Dataset Information

Predicting CYP3A-mediated midazolam metabolism in critically ill neonates, infants, children and adults with inflammation and organ failure.

ABSTRACT:

Aims

Inflammation and organ failure have been reported to have an impact on cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed population pharmacokinetic model both in critically ill children and other populations, in order to allow the model to be used to guide dosing in clinical practice.

Methods

The model was evaluated externally in 136 individuals, including (pre)term neonates, infants, children and adults (body weight 0.77-90 kg, C-reactive protein level 0.1-341 mg l^-1 and 0-4 failing organs) using graphical and numerical diagnostics.

Results

The pharmacokinetic model predicted midazolam clearance and plasma concentrations without bias in postoperative or critically ill paediatric patients and term neonates [median prediction error (MPE) <30%]. Using the model for extrapolation resulted in well-predicted clearance values in critically ill and healthy adults (MPE <30%), while clearance in preterm neonates was over predicted (MPE >180%).

Conclusion

The recently published pharmacokinetic model for midazolam, quantifying the influence of maturation, inflammation and organ failure in children, yields unbiased clearance predictions and can therefore be used for dosing instructions in term neonates, children and adults with varying levels of critical illness, including healthy adults, but not for extrapolation to preterm neonates.

SUBMITTER: Brussee JM

PROVIDER: S-EPMC5777436 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Predicting CYP3A-mediated midazolam metabolism in critically ill neonates, infants, children and adults with inflammation and organ failure.

Brussee Janneke M JM Vet Nienke J NJ Krekels Elke H J EHJ Valkenburg Abraham J AJ Jacqz-Aigrain Evelyne E van Gerven Joop M A JMA Swart Eleonora L EL van den Anker Johannes N JN Tibboel Dick D de Hoog Matthijs M de Wildt Saskia N SN Knibbe Catherijne A J CAJ

British journal of clinical pharmacology 20171129 2

<h4>Aims</h4>Inflammation and organ failure have been reported to have an impact on cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed population pharmacokinetic model both in critically ill children and other populations, in order to allow the model to be used to guide dosing in clinical practice.<h4>Methods</h4>The model was evaluated externally in 136 individuals, including (pre)term neonates, infants, children a ...[more]

PMID: 29072785

Similar Datasets

Project description:ObjectivesTo determine clinician accuracy in the identification and prediction of multiple organ dysfunction syndrome.DesignProspective cohort study.SettingUniversity of Michigan's C.S. Mott Children's Hospital PICU.PatientsPatients admitted to the PICU with an anticipated PICU length of stay greater than 48 hours.InterventionsNone.Measurements and main resultsFor each patient, the clinical team (attending, fellow, resident/nurse practitioner) was surveyed regarding existing and anticipated organ dysfunction. The primary outcomes were clinicians' accuracy at identifying multiple organ dysfunction syndrome and predicting new or progressive multiple organ dysfunction syndrome, compared to the objective assessment of multiple organ dysfunction syndrome using Proulx criteria. We also measured sensitivity, specificity, negative and positive predictive values, and negative and positive likelihood ratios of clinician assessments. We tested for differences in accuracy by clinician type using chi-square tests. Clinicians rated their confidence in prediction on a 5-point Likert scale. There were 476 eligible PICU admissions, for whom 1,218 surveys were completed. Multiple organ dysfunction syndrome was present in 89 patients (18.7%) at enrollment, and new or progressive multiple organ dysfunction syndrome occurred in 39 (8.2%). Clinicians correctly identified multiple organ dysfunction syndrome with 79.9% accuracy and predicted additional organ dysfunction with 82.6% accuracy. However, the positive and negative likelihood ratios for new or progressive multiple organ dysfunction syndrome prediction were 3.0 and 0.7, respectively, indicating a weak relationship between the clinician prediction and development of new or progressive multiple organ dysfunction syndrome. The positive predictive value of new or progressive multiple organ dysfunction syndrome prediction was just 22.1%. We found no differences in accuracy by clinician type for either identification of multiple organ dysfunction syndrome (80.2% vs 78.2% vs 81.0%; p = 0.57) or prediction of new or progressive multiple organ dysfunction syndrome (84.8% vs 82.8% vs 80.3%; p = 0.26) for attendings, fellows, and residents/nurse practitioners, respectively. There was a weak correlation between the confidence and accuracy of prediction (pairwise correlation coefficient, 0.26; p < 0.001).ConclusionsPICU clinicians correctly identified multiple organ dysfunction syndrome and predicted new or progressive multiple organ dysfunction syndrome with 80% accuracy. However, only 8% of patients developed new or progressive multiple organ dysfunction syndrome, so accuracy was largely due to true negative predictions. The positive predictive value for new or progressive multiple organ dysfunction syndrome prediction was just 22%. Accuracy did not differ by clinician type, but was correlated with self-rated confidence and was higher for negative predictions.

