Theophylline Toxicity

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Background

Theophylline (1,3-dimethylxanthins) can indirectly stimulate both β1 and β2 receptors through release of endogenous catecholamines. It is used for the treatment of pulmonary conditions, including asthma and chronic obstructive pulmonary disease (COPD). In neonates, theophylline can be used for the treatment of apnea.

Medication, diet, and underlying diseases can alter its narrow therapeutic window. Adverse effects can be evident at therapeutic serum levels. The use of theophylline for the treatment of asthma and chronic obstructive pulmonary disease has decreased significantly in recent years.[1] This has greatly decreased the incidence of theophylline overdose.[2]

Pathophysiology

Major mechanisms of theophylline therapeutic efficacy and its toxicity are through the excess of catecholamines and adenosine antagonism. Adenosine blockade can theoretically reduce histamine release and indirectly reverse bronchospasm. In addition, high levels of theophylline inhibit phosphodiesterase, resulting in elevation of cyclic adenosine monophosphate (cAMP) and consequent adrenergic stimulation.

Theophylline is absorbed rapidly and completely after oral administration. Peak serum levels for immediate release preparations are relatively rapid and can range from 30-120 minutes. Fasting or large volumes of fluid enhance absorption. Enteric-coated and sustained-release tablets have a delayed absorption with peak between 6 and 10 hours. It is important to recognize that these time intervals are much longer in the setting of overdose. The intravenous form of theophylline (aminophylline) reaches peak serum levels in 30 minutes.[3]

Theophylline is around 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. Severe complications including cardiac dysrhythmias, seizures, and death can be observed with the levels of 80-100 mcg/mL. In chronic exposure, those levels could be lower (40-60 mcg/mL).

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 (cimetidine, erythromycin, oral contraceptives) affecting the cytochrome P-450 system (CYP1A2) can affect the half-life.

Theophylline affects the cardiovascular (CV), central nervous (CN), gastrointestinal (GI), pulmonary, musculoskeletal, and metabolic systems. Hypokalemia, hyperglycemia, hypercalcemia, hypophosphatemia, and acidosis commonly occur after an acute overdose.

Epidemiology

Frequency

United States

The 2014 annual report of the American Association of Poison Control Centers' National Poison Data System documented 133 exposures to theophylline, with 14 in children younger than 6 years and 107 in persons older than 19 years.[2] Of the 81 theophylline exposures treated in health care facilities, eight were reported to have major adverse outcomes and two deaths were noted. Documented toxic exposures have decreased markedly over the past decade as the use of theophylline for the management of asthma has diminished.[4]

History

Symptomology correlates better with single acute ingestions than with chronic overexposures. Symptoms of acute theophylline overdose are as follows:

Chronic theophylline overdose has minimal GI signs or symptoms.

Seizures, hypotension, and significant dysrhythmias usually are observed when serum levels approach 80 mcg/mL.

Seizures are more common with acute overdose than with chronic overdose. In chronic exposures, seizures may develop at lower serum concentrations (40-60 mcg/mL).

Cardiac dysrhythmias are more common following a chronic overdose rather than acute overdose and with lower serum concentrations.

Physical

Cardiovascular

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Pulmonary

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Neurological

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Gastrointestinal

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Causes

Chronic theophylline toxicity

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Acute theophylline toxicity

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Laboratory Studies

Obtain serum theophylline level upon presentation and then every 2 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.

WBC can be elevated (due to increased catecholamine activity).

Obtain acetaminophen (paracetamol) level.

Obtain aspirin (ASA) level, particularly in patients with history and findings suggestive of aspirin toxicity, including but not limited to metabolic acidosis, respiratory alkalosis, and change of mental status.

Order electrolytes and glucose tests to evaluate for the following:

Test for pregnancy in women of childbearing age.

Imaging Studies

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Other Tests

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Prehospital Care

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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 of theophylline or if theophylline bezoar formation is suspected. Gastric lavage should be considered in intubated patients. Endoscopic bezoar fragmentation and retrieval may be utilized if lavage is not efficacious.

Administer activated charcoal. Multidose activated charcoal (MDAC) enhances elimination of theophylline. It is a very effective method of elimination, and it is considered the mainstay treatment of theophylline toxicity. It is important to aggressively control nausea and vomiting in order to perform MDAC treatment. It is also important that the patient is able to protect his or her airway in order to prevent aspiration of activated charcoal, which can be detrimental. Administer the cathartic, sorbitol, with the activated charcoal one time.

