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Biomedical subjects

J N van den Anker

Publications and source records attributed to J N van den Anker.

At least 19 recordsLinked to original sources
PubMed2006

Life threatening central nervous system manifestations and hypothermia due to maneb intoxication in a child: a case report.

Maneb, manganese ethylene-bis-dithiocarbamate, is a fungicide pesticide used in the agriculture and bulb flower culture sector. Toxicological effects for humans have been reported in literature and are diverse. They vary from allergic reactions (dermatitis, conjunctivitis, and bronchitis), central nervous system effects (muscarinic, nicotinic, central and extrapyramidal) and renal toxicity (acute renal failure).A 7-year old girl was admitted to the pediatric intensive care unit because of status epilepticus. Physical examination showed respiratory insufficiency, convulsions, and severe hypothermia (32.5 degrees C). The patient was intubated and her convulsions were successfully treated with benzodiazepines. Except for a combined metabolic and respiratory acidosis and hyperglycemia, diagnostic investigations on admission (full blood count, electrolytes, liver and renal functions, cerebrospinal fluid investigation, toxicology screening of blood and urine for barbiturates and benzodiazepines, blood culture, herpes PCR, and a CT scan of the brain) were normal. Within 24 hours, there was a complete recovery of all neurological signs. Within 72 hours, the patient was discharged from the hospital. Liquid chromatography-mass spectrometric investigation of her blood showed amounts of maneb, which can explain all symptoms and signs. However, effects of this magnitude on the central nervous system have not previously been reported in humans.

Child↗
PubMed2005

Morphine in ventilated neonates: its effects on arterial blood pressure.

OBJECTIVE: To study the effects of continuous morphine infusion on arterial blood pressure in ventilated neonates. DESIGN: Blinded randomised placebo controlled trial. SETTING: Level III neonatal intensive care unit in two centres. PATIENTS: A total of 144 ventilated neonates. Inclusion criteria were postnatal age <3 days, ventilation <8 hours, and indwelling arterial line. Exclusion criteria were severe asphyxia, severe intraventricular haemorrhage, major congenital anomalies, neuromuscular blockers. INTERVENTION: Arterial blood pressure was measured before the start and during the first 48 hours of masked infusion of drug (morphine/placebo; 100 microg/kg + 10 microg/kg/h). OUTCOME MEASURES: Arterial blood pressure and blood pressure variability. RESULTS: There were no significant differences in overall mean arterial blood pressure between the morphine group (median (interquartile range) 36 mm Hg (6) and the placebo group (38 mm Hg (6)) (p = 0.11). Although significantly more morphine treated patients (70%) showed hypotension than the placebo group (47%) (p = 0.004), the use of volume expanders and vasopressor drugs was not significantly different (morphine group, 44%; placebo group, 48%; p = 0.87), indicating the limited clinical significance of this side effect. Blood pressure variability was not influenced by routine morphine analgesia (p = 0.81) or additional morphine (p = 0.80). Patients with and without intraventricular haemorrhage showed no differences in blood pressure (Mann-Whitney U test 1953; p = 0.14) or incidence of hypotension (chi(2) test 1.16; df 1; p = 0.28). CONCLUSIONS: Overall arterial blood pressure, use of inotropes, and blood pressure variability were not influenced by morphine infusion. Therefore the clinical impact of hypotension as a side effect of low dose morphine treatment in neonates is negligible.

Analgesics, Opioid↗
PubMed2005

The pharmacological treatment of neonatal pain.

Optimal analgesia remains a major challenge for all involved in the care of (critically) ill newborns. The rapid changes in liver metabolism involving maturation of liver enzymes and renal clearance of drugs render (extreme) very low birth weight infants different from newborns of later postconceptional age with regards to the use of opioids such as morphine and fentanyl. Acute and/or procedural pain has been investigated fairly recently in randomized controlled trials and there are now guidelines. The long-term effects of opioid use in this particular age group of vulnerable babies await further evaluation.

Analgesics, Opioid↗
PubMed2005

Randomised controlled trial evaluating effects of morphine on plasma adrenaline/noradrenaline concentrations in newborns.

