Comparison of antibiotic dosing recommendations for neonatal sepsis from established reference sources.

Background Incorrect dosing is the most frequent prescribing error in neonatology, with antibiotics being the most frequently prescribed medicines. Computer physician order entry and clinical decision support systems can create consistency contributing to a reduction of medication errors. Although evidence-based dosing recommendations should be included in such systems, the evidence is not always available and subsequently, dosing recommendations mentioned in guidelines and textbooks are often based on expert opinion. Objective To compare dosage recommendations for antibiotics in neonates with sepsis provided by eight commonly used and well-established international reference sources. Setting An expert team from our Dutch tertiary care neonatal intensive care unit selected eight well-established international reference sources. Method Daily doses of the seven most frequently used antibiotics in the treatment of neonatal sepsis, classified by categories for birth weight and gestational age, were identified from eight well-respected reference sources in neonatology/pediatric infectious diseases. Main outcome measure Standardized average daily dosage. Results A substantial variation in dosage recommendations of antibiotics for neonatal sepsis between the reference sources was shown. Dosage recommendations of ampicillin, ceftazidime, meropenem and vancomycin varied more than recommendations for benzylpenicillin, cefotaxime and gentamicin. One reference source showed a larger variation in dosage recommendations in comparison to the average recommended daily dosage, compared to the other reference sources. Conclusion Antibiotic dosage recommendations for neonates with sepsis can be derived from important reference sources and guidelines. Further exploration to overcome variation in dosage recommendations is necessary to obtain standardized dosage regimens.

Rapid target allopurinol concentrations in the hypoxic fetus after maternal administration during labour.

OBJECTIVE: Perinatal hypoxia-induced free radical formation is an important cause of hypoxic-ischaemic encephalopathy and subsequent neurodevelopmental disabilities. Allopurinol reduces the formation of free radicals, which potentially limits hypoxia-induced brain damage. We investigated placental transfer and safety of allopurinol after maternal allopurinol treatment during labour to evaluate its potential role as a neuroprotective agent in suspected fetal hypoxia. DESIGN: We used data from a randomised, double-blind multicentre trial comparing maternal allopurinol versus placebo in case of imminent fetal hypoxia (NCT00189007). PATIENTS: We studied 58 women in labour at term, with suspected fetal hypoxia prompting immediate delivery, in the intervention arm of the study. SETTING: Delivery rooms of 11 Dutch hospitals. INTERVENTION: 500 mg allopurinol, intravenously to the mother, immediately prior to delivery. MAIN OUTCOME MEASURES: Drug disposition (maternal plasma concentrations, cord blood concentrations) and drug safety (maternal and fetal adverse events). RESULTS: Within 5 min after the end of maternal allopurinol infusion, target plasma concentrations of allopurinol of ≥2 mg/L were present in cord blood. Of all analysed cord blood samples, 95% (52/55) had a target allopurinol plasma concentration at the moment of delivery. No adverse events were observed in the neonates. Two mothers had a red and/or painful arm during infusion. CONCLUSIONS: A dose of 500 mg intravenous allopurinol rapidly crosses the placenta and provides target concentrations in 95% of the fetuses at the moment of delivery, which makes it potentially useful as a neuroprotective agent in perinatology with very little side effects. TRIAL REGISTRATION: The study is registered in the Dutch Trial Register (NTR1383) and the Clinical Trials protocol registration system (NCT00189007).

Pharmacokinetics and clinical efficacy of phenobarbital in asphyxiated newborns treated with hypothermia: a thermopharmacological approach.