Project description:ObjectivesTo develop a pharmacokinetic-pharmacogenomic population model of midazolam in critically ill children with primary respiratory failure.DesignProspective pharmacokinetic-pharmacogenomic observational study.SettingThirteen PICUs across the United States.PatientsPediatric subjects mechanically ventilated for acute respiratory failure, weight greater than or equal to 7 kg, receiving morphine and/or midazolam continuous infusions.InterventionsSerial blood sampling for drug quantification and a single blood collection for genomic evaluation.Measurements and main resultsConcentrations of midazolam, the 1' (1`-hydroxymidazolam metabolite) and 4' (4`-hydroxymidazolam metabolite) hydroxyl, and the 1' and 4' glucuronide metabolites were measured. Subjects were genotyped using the Illumina HumanOmniExpress genome-wide single nucleotide polymorphism chip. Nonlinear mixed effects modeling was performed to develop the pharmacokinetic-pharmacogenomic model. Body weight, age, hepatic and renal functions, and the UGT2B7 rs62298861 polymorphism are relevant predictors of midazolam pharmacokinetic variables. The estimated midazolam clearance was 0.61 L/min/70kg. Time to reach 50% complete mature midazolam and 1`-hydroxymidazolam metabolite/4`-hydroxymidazolam metabolite clearances was 1.0 and 0.97 years postmenstrual age. The final model suggested a decrease in midazolam clearance with increase in alanine transaminase and a lower clearance of the glucuronide metabolites with a renal dysfunction. In the pharmacogenomic analysis, rs62298861 and rs28365062 in the UGT2B7 gene were in high linkage disequilibrium. Minor alleles were associated with a higher 1`-hydroxymidazolam metabolite clearance in Caucasians. In the pharmacokinetic-pharmacogenomic model, clearance was expected to increase by 10% in heterozygous and 20% in homozygous for the minor allele with respect to homozygous for the major allele.ConclusionsThis work leveraged available knowledge on nonheritable and heritable factors affecting midazolam pharmacokinetic in pediatric subjects with primary respiratory failure requiring mechanical ventilation, providing the basis for a future implementation of an individual-based approach to sedation.

