AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

The frequency of theophylline overdose has decreased greatly as the use of theophylline for the treatment of asthma and chronic obstructive pulmonary disease (COPD) has declined because of its narrow therapeutic window and the effectiveness of inhaled beta-agonists. The occurrence of adverse effects with theophylline, even at levels in the therapeutic range, and the severity of its effects in acute and chronic overdose are notable; however, theophylline continues to be prescribed for some patients.

Pathophysiology

Theophylline is a methylxanthine derivative that works by inhibiting phosphodiesterase and potentiating intracellular levels of cyclic adenosine monophosphate (cAMP). It is also an antagonist at adenosine receptors in the bronchial smooth muscle, peripheral vasculature, CNS, and myocardium. Peak serum levels occur 90-120 minutes after oral administration, and sustained-release preparations are common; these preparations cause delayed absorption and potential bezoar formation.

Theophylline is 56% protein bound and has a volume of distribution of 0.5 L/kg. Approximately 90% of it is metabolized by the CYP1A2 isozyme of the hepatic cytochrome P450 system to form inactive substances, and 10% is excreted unchanged in the urine. The elimination half-life is significantly longer in neonates than in children and adolescents and is increased in patients with viral illness, congestive heart failure, and hepatic disease. Theophylline metabolism is inhibited by drugs that affect the cytochrome P450 system such as cimetidine, macrolides, and fluoroquinolones. Drugs such as phenytoin, barbiturates, carbamazepine, and tobacco can increase the metabolism of theophylline and lead to toxicity when they are discontinued.

Theophylline affects various body systems, as follows:

• Cardiovascular system: Theophylline stimulates beta1-receptors and can cause atrial tachydysrhythmias such as sinus and supraventricular tachycardia, even at therapeutic levels. Higher levels also can cause atrial fibrillation, multifocal atrial tachycardia in patients with COPD, and occasionally, ventricular tachycardia or fibrillation. Hypotension may occur in severe overdoses secondary to beta2-receptor–stimulated vasodilatation. It may be refractory to fluids and conventional vasopressors.
• CNS: Neurologic adverse effects, including tremor, restlessness, and agitation, also can occur at therapeutic levels. Seizure is the most severe neurologic effect, occurring at levels higher than 90 mcg/mL in acute overdose, higher than 30 mcg/mL in acute-on-chronic ingestion, and as low as 20 mcg/mL in chronic toxicity.
• Gastrointestinal system: Nausea and vomiting are common in acute overdose. Abdominal pain and diarrhea can occur, and drug bezoars may occur with ingestion of sustained-release products.
• Metabolic system: Hypokalemia, hyperglycemia, hypercalcemia, hypophosphatemia, hypomagnesemia, and metabolic acidosis can occur secondary to beta-adrenergic stimulation.

Frequency

United States

In 2004, the American Association of Poison Control Centers (AAPCC) reported 757 exposures to theophylline or aminophylline; 167 of those exposures were in children younger than 19 years. The incidence of theophylline toxicity has decreased greatly over the past decade. This decline in the prescription of theophylline is secondary to the safety and efficacy of the inhaled beta2-agonists in the treatment of asthma and COPD.

International

No current statistics on the international use of theophylline exist, although the drug continues to be available. It is potentially available without prescription in some countries.

Mortality/Morbidity

The most significant morbidity and mortality of theophylline toxicity in acute overdose are secondary to the cardiovascular and CNS effects. Life-threatening tachydysrhythmias and hypotension, as well as refractory seizures, can occur.

Age

Although theophylline toxicity can occur in people of any age, it is more severe in neonates than in children and adolescents.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Acute theophylline overdose causes nausea and vomiting, abdominal pain, tachycardia, mild metabolic acidosis, hypokalemia, hypercalcemia, hypophosphatemia, hypomagnesemia, and hyperglycemia. Severe symptoms such as seizures, dysrhythmias, and hypotension usually do not occur with acute overdose until levels are 80-100 mcg/mL.
• Chronic intoxication often causes milder GI symptoms and does not cause electrolyte shifts or hypotension, as observed in acute overdose. However, significant dysrhythmias and seizures commonly occur with lower levels of the drug in chronic intoxication and in acute-on-chronic overdose.
• Theophylline toxicity should be considered in patients with new-onset seizures or status epilepticus.

Physical

• Cardiovascular findings: Sinus tachycardia is the most common finding. Supraventricular tachycardia, atrial fibrillation, atrial flutter, multifocal atrial tachycardia, and, less commonly, ventricular dysrhythmias can occur. Hypotension commonly occurs in acute overdose.
• Neurologic findings: Tremors, restlessness, agitation, and seizures are common.
• Gastrointestinal findings: Nausea, vomiting, abdominal pain, and diarrhea can occur.