BACKGROUND AND OBJECTIVES: Therapeutic hypothermia can influence the pharmacokinetics and pharmacodynamics of drugs, the discipline which is called thermopharmacology. We studied the effect of therapeutic hypothermia on the pharmacokinetics of phenobarbital in asphyxiated neonates, and the clinical efficacy and the effect of phenobarbital on the continuous amplitude-integrated electroencephalography (aEEG) in a prospective study. PATIENTS AND METHODS: Data were obtained from the prospective SHIVER study, performed in two of the ten Dutch level III neonatal intensive care units. Phenobarbital data were collected between 2008 and 2010. Newborns were eligible for inclusion if they had a gestational age of at least 36 weeks and presented with perinatal asphyxia and encephalopathy. According to protocol in both hospitals an intravenous (repeated) loading dose of phenobarbital 20 mg/kg divided in 1-2 doses was administered if seizures occurred or were suspected before or during the hypothermic phase. Phenobarbital plasma concentrations were measured in plasma using a fluorescence polarization immunoassay. aEEG was monitored continuously. RESULTS AND CONCLUSION: A one-compartmental population pharmacokinetic/pharmacodynamic model was developed using a multi-level Markov transition model. No (clinically relevant) effect of moderate therapeutic hypothermia on phenobarbital pharmacokinetics could be identified. The observed responsiveness was 66%. While we still advise an initial loading dose of 20 mg/kg, clinicians should not be reluctant to administer an additional dose of 10-20 mg/kg. An additional dose should be given before switching to a second-line anticonvulsant drug. Based on our pharmacokinetic/pharmacodynamic model, administration of phenobarbital under hypothermia seems to reduce the transition rate from a continuous normal voltage (CNV) to discontinuous normal voltage aEEG background level in hypothermic asphyxiated newborns, which may be attributed to the additional neuroprotection of phenobarbital in infants with a CNV pattern.

Quantifying antibiotic use in paediatrics: a proposal for neonatal DDDs.

The defined daily dose (DDD) as defined by the World Health Organization (WHO) has been the most frequently used unit of measurement to measure antibiotic use. However, measuring antibiotic use in paediatrics is a problem as the WHO DDD methodology is not applicable in children (aged >1 month) due to the large variation in body weight within this population. Based on the narrow range of body weights in the neonatal population, we therefore aimed to develop a set of neonatal DDDs for antibiotics. Eight well-respected (inter)national sources for dosage recommendations of antibiotics in children and neonates were consulted for the assumed maintenance dose of the ten most frequently used antibiotics in neonatal intensive care units in its main indication for neonates. A set of neonatal DDDs for ten commonly used antibiotics in neonates based on an assumed neonatal weight of 2 kg was proposed. Primarily in children DDDs are not applicable to quantify antibiotic use since there is large variation in body weight. In the neonatal population, however, based on its narrow range of body weights and when access to patient level data is not available, neonatal DDDs can be used as a unit of measurement.

Psychological side effects of MTX treatment in juvenile idiopathic arthritis: a pilot study.

OBJECTIVE: To document the psychological side effects of methotrexate (MTX) treatment in children with juvenile idiopathic arthritis (JIA) and to explore the usefulness of psychological therapy to ameliorate these side effects. METHODS: The patients included in this study consisted of 29 patients with JIA using MTX. Of these, ten were referred to a pediatric psychologist because of MTX side effects, and had behavioural therapy to cope with these side effects with a strong behavioural component (anticipatory nausea, anxiety). The behavioural therapy was adapted to age and used systemic desensitization (distraction in a positive atmosphere) or cognitive behavioural therapy (relaxation and overruling negative thoughts by positive ones). The parents of the 29 children were interviewed about MTX treatment and the side effects their child had developed. Parents of children referred to the psychologist were also interviewed for their impression of the results of the behavioural therapy. RESULTS: Prior to the behavioural therapy, nine out of 10 children reported MTX related nausea. Six of these ten were nauseous even before the administration and developed anticipatory nausea. Nine out of ten patients also showed some sign of distress in anticipation of MTX treatment, either orally of via injections. The behavioural therapy they had fully abolished side effects in five children and decreased the severity of nausea and distress in two children. Of the remaining nineteen children, not referred to the pediatric psychologist, 11 reported nausea after MTX treatment and four of these developed anticipatory nausea. In addition, eight of these 18 developed behavioural distress in anticipation of the treatment. CONCLUSION: This study showed that children with JIA who receive MTX treatment frequently develop psychological side effects, such as anticipatory nausea and behavioural distress in anticipation of treatment. This is true for patients selected for reported MTX side effects, as well as for randomly chosen JIA patients using MTX. As MTX is still the first choice in the treatment of severe JIA, more attention should be given to the treatment and prevention of side effects. Psychological intervention can be of help, but further studies are needed on the nature of the side effects, as well as on the prerequisites and efficacy of behavioural therapy.

Health Care Failure Mode and Effect Analysis: a useful proactive risk analysis in a pediatric oncology ward.

