospital

Objective: The use of complementary and alternative medicine (CAM) within the Australian community is common. The objective of this study was to determine the prevalence and pattern of CAM usage in children attending a tertiary childrens hospital.

Comparison of complementary and alternative medicine use: reasons and motivations between two tertiary children’s hospitals

Aims: To compare prevalence, reasons, motivations, initiation, perceived helpfulness, and communication of complementary and alternative medicine (CAM) use between two tertiary children’s hospitals. Methodology: A study, using a face-to-face questionnaire, of 500 children attending the University Hospital of Wales, Cardiff, UK was compared to an identical study of 503 children attending the Royal Children’s Hospital, Melbourne, Australia. Results: One year CAM use in Cardiff was lower than Melbourne (41% v 51%; OR = 0.67, 95% CI 0.52–0.85), reflected in non-medicinal use (OR = 0.41, 95% CI 0.29–0.58) and general paediatric outpatients (OR = 0.38, 95% CI 0.21–0.67). Compared to Melbourne, factors associated with lower CAM use in Cardiff included families born locally (father: OR = 0.58, 95% CI 0.44–0.77) or non-tertiary educated parents (mother: OR = 0.54, 95% CI 0.38–0.77). Cardiff participants used less vitamin C (OR = 0.31, 95% CI 0.18–0.51) and herbs (OR = 0.49, 95% CI 0.34–0.71), attended less chiropractors (OR = 0.25, 95% CI 0.06–0.37) and naturopaths (OR = 0.08, 95% CI 0.02–0.33), but saw more reflexologists (OR = 3.33, 95% CI 1.08–10.29). In Cardiff, CAM was more popular for relaxation (OR = 1.92, 95% CI 1.03–3.57) but less for colds/coughs (OR = 0.4, 95% CI 0.27–0.73). Most CAM was self-initiated (by parent) in Cardiff and Melbourne (74% v 70%), but Cardiff CAM users perceived it less helpful (OR = 0.46, 95% CI 0.31–0.68). Non-disclosure of CAM use was high in Cardiff and Melbourne (66% v 63%); likewise few doctors/nurses documented recent medicinal CAM use in inpatient notes (0/21 v 2/22). Conclusions: The differences in CAM use may reflect variation in sociocultural factors influencing reasons, motivations, attitudes, and availability. The regional variation in use and poor communication highlights the importance of local policy development.

Paracetamol efficacy and safety in children: the first 40 years.

&NA; Paracetamol (acetaminophen) has a unique role in children because it is the first-line choice for the treatment of both fever and pain. When used in the recommended doses, it has few side effects and is remarkably well tolerated. While fever alone requires no treatment, when associated with discomfort or pain, paracetamol offers relief. Also, for mild to moderate pain, paracetamol, either alone or in combination with another drug, is effective. Even in severe pain, paracetamol offers a significant additive analgesic effect to opiates. Globally, the pediatric dose varies between 10 and 15 mg/kg. In the United Kingdom, 10 mg/kg is given every 4 hours, up to a maximum of four doses per day; in Australia, 15 mg/kg is administered 4-hourly up to a total dose of 60 mg/kg/day. In overdose, paracetamol is hepatotoxic. Single ingestions of more than ten times the recommended dose are potentially toxic. The development of specific antidotes and the universal availability of the Rumack-Matthew Nomogram have made the early treatment of overdose effective without long-term sequelae. There are sporadic case reports of chronic overdosing resulting in liver failure. Although the specific predictors are still being defined, exposures greater than 140 mg/kg/day for several days carry a risk of serious toxicity. In children, aspirin use has almost disappeared with the concurrent decline in Reye Syndrome. Less clinical experience has accumulated with ibuprofen, and it remains the second-line treatment for fever and pain. In conclusion, paracetamol remains the first-choice over-the-counter treatment for analgesia and antipyresis in children.

Risk factors associated with adverse drug reactions in hospitalised children: international multicentre study

BackgroundUnderstanding the epidemiology and risk factors of adverse drug reactions (ADRs) is important in order to develop appropriate prevention strategies. This study aimed to identify risk factors associated with ADRs in hospitalised children and recommend strategies to minimise ADRs.MethodsA prospective multicentre cohort study was conducted on paediatric general medical wards in five European and non-European hospitals. ADRs were identified by intensive chart review. Multivariable logistic regression was used to investigate risk factors associated with ADRs. For the risk factor analysis, prescribed drugs were divided into high-risk and low-risk drug groups. Analgesics, anti-epileptics, antibacterials and antimycotics for systemic use, corticosteroids for systemic use and immunosuppressant agents were considered as high-risk groups whereas the remaining drug classes were defined as low-risk drug groups.ResultsA total of 1,253 paediatric patients were identified [Australia (n = 145), Germany (n = 372), Hong Kong (n = 138), Malaysia (n = 291), UK (n = 307)]. A total of 328 ADRs were observed in 16.7% of patients (186/1,115). Use of five or more low-risk drugs per patient or  three or more high-risk drugs was a strong predictor for ADRs (OR 4.7, 95% CI 2.4–9.3; OR 6.5, 95% CI 2.7–16.0 respectively; p < 0.001). Older children were more likely to experience ADRs; gender was not significantly associated.ConclusionTo reduce the risk of ADRs in children, clinicians and pharmacists should aim to minimise polypharmacy and be aware of higher ADR risks associated with some drug groups.

