Derivation and Validation of a New Equation for Estimating Free Valproate Concentration in Critically Ill Adult Patients

Ji Tong Liu; Caitlin S. Brown; Kristin C. Mara; Richard R. Riker; Alejandro A. Rabinstein; Gilles L. Fraser; Teresa L. May; Kaitlin J. Armstrong; David B. Seder; David J. Gagnon

doi:10.1097/CCE.0000000000000987

Derivation and Validation of a New Equation for Estimating Free Valproate Concentration in Critically Ill Adult Patients

Ji Tong Liu, Caitlin S. Brown, Kristin C. Mara, Richard R. Riker, Alejandro A. Rabinstein, Gilles L. Fraser, Teresa L. May, Kaitlin J. Armstrong, David B. Seder, David J. Gagnon

Neurology

Research output: Contribution to journal › Article › peer-review

Abstract

IMPORTANCE: Protein binding of valproate varies among ICU patients, altering the biologically active free valproate concentration (VPAC). Free VPAC is measured at few laboratories and is often discordant with total VPAC. Existing equations to predict free VPAC are either not validated or are inaccurate in ICU patients. OBJECTIVES: We designed this study to derive and validate a novel equation to predict free VPAC using data from ICU patients and to compare its performance to published equations. DESIGN: Retrospective cohort study. SETTING: Two academic medical centers. PARTICIPANTS: Patients older than 18 years old with concomitant free and total VPACs measured in the ICU were included in the derivation cohort if admitted from 2014 to 2018, and the validation cohort if admitted from 2019 to 2022. MAIN OUTCOMES AND MEASURES: Multivariable linear regression was used to derive an equation to predict free VPAC. Modified Bland-Altman plots and the rate of therapeutic concordance between the measured and predicted free VPAC were compared. RESULTS: Demographics, median free and total VPACs, and valproate free fractions were similar among 115 patients in the derivation cohort and 147 patients in the validation cohort. The Bland-Altman plots showed the new equation performed better (bias, 0.3 [95% limits of agreement, -13.6 to 14.2]) than the Nasreddine (-9.2 [-26.5 to 8.2]), Kodama (-9.7 [-30.0 to 10.7]), Conde Giner (-7.9 [-24.9 to 9.1]), and Parent (-9.9 [-30.7 to 11.0]) equations, and similar to Doré (-2.0 [-16.0 to 11.9]). The Doré and new equations had the highest therapeutic concordance rate (73%). CONCLUSIONS AND RELEVANCE: For patients at risk of altered protein binding such as ICU patients, existing equations to predict free VPAC are discordant with measured free VPAC. A new equation had low bias but was imprecise. External validation should be performed to improve its precision and generalizability. Until then, monitoring free valproate is recommended during critical illness.

Original language	English (US)
Pages (from-to)	E0987
Journal	Critical Care Explorations
Volume	5
Issue number	10
DOIs	https://doi.org/10.1097/CCE.0000000000000987
State	Published - Oct 18 2023

Keywords

critical care
pharmacology
therapeutic drug monitoring
valproate
valproic acid

ASJC Scopus subject areas

Critical Care and Intensive Care Medicine

Access to Document

10.1097/CCE.0000000000000987

Cite this

@article{9bad8fa1726c465cbac09edaf07352f3,

title = "Derivation and Validation of a New Equation for Estimating Free Valproate Concentration in Critically Ill Adult Patients",

abstract = "IMPORTANCE: Protein binding of valproate varies among ICU patients, altering the biologically active free valproate concentration (VPAC). Free VPAC is measured at few laboratories and is often discordant with total VPAC. Existing equations to predict free VPAC are either not validated or are inaccurate in ICU patients. OBJECTIVES: We designed this study to derive and validate a novel equation to predict free VPAC using data from ICU patients and to compare its performance to published equations. DESIGN: Retrospective cohort study. SETTING: Two academic medical centers. PARTICIPANTS: Patients older than 18 years old with concomitant free and total VPACs measured in the ICU were included in the derivation cohort if admitted from 2014 to 2018, and the validation cohort if admitted from 2019 to 2022. MAIN OUTCOMES AND MEASURES: Multivariable linear regression was used to derive an equation to predict free VPAC. Modified Bland-Altman plots and the rate of therapeutic concordance between the measured and predicted free VPAC were compared. RESULTS: Demographics, median free and total VPACs, and valproate free fractions were similar among 115 patients in the derivation cohort and 147 patients in the validation cohort. The Bland-Altman plots showed the new equation performed better (bias, 0.3 [95% limits of agreement, -13.6 to 14.2]) than the Nasreddine (-9.2 [-26.5 to 8.2]), Kodama (-9.7 [-30.0 to 10.7]), Conde Giner (-7.9 [-24.9 to 9.1]), and Parent (-9.9 [-30.7 to 11.0]) equations, and similar to Dor{\'e} (-2.0 [-16.0 to 11.9]). The Dor{\'e} and new equations had the highest therapeutic concordance rate (73%). CONCLUSIONS AND RELEVANCE: For patients at risk of altered protein binding such as ICU patients, existing equations to predict free VPAC are discordant with measured free VPAC. A new equation had low bias but was imprecise. External validation should be performed to improve its precision and generalizability. Until then, monitoring free valproate is recommended during critical illness.",

