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Introduction: There are profound changes that take place in drug metabolism enzymes during fetal and postnatal development. These changes may significantly impact drug therapy in children. Areas covered: A combination of focused and comprehensive literature searches using PubMed and reference lists (from inception to 7 November 2009) is undertaken to identify reports on in vitro and in vivo development of drug metabolism enzymes as well disposition of selected drugs and their effect in children. The article provides an update on development of drug metabolism enzymes and their impact on drug substrate disposition and disease, which may aid to improve clinical practice and optimally design clinical trials in children. Expert opinion: Drug metabolism enzyme activity changes profoundly throughout the continuum of postnatal development and often results in different disposition pathways than in adults. Genetics and co-morbidity interact significantly with these developmental changes. Translation of existing knowledge into age-adjusted dosing guidelines and clinical trial design is highly needed for there to be an improvement in drug therapy in children.

Objective: Excipients used in oral or intravenous preparations may cause serious adverse events. Case Summary: We present the case of a 15-year-old boy with hypertrophic cardiomyopathy. In the pediatric intensive care unit, he received high doses of continuous intravenous esmolol (range = 20-400 µg/kg/min) for cardiac rhythm control. After a few days he developed a delirium not responding to high doses of antipsychotics or discontinuation of benzodiazepines. We eventually realized that the IV esmolol formulation contained high doses of propylene glycol and ethanol, which may accumulate after prolonged infusion and cause intoxication. Intoxication with propylene glycolcan cause neuropsychiatric symptoms. The boy’s propylene glycol plasma concentration was approximately 4 g/L, whereas clinical symptoms arise at concentrations above 1 to 1.44 g/L. Application of the Naranjo adverse drug reaction probability scale suggested a probable relationship (score 6) between the propylene glycol infusion and the delirium. After discontinuation of esmolol, the delirium disappeared spontaneously. Discussion: This is the first case describing excipient toxicity of esmolol, with an objective causality assessment revealing a probable relationship for the adverse event—namely, delirium—and esmolol. Conclusion: Although excipient toxicity is a well-known adverse drug reaction, this case stresses the importance for easily available information for and education of physicians.

Rational dosing guidelines for drugs in pediatrics are urgently needed. To develop these guidelines, we use population pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation by: (i) optimization of clinical trial designs based on preliminary data; (ii) development and internal validation of population PK-PD models using sparse data; (iii) external validation using independent data; and (iv) prospective clinical evaluation. Optimized dosing regimens for specific drugs may then serve as a basis to develop dosing guidelines for existing or newly developed drugs with similar disposition and/or effect. In addition to modeling of drug disposition (PK) pathways, we emphasize the need for modeling of effect (PD) pathways and the use of a multidisciplinary infrastructure for data-sharing.

A paucity of data exists on the disposition and effect of drugs in young children. This information gap can be reduced by elucidating developmental principles of absorption, distribution, metabolism and excretion (ADME) in vivo. Such knowledge might enable the prediction of the disposition of individual drugs in children over the whole pediatric age range. CYP3A, the most abundant human drug metabolizing enzyme, is involved in the metabolism of more than 50% of all marketed drugs. Hence, elucidating the developmental pattern of CYP3A in relation to genetic background, disease and comedications might greatly enhance our knowledge on drug disposition in children. Several methods have been used to determine in vivo CYP3A activity in human adults, while similar studies in children face several ethical, practical and scientific challenges. The aim of this review is to identify these challenges and offer feasible solutions for studying drugs in young children, with an emphasis on CYP3A phenotyping as an example.

Item does not contain fulltext BACKGROUND: This study determined whether the SLC22A1 [encoding the organic cation transporter 1 (OCT1)] genotype could explain, in addition to the postmenstrual age (referring to gestational plus postnatal age) and CYP2D6 genotype, the tramadol (M) pharmacokinetic variability in early infancy. METHODS: Fifty infants, median postmenstrual age 39.5 (interquartile range: 36.8-41.3) weeks, received an i.v. M loading dose (2 mg/kg) followed by a continuous infusion (5-8 mg.kg.24 h). Blood was sampled from 4 to 24 hours after start of the M treatment, which generated 230 observations. M and O-desmethyltramadol (M1) concentrations were measured by high-performance liquid chromatography. RESULTS: Linear mixed-model analysis illustrated that the SLC22A1/OCT1 genotype was independently associated with a log-transformed M1/M ratio (P = 0.013), with carriers of /=2 CYP2D6 functional gene copies and

Item does not contain fulltext OBJECTIVES: To determine the cardiovascular tolerance of clonidine used as a first-line sedative after cardiac surgery in small infants. DESIGN: Retrospective chart review. SETTING: A tertiary and quaternary referral cardiac PICU. PATIENTS: All infants younger than 2 months who received a clonidine infusion for sedation after cardiac surgery from October 2011 to July 2013. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Heart rate, blood pressure, central venous and left atrial pressure, vasoactive inotropic score, volume of fluid bolus, and lactate and central mixed venous saturation were assessed. Preinfusion values were compared with postinfusion values. Of 224 potentially eligible patients, only 23 infants met inclusion criteria, as most patients only received high doses of morphine and some received midazolam instead of clonidine. Clonidine administration was started at a median of 12 hours after surgery (Q1-Q3, 5-23), and infusion rate was 0.5-2 mug/kg/hr for a median duration of 30 hours (Q1-Q3, 12-54). Heart rate decreased (maximal mean decrease: 12% [149 beats/min (SD, 17) to 131 beats/min (SD, 17)]; p < 0.0001). Apart from a transient and limited drop in diastolic blood pressure of 13% (maximal mean decrease: from 42.8 mm Hg [SD, 5.9] to 37.1 mm Hg [SD, 4.0]; p = 0.018), all other cardiovascular variables were stable or improved. A contemporaneous cohort of patients who received midazolam, did so sooner after surgery, stayed longer in the PICU and showed less favorable hemodynamics. CONCLUSIONS: IV clonidine as sedative added to morphine in selected patients seems hemodynamically safe. The observed decrease in heart rate and diastolic blood pressure seems of minimal clinical importance as all other hemodynamic variables remained stable or improved. The safety of clonidine given early after cardiac surgery as alternative to midazolam merits further study.

