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.
Disclaimer In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose To manage factor Xa (FXa) inhibitor–associated bleeding, andexanet alfa or 4-factor prothrombin concentrate (4F-PCC) has been used to restore hemostasis. However, literature on the outcomes for patients who received both andexanet alfa and 4F-PCC is limited. Summary We report a case series of 5 patients who received andexanet alfa plus 4F-PCC for reversal of FXa inhibitor–associated bleeding. Patients were included in this case series if they received both andexanet alfa and 4F-PCC for reversal of FXa inhibitor–associated bleeding. They were followed to either discharge or death, and in-hospital complications related to concurrent use of andexanet alfa and 4F-PCC were documented. We report an incidence of thromboembolism of 40% (2 of 5 cases) and an in-hospital mortality rate of 60% (3 of 5 cases). Taking these cases together with those in the existing literature, we found a total of 23 reported cases of safety outcomes with andexanet alfa plus 4F-PCC. The overall incidence of thromboembolism was 35% (8 of 23 cases). Conclusion This case series adds to the limited literature describing the outcomes for patients receiving andexanet alfa plus 4F-PCC. We encourage other institutions to report safety data on administering both agents.
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