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Theophylline poisoning

Theophylline poisoning
Literature review current through: Jan 2024.
This topic last updated: Aug 16, 2022.

INTRODUCTION — This topic will review the clinical features and management of theophylline overdose in infants, children, and adults.

EPIDEMIOLOGY — Historically, theophylline has had two primary indications: as a bronchodilator for patients with asthma or chronic obstructive pulmonary disease and as an agent to treat apnea and bradycardia in premature newborns.

Nevertheless, theophylline remains an important drug:

It is still used within the United States to treat apnea and bradycardia of prematurity and remains widely used in countries outside the United States as a bronchodilator.

Other indications that have been explored include treatment of postlumbar puncture headache [1], prevention of nephropathy due to contrast agents [2], lymphedema [3], out-of-hospital cardiac arrest [4], prevention of obstructive sleep apnea [5], reversal of bradycardia in spinal cord injury patients [6], and hyposmia (loss of smell) [7].

Most theophylline exposures are unintentional and occur in patients over 20 years of age [8]. Oral overdose of sustained release preparations is most commonly reported [9,10]. As therapeutic use has declined, the frequency of serious theophylline poisoning has also decreased. Over eight years, the number of annual cases of theophylline exposure reported to United States poison control centers decreased from 1395 to 347 [11,12]. In the United States during the period of 1985 to 1995, theophylline poisoning requiring hemodialysis or hemoperfusion accounted for 49 cases per one million poison center calls, versus only 6 cases per one million poison center calls from 1996 to 2005 [13]. Only 140 exposures and one death were reported to United States poison control centers in 2020 [14]. However, life-threatening theophylline poisoning remains a concern, especially in older adults.

PHARMACOLOGY AND CELLULAR TOXICOLOGY

Therapeutic serum levels and dosing — The therapeutic steady state serum concentration for theophylline ranges from 10 to 20 mcg/mL (56 to 111 micromol/L) when used to treat asthma. Other indications have lower therapeutic ranges. Theophylline has a narrow clinical therapeutic index (ratio of 50 percent toxic dose to 50 percent effective dose) of 1 to 1.5. Theophylline is available as an elixir, extended release capsule, and controlled release tablet.

The intravenous form of the drug, aminophylline, is a 2:1 complex of theophylline and ethylenediamine. It contains approximately 80 percent theophylline by weight.

Theophylline metabolism, and consequently half-life, shows a wide variation as a function of age. Clearance is low at birth, increases dramatically after six months of age, peaks at age two years, and then gradually falls to adult levels by age 16 years. Thus, intravenous and oral maintenance dosing is highly variable. In addition, the narrow therapeutic index requires frequent evaluation of serum theophylline concentration in individual patients to ensure safe administration.

Toxic dose — Manifestations of acute toxicity (eg, vomiting) may occur with ingested or administered doses as low as 7.5 mg/kg (expected peak level 15 mcg/mL [84 micromol/L]).

Since chronic theophylline toxicity often results from accumulation of the drug due to saturation of the metabolic pathways, decreased clearance, and/or inhibition by coadministered drugs or herbal medications, serious toxicity may occur despite regular daily dosing within the normal range for weight. (See 'Kinetics' below.)

Mechanism of action — Theophylline's effects arise from antagonism of adenosine receptors and indirect adrenergic activity.

Adenosine receptors are widely distributed throughout the body. Antagonism of these receptors has both therapeutic and toxic effects, including:

Bronchodilation

Tachycardia

Cardiac arrhythmias

Seizures

Cerebral vasoconstriction [15-17]

Theophylline intoxication has also been shown to be associated with increased plasma catecholamines in animal models [18,19] as well as in case series of human victims of theophylline intoxication [20,21]. The magnitude of catecholamine elevation and the specific catecholamines released vary depending on the type of intoxication:

Acute intoxication has been shown to be associated with epinephrine concentrations four- to eightfold higher than controls and norepinephrine concentrations four- to tenfold higher than controls [20,21].

In the few patients with chronic overdose who have been studied, norepinephrine and dopamine levels were elevated compared with normal patients [20].

At toxic concentrations, theophylline is a phosphodiesterase inhibitor. Phosphodiesterase inhibition increases levels of cyclic adenosine monophosphate, which augments beta-adrenergic effects. Adrenergic hyperstimulation results in the metabolic abnormalities frequently seen with theophylline intoxication (eg, hypokalemia, hyperglycemia, metabolic acidosis). Excess catecholamines may also predispose to arrhythmias as well as contribute to hypotension through beta-adrenergic-mediated vasodilation.