Item does not contain fulltext The authors discuss the case of a 14-year-old girl who was transferred to the ICU of our hospital with ethanol intoxication (3.3 g/L), loss of consciousness (E5M3V1), and severe amnesia on recovery that was suspected of gamma-hydroxybutyric acid (GHB) intoxication. STAT toxicology screening may be necessary, when sexual assault under GHB intoxication is suspected. Therefore, the initial analysis of a urine sample was performed with a new enzymatic assay analysis for GHB. The enzymatic assay reported a GHB concentration of 26 mg/L, which is above the cut-off value of 10 mg/L. This cut-off value is to differentiate endogenous and exogenous levels because low levels of GHB occur naturally in the body. However, confirmation of these results by gas chromatography, which is common practice to confirm a positive GHB, gave a negative result. This discrepancy is probably contributed to interference of ethanol with the assay. This is a substantial downside of the GHB rapid screening, since the combination of GHB and ethanol is common. It is therefore advised to confirm that the positive GHB results are lower than 50 mg/L by gas chromatography, when using the rapid screening. This way the false-positive results and consequent inappropriate social and legal actions may be avoided.

Item does not contain fulltext The intestinal influx oligopeptide transporter peptide transporter 1 (PEPT1) (SLC15A1) is best known for nutrient-derived di- and tripeptide transport. Its role in drug absorption is increasingly recognized. To better understand the disposition of PEPT1 substrate drugs in young infants, we studied intestinal PEPT1 mRNA expression and tissue localization across the pediatric age range. PEPT1 mRNA expression was determined using real-time reverse-transcription polymerase chain reaction in small intestinal tissues collected from surgical procedures (neonates and infants) or biopsies (older children and adolescents). PEPT1 mRNA relative to villin mRNA expression was compared between neonates/infants and older children/adolescents. PEPT1 was visualized in infant tissue using immunohistochemical staining. Other transporters [multidrug resistance protein 1 (MDR1), multidrug resistance-like protein 2 (MRP2), and organic anion transporter polypeptide 2B1 (OATP2B1)] were also stained to describe the localization in relation to PEPT1. Twenty-six intestinal samples (n = 20 neonates/infants, n = 2 pediatric, n = 4 adolescents) were analyzed. The young infant samples were collected at a median (range) gestational age at birth of 29.2 weeks (24.7-40) and postnatal age of 2.4 weeks (0-16.6). The PEPT1 mRNA expression of the neonates/infants was only marginally lower (0.8-fold) than the older children (P < 0.05). Similar and clear apical PEPT1 and MRP2 staining, apical and lateral MDR1 staining, and intraepithelial OATP2B1 staining at the basolateral membrane of the enterocyte were detected in 12 infant and 2 adolescent samples. Although small intestinal PEPT1 expression tended to be lower in neonates than in older children, this difference is small and tissue distribution is similar. This finding suggests similar oral absorption of PEPT1 substrates across the pediatric age range.

Human hepatic membrane-embedded transporter proteins are involved in trafficking endogenous and exogenous substrates. Even though impact of transporters on pharmacokinetics is recognized, little is known on maturation of transporter protein expression levels, especially during early life. We aimed to study the protein expression of 10 transporters in liver tissue from fetuses, infants, and adults. Transporter protein expression levels [ATP-binding cassette transporter (ABC)B1, ABCG2, ABCC2, ABCC3, bile salt efflux pump, glucose transporter 1, monocarboxylate transporter 1, organic anion transporter polypeptide (OATP)1B1, OATP2B1, and organic cation/carnitine transporter 2) were quantified using ultraperformance liquid chromatography tandem mass spectrometry in snap-frozen postmortem fetal, infant, and adult liver samples. Protein expression was quantified in isolated crude membrane fractions. The possible association between postnatal and postmenstrual age versus protein expression was studied. We studied 25 liver samples, as follows: 10 fetal [median gestational age 23.2 wk (range 16.4-37.9)], 12 infantile [gestational age at birth 35.1 wk (27.1-41.0), postnatal age 1 wk (0-11.4)], and 3 adult. The relationship of protein expression with age was explored by comparing age groups. Correlating age within the fetal/infant age group suggested four specific protein expression patterns, as follows: stable, low to high, high to low, and low-high-low. The impact of growth and development on human membrane transporter protein expression is transporter-dependent. The suggested age-related differences in transporter protein expression may aid our understanding of normal growth and development, and also may impact the disposition of substrate drugs in neonates and young infants. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

ObjectivePaediatric clinical trials are often conducted as multinational trials. Informed consent or assent is part of the ethics committee approval for clinical trials. The consent requirements vary between countries due to national laws and regulations, which are not harmonised in Europe. These discrepancies can present challenges for paediatric clinical trials. The aim of this study was to assemble these consent and assent requirements across the European Economic Area. The collated national requirements have not been publicly available before, despite a real need for this data.MethodsNational consent and assent requirements for paediatric clinical trials were analysed and collated for 25 European Union Member States and 2 European Free Trade Association countries until the end of 2014. The data were retrieved from existing databases and through communication with the competent authorities and selected ethics committees. Results from a literature search for international or national guidelines, declarations and conventions and academic societies' publications served as comparison material.ResultsConsent and assent requirements are heterogeneous across these countries. We compiled our findings in ‘The Informed Consent and Assent Tool Kit’, a table including 27 national consent and assent requirements listed by individual country.ConclusionsWide variation in paediatric consents and assents presents challenges for multinational paediatric trials in Europe. The toolkit is available for all those involved in paediatric clinical trials and ethics committees, providing a new platform for proactive feedback on informed consent requirements, and may finally lead to a needed harmonisation process, including uniform standards accepted across Europe.

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The intravenous C-erythromycin breath test (EBMT) has been largely used in adults as a validated probe to measure hepatic cytochrome P450 3A4 and 3A5 (CYP3A4/5) activity in vivo. Additionally, the oral EBMT has been suggested to measure combined hepatic and intestinal CYP3A4/5 activity. Both hepatic and intestinal CYP3A4/5 activities are low in neonates, but the exact developmental pattern is not known. Also, a knowledge gap exists on the impact of comedication or disease state on CYP3A4/5 activity in this population. However, to use the radioactive test in newborns is not feasible, for obvious ethical reasons. Hence, the aim of this pilot study was to determine if stable isotope-labeled C-erythromycin could be used alternatively. Preterm infants who needed treatment with erythromycin for ureaplasma infection were given an oral 10 to 15 mg/kg C-(N-dimethyl)-erythromycin dose. Pharmacy regulations did not permit intravenous administration. Exhaled air samples were collected predose and up to 24 hours post-dose and analyzed for CO2 and CO2 with gas chromatography-mass spectrometry. Three patients received oral C-erythromycin. CO2 did not change significantly from baseline, showed a maximum blood concentration at 20 hours (+12%), and decreased over 24 hours (-16%) in these patients, respectively. Because none of these patients showed a consistent peak in C enrichment, in accordance with maximum blood concentration of oral erythromycin in preterms, we stopped this pilot trial after 3 patients. In conclusion, the lack of a consistent change in exhaled CO2 after oral C-erythromycin in this pilot study precludes the routine use of oral 13C-EBMT in preterm infants as a noninvasive probe of CYP3A4/5 activity. We speculate that this lack of change is due to developmentally low intestinal and hepatic CYP3A activity.

