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

Theophylline has indications for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Medication, diet, and underlying diseases can alter its narrow therapeutic window. Adverse effects can be evident at therapeutic serum levels.

Pathophysiology

Theophylline is absorbed rapidly after oral administration. Peak serum levels occur in 90-120 minutes. Fasting or large volumes of fluid enhance absorption. Enteric-coated and sustained-release tablets have a delayed absorption. Intravenous aminophylline reaches peak serum levels in 30 minutes.

Theophylline is 60% protein bound and has a distribution volume of 0.5 L/kg. Therapeutic serum levels range from 10-20 mcg/mL. Toxic levels are considered to be higher than 20 mcg/mL; however, adverse effects may be evident within the normal therapeutic range.

Theophylline is eliminated by the hepatic cytochrome P-450 system (85-90%) and by urinary excretion (10-15%). The half-life is 4-8 hours in young adults and is shorter in children and smokers. Diet, cardiac or liver disease, tobacco use, and medications affecting the cytochrome P-450 system can affect the half-life.

Theophylline affects the cardiovascular (CV), neurological, GI, and metabolic systems. Hypokalemia, hyperglycemia, hypercalcemia, hypophosphatemia, and acidosis commonly occur after an acute overdose.

Frequency

United States

The 2002 annual report of the American Association of Poison Control Centers' Toxic Exposure Surveillance System documented 1030 exposures to theophylline, with 170 in children younger than 6 years and 757 in persons older than 19 years. Of the 585 theophylline exposures treated in health care facilities, 39 were reported to have major adverse outcomes and 8 fatalities were noted. The documented toxic exposures have decreased markedly over the past decade as the utilization of theophylline for the management of asthma has diminished.

Race

No scientific data have demonstrated that outcomes of theophylline toxicity are dependent on race.

Sex

No scientific data have demonstrated that outcomes of theophylline toxicity are dependent on sex.

CLINICAL

Section 3 of 10  

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

History

• Symptomology correlates better with single acute ingestions than with chronic overexposures. Symptoms of acute theophylline overdose are as follows:
• • Nausea
  • Vomiting
  • Abdominal pain
  • Mild metabolic acidosis
  • Hypokalemia
  • Hypophosphatemia
  • Hypomagnesemia
  • Hyperglycemia
  • Tachycardia
• Chronic theophylline overdose has minimal GI signs or symptoms.
• Seizures, hypotension, and significant dysrhythmias usually are not observed until serum levels approach 80 mcg/mL.
• Seizures are more common with acute overdose than with chronic overdose and may develop at lower serum concentrations (40-60 mcg/mL).
• Cardiac dysrhythmias are more common following an acute overdose than chronic overdose.

Physical

• Cardiovascular
• • Sinus tachycardia (most common)
  • Atrial fibrillation
  • Atrial flutter
  • Supraventricular tachycardia (SVT)
  • Multifocal atrial tachycardia
  • Ventricular tachycardia
  • Hypotension (severe overdoses)
  • Ventricular fibrillation
  • Pulseless electrical activity (PEA)
  • Cardiac arrest
• Neurological
• • Tremors (most common)
  • Restlessness
  • Agitation
  • Hallucinations
  • Headaches
  • Irritability
  • Seizures (Persistent seizures may occur with serum levels >25 mcg/mL.)
• Gastrointestinal
• • Nausea
  • Vomiting
  • Abdominal cramps
  • Diarrhea

Causes

• Chronic toxicity
• • Drug interactions (eg, ethanol [ETOH], cimetidine, oral contraceptives, allopurinol, macrolide, quinolone antibiotics)
  • Liver disease
  • Congestive heart failure
  • Febrile viral upper respiratory illness
• Acute toxicity
• • Accidental overdose
  • Intentional overdose

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

• Obtain serum theophylline levels every 2-4 hours until the level falls.
• • This is especially important following ingestion of extended-release formulations.
  • Theophylline can form bezoars, resulting in ongoing absorption and toxicity despite general measures at GI decontamination.
• Order electrolytes and glucose tests to evaluate for the following:
• • Hypokalemia
  • Hyperglycemia
  • Metabolic acidosis
  • Hypercalcemia
  • Hypophosphatemia
• Test for pregnancy in women of childbearing age.