OBJECTIVES: To determine the effects of continuous morphine infusion in ventilated newborns on plasma concentrations of adrenaline (epinephrine) and noradrenaline (norepinephrine) and their relation to clinical outcome. DESIGN: Blinded, randomised, placebo controlled trial. SETTING: Level III neonatal intensive care units in two centres. PATIENTS: A total of 126 ventilated neonates (inclusion criteria: postnatal age <3 days, duration of ventilation <8 hours, indwelling arterial catheter for clinical purposes; exclusion criteria: severe asphyxia, severe intraventricular haemorrhage, major congenital anomalies, neuromuscular blockers). INTERVENTIONS: Plasma adrenaline and noradrenaline concentrations were determined in patients during blinded morphine (n = 60) and placebo (n = 66) infusion (100 microg/kg plus 10 microg/kg/h). RESULTS: Plasma concentrations at baseline (nmol/l with interquartile range in parentheses) were comparable in infants treated with morphine (adrenaline, 0.22 (0.31); noradrenaline, 2.52 (2.99)) or placebo (adrenaline, 0.29 (0.46); noradrenaline, 2.44 (3.14)). During infusion, median adrenaline concentrations were 0.12 (0.28) and 0.18 (0.35) and median noradrenaline concentrations were 2.8 (3.7) and 3.8 (4.0) for the morphine and placebo treated infants respectively. Multivariate analyses showed that noradrenaline (p = 0.029), but not adrenaline (p = 0.18), concentrations were significantly lower in the morphine group than the placebo group. Furthermore, noradrenaline concentrations were related to the length of stay in the neonatal intensive care unit. CONCLUSIONS: Continuous morphine infusion significantly decreased plasma noradrenaline concentrations in ventilated newborns compared with placebo treatment. The results of this study support the idea that routine morphine administration decreases stress responses in ventilated neonates.

Analgesics, Opioid↗
PubMed2004

Unlicensed and off-label prescription of respiratory drugs to children.

Many respiratory drugs are not available in formulations suitable for infants and toddlers. Efficacy and safety research is mostly restricted to older children. However, respiratory drugs are frequently used in children for common diseases like asthma, upper and lower respiratory tract infections, rhinitis and sinusitis. The unlicensed and off-label use of respiratory drugs in children were studied. A population-based cohort study was conducted by using the computerised medical records in the Integrated Primary Care Information project. The study population comprised a random sample from all children aged 0-16 yrs who were registered with a general practitioner in 1998. All prescriptions for respiratory drugs during the study period were classified according to their licensing and off-label status. The study population comprised 13,426 patients (51.7% male, median age 8.7 yrs), of whom 2,502 (19%) received 5,253 prescriptions for respiratory drugs in 1998. A total of 3,306 (62.9%) prescriptions concerned licensed drugs. Of the remaining 1,947 prescriptions (37.1%), 882 (16.8%) were unlicensed for use in children, and 1,065 (20.3%) were prescribed off-label. The 1-yr cumulative risk of receiving an unlicensed or off-label prescription was 45% among children with at least one prescription for a respiratory drug. This population-based study showed that a large proportion of respiratory drugs prescribed by the general practitioner are unlicensed for use in children, or licensed but prescribed in an off-label manner. Results have to be interpreted with caution because they may unjustly suggest inaccurate prescribing, whereas it may be difficult to treat children with respiratory symptoms and diseases, because for many respiratory drugs paediatric data on safety and efficacy are insufficient. These findings underline the importance of research on suitable formulations, dosages and efficacy of respiratory drugs in children.

Adolescent↗
PubMed2003

Age- and therapy-related effects on morphine requirements and plasma concentrations of morphine and its metabolites in postoperative infants.

BACKGROUND: To investigate clinical variables such as gestational age, sex, weight, the therapeutic regimens used and mechanical ventilation that might affect morphine requirements and plasma concentrations of morphine and its metabolites. METHODS: In a double-blind study, neonates and infants stratified for age [group I 0-4 weeks (neonates), group II > or =4-26 weeks, group III > or =26-52 weeks, group IV > or =1-3 yr] admitted to the paediatric intensive care unit after abdominal or thoracic surgery received morphine 100 micro g kg(-1) after surgery, and were randomly assigned to either continuous morphine 10 micro g kg(-1) h(-1) or intermittent morphine boluses 30 micro g kg(-1) every 3 h. Pain was measured using the COMFORT behavioural scale and a visual analogue scale. Additional morphine was administered on guidance of the pain scores. Morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) plasma concentrations were measured before, directly after, and at 6, 12 and 24 h after surgery. RESULTS: Multiple regression analysis of different variables revealed that age was the most important factor affecting morphine requirements and plasma morphine concentrations. Significantly fewer neonates required additional morphine doses compared with all other age groups (P<0.001). Method of morphine administration (intermittent vs continuous) had no significant influence on morphine requirements. Neonates had significantly higher plasma concentrations of morphine, M3G and M6G (all P<0.001), and significantly lower M6G/morphine ratio (P<0.03) than the older children. The M6G/M3G ratio was similar in all age groups. CONCLUSIONS: Neonates have a narrower therapeutic window for postoperative morphine analgesia than older age groups, with no difference in the safety or effectiveness of intermittent doses compared with continuous infusions in any of these age groups. In infants >1 month of age, analgesia is achieved after morphine infusions ranging from 10.9 to 12.3 micro g kg(-1) h(-1) at plasma concentrations of <15 ng ml(-1).

