Crisamore, Karryn Renee
(2022)
Approaches for Precision Sedation with Dexmedetomidine in Critically Ill Children.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Sedation is a fundamental aspect of care to promote safety and recovery in critically ill children. Achievement of target sedation levels through goal-directed medication titration is paramount to avoid negative sequalae associated with suboptimal sedation. Increasing evidence supports attainment of a lighter sedation levels with avoidance of benzodiazepines. Dexmedetomidine has emerged as a novel sedative with many potential benefits and increasing off-label use in pediatrics. Substantial variability in dosing requirements exists, but drivers of variability largely remain unknown. The objective of this work was to identify sources of variability, including patient-specific and genomic factors, associated with dexmedetomidine dose requirements in critically ill children with an emphasis on a practical approach to precision sedation in this unique patient population.
We comprehensively evaluated associations with patient-specific factors (demographics, illness severity, pharmacokinetic, pharmacodynamic, and infusion characteristics) and daily dexmedetomidine dose through EHR-derived data for critically ill children who received a continuous infusion. High variability in median daily dexmedetomidine doses and significant associations with concomitant doses of opioids and ketamine, infusion duration, sex, and reported race were found. Findings suggested a potential role for pharmacogenomic drivers of variability. Therefore, we developed a reliable approach to extract high yield, high quality DNA from frozen pediatric remnant blood clots leftover after serum collection. Use of a plastic sieve and proteinase for clot fragmentation and a modified salting out procedure with glycogen led to DNA with yields and quality suitable for downstream genomic research. A leading pharmacogenomics-focused microarray was evaluated for accuracy by comparison with an OpenArray panel from a clinical laboratory and whole genome sequencing. Robust performance was confirmed across many pharmacogenes, including dexmedetomidine candidate genes. In a pilot study, associations of genotypes in dexmedetomidine candidate genes with median daily dexmedetomidine dose was evaluated. A trend of higher dose requirements for ADRA2A rs1800544 G allele carriers was found.
Taken together, this work has advanced robust and practical approaches to study precision sedation as well as identified patient-specific and potential pharmacogenomic factors associated with dexmedetomidine dose requirements in critically ill children. These findings are integral to support future efforts towards preemptive precision sedation.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
25 October 2022 |
| Date Type: |
Publication |
| Defense Date: |
13 September 2022 |
| Approval Date: |
25 October 2022 |
| Submission Date: |
21 October 2022 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
227 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
sedation, pediatrics, intensive care unit, precision medicine, pharmacogenomics |
| Date Deposited: |
25 Oct 2022 17:12 |
| Last Modified: |
25 Oct 2022 17:12 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/43747 |
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