Toxicology Case Files from the Utah Poison Control Center
Teaching Points
- Caffeine and theophylline are methylxanthine adenosine antagonists and phosphodiesterase inhibitors that cause catecholamine release and vasodilation
- Theophylline was historically a common cause of severe poisoning but exposures have declined substantially
- Supportive treatment includes fluid resuscitation and benzodiazepines. Beta-blockers may be used to treat severe tachycardia and paradoxically improve blood pressure
- Removal of both agents may be enhanced by multidose activated charcoal or hemodialysis
Case
A 34-year-old female ingested 20 tabs of her family member’s theophylline (unknown strength) in a suicide attempt.
She presented to the emergency department shortly after with nausea, vomiting, and tremor. Her heart rate eventually increased to 144 but she remained normotensive.
Her potassium declined to 2.1 mEq/L and white count rose to 31. Initial theophylline concentration was 65.6 mg/L which then rose to >80 mg/L (greater than upper limit of quantitation); however the patient’s symptoms remained mild. Concentrations downtrended to 50.6, 36.4, 21.8, and 5.1
Despite significantly elevated theophylline concentrations, she did not experience any hypotension, dysrhythmias, or seizures. She was unable to tolerate activated charcoal due to nausea and vomiting.
She remained symptomatic for 4 days, recovered, and was transferred to psychiatry.
Methylxanthine Toxicity
Caffeine (1,3,7-trimethylxanthine) and theophylline (1,3-dimethylxanthine) act as adenosine antagonists, which cause catecholamine release. Caffeine has greater blood-brain barrier penetration and may lead to more CNS effects though both drugs may cause seizures.
The stimulant effects are familiar to anyone who has consumed too much caffeine: palpitations, tremor, nausea, and insomnia.
Somewhat paradoxically, vasodilation also occurs, leading to a very wide pulse pressure in moderate toxicity or overt hypotension in severe toxicity. Beta-2 agonism causes vasodilation along with phosphodiesterase inhibition. As tachycardia worsens, cardiac output may decrease with diminished ventricular filling. Thus, a beta antagonist such as propranolol, metoprolol, or esmolol may actually improve hypotension.
Numerous tachydysrhythmias may occur with methylxanthine poisoning, including sinus tachycardia, supraventricular tachycardia, atrial fibrillation, multifocal atrial tachycardia, and ventricular tachycardia. As mentioned above, AV nodal blocking agents may be useful in treating these dysrhythmias. Adenosine would not be beneficial with the existing adenosine antagonism and exceedingly short duration of action. In contrast to usual therapy, beta-blockers may also be useful in treating ventricular tachycardia.
A natural mechanism for the termination of seizures is buildup of adenosine as ATP is cleaved to ADP, AMP, and then adenosine in the brain. As methylxanthines are adenosine antagonists, seizures may be refractory and difficult to treat. Traditional anticonvulsants such as phenytoin are ineffective in treating these seizures. Escalating doses of benzodiazepines and/or barbiturates are recommended as first-line agents. It is unknown whether levetiracetam, which inhibits excitatory neurotransmitter release, would be helpful.
Laboratory abnormalities are related to the sympathetic stimulation: intracellular shift of potassium, elevated glucose, and demargination of white blood cells.
The entire gamut of gastrointestinal decontamination and enhanced elimination procedures are options for treatment of methylxanthine overdose. Activated charcoal adsorbs methylxanthines though vomiting may limit its use. Antiemetics should be given liberally to control vomiting (once the patient has stopped vomiting up pill fragments) and facilitate charcoal administration.
As methylxanthines undergo enterohepatic recirculation, multi-dose activated charcoal is helpful to bind the drug as it passes back through the gut, even after initial absorption is complete.
Whole bowel irrigation could also be used in the case of extended-release theophylline ingestion, though there is little data to guide use. Gastric lavage would be reasonable in very large ingestions as overdose may be fatal and refractory to treatment.
Hemodialysis removes both caffeine and theophylline. As with any poisoning, indications for hemodialysis are severe toxicity (seizures, hypotension, unstable dysrhythmias). Theophylline and caffeine concentrations are readily available at most hospitals and can also be used to guide management decisions. Dialysis is recommended in acute exposures with a caffeine or theophylline concentration > 100 mg/L. Chronic exposures result in toxicity at lower concentrations given saturation of tissues with the drug, and dialysis is suggested for concentrations > 60 mg/L in such cases.1
Reference
- Hemodialysis in theophylline poisoning https://www.extrip-workgroup.org/theophylline