Acute caffeine poisoning

INTRODUCTION — Caffeine is a widely consumed, plant-derived methylxanthine alkaloid and psychostimulant. Caffeine is found in coffee, tea, chocolate, carbonated sodas, energy drinks, various foods, and powder and tablet forms (including dietary supplements). Although relatively uncommon, fatal poisoning can occur after a large caffeine overdose. Caffeine poisoning remains an ongoing problem given the widespread availability of concentrated caffeine products.

This topic will review the clinical features, evaluation, and management of acute caffeine poisoning in children and adults. The general management of the poisoned patient, effects of chronic caffeine use, and high-risk dietary supplements are discussed separately.

●(See "General approach to drug poisoning in adults".)

●(See "Initial management of the critically ill adult with an unknown overdose".)

●(See "Cardiovascular effects of caffeine and caffeinated beverages".)

●(See "Benefits and risks of caffeine and caffeinated beverages".)

●(See "Caffeine: Effects on reproductive outcomes in females".)

●(See "High-risk dietary supplements: Patient evaluation and counseling".)

EPIDEMIOLOGY — Severe and lethal caffeine poisoning tends to involve the ingestion of concentrated caffeine products (eg, caffeine-containing medications or pure anhydrous caffeine powder) rather than beverages or foods containing caffeine [1-3]. Approximately 3000 single-substance caffeine exposures involving two or fewer fatalities are reported annually to United States regional poison control centers [4-7]. Approximately 1000 energy drink exposures are reported annually to United States regional poison control centers (with one fatality reported between 2017 and 2020).

Cases of intentional and unintentional caffeine poisoning in the United States have increased since the widespread use of caffeine-enhanced items (eg, energy drinks) and highly concentrated caffeine products [8-10]. Excess consumption of energy drinks can cause severe toxicity; these make up a small percentage of the overall consumed caffeine, but their consumption appears to be increasing [10-14]. In 2014, the US Food and Drug Administration warned consumers about dietary supplements containing pure or highly concentrated caffeine and the potential for dangerous and serious adverse events [15].

PHARMACOLOGY AND CELLULAR TOXICOLOGY

Sources and toxic dose

●Sources — Caffeine is a common component of various beverages, energy drinks, and chocolates (table 1). In the United States, the majority of consumed caffeine is from beverages such as coffee, tea, and soft drinks [14]. Caffeine occurs naturally in a wide variety of seeds, nuts, and plant species. Caffeine is present in many over-the-counter (OTC) weight-loss and pre-workout supplements (table 2), combination analgesics (eg, Excedrin Extra Strength), and concentrated powders and liquids. Almost pure caffeine powder containing up to 5 grams caffeine per teaspoon is available for bulk purchase on the internet. Caffeine is also a common adulterant in illicit stimulants sold by internet vendors [16].

●Toxic dose — Ingestion of greater than 150 to 200 mg/kg of caffeine has a high risk of lethality. In general, intentional ingestion (ie, overdose) is the most dangerous form of exposure since it often involves very high doses of caffeine. Fatalities have been reported with the ingestion of 5 to 50 g, but recovery after ingestion of up to 50 g has also been described [17-19]. In a study of 101 patients hospitalized for caffeine poisoning, the mean dose of caffeine ingested was 7.2 g (range of 1.2 to 82.6 g) [20]. Seven of these hospitalized patients had a cardiac arrest (all consumed ≥6 g), and three patients died.

In most adults, consumption of up to 400 mg per day of caffeine appears to be safe. In children and adolescents, consumption of 2.5 mg/kg per day is not associated with adverse effects. The amount of caffeine consumed in beverages and other forms is discussed separately. (See "Benefits and risks of caffeine and caffeinated beverages", section on 'Consumption'.)

Therapeutic and toxic serum concentrations — When used for treatment of apnea of prematurity, the therapeutic range of caffeine concentrations is 8 to 20 mg/L (44 to 111 mmol/L).

The range of toxic caffeine concentrations reported in the literature varies greatly [21]. In general, concentrations >20 mg/L (111 mmol/L) are potentially toxic, and concentrations >50 mg/L (278 mmol/L) are consistently toxic.

Concentrations >80 mg/L (444 mmol/L) are associated with fatality, but survival after acute caffeine overdose has been reported with much higher serum concentrations [2,21,22]. In a study of 51 caffeine-related fatalities, the mean postmortem concentration was 187 mg/L (1038 mmol/L), and the range was 33 to 567 mg/L (183 to 3147 mmol/L) [23].

Pharmacology and mechanisms of toxicity — Caffeine is a trimethylxanthine, a structural analog of adenosine and the dimethylxanthines (ie, theophylline, theobromine). Compared with the dimethylxanthines, caffeine's extra methyl group increases central nervous system (CNS) penetration. The physiologic effects of caffeine are discussed in detail separately. (See "Cardiovascular effects of caffeine and caffeinated beverages", section on 'Physiologic effects'.)

Caffeine is a nonselective adenosine receptor antagonist. Presynaptic adenosine-2 receptor antagonism promotes catecholamine (eg, norepinephrine) release, resulting in increased myocardial inotropy and chronotropy, peripheral vasoconstriction, and indirect excitatory effects [24]. At recommended doses, caffeine acts as a mild CNS stimulant, but in overdose, seizures can develop from antagonism of CNS adenosine receptors [3].

