J. N. van den Anker

Population pharmacokinetics and metabolism of midazolam in pediatric intensive care patients

ObjectiveTo determine the pharmacokinetics and metabolism of midazolam in pediatric intensive care patients. DesignProspective population pharmacokinetic study. SettingPediatric intensive care unit. PatientsTwenty-one pediatric intensive care patients aged between 2 days and 17 yrs. InterventionsThe 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 ResultsBlood 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. ConclusionsWe 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.

Pharmacokinetics and metabolism of intravenous midazolam in preterm infants.

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.

DEVELOPMENTAL PHARMACOLOGY: NEONATES ARE NOT JUST SMALL ADULTS…

Abstract Neonatal drug dosing needs to be based on the physiological characteristics of the newborn and the pharmacokinetic parameters of the drug. Size-related changes can in part be modelled based on allometry and relates to the observation that metabolic rate relates to weight by a kg0.75 trend. Until adult metabolic activity has been reached, ontogeny, i.e. isoenzyme-specific maturation and maturation of renal clearance also contributes to drug metabolism, making isoenzyme-specific documentation of maturation necessary. Changes in body composition and ontogeny are most prominent in neonates. The body fat content (/kg) is markedly lower and the body water content (/kg) is markedly higher in neonates. These findings have an impact on the distribution volume of both lipophilic and hydrophilic drugs. Drugs are cleared either by metabolism or elimination. While the first is mainly hepatic, the second route is mainly renal. Both hepatic metabolism and renal clearance display maturation in early life although other covariables (e.g. polymorphisms, co-administration of drugs, first pass metabolism, disease characteristics) further contribute to the interindividual variability in drug disposition. Documentation of these maturational processes based on in vivo ‘case’ studies is of value since these drug-specific observations can subsequently be extrapolated to other drugs which are either already being prescribed or even considered for use in neonates by the introduction of these observations in ‘generic physiologically-based pharmacokinetic’ models.

Covariates of tramadol disposition in the first months of life

BACKGROUND Data on contributors to between-individual variability in overall tramadol clearance and O-demethyl tramadol (M1) formation in preterm neonates and young infants are limited. METHODS A population pharmacokinetic analysis of tramadol and M1 was undertaken using non-linear mixed effects model. Covariate analysis included weight, postmenstrual age (PMA), postnatal age (PNA), creatinaemia, (cardiac) surgery, cardiac defect, and cytochrome (CYP)2D6 polymorphisms, classified by CYP2D6 activity score. RESULTS In 57 patients (25-54 weeks PMA), 593 observations were collected. Tramadol clearance was described using a two-compartment, zero-order input, first-order elimination linear model. An additional compartment was used to characterize M1. Tramadol clearance at term age was 17.1 litre h(-1) (70 kg)(-1) (CV, 37.2%). Size (37.8%) and PMA (27.3%) contribute to this variability. M1 formation clearance (CL2M1, i.e. the contribution of M1 synthesis to M clearance) was 4.11 litre h(-1) (70 kg)(-1) (CV, 110.9%) at term age. Size and PMA were the major contributors to the variability (52.7%); the CYP2D6 activity score contributes 6.4% to this variability. CONCLUSIONS Overall tramadol clearance estimates confirm earlier reports while CL2M1 variability is explained by size, PMA, and CYP2D6 polymorphisms. The CL2M1 is very low in preterm neonates, irrespective of the CYP2D6 polymorphism with subsequent rapid maturation. The slope of this increase depends on the CYP2D6 activity score. The current pharmacokinetic observations suggest a limited micro-opioid receptor-mediated analgesic effect of M1 in preterm neonates and a potential CYP2D6 polymorphism-dependent effect beyond term age.

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 μg/kg plus 10 μg/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.

Neonatal drug therapy: The first frontier of therapeutics for children

Knowledge about the safe and effective use of medicines in neonates has increased substantially but has resulted in few label changes. Drugs developed for use in adults are reshaped and tailored to specific neonatal indications. However, the use of drugs in neonates should not only mirror adult pharmacotherapy, but should be driven by their own specific needs. Therefore, building collaborative networks may assist to develop a newborn‐driven research agenda addressing their clinical needs and diseases.

