Caffeine (1,3,7-trimethylxanthine), a methylxanthine and structural analog of adenosine, is the most commonly used psychoactive drug in the world and the only one that can be legally purchased by children. It is found in varying amounts in beverages and "energy-enhanced" foods, such as candy bars, potato chips, and oatmeal (Table 192-1).3 Nearly 6 billion caffeinated "energy drinks" were purchased in the United States in 2012.4 Many "energy drinks" contain guarana, a plant whose seeds contain high concentrations of caffeine and other methylxanthines. Drinks with guarana may not list caffeine as an ingredient.5 Other uses for caffeine include apnea of prematurity, analgesic adjuncts, appetite suppression for weight loss, sleep prevention, and diuresis.
TABLE 192-1Caffeine Content of Various Products ||Download (.pdf) TABLE 192-1 Caffeine Content of Various Products
|Source ||Caffeine Content (milligrams) |
|Coffee (8 oz or 240 mL, brewed) ||60–120 |
|Tea (8 oz or 240 mL, brewed) ||20–90 |
|Colas, caffeinated (8 oz or 240 mL) ||20–40 |
|Dark chocolate (1 oz or 30 mL) ||5–35 |
|"Higher caffeine energy drinks" (8–24 oz) ||70–505 |
|Acetaminophen-aspirin-caffeine tablet ||65 |
|Nonprescription antidrowsiness tablet ||200 |
Theophylline (1,3-dimethylxanthine) and its water-soluble salt, aminophylline, were used extensively in the past for the treatment of asthma and chronic obstructive pulmonary disease. However, theophylline's use has declined due to its narrow therapeutic window and the development of safer agents. Theophylline is still used in patients with debilitating bronchospastic disease, particularly outside the United States, and has been studied for the treatment of other diseases, including acute mountain sickness and contrast-induced nephropathy.6,7
Theobromine (3,7-dimethylxanthine) is found in the seeds of Theobroma cacao, from which chocolate and cocoa are derived; and Commelia thea, from which teas are steeped; and is an ingredient in numerous "energy drinks" in addition to caffeine. There are very few cases of human toxicity, but theobromine has been associated with atrial fibrillation.8
Caffeine is most commonly consumed orally; however, it can be administered rectally or parenterally. Theophylline is usually taken orally, although its absorption may be affected by food. It is available as an elixir or as extended-release and controlled-release tablets. Controlled-release tablets can result in erratic or rapid absorption. Theophylline can also be administered IV as aminophylline.
All methylxanthines are rapidly absorbed with early peak levels; they cross the blood–brain barrier and placenta and are excreted in breast milk (Table 192-2). Half-lives are only accurate at therapeutic concentrations and vary based on several factors, including drug level, age extremes, smoking, organ system dysfunction (e.g., cirrhosis), infection, and cytochrome P-450 inhibition (Table 192-3).
TABLE 192-2Pharmacokinetics of Methylxanthines ||Download (.pdf) TABLE 192-2 Pharmacokinetics of Methylxanthines
|Parameter ||Caffeine ||Theophylline |
|Therapeutic serum concentration ||5–20 micrograms/mL (25–100 micromoles/L) ||8–20 micrograms/mL (44–110 micromoles/L) |
|Bioavailability (oral) ||~100% ||~100% |
|Oral peak absorption (h) (delayed in overdose) ||0.5–1.0 ||1–2 (up to 8 h with sustained release preparations) |
|Volume of distribution (L/kg) ||~0.6 ||~0.5 |
|Protein binding ||~35% ||~60% |
|Major active metabolites || |
|Caffeine (only if <6 mo old) |
|Clearance ||Hepatic || |
<1 y old: 50% hepatic and 50% renal
>1 y old: 90% hepatic and 10% renal
|Half-life (accurate only at therapeutic concentrations) || |
Neonates: >50 h
<1 y old: 20 h
>1 y old: 5 h
Neonates: 20–30 h
Children and adults: 5 h
> 60 y old: 10 h
Methylxanthines exhibit Michaelis-Menten kinetics; that is, metabolism changes from first-order to zero-order kinetics at increased concentrations such that a fixed amount, not percentage, of drug is eliminated per unit of time, making accurate half-life calculations impossible following an overdose. This also explains why patients who chronically use theophylline may develop a large increase in serum theophylline concentration with only a small increase in dose. Methylxanthines are metabolized in the liver by the cytochrome P-450 1A2 pathway. Theophylline undergoes significant enterohepatic recirculation, so toxic serum levels can be maintained longer than anticipated.