Imaging Studies

• Obtain a CT scan of the brain if seizures occur.

Other Tests

• Electrocardiogram

TREATMENT

Section 6 of 10  

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

Prehospital Care

• Establish airway, breathing, and circulation (ABCs).
• Intravenous benzodiazepines may abort seizures.

Emergency Department Care

Evaluate ABCs and, if indicated, perform endotracheal intubation.

• Vascular access for hemoperfusion may be required.
• Endotracheal intubation may be needed in patients who require high dose benzodiazepines or barbiturates to control seizures.
• Consider gastric lavage (unless contraindicated) if the patient has recently ( <1 h) ingested a significant amount or a sustained-release preparation or if bezoar formation is suspected. Endoscopic bezoar fragmentation and retrieval may be utilized if lavage is not efficacious.
• Administer activated charcoal.
• • Multidose charcoal enhances elimination of theophylline.
  • Administer the cathartic, sorbitol, with the activated charcoal one time.
• Phenobarbital prophylaxis may benefit patients at high risk for seizures. Similarly, benzodiazepines will increase the seizure threshold. High-risk cases include the following:
• • Acute overdose with theophylline levels higher than 80 mcg/mL
  • Chronic toxicity with levels higher than 40 mcg/mL
  • Patients older than 60 years or younger than 3 years
• Benzodiazepines (IV) and phenobarbital may be used to treat seizures.
• Phenobarbital has the added advantage of enhancing the hepatic metabolism of theophylline.
• Hypotension resistant to isotonic fluids (10-20 cc/kg) may require vasopressors with predominantly alpha-agonistic activity (eg, dopamine, norepinephrine).
  • In patients with theophylline toxicity, beta-blockade with propranolol has been shown to successfully reverse peripheral beta receptor-mediated hypotension without apparent effect on concomitant tachycardia.
  • However, always consider the risk of beta-adrenergic blockade to patients with pre-existent bronchospastic disease.
• Esmolol, a short-acting beta-blocker, has been used successfully for unstable SVT and related hypotension in theophylline overdose.
• • Exercise caution with beta-blocking agents because of their negative inotropic effects.
  • Esmolol is a relatively selective beta1-receptor antagonist; thus, it may not have as much affect on beta2-mediated hypotension as less-selective agents (eg, propranolol), although it is less likely to induce bronchospasm than other beta-blockers.
• Consider hemoperfusion with the following:
• • Theophylline concentrations exceed 40 mcg/mL (chronic ingestion)
  • Presence of life-threatening toxicity
  • Levels exceeding 90 mcg/mL in acute ingestions
• Hemodialysis is an alternative method of elimination enhancement but is considerably less effective than hemoperfusion.
• Current recommendations for treating patients with tachycardia, hypotension, anxiety, and vomiting from theophylline-overdose may include the following:
• • Fluid bolus with isotonic fluid
  • Metoclopramide to help control vomiting
  • Propranolol to increase blood pressure
  • Benzodiazepine to decrease anxiety, decrease risk of seizures, and help control vomiting
  • Phenylephrine to further increase blood pressure
  • Hemoperfusion guided by response to treatment, underlying medical problems, and theophylline level

Consultations

• Consult the regional poison control center or local medical toxicologist (certified through the American Board of Medical Toxicology or the American Board of Emergency Medicine) for additional information and patient care recommendations.
• Consult a nephrologist if hemoperfusion is needed

MEDICATION

Section 7 of 10  

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

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Drug Category: GI decontaminant

Empirically used to minimize systemic absorption of the toxin. May only be of benefit if administered within 1-2 h of ingestion.

Drug Category: Antiemetics

Persistent vomiting may interfere with decontamination.

