Most physicians are aware of the use of liver function tests to detect hepatotoxicity in patients with tuberculosis who are being treated with isoniazid (INH; Laniazid, Nydrazid). However, physicians may not be aware that the acute ingestion of as little as 1.5 g of this drug can be toxic. In doses of 30 mg per kg or more, isoniazid often produces seizures. If large quantities of the drug (80 to 150 mg per kg or more) are taken intentionally or accidentally, recurrent seizures, profound metabolic acidosis, coma and even death can occur.1
A previously healthy 17-year-old boy ingested 20 to 30 300-mg tablets of isoniazid (75 to 112 mg per kg) in an attempt to commit suicide after a breakup with his girlfriend. Two hours after ingesting the drug, he collapsed while at church. Rescue personnel described him as lethargic and diaphoretic at the scene. In the ambulance on the way to the hospital, he began having seizures, became unresponsive for five minutes and then was either somnolent or combative. When the seizures started again, an endotracheal tube was inserted and diazepam was administered intravenously.
The patient's medical history was significant only for a positive purified protein derivative test with a negative chest radiograph several months earlier. He had no previous suicide attempts. His only medication was isoniazid, 300 mg per day.
On arrival at the hospital emergency department, the patient had another seizure. He then became comatose, with a blood pressure of 179/83 mm Hg, a pulse rate of 100 beats per minute, a respiratory rate of 28 breaths per minute and an oral temperature of 37.7°C (100°F).
The physical examination revealed an 80-kg (176-lb), 17-year-old, intubated boy who was fighting the ventilator. He was verbally unresponsive, but the other physical findings were normal. The neurologic examination revealed no focal abnormalities. Deep tendon reflexes were normal. No clonus was present, and the plantar response was normal.
Blood gas measurements revealed an arterial pH of 7.03, a partial pressure of arterial oxygen of 298 mm Hg, a partial pressure of arterial carbon dioxide of 37 mm Hg and a bicarbonate concentration of 9.3 mEq per L (9.3 mmol per L). The sodium concentration was 144 mEq per L (144 mmol per L), the chloride level was 104 mEq per L (104 mmol per L), the potassium concentration was 3.5 mEq per L (3.5 mmol per L), and the carbon dioxide content was 10 mEq per L (10 mmol per L). The anion gap was 30. The blood sugar level was 150 mg per dL (8.3 mmol per L). The serum calcium and magnesium levels were normal.
The serum and urine toxicology screens were negative, and the initial liver function tests were normal. Urinalysis was negative. The white blood cell count was 18,800 per mm3 (18.8 × 109 per L), with a differential of 24 percent (0.24) lymphocytes, 68 percent (0.68) neutrophils, 5 percent (0.05) monocytes, 2 percent (0.02) band cells and 1 percent (0.01) eosinophils.
The electrocardiogram revealed sinus tachycardia. The chest radiograph and a computed tomographic scan of the brain were normal.
Acute emergency department management for an unknown toxic ingestion was initiated. Gastric lavage revealed no pill fragments. The patient was given 60 g of activated charcoal with 30 g of sorbitol via a nasogastric tube and three ampules of sodium bicarbonate (1.8 mEq per kg) intravenously. He was subsequently transferred to the medical intensive care unit on mechanical ventilation.
Once it was learned that the patient had ingested isoniazid, 5 g (61.5 mg per kg) of pyridoxine (vitamin B6) was administered. Soon afterward he became awake, alert and responsive. Repeat arterial blood gas measurements revealed correction of the metabolic acidosis. The patient was then successfully extubated. He remained alert and oriented, with slightly slurred speech. He exhibited mild ataxia, a positive Romberg sign and nystagmus, but these problems resolved over the next few days.
Clinical Syndrome of Isoniazid Toxicity
Isoniazid toxicity is associated with a high mortality rate.2 If isoniazid is taken acutely, as little as 1.5 g (five 300-mg tablets) can cause toxicity. Doses larger than 30 mg per kg often produce seizures. Ingestion of the drug in amounts greater than 80 to 150 mg per kg can rapidly lead to death.1
The first signs and symptoms of isoniazid toxicity may appear within 30 minutes to two hours after ingestion and may include nausea, vomiting, rash, fever, ataxia, slurring of speech, peripheral neuritis, dizziness and stupor.3 These symptoms are usually followed by grand mal seizures and coma. The seizures are often refractory to anticonvulsants, particularly phenytoin (Dilantin) and barbiturates. Respiratory failure and death can follow.
|Indirect (via lactic acidosis)
|Isoniazid (Laniazid, Nydrazid)
Mechanism of Isoniazid Toxicity
Peak blood levels of isoniazid are reached one to two hours after ingestion, although toxic effects can begin to appear much sooner.3 The drug readily diffuses to all body fluids and tissues, with the largest concentration occurring in the liver.4 The ingestion of 80 to 150 mg per kg is likely to result in severe seizure activity.5 Blood levels are not helpful in managing an acute isoniazid overdose.
Pyridoxine is a necessary cofactor for production of the neurotransmitter gamma-aminobutyric acid (GABA). Pyridoxine must be activated to produce GABA. Isoniazid combines with pyridoxine and renders the pyridoxine inactive, resulting in a depletion of GABA in the brain. This reduction in GABA levels increases the susceptibility to seizures. Thus, the neurotoxic effects of isoniazid are specifically counteracted by the administration of pyridoxine.6
Management of Isoniazid Toxicity
Control of Life-Threatening Events
A secure airway should be established and maintained if the patient is having seizures, is comatose or is unresponsive.
