Abstracts

Rationale: Valproate (VPA) has complex, saturable protein binding and VPA free fraction (FF) is often elevated in critically ill patients. Normal VPA FF ranges from 5-30% but is increased in the elderly, critically ill, through competitive albumin binding interactions, or from higher doses. Elevated free VPA concentrations are associated with adverse effects (AEs). In the following cases, we highlight changes in FF after the addition of ketogenic diets (KD) for super refractory status epilepticus (SRSE).

Methods: Patients with SRSE at a tertiary academic medical center on VPA who initiated KD and had total and free VPA concentrations collected pre- and post-KD initiation were identified. Patient demographics, treatment courses, and VPA FF pre- and post-KD initiation were collected. The primary outcome was the change in VPA FF after KD initiation.

Results:
Three patient with SRSE on VPA initiated on KD were identified (Table 1). Free and total VPA concentrations pre- and post-KD initiation are depicted in Figure 1.




Case 1 was a 72-year-old male with history of traumatic brain injury and epilepsy for six months managed with an RNS device, levetiracetam (LEV), and VPA who presented with focal SRSE. The patient was on LEV, VPA, oxcarbazepine (OXC), and primidone (PRM) prior to KD initiation. VPA FF increased from 34% pre-initiation to 40% post-initiation. Despite escalation of ASMs and KD initiation, focal SRSE continued and the patient was transitioned to comfort care and died prior to discharge.




Case 2 was a 24-year-old female with a history of NORSE two years prior to admission managed with an occipital RNS device, diazepam, lacosamide (LCM), and LEV who presented with multiple breakthrough seizures which progressed to SRSE. SRSE resolved after multiple burst suppression trials and initiation of clobazam (CLB), VPA, and KD. VPA FF increased from 33% pre-initiation to 62% post-initiation. Despite SRSE resolution, the patient experienced acute respiratory decline and was transitioned to comfort care.




Case 3 was a 44-year-old male who presented after cardiac arrest leading to diffuse anoxic brain injury complicated by SRSE. SRSE was treated with three rounds of burst suppression and initiation on CLB, LEV, VPA, zonisamide (ZNS), and KD. VPA FF increased from 16% pre-KD initiation to 65% post-KD initiation. Despite aggressive efforts, SRSE recurred, and the patient was transitioned to comfort care.




Conclusions: In this case series, VPA FF increased by 28% on average after KD initiation in three patients with SRSE. Total VPA concentrations decreased while free VPA concentrations increased after KD initiation, potentially increasing the risk of AEs. Critical illness, hypoalbuminemia, uremia, and elevated free fatty acids (FFAs) can increase VPA FF, and this series suggests KD initiation also increases VPA FF and that free VPA concentrations should be monitored in patients initiated on KD. The pharmacokinetic impact of KD initiation on protein-bound medications should be further investigated.

Funding: No funding was received in support of this abstract