eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Theophylline

Greg Hymel, MD, Consulting Staff, Department of Emergency Medicine, Saint Vincent Mercy Medical Center

Updated: Sep 2, 2009

Introduction

Background

Theophylline (1,3-dimethylxanthins) can indirectly stimulate both β₁ and β₂ receptors through release of endogenous catecholamines. It is used for the treatment of pulmonary conditions, including asthma and chronic obstructive pulmonary disease (COPD). In neonates, theophylline can be used for the treatment of apnea.

Medication, diet, and underlying diseases can alter its narrow therapeutic window. Adverse effects can be evident at therapeutic serum levels.

Pathophysiology

Major mechanisms of theophylline therapeutic efficacy and its toxicity are through the excess of catecholamines and adenosine antagonism. Adenosine blockade can theoretically reduce histamine release and indirectly reverse bronchospasm. In addition, high levels of theophylline inhibit phosphodiesterase, resulting in elevation of cyclic adenosine monophosphate (cAMP) and consequent adrenergic stimulation.

Theophylline is absorbed rapidly and completely after oral administration. Peak serum levels for immediate release preparations are relatively rapid and can range from 30-120 minutes. Fasting or large volumes of fluid enhance absorption. Enteric-coated and sustained-release tablets have a delayed absorption with peak between 6 and 10 hours. It is important to recognize that these time intervals are much longer in the setting of overdose. The intravenous form of theophylline (aminophylline) reaches peak serum levels in 30 minutes.

Theophylline is around 60% protein bound and has a distribution volume of 0.5 L/kg. Therapeutic serum levels range from 10-20 mcg/mL. Toxic levels are considered to be higher than 20 mcg/mL; however, adverse effects may be evident within the normal therapeutic range. Severe complications including cardiac dysrhythmias, seizures, and death can be observed with the levels of 80-100 mcg/mL. In chronic exposure, those levels could be lower (40-60 mcg/mL).

Theophylline is eliminated by the hepatic cytochrome P-450 system (85-90%) and by urinary excretion (10-15%). The half-life is 4-8 hours in young adults and is shorter in children and smokers. Diet, cardiac or liver disease, tobacco use, and medications (cimetidine, erythromycin, oral contraceptives) affecting the cytochrome P-450 system (CYP1A2) can affect the half-life.

Theophylline affects the cardiovascular (CV), central nervous (CN), gastrointestinal (GI), pulmonary, musculoskeletal, and metabolic systems. Hypokalemia, hyperglycemia, hypercalcemia, hypophosphatemia, and acidosis commonly occur after an acute overdose.

Frequency

United States

The 2007 annual report of the American Association of Poison Control Centers' National Poison Data System documented 230 exposures to theophylline, with 39 in children younger than 6 years and 163 in persons older than 19 years.¹ Of the 118 theophylline exposures treated in health care facilities, 8 were reported to have major adverse outcomes and no fatalities were noted. The documented toxic exposures have decreased markedly over the past decade as the utilization of theophylline for the management of asthma has diminished.

Race

No scientific data have demonstrated that outcomes of theophylline toxicity are dependent on race.

Sex

No scientific data have demonstrated that outcomes of theophylline toxicity are dependent on sex.

Clinical

History

• Symptomology correlates better with single acute ingestions than with chronic overexposures. Symptoms of acute theophylline overdose are as follows:
  • Nausea
  • Vomiting
    • Severe and protracted
    • Acute overdose >>> Chronic overdose
    • Sustained-release preparations >>> Immediate-release preparation
  • Abdominal pain
  • Mild metabolic acidosis
  • Hypokalemia
  • Hypophosphatemia
  • Hypomagnesemia
  • Hypocalcemia/hypercalcemia
  • Hyperglycemia
  • Tachycardia
• Chronic theophylline overdose has minimal GI signs or symptoms.
• Seizures, hypotension, and significant dysrhythmias usually are observed when serum levels approach 80 mcg/mL.
• Seizures are more common with acute overdose than with chronic overdose. In chronic exposures, seizures may develop at lower serum concentrations (40-60 mcg/mL).
• Cardiac dysrhythmias are more common following a chronic overdose rather than acute overdose and with lower serum concentrations.

