THEOPHYLLINE

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) 1,3-Dimethylxanthine
2) 3,7-Dihydro-1,3-Dimethylpurine 2,6(IH)-dione
3) Anhydrous Theophylline
4) Teofilina
5) Theocin
6) Methylxanthines (Theophylline)
7) Theophyll
8) Theophyllinum

Available Forms Sources

1) Theophylline is available in following formulations: oral elixir (80 mg/15 mL; 100 mg/18.75 mL), oral solution (80 mg/15 mL), tablets extended-release (100 mg, 200 mg, 300 mg, 400 mg, 450 mg, 600 mg) and theophylline in 5% dextrose for IV administration (Prod Info THEOPHYLLINE ANHYDROUS oral extended-release tablets, 2014; Prod Info ELIXOPHYLLIN(R) oral liquid elixir, 2012; Prod Info THEO-24(R) extended-release oral capsules, 2005; Prod Info theophylline in 5% dextrose intravenous injection solution, 2011).

1) Theophylline is indicated for the treatment of symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung disease (eg, emphysema and chronic bronchitis) (Prod Info THEOPHYLLINE ANHYDROUS oral extended-release tablets, 2014; Prod Info ELIXOPHYLLIN(R) oral liquid elixir, 2012; Prod Info THEO-24(R) extended-release oral capsules, 2005). Intravenous administration of theophylline is indicated as an adjunct to inhaled beta-2 selective agonists and systemically administered corticosteroids for the treatment of acute exacerbations of symptoms associated with asthma and other chronic lung diseases (Prod Info theophylline in 5% dextrose intravenous injection solution, 2011).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Theophylline has been used as a bronchodilator for asthma and COPD and is commonly used to treat neonatal apnea of preterm infants.
B) PHARMACOLOGY: It inhibits phosphodiesterase, which increases in cyclic adenine monophosphate and catecholamine release, and is also an adenosine receptor antagonist.
C) TOXICOLOGY: Increase catecholamine levels (epinephrine and norepinephrine) cause tachycardia, hypotension, anxiety and hyperglycemia. Adenosine receptor antagonism may cause seizures.
D) EPIDEMIOLOGY: The incidence of poisoning has declined dramatically in recent years. Poisoning is uncommon, but serious toxicity and deaths are reported every year.
E) WITH THERAPEUTIC USE

1) ADVERSE EFFECTS: Palpitations, tachycardia, chest pain, headache, tremor, insomnia, irritability, psychosis, visual hallucinations, nausea, vomiting, abdominal pain, and a decrease in esophageal sphincter tone can develop.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Nausea, vomiting, abdominal pain, sinus tachycardia, sustained complex atrial or ventricle ectopy, tremor, agitation, hypokalemia, hyperglycemia, hypophosphatemia and hypocalcemia can develop.
2) SEVERE TOXICITY: Seizures, rhabdomyolysis, hypotension, and ventricular dysrhythmias can occur.
3) CHRONIC OVERDOSE: Gastrointestinal symptoms may be mild or absent and metabolic acidosis, hypokalemia and hyperglycemia generally do not develop. Severe effects, such as seizures and hemodynamically significant dysrhythmias, are more common with chronic overdoses than with acute overdoses. Onset of symptoms may occur abruptly.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Tachycardia is common, hypotension occurs with severe overdose.

0.2.5)

A) WITH POISONING/EXPOSURE

1) Sinus tachycardia is common. Other dysrhythmias including atrial fibrillation or flutter, supraventricular tachycardia, multifocal atrial tachycardia, ventricular tachycardia, ventricular fibrillation, pulseless electrical activity and cardiac arrest may occur, most often with chronic intoxication.
2) Mild transient hypertension may develop. Hypotension may develop with severe overdose.

0.2.7)

A) WITH POISONING/EXPOSURE

1) Tremors are common. Restlessness, agitation, hallucinations and headache may occur. Seizures may develop abruptly, more commonly after chronic overdose, and may progress to status epilepticus. Seizures may be focal.

0.2.8)

A) WITH THERAPEUTIC USE

1) Sustained release formulations may form bezoars.

B) WITH POISONING/EXPOSURE

1) Nausea, vomiting, abdominal cramps and diarrhea are common, particularly with acute intoxication. Bloody and coffee ground emesis may occur in severe theophylline intoxication. Sustained release formulations may form bezoars.

0.2.10)

A) WITH POISONING/EXPOSURE

1) Renal failure is an unusual complication associated with prolonged hypotension or rhabdomyolysis.

0.2.11)

A) WITH POISONING/EXPOSURE

1) Mild metabolic acidosis is common with acute overdose. Acute theophylline overdose may also cause respiratory alkalosis. Severe metabolic acidosis may develop in patients with seizures or hypotension.

0.2.12)

A) WITH POISONING/EXPOSURE

1) Hypokalemia, hypercalcemia, hypophosphatemia, and acidosis may occur, especially after acute and acute-on-therapeutic overdoses. Severe hyperkalemia is a rare complication that may develop in patients with rhabdomyolysis.

0.2.15)

A) WITH POISONING/EXPOSURE

1) Rhabdomyolysis and compartment syndrome are rare complications most often seen in patients with prolonged seizures.

0.2.20)

A) Aminophylline and theophylline have been classified as FDA pregnancy category C. There are no adequate and well-controlled studies with theophylline in pregnant women. Cardiac abnormalities have been associated with theophylline use by the mother during pregnancy. Theophylline crosses the placental barrier and it is possible that therapeutic maternal levels could potentially cause toxicity in the neonate. In general, the management of asthma in pregnant patients should be the same as that of nonpregnant patients. Poor oxygenation due to uncontrolled asthma represents a greater danger to the fetus than any potential harm associated with the drugs used to treat the disease.

0.2.22)

A) DRUG INTERACTION: Drugs that inhibit theophylline metabolism which may result in chronic theophylline intoxication include: allopurinol, cimetidine, ciprofloxacin, clarithromycin, diltiazem, disulfiram, enoxacin, erythromycin, estrogen, ethanol, etintidine, fluvoxamine, furosemide, idrocilamide, interferon (human recombinant alpha-A), methotrexate, mexiletine, nifedipine, norfloxacin, ofloxacin, pefloxacin, pentoxifylline, pipemidic acid, propafenone, propranolol, roxithromycin, tacrine, thiabendazole, ticlopidine, troleandomycin, verapamil, viloxazine.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Establish IV access and place the patient on a cardiac monitor. Treat nausea with an antiemetic and administer IV fluids. Monitor electrolytes.

B) MANAGEMENT OF SEVERE TOXICITY

1) The primary effect of theophylline is increased sympathomimetic effects. The primary treatment is sedation with benzodiazepines (such as lorazepam 1 to 2 mg IV every 5 min titrated to effect); high doses may be required. Hemodynamically significant tachycardia should be treated with esmolol, which can paradoxically improve blood pressure in severely tachycardic patients. Hypotension should be treated with IV fluids. Adrenergic vasopressors can theoretically make tachycardia worse, but there are numerous reports of successful treatment of severe toxicity with these agents. Vasopressin is of theoretical value and has been used effectively in a case of caffeine poisoning. Lidocaine administration has been associated with successful treatment of ventricular fibrillation. Hemodialysis should be performed in patients with severe toxicity, and patients with high serum theophylline concentrations (80 to 100 mcg/mL after acute overdose, 40 to 60 mcg/mL with chronic toxicity).

C) DECONTAMINATION

1) PREHOSPITAL: Avoid GI decontamination as patients are at high risk to vomit and suffer abrupt deterioration.
2) HOSPITAL: Activated charcoal should be administered to patients who have a significant acute ingestion. As theophylline causes seizures and vomiting, most patients should be intubated prior to charcoal administration. Whole bowel irrigation may be helpful in the case of a sustained-release overdose, if there is evidence of ongoing theophylline absorption; however, it can be difficult to perform in patients with severe toxicity or persistent emesis.

D) INTRATHECAL INJECTION

1) Severe neurotoxicity (ie, tetanic muscle spasm, leg cramps, and paraplegia) have been reported following inadvertent intrathecal injection of aminophylline. The following recommendations are based on experience with other drugs. Keep patients upright if possible. Immediately drain at least 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free saline). For large overdoses, consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 mL/hr). Albumin (5%) has also been used for perfusion; may be useful because of high protein binding. Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.

E) AIRWAY MANAGEMENT

1) Perform early in patients with severe intoxication.

F) ANTIDOTE

1) There is no specific antidote.

G) ENHANCED ELIMINATION

1) Multiple dose activated charcoal administration (25 g every 4 hours) increases elimination of theophylline from the plasma, but administration may be difficult in patients with severe toxicity or persistent vomiting. Ondansetron and metoclopramide may facilitate charcoal administration.
2) HEMODIALYSIS (treatment of choice) increases the elimination rate of theophylline. Consider dialysis early, if the plasma theophylline concentration approaches 40 to 60 mcg/mL in CHRONIC overdose, or 80 to 100 mcg/mL in ACUTE intoxications and/or significant signs of intoxication are present (hemodynamic compromise, seizures, mental status changes). Elderly patients and those with underlying disease, particularly cardiac, may require dialysis at lower concentrations.
3) HEMOPERFUSION: In the past, hemoperfusion has been recommended. However, few facilities currently offer hemoperfusion and current dialysis membranes provide theophylline clearance rates similar to those provided by hemoperfusion.

H) PATIENT DISPOSITION

1) HOME CRITERIA: Patients who are not chronically taking theophylline and who unintentionally ingest 10 mg/kg or less can be managed at home.
2) OBSERVATION CRITERIA: Patients with an acute ingestion of an immediate-release preparation who have only mild clinical effects (ie, mild tachycardia, nausea, vomiting, tremor) can be observed in the ED with activated charcoal therapy, cardiac monitoring and serial theophylline levels. Patients may be discharged when serum theophylline levels fall below 20 mcg/mL and symptoms resolve. Patients with worsening signs and symptoms, ingestion of a sustained-release product or rising levels should be admitted to a monitored setting.
3) ADMISSION CRITERIA: Admit all patients with chronic intoxication, patients with an acute ingestion of a sustained-release product and those with acute ingestions in whom serum theophylline levels are not falling. Patients with symptoms beyond mild tachycardia, nausea, vomiting and tremor and those whose symptoms do not resolve should be admitted. Because of the potential for severe toxicity, most patients should be admitted to an intensive care setting.
4) TRANSFER CRITERIA: Patients who are at risk for developing life-threatening toxicity (chronic overdose with serum theophylline levels greater than 40 to 60 mcg/mL, age greater than 60 years of age or less than 3 years, acute overdose and serum levels greater than 80 to 100 mcg/mL) should be transferred to a facility where emergent hemodialysis is available.
5) CONSULT CRITERIA: Consult a medical toxicologist or poison center for any patient with severe toxicity or in whom the diagnosis is unclear. Consult a nephrologist early in any patient with severe toxicity or rapidly rising theophylline concentrations.

I) PITFALLS

1) The control of nausea and vomiting with an antiemetic and the early administration of activated charcoal is crucial in order to prevent further absorption and enhance elimination of theophylline. Patients who have ingested sustained-release formulations may not develop peak serum concentrations for 24 hours. Patients with chronic toxicity may develop severe clinical effects abruptly.

J) PHARMACOKINETICS

1) Rapid absorption of liquid and immediate-release products; sustained-release products are absorbed more erratically with peak concentrations of approximately 4 to 6 hours. Protein binding 40%, volume of distribution 0.3% to 0.7% L/kg, extensive hepatic metabolism. Half-life is 8.7 hours (range: 6.1 to 12.8) in adults and 27 to 7 hours in children and longer in neonates and the elderly (greater than 60 years; 9.8 hours (range: 1.6 to 18)).

K) TOXICOKINETICS

1) Delayed absorption, peak concentrations may not be reached for 24 hours or more after a sustained-release overdose. Hepatic metabolism is saturable, leading to zero order kinetics and prolonged half-life, 24 hours or more.

L) PREDISPOSING CONDITIONS

1) Patients 60 years of age or older and those aged 3 years and younger are at increased risk for developing life-threatening clinical effects, as are patients with significant underlying medical conditions. Half-life is longer in patients with liver disease or heart failure.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Tachycardia is common, hypotension occurs with severe overdose.

3.3.3)

A) WITH POISONING/EXPOSURE

1) HYPERTHERMIA

a) Hyperthermia has been reported after theophylline overdose associated with prolonged seizures (Higgins et al, 1994).
b) CASE REPORT: Evidence of ongoing hypermetabolism and hyperthermia developed in a 22-year-old man following an ingestion of 17.5 g of slow-release theophylline (Parr & Willatts, 1991).

3.3.4)

A) WITH POISONING/EXPOSURE

1) HYPOTENSION

a) Hypotension may develop in severe overdose (Prod Info THEOCHRON(TM) extended release oral tablets, 2008; Paloucek & Rodvold, 1988; Henderson et al, 1992) (Detloff et al, 1993).

2) HYPERTENSION

a) Transient hypertension may develop after overdose (Powell et al, 1993).

