Continuing Education Activity

Around the world, theophylline (1,3-dimethylxanthine) is primarily used as a bronchodilator for patients with asthma and chronic obstructive pulmonary disease (COPD). However, in the United States, asthma and COPD are mainly treated with other agents, and theophylline is predominantly used to treat bradycardia and apnea in premature newborns. Theophylline causes the endogenous release of catecholamines via indirect stimulation of beta-1 and beta-2 receptors, which, at therapeutic levels lead to bronchodilation, the goal of treatment. Unfortunately, theophylline has a narrow therapeutic window, and levels even slightly above the therapeutic range can have adverse effects both acutely and chronically. This activity will review the most common causes of theophylline toxicity and outline the treatment approach according to current evidence. This activity will highlight the role of the interprofessional team in recognizing and treating theophylline toxicity.

Objectives:

• Explain strategies for preventing theophylline toxicity.
• Describe which organs are commonly affected by theophylline toxicity.
• Explain the treatment strategy for a patient with theophylline toxicity.
• Explain how the facilitation of interprofessional team education and discussion can optimize the effective detection of theophylline toxicity and inform the need for subsequent evaluations.

Introduction

Around the world, theophylline (1,3-dimethylxanthine) is primarily used as a bronchodilator for patients with asthma and chronic obstructive pulmonary disease (COPD). However, in the United States, asthma and COPD are mainly treated with other agents, and theophylline is largely used to treat bradycardia and apnea in premature newborns. Theophylline causes the endogenous release of catecholamines through indirect stimulation of beta-1 and beta-2 receptors, which at therapeutic levels cause desired bronchodilation. Unfortunately, theophylline has a narrow therapeutic window, and even levels slightly above this therapeutic window can have many adverse effects in the setting of acute and chronic toxicity. The excess circulating catecholamines cause serious clinical effects that are associated with theophylline toxicity. Depending on the dose and route of administration, theophylline can have a wide range of cardiovascular, neurologic, metabolic, musculoskeletal, and gastrointestinal manifestations. Emergency department providers should become familiar with managing patients with theophylline toxicity since arrhythmias, seizures, hyperglycemia, and rhabdomyolysis are several of the complications that can arise.[1][2][3]

Etiology

Theophylline has an extremely narrow therapeutic window. Therefore, Theophylline toxicity occurs when serum theophylline levels surpass the levels in the therapeutic range. This can occur by intentional overdose or unintentionally when metabolism and/or clearance of theophylline is altered due to certain physiological stressors.

Epidemiology

Toxic exposures to theophylline have decreased significantly since its management for asthma and COPD has declined. From 1985 to 1995 in the United States, theophylline poisoning requiring hemodialysis or hemoperfusion accounted for 49 cases per one million poison center calls, compared to the 6 cases per one million poison center calls from 1996 to 2005. According to the American Association of Poison Control Centers, there were 133 exposures to theophylline in 2014. Of these, 14 were in children younger than 6 years old, and 107 were in patients older than 19 years old. There were 2 deaths out of 81 patients treated for theophylline exposure treated at healthcare facilities.

Pathophysiology

Theophylline has 2 primary mechanisms. One mechanism is that theophylline blocks adenosine receptors, which has both therapeutic and toxic effects such as bronchodilation, tachycardia, cardiac arrhythmias, seizures, and cerebral vasoconstriction. At larger doses, theophylline inhibits phosphodiesterase, causing increased cyclic adenosine monophosphate resulting in increased adrenergic activation and catecholamine release levels. In theophylline toxicity, epinephrine levels can be 4- to 8-times higher than normal, and norepinephrine concentrations can be 4- to 10-times higher than normal. Increased catecholamine concentrations have a variety of adverse effects such as cardiac arrhythmias, metabolic acidosis, hyperglycemia, and hypokalemia. Chronic theophylline toxicity can occur when there is an accumulation of the drug due to metabolism being overwhelmed or inhibited. It can also occur when clearance is decreased.[1][4]

Toxicokinetics

Toxic doses of theophylline can be as low as 7.5 mg/kg. When taken orally, 80% to 100% of theophylline is absorbed in the gastrointestinal tract. Peak serum levels can occur from 30 to 120 minutes for immediate release formulations. Sustained-release formulations have peak levels between 6 and 10 hours. Intravenously, theophylline takes 30 minutes to reach peak levels. Therapeutic serum levels range from 10 to 20 mcg/mL. Toxic levels are considered to be 20 mcg/mL or higher. However, toxic effects can be seen within therapeutic levels as well.   Cardiac dysrhythmias, seizures, and death can be seen with 80 to 100 mcg/mL levels. Chronic toxicity can be seen at levels of 40 to 60 mcg/mL. Fifty percent to 65% of theophylline is protein-bound in the circulation. The volume of distribution is small, at 0.45 L/kg. The half-life varies with age. A half-life of 4 to 8 hours is seen in young adults. A shorter half-life is seen in newborns. Theophylline is metabolized in the liver by the cytochrome P450 system and excreted by the kidneys. Therefore, any agents or pathology that alters the cytochrome P450 system or renal function can have a substantial effect on theophylline levels.[1][5]

History and Physical

Depending on the dose, route of administration, and coingestants, there is a wide spectrum of clinical effects of theophylline toxicity, ranging from abdominal pain to cardiac arrhythmias to seizures. Often, patients cannot give a clear history, so it is imperative to obtain a history from EMS personnel, family, friends, and witnesses.