KINETICS — Theophylline is notable for having a low volume of distribution, high absorption, and highly variable metabolism that is altered by age, viral illness, cardiac failure, and liver disease. Chronic intoxication is typically due to theophylline's complicated metabolism. At levels only slightly above therapeutic range, its kinetics converts from first order to zero order. This conversion causes small changes in either dosing or metabolism to result in large changes in serum concentration.

Absorption – When taken orally, theophylline is 80 to 100 percent absorbed, and there is no significant first-pass metabolism.

Protein bindingTheophylline is 50 to 65 percent protein bound in the circulation.

Volume of distributionTheophylline has a relatively small volume of distribution (Vd) of 0.45 L/kg. The Vd is slightly larger at the extremes of age [22]. These factors allow the clinician to accurately estimate the anticipated peak level following an acute ingestion of theophylline. For every 1 mg/kg ingested, the peak level is expected to rise 2 micrograms/mL. Similarly, since 1 mg of aminophylline is equivalent to 0.8 mg of theophylline, each 1.2 mg/kg administered intravenously is anticipated to raise the serum level of theophylline 2 microgram/mL.

MetabolismTheophylline metabolism and half-life show a wide variation as a function of age. Clearance is low at birth, increases dramatically after six months of age, peaks at age two years, and then gradually falls to adult levels by age 16 years.

In newborns, 50 percent is excreted unchanged in the urine with the remainder being metabolized in the liver [22]. Because the mixed function oxidase system is not mature, N-methylation to caffeine is an important metabolic pathway. Caffeine accumulates in newborns on theophylline treatment [22,23].

As the mixed function oxidase system develops, approximately 90 percent is metabolized through that system by CYP1A2, CYP2E1, and CYP3A4. Changes in metabolism translate into a half-life, which is a function of age. In premature infants, half-life is 30 hours, falling to 25 hours in term infants, three hours in young children, and gradually rising to an adult half-life of eight hours by age 16 years [22].

For all ages, theophylline metabolism follows Michaelis-Menten (saturable) kinetics. Over the therapeutic range, metabolism follows first order kinetics (ie, 50 percent of the drug is metabolized during one half-life). Slightly above the therapeutic range, however, the kinetics shift to zero order (ie, a set amount of drug is metabolized per unit time) and small increases in theophylline dosing can lead to rapid increases in serum concentrations.

Drug interactions – Metabolism of theophylline is affected by any process that alters activity of the cytochrome oxidases CYP1A2, CYP2E1, and CYP3A4 located in the liver. These isoenzymes have been shown to be inhibited by a wide variety of intercurrent diseases such as upper respiratory infections associated with fever, as well as a large number of pharmaceuticals including cimetidine, ciprofloxacin, erythromycin, clarithromycin, and verapamil [22]. Herbal preparations (eg, St. John's wort) have also been shown to interfere with theophylline metabolism (table 1) [24]. Concurrent use of theophylline and a number of drugs (eg, cimetidine) has been shown to be associated with a significantly increased risk of hospitalization [25]. Thus, prior to prescribing a new agent to a patient who is chronically on theophylline, it is prudent to check that there is no documented inhibition of the mixed function oxidase system.

CLINICAL FEATURES OF OVERDOSE — A rapid overview provides the common clinical findings after theophylline poisoning (table 2).

History — Theophylline intoxication is classified as acute or chronic. It is one of a handful of drugs where the method of intoxication (ie, acute versus chronic) has significant implications both for clinical presentation as well as for management. (See 'Extracorporeal removal' below.)

Three common scenarios that result in theophylline intoxication include:

The patient intentionally overdoses acutely either as an exploratory ingestion (toddler) or suicide attempt (school age and older).

An inadvertent substitution of aminophylline for another medication.

A patient on maintenance therapy develops toxic levels secondary to a decrease in theophylline metabolism, usually due to addition of another drug or an intercurrent illness.

Physical findings — Symptoms can be grouped into five major areas: metabolic, musculoskeletal, gastrointestinal, cardiac, and neurologic. The spectrum of toxicity varies widely. Patients suffering from chronic intoxication may have few initial symptoms but are at risk for major complications including arrhythmias and seizures. Minor symptoms include metabolic abnormalities, coarse muscle tremor, vomiting, and abdominal pain. Seizures, hypotension, and arrhythmias are the life-threatening symptoms seen following intoxication. Death typically results from intractable ventricular arrhythmias [26].

Morbidity correlates with serum theophylline concentration in patients with acute toxicity but not in patients with chronic toxicity where extremes of age are more predictive. (See 'Ancillary studies' below.)