Cardiovascular

3.5.1)

A) WITH POISONING/EXPOSURE

3.5.2)

A) TACHYARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) Sinus tachycardia is the most common dysrhythmia observed after a theophylline overdose (Prod Info THEOCHRON(TM) extended release oral tablets, 2008).
b) INCIDENCE: The incidence of sinus tachycardia ranged from to 47% to 100% in several large case series (Visitsunthorn et al, 2001; Olson et al, 1985; Powell et al, 1993; Shannon, 1993).

B) SUPRAVENTRICULAR TACHYCARDIA

1) WITH POISONING/EXPOSURE

a) Supraventricular tachycardia, atrial fibrillation and flutter, multifocal atrial tachycardia and premature atrial contractions have been reported (Olson et al, 1985; Shannon & Lovejoy, 1992; Powell et al, 1993; Shannon, 1993; Bender et al, 1991; Sessler & Cohen, 1990; Henderson et al, 1992; Varriale & Ramaprasad, 1993).
b) INCIDENCE: Significant supraventricular dysrhythmias are more common after chronic overdose. In a prospective series of 92 patients with chronic theophylline overdose, 13 patients (14%) developed supraventricular tachycardia, 2 (2%) developed premature atrial contractions, 11 (12%) developed atrial fibrillation or flutter, and 2 (2%) developed multifocal atrial tachycardia. In comparison, of 119 patients with acute intoxication in the same series, 4 developed supraventricular tachycardia and one developed atrial fibrillation or flutter; no other supraventricular dysrhythmias developed (Shannon, 1993).

C) VENTRICULAR ARRHYTHMIA

1) WITH THERAPEUTIC USE

a) RISK FACTORS: Tachycardia and dysrhythmias may occur at serum concentrations considered therapeutic, particularly in patients with underlying medical conditions (Bittar & Friedman, 1991; Chazan et al, 1995).

2) WITH POISONING/EXPOSURE

a) Ventricular premature beats, bigeminy, ventricular tachycardia, ventricular fibrillation, pulseless electrical activity, and cardiac arrest have been reported (Russo, 1979; Bender et al, 1991; Sessler & Cohen, 1990; Henderson et al, 1992; Shannon, 1993; Tsai et al, 1994; Higgins et al, 1995).
b) INCIDENCE: Significant ventricular dysrhythmias are more common after chronic overdose. In a prospective series of 92 patients with chronic theophylline overdose, 9 patients (10%) developed ventricular premature beats, 6 (7%) developed ventricular tachycardia, 2 (2%) developed multifocal ventricular premature beats, 3 (3%) developed bigeminy and 1 developed pulseless electrical activity. In comparison, of 119 patients with acute intoxication in the same series, 4 developed ventricular premature beats, 1 developed ventricular tachycardia, one developed multifocal ventricular premature beats and 3 developed pulseless electrical activity (Shannon, 1993).

1) Shannon (1999) reported that among individuals who received chronic overmedication of theophylline, 35% developed arrhythmias versus 10% in patients with acute intoxication; patients with chronic intoxication also had a higher incidence of death (8% vs 2.5%).

c) ETIOLOGY: Although the exact cause is unknown, its believed that ventricular arrhythmias are probably due to a combination of hypokalemia and increased sympathomimetic activity (Britt & Burkhart, 1993).
d) CHRONIC EXPOSURE: In patients with chronic theophylline intoxication, significant dysrhythmias may develop at serum levels of 40 to 60 mcg/mL or lower and are more likely to develop in those 60 years of age or greater and those 3 years of age or younger (Olson et al, 1985; Shannon & Woolf, 1991; Shannon et al, 1992; Shannon & Lovejoy, 1992; Shannon, 1993).
e) ACUTE EXPOSURE: In patients with acute theophylline intoxication, significant dysrhythmias generally develop at serum levels of 80 to 100 mcg/mL or higher (Olson et al, 1985; Shannon & Lovejoy, 1992; Shannon & Lovejoy, 1992; Shannon, 1993).

D) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypotension may develop in severe overdose, and may be refractory to conventional vasopressors (Paloucek & Rodvold, 1988; Henderson et al, 1992) (Detloff et al, 1993).
b) INCIDENCE: In a retrospective case series hypotension developed in 12 of 27 patients with acute theophylline overdose and 0 of 15 patients with chronic overdose. Of 8 patients with serum theophylline levels greater than 100 mcg/mL, 7 (88%) developed hypotension, while only 5 of 19 patients (26%) with serum levels below 100 mcg/mL developed hypotension (Olson et al, 1985).
c) CASE REPORT: Hypotension developed in a 62-year-old woman who ingested 12 g sustained release theophylline and 32 g acetaminophen (Amitai & Lovejoy, 1987).

E) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Mild transient hypertension may develop after overdose.
b) INCIDENCE: In a retrospective series of 163 children with theophylline overdose, 16 (10%) developed transient hypertension (Powell et al, 1993).

F) MYOCARDIAL INFARCTION

1) WITH POISONING/EXPOSURE

a) In a prospective series of 249 patients with theophylline overdose, 5 (2%) developed myocardial infarction (Shannon, 1993).
b) CASE REPORT: A 26-year-old woman with severe theophylline overdose complicated by hypotension and ventricular tachycardia sustained a myocardial infarction. Angiography 35 hours after overdose revealed complete proximal occlusion of the left anterior descending artery, treated with intracoronary thrombolysis. Repeat angiography 21 days later revealed normal coronary vessels (Hantson et al, 1992).

G) ELECTROCARDIOGRAM ABNORMAL

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Primary T-wave inversion was reported in a 33-year-old woman with an acute-on-chronic overdose and a plasma level of 50.4 mcg/mL (Kolander et al, 1989).

Neurologic

3.7.1)

A) WITH POISONING/EXPOSURE

3.7.2)

A) NEUROTOXICITY

1) WITH POISONING/EXPOSURE

a) PEDIATRIC: Children are more likely to develop CNS symptoms at levels that are considered normal in adults which may be related in part to immaturity of the blood-brain barrier (permits higher CNS theophylline levels) (Britt & Burkhart, 1993).

B) SEIZURE

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 30-month-old girl developed multiple right-sided focal seizures following the administration of aminophylline (200 mg, 16 mg/kg) suppositories for acute bronchitis; admitting serum theophylline was 21.2 mcg/mL and cerebrospinal fluid was 11.4 mcg/mL. Brain CT showed atrophy of the brain including the basal ganglia; residual quadriplegia with severe psychomotor impairment occurred. Due to the increased serum concentration and its enhanced absorption compared to oral administration, the authors recommended that aminophylline suppositories should be used only for short-term care (a single dose) versus maintenance therapy (Kato et al, 1997).

2) WITH POISONING/EXPOSURE

a) Severe restlessness, agitation, and generalized seizures, which may be refractory to standard anticonvulsant therapy, have been reported with theophylline overdose (Liu et al, 2008; Visitsunthorn et al, 2001; Olson et al, 1985; Henderson et al, 1992; Powell et al, 1993; Olson et al, 1993; Shannon, 1997).
b) INCIDENCE, ACUTE: In comparison, of 119 patients with acute intoxication in the same series, 6 (5%) developed seizures.
c) INCIDENCE, CHRONIC: Seizures are more common after chronic overdose. In a prospective series of 92 patients with chronic theophylline overdose, 13 (14%) developed seizures (Shannon, 1993).
d) RISK FACTORS, ACUTE: In patients with acute theophylline intoxication, seizures generally develop at serum levels of 80 to 100 mcg/mL or higher (Olson et al, 1985; Shannon & Lovejoy, 1992; Shannon, 1993).
e) RISK FACTORS, CHRONIC: In patients with chronic theophylline intoxication, seizures may develop at serum levels of 40 to 60 mcg/mL or lower, and are more likely to develop in those 60 years of age or greater, and those 3 years of age or younger (Shannon & Lovejoy, 1992; Shannon, 1993).

C) TOXIC ENCEPHALOPATHY

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 3.5-month-old and 12-month-old developed brain damage associated with profound mental and motor retardation after theophylline overdose (Noetzel, 1985; Bigler, 1991). A cause and effect relationship could not be established in either case due to multiple confounding factors.

D) HALLUCINATIONS

1) WITH POISONING/EXPOSURE

a) Hallucinations have been reported in children with a serum theophylline concentration greater than 30 mcg/mL (Baker, 1986).

E) TREMOR

1) WITH POISONING/EXPOSURE

a) Tremors are frequently associated with theophylline toxicity (Paloucek & Rodvold, 1988).
b) CASE SERIES: In a retrospective series of 53 patients with theophylline intoxication, 9 (17%) developed tremors (Tsai et al, 1994).
c) CASE SERIES: In a prospective series of patients with theophylline overdose, tremors developed in 45 of 119 (38%) patients with acute intoxication, 15 of 92 (16%) patients with chronic intoxication and 16 of 38 (42%) patients with acute overdose on top of chronic therapeutic use (Shannon, 1993).

F) HEADACHE

1) WITH POISONING/EXPOSURE

a) Severe headaches also can occur at serum concentrations of theophylline above the therapeutic range (10 to 20 mcg/mL) (55 to 111 mcmol/L).

G) CENTRAL STIMULANT ADVERSE REACTION

1) WITH THERAPEUTIC USE

a) Agitation, insomnia, nervousness, and irritability are common following initial administration. Tolerance to these adverse effects usually develops with continued usage (Tsiu et al, 1990).

H) AMNESIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: An amnestic syndrome developed in 2 patients after prolonged theophylline-induced seizures (O'Riordan et al, 1994).

I) SPASM

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 6-month-old with a family history of epilepsy developed jerking movements and hypsarrhythmia on EEG associated with serum theophylline levels of 108 mcmol/L. Spasms resolved and EEG normalized after theophylline was discontinued (Shields et al, 1995).

J) CEREBRAL HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: An infant suffered severe neurologic sequelae following intracranial hemorrhage associated with theophylline overdose. The serum level was 42.4 mcg/mL and there was no evidence of intracranial infection, trauma, vascular disease or coagulopathy. Detoxifying infants with high concentrations of theophylline should be done cautiously through the use of anticoagulation with hemoperfusion (Woody & Laney, 1986).

K) PARAPLEGIA

1) WITH POISONING/EXPOSURE

a) INTRATHECAL INJECTION CASE REPORT: A 64-year-old man (70 kg) received 3 mL of aminophylline 2.5% intrathecally from a 10 mL syringe instead of 3 mL of bupivacaine 0.5% for a scheduled transurethral prostate resection for benign hyperplasia. He immediately developed tetanic muscle spasm of his lower limbs and leg cramps. He underwent the scheduled surgical procedure and remained stable during the procedure and for the next 24 hours. He was discharged home without any other intervention (eg, intrathecal lavage). He presented again with weakness in his lower limbs within 24 hours of his release. At this time, he was treated with high dose vitamin B-complex oral supplements and a lumbar puncture was performed to obtain cerebrospinal fluid specimen and a myelogram was performed. The CSF analysis was considered normal, except for mildly elevated protein concentrations (54 mg/dL; normal, 15 to 45 mg/dL). The lumbar myelogram revealed mild external compression on the thecal sac at L3-L5. All other findings were normal. No other medical interventions were performed. He remained a paraplegic and died 2 years after the inadvertent intrathecal use (Ajmal, 2011).

Gastrointestinal

3.8.1)

A) WITH THERAPEUTIC USE

1) Sustained release formulations may form bezoars.

B) WITH POISONING/EXPOSURE

3.8.2)

A) VOMITING

1) WITH POISONING/EXPOSURE

a) Nausea, vomiting, and abdominal pain are common, particularly with acute intoxication (Prod Info THEOCHRON(TM) extended release oral tablets, 2008; Visitsunthorn et al, 2001; Amitai & Lovejoy, 1987; Henderson et al, 1992; Powell et al, 1993).
b) INCIDENCE, ACUTE: Vomiting occurred in 73% to 82% of patients with acute toxicity in several large series (Sessler et al, 1985; Gaudreault et al, 1983; Shannon, 1993).
c) INCIDENCE, CHRONIC: In a prospective series of 92 patients with chronic theophylline intoxication, 28 (30%) developed vomiting (Shannon, 1993).
d) DURATION: Vomiting may be prolonged, particularly after ingestion of sustained release products (Amitai & Lovejoy, 1987). In a prospective series of 25 patients with acute overdose of sustained release theophylline preparations, the mean duration of vomiting was 10.6 hours (Amitai & Lovejoy, 1987).

B) GASTROINTESTINAL HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) Gastrointestinal bleeding can also result from severe theophylline intoxication (Visitsunthorn et al, 2001; Vaucher et al, 1977; Paloucek & Rodvold, 1988).

C) BEZOAR

1) WITH THERAPEUTIC USE

a) CASE REPORT: A bezoar of congealed Theo-Dur(R) tablets was seen by gastroscopy (Cereda et al, 1986).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: A bezoar of congealed Theo-Dur(R) tablets was seen by gastroscopy (Cereda et al, 1986).
b) CASE REPORT: A 318.8 g white waxy mass was found on autopsy after ingestion of estimated 29 g of Theo-Dur(R) tablets (Bernstein et al, 1992).

