One Pill Can Kill: Isoniazid Poisoning

You are called to an apartment building in a community housing complex known for its poor social determinants of health for a seizing 4-year-old child. You arrive with the fire department and claim the first elevator, which is so small you have to break down the head of your stretcher to squeeze in. You get off on the 11th floor and make your way to a small apartment, where a woman meets you at the door holding her young son, who is in active tonic-clonic seizure.

While benign febrile seizure is the most common type of seizure in small children, serious causes of seizure must be excluded. These include trauma, hypoglycemia, and central nervous system infections such as bacterial meningitis. But toxic causes of seizures should also be considered. Here’s another One Pill Can Kill mnemonic: drugs that cause seizure.

OTIS CAMPBEL

• Organophosphates
• Tricyclic antidepressants
• Isoniazid
• Salicylates 
• Camphor 
• Amphetamines like cocaine, MDMA
• Methylxanthines
• PCP
• Benzodiazepine withdrawal
• Ethanol withdrawal
• Lithium

Pop quiz: Which benzodiazepine do you prefer for children in seizure? What is the evidence for various benzodiazepines and routes of administration for children?

Back to the Case

You rapidly establish IV access while your partner checks the child’s glucose, which is normal. A firefighter attaches a nonrebreather to oxygen and places it on the child’s face while opening his airway. You push a dose of a benzodiazepine intravenously and begin to secure the child to the stretcher. Your physical exam reveals normothermia and good signs of perfusion. There is no rash or nuchal rigidity.

In the elevator the child continues to seize. You redose the benzodiazepine, making sure your line flushes well. In the back of the ambulance, the seizure continues. You call medical control, which authorizes a third dose of intravenous benzodiazepine. You recheck sugar—still normal. The child continues to seize.

Recognizing this case of status epilepticus, you call your medical director back, still 10 minutes from the nearest ER. Your medical director is convinced the child has been poisoned. He asks about exposures; you realize you never even made it into the apartment and radio to your dispatch to ask the police to search for possible poisons. Your medical director asks you to give a fourth dose of benzos, then 2 mg/kg of ketamine IV to try to abort the refractory seizure.

Treating Status Epilepticus

Status epilepticus has been defined a few ways, most recently as a seizure that lasts more than five minutes or having two seizures without a return to baseline between. Benzodiazepines are the mainstay of therapy to abort status seizures, but it’s important to think about treating the underlying cause, such as cooling the patient, providing dextrose if glucose is low, or using cause-specific treatments like magnesium sulfate in preeclampsia and sodium bicarbonate in amitriptyline overdose. Diazepam was once the favored benzodiazepine, often administered to children rectally. Midazolam and lorazepam are more contemporary choices. While lorazepam has a longer duration of action, its onset is slower than midazolam. Note diazepam cannot be given by the intramuscular route.

More recently studies have investigated if IM, IN, or IV routes led to faster termination of seizures. In patients with existing IV access, the intravenous route wins; but in the field the time it takes to establish IV access often means quick IM or IN administration kicks in at the same time.

Regardless of the route and choice of medication to abort status seizure, redosing is important; longer seizures are associated with worse outcomes.

Case Conclusion

You arrive at the ER and proceed directly to the resuscitation room, where you are met by three nurses, a physician, and a respiratory therapist. The physician gives 1 mg of naloxone, an amp of dextrose, and 5 g of pyridoxine. While the team prepares for rapid sequence intubation with propofol and succinylcholine, the child stops seizing.

A few minutes later a police officer arrives with a bag of medications found in the kitchen. He tells you the family recently arrived from Afghanistan under refugee status and the mother is being treated for tuberculosis. The medication list includes rifampin, pyrazinamide, isoniazid, and ethambutol.

In our case the emergency doctor empirically treated the child for isoniazid poisoning along with other reversible toxins. Status seizure was a frequent scenario in my residency simulation program. Isoniazid, with its antidote pyridoxine, is an easy toxin to treat.

Why don’t benzodiazepines work in isoniazid seizures? Isoniazid depletes the body of vitamin B6, which is needed to produce GABA. This leads to low levels of this important inhibitory neurotransmitter, which provokes seizures.

Benzodiazepines affect the GABA receptor, but not the way you might think. Think of the GABA receptor as a lock and the GABA neurotransmitter as a key. Rather than directly open the receptor like a key, benzos alter the conformation of the receptor such that the lock becomes exposed, allowing the key, GABA neurotransmitter molecules, to make contact with the lock, opening chloride channels that inhibit seizure. Pyridoxine restores GABA levels, at which point benzodiazepines would once again be effective at exposing the lock to the key.

After a decade working as a helicopter paramedic, Blair Bigham, MD, MSc, EMT-P, completed medical school in Ontario, Canada, where he is now a resident physician in the emergency department. He has authored over 30 scientific articles, led major national projects to advance prehospital research and participated in multiple collaboratives, including the Resuscitation Outcomes Consortium.