Physical

• Cardiovascular
  • Sinus tachycardia (most common)
  • Atrial fibrillation
  • Atrial flutter
  • Supraventricular tachycardia (SVT)
  • Multifocal atrial tachycardia
  • Ventricular tachycardia
  • Hypotension (severe overdoses) - Due to β₂ effect/agonsim
  • Ventricular fibrillation
  • Pulseless electrical activity (PEA)
  • Cardiac arrest
• Pulmonary
  • Increased respiratory rate leads to respiratory alkalosis
  • Acute lung injury (ALI)
  • Respiratory failure leads to arrest
• Neurological
  • Tremors (most common)
  • Restlessness
  • Agitation
  • Hallucinations
  • Headaches
  • Irritability
  • Seizures (Persistent seizures may occur with serum levels >25 mcg/mL.)
• Gastrointestinal
  • Nausea
  • Vomiting
  • Abdominal cramps
  • Diarrhea

Causes

• Chronic theophylline toxicity
  • Drug interactions (eg, ethanol [ETOH], cimetidine, oral contraceptives, allopurinol, macrolide, quinolone antibiotics)
  • Liver disease
  • Congestive heart failure
  • Febrile viral upper respiratory illness
• Acute theophylline toxicity
  • Nonintentional overdose
  • Intentional overdose

Differential Diagnoses

Workup

Laboratory Studies

• Obtain serum theophylline level upon presentation and then every 2 hours until the level falls.
  • This is especially important following ingestion of extended-release formulations.
  • Theophylline can form bezoars, resulting in ongoing absorption and toxicity despite general measures at GI decontamination.
• WBC can be elevated (due to increased catecholamine activity).
• Obtain acetaminophen (paracetamol) level.
• Obtain aspirin (ASA) level, particularly in patients with history and findings suggestive of aspirin toxicity, including but not limited to metabolic acidosis, respiratory alkalosis, and change of mental status.
• Order electrolytes and glucose tests to evaluate for the following:
  • Hypokalemia (serial testing of serum potassium levels may be required)
  • Hyperglycemia
  • Metabolic acidosis (lactate) 
  • Hypocalcemia/hypercalcemia
  • Hypophosphatemia
  • Ketosis
• Test for pregnancy in women of childbearing age.

Imaging Studies

• Obtain a CT scan of the brain if seizures occur.

Other Tests

• Electrocardiogram, looking for evidence of electrolyte abnormalities and dysrhythmias. Also, ECG should be used to evaluate for the signs of TCAs or other cardioactive drug toxicity.
• Lumbar puncture may be required for the evaluation of new-onset seizures.

Treatment

Prehospital Care

• Establish airway, breathing, and circulation (ABCs).
• Intravenous benzodiazepines may abort seizures.

Emergency Department Care

Evaluate ABCs and, if indicated, perform endotracheal intubation.

