TY - JOUR
T1 - Evaluation of Free Valproate Concentration in Critically Ill Patients
AU - Brown, Caitlin S.
AU - Liu, Ji Tong
AU - Riker, Richard R.
AU - Mara, Kristin C.
AU - Rabinstein, Alejandro A.
AU - Fraser, Gilles L.
AU - May, Teresa L.
AU - Seder, David
AU - Gagnon, David J.
N1 - Publisher Copyright:
© 2022 Wolters Kluwer Health. All rights reserved.
PY - 2022/9/7
Y1 - 2022/9/7
N2 - OBJECTIVES: Protein binding of valproate is variable in ICU patients, and the total valproate concentration does not predict the free valproate concentration, even when correcting for albumin. We sought to quantify valproate free concentration among ICU patients, identify risk factors associated with an increasing free valproate concentration, and evaluate the association between free valproate concentration with potential adverse drug effect. DESIGN: Retrospective multicenter cohort study. SETTING: Two academic medical centers. PATIENTS: Patients greater than or equal to 18 years of age with concomitant free and total valproate concentrations collected in the ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two-hundred fifty-six patients were included in the study, with a median age of 56 years (42-70) and 65% of patients were male. The median total valproate concentration was 53 µg/mL (38-70 µg/mL), the free valproate concentration was 12 µg/mL (7-20 µg/mL), and the free fraction was 23.6% (17.0-33.9%). Therapeutic discordance between the free and total valproate concentration occurred in 70% of patients. On multivariable analysis, increased free valproate concentration was associated with higher total valproate concentration (per 5 µg/mL increase, increase 1.72 µg/mL, 95% CI, 1.48-1.96) and lower serum albumin (per 1 g/dL decrease, increase 4.60 µg/mL, 95% CI, 2.71-6.49). There was no association between free valproate concentration and adverse effects. CONCLUSIONS: The valproate total and free concentration was discordant in the majority of patients (70%). Increased valproate free concentration was associated with hypoalbuminemia and total valproate concentration. Clinical decisions based on total valproate concentration may be incorrect for many ICU patients. Prospective, controlled studies are needed to confirm these findings and their clinical relevance.
AB - OBJECTIVES: Protein binding of valproate is variable in ICU patients, and the total valproate concentration does not predict the free valproate concentration, even when correcting for albumin. We sought to quantify valproate free concentration among ICU patients, identify risk factors associated with an increasing free valproate concentration, and evaluate the association between free valproate concentration with potential adverse drug effect. DESIGN: Retrospective multicenter cohort study. SETTING: Two academic medical centers. PATIENTS: Patients greater than or equal to 18 years of age with concomitant free and total valproate concentrations collected in the ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two-hundred fifty-six patients were included in the study, with a median age of 56 years (42-70) and 65% of patients were male. The median total valproate concentration was 53 µg/mL (38-70 µg/mL), the free valproate concentration was 12 µg/mL (7-20 µg/mL), and the free fraction was 23.6% (17.0-33.9%). Therapeutic discordance between the free and total valproate concentration occurred in 70% of patients. On multivariable analysis, increased free valproate concentration was associated with higher total valproate concentration (per 5 µg/mL increase, increase 1.72 µg/mL, 95% CI, 1.48-1.96) and lower serum albumin (per 1 g/dL decrease, increase 4.60 µg/mL, 95% CI, 2.71-6.49). There was no association between free valproate concentration and adverse effects. CONCLUSIONS: The valproate total and free concentration was discordant in the majority of patients (70%). Increased valproate free concentration was associated with hypoalbuminemia and total valproate concentration. Clinical decisions based on total valproate concentration may be incorrect for many ICU patients. Prospective, controlled studies are needed to confirm these findings and their clinical relevance.
KW - adverse drug effects
KW - critical care
KW - pharmacology
KW - therapeutic drug monitoring
KW - valproate
KW - valproic acid
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U2 - 10.1097/CCE.0000000000000746
DO - 10.1097/CCE.0000000000000746
M3 - Article
AN - SCOPUS:85139433593
SN - 2639-8028
VL - 4
SP - E0746
JO - Critical Care Explorations
JF - Critical Care Explorations
IS - 9
ER -