BACKGROUND: Pediatric inpatient settings are known for their high medication error rate. The aim of this study was to investigate whether the Health Care Failure Mode and Effect Analysis (HFMEA) is a valid proactive method to evaluate circumscribed health care processes like prescription up to and including administration of chemotherapy (vincristine) in the pediatric oncology inpatient setting. METHODS: A multidisciplinary team consisting of a team leader, pharmacy, nursing and medical staff and a patient's parent was assembled in a pediatric oncology ward with a computerized physician order entry system. A flow diagram of the process was made and potential failure modes were identified and evaluated using a hazard scoring matrix. Using a decision tree, it was determined for which failure mode recommendations had to be made. RESULTS: The process was divided into three main parts: prescription, processing by the pharmacy, and administration. Fourteen out of 61 failure modes were classified as high risk, 10 of which were sufficiently covered by current protocols. For the other four failure modes, five recommendations were made. Four additional recommendations were made concerning non-high risk failure modes. Most of them were implemented by the hospital management. The whole process took seven meetings and a total of 140 man-hours. CONCLUSIONS: The systematic approach of HFMEA by a multidisciplinary team is a useful method for detecting failure modes. A patient or a parent of a patient contributes to the multidisciplinarity of the team.

Early postnatal allopurinol does not improve short term outcome after severe birth asphyxia.

OBJECTIVE: To investigate whether postnatal allopurinol would reduce free radical induced reperfusion/reoxygenation injury of the brain in severely asphyxiated neonates. METHOD: In an interim analysis of a randomised, double blind, placebo controlled study, 32 severely asphyxiated infants were given allopurinol or a vehicle within four hours of birth. RESULTS: The analysis showed an unaltered (high) mortality and morbidity in the infants treated with allopurinol. CONCLUSION: Allopurinol treatment started postnatally was too late to reduce the early reperfusion induced free radical surge. Allopurinol administration to the fetus with (imminent) hypoxia via the mother during labour may be more effective in reducing free radical induced post-asphyxial brain damage.

Midazolam and amplitude-integrated EEG in asphyxiated full-term neonates.

AIM: In the present, prospective study, the relation between the levels of midazolam, its two active metabolites--1-hydroxy-midazolam (OH-midazolam) and 1-hydroxy-midazolam-glucuronide (glu-midazolam)--and the aEEG were examined. PATIENTS AND METHODS: Fifteen full-term neonates with seizures due to hypoxic-ischaemic encephalopathy admitted to our NICU were included. Midazolam (loading dose 0.05 mg/kg in 10 min, maintenance dose 0.15 mg/kg/h) was used as an add-on anti-convulsant after phenobarbital and lidocaine because of continuing seizures. Amplitude-integrated EEG background pattern was scored at the start of midazolam and at the time of blood sampling as continuous normal voltage (CNV), discontinuous normal voltage (DNV), burst suppression (BS), continuous low voltage (CLV) or flat trace (FT). Serum levels of midazolam, OH-midazolam and glu-midazolam were measured at least 8 h after the start with HPLC. RESULTS: In 11/15 patients, seizures were abolished with the addition of midazolam. In the remaining patients, seizure frequency was reduced in one and unchanged in three. Amplitude-integrated EEG background pattern at the start of midazolam was CNV in two, DNV in six, BS in five and CLV in two. Moderate, temporary suppression of the aEEG background pattern lasting less than 2 h was seen in four neonates. Amplitude-integrated EEG at midazolam sampling was CNV in two, DNV in seven, CLV in two and FT in four. Serum levels of midazolam ranged from 0.10 to 1.76 mg/l, OH-midazolam from 0.05 to 0.28 mg/l and glu-midazolam from 0.85 to 4.36 mg/l. CONCLUSIONS: A brief and moderate suppression of the aEEG background pattern immediately after midazolam was seen in four neonates for less than 2 h. Suppression at a later time point, i.e. after more than 8 h of midazolam infusion, was demonstrated almost exclusively in neonates with a poor background pattern, and therefore these patterns appear to be determined mainly by the severity of hypoxic-ischaemic encephalopathy.

Safety of anti-TNFalpha therapy in children with juvenile idiopathic arthritis.

Anti-TNFalpha agents are frequently used in the treatment of severe JIA. Etanercept, a fully human soluble recombinant tumour necrosis factor p75 receptor Fc fusion protein, has been registered for the treatment of polyarticular course JIA patients who fail to respond to or do not tolerate methotrexate (MTX). Infliximab, a chimeric human-mouse monoclonal antibody to TNFalpha, is expected to be registered soon for JIA and Crohn's disease (CD) in children. As in adults, both agents are effective in controlling inflammation and inhibiting the progression of joint destruction. Despite this good clinical efficacy, the physician must remain alert for potential side effects, especially after prolonged use. This review gives an overview of the reported adverse events.