• General: Agitation, irritability, restlessness
• Cardiovascular: Sinus tachycardia, ventricular tachycardia atrial fibrillation, supraventricular tachycardia, hypotension, cardiac arrest
• Respiratory: Tachypnea, acute lung injury, respiratory alkalosis
• Gastrointestinal (GI): Nausea, vomiting, abdominal pain
• Neurological: Tremors, hallucinations, seizures[1][3]

Evaluation

 Workup should include the following:

• Serum theophylline level
• Serum glucose: Hyperglycemia is common theophylline toxicity
• Complete metabolic panel: Hypokalemia and metabolic acidosis are common with theophylline toxicity
• Complete blood count (CBC): White blood cells can be elevated due to increase catecholamine release
• Serum calcium: Hypercalcemia is seen in theophylline toxicity
• Serum acetaminophen level, serum salicylate level, urine drug screen: Evaluate for co-ingestion or unknown ingestion
• Serum iron level: Iron toxicity can have a similar presentation to theophylline toxicity
• Creatine kinase: Evaluation for rhabdomyolysis
• Liver function tests: Evaluation of liver dysfunction as the liver metabolizes theophylline.
• ECG to evaluate arrhythmias, ischemia, or other toxic ingestions
• Consider CT Head: Evaluation of other potential causes of altered mental status or seizures[1][3]

Treatment / Management

Most patients with theophylline toxicity are successfully managed with supportive care. Airway, breathing, circulation, and hemodynamic monitoring are essential to patient care with theophylline toxicity. Intubation with ventilator support may be required for airway protection.

GI decontamination: Activated charcoal (1 g/kg) by mouth or nasogastric tube is recommended in patients who present to the emergency department if there are no contraindications to activated charcoal. Gastric lavage or induced emesis is not recommended in theophylline toxicity. Whole bowel irrigation is controversial as animal models do not demonstrate that it is a beneficial therapy. Multiple-dose activated charcoal is recommended for acute theophylline toxicity if there are no contraindications.

Hypotension-isotonic saline (20 mL/kg): Hypotension refractory to IV fluid administration, an alpha agonist such as phenylephrine is recommended. Primarily alpha agonists such as norepinephrine can be used as well. Treatment of hypotension with a beta antagonist should only be used in consultation with a toxicologist.

Nausea and vomiting: Ondansetron is recommended. Metoclopramide can be used in cases that are refractory to ondansetron.

Cardiac arrhythmias: Treatment of cardiac arrhythmias should be managed according to advanced cardiac life support and pediatric advanced life support protocols.

Seizures: In adults, benzodiazepines (lorazepam, midazolam, diazepam) are the first-line treatment for theophylline-induced seizures.  Phenobarbital and continuous infusion of propofol or midazolam can be used for seizures refractory to benzodiazepines. In pediatrics, benzodiazepines are the first-line treatment for seizures. Phenobarbital or continuous infusion of midazolam or pentobarbital or propofol can be used for refractory seizures.

Hemodialysis: In acute overdose, hemodialysis is indicated for life-threatening arrhythmias and seizures, theophylline levels greater than 100 mcg/mL, clinical instability, or increased theophylline levels despite appropriate care. In chronic theophylline toxicity, hemodialysis is indicated with severe symptoms, such as life-threatening arrhythmias, seizures, and theophylline levels greater than 60 mcg/mL in patients between the ages of 6 months to 60 years, or levels greater than 50 mcg/mL in patients of age less than 6 months or greater than 60 years. Hemodialysis is preferred as opposed to hemoperfusion. However, if hemodialysis is not available, hemoperfusion may be used instead. Decisions to initiate hemodialysis or hemoperfusion should always be made in consultation with a medical toxicologist.

Hypokalemia: Potassium supplementation Is recommended for patients with ventricular arrhythmias or potassium levels less than 3 mEq/L.[1][3][5]

Differential Diagnosis

• Alcoholic ketosis
• Amphetamine intoxication
• Anticholinergic poisoning
• Atrial fibrillation
• Atrial flutter
• Bipolar disorder
• Cocaine intoxication
• Carbon monoxide toxicity
• Diphenhydramine toxicity
• Delirium tremors
• Diabetic ketoacidosis
• Encephalitis
• Hypercalcemia
• Hyperthyroidism
• Hyponatremia
• Hypoxia
• Iron toxicity
• Monoamine oxidase inhibitor toxicity
• Salicylates toxicity
• Sepsis
• Status epilepticus
• Ventricular tachycardia

Complications

• Arrhythmias
• Cardiac arrest
• Acute lung injury
• Agitation, hallucinations
• Seizures
• Heart failure
• Liver dysfunction

Enhancing Healthcare Team Outcomes

Theophylline toxicity is best managed in an interprofessional fashion. The drug can affect many organ systems, including the heart, lung, central nervous system (CNS), and GI tract. The key to theophylline toxicity is prevention. First, healthcare providers should avoid prescribing this agent for asthma when other safer drugs are available. All patients should be educated about the dangers of theophylline. Parents should be told to store theophylline in a safe place away from the reach of children. For those who intentionally overdose on the drug, a mental health consult is recommended before discharge.[6] [Level V]

Outcomes

Only anecdotal reports and small case series exist on short-term outcomes after theophylline toxicity. However, despite the few cases being reported, the drug is associated with high morbidity and mortality. Several deaths have been reported both in the United States and abroad following theophylline toxicity. But overall, the number of cases of theophylline toxicity subsides as healthcare providers no longer prescribe this agent for asthma.[7][8] [Level V]