Drug Name	Metoclopramide (Reglan)
Description	Works as antiemetic by blocking dopamine receptors in the chemoreceptor trigger zone of the CNS. Generally drug of choice because lower cost than ondansetron (Zofran).
Adult Dose	10-20 mg IV; not to exceed 1 mg/kg; up to 3 mg/kg/d IV in divided doses prn
Pediatric Dose	<6 years: 0.1 mg/kg IV slowly over 1-2 min
Contraindications	Documented hypersensitivity; pheochromocytoma or GI hemorrhage, obstruction or perforation; history of seizure disorders
Interactions	May antagonize effects of metoclopramide; opiate analgesics may increase metoclopramide toxicity in CNS
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in history of mental illness and Parkinson disease; adverse effects include drowsiness, hypotension, and acute dystonia, especially at high doses; may increase frequency of seizure in individuals with epilepsy

Drug Name	Droperidol (Inapsine)
Description	Neuroleptic agent that may reduce emesis by blocking dopamine stimulation of chemoreceptor trigger zone.
Adult Dose	1.25 - 5 mg IV
Pediatric Dose	0.05-0.25 mg/kg IV
Contraindications	Documented hypersensitivity
Interactions	May increase toxicity of CNS depressants; cabergoline and levodopa may potentiate antipsychotic effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hypovolemic patients may experience hypotension; may decrease pulmonary arterial pressure; tardive dyskinesia in patients receiving droperidol is 40%; elderly persons may experience high rate of extrapyramidal reactions; life-threatening arrhythmias may occur; watch for QT prolongation

Drug Name	Prochlorperazine (Compazine)
Description	May relieve nausea and vomiting by blocking postsynaptic mesolimbic dopamine receptors through anticholinergic effects and depressing reticular activating system. In addition to antiemetic effects, has the advantage of augmenting hypoxic ventilatory response, acting as a respiratory stimulant at high altitude.
Adult Dose	10 mg IV slowly; may repeat once; not to exceed 40 mg/d; 25 mg PR q12h
Pediatric Dose	<20 pounds: Not recommended 20-29 pounds: 2.5 mg PR bid 30-39 pounds: 2.5 mg PR tid <12 years: 0.06 mg/lb IM
Contraindications	Documented hypersensitivity; bone marrow suppression, narrow-angle glaucoma, and severe liver or cardiac disease; parkinsonism; depression
Interactions	Coadministration with other CNS depressants or anticonvulsants may cause additive effects; may cause hypotension with epinephrine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Drug-induced Parkinson syndrome or pseudoparkinsonism occurs quite frequently; akathisia is most common extrapyramidal reaction in elderly persons; lowers seizure threshold; caution with history of seizures; may cause hypotension, altered mental status, and NMS

Drug Category: Benzodiazepines and other sedative agents

Used to terminate seizures and for seizure prophylaxis in high-risk patients. Helps to alleviate nausea and vomiting. Decreases tremors and anxiety induced by theophylline.

Drug Name	Lorazepam (Ativan)
Description	Sedative hypnotic with short onset of effects and relatively long half-life. By increasing the action of GABA, a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation. Monitoring blood pressure after administering dose is important. Adjust prn.
Adult Dose	0.044 mg/kg (2-4 mg) IV; titrate to effect Status epilepticus: 4 mg IV over 2-5 min; may repeat second dose in 10-15 min prn; not to exceed 8 mg
Pediatric Dose	Infants and children: 0.02-0.1 mg/kg IV slowly over 2-5 min; repeat prn in 10-15 min at 0.05 mg/kg; not to exceed 4 mg/dose Adolescents: 0.07 mg/kg IV slowly over 2-5 min; repeat in 10-15 min prn; not to exceed 4 mg/dose
Contraindications	Documented hypersensitivity; preexisting CNS depression, hypotension, and narrow-angle glaucoma
Interactions	Toxicity of benzodiazepines in CNS increases when used concurrently with alcohol, phenothiazines, barbiturates, and MAOIs
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in renal or hepatic impairment, myasthenia gravis, organic brain syndrome, or Parkinson disease; monitor for respiratory depression with high or repeated doses; contains benzyl alcohol, which may be toxic to infants in high doses

