Richard A. van Lingen

Acetaminophen developmental pharmacokinetics in premature neonates and infants: A pooled Population analysis

Background The aim of this study was to describe acetaminophen developmental pharmacokinetics in premature neonates through infancy to suggest age-appropriate dosing regimens. Methods A population pharmacokinetic analysis of acetaminophen time–concentration profiles in 283 children (124 aged ≤ 6 months) reported in six studies was undertaken using nonlinear mixed-effects models. Neonates and infants were given either single or multiple doses of four different formulations: oral elixir, rectal solution, or triglyceride or capsular suppository. The median postnatal age of children younger than 6 months was 1 day (range, birth to 6 months), median postconception age was 40 weeks (range, 28–64 weeks), and median weight was 3.1 kg (range, 1.2–9.0 kg). Results Population pharmacokinetic parameter estimates and their variability (percent) for a one-compartment model with first-order input, lag time, and first-order elimination were as follows: volume of distribution, 66.6 l (20%); clearance, 12.5 l/h (44%); standardized to a 70-kg person using allometric “1/4 power” models. The volume of distribution decreased exponentially with a maturation half-life of 11.5 weeks from 109.7 l/70 kg at 28 weeks after conception to 72.9 l/70 kg by 60 weeks. Clearance increased from 28 weeks after conception (0.74 l · h−1 · 70 kg−1) with a maturation half-life of 11.3 weeks to reach 10.8 l · h−1 · 70 kg−1 by 60 weeks. The absorption half-life for the oral elixir preparation was 0.21 h (120%) with a lag time of 0.42 h (70%), but absorption was further delayed (2 h) in premature neonates in the first few days of life. Absorption half-life parameters for the triglyceride base and capsule suppositories were 0.80 h (100%) and 1.4 h (57%), respectively. The absorption half-life for the rectal solution was 0.33 h. Absorption lag time was negligible by the rectal route for all three formulations. The bioavailability of the capsule suppository relative to elixir decreased with age from 0.92 (22%) at 28 weeks after conception to 0.86 at 2 yr of age, whereas the triglyceride base decreased from 0.86 (35%) at 28 weeks postconception to 0.5 at 2 yr of age. The relative bioavailability of the rectal solution was 0.66. Conclusions A mean steady state target concentration greater than 10 mg/l at trough can be achieved by an oral dose of 25 mg · kg−1 · d−1 in premature neonates at 30 weeks’ postconception, 45 mg · kg−1 · d−1 at 34 weeks’ gestation, 60 mg · kg−1 · d−1 at term, and 90 mg · kg−1 · d−1 at 6 months of age. The relative rectal bioavailability is formulation dependent and decreases with age. Similar concentrations can be achieved with maintenance rectal doses of 25 (capsule suppository) or 30 (triglyceride suppository) mg · kg−1 · d−1 in premature neonates at 30 weeks’ gestation, increasing to 90 (capsule suppository) or 120 (triglyceride suppository) mg · kg−1 · d−1 at 6 months. These regimens may cause hepatotoxicity in some individuals if used for longer than 2–3 days.

Morphine glucuronidation in preterm neonates, infants and children younger than 3 years

Background and objectiveA considerable amount of drug use in children is still unlicensed or off-label. In order to derive rational dosing schemes, the influence of aging on glucuronidation capacity in newborns, including preterms, infants and children under the age of 3 years was studied using morphine and its major metabolites as a model drug.MethodsA population pharmacokinetic model was developed with the nonlinear mixed-effects modelling software NONMEM® V, on the basis of 2159 concentrations of morphine and its glucuronides from 248 infants receiving intravenous morphine ranging in bodyweight from 500 g to 18 kg (median 2.8 kg). The model was internally validated using normalized prediction distribution errors.ResultsFormation clearances of morphine to its glucuronides and elimination clearances of the glucuronides were found to be primarily influenced by bodyweight, which was parameterized using an allometric equation with an estimated exponential scaling factor of 1.44. Additionally, a postnatal age of less than 10 days was identified as a covariate for formation clearance to the glucuronides, independent of birthweight or postmenstrual age. Distribution volumes scaled linearly with bodyweight.ConclusionsModel-based simulations show that in newborns, including preterms, infants and children under the age of 3 years, a loading dose in µg/kg and a maintenance dose expressed in µg/kg1.5/h, with a 50% reduction of the maintenance dose in newborns younger than 10 days, results in a narrow range of morphine and metabolite serum concentrations throughout the studied age range. Future pharmacodynamic investigations are needed to reveal target concentrations in this population, after which final dosing recommendations can be made.