Caffeine stimulates the CNS respiratory center and is used therapeutically to treat apnea of prematurity [25,26]. (See "Management of apnea of prematurity", section on 'Caffeine'.)

At high concentrations, caffeine inhibits phosphodiesterase, thus increasing cyclic adenosine monophosphate (cAMP) and intracellular calcium concentrations [27]. Increased cAMP, which is part of the postsynaptic beta-adrenergic second messenger system, results in the beta-adrenergic effects of smooth muscle relaxation, peripheral vasodilation, increased myocardial inotropy and chronotropy, skeletal muscle contractility, and CNS excitation. (See "Excitation-contraction coupling in myocardium", section on 'Cyclic adenosine monophosphate'.)

Pharmacokinetics

●Absorption – Caffeine is rapidly absorbed from the stomach and small intestine with 90 to 100 percent bioavailability [24,28]. Peak caffeine concentrations occur 30 to 60 minutes after oral intake [24,29]. Food slows the rate of absorption but does not limit the extent [30].

●Distribution – Caffeine distributes into the total body water compartment and has a volume of distribution of approximately 0.7 L/kg, and 10 to 35 percent is bound to plasma protein [31,32]. Caffeine crosses the placenta and passes into breast milk.

●Metabolism – Caffeine is hepatically metabolized via cytochrome P450 (CYP1A2) into paraxanthine (1,7-dimethylxanthine; major metabolite), theobromine, and theophylline (minor metabolites) [33]. Paraxanthine is further metabolized to the principal urinary metabolites, 1-methylxanthine, 1-methyluric acid, and an acetylated uracil derivative. Caffeine biotransformation manifests significant inter-individual variability [34]. For example, individuals homozygous for the CYP1A2*1A allele are rapid metabolizers of caffeine, while carriers of the CYP1A2*1F allele are slow metabolizers [35]. In a study of healthy volunteers, lower CYP1A2 activity was associated with increased reports of symptoms of toxicity [36].

●Elimination – The mean plasma elimination half-life is approximately five hours (range three to seven hours) in healthy adults and shorter in children (three to four hours). The half-life is shortened in smokers and prolonged in the last trimester of pregnancy, patients with cirrhosis, and infants. Less than 5 percent of caffeine is excreted unchanged in the urine. Caffeine obeys first-order kinetics, but zero-order kinetics occur at supratherapeutic concentrations because of saturation of metabolic enzymes [37]. There is marked interindividual variation in the rate of elimination.

CLINICAL FEATURES OF OVERDOSE

Overview — Caffeine toxicity can present with a range of gastrointestinal, cardiovascular, metabolic, muscular, and central nervous system (CNS) effects. The characteristic caffeine poisoning syndrome (ie, toxidrome) is the combination of vomiting, tachycardia, hypokalemia, and hyperglycemia. Toxicity is generally dose dependent, and at higher doses, agitation, seizures, ventricular dysrhythmias, hypotension, and shock can occur [8,38-41].

A study of 101 patients hospitalized for caffeine toxicity (most from caffeine tablet overdose) found that commonly reported symptoms and signs included [20]:

●Hypokalemia: 85 percent

●Nausea: 81 percent

●Vomiting: 74 percent

●Tachycardia: 59 percent

●Tachypnea: 57 percent

●Hyperglycemia: 47 percent

●Depressed consciousness: 37 percent

●Hyperlactatemia: 34 percent

●Agitation or excitement: 27 percent

●Headache: 14 percent

●Irritability: 10 percent

●Tremulousness: 8 percent

●Hypotension: 7 percent

●Cardiac arrest: 7 percent

The caffeine poisoning toxidrome is essentially equivalent to the beta-adrenergic agonist poisoning toxidrome, which occurs with toxicity from theophylline, albuterol, clenbuterol, and others (table 3). The preferential beta-adrenergic stimulation due to phosphodiesterase inhibition by caffeine accounts for the clinical overlap with beta-adrenergic agonists (eg, albuterol). (See 'Pharmacology and mechanisms of toxicity' above.)

A rapid overview table provides the common clinical findings after caffeine poisoning (table 4).

Vomiting and other gastrointestinal symptoms — Gastrointestinal symptoms such as nausea, vomiting, abdominal pain, and diarrhea are frequently reported after acute caffeine overdose. In large overdoses, vomiting may be severe, recurrent, and difficult to control [42].

Tachycardia and other cardiovascular signs — Cardiovascular findings include hypertension (early or mild toxicity), hypotension (severe or late toxicity), tachycardia, ventricular extrasystoles, myocardial ischemia, atrioventricular block, supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation, and cardiac arrest.

Sinus tachycardia occurs in almost every patient with caffeine toxicity but can degenerate to a more dangerous dysrhythmia. Other tachydysrhythmias (eg, atrial fibrillation) are common in patients with acute caffeine toxicity and are frequently supraventricular in origin [21,43,44]. Ventricular tachycardia or fibrillation occurs with severe toxicity and is typically the proximate cause of death.

Hypertension can occur with mild toxicity or early in the course of severe toxicity from stimulation of post-synaptic alpha-1 adrenergic receptors. As toxicity progresses, hypotension may develop from beta-2-adrenergic-induced vasodilation, reduced cardiac filling and output from recurrent dysrhythmias, and volume loss from vomiting.

