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Isoniazid (INH) poisoning

Isoniazid (INH) poisoning
Author:
Rama B Rao, MD
Section Editors:
Stephen J Traub, MD
Michele M Burns, MD, MPH
Deputy Editor:
Michael Ganetsky, MD
Literature review current through: Dec 2022. | This topic last updated: Jan 25, 2021.

INTRODUCTION — Isoniazid (INH) is an antibiotic used to treat infection with Mycobacterium tuberculosis (TB). A large portion of the world's population is infected with TB. Although the disease is inactive in the majority, up to 10 percent of these persons may become infectious in their lifetime [1-3]. Many patients who are identified as being at risk of developing active, infectious TB or who suffer from active disease are treated with INH.

Acute INH toxicity frequently manifests as altered mental status or seizures. Poisoning may occur with unintentional ingestion in children, suicidal intent, or in patients taking extra tablets to compensate for missed doses [4-6]. Chronic INH toxicity frequently manifests as peripheral neuropathy or hepatotoxicity, although other chronic conditions are described.

The presentation and management of acute INH poisoning will be reviewed here. Chronic INH hepatotoxicity and the clinical use of INH are discussed separately. (See "Isoniazid hepatotoxicity" and "Isoniazid: An overview".)

PHARMACOLOGY AND CELLULAR TOXICOLOGY — The antimicrobial activity of Isoniazid (INH) is selective for mycobacteria, probably resulting from its ability to inhibit mycolic acid synthesis. This inhibition interferes with cell wall synthesis, producing a bactericidal effect. (See "Isoniazid: An overview".)

INH toxicity stems from several causes, including deficiencies of pyridoxine (vitamin B6) and gamma amino butyric acid (GABA). INH induces a state of functional pyridoxine deficiency by at least two mechanisms. First, INH metabolites directly attach to and inactivate pyridoxine species. Second, INH inhibits the enzyme pyridoxine phosphokinase; this enzyme is necessary to activate pyridoxine to pyridoxal 5' phosphate, the cofactor in many "pyridoxine-dependent" reactions. Functional pyridoxine deficiency is the likely mechanism of INH-induced peripheral neuropathy.

INH may induce a critical deficiency in GABA, an inhibitory neurotransmitter that modifies or suppresses excitatory neurons [7,8]. GABA is produced in a pyridoxine-dependent decarboxylation reaction. The functional pyridoxine deficiency induced by INH leads to a reduction in GABA production. In addition, INH inhibits glutamate dehydrogenase, the enzyme which catalyzes the conversion of glutamate to GABA. GABA deficiency may manifest as seizures, particularly in acute overdose.

INH metabolites, such as acetylhydrazine, cause idiosyncratic direct hepatocellular toxicity. The mechanisms of chronic INH hepatotoxicity are discussed separately. (See "Isoniazid hepatotoxicity", section on 'Mechanism of hepatotoxicity'.)

KINETICS — INH is rapidly absorbed from the gastrointestinal tract. Its volume of distribution is between 0.6 and 1.2 L/kg. INH undergoes hepatic metabolism to hydrazones, as well as acetylation to hydrazine and hydrazides. The rate of acetylation may vary by population and affects the elimination half-life. INH may inhibit hepatic enzymes CYP2C9, 2C19, 3A4, and 2E1. The major route of elimination is via the kidney. The pharmacokinetics of INH are discussed in greater detail separately. (See "Isoniazid: An overview", section on 'Pharmacokinetics'.)

CLINICAL FEATURES OF ACUTE TOXICITY — Acute INH overdose usually manifests as altered or depressed mental status or seizures, including status epilepticus [9]. Higher ingestion doses (≥20 mg/kg) increase the likelihood of seizures [7]. An acute ingestion of 2 g may cause toxicity in some adults [8].

Clinically, seizures may be discrete and isolated, or in severe overdoses, present as status epilepticus. Seizures most commonly start within 30 minutes of the exposure, but may begin up to two hours later and persist for many hours. The patient may also have an altered or depressed mental status in the absence of seizure activity [6,10-13]. Coingestants may alter the time of onset or duration of toxicity.