Drug Name	Midazolam (Versed)
Description	Used as alternative in termination of refractory status epilepticus. Because water soluble, takes approximately 3 times longer than diazepam to peak EEG effects. Thus, clinician must wait 2-3 min to fully evaluate sedative effects before initiating procedure or repeating dose. Has twice the affinity for benzodiazepine receptors than diazepam. May be administered IM if unable to obtain vascular access.
Adult Dose	0.01-0.05 mg/kg (usually 0.5-4 mg; up to 10 mg) IV slowly over several min; may repeat q10-15min until adequate response achieved
Pediatric Dose	<32 weeks: 0.5 mcg/kg/min IV infusion >32 weeks: 1 mcg/kg/min IV infusion Children: 0.05-0.2 mg/kg IV over 2-3 min, followed by 1-2 mcg/kg/min continuous infusion Status epilepticus (refractory to standard therapy), > 2 months and children: 0.15 mg/kg, followed by continuous infusion of 1 mcg/kg/min; titrate upward q5min until seizures controlled
Contraindications	Documented hypersensitivity; preexisting hypotension, narrow-angle glaucoma, and sensitivity to propylene glycol (diluent)
Interactions	Sedative effects may be antagonized by theophyllines; narcotics, cimetidine, ethanol, and erythromycin may accentuate sedative effects because of decreased clearance; reduce dose of thiopental by 15% when using together
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in congestive heart failure, pulmonary disease, renal impairment, hepatic failure, neuromuscular disease, hypotension, and patients >60 y; monitor for respiratory depression with high or repeated doses; consider lower dosages in patients with organic brain syndrome and patients who may have inhibition of benzodiazepine metabolism and clearance (eg, using nicotine, taking cimetidine)

Drug Name	Phenobarbital (Barbita, Luminal)
Description	Interferes with transmission of impulses from thalamus to cortex of brain.
Adult Dose	10-20 mg/kg IV; not to exceed 50 mg/min
Pediatric Dose	15-20 mg/kg IV; not to exceed 50 mg/min
Contraindications	Documented hypersensitivity; severe respiratory disease, marked impairment of liver function, and nephritic patients
Interactions	May decrease effects of chloramphenicol, digitoxin, corticosteroids, carbamazepine, theophylline, verapamil, metronidazole, and anticoagulants (patients stabilized on anticoagulants may require dosage adjustments if added to or withdrawn from their regimen); coadministration with alcohol may produce additive CNS effects and fatality; chloramphenicol, valproic acid, and MAOIs may increase toxicity; rifampin may decrease effects; induction of microsomal enzymes may result in decreased effects of oral contraceptives in women (must use additional contraceptive methods to prevent unwanted pregnancy); menstrual irregularities also may occur
Pregnancy	D - Unsafe in pregnancy
Precautions	In prolonged therapy, evaluate hematopoietic, renal, hepatic, and other organ systems; caution in fever, hyperthyroidism, diabetes mellitus, and severe anemia because adverse reactions can occur; caution in myasthenia gravis and myxedema; monitor for hypotension, respiratory depression, and need for intubation

Drug Category: Cardiovascular agents

Alpha-agonists are used to treat persistent hypotension not responding to fluid challenges. Beta-blockers are used for treating severe tachycardia with ischemia or severe hypotension.