• Vascular access for hemoperfusion may be required.
• Endotracheal intubation may be needed in patients who require high-dose benzodiazepines or barbiturates to control seizures.
• Consider gastric lavage (unless contraindicated) if the patient has recently (<1 h) ingested a significant amount or a sustained-release preparation of theophylline or if theophylline bezoar formation is suspected. Gastric lavage should be considered in intubated patients. Endoscopic bezoar fragmentation and retrieval may be utilized if lavage is not efficacious.
• Administer activated charcoal.
  • Multidose activated charcoal (MDAC) enhances elimination of theophylline.
    • It is a very effective method of elimination, and it is considered the mainstay treatment of theophylline toxicity.
    • It is important to aggressively control nausea and vomiting in order to perform MDAC treatment.
    • It is also important that the patient is able to protect his or her airway in order to prevent aspiration of activated charcoal, which can be detrimental.
  • Administer the cathartic, sorbitol, with the activated charcoal one time.
• Perform whole-bowel irrigation (WBI) in patients with exposure to sustained-release theophylline preparations.
  • Administer polyethylene glycol electrolyte solution.
    • Adults: 2 liters per hour until clear rectal effluent
    • Children: 500 mL/h until clear rectal effluent
• Theophylline-induced seizures tend to be resistant to treatment. Benzodiazepines (eg, lorazepam) are considered the first line of treatment. Historically, phenobarbital prophylaxis was used in patients at high risk for seizures. High-risk cases include the following:
  • Acute overdose with theophylline levels higher than 80 mcg/mL
  • Chronic toxicity with levels higher than 40 mcg/mL
  • Patients older than 60 years or younger than 3 years
• Benzodiazepines (IV) and phenobarbital may be used to treat seizures.
  • CAVEAT: Barbiturates can precipitate hypotension.
  • Phenobarbital has the added advantage of enhancing the hepatic metabolism of theophylline.
• Hypotension resistant to isotonic fluids (10-20 mL/kg) may require vasopressors with predominantly alpha-agonistic activity (eg, phenylephrine, norepinephrine).
  • In patients with theophylline toxicity, beta-blockade with propranolol has been shown to successfully reverse peripheral beta receptor-mediated hypotension without apparent effect on concomitant tachycardia.
  • However, always consider the risk of beta-adrenergic blockade to patients with preexistent bronchospastic disease.
• Esmolol, a short-acting beta-blocker, has been used successfully for unstable SVT and related hypotension in theophylline overdose.²
  • Exercise caution with beta-blocking agents because of their negative inotropic effects.
  • Esmolol is a relatively selective beta1-receptor antagonist; thus, it may not have as much effect on beta2-mediated hypotension as less-selective agents (eg, propranolol), although it is less likely to induce bronchospasm than other beta-blockers.
• Consider hemoperfusion with the following:
  • Symptomatic patients with levels exceeding 90 mcg/mL in acute ingestions
  • Theophylline concentrations exceeding 40 mcg/mL (chronic ingestion)
  • Presence of life-threatening toxicity
    • Persistent seizures
    • Hypotension that is not responding to IV fluids
    • Ventricular dysrhythmias
  • Hemodialysis is an alternative method of elimination enhancement but is considerably less effective than hemoperfusion.
• Correct electrolyte abnormalities in patients with ECG changes (eg, QTc prolongation) and/or ventricular dysrhythmias.
  • Hypocalcemia
  • Hypophosphatemia
  • Hypokalemia
• Current recommendations for treating patients with tachycardia, hypotension, anxiety, and vomiting from theophylline overdose may include the following:
  • Fluid bolus with isotonic fluid (20 mL/kg)
  • Metoclopramide or ondansetron to help control vomiting
  • Propranolol to increase blood pressure - Reportedly propranolol treatment can correct hypokalemia.³
  • Benzodiazepine to decrease anxiety, decrease risk of seizures, and help control vomiting
  • Phenylephrine or norepinephrine to further increase blood pressure
  • Charcoal hemoperfusion guided by response to treatment, underlying medical problems, and theophylline level
    • Because charcoal hemoperfusion is a somewhat complicated process that is not routinely used lately, most of the centers will perform routine hemodialysis.
    • Hemodialysis in combination with MDAC will most of the time be sufficient for the treatment of severe theophylline toxicity.

Consultations

• Consult the regional poison control center or local medical toxicologist (certified through the American Board of Medical Toxicology or the American Board of Emergency Medicine) for additional information and patient care recommendations.
• Consult a nephrologist if hemoperfusion is needed.

Medication

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

GI decontaminant

GI decontaminants are empirically used to minimize systemic absorption of the toxin. They may only be of benefit if administered within 1-2 h of ingestion.

Activated charcoal (Liqui-Char)

Prevents absorption by adsorbing drug in intestine. Multidose charcoal may interrupt enterohepatic recirculation and enhance elimination by enterocapillary exsorption. Theoretically, by constantly bathing the GI tract with charcoal, the intestinal lumen serves as a dialysis membrane for reverse absorption of drug from intestinal villous capillary blood into intestine. Supplied as an aqueous mixture or in combination with a cathartic (usually sorbitol 70%).