Intravenous access should be obtained, and fluids should be administered. Diazepam (Valium), 5 to 10 mg administered intravenously, is the initial approach to seizure control, with the dose repeated as necessary. Diazepam has been found to be more effective in controlling isoniazid-induced seizures than anticonvulsants such as phenytoin (Dilantin) or barbiturates.7
The acidosis associated with isoniazid toxicity appears to be lactic acidosis secondary to the seizure activity. Therefore, as the seizures are controlled, the acidosis usually decreases in severity. Since sodium bicarbonate may assist in correcting severe cases of acidosis, its administration should be considered if the pH is less than 7.1. A good starting dose is 1 to 3 mEq per kg, with frequent monitoring of blood gases to guide further bicarbonate administration.
Correction of Gaba Deficiency by Pyridoxine Replacement
Pyridoxine should be administered in a dose equivalent to the suspected maximum amount of isoniazid ingested (i.e., gram-per-gram replacement).8 If the amount of ingested isoniazid is unknown, 5 g of pyridoxine is given intravenously over five to 10 minutes. Repeat dosing may be needed for persistent seizure activity and may also be used to reverse deep coma.
After the initial stabilization efforts, attempts should be made to prevent the absorption of isoniazid and to hasten elimination of the drug. Gastric lavage is indicated if it can be done within one hour of isoniazid ingestion.
Charcoal, if administered within one hour of the ingestion of isoniazid, has been shown to be effective in preventing absorption of the drug. Charcoal should initially be given as a slurry with sorbitol.12 The usual charcoal dose is 30 to 100 g for adults (1 to 2 g per kg) and 15 to 30 g for children (1 to 2 g per kg). The sorbitol dose in adults is 1 to 2 g per kg, with a maximum dose of 150 g. In children, the sorbitol dose is 1.0 to 1.5 g per kg to a maximum dose of 50 g.
Prevention of Isoniazid Toxicity
Before isoniazid is prescribed, patients should be screened for depression. If a patient with depression needs isoniazid therapy but is considered to be at high risk for misusing the drug, it may be prudent to prescribe only two weeks' worth of the drug at a time. Bimonthly tablet counts and isoniazid blood levels may also be advised. In patients without depression, isoniazid should be dispensed in a one-month supply to prevent access to large amounts of the drug.
The toxic effects of isoniazid should be explained to all patients. Keeping the drug away from children must be stressed.
Isoniazid toxicity should be suspected in any patient who presents with refractory seizures and metabolic acidosis. One study15 found that isoniazid toxicity was responsible for 5 percent of all cases of seizures associated with drug intoxications.
As tuberculosis increases, physicians will prescribe more isoniazid. A consequent increase in accidental and intentional ingestions of this drug should be expected. Physicians must be prepared to counteract the potentially fatal toxic effects of isoniazid. A simple stepwise approach (Table 2) can help.
|Many of the steps listed below can be carried out concurrently.
|1. Secure the airway. Remember ABC (airway, breathing, circulation).
|2. Obtain intravenous access, and administer intravenous fluids.
|3. For seizures:
|a. In adults, administer diazepam (Valium) intravenously in a dose of 5 to 10 mg, and repeat the dose if necessary.
|b. In children, administer diazepam intravenously in a dose of 0.25 to 0.40 mg per kg, up to 10 mg per dose. The dose can be repeated if necessary.
|4. Obtain arterial blood gases. If the pH is 7.1 or less, give sodium bicarbonate, 1 to 3 mEq per kg intravenously.
|5. Replace pyridoxine:
|a. If the amount of ingested isoniazid is known, administer a gram-per-gram dose* of pyridoxine (diluted to a concentration of 50 mL per g) intravenously over five to 10 minutes.† The pyridoxine dose may be repeated every five to 20 minutes until the seizures stop or the patient regains consciousness. Pyridoxine can also be given to resolve residual neurologic defects.
|b. If the amount of ingested isoniazid is unknown, give 5 g of pyridoxine (diluted to 50 mL per g) intravenously over five to 10 minutes.
|6. Perform gastric lavage if within one hour of isoniazid ingestion. Remember to protect the airway: use an endotracheal tube with the cuff inflated, or place the patient in the Trendelenburg and left lateral decubitus position.
|7. Administer charcoal and sorbitol if within one hour of isoniazid ingestion:
|a. In adults, give 30 to 100 g (1 to 2 g per kg) of charcoal as a slurry with 1 to 2 g per kg of sorbitol, up to 150 g. Repeat the charcoal dose only.
|b. In children, give 15 to 30 g (1 to 2 g per kg) of charcoal as a slurry with 1.0 to 1.5 g per kg of sorbitol, up to 50 g. Repeat the charcoal dose only.
|8. If the above methods fail to control seizures, consider hemodialysis or the administration of thiopental by an anesthesiologist.
|9. If the patient remains symptomatic, obtain a complete blood count, urinalysis and measurements of electrolytes, blood urea nitrogen, creatinine, glucose, creatinine kinase and liver enzymes. If the patient has liver damage, monitor the prothrombin time or the International Normalized Ratio.