Long-term effects of routine morphine infusion in mechanically ventilated neonates on children’s functioning: Five-year follow-up of a randomized controlled trial

&NA; Newborns on ventilatory support often receive morphine to induce analgesia. Animal experiments suggest that this may impair subsequent cognitive and behavioral development. There are sparse human data on long‐term effects of neonatal morphine. We aimed to investigate the effects of continuous morphine administered in the neonatal period on the child’s functioning. We conducted a follow‐up study among 5‐year‐olds who, as mechanically ventilated neonates, had participated in a placebo‐controlled trial on effects of morphine administration on pain and neurologic outcome. They were now tested on intelligence, visual motor integration, behavior, chronic pain, and health‐related quality of life. Univariate analyses showed significantly lower overall intelligence quotient (IQ) scores for children who earlier had received morphine, that is, mean 94 (SD 14.5) versus 100 (SD 12.9) for those who received placebo (P = 0.049). Other between‐group differences in outcomes were not found. The statistical difference disappeared after correction for treatment condition, open‐label morphine consumption over the first 28 days, and a propensity score for clinically relevant co‐variables in multiple regression analyses. However, scores on one IQ subtest, “visual analysis,” were significantly negatively related to having received morphine and to open‐label morphine consumption the first 28 days. The finding of a significant effect of morphine on the “visual analysis” IQ subtest calls for follow‐up at a later age focusing on the higher‐order neurocognitive functions. Morphine received in the neonatal period has negative effects on the child’s cognitive functioning at the age of 5 years which warrants follow‐up at a later age.

Does neonatal morphine use affect neuropsychological outcomes at 8 to 9 years of age

Summary Neonatal morphine infusion of 10 μg/kg/h does not affect general functioning 8 to 9 years later and may even have a positive effect on executive function skills. ABSTRACT Morphine is widely used to treat severe pain in neonatal intensive care unit patients. Animal studies suggest adverse long‐term side effects of neonatal morphine, but a follow‐up study of 5‐year‐old children who participated in a morphine‐placebo controlled trial as newborns found no such effects on the child’s general functioning. This study indicated that morphine may negatively affect response inhibition, a domain of executive functions. Therefore, we performed a second follow‐up study in the same population at the age of 8 to 9 years, focused on the child’s general functioning in terms of intelligence, visual motor integration, and behavior and on executive functions. Children in the morphine group showed significantly less externalizing problems according to the parents but more internalizing behavior according to the teachers, but only after adjustment for intelligence quotient (IQ), potential confounders using a propensity score, and additional open‐label morphine. Morphine‐treated children showed significantly fewer problems with executive functions in daily life as rated by parents for the subscales inhibition and organization of materials and for planning/organizing as rated by the teachers. After adjustment for IQ and the propensity score, executive functioning as rated by the parents remained statistically significantly better in the morphine‐treated group. The influence of the additional morphine given was not of a significant influence for any of the outcome variables. Overall, the present study demonstrates that continuous morphine infusion of 10 μg/kg/h during the neonatal period does not harm general functioning and may even have a positive influence on executive functions at 8 to 9 years.

Multiple-dose pharmacokinetics of rectally administered acetaminophen in term infants

To investigate pharmacokinetics and pharmacodynamics of rectally administered acetaminophen (INN, paracetamol) in term neonates directly after birth.

Analgesic efficacy of rectal versus oral acetaminophen in children after major craniofacial surgery

Analgesic acetaminophen (INN, paracetamol) plasma concentrations after major surgery in neonates and infants have not yet been established in the literature. We therefore conducted a study in our intensive care unit.

The effects of analgesia in the vulnerable infant during the perinatal period

Although our knowledge of pain and its management in the perinatal period has increased, little is known about the first hours and days of life when major physiologic transition events occur. Prematurity and critical illnesses further complicate analgesic use during this time. Increased morbidity and mortality have been shown in infants receiving placebo infusions after surgery compared with infants with analgesia, highlighting the negative consequences of pain in infants. Opioids can help promote hemodynamic stability, promote respirator synchrony, and decrease the incidence of grade III & IV intraventricular hemorrhage in ventilated preterm neonates. Long-term follow-up studies suggest improved behavioral and cognitive outcomes in children given morphine infusions during NICU confinement. The necessity of fetal analgesia is dictated by the ability of the fetus to feel pain and by the adverse effects of noxious stimuli on future sensory development. Effects of drugs given to the pregnant woman on the (preterm) newborn might be influenced by decreased or absent transplacental transport, compression of the umbilical cord during delivery, or diminished blood flow in the placenta in pre-eclamptic women, resulting in higher serum concentrations. Pharmacokinetics and drug metabolism change in the last trimester, and pain sensitivity may be altered after 32 weeks of gestation. Consequently, dose and dose interval may vary considerably between neonates and within an individual during the first days of life. This subpopulation is not homogenous, and drug doses in a term neonate with a postnatal age of 2 weeks may be quite different from those at birth and are certainly different from those in a premature neonate. Size must be disentangled from age-related factors when examining developmental pharmacokinetic parameters. There are no longitudinal studies published investigating the pharmacokinetic properties of any analgesic more than once per infant. Polymorphisms of the genes encoding for the enzymes involved in the metabolism of analgesics or in genes involved in receptor expression may contribute to the large interindividual pharmacokinetic parameter variability. Polymorphism of the human mu opioid receptor has not yet satisfactorily explained pharmacodynamic variability.