In a prospective observational study of 249 children and adults with theophylline overdose, major toxicity (seizures or cardiac arrhythmias) was significantly associated with serum theophylline concentration in patients with acute overdose (n = 119) but not in patients with chronic overdose (n = 92). Age greater than 60 years was the best predictor of serious toxicity in patients with chronic toxicity [26].

Chronic intoxication was the primary risk factor for life-threatening events in a prospective observational study of 125 pediatric victims of theophylline toxicity [27]. Victims of chronic intoxication who suffered life-threatening events were significantly younger (1.6 versus 8.0 years; p<0.001) but did not have higher peak theophylline levels. In contrast, those children who were victims of an acute overdose with life-threatening events had significantly higher peak serum theophylline concentrations (100 versus 57 micrograms/mL [550 versus 319 micromols/L]; p<0.004), and age was not a risk factor [27].

Metabolic — Hypokalemia and hyperglycemia are seen frequently in patients with theophylline intoxication (79 percent acute versus 43 percent chronic) [9]. They result from adrenergic stimulation and are rarely clinically important. Other metabolic abnormalities less commonly seen include metabolic acidosis [28], hypercalcemia [29], and hypophosphatemia [30].

Musculoskeletal — Coarse tremor is another minor symptom that is frequently noted [31] and thought to result from disturbances in skeletal muscle homeostasis of potassium. Rhabdomyolysis has also been noted in 4 to 7 percent of adults with theophylline toxicity [9,30,32].

Gastrointestinal — Vomiting or abdominal pain occurs almost universally following acute overdose (79 to 97 percent) [30,33] and less commonly following chronic overmedication (40 to 66 percent) [9,30]. Vomiting tends be persistent [34] and difficult to control [10]. It may interfere with the ability to administer multiple-dose activated charcoal successfully and can be forceful enough to result in a Mallory-Weiss tear [30]. (See "Mallory-Weiss syndrome".)

Neurologic — Seizures are the most concerning of the neurologic symptoms following theophylline poisoning and may be the first sign of toxicity, particularly in infants or in patients with chronic poisoning. Seizures are most frequently multiple and generalized, focal seizures and simple complex with secondary generalization also occur, most commonly in patients with chronic toxicity [30]. Several authors have suggested that underlying neurologic abnormalities may be a risk factor for development of seizures [35,36].

Seizures are a concerning finding in adults because they can be difficult to control [30], may have significant morbidity, and, in older adults, mortality as high as 50 percent [37-39].

In contrast, case series indicate that most seizures in children are easily controlled by benzodiazepines and occur in approximately 5 percent of patients [27,33,40]. Although there was no long-term follow-up to evaluate for neurological sequelae reported for these children, our experience suggests that full recovery should be expected if children do not experience prolonged hypoxemia or hypotension.

Lethargy and visual hallucinations are less common neurologic findings in patients with theophylline poisoning [33].

Cardiovascular — With the exception of sinus tachycardia, which is seen in most patients [9,30,33], cardiac manifestations of theophylline toxicity appear to be quite different between adults and children:

Intractable ventricular arrhythmias are the most common cause of death in adults and occur in 2 to 20 percent of patients studied [9,26,30].

In contrast, children are most likely to have supraventricular tachycardia or multifocal premature ventricular or atrial contractions [27,33,40]. Transient alterations in blood pressure have also been reported [33,40].

ANCILLARY STUDIES — The clinician should obtain the following studies on an emergency basis in patients with suspected theophylline poisoning (table 2):

Theophylline levels – If a sustained-release preparation has been ingested acutely, the theophylline level should be measured every two hours until it peaks and then every four hours up to 24 hours after ingestion. In situations where an unknown formulation was ingested, the clinician should always assume that a sustained-release preparation is the toxic agent. The wax-matrix found in many sustained-release preparations can result in bezoar formation with erratic and delayed absorption, sometimes with lethal consequences [10,41].

In patients with chronic theophylline poisoning, once a peak elevated level is established, theophylline levels should be assessed on a daily basis until clinical signs resolve.

Serum glucose – Hyperglycemia is found in the majority of patients with serious acute theophylline poisoning.

Serum electrolytes – Theophylline toxicity results in hypokalemia and metabolic acidosis with decreased serum bicarbonate.

Serum calciumTheophylline poisoning is associated with hypercalcemia.

Electrocardiogram – An initial 12-lead electrocardiogram (ECG) is essential to evaluate for the presence of rhythm disturbance and, in adult patients, evidence of myocardial ischemia. Continuous cardiac monitoring is also warranted.