Adverse events associated with the use of complementary and alternative medicine in children

Objective To determine the types of adverse events associated with the use of complementary and alternative medicine (CAM) that come to the attention of Australian paediatricians. Design Monthly active surveillance study of CAM-associated adverse events as reported to the Australian Paediatric Surveillance Unit between January 2001 and December 2003. Results There were 39 reports of adverse events associated with CAM use, including four reported deaths. Reports highlighted several areas of concern, including the risks associated with failure to use conventional medicine, the risks related to medication changes made by CAM practitioners and the significant dangers of dietary restriction. The reported deaths were associated with a failure to use conventional medicine in favour of a CAM therapy. Conclusion CAM use has the potential to cause significant morbidity and fatal adverse outcomes. The diversity of CAM therapies and their associated adverse events demonstrate the difficulty addressing this area and the importance of establishing mechanisms by which adverse effects may be reported or monitored.

Randomized, controlled trial comparing once daily and three times daily gentamicin in children with urinary tract infections

Objective. To undertake population pharmacokinetic modeling and to determine the safety and efficacy of once daily (OD) gentamicin dosing in children with severe urinary tract infections (UTI). Methods. An open, randomized, controlled trial comparing OD with three times daily (TD) gentamicin dosing in hospitalized children ages 1 month to 12 years with UTI. Daily doses (milligrams per kg per day) of gentamicin in both groups were 7.5 (<5 years old), 6.0 (5 to 10 years old) and 4.5 (>10 years old). Results. There were 179 children enrolled (90 OD, 89 TD). Baseline clinical characteristics and pathogens were similar, except that circulatory compromise and renal cortical scintigraphic defects were more common in the OD group. Median gentamicin treatment durations were 3.0 (OD) and 2.7 (TD) days. Mean peak gentamicin concentrations were 17.3 (OD) vs. 6.4 (TD) mg/l; 99% of peak concentrations were >7 mg/l in the OD group whereas 16% of peak concentrations were <5 mg/l in the TD group. Mean trough concentrations were 0.35 (OD) vs. 0.55 (TD) mg/l. In the OD group 4% of trough concentrations were ≥2 mg/l, whereas in the TD group only 0.7% were ≥2 mg/l. Age or prior elevated peak concentrations did not predict high trough concentrations. Population pharmacokinetic modeling of the data fitted a one-compartment model with first order elimination. There were no clinical or bacteriologic failures. The two disease-related complications were confined to the OD group. No nephro- or ototoxicity was identified. Conclusions. With age-appropriate dosing and measurement of serum trough concentrations before the second dose, OD gentamicin is safe and effective for the treatment of UTI requiring parenteral treatment in children aged 1 month to 12 years.

Age is a determinant factor for measures of concentration and effect in children requiring unfractionated heparin

Previous studies investigating continuous unfractionated heparin (UFH) therapy report age-related differences in UFH response in children, as measured by APTT and anti-Xa assay. This study determined the age-related response following administration of a single UFH bolus of 75-100 IU/kg in children. Venous blood samples were collected from children (n=56) at 15, 30, 45 and 120 minutes post-UFH. Anti-Xa, anti-IIa, APTT, TCT and protamine titration were performed on all samples. Age-dependent differences in the effect and concentration of UFH were identified for the anti-Xa, anti-IIa and protamine titration assays, respectively. In addition, a trend suggesting a proportional increase in anti-Xa and anti-IIa-mediated UFH effect with age was evident. Logistic regression demonstrated an increase in protamine titration of 0.6 IU/ml for every year of age in samples collected 15 minutes post-UFH. UFH-mediated anti-IIa activity was reduced compared to anti-Xa activity across childhood, with a two-fold increase in anti-Xa to anti-IIa ratio in infants less than one year of age compared to teenagers in the setting of high UFH concentrations. This study demonstrates that the previously reported age-dependent response to UFH occurs in the context of an age-dependent serum concentration of UFH. The trend toward increased UFH serum concentration and anticoagulant activity with age may be related to short-term differences in UFH binding to coagulant and competitive plasma proteins in vivo.