Vital sign abnormalities such as tachycardia, tachypnea, and elevations in temperature may occur as a result of seizure activity. Anoxia and aspiration may also occur. Long-term sequelae include anoxic encephalopathy and dementia [14]. The management of INH-induced seizures is described below. (See 'Seizure management' below.)

CLINICAL FEATURES OF CHRONIC TOXICITY

Hepatotoxicity — Chronic hepatotoxicity from INH can develop within the first eight weeks of therapy but may develop months later. INH-induced hepatotoxicity is defined as an AST elevation of three times the upper limit of normal in a patient with symptoms including nausea, vomiting, abdominal pain, or jaundice, or an AST elevation five times the upper limit of normal in an asymptomatic patient. The diagnosis, management, and monitoring of chronic INH hepatotoxicity are discussed separately. (See "Isoniazid hepatotoxicity".)

Peripheral neuropathy — A sensory peripheral neuropathy can occur in patients taking INH and may be prevented by administering supplemental pyridoxine. Often, patients complain of bilateral numbness and tingling or burning of upper and lower extremities.

Rarely, INH-induced neuropathy may include central features such as ataxia and nystagmus [15]. Other reactions to INH therapy have been reported and are listed in the attached table (table 1).

DIFFERENTIAL DIAGNOSIS — Patients without a clear history of INH exposure who present with seizures should undergo a comprehensive evaluation for non-toxicologic causes (see "Evaluation and management of the first seizure in adults"). If a toxic ingestion is suspected, other (non-INH) causes of seizures should also be entertained (table 2).

No focal findings distinguish INH-induced status epilepticus from other types of prolonged seizures. The key difference is that seizures due to INH poisoning are often refractory to treatment with benzodiazepines and are difficult to manage without pyridoxine. (See 'Seizure management' below.)

Clinicians should suspect INH as a possible cause of seizures when the patient or a patient's family member is being treated with INH or has emigrated from an area where tuberculosis infection is endemic.

LABORATORY EVALUATION — Metabolic abnormalities in acute INH toxicity relate directly to seizure activity and may include metabolic acidosis (due to lactate production), an elevated creatine kinase, and (later) renal insufficiency from rhabdomyolysis [4]. Therefore, laboratory evaluation should include a basic metabolic profile, serum lactate, and creatine kinase, as well as a pregnancy test in women of childbearing age. INH concentrations are not clinically useful as results may take days or weeks to perform.

Additional tests for patients with an intentional overdose also include:

Fingerstick glucose, to rule out hypoglycemia as the cause of any seizure or alteration in mental status

Acetaminophen and salicylate testing to rule out these common coingestants

An electrocardiogram to rule out conduction system poisoning by drugs that effect the QRS or QTc intervals

MANAGEMENT OF ACUTE TOXICITY

Airway management — The clinician should be prepared to establish a definitive airway with an endotracheal tube for patients with coma, seizures, or status epilepticus. Patients with a clinically severe INH overdose are at high risk for aspiration and prolonged hypoxia. Airway management is discussed separately. (See "Rapid sequence intubation for adults outside the operating room" and "Approach to advanced emergency airway management in adults" and "Rapid sequence intubation (RSI) outside the operating room in children: Approach" and "Emergency endotracheal intubation in children".)

If a neuromuscular blocking agent is used for intubation, a short-acting drug such as succinylcholine is preferred. Longer-acting agents may mask seizure activity and should be avoided if possible, unless monitoring with an electroencephalogram (EEG) is performed.

During any period of drug-induced paralysis, pupillary response may help to determine the presence of an active seizure. Pupillary reactivity is not typically affected by nicotinic neuromuscular antagonists (eg, succinylcholine). Nonreactive pupils suggest active seizures and require therapy with pyridoxine as well as GABA agonist medications, such as benzodiazepines. (See 'Seizure management' below.)