Additional studies may be indicated depending on patient characteristics:

Serum acetaminophen level in patients who ingest theophylline with intent for self-harm.

Serum aspartate transferase (AST), alanine transferase (ALT), prothrombin time, and partial thromboplastin time in patients with suspected baseline alteration in liver function.

Rapid urine pregnancy test in postmenarcheal women.

Serum salicylate concentration, serum iron concentration, and urine screen for drugs of abuse in patients with an unknown ingestion and clinical findings suggestive of theophylline poisoning.

DIAGNOSIS — The diagnosis of acute theophylline poisoning is suspected in patients with a history of ingestion or access to theophylline and/or clinical findings of overdose including vomiting, agitation, tremors, seizures, tachyarrhythmias, hypotension, or hypokalemia with metabolic acidosis. An elevated theophylline level confirms the diagnosis.

Patients with chronic intoxication may present with few overt symptoms despite a markedly elevated theophylline level. Seizures may be the first clinical manifestation of toxicity in these patients.

DIFFERENTIAL DIAGNOSIS — Theophylline toxicity should be considered in any patient presenting with seizures, agitation, tachyarrhythmias, hypotension, or persistent vomiting, particularly if there is hypokalemia and hyperglycemia. Other toxic agents to consider in patients with these symptoms include:

Beta-2 adrenergic agonists – Agents such as albuterol (also known as salbutamol), clenbuterol, and terbutaline also cause vomiting, sinus tachycardia, muscle tremor, hypokalemia, hyperglycemia, and metabolic acidosis in overdose. However, seizures and cardiac arrhythmias are rare [42].

Cocaine and amphetamines – Cocaine or amphetamine intoxication may cause agitation, seizures, cardiac arrhythmias, and tremulousness. However, hypertension, diaphoresis, and hyperthermia are additional features of severe poisoning with these agents that are not commonly seen in patients with theophylline poisoning. Furthermore, vomiting, an early and prominent finding in acute theophylline overdose, is not commonly seen in patients with cocaine or amphetamine intoxication. (See "Cocaine: Acute intoxication", section on 'Clinical manifestations' and "Methamphetamine: Acute intoxication", section on 'Examination findings associated with intoxication and complications'.)

Iron – Vomiting is an early and consistent sign of iron poisoning and may be accompanied by leukocytosis, hyperglycemia, metabolic acidosis, sinus tachycardia, and hypotension. Severe iron overdose typically causes coma and cardiogenic shock. Seizures are less common. (See "Acute iron poisoning".)

Salicylates – Vomiting, sinus tachycardia, hypotension, altered mental status with coma or seizures, and hyperglycemia are potential findings after salicylate poisoning. However, salicylates typically cause a respiratory alkalosis with marked tachypnea soon after an acute overdose. Hyperthermia may be seen in patients with severe poisoning. (See "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation".)

MANAGEMENT — Recommendations for care of children and adults with theophylline poisoning are derived from case series and reports. Management is determined by signs of poisoning, the peak serum theophylline concentration following acute overdose, and, in chronic overdoses, physical findings and age. Management is summarized in the rapid overview (table 2).

Good outcomes in these patients depend on supportive care that focuses on the metabolic, cardiovascular, and neurologic manifestations of toxicity and timely use of elimination enhancement.

Supportive care

Hypokalemia and metabolic acidosis — Hypokalemia and metabolic acidosis arise from catecholamine excess and are rapidly reversible by appropriate enhancement of theophylline elimination. (See 'Mechanism of action' above.)

We suggest potassium supplementation (eg, 40 mEq KCL/L in intravenous fluids run at 1 to 1.5 times maintenance) for hypokalemic theophylline poisoned patients with potassium <3 mEq/L or with ventricular arrhythmias [43]. In patients with theophylline poisoning, hypokalemia typically reflects a shift of potassium into the tissues rather than total body potassium depletion. Thus, the need for potassium supplementation decreases as the theophylline concentration decreases, and close monitoring of serum potassium levels and reduction of potassium supplementation is important. Mild hyperkalemia frequently results from potassium replacement [10].

Metabolic acidosis after theophylline poisoning rarely requires specific intervention (eg, administration of sodium bicarbonate), unless severe (eg, pH <7).

Vomiting — Emesis in patients with theophylline poisoning is frequently persistent and difficult to treat but must be controlled to permit administration of multiple-dose activated charcoal [44].

