Theophylline Toxicity

Theophylline (and aminophylline, its ethylenediamine salt) has a narrow therapeutic index (10 to 20 mg/L, or 55 to 110 micromol/L). It is metabolized in the liver by CYP1A2 and CYP3A4 and cleared by saturable kinetics.

Toxicity follows overdose, dose accumulation, intravenous loading in a patient already taking the drug, and interacting drugs that inhibit its clearance (ciprofloxacin, clarithromycin, erythromycin, cimetidine, fluvoxamine, oral contraceptives), or conditions that impair it (heart failure, cirrhosis, viral illness, fever, age over 60 years).

Mechanisms: phosphodiesterase inhibition, adenosine receptor antagonism (seizures, tachycardia), and beta-adrenergic stimulation through catecholamine release (hypokalemia, hypotension, tachyarrhythmia, hyperglycemia, metabolic acidosis).

Two patterns

• Acute overdose: severe vomiting, hypokalemia and metabolic acidosis, seizures at levels over 100 mg/L (550 micromol/L)
• Chronic toxicity (the commoner and deadlier): seizures and arrhythmia at lower levels (40 to 60 mg/L), often without preceding vomiting

Peak levels are delayed with sustained-release preparations for up to 12 to 24 hours. Complications: refractory status epilepticus, ventricular arrhythmia, rhabdomyolysis, aspiration, and permanent brain injury.

• Persistent vomiting (often hematemesis), abdominal pain, tremor, agitation, tachypnea
• Sinus tachycardia, supraventricular and ventricular arrhythmias, hypotension (beta-2 vasodilation)
• Hypokalemia, hypophosphatemia, hypomagnesemia, hyperglycemia, hypercalcemia, metabolic acidosis, leukocytosis
• Seizures (often multiple and prolonged), delirium, coma
• Rhabdomyolysis
• Red flags: seizures, ventricular arrhythmia, a level over 100 mg/L after acute overdose, a level over 60 mg/L in chronic toxicity, and age over 60 years

1. Serum theophylline level at presentation and every 2 to 4 hours until falling twice (sustained-release products produce a late peak).
2. 12-lead ECG and continuous monitoring.
3. Potassium, magnesium, phosphate, calcium, glucose, creatinine, creatine kinase, blood gases, lactate.
4. Paracetamol and salicylate levels for deliberate overdose.
5. Medication history for interacting drugs and for recent dose changes.

Differentials: salicylate poisoning, sympathomimetic toxicity, caffeine poisoning, thyrotoxicosis, withdrawal states, sepsis, status epilepticus of other cause.

1. Resuscitation: airway protection, oxygen and IV crystalloid.
2. Multiple-dose activated charcoal: 50 g orally or by tube (children 1 g/kg) every 2 to 4 hours (or 25 g every 2 hours) until the level is under 20 mg/L, with ondansetron 4 to 8 mg IV (children 0.15 mg/kg) beforehand for vomiting. Use only with an intact airway and no ileus.
3. Whole bowel irrigation for large sustained-release ingestions, with polyethylene glycol 2 L/h orally or by tube (children 25 mL/kg/h).
4. Seizures: lorazepam 4 mg IV (children 0.1 mg/kg), repeated, then phenobarbital 15 to 20 mg/kg IV over 20 minutes. Avoid phenytoin, which is ineffective. Propofol infusion for refractory status.
5. Tachyarrhythmias and hypotension from beta-2 effect: esmolol 500 micrograms/kg IV over 1 minute, then 50 to 200 micrograms/kg/min, or propranolol 1 mg IV every 5 minutes up to 5 mg, with caution in asthma and with ventilatory support available. Phenylephrine for refractory hypotension.
6. Potassium: replace gently, since hypokalemia is a redistribution (total body potassium is often normal). Give potassium chloride 10 to 20 mmol IV over 1 to 2 hours and recheck, aiming for 3.5 to 4.0 mmol/L. Correct magnesium with magnesium sulfate 2 g IV.
7. Metabolic acidosis: sodium bicarbonate only for severe acidosis (pH under 7.1).
8. Haemodialysis (the extracorporeal treatment of choice): indicated for seizures, life-threatening arrhythmia, shock, rising levels despite charcoal, or a level over 100 mg/L (555 micromol/L) after acute overdose, or over 60 mg/L (330 micromol/L) in chronic toxicity. Suggested for a level over 90 mg/L in an acute overdose with severe symptoms or age under 1 year or over 60 years, and chronic levels over 40 mg/L. Stop when the level is under 15 mg/L, with a check 6 hours later for rebound. Charcoal haemoperfusion is an alternative.
9. Rhabdomyolysis: IV crystalloid to maintain urine output over 1 mL/kg/h.

Observation at least 6 hours for immediate-release and 24 hours for sustained-release overdose. Review of drug interactions and dose before restarting.