D) ENTEROCOLITIS

1) WITH THERAPEUTIC USE

a) In a retrospective study of low birthweight (less than 1250 g) infants, use of enteral theophylline was associated with an increased incidence of feeding intolerance and, necrotizing enterocolitis (NEC), and NEC scares, defined as an increase in gastric aspirates or emesis and either gastrointestinal bleeding, abdominal radiographic changes (persistently enlarged bowel loops or thickened bowel wall without pneumatosis) or systemic illness (increased apnea or bradycardia and increased ventilatory support) (Hufnal-Miller et al, 1993).

E) ACUTE PANCREATITIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 39-year-old man, with no known predisposing risk factors, developed acute pancreatitis several days after intentionally ingesting 20 sustained-release theophylline tablets. His initial serum theophylline concentration was 777 micromol/L (140 mcg/mL). Early symptoms included tonic-clonic seizures, rhabdomyolysis and acute renal failure. Clinical improvement was observed by day 4 and the patient was extubated. On day 5, the patient had a new complaint of worsening epigastric and left upper quadrant abdominal pain. Serum amylase was 386 Units/L, lipase 2574 Units/L; other laboratory studies were within normal limits. An abdominal CT showed focal enlargement of the pancreas. The patient was treated with IV fluids and supportive care and gradually improved over 48 hours (Liu et al, 2008).

Genitourinary

3.10.1)

A) WITH POISONING/EXPOSURE

1) Renal failure is an unusual complication associated with prolonged hypotension or rhabdomyolysis.

3.10.2)

A) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) Acute renal failure is an unusual complication that may develop secondary to severe hypotension or rhabdomyolysis secondary to prolonged seizures (MacDonald et al, 1985; Rumpf et al, 1985; Parr & Willatts, 1991; Higgins et al, 1995; Titley & Williams, 1992; Wight et al, 1987) .

B) BLOOD IN URINE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 19-year-old overdose patient developed prolonged microscopic hematuria in the absence of myoglobinuria or oliguria (Anderson et al, 1991).

C) SERUM CREATININE RAISED

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Elevations of serum creatinine developed in the first 24 hours of an overdose of a sustained-release agent (Anderson et al, 1991).

Acid-Base

3.11.1)

A) WITH POISONING/EXPOSURE

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Mild metabolic acidosis is common with acute intoxication or acute intoxication on top of chronic therapeutic use (Visitsunthorn et al, 2001; Shannon, 1993; Hagley et al, 1994). Severe metabolic acidosis has resulted from acute overdoses (Bernard, 1991; Ker & Newman, 1993).
b) INCIDENCE: In a retrospective series of 19 patients with acute theophylline overdose who did not develop seizures, 15 (79%) developed mild metabolic acidosis (Olsen et al, 1985). In comparison, of 8 patients with chronic intoxication who did not develop seizures, 0 had a metabolic acidosis.
c) CASE REPORT: A pure metabolic acidosis with elevated serum lactate levels was reported in an 18-year-old man who ingested 9 g of sustained release theophylline (Leventhal et al, 1989).
d) CASE REPORT: Bernard (1991) reported 2 cases in which the presentation of theophylline overdose included severe metabolic acidosis (pH 6.67 and 6.63) due to lactic acidosis (24.5 mmol/L and 21 mmol/L), not seizures. Administration of modest amounts of sodium bicarbonate was associated with resolution of the acidosis prior to institution of charcoal hemoperfusion.
e) CASE REPORT: A 47-year-old woman developed severe acidemia (pH 6.67) from status epilepticus after theophylline overdose (Ker & Newman, 1993).

B) RESPIRATORY ALKALOSIS

1) WITH POISONING/EXPOSURE

a) Respiratory alkalosis may occur in acute overdose (Hall et al, 1984).

Hematologic

3.13.2)

A) LEUKOCYTOSIS

1) WITH POISONING/EXPOSURE

a) INCIDENCE: An 86% incidence of neutrophil leukocytosis was noted in one series of 64 cases of theophylline poisoning (Parr et al, 1990). Acute, chronic, or acute-on-chronic poisoning was not addressed.

1) SEVERITY: The maximum leukocyte count ranged from 7.3 to 29 x 10(9)/L with a mean of 17.7 X 10(9)/L.

b) CASE REPORT: Anderson et al (1991) reported a 19-year-old asthmatic man with marked leukocytosis of 47.8 x 10(-9)/L following an overdose of 6 g slow-release theophylline. This patient had no signs of inflammation and fever was absent. The leukocytosis lasted 4 days (Anderson et al, 1991).

Dermatologic

3.14.2)

A) DERMATITIS

1) WITH POISONING/EXPOSURE

a) HYPERSENSITIVITY reactions including dermatitis have been reported following exposure to aminophylline. Skin testing usually demonstrated sensitivity to the ethylenediamine component and not theophylline itself.

Musculoskeletal

3.15.1)

A) WITH POISONING/EXPOSURE

1) Rhabdomyolysis and compartment syndrome are rare complications most often seen in patients with prolonged seizures.

3.15.2)

A) COMPARTMENT SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Compartment syndrome of the calves, measured by slit catheter technique, developed in a 41-year-old woman following an ingestion of an unknown amount of slow-release aminophylline (225 mg tablets) (Lloyd et al, 1990).
b) CASE REPORT: Bilateral calf compartment syndrome requiring surgical decompression developed in a 22-year-old man following an ingestion of 17.5 g of slow-release theophylline (Parr & Willatts, 1991).
c) CASE REPORT: A 24-year-old man developed profound hypokalemia, seizures, rhabdomyolysis and acute lower and upper limb compartment syndrome after ingesting 20 slow-release 400 mg theophylline tablets. He died despite hemoperfusion and bilateral decompression (Titley & Williams, 1992).
d) CASE REPORT: A 38-year-old man developed status epilepticus, hypotension, hyperthermia, acute renal failure and bilateral compartment syndrome of the calves after ingesting 25,000 mg of sustained release theophylline. He died despite hemodialysis, hemoperfusion and bilateral fasciotomies (Higgins et al, 1995).

B) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) Rhabdomyolysis leading to acute renal failure has been described following several overdoses, usually associated with prolonged seizures (Liu et al, 2008; MacDonald et al, 1985; Rumpf et al, 1985; Wight et al, 1987; Parr & Willatts, 1991; Titley & Williams, 1992; Higgins et al, 1995).

Endocrine

3.16.2)

A) HYPERGLYCEMIA

1) WITH POISONING/EXPOSURE

a) Hyperglycemia is a consistent finding in acute theophylline overdose (Prod Info THEOCHRON(TM) extended release oral tablets, 2008; Visitsunthorn et al, 2001; Biberstein et al, 1984; Tsiu et al, 1990; Shannon & Lovejoy, 1992).
b) INCIDENCE

1) The incidence of hyperglycemia ranged from 72% to 89% in several large studies of theophylline overdose (Parr et al, 1990; Shannon & Lovejoy, 1992; Shannon, 1993).
2) Serum glucose levels were higher in patients with acute overdose or acute overdose on top of chronic therapeutic use than after chronic overdose in two large case series (Shannon & Lovejoy, 1992; Shannon, 1993).

c) SEVERITY

1) ACUTE: Mean serum glucose levels after acute intoxication were 196 +/- 63 mg/dL and 196 +/- 69 mg/dL in 2 large case series (Shannon & Lovejoy, 1992; Shannon, 1993).
2) CHRONIC: Mean serum glucose levels after chronic intoxication were 127 +/- 44 mg/dL and 150 +/- 4.9 mg/dL in 2 large case series (Shannon & Lovejoy, 1992; Shannon, 1993).
3) ACUTE ON CHRONIC: Mean serum glucose levels after acute intoxication on top of chronic therapeutic use were 218 +/- 117 mg/dL and 204 +/- 88 mg/dL in 2 large case series (Shannon & Lovejoy, 1992; Shannon, 1993).

B) KETOSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Ketones were detected in the urine and on the breath of a nondiabetic overdose patient. Resolution of ketoacidosis in this patient coincided with resolution of theophylline intoxication (Ryan et al, 1989).

C) CATECHOLAMINE LEVEL - FINDING

1) WITH POISONING/EXPOSURE

a) Plasma catecholamine levels are elevated after theophylline overdose.
b) In a study of 10 patients with acute theophylline intoxication and 3 patients with chronic intoxication, epinephrine levels were higher after acute intoxication while norepinephrine and dopamine levels were higher after chronic intoxication (Shannon & Maher, 1994).

Immunologic

3.19.2)

A) ACUTE ALLERGIC REACTION

1) WITH POISONING/EXPOSURE

a) Hypersensitivity reactions to aminophylline have been associated with the ethylenediamine component and not with theophylline itself.
b) Reactions usually manifest as dermatitis, however, bronchospasm has also been reported in sensitized individuals.

Reproductive

3.20.1)

3.20.2)

A) HEART MALFORMATION

1) Three cases of cardiac abnormalities associated with theophylline used by the mother during pregnancy have been reported (Park et al, 1990). A double-outlet right ventricle has been associated with Tedral(R) use (Matsuoka et al, 1985).

B) ANIMAL STUDIES

1) MICE: Cleft palate and digital abnormalities were reported in mice administered a single intraperitoneal dose of theophylline at and above 100 mg/kg (approximately equal to the maximum recommended oral dose for adults on a mg/m(2) basis) during organogenesis. Doses that are approximately 2 times the maximum recommended oral dose for adults on a mg/m(2) basis resulted in micromelia, micrognathia, clubfoot, subcutaneous hematoma, open eyelids, and embryolethality (Prod Info theophylline in dextrose 5% IV injection solution, 2010; Prod Info THEO-24(R) extended-release oral capsules, 2005).
2) RABBITS: Cleft palate and embryolethality were reported in rabbits administered IV theophylline 60 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m(2) basis) throughout organogenesis. An increased incidence of skeletal variations was reported with doses at and above 15 mg/kg/day (less than the maximum recommended oral dose for adults on a mg/m(2) basis) (Prod Info theophylline in dextrose 5% IV injection solution, 2010; Prod Info THEO-24(R) extended-release oral capsules, 2005).
3) RATS: Digital abnormalities were reported in rats administered theophylline 150 mg/kg/day orally (approximately 2 times the maximum recommended oral dose for adults on a mg/m(2) basis) from conception through organogenesis. Embryolethality was reported with subcutaneous doses of theophylline of 200 mg/kg/day (approximately 4 times the maximum recommended oral dose for adults on a mg/m2 basis) (Prod Info theophylline in dextrose 5% IV injection solution, 2010; Prod Info THEO-24(R) extended-release oral capsules, 2005).
4) Theophylline has been shown to be a cardiovascular teratogen in test animals (Matsuoka et al, 1985; Ishikawa et al, 1978; Gilbert et al, 1977).

3.20.3)

A) LACK OF INFORMATION

1) There are no adequate and well-controlled studies with theophylline in pregnant women (Prod Info ELIXOPHYLLIN(R) oral liquid elixir, 2010; Prod Info theophylline in dextrose 5% IV injection solution, 2010).

B) AMINOPHYLLINE

1) A 36-year-old asthmatic female took aminophylline during her pregnancy and on the day prior to delivery was administered furosemide, nitroglycerin, and aminophylline. Aminophylline was then continued every 4 hours in a dose of 100 mg with the last dose given one hour prior to delivery. At 6 hours of age, the infant was found to be jittery and vomited which recurred following his first and second feedings. The infant became irritable and exhibited 2 further episodes of gagging and vomiting, the second of which was associated with opisthotonus and jitteriness. Blood analysis determined that aminophylline was present in the infant's cord serum, as well as in his serum at age 52 hours. The infant's condition improved with no special treatment and tolerated oral feedings from then on (Yeh & Pildes, 1977).

C) THEOPHYLLINE

1) PHARMACOKINETICS DURING PREGNANCY: Theophylline pharmacokinetics were studied in 5 women during and after pregnancy. Protein binding was reduced to 11.1 +/- 4.7% and 13 +/- 5.9% during second and third trimester, respectively. Distribution volume and elimination t1/2 were increased in the third trimester. Intrinsic nonrenal clearance was reduced while intrinsic renal clearance increased (Frederiksen et al, 1986).
2) There have been no reports of congenital abnormalities caused by maternal use of theophylline. Transfer of theophylline across the placental barrier has been established. Maternal and cord theophylline levels do not differ significantly; however, heel stick levels tend to be higher than maternal levels. Although it is concluded that newborns seem to tolerate theophylline levels corresponding to maternal levels, 5 out of 9 mothers in this study had serum theophylline levels below therapeutic parameters (less than 10 mcg/mL). A transient toxicity including tachycardia and jitteriness was reported in newborns having theophylline concentrations greater than 10 mcg/mL. Since fetal cord levels so closely approximate maternal levels, it is possible that therapeutic maternal levels could potentially cause toxicity in the neonate (Labovitz & Spector, 1982). In one case report, a neonate with a serum theophylline concentration of 14 mcg/mL at delivery did not demonstrate signs of theophylline toxicity (Arwood et al, 1979).