Age Factors↗
PubMed2003

Population pharmacokinetics and metabolism of midazolam in pediatric intensive care patients.

OBJECTIVE: To determine the pharmacokinetics and metabolism of midazolam in pediatric intensive care patients. DESIGN: Prospective population pharmacokinetic study. SETTING: Pediatric intensive care unit. PATIENTS: Twenty-one pediatric intensive care patients aged between 2 days and 17 yrs. INTERVENTIONS: The pharmacokinetics of midazolam and metabolites were determined during and after a continuous infusion of midazolam (0.05-0.4 mg/kg/hr) for 3.8 hrs to 25 days administered for conscious sedation. MEASUREMENTS AND MAIN RESULTS: Blood samples were taken at different times during and after midazolam infusion for determination of midazolam, 1-OH-midazolam, and 1-OH-midazolam-glucuronide concentrations via high-performance liquid chromatography-ultraviolet detection. A population analysis was conducted via a two-compartment pharmacokinetic model by the NPEM program. The final population model was used to generate individual Bayesian posterior pharmacokinetic parameter estimates. Total body clearance, apparent volume distribution in terminal phase, and plasma elimination half-life were (mean +/- sd, n = 18): 5.0 +/- 3.9 mL/kg/min, 1.7 +/- 1.1 L/kg, and 5.5 +/- 3.5 hrs, respectively. The mean 1-OH-midazolam/midazolam ratio and (1-OH-midazolam + 1-OH-midazolam-glucuronide)/midazolam ratio were 0.14 +/- 0.21 and 1.4 +/- 1.1, respectively. Data from three patients with renal failure, hepatic failure, and concomitant erythromycin-fentanyl therapy were excluded from the final pharmacokinetic analysis. CONCLUSIONS: We describe population and individual midazolam pharmacokinetic parameter estimates in pediatric intensive care patients by using a population modeling approach. Lower midazolam elimination was observed in comparison to other studies in pediatric intensive care patients, probably as a result of differences in study design and patient differences such as age and disease state. Covariates such as renal failure, hepatic failure, and concomitant administration of CYP3A inhibitors are important predictors of altered midazolam and metabolite pharmacokinetics in pediatric intensive care patients. The derived population model can be useful for future dose optimization and Bayesian individualization.

Adolescent↗
PubMed2002

A pilot case control follow-up study on hearing in children treated with tobramycin in the newborn period.

OBJECTIVE: To assess the occurrence of hearing loss in children due to neonatal exposure to long courses of tobramycin and/or high tobramycin serum concentrations. METHODS: This was a pilot case-control study in 3-4-year old children. Data on tobramycin administration were abstracted from the patient files of an earlier study. Patients exposed in the neonatal period to either long courses (>7 days) or high serum concentrations of tobramycin constituted the study group. The control group consisted of patients without tobramycin exposure. Patients were matched for other risk factor according to criteria of the joint committee on infant hearing. All patients underwent the following investigations: otoscopy and pneumatic otoscopy, followed by impedance audiometry, to exclude middle ear effusion. Click-evoked oto-acoustic emissions (ce-OAE) as well as distortion product oto-acoustic emissions (dp-OAE), tested at f2 frequencies ranging from 1 to 10 kHz, were measured to assess hearing. All patients with abnormal ce-OAE results underwent brainstem electric response audiometry (BERA) as well. Since aminoglycoside ototoxicity is usually bilateral, results were compared per patient and not per ear. RESULTS: A total of 29 patients were tested. Eleven patients were excluded due to middle ear effusion. Data for 18 patients were analyzed. In the tobramycin treated group (n=9) both ce-OAE and dp-OAE (at all tested frequencies) were not detectable in six ears of three patients. All other patients had normal ce-OAE's as well as normal dp-OAE's in this frequency range. Difference between the tobramycin treated and control group for OAE as well as dp-OAE showed a trend (P=0.08). In all three patients with undetectable emissions BERA confirmed a cochlear loss of 60-70 dB at 3 kHz in both ears. These three patients had the longest total exposure to tobramycin: 20-24 days and 84-92 mg/kg, respectively. No relation to either peak or trough serum concentrations could be detected. CONCLUSION: There was no statistical relation between hearing loss and tobramycin exposure, probably due to sample size. Our results do indicate a need for a case-control follow-up study of hearing in neonates exposed to long courses of aminoglycosides.

