Theophylline Toxicity - Pathophysiology, Diagnosis, and Treatment

Introduction:

Theophylline (1,3-dimethylxanthine) is mostly utilized as a bronchodilator for asthma and chronic obstructive pulmonary disease (COPD) patients around the world. Theophylline is mostly used to treat bradycardia (slow heart rate) and apnea in premature neonates, while asthma and COPD (lung diseases) are primarily treated with different medications in the United States. Through indirect activation of beta-1 and beta-2 receptors (components responsible for signaling the nervous system), theophylline triggers the endogenous release of catecholamines (neurotransmitters), which at therapeutic doses results in desirable bronchodilation.

Theophylline, unfortunately, has a limited therapeutic window, and even concentrations just a little bit above this therapeutic window can have a wide range of negative effects in the context of acute and chronic toxicity. Theophylline toxicity is linked to the significant clinical symptoms brought on by the high levels of circulating catecholamines. Theophylline can cause a variety of cardiovascular, neurologic, metabolic, musculoskeletal, and gastrointestinal symptoms, depending on the amount and method of administration. Since theophylline poisoning can cause problems such as arrhythmias (irregular heart rate), seizures, hyperglycemia (increased blood glucose), and rhabdomyolysis (medical condition due to rapid dissolution of damaged or injured skeletal muscle), emergency department staff members should learn how to handle these patients.

What Is the Cause of Theophylline Toxicity?

There is a very small therapeutic window for theophylline. As a result, theophylline toxicity happens when serum levels are higher than those that fall within the therapeutic range. This can happen intentionally by taking too much theophylline or unintentionally when theophylline metabolism or clearance is changed as a result of certain physiological stresses.

What Is the Pathophysiology of Theophylline Toxicity?

There are two main pathways for theophylline. Theophylline has several mechanisms, one of which is the blocking of adenosine receptors, which has both beneficial and harmful effects, including bronchodilation (widening the airways), tachycardia (rapid heart rate), cardiac arrhythmias, seizures, and cerebral vasoconstriction. Theophylline inhibits phosphodiesterase (enzyme) at higher doses, increasing levels of cyclic adenosine monophosphate (second messenger in many biological processes), which in turn increases levels of adrenergic activation and catecholamine (neurotransmitter) release. Epinephrine levels can be four to eight times greater than normal in theophylline toxicity, while norepinephrine concentrations can be four to ten times higher. Numerous negative consequences of elevated catecholamine levels include cardiac arrhythmias, metabolic acidosis (a clinical disturbance due to low pH and bicarbonate levels), hyperglycemia, and hypokalemia (abnormally low potassium in the blood). When there is an accumulation of the substance as a result of metabolism being overloaded or hindered, chronic theophylline toxicity can happen. Additionally, it might happen if clearance is reduced.

How Is Theophylline Toxicity Diagnosed?

History and Physical Examination:

There is a wide range of clinical theophylline toxicity consequences, from abdominal pain to cardiac arrhythmias to convulsions, depending on the dose, route of administration, and co-ingestants. Since patients frequently struggle to provide a detailed history, it is crucial to get one from EMS staff, family, friends, and bystanders.

• General: Angry, irritable, and restless.

• Cardiovascular: Cardiac arrest, atrial fibrillation, supraventricular tachycardia, sinus tachycardia, and ventricular tachycardia.

• Respiratory Conditions: Tachypnea, acute lung damage, and respiratory alkalosis.

• Gastrointestinal Tract (GI) Symptoms: Nausea, vomiting, and stomach pain.

• Neurological Symptoms: Seizures, hallucinations, and tremors.

How Is the Patient Evaluated for Theophylline Toxicity?

The following should be part of the workup:

• Serum theophylline concentration.

• Serum Glucose: Theophylline poisoning frequently manifests as hyperglycemia.

• Comprehensive Metabolic Panel: Metabolic acidosis and hypokalemia are frequent symptoms of theophylline poisoning.

• Complete Blood Count (CBC): Increased catecholamine release can increase white blood cells.

