Theophylline (1,3-dimethylxanthine) 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. However, medication, diet, and underlying diseases can alter its narrow therapeutic window. Drug interactions, adverse effects, and limited efficacy curb its use when other agents are available.
The 2016 Global Intitiative for Chronic Obstructive Lung Disease (GOLD) guidelines for management of COPD recommended theophylline only if other bronchodilators were unavailable or unaffordable, but in the 2018 guidelines, no situations are suggested for theophylline use.[1] In addition, evidence regarding the effect of low-dose theophylline on exacerbation rates is not clear and a meta-analysis suggested that theophylline slightly increases all-cause death in COPD patients.[2] This has all led to significantly diminished use of theophylline and, consequently, decreased reports of theophylline toxicity.[3]
Acute theophylline overdose presents as follows:
Chronic intoxication often causes milder gastrointestinal symptoms and does not cause electrolyte shifts or hypotension, as is observed in acute overdose. However, significant dysrhythmias and seizures are common with lower levels of the drug in chronic intoxication and in acute-on-chronic overdose. See Presentation and Workup.
Treatment consists of decontamination and supportive care. 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 cases, as well as in patients who develop seizures, refractory hypotension that is unresponsive to fluids, or unstable dysrhythmias, regardless of the theophylline level. See Treatment.
For patient education information, see First Aid and Emergency Center and Poison Proofing Your Home.
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 approximately 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, particularly in elderly patients.[5]
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:
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.[6]
Acute theophylline toxicity is caused by intentional or accidental overdose.
The 2021 annual report of the American Association of Poison Control Centers' National Poison Data System documented 83 single exposures to aminophylline or theophylline, with 9 in children younger than 6 years, none in those 6 to 12 years, 2 in adolescents age 13-19 years, and 68 in persons 20 years or older. Of the 49 patients treated in health care facilities, 2 were reported to have major adverse outcomes and 2 died.[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.[7]
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:
In addtion, patients may manifest features of the following:
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:
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:
Other tests to obtain include the following:
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:
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:
Hypotension resistant to isotonic fluids (20 mL/kg) may require vasopressors with predominantly alpha-agonist 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. Exercise caution with beta-blockers, however, as the evidence for efficacy is limited and they pose a risk of beta-adrenergic blockade in 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.[9] Esmolol is a relatively selective beta1-receptor antagonist, and thus may not have as much effect on beta2-mediated hypotension as do 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 its ability to both enhance the clearance of the toxin and help correct metabolic derangements. In cases of acute toxicity, the Extracorporeal Treatments in Poisoning (EXTRIP) workgroup recommends extracorporeal treatments for patients with any of the following:[10]
In cases of chronic toxicity, the EXTRIP workgroup suggests the following as indications for extracorporeal treatments[10] :
Hemodialysis can be stopped when there is apparent clinical improvement or theophylline concentration < 15 mg/L.
Correct electrolyte abnormalities in patients with electrocardiographic changes (eg, corrected QT interval prolongation) and/or ventricular dysrhythmias. Current recommendations for treating patients with tachycardia, hypotension, anxiety, and vomiting from theophylline overdose may include the following:
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 followup is recommended. For asymptomatic patients with therapeutic levels following intentional overdose, consider discharge 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.[6]
Routine theophylline level monitoring is required annually for well-managed adults and once every six months for children when given orally. Patients should receive education on theophylline toxicity and side effects as delays in diagnosis and treatment of toxicity can be life-threatening.[8]
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.
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%).
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.
Clinical Context: 5HT-3 antagonist acting both on the vagus nerve peripherally and at the CTZ in the CNS.
Clinical Context: H2 antagonist that may be a useful adjunct in reducing emesis volume.
Clinical Context: Works as antiemetic by blocking dopamine receptors in the chemoreceptor trigger zone of the CNS.
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.
Clinical Context: Neuroleptic agent that may reduce emesis by blocking dopamine stimulation of chemoreceptor trigger zone.
Clinical Context: Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA.
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.
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.
Clinical Context: Interferes with transmission of impulses from thalamus to cortex of brain.
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.
Clinical Context: Strong postsynaptic alpha-receptor stimulant with little beta-adrenergic activity that produces vasoconstriction of arterioles. Increases peripheral venous return.
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 as necessary.
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.
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.