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 μg/kg + 10 μg/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 (χ2 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.

Use of saliva in therapeutic drug monitoring of caffeine in preterm infants.

Caffeine is frequently used to treat apnea of prematurity in preterm infants. Because caffeine has a narrow therapeutic window, plasma concentrations are generally monitored weekly. It would be advantageous to monitor this therapy without blood sampling; saliva might offer this possibility. Paired plasma–saliva and saliva–saliva observations were made in preterm infants (n = 140, gestational ages between 24 and 34 weeks) who received caffeine for the treatment of apnea of prematurity. Three methods were used to collect saliva: no stimulation, dilute citric acid on collection gauze, and dilute citric acid in the cheek pouch before collection. Plasma and saliva caffeine concentrations were determined using high-performance liquid chromatography (HPLC). For all collection methods, the plots of the plasma/saliva outcomes showed linear relationships. The correlation between caffeine concentration in plasma and saliva and the reproducibility of saliva sampling was better with stimulation of saliva production using citric acid in the cheek pouch (r = 0.89) than with no stimulation (r = 0.68) or with stimulation using citric acid on the collection swab (r = 0.79). Monitoring of caffeine therapy in saliva can be applied reliably for routine use in clinical practice, but its reliability and reproducibility depend on the saliva sampling method used; saliva stimulation with citric acid in the cheek pouch is the best method studied.

Optimising the management of fever and pain in children

Fever and pain in children, especially associated with infections, such as otitis media, are very common. In paediatric populations, ibuprofen and paracetamol (acetaminophen) are both commonly used over‐the‐counter medicines for the management of fever or mild‐to‐moderate pain associated with sore throat, otitis media, toothache, earache and headache. Widespread use of ibuprofen and paracetamol has shown that they are both effective and generally well tolerated in the reduction in paediatric fever and pain. However, ibuprofen has the advantage of less frequent dosing (every 6–8 h vs. every 4 h for paracetamol) and its longer duration of action makes it a suitable alternative to paracetamol. In comparative trials, ibuprofen has been shown to be at least as effective as paracetamol as an analgesic and more effective as an antipyretic. The safety profile of ibuprofen is comparable to that of paracetamol if both drugs are used appropriately with the correct dosing regimens. However, in the overdose situation, the toxicity of paracetamol is not only reached much earlier, but is also more severe and more difficult to manage as compared with an overdose of ibuprofen. There is clearly a need for advanced studies to investigate the safety of these medications in paediatric populations of different ages and especially during prolonged use. Finally, the recently reported association between frequency and severity of asthma and paracetamol use needs urgent additional investigations.

Emerging Biomarkers and Metabolomics for Assessing Toxic Nephropathy and Acute Kidney Injury (AKI) in Neonatology

Identification of novel drug-induced toxic nephropathy and acute kidney injury (AKI) biomarkers has been designated as a top priority by the American Society of Nephrology. Increasing knowledge in the science of biology and medicine is leading to the discovery of still more new biomarkers and of their roles in molecular pathways triggered by physiological and pathological conditions. Concomitantly, the development of the so-called “omics” allows the progressive clinical utilization of a multitude of information, from those related to the human genome (genomics) and proteome (proteomics), including the emerging epigenomics, to those related to metabolites (metabolomics). In preterm newborns, one of the most important factors causing the pathogenesis and the progression of AKI is the interaction between the individual genetic code, the environment, the gestational age, and the disease. By analyzing a small urine sample, metabolomics allows to identify instantly any change in phenotype, including changes due to genetic modifications. The role of liquid chromatography-mass spectrometry (LC-MS), proton nuclear magnetic resonance (1H NMR), and other emerging technologies is strategic, contributing basically to the sudden development of new biochemical and molecular tests. Urine neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury molecule-1 (KIM-1) are closely correlated with the severity of kidney injury, representing noninvasive sensitive surrogate biomarkers for diagnosing, monitoring, and quantifying kidney damage. To become routine tests, uNGAL and KIM-1 should be carefully tested in multicenter clinical trials and should be measured in biological fluids by robust, standardized analytical methods.