Cma Rademaker

The Effect of Computerized Physician Order Entry on Medication Prescription Errors and Clinical Outcome in Pediatric and Intensive Care: A Systematic Review

CONTEXT. Pediatric and intensive care patients are particularly at risk for medication errors. Computerized physician order entry systems could be effective in reducing medication errors and improving outcome. Effectiveness of computerized physician order entry systems has been shown in adult medical care. However, in critically ill patients and/or children, medication prescribing is a more complex process, and usefulness of computerized physician order entry systems has yet to be established. OBJECTIVE. To evaluate the effects of computerized physician order entry systems on medication prescription errors, adverse drug events, and mortality in inpatient pediatric care and neonatal, pediatric or adult intensive care settings. METHODS. PubMed, the Cochrane library, and Embase up to November 2007 were used as our data sources. Inclusion criteria were studies of (1) children 0 to 18 years old and/or ICU patients (including adults), (2) computerized physician order entry versus no computerized physician order entry as intervention, and (3) randomized trial or observational study design. All studies were validated, and data were analyzed. RESULTS. Twelve studies, all observational, met our inclusion criteria. Eight studies took place at an ICU: 4 were adult ICUs, and 4 were PICUs and/or NICUs. Four studies were pediatric inpatient studies. Meta-analysis showed a significant decreased risk of medication prescription errors with use of computerized physician order entry. However, there was no significant reduction in adverse drug events or mortality rates. A qualitative assessment of studies revealed the implementation process of computerized physician order entry software as a critical factor for outcome. CONCLUSIONS. Introduction of computerized physician order entry systems clearly reduces medication prescription errors; however, clinical benefit of computerized physician order entry systems in pediatric or ICU settings has not yet been demonstrated. The quality of the implementation process could be a decisive factor determining overall success or failure.

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 (glumidazolam)—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 10min, maintenance dose 0.15mg/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 2h 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.

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

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.

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).

Treatment of methotrexate (MTX) intolerance: behavioural therapy, versus switch to parenteral MTX versus oral MTX

Methods 45 JIA patients with MTX intolerance were randomised to receive oral MTX with anti-emetics (standard of care), parenteral MTX or oral MTX with behavioural therapy. Primary outcome was the occurrence of MTX intolerance, defined as ≥5 points on a validated MISS questionnaire, after a 3-month intervention period. Secondary outcome measures were: MTX intolerance after 6 and 12 months and the number of patients that discontinued MTX or switched to another treatment arm due to intolerance.

131 Pharmacokinetics and Clinical Efficacy of Phenobarbital in Asphyxiated Newborns Treated with Therapeutic Hypothermia

Background and aims Therapeutic moderate hypothermia for neuroprotection in the asphyxiated newborn can influence pharmacokinetics and pharmacodynamics. If seizures occur, phenobarbital is the anticonvulsant of first choice. The aim of this study was to evaluate the effect of therapeutic hypothermia on phenobarbital pharmacokinetics and to evaluate the clinical efficacy of phenobarbital under hypothermia. Methods Data were obtained from a prospective study in two Dutch level III NICUs (SHIVER-study). Term born newborns with criteria of perinatal asphyxia and encephalopathy were included. Therapeutic hypothermia (33.5oC) was started within 6 hours after birth and was maintained for 72 hours. Pharmacokinetic modelling was performed using NONMEM. Results In total, 31 term-born newborns were included of which 87 plasma samples were obtained (69 samples during the hypothermic phase). Based on a one-compartmental model with allometric relationships, clearance and distribution volume were estimated at 17.2 mL/h/3.5kg and 3450 mL/3.5kg respectively. No relationship between hypothermia and pharmacokinetic parameters was identified. Overall, 66% of all neonates demonstrated sufficient seizure control with phenobarbital monotherapy, even though 69% of all measured concentrations were below 20 mg/L. In 88% of neonates with recurrent seizures during phenobarbital therapy, plasma concentrations were predicted to be < 20 mg/L at the moment of recurrent seizures. This supports a minimal effective concentration of about 20 mg/L. Conclusion Also during hypothermia we advise an initial 20 mg/kg loading dose. However, clinicians should not be reluctant to administer an additional dose of 10–20 mg/kg, as we have shown that the blood levels were often below the therapeutic range (20–40 mg/L).

