Valproate overdose leading to hyperammonaemic encephalopathy

Background

Sodium valproate is a commonly prescribed anticonvulsant drug used to treat epilepsy and bipolar disorder.1 Although the British National Formulary (BNF) lists encephalopathy as an uncommon and hyperammonaemia as a rare side effect of sodium valproate use, the incidence of these side effects in the current literature is higher and well known.1 2 Although these side effects are rare in therapeutic doses, they are common in overdoses. However, in our case, the reported side effects were seen with an ingestion of 2.1 g of sodium valproate, which is lower than the amount of sodium valproate (20 g) that is typically associated with these side effects in the current literature.3 Hyperammonaemic encephalopathy is often associated with liver disease or urea cycle enzyme deficiencies; however, it can also occur in people without these conditions who are taking sodium valproate.4

No established guidelines currently exist for the management of valproate-induced hyperammonaemic encephalopathy; treatment options include discontinuation of the drug, use of medications to reduce blood ammonia levels (such as lactulose, rifaximin or neomycin) and/or supplements (eg, levocarnitine or carglumic acid), and hemodialysis in severe cases.5 6 Therefore, early recognition is essential to prevent potentially life-threatening complications.

Case presentation

A man in his 50s, weighing 70 kg and height 170 cm was brought to the emergency department (ED) by ambulance after being found to have collapsed with noisy breathing by his wife in the early hours of the morning. The patient’s wife found him lying at the bottom of the stairs with 2.1 g of sodium valproate (21 tablets of 100 mg) missing from his pill organiser box but last seen before midnight. There was no evidence of vomiting at the scene and wife reported he was lying on the floor for more than 6 hours. The patient had no known drug allergies, and paramedics had administered two naloxone boluses of 400 μg each, but there was no clinical improvement. A few days before being brought to the ED, the patient had visited the ED with suicidal ideation but left without being assessed by the mental health team. His medical history included hypertension, for which he was taking amlodipine 5 mg, and his wife denied concurrent use of alcohol, other recreational drugs or previous use of sodium valproate by the patient.

On initial assessment in the ED, the patient had an oropharyngeal airway as an airway adjunct, was breathing at a rate of 9 breaths per min, had audible and clear bilateral breath sounds, an oxygen saturation of 100% on a non-rebreathing face mask with 15 L/min oxygen flow, a blood pressure of 124/57 mm Hg, a capillary refill time of less than 2 s and a heart rate of 75 beats per min. His body temperature was normal, and there were no skin rashes or signs of trauma. Neuro-assessment using the Glasgow Coma Scale showed a score of 5 with E2V2M1, bilateral equal pupils of size 3 mm, a brisk reaction to light, no lateralising signs and a normal blood glucose of 3.8 mmol/L.

Differential diagnosis

The diagnosis of valproate-induced hyperammonaemic encephalopathy can be established by ruling out other causes of reduced consciousness with the help of blood and urine workups. CT of the head and cervical spine was done to rule out structural lesions in brain or cervical spine, which could cause collapse and unresponsiveness. Liver and kidney functions were normal, indicating no chronic or acute disease causing these symptoms. Toxicology screening did not reveal any other reason for these symptoms. The patient’s history of ingesting 2.1 g of sodium valproate, combined with the time frame of ingestion and the patient’s collapse, was suggestive of an acute severe overdose of sodium valproate.

Treatment

While in the ED, correction of hypoglycaemia with dextrose 25% and a further naloxone bolus of 400 μg failed to improve his consciousness. As he required airway protection, rapid sequence induction and intubation were performed, and the patient was transferred to the intensive care unit (ICU) for further management. Initial workup revealed elevated ammonia and valproate levels along with unconsciousness at the time of admission; thus, continuous renal replacement therapy (CRRT) was initiated within 6 hours of admission to hospital to treat this severe valproate overdose. CRRT was performed using the Fresenius Multifiltrate pro machine, continuous veno-venous haemodialysis mode with citrate anticoagulation. Lactulose was administered enterally as the ammonia-lowering agent. The patient remained haemodynamically stable throughout his ICU stay. The toxicology team was consulted for further input regarding the case, and serial ammonia and valproate levels were monitored. On day 2, after a successful sedation hold and spontaneous breathing trial, the patient was extubated, and CRRT was discontinued after total of 36 hours of therapy and on symptomatic improvement and a reduction in valproate and ammonia levels (figure 1).

Figure 1

Serum ammonia and valproate levels during hospitalisation.

Outcome and follow-up

On day 3, the patient was moved to a ward, where he underwent a formal mental health assessment. After a 2-day stay in the ward, he was discharged home with a 2-week follow-up with his primary care physician. The GP further assessed him and arranged a follow-up appointment with the community mental health team, which offered antidepressant medication, counselling and cognitive behavioural therapy.