Theophylline Toxicity

The primary 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, theophylline inhibits phosphodiesterase, resulting in elevation of cyclic adenosine monophosphate (cAMP) and consequent beta-adrenergic enhancement.

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 within 30 minutes.[4]

Theophylline is ~60% protein bound and has a volume of distribution 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 levels of 80-100 mcg/mL. With long-term exposure, those levels causing such adverse clinical outcomes are lower (40-60 mcg/mL).

Theophylline is eliminated by the hepatic cytochrome P450 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 (eg, cimetidine, erythromycin, oral contraceptives) affecting the cytochrome P450 system (CYP1A2) can alter the half-life.

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

Causes of chronic theophylline toxicity include the following:

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

Congestive heart failure with hepatic congestion has been demonstrated to reduce the clearance of theophylline by 50% while doubling the half life, thereby reducing drug elimination, increasing concentrations, and leading to toxic effects.  Other factors known to reduce theophylline clearance include increased age and liver enzyme–inhibiting medications.[5]  

Acute theophylline toxicity is caused by intentional or accidental overdose. 

The 2018 annual report of the American Association of Poison Control Centers' National Poison Data System documented 88 single exposures to aminophylline or theophylline, with 3 in children younger than 6 years, 3 in those 6 to 12 years, 34 in adolescents ages 13-19 years and 75 in persons 20 years or older. Of the 46 exposures treated in health care facilities, 8 were reported to have major adverse outcomes with one death.[3]  Documented toxic exposures have decreased markedly over the past decade as the use of theophylline for the management of asthma and COPD has diminished.[6]

Signs and symptoms of theophylline toxicity correlate better with single acute ingestions than with chronic overexposures. Clinical manifestations of acute theophylline overdose are as follows:

• Nausea
• Vomiting
• Abdominal pain
• Tachycardia

In addtion, patients may manifest features of the following:

• Metabolic acidosis
• Hypokalemia
• Hypophosphatemia
• Hypomagnesemia
• Hypocalcemia/hypercalcemia
• Hyperglycemia

Chronic theophylline overdose has minimal gastrointestinal clinical effects. Seizures, hypotension, and significant dysrhythmias usually are observed when serum levels approach 80 mcg/mL. Seizures were more commonly reported with acute overdose than with chronic overdose. In long-term exposures, seizures may develop at lower serum concentrations (40-60 mcg/mL). Cardiac dysrhythmias are more common following a chronic overdose with lower serum concentrations.

Cardiovascular findings include the following:

• Sinus tachycardia (most common)
• Atrial fibrillation
• Atrial flutter
• Supraventricular tachycardia (SVT)
• Multifocal atrial tachycardia
• Hypotension (severe overdoses) - Due to β ₂ effect/agonism
• Ventricular fibrillation
• Pulseless electrical activity (PEA)
• Cardiac arrest

Pulmonary findings include increased respiratory rate leading to respiratory alkalosis, acute lung injury (ALI), and respiratory failure. Neurological signs include tremors (most common), restlessness, agitation, and altered mental status. Persistent seizures may occur with serum levels > 25 mcg/mL. Gastrointestinal manifestions are nausea, vomiting, abdominal cramps, and diarrhea.

Obtain a serum theophylline level upon presentation and then every 2 hours until the level falls significantly. This is especially important following ingestion of extended-release formulations. Theophylline capsules can form bezoars, resulting in ongoing absorption and toxicity despite gastrointestinal decontamination.

Order electrolytes and glucose tests to evaluate for the following:

• Hypokalemia (serial testing of serum potassium levels may be required)
• Hyperglycemia
• Metabolic acidosis (lactate)
• Hypocalcemia/hypercalcemia
• Hypophosphatemia
• Ketosis

Other tests to obtain include the following:

• Pregnancy test in women of childbearing age
• Acetaminophen (paracetamol) level in sucidal ingestions
• 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

On a complete  blood cell count, the white blood cell count may be elevaed, as a result of increased catecholamine activity.

A computed tomography (CT) scan of the brain is indicated if seizures occur.