D) PREGNANCY CATEGORY

1) Aminophylline has been classified as FDA pregnancy category C (Prod Info aminophylline IV injection, 2009).
2) Theophylline has been classified as FDA pregnancy category C (Prod Info ELIXOPHYLLIN(R) oral liquid elixir, 2010; Prod Info theophylline in dextrose 5% IV injection solution, 2010).

E) ANIMAL STUDIES

1) No teratogenic effects were noted when theophylline was administered to CD-1 mice at oral doses up to 400 mg/kg (approximately 2 times the human dose on a mg/m(2) basis) or CD-1 rats at oral doses up to 260 mg/kg (approximately 3 times the recommended human dose on a mg/m(2) basis); however, embryotoxicity without maternal toxicity was reported in rats administered theophylline 220 mg/kg (Prod Info ELIXOPHYLLIN(R) oral liquid elixir, 2010; Prod Info aminophylline IV injection, 2009).

3.20.4)

A) BREAST MILK

1) Theophylline is excreted into human breast milk at concentrations approximately equivalent to the maternal serum concentration. A liter of breast milk containing 10 to 20 mcg/mL of theophylline is likely to deliver 10 to 20 mg of theophylline to the nursing infant. Such exposure may cause mild signs of toxicity (eg, irritability) in the infant; however, serious adverse effects are unlikely unless the mother has toxic serum theophylline concentrations (Prod Info ELIXOPHYLLIN(R) oral liquid elixir, 2010; Prod Info aminophylline IV injection, 2009; Prod Info THEO-24(R) extended-release oral capsules, 2005).
2) Theophylline is excreted in the breast milk with less than 1% of the maternal dose excreted into breast milk (Briggs et al, 1998).
3) Theophylline is secreted in breast milk in concentrations of about 70% of the plasma. However, theophylline has never been associated with serious side effects. A mother took 200 mg of aminophylline every 6 hours and was breastfeeding her infant. On days when aminophylline was taken, the child became irritable and slept fretfully. It was concluded that this particular child, who was found to have peak serum theophylline concentration of 6.8 mg/L, was unusually sensitive to theophylline effects. Pharmacokinetic studies in this mother and 4 others determined mean milk to serum ratios for theophylline of 0.73. The maximum theophylline concentration in the breast milk appeared about 1 to 3 hours after an oral dose. Maximum amounts of theophylline that an infant could ingest following nursing of 1 L of milk per day were estimated to be 8 mg (normal pediatric dose, 12 to 26 mg/kg/24 hours orally). This was assuming therapeutic doses were ingested by the mother (16 mg/kg/day) and the infant was nursed near the time the drug level peaked in the serum (Yurchak & Jusko, 1976).

3.20.5)

A) ANIMAL STUDIES

1) MICE AND RATS: Impaired fertility (increases in the gestation period at the highest dose and decreases in the number of live pups per litter and the mean number of litters per fertile pair), as well as decreases in the proportion of pups born alive at the mid and high doses were reported in mating pairs of B6C3F1 mice administered oral theophylline 120, 270, and 500 mg/kg (approximately 1 to 3 times the human dose on a mg/m(2) basis) during a 14-week continuous breeding study. Systemic toxicity (including decreases in testicular weight) was observed with the highest dose in F344 rats and B6C3F1 mice administered oral theophylline 40 to 300 mg/kg (approximately 2 times the human dose on a mg/m(2) basis) during 13-week toxicity studies (Prod Info theophylline in dextrose 5% IV injection solution, 2010; Prod Info ELIXOPHYLLIN(R) oral liquid elixir, 2010).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and mental status.
B) Determine serial (every 1 to 2 hours) serum theophylline concentrations until the concentration is clearly decreasing (at lest two consecutive declining concentrations). A peak theophylline level may not occur for many hours after overdose of a sustained-release preparation and can be delayed for up to 24 hours.
C) Monitor serum glucose and serum electrolytes.
D) Monitor CPK levels and renal function in patients with seizures. Institute continuous cardiac monitoring and obtain an ECG.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) SERIAL LEVELS: Follow serial theophylline levels every 1 to 2 hours until the concentration is clearly decreasing (at lest two consecutive declining concentrations) and the patient's clinical status is improving.

a) In overdose involving sustained release products, initial theophylline levels may be misleading since levels can increase significantly over the subsequent hours and may not peak for 12 to 24 hours (Buckley et al, 1983). A peak concentration can be delayed up to 24 hours after the ingestion of a controlled- or extended-release theophylline product (Dawson & Whyte, 2001).
b) Initial levels of 31.3 mcg/mL in a 54-year-old woman elevated over 24 hours to 190.1 mcg/mL as measured at autopsy (Bernstein et al, 1992).

2) ELECTROLYTES: Monitor serum glucose and electrolytes, especially potassium.
3) Monitor CPK levels and renal function in patients with seizures, compartment syndrome or other manifestations of severe toxicity.

B) ACID/BASE

1) Monitor arterial blood gases in patients with seizures, compartment syndrome or other manifestations of severe toxicity.

4.1.4)

A) OTHER

1) MONITORING

a) Monitor ECG for possible cardiac dysrhythmias and maintain continuous cardiac monitoring.
b) Monitor blood gases and pulmonary function tests.

Methods

1) An EMIT(R) homogeneous enzyme immunoassay is available for measurement of theophylline in serum or plasma. The assay's range of quantitation is 2.5 to 40 mcg/mL for theophylline. Clinical studies show excellent correlation between this method and high performance liquid chromatography (HPLC).
2) In one study, plasma theophylline levels were measured by using fluorescence polarization immunoassay method (Visitsunthorn et al, 2001).

1) Several HPLC procedures for the determination of theophylline have been described. This method allows rapid measurement of theophylline in very small samples (ie, 0.5 mL of serum) (Anon, 1985).

1) Citric acid-induced saliva theophylline concentrations were found to correlate well with paired plasma theophylline concentrations. A citric acid crystal (5 mg) was placed on the tongue to stimulate saliva production for theophylline concentration measurements. This technique was painless and well tolerated in infants and children with asthma. Therapeutic range limits of this technique have not been established (Aviram et al, 1987)

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Admit all patients with chronic intoxication, patients with an acute ingestion of a sustained-release product and those with acute ingestions in whom serum theophylline levels are not falling. Patients with symptoms beyond mild tachycardia, nausea, vomiting and tremor and those whose symptoms do not resolve should be admitted. Because of the potential for severe toxicity, most patients should be admitted to an intensive care setting.

6.3.1.2) HOME CRITERIA/ORAL

A) Patients who are not chronically taking theophylline and who unintentionally ingest 10 mg/kg or less can be managed at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a medical toxicologist or poison center for any patient with severe toxicity or in whom the diagnosis is unclear. Consult a nephrologist early in any patient with severe toxicity or rapidly rising theophylline concentrations.

6.3.1.4) PATIENT TRANSFER/ORAL

A) Patients who are at risk for developing life-threatening toxicity (chronic overdose with serum theophylline levels greater than 40 to 60 mcg/mL, age greater than 60 years or less than 3 years, acute overdose and serum level greater than 80 to 100 mcg/mL) should be transferred to a facility where emergent hemodialysis is available.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with an acute ingestion of immediate-release preparations who have only mild clinical effects (ie, mild tachycardia, nausea, vomiting, tremor) can be observed in the ED with activated charcoal therapy, cardiac monitoring and serial theophylline levels. Patients may be discharged when serum theophylline levels fall below 20 mcg/mL and symptoms resolve. Patients with worsening signs and symptoms, ingestion of a sustained-release product or rising levels should be admitted to a monitored setting.

Monitoring

Oral Exposure

6.5.1)

A) Avoid prehospital gastrointestinal decontamination as patients are at high risk to vomit and suffer abrupt deterioration.

6.5.2)

A) SUMMARY

1) Activated charcoal should be administered to patients who have a significant acute ingestion. As theophylline causes seizures and vomiting, most patients should be intubated prior to charcoal administration. Whole bowel irrigation may be helpful in the case of a sustained-release overdose, if there is evidence of ongoing theophylline absorption; however, it can be difficult to perform in patients with severe toxicity or persistent emesis.

B) ACTIVATED CHARCOAL

1) Activated charcoal has been shown to effectively adsorb theophylline in vitro and to decrease theophylline absorption in human volunteer studies (Cooney, 1995; Minton et al, 1995; Minton et al, 1995).
2) MECHANISM: It has been shown that activated charcoal may decrease theophylline by (Minton & Henry, 1996):

1) possible adsorption of theophylline in the lumen of the gut;
2) possible interruption of enterohepatic circulation of the drug, (probably a small effect);
3) it may promote back-diffusion of theophylline from the blood to the intestine known as "gastrointestinal dialysis" which is facilitated by repeated doses of charcoal.

3) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

4) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

C) PERSISTENT VOMITING

1) Persistent vomiting may interfere with attempts to administer activated charcoal (Sessler et al, 1987).
2) RANITIDINE: Ranitidine may be useful in controlling excess gastric secretions that may lead to the persistent vomiting (Amitai et al, 1986). Cimetidine may interfere with theophylline clearance.
3) ONDANSETRON: Several case reports suggest that ondansetron may be effective in intractable nausea and vomiting associated with theophylline toxicity (Sage et al, 1993; Brown & Prentice, 1992; Daly & Taylor, 1993; Roberts et al, 1993). Usual adult dose is 8 mg IV.
4) OTHER: Another effective antiemetic can include metoclopramide (0.4 to 1 mg/kg). Phenothiazines (ie, prochlorperazine or perphenazine) should be avoided.

D) GASTRIC LAVAGE

1) Gastric lavage should be considered in substantial recent ingestions. It may be indicated after ingestion of a sustained-release formulation even if delayed, as these products may form bezoars.
2) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

3) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

4) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

5) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

6) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

E) MULTIPLE DOSE ACTIVATED CHARCOAL

1) SUMMARY

a) Multiple-dose activated charcoal should be considered in patients with serious or potentially life-threatening overdose.

1) In general, individuals who have ingested more than 10 mg/kg should receive repeated doses of activated charcoal (Dawson & Whyte, 2001).
2) Multiple dose activated charcoal (MDAC) can enhance elimination and may prevent ongoing absorption and can reduce overall toxicity in theophylline-poisoned patients. It has been recommended that MDAC should be continued during extracorporeal treatment in patients with no contraindications. MDAC is likely an additive effect to enhanced elimination (see Enhanced Elimination section) (Ghannoum et al, 2015).

2) EFFICACY

a) It has been shown to be effective in enhancing the elimination of theophylline in the following patients:

1) In case reports of patients with either a deliberate (Radomski et al, 1984; Hendeles & Weinberger, 1980; Sessler et al, 1987; Gal et al, 1984; Corser et al, 1985), or iatrogenic (Radomski et al, 1984; Hendeles & Weinberger, 1980; Sessler et al, 1987; True et al, 1984) overdose; treatment with multiple dose activated charcoal was associated with reduced theophylline half-life.

a) CASE REPORT: Multiple doses (total dose 150 g divided in 3 doses) of activated charcoal successfully lowered a serum theophylline level of 105 mg/L to 48 mg/L in a young woman who intentionally ingested 20 g of sustained-release theophylline. The patient was intubated and administered charcoal by a gastric tube due to severe nausea and vomiting unresponsive to antiemetics. Magnesium sulfate was also given to accelerate enteral passage and was stopped with the first charcoal stool. Additional theophylline clearance was provided by hemoperfusion (approximately 6.5 hours after admission) until the serum theophylline level reached 24 mg/L. The patient was extubated the following day and made a complete recovery (Rutten et al, 2005).

2) PREGNANCY: MDAC therapy has been used successfully in a pregnant patient (Davis et al, 1985), a premature newborn (Strauss et al, 1985), in infants (Bronstein et al, 1984; Ginoza et al, 1987; Shannon et al, 1987) and in children (Lim et al, 1986).