Other reported cardiovascular effects include fluctuations in T-wave morphology [44], QTc interval prolongation [44,45], myocardial ischemia and infarction [46], and cardiac arrest [41,45].

Tachypnea and respiratory failure — Tachypnea and respiratory alkalosis can occur. Severe overdose can cause hyperventilation, respiratory alkalosis, respiratory failure, respiratory arrest, and acute respiratory distress syndrome.

Hypokalemia, hyperglycemia, and other metabolic findings — Hypokalemia and hyperglycemia occur in most patients with caffeine toxicity. Other metabolic findings after acute caffeine overdose can include leukocytosis, hyponatremia, hypocalcemia, hyperlactatemia, metabolic acidosis, diuresis, and hyperthermia.

Increased catecholamine release and beta-2-agrenergic agonism are responsible for the hypokalemia, hyperglycemia, and leukocytosis. Potassium is shifted intracellularly, while total body potassium stores are unchanged. Several studies have found that the extent of hypokalemia correlates with the severity of caffeine toxicity [47-49]. Serum glucose can increase to approximately 200 mg/dL (11.1 mmol/L) in patients without diabetes.

Tremor, seizures, and other neurologic findings — Common neurologic signs and symptoms include headache, tremor, weakness, anxiety, agitation, and dizziness. Delusions, hallucinations, and seizures can occur. Seizures tend to be severe, recurrent, and refractory to conventional treatment [50]. Muscular rigidity can cause rhabdomyolysis and kidney failure [51].

DIFFERENTIAL DIAGNOSIS — Caffeine poisoning should be suspected in any patient with vomiting, tachycardia, hypokalemia, and hyperglycemia. Other ingestions and exposures that can present with similar symptoms include:

●Beta-adrenergic agonists – Agents such as albuterol (also known as salbutamol), clenbuterol, and terbutaline can cause similar symptoms, but seizures and cardiac dysrhythmias are rare [52]. Clenbuterol has been used as a performance-enhancing drug and as an adulterant in illicit opioids. Poisoning with these can only be differentiated by history of ingestion/use or caffeine concentration (if available). (See "Prohibited non-hormonal performance-enhancing drugs in sport", section on 'Beta agonists'.)

●Theophylline and theobromine – These dimethylxanthines have toxicity similar to caffeine. Poisoning with these can only be differentiated by history of ingestion/use or caffeine/theophylline concentrations (if available). (See "Theophylline poisoning".)

●Cocaine, amphetamine, and cathinone – Cocaine, amphetamine, or synthetic cathinone intoxication can cause tremulousness, agitation, seizures, and tachydysrhythmias. Compared with caffeine poisoning, these agents are more likely to cause hypertension, diaphoresis, and hyperthermia and less likely to cause vomiting. (See "Cocaine: Acute intoxication", section on 'Clinical manifestations' and "Methamphetamine: Acute intoxication", section on 'Examination findings associated with intoxication and complications' and "Acute amphetamine and synthetic cathinone ("bath salt") intoxication".)

●Iron – Vomiting is an early and consistent sign of iron poisoning, which can be accompanied by leukocytosis, hyperglycemia, metabolic acidosis, tachycardia, and hypotension. Compared with caffeine poisoning, vomiting is more likely to be bloody, and seizures are uncommon. Iron poisoning can be differentiated by obtaining a serum iron concentration. (See "Acute iron poisoning".)

●Salicylates – Vomiting, tachycardia, hypotension, altered mental status, and seizures can occur with salicylate poisoning. However, salicylate poisoning typically causes a respiratory alkalosis with hyperpnea and can be differentiated by obtaining a serum salicylate concentration. (See "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation".)

EVALUATION AND DIAGNOSTIC TESTING

History and examination — In a patient with possible caffeine toxicity, we inquire regarding the details of the ingestion or caffeine use, such as the following:

●How much caffeine was ingested, including the formulation (eg, tablet, liquid, powder), concentration or dose per tablet, and amount? Was the ingestion intentional or accidental?

●Does the patient have symptoms attributable to caffeine toxicity (eg, nausea, vomiting, headache, tremor, anxiety, agitation, restlessness)? (See 'Clinical features of overdose' above.)

●If the patient does not recall taking caffeine, could they have taken another source of caffeine such as beverages, energy drinks, over-the-counter (OTC) weight-loss or pre-workout supplements (table 2), or combination analgesics? (See 'Sources and toxic dose' above.)

The physical examination helps determine the severity of toxicity and guides treatment. We assess for hemodynamic instability, seizure activity, altered mental status, signs of hypovolemia (eg, decreased turgor, cool extremities), tremor, restlessness, and anxiety.

Laboratory and ancillary studies — We obtain the following studies in a patient with suspected caffeine poisoning:

●Serum caffeine concentration – Unless a hospital uses caffeine therapeutically (eg, to treat apnea of prematurity), a serum caffeine assay with rapid turnaround-time is typically unavailable (see 'Caffeine in-house assay available' below and 'Caffeine in-house assay not available' below)

●Serum electrolytes and glucose

●Complete blood count

●Electrocardiogram (ECG)

Additional studies may be indicated depending on the clinical situation:

●In a patient with hyperthermia or evidence of increased muscle tone: creatinine kinase and urinalysis

●In a patient with an intentional ingestion to rule out common co-ingestants: serum acetaminophen, salicylate, and ethanol concentrations

●In a female of childbearing age: urine pregnancy test

Caffeine in-house assay available — If the hospital laboratory performs a caffeine assay that results promptly, we obtain serum concentrations immediately and every one to two hours until there is a downward trend [42]. Serum caffeine concentrations generally correlate with clinical severity of intoxication.