All critically ill children admitted to a paediatric intensive care unit (PICU) receive drug treatment. However, the majority of these drugs has never been tested in these children, and their safety and efficacy have not been proven. Clinical drug research is therefore required in this patient group. While doing this research we need to balance between the advancement of knowledge--and thereby potential improvements in clinical care--and protection of a vulnerable population against harm and exploitation. The PICU environment and the vulnerable population raise specific ethical challenges and mean that the research should be designed and conducted with care. The ethical challenges are related to 4 areas: a) study design and conduct; b) informed consent from parents and children; c) burden and risk for the child; and d) research or experimental treatment. These challenges and possible solutions will be discussed in this article.

The aim of this study was to evaluate the pharmacodynamics and safety of midazolam after intravenous infusion or oral administration in preterm infants. METHODS ]PATIENTS WERE RANDOMLY ASSIGNED TO INITIALLY RECEIVE MIDAZOLAM 0.1 MG/KG AS A 30-MINUTE INTRAVENOUS INFUSION OR AN ORAL BOLUS DOSE. IF PATIENTS STILL MET THE INCLUSION CRITERIA, THEY THEN RECEIVED MIDAZOLAM VIA THE ALTERNATE ROUTE (AFTER AN INTERVAL OF ≥72 HOURS). PHARMACODYNAMIC MEASUREMENTS CONSISTED OF A COMFORT® SCORE (A PREVIOUSLY VALIDATED SEDATION SCALE FOR PAEDIATRIC PATIENTS) AT BASELINE AND AT 0.5, 1, 2, 4 AND 6 HOURS POSTDOSE. MIDAZOLAM AND 1-OH-MIDAZOLAM CONCENTRATIONS WERE MEASURED AND VITAL SIGNS WERE RECORDED AT ALL PHARMACODYNAMIC MEASUREMENT TIMEPOINTS:A total of 24 infants were enrolled of whom seven received both intravenous and oral midazolam, 13 received only intravenous midazolam, and four received only oral midazolam. Overall, mean COMFORT® scores decreased (i.e. sedation increased) significantly within 30 minutes after intravenous (p S 0.05) and within 1 hour after oral (p = 0.003) midazolam administration. In 45% of patients the COMFORT® scores decreased little or not at all after midazolam, which was similar after both oral and intravenous administration. The sedative response to midazolam did not differ after intravenous or oral administration. No relationship was found between overall COMFORT® scores or change in COMFORT® score from baseline and midazolam, 1-OH-midazolam, or midazolam plus 1-OH-midazolam concentrations. Diastolic blood pressure decreased significantly after intravenous (approximately 11%) but not after oral midazolam administration. No serious adverse events were reported.Midazolam administered as a 30-minute intravenous infusion or oral bolus dose appears to be effective and well tolerated in a small majority of preterm infants. However, a considerable number of neonates do not appear to respond to midazolam. The lack of response may be due to the fact that patients truly experienced therapeutic failure and/or consequent to the inability of the COMFORT® score to adequately reflect sedation uniformly in sick preterm infants.

Item does not contain fulltext Dipyrone has analgesic, spasmolytic, and antipyretic effects and is used to treat pain. Due to a possible risk of agranulocytosis with the use of dipyrone, it has been banned in a number of countries. The most commonly used data for the use of dipyrone are related to adults. Information relating to the use of dipyrone in children is scarce. Given the potential added value of dipyrone in the treatment of pain, a review of the literature was conducted to obtain more insight into the analgesic efficacy of dipyrone in children as well as the safety of dipyrone in terms of adverse events. A literature search was done for original articles (in English, German, or Spanish language) which met the following criteria: the use of dipyrone for pain and children up to the age of 17 years old. All titles and abstracts retrieved were reviewed, independently, by two of the authors, for their suitability for inclusion. The references of the selected articles were also checked for additional relevant papers. The publications were categorized into case reports, observational studies, or randomized controlled trials. To assess the methodological quality of the studies, the Jadad score was used. In the limited available data, the analgesic efficacy of intravenous dipyrone appears similar to that of intravenous paracetamol. Evidence is lacking to support the claim that dipyrone is equivalent or even superior to Non-Steroid-Anti-Inflammatory-Drugs in pediatric pain. While the absolute risk of agranulocytosis with dipyrone in children, based on available literature, cannot be determined, case reports suggest that this risk is not negligible.

Starting doses of tacrolimus and ciclosporin are typically chosen on a calculated mg/kg bodyweight basis. After initiation of treatment, doses are adjusted with therapeutic drug monitoring (TDM). This trial-and-error approach has been accepted by most physicians and pharmacists involved in the care of transplanted patients.Dosing algorithms have only fairly recently been proposed to better individualize the starting dose. This review provides an overview of all the currently available dosing algorithms in adult and children for the starting dose of ciclosporin, tacrolimus and mycophenolic acid. In these algorithms, multiple other covariates influencing the starting dose, such as age, hematocrit, comedication and genotype are taken into account. After selecting the starting dose with an algorithm and after initiation of treatment, TDM will, however, remain necessary. Whether or not implementation of such algorithms will improve clinical outcome remains to be demonstrated.First of all an algorithm needs to be validated, against an independent dataset. Second, in a prospective study the algorithm should prove to reduce the time to reach the target concentration, and to reduce the number of patients with drug concentrations (far) outside the therapeutic window. Finally, a clinical trial demonstrating a benefit on clinical outcome will be crucial in achieving broad acceptance of calculating starting dose using individualized dosing algorithms.

Reliable reference intervals for two novel urinary biomarkers of renal injury, neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury molecule-1 (uKIM-1) are lacking for infants. Therefore, the aim of our study was to establish reference intervals for urinary NGAL and KIM-1 absolute concentrations as well as normalized to urinary creatinine in young infants categorized in small age intervals.From June 2010 to March 2014, serum and urine samples of 106 basically healthy infants (born between 37 and 42 weeks of gestation) aged 1 day to 1 year were collected. Blood samples were assayed for serum creatinine levels to confirm a healthy renal status. Urine samples were assayed for creatinine, uNGAL (ng/mL) and uKIM-1 (ng/mL).Two thirds of the study cohort were boys. uNGAL concentrations declined with increasing age (likelihood ratio test, p=0.001). Also, uNGAL concentrations were higher in girls (50th centile uNGAL was 27.1 ng/mL) than boys (50th centile uNGAL was 14.3 ng/mL) (two tailed Wald test, p0.05).Our data uniquely provide uNGAL and uKIM-1 reference intervals for the first year of life. Notably, only uNGAL levels decreased with increasing age and were higher in girls. These reference intervals enable future studies to evaluate the performance of both biomarkers in detecting early kidney tubular injury, particularly in the setting of critical care.