We suggest that patients with theophylline poisoning and persistent vomiting receive high-dose ondansetron (initial dose: 0.15 mg/kg up to 16 mg intravenously). This recommendation is based on case reports that describe reduced vomiting in patients who received ondansetron after standard antiemetics, including phenothiazines and metoclopramide, were ineffective [45,46].

Metoclopramide intravenously may be used in addition to ondansetron or as an alternative agent. If used as a single agent, however, high doses (up to 0.5 to 1 mg/kg, maximum dose 50 mg) may be necessary [47]. High doses have been associated with acute dystonic reactions and may be treated with diphenhydramine.

In addition to an antiemetic, we suggest that patients with theophylline poisoning and vomiting receive the H2 blocker famotidine. H2 blockers are an important adjunct because they decrease theophylline-induced gastric acid hypersecretion [48]. Famotidine has the theoretical advantage over cimetidine in not interfering with theophylline metabolism at cytochrome 3A4.

Hypotension — Hypotension is caused by beta-2 adrenergic stimulation and vasodilation. Initial treatment consists of rapid infusion of isotonic saline (initial dose: 20 mL/kg, up to 1 L) and treatment of any cardiac arrhythmias (algorithm 1 and algorithm 2 and algorithm 3). (See 'Cardiac arrhythmias' below.)

If hypotension is not responsive to fluid administration and/or treatment of cardiac arrhythmias, a pure alpha-adrenergic agonist (such as phenylephrine) or a predominant alpha-adrenergic agonist (such as norepinephrine) should be used. Selective beta-adrenergic agonists (such as dobutamine) and mixed alpha-beta adrenergic agonists (such as epinephrine) should not be used, as many of the cardiovascular derangements of theophylline toxicity are caused by cellular effects that may be exacerbated by beta-2 adrenergic agonism.

For patients refractory to the above measures, hypotension may also be reversed by propranolol [18,49] or other beta-adrenergic antagonists such as esmolol. Propranolol must be used cautiously in patients with asthma or chronic obstructive pulmonary disease. The decision to use a beta-adrenergic antagonist to treat a hypotensive patient is very difficult, and should only be made in consultation with a medical toxicologist. In the United States, call 1-800-222-1222 to be connected to the nearest poison control center. Contact information for poison centers around the world is provided separately. (See 'Additional resources' below.)

Cardiac arrhythmias — Arrhythmias should be treated initially according to advanced cardiac life support or pediatric advanced life support recommendations (algorithm 1 and algorithm 3). Arrhythmias are much more common in adults, especially older adults, than in children [9,26,40]. Supraventricular tachycardia and other atrial tachycardias are the most common arrhythmias induced by theophylline [26]. Ventricular arrhythmias are rare in children [50].

Supraventricular tachycardia – Pharmacologic or electrical cardioversion should be performed according to advanced cardiac life support or pediatric advanced life support recommendations (algorithm 1 and algorithm 3).

Rapid intravenous infusion of adenosine (0.1 mg/kg, maximum initial: dose 6 mg) has reversed theophylline-induced supraventricular tachycardia (SVT) [51] and is recommended as first-line therapy by some experts [43,47]. Given that theophylline is a potent adenosine antagonist, however, treatment failure should be anticipated. Adenosine's ultra-short half-life may also leave the patient susceptible to recurrent SVT. In addition, adenosine poses a risk for bronchoconstriction in patients with asthma or chronic obstructive pulmonary disease [52].

Alternatively, esmolol, a selective beta-1 antagonist, is safe for use in theophylline-poisoned patients with asthma and has also been used effectively to terminate supraventricular tachycardia [52,53]. In children, the dose is 100 to 500 mcg/kg, intravenously, given over one minute. In adults, rapid intravenous infusion of 500 mcg/kg over one minute is followed by a continuous infusion of 50 mcg/kg infusion for at least four minutes.

In adults, intravenous therapy with calcium channel blockers (eg, verapamil, initial dose 2.5 to 5 mg; or diltiazem 0.25 mg/kg, typical initial dose 20 mg) may be useful but should be administered with caution in patients with hypotension. (See "Calcium channel blockers in the treatment of cardiac arrhythmias", section on 'Supraventricular tachycardia'.)

Calcium channel blockers should be avoided in infants and children under three years of age with SVT because these agents may cause hypotension, myocardial depression, sudden cardiovascular collapse, and death.

Ventricular arrhythmias – Patients with ventricular fibrillation or pulseless ventricular tachycardia should receive defibrillation and medication administration according to the advanced cardiac life support or pediatric advanced life support recommendations (algorithm 4 and algorithm 5).

