Caffeine Poisoning: A Scientific Guideline

Epidemiology

Severe and lethal caffeine poisoning tends to involve the ingestion of concentrated caffeine products (e.g., caffeine-containing medications or pure anhydrous caffeine powder) rather than beverages or foods containing caffeine. Approximately 3000 single-substance caffeine exposures involving two or fewer fatalities are reported annually to United States regional poison control centers. Approximately 1000 energy drink exposures are reported annually, with one fatality reported between 2017 and 2020. Cases of intentional and unintentional caffeine poisoning have increased with the use of caffeine-enhanced items and highly concentrated caffeine products.

Pharmacokinetics

Absorption: Caffeine is rapidly absorbed from the stomach and small intestine with 90 to 100 percent bioavailability. Peak caffeine concentrations occur 30 to 60 minutes after oral intake.

Distribution: Caffeine distributes into the total body water compartment and has a volume of distribution of approximately 0.7 L/kg. Caffeine crosses the placenta and passes into breast milk. It has a relatively low volume of distribution and low plasma protein binding.

Metabolism: Caffeine is hepatically metabolized via cytochrome P450 (CYP1A2) into paraxanthine (major metabolite), theobromine, and theophylline (minor metabolites). There is significant inter-individual variability in caffeine biotransformation.

Elimination: The mean plasma elimination half-life is approximately five hours in healthy adults. 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 has a half-life of 2 to 12 hours, is nearly 100% bioavailable, and reaches maximal concentrations in the body within an hour of ingestion.

Mechanisms of Toxicity

Caffeine is a nonselective adenosine receptor antagonist. This antagonism promotes catecholamine release, resulting in increased myocardial inotropy and chronotropy, peripheral vasoconstriction, and CNS excitation. At high concentrations, caffeine inhibits phosphodiesterase, increasing cyclic adenosine monophosphate (cAMP) and intracellular calcium concentrations. This leads to beta-adrenergic effects such as smooth muscle relaxation, peripheral vasodilation, increased myocardial inotropy and chronotropy, skeletal muscle contractility, and further CNS excitation.

Toxic Dose

• High Risk: Ingestion of >150 to 200 mg/kg poses a high risk of lethality.

• Potential Risk: Toxicity symptoms can occur with doses as low as 30 mg/kg.

• Fatal Ingestions: Fatalities have been reported with doses between 5 to 50 grams.

• Therapeutic Consumption: Up to 400 mg per day is generally safe for adults. For children and adolescents, up to 2.5 mg/kg per day is not associated with adverse effects.

Sources

Caffeine is a common component of various beverages, energy drinks, and chocolates. It is present in many over-the-counter weight-loss and pre-workout supplements, combination analgesics, and concentrated powders and liquids.

Therapeutic and Toxic Serum Concentrations

• Therapeutic Range: 8 to 20 mg/L for treating apnea of prematurity.

• Potentially Toxic: >20 mg/L

• Consistently Toxic: >50 mg/L

• Associated with Fatality: >80 mg/L

• Postmortem Concentrations: Mean of 187 mg/L in fatal cases.

Clinical Presentation and Signs and Symptoms Based on Severity

Mild to Moderate Toxicity

• Symptoms: Anorexia, tremor, restlessness, nausea, vomiting, tachycardia, nervousness, twitching, anxiety, tremulousness, insomnia, palpitations, hyperreflexia.

Severe Toxicity

• Symptoms: Hypokalemia, hyperglycemia, metabolic acidosis, rhabdomyolysis, hypotension, confusion, seizures, tachycardia, nonfatal dysrhythmia.

Management of Toxicity Based on Severity

Management of Mild to Moderate Toxicity

• Initial Management and Supportive Care:

  • ABCs: Assess and stabilize airway, breathing, and circulation. Obtain intravenous (IV) access and establish cardiac monitoring.

  • Gastrointestinal Decontamination: Administer single-dose activated charcoal (AC) within two hours of ingestion if the patient has preserved mental status and no emesis.

  • Symptom Management: Treat symptoms such as tremor, anxiety, and restlessness with benzodiazepines (e.g., lorazepam or diazepam) orally or IV.

Management of Severe Toxicity

• Initial Management and Supportive Care:

  • ABCs: Assess and stabilize airway, breathing, and circulation. Obtain intravenous (IV) access and establish cardiac monitoring.

  • Gastrointestinal Decontamination: Administer single-dose activated charcoal (AC) within two hours of ingestion if the patient has preserved mental status and no emesis. Use nasogastric lavage within one hour for large ingestions of caffeine powder or concentrated liquid.

• Dysrhythmias:

  • Supraventricular Tachycardias (SVTs): Administer benzodiazepines or a beta-1-selective-adrenergic antagonist. Use esmolol or metoprolol for severe sinus tachycardia. Consult nephrology for hemodialysis in life-threatening dysrhythmias.

  • Ventricular Dysrhythmias: Administer a beta-adrenergic antagonist (e.g., esmolol) in addition to standard resuscitation measures.

• Seizures: Administer benzodiazepines (lorazepam or diazepam) for first-line treatment, followed by barbiturates (phenobarbital) or propofol for persistent or recurrent seizures.

• Hypotension:

  • Initial Treatment: Isotonic IV fluids. Escalate to vasopressor therapy with phenylephrine or norepinephrine, or use a beta-adrenergic antagonist (esmolol) for refractory hypotension.

• Vomiting: Use ondansetron or metoclopramide for severe and prolonged vomiting. Avoid cimetidine as it may reduce caffeine clearance.

• Tremulousness, Anxiety, Restlessness: Administer benzodiazepines (lorazepam or diazepam) orally or IV.

• Hypokalemia: Administer potassium supplementation in symptomatic hypokalemia. Monitor serum potassium every two to four hours.

Antidote

Currently, there is no specific antidote for caffeine toxicity. Management is primarily supportive and symptomatic, focusing on stabilizing the patient's cardiovascular and neurological status, enhancing the elimination of caffeine, and addressing specific symptoms as they arise.

Observation Criteria

• Acute Care Facility: Admit patients with ongoing tachydysrhythmias, hypotension, seizures, hemodynamic instability, persistent vomiting, requiring extracorporeal removal, serum potassium <2.9 mEq/L, or serum caffeine concentration >50 mg/L to a critical care setting.

• Outside Acute Care Facility: Refer patients with intentional ingestion, symptomatic palpitations, agitation, seizure, nausea, vomiting, pediatric ingestions >30 mg/kg, or asymptomatic adult ingestion >2 g or >30 mg/kg to an acute care facility.