Predictive Performance of a Recently Developed Population Pharmacokinetic Model for Morphine and its Metabolites in New Datasets of (Preterm) Neonates, Infants and Children

Background and ObjectiveModel validation procedures are crucial when models are to be used to develop new dosing algorithms. In this study, the predictive performance of a previously published paediatric population pharmacokinetic model for morphine and its metabolites in children younger than 3 years (original model) is studied in new datasets that were not used to develop the original model.MethodsSix external datasets including neonates and infants up to 1 year were obtained from four different research centres. These datasets contained postoperative patients, ventilated patients and patients on extracorporeal membrane oxygenation (ECMO) treatment. Basic observed versus predicted plots, normalized prediction distribution error analysis, model refitting, bootstrap analysis, subpopulation analysis and a literature comparison of clearance predictions were performed with the new datasets to evaluate the predictive performance of the original morphine pharmacokinetic model.ResultsThe original model was found to be stable and the parameter estimates were found to be precise. The concentrations predicted by the original model were in good agreement with the observed concentrations in the four datasets from postoperative and ventilated patients, and the model-predicted clearances in these datasets were in agreement with literature values. In the datasets from patients on ECMO treatment with continuous venovenous haemofiltration (CVVH) the predictive performance of the model was good as well, whereas underprediction occurred, particularly for the metabolites, in patients on ECMO treatment without CVVH.ConclusionThe predictive value of the original morphine pharmacokinetic model is demonstrated in new datasets by the use of six different validation and evaluation tools. It is herewith justified to undertake a proof-of-principle approach in the development of rational dosing recommendations — namely, performing a prospective clinical trial in which the model-based dosing algorithm is clinically evaluated.

Oligosaccharides in feces of breast- and formula-fed babies

So far, little is known on the fate of oligosaccharides in the colon of breast- and formula-fed babies. Using capillary electrophoresis with laser induced fluorescence detector coupled to a mass spectrometer (CE-LIF-MS(n)), we studied the fecal oligosaccharide profiles of 27 two-month-old breast-, formula- and mixed-fed preterm babies. The interpretation of the complex oligosaccharide profiles was facilitated by beforehand clustering the CE-LIF data points by agglomerative hierarchical clustering (AHC). In the feces of breast-fed babies, characteristic human milk oligosaccharide (HMO) profiles, showing genetic fingerprints known for human milk of secretors and non-secretors, were recognized. Alternatively, advanced degradation and bioconversion of HMOs, resulting in an accumulation of acidic HMOs or HMO bioconversion products was observed. Independent of the prebiotic supplementation of the formula with galactooligosaccharides (GOS) at the level used, similar oligosaccharide profiles of low peak abundance were obtained for formula-fed babies. Feeding influences the presence of diet-related oligosaccharides in baby feces and gastrointestinal adaptation plays an important role herein. Four fecal oligosaccharides, characterized as HexNAc-Hex-Hex, Hex-[Fuc]-HexNAc-Hex, HexNAc-[Fuc]-Hex-Hex and HexNAc-[Fuc]-Hex-HexNAc-Hex-Hex, highlighted an active gastrointestinal metabolization of the feeding-related oligosaccharides. Their presence was linked to the gastrointestinal mucus layer and the blood-group determinant oligosaccharides therein, which are characteristic for the hosts genotype.

Which aspects of safety culture predict incident reporting behavior in neonatal intensive care units? A multilevel analysis.

Objectives:Safety culture assessments are increasingly used to evaluate patient-safety programs. However, it is not clear which aspects of safety culture are most relevant in understanding incident reporting behavior, and ultimately improving patient safety. The objective of this study was to examine which aspects of safety culture predict incident reporting behavior in the neonatal intensive care unit (NICU), before and after implementation of a voluntary, nonpunitive incident reporting system. Design:Survey study based on a translated, validated version of the Agency for Healthcare Research and Quality Hospital Survey on Patient Safety Culture. This survey incorporates two outcome measures, 11 dimensions of patient-safety culture as well as demographic data. Setting:Eight tertiary care NICUs and one surgical pediatric ICU. Subjects:All unit personnel. Intervention:Implementation of a specialty-based, voluntary, nonpunitive incident reporting system. Measurements and Main Results:The survey was conducted before (t = 0) and after (t = 1 yr) the intervention. Primary outcome: number of self-reported incidents in the past 12 months. Overall response rate was 80% (n = 700) at t = 0 and 76% (n = 670) at t = 1 yr. Based on a multivariate multilevel regression prediction model, the number of self-reported incidents increased after the intervention and was positively associated with a nonpunitive response to error and negatively associated with overall perceptions of safety and hospital management support for patient safety. Conclusions:A nonpunitive approach to error, hospital management support for patient safety, and overall perceptions of safety predict incident reporting behavior in the NICU. The relation between these aspects of safety culture and patient outcome requires further scrutiny and therefore remains an important issue to address in future research.