217 Acceptance and Preference of Four Oral Dosage forms in Infants and Pre-School Children in the Netherlands

Background and aims Liquid formulations are easy to swallow but they may have disadvantages such as a bad taste, preservatives or restricted storage conditions. These disadvantages may be overcome by oral solid flexible dosage forms such as powders or mini-tablets. The aim of this study was to investigate the acceptance and preference of four oral dosage forms in children aged 1–4 years in the Netherlands. Methods Parents administered four different placebo formulations: a 4-mm round, uncoated mini-tablet, powder, suspension and syrup at home to their (healthy) child twice on one day following a randomized cross-over design. They were asked to report the child acceptance by the result of the intake and by a child acceptance score on a 10-cm visual analogue scale (VAS). At the end of the study parents were asked to report the child and parent preference. Results 183 children were included and 151 children were evaluated. The mini-tablet was fully swallowed in 97% of all cases, the powder 81%, the suspension 86% and the syrup 83%. The mean VAS-scores were: tablet 9.01; powder 8.00; suspension 7.78; syrup 8.04. The mini-tablet was significantly better accepted than the three other dosage forms (p<0.05). The same pattern was observed when only the first intake was considered given a carry-over effect. Children and parents preferred the tablet and syrup over the suspension and the suspension over the powder (p<0.05). Conclusions All dosage forms were well accepted, but the mini-tablets were the best accepted and preferred dosage form.

479 Model-Based Lidocaine Dosing Regimen for Seizure Control in Preterm and Term Neonates

Objectives: Lidocaine is administered as an anticonvulsant to neonates that are not responding to first-line anticonvulsants. For term neonates a dosing regimen has been developed (Malingre et al., 2006), but it has not been evaluated for preterm neonates. The objective of this study was to develop an optimal dosing strategy for lidocaine in preterm and term neonates on basis of a newly developed population PK model. Methods: Simulations were performed using NONMEM 6.2. Several requirements were defined: Results: A body weight-based infusion strategy was developed using simulations. First, a bolus injection was chosen for all weight categories for rapid achievement rapid seizure control. This was followed by a 4-hour loading infusion. Then dosing was reduced in two steps during 6 and 12 hours, respectively. (regimen not shown) With this regimen, the median concentration achieved at the end of the 4-hour infusion was 6.3 mg/L, (IQR 1.8 mg/L). Only 3.6% of the simulated individuals had concentrations >9.0 mg/L. This new strategy should be a safe and effective regimen for neonatal seizure control. Prospective validation is in progress.

1259 The Availability and Ageappropriateness of Paediatric Medicines

Background: Optimal paediatric pharmacotherapy requires licensed, commercially available and ageappropriate medicines. In lack of these, health care professionals need to resort to extemporaneous preparations or off-label prescriptions. The EU Paediatric Regulation aims to improve this situation by incentives to increase the number of medicines approved for children. The aim of this study was to provide baseline information to evaluate the effect of the Paediatric Regulation by reviewing the availability and age-appropriateness of licensed, paediatric medicines in the Netherlands. Methods: The availability of licensed, paediatric medicines was studied with help of the Z-index, the Informatorium Medicamentorum and the Summary of Product Characteristics. The nature of the medicines and the data for adults was studied as well. The age-appropriateness for children was evaluated concerning age, the ability to follow the authorised dosing recommendation, the suitability of the dosage form and the inclusion of potentially harmful excipients. Results: 3542 licensed, paediatric medicines were identified containing 703 active chemical entities. The proportion of paediatric versus all human medicines increased with age from 37-96%. The proportion varied for the administration route from 22% (dermals) to 81% (inhalation products) and for the therapeutic category from 11% (genito-urinary medicines) to 89% (antiparasites). When considering the real age-appropriateness of licenced medicines the available formulations were acceptable for 27- 88%, depending on age. Conclusion: The current baseline information confirms a limited availability of paediatric medicines, especially for younger children. Health care professionals should realize that licensed, paediatric medicines may not be age-appropriate.