eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Toxicology
Toxicity, Theophylline: Treatment & Medication
Updated: Dec 9, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
Treatment
Medical Care
- Initial stabilization: Initial treatment of theophylline poisoning involves assessment of the ABCs, cardiac monitoring, administration of isotonic fluids for rehydration, and determination of glucose level. Perform endotracheal intubation as indicated for airway protection and ventilatory assistance.
- Treatment of cardiovascular effects: Observe for hypotensive effects. Administer isotonic fluids for hypotension. Refractory hypotension may require administration of a pure alpha-agonist vasopressor agent (eg, phenylephrine). Most patients tolerate theophylline-induced tachycardia without difficulty. Beta-blockers should be used with extreme caution, as mixed results following administration have been reported in the literature. Theophylline toxicity is refractory to adenosine. Ventricular dysrhythmias should be treated in the usual manner.
- CNS hyperstimulation treatment: Patients who are preseizurogenic (ie, manifesting signs of hyperreflexia, clonus, and marked tremor) should be treated with either benzodiazepines or phenobarbital. If seizures develop, prompt therapy with benzodiazepines and phenobarbital should be initiated. Phenytoin may worsen theophylline-induced seizures and should be avoided.
- Decontamination: Administer activated charcoal (1-2 g/kg). Consider whole-bowel irrigation for massive ingestion of sustained-release preparations. Multidose activated charcoal has been beneficial in the treatment of theophylline toxicity because it binds theophylline that diffuses through the small intestine ("gut dialysis"). Recurrent vomiting may be treated with metoclopramide or ondansetron.
- Treatment of electrolyte disturbances: Treat hypokalemia cautiously in patients with acute ingestions. Hypokalemia is secondary to an intracellular shift, rather than total-body depletion. Potassium replacement may cause hyperkalemia as theophylline levels decrease. Most electrolyte disturbances are asymptomatic and do not require treatment.
- Extracorporeal elimination: Hemodialysis is as efficacious as hemoperfusion and is the preferred method of extracorporeal elimination. Hemodialysis should be considered if the theophylline level is more than 100 mcg/mL in acute ingestions and more than 60 mcg/mL in chronic. In patients who develop seizures, refractory hypotension that is unresponsive to fluids, and unstable dysrhythmias, hemodialysis should be considered, regardless of the theophylline level. The molecular adsorbent recirculating system (MARS) has been cited in case reports as being efficacious in the removal of protein-bound drugs such as theophylline. However, the literature is quite limited in the use of MARS in the pediatric population, especially for the treatment of drug toxicity.2
Consultations
- Consult a toxicologist.
- A nephrologist may be consulted in cases of severe toxicity requiring charcoal hemoperfusion or hemodialysis.
Medication
Antiemetics
These agents may be used to control vomiting. Phenothiazine antiemetics should be avoided to prevent potentiation of theophylline toxicity.
Metoclopramide (Reglan)
Dopamine antagonist that stimulates acetylcholine release in myenteric plexus. Centrally acts on chemoreceptor triggers in floor of fourth ventricle, which provides important antiemetic activity.
Adult
0.4-1 mg/kg IV q6-8h; not to exceed 10-20 mg/dose
Pediatric
<6 years: 0.1 mg/kg IV infused over 1-2 min
6-14 years: 2.5-5 mg IV infused over 1-2 min
>14 years: Administer as in adults
Anticholinergic drugs may antagonize effects; opiate analgesics may increase toxicity in CNS
Documented hypersensitivity; pheochromocytoma or GI hemorrhage, obstruction, or perforation; history of seizure disorders
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in history of mental illness and Parkinson disease; monitor for EPS
Ondansetron (Zofran)
Selective 5-HT3-receptor antagonist that blocks serotonin peripherally and centrally. Prevents nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin) and complete-body radiation therapy.
Adult
0.15 mg/kg/dose IV prn; not to exceed 32 mg/d
Pediatric
>3 years: Administer as in adults
Cytochrome P450 inducers (eg, barbiturates, rifampin, carbamazepine, phenytoin) may change half-life and clearance; dose adjustment usually not required
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
For prevention of nausea and vomiting, not for rescue of nausea and vomiting
Drug absorption reducers
Activated charcoal is used to decrease drug absorption and may be all that is required in mild-to-moderate toxicity. It is not absorbed and is excreted entirely through the GI tract.
Activated charcoal (Actidose-Aqua, Liqui-Char)
Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal absorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water. For maximum effect, administer within 30 min after poison ingestion.