Acoustic Impedance Tests↗
PubMed2002

Unlicensed and off-label drug use in a paediatric ward of a general hospital in the Netherlands.

OBJECTIVES: Many drugs used in paediatric care are not licensed for that use or are prescribed outside the terms of the product license (off-label). Studies in the UK and Europe showed a large number of unlicensed and off-label drug prescription in specialised paediatric health care centres. We determined the extent and nature of use of unlicensed drugs and off-label prescriptions in children in a general hospital in the Netherlands. METHODS: We conducted a longitudinal prospective cohort study in a dynamic population consisting of patients admitted to the paediatric ward and the neonatology unit of a general hospital during a 19-week period. Drug-licensing status of all prescriptions given to these patients was determined. RESULTS: A total of 1017 prescriptions was administered to 293 paediatric patients for 114 different drugs. The median number of prescriptions per patient was three (interquartile range 2-5). The most commonly administered drugs were acetaminophen (14%), cefotaxime (8%), amoxicillin (7%), caffeine (4%) and prednisolone (4%). Four hundred and forty-three (44%) prescriptions were off-label, and 285 (28%) were for unlicensed drugs. Ninety-two percent of patients received one or more unlicensed or off-label prescriptions, and this proportion was significantly higher in children below 6 months of age than in older children. CONCLUSIONS: This study shows that the extent of unlicensed and off-label drug prescription in a paediatric ward and neonatology unit of a general hospital is large and not smaller than in an academic paediatric setting. Lack of paediatric drug labelling is therefore not solely a problem with drugs used in university hospitals, but also in general hospitals. Efforts must be taken to change the current situation.

Adolescent↗
PubMed2002

Pharmacokinetics and metabolism of oral midazolam in preterm infants.

AIMS: To characterize the pharmacokinetics and metabolism of oral midazolam in 15 preterm infants. METHODS: After an oral dose (0.1 mg kg(-1)), blood was drawn up to 24 h after administration. Midazolam and 1-OH-midazolam concentrations were determined with GC-MS. In 8 out of these 15 patients the pharmacokinetics of intravenous midazolam was also studied. RESULTS: Apparent oral clearance, apparent volume of distribution, plasma half-life and 1-OH-Midazolam/Midazolam AUC ratio were [median (range)]: 2.7 [0.67-15.5] ml kg(-1) min(-1), 1.4 [0.3-12.1] l kg(-1), 7.6 [1.2-15.1], h and 0.03 [0.01-0.96], respectively. Absolute bioavailability was 0.49 [0.12-1.0]. CONCLUSIONS: Midazolam oral clearance is markedly decreased in preterm infants as compared with older children, probably because of immature CYP3A4 activity.

Administration, Oral↗
PubMed2002

Lack of effect of the European guidance on clinical investigation of medicines in children.

AIM: To evaluate the registration for paediatric use of new chemical entities (NCEs) granted a marketing authorization (product licence). METHODS: European Public Assessment Reports (EPARs) published on the Internet from January 1995 to May 2001 were analysed. RESULTS: Of 120 new substances licensed since January 1995, 70 (58%) were of potential use in children. Of these, only 17 were licensed for all paediatric uses, and 15 for some paediatric age groups. Hence, the majority (54%) of these substances were probably not tested in paediatric age groups. CONCLUSION: Many of the new drugs granted marketing authorization lack sufficient paediatric labelling. The proportion of drugs for which full labelling was available has not increased in recent years. The European Medicines Evaluation Agency should make an effort to improve this situation.

Child↗
PubMed2001

Pharmacokinetics and metabolism of intravenous midazolam in preterm infants.

