S.N. de Wildt

Population pharmacokinetics and metabolism of midazolam in pediatric intensive care patients

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

Pharmacokinetics and metabolism of intravenous midazolam in preterm infants.

Midazolam, a benzodiazepine, is finding expanded use in neonatal intensive care units. We studied the pharmacokinetics and metabolism of midazolam after a single intravenous dose in preterm infants.

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

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

Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development

A number of drivers and developments suggest that microdosing and other phase 0 applications will experience increased utilization in the near-to-medium future. Increasing costs of drug development and ethical concerns about the risks of exposing humans and animals to novel chemical entities are important drivers in favor of these approaches, and can be expected only to increase in their relevance. An increasing body of research supports the validity of extrapolation from the limited drug exposure of phase 0 approaches to the full, therapeutic exposure, with modeling and simulations capable of extrapolating even non-linear scenarios. An increasing number of applications and design options demonstrate the versatility and flexibility these approaches offer to drug developers including the study of PK, bioavailability, DDI, and mechanistic PD effects. PET microdosing allows study of target localization, PK and receptor binding and occupancy, while Intra-Target Microdosing (ITM) allows study of local therapeutic-level acute PD coupled with systemic microdose-level exposure. Applications in vulnerable populations and extreme environments are attractive due to the unique risks of pharmacotherapy and increasing unmet healthcare needs. All phase 0 approaches depend on the validity of extrapolation from the limited-exposure scenario to the full exposure of therapeutic intent, but in the final analysis the potential for controlled human data to reduce uncertainty about drug properties is bound to be a valuable addition to the drug development process.

Pediatric microdose and microtracer studies using 14C in Europe

Important information gaps remain on the efficacy and safety of drugs in children. Pediatric drug development encounters several ethical, practical, and scientific challenges. One barrier to the evaluation of medicines for children is a lack of innovative methodologies that have been adapted to the needs of children. This article presents our successful experience of pediatric microdose and microtracer studies using 14C‐labeled probes in Europe to illustrate the strengths and limitations of these approaches.

The use of dipyrone (metamizol) as an analgesic in children: What is the evidence? A review

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.

Clonidine as a First-Line Sedative Agent After Neonatal Cardiac Surgery: Retrospective Cohort Study.

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 &mgr;g/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.

Short-Term Health-Related Quality of Life of Critically Ill Children Following Daily Sedation Interruption

Objective: Our earlier pediatric daily sedation interruption trial showed that daily sedation interruption in addition to protocolized sedation in critically ill children does not reduce duration of mechanical ventilation, length of stay, or amounts of sedative drugs administered when compared with protocolized sedation only, but undersedation was more frequent in the daily sedation interruption + protocolized sedation group. We now report the preplanned analysis comparing short-term health-related quality of life and posttraumatic stress symptoms between the two groups. Design: Preplanned prospective part of a randomized controlled trial. Setting: Two tertiary medical-surgical PICUs in the Netherlands. Patients: Critically ill children requiring mechanical ventilation. Interventions: None. Measurements and Main Results: Eight weeks after a child’s discharge from the PICU, health-related quality of life was assessed with the validated Child Health Questionnaire and, only for children above 4 years old, posttraumatic stress was assessed with the Dutch Children’s Responses to Trauma Inventory. Additionally, health-related quality of life of all study patients was compared with Dutch normative data. Of the 113 patients from two participating centers in the original study, 96 patients were eligible for follow-up and 64 patients were included (response rate, 67%). No difference was found with respect to health-related quality of life between the two study groups. None of the eight children more than 4 years old showed posttraumatic stress symptoms. Conclusions: Daily sedation interruption in addition to protocolized sedation for critically ill children did not seem to have an effect on short-term health-related quality of life. Also in view of the earlier found absence of effect on clinical outcome, we cannot recommend the use of daily sedation interruption + protocolized sedation.

The research gap in chronic paediatric pain: A systematic review of randomised controlled trials

Chronic pain is associated with significant functional and social impairment. The objective of this review was to assess the characteristics and quality of randomized controlled trials (RCTs) evaluating pain management interventions in children and adolescents with chronic pain.

A Comparative Analysis of Preemptive Versus Targeted Sedation on Cardiovascular Stability After High-Risk Cardiac Surgery in Infants.

Objective: To compare the effect of two sedation practices on cardiovascular stability during the early postoperative period in young infants following cardiac surgery: the routine early use of midazolam infusion (preemptive sedation) and the discretionary use of sedatives tailored to the patient’s clinical condition (targeted sedation). Design: Retrospective cohort study with matched controls. Setting: A 15-bedded pediatric cardiac ICU. Patients: Sedation strategies were compared by matching patients before and after the introduction of a targeted sedation guideline, replacing the existing practice of preemptive sedation. Inclusion criteria were age less than 6 months and cardiopulmonary bypass time greater than 150 minutes. Matching criteria were surgical procedure, age, and duration of cardiopulmonary bypass and cross-clamp. The main outcome was cardiovascular instability, defined by the presence of one of the following criteria in the first 12 hours after PICU admission: 1) simultaneous administration of greater than or equal to two inotropic or vasopressor drugs; 2) administration of greater than 60 mL/kg fluid boluses. Secondary outcomes were: 1) markers of cardiac output adequacy (heart rate, blood pressure, vasoactive inotropic score, urine output, volume of fluid boluses, central venous oxygen saturation, lactate); 2) occurrence of adverse events (cardiac arrest, extracorporeal membrane oxygenation, death); 3) sedatives administered and depth of sedation. Interventions: Introduction of a guideline of targeted sedation. Measurements and Main Results: Thirty-three patients with preemptive sedation were matched to 33 patients with targeted sedation. Targeted sedation resulted in less frequent oversedation, without compromising cardiovascular stability, as indicated by similar occurrence of cardiovascular instability (68.8% with preemptive sedation vs 62.5% with targeted sedation; p = 0.53) and adverse events, and similar markers of cardiac output adequacy. Although all preemptively sedated patients received an infusion of midazolam in the first 12 hours after surgery, only 19.4% of patients in the targeted sedation group received a sedative infusion (p < 0.001). Conclusions: Our data suggest that after high-risk cardiac surgery in young infants, routine sedation with midazolam may not prevent low cardiac output syndrome. When accompanied by a careful assessment of level of sedation, routine sedation of infants after high-risk cardiac surgery can be avoided without compromising hemodynamic stability or patient safety. The potential benefit of this approach is reduced exposure to sedative.