In patients with stable ventricular tachycardia, lidocaine or amiodarone may be administered. Selective beta adrenergic antagonists (eg, esmolol) or, in patients without asthma or chronic obstructive pulmonary disease, nonselective beta adrenergic antagonists (eg, propranolol) are adjunct therapies that target the catecholamine excess seen in patients with theophylline overdose. In addition, patients with ventricular arrhythmias and hypokalemia warrant intravenous potassium supplementation. (See 'Hypokalemia and metabolic acidosis' above.)

Although successful treatment of theophylline-induced ventricular arrhythmias with amiodarone has not been described, this approach seems reasonable given that intravenous amiodarone has a rapid onset of an antiadrenergic effect. (See "Amiodarone: Clinical uses".)

Seizures — Patients with seizures require treatment for status epilepticus as described in the algorithm for children (algorithm 6) and adults (algorithm 7) and are discussed in detail separately. (See "Management of convulsive status epilepticus in children" and "Convulsive status epilepticus in adults: Management" and "Refractory status epilepticus in adults".)

Phenytoin or fosphenytoin should be avoided in all patients with theophylline-induced seizures because it has not been effective at terminating seizures in human victims [30] and, in animal models, leads to increased mortality [54].

Patients with the following characteristics may also benefit from prophylactic anticonvulsant therapy with either benzodiazepines (eg, lorazepam) or phenobarbital because of the high likelihood that seizures will develop [22]:

Evidence of neuromuscular excitability

Acute overdose with serum theophylline concentration ≥80 micrograms/mL (448 micromol/L)

Infants <6 months old or adults ≥65 years of age with chronic intoxication and a serum theophylline concentration ≥30 micrograms/mL (168 micromol/L)

Gastrointestinal decontamination — Theophylline binds well to activated charcoal (AC). Theophylline also is cleared more rapidly from the blood in patients who receive multiple-dose AC. (See 'Multiple-dose activated charcoal' below.)

For all patients with an acute theophylline overdose, we recommend an initial dose of AC (1 g/kg, maximum dose: 50 g) by mouth or, after consultation with a medical toxicologist, nasogastric tube (table 2). AC should be withheld in patients who have altered mental status and may not be able to protect their airway, unless endotracheal intubation is performed first. However, endotracheal intubation should not be performed solely for the purpose of giving AC.

The recommendation of AC administration following theophylline overdose derives from direct evidence that multiple doses of AC increase the clearance of theophylline from the blood stream and appear to shorten the duration of toxicity. (See 'Multiple-dose activated charcoal' below.)

There is also indirect evidence of benefit in volunteers, animal studies, and evidence of benefit following ingestions of other medications. Because of adverse effects, such as vomiting and dehydration, the combination of a cathartic (eg, sorbitol) and AC should be used sparingly, if at all, and only a single dose of a cathartic should be given to any patient. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Cathartics' and "Gastrointestinal decontamination of the poisoned patient", section on 'Activated charcoal'.)

There is no role for gastric emptying by gastric lavage or by syrup of ipecac-induced emesis in patients who ingest theophylline. Randomized controlled trials show minimal benefit and possible risk to patients who undergo gastric emptying after poisoning. (See "Gastrointestinal decontamination of the poisoned patient".)

The use of whole bowel irrigation (WBI) in patients who have ingested sustained-release preparations of theophylline is controversial. The American Academy of Clinical Toxicologists and the European Association of Poison Control Centers and Clinical Toxicologists determined that a toxic ingestion of a sustained release preparation is a possible indication for WBI [55]. However, animal models of WBI for sustained release theophylline ingestion did not demonstrate any benefit [56,57]. Because WBI requires a nasogastric tube and may also promote vomiting, we do not routinely use it in the treatment of theophylline poisoning.

Elimination enhancement — After gastrointestinal decontamination, elimination enhancement is indicated for patients with symptomatic theophylline poisoning and for asymptomatic patients with significantly elevated theophylline levels regardless of symptoms.

Multiple-dose activated charcoal — For patients with symptomatic theophylline poisoning, we recommend multiple-dose activated charcoal (MDAC) (table 2). When administering MDAC, the initial dose of 1 g/kg of activated charcoal with or without sorbitol is followed by 0.5 to 1 g/kg of activated charcoal in aqueous suspension without sorbitol every two to four hours. High-dose antiemetic therapy and use of a nasogastric tube are frequently necessary to ensure effective administration. Multiple doses of sorbitol may produce profound dehydration and life-threatening hypernatremia, and inadvertent administration of multiple doses of sorbitol must be avoided. (See "Enhanced elimination of poisons", section on 'Multiple-dose activated charcoal' and "Gastrointestinal decontamination of the poisoned patient", section on 'Cathartics'.)

