M. de Hoog

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.

Randomized controlled trial of daily interruption of sedatives in critically ill children.

To study the feasibility of daily interruption of sedatives in critically ill children.

Sevoflurane therapy for life-threatening asthma in children

BACKGROUND Asthma is a common disease in children and often develops early in life. This multicentre retrospective case series describe the use and effectiveness of sevoflurane inhalation therapy in a series of children with severe asthma in the paediatric intensive care unit (PICU). METHODS Seven children ranging from 4 to 13 yr of age admitted to the PICU of two tertiary care hospitals in the Netherlands were included. They all were admitted with the diagnosis of severe asthma requiring invasive mechanical ventilation and were treated with sevoflurane inhalation therapy. RESULTS The median (range) Pco2 level at the start, after 2 h, and at the end of sevoflurane treatment were 14 (5.1-24.8), 9.8 (5.4-17.0), and 6.2 (4.5-11.4) kPa (P=0.05) while the median (range) pH was 7.02 (6.97-7.36), 7.18 (7.04-7.35), and 7.43 (7.15-7.47) kPa (P=0.01), respectively. The median (range) peak pressure values declined from 30 (23-56) to 20.4 (14-33) cm H2O (P=0.03). No severe adverse effects besides hypotension, with sufficient response to norepinephrine treatment, were seen. CONCLUSIONS Sevoflurane inhalation corrects high levels of Pco2 and provides clinical improvement in mechanically ventilated children with life-threatening asthma who fail to respond to conventional treatment.

Life Threatening Central Nervous System Manifestations and Hypothermia due to Maneb Intoxication in a Child: A Case Report

Abstract: Maneb, manganese ethylene-bis-dithiocarbamate, is a fungicide pesticide used in the agriculture and bulb flower culture sector. Toxicological effects for humans have been reported in literature and are diverse.1-4 They vary from allergic reactions (dermatitis, conjunctivitis, and bronchitis), central nervous system effects (muscarinic, nicotinic, central and extrapyramidal) and renal toxicity (acute renal failure). A 7-year old girl was admitted to the pediatric intensive care unit because of status epilepticus. Physical examination showed respiratory insufficiency, convulsions, and severe hypothermia (32.5°C). The patient was intubated and her convulsions were successfully treated with benzodiazepines. Except for a combined metabolic and respiratory acidosis and hyperglycemia, diagnostic investigations on admission (full blood count, electrolytes, liver and renal functions, cerebrospinal fluid investigation, toxicology screening of blood and urine for barbiturates and benzodiazepines, blood culture, herpes PCR, and a CT scan of the brain) were normal. Within 24 hours, there was a complete recovery of all neurological signs. Within 72 hours, the patient was discharged from the hospital. Liquid chromatography-mass spectrometric investigation of her blood showed amounts of maneb, which can explain all symptoms and signs. However, effects of this magnitude on the central nervous system have not previously been reported in humans.

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.

Adverse drug reactions of haloperidol used in critically ill children for the treatment of delirium

Clinical Pharmacology & Therapeutics (2013) 93, S88–S122. doi:10.1038/clpt.2012.258

Abstract P-589: INTRAVENOUS SALBUTAMOL IN SEVERE ACUTE ASTHMA OUTSIDE THE PICU - YES WE CAN!

Data were collected on all children referred to a regional PICU transport service with the clinical diagnosis of bronchiolitis (< 1 year if age) during the winter prior to the guideline consultation period (2011–2012) and during the winter after publication (2015–2016). Children with previous episode of wheeze were excluded. Management initiated by the referring hospital with regard to nebulised medication was assessed.

419 Sevoflurane Therapy for Life Threatening Asthma in Children

Background Severe asthma is treated with bronchodilators like salbutamol, corticosteroids, magnesium sulphate, and if necessary mechanical ventilation. If these options fail, volatile anesthetic agents can be used. This is the first multicentre case series that describes the effectiveness of sevoflurane therapy in children with life-threatening asthma. Methods Pediatric patients admitted to the pediatric intensive care unit (PICU) with severe asthma and sevoflurane treatment were included. A retrospective review of demographic, medical, laboratory and ventilation parameters was performed. Results 7 children from two PICU’s in the Netherlands with age ranging from 4 to 13 years were included. The mean length of PICU stay was 6.7 days (range 3–10). Mean (range) dose of sevoflurane and duration of treatment were 2.2% (1–4%) and 24h (0.5–90h). Mean (range) pH at the beginning and at the end of sevoflurane treatment were 7.11 (6.97–7.36) and 7.35 (7.15–7.47)kPa (p<0.01). Mean (range) pCO2 were respectively 14.3 (5.1–24.8) and 7.1 (4.5–11.4)kPa (p<0.05). Mean (range) peak pressure declined from 33 (23–56) to 22 (14–33) cmH2O (p<0.03). Four patients developed hypotension, which was successfully treated with norepinephrine. One patient (dotted line figure), was afterwards judged to suffer from ARDS and indeed failed to respond to sevoflurane therapy. Conclusion Mechanical ventilation with Sevoflurane inhalation is a safe and effective treatment for children with life-threatening asthma. Abstract 419 Figure 1 pCO2 before and after sevofl urane treatment