• Serum Calcium: Hypercalcemia is a sign of theophylline poisoning.

• Blood Tests: For Acetaminophen, Salicylate, and a urine drug screen, check for concurrent consumption or unidentified ingestion.

• Serum Iron Content: Theophylline toxicity and iron toxicity can both present identically.

• Creatine Kinase: Rhabdomyolysis testing.

• Liver Function Tests: Assessment of liver dysfunction concerning theophylline metabolism by the liver.

• Electrocardiogram (ECG): To assess ischemia, arrhythmias, or other hazardous ingestions.

• Computed Tomography (CT) Head: Evaluation of additional potential sources of seizures or a change in mental condition.

How Is Theophylline Toxicity Managed?

Supportive treatment is an effective management strategy for the majority of individuals with theophylline toxicity. When a patient has theophylline poisoning, monitoring their airways, breathing, heart rate, and hemodynamics is crucial. For airway protection, intubation with ventilator assistance can be necessary.

• GI Decontamination: If there are no activated charcoal contraindications, activated charcoal (1 g/kg - gram per kilogram) through the mouth or nasogastric tube is advised for patients who arrive at the emergency room. It is not advised to induce emesis or lavage the stomach when theophylline poisoning occurs. Whole bowel irrigation is debatable because there is no evidence from animal models that it is a helpful treatment. If there are no contraindications, multiple doses of activated charcoal are advised for treating acute theophylline poisoning.

• Hypotension-Isotonic Saline (20 ml/Kg): When hypotension is resistant to intravenous fluid delivery, an alpha agonist such as Phenylephrine is advised. It is also possible to use alpha agonists in general, such as norepinephrine. A beta antagonist should only be used to treat hypotension after consulting a toxicologist.

• Nausea and Vomiting: Ondansetron is suggested for experiencing nausea and vomiting. When Ondansetron fails to work, Metoclopramide might be administered.

• Cardiac Arrhythmias: Advanced cardiac life support and pediatric advanced life support protocols should be followed when treating cardiac arrhythmias.

• Seizures: Theophylline-induced seizures in adults are treated with Benzodiazepines (Lorazepam, Midazolam, and Diazepam). For seizures resistant to Benzodiazepines, Phenobarbital with continuous infusions of Propofol or Midazolam can be utilized. Benzodiazepines are the first-line treatment for seizures in kids. Refractory seizures can be treated with Phenobarbital, Midazolam, Pentobarbital, or Propofol given continuously.

• Hemodialysis: In cases of acute overdose, hemodialysis is recommended for patients who are experiencing life-threatening arrhythmias, seizures, clinical instability, or elevated theophylline levels despite receiving the right therapy. Hemodialysis is recommended for patients with severe symptoms of chronic theophylline toxicity, such as seizures, life-threatening arrhythmias, and theophylline concentrations higher than 60 mcg/mL (microgram per milligram) or levels greater than 50 mcg/mL in patients aged 6 months or older or greater than 60 years. Hemoperfusion is not recommended over hemodialysis. Hemodialysis may be substituted by hemoperfusion if available. A physician toxicologist should always be consulted before starting hemodialysis or hemoperfusion.

• Hypokalemia: Potassium supplements for hypokalemia are advised for people who have ventricular arrhythmias or potassium levels that are below 3 mEq/L (milliequivalents per liter).

Conclusion:

The best way to treat theophylline toxicity is through inter-professional collaboration. The heart, lungs, central nervous system (CNS), and GI tract are just a few of the organ systems that the medication may have an impact on. Theophylline toxicity can be prevented. Theophylline risks should be made clear to all patients. Theophylline should be kept out of children's reach in a safe place. A mental health consultation is advised before discharge for those who purposefully overdose on the substance. On the short-term results following theophylline intoxication, only anecdotal data and limited case series exist. Despite the small number of cases that have been documented, the medication is linked to substantial morbidity and mortality rates. Theophylline poisoning has been linked to several recorded deaths both domestically and overseas. However, since doctors no longer recommend theophylline for treating asthma, the overall number of cases of theophylline poisoning decreases.