Caffeine in-house assay not available — If the serum caffeine concentration will not result rapidly enough to guide evaluation and management, we obtain it if the result will be helpful for confirmatory or forensic purposes (eg, unclear if caffeine ingestion). Several analytical methods can quantify caffeine in biological samples, including gas chromatography, gas chromatography–mass spectrometry, high-performance liquid chromatography, and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), but these require sophisticated technology and are time consuming to perform [23,43,53-56].

The serum potassium concentration has been studied as a surrogate marker that inversely correlates with serum caffeine concentrations. A study of 85 patients with acute caffeine intoxication found that serum potassium concentrations <3.3 mEq/L and <2.9 mEq/L correlated with serum caffeine concentrations ≥20 mg/L (111 mmol/L) and ≥80 mg/L (444 mmol/L), respectively [47].

DIAGNOSIS — The diagnosis of acute caffeine poisoning is suspected in a patient with concern for an ingestion or supratherapeutic use and characteristic findings (ie, vomiting, tremors, tachycardia, hypokalemia, hyperglycemia, seizures, tachydysrhythmia, and hypotension). The diagnosis is confirmed with an elevated serum caffeine concentration (>20 mg/L [111 mmol/L]), if available, or with a compelling history of an ingestion (eg, suicide note, empty pill bottle) combined with characteristic findings.

MANAGEMENT

ABCs and supportive care — In a patient with concern for caffeine poisoning, initial management focuses on assessing and stabilizing airway, breathing, and circulation ("ABCs"). We obtain intravenous (IV) access and establish cardiac monitoring. Tracheal intubation and mechanical ventilation may be warranted in cases of severely impaired mentation or recurrent seizures. (See "Initial management of the critically ill adult with an unknown overdose".)

Further management is mostly supportive and based on the patient's symptoms, signs, and hemodynamic findings. Intermittent hemodialysis and multiple-dose activated charcoal (MDAC) can effectively enhance elimination. Management is summarized in the rapid overview table (table 4).

Role of gastrointestinal decontamination

●Single-dose activated charcoal (AC) – In a patient who presents within two hours of a reported caffeine ingestion with preserved mental status and no emesis, we suggest administration of AC 50 g orally (1 g/kg to maximum dose 50 g). AC should not be given to a patient with depressed mental status without airway protection, but tracheal intubation should not be performed for the sole purpose of giving AC. The evidence for single-dose AC adsorbing organic compounds and limiting absorption is provided elsewhere. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Activated charcoal'.)

●Orogastric lavage – In the rare case that a patient presents within one hour of a reported large ingestion of caffeine powder or concentrated liquid and has preserved mental status and no emesis, we place a nasogastric tube for aspiration and lavage [42]. A standard (eg, 8 to 12 French) nasogastric tube is better tolerated and safer than traditional gastric lavage with a large-bore orogastric tube. The risks of orogastric lavage with a large-bore tube likely outweigh the benefits since caffeine is rapidly absorbed from the stomach (especially in powder or liquid form). (See "Gastrointestinal decontamination of the poisoned patient", section on 'Gastric lavage'.)

Management based on specific toxicity

Dysrhythmias — The presence of a life-threating dysrhythmia is an indication for hemodialysis. (See 'Indications for extracorporeal removal' below.)

●Supraventricular tachycardias (SVTs) – In a patient with caffeine-induced SVT (other than mild sinus tachycardia), we suggest administration of a benzodiazepine (eg, lorazepam) or a beta-1-selective-adrenergic antagonist [42]. In a patient with a symptomatic, hemodynamically stable sinus tachycardia, a benzodiazepine (eg, lorazepam) is a reasonable option for first-line therapy. Benzodiazepines reduce central nervous system (CNS) catecholamine concentrations and potentially increase adenosine concentrations by inhibiting reuptake.

In a patient with a severe sinus tachycardia (ie, heart rate >150 beats per minute) or other SVT from caffeine toxicity, esmolol is a reasonable option for first-line therapy [57]. Both esmolol and metoprolol are selective antagonists of the beta-1 adrenergic receptor and have minimal effect on beta-2 adrenergic receptors, thus preventing adverse effects such as exacerbation of reactive airway disease. Esmolol effects can be quickly titrated or turned off since it has the additional advantage of being ultra-short acting. Dosing is as follows:

•Esmolol: Loading dose (optional) 500 mcg/kg over one minute; follow with a 50 mcg/kg/minute infusion for four minutes; infusion may be continued at 50 mcg/kg/minute or, if the response is inadequate, bolus (optional) 500 mcg/kg over one minute followed by titrating upward in 50 mcg/kg/minute increments (increased no more frequently than every four minutes) up to infusion rate of 300 mcg/kg/minute

•Metoprolol: 2.5 to 5mg IV repeated every 5 minutes; maximum dose 15 mg

Beta-adrenergic antagonists decrease cardiac and peripheral beta-stimulation induced by caffeine. Many case reports have described the safe and successful use of beta-adrenergic antagonists for controlling caffeine-induced dysrhythmias [21,44,57-59]. However, patients in these reports often receive many different pharmacologic agents, thus complicating the ability to draw conclusions regarding any individual agent.

