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Methylxanthines, including theophylline and caffeine, are nonselective adenosine receptor antagonists. In overdose, toxicity results from the release of endogenous catecholamines with beta-1- and beta-2-adrenergic stimulation. Theophylline may cause intoxication after an acute single overdose, or intoxication may occur as a result of chronic accidental repeated overmedication or reduced elimination resulting from hepatic dysfunction or interacting drug (eg, cimetidine, erythromycin). The usual serum half-life of theophylline is 4–6 hours, but this may increase to more than 20 hours after overdose. Caffeine in energy drinks or herbal or dietary supplement products can produce similar toxicity.


Mild intoxication causes nausea, vomiting, tachycardia, and tremulousness. Severe intoxication is characterized by ventricular and supraventricular tachyarrhythmias, hypotension, and seizures. Status epilepticus is common and often intractable to the usual anticonvulsants. After acute overdose (but not chronic intoxication), hypokalemia, hyperglycemia, and metabolic acidosis are common. Seizures and other manifestations of toxicity may be delayed for several hours after acute ingestion, especially if a sustained-release preparation such as Theo-Dur was taken.

Diagnosis is based on measurement of the serum theophylline concentration. Seizures and hypotension are likely to develop in acute overdose patients with serum levels greater than 100 mg/L (555 mcmol/L). Serious toxicity may develop at lower levels (ie, 40–60 mg/L [222–333 mcmol/L]) in patients with chronic intoxication. Serum caffeine levels are not routinely available in clinical practice, but in a study of 51 fatal cases the median level was 180 mg/L (range 33–567 mg/L).


A. Emergency and Supportive Measures

After acute ingestion, administer activated charcoal. Repeated doses of activated charcoal may enhance theophylline elimination by “gut dialysis.” Addition of whole bowel irrigation should be considered for large ingestions involving sustained-release preparations.

Hemodialysis is effective in removing theophylline and is indicated for patients with status epilepticus or markedly elevated serum theophylline levels (eg, greater than 100 mg/L [555 mcmol/L] after acute overdose or greater than 60 mg/L [333 mcmol/L] with chronic intoxication).

B. Specific Treatment

Treat seizures with benzodiazepines (lorazepam, 2–3 mg intravenously, or diazepam, 5–10 mg intravenously) or phenobarbital (10–15 mg/kg intravenously). Phenytoin is not effective. Hypotension and tachycardia—which are mediated through excessive beta-adrenergic stimulation—may respond to beta-blocker therapy even in low doses. Administer esmolol, 25–50 mcg/kg/min by intravenous infusion, or propranolol, 0.5–1 mg intravenously.

Aggelopoulou  E  et al. Atrial fibrillation and shock: unmasking theophylline toxicity. Med Princ Pract. 2018;27(4):387–91.
[PubMed: 29936503]  
Andrade  A  et al. Dangerous mistake: an accidental caffeine overdose. BMJ Case Rep. 2018 Jun 8;2018.
[PubMed: 29884665]
Carreon  CC  et al. How to recognize caffeine overdose. Nursing. 2019 Apr;49(4):52–5.
[PubMed: 30893206]  
Jones  AW. Review of caffeine-related fatalities along with postmortem blood concentrations in 51 poisoning deaths. J Anal Toxicol. 2017 Apr 1;41(3):167–72.
[PubMed: 28334840]  

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