Jenny J. Lu
HIGH-YIELD FACTS
• Isoniazid (INH) toxicity should be considered in any patient with metabolic acidosis and seizures refractory to conventional therapy.
• Altered sensorium, slurred speech, ataxia, coma, and seizures can occur rapidly after INH ingestion.
• INH toxicity is associated with profound metabolic acidosis and increased serum lactate.
• The antidote for INH poisoning is pyridoxine (Vitamin B6). Administer an amount of pyridoxine equivalent to the amount of INH ingested on a gram-for-gram basis. If the ingested dose is unknown, administer 70 mg/kg (up to a total of 5.0 g) intravenously and repeat if seizures continue.
Although efforts to decrease incidence rates and mortality from tuberculosis (TB) infections have made considerable progress in recent years, the burden of TB continues to be enormous. The World Health Organization reported an estimated 8.7 million new cases of TB and 1.4 million deaths in 2011.1 The main treatment, isoniazid (INH), has been used for the last several decades as the first-line medication against active tuberculosis and as prophylactic therapy for positive tuberculin skin test reactions. As such, toxic exposures to INH still occur. Within the United States, the 2011 Annual Report of the American Association of Poison Control Centers’ National Poison Data System reported 249 INH exposures, of which 42 were in children younger than 5 years, and 69 cases in children between the ages of 6 and 19 years.2 A high index of suspicion for INH toxicity in cases of refractory seizures, coupled with prompt, aggressive treatment by the health care provider, is needed to prevent morbidity and mortality in the acute overdose scenario.
PHARMACOLOGY
Isoniazid, or isonicotinic acid hydrazide, is an antimycobacterial agent whose mechanism of action is believed to be the disruption of mycolic acid synthesis, a process essential to the mycobacterial cell wall. Structurally, INH is similar to the metabolic cofactors nicotinic acid (niacin), nicotinamide adenosine dinucleotide (NAD), and pyridoxine (vitamin B6). The pyridine ring is a critical component of its antituberculous activity. Ninety percent of ingested INH is readily absorbed from the gastrointestinal tract, with serum concentrations usually peaking within 2 hours. Peak cerebrospinal fluid levels reach approximately 10% of serum levels. INH is highly water soluble, with an apparent volume of distribution of 0.6 L/kg. It exhibits less than 10% protein binding.3
Metabolic degradation of INH is complex and occurs primarily by hepatic acetylation. The ability to inactivate INH by acetylation via the enzyme N-acetyltransferase is genetically determined in an autosomal dominant fashion. Slow acetylators are autosomal recessive for the acetylation gene. Fifty to sixty percent of Caucasians and Blacks are slow acetylators, while up to 90% of Asians and Inuits are rapid acetylators.3 The effectiveness of the drug is not significantly affected by the rate of acetylation, although slow acetylation can lead to higher peak plasma concentrations, potentially increasing the risk for toxic side effects. The elimination half-life in fast acetylators is approximately 70 minutes, compared to 180 minutes in slow acetylators.3 Following acetylation, the INH metabolites are excreted via the urine, with 75–95% of a single dose eliminated within 24 hours.3
INH can inhibit several cytochrome P450-mediated functions, such as demethylation, oxidation, and hydroxylation. INH has been associated with interactions with several drugs, including theophylline, phenytoin, warfarin, valproic acid, and carbamazepine.3 Adverse effects of these drugs result from elevated drug levels due to INH inhibition of their metabolism. Interactions with food (e.g., tyramine reactions) from its weak monoamine oxidase inhibitor activity have also been reported.
PATHOPHYSIOLOGY
The process by which INH toxicity occurs is complex but includes two main mechanisms which have the overall effect of depleting gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the CNS. First, INH creates a functional deficiency of pyridoxine by inhibiting pyridoxine phosphokinase, the enzyme which converts pyridoxine to its active form, pyridoxal-5′-phosphate. Pyridoxal-5′-phosphate is a necessary cofactor in the conversion of glutamic acid to GABA. INH itself also combines with pyridoxine-5′-phosphate, forming inactive INH pyridoxal hydrazones, which are renally excreted.3
Second, INH inhibits the enzyme glutamic acid decarboxylase which, along with pyridoxine-5′-phosphate, is also required for the synthesis of GABA. Depletion of GABA leading to increased CNS excitability is believed to be the etiology of INH-induced seizures (Figure 123-1).
