Matthijs de Hoog

Maturation of the glomerular filtration rate in neonates, as reflected by amikacin clearance

Background and ObjectivesDuring the newborn period and early infancy, renal function matures, resulting in changes in the glomerular filtration rate (GFR). This study was performed to quantify developmental changes in the GFR in (pre)term neonates by use of amikacin clearance as proof of concept. The model was used to derive a rational dosing regimen in comparison with currently used dosing regimens for amikacin.MethodsPopulation pharmacokinetic modelling was performed in nonlinear mixed-effect modelling software (NONMEM version 6.2) using data from 874 neonates obtained from two previously published datasets (gestational age 24–43 weeks; postnatal age 1–30 days; birthweight 385–4650 g). The influence of different age-related, weight-related and other covariates was investigated. The model was validated both internally and externally.ResultsPostmenstrual age was identified as the most significant covariate on clearance. However, the combination of birthweight and postnatal age proved to be superior to postmenstrual age alone. Birthweight was best described using an allometric function with an exponent of 1.34. Postnatal age was identified using a linear function with a slope of 0.2, while co-administration of ibuprofen proved to be a third covariate. Current bodyweight was the most important covariate for the volume of distribution, using an allometric function. The external evaluation supported the prediction of the final pharmacokinetic model. This analysis illustrated clearly that the currently used dosing regimens for amikacin in reference handbooks may possibly increase the risk of toxicities and should be revised. Consequently, a new model-based dosing regimen based on current bodyweight and postnatal age was derived.ConclusionsAmikacin clearance, reflecting the GFR in neonates, can be predicted by birthweight representing the antenatal state of maturation of the kidney, postnatal age representing postnatal maturation, and co-administration of ibuprofen. Finally, the model reflects maturation of the GFR, allowing for adjustments of dosing regimens for other renally excreted drugs in preterm and term neonates.

A Neonatal Amikacin Covariate Model Can Be Used to Predict Ontogeny of Other Drugs Eliminated Through Glomerular Filtration in Neonates

ABSTRACTPurposeRecently, a covariate model characterizing developmental changes in clearance of amikacin in neonates has been developed using birth bodyweight and postnatal age. The aim of this study was to evaluate whether this covariate model can be used to predict maturation in clearance of other renally excreted drugs.MethodsFive different neonatal datasets were available on netilmicin, vancomycin, tobramycin and gentamicin. The extensively validated covariate model for amikacin clearance was used to predict clearance of these drugs. In addition, independent reference models were developed based on a systematic covariate analysis.ResultsThe descriptive and predictive properties of the models developed using the amikacin covariate model were good, and fairly similar to the independent reference models (goodness-of-fit plots, NPDE). Moreover, similar clearance values were obtained for both approaches. Finally, the same covariates as in the covariate model of amikacin, i.e. birth bodyweight and postnatal age, were identified on clearance in the independent reference models.ConclusionsThis study shows that pediatric covariate models may contain physiological information since information derived from one drug can be used to describe other drugs. This semi-physiological approach may be used to optimize sparse data analysis and to derive individualized dosing algorithms for drugs in children.

Recombinant Human Deoxyribonuclease in Infants With Respiratory Syncytial Virus Bronchiolitis

BACKGROUND Treatment of hospitalized infants with respiratory syncytial virus (RSV) bronchiolitis is mainly supportive. Bronchodilators and systemic steroids are often used but do not reduce the length of hospital stay. Because hypoxia and airways obstruction develop secondary to viscous mucus in infants with RSV bronchiolitis, and because free DNA is present in RSV mucus, we tested the efficacy of the mucolytic drug recombinant human deoxyribonuclease (rhDNase). METHODS In a multicenter, randomized, double-blind, controlled clinical trial, 225 oxygen-dependent infants admitted to the hospital for RSV bronchiolitis were randomly assigned to receive 2.5 mg bid of nebulized rhDNase or placebo until discharge. The primary end point was length of hospital stay. Secondary end points were duration of supplemental oxygen, improvement in symptom score, and number of intensive care admissions. RESULTS There were no significant differences between the groups with regard to the length of hospital stay (p = 0.19) or the duration of supplemental oxygen (p = 0.07). The ratio (rhDNase/placebo) of geometric means of length of stay was 1.12 (95% confidence interval, 0.96 to 1.33); for the duration of supplemental oxygen, the ratio was 1.28 (95% confidence interval, 0.97 to 1.68). There were no significant differences in the rate of improvement of the symptom score or in the number of intensive care admissions. CONCLUSIONS Administration of rhDNase did not reduce the length of hospital stay or the duration of supplemental oxygen in oxygen-dependent infants with RSV bronchiolitis.

