Isoniazid toxicity

Reviewed and revised 8 April 2014

OVERVIEW

  • isoniazid toxicity, like other hydrazines, primarily cause life-threatening seizures and lactic acidosis through depletion of vitamin B6
  • the antidote is pyridoxine

BASIC TOXICOLOGY

Toxicodynamics

  • hydrazines like isoniazid decreased pyridoxal 5-phosphate levels (by inhibiting formation, binding and inactivating free P5P and increasing rate of P5P elimination)
  • P5P is vitamin B6
  • P5P is a cofactor in >100 enzyme reactions, including conversion of glutamate to GABA
  • thus hydrazines cause GABA depletion resulting CNS excitation and seizures
  • lactic acidosis results from seizures and from impaired conversion of lactate to pyruvate

Toxicokinetics

  • rapid and complete oral absorption
  • peak levels at 1-2 hours
  • hepatic metabolism via acetylation or cytochrome P450 mediated hydrolysis
  • half life varies from 1-4 hours depending on whether the patient is a ‘fast’ or ‘slow’ acetylator

RISK ASSESSMENT

Toxicity is rapid (30 min to 2 hours) and predictable

  • >1.5g (20mg/kg) – symptoms may develop
  • >3g (40mg/kg) – seizures, metabolic acidosis, coma
  • >10g (130 mg/kg) – always lethal without treatment

CLINICAL FEATURES

  • dizziness, blurred vision, photophobia, nausea and vomiting
  • tachycardia, mydriasis, dysarthria, ataxia and hyperreflexia
  • rapid confusion, coma, seizures, lactic acidosis in large overdoses
  • seizures are usually generalised tonic-clonic in nature, and may resolve spontaneously then recur rapidly
  • complications of prolonged seizures

INVESTIGATIONS

  • screening ECG and paracetamol
  • lactate and HAGMA on ABD
  • isoniazid levels are rarely available, and only have a potential role in retrospectively confirming the diagnosis

MANAGEMENT

Resuscitation

  • attend to ABCs
  • treat seizures with benzodiazepines (high doses may be needed), escalate to barbiturates and give pyridoxine as soon as available (See below)
  • prepare for and perform intubation in the event of prolonged seizures

Supportive care and monitoring

Decontamination

  • only give activated charcoal after securing the airway by intubation

Enhanced elimination

  • hemodialysis is not indicated even though it removes isoniazid because it is too slow

Antidote

  • pyridoxine is indicated for isoniazid-induced seizures
  • give 1g pyridoxine for each gram of isonizid ingested up to a maximum of 5g (70mg/kg in children) – give 5g IV if isonizid dose is unknown
  • give as slow infusion of 0.5g/min until seizures stop
  • also used for toxicity from other hydrazines e.g. Gyromitra mushrooms, rocket fuel (give 25mg/kg slow IV bolus initially); and as an adjunct in ethylene glycol toxicity (give 50mg IV q6h)
  • 50% oral bioavailability and VD of 0.6L/kg, undergoes rapid extra-hepatic metabolism
  • peripheral neuropathy from high chronic oral dosing of pyridoxine does not occur from acute treatment of an overdose
  • only comes in 50mg vials!
  • role of prophylactic isoniazid in asymptomatic overdoses is controversial

Disposition

  • observe asymptomatic overdoses for 6 hours, then discharge if remain well and no treatment required
  • symptomatic patients required HDU/ ICU admission

CCC 700 6

Critical Care

Compendium

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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