Drug Name	Esmolol (Brevibloc)
Description	Short-acting IV cardioselective beta-adrenergic blocker with no membrane depressant activity. Half-life of 8 min allows for titration to effect and quick discontinuation prn.
Adult Dose	Loading dose: 500 mcg/kg IV for 1 min Maintenance infusion: 100 mcg/kg/min IV for 4 min; repeat if inadequate; if still inadequate, repeat loading dose, then increase maintenance dose by increments of 50 mcg/kg/min IV
Pediatric Dose	300 mcg/kg/min IV with continuous heart rate and blood pressure monitoring to determine onset of beta-blockade (equal to >10% reductions); titrate upward in 50-100 mcg/kg/min increments IV q10min prn
Contraindications	Documented hypersensitivity; asthma; COPD; CHF; moderate-to-severe left ventricular dysfunction; hypotension <90 mm Hg; bradycardia <60/min, second- and third-degree AV block
Interactions	Aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease bioavailability and plasma levels, possibly resulting in decreased pharmacologic effect; cardiotoxicity may increase when administered concurrently with sparfloxacin, astemizole, calcium channel blockers, quinidine, flecainide, and contraceptives; toxicity increases when administered concurrently with digoxin, flecainide, acetaminophen, clonidine, epinephrine, nifedipine, prazosin, haloperidol, phenothiazines, and catecholamine-depleting agents
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Beta-adrenergic blockers may mask signs and symptoms of acute hypoglycemia and clinical signs of hyperthyroidism; symptoms of hyperthyroidism, including thyroid storm may worsen when medication is abruptly withdrawn; withdraw drug slowly and monitor patient closely

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 and symptoms of toxicity (acute or chronic), or observe them in the ED until their theophylline level decreases and their symptoms have resolved.
• Admit patients with levels higher than 30 mcg/mL.
• Admit patients demonstrating cardiovascular or neurologic dysfunction to the critical care unit.

Further Outpatient Care

• Accidental overdose: For patients with therapeutic theophylline levels and minimal or no toxicity and acute ingestions less than 10 mg/kg, discharge and follow up within 24 hours.
• Intentional overdose: Consider discharge after psychiatric evaluation.

Patient Education

• 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

• Failure to aggressively treat a theophylline intoxicated patient in a manner to prevent risk of seizures
• Failure to initiate access to hemoperfusion in the severely intoxicated patient
• Failure to diagnose chronic theophylline overdose because of the vague signs and symptoms of anxiety and nausea, thereby inappropriately discharging them from the ED

REFERENCES

Section 10 of 10

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

• Brashear RE, Aronoff GR, Brier RA. Activated charcoal in theophylline intoxication. J Lab Clin Med. Sep 1985;106(3):242-5. [Medline].
• Charytan D, Jansen K. Severe metabolic complications from theophylline intoxication. Nephrology (Carlton). Oct 2003;8(5):239-242. [Medline].
• Cooling DS. Theophylline toxicity. J Emerg Med. Jul-Aug 1993;11(4):415-25. [Medline].
• Gaudreault P, Harwood-Nuss. Methylxanthines, Toxicology. In: Clinical Practice of Emergency Medicine. 4th ed. 2005:1649-1652.
• Henderson A, Wright DM, Pond SM. Management of theophylline overdose patients in the intensive care unit. Anaesth Intensive Care. Feb 1992;20(1):56-62. [Medline].
• Kallstrom TJ. Evidence-based asthma management. Respir Care. Jul 2004;49(7):783-92. [Medline].
• Kearney TE, Manoguerra AS, Curtis GP, Ziegler MG. Theophylline toxicity and the beta-adrenergic system. Ann Intern Med. Jun 1985;102(6):766-9. [Medline].
• Marshall H, Emerman CL, Tintinalli J. Theophylline, Toxicology and Pharmacology. In: Emergency Medicine, A Comprehensive Study Guide. 6th ed. 2004:1098-1101.
• Medical Economics Staff. Drugs. In: Physician's Desk Reference. Medical Economics Co;1997.
• Micromedex. Theophylline. In: Micromedex. 1974-2006:36.
• Seneff M, Scott J, Friedman B, Smith M. Acute theophylline toxicity and the use of esmolol to reverse cardiovascular instability. Ann Emerg Med. Jun 1990;19(6):671-3. [Medline].

Article Last Updated: Jun 13, 2006