Causes

• Acute toxicity occurs with accidental or intentional overdose.
• Chronic toxicity is caused by excessive daily dosing or interactions of drugs such as macrolide or quinolone antibiotics, allopurinol, oral contraceptives, and cimetidine, which lower the metabolism of theophylline and thereby increase its serum concentrations. Anticonvulsant medications such as phenytoin, phenobarbital, and carbamazepine enhance theophylline metabolism and increase levels of theophylline when they are discontinued.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Serum theophylline levels should be determined every 2 hours until levels decline and every 4 hours until 2 successive findings are below therapeutic levels.
• Check the basic metabolic panel (BMP) for metabolic acidosis and hyperglycemia and determine calcium, phosphorus, and magnesium levels. In the most severe cases, all organ systems may be affected and appropriate laboratory levels, such as creatine kinase and urine myoglobin levels, should be obtained to determine if rhabdomyolysis has occurred.

Imaging Studies

• A kidneys, ureters, and bladder (KUB) radiograph may reveal radiopacities from undissolved sustained-release tablets or pharmacobezoars. Bead-filled capsules may appear as radiolucencies.
• Nonenhanced head CT scans may be obtained if seizures occur.

Other Tests

• Electrocardiography and ECG monitoring may be needed to observe for the development of atrial and ventricular tachydysrhythmias.

Procedures

• Endotracheal intubation should be performed as indicated for airway protection in patients with an altered mental status and vomiting, status epilepticus, or hemodynamic instability.
• Nasogastric tube placement may be required to deliver multidose activated charcoal.
• Hemodialysis may be required in cases of severe toxicity.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Initial stabilization: Initial treatment involves assessment of the ABCs, cardiac monitoring, administration of isotonic fluids for rehydration, and determination of glucose level. Perform endotracheal intubation as indicated for airway protection and ventilatory assistance.
• Treatment of cardiovascular effects: Observe for hypotensive effects. Administer isotonic fluids for hypotension. Refractory hypotension may require administration of a pure alpha-agonist vasopressor agent (eg, phenylephrine). Most patients tolerate theophylline-induced tachycardia without difficulty. Beta-blockers should be used with extreme caution, as mixed results following administration have been reported in the literature. Theophylline toxicity is refractory to adenosine. Ventricular dysrhythmias should be treated in the usual manner.
• CNS hyperstimulation treatment: Patients who are preseizurogenic (ie, manifesting signs of hyperreflexia, clonus, and marked tremor) should be treated with either benzodiazepines or phenobarbital. If seizures develop, prompt therapy with benzodiazepines and phenobarbital should be initiated. Phenytoin may worsen theophylline-induced seizures and should be avoided.
• Decontamination: Administer activated charcoal (1-2 g/kg). Consider whole-bowel irrigation for massive ingestion of sustained-release preparations. Multidose activated charcoal has been beneficial in the treatment of theophylline toxicity because it binds theophylline that diffuses through the small intestine ("gut dialysis"). Recurrent vomiting may be treated with metoclopramide or ondansetron.
• Treatment of electrolyte disturbances: Treat hypokalemia cautiously in patients with acute ingestions. Hypokalemia is secondary to an intracellular shift, rather than total-body depletion. Potassium replacement may cause hyperkalemia as theophylline levels decrease. Most electrolyte disturbances are asymptomatic and do not require treatment.
• Extracorporeal elimination: Hemodialysis is as efficacious as hemoperfusion and is the preferred method of extracorporeal elimination. Hemodialysis should be considered if the theophylline level is more than 100 mcg/mL in acute ingestions and more than 60 mcg/mL in chronic. In patients who develop seizures, refractory hypotension that is unresponsive to fluids, and unstable dysrhythmias, hemodialysis should be considered, regardless of the theophylline level.

Consultations

Consult a toxicologist. A nephrologist may be consulted in cases of severe toxicity requiring charcoal hemoperfusion or hemodialysis.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug Category: Antiemetics

These agents may be used to control vomiting. Phenothiazine antiemetics should be avoided to prevent potentiation of theophylline toxicity.

Drug Category: Drug absorption reducers

Activated charcoal is used to decrease drug absorption and may be all that is required in mild-to-moderate toxicity. It is not absorbed and is excreted entirely through the GI tract.

Drug Category: Whole bowel irrigation agents

Polyethylene glycol is used to increase GI transit time, decreasing absorption of theophylline. It may be used in older children or adults who have ingested significant amounts of products with delayed absorption. It is not absorbed and is excreted entirely through the GI tract.

Drug Category: Benzodiazepines

These agents may be needed to control agitation and seizures.

Drug Category: Alpha agonists

These agents are used to treat hypotension refractory to fluid challenge.