Dosing

Adult

1 g/kg PO; may repeat in 2-4 h at one-half original dose

Pediatric

1 g/kg PO (typical 12.5-25 g)
<2 years: Use aqueous charcoal without cathartic

Interactions

May inactivate ipecac syrup if used concomitantly; effectiveness of other medications decreases with coadministration; sherbet, milk, or ice cream decreases adsorption

Contraindications

Documented hypersensitivity; poisoning or overdose of mineral acids and alkalies; unprotected airway and absent gag reflex

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Not very effective in poisonings of ethanol, methanol, and iron salts; induce emesis before administration; after emesis with ipecac syrup, patient may not tolerate activated charcoal for 1-2 h; can administer in early stages of gastric lavage; without sorbitol, gastric lavage returns are black; protect airway in patients with depressed level of consciousness; if using multiple dose charcoal, monitor for presence of bowel sounds to minimize risk of charcoal ileus and vomiting with subsequent pulmonary aspiration

Antiemetics

Persistent vomiting may interfere with decontamination.

Ondansetron (Zofran)

5HT-3 antagonist acting both on the vagus nerve peripherally and at the CTZ in the CNS.

Dosing

Adult

4-8 mg IV or 0.15 mg/kg IV q4-6h prn; not to exceed 32 mg/d
Infuse over 0.5-5 min

Pediatric

<2 years: Not established
2-12 years: 100 mcg/kg/dose IV infused over 0.5-5 min; may repeat q8h prn
>40 kg: Administer as in adults

Interactions

Although there is potential for cytochrome P-450 inducers (barbiturates, rifampin, carbamazepine, and phenytoin) to change half-life and clearance of ondansetron, dosage adjustment is not usually required

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause headache

Ranitidine (Zantac)

H2 antagonist that may be a useful adjunct in reducing emesis volume.

Dosing

Adult

50 mg IV q8h

Pediatric

1 mg/kg IV q6-8h

Interactions

May decrease effects of ketoconazole and itraconazole; may alter serum levels of ferrous sulfate, diazepam, nondepolarizing muscle relaxants, and oxaprozin

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in renal or liver impairment; if changes in renal function occur during therapy, consider adjusting dose or discontinuing treatment

Metoclopramide (Reglan)

Works as antiemetic by blocking dopamine receptors in the chemoreceptor trigger zone of the CNS.

Dosing

Adult

10-20 mg IV; not to exceed 1 mg/kg; up to 3 mg/kg/d IV in divided doses prn

Pediatric

<6 years: 0.1 mg/kg IV slowly over 1-2 min

Interactions

May antagonize effects of metoclopramide; opiate analgesics may increase metoclopramide toxicity in CNS

Contraindications

Documented hypersensitivity; pheochromocytoma or GI hemorrhage, obstruction, or perforation; history of seizure disorders

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in history of mental illness and Parkinson disease; adverse effects include drowsiness, hypotension, and acute dystonia, especially at high doses; may increase frequency of seizure in individuals with epilepsy

Prochlorperazine (Compazine)

May relieve nausea and vomiting by blocking postsynaptic mesolimbic dopamine receptors through anticholinergic effects and depressing reticular activating system.
In addition to antiemetic effects, has the advantage of augmenting hypoxic ventilatory response, acting as a respiratory stimulant at high altitude.

Dosing

Adult

10 mg IV slowly; may repeat once; not to exceed 40 mg/d; 25 mg PR q12h

Pediatric

<20 pounds: Not recommended
20-29 pounds: 2.5 mg PR bid
30-39 pounds: 2.5 mg PR tid
<12 years: 0.06 mg/lb IM

Interactions

Coadministration with other CNS depressants or anticonvulsants may cause additive effects; may cause hypotension with epinephrine

Contraindications

Documented hypersensitivity; bone marrow suppression, narrow-angle glaucoma, and severe liver or cardiac disease; parkinsonism; depression

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Drug-induced Parkinson syndrome or pseudoparkinsonism occurs frequently; akathisia is most common extrapyramidal reaction in elderly persons; lowers seizure threshold; caution with history of seizures; may cause hypotension, altered mental status, and NMS

Droperidol (Inapsine)

Neuroleptic agent that may reduce emesis by blocking dopamine stimulation of chemoreceptor trigger zone.