The recommendation for MDAC is based on the following observations:

A crossover trial in six healthy adults who received intravenous aminophylline demonstrated that repeated doses of AC reduced the serum half-life for theophylline by 50 percent [58].

A crossover trial in seven healthy adults who received intravenous aminophylline found that repeated doses of AC significantly reduced the serum half-life for theophylline from 10.2 to 4.6 hours [59].

MDAC markedly reduced the half-life of theophylline in four severely poisoned adults with theophylline overdose including a 72-year-old man with a serum theophylline of 31 mcg/mL (172 micromol/L), cardiac arrhythmias, and seizures whose half-life decreased from 34.4 to 5.7 hours with rapid resolution of clinical toxicity after MDAC therapy [59].

In addition to directly binding theophylline in the gut, the effect of MDAC appears to occur through a process termed "gastrointestinal dialysis": promotion of back diffusion of theophylline from the blood to the intestinal lumen where it is bound to charcoal. This mechanism of action is supported by the ability of MDAC to decrease the half-life of theophylline despite intravenous administration in humans and by the impact of luminal AC on intestinal theophylline diffusion in a rat model [50,59,60].

Extracorporeal removal — In patients with severe life-threatening theophylline poisoning (exhibiting seizures, cardiac arrhythmias, or hypotension) or with markedly elevated theophylline levels, regardless of symptoms (table 3) and those with symptomatic theophylline poisoning but without a functioning gastrointestinal tract, we recommend extracorporeal removal (ECR) [26,61]. For patients receiving ECR, we suggest high efficiency hemodialysis rather than hemoperfusion or continuous kidney replacement therapy. Whenever possible, ECR should be used to treat patients with severe theophylline poisoning before seizures or cardiac arrhythmias develop because hemodialysis or hemoperfusion has not been shown to reliably terminate these life-threatening events [62]. When deciding about the initiation of ECR in patients with severe theophylline poisoning, we encourage consultation with a medical toxicologist or regional poison control center. (See 'Additional resources' below.)

Although high efficiency hemodialysis is strongly preferred, if it is not available or feasible, other modalities (such as hemoperfusion or continuous kidney replacement therapy) may be used instead. In neonates who are too ill to withstand hemodialysis, hemoperfusion, or continuous kidney replacement therapy, triple volume exchange transfusions may be effective [63]. Peritoneal dialysis removes theophylline but too slowly to have a role in the treatment of theophylline poisoning [64].

Theophylline has the physical characteristics (low volume of distribution without extensive protein binding) that make it amenable to ECR. The risk for developing life-threatening arrhythmias or seizures after theophylline overdose varies based on type of poisoning (acute versus chronic), serum theophylline concentration in acutely poisoned patients, and individual patient factors [26,47,61,65,66]. Historically, charcoal hemoperfusion has been considered as a treatment modality for theophylline toxicity. However, high efficiency hemodialysis is as effective as charcoal hemoperfusion for removing theophylline from the bloodstream, is safer, and is more readily available [52,62,67].

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment" and "Society guideline links: Treatment of acute poisoning caused by specific agents other than drugs of abuse".)

SUMMARY AND RECOMMENDATIONS

Rapid overview – A rapid overview (table 2) provides the clinical features, diagnostic evaluation, and initial management of theophylline poisoning. (See 'Management' above.)

Mechanism of actionTheophylline's toxic effects arise from antagonism of adenosine receptors and indirect adrenergic activity. (See 'Mechanism of action' above.)

Toxic dose – After acute overdose, manifestations of theophylline toxicity may occur with an ingested or administered dose >7.5 mg/kg (expected peak serum theophylline concentration >15 mcg/mL [84 micromol/L]). Patients with chronic toxicity can have serious toxicity despite regular daily dosing within the normal range for weight. (See 'Toxic dose' above and 'Clinical features of overdose' above and 'Ancillary studies' above.)

Clinical features – Clinical features of theophylline poisoning include (see 'Clinical features of overdose' above):

Vomiting

Abdominal pain

Coarse muscle tremor

Seizures

Hypotensive shock

Cardiac arrhythmias

Death typically results from intractable ventricular arrhythmias.