●Ventricular dysrhythmias and other malignant rhythms (eg, SVT with hemodynamic instability) – These should be treated based on advanced cardiac life support or pediatric advanced life support guidelines. In a patient with a ventricular dysrhythmia, we administer a beta-adrenergic antagonist (eg, esmolol as described above) in addition to standard resuscitation measures. We consult nephrology early in the patient’s course to arrange for hemodialysis. (See "Advanced cardiac life support (ACLS) in adults", section on 'Management of specific arrhythmias' and "Pediatric advanced life support (PALS)", section on 'Heart rate and rhythm'.)

●Adenosine or electrical cardioversion unlikely to have sustained effect – In a patient with caffeine-induced SVT, administration of adenosine (which is a common treatment for other paroxysmal SVTs) will likely be ineffective or only provide a transient response [59,60]. Electrical cardioversion can be attempted for an SVT refractory to pharmacologic intervention but is unlikely to result in a sustained normal heart rhythm [21]. Defibrillation should be performed for a hemodynamically unstable dysrhythmia.

●Extracorporeal membrane oxygenation as salvage option – In a patient with cardiovascular collapse that is refractory to conventional medical strategies, venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a salvage option that can provide circulatory support while the intoxicant is cleared. In a case report, a patient with recurrent refractory ventricular fibrillation following a caffeine and amitriptyline overdose survived neurologically intact after treatment with VA-ECMO, which allowed time and circulatory support for correction of severe hypokalemia and for institution of hemodialysis to clear caffeine [45]. (See "Extracorporeal life support in adults in the intensive care unit: Overview".)

Seizure — In a patient with caffeine-induced seizures, we administer benzodiazepines for first-line treatment. Repeated dosing may be required and should be titrated until clinical effect is achieved. Options include the following (see "Convulsive status epilepticus in adults: Management", section on 'First therapy: Benzodiazepines'):

●Lorazepam: 4 mg IV (0.1 mg/kg IV; maximum 4 mg/dose), may repeat after three to five minutes

●Diazepam: 10 mg IV (0.15 to 0.2 mg/kg/dose IV; maximum 10 mg/dose), may repeat after three to five minutes; or 20 mg rectally (0.2 to 0.5 mg/kg rectally; maximum dose 20 mg/dose) once (preferred for rectal administration until IV access is obtained)

●Midazolam: 10 mg intramuscularly (IM; 0.2 mg/kg IM; maximum dose 10 mg) once (preferred for IM administration until IV access is obtained)

Caffeine-induced seizures may be severe and refractory to treatment. In a patient with persistent or recurrent seizures after two doses of a benzodiazepine, we administer a barbiturate (eg, phenobarbital, pentobarbital) or propofol. Tracheal intubation and close hemodynamic monitoring are typically required since these agents suppress respiratory drive and may exacerbate hypotension. Dosing is as follows (see "Refractory status epilepticus in adults", section on 'Infusion therapies and other treatments'):

●Phenobarbital: 20 mg/kg IV (infused at 50 to 100 mg/minute); if necessary, may repeat once after 10 minutes with an additional 5 to 10 mg/kg

●Propofol: Loading dose 1 to 2 mg/kg followed by 0.5 to 2 mg/kg every three to five minutes until seizures are suppressed (maximum total dose 10 mg/kg), then followed by continuous infusion at an initial rate of 20 mcg/kg/minute

The presence of a seizure is an indication for hemodialysis. (See 'Indications for extracorporeal removal' below.)

Phenytoin and fosphenytoin are not beneficial and may be harmful in the treatment of caffeine-induced seizures. Phenytoin was found to increase mortality when administered to animals with methylxanthine toxicity [61].

Hypotension — Hypotension is initially treated with IV fluids, and therapy can be escalated to vasopressors or beta-adrenergic antagonists. The presence of persistent hypotension or shock is an indication for hemodialysis. (See 'Indications for extracorporeal removal' below.)

●IV fluids – In a patient with hypotension, we administer bolus volumes (10 to 20 mL/kg) of isotonic IV fluids (0.9% sodium chloride or lactated Ringer solution). If blood pressure does not adequately improve after three fluid boluses, we start a vasopressor and/or beta-adrenergic antagonist.

●Vasopressor therapy – In a patient with persistent hypotension despite IV fluids or with contraindications to repeated fluid boluses (eg, pulmonary edema), we initiate vasopressor therapy with phenylephrine or norepinephrine. Vasopressors with beta-adrenergic agonist effects (eg, epinephrine, dobutamine, isoproterenol) should be avoided as they may worsen hypotension [42]. Dosing is as follows (table 5):

•Phenylephrine continuous IV infusion: Initial dose 40 to 160 mcg/minute (adults: 0.5 to 2 mcg/kg/minute; children: 0.1 to 0.5 mcg/kg/minute), titrate to effect

•Norepinephrine continuous IV infusion: Initial dose 5 to 15 mcg/minute (0.05 to 0.15 mcg/kg/minute), titrate to effect

●Beta-adrenergic antagonist – In a patient with refractory hypotension despite vasopressor therapy or as an alternative to vasopressor therapy, we suggest administering a beta-adrenergic antagonist (eg, esmolol, propranolol). Esmolol is the ideal agent since it has an ultra-short duration of action and its effects can easily be titrated or turned off if it does not produce the desired outcome.

