How is acute isoniazid-induced seizure managed?
Management of patients with refractory seizure should initially include an assessment and management of the patient’s airway, breathing, and circulation. Although seizures induced by INH toxicity are often resistant to benzodiazepines, these agents remain the first-line therapy. For patients who fail to respond to a reasonable trial of benzodiazepines (eg, lorazepam 6 mg intravenously [IV]), pyridoxine should be administered.3 The recommended dose is 1 g pyridoxine per every 1 g of INH ingested—if the initial dose ingested is known—with a maximum dose of 5 g pyridoxine. If the initial dose of INH is not known, 70 mg/kg of pyridoxine, up to 5 g, is recommended. Repeated doses of pyridoxine can be administered if the seizure continues, up to a total dose of 10 g in an adult. At extremely high doses, pyridoxine itself can be neurotoxic, limiting the maximal antidotal dose.
Rapid initiation of pyridoxine is a challenge since typical stocks in most EDs are not in an adequate supply required for treatment. Additionally, a typical vial of pyridoxine contains 100 mg, highlighting the rare need to open dozens of vials for a single patient. Drawing up adequate doses of the IV formulation can be a challenge and time-consuming.
Regardless, the most reliable and rapid route of administration for pyridoxine is IV, at a rate of 0.5 to 1 g/min. Even if the seizure resolves prior to completion of the initial dose, the remaining doses should still be administered over a 4- to 6-hour period. Oral or (more likely) nasogastric administration of pyridoxine can be administered if the IV formulation is not available, but neither are optimal routes of delivery. Every effort should be made to stock pyridoxine in the antidote supply in the ED to avoid time delays involving finding, preparing, and administering the drug in these scenarios. Previous studies have found that most EDs are not prepared to handle pyridoxine replacement.4,5
Since benzodiazepines and barbiturates are GABA agonists with complementary mechanisms of actions to pyridoxine, they should be administered to potentiate the antiseizure effect of pyridoxine. If the seizure does not terminate, the use of propofol or general anesthesia may be required. Once the seizure is terminated, oral activated charcoal can be administered if the ingestion occurred within several hours of presentation. Given the rapid onset of effect of a large dose of INH, most patients will develop seizure shortly after exposure, limiting the benefits of both aggressive gastrointestinal decontamination and delayed activated charcoal. Charcoal also can be used for patients who overdose on INH but do not develop seizures.
Although the utility of a head computed tomography (CT) scan or laboratory studies is limited given the context of the exposure, these are generally obtained for patients with new-onset seizure. Since many patients with INH toxicity do not seize, such a patient may have a lower seizure threshold due to the existence of a subclinical cerebral lesion or metabolic abnormality.
Case Conclusion
The patient’s INH-induced refractory seizure was treated with pyridoxine. Her history suggested that she had ingested an unknown number of INH tablets within an hour. On this initial basis, an IV dose of 5,000 mg of pyridoxine was administered. The patient’s seizures terminated within 2 minutes of the infusion, and no additional doses of pyridoxine were required. Given the lack of concern for self-harm, an acetaminophen concentration was not obtained. A urine toxicology screen was negative for cocaine and amphetamines, and a CT scan of the head was negative for any abnormality. The patient was admitted to the pediatric intensive care unit for status epileptics and was discharged home on hospital day 2 after an uneventful stay.