3) MULTIPLE DOSE ACTIVATED CHARCOAL

a) ADULT DOSE: Optimal dose not established. After an initial dose of 50 to 100 grams of activated charcoal, subsequent doses may be administered every 1, 2 or 4 hours at a dose equivalent to 12.5 grams/hour (Vale et al, 1999), do not exceed: 0.5 g/kg charcoal every 2 hours (Ghannoum & Gosselin, 2013; Mauro et al, 1994). There is some evidence that smaller more frequent doses are more effective at enhancing drug elimination than larger less frequent doses (Park et al, 1983; Ilkhanipour et al, 1992). PEDIATRIC DOSE: Optimal dose not established. After an initial dose of 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) (Chyka & Seger, 1997), subsequent doses may be administered every 1, 2 or 4 hours (Vale et al, 1999) in a dose equivalent to 6.25 grams/hour in children 1 to 12 years old.
b) Activated charcoal should be continued until the patient's clinical and laboratory parameters, including drug concentrations if available, are improving (Vale et al, 1999). The patient should be frequently assessed for the ability to protect the airway and evidence of decreased peristalsis or intestinal obstruction.
c) Use of cathartics has not been shown to increase drug elimination and may increase the likelihood of vomiting. Routine coadministration of a cathartic is NOT recommended (Vale et al, 1999).
d) AGENTS AMENABLE TO MDAC THERAPY: The following properties of a drug that are likely to allow MDAC therapy to be effective include: small volume of distribution, low protein binding, prolonged half-life, low intrinsic clearance, and a nonionized state at physiologic pH (Chyka, 1995; Ghannoum & Gosselin, 2013).
e) Vomiting is a common adverse effect; antiemetics may be necessary.
f) CONTRAINDICATIONS: Absolute contraindications include an unprotected airway, intestinal obstruction, a gastrointestinal tract that is not intact and agents that may increase the risk of aspiration (eg, hydrocarbons). Relative contraindications include decreased peristalsis (eg, decreased bowel sounds, abdominal distention, ileus, severe constipation) (Vale et al, 1999; Mauro et al, 1994).
g) COMPLICATIONS: Include constipation, intestinal bleeding, bowel obstruction, appendicitis, charcoal bezoars, and aspiration which may be complicated by acute respiratory failure, adult respiratory distress syndrome or bronchiolitis obliterans (Ghannoum & Gosselin, 2013; Ray et al, 1988; Atkinson et al, 1992; Gomez et al, 1994; Mizutani et al, 1991; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Mina et al, 2002; Harsch, 1986; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002).

4) ADVERSE EFFECTS

a) CASE REPORTS: Intestinal pseudo-obstruction developed in 2 cases (one fatal), following the use of enteral charcoal, sorbitol and mechanical ventilation with papaveretum sedation and neuromuscular blockade. Sympathomimetic stimulation by theophylline and reduced intestinal peristalsis from opioids probably contributed to this effect (Longdon & Henderson, 1992).
b) CASE REPORT: A 45-year-old man with acute theophylline overdose developed intestinal pseudo-obstruction after treatment including 1000 g of charcoal without cathartic, haloperidol and mechanical ventilation (Brubacher et al, 1995).
c) CASE REPORT: A 64-year-old woman developed small bowel obstruction after treatment with multiple dose activated charcoal for theophylline overdose. Adhesion probably contributed to this event (Goulbourne & Cisek, 1994).

F) WHOLE BOWEL IRRIGATION

1) INDICATIONS: Based on limited clinical data, whole bowel irrigation with polyethylene glycol solution (eg, Golytely(R)) may be considered in cases of extremely large amounts of a sustained-release theophylline preparation with rising serum levels (Tenenbein et al, 1987).
2) ACTIVATED CHARCOAL INTERACTION: Hoffman et al (1989) and (1991) reported that polyethylene glycol electrolyte lavage solution is able to displace aminophylline (theophylline) from activated charcoal in-vitro (Hoffman et al, 1991).
3) No additional benefit of whole bowel irrigation treatment over activated charcoal alone was observed following sustained-release theophylline poisoning (Burkhart et al, 1991).

6.5.3)

A) SUPPORT

1) MANAGEMENT OF MILD TO MODERATE TOXICITY

a) Establish IV access and place the patient on a cardiac monitor. Treat nausea with an antiemetic and administer IV fluids. Monitor electrolytes.

2) MANAGEMENT OF SEVERE TOXICITY

a) The primary effect of theophylline is increased sympathomimetic effects. The primary treatment is sedation with benzodiazepines (such as lorazepam 1 to 2 mg IV every 5 min titrated to effect); high doses may be required. Hemodynamically significant tachycardia should be treated with esmolol, which can paradoxically improve blood pressure in severely tachycardic patients. Hypotension should be treated with IV fluids. Adrenergic vasopressors can theoretically make tachycardia worse, but there are numerous reports of successful treatment of severe toxicity with these agents. Vasopressin is of theoretical value and has been used effectively in a case of caffeine poisoning. Lidocaine administration has been associated with successful treatment of ventricular fibrillation. Hemodialysis should be performed in patients with severe toxicity, and patients with high serum theophylline concentrations (80 to 100 mcg/mL after acute overdose, 40 to 60 mcg/mL with chronic toxicity).

B) MONITORING OF PATIENT

1) Monitor vital signs and mental status.
2) Determine serial (every 1 to 2 hours) serum theophylline concentrations until the concentration begins to fall. Peak theophylline levels may not occur for many hours after overdose of a sustained-release preparation and can be delayed for up to 24 hours.
3) Monitor serum glucose and serum electrolytes.
4) Monitor CPK levels and renal function in patients with seizures. Institute continuous cardiac monitoring and obtain an ECG.

C) SEIZURE

1) SEIZURE PROPHYLAXIS

a) SUMMARY: Several studies have demonstrated that prophylaxis with phenobarbital prior to the onset of seizures in theophylline-toxic animals delays or prevents seizures and improves survival.
b) Prospective clinical studies are not available. Consider phenobarbital prophylaxis in patients at high risk for developing seizures, where the potential benefits exceed the risks of therapy. Patients at high risk include:

1) Those with a serum theophylline level of 40 to 60 mcg/mL and age greater than 60 or less than 3 years following chronic overdose (Olson et al, 1985; Shannon & Lovejoy, 1992; Shannon, 1993).
2) Those with a serum level greater than 80 to 100 mcg/mL following acute overdose (Olson et al, 1983; Gaudreault et al, 1983; Goldberg et al, 1986).

c) Monitor carefully for respiratory depression and hypotension; be prepared to intubate and provide mechanical ventilation (Shaner et al, 1988). Use of a propylene glycol-free preparation may lessen the risk of hypotension (ie, sodium phenobarbital).

2) SEIZURE TREATMENT

a) SUMMARY: Attempt initial control with a benzodiazepine (diazepam or lorazepam). If seizures persist or recur administer phenobarbital. Based on animal and limited human data, phenytoin does NOT appear to be effective in theophylline-induced seizures.

1) PHENYTOIN/LACK OF EFFECT: In a retrospective review of 100 cases of theophylline-induced seizures, phenytoin was ineffective in 21 of 22 cases. In the patient who responded, diazepam was also given (Jacobs & Senior, 1974).

b) Monitor for respiratory depression, hypotension, dysrhythmias, and the need for endotracheal intubation.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia.
d) DIAZEPAM

1) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
2) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
3) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

e) NO INTRAVENOUS ACCESS

1) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
2) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

f) LORAZEPAM

1) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
2) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
3) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

g) PHENOBARBITAL

1) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
2) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
3) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
4) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
5) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
6) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

h) OTHER AGENTS

1) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

a) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
b) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
c) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
d) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

i) RECURRING SEIZURES

1) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:

a) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
b) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
c) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
d) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)

2) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
3) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).

D) FLUID/ELECTROLYTE BALANCE REGULATION

1) Monitor serum electrolytes. Severe hypokalemia, hypophosphatemia, and hypomagnesemia should be corrected with replacement therapy. Cautious replacement of potassium is required; hyperkalemia can occur as serum theophylline levels decrease (Britt & Burkhart, 1993).

E) HYPOTENSIVE EPISODE

1) Patients with severe theophylline overdose generally have excessive beta adrenergic stimulation. In theory, agents with predominantly alpha agonist effects may be more effective for hypotension unresponsive to fluids. If hypotension is secondary to severe tachycardia, a short acting cardioselective beta antagonist such as esmolol may be indicated.
2) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

3) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

4) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

5) PHENYLEPHRINE

a) Add 10 mg phenylephrine to 500 mL of normal saline and infuse at a rate of 100 to 180 mcg/min initially, then decrease the infusion to 40 to 60 mcg/min as tolerated (Prod Info Neo-Synephrine(R), phenylephrine, 1996).

F) PROPRANOLOL

1) Although propranolol has been used to treat theophylline-induced hypotension (Biberstein et al, 1984), its use cannot be routinely recommended.
2) It may be hazardous in asthmatic patients.
3) ANIMAL STUDIES

a) Administration of propranolol 0.6 mg/kg IV following infusion of aminophylline delayed the onset of seizures (from 46 to 55 minutes) and increased the total dose of aminophylline tolerated in rats (from 385 to 473 mg/kg) (Schneider et al, 1987).
b) In another study in mice, propranolol, in doses up to 20 mg/kg intraperitoneally, prevented tonic, but not clonic seizure activity (Czuczwar et al, 1987). Propranolol may be hazardous in asthmatic and COPD patients.

G) VENTRICULAR ARRHYTHMIA

1) MONITOR CARDIAC FUNCTION closely. Sinus tachycardia and minor premature ventricular beats with no evidence of hemodynamic compromise usually improve as serum theophylline levels decline. Use standard antiarrhythmic therapy as needed (Prod Info THEOCHRON(TM) extended release oral tablets, 2008).
2) VERAPAMIL: 3 mg of IV verapamil was associated with prolongation of the cycle length and termination of ventricular tachycardia following a ventricular premature beat that was unresponsive to lidocaine therapy in a patient treated with theophylline (58 mcg/mL in plasma) (Taniguchi et al, 1989).

H) ESMOLOL

1) TACHYCARDIA SUMMARY

a) Evaluate patient to be sure that tachycardia is not a physiologic response to dehydration, anemia, hypotension, fever, sepsis, or hypoxia. Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops.
b) If therapy is required, a short acting, cardioselective agent such as esmolol is generally preferred (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
c) ESMOLOL/ADULT LOADING DOSE

1) Infuse 500 micrograms/kilogram (0.5 mg/kg) IV over 1 minute (Neumar et al, 2010).

d) ESMOLOL/ADULT MAINTENANCE DOSE

1) Follow loading dose with infusion of 50 mcg/kg per minute (0.05 mg/kg per minute) (Neumar et al, 2010).
2) EVALUATION OF RESPONSE: If response is inadequate, infuse second loading bolus of 0.5 mg/kg over 1 minute and increase the maintenance infusion to 100 mcg/kg (0.1 mg/kg) per minute. Reevaluate therapeutic effect, increase in the same manner if required to a maximum infusion rate of 300 mcg/kg (0.3 mg/kg) per minute (Neumar et al, 2010).
3) The manufacturer recommends that a maximum of 3 loading doses be used (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
4) END POINT OF THERAPY: As the desired heart rate or blood pressure is approached, omit loading dose and adjust maintenance infusion as required (Prod Info BREVIBLOC(TM) intravenous injection, 2012).

e) CAUTION

1) Esmolol is a short acting beta-adrenergic blocking agent with negative inotropic effects. Esmolol should be avoided in patients with asthma, obstructive airway disease, decompensated heart failure and pre-excited atrial fibrillation (wide complex irregular tachycardia) or atrial flutter (Neumar et al, 2010).

2) CASE REPORTS

a) UNSTABLE SUPRAVENTRICULAR TACHYCARDIA was successfully treated in a theophylline toxic patient (107.4 mcg/mL) with a continuous esmolol infusion, 50 mcg/kg/min, after a 500 mcg/kg bolus. Initial treatment with carotid massage, Valsalva, adenosine, verapamil, digoxin, and cardioversion was unsuccessful (Vanden Hoek et al, 1991).
b) Tachycardia and hypotension, thought to be secondary to theophylline toxicity, responded immediately to administration of esmolol in a 28-year-old man who ingested 5,400 mg anhydrous theophylline 8 hours prior to admission. Other drugs ingested included: 12.5 mg flurazepam, 750 mg desipramine, 750 mg doxepin, and 60 mg lorazepam 24 hours prior to admission (Seneff et al, 1990).

I) ADENOSINE

1) This short-acting agent is effective treatment for supraventricular tachycardias.
2) Because theophylline's mechanism of pharmacologic and toxic effects may involve adenosine antagonism, this agent may be useful therapy in theophylline-induced supraventricular tachycardias.
3) In a rat model of severe aminophylline intoxication, pretreatment with intracerebroventricular or intravenous adenosine increased the dose of aminophylline required to induce seizures and delayed the onset of seizures (Shannon & Maher, 1994; Shannon & Maher, 1994; Shannon & Maher, 1995).
4) In a mouse model of severe aminophylline intoxication, treatment with adenosine 5 minutes after aminophylline infusion delayed the onset of seizures and death (Wang, 1994).