Dosing

Adult

1.25-5 mg IV

Pediatric

0.05-0.25 mg/kg IV

Interactions

May increase toxicity of CNS depressants; cabergoline and levodopa may potentiate antipsychotic effects

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hypovolemic patients may experience hypotension; may decrease pulmonary arterial pressure; tardive dyskinesia in patients receiving droperidol is 40%; elderly persons may experience high rate of extrapyramidal reactions; life-threatening arrhythmias may occur; watch for QT prolongation

Benzodiazepines and other sedative agents

These agents are used to terminate seizures and for seizure prophylaxis in high-risk patients. They help to alleviate nausea and vomiting and decrease tremors and anxiety induced by theophylline.

Diazepam (Valium)

Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA.

Dosing

Adult

0.2 mg/kg IV at 2 mg/min; not to exceed 20 mg (as a single dose); may repeat, monitoring for respiratory depression

Pediatric

0.2-0.5 mg/kg IV
<5 years: Not to exceed 5 mg
> 5 years: Not to exceed 10 mg

Interactions

Increases toxicity of benzodiazepines in CNS with coadministration of phenothiazines, cimetidine, barbiturates, alcohols, and MAOIs

Contraindications

Documented hypersensitivity; altered mental status; low BP or RR; narrow-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution with other CNS depressants, low albumin levels, hepatic disease (may increase toxicity), altered mental status, respiratory depression, or hypotension

Lorazepam (Ativan)

Sedative-hypnotic with short onset of effects and relatively long half-life.
By increasing the action of GABA, a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.
Monitoring blood pressure after administering dose is important. Adjust prn.

Dosing

Adult

0.044 mg/kg (2-4 mg) IV; titrate to effect
Status epilepticus: 4 mg IV over 2-5 min; may repeat second dose in 10-15 min prn; not to exceed 8 mg

Pediatric

Infants and children: 0.02-0.1 mg/kg IV slowly over 2-5 min; repeat prn in 10-15 min at 0.05 mg/kg; not to exceed 4 mg/dose
Adolescents: 0.07 mg/kg IV slowly over 2-5 min; repeat in 10-15 min prn; not to exceed 4 mg/dose

Interactions

Toxicity of benzodiazepines in CNS increases when used concurrently with alcohol, phenothiazines, barbiturates, and MAOIs

Contraindications

Documented hypersensitivity; preexisting CNS depression, hypotension, and narrow-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal or hepatic impairment, myasthenia gravis, organic brain syndrome, or Parkinson disease; monitor for respiratory depression with high or repeated doses; contains benzyl alcohol, which may be toxic to infants in high doses

Midazolam (Versed)

Used as alternative in termination of refractory status epilepticus. Because water soluble, takes approximately 3 times longer than diazepam to peak EEG effects. Thus, clinician must wait 2-3 min to fully evaluate sedative effects before initiating procedure or repeating dose. Has twice the affinity for benzodiazepine receptors than diazepam. May be administered IM if unable to obtain vascular access.

Dosing

Adult

0.01-0.05 mg/kg (usually 0.5-4 mg; up to 10 mg) IV slowly over several min; may repeat q10-15min until adequate response achieved

Pediatric

<32 weeks: 0.5 mcg/kg/min IV infusion
>32 weeks: 1 mcg/kg/min IV infusion
Children: 0.05-0.2 mg/kg IV over 2-3 min, followed by 1-2 mcg/kg/min continuous infusion
Status epilepticus (refractory to standard therapy), > 2 months and children: 0.15 mg/kg, followed by continuous infusion of 1 mcg/kg/min; titrate upward q5min until seizures controlled

Interactions

Sedative effects may be antagonized by theophyllines; narcotics, cimetidine, ethanol, and erythromycin may accentuate sedative effects because of decreased clearance; reduce dose of thiopental by 15% when using together

Contraindications

Documented hypersensitivity; preexisting hypotension, narrow-angle glaucoma, and sensitivity to propylene glycol (diluent)

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in congestive heart failure, pulmonary disease, renal impairment, hepatic failure, neuromuscular disease, hypotension, and patients >60 y; monitor for respiratory depression with high or repeated doses; consider lower dosages in patients with organic brain syndrome and patients who may have inhibition of benzodiazepine metabolism and clearance (eg, using nicotine, taking cimetidine)

Phenobarbital (Barbita, Luminal)

Interferes with transmission of impulses from thalamus to cortex of brain.

