eMedicine Specialties > Emergency Medicine > Toxicology
Toxicity, Theophylline: Treatment & Medication
Updated: Sep 2, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
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.
- Multidose activated charcoal (MDAC) enhances elimination of theophylline.
- 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
- Administer polyethylene glycol electrolyte solution.
- 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%).
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
May inactivate ipecac syrup if used concomitantly; effectiveness of other medications decreases with coadministration; sherbet, milk, or ice cream decreases adsorption
Documented hypersensitivity; poisoning or overdose of mineral acids and alkalies; unprotected airway and absent gag reflex
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.
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
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
Documented hypersensitivity
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.
Adult
50 mg IV q8h
Pediatric
1 mg/kg IV q6-8h
May decrease effects of ketoconazole and itraconazole; may alter serum levels of ferrous sulfate, diazepam, nondepolarizing muscle relaxants, and oxaprozin
Documented hypersensitivity
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.
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
May antagonize effects of metoclopramide; opiate analgesics may increase metoclopramide toxicity in CNS
Documented hypersensitivity; pheochromocytoma or GI hemorrhage, obstruction, or perforation; history of seizure disorders
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.
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
Coadministration with other CNS depressants or anticonvulsants may cause additive effects; may cause hypotension with epinephrine
Documented hypersensitivity; bone marrow suppression, narrow-angle glaucoma, and severe liver or cardiac disease; parkinsonism; depression
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.
Adult
1.25-5 mg IV
Pediatric
0.05-0.25 mg/kg IV
May increase toxicity of CNS depressants; cabergoline and levodopa may potentiate antipsychotic effects
Documented hypersensitivity
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.
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
Increases toxicity of benzodiazepines in CNS with coadministration of phenothiazines, cimetidine, barbiturates, alcohols, and MAOIs
Documented hypersensitivity; altered mental status; low BP or RR; narrow-angle glaucoma
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.
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
Toxicity of benzodiazepines in CNS increases when used concurrently with alcohol, phenothiazines, barbiturates, and MAOIs
Documented hypersensitivity; preexisting CNS depression, hypotension, and narrow-angle glaucoma
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.
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
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
Documented hypersensitivity; preexisting hypotension, narrow-angle glaucoma, and sensitivity to propylene glycol (diluent)
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.
Adult
10-20 mg/kg IV; not to exceed 50 mg/min
Pediatric
15-20 mg/kg IV; not to exceed 50 mg/min
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
Documented hypersensitivity; severe respiratory disease, marked impairment of liver function, and nephritic patients
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.
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
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
Documented hypersensitivity; anatomical narrow-angle; narrow-angle glaucoma; severe hypertension; tachycardia
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.
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
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
Documented hypersensitivity; asthma; COPD; CHF; moderate-to-severe left ventricular dysfunction; hypotension <90 mm Hg; bradycardia <60/min, second- and third-degree AV block
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.
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
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
Documented hypersensitivity; peripheral or mesenteric vascular thrombosis because ischemia may be increased and the area of the infarct extended
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
More on Toxicity, Theophylline |
| Overview: Toxicity, Theophylline |
| Differential Diagnoses & Workup: Toxicity, Theophylline |
 Treatment & Medication: Toxicity, Theophylline |
| Follow-up: Toxicity, Theophylline |
| References |
| « Previous Page | Next Page » |
References
Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Heard SE. 2007 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 25th Annual Report. Clin Toxicol (Phila). Dec 2008;46(10):927-1057. [Medline]. [Full Text].
Seneff M, Scott J, Friedman B, Smith M. Acute theophylline toxicity and the use of esmolol to reverse cardiovascular instability. Ann Emerg Med. Jun 1990;19(6):671-3. [Medline].
Kearney TE, Manoguerra AS, Curtis GP, Ziegler MG. Theophylline toxicity and the beta-adrenergic system. Ann Intern Med. Jun 1985;102(6):766-9. [Medline].
Brashear RE, Aronoff GR, Brier RA. Activated charcoal in theophylline intoxication. J Lab Clin Med. Sep 1985;106(3):242-5. [Medline].
Charytan D, Jansen K. Severe metabolic complications from theophylline intoxication. Nephrology (Carlton). Oct 2003;8(5):239-42. [Medline].
Cooling DS. Theophylline toxicity. J Emerg Med. Jul-Aug 1993;11(4):415-25. [Medline].
Gaudreault P, Harwood-Nuss. Methylxanthines, Toxicology. In: Clinical Practice of Emergency Medicine. 4th ed. 2005:1649-1652.
Henderson A, Wright DM, Pond SM. Management of theophylline overdose patients in the intensive care unit. Anaesth Intensive Care. Feb 1992;20(1):56-62. [Medline].
Kallstrom TJ. Evidence-based asthma management. Respir Care. Jul 2004;49(7):783-92. [Medline].
Marshall H, Emerman CL, Tintinalli J. Theophylline, Toxicology and Pharmacology. In: Emergency Medicine, A Comprehensive Study Guide. 6th ed. 2004:1098-1101.
Medical Economics Staff. Drugs. In: Physician's Desk Reference. Medical Economics Co; 1997.
Micromedex. Theophylline. In: Micromedex. 1974-2008:36.
Further Reading
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
