Author:
Brian R.Bush
NavneetCheema
Description
- Theophylline is a methylxanthine, related to caffeine and theobromine
- Clinical uses of theophylline include:
- Theophylline mechanism of action:
- Stimulates the release of endogenous catecholamines resulting in stimulation of β1- and β2-receptors
- Antagonist of adenosine receptor
- Inhibition of phosphodiesterase (at supratherapeutic levels)
- Increases intracellular cAMP
- cAMP augments β-adrenergic stimulation
- Available in immediate- and sustained-release formulations
- Peak absorption is 60-90 min with immediate-release and 6-10 hr with sustained-release formulations
- Half-life is highly variable
- In a healthy, nonsmoker adult half-life is typically 4.5 hr
- Therapeutic serum concentration 5-15 mcg/mL
- 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 mcg/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
- Oral contraceptives
- Interferons
- Enhances theophylline metabolism (leads to toxicity when discontinued):
- Chronic theophylline accumulation:
- Uncontrolled CHF
- Liver disease (cirrhosis or severe hepatitis)
- Acute viral infections
Signs and Symptoms
- Cardiovascular:
- Sinus, atrial, and ventricular tachycardias:
- Multifocal atrial tachycardia
- Atrial fibrillation
- Premature ventricular contractions
- Ventricular tachycardia
- Due to β1-receptor stimulation and adenosine antagonism
- Hypotension:
- Usually associated with acute ingestion and theophylline >100 mcg/mL
- Due to vasodilatation induced by β2-receptor stimulation
- May be refractory to fluids, positioning, and conventional vasopressors
- Myocardial ischemia/acute myocardial infarction
- CNS:
- Tremor
- Mental status changes
- Seizures:
- 14% of chronic intoxications
- 5% of acute intoxications
- Tend to be severe and recurrent
- Often refractory to anticonvulsant drugs
- GI:
- Nausea, vomiting:
- Protracted and may be refractory to antiemetics
- 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 to ∼3 mEq/L
- Due to β-receptor stimulation
- Hyperglycemia (>200 mg/dL)
- Leukocytosis
- Hypophosphatemia and hypomagnesemia
- Metabolic acidosis with increased serum lactate levels
- Increased respiratory rate resulting in respiratory alkalosis from activation of CNS respiratory center
Essential Workup
- Serum theophylline level:
- Finding of ≥20 mcg/mL confirms diagnosis
- Can expect severe symptoms when serum level is:
- 90-100 mcg/mL or greater (acute intoxication)
- 40-60 mcg/mL (chronic intoxication)
- ECG, troponin, and cardiac monitoring
- Detailed history to differentiate acute from acute-on-chronic from chronic intoxication, focusing on:
- Timing and amount of theophylline ingested
- If prescribed to patient, dose of theophylline
- Medical comorbidities/conditions
- Current medications
Diagnostic Tests & Interpretation
Lab
- Serum theophylline level:
- Repeat every 1-2 hr until decreasing to confirm immediate absorption is complete and peak value has occurred
- Serious morbidity in acute overdose if ≥100 mcg/mL
- CBC
- Serum electrolytes (especially potassium)
- If patient has increased muscle tone, hyperthermia, or systemic illness, assess for rhabdomyolysis with:
Differential Diagnosis
- Caffeine/β-agonist bronchodilator overdose
- Amphetamines
- Sympathomimetics
- Anticholinergic agents
- Drug withdrawal syndromes
- Pheochromocytoma
- Thyrotoxicosis
Prehospital
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:
- ECG to evaluate for dysrhythmias, evaluate for cardiac ischemia or acute MI
- Initiate β-blockers or calcium-channel blockers for rate control with supraventricular tachydysrhythmias (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 β-blocker to reverse theophylline-induced β2-receptor-stimulated vasodilation
- If vasopressors are needed, choose vasopressor that is not a β-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, essential in treatment
- Multidose activated charcoal:
- Especially with sustained-release products
- For mild to moderate toxicity
- 25-50 g q4-6h until theophylline level ≤20 mcg/mL
- Consider 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 mcg/mL
- Avoid syrup of ipecac, induced emesis not indicated
Electrolyte Disturbances
- Treat hypokalemia in acute ingestions cautiously:
- Relative hypokalemia owing to β-receptor-mediated intracellular shift of extracellular potassium
- Will usually resolve spontaneously without aggressive intervention
- Aggressive correction leads to potentially serious hyperkalemia as theophylline concentrations decrease
- Most electrolyte imbalances respond to β-blocker therapy:
- Generally not indicated; however, because of absence of associated morbidity and potential for β-blocker-induced bronchospasm in pulmonary patients
Vomiting
- Avoid phenothiazine antiemetics as they may lower seizure threshold
- Treat protracted vomiting with metoclopramide or 5-HT3-receptor antagonists
Extracorporeal Elimination
Initiate hemodialysis or hemoperfusion if theophylline level:
- ≥90-100 mcg/mL and any symptom in acute ingestions
- ≥40 mcg/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 25-50 g q4-6h until theophylline level ≤20 mcg/mL
- Diazepam: 0.1 mg/kg IV q5-10 min until seizures controlled, up to 30 mg
- Diltiazem: 0.25 mg/kg IV bolus; may repeat after 15 min, then 5-15 mg/hr infusion for control of heart rate in patients with contraindication to β-blockade
- Esmolol: 500 mcg/kg IV bolus, followed by 50 mcg/kg/min infusion; increase by 50 mcg/kg/min increments to max of 200 mcg/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/hr via nasogastric tube
Disposition
Admission Criteria
ICU:
- Acute overdoses with serum theophylline concentrations ≥100 mcg/mL
- Acute-on-chronic or chronic theophylline with either serum concentration ≥60 mcg/mL or severe symptoms (seizures, hypotension) with a lower theophylline concentration
Discharge Criteria
- 2 consecutive (≥2 hr apart) decreasing serum theophylline concentrations with most recent concentration <30 mcg/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
ICD9
975.7 Poisoning by antiasthmatics
ICD10
T48.6X1A Poisoning by antiasthmatics, accidental, init
T48.6X5A Adverse effect of antiasthmatics, initial encounter
SNOMED