Psychometric evaluation of the sophia observation withdrawal symptoms scale in critically ill children

Objective: The Sophia Observation withdrawal Symptoms scale is an instrument for screening benzodiazepine and opioid withdrawal syndrome in pediatric critical care patients. The objectives of this study were to establish cutoff scores and to test sensitivity to change. Second, risk factors for withdrawal syndrome were explored. Design: Prospective observational study with repeated measures. Setting: Level IV ICU at a university children’s hospital. Patients: A total of 154 children with median age 5 months (interquartile range, 0–42 mo) who received continuous infusion of benzodiazepines and/or opioids for 5 or more days. Interventions: None. Measurements and Main Results: Nurses repeatedly applied the Sophia Observation withdrawal Symptoms scale and the Numeric Rating Scale withdrawal when children were weaned off benzodiazepines and opioids. The latter represents the nurse’s expert opinion. We analyzed 3,754 paired assessments; the median number per child was 15 (interquartile range, 7–31) over a median of 5 days (interquartile range, 3–11 d). Sensitivity and specificity were 0.83 and 0.93, respectively, for the Sophia Observation withdrawal Symptoms scale cutoff score of 4 or higher against a Numeric Rating Scale-withdrawal score of 4 or higher. Sensitivity to change was determined by comparing 156 Sophia Observation withdrawal Symptoms scale assessments (n = 51 patients) before and after additional sedatives or opioids. Multilevel regression analysis showed a mean decline of 1.5 points (at score range 0–15) after intervention (p < 0.0001). Logistic regression analysis identified duration of preweaning of midazolam, duration of weaning of midazolam, duration of preweaning of morphine, duration of weaning of morphine, and number of additional sedatives/opioids as statistically significant risk factors for withdrawal syndrome in these children. Conclusions: The Sophia Observation withdrawal Symptoms scale is a valid tool with good psychometric properties to assess withdrawal symptoms in PICU patients.

Plasma Concentrations of Oseltamivir and Oseltamivir Carboxylate in Critically Ill Children on Extracorporeal Membrane Oxygenation Support

Introduction To evaluate the effect of extracorporeal membrane oxygenation (ECMO) support on pharmacokinetics of oseltamivir and oseltamivir carboxylate (OC) in children. Methodology Steady state 0–12 hour pharmacokinetic sampling was performed in new influenza A (H1N1) infected children treated with oseltamivir while on ECMO support. Cmax, Cmin and AUC0–12 h were calculated. The age-specific oseltamivir dosage was doubled to counter expected decreased plasma drug concentrations due to increased volume of distribution on ECMO support. Principal Findings Three patients were enrolled aged 15, 6 and 14 years in this pharmacokinetic case series. For two children the OC plasma concentrations were higher than those found in children and adults not on ECMO. These increased plasma concentrations related to the increased oseltamivir dosage and decreased kidney function. In one patient suboptimal plasma concentrations coincided with a decreased gastric motility. Conclusion Oseltamivir pharmacokinetics do not appear to be significantly influenced by ECMO support. Caution is required in case of nasogastric administration and decreased gastric motility. Due to the limited number of (paediatric) patients available further multicenter studies are warranted.

Inflammation and Organ Failure Severely Affect Midazolam Clearance in Critically Ill Children

RATIONALE Various in vitro, animal, and limited human adult studies suggest a profound inhibitory effect of inflammation and disease on cytochrome P-450 3A (CYP3A)-mediated drug metabolism. Studies showing this relationship in critically ill patients are lacking, whereas clearance of many CYP3A drug substrates may be decreased, potentially leading to toxicity. OBJECTIVES To prospectively study the relationship between inflammation, organ failure, and midazolam clearance as a validated marker of CYP3A-mediated drug metabolism in critically ill children. METHODS From 83 critically ill children (median age, 5.1 mo [range, 0.02-202 mo]), midazolam plasma (n = 532), cytokine (e.g., IL-6, tumor necrosis factor-α), and C-reactive protein (CRP) levels; organ dysfunction scores (Pediatric Risk of Mortality II, Pediatric Index of Mortality 2, Pediatric Logistic Organ Dysfunction); and number of failing organs were prospectively collected. A population pharmacokinetic model to study the impact of inflammation and organ failure on midazolam pharmacokinetics was developed using NONMEM 7.3. MEASUREMENTS AND MAIN RESULTS In a two-compartmental pharmacokinetic model, body weight was the most significant covariate for clearance and volume of distribution. CRP and organ failure were significantly associated with clearance (P < 0.01), explaining both interindividual and interoccasional variability. In simulations, a CRP of 300 mg/L was associated with a 65% lower clearance compared with 10 mg/L, and three failing organs were associated with a 35% lower clearance compared with one failing organ. CONCLUSIONS Inflammation and organ failure strongly reduce midazolam clearance, a surrogate marker of CYP3A-mediated drug metabolism, in critically ill children. Hence, critically ill patients receiving CYP3A substrate drugs may be at risk of increased drug levels and associated toxicity.