J) INTRATHECAL INJECTION

1) INTRATHECAL AMINOPHYLLINE INJECTION/CASE REPORT: A 64-year-old man (70 kg) received 3 mL of aminophylline 2.5% intrathecally from a 10 mL syringe instead of 3 mL of bupivacaine 0.5% for a scheduled transurethral prostate resection for benign hyperplasia. He immediately developed tetanic muscle spasm of his lower limbs and leg cramps. He underwent the scheduled surgical procedure and remained stable during the procedure and for the next 24 hours. He was discharged home without any other intervention (eg, intrathecal lavage). He presented again with weakness in his lower limbs within 24 hours of his release. At this time, he was treated with high dose vitamin B-complex oral supplements and a lumbar puncture was performed to obtain cerebrospinal fluid specimen and a myelogram was performed. The CSF analysis was considered normal, except for a mildly elevated protein concentration (54 mg/dL; normal, 15 to 45 mg/dL). The lumbar myelogram revealed mild external compression on the thecal sac at L3-L5. All other findings were normal. No other medical interventions were performed. He remained a paraplegic and died 2 years after inadvertent intrathecal administration (Ajmal, 2011).
2) The following recommendations are based on experience with other drugs.
3) POSITIONING: Keep the patient upright if possible to delay the flow of drug to the cisterna magnum (Blaney et al, 1995).
4) CEREBROSPINAL FLUID DRAINAGE: Immediately remove at least 20 mL of CSF through a lumbar catheter. The optimal amount of CSF to remove is unknown. Adults have tolerated removal of 10 mL to 70 mL CSF after intrathecal methotrexate overdose (Gosselin & Isbister, 2005; Addiego et al, 1981).
5) CSF EXCHANGE: Serial removal of 20 mL portions of CSF and replacement with corresponding volumes of warmed normal saline should be performed after CSF removal, while preparations for ventriculolumbar perfusion are being made.
6) VENTRICULOLUMBAR PERFUSION: For large overdoses, consider ventriculolumbar perfusion. Consult a neurosurgeon for placement of a ventricular catheter. Infuse warmed, preservative free saline through the ventricular catheter and drain fluid from the lumbar catheter. Typical volumes in case reports have been in the range of 80 mL/hr (O'Marcaigh et al, 1996). Albumin 5% has also been used, and may be advantageous because of the high protein binding of mitoxantrone. Ventriculolumbar perfusion is likely to be more effective at removing the drug from the CSF than simple CSF exchange (Addiego et al, 1981).
7) STEROIDS: Steroids are usually administered to prevent arachnoiditis. A typical regimen is dexamethasone 4 mg IV every 6 hours (Widemann et al, 2004).

Enhanced Elimination

1) Hemodialysis rapidly increases the elimination rate of theophylline and is the treatment of choice in patients with severe toxicity. Consider dialysis early, if the plasma theophylline concentration approaches 40 to 60 mcg/mL in CHRONIC overdose, or 80 to 100 mcg/mL in ACUTE intoxications and/or significant signs of intoxication are present (hemodynamic compromise, seizures, mental status changes). Elderly patients and those with underlying disease, particularly cardiac, may require dialysis at lower concentrations. In the past, hemoperfusion has been recommended.

1) If the fetus develops severe distress, then hemodialysis of the mother should be considered.
2) Prematurity and low birth weights in newborns, hypotension and vaginal bleeding in the mother, and premature contractions or labor during or immediately after hemodialysis have been reported.
3) Hemodialysis in pregnant patients should include the use of isolated ultrafiltration for volume removal, the support of blood pressure with albumin, the use of a dialysate containing glucose and bicarbonate, and the use of low-dose heparin regimen (Nissenson, 1981).
4) Hemodialysis performed on a 21-year-old pregnant woman resulted in mild uterine contractions immediately following dialysis which terminated spontaneously after 4 hours. Fetal heart tones were not audible during dialysis or for 14 hours after dialysis but were heard again approximately 30 hours after admission. The patient delivered a normal, full-term viable baby 4 months later (Kurtz et al, 1966).

1) SUMMARY: Hemodialysis increased the elimination rate of theophylline with clearances of 33 mL/min (Levy, 1977), 74 miL/min (Snodgrass, 1980), 88 mL/min (Lee, 1979), and 128 mL/min (Bouffard et al, 1993) in several case reports.
2) THEOPHYLLINE LEVEL: A high theophylline level, a concentration over 80 to 100 mg/L (444 to 555 micromol/L), appears to be an independent predictor of morbidity and identifies patients who might benefit most from extracorporeal treatment. However, clinical events including intractable seizures, life-threatening dysrhythmias and shock are also indications for extracorporeal treatment (Ghannoum et al, 2015).
3) INDICATIONS: Should be considered if the plasma theophylline concentration exceeds 40 to 60 mcg/mL in CHRONIC overdose (222 to 333 micromoles/L) and/or significant signs of intoxication are present (Chang et al, 1980; Hendeles & Weinberger, 1980; Sahney et al, 1983).
4) SEVERE SYMPTOMS (cardiac arrhythmias, hemodynamic instability, seizures) generally occur at levels greater than 40 to 60 mcg/mL in CHRONIC intoxications and at levels greater than 80 to 100 mcg/mL in ACUTE intoxications (Olson et al, 1983; Gaudreault et al, 1983; Shannon, 1993).
5) SYSTEMATIC REVIEW AND RECOMMENDATIONS: Theophylline can be eliminated by extracorporeal treatment and it can augment total body clearance and can also promote the removal of methylxanthines from the CNS. In a systematic review of the literature, the Extracorporeal Treatments in Poisoning (EXTRIP) workgroup (includes international experts from the US, Canada, Europe, Australia, Brazil and China) recommends extracorporeal removal following severe theophylline poisoning. It was found that in most patients that received extracorporeal treatment (ECTR), in particular hemodialysis and hemoperfusion, theophylline was dialyzable (Level of Evidence = grade A; high level of evidence) (Ghannoum et al, 2015). ECTR is indicated in the following settings:

a) ECTR is recommended if:

1) Theophylline level is greater than 100 mg/L (555 micromol/L) in acute exposure
2) Seizures are present
3) Life-threatening dysrhythmias are present
4) Shock is present
5) There is a rising serum theophylline level, despite optimal therapy
6) There is clinical deterioration despite optimal therapy

b) ECTR is suggested if*:

1) Theophylline level is greater that 60 mg/L (333 micromol/L) in chronic exposure
2) The patient is less than 6 months or over 60 years old and the theophylline level is greater than 50 mg/L (278 micromol/L) in chronic exposure
3) Gastrointestinal decontamination cannot be administered

1) *The workgroup suggests this strategy for ECTR in asymptomatic patients at high risk of developing toxicity, and those exhibiting known complications associated with morbidity.

c) Cessation of ECTR:

1) ECTR should be continued until clinically improvement is apparent OR the theophylline level is less than 15 mg/L (83 micromol/L).

d) Choice of Extracorporeal Method:

1) Intermittent hemodialysis is the preferred method of enhanced elimination
2) The following are acceptable alternative if hemodialysis is not available: hemoperfusion, continuous renal replacement therapy (CRRT), and exchange transfusion can be an adequate alternative to hemodialysis in neonates.

e) Continuation of multiple dose activated charcoal (MDAC) during ECTR:

1) MDAC can enhance elimination and may prevent ongoing absorption and can reduce overall toxicity in theophylline-poisoned patients. The workgroup supports MDAC during ECTR in patients with no contraindications. It is likely an additive effect to ECTR.

6) PEDIATRIC: Consider in pediatric patients who deteriorate despite conventional therapy or in those patients with serum concentrations greater than 80 to 100 micrograms/milliliter (444 to 555 micromoles/liter) (Gaudreault et al, 1983).
7) SUSTAINED-RELEASE: Hemodialysis may also be indicated following massive overdose with sustained-release theophylline products due to rising and sustained toxic plasma concentrations (Connell et al, 1982).
8) CASE SERIES: In a series of 56 patients who underwent hemodialysis (n=39) or hemoperfusion (n=17) for the treatment of theophylline toxicity, there was no difference in the percentage of patients developing severe toxicity (seizures, severe dysrhythmias) during or after the procedure or in the post-procedure theophylline concentration (Shannon, 1997). Theophylline clearance rates were higher with hemoperfusion (294.8 mL/kg/hour vs 185.1 mL/kg/hour for hemodialysis). Three patients developed complications after hemoperfusion (hypocalcemia and bleeding diatheses) while no complications developed after hemodialysis.

1) CASE REPORT: A 61-year-old man intentionally ingested 24 g of theophylline SR, 240 mg of diazepam and 2 g of gabapentin. He arrived in the ED 2 hours after exposure without symptoms. An initial theophylline level was 233 micromol/L (reference range, 55 to 110). He was immediately decontaminated with activated charcoal and whole bowel irrigation with polyethylene glycol-electrolyte solution. The patient became symptomatic (ie, agitation, vomiting) along with supraventricular tachycardia (heart rate 190 beats/min) and hypotension (systolic BP 70 mmHg) about 4.5 hours after ingestion. A repeat theophylline level was 423 micromol/L (peaked at 636 micromol/L) at five hours. Approximately, 9.5 hours after exposure, intermittent hemodialysis was begun with a duration of 4 hours; post theophylline concentration was 351 micromol/L. Following hemodialysis, treatment was followed by sustained low-efficiency dialysis (SLED) for 7 hours; post theophylline concentration was 187 micromol/L but rebounded to 319 micromol/L 3 hours later. This was followed by another 6 hours of SLED; theophylline concentration decreased to 178 micromol/L. At this time, the SLED machine malfunctioned and the patient was further treated with continuous veno-venous hemodialysis for 6 hours. A second regimen of multidose activated charcoal was given during CVVHD to further lower the patient's theophylline concentration. After completing therapy, elimination half-life was 26 hours. His clinical course was complicated by ventilator associated pneumonia, but he was successfully extubated on day 5 and recovered completely (Fisher & Graudins, 2015).

1) SUMMARY: In the past, hemoperfusion has been recommended. However, few facilities currently offer hemoperfusion and current dialysis membranes provide theophylline clearance rates similar to those provided by hemoperfusion.
2) Charcoal hemoperfusion increases theophylline clearance in overdose and is associated with a theophylline half-life of approximately 2 hours (Burgess & Sargious, 1995). It is estimated that hemoperfusion may increase clearance 4- to 6-fold (Britt & Burkhart, 1993).
3) INDICATIONS: Should be considered if the plasma theophylline concentration exceeds 40 to 60 mcg/mL in CHRONIC overdose (222 to 333 mcmol/L) and/or significant signs of intoxication are present (Chang et al, 1980; Hendeles & Weinberger, 1980; Sahney et al, 1983; Britt & Burkhart, 1993).
4) SEVERE SYMPTOMS (cardiac dysrhythmias, hemodynamic instability, seizures) generally occur at levels greater than 40 to 60 mcg/mL in CHRONIC intoxications and at levels greater than 80 to 100 mcg/mL in ACUTE intoxications (Olson et al, 1983; Gaudreault et al, 1983; Shannon, 1993).
5) SYSTEMATIC REVIEW AND RECOMMENDATIONS: Theophylline can be eliminated by extracorporeal treatment and it can augment total body clearance and can also promote the removal of methylxanthines from the CNS. In a systematic review of the literature, the Extracorporeal Treatments in Poisoning (EXTRIP) workgroup (includes international experts from the US, Canada, Europe, Australia, Brazil and China) recommends extracorporeal removal following severe theophylline poisoning. It was found that in most patients that received extracorporeal treatment (ECTR), in particular hemodialysis and hemoperfusion, theophylline was dialyzable (Level of Evidence = grade A; high level of evidence) (Ghannoum et al, 2015). ECTR is indicated in the following settings:

a) ECTR is recommended if:

b) ECTR is suggested if*:

1) *The workgroup suggests this strategy for ECTR in asymptomatic patients at high risk of developing toxicity, and those exhibiting known complications associated with morbidity.

c) Cessation of ECTR:

1) ECTR should be continued until clinically improvement is apparent OR the theophylline level is less than 15 mg/L (83 micromol/L).

d) Choice of Extracorporeal Method:

e) Continuation of multiple dose activated charcoal (MDAC) during ECTR:

6) ENHANCED RECOVERY: Enhanced recovery without neurologic defects was seen in 3 pediatric patients with severe theophylline toxicity (theophylline levels of 60 to 180 mcg/mL (333 to 999 mcmol/L)) when hemoperfused early after seizure onset (Sahney et al, 1983)
7) PEDIATRIC: Consider in pediatric patients who deteriorate despite conventional therapy or in those patients with serum concentrations greater than 80 to 100 mcg/milliliter (444 to 555 micromoles/liter) (Gaudreault et al, 1983).
8) SUSTAINED-RELEASE: HEMOPERFUSION (HP) may also be indicated following massive overdose with sustained-release theophylline products due to rising and sustained toxic plasma concentrations (Connell et al, 1982).
9) REBOUND: Cessation of HP may lead to small (5 mcg/mL) rebound toxic theophylline levels (Connell et al, 1982).
10) ADVERSE EFFECTS: Associated with hemoperfusion utilizing a coated-charcoal cartridge included a transient decrease in platelets, calcium, and blood pressure and one case of possible hemolysis (Gallagher et al, 1987).
11) CONTINUOUS ARTERIOVENOUS HEMOPERFUSION

a) In one case of theophylline intoxication continuous arteriovenous hemoperfusion was associated with a theophylline clearance of 193 mL/min (Lin & Jeng, 1995).

1) Combined use of hemodialysis and charcoal hemoperfusion, along with oral activated charcoal, for 7 hours was successful in decreasing the serum theophylline level from 1000 micromoles/liter to about 100 micromoles/liter (from 180 mcg/mL to 18 mcg/mL) (Stegmayr, 1988).
2) Combined treatment cannot be expected to increase the total body clearance more than for hemoperfusion alone (Ahlmen et al, 1984).

