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Approaches for Precision Sedation with Dexmedetomidine in Critically Ill Children

Crisamore, Karryn Renee (2022) Approaches for Precision Sedation with Dexmedetomidine in Critically Ill Children. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Crisamore, Karryn Reneekarryn.crisamore@wilkes.edukrc1050000-0001-6654-7357
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairEmpey, Philippempey@pitt.edupempey
Committee MemberBeumer, Janbeumerjh@upmc.edujhb11
Committee MemberClark,
Committee MemberConley, Yvetteyconley@pitt.eduyconley
Committee MemberFernandez, Christianchf63@pitt.educhf63
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


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