Introduction Children admitted to a pediatric intensive care unit (ICU) are at high risk of developing acute kidney injury (AKI). Although serum creatinine (SCr) levels are used in clinical practice, they are insensitive for early diagnosis of AKI. Urinary neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury molecule-1 (KIM-1) are novel AKI biomarkers whose performance in pediatric ICU patients is largely unknown. In this study, we aimed to characterize uNGAL and KIM-1 patterns in children following ICU admission and to assess their properties in relation to identifying children at risk for AKI development. Methods From June 2010 until January 2014, we conducted a prospective observational cohort study of term-born children ages 1 day to 1 year on mechanical ventilation. Blood and urine samples were obtained every 6 to 12 hours up to 72 hours post-admission. Blood samples were assayed for SCr, and urine samples were assayed for uNGAL and KIM-1. The RIFLE (risk, injury, failure, loss, end-stage renal disease) classification as 150%, 200% or 300% of median SCr reference values was used to define AKI. Results A total of 100 children were included (80 survived). Their median age at admission was 27.7 days (interquartile range (IQR), 1.5 to 85.5). The median duration of mechanical ventilation was 5.8 days (IQR, 3.1 to 11.4). Thirty-five patients had evidence of AKI within the first 48 hours post-admission, of whom 24 (69%) already had AKI when they entered the ICU. uNGAL and KIM-1 concentrations in AKI peaked between 6 to 12 hours and between 12 to 24 hours post-admission, respectively. The maximal area under the receiver operating characteristic curve (AUC) for uNGAL was 0.815 (95% confidence interval (CI), 0.685 to 0.945, P P Conclusions Levels of uNGAL and KIM-1 increase in patients with AKI following ICU admission and peak at 6 to 12 hours and 12 to 24 hours post-admission, respectively. uNGAL seems to be a reliable marker for identifying children who will develop AKI 24 hours later.

Cardiopulmonary bypass (CPB) induces a systemic inflammatory response syndrome (SIRS) by factors such as contact of the blood with the foreign surface of the extracorporeal circuit, hypothermia, reduction of pulmonary blood flow during CPB and endotoxemia. SIRS is maintained in the postoperative phase, co-occurring with a counter anti-inflammatory response syndrome. Research on the effects of drugs administered before the surgery, especially in the induction phase of anesthesia, as well as drugs used during extracorporeal circulation, has revealed that they greatly influence these postoperative inflammatory responses. A better understanding of these processes may not only improve postoperative recovery but also enable tailor-made pharmacotherapy, with both health and economic benefits. In this review, we describe the pathophysiology of SIRS and counter anti-inflammatory response syndrome in the light of CPB in children and the influence of drugs used on these syndromes.

BACKGROUND β-Trace protein (BTP) has been proposed as an alternative endogenous marker of glomerular filtration rate. Data on BTP reference ranges in young children are scarce. We therefore aim to establish reference ranges and examine the developmental course of serum BTP in basically healthy children younger than 1 year of age. METHODS Single blood samples were taken from healthy children (born at gestational age ≥37 weeks)

Objective: To describe a child who developed a skin reaction during gabapentin therapy and discuss how we evaluated the probability of an adverse drug reaction. Case Summary: An 8-year-old boy with a neurodegenerative disease of unknown origin and an epilepsy disorder developed an urticarial rash and irritability 10 and 4 days, respectively, after the start of gabapentin 20 mg/kg 3 times a day for epilepsy control. Otherwise, the child was well; no changes in other medication or diet had recently been made. After gabapentin discontinuation and administration of one dose of methylprednisolone 10 mg/kg intravenously and diphenhydramine 1 mg/kg every 4 hours via gastric tube, the rash disappeared over 3 weeks. Discussion: In contrast to other antiepileptic drugs, skin reactions to gabapentin are considered uncommon. In adults, reported prevalence of rash possibly related to gabapentin range from 1% to 10%. A postmarketing surveillance study reported gabapentin treatment failure as a consequence of rash in 0.4% of 3000 patients. The product monograph does not mention rash in children. In our patient, assessment using an objective causality scale revealed that the rash was probably caused by gabapentin. Conclusions: This case, and limited literature data, suggest that gabapentin may cause rash that is severe enough to necessitate discontinuation in a small percentage of children. Further research is needed to determine the actual incidence and severity of gabapentin-related rash in this population.

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Within the wide off-label use of drugs in children, there is a need for proven effectiveness of drugs in children. Although new drugs need to be studied in children as per European and US regulations, new evidence is only very slowly generated because of ethical, financial, and practical barriers to conduct trials in children. Janiaud et al. now challenge the current paradigm that drugs always need to be studied in children and question if data cannot be extrapolated from adults. [...]

From a previously validated paediatric population pharmacokinetic model, it was derived that non-linear morphine maintenance doses of 5 μg/kg1.5/h, with a 50 % dose reduction in neonates with a postnatal age (PNA)

Background Pediatric drug development is hampered by practical, ethical, and scientific challenges. Microdosing is a promising new method to obtain pharmacokinetic data in children with minimal burden and minimal risk. The use of a labeled oral microdose offers the added benefit to study intestinal and hepatic drug disposition in children already receiving an intravenous therapeutic drug dose for clinical reasons. Objective The objective of this study was to present pilot data of an oral [14C]paracetamol [acetaminophen (AAP)] microdosing study as proof of concept to study developmental pharmacokinetics in children. Methods In an open-label microdose pharmacokinetic pilot study, infants (0–6 years of age) received a single oral [14C]AAP microdose (3.3 ng/kg, 60 Bq/kg) in addition to intravenous therapeutic doses of AAP (15 mg/kg intravenous every 6 h). Blood samples were taken from an indwelling catheter. AAP blood concentrations were measured by liquid chromatography–tandem mass spectrometry (LC-MS/MS) and [14C]AAP and metabolites ([14C]AAP-Glu and [14C]AAP-4Sul) were measured by accelerator mass spectrometry. Results Ten infants (aged 0.1–83.1 months) were included; one was excluded as he vomited shortly after administration. In nine patients, [14C]AAP and metabolites in blood samples were detectable at expected concentrations: median (range) maximum concentration (Cmax) [14C]AAP 1.68 (0.75–4.76) ng/L, [14C]AAP-Glu 0.88 (0.34–1.55) ng/L, and [14C]AAP-4Sul 0.81 (0.29–2.10) ng/L. Dose-normalized oral [14C]AAP Cmax approached median intravenous average concentrations (Cav): 8.41 mg/L (3.75–23.78 mg/L) and 8.87 mg/L (3.45–12.9 mg/L), respectively. Conclusions We demonstrate the feasibility of using a [14C]labeled microdose to study AAP pharmacokinetics, including metabolite disposition, in young children. Electronic supplementary material The online version of this article (doi:10.1007/s40262-014-0176-8) contains supplementary material, which is available to authorized users.