The effect of inflammation on drug metabolism: A focus on pediatrics

Inflammation is associated with downregulation of the expression and activity of cytochrome P450 enzymes (CYP450) involved in hepatic drug metabolism. Elevated plasma drug levels and increased toxicity might be the consequences of this downregulation. Few clinical studies have investigated these consequences of inflammation in children, who are prescribed many off-label or unlicensed drugs. This review describes the impact of inflammation on CYP450 drug metabolism and drug effect in children, with the consequent implications for drug studies and clinical therapy in this group.

Novel model-based dosing guidelines for gentamicin and tobramycin in preterm and term neonates

OBJECTIVES In the heterogeneous group of preterm and term neonates, gentamicin and tobramycin are mainly dosed according to empirical guidelines, after which therapeutic drug monitoring and subsequent dose adaptation are applied. In view of the variety of neonatal guidelines available, the purpose of this study was to evaluate target concentration attainment of these guidelines, and to propose a new model-based dosing guideline for these drugs in neonates. METHODS Demographic characteristics of 1854 neonates (birth weight 390-5200 g, post-natal age 0-27 days) were extracted from earlier studies and sampled to obtain a test dataset of 5000 virtual patients. Monte Carlo simulations on the basis of validated models were undertaken to evaluate the attainment of target peak (5-12 mg/L) and trough (<0.5 mg/L) concentrations, and cumulative AUC, with the existing and proposed guidelines. RESULTS Across the entire neonatal age and weight range, the Dutch National Formulary for Children, the British National Formulary for Children, Neofax and the Red Book resulted in adequate peak but elevated trough concentrations (63%-90% above target). The proposed dosing guideline (4.5 mg/kg gentamicin or 5.5 mg/kg tobramycin) with a dosing interval based on birth weight and post-natal age leads to adequate peak concentrations with only 33%-38% of the trough concentrations above target, and a constant AUC across weight and post-natal age. CONCLUSIONS The proposed neonatal dosing guideline for gentamicin and tobramycin results in improved attainment of target concentrations and should be prospectively evaluated in clinical studies to evaluate the efficacy and safety of this treatment.

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-OAEs as well as normal dp-OAEs 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.

Continuous noninvasive monitoring of barbiturate coma in critically ill children using the Bispectral™ index monitor

IntroductionTraumatic brain injury and generalized convulsive status epilepticus (GCSE) are conditions that require aggressive management. Barbiturates are used to lower intracranial pressure or to stop epileptiform activity, with the aim being to improve neurological outcome. Dosing of barbiturates is usually guided by the extent of induced burst-suppression pattern on the electroencephalogram (EEG). Dosing beyond the point of burst suppression may increase the risk for complications without offering further therapeutic benefit. For this reason, careful monitoring of EEG parameters is mandatory. A prospective study was conducted to evaluate the usefulness of the bispectral index suppression ratio for monitoring barbiturate coma.MethodsA prospective observational pilot study was performed at a paediatric (surgical) intensive care unit, including all children with barbiturate-induced coma after traumatic brain injury or GCSE. The BIS™ (Bispectral™ index) monitor expresses a suppression ratio, which represents the percentage of epochs per minute in which the EEG was suppressed. Suppression ratios from the BIS monitor were compared with suppression ratios of full-channel EEG as assessed by quantitative visual analysis.ResultsFive patients with GCSE and three patients after traumatic brain injury (median age 11.6 years, range 4 months to 15 years) were included. In four patients the correlation between the suppression ratios of the BIS and EEG could be determined; the average correlation was 0.68. In two patients, suppression ratios were either high or low, with no intermediate values. This precluded determination of correlation values, as did the isoelectric EEG in a further two patients. In the latter patients, the mean ± standard error BIS suppression ratio was 95 ± 1.6.ConclusionCorrelations between suppression ratios of the BIS and EEG were found to be only moderate. In particular, asymmetrical EEGs and EEGs with short bursts (less than 1 second) may result in aberrant BIS suppression ratios. The BIS monitor potentially aids monitoring of barbiturate-induced coma because it provides continuous data on EEG suppression between full EEG registrations, but it should be used with caution.