Dosing

Adult

10-20 mg/kg IV; not to exceed 50 mg/min

Pediatric

15-20 mg/kg IV; not to exceed 50 mg/min

Interactions

May decrease effects of chloramphenicol, digitoxin, corticosteroids, carbamazepine, theophylline, verapamil, metronidazole, and anticoagulants (patients stabilized on anticoagulants may require dosage adjustments if added to or withdrawn from their regimen); coadministration with alcohol may produce additive CNS effects and fatality; chloramphenicol, valproic acid, and MAOIs may increase toxicity; rifampin may decrease effects; induction of microsomal enzymes may result in decreased effects of oral contraceptives in women (must use additional contraceptive methods to prevent unwanted pregnancy); menstrual irregularities also may occur

Contraindications

Documented hypersensitivity; severe respiratory disease, marked impairment of liver function, and nephritic patients

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

In prolonged therapy, evaluate hematopoietic, renal, hepatic, and other organ systems; caution in fever, hyperthyroidism, diabetes mellitus, and severe anemia because adverse reactions can occur; caution in myasthenia gravis and myxedema; monitor for hypotension, respiratory depression, and need for intubation

Cardiovascular agents

Alpha-agonists are used to treat persistent hypotension not responding to fluid challenges. Beta-blockers are used for treating severe tachycardia with ischemia or severe hypotension.

Phenylephrine (Neo-Synephrine)

Strong postsynaptic alpha-receptor stimulant with little beta-adrenergic activity that produces vasoconstriction of arterioles. Increases peripheral venous return.

Dosing

Adult

100-180 mcg/min IV initial, then 40-60 mcg/min IV as tolerated

Pediatric

0.1 mg/kg (3 mg/m²) as a single IM/SC dose; repeat q1-2h; not to exceed 5 mg total

Interactions

Bretylium may potentiate action of vasopressors on adrenergic receptors, possibly resulting in arrhythmias; MAOIs may significantly enhance adrenergic effects, and pressor response may be increased 2- to 3-fold
Guanethidine may increase pressor response of direct-acting vasopressors, possibly resulting in severe hypertension

Contraindications

Documented hypersensitivity; anatomical narrow-angle; narrow-angle glaucoma; severe hypertension; tachycardia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in elderly patients, hyperthyroidism, myocardial disease, bradycardia, partial heart block, or severe arteriosclerosis; in hypovolemia, use is not substitute for replacement of blood, fluids and electrolytes, and plasma (these should be restored promptly when loss occurs)

Esmolol (Brevibloc)

Short-acting IV cardioselective beta-adrenergic blocker with no membrane depressant activity. Half-life of 8 min allows for titration to effect and quick discontinuation prn.

Dosing

Adult

Loading dose: 500 mcg/kg IV for 1 min
Maintenance infusion: 100 mcg/kg/min IV for 4 min; repeat if inadequate; if still inadequate, repeat loading dose, then increase maintenance dose by increments of 50 mcg/kg/min IV

Pediatric

300 mcg/kg/min IV with continuous heart rate and blood pressure monitoring to determine onset of beta-blockade (equal to >10% reductions); titrate upward in 50-100 mcg/kg/min increments IV q10min prn

Interactions

Aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease bioavailability and plasma levels, possibly resulting in decreased pharmacologic effect; cardiotoxicity may increase when administered concurrently with sparfloxacin, astemizole, calcium channel blockers, quinidine, flecainide, and contraceptives; toxicity increases when administered concurrently with digoxin, flecainide, acetaminophen, clonidine, epinephrine, nifedipine, prazosin, haloperidol, phenothiazines, and catecholamine-depleting agents

Contraindications

Documented hypersensitivity; asthma; COPD; CHF; moderate-to-severe left ventricular dysfunction; hypotension <90 mm Hg; bradycardia <60/min, second- and third-degree AV block

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Beta-adrenergic blockers may mask signs and symptoms of acute hypoglycemia and clinical signs of hyperthyroidism; symptoms of hyperthyroidism, including thyroid storm, may worsen when medication is abruptly withdrawn; withdraw drug slowly and monitor patient closely

Norepinephrine (Levophed)

For protracted hypotension following adequate fluid-volume replacement. Stimulates beta1- and alpha-adrenergic receptors, which, in turn, increases cardiac muscle contractility and heart rate as well as vasoconstriction. As a result, systemic blood pressure and coronary blood-flow increases.
After obtaining a response, the rate of flow should be adjusted and maintained at a low normal blood pressure, such as 80-100 mm Hg systolic, sufficient to perfuse vital organs.