Gastrointestinal decontamination — There are limited data regarding the role of activated charcoal (AC) or gastric lavage in INH poisoning. While INH is readily bound by AC, the drug is absorbed rapidly and patients with INH overdose are at high risk for aspiration. Thus, we give AC (1 g/kg by mouth or by nasogastric or orogastric tube) only to patients who present early (within one to two hours) following an acute ingestion. AC should be withheld in patients who are sedated and may not be able to protect their airway, unless the patient is intubated. However, tracheal intubation should not be performed solely for the purpose of giving AC.

Gastric lavage is rarely indicated. Patients with evidence of severe toxicity (eg, status epilepticus) who present within one to two hours of ingestion and who are either protecting their airway (uncommon with severe toxicity) or are intubated, are candidates for gastric lavage. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Gastric lavage'.)

Whole bowel irrigation is unlikely to empty the bowels prior to the onset of central nervous system toxicity and is not recommended. Syrup of ipecac should be avoided, even in the otherwise asymptomatic patient, since seizures may begin during the induction of emesis, increasing the risk of aspiration.

Seizure management — The goal of seizure management in acute INH poisoning is to repair the critical deficiency in the inhibitory neurotransmitter gamma amino butyric acid (GABA). This is accomplished by intravenous (IV) administration of both pyridoxine (to overcome functional pyridoxine deficiency) and a benzodiazepine (eg, lorazepam), which potentiates the effects of available GABA [7,8,10,16]. The use of either agent alone may be inadequate to control seizure activity.

Pyridoxine — Pyridoxine (vitamin B6) binds to INH, replaces stores of pyridoxine and pyridoxal 5' phosphate, and facilitates the production of GABA [7,10,11]. The onset of action is rapid. Patients in status epilepticus refractory to benzodiazepines often stop seizing within minutes of pyridoxine administration. (See 'Pharmacology and cellular toxicology' above.)

The dose of pyridoxine is 1 g intravenously for every gram of INH ingested [9]. When the quantity of INH ingested is unknown, 5 g IV may be administered to an adult and 70 mg/kg (maximum 5 g) to a child. The dose can be administered at a rate of 0.5 g/min, and may be repeated in patients with refractory seizure activity [7,8,17,18].

Pyridoxine is a water-soluble vitamin with a wide therapeutic margin. Acute pyridoxine-induced neuropathy is reported at doses of 1 g/kg, a dose unlikely to be required for the management of INH overdose [8].

Benzodiazepines — Benzodiazepines act on the GABA receptor and enhance neuroinhibition. Lorazepam may be used to terminate seizure activity from INH poisoning, but may need to be administered repeatedly in escalating doses. In adults, lorazepam 2 mg IV can be given every five minutes until seizures are controlled. The dose may be doubled in cases of persistent seizures. In children, lorazepam (0.05 to 0.1 mg/kg IV, up to 2 mg per dose) may be given and repeated as necessary every five minutes. Alternative benzodiazepines may be used if lorazepam is unavailable. Patients requiring more than 3 doses of lorazepam should be monitored closely, as respiratory depression may ensue even after seizures are controlled.

Other sedative hypnotic medications — Ultra-short acting barbiturates are useful for intubation and terminating status epilepticus, but these agents do not have a sustained duration of action for controlling seizures. In addition, they can cause hypotension and should be avoided in hypotensive or hypovolemic patients.

Phenobarbital, a longer acting barbiturate, may be used as adjunctive therapy for patients with persistent seizures or when there is a delay in obtaining pyridoxine. The dose is 20 mg/kg by slow IV push. Endotracheal intubation is usually required when phenobarbital is combined with other sedative-hypnotic agents.

Phenytoin and fosphenytoin — Phenytoin and fosphenytoin are unlikely to be efficacious in treating INH-induced seizures and status epilepticus and are not indicated.

Metabolic acidosis — Nearly all the metabolic derangements associated with severe INH toxicity are the result of status epilepticus or refractory seizure activity, which can be associated with lactic acidosis [7]. Stopping the seizure activity and providing adequate ventilatory support usually results in rapid reversal of acidemia, since metabolism of the excess lactate regenerates bicarbonate.

