The effect of critical illness and inflammation on midazolam therapy in children*

Vet, Nienke J.; Hoog, Matthijs de; Tibboel, Dick; Wildt, Saskia N. de

doi:10.1097/pcc.0b013e3181fe406d

Cited by 36 publications

(31 citation statements)

References 12 publications

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“…Simulations using a physiology-based PK model suggested a major impact of reduced CYP3A4 and 3A5 enzyme abundance on the midazolam clearance. These results were confirmed by another study by Vet et al (2012), in which a reduced midazolam clearance was observed with increasing critical illness in children on the pediatric intensive care unit. The authors suggested that a reduced CYP3A activity could be the cause for the reduced midazolam clearance.…”

Section: Discussionsupporting

confidence: 79%

In Vitro Cytochrome P450 Activity Decreases in Children with High Pediatric End-Stage Liver Disease Scores

et al. 2012

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To improve the modeling and simulation of pharmacokinetics in pediatric patients, research into developmental and disease-specific determinants is needed. This article describes the evaluation of the activity of in vitro cytochrome P450 (P450), an important enzyme family in drug metabolism, in children with hepatic dysfunction. The activity of six P450 isoforms (CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4) was evaluated in 31 patients with different pathologies, predominantly biliary atresia (n = 23). Hypervariable activity was observed for all the isoforms. Compared with average adult activity, low activity levels were seen for CYP1A2, 2C19, 2E1, and 3A4. For CYP2E1 and 3A4, a positive correlation between activity and abundance was observed. Age, comedication, and genotype could not be used as predictors for P450 activity in this patient population. In contrast, the pediatric end-stage liver disease score was negatively correlated with the ln(activity). This finding suggests a decrease in P450 activity with deteriorating hepatic function. Moreover, the activity of all isoforms was correlated, demonstrating a concomitant decrease of all isoforms in young patients with liver disease. To our knowledge, this is the first study to evaluate P450 activity in children with hepatic impairment. The presented data may provide support in the further optimization of a diseasespecific model in this patient population.

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Section: Discussionsupporting

confidence: 79%

In Vitro Cytochrome P450 Activity Decreases in Children with High Pediatric End-Stage Liver Disease Scores

et al. 2012

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“…Inflammation has been shown to affect drug metabolism and transport. Decreased midazolam clearance in critically ill children is likely a result of reduced CYP3A activity (Vet et al, 2012). Inconsistency has been reported from studies assessing the effect of proinflammatory cytokines on intestinal MDR1 expression in vitro and in animal models, but they suggest a trend toward decreased expression (Fernandez et al, 2004).…”

Section: Discussionmentioning

confidence: 75%

Ontogeny of Human Hepatic and Intestinal Transporter Gene Expression during Childhood: Age Matters

et al. 2014

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Many drugs prescribed to children are drug transporter substrates. Drug transporters are membrane-bound proteins that mediate the cellular uptake or efflux of drugs and are important to drug absorption and elimination. Very limited data are available on the effect of age on transporter expression. Our study assessed agerelated gene expression of hepatic and intestinal drug transporters. Multidrug resistance protein 2 (MRP2), organic anion transporting polypeptide 1B1 (OATP1B1), and OATP1B3 expression was determined in postmortem liver samples (fetal n = 6, neonatal n = 19, infant n = 7, child n = 2, adult n = 11) and multidrug resistance 1 (MDR1) expression in 61 pediatric liver samples. Intestinal expression of MDR1, MRP2, and OATP2B1 was determined in surgical small bowel samples (neonates n = 15, infants n = 3, adults n = 14). Using real-time reverse-transcription polymerase chain reaction, we measured fetal and pediatric gene expression relative to 18S rRNA (liver) and villin (intestines), and we compared it with adults using the 2 2ΔΔCt method. Hepatic expression of MRP2, OATP1B1, and OATP1B3 in all pediatric age groups was significantly lower than in adults. Hepatic MDR1 mRNA expression in fetuses, neonates, and infants was significantly lower than in adults. Neonatal intestinal expressions of MDR1 and MRP2 were comparable to those in adults. Intestinal OATP2B1 expression in neonates was significantly higher than in adults. We provide new data that show organ-and transporter-dependent differences in hepatic and intestinal drug transporter expression in an age-dependent fashion. This suggests that substrate drug absorption mediated by these transporters may be subject to age-related variation in a transporter dependent pattern.

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“…Changes in pharmacokinetics due to critical illness can include a slower metabolism or renal excretion, caused by an impaired hepatic or renal function, or an altered midazolam distribution due to decreased albumin binding and an increased volume of distribution due to oedema or sepsis [64]. Also, although less clear, pharmacodynamics can be altered during critical illness, manifesting itself in more side effects or more difficulties in achieving therapeutic effect.…”

Section: Future Research Topicsmentioning

confidence: 95%

Growing up with Midazolam in the Neonatal and Pediatric Intensive Care

Swart

Slort²,

Plötz³

2012

CDM

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A variety of developmental changes is of influence on the pharmacokinetics and pharmacodynamics of midazolam in neonatal and pediatric intensive care patients. However, dosing regimens in children are based upon rather empirical extrapolations from the dosing regimens in adults. Based on current available studies it appears that with the rising of age, the pharmacokinetics of intravenously administered midazolam alter, resulting in a shorter half-life due to a higher hepatic clearance in older children as compared to newborn. Also, with the rising of age, the pharmacodynamics of intravenously administered midazolam may alter due to a decrease in density of receptors, possibly leading to a decreased clinical response. These findings implicate opposite effects and it is uncertain which of these effects are predominant. In conclusion, there is a large interindividual variability in the response to midazolam in children, which may be caused by differences in pharmacokinetics and pharmacodynamics. Both are subject to considerable developmental changes. It remains remarkable that high-quality evidence to support the use of midazolam for continuous sedation in the neonatal and pediatric intensive care setting is lacking.

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The effect of critical illness and inflammation on midazolam therapy in children*

Cited by 36 publications

References 12 publications

In Vitro Cytochrome P450 Activity Decreases in Children with High Pediatric End-Stage Liver Disease Scores

In Vitro Cytochrome P450 Activity Decreases in Children with High Pediatric End-Stage Liver Disease Scores

Ontogeny of Human Hepatic and Intestinal Transporter Gene Expression during Childhood: Age Matters

Growing up with Midazolam in the Neonatal and Pediatric Intensive Care

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