FIGURE 123-1. Mechanisms of INH toxicity.
The metabolic acidosis associated with INH toxicity is most likely due to lactate production, secondary to intense seizure-induced muscle activity. Other theories include decreased clearance of lactate, as a result of a blockade in the conversion of lactate to pyruvate, as well as generation of acidic INH metabolites and increased serum ketoacids from increased fatty acid oxidation.
The toxic dose of INH is highly variable. The pediatric therapeutic dose is 10–20 mg/kg per day, up to 300 mg/kg per day. An acute ingestion of as little as 1.5–2.0 g of INH can lead to neurotoxicity, with 6–10 g or more (or 80–150 mg/kg) leading to severe symptoms or fatality without medical intervention.4,5 Patients with underlying seizure disorders may develop seizures with ingestions of lower doses.
DIAGNOSIS
CLINICAL PRESENTATION OF ACUTE TOXICITY
Because of rapid gastrointestinal absorption, symptoms of INH toxicity typically occur within 30 minutes to 1 hour after ingestion. Initial symptoms and signs include nausea, vomiting, fever, dizziness, ataxia, altered sensorium, and slurred speech. Toxicity can quickly progress to the triad of refractory seizures, metabolic acidosis, and coma. Seizures are often the presenting sign and can persist until GABA stores are replenished. Hyperthermia, hypotension, hyperglycemia, ketonemia, and ketonuria have also been observed in overdose. INH toxicity may initially be confused with diabetic ketoacidosis.4 The duration of coma can be protracted, lasting as long as 24–36 hours after the termination of seizures and resolution of acidosis. The diagnosis of a toxic INH ingestion in the convulsing pediatric patient is frequently missed and the antidotal treatment delayed. A high index of suspicion for INH toxicity is necessary in the evaluation of any child or adolescent who presents with acute-onset seizures, especially when the seizures are refractory to conventional therapy.
In the acute ingestion, quantitative INH levels are typically unavailable. Levels may be helpful in confirming the diagnosis, but treatment of toxicity should never be withheld while awaiting results. A serum level of 10 mg/mL, a level greater than 3.2 mg/mL 2 hours after ingestion, or a level greater than 0.2 mg/mL after 6 hours are considered toxic.4 Other causes of altered mental status, seizures, or anion gap acidosis should be considered as part of the patient’s complete evaluation.
TREATMENT
STABILIZATION
Airway control, stabilization of breathing and circulation, and seizure management in an environment of attentive supportive care are the priorities in caring for the symptomatic patient with INH toxicity.
DECONTAMINATION
Activated charcoal could be considered if the patient presents within minutes after an ingestion, although the risk of seizures and aspiration exists. Endotracheal intubation should never be performed for the sole purpose of administering activated charcoal. There is no role for whole bowel irrigation.
ANTIDOTAL THERAPY
Correction of GABA deficiency through the administration of pyridoxine (B6) is the antidotal therapy for INH toxicity. Commercially available as 100 mg/mL (1 mL and 30 mL) vials; pyridoxine hydrochloride is mixed in dextrose or saline. If the ingested INH dose is known, the amount of pyridoxine administered should equal the amount of INH ingested on a gram-for-gram basis, slowly administered intravenously over 5–10 minutes. If the dose of INH ingested is unknown, 5 g is given (5 g or 70 mg/kg maximum in a child), and repeated at 5–20 minute intervals until the seizures are controlled. If the parenteral form of pyridoxine is unavailable or in inadequate supply, similar doses of crushed pyridoxine tablets (10–500 mg tabs depending on manufacturer) may be given orally or as a slurry through a nasogastric tube.6,7 A minimum of 10–20 g of pyridoxine has been suggested as minimum stocking levels. The severe acidosis seen in INH overdose may require sodium bicarbonate administration, but in most cases control of seizures with pyridoxine, benzodiazepines, and adequate fluid resuscitation will improve the acidosis. Bicarbonate therapy is reserved for severe, persistent acidemia (pH < 7.1). Electrolytes, specifically sodium, should be carefully followed in the pediatric patient if bicarbonate therapy is administered.