CLINICAL FEATURES OF TOXICITY
Theophylline has the most potential for significant toxicity, followed by caffeine and then theobromine. The underlying pathophysiology involves adenosine antagonism, increased endogenous adrenergic stimulation, and, at toxic levels, phosphodiesterase inhibition (Table 192-4).
TABLE 192-4Methylxanthine Mechanisms of Action and Toxicity ||Download (.pdf) TABLE 192-4 Methylxanthine Mechanisms of Action and Toxicity
| ||Adenosine Antagonism ||Increased Catecholamines ||Inhibition of Phosphodiesterase |
|Mechanism ||Inhibition of adenosine-1 and adenosine-2 > adenosine-3 receptors ||Increased circulating catecholamines (epinephrine and norepinephrine) ||Phosphodiesterase inhibition (at toxic levels) |
|Effect || |
Decreased adenosine activity
Increased excitatory neurotransmitters activity
|Stimulation of β1 and β2 receptors ||Increased concentration of cyclic adenosine monophosphate and catecholamine effects |
|Therapeutic effect ||Bronchodilation ||Bronchodilation ||No role at therapeutic doses |
|Clinical toxicity || |
|Enhanced β-adrenergic effects |
The main organ systems involved in methylxanthine toxicity are GI, neurologic, cardiovascular, and metabolic (Table 192-5).
TABLE 192-5Clinical Manifestations of Methylxanthine Toxicity ||Download (.pdf) TABLE 192-5 Clinical Manifestations of Methylxanthine Toxicity
|Organ System ||Manifestation |
|GI || |
|Neurologic || |
|Cardiovascular || |
|Metabolic || |
Nausea and vomiting are reported in >70% of acute overdoses.9 Theophylline can also induce esophageal reflux by decreasing lower esophageal sphincter pressure.
Methylxanthine-induced seizures can be severe and refractory to treatment. First-time seizures in the setting of heavy caffeinated "energy drink" consumption have been reported.4,10 In theophylline toxicity, incidence of seizures is approximately 50% when serum levels are >40 micrograms/mL (>200 micromoles/L) during chronic therapy and >120 micrograms/mL (>600 micromoles/L) after an acute ingestion.9 Seizures at a lower serum concentration, even as low as 20 micrograms/mL (100 micromoles/L), are more likely in chronic toxicity due to relatively higher tissue levels. In chronic toxicity, seizures can occur without prior neurologic symptoms of tremor or agitation.
Cardiovascular Toxic Effects
Methylxanthines induce the release of endogenous catecholamines, stimulating β-adrenergic receptors, resulting in increased inotropy and chronotropy, vasodilation, hypotension, and reflex tachycardia. Sinus tachycardia is the most common cardiac manifestation of both caffeine and theophylline use and toxicity. Atrial fibrillation and supraventricular tachycardia are described with excessive caffeine intake.11,12 Theophylline toxicity may result in atrial arrhythmias such as multifocal tachycardia and fibrillation/flutter. Ventricular ectopy are more common with chronic toxicity and in patients with advanced age or underlying cardiac dysfunction.13 Ventricular fibrillation and tachycardia are rare.
Methylxanthine toxicity is associated with hypokalemia, hyperglycemia, and metabolic acidosis. Hypokalemia is most common in acute overdose, due to increased catecholamines. Rhabdomyolysis has been reported in caffeine and theophylline overdoses, presumably due to the hypermetabolic state, agitation, and seizures.
Chronic use of methylxanthines, particularly caffeine, can lead to tolerance, dependence, or withdrawal. Caffeine withdrawal syndrome has a varied course depending on use. Withdrawal symptoms typically start at 6 to 24 hours after the last dose, peak at about 36 hours, and can last for several days. Headache and fatigue are the most common symptoms and are seen after either chronic use or short-term, high-dose exposures. Caffeine withdrawal headaches can be debilitating and should be included in the differential diagnosis of ED patients with headache.
There is no clearly defined toxic dose or level of caffeine. Following a single ingestion of 120 milligrams of caffeine, an average peak serum concentration of 3 micrograms/mL (15 micromoles/L) results at 1 hour. Caffeine doses around 120 milligrams enhance arousal and performance of both cognitive and psychomotor skills.14
Ingestions of 100 to 150 milligrams/kg or serum levels >100 micrograms/mL (>500 micromoles/L) are likely to cause life-threatening toxicity, and an acute ingestion of >200 milligrams/kg can be lethal.5,15 Serum caffeine concentrations are not readily available in most clinical settings and offer little in terms of clinical decision making, so management of caffeine toxicity is guided by clinical findings.