The appropriate role of sodium bicarbonate administration in INH toxicity remains unclear. Sodium bicarbonate has been used in severe cases of lactic acidosis from status epilepticus [19]. In general, most physicians would limit the use of sodium bicarbonate to patients with severe metabolic acidemia (arterial pH below 7.10 to 7.15) who are otherwise ventilating adequately, with the aim being to maintain the pH above 7.15 until the primary process can be reversed. The administration of sodium bicarbonate should not precede treatment with a benzodiazepine and pyridoxine, as the cause of the acidosis will persist despite attempts to correct the pH. (See "Bicarbonate therapy in lactic acidosis".)

Enhanced elimination — Hemodialysis is generally not indicated in INH poisoning. While hemodialysis may remove INH from the circulation, patients with severe toxicity become symptomatic before it is feasible to perform the procedure. Adequate pyridoxine and benzodiazepine therapy generally obviate the need for hemodialysis [7]. Hemodialysis may be helpful in the rare setting of a massive overdose when adequate pyridoxine is unavailable [18].

Prolonged coma — Patients with adequate seizure control may develop a persistent coma from INH toxicity or the administration of sedative hypnotic agents. There are reports of supplemental pyridoxine being used to reverse prolonged comas lasting up to 42 hours [11]. The mechanism by which pyridoxine causes such a reversal, remains unclear. Pyridoxine doses of 3 to 5 g in adults (in addition to the initial doses used to treat seizures) were used in these cases. We suggest obtaining consultation with a medical toxicologist or through a poison control center when such treatment is considered. (See 'Additional resources' below.)

Other causes of persistent coma, such as a closed head injury sustained during seizure activity, hypoglycemia, or coingestants, should be considered simultaneously when considering treatment with additional pyridoxine. Once a patient regains consciousness from a prolonged coma, they should be assessed for injuries associated with the initial seizure. Spinal compression fractures are among the injuries that have been reported [20]. (See "Stupor and coma in adults".)

Hyperthermia — Hyperthermia is generally the result of seizure activity and should spontaneously resolve once seizures are controlled. Antipyretics are unnecessary. Causes other than seizure (eg, aspiration pneumonia) should be investigated in patients with a delayed presentation of hyperthermia.

PEDIATRIC CONSIDERATIONS — The management of INH overdose is fundamentally the same in children and adults with the exception of medication dosing. Therapeutic dosing for children with INH induced seizures is as follows:

Lorazepam – 0.05 to 0.1 mg/kg intravenously (IV); doses may be repeated every five minutes up to 10 mg total over 20 minutes.

Pyridoxine – 70 mg/kg IV, up to 5 g in a child, with supplemental dosing if this is ineffective. A dose of 1 gram pyridoxine per gram of INH ingested can be used (and may be necessary) if the quantity of INH ingested is known [21].

Serum INH concentrations are not typically indicated for clinical management but may be used with infant ingestions to confirm the etiology of seizures after the patient recovers [12].

When intravenous access is delayed, as may be the case in infants and toddlers, rectal diazepam may be administered. The dose in younger children is 0.5 mg/kg. Intraosseous access is a viable alternative when IV access cannot be obtained (see "Intraosseous infusion"). Oral pyridoxine per nasogastric tube may be used initially (provided the airway is secure), but IV pyridoxine should be administered as soon as IV access is established.

On occasion, a child is brought for evaluation after a reported exposure to INH but neither seizures nor altered mental status is observed. In such cases, the child should be observed for six hours to ensure that no signs of toxicity develop and then may be discharged with a responsible adult.

The circumstance of any possible pediatric exposure should be carefully evaluated to ensure that the safety of the child (and other children who live where the exposure occurred) is adequately addressed. A child prescribed INH who presents with seizures should have their prescription bottles carefully inspected for dosing errors.

