Midazolam Dose Optimization in Critically Ill Pediatric Patients With Acute Respiratory Failure: A Population Pharmacokinetic-Pharmacogenomic Study

Zuppa, Athena F.; Conrado, Daniela J.; Zane, Nicole R.; Curley, Martha A. Q.; Bradfield, Jonathan P.; Hákonarson, Hákon; Gastonguay, Madeleine S; Moorthy, Ganesh S.; Prodell, Janice L.; Gastonguay, Marc R.

doi:10.1097/ccm.0000000000003638

Cited by 13 publications

(12 citation statements)

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“…Such frequent use of esketamine as a substance rarely used in modern intensive care was similarly found in another study [2]. For effective sedation with midazolam, a mean dosage of 0.15 (±0.1) mg�kg -1 �h -1 was found necessary in several studies [31][32][33][34]. In our patient cohort, midazolam was used at a similar mean dosage 0.14 (±0.10) mg�kg -1 �h -1 to obtain prescribed sedation.…”

Section: Plos Onesupporting

confidence: 77%

High sedation needs of critically ill COVID-19 ARDS patients—A monocentric observational study

et al. 2021

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Background Therapy of severely affected coronavirus patient, requiring intubation and sedation is still challenging. Recently, difficulties in sedating these patients have been discussed. This study aims to describe sedation practices in patients with 2019 coronavirus disease (COVID-19)-induced acute respiratory distress syndrome (ARDS). Methods We performed a retrospective monocentric analysis of sedation regimens in critically ill intubated patients with respiratory failure who required sedation in our mixed 32-bed university intensive care unit. All mechanically ventilated adults with COVID-19-induced ARDS requiring continuously infused sedative therapy admitted between April 4, 2020, and June 30, 2020 were included. We recorded demographic data, sedative dosages, prone positioning, sedation levels and duration. Descriptive data analysis was performed; for additional analysis, a logistic regression with mixed effect was used. Results In total, 56 patients (mean age 67 (±14) years) were included. The mean observed sedation period was 224 (±139) hours. To achieve the prescribed sedation level, we observed the need for two or three sedatives in 48.7% and 12.8% of the cases, respectively. In cases with a triple sedation regimen, the combination of clonidine, esketamine and midazolam was observed in most cases (75.7%). Analgesia was achieved using sufentanil in 98.6% of the cases. The analysis showed that the majority of COVID-19 patients required an unusually high sedation dose compared to those available in the literature. Conclusion The global pandemic continues to affect patients severely requiring ventilation and sedation, but optimal sedation strategies are still lacking. The findings of our observation suggest unusual high dosages of sedatives in mechanically ventilated patients with COVID-19. Prescribed sedation levels appear to be achievable only with several combinations of sedatives in most critically ill patients suffering from COVID-19-induced ARDS and a potential association to the often required sophisticated critical care including prone positioning and ECMO treatment seems conceivable.

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Section: Plos Onesupporting

confidence: 77%

High sedation needs of critically ill COVID-19 ARDS patients—A monocentric observational study

et al. 2021

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“…The majority of the 4-OH-midazolam concentrations were below the LLQ (2 ng/mL). The reported metabolic conversion fraction of midazolam to 4-OH-midazolam is 0.03 (19). It is understandable; therefore, that in view of the relatively low midazolam doses in this study, most of the 4-OH-midazolam concentrations were below the LLQ.…”

Section: Pharmacokinetics Of Midazolam After Cardiac Surgerymentioning

confidence: 60%

Sedation With Midazolam After Cardiac Surgery in Children With and Without Down Syndrome: A Pharmacokinetic-Pharmacodynamic Study

