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Theophylline Poisoning, Emergency Medicine

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)

- 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

- 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

- CNS: - Tremor - Mental status changes - Seizures: - 14% of chronic intoxications - 5% of acute intoxications

- Abdominal pain - Pharmacobezoar: - From sustained-release preparations in acute ingestions - Delays peak concentrations

- Hyperglycemia - Leukocytosis - Hypophosphatemia and hypomagnesemia - Metabolic acidosis with increased serum lactate levels

- 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

  • Theophylline causes:Release of endogenous catecholamines resulting in stimulation of ˇ ²1- and ˇ ²2-receptorsAdenosine antagonismInhibition 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 interactionsUse 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 antagonistsMacrolide antibioticsFluoroquinolonesAllopurinolInfluenza vaccineInterferonsEnhances theophylline metabolism (leads to toxicity when discontinued):CarbamazepineBarbituratesSmokingRifampin
  • Chronic theophylline accumulation:Uncontrolled CHFLiver disease (cirrhosis or severe hepatitis)Acute viral infections

Diagnosis

Signs and Symptoms

  • Cardiovascular:Sinus, atrial, and ventricular tachycardias:Multifocal atrial tachycardiaAtrial fibrillationPremature ventricular contractionsVentricular tachycardiaDue to ˇ ²1-receptor stimulation and adenosine antagonismHypotension:Associated with theophylline >100 ˇ ¼g/mL (acute ingestion)Due to vasodilatation induced by ˇ ²2-receptor stimulationMay be refractory to fluids, positioning, and conventional vasopressors
  • CNS:TremorMental status changesSeizures:14% of chronic intoxications5% of acute intoxications
  • GI:Nausea, vomiting:Protracted and may be refractory to antiemetics at usual doses75% of acute intoxications30% of chronic intoxicationsAbdominal painPharmacobezoar:From sustained-release preparations in acute ingestionsDelays peak concentrations
  • Metabolic:Hypokalemia:Typically decreases approximately to 3 mEq/LDue to ˇ ²-receptor stimulationHyperglycemiaLeukocytosisHypophosphatemia and hypomagnesemiaMetabolic 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 monitorIsotonic 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 productsBinds theophylline, which back-diffuses in to the small intestineFor mild to moderate toxicity25 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 orHTN unresponsive to IV fluid orVentricular dysrhythmias

Medication

  • Activated charcoal: 1 g/kg PO, if dose ingested is known, 10 g/1 g theophylline ingested, max. dose 100 gMultidose-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