Contains fulltext : 137736.pdf (Publisher’s version ) (Open Access) BACKGROUND: In adult patients who are critically ill and mechanically ventilated, daily interruption of sedation (DSI) is an effective method of improving sedation management, resulting in a decrease of the duration of mechanical ventilation, the length of stay in the intensive care unit (ICU) and the length of stay in the hospital. It is a safe and effective approach and is common practice in adult ICUs. For critically ill children it is unknown if DSI is effective and feasible. The aim of this multicenter randomized controlled trial is to evaluate the safety and efficacy of daily sedation interruption in critically ill children. METHODS/DESIGN: Children between 0 and 18 years of age who require mechanical ventilation, with an expected duration of at least 48 h and need for sedative infusion, will be included. After enrollment patients will be randomly assigned to DSI in combination with protocolized sedation (intervention group) or protocolized continuous sedation (control group). A sedation protocol that contains an algorithm for increasing and weaning of sedatives and analgesics will be used. The sedative infusion will be restarted if the patient becomes uncomfortable or agitated according to the sedation protocol. The primary endpoint is the number of ventilator-free days at 28 days. TRIAL REGISTRATION: NTR2030.

Pharmacotherapy in children often consists of oral medication. Effectiveness of oral prescriptions may be influenced by extrinsic (formulation, nutrition, and co-medication) and intrinsic factors (physiological and disease-related variation).

Background and objectives Many children receiving extracorporeal membrane oxygenation develop AKI. If AKI leads to permanent nephron loss, it may increase the risk of developing CKD. The prevalence of CKD and hypertension and its predictive factors during long-term follow-up of children and adolescents previously treated with neonatal extracorporeal membrane oxygenation were determined. Design, setting, participants, & measurements Between November of 2010 and February of 2014, neonatal survivors of extracorporeal membrane oxygenation who visited the prospective follow-up program at 1, 2, 5, 8, 12, and 18 years of age were screened for CKD and hypertension (BP≥95th percentile of reference values). CKD was suspected in children with either an eGFR 0.50 for children ages ≤24 months and >0.20 at >24 months). The RIFLE classification (risk, injury, or failure as 150%, 200%, or 300% of serum creatinine reference values) was used to define AKI during extracorporeal membrane oxygenation without preemptive hemofiltration. Results Median follow-up of 169 screened participants was 8.2 years (interquartile range=5.2–12.1 years). Nine children had a lower eGFR, but all rates were >60 ml/min per 1.73 m2. Proteinuria was observed in 20 children (median=0.26 mg protein/mg creatinine; interquartile range=0.23–0.32 mg protein/mg creatinine), and 32 children had hypertension. Only history of AKI was associated with CKD (P=0.004). Children with RIFLE scores injury and failure had 4.3 times higher odds of CKD signs or hypertension than those without AKI (95% confidence interval, 1.6 to 12.1; P=0.004). Conclusions Altogether, 54 participants (32%) had at least one sign of CKD and/or hypertension. However, most values were marginally abnormal, with no immediate consequences for clinical care. Nevertheless, a prevalence of 32% clearly indicates that survivors of neonatal extracorporeal membrane oxygenation, especially those with AKI, are at risk of a more rapid decline of kidney function with increasing age. Therefore, screening for CKD development in adulthood is recommended.

BACKGROUND:: Both age and CYP3A5 genotype are important determinants of tacrolimus disposition in pediatric kidney transplant recipients. In a recent study in adults, POR*28 was associated with increased dosing requirements early after transplant of CYP3A5-expressing kidney transplant recipients. The authors aimed to evaluate the additional contribution of POR*28 to early tacrolimus disposition in pediatric kidney transplant recipients. METHODS:: Retrospective data of 43 pediatric kidney transplant recipients up to 14 days posttransplant were evaluated on tacrolimus dose and tacrolimus predose blood concentrations. Recipient POR*28 and CYP3A5 genotype were determined. RESULTS:: CYP3A5 expressers carrying at least 1 POR*28 allele had on average 18.3% lower tacrolimus predose concentrations and 20.2% lower concentration/dose ratios compared with CYP3A5 expressers with POR*1/*1 genotype (P = 0.002 and P = 0.001, respectively). In CYP3A5 nonexpressers, tacrolimus disposition did not significantly differ between POR genotypes. CONCLUSIONS:: In this small cohort of pediatric kidney transplant recipients, POR*28 genotype seems to explain part of the variability found in tacrolimus disposition, in addition to age and CYP3A5 genotype. This finding should be validated in a larger population, and it would be worthwhile to evaluate the clinical impact of this genotype.

Despite well-known differences in drug response between children and adults, dosing guidelines for children are usually developed by extrapolating the results from studies in adults. Instead of body weight, insight into the pharmacokinetics and pharmacodynamics of drugs should serve as the basis for dosing in children. In studies into drug dosing in children, the 'population approach' should be chosen to minimize the burden for the child. With a population approach, the covariates that affect the pharmacokinetics and pharmacodynamics of drugs can be identified in a covariate analysis; examples of covariates include body weight, age, degree of illness and genetic factors. Drugs that serve as a model for a specific elimination route provide the basis for individualized dosing guidelines for children.

Major changes in cytochrome P450 (CYP) 3A activity may be expected in the first few months of life with, later, relatively limited changes. In this analysis we studied the maturation of in vivo CYP3A-mediated clearance of midazolam, as model drug, from preterm neonates of 26 weeks gestational age (GA) to adults. Pharmacokinetic data after intravenous administration of midazolam were obtained from six previously reported studies. Subjects were premature neonates (n = 24; GA 26-33.5 weeks, postnatal age (PNA) 3-11 days, and n = 24; GA 26-37 weeks, PNA 0-1 days), 23 children after elective major craniofacial surgery (age 3-23 months), 18 pediatric intensive-care patients (age 2 days-17 years), 18 pediatric oncology patients (age 3-16 years), and 20 healthy male adults (age 20-31 years). Population pharmacokinetic modeling with systematic covariate analysis was performed by use of NONMEM v6.2. Across the entire lifespan from premature neonates to adults, bodyweight was a significant covariate for midazolam clearance. The effect of bodyweight was best described by use of an allometric equation with an exponent changing with bodyweight in an exponential manner from 0.84 for preterm neonates (0.77 kg) to 0.44 for adults (89 kg), showing that the most rapid maturation occurs during the youngest age range. An in-vivo maturation function for midazolam clearance from premature neonates to adults has been developed. This function can be used to derive evidence-based doses for children, and to simulate exposure to midazolam and possibly other CYP3A substrates across the pediatric age range in population pharmacokinetic models or physiologically based pharmacokinetic models.