An electrocardiogram (ECG) is performed to look for evidence of dysrhythmias from electrolyte abnormalities. The ECG should also be used to evaluate for the signs of other cardioactive drug toxicity, especially in cases of suicidal overdose.

Lumbar puncture may be required for the evaluation of altered mental status and/or new-onset seizures.

Evaluate ABCs (airway, breathing, circulation) and intervene as necessary. Endotracheal intubation may be needed in patients who require high-dose benzodiazepines or barbiturates to control seizures. Vascular access for hemoperfusion may be required.

Administer activated charcoal if the airway is patent and the patient is alert. Multidose activated charcoal (MDAC) enhances elimination of theophylline. It is important to control nausea and vomiting in order to perform MDAC treatment. It is also important that the patient is able to protect the airway, in order to prevent aspiration of activated charcoal. Administer sorbitol (as a cathartic) with the activated charcoal no more than one time.

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

Administer polyethylene glycol electrolyte solution, as follows:

• Adults: 2 liters per hour until clear rectal effluent
• Children: 500 mL/h until clear rectal effluent

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:

• 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 with toxic levels

Benzodiazepines and phenobarbital may be used to treat seizures. 

Hypotension resistant to isotonic fluids (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 only in case reports to successfully reverse peripheral beta receptor-mediated hypotension without apparent effect on concomitant tachycardia. However, use caution using beta-blockers as the evidence for efficacy is limited and their is a risk of beta-adrenergic blockade to patients with preexistent bronchospastic disease.

Esmolol, a short-acting beta-blocker, has been used successfully for unstable supraventricular tachycardia and related hypotension in theophylline overdose.[7] 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.

Extracorporeal treatments can be used in the treatment of theophylline poisoning, with hemodialysis being the preferred method due to it being able to both enhance the clearance of the toxin and help correct metabolic derangements. The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup recommends extracorporeal treatments if:[8]

• Theophylline concentration >100 mg/L in acute exposures

• Seizures are present

• Life-threatening dysthymias are present

• Shock is present

• There is a rising serum theophylline concentration despite optimal therapy

• There is clinical deterioration despite optimal therapy

The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup suggests extracorporeal treatments if:

• Theophylline concentration > 60 mg/L in chronic exposures

• The patient is less than 6 months or over 60 years old and the theophylline concentration >50 mg/L in chronic exposure

• Gastrointestinal decontamination cannot be administered

Hemodialysis can be stopped when there is apparent clinical improvement or theophylline concentration < 15 mg/L.

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:

• Fluid bolus with isotonic fluid (20 mL/kg)
• Ondansetron to help control vomiting
• Benzodiazepine to decrease anxiety, decrease risk of seizures, and help control vomiting
• Phenylephrine or norepinephrine to = increase blood pressure if fluid resuscitation fails.  

Because charcoal hemoperfusion is a complicated process that is not routinely used in healthcare facilities, most medical centers will perform  hemodialysis. Hemodialysis in combination with MDAC often is sufficient for the treatment of severe theophylline toxicity.

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 theophylline levels higher than 30 mcg/mL. Admit patients demonstrating cardiovascular or neurologic dysfunction to the critical care unit.

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

For patients with therapeutic theophylline levels that are not rising, discharge with follow is recommended.  For asymptomatic patients with therapeutic levels following intentional overdose, consider discharge of after psychiatric evaluation.

Patients prescribed theophylline who have risk factors for reduced elimination or metabolism of the drug, such as congestive heart failure or liver disease, should be more closely monitored to avoid significant intoxication.[5]

The goals of pharmacotherapy are to reduce morbidity and prevent complications. An antidote to theophylline is not available, so treatment consists of gastrointestinal decontamination and alleviation of signs and symptoms. 

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.

Activated charcoal (Liqui-Char)

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

Persistent vomiting may interfere with decontamination.

Ondansetron (Zofran)

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

Ranitidine (Zantac)

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

Metoclopramide (Reglan)

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

Prochlorperazine (Compazine)

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)

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

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.

Diazepam (Valium)

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

Lorazepam (Ativan)

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)

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)

Interferes with transmission of impulses from thalamus to cortex of brain.

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.

Phenylephrine (Neo-Synephrine)

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

Esmolol (Brevibloc)

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)

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.