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Isoniazid Poisoning, Emergency Medicine

Basics

Description

- Pharmacokinetics: - Rapidly absorbed, peak levels within 1 " 2 hr - Volume of distribution is 0.6 L/kg and protein binding is low (10%) - Renally excreted within 24 hr after acetylation in the liver - Half-life is <1 hr in fast acetylators and 2 " 4 hr in slow-acetylating individuals

- GI: - Renal: - Cardiovascular: - Hypotension - Tachycardia - Shock - Cyanosis

- GI hepatitis: - Liver failure, hepatitis - Nausea, vomiting, constipation - Anorexia

- CBC: - Acute toxicity: - Chronic toxicity: - Agranulocytosis - Eosinophilia - Hemolysis - Anemia

- CNS: - Cerebrovascular accident - Intracranial hemorrhage/mass/trauma/abscess

- Seizure control: - Pyridoxine restores deficiency in GABA - Benzodiazepines are synergistic with pyridoxine - Phenytoin has no role

  • Complexes with and inactivates pyridoxal-5 phosphate, the active form of pyridoxine (vitamin B6)
  • Inhibits pyridoxine phosphokinase, hindering the conversion of pyridoxine to its active form
  • Yields a net decrease in ³-aminobutyric acid (GABA) production:Depressed GABA causes cerebral excitability and seizures
  • Inhibits lactate dehydrogenase, decreasing the conversion of lactate to pyruvate:Contributes to the profound anion gap metabolic acidosis
  • Chronic toxicity:Interferes with synthesis of nicotinic acid (niacin)May cause syndrome indistinguishable from pellagra after months of therapy (niacin deficiency)
  • Some actions similar to the monoamine oxidase inhibitors:Reports of a tyramine-like reaction to isoniazid (INH)Rare cases of mania, diaphoresis, depression, obsessive " compulsive disorder, and psychosis
  • Pharmacokinetics:Rapidly absorbed, peak levels within 1 " 2 hrVolume of distribution is 0.6 L/kg and protein binding is low (10%)Renally excreted within 24 hr after acetylation in the liverHalf-life is <1 hr in fast acetylators and 2 " 4 hr in slow-acetylating individuals

Etiology

  • High-risk groups include:ImmigrantsHomelessHIV infectedAlcoholicsLower socioeconomic status populations
  • Slow acetylators (60% of African Americans and Whites compared to 20% of Asians) are more prone to chronic effects/toxicity
  • LD50 estimated at 80 " 150 mg/kg
  • Ingestions <1.5 g lead to mild toxicity, and those of 10 g or more often result in fatality

Diagnosis

Signs and Symptoms

  • Acute toxicity:Neurologic:Altered mental statusSeizures refractory to standard therapyAgitationComaDizzinessAtaxiaHyper-reflexiaSlurred speechHallucinationsPsychosisGI:Renal:Cardiovascular:HypotensionTachycardiaShockCyanosisMetabolic:Profound anion gap metabolic acidosis (elevated lactate)Hyperthermia
  • Chronic toxicity:Neurologic:Peripheral neuropathyOptic neuritis, optic atrophyPsychosisInsomniaVertigoPellagra
  • GI hepatitis:Liver failure, hepatitisNausea, vomiting, constipationAnorexia

Essential Workup

Without specific history of ingestion, initiate general workup for:

  • Altered mental status
  • Seizures
  • Metabolic acidosis

Diagnosis Tests & Interpretation

Lab

  • Arterial blood gas:Profound metabolic acidosis
  • Electrolytes, BUN/creatinine, glucose:Elevated anion gap acidosisHyperglycemia
  • CBC:Acute toxicity:Chronic toxicity:AgranulocytosisEosinophiliaHemolysisAnemia

Imaging

  • CXR:Evidence of tuberculosis increases suspicion for ingestion/toxicity.Evaluate for aspiration pneumonia.
  • CT/lumbar puncture if indicated and questionable history

Differential Diagnosis

  • Toxins:Tricyclic antidepressantsSalicylates (aspirin)TheophyllineMethanol/ethylene glycolLithiumCarbon monoxideCocaine/cyanideAgents that cause metabolic acidosis
  • CNS:Cerebrovascular accidentIntracranial hemorrhage/mass/trauma/abscess
  • Hypoglycemia
  • Uremia
  • Thyrotoxicosis