Renal dysfunction after non-renal transplantation in adult tacrolimus-treated transplant patients is well documented. Little is known about its prevalence in children. Age-related changes in both disposition and effect of tacrolimus as well as renal function may preclude extrapolation of adult data to children. To systematically review the literature on renal dysfunction in non-renal pediatric transplant recipients treated with tacrolimus. PubMed/Medline, Embase, and Google were searched from their inception until April 19, 2012, with the search terms "tacrolimus," "renal function," "transplantation," and "children." Eighteen of 385 retrieved papers were considered relevant. Twelve dealt with liver, four with heart transplant, one with heart and lung transplant, and one with intestinal recipients. Reported prevalences of mild and severe chronic kidney disease ranged from 0% to 39% and 0% to 71.4%, respectively, for liver, and from 22.7% to 40% and 6.8% to 46%, respectively, for heart and/or lung transplant recipients. Ranges remained wide after adjusting for follow-up time and disease severity. Possible explanations are inclusion bias and definitions used for renal dysfunction. A considerable proportion of pediatric non-renal transplant patients who receive tacrolimus-based immunosuppression, appear to suffer from chronic kidney disease. This conclusion warrants further research into the real risk, its risk factors, and individualization of immunosuppressant therapy.

Newborns in need of extracorporeal membrane oxygenation (ECMO) support are at high risk of developing acute kidney injury (AKI). AKI may occur as part of multiple organ failure and can be aggravated by exposure to components of the extracorporeal circuit. AKI necessitates adjustment of dosage of renally eliminated drugs and avoidance of nephrotoxic drugs. We aimed to define systematically the incidence and clinical course of AKI in critically ill neonates receiving ECMO support. This study reviewed prospectively collected clinical data (including age, diagnosis, ECMO course, and serum creatinine (SCr)) of all ECMO-treated neonates within our institution spanning a 14-year period. AKI was defined by using the Risk, Injury, Failure, Loss of renal function, and End-stage renal disease (RIFLE) classification. SCr data were reviewed per ECMO day and compared with age-specific SCr reference values. Accordingly, patients were assigned to RIFLE categories (Risk, Injury, or Failure as 150%, 200%, or 300% of median SCr reference values). Data are presented as median and interquartile range (IQR) or number and percentage. Of 242 patients included, 179 (74%) survived. Median age at the start of ECMO was 39 hours (IQR, 26 to 63); median ECMO duration was 5.8 days (IQR, 3.9 to 9.4). In total, 153 (64%) patients had evidence of AKI, with 72 (30%) qualifying as Risk, 55 (23%) as Injury, and 26 (11%) as Failure. At the end of the study period, only 71 (46%) patients of all 153 AKI patients improved by at least one RIFLE category. With regression analysis, it was found that nitric oxide ventilation (P = 0.04) and younger age at the start of ECMO (P = 0.004) were significant predictors of AKI. Survival until intensive care unit discharge was significantly lower for patients in the Failure category (35%) as compared with the Non-AKI (78%), Risk (82%), and Injury category (76%), with all P < 0.001, whereas no significant differences were found between the three latter RIFLE categories. Two thirds of neonates receiving ECMO had AKI, with a significantly increased mortality risk for patients in the Failure category. As AKI during childhood may predispose to chronic kidney disease in adulthood, long-term monitoring of kidney function after ECMO is warranted.

In children, a large variability in pharmacokinetics of midazolam, a cytochrome P450 3A4/5 (CYP3A4/5) enzyme substrate, has been described, which cannot be explained by age-related changes alone. In this study, these age-related changes are studied in relation to other covariates to explain the variability in the pharmacokinetics of midazolam in children.Population pharmacokinetic modeling was performed using a joint dataset of 3 studies conducted previously: study 1: pediatric intensive care patients requiring sedation in the intensive care unit; study 2: pediatric oncology patients undergoing an invasive procedure; study 3: otherwise healthy infants admitted for postoperative monitoring after elective major craniofacial surgery. Midazolam, 1-hydroxymidazolam, and 1-hydroxymidazolam glucuronide concentrations were considered to determine the pharmacokinetics of midazolam and metabolites using NONMEM 6.2. SimCYP pediatric simulator was used for simulation.Fifty-four children aged between 1 month and 17 years who received intravenous midazolam (bolus and/or continuous infusion) for sedation were included in this study. A reduction of 93% for CYP3A4/5 (midazolam to 1-hydroxymidazolam) and 86% for uridine diphosphate glucuronosyltransferase (1-hydroxymidazolam to 1-hydroxymidazolam glucuronide) mediated clearance was found in pediatric intensive care patients compared with the other 2 patient groups. We did not find a significant influence of age or bodyweight on CYP3A4/5-mediated total clearance. For uridine diphosphate glucuronosyltransferase-mediated clearance, bodyweight explained 41.5% of the variability.From infancy to adolescence, critical illness seems to be a major determinant of midazolam clearance, which may result from reduced CYP3A4/5 activity due to inflammation. This may have important implications for dosing of midazolam and other CYP3A drug substrates in critically ill children.

Cardiopulmonary bypass (CPB) is known to have important effects on the disposition of drugs, which in turn may have important implications for the efficacy and toxicity of drug therapy. These effects constantly change throughout CPB and some continue to exert influence after the patient has been successfully weaned. In children, developmental and disease specific changes in drug disposition and effect also need to be taken into account when studying the effects of CPB. This review will provide an extensive overview of the current literature concerning the mechanisms behind the effects CPB has on pharmacokinetic and pharmacodynamic parameters. Also the effects of CPB on individual anesthetic drugs and sedatives, opioids, neuromuscular blocking agents, antibiotics and miscellaneous medications will be reviewed. Special attention will be paid to the pediatric population.

textabstractOBJECTIVE:: To determine the effect of inflammation and disease severity on midazolam pharmacokinetics (as surrogate marker of cytochrome 3A activity) and pharmacodynamics in critically ill children. DESIGN:: Analysis of prospectively collected pharmacokinetic and pharmacodynamic data from a midazolam study in critically ill children. SETTING:: Pediatric intensive care unit of a university hospital. PATIENTS:: Twenty-one critically ill children who needed midazolam for sedation. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: We determined the relationship between inflammation (using C-reactive protein and leukocyte count as surrogate markers) and disease severity (Pediatric Logistic Organ Dysfunction and Pediatric Risk of Mortality scores) vs. the pharmacokinetics (clearance) and pharmacodynamics (COMFORT score, dose requirement) of midazolam. We found a significant negative correlation between disease severity and midazolam clearance corrected for body weight (r =-0.49, p = .02). Midazolam clearance was significantly lower in children with multiple organ failure (defined as Pediatric Logistic Organ Dysfunction ≥10, n = 11) compared with children without multiple organ failure (Pediatric Logistic Organ Dysfunction

Pediatric pharmacokinetic studies require sampling of biofluids from neonates and children. Limitations on sampling frequency and sample volume complicate the design of these studies. In addition, strict guidelines, designed to guarantee patient safety, are in place. This chapter describes the practical implications of sample collection and their storage, with special focus on the selection of the appropriate type of biofluid and withdrawal technique. In addition, we describe appropriate measures for storage of these specimens, for example, in the context of biobanking, and the requirements on drug assay methods that they pose. Pharmacokinetic studies in children are possible, but they require careful selection of an appropriate sampling method, specimen volume, and assay method. The checklist provided could help prospective researchers with the design of an appropriate study protocol and infrastructure.