Toxicity Although there is an established therapeutic serum concentration for theophylline, clinical effects are determined by the amount of free drug in tissue, not the serum. The best predictor of major theophylline toxicity after an acute overdose—seizures, hypotension, or cardiac arrhythmias—is the peak serum concentration. In chronic toxicity, although serum levels are elevated, the level itself does not necessarily predict major toxicity. An elevated theophylline level is more likely to be associated with major toxicity in those >65 years old (odds ratio, 7.8; 95% confidence interval, 2.9–21.1) than in those 30 to 65 years old (odds ratio, 3.2; 95% confidence interval, 1.03–10.1).16 In an acute ingestion, monitor serial theophylline levels to establish a trend in absorption, document the peak concentration, and assist in the medical clearance of patients as peak levels may be delayed many hours following a massive, acute overdose (Table 192-6). Conversely, management decisions should be based on symptoms and the patient's clinical condition, not on drug levels alone.
TABLE 192-6Methylxanthine Toxicity Classifications ||Download (.pdf) TABLE 192-6 Methylxanthine Toxicity Classifications
| ||Acute Toxicity ||Acute on Chronic Toxicity ||Chronic Toxicity |
|Clinical scenario ||Acute exposure: one-time ingestion of a bottle of theophylline or caffeine tablets ||Acute exposure in a person chronically using that methylxanthine: an acute ingestion of a bottle of theophylline in a patient taking theophylline ||An ongoing exposure to a stable amount with bioaccumulation; typically due to decreased clearance: a newly prescribed medication inhibits theophylline metabolism, leading to slowly increasing tissue concentrations |
|Risk of clinical effects ||Variable, depends on amount ||High, depends on amount ingested and comorbidities ||High, depends on tissue level of drug, age, and comorbidities |
|Timing of peak serum concentration ||Often delayed for many hours ||Usually delayed ||Often immediately available |
|Correlation of peak serum concentration with clinical effects ||Moderate correlation ||Moderate correlation ||Weak correlation |
As with the majority of poisoned patients, there are three main components to caring for a patient with methylxanthine toxicity: resuscitation (stabilizing cardiovascular and pulmonary function), GI decontamination to interrupt continued absorption (when appropriate), and minimizing end-organ effects. Supportive care and an appropriate observation period are required to prevent secondary sequelae. Monitor patients in a high-acuity setting. Treatments specific to methylxanthines, particularly theophylline, include use of activated charcoal, treatment of arrhythmias and seizures, and enhanced elimination.
Initial ancillary studies should include ECG, serum electrolytes, creatinine, urea, glucose, and total creatinine kinase. Other laboratory tests may be required based on patient presentation, available medications, and comorbidities. After an intentional ingestion, consider comorbid poisonings, such as with acetaminophen or salicylate. Consult with a medical toxicologist or a regional poison control center to discuss optimal, case-specific treatment.
Consider GI decontamination when dealing with a potentially life-threatening theophylline poisoning provided there are no contraindications, such as an unprotected airway, intracTable nausea or vomiting, ileus, bowel obstruction, or need for emergent endoscopy (Table 192-7).17 In caffeine ingestion, there is little benefit to GI decontamination because of the rapid absorption and associated nausea.
TABLE 192-7GI Decontamination for Methylxanthine Toxicity ||Download (.pdf) TABLE 192-7 GI Decontamination for Methylxanthine Toxicity
|GI Decontamination Technique ||Indication* ||Dosing |
|Activated charcoal (single dose) ||Acute ingestion || |
<12 y old: 0.5–1.0 gram/kg PO
>12 y old: 25–100 grams PO
|Multidose activated charcoal (requires close observation) ||Acute ingestion ||Normal activated charcoal loading dose, followed by: 0.25–0.5 gram/kg PO every 2–4 h for 12 h (frequency and duration may vary) |
|Whole-bowel irrigation using iso-osmolar polyethylene glycol electrolyte solution ||Acute ingestion of sustained-release preparations || |
9 mo–6 y: 25 mL/kg per hour
6–12 y old: 1000 mL/h
>12 y old: 1500–2000 mL/h
Duration: 4–6 h or until clear rectal effluent
Ondansetron is the preferred antiemetic to control any associated nausea or vomiting. Do not use phenothiazines (i.e., promethazine) because these agents lower the seizure threshold. Ranitidine can be used to decrease gastric acid hypersecretion. Do not give cimetidine as it can prolong methylxanthine half-life.
