VPA increases the levels of gamma-amino butyric acid (GABA) and prolongs the recovery of inactivated sodium channels, thereby causing central nervous system (CNS) depression. This may partially contribute to its anticonvulsant activity. VPA may also cause impairments in fatty-acid metabolism and disrupt the urea cycle, leading to hyperammonemia.[³]

VPA is well absorbed from the gastrointestinal tract. However, time to maximum concentration (T _max and C_max), which represents the rate of absorption, depends on the preparation from VPA syrup (34.2 mg/L, 0.9 h) and VPA capsule (31.4 mg/L, 2.2 h) to enteric-coated delayed-release tablet (26.0 mg/L, 3.4 h) and finally, extended-release tablet (11.8 mg/L, 19.7 h).[⁴] In our case, the patient took enteric-coated delayed-release preparation, and thus he started deteriorating after 4 hours of ingestion, and serum levels taken 9 hours after ingestion were very high.

VPA is a small molecule (MW 144.2) and is highly protein bound (85-90%). It has a half-life of 10-20 hours (mean, 15 h) and has an apparent volume of distribution (Vd) that is in the range of 0.1-0.4 L/kg, at therapeutic levels. After an overdose, at serum concentrations of more than 300 μg/mL, protein-binding sites are saturated and only 35% binds to protein, increasing the free fraction of VPA and Vd.[⁴] Low molecular weight and decreased protein binding during toxicity make valproate make it ideal for removal through extracorporeal circulation. Hemodiafiltration (HDF) and high-flux HD are effective in reducing serum valproate levels during valproate toxicity.[^{5, 6}]

VPA overdose most commonly presents with nausea and vomiting closely followed by CNS symptoms of headache, ataxia, decreased level of consciousness, confusion and coma. With serum levels more than 850 μg/ml, hypotension, cardiac arrest, respiratory depression requiring intubation has been reported.[⁴] The coma is multifactorial, with the contributory factors including hyperammonemia, high anion gap lactic acidosis, direct sedative effects, cerebral edema and mitochondrial dysfunction.[⁷] Pancreatitis, elevated hepatic transaminases and bone marrow suppression may complicate both overdose and therapeutic dosing. Laboratory manifestations include hypernatraemia (sodium salt of valproate), hypocalcaemia, hyper or hypophosphataemia, high anion and osmolar gap. Our patient showed hypernatraemia, high anion and osmolar gap.

Cerebral edema is a delayed presentation and usually occurs 48-72 hours after ingestion, even as serum levels are decreasing. The disruption of the osmotic gradient, caused by elevated serum ammonia levels is thought to be the precipitating cause of the edema.[³] Our patient did not show secondary deterioration, may be due to early institution of hemodialysis, and hence correction of hyperammonemia.

The management of sodium valproate overdose remains largely supportive. Oral activated charcoal 1 mg/kg can be administered to reduce gastrointestinal adsorption, especially if presented within the first hour.[³] In our patient, charcoal 1 mg/kg was used.

Medical management for coma using naloxone and l-carnitine has been described in isolated case reports.[^{8, 9}] Naloxone acts as a GABA antagonist. Our patient did not show any improvement with naloxone.

Long-term use of VPA is associated with depletion of serum carnitine levels. l-Carnitine supplementation is indicated in patients with concomitant hyperammonemia, encephalopathy, and/or hepatotoxicity.[^{3, 9}] We used L- carnitine in our patient.

Hemodialysis, haemoperfusion, and a combination of the two, all appear to effectively reduce the serum levels of valproate. VPA because of its low molecular weight (144.2) is highly dialysable, which is partially opposed by its high protein binding. In a meta-analysis, it was found that low-efficiency or low-flux HD removes only 20% of administered dose at therapeutic levels.[¹⁰] However, in toxic levels due to saturation of plasma protein binding sites, clinically significant removal of valproate can be done with dialysis.[⁴] High-flux HD and HDF are effective in reducing serum valproate levels both during toxic and therapeutic states.[^{5, 6, 11}]

Recommended indications for renal replacement therapy during sodium valproate intoxication are plasma levels above 700 μg/ml, rapid clinical deterioration, evidence of hepatic dysfunction, and continued drug absorption.[³] In our patient, we used high-flux HD without haemoperfusion and found significant drop in both serum valproate and serum ammonia levels.

In conclusion, the use of renal replacement therapies seems the most effective treatment for valproate overdose and should be strongly considered besides other supportive therapies in a patient with refractory coma and serum valproate levels above 700 μg/dl.