1) CASE REPORT: A 45-year-old man intentionally ingested 9 g of a modified release aminophylline and was treated successfully with the molecular adsorbent recirculating system (MARS). Approximately, 6 hours after exposure the patient's serum theophylline level had risen to greater than 100 mg/L and fluid resuscitation did not improve hypotension. Theophylline levels rapidly declined over 4 hours and remained low during the 8 hours of treatment, along with a rapid improvement in blood pressure. Potassium and magnesium supplements were also given (Korsheed et al, 2007).

a) TECHNIQUE: MARS is a closed circuit containing an albumin-rich solution which permits diffusion of protein-bound and water-soluble substances from circulation. The albumin solution is then regenerated by passing it through a standard dialyzer plus ion-exchange and charcoal columns. It is hypothesized that it may be able to remove both free and protein-bound theophylline (Korsheed et al, 2007).

1) ENDOGENOUS CLEARANCE

1) Non-smoking Adult: 40 mL/kg/hr
2) Smoking Adult: 65 mL/kg/hr

2) HEMODIALYSIS CLEARANCE

Levy et al, 1977	33 mL/min
Lee et al, 1979	88 mL/min
Snodgrass et al, 1980	74 mL/min
Bouffard et al, 1993	128 mL/min
Nogue et al, 1994	92 to 137 mL/min

3) HEMOPERFUSION CLEARANCE

Chang et al, 1980	90 mL/min
Russo, 1979	100 mL/min
Lawyer et al, 1978	225 mL/min
Zwillich et al, 1975	140 mL/min

4) ACTIVATED CHARCOAL, MULTIPLE DOSE CLEARANCE

1) 95 to 145 mL/kg/hr

5) CONTINUOUS ARTERIOVENOUS HEMOPERFUSION CLEARANCE

1) 193 mL/min (Lin & Jeng, 1995)

6) PERITONEAL DIALYSIS, NOT EFFECTIVE

Miceli et al, 1980	5 mL/min
Weinberger & Hendeles, 1980	10 to 49 mL/min

1) EXCHANGE TRANSFUSION

a) LIMITED EFFECT: Exchange transfusion is less effective in removing substantial amounts of drug, but may be useful in infants in whom hemodialysis and hemoperfusion is difficult.
b) Exchange transfusion has been minimally effective in neonates (Prod Info THEOCHRON(TM) extended release oral tablets, 2008). However, several reports suggest single and triple volume exchange transfusions are a potentially useful alternative to hemodialysis, hemoperfusion, and repetitive oral charcoal in the critically ill newborn and premature neonate suffering from the theophylline overdose (Shannon & Lovejoy, 1992; Henry et al, 1991; Barazarte et al, 1992; Osborn et al, 1993)
c) CASE REPORT

1) A newborn with a serum theophylline level of 93.3 mcg/mL was treated with triple volume whole blood exchange transfusion (total exchange volume 600 mL) successfully. Pre-exchange elimination half-life of theophylline was 39 hours; postexchange was 9.2 hours. Serum theophylline concentration was decreased to 37.8 mcg/mL (Shannon & Lovejoy, 1992).

2) PLASMAPHERESIS

a) Plasmapheresis should NOT be used instead of hemoperfusion or hemodialysis in theophylline intoxication as it offers little compared with endogenous clearance (Bania et al, 1992).
b) CASE REPORT: A 14-year-old girl was treated successfully with plasmapheresis (using a PF1000 plasmafilter and a veno-venous extracorporeal circuit), charcoal hemoperfusion, and multiple dose activated charcoal for severe theophylline toxicity. The serum theophylline concentration fell from 100 to 64 mg/L during the 3 hour procedure. She subsequently underwent 6 hours of charcoal hemoperfusion. The serum theophylline concentration at the end of the charcoal hemoperfusion procedure was 17.5 mg/L. Approximately 3 hours into the hemoperfusion, she was extubated and received 12.5 g of activated charcoal and 7.5 g of magnesium sulfate by nasogastric tube every hour until charcoal appeared in the stool. The calculated elimination half-lives during plasmapheresis and hemoperfusion were 1.4 hours and 1.7 hours, respectively (Laussen et al, 1991).

3) DIURESIS

a) LACK OF EFFECT: Since only small amounts of unchanged theophylline are excreted by the kidneys, forced diuresis is ineffective in enhancing elimination.

4) PERITONEAL DIALYSIS

a) LACK OF EFFECT: Peritoneal dialysis is ineffective for theophylline removal (Prod Info THEOCHRON(TM) extended release oral tablets, 2008). In one study it was ineffective, with theophylline clearances of 5 mL/min (Miceli et al, 1980) and 10 to 49 mL/min reported (Hendeles & Weinberger, 1980).

Abstracts

Case Reports

1) Camarata et al (1971) reported that death in adults due to cardiac arrest has been associated with the rapid administration of an IV bolus of theophylline into a central venous catheter (Camarata et al, 1971).

1) CASE REPORT: Ehlers et al (1978) described a case of theophylline overdose in a 48-year-old woman. Two hours before admission she consumed 10 g of aminophylline (8.5 g theophylline). Gastric lavage was performed with no tablets seen. Four hours after ingestion she had a grand mal seizure and respiratory arrest. She subsequently developed anuria, hypotension, 3 more grand mal seizures, and cardiac arrhythmias. Cardiac arrest occurred requiring external massage. Charcoal hemoperfusion was used. Within 1 hour, blood pressure and urine output increased. Maximum clearance achieved was 163 mL/kg/hour. Patient's condition improved and perfusion was discontinued after 6 hours, but she sustained permanent anoxic CNS damage (Ehlers et al, 1978).
2) CASE REPORT/SUSTAINED RELEASE: A 64-year-old woman was admitted after ingesting approximately 40 sustained release theophylline tablets. Gastric lavage recovered a few tablets. Cardiac arrest occurred a short time later. Cardiopulmonary resuscitation was unsuccessful. A mass of tablets 7cm x 4cm containing 3.3 g of theophylline was found in the stomach on autopsy. A smaller mass of tablets was located in the duodenum (Coupe, 1986).

1) CHILDREN

a) "Dumping" of a once-a-day theophylline preparation (Theo-24(R)) occurred in an 11-year-old girl following administration of the preparation with food, resulting in toxic theophylline concentrations (42 mcg/mL) and hospital admission. The mechanism for the dumping is reportedly secondary to pH changes in the duodenum occurring in response to food, since the coating on the beads dissolves rapidly at a pH of 7.4 (Hendeles et al, 1984).

2) INFANT

a) Three infants presented with seizures following treatment with theophylline for bronchiolitis or asthma. One patient received 13 mg/kg/day and had a peak theophylline level of 41 mcg/mL. One patient received 16 mg/kg/day and had a peak theophylline level of 45 mcg/mL. The third infant received 25 mg/kg/day and had a theophylline level of 59 mcg/mL (Augenstein et al, 1987).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) EXTENDED-RELEASE CAPSULE AND TABLET

1) 12-HOUR FORMULATION

a) The recommended initial dose is 300 mg/day divided every 12 hours. After 3 days if tolerated, 400 mg/day divided every 12 hours. After 3 more days if tolerated, 600 mg/day divided every 12 hours (Prod Info THEOCHRON(TM) extended release oral tablets, 2008; Prod Info theophylline extended-release oral capsules, 2005).

2) 24-HOUR FORMULATION

a) The recommended dose for patients previously stable on another oral formulation is 400 or 600 mg once daily. The dose should be same mg as previous immediate- or controlled-release dosing (Prod Info THEOPHYLLINE ANHYDROUS oral extended-release tablets, 2014).
b) The recommended initial dose is 300 to 400 mg once daily. After 3 days if tolerated, 400 to 600 mg once daily. After 3 more days if tolerated, titrate according to blood levels if dose is greater than 600 mg (Prod Info THEOPHYLLINE ANHYDROUS oral extended-release tablets, 2014; Prod Info THEO-24(R) extended-release oral capsules, 2005).

B) IMMEDIATE-RELEASE TABLET, ORAL SOLUTION, AND ELIXIR

1) The recommended initial loading dose for acute bronchodilation is 5 mg/kg of lean (ideal) body weight to peak serum concentration of 5 to 15 mcg/mL (Prod Info theophylline oral solution, 2013; Prod Info ELIXOPHYLLIN(R) oral liquid elixir, 2012; Prod Info THEOLAIR(TM) oral tablets, 1998).
2) The recommended initial dose is 300 mg/day in divided doses over 6 to 8 hours. After 3 days (if tolerated), increase to 400 mg/day in divided doses over 6 to 8 hours. After 3 more days (if tolerated and needed), increase to 600 mg/day in divided doses over 6 to 8 hours (Prod Info theophylline oral solution, 2013; Prod Info ELIXOPHYLLIN(R) oral liquid elixir, 2012; Prod Info THEOLAIR(TM) oral tablets, 1998).

C) INTRAVENOUS

1) The recommended loading dose for acute bronchodilation in a theophylline-naive patient is 4.6 mg/kg (based on ideal body weight) IV over 30 minutes (Prod Info theophylline in 5% dextrose intravenous injection solution, 2011).
2) UP TO 60 YEARS OF AGE: The recommended initial dose (after loading dose) is 0.4 mg/kg/hr. MAXIMUM DOSE: 900 mg/day (unless serum levels indicate need for larger dose) (Prod Info theophylline in 5% dextrose intravenous injection solution, 2011).
3) GREATER THAN 60 YEARS OF AGE: The recommended initial dose (after loading dose) is 0.3 mg/kg/hr. MAXIMUM DOSE: 400 mg/day (unless serum levels indicate need for larger dose) (Prod Info theophylline in 5% dextrose intravenous injection solution, 2011).

7.2.2)

A) EXTENDED-RELEASE CAPSULE AND TABLET

1) 12-HOUR FORMULATION

a) LESS THAN 45 KG: The recommended initial dose is 12 to 14 mg/kg/day (MAXIMUM DOSE: 300 mg/day) divided every 12 hours; after 3 days if tolerated, 16 mg/kg/day (MAXIMUM DOSE: 400 mg/day) divided every 12 hours; after 3 more days if tolerated, 20 mg/kg/day (MAXIMUM DOSE: 600 mg/day) divided every 12 hours (Prod Info theophylline extended-release oral capsules, 2005).
b) GREATER THAN 45 KG: The recommended initial dose is 300 mg/day divided every 12 hours; after 3 days if tolerated, 400 mg/day divided every 12 hours; after 3 more days if tolerated, 600 mg/day divided every 12 hours (Prod Info theophylline extended-release oral capsules, 2005).

2) 24-HOUR FORMULATION

a) LESS THAN 45 KG: The recommended initial dose is 12 to 14 mg/kg once daily (MAXIMUM DOSE: 300 mg/day); after 3 days if tolerated, 16 mg/kg once daily (MAXIMUM DOSE: 400 mg/day); after 3 more days if tolerated, 20 mg/kg once daily (MAXIMUM DOSE: 600 mg/day) (Prod Info THEOPHYLLINE ANHYDROUS oral extended-release tablets, 2014).
b) GREATER THAN 45 KG: The recommended dose is 300 to 600 mg once daily. Doses greater than 600 mg should be titrated according to blood levels (Prod Info THEOPHYLLINE ANHYDROUS oral extended-release tablets, 2014).

B) IMMEDIATE-RELEASE TABLET, ORAL SOLUTION, AND ELIXIR

1) PREMATURE NEONATES

a) LESS THAN 24 DAYS OF AGE: The recommended initial dose is 1 mg/kg every 12 hours (Prod Info theophylline oral solution, 2013; Prod Info ELIXOPHYLLIN(R) oral liquid elixir, 2012; Prod Info THEOLAIR(TM) oral tablets, 1998).
b) 24 DAYS OF AGE OR GREATER: The recommended initial dose is 1.5 mg/kg every 12 hours (Prod Info theophylline oral solution, 2013; Prod Info ELIXOPHYLLIN(R) oral liquid elixir, 2012; Prod Info THEOLAIR(TM) oral tablets, 1998).
c) MAINTENANCE: Individualize to maintain a peak steady-state serum theophylline of 5 to 10 mcg/mL; time to reach steady-state may take 5 days; maintenance dose should not be increased until steady-state is achieved (Prod Info theophylline oral solution, 2013; Prod Info ELIXOPHYLLIN(R) oral liquid elixir, 2012; Prod Info THEOLAIR(TM) oral tablets, 1998).

2) FULL-TERM INFANTS

a) UP TO 52 WEEKS OF AGE: The recommended total daily dose (mg) is ((0.2 x age in weeks) + 5) x (body weight in kg) per day in divided doses every 8 hours (up to 26 weeks of age) or every 6 hours (over 26 weeks of age) (Prod Info theophylline oral solution, 2013; Prod Info ELIXOPHYLLIN(R) oral liquid elixir, 2012; Prod Info THEOLAIR(TM) oral tablets, 1998).
b) MAINTENANCE: Individualize to maintain a peak steady-state serum theophylline of 10 to 15 mcg/mL; time to reach steady-state may take 2 to 3 days; maintenance dose should not be increased until steady-state is achieved (Prod Info theophylline oral solution, 2013; Prod Info ELIXOPHYLLIN(R) oral liquid elixir, 2012; Prod Info THEOLAIR(TM) oral tablets, 1998).