Drug Category: Beta-adrenergic blocking agents

These agents are used to treat severe tachycardia with ischemia or severe hypertension. Short-acting agents should be used because of the potential for significant hypotension in theophylline toxicity.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Admit all patients with signs or symptoms of toxicity.
• Admit patients with serial unchanged or increasing theophylline levels of more than 30 mcg/mL in acute or acute-on-chronic ingestions of sustained-release preparations.
• Admit patients with cardiovascular or neurologic symptoms to the ICU, with airway management, monitoring, and supportive care as indicated.
• Patients with significant cardiovascular or neurologic symptoms should receive hemodialysis. Multidose activated charcoal should be used for patients with less severe toxicity.

Further Outpatient Care

• Patients with 2 consecutive decreasing theophylline levels of less than 30 mcg/mL, determined at least 2 hours apart, who are asymptomatic and who have no comorbid conditions may be considered for discharge.

In/Out Patient Meds

• Inpatient medications have been discussed previously (see Medication).
• Patients with 2 consecutive decreasing levels of less than 30 mcg/mL who are asymptomatic may be discharged, and further doses of theophylline should not be resumed until levels are within the therapeutic range (10-20 mcg/mL).
• No outpatient medications are required for the treatment of theophylline toxicity.

Transfer

• Patients with dysrhythmias, hemodynamic instability, or severe agitation, altered mental status, or seizures after ingestions of significant amounts of theophylline should be transferred to the ICU. These patients also should be transferred to facilities that can provide hemodialysis.

Deterrence/Prevention

• Drug levels should be monitored periodically in patients who are being treated with theophylline.
• Particular attention should be paid to potential drug interactions.
• Macrolide and quinolone antibiotics should be avoided. If they are administered, theophylline levels should be monitored carefully.
• Patients should be counseled about the potential for serious toxicity in acute and chronic overdose and about the potential for drug interactions.

Prognosis

• The prognosis of patients with theophylline toxicity depends on the amount and severity of the ingestion. Significant ingestions increase the risk of death from dysrhythmias, refractory hypotension, or status epilepticus.
• A risk of hypoxic brain injury exists in patients with status epilepticus, prolonged hypotension, or significant aspiration causing hypoxia.

Patient Education

• Patients should be advised of the potential for serious toxicity in acute and chronic overdose and of the potential for serious drug interactions.
• Patients should be advised that current drugs for the treatment of asthma and COPD, such as inhaled beta-agonists and inhaled steroids, offer better therapeutic effects without the risk of significant toxicity associated with theophylline.
• For excellent patient education resources, visit eMedicine's Drug Overdose Center and Poisoning - First Aid and Emergency Center. Also, see eMedicine's patient education articles Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Because inhaled beta-agonists and steroids are effective in the treatment of asthma and COPD and because they do not have the risk of serious or fatal toxicity, a potential liability exists with the continued prescription of theophylline for patients with these conditions.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Charytan D, Jansen K. Severe metabolic complications from theophylline intoxication. Nephrology (Carlton). Oct 2003;8(5):239-242. [Medline].
• Holstege CP, Hunter Y, Baer AB, et al. Massive caffeine overdose requiring vasopressin infusion and hemodialysis. J Toxicol Clin Toxicol. 2003;41(7):1003-7. [Medline].
• Holstege CP, Dobmeier S. Cardiovascular challenges in toxicology. Emerg Med Clin North Am. Nov 2005;23(4):1195-217. [Medline].
• Lheureux P, Penaloza A, Gris M. Pyridoxine in clinical toxicology: a review. Eur J Emerg Med. Apr 2005;12(2):78-85. [Medline].
• Minton NA, Henry JA. Treatment of theophylline overdose. Am J Emerg Med. Oct 1996;14(6):606-12. [Medline].
• Minton NA, Henry JA. Acute and chronic human toxicity of theophylline. Hum Exp Toxicol. Jun 1996;15(6):471-81. [Medline].
• Rutten J, van den Berg B, van Gelder T, van Saase J. Severe theophylline intoxication: a delay in charcoal haemoperfusion solved by oral activated charcoal. Nephrol Dial Transplant. Dec 2005;20(12):2868-9. [Medline].
• Shannon MW. Comparative efficacy of hemodialysis and hemoperfusion in severe theophylline intoxication. Acad Emerg Med. Jul 1997;4(7):674-8. [Medline].
• Stork CM, Howland MA, Goldfrank LR. Concepts and controversies of bronchodilator overdose. Emerg Med Clin North Am. May 1994;12(2):415-36. [Medline].
• Watson WA, Litovitz TL, Rodgers GC, et al. 2004 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. Sep 2005;23(5):589-666. [Medline].

Article Last Updated: Aug 29, 2006