Basics
Description
- Theophylline causes:
- Release of endogenous catecholamines resulting in stimulation of ˇ ²1- and ˇ ²2-receptors
- Adenosine antagonism
- Inhibition of phosphodiesterase (at supratherapeutic levels)
- Available in immediate- and sustained-release formulations
- Peak absorption is 60 " “90 min with immediate-release and 6 " “10 hr with sustained-release formulations
- Acute overdose:
- Ingestion within an 8-hr interval in a patient with no prior theophylline use
- Acute-on-chronic overdose:
- Single excessive dose in a patient previously receiving usual therapeutic doses for ≥24 hr
- Chronic intoxication:
- Accumulation of theophylline >20 ˇ ¼g/mL associated with prior therapeutic use for ≥24 hr secondary to:
- Drug " “drug, drug " “diet, or drug " “disease interactions
- Use of serial excessive doses
Etiology
- Acute ingestions require larger concentrations to achieve specific toxic effects compared with acute-on-chronic or chronic overdoses.
- Drug " “drug interactions:
- Inhibiting theophylline metabolism (leads to toxicity when started):
- H2-receptor antagonists
- Macrolide antibiotics
- Fluoroquinolones
- Allopurinol
- Influenza vaccine
- Interferons
- Enhances theophylline metabolism (leads to toxicity when discontinued):
- Carbamazepine
- Barbiturates
- Smoking
- Rifampin
- Chronic theophylline accumulation:
- Uncontrolled CHF
- Liver disease (cirrhosis or severe hepatitis)
- Acute viral infections
Diagnosis
Signs and Symptoms
- Cardiovascular:
- Sinus, atrial, and ventricular tachycardias:
- Multifocal atrial tachycardia
- Atrial fibrillation
- Premature ventricular contractions
- Ventricular tachycardia
- Due to ˇ ²1-receptor stimulation and adenosine antagonism
- Hypotension:
- Associated with theophylline >100 ˇ ¼g/mL (acute ingestion)
- Due to vasodilatation induced by ˇ ²2-receptor stimulation
- May be refractory to fluids, positioning, and conventional vasopressors
- CNS:
- Tremor
- Mental status changes
- Seizures:
- 14% of chronic intoxications
- 5% of acute intoxications
- GI:
- Nausea, vomiting:
- Protracted and may be refractory to antiemetics at usual doses
- 75% of acute intoxications
- 30% of chronic intoxications
- Abdominal pain
- Pharmacobezoar:
- From sustained-release preparations in acute ingestions
- Delays peak concentrations
- Metabolic:
- Hypokalemia:
- Typically decreases approximately to 3 mEq/L
- Due to ˇ ²-receptor stimulation
- Hyperglycemia
- Leukocytosis
- Hypophosphatemia and hypomagnesemia
- Metabolic acidosis with increased serum lactate levels
Essential Workup
- Serum theophylline concentration:
- Finding of ≥20 ˇ ¼g/mL confirms diagnosis.
- ECG and cardiac monitoring
- Detailed history to differentiate acute from acute-on-chronic from chronic intoxication
Diagnosis Tests & Interpretation
Lab
- Serum theophylline level:
- Repeat every 2 hr until decreasing to confirm immediate absorption is complete and peak value has occurred.
- Serious morbidity in acute overdose if ≥100 ˇ ¼g/mL
- CBC
- Electrolytes
Imaging
- KUB (kidneys, ureters, bladder):
- Undissolved sustained-release tablets or pharmacobezoars may appear as radiopacities.
- Bead-filled capsules may appear as radiolucencies.
- US of stomach may detect intact sustained-release dosage forms.
Differential Diagnosis
- Caffeine/ ˇ ²-agonist bronchodilator overdose
- Amphetamines
- Sympathomimetics
- Anticholinergic agents
- Drug withdrawal syndromes
- Pheochromocytoma
- Thyrotoxicosis
Treatment
Pre-Hospital
Bring pill bottles/pill samples in suspected overdose. ‚
Initial Stabilization/Therapy
- ABCs:
- Cardiac monitor
- Isotonic crystalloids as needed for hypotension
- Naloxone, thiamine, and dextrose (D50W) as indicated for altered mental status
- Cardiovascular:
- Initiate ˇ ²-blockers or calcium channel blockers for rate control with supraventricular tachyarrhythmias (SVT).
- Adenosine is antagonized by theophylline and may not be effective to treat SVT.
- Administer isotonic crystalloid IV fluid resuscitation for hypotension:
- With treatment failure, consider ˇ ²-blocker to reverse theophylline-induced ˇ ²2-receptor " “stimulated vasodilation.
- If vasopressors are needed, choose vasopressor that is not a ˇ ²-agonist, such as phenylephrine.
- Treat ventricular dysrhythmias conventionally.
- Seizures:
- Administer benzodiazepines.
- Phenytoin is contraindicated; it is usually ineffective and may paradoxically worsen seizures in theophylline intoxications.