This review was conducted to examine the current status of paediatric medicines initiatives across the globe.The authors made a non-systematic descriptive review of current world situation.Two regions, the United States (US) and the European Union (EU), and the World Health Organization (WHO) have introduced strong paediatric initiatives to improve children's health through improving access to better paediatric medicines. The experience from the US initiative indicates that it is possible to stimulate development and study of paediatric medicines and provide important new information for improvement of paediatric therapy. The early results from the EU initiative are similarly encouraging. In Canada, Japan, Australia and other developed countries, specific paediatric medicines initiatives have been less extensive and weaker, with modest results. Disappointingly, current evidence suggests that results from clinical trials outside the US often do not benefit children in the country in which the trials were largely conducted. Pharmaceutical companies that have derived a financial benefit commensurate with the cost of doing the paediatric trials in one country do not seem to be making the results of these trials available to all countries if there is no financial incentive to the company. The WHO campaign 'make medicines child size' has produced substantive accomplishments in building improved foundations to improve mechanisms that will enhance children's access to critical medicines in resource-limited settings. However, practically all of this work has been performed using an amalgamation of short-term funding from a variety of sources as opposed to a sustained, programmatic commitment.Although much still needs to be done, it's clear that with concerted efforts and appropriate resources, change is possible but slow. Retaining and fostering public and political interest in paediatric medicines is challenging, but pivotal for success.

Introduction Approximately 25% of all babies in North America are delivered via Caesarean section (C-section). Though a common surgical procedure, C-section recovery can be painful. Opioids, specifically codeine, are commonly used to ease pain; however, its active metabolite, morphine, passes into breast milk, and may produce unwanted side effects in neonates; therefore, alternatives to opioids are being sought. Reiki is an ancient Japanese form of healing where practitioners transfer healing energy through light touch and positive healing intention. Although 1.2 million Americans use reiki to reduce pain or depression, there is a lack of strong evidence supporting its effectiveness. A recent systematic review showed existing studies to be of poor methodological quality, with the common limitation of lack of blinding. To overcome this issue, the authors used distant reiki to assess its effectiveness in reducing pain following an elective C-section. Methods In this randomised, double-blinded study, women who underwent an elective C-section were allocated to either usual care (control, n=40) or three distant reiki sessions in addition to usual care (n=40). Pain was assessed using a visual analogue scale (VAS). The primary endpoint was the Area Under the VAS-Time Curve (AUC) for days 1–3. Secondary measures included: the proportion of women who required opioid medications and dose consumed, rate of healing and vital signs. Results AUC for pain was not significantly different in the distant reiki and control groups (mean±SD; 212.1±104.7 vs 223.1±117.8; p=0.96). There were no significant differences in opioid consumption or rate of healing; however, the distant reiki group had a significantly lower heart rate (74.3±8.1 bpm vs 79.8±7.9 bpm, p=0.003) and blood pressure (106.4±9.7 mm Hg vs 111.9±11.0 mm Hg, p=0.02) post surgery. Conclusion Distant reiki had no significant effect on pain following an elective C-section. Clinical Trial Registration Number ISRCTN79265996., Article summary Article focus This is the first randomised, double-blinded trial conducted on distant reiki. The focus in on distant reiki's effects on pain after Caesarean section. Special attention was paid to the methods of proper randomisation, patient allocation concealment and blinding. Key messages Our trial suggests that distant reiki had no benefit in reducing patients' postpartum pain over usual care for elective Caesarean section. Strengths and limitations of this study We engaged a highly experienced reiki master to administer distant reiki removing the placebo effect which was present in all other pain trials. In addition, we maintained a high adherence to protocol, successful blinding of the research team, successful randomisation and patient allocation concealment, and diligent data collection with extremely few data points missed. We had good credibility with research participants, as all but 10 women refused to participate. We evaluated other aspects of healing after elective Caesarean section, beyond patients' perceived pain levels, by including the previously developed and published Milestone Questionnaire. A potential limitation was the magnitude of pain on which we were attempting to show an impact. Just as acetaminophen is not suitable as pain medication after Caesarean section, distant reiki may also not be suitable for this magnitude of pain. In addition, since some patients were discharged early, our complete dataset is limited to 48 h, with gaps in data for 16 patients (20%) accounted for by carrying the last pain score forward. To ensure that this method did not distort the results, we also evaluated AUC for pain on day 1 and day 2 individually and found no differences between groups for both these time periods.

Pediatric pharmacokinetic studies require sampling of biofluids from neonates and children. Limitations on sampling frequency and sample volume complicate the design of these studies. In addition, strict guidelines, designed to guarantee patient safety, are in place. This chapter describes the practical implications of sample collection and their storage, with special focus on the selection of the appropriate type of biofluid and withdrawal technique. In addition, we describe appropriate measures for storage of these specimens, for example, in the context of biobanking, and the requirements on drug assay methods that they pose. Pharmacokinetic studies in children are possible, but they require careful selection of an appropriate sampling method, specimen volume, and assay method. The checklist provided could help prospective researchers with the design of an appropriate study protocol and infrastructure.