Multidose activated charcoal can enhance theophylline elimination by interrupting enterohepatic recirculation.18 Consult with a toxicologist or poison center regarding the use of whole-bowel irrigation for the ingestion of sustained-release preparations.19 Endoscopic removal of a slow-release, theophylline-containing bezoar may be necessary. Ipecac syrup, cathartics, and gastric lavage after theophylline ingestion have no proven benefit, have potential adverse effects, and are not recommended.20,21
Due to adenosine antagonism, seizures may be difficult to control, particularly with theophylline toxicity. Benzodiazepines, such as lorazepam 2 to 4 milligrams IV or diazepam 5 to 10 milligrams IV in adults, are first-line agents. Repeated, larger doses may be necessary. Barbiturates, such as phenobarbital 10 to 20 milligrams/kg IV in adults, should be used if escalating doses of benzodiazepines are ineffective. At high doses, benzodiazepines and barbiturates can compromise the airway or lead to respiratory depression, so maintain a low threshold for endotracheal intubation. Phenytoin is not useful or recommended.22
Patients who fail to respond to anticonvulsant therapy should be sedated, intubated, and paralyzed with a neuromuscular blocking agent; general anesthesia may be required. Paralyzed patients should have an electroencephalogram to monitor for continued seizure activity. Due to the severity of theophylline-induced seizures, some toxicologists recommend prophylactic use of a γ-aminobutyric acid agonist (e.g., lorazepam) to raise seizure threshold in patients presenting with markedly elevated theophylline levels, but this approach has not been validated in human studies.
Manage hypotension initially with IV fluids. The most commonly reported methylxanthine-induced tachyarrhythmias are atrial fibrillation and supraventricular tachycardia, presumably due to excessive β-adrenergic stimulation. Ventricular arrhythmias are uncommon.23 Cardioselective β-blockers (esmolol or metoprolol) are an option for serious supraventricular dysrhythmias if routine interventions (vagal maneuvers, adenosine) are ineffective. Nonspecific β-blockers, such as propranolol, can lead to bronchospasm, so cardioselective β-blockers, such as esmolol or metoprolol, are preferred.
The use of enhanced elimination techniques can prevent or help treat significant toxicity following methylxanthine poisonings. Multidose activated charcoal is recommended for toxic or potentially toxic theophylline ingestions.18
Hemodialysis is safe and is as efficacious as hemoperfusion for the treatment of theophylline toxicity.24 Hemodialysis is also effective for massive caffeine ingestions and pentoxifylline toxicity.25,26
Hemodialysis is readily available in many centers and provides fluid and electrolyte correction. The criteria for using hemodialysis in methylxanthine toxicity vary, but most experts suggest that a methylxanthine-induced life-threatening event, such as seizures or intracTable arrhythmias, is an indication. In addition, we suggest that dialysis should be considered when (1) after an acute ingestion, a symptomatic patient has a serum theophylline level >90 micrograms/mL (>500 micromoles/L), or (2) a chronic toxicity patient has a serum theophylline level >40 micrograms/mL (>220 micromoles/L) with significant symptoms or comorbidities. Published experience suggests that most patients who receive hemodialysis after a methylxanthine-induced life-threatening event, such as a seizure or arrhythmia, will continue to have them, whereas as few as 5% of patients who received hemodialysis before manifesting severe toxicity will go on to develop a life-threatening event.27
Treat vomiting with antiemetics, and correct volume depletion with isotonic fluids. Hypokalemia may not require treatment unless there are clinical findings such as ECG changes, cardiac ectopy, or muscle weakness, because potassium is shifted intracellularly and total body potassium is only mildly depleted. Provide continuous cardiac monitoring until toxicity has resolved. Assess for hyperthermia, rhabdomyolysis, and compartment syndrome, and provide specific treatment. Patients who are sedated and paralyzed should undergo continuous electroencephalographic monitoring to evaluate for occult sustained or recurrent seizures.
DISPOSITION AND FOLLOW-UP
Following an intentional or accidental methylxanthine ingestion, patients are judged nontoxic when they are asymptomatic, have a normal physical examination and vital signs, and, if available, have normal or decreasing serum concentrations. Patients who remain asymptomatic for at least 6 hours after an acute ingestion of immediate-release tablets can be considered nontoxic. Patients with an ingestion of sustained-release medication should be monitored for 12 hours or longer. Patients with intentional ingestions should receive a behavioral health or psychiatric evaluation to assist with appropriate disposition and follow-up.