BACKGROUND: Midazolam, a benzodiazepine, is finding expanded use in neonatal intensive care units. We studied the pharmacokinetics and metabolism of midazolam after a single intravenous dose in preterm infants. METHODS: The pharmacokinetics of midazolam and its hydroxylated metabolite (1-OH-midazolam) after a single 0.1 mg/kg intravenous dose of midazolam were determined in 24 preterm infants (gestational age, 26 to 34 weeks; postnatal age, 3 to 11 days). Blood samples were obtained before drug administration and at 0.5, 1, 2, 4, 6, 12, and 24 hours after the start of the infusion. Midazolam and 1-OH-midazolam concentrations were determined by use of gas chromatography-mass spectrometry. RESULTS: Total body clearance, apparent volume of distribution, and plasma half-life of midazolam were (median [range]): 1.8 (0.7-6.7) ml/kg per min, 1.1 (0.4-4.2) L/kg, and 6.3 (2.6-17.7) h, respectively. In 19 of 24 preterm infants, 1-OH-midazolam concentrations could be detected: 1-OH-midazolam (1-OH-M) maximal concentration of drug in plasma (C(max)), time to reach C(max) (T(max)), and 1-OH-M/M area under the concentration-time curve from time zero to the last sampling time point (AUC(0-t)) ratio were [median (range)]: 8.2 (<0.5-68.2) ng/ml, 6 (1-12) h, and 0.09 (<0.001-1), respectively. Midazolam plasma clearance was increased in those infants who had indomethacin (INN, indometacin) exposure. DISCUSSION: Consequent to immature hepatic cytochrome P450 3A4 (CYP3A4) activity, midazolam clearance and 1-OH-midazolam concentrations are reduced markedly in preterm infants as compared to concentrations in previous reports from studies in older children and adults. Indomethacin exposure and its apparent impact on midazolam clearance support alteration of drug disposition produced by a patent ductus arteriosus or by the direct effects of indomethacin on hemodynamic or renal function.

Anti-Anxiety Agents↗
PubMed2001

A survey of the use of off-label and unlicensed drugs in a Dutch children's hospital.

BACKGROUND: The treatment of pediatric patients with drugs in hospitals is being impeded by a shortage in the availability of licensed drugs in an appropriate formulation. We have studied the extent of use of drugs that are not licensed for use in children (unlicensed) and drugs that are used outside the terms of the product license (off-label). We conducted this study in a Dutch academic children's hospital. METHODS: In a prospective study of 5 weeks' duration, we reviewed drug prescriptions in a pediatric ward and 3 intensive care units. We classified the prescribed drugs in 3 main categories-licensed, unlicensed, and off-label-and determined the nature of their unlicensed and off-label use. RESULTS: Two thousand one hundred thirty-nine courses of drugs were administered to 237 patients in 442 patient-days. Of 2139 prescriptions, 725 (34%) were licensed, 1024 (48%) were unlicensed, and 390 (18%) were off-label. In 392 (90%) of 435 patient-days, children received 1 or more courses of an unlicensed or off-label drug prescription in hospital. CONCLUSION: With regard to the availability of drugs of proven quality and adequate license for pediatric patients in hospital, dramatic shortcomings exist. As a result, drug legislation originally designed to protect patients and prescribing physicians against unsafe drug use and unjustified claims has turned into an insurmountable threshold to make proper drugs available for a vulnerable minority of patients.

Adolescent↗
PubMed2001

Ibuprofen pharmacokinetics in preterm infants with patent ductus arteriosus.

OBJECTIVE: Our objective was to study the pharmacokinetics of ibuprofen in premature infants with patent ductus arteriosus on day 3 and day 5 after birth. METHODS: Ibuprofen was administered on days 3, 4, and 5 by a 15-minute intravenous infusion of 10, 5, and 5 mg/kg, respectively, with the aim of closing the ductus arteriosus. Blood samples were drawn at time zero and at 0.5, 1, 2, 4, 12, and 24 hours after the first and third doses. Ibuprofen plasma concentrations were assayed by HPLC. RESULTS: A total of 27 premature infants were included (gestational age, 28.6 +/- 1.9 weeks; birth weight, 1250 +/- 460 g; values are mean +/- standard deviation). Ibuprofen pharmacokinetics followed a 2-compartment open model. Between the first and third doses (day 3 and day 5) there was a significant decrease of the volume of distribution of the central compartment (Vd(c)) (0.244 versus 0.171 L/kg; P =.03) and area under the plasma concentration-time curve (524 versus 447 mg. h/L; P =.01). The decrease in Vd(c) was most pronounced in patients with a closing ductus. Total body clearance and plasma half-life did not change significantly. No significant differences were observed in ibuprofen peak plasma concentrations after the first and third doses in relation to ductal status after treatment. CONCLUSION: Ibuprofen pharmacokinetics showed a large interindividual variation in premature infants during treatment for patent ductus arteriosus, and significant changes may occur between day 3 and day 5 after birth in those infants with a closing ductus. These findings may have implications for the treatment schedule with ibuprofen in patients with patent ductus arteriosus.

Anti-Inflammatory Agents, Non-Steroidal↗