DISPOSITION — Patients with unintentional exposures who remain asymptomatic with normal vital signs for six hours are unlikely to manifest delayed toxicity and may be medically cleared for discharge.

Patients with a suicidal overdose who present with seizures should be admitted to an intensive care unit for treatment and observation.

Patients who are symptomatic from taking extra doses of INH, with the intent of compensating for missed doses, may require admission. The clinician may use discretion if the patient had one seizure that responds to dose-appropriate treatment and then returns to baseline function. Such a patient may be a candidate for discharge if the following conditions are met over a six hour observation period:

The history of an isolated, accidental overdose is verified.

The patient remains hemodynamically stable.

The patient remains free of any seizure activity or alterations in mental status, and maintains a normal level of function.

However, should the clinician harbor any doubts about the patient's medical condition or whether there is adequate assistance at home, the patient should be admitted for observation.

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment".)

SUMMARY AND RECOMMENDATIONS

Pharmacology and cellular toxicologyIsoniazid (INH) is an antibiotic widely used to treat infection with Mycobacterium tuberculosis (TB). INH toxicity stems from several causes, including deficiencies of pyridoxine (vitamin B6) and gamma amino butyric acid (GABA). These deficiencies can cause seizures that do not respond to standard therapy. INH is rapidly absorbed from the gastrointestinal tract. (See 'Pharmacology and cellular toxicology' above and 'Kinetics' above.)

Clinical features – Acute INH overdose usually manifests as altered or depressed mental status or seizures, including status epilepticus. Seizures may be discrete and isolated, or in severe overdoses, present as status epilepticus. Seizures most commonly start within 30 minutes of the exposure but may begin up to two hours later and persist for many hours. Hepatotoxicity and peripheral neuropathy are potential chronic effects of INH treatment. (See 'Clinical features of acute toxicity' above.)

Seizures – Patients without a clear history of INH exposure who present with seizures should undergo a comprehensive evaluation for non-toxicologic causes. Clinicians should suspect INH as a possible cause of seizures when the patient or a patient's family member is being treated with INH or has emigrated from an area where tuberculosis infection is endemic, or when seizures fail to respond to appropriate benzodiazepine therapy. (See 'Differential diagnosis' above.)

Metabolic abnormalities in acute INH toxicity relate directly to seizure activity. Laboratory evaluation should include a basic metabolic profile, serum lactate, and creatine kinase, as well as a pregnancy test in women of childbearing age. INH concentrations are not clinically useful. Standard testing for coingestants should be performed. (See 'Laboratory evaluation' above.)

Airway management – The clinician should be prepared to establish a definitive airway for patients with coma, seizures, or status epilepticus. Patients with a clinically severe INH overdose are at high risk for aspiration and prolonged hypoxia. (See 'Airway management' above.)

Gastrointestinal decontamination – We give AC (1 g/kg by mouth or by nasogastric or orogastric tube) only to patients who present early (within one to two hours) following an acute ingestion. AC should be withheld in patients who are sedated and may not be able to protect their airway, unless the patient is intubated. However, tracheal intubation should not be performed solely for the purpose of giving AC. (See 'Gastrointestinal decontamination' above.)

Seizure treatment with pyridoxine and benzodiazepine – We recommend treatment with pyridoxine for all patients with seizures from acute INH poisoning (Grade 1B). In addition, these patients should receive standard seizure treatment with a benzodiazepine. The use of either agent alone may be inadequate to control seizure activity. The dose of pyridoxine is 1 g IV for every gram of INH ingested. When the quantity of INH ingested is unknown, 5 g IV may be administered to an adult and 70 mg/kg (maximum 5 g) to a child; additional pyridoxine may be needed. For a benzodiazepine, we give lorazepam 1 to 2 mg IV every five minutes. In children, lorazepam (0.05 to 0.1 mg/kg IV, up to 2 mg per dose) may be given and repeated as necessary every five minutes. Alternative benzodiazepines may be used if lorazepam is unavailable. (See 'Seizure management' above.)

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