keywords = "critical care, pharmacology, therapeutic drug monitoring, valproate, valproic acid",

author = "Liu, {Ji Tong} and Brown, {Caitlin S.} and Mara, {Kristin C.} and Riker, {Richard R.} and Rabinstein, {Alejandro A.} and Fraser, {Gilles L.} and May, {Teresa L.} and Armstrong, {Kaitlin J.} and Seder, {David B.} and Gagnon, {David J.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s).",

year = "2023",

month = oct,

day = "18",

doi = "10.1097/CCE.0000000000000987",

language = "English (US)",

volume = "5",

pages = "E0987",

journal = "Critical Care Explorations",

issn = "2639-8028",

publisher = "Lippincott Williams and Wilkins",

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TY - JOUR

T1 - Derivation and Validation of a New Equation for Estimating Free Valproate Concentration in Critically Ill Adult Patients

AU - Liu, Ji Tong

AU - Brown, Caitlin S.

AU - Mara, Kristin C.

AU - Riker, Richard R.

AU - Rabinstein, Alejandro A.

AU - Fraser, Gilles L.

AU - May, Teresa L.

AU - Armstrong, Kaitlin J.

AU - Seder, David B.

AU - Gagnon, David J.

PY - 2023/10/18

Y1 - 2023/10/18

N2 - IMPORTANCE: Protein binding of valproate varies among ICU patients, altering the biologically active free valproate concentration (VPAC). Free VPAC is measured at few laboratories and is often discordant with total VPAC. Existing equations to predict free VPAC are either not validated or are inaccurate in ICU patients. OBJECTIVES: We designed this study to derive and validate a novel equation to predict free VPAC using data from ICU patients and to compare its performance to published equations. DESIGN: Retrospective cohort study. SETTING: Two academic medical centers. PARTICIPANTS: Patients older than 18 years old with concomitant free and total VPACs measured in the ICU were included in the derivation cohort if admitted from 2014 to 2018, and the validation cohort if admitted from 2019 to 2022. MAIN OUTCOMES AND MEASURES: Multivariable linear regression was used to derive an equation to predict free VPAC. Modified Bland-Altman plots and the rate of therapeutic concordance between the measured and predicted free VPAC were compared. RESULTS: Demographics, median free and total VPACs, and valproate free fractions were similar among 115 patients in the derivation cohort and 147 patients in the validation cohort. The Bland-Altman plots showed the new equation performed better (bias, 0.3 [95% limits of agreement, -13.6 to 14.2]) than the Nasreddine (-9.2 [-26.5 to 8.2]), Kodama (-9.7 [-30.0 to 10.7]), Conde Giner (-7.9 [-24.9 to 9.1]), and Parent (-9.9 [-30.7 to 11.0]) equations, and similar to Doré (-2.0 [-16.0 to 11.9]). The Doré and new equations had the highest therapeutic concordance rate (73%). CONCLUSIONS AND RELEVANCE: For patients at risk of altered protein binding such as ICU patients, existing equations to predict free VPAC are discordant with measured free VPAC. A new equation had low bias but was imprecise. External validation should be performed to improve its precision and generalizability. Until then, monitoring free valproate is recommended during critical illness.

AB - IMPORTANCE: Protein binding of valproate varies among ICU patients, altering the biologically active free valproate concentration (VPAC). Free VPAC is measured at few laboratories and is often discordant with total VPAC. Existing equations to predict free VPAC are either not validated or are inaccurate in ICU patients. OBJECTIVES: We designed this study to derive and validate a novel equation to predict free VPAC using data from ICU patients and to compare its performance to published equations. DESIGN: Retrospective cohort study. SETTING: Two academic medical centers. PARTICIPANTS: Patients older than 18 years old with concomitant free and total VPACs measured in the ICU were included in the derivation cohort if admitted from 2014 to 2018, and the validation cohort if admitted from 2019 to 2022. MAIN OUTCOMES AND MEASURES: Multivariable linear regression was used to derive an equation to predict free VPAC. Modified Bland-Altman plots and the rate of therapeutic concordance between the measured and predicted free VPAC were compared. RESULTS: Demographics, median free and total VPACs, and valproate free fractions were similar among 115 patients in the derivation cohort and 147 patients in the validation cohort. The Bland-Altman plots showed the new equation performed better (bias, 0.3 [95% limits of agreement, -13.6 to 14.2]) than the Nasreddine (-9.2 [-26.5 to 8.2]), Kodama (-9.7 [-30.0 to 10.7]), Conde Giner (-7.9 [-24.9 to 9.1]), and Parent (-9.9 [-30.7 to 11.0]) equations, and similar to Doré (-2.0 [-16.0 to 11.9]). The Doré and new equations had the highest therapeutic concordance rate (73%). CONCLUSIONS AND RELEVANCE: For patients at risk of altered protein binding such as ICU patients, existing equations to predict free VPAC are discordant with measured free VPAC. A new equation had low bias but was imprecise. External validation should be performed to improve its precision and generalizability. Until then, monitoring free valproate is recommended during critical illness.

KW - critical care

KW - pharmacology

KW - therapeutic drug monitoring

KW - valproate

KW - valproic acid

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Derivation and Validation of a New Equation for Estimating Free Valproate Concentration in Critically Ill Adult Patients

Abstract

Keywords

ASJC Scopus subject areas

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