3) 1 YEAR OF AGE AND OLDER

a) LESS THAN 45 KG: The recommended initial dose is 12 to 14 mg/kg/day in divided doses over 4 to 6 hours (MAXIMUM DOSE: 300 mg/day). After 3 days (if tolerated), increase to 16 mg/kg/day in divided doses over 4 to 6 hours (MAXIMUM DOSE: 400 mg/day). After 3 more days (if tolerated and needed), increase to 20 mg/kg/day in divided doses over 4 to 6 hours (MAXIMUM DOSE: 600 mg/day) (Prod Info theophylline oral solution, 2013; Prod Info ELIXOPHYLLIN(R) oral liquid elixir, 2012; Prod Info THEOLAIR(TM) oral tablets, 1998).
b) GREATER THAN 45 KG: The recommended initial dose is 300 mg/day in divided doses over 6 to 8 hours; after 3 days (if tolerated), increase to 400 mg/day in divided doses over 6 to 8 hours; after 3 more days (if tolerated and needed), increase to 600 mg/day in divided doses over 6 to 8 hours (Prod Info theophylline oral solution, 2013; Prod Info ELIXOPHYLLIN(R) oral liquid elixir, 2012; Prod Info THEOLAIR(TM) oral tablets, 1998).

C) INTRAVENOUS

a) UP TO 24 DAYS: The recommended initial dose (after loading dose) is 1 mg/kg IV every 12 hours (Prod Info theophylline in 5% dextrose intravenous injection solution, 2011).
b) OVER 24 DAYS: The recommended initial dose (after loading dose) is 1.5 mg/kg IV every 12 hours (Prod Info theophylline in 5% dextrose intravenous injection solution, 2011).

3) INFANTS

a) 6 TO 52 WEEKS OF AGE: The recommended initial dose (after loading dose) is calculated as mg/kg/hr = (0.008) x (age in weeks) + 0.21 IV (Prod Info theophylline in 5% dextrose intravenous injection solution, 2011).

4) CHILDREN

a) 1 TO 9 YEARS OF AGE: The recommended initial dose (after loading dose) is 0.8 mg/kg/hr (Prod Info theophylline in 5% dextrose intravenous injection solution, 2011).
b) 9 TO 12 YEARS OF AGE: The recommended initial dose (after loading dose) is 0.7 mg/kg/hr (Prod Info theophylline in 5% dextrose intravenous injection solution, 2011).
c) 12 TO 16 YEARS OF AGE, SMOKERS: The recommended initial dose (after loading dose) is 0.7 mg/kg/hr (Prod Info theophylline in 5% dextrose intravenous injection solution, 2011).
d) 12 TO 16 YEARS OF AGE, NONSMOKERS: The recommended initial dose (after loading dose) is 0.5 mg/kg/hr. MAXIMUM DOSE: 900 mg/day (unless serum levels indicate need for larger dose) (Prod Info theophylline in 5% dextrose intravenous injection solution, 2011).
e) 16 YEARS OF AGE AND OLDER, NONSMOKERS: The recommended initial dose (after loading dose) is 0.4 mg/kg/hr. MAXIMUM DOSE: 900 mg/day (unless serum levels indicate need for larger dose) (Prod Info theophylline in 5% dextrose intravenous injection solution, 2011).

Minimum Lethal Exposure

1) VARIABLE-LEVELS RESULTING IN DEATH

a) Four patients died following acute intoxication with variable peak theophylline concentrations of 435, 916, 999, and 1171 mmol/L (78, 165, 18, and 211 mcg/mL) (Shannon, 1999).
b) A 62-year-old developed a peak theophylline level of 144 mcg/mL following an ingestion of 12 g of sustained release theophylline. Treatment included charcoal hemoperfusion. The level of theophylline decreased temporarily, then rebounded and remained relatively constant at greater than 80 mcg/mL over 40 hours. This occurred despite multiple courses of hemoperfusion with an extraction ratio of 0.65. The patient expired 5 days postingestion with multiple organ failure (Amitai & Lovejoy, 1987).

Maximum Tolerated Exposure

1) Serum concentrations do not always accurately predict acute toxicity. Chronicity of the ingestion (chronic toxicity is more severe at a given serum concentration than acute on chronic which is more severe than acute toxicity in a patient not taking theophylline). Underlying disease (particularly cardiac) and advanced age also predispose to increased toxicity at a give serum concentration. However, severe toxicity (ie, seizures, ventricular dysrhythmias, and death) generally occurs at levels greater than 40 to 60 mcg/mL in CHRONIC intoxications and at levels greater than 80 to 100 mcg/mL in ACUTE intoxications (Olson et al, 1983; Gaudreault et al, 1983; Shannon, 1993).

1) LIFE-THREATENING EVENTS

2) LIFE-THREATENING EVENTS AND ELEVATED LEVELS

a) The risk of toxicity appears greater in patients with theophylline concentrations above 25 mcg/mL or with significant coincident risk factors (Emerman et al, 1990).

1) RISK FACTORS: Age, congestive heart failure, ICU admission, prior seizures, or prior antiarrhythmic therapy. This information was derived from a retrospective study of 214 hospitalized patients with 558 episodes of elevated serum theophylline concentrations (Emerman et al, 1990).

b) In one study of Thai children (n=44), it was determined that the possible causes of theophylline toxicity were dose error (n=6), impaired liver function (n=7; test obtained in only 12 patients), drug interactions (n=12), use in neonates (premature n=7; full term n=5), congestive heart failure (n=8), and respiratory tract infection (n=25). Theophylline toxicity was more common in infants, neonates and premature infants because of reduced theophylline clearance in very young children. In addition, clinical evidence of toxicity (eg, nausea, vomiting, GI bleeding, tachycardia, dysrhythmia, seizure, hyperglycemia, hyponatremia, hypokalemia, metabolic acidosis, hypercalcemia) was observed in 34% of patients with theophylline levels of less than 30 mcg/mL and 78% of patients with levels more than 30 mcg/mL (Visitsunthorn et al, 2001).
c) Shannon (1999) reported that a patient survived a serum theophylline level of 1360 mmol/L (245 mcg/mL).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) THERAPEUTIC SERUM LEVELS

a) 10 to 20 mcg/mL (55 to 111 mcmol/L)

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) TOXIC SERUM LEVELS

a) Serum concentrations do not always accurately predict acute toxicity. However, severe toxicity (ie, seizures, ventricular dysrhythmias, and death) generally occurs at levels greater than 40 to 60 mcg/mL in CHRONIC intoxications and at levels greater than 80 to 100 mcg/mL in ACUTE intoxications (Olson et al, 1983; Gaudreault et al, 1983; Shannon, 1993).
b) At serum levels above 20 mcg/mL (111 mcmol/L), there is an increased risk of toxicity.
c) Patients with levels above 30 mcg/mL (166 micromoles/liter) should be observed at least until the level returns to the therapeutic range.
d) Levels above 60 mcg/mL (333 micromoles/liter) are felt by some authors to warrant hemoperfusion, especially in cases of chronic intoxication.
e) ACUTE vs CHRONIC INGESTIONS: Concentrations of theophylline associated with major toxicity differ for acute single ingestions (100 mg/L or 550 mcmol/L) and chronic ingestions (40 mg/L or 220 mcmol/L). Differences in toxic concentration between the two groups probably reflects differences in the rate of accumulation and absolute concentration of intracellular cyclic AMP (Dawson & Whyte, 2001).

2) LIFE THREATENING TOXICITY LEVELS

a) Severity of toxicity of theophylline is not only related to the serum concentration. Chronicity of the ingestion (chronic toxicity is more severe at a given serum concentration than acute on chronic which is more severe than acute toxicity in a patient not taking theophylline). Underlying disease (particularly cardiac) and advanced age also predispose to increased toxicity at a give serum concentration.
b) Life-threatening toxicity was not predictable by serum levels in some studies (Aitken & Martin, 1987), but was predicted by levels of 117.6 mcg/mL after acute overdose in another study (Shannon & Lovejoy, 1989).
c) In a longitudinal cohort study of 356 patients, peak theophylline concentrations among patients who survived and fatalities did not differ significantly (262 vs 306 mmol/L (47 vs 55 mcg/mL) (Shannon, 1999)

3) SERUM LEVEL/SYMPTOM CORRELATION

a) A retrospective review of 20 inpatients with theophylline levels above 20 mcg/mL found no correlation between the theophylline levels and gastrointestinal, central nervous system, or metabolic abnormalities (Bertino et al, 1987).

4) AGE FACTORS

a) PEDIATRIC: A study of 28 cases of acute PEDIATRIC theophylline overdoses reports that children and young adults rarely develop seizures or life-threatening dysrhythmias with theophylline serum concentrations less than 80 mcg/mL (444 mcmol/L) (Gaudreault et al, 1983).
b) Among 125 pediatric patients with theophylline overdoses, 10% developed seizures or arrhythmias (Shannon & Lovejoy, 1992). The mean peak theophylline levels were 100 mcg/mL for acute cases and 42 mcg/mL for chronic and acute-on-chronic cases.
c) ELDERLY: Elderly patients with chronic intoxication are at a much greater risk of developing a life-threatening event than are younger adults (Shannon & Lovejoy, 1990).
d) Seizures, tachycardia, hypokalemia, and hypotension were reported after "acute" overdoses with serum levels greater than 100 mcg/mL, but patients with "chronic" accidental overdoses seized at levels greater than 40 mcg/mL (Olson et al, 1985).
e) Dean and Brown (1982) reported a case of a 58-year-old woman who survived a theophylline level of 203 mcg/mL (1126 mcmol/L) following ingestion of 12.8 g of anhydrous theophylline without hemoperfusion. The patient experienced ventricular ectopy, supraventricular tachycardia, hypotension, two grand mal seizures, bradycardia, and loss of consciousness.

5) CASE REPORTS

a) SUSTAINED RELEASE PRODUCTS

1) GENERAL: Overdosage with SUSTAINED RELEASE/ACTION preparations appear to result in severe and prolonged CNS and cardiovascular toxicity (Connell et al, 1982). Shannon & Woolf (1991a) reported that theophylline concentrations can continue to rise for up to 16 hours after acute ingestion of a sustained-release product. Development of seizures and dysrhythmias was correlated with a more rapid rate of rise (6.3 mcg/mL/hour vs 1.5 mcg/mL/hour).

a) A 62-year-old developed a peak theophylline level of 144 mcg/mL following an ingestion of 12 g of sustained release theophylline. Treatment included charcoal hemoperfusion. The level of theophylline decreased temporarily, then rebounded and remained relatively constant at greater than 80 mcg/mL over 40 hours. This occurred despite multiple courses of hemoperfusion with an extraction ratio of 0.65. The patient expired 5 days postingestion with multiple organ failure (Amitai & Lovejoy, 1987).

b) BAMIFYLLINE

1) POSTMORTEM serum bamifylline level was 205 mcg/mL in one case of bamifylline overdose (Offidani et al, 1993).

6) ANIMAL DATA

a) Recent animal experiments in rats reveal that CSF concentrations correlate with the site of action responsible for theophylline-induced seizures, more closely than serum or homogenized brain (Razman & Levy, 1986).

Toxicity Information

7.7.1)

A) ANIMAL DATA

1) LD50- (INTRAMUSCULAR)MOUSE:

a) 271 mg/kg (RTECS, 2001)

2) LD50- (INTRAPERITONEAL)MOUSE:

a) 70 mg/kg (RTECS, 2001)

3) LD50- (ORAL)MOUSE:

a) 235 mg/kg (RTECS, 2001)

4) LD50- (SUBCUTANEOUS)MOUSE:

a) 138 mg/kg (RTECS, 2001)

5) LD50- (INTRAPERITONEAL)RAT:

a) 150 mg/kg (RTECS, 2001)

6) LD50- (ORAL)RAT:

a) 225 mg/kg (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

Toxicologic Mechanism

Physicochemical

Animal Toxicology

Kinetics

11.5.1)

A) LACK OF INFORMATION

1) There was no specific information on absorption at the time of this review.

11.5.4)

A) HORSE

1) Theophylline plasma concentrations decreased triexponentially. The first distribution T1/2 was 3.5 to 4 minutes. The second distribution phase was 1.5 to 2 hours. The overall T1/2 was 9.7 to 19.3 hours (Ayres et al, 1985). This was after IV infusion of 10 mg aminophylline per kilogram body weight.

References

General Bibliography

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THEOPHYLLINE

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Cardiovascular

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Hematologic

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Endocrine

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Monitoring Parameters Levels

Methods

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Case Reports

Summary

Therapeutic Dose

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Toxicity Information

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General Bibliography