In general, for toxicant-induced seizures, benzodiazepines such as diazepam and lorazepam are the first line of treatment.8 Phenytoin is not recommended as a first-line anticonvulsant for toxicant-induced seizures. In INH-induced seizures, because of depletion of GABA, pyridoxine may be the only effective therapy. Short-acting barbiturates or inhaled anesthetics (in consultation with an anesthesiologist) could be considered if the seizures are unresponsive to benzodiazepines and pyridoxine. It should be noted that paralytic agents control only the muscular activity seen with convulsive seizures and that the electrical hyperactivity in the brain may continue despite muscular paralysis. EEG monitoring should be in place if paralytics are used.
ENHANCED ELIMINATION
INH is dialyzable, but hemodialysis is usually unnecessary if adequate doses of pyridoxine and benzodiazepines have been given. Hemodialysis, hemoperfusion, and exchange transfusion have all been described in case reports as useful but are procedures reserved for the most severe, refractory cases, or for patients with renal failure.6 In one report of an intentional 12 g ingestion of INH, a persistently comatose patient was hemodialyzed with a concentration of 28.9 μg/mL (therapeutic: ≤5 μg/mL).9
DISPOSITION
All patients suspected of toxic exposures to INH require close observation in a setting with capabilities for rapid airway and seizure management. Patients who remain completely symptom-free after 8 hours following an alleged isolated ingestion with INH may be medically cleared in the ED. Symptomatic patients should be admitted to an intensive care unit. Consultation with a regional poison control center or medical toxicology service for guidance is prudent. Psychiatric evaluation should be obtained for all intentional ingestions once the patient has been medically cleared.
CHRONIC TOXICITY
Chronic INH toxicity is uncommon in the normal pediatric population and is usually encountered in children receiving active or prophylactic treatment. The appearance of nausea, vomiting, fever, abdominal pain, or pruritus may herald hepatic insult that, if not treated, can progress to fulminant hepatic failure necessitating liver transplantation. Chronic INH use has also been associated with optic neuritis, hepatitis, peripheral neuropathy, a pellagra-like syndrome of dermatitis, diarrhea, dementia, and a variety of psychological reactions. During treatment or prophylaxis of TB with INH, serum transaminase levels should be evaluated periodically to screen for early signs of hepatotoxicity.
REFERENCES
1. World Health Organization (WHO) global tuberculosis report 2012. http://www.who.int/tb/publications/global_report/gtbr12_main.pdf. Accessed February 25, 2013.
2. Bronstein AC, Spyker DA, Cantilena LR Jr, Rumack BH, Dart RC. 2011 Annual report of the American Association of Poison Control Centers’ National Poison Data System. Clin Toxicol (Phila). 2012;50(10):911–1164. http://www.aapcc.org/annual-reports./ Accessed May 15, 2013.
3. Hernon CH, Boyer EW. Antituberculous medications. In: Nelson LS, Lewin NA, Howland MA, et al., eds. Goldfrank’s Toxicologic Emergencies. 9th ed. The McGraw-Hill companies; 2011:834–844.
4. Maw G, Aitken P. Isoniazid overdose: a case series, literature review and survey of antidote availability. Clin Drug Investig. 2003;23(7): 479–485.
5. Khoharo HK, Ansari S, Abro A, et al. Suicidal Isoniazid poisoning. J Ayub Med Coll Abbottabad. 2009;21(2):178–179.
6. Morrow LE, Wear RE, Schuller D, Malesker M. Acute isoniazid toxicity and the need for adequate pyridoxine supplies. Pharmacotherapy. 2006;26(10):1529–1532.
7. Howland MA. Pyridoxine. In: Nelson LS, Lewin NA, Howland MA, et al., eds. Goldfrank’s Toxicologic Emergencies. 9th ed. The McGraw-Hill companies; 2011:845–847.
8. Wills B, Erickson T. Chemically induced seizures. Clin Lab Med. 2006;26(1):185–209.
9. Tai WP, Yue H, Hu PJ. Coma caused by isoniazid poisoning in a patient treated with pyridoxine and hemodialysis. Adv Ther. 2008;25(10):1085–1088.
SUGGESTED READING
Minns AB, Ghafouri N, Clark RF. Isoniazid-induced status epilepticus in a pediatric patient after inadequate pyridoxine therapy. Pediatr Emerg Care. 2010;26(5):380–381.
Erdman A. Isoniazid (INH). In: Olson KR, ed. Poisoning & Drug Overdose. 5th ed. The McGraw-Hill companies; 2007:233–234.