Ancillary studies – Patients with suspected theophylline poisoning require the following studies (see 'Ancillary studies' above):

Theophylline level; for acute ingestion of a sustained-release or unknown preparation, measure every two hours until it peaks and then every four hours for the first 24 hours

Serum glucose

Serum electrolytes

Serum calcium

ECG

Other studies may also be indicated depending upon the clinical situation as described above.

Diagnosis – The diagnosis of acute theophylline poisoning is suspected in patients with a history of ingestion or access to theophylline and/or clinical findings of overdose including vomiting, agitation, tremors, seizures, tachyarrhythmias, hypotension or hypokalemia with metabolic acidosis.

Patients with chronic intoxication may present with few overt symptoms despite a markedly elevated theophylline level. Seizures may be the first clinical manifestation of toxicity in these patients. (See 'Diagnosis' above and 'Differential diagnosis' above.)

Gastrointestinal decontamination – For all patients with an acute theophylline overdose, we recommend an initial dose of activated charcoal (AC, 1 g/kg, maximum dose 50 g) by mouth or nasogastric tube (Grade 1B). AC should be withheld in patients who have altered mental status and may not be able to protect their airway, unless endotracheal intubation is performed first. There is no role for gastric emptying (gastric lavage or syrup of ipecac). (See 'Gastrointestinal decontamination' above.)

Elimination enhancement

Multiple-dose activated charcoal (MDAC) – For patients with signs or symptoms of theophylline poisoning, we recommend MDAC (Grade 1B). When administering MDAC, the clinician should avoid inadvertent administration of multiple doses of sorbitol that can cause life-threatening hypernatremia and severe dehydration. High-dose antiemetic therapy and use of a nasogastric tube are frequently necessary to ensure effective administration. (See 'Multiple-dose activated charcoal' above.)

Hemodialysis – We encourage clinicians to seek advice from a medical toxicologist or regional poison control center when making decisions about the initiation of extracorporeal removal (ECR) in patients with severe theophylline poisoning (see 'Additional resources' above). Whenever possible, start ECR before seizures or cardiac arrhythmias develop.

For patients with severe life-threatening theophylline poisoning as described in the table (table 3), we recommend ECR in addition to MDAC (Grade 1C). For patients undergoing ECR for theophylline poisoning, we suggest high efficiency hemodialysis rather than hemoperfusion or continuous kidney replacement therapy; charcoal hemoperfusion or CRRT are alternative methods if hemodialysis is not feasible (Grade 2C). (See 'Extracorporeal removal' above.)

In neonates who are too ill to withstand hemodialysis, hemoperfusion, or continuous kidney replacement therapy, triple volume exchange transfusions in addition to MDAC may be effective.

Supportive care

Hypokalemia and metabolic acidosis – Treatment of hypokalemia and metabolic acidosis are rapidly reversed by effective theophylline elimination enhancement. We give potassium supplementation (eg, 40 mEq KCL/L in intravenous fluids run at 1 to 1.5 times maintenance) for hypokalemic theophylline poisoned patients with potassium <3 mEq/L or those with ventricular arrhythmias. (See 'Hypokalemia and metabolic acidosis' above.)

Persistent vomiting – We suggest that patients with theophylline poisoning and persistent vomiting receive high-dose ondansetron (initial dose: 0.15 mg/kg up to 16 mg intravenously) rather than phenothiazines or metoclopramide (Grade 2C). An ECG should be obtained to screen for a prolonged QTc prior to ondansetron administration. In addition to an antiemetic, we suggest that patients with theophylline poisoning and vomiting receive famotidine (Grade 2C). (See 'Vomiting' above.)

Hypotension and cardiac arrhythmias – Initial treatment for hypotension consists of rapid infusion of isotonic saline or balanced crystalloid solution such as lactated Ringer. Manage cardiac arrhythmias according to advanced cardiac life support or pediatric advanced life support recommendations (algorithm 1 and algorithm 2 and algorithm 3).

For patients who require continuous infusions of vasoactive medications, we suggest norepinephrine or phenylephrine as first-line therapies (Grade 2C). If shock is refractory to these measures, use of beta-blockers (eg, propranolol or esmolol) in consultation with a medical toxicologist may be effective but requires caution in patients with asthma or chronic obstructive pulmonary disease. Epinephrine and dobutamine should be avoided. (See 'Hypotension' above and 'Cardiac arrhythmias' above.)

Seizures – Patients with seizures require treatment for status epilepticus as described in the algorithm for children (algorithm 6) and adults (algorithm 7) and discussed in detail separately. (See "Management of convulsive status epilepticus in children" and "Convulsive status epilepticus in adults: Management" and "Refractory status epilepticus in adults".)

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References

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