Effects of magnesium sulphate on amplitude-integrated continuous EEG in asphyxiated term neonates.

UNLABELLED: In this study it is hypothesized that magnesium sulphate in asphyxiated full-term neonates could lead to a gradual improvement in background pattern of the amplitude integrated EEG (aEEG), an early marker of hypoxic-ischaemic brain injury. In a double-blind, randomized, controlled pilot study of 22 asphyxiated full-term neonates 8 received magnesium sulphate, reaching serum Mg2+ levels of 2.5 mmol/L. Magnesium sulphate had no immediate effect on aEEG-patterns. At 12 h of age, aEEG was more depressed compared with aEEG at 3 h in 6 of the 8 magnesium-treated neonates, and in 3 of the 14 placebo-treated neonates (Mg2+ vs placebo: p < 0.05, Mann-Whitney). No further significant changes in aEEG were seen between 12 and 24 h. Outcome was unfavourable in 4 of the 8 magnesium-treated neonates, and in 8 of the 14 placebo-treated neonates. CONCLUSION: Magnesium sulphate did not have a positive effect on aEEG patterns in this small group of asphyxiated term neonates.

Once-daily versus multiple-daily gentamicin in infants and children.

In this prospective randomized trial, the efficacy and safety of once-daily administration of gentamicin were compared with multiple-daily administration in infants and children. In addition, pharmacokinetic variables were calculated. Gentamicin therapy was started at a dose of 5 mg/kg per day under individual dose or dosage interval adjustments to achieve target levels. Fifty-two infants and children aged 1 month (postterm) to 16 years were enrolled. The duration of fever from the start of therapy, the percentage decline of C-reactive protein (CRP) on day 3 of treatment, and the clinical outcome were used as efficacy parameters. Nephrotoxicity was evaluated using creatinine serum levels. Basic characteristics in both groups were comparable. A good clinical response was observed in both groups. Fever may have resolved faster with multiple-daily administration, but this was not statistically significant. The percentage of decline of CRP was also comparable in both groups. Nephrotoxicity occurred in six patients, three per group. Many patients were too ill or too young to perform hearing tests, but no clinical signs of ototoxicity were observed. Mean doses of 6.8 mg/kg per day (multiple-daily administration) and 7.3 mg/kg per day (once-daily administration) were necessary to meet the target gentamicin levels. Triple-daily doses had to be reduced to a twice-daily regimen in 17 of 26 children. Dose and dosage interval adaptations can be performed by Bayesian forecasting using a one-compartment model with one set of K(e) and V(d) parameters. The authors consider both regimens equally effective, with a comparable incidence of nephrotoxicity. A starting dose of 6.5 mg/kg once daily is advised.

Population pharmacokinetics of gentamicin in preterm neonates: evaluation of a once-daily dosage regimen.

Population pharmacokinetic parameters of gentamicin in preterm neonates on a once-daily dosage regimen of 3.0 mg/kg given intravenously every 24 hours were established prospectively. In 34 preterm neonates with a mean gestational age of 32 +/- 4 (SD), 182 serum gentamicin levels (91 peak/trough pairs) were determined. Individual adjustments of dose or dosage interval were calculated by computer-aided Bayesian forecasting. The parameters Vd, ke, and CL for each patient were obtained by the nonparametric estimation of maximization method. The predictive power of the model was calculated and the pharmacokinetic estimates were statistically analyzed with SPSS/PC. Cluster analysis showed a division into 2 subpopulations (designated 1 and 2) on the basis of postnatal age. The mean +/- SD postnatal age of subpopulation 1 (n = 29) was 6 +/- 2 days (range 1-7) and of subpopulation 2 (n = 5) 15 +/- 4 days (range 12-24). The mean +/- SD gentamicin relative clearances of subpopulation 1 and subpopulation 2 were 0.0515 +/- 0.0128 and 0.1026 +/- 0.0102 L kg(-1) hr(-1), respectively (p < 0.05). The mean +/- SD values for Vd (Lkg(-1)) in both populations 1 and 2 were 0.6916 +/- 0.1670 and 0.7509 +/- 0.1961, respectively (not significantly different). For ke these data were 0.0744 +/- 0.0200 and 0.1366 +/- 0.0522 (p < 0.05). Statistics showed that the data for Vd and ke of subpopulation 1 were normally distributed (Vd and ke skewness 1.61 and 1.46; kurtosis 3.09 and 3.10 respectively). The model yielded a bias of -0.11 mg/L and a precision of 0.36 mg/L. It is recommended that gentamicin be started in a dosage of 3.5 mg/kg intravenously once-daily under close monitoring.