Although counterintuitive, a beta-adrenergic antagonist can actually increase blood pressure due to caffeine toxicity by inhibiting the beta-2-induced vasodilation and improve cardiac output by inhibiting the beta-1-induced tachycardia and increasing filling time. Evidence is limited to case reports, case series, and animal studies [21,44,57,59,62,63]. Beta-adrenergic antagonists are recommended for treatment of hypotension from other methylxanthines, such as theophylline. (See "Theophylline poisoning", section on 'Hypotension'.)

The decision to use a beta-adrenergic antagonist to treat a hypotensive patient can be very difficult, and consultation with a medical toxicologist is often helpful. (See 'Regional poison control centers' below.)

Vomiting — Ondansetron or metoclopramide, often in large doses, may be required since caffeine-induced vomiting is frequently prolonged and severe. We ensure that the patient has a normal QTc interval prior to administering a 5-HT3 receptor antagonist (eg, ondansetron) or a dopamine receptor antagonist (eg, metoclopramide) given the association with QTc prolongation, especially in the presence of hypokalemia or hypomagnesemia [64]. The ondansetron initial dose is 0.15 mg/kg IV (maximum dose 16 mg). High doses of metoclopramide (up to 0.5 to 1 mg/kg; maximum dose 50 mg) may be necessary but have been associated with acute dystonic reactions, which can be treated with IV diphenhydramine. Antiemetic drugs and potential adverse effects are discussed separately. (See "Characteristics of antiemetic drugs".)

Cimetidine is contraindicated as it may reduce clearance of caffeine due to inhibition of multiple CYP enzymes [42].

Tremulousness, anxiety, restlessness — We administer benzodiazepines (eg, lorazepam, diazepam) for these CNS findings. In a patient with mild toxicity who is not vomiting, these can be administered orally; otherwise, these should be given IV. Doses are similar to those used for anxiety (eg, lorazepam 0.5 to 2mg; diazepam 2 to 5 mg).

Hypokalemia — In a patient with caffeine-induced symptomatic hypokalemia, especially in the presence of muscle weakness, ventricular dysrhythmias, abnormal T waves, or prolonged QTc, we administer potassium supplementation [42]. Since hypokalemia is from potassium shift rather than potassium loss, lesser doses are needed compared with a patient with low total-body potassium. We administer 10 mEq/hour IV to most patients. There is no established serum potassium target, but a reasonable approach is to replete potassium until cardiac manifestations (eg, prolonged QTc) resolve. Details of potassium infusions are described in detail elsewhere. (See "Clinical manifestations and treatment of hypokalemia in adults", section on 'Recommended approach'.)

In a patient who remains symptomatic or is receiving potassium supplementation, we measure a serum potassium every two to four hours. (See "Clinical manifestations and treatment of hypokalemia in adults", section on 'Careful monitoring'.)

Asymptomatic hypokalemia (ie, no muscle weakness or ECG changes, except for sinus tachycardia) is generally well tolerated, and potassium supplementation is not needed. Aggressive correction of hypokalemia may cause hyperkalemia as toxicity resolves and potassium shifts out of the intracellular compartment.

Role of elimination enhancement — Caffeine elimination can be enhanced by MDAC or extracorporeal removal (ie, hemodialysis). In general, we use MDAC in a patient with moderate toxicity and hemodialysis in a patient with life-threatening toxicity.

Multiple-dose activated charcoal — In a patient with a caffeine overdose and anything beyond mild symptoms (eg, sinus tachycardia, restlessness), we suggest treatment with MDAC. The initial dose is 0.5 g/kg (maximum dose 50 g) AC followed by 0.5 g/kg (maximum dose 50 g) every four hours or 0.25 g/kg (maximum dose 25 g) every two hours of AC without sorbitol. MDAC should be continued until the patient's clinical status is improving or the serum drug concentration (if available) is decreasing. MDAC may not be tolerated due to emesis. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Multidose activated charcoal'.)

We do not administer AC to a patient with altered mental status who may not be able to protect their airway, unless tracheal intubation is performed first. AC can be administered via orogastric tube to an intubated patient, but do not tracheally intubate solely for the purpose of administering AC.

Avoid an AC formulation combined with a cathartic (eg, sorbitol) because of potential for adverse effects such as vomiting and dehydration. It is reasonable to administer a combined formulation if a formulation of AC without a cathartic is unavailable, but limit treatment to a single dose in such cases.

Unlike single-dose AC (discussed above), MDAC can be started beyond two hours after ingestion because the mechanism of benefit is not just adsorbing caffeine in the gastrointestinal tract. MDAC increases elimination of caffeine by interrupting its enterohepatic recirculation [42]. The evidence for MDAC enhancing elimination of toxins that undergo enterohepatic recirculation is presented elsewhere. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Evidence of efficacy and adverse effects'.)