Dosing

Adult

4 mcg/min IV; titrate to desired blood pressure response

Pediatric

0.05-0.1 mcg/kg/min IV; titrate to blood pressure response; not to exceed 1-2 mcg/kg/min

Interactions

Effects increase when administered concurrently with tricyclic antidepressants, MAO inhibitors, antihistamines, guanethidine, methyldopa, ergot alkaloids; atropine may block reflex tachycardia caused by norepinephrine and enhances pressor response

Contraindications

Documented hypersensitivity; peripheral or mesenteric vascular thrombosis because ischemia may be increased and the area of the infarct extended

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Correct blood-volume depletion, if possible, before giving norepinephrine therapy; extravasation may cause severe tissue necrosis and, thus, should be administered into a large vein; caution in occlusive vascular disease

Follow-up

Further Inpatient Care

• Admit all patients with signs and symptoms of toxicity (acute or chronic), or observe them in the ED until their theophylline level decreases and their symptoms have resolved.
• Admit patients with theophylline levels higher than 30 mcg/mL.
• Admit patients demonstrating cardiovascular or neurologic dysfunction to the critical care unit.

Further Outpatient Care

• Unintentional overdose: For patients with therapeutic theophylline levels and minimal or no toxicity and acute ingestions less than 10 mg/kg, discharge and follow up within 24 hours.
• Intentional overdose: Consider discharge of asymptomatic patients with therapeutic levels after psychiatric evaluation.

Patient Education

• For excellent patient education resources, visit eMedicine's Drug Overdose Center and Poisoning - First Aid and Emergency Center. Also, see eMedicine's patient education articles Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

Miscellaneous

Medicolegal Pitfalls

• Failure to aggressively treat a theophylline intoxicated patient in a manner to prevent risk of seizures
• Failure to aggressively decontaminate patient with the exposure to sustained-release drug formulation, including whole-bowel irrigation (WBI)
• Failure to initiate access to hemoperfusion/hemodialysis in the severely intoxicated patient
• Failure to diagnose chronic theophylline overdose because of the vague signs and symptoms of anxiety and nausea, thereby inappropriately discharging them from the ED
• Failure to address exposure to coingestants
• Failure to ensure airway protection before an administration of activated charcoal, particularly in patients with altered mental status and seizures
• Failure to consider, diagnose, and treat other causes of seizures

References

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Keywords

theophylline overdose, theophylline poisoning, theophylline exposure, acute theophylline overdose, chronic theophylline intoxication, methylxanthine, asthma treatment, chronic obstructive pulmonary disease treatment, COPD treatment, theophylline adverse affects, methylxanthine derivative, 1,3-dimethylxanthine, angina pectoris treatment, peripheral vascular disease treatment, bronchial asthma treatment

Contributor Information and Disclosures

Author

Greg Hymel, MD, Consulting Staff, Department of Emergency Medicine, Saint Vincent Mercy Medical Center
Greg Hymel, MD is a member of the following medical societies: American Academy of Emergency Medicine
Disclosure: Nothing to disclose.

Medical Editor

Lance W Kreplick, MD, MMM, FAAEM, FACEP, Medical Director of Hyperbaric Medicine, Fawcett Wound Management and Hyperbaric Medicine; Consulting Staff in Occupational Health and Rehabilitation, Company Care Occupational Health Services; President and Chief Executive Officer, QED Medical Solutions, LLC
Lance W Kreplick, MD, MMM, FAAEM, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physician Executives
Disclosure: Nothing to disclose.

Pharmacy Editor

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists
Disclosure: Nothing to disclose.

Managing Editor

Fred Harchelroad, MD, FACMT, FAAEM, FACEP, Chair, Department of Emergency Medicine, Director of Medical Toxicology - Allegheny General Hospital, Associate Professor, Department of Emergency Medicine, Drexel University College of Medicine
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Department of Surgery, Section of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.

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