Adult
1 g/kg (50-100 g) PO; usually given with sorbitol the first dose only
Pediatric
1-2 g/kg PO; avoid cathartic (ie, sorbitol) in patients <2 y
May inactivate ipecac syrup if used concomitantly; effectiveness of other medications decreases with coadministration; do not mix with sherbet, milk, or ice cream (decreases absorbent properties)
Documented hypersensitivity; poisoning or overdose of mineral acids and alkalis; unprotected airway with absent gag reflex
Pregnancy
A - Fetal risk not revealed in controlled studies in humans
Precautions
Assess bowel sounds prior to administration to minimize occurrence of charcoal ileus; not effective in ethanol, methanol, and iron salt poisoning; induce emesis before administration; after emesis with ipecac, 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; repeated doses of cathartics can cause severe volume loss and electrolyte disturbance, especially in children
Whole bowel irrigation agents
Polyethylene glycol is used to increase GI transit time, decreasing absorption of theophylline. It may be used in older children or adults who have ingested significant amounts of products with delayed absorption. It is not absorbed and is entirely excreted through the GI tract.
Polyethylene glycol (GoLYTELY, NuLytely, Colovage, Colyte)
Laxative with strong electrolyte and osmotic effects that has cathartic actions in GI tract.
Adult
2 L/h NG
Pediatric
1-2 mL/kg/h PO/NG
Reduces effectiveness and absorption of oral medications
Documented hypersensitivity; colitis; megacolon; bowel perforation; gastric retention; GI obstruction
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 ulcerative colitis and hot loop polypectomy
Benzodiazepines
These agents may be needed to control agitation and seizures.
Diazepam (Valium)
Depresses all levels of CNS (eg, limbic system, reticular formation), possibly by increasing activity of GABA. Individualize dose and increase doses cautiously to avoid adverse effects.
Adult
0.2 mg/kg IV at 2 mg/min, not to exceed 20 mg; may titrate dose according to adverse effects (ie, monitor for respiratory depression)
Pediatric
<5 years: 0.2-0.5 mg/kg IV, not to exceed 5 mg/dose
>5 years: 0.2-0.5 mg/kg IV, not to exceed 10 mg/dose
Titrate dose according to adverse effects (ie, monitor for respiratory depression); administer IV by slow injection, not to exceed 5 mg/min
CNS toxicity of benzodiazepines increases with coadministration of phenothiazines, barbiturates, alcohols, and MAOIs
Documented hypersensitivity; narrow-angle glaucoma; altered mental status; hypotension; respiratory depression
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Caution with other CNS depressants, low albumin levels, and hepatic disease (may increase toxicity)
Lorazepam (Ativan)
Sedative hypnotic with short onset of effects and relatively long half-life. May depress all levels of CNS, including limbic system and reticular formation, by increasing action of GABA, a major inhibitory neurotransmitter in the brain. Excellent when sedation longer than 24 hours is needed.
Adult
0.04 mg/kg (2-4 mg) IV; titrate to effect
Status epilepticus: 4 mg IV infused slowly over 2-5 min; may repeat in 10-15 min prn; not to exceed 8 mg/12 h
Pediatric
0.05 mg/kg IV (range 0.02-0.1 mg/kg)
Status epilepticus:
Neonates: 0.05 mg/kg IV infused slowly over 2-5 min; may repeat in 10-15 min prn
Infants and children: 0.1 mg/kg IV infused slowly over 2-5 min; second dose of 0.05 mg/kg after 10-15 min prn
Adolescents: Administer as in adults; not to exceed 4 mg/12 h
CNS toxicity of benzodiazepines increases with concurrent administration of alcohol, phenothiazines, barbiturates, and MAOIs
Documented hypersensitivity; preexisting CNS depression; hypotension; 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, altered mental status, respiratory depression, hypotension, organic brain syndrome, and Parkinson disease
Alpha agonists
These agents are used to treat hypotension refractory to fluid challenge.
Phenylephrine (Neo-Synephrine)
Strong postsynaptic alpha-receptor stimulant with little beta-adrenergic activity that produces vasoconstriction of arterioles in the body. Increases peripheral venous return.