Detection of toxigenic Clostridium difficile in fecal samples by colony blot hybridization.

A hybridization assay for detection of toxigenic Clostridium difficile in fecal samples was developed and compared with the classical tissue culture cytotoxicity assay. A DNA fragment probe specific for the toxin B gene of Clostridium difficile was synthesized by the polymerase chain reaction and labelled with digoxigenin. Fecal samples were cultured for 24 hours, replica-plated and hybridized with the probe. The hybridization assay had a sensitivity of 100%, specificity of 96.7%, positive predictive value of 86.7% and negative predictive value of 100% compared with the cytotoxicity assay.

Detection of enterovirulent Escherichia coli associated with diarrhoea in Seville, southern Spain, with non-radioactive DNA probes.

To assess the role of diarrhoeagenic Escherichia coli in Southern Spain, faecal samples from 135 patients with diarrhoea and 40 healthy subjects from Seville, Andalusia, were investigated. In this prospective study, enterovirulent E. coli were identified by hybridisation with five non-radioactive DNA probes specific for enterotoxigenic E. coli (ETEC), enteropathogenic E. coli (EPEC) and verocytotoxin-producing E. coli (VTEC). Probe-positive strains were isolated from four patients (3%) with diarrhoea and from none of the healthy controls. Two patients harboured ETEC and two patients had EPEC probe-positive strains in their faeces. No VTEC were isolated during this study. Salmonella spp. were the most frequently identified enteric pathogens, accounting for 10% of the cases, followed by Campylobacter jejuni (3%) and diarrhoeagenic E. coli (3%). This study indicates that enterovirulent E. coli play a modest role in the aetiology of diarrhoea among the indigenous population of Southern Spain.

Frequency of enterovirulent Escherichia coli in diarrhoeal disease in The Netherlands.

To assess the role of enterovirulent Escherichia coli in The Netherlands, faecal samples of 279 patients (108 children, 171 adults) with diarrhoea and 100 healthy controls were investigated in a prospective study. Enterovirulent Escherichia coli were identified by hybridization with five different non-radioactively labelled DNA probes specific for enteropathogenic Escherichia coli (EPEC), verocytotoxin producing Escherichia coli (VTEC) and enterotoxigenic Escherichia coli (ETEC). The rate of isolation of EPEC was 6.5% in patients with diarrhoea and 2.0% in asymptomatic persons. During the study period, no VTEC were isolated from patients with diarrhoea. ETEC were isolated from two persons, both of whom had experienced diarrhoea and had returned from travel in (sub)tropical areas. Our results suggest that diarrhoea is sporadically caused by ETEC among the indigenous population of The Netherlands, and is mainly associated with travel in endemic areas. Furthermore, the presence of EPEC probe-positive strains in the stool need not always be accompanied by symptoms of diarrhoea.

[Detection of diarrhea-causing Escherichia coli using DNA-probes]. / Het opsporen van diarree-veroorzakende Escherichia coli met behulp van DNA-probes.

To assess the role of enterovirulent Escherichia coli at home and abroad, faeces samples of patients with diarrhoea and of healthy controls in Tunisia, Seville (southern Spain) and the Netherlands were investigated. Enterovirulent E. coli were identified by hybridization with five different non-radioactively labelled DNA probes specific for enterotoxigenic E. coli (ETEC), enteropathogenic E. coli (EPEC) and verocytotoxin producing E. coli (VTEC). ETEC was the main causative agent of travellers' diarrhoea in Tunisia. The isolation of ETEC in the Netherlands was shown to be related to travel in endemic areas. EPEC probe positive strains were isolated in children and in adults, but were not in all cases associated with intestinal disease. During this study no VTEC were detected. From an immunocompromised kidney transplantation patient with sepsis and diarrhoea ETEC were isolated from blood.