Background Valproic acid (VPA) frequently causes severe intoxication which is difficult to recognise in critically ill patients (CIP). Hypoalbuminaemia is a common finding in CIP associated with changes in drug protein binding. VPA is extensively bound to albumin and the unbound fraction is pharmacologically active. In patients with hypoalbuminaemia, total serum concentration (TSC) of VPA offers poor clinical usefulness and in several cases, monitoring free VPA has shown to be of greater benefit. However, very few clinical laboratories routinely analyse free VPA concentration. Nowadays, there are methods that predict normalised VPA concentrations in patients with hypoalbuminaemia. These are used by our clinical pharmacists to make dosing recommendations.

Purpose We aimed to determine the usefulness of assessing normalised VPA concentrations to take dosing decisions and the rate of intoxication in CIP with hypoalbuminaemia ≤3.5g/dL and VPA TSC ≤75 mg/L.

Material and methods A retrospective and observational study was conducted from September 2014 to September 2016. Inclusion criteria: all CIP who had been treated with VPA, with at least one VPA TSC determination ≤75 mg/L and hypoalbuminaemia ≤3.5g/dL. Data collected: VPA dose, VPA TSC ( mg/L), serum albumin concentration (g/dL) and serum ammonia level (SAL) (µmol/L). Therapeutic range for VPA was 50–100 mg/L. Normalised VPA concentration was calculated based on free VPA and albumin concentration. Intoxication was considered as SAL ≥32µmol/L.

Results 15 CIP were included. 5 CIP (33.3%) were within the therapeutic range while the others (66.7%) had subtherapeutic VPA TSC (<50 mg/L). VPA dose was increased in 5 CIP based on subtherapeutic VPA TSC without considering normalised VPA concentration. After adjusting TSC according to albumin concentration, 80% (12 CIP) of all patients reached supratherapeutic levels. Serum ammonia levels were evaluated in 7 CIP confirming VPA intoxication in all cases.

Conclusion Despite obvious limitations, clinicians often take incorrect dosing decisions based on VPA TSC. Patients with therapeutic and subtherapeutic TSC, after normalisation, frequently reached supratherapeutic levels. Predicted adjusted VPA concentrations show approximate results but these are reasonably concordant with intoxication confirmed by serum ammonia levels. Normalisation of VPA concentrations in hypoalbuminaemic CIP may have a significant influence on dose adjustment.

No conflict of interest