Indications for extracorporeal removal

Intermittent hemodialysis — The following are indications for enhancing caffeine elimination with extracorporeal treatment (ECTR) (table 6):

●Serum caffeine concentration (if available) >100 mg/L (555 mmol/L) in acute exposure, >60 mg/L (333 mmol/L) in chronic exposure

●Presence of seizures

●Life-threatening dysrhythmias or shock

●Caffeine concentration (if available) that is rising despite MDAC

●Clinical deterioration despite optimal therapy

●Progressively worsening moderate to severe symptoms and inability to tolerate MDAC

Intermittent hemodialysis is the preferred choice of ECTR since it effectively and rapidly clears various toxins. The duration of a hemodialysis session is usually four to eight hours but should be governed by the clinical response and serum caffeine concentrations (if available). Cessation of ECTR is recommended when clinical improvement is apparent or the caffeine concentration is <15 mg/L (83 micromol/L). Repeat treatment with ECTR may be needed if there is clinically significant redistribution (which is unlikely) or ongoing gastrointestinal absorption. (See "Enhanced elimination of poisons", section on 'Hemodialysis and hemoperfusion'.)

We continue MDAC treatment (if tolerated) during ECTR. (See 'Multiple-dose activated charcoal' above.)

If hemodialysis is not available, alternative techniques to enhance elimination include hemoperfusion, continuous renal replacement therapy (CRRT), and exchange transfusion in neonates [31,65]. CRRT is better tolerated in hemodynamically unstable and/or hypotensive patients but has lower toxin clearance rates compared with conventional hemodialysis. (See "Enhanced elimination of poisons", section on 'Continuous renal replacement therapy (hemofiltration)'.)

The evidence in support of ECTR to enhance caffeine elimination is based on its pharmacokinetic properties, its similarities with theophylline, and case reports. Caffeine is effectively cleared by hemodialysis because it has low protein binding (10 to 35 percent), small molecular mass (194 Daltons), and low volume of distribution (0.7 L/kg) [31,32]. Consensus guidelines developed for ECTR in theophylline poisoning can be extrapolated to caffeine poisoning since it is a structurally related methylxanthine with similar toxicity and pharmacokinetic properties [32,42]. (See "Theophylline poisoning", section on 'Extracorporeal removal'.)

In many case reports, patients with life-threatening toxicity (eg, ventricular dysrhythmias) after a caffeine overdose who were treated with hemodialysis had improved elimination and good clinical outcomes [21,31,41,66,67]. In a patient with an initial serum caffeine concentration of 170 mg/L, the removal rate of caffeine with hemodialysis was 15.5 mg/L/hour, which is much higher than the approximate removal rate of 2 mg/L/hour in two patients not treated with hemodialysis (initial concentration 97 to 100 mg/L) [21,68,69].

The caffeine concentration thresholds for dialysis are extrapolated from theophylline data. Following an acute ingestion, theophylline serum concentrations >80 to 100 mg/L are likely to cause significant toxicity and death [32]. There are less robust data for caffeine. However, in two studies and a systematic review of caffeine fatalities, the majority of serum concentrations exceeded 100 mg/L, and almost all exceeded 80 mg/L, suggesting that 80 to 100 mg/L is a reasonable concentration threshold for hemodialysis [2,23,70]. Since no effective antidote for caffeine toxicity exists and initiating emergency dialysis takes time, if a caffeine concentration is available and potentially lethal, we would not delay consulting nephrology while waiting for life-threatening toxicity to develop.

DISPOSITION

●Patient being evaluated in an acute care facility – We admit to a critical care setting a patient who has any of the following:

•Ongoing tachydysrhythmias

•Hypotension that does not resolve with intravenous (IV) fluids

•Seizures

•Hemodynamic instability

•Persistent vomiting

•Requiring extracorporeal removal

•Serum potassium <2.9 mEq/L

•Serum caffeine concentration (if available) >50 mg/L (278 mmol/L)

In a patient who is symptomatic but does not meet the above criteria for critical care admission, we will observe (either in the emergency department or inpatient setting) until signs and symptoms have resolved.

●Patient outside an acute care facility (eg, home) – We refer a patient with any of the following to an acute care facility (transfer via emergency medical services is strongly encouraged):

•Intentional ingestion (suicide or recreational)

•Any of the following symptoms: palpitations, agitation, seizure, nausea, vomiting

•Pediatric ingestions >30 mg/kg

•Asymptomatic adult with an ingestion >2 g or >30 mg/kg

In an asymptomatic child or adult with an unintentional ingestion <30 mg/kg or <2 g, respectively, we will recommend home observation. We will call back after two hours to assess for development of any symptoms since the concentration is expected to peak within two to three hours. We will refer to an acute care setting if the patient develops any of the above symptoms.

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

●Sources and toxic dose – Caffeine is found in beverages, energy drinks, foods (table 1), weight-loss and pre-workout supplements (table 2), combination analgesics, and concentrated powders and liquids. Ingestion of >150 to 200 mg/kg has a high risk of lethality, which tends to occur from concentrated caffeine products rather than beverages or foods. (See 'Sources and toxic dose' above.)

●Clinical features – The characteristic caffeine toxidrome includes vomiting, tachycardia, hypokalemia, and hyperglycemia. Toxicity is generally dose dependent, and at higher doses, agitation, seizures, ventricular dysrhythmias, hypotension, and shock can occur. (See 'Clinical features of overdose' above.)