Adult
100-180 mcg/min IV initially; decrease to 40-60 mcg/min as tolerated
Pediatric
0.1 mg/kg (3 mg/m2) IM/SC; repeat q1-2h; not to exceed 5 mg/dose
0.1-0.5 mcg/kg/min IV infusion; titrate to desired effect
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-fold to 3-fold; guanethidine may increase pressor response of direct-acting vasopressors, possibly resulting in severe hypertension
Documented hypersensitivity; 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 and those with asthma, thyroid disease, BPH, hyperthyroidism, myocardial disease, bradycardia, partial heart block, or severe arteriosclerosis; in hypovolemia, use is not a substitute for replacement of blood, fluids and electrolytes, and plasma (promptly restore with loss); dilute IV and administer via large vein; extravasation precautions required
Beta-adrenergic blocking agents
These agents are used to treat severe tachycardia with ischemia or severe hypertension. Short-acting agents should be used because of the potential for significant hypotension in theophylline toxicity.
Esmolol (Brevibloc)
Excellent in patients at risk for complications from beta-blockade, particularly those with reactive airway disease, mild-to-moderate LV dysfunction, and/or peripheral vascular disease. Short half-life of 8 min allows for titration to desired effect and quick discontinuation if needed.
Adult
500 mcg/kg IV bolus initially, followed by 50 mcg/kg/min IV infusion; may increase by increments of 50 mcg/kg/min q4-5min prn; not to exceed 200 mcg/kg/min
Pediatric
300 mcg/kg/min IV infusion with continuous heart rate and BP monitoring to determine onset of beta-blockade (ie, >10% reduction); titrate upward by 50-100 mcg/kg/min q10min to desired effect
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; uncompensated CHF; bradycardia; cardiogenic shock; AV conduction abnormalities
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 atrial fibrillation and bronchospasm; use infusion pump; beta-adrenergic blockers may mask signs and symptoms of acute hypoglycemia and clinical signs of hyperthyroidism; symptoms of hyperthyroidism, including thyroid storm, may worsen with abrupt withdrawal (withdraw drug slowly and monitor patient closely)
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, et al. 2006 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS). Clin Toxicol (Phila). Dec 2007;45(8):815-917. [Medline].
Novelli G, Rossi M, Morabito V, et al. Pediatric acute liver failure with molecular adsorbent recirculating system treatment. Transplant Proc. Jul-Aug 2008;40(6):1921-4. [Medline].
Charytan D, Jansen K. Severe metabolic complications from theophylline intoxication. Nephrology (Carlton). Oct 2003;8(5):239-242. [Medline].
de Pont AC. Extracorporeal treatment of intoxications. Curr Opin Crit Care. Dec 2007;13(6):668-73. [Medline].
Holstege CP, Dobmeier S. Cardiovascular challenges in toxicology. Emerg Med Clin North Am. Nov 2005;23(4):1195-217. [Medline].
Holstege CP, Hunter Y, Baer AB, et al. Massive caffeine overdose requiring vasopressin infusion and hemodialysis. J Toxicol Clin Toxicol. 2003;41(7):1003-7. [Medline].
Lheureux P, Penaloza A, Gris M. Pyridoxine in clinical toxicology: a review. Eur J Emerg Med. Apr 2005;12(2):78-85. [Medline].
Minton NA, Henry JA. Acute and chronic human toxicity of theophylline. Hum Exp Toxicol. Jun 1996;15(6):471-81. [Medline].
Minton NA, Henry JA. Treatment of theophylline overdose. Am J Emerg Med. Oct 1996;14(6):606-12. [Medline].
Rutten J, van den Berg B, van Gelder T, van Saase J. Severe theophylline intoxication: a delay in charcoal haemoperfusion solved by oral activated charcoal. Nephrol Dial Transplant. Dec 2005;20(12):2868-9. [Medline].
Shannon MW. Comparative efficacy of hemodialysis and hemoperfusion in severe theophylline intoxication. Acad Emerg Med. Jul 1997;4(7):674-8. [Medline].
Stork CM, Howland MA, Goldfrank LR. Concepts and controversies of bronchodilator overdose. Emerg Med Clin North Am. May 1994;12(2):415-36. [Medline].
Watson WA, Litovitz TL, Rodgers GC, et al. 2004 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. Sep 2005;23(5):589-666. [Medline].
Further Reading
Keywords
theophylline toxicity, theophylline overdose, acute theophylline overdose, chronic theophylline intoxication, methylxanthine, asthma treatment, chronic obstructive pulmonary disease treatment, COPD treatment, theophylline adverse affects, theophylline prescription, methylxanthine derivative, 1, 3-dimethylxanthine, smooth muscle relaxant, diuretic, cardiac stimulant, vasodilator, angina pectoris treatment, peripheral vascular disease treatment, bronchial asthma treatment, hypokalemia, hyperglycemia, hypercalcemia, hypophosphatemia, hypomagnesemia, and metabolic acidosis, atrial fibrillation, atrial flutter, multifocal atrial tachycardia