Treatment

Pre-Hospital

Collect prescription bottles/medications for identification in the ED

Initial Stabilization/Therapy

  • ABCs:Supplemental oxygenIntubate if necessary for airway protectionSecure IV accessCardiac monitor0.9% NS access
  • Naloxone, thiamine, D50W (Accu-Chek) if altered mental status

Ed Treatment/Procedures

  • Vitamin B6 (pyridoxine):Specific antidotal treatment for INH toxicityGoal: 1 g of pyridoxine for each gram of INH ingested (1 g q2 " 3min)5 g for unknown amount ingestedMay repeat in 20 min for refractory seizures or persistent comaIf insufficient quantity of pyridoxine available, contact other hospital pharmacies and the regional poison control center to obtain moreIf no parenteral pyridoxine available, crush tablets and give as a slurry via NG tube
  • Seizure control:Pyridoxine restores deficiency in GABABenzodiazepines are synergistic with pyridoxinePhenytoin has no role
  • Gastric decontamination after stabilization:Consider gastric lavage only in life-threatening ingestions presenting within 1 hr with a protected airway (being aware of potential seizure activity and obtundation)Activated charcoal (AC) dosed at 10:1 ratio (AC:drug)
  • Hemodialysis:Persistent symptoms despite adequate therapyRenal insufficiency in symptomatic patients
  • Sodium bicarbonate:Acidosis usually resolves spontaneously after elimination of seizures

Medication

  • Dextrose: D50W 1 amp (50 mL or 25 g) (peds: D25W 2 " 4 mL/kg) IV
  • Diazepam (benzodiazepine): 5 " 10 mg (peds: 0.2 " 0.5 mg/kg) IV
  • Lorazepam (benzodiazepine): 2 " 6 mg (peds: 0.03 " 0.05 mg/kg) IV
  • Naloxone (Narcan): 2 mg (peds: 0.1 mg/kg) IV/IM initial dose
  • Pyridoxine (vitamin B6): 1 g IV for each gram of INH ingested (see above)
  • Thiamine (vitamin B1): 100 mg (peds: 50 mg) IV/IM

Follow-Up

Disposition

Admission Criteria

  • ICU admission for refractory seizures, severe acidosis, coma, altered mental status
  • Uncontrolled nausea/vomiting, unclear history of ingestion, or suicidal
  • Consult regional poison center:

Discharge Criteria

  • Symptoms are usually observed within 45 min of an acute overdose but may be delayed for ≥2 hr
  • Discharge if asymptomatic after 6 hr

Followup Recommendations

Psychiatric referral for intentional overdoses or suicidal patients

Pearls and Pitfalls

  • Inadequate appreciation and management of INH poisoning:Refractory seizures to standard treatments is a fundamental clue to INH poisoningSevere acidemia with elevated lactate in altered patients with seizures
  • Never paralyze a seizing patient without the use of continuous EEG monitoring
  • Goal of pyridoxine therapy is gram for gram of INH
  • If pyridoxine adequately treats seizures, may give more if patient remains comatose

Additional Reading

  • Minns AB, Ghafouri N, Clark RF. Isoniazid-induced status epilepticus in a pediatric patient after inadequate pyridoxine therapy. Pediatr Emerg Care. 2010;26:380 " 381.
  • Osterhoudt KC, Henretig FM. A 16-year-old with recalcitrant seizures. Pediatr Emerg Care. 2012;28:304 " 306.
  • Tajender V, Saluja J. INH inducted status epilepticus: Response to pyridoxine. Indian J Chest Dis Allied Sci. 2006;48:205 " 206.

See Also (Topic, Algorithm, Electronic Media Element)

Seizures

Codes

ICD9

961.8 Poisoning by other antimycobacterial drugs

ICD10

  • T37.1X1A Poisoning by antimycobac drugs, accidental, init
  • T37.1X4A Poisoning by antimycobacterial drugs, undetermined, init

SNOMED

  • 67933004 Poisoning by isoniazid (disorder)
  • 291679008 Accidental isoniazid poisoning (disorder)
  • 291681005 Isoniazid poisoning of undetermined intent (disorder)