Valkenburg

Goulooze

Breatnach

et al. 2020

Pediatric Critical Care Medicine

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To compare the pharmacokinetics and pharmacodynamics of IV midazolam after cardiac surgery between children with and without Down syndrome. DESIGN: Prospective, single-center observational trial. SETTING: PICU in a university-affiliated pediatric teaching hospital.PATIENTS: Twenty-one children with Down syndrome and 17 without, 3-36 months, scheduled for cardiac surgery with cardiopulmonary bypass. INTERVENTIONS:Postoperatively, nurses regularly assessed the children's pain and discomfort with the validated COMFORT-Behavioral scale and Numeric Rating Scale for pain. A loading dose of morphine (100 µg/ kg) was administered after coming off bypass; thereafter, morphine infusion was commenced at 40 µg/kg/hr. Midazolam was started if COMFORT-Behavioral scale score of greater than 16 and Numeric Rating Scale score of less than 4 (suggestive of undersedation). Plasma midazolam and metabolite concentrations were measured for population pharmacokineticand pharmacodynamic analysis using nonlinear mixed effects modeling (NONMEM) (Version VI; GloboMax LLC, Hanover, MD) software. MEASUREMENTS AND MAIN RESULTS:Twenty-six children (72%) required midazolam postoperatively (15 with Down syndrome and 11 without; p = 1.00). Neither the cumulative midazolam dose (p = 0.61) nor the time elapsed before additional sedation was initiated (p = 0.71), statistically significantly differed between children with and without Down syndrome. Population pharmacokinetic and pharmacodynamics analysis revealed no statistically significant differences between the children with and without Down syndrome. Bodyweight was a significant covariate for the clearance of 1-OH-midazolam to 1-OH-glucuronide (p = 0.003). Pharmacodynamic analysis revealed a marginal effect of the midazolam concentration on the COMFORT-Behavioral score. CONCLUSIONS:The majority of children with and without Down syndrome required additional sedation after cardiac surgery. This pharmacokinetic and pharmacodynamic analysis does not provide evidence for different dosing of midazolam in children with Down syndrome after cardiac surgery.

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“…[15] Recent studies on morphine and midazolam in ventilated children reported a possible role of UGT2BT polymorphism in midazolam metabolism. [16,17] Therefore, genotype identi cation may be relevant to predict dosing requirements and treatment e cacy.…”

Section: Which Is the Best Pharmacologic Treatment To Ensure An Adequate Analgesia And Sedation In Children In Icu?mentioning

confidence: 99%

Recommendations for Analgesia and Sedation in Critically ill Children Admitted to Intensive Care Unit

Amigoni¹,

Conti²,

Conio³

et al. 2021

Preprint

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We aim to develop evidence-based recommendations for intensivists caring for children admitted to intensive care units and requiring analgesia and sedation. A panel of national pediatric intensivists expert in the field of analgesia and sedation and other specialists (a pediatrician, a neuropsychiatrist, a psychologist, a neurologist, a pharmacologist, an anesthesiologist, two critical care nurses, a methodologist) started in 2018 a 2- years process. Three meetings and one electronic-based discussion were dedicated to the development of the recommendations (presentation of the project, selection of research questions, overview of text related to the research questions, discussion of recommendations). A telematic anonymous consultation was adopted to reach the final agreement on recommendations. A formal conflict-of-interest declaration was obtained from all the authors. Eight areas of direct interest and one additional topic were considered to identify the best available evidence and to develop the recommendations using the Evidence-to-Decision framework according to Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. For each recommendation, the level of evidence, the strength of the recommendation, the benefits, the harms and the risks, the benefit/harm balance, the intentional vagueness, the values judgment, the exclusions, the difference of the opinions, the knowledge gaps and the research opportunities were reported. The panel produced 17 recommendations. Nine were evaluated as strong, 3 as moderate, 5 as weak. Conclusion: a panel of national experts achieved consensus regarding recommendations for the best care in terms of analgesia and sedation in critically ill children.

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Midazolam Dose Optimization in Critically Ill Pediatric Patients With Acute Respiratory Failure: A Population Pharmacokinetic-Pharmacogenomic Study

Abstract: Objective: To develop a pharmacokinetic-pharmacogenomic (PK-PG) population model of morphine in critically ill children with acute respiratory failure.

Cited by 13 publications

References 84 publications

High sedation needs of critically ill COVID-19 ARDS patients—A monocentric observational study

High sedation needs of critically ill COVID-19 ARDS patients—A monocentric observational study

Sedation With Midazolam After Cardiac Surgery in Children With and Without Down Syndrome: A Pharmacokinetic-Pharmacodynamic Study

Recommendations for Analgesia and Sedation in Critically ill Children Admitted to Intensive Care Unit

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