Ed Treatment/Procedures
Decontamination
- Administer activated charcoal
- Multidose activated charcoal:
- Especially with sustained-release products
- Binds theophylline, which back-diffuses in to the small intestine
- For mild to moderate toxicity
- 25 g q2h until theophylline level ≤20 ˇ ¼g/mL
- Initiate whole-bowel irrigation with sustained-release products:
- Administer 1 " “2 L/hr of polyethylene glycol until a clear, colorless rectal effluent or theophylline level ≤20 ˇ ¼g/mL
- Treat protracted vomiting with metoclopramide or 5-HT3-receptor antagonists.
- Avoid syrup of ipecac.
Electrolyte Disturbances
- Treat hypokalemia in acute ingestions cautiously:
- Relative hypokalemia owing to ˇ ²-receptor " “mediated intracellular shift of extracellular potassium.
- Aggressive correction leads to potentially serious hyperkalemia as theophylline concentrations decrease.
- Most electrolyte imbalances respond to ˇ ²-blocker therapy:
- Generally not indicated; however, because of absence of associated morbidity and potential for ˇ ²-blocker " “induced bronchospasm in pulmonary patients
Extracorporeal Elimination
Initiate hemodialysis or hemoperfusion if theophylline level: ‚
- ≥90 ˇ ¼g/mL and symptomatic in acute ingestions
- ≥40 ˇ ¼g/mL and:
- Seizures or
- HTN unresponsive to IV fluid or
- Ventricular dysrhythmias
Medication
- Activated charcoal: 1 g/kg PO, if dose ingested is known, 10 g/1 g theophylline ingested, max. dose 100 g
- Multidose-activated charcoal 25 g q2h until theophylline level ≤20 ˇ ¼g/mL
- Diazepam: 0.1 mg/kg IV q5 " “10min until seizures controlled, up to 30 mg
- Diltiazem: 0.25 mg/kg IV bolus; may repeat after 15 min, then 5 " “15 mg/h infusion for control of heart rate in patients with contraindication to ˇ ²-blockade
- Esmolol: 500 ˇ ¼g/kg IV bolus, followed by 50 ˇ ¼g/kg/min infusion; increase by 50 ˇ ¼g/kg/min increments to max. of 200 ˇ ¼g/kg/min
- Metoclopramide: 10 mg IV bolus; may repeat to max. of 1 mg/kg
- Ondansetron: 0.15 mg/kg IV bolus up to max. of 16 mg total
- Polyethylene glycol (high molecular weight): 1 " “2 L/h via nasogastric tube
Follow-Up
Disposition
Admission Criteria
ICU: ‚
- Acute overdoses with serum theophylline concentrations ≥100 ˇ ¼g/mL
- Acute-on-chronic or chronic theophylline with either serum concentration ≥60 ˇ ¼g/mL or patient >60 yr old
- Seizures or hypotension refractory to fluids and vasopressors in a patient with serum theophylline concentration ≥40 ˇ ¼g/mL
Discharge Criteria
- 2 consecutive ( ≥2 hr apart) decreasing serum theophylline concentrations with most recent concentration <30 ˇ ¼g/mL
- Mildly symptomatic or asymptomatic patient meeting above criterion and no evidence of suicidal intention
Follow-Up Recommendations
- Follow up with medical toxicologist or primary care doctor
- If patient is on chronic theophylline, dosing regimen may have to be adjusted.
Pearls and Pitfalls
- Seizures are a major complication.
- Tachydysrhythmias are common in overdose.
- Multi-dose activated charcoal is beneficial in theophylline overdose.
A special thanks to Dr. Harry Karydes who contributed to the previous edition. ‚
Additional Reading
- Henderson ‚ A, Wright ‚ DM, Pond ‚ SM. Management of theophylline overdose patients in the intensive care unit. Anaesth Intensive Care. 1992;20:56 " “62.
- Hoffman ‚ RJ. Methylxanthines and selective ˇ ²2-adrenergic agonists. In: Flomenbaum ‚ NE, Goldfrank ‚ LR, Hoffman ‚ RS, et al., eds. Goldfrankss Toxicologic Emergencies. 9th ed. New York, NY: McGraw-Hill Medical; 2011.
- Shannon ‚ M. Life-threatening events after theophylline overdose: A 10-year prospective analysis. Arch Intern Med. 1999;159:989 " “994.
- Shannon ‚ MW. Comparative efficacy of hemodialysis and hemoperfusion in severe theophylline intoxication. Acad Emerg Med. 1997;4:674 " “678.
Codes
ICD9
975.7 Poisoning by antiasthmatics ‚
ICD10
- T48.6X1A Poisoning by antiasthmatics, accidental, init
- T48.6X5A Adverse effect of antiasthmatics, initial encounter
SNOMED
- 64808005 Poisoning by theophylline
- 291363004 Accidental theophylline poisoning