Perform whole-bowel irrigation (WBI) in patients with exposure to sustained-release theophylline preparations.

Administer polyethylene glycol electrolyte solution.

Theophylline-induced seizures tend to be resistant to treatment. Benzodiazepines (eg, lorazepam) are considered the first line of treatment. Historically, phenobarbital prophylaxis was used in patients at high risk for seizures. High-risk cases include the following:

Benzodiazepines (IV) and phenobarbital may be used to treat seizures.

Hypotension resistant to isotonic fluids (10-20 mL/kg) may require vasopressors with predominantly alpha-agonistic activity (eg, phenylephrine, 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 preexistent bronchospastic disease.

Esmolol, a short-acting beta-blocker, has been used successfully for unstable SVT and related hypotension in theophylline overdose.[5] 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 effect 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:

Hemodialysis is an alternative method of elimination enhancement but is considerably less effective than hemoperfusion.

Correct electrolyte abnormalities in patients with ECG changes (eg, QTc prolongation) and/or ventricular dysrhythmias.

Current recommendations for treating patients with tachycardia, hypotension, anxiety, and vomiting from theophylline overdose may include the following:

Consultations

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Medication Summary

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

Activated charcoal (Liqui-Char)

Clinical Context:  Prevents absorption by adsorbing drug in intestine. Multidose charcoal may interrupt enterohepatic recirculation and enhance elimination by enterocapillary exsorption. Theoretically, by constantly bathing the GI tract with charcoal, the intestinal lumen serves as a dialysis membrane for reverse absorption of drug from intestinal villous capillary blood into intestine. Supplied as an aqueous mixture or in combination with a cathartic (usually sorbitol 70%).

Class Summary

GI decontaminants are empirically used to minimize systemic absorption of the toxin. They may only be of benefit if administered within 1-2 h of ingestion.

Ondansetron (Zofran)

Clinical Context:  5HT-3 antagonist acting both on the vagus nerve peripherally and at the CTZ in the CNS.

Ranitidine (Zantac)

Clinical Context:  H2 antagonist that may be a useful adjunct in reducing emesis volume.

Metoclopramide (Reglan)

Clinical Context:  Works as antiemetic by blocking dopamine receptors in the chemoreceptor trigger zone of the CNS.

Prochlorperazine (Compazine)

Clinical Context:  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.

Droperidol (Inapsine)

Clinical Context:  Neuroleptic agent that may reduce emesis by blocking dopamine stimulation of chemoreceptor trigger zone.

Class Summary

Persistent vomiting may interfere with decontamination.

Diazepam (Valium)

Clinical Context:  Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA.

Lorazepam (Ativan)

Clinical Context:  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.

Midazolam (Versed)

Clinical Context:  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.

Phenobarbital (Barbita, Luminal)

Clinical Context:  Interferes with transmission of impulses from thalamus to cortex of brain.

Class Summary

These agents are used to terminate seizures and for seizure prophylaxis in high-risk patients. They help to alleviate nausea and vomiting and decrease tremors and anxiety induced by theophylline.

Phenylephrine (Neo-Synephrine)

Clinical Context:  Strong postsynaptic alpha-receptor stimulant with little beta-adrenergic activity that produces vasoconstriction of arterioles. Increases peripheral venous return.

Esmolol (Brevibloc)

Clinical Context:  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.

Norepinephrine (Levophed)

Clinical Context:  For protracted hypotension following adequate fluid-volume replacement. Stimulates beta1- and alpha-adrenergic receptors, which, in turn, increases cardiac muscle contractility and heart rate as well as vasoconstriction. As a result, systemic blood pressure and coronary blood-flow increases.

After obtaining a response, the rate of flow should be adjusted and maintained at a low normal blood pressure, such as 80-100 mm Hg systolic, sufficient to perfuse vital organs.

Class Summary

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.

Further Outpatient Care

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Further Inpatient Care

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Patient Education

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Author

Greg Hymel, MD, Assistant Medical Director, Associate Chairman, Department of Emergency Medicine, Mercy St Vincent Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

Disclosure: Nothing to disclose.

Fred Harchelroad, MD, FACMT, FAAEM, FACEP, Attending Physician in Emergency Medicine and Medical Toxicology, Excela Health System

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

Additional Contributors

Lance W Kreplick, MD, FAAEM, MMM, UHM, Staff Physician for Occupational Health and Rehabilitation, Company Care Occupational Health Services; President and Chief Executive Officer, QED Medical Solutions, LLC

Disclosure: Nothing to disclose.

References

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