Objective: To determine the likelihood that recommended doses of acetaminophen are associated with acute liver failure in patients with myopathies. Design: Retrospective analysis. Setting: Level III pediatric intensive care unit. Patients: Two pediatric patients with myopathies and acute liver failure. Clinical Investigations: We determined acetaminophen protein adduct levels, in combination with a literature review and systematic evaluation of the cases, using the Roussel Uclaf Causality Assessment Method for drug-induced liver injury to assess causality between recommended acetaminophen dosing and acute liver failure in two children with myopathies. Main Results: The serum adduct levels were consistent with the values previously reported in children with acute liver injury following acetaminophen overdose. We found four similar cases of acute liver failure in pediatric and adult patients with myopathies following recommended acetaminophen doses in the literature (n = 3) and personal communication (n = 1). The Roussel Uclaf Causality Assessment Method suggested a probable relationship between acetaminophen use at recommended doses and acute liver failure in our myopathy patients. Conclusion: Our data suggest that some patients with myopathies who are receiving recommended doses of acetaminophen may be at increased risk for the development of toxicity resulting in acute liver failure. More studies are needed to corroborate these findings. In the meantime, we would advise physicians to be alert in these patients while taking acetaminophen, especially when critically ill or postoperative. (Crit Care Med 2011; 39:678-682)

Enzymes of the cytochrome P450 system are involved in the metabolism of a broad range of foreign compounds, such as drugs, environmental pollutants, and carcinogens (1). The most abundant enzyme in the human liver is cytochrome P450 3A4 (CYP3A4) (2). This enzyme is involved in the metabolism of >50% of all drugs used in humans (3)(4), and the interindividual differences in the pharmacokinetics of these drugs are thought to be related to variations in CYP3A4 activity (4)(5)(6). These variations may be caused by age and disease-related differences, by drugs inducing or repressing transcription/translation, or by genetic polymorphisms. Although the CYP3A4 gene was initially thought not to be polymorphic, recent reports have described three genetic variants of this gene: CYP3A41B , CYP3A42 , and CYP3A43 (7)(8). The allelic frequency for the CYP3A41B allele, which contains an A(−290)G substitution in the promoter region of CYP3A4 , ranges from 0.0% in Chinese and Japanese Americans to >54% in African Americans (8)(9). American and European Caucasians were reported to have an allelic frequency of ∼4–5% (8)(9)(10)(11). The CYP3A42 allele, which encodes a Ser222Pro change, has an allelic frequency of 2.7% in the white (Finnish) population (8). Because variant alleles that are found in >1% of the population are defined as genetic polymorphisms (12), both the CYP3A41B and the CYP3A42 allele are considered to be genetic polymorphisms of CYP3A4 . In addition, a variant allele found in the DNA of a single Chinese subject contained a T1437C substitution (8). Because this allele, encoding a Met445Thr …

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.

Objectives: To evaluate availability and reliability of pediatric drug dosing guidelines in selected formularies for intensive care patients. Most drugs used in the pediatric intensive care unit are prescribed off-label, often on the guidance of limited information from commonly used drug formularies. Design: Availability of dosing information on prescribed drugs in a Dutch intensive care unit from January 1, 2005 to December 31, 2006 was compared among four selected formularies (Micromedex, Lexi-Comp, Drug Formulary for Children, Drug Doses). Reliability of dosing guidelines was assessed by evaluating labeling status and literature data for the three most (midazolam, acetaminophen, and amoxicillin/clavulanic acid) and the three least (bosentan, ketanserin, and iloprost) prescribed drugs. Measurements and Main Results: The selected formularies covered 68% to 86% of all 257 prescribed drugs. Guidelines differ widely on daily doses per kilogram, dose description, dosing regimen, and age ranges. For the three most prescribed and one of the least prescribed drugs (bosentan), dosing guidelines adequately reflected labeling status and existing (but scarce) literature. No dosing guidelines were available for iloprost, and only one dosing guideline was available for ketanserin. Conclusions: This study shows that four commonly used drug formularies give few and widely differing dosing guidelines for drugs prescribed in the intensive care unit. If guidelines exist, they seem to reflect labeling status (if present) and limited literature available. Findings from this study likely reflect the scarcity of drug studies in this population. Physicians should be aware of the limitations of these formularies for daily practice in this group of vulnerable patients. (Pediatr Crit Care Med 2011; 12:e14-e19)

Reiki is an ancient form of Japanese healing. While this healing method is widely used for a variety of psychologic and physical symptoms, evidence of its effectiveness is scarce and conflicting. The purpose of this systematic review was to try to evaluate whether Reiki produces a significant treatment effect.Studies were identified using an electronic search of Medline, EMBASE, Cochrane Library, and Google Scholar. Quality of reporting was evaluated using a modified CONSORT Criteria for Herbal Interventions, while methodological quality was assessed using the Jadad Quality score.Two (2) researchers selected articles based on the following features: placebo or other adequate control, clinical investigation on humans, intervention using a Reiki practitioner, and published in English. They independently extracted data on study design, inclusion criteria, type of control, sample size, result, and nature of outcome measures.The modified CONSORT Criteria indicated that all 12 trials meeting the inclusion criteria were lacking in at least one of the three key areas of randomization, blinding, and accountability of all patients, indicating a low quality of reporting. Nine (9) of the 12 trials detected a significant therapeutic effect of the Reiki intervention; however, using the Jadad Quality score, 11 of the 12 studies ranked "poor."The serious methodological and reporting limitations of limited existing Reiki studies preclude a definitive conclusion on its effectiveness. High-quality randomized controlled trials are needed to address the effectiveness of Reiki over placebo.

Objective: To describe a potentially fatal adverse drug event after administration of morphine to a term neonate. Case Summary: A 2-day-old term neonate experienced generalized muscle rigidity and laryngeal spasm resulting in acute respiratory failure on 2 separate occasions after morphine administration. The first occasion was after administration of bolus doses of fentanyl and morphine 100 μg/kg in the operating theater; administration of intravenous propofol 2 mg/kg resulted in relief of muscle rigidity. The second occasion occurred a few hours later, when the patient received a continuous infusion of morphine 4.4 μg/kg/h in the intensive care unit and experienced generalized muscle rigidity with respiratory compromise. The opioid antagonist naloxone 30 μg/kg was administered intravenously, which immediately resulted in a patent airway and spontaneous breathing. An objective causality assessment using the Naranjo probability scale revealed that the likelihood of morphine causing the patient's muscle rigidity on the second occasion was highly probable to definite. It is not clear whether the first occurrence of muscle rigidity was morphine-induced. Discussion: We searched PubMed and EMBASE (through August 2009) for previous reports of morphine-related muscle rigidity and/or laryngeal spasm, using the search terms (muscle rigidity OR chest rigidity OR laryngeal spasm) AND (morphine OR fentanyl OR opioid). Sudden onset of muscle rigidity and laryngeal spasm is described in the literature as a rare but serious adverse event after infusion of fentanyl and similar opioids in both adults and young infants. However, there are no reports of this potentially fatal adverse event after administration of morphine. To our knowledge this is the first case reported of life-threatening muscle rigidity and laryngeal spasm after therapeutic doses of morphine in humans. Conclusions: A serious adverse event consisting of generalized muscle rigidity and laryngospasm can occur after bolus administration of morphine as well as during continuous infusion. Clinicians should be aware of this possibility.