●Evaluation and testing – We obtain the following studies: serum caffeine concentration, serum electrolytes and glucose, complete blood count, and electrocardiogram (ECG). (See 'Laboratory and ancillary studies' above.)

If the hospital laboratory can perform a caffeine assay that results promptly, we obtain serum concentrations immediately and every one to two hours. (See 'Caffeine in-house assay available' above.)

If the caffeine concentration will not result promptly, we obtain it for confirmatory or forensic purposes. The serum potassium concentration can be a surrogate marker that inversely correlates with caffeine concentrations. (See 'Caffeine in-house assay not available' above.)

●Diagnosis – The diagnosis of acute caffeine poisoning is suspected in a patient with concern for an ingestion or supratherapeutic use and characteristic findings (eg, vomiting, tremors, tachycardia, hypokalemia, hyperglycemia). The diagnosis is confirmed with an elevated serum caffeine concentration (>20 mg/L [111 mmol/L]) or a compelling history of an ingestion combined with characteristic findings. (See 'Diagnosis' above.)

●Management by toxicity – A rapid overview table is provided to guide management (table 4).

•Dysrhythmias – In a patient with caffeine-induced supraventricular tachycardia (SVT; other than mild sinus tachycardia), we suggest administration of a benzodiazepine or a beta-1-selective-adrenergic antagonist (Grade 2C). In a patient with a symptomatic, hemodynamically stable sinus tachycardia, a benzodiazepine (eg, lorazepam) is a reasonable option for first-line therapy. In a patient with a severe sinus tachycardia (ie, heart rate >150 beats per minute) or other SVT, either esmolol or metoprolol is an option, but esmolol has the advantage of being ultra-short acting. (See 'Dysrhythmias' above.)

In a patient with a ventricular dysrhythmia, we suggest administration of a beta-adrenergic antagonist (eg, esmolol) in addition to standard resuscitation measures (Grade 2C). (See "Advanced cardiac life support (ACLS) in adults", section on 'Management of specific arrhythmias' and "Pediatric advanced life support (PALS)", section on 'Heart rate and rhythm'.)

•Seizure – We administer benzodiazepines (eg, lorazepam 4 mg [0.1 mg/kg intravenously (IV); maximum 4 mg/dose]) for first-line treatment followed by a barbiturate (eg, phenobarbital) or propofol for persistent or recurrent seizures. Phenytoin and fosphenytoin may be harmful. (See 'Seizure' above.)

•Hypotension – We initially administer isotonic IV fluid boluses, escalating to vasopressor therapy as needed (eg, phenylephrine) (table 5).

In a patient with refractory hypotension or as an alternative to vasopressor therapy, we suggest administering a beta-adrenergic antagonist (eg, esmolol) (Grade 2C). Although counterintuitive, this can actually increase blood pressure by inhibiting the beta-2-induced vasodilation and beta-1-induced tachycardia. (See 'Hypotension' above.)

•Vomiting – Ondansetron (if normal QTc interval) or metoclopramide, often in large doses, may be required. (See 'Vomiting' above.)

•Tremulousness, anxiety, and restlessness – We administer benzodiazepines (eg, lorazepam 0.5 to 2 mg IV or orally). (See 'Tremulousness, anxiety, restlessness' above.)

•Hypokalemia – We replete potassium only if hypokalemia is symptomatic (eg, muscle weakness, ventricular dysrhythmias, abnormal T waves, prolonged QTc interval). Aggressive correction of hypokalemia may cause hyperkalemia as toxicity resolves and potassium shifts out of the intracellular compartment. (See 'Hypokalemia' above.)

●Role of gastrointestinal decontamination – In a patient who presents within two hours of a reported caffeine ingestion with preserved mental status and no emesis, we suggest administration of single-dose activated charcoal (AC) (Grade 2C). The dose of AC is 50 g orally (1 g/kg to maximum dose 50 g). We lavage with a standard nasogastric tube if the patient is within one hour of a reported ingestion of concentrated powder or liquid but do not perform lavage with a large-bore orogastric tube. (See 'Role of gastrointestinal decontamination' above.)

●Role of elimination enhancement

•Multiple-dose activated charcoal (MDAC) – In a patient with anything beyond mild symptoms (eg, sinus tachycardia, restlessness), we suggest treatment with MDAC (Grade 2C). The initial dose is 0.5 g/kg (maximum dose 50 g) AC followed by 0.5 g/kg (maximum dose 50 g) every four hours or 0.25 g/kg (maximum dose 25 g) every two hours of AC without sorbitol. (See 'Multiple-dose activated charcoal' above.)

MDAC increases elimination by limiting enterohepatic recirculation; the evidence is discussed separately. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Multidose activated charcoal'.)

•Extracorporeal removal – In a patient with any of the following (table 6), we recommend enhancing caffeine elimination with hemodialysis (Grade 1B) (see 'Indications for extracorporeal removal' above):

-Presence of seizures

-Life-threatening dysrhythmias or shock

-Clinical deterioration despite optimal therapy

-Progressively worsening moderate to severe symptoms and inability to tolerate MDAC

-Serum caffeine concentration (if available) >100 mg/L (555 mmol/L) in acute exposure

We also suggest hemodialysis for the following indications (Grade 2C):

-Serum caffeine concentration (if available) >60 mg/L (333 mmol/L) in chronic exposure

-Caffeine concentration (if available) that is rising despite MDAC