Project description:BackgroundPrevalence of multiple organ failure (MOF) in critically ill patients is increasing and associated mortality remains high. Extracorporeal organ support is a cornerstone in the management of MOF. We report data of an advanced hemodialysis system based on albumin dialysis (ADVOS multi device) that can regulate acid-base balance in addition to the established properties of renal replacement therapy and albumin dialysis systems in critically ill patients with MOF.Methods34 critically ill patients with MOF received 102 ADVOS treatment sessions in the Department of Intensive Care Medicine of the University Medical Center Hamburg-Eppendorf. Markers of metabolic detoxification and acid-base regulation were collected and blood gas analyses were performed. A subgroup analyses were performed in patients with severe acidemia (pH < 7.2).ResultsMedian number of treatment sessions was 2 (range 1-9) per patient. Median duration of treatment was 17.5 (IQR 11-23) hours per session. Treatment with the ADVOS multi-albumin dialysis device caused a significant decrease in bilirubin levels, serum creatinine, BUN and ammonia levels. The relative elimination rate of bilirubin was concentration dependent. Furthermore, a significant improvement in blood pH, HCO3- and PaCO2, was achieved during ADVOS treatment including six patients that suffered from severe metabolic acidosis refractory to continuous renal replacement therapy. Delta pH, HCO3- and PaCO2 were significantly affected by the ADVOS blood flow rate and pH settings. This improvement in the clinical course during ADVOS treatments allowed a reduction in norepinephrine during ADVOS therapy. Treatments were well tolerated. Mortality rates were 50% and 62% for 28 and 90 days, respectively.ConclusionsIn this case series in patients with MOF, ADVOS was able to eliminate water-soluble and albumin-bound substances. Furthermore, the device corrected severe metabolic and respiratory acid-base disequilibrium. No major adverse events associated with the ADVOS treatments were observed.

Project description:ImportanceUnplanned extubations (UEs) in children contribute to significant morbidity and mortality, with an arbitrary benchmark target of less than 1 UE per 100 ventilator days. However, there have been no multicenter initiatives to reduce these events.ObjectiveTo determine if a multicenter quality improvement initiative targeting all intubated neonatal and pediatric patients is associated with a reduction in UEs and morbidity associated with UE events.Design, setting, and participantsThis multicenter quality improvement initiative enrolled patients from pediatric, neonatal, and cardiac intensive care units (ICUs) in 43 participating children's hospitals from March 2016 to December 2018. All patients with an endotracheal tube requiring mechanical ventilation were included in the study.InterventionsParticipating hospitals implemented a quality improvement bundle to reduce UEs, which included standardized anatomic reference points and securement methods, protocol for high-risk situations, and multidisciplinary apparent cause analyses.Main outcomes and measuresThe main outcome measures for this study included bundle compliance with each factor tested and UE rates on the center level and on the cohort level.ResultsAmong the 43 children's hospitals, the quality improvement initiative was associated with an aggregate 24.1% reduction in UE events, from a baseline rate of 1.135 UEs per 100 ventilator days to 0.862 UEs per 100 ventilator days. Across ICU settings studied, the pediatric ICU and neonatal ICU demonstrated centerline shifts, with an absolute reduction in events of 20.6% (from a baseline rate of 0.729 UEs per 100 ventilator days to 0.579 UEs per 100 ventilator days) and 17.6% (from a baseline rate of 1.555 UEs per 100 ventilator days to 1.282 UEs per 100 ventilator days), respectively. Most UEs required reintubation within 1 hour (mean of 120 of 206 events per month [58.3%]), followed by UEs that did not require reintubation (mean of 78 of 206 events per month [37.9%]) and UEs that resulted in cardiovascular collapse (mean of 8 of 206 events per month [3.9%]). Cardiovascular collapse events represented the most significant consequence of UE studied, and the collaborative reduced these UE events by 36.6%, from a study baseline rate of 0.041 UEs per 100 ventilator days to 0.026 UEs per 100 ventilator days.Conclusions and relevanceThis multicenter quality improvement initiative was associated with a reduction in UEs across different pediatric populations in diverse settings. A significant reduction in event rate and rate of harm (cardiovascular collapse) was observed, which was sustained over the time course of the intervention. This quality improvement process and UE bundle may be considered standard of care for pediatric hospitals in the future.

Dataset Information

Predicting CYP3A-mediated midazolam metabolism in critically ill neonates, infants, children and adults with inflammation and organ failure.

Aims

Methods

Results

Conclusion

Publications

Predicting CYP3A-mediated midazolam metabolism in critically ill neonates, infants, children and adults with inflammation and organ failure.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets