DESCRIPTION

Caffeine is a methylxanthine medication most commonly used as a mild stimulant.

FORMS AND USES

• Caffeine, coffeinum, theobromine, and theophylline are methylxanthines.
  • Caffeine is found in a wide variety of beverages
  • Caffeine is a component in pharmaceutical preparations, including BC Remedy, Cafergot, Darvon Compound, DHC Plus, Esgic-Plus, Excedrin Asprin Free, Excedrin Extra Strength, Fioricet, Fiorinal, Goody's Headache Powders, Midol Maximum Strength, NoDoz, Norgesic Tablets, and Vanquish.
• Apnea of prematurity. Loading dose is 20 mg/kg caffeine citrate intravenously or orally, followed 2 to 3 days later by 5 to 10 mg/kg every 12 hours.
• Headache. Adult dose is 500 mg caffeine sodium benzoate intravenously for two doses.
• Prolongation of electroconvulsive seizures. Adult dose is 500 mg caffeine sodium benzoate 5 minutes before treatment.

TOXIC DOSE

• Adults may develop overt toxicity beginning at 1 g, with death reported at doses of 5 to 10 grams.
• Children have developed toxicity at doses of 36 mg/day.

PATHOPHYSIOLOGY

• Caffeine produces direct antagonism of adenosine receptors and inhibits phosphodiesterase, increasing intracellular cyclic adenosine monophosphate and calcium.
• In overdose, caffeine is associated with elevated levels of epinephrine and norepinephrine. These effects result in smooth muscle relaxation, vasodilation as well as cardiac and CNS stimulation.

EPIDEMIOLOGY

• Poisoning is common.
• Toxic effects are typically mild to moderate.
• Severe toxicity is rare, with death occurring only after massive ingestion or therapeutic dosing errors in infants.

CAUSES

• Poisoning is usually accidental in children or the result of therapeutic misuse in an adult.
• Child neglect or abuse should be considered if the patient is less than 1 year of age, suicide attempt if the patient is greater than 6 years of age.

RISK FACTORS

Patients at the extremes of age are more susceptible to the effects of caffeine.

DRUG AND DISEASE INTERACTIONS

Caffeine produces additive effects with sympathomimetic drugs.

PREGNANCY AND LACTATION

• US FDA pregnancy category B. Animal studies do not indicate fetal risk, and there are no controlled human studies, or animal studies do show an adverse effect but well-controlled human studies have failed to demonstrate fetal risk.
• Caffeine may potentiate the teratogenic effects of alcohol and tobacco.

Section Outline:

• DESCRIPTION
• FORMS AND USES
• TOXIC DOSE
• PATHOPHYSIOLOGY
• EPIDEMIOLOGY
• CAUSES
• RISK FACTORS
• DRUG AND DISEASE INTERACTIONS
• PREGNANCY AND LACTATION

• Caffeine is similar to theophylline.
• Severe caffeine toxicity causes nausea, vomiting, anxiety, tremors, seizures, dysrhythmia, hypotension, hypokalemia, and an increased anion gap metabolic acidosis.

DIFFERENTIAL DIAGNOSIS

• Toxicologic causes include intoxication with other sympathomimetic drugs (e.g., theophylline, cocaine, amphetamines, ephedrine, phenylpropanolamine) as well as lithium and monoamine oxidase inhibitors. The early stages of serotonin syndrome or neuroleptic malignant syndrome also may appear similar.
• Nontoxicologic causes include agitation from any cause (withdrawal, hypoglycemia, psychiatric disease, etc.).

SIGNS AND SYMPTOMS

Vital Signs

• Tachycardia is common, even with mild toxicity.
• Hypertension may be present early, but progresses to hypotension in more severe cases.
• Hyperthermia may develop in severe toxicity.

HEENT

Mydriasis is common as part of the sympathomimetic state.

Dermatologic

Diaphoresis may develop as part of the sympathomimetic state.

Cardiovascular

• Sinus tachycardia is common.
• A variety of either supraventricular or ventricular dysrhythmias may develop with severe toxicity.
• Hypotension may be heart rate related or a component of generalized cardiovascular collapse seen in severe toxicity.

Pulmonary

Respiratory failure develops rarely, following massive overdose.

Gastrointestinal

Nausea and vomiting are very common.

Fluids and Electrolytes

• Hypokalemia and hyperglycemia are common.
• Lactic acidosis may occur.

Musculoskeletal

Rhabdomyolysis may occur with psychomotor agitation.

Neurologic

• Anxiety, restlessness, insomnia, headache, and tremor are common following mild to moderate overdose.
• Tinnitus, altered mental status, hyperreflexia, clonus, photophobia, and seizures occur with severe intoxication.

Psychiatric

Delirium, psychosis, and hallucinations occur rarely.

PROCEDURES AND LABORATORY TESTS

Essential Tests

• Serum electrolytes, BUN, creatinine concentrations.
  • The diuretic effect of caffeine may cause fluid and electrolyte abnormalities.
  • An increased anion gap lactic acidosis may be associated with seizures, hypotension, or a hyperadrenergic state.
• ECG
  • Sinus tachycardia is common.
  • Various tachydysrhythmias may develop.
  • Myocardial ischemia is possible.

Recommended Tests

• Serum creatine kinase concentration determination is recommended in symptomatic patients with agitation to detect rhabdomyolysis and guide fluid therapy.
• Urine or serum toxicology screen confirms exposure if history of exposure is absent.
• Serum theophylline level. Caffeine is metabolized to theophylline, and a nontoxic serum level of theophylline may be detected.

Section Outline:

• DIFFERENTIAL DIAGNOSIS
• SIGNS AND SYMPTOMS
  • Vital Signs
  • HEENT
  • Dermatologic
  • Cardiovascular
  • Pulmonary
  • Gastrointestinal
  • Fluids and Electrolytes
  • Musculoskeletal
  • Neurologic
  • Psychiatric
• PROCEDURES AND LABORATORY TESTS
  • Essential Tests
  • Recommended Tests

• Focus treatment on decontamination, control of vomiting, support of hemodynamic function, and control of agitation.
• Dose and time of exposure should be determined for all substances involved.

DIRECTING PATIENT COURSE

The health-care professional should call the poison control center when:

• Persistent agitation, seizure, hypotension, or serious dysrhythmia is present.
• Signs and symptoms are not consistent with caffeine poisoning.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

The patient should be referred to a health-care facility when:

• Attempted suicide or homicide is possible.
• The patient or caregiver seems unreliable.
• Serious symptoms have developed.
• Coingestant, drug interaction, or underlying disease presents unusual challenge.

Admission Considerations

Inpatient management is warranted for patients with serious effects: cardiac dysrhythmia, seizures, hypotension, persistent vomiting or agitation, or electrolyte abnormalities.

DECONTAMINATION

Out of Hospital

Emesis should not be induced because of the risk of seizures and possibility of persistent emesis.

In Hospital

• Emesis should not be induced.
• Gastric lavage should be performed in pediatric (tube size 24-32 French) or adult (tube size 36-42 French) patients presenting within 1 hour of substantial ingestion or if serious effects are present. Gastric lavage is not indicated following repeated spontaneous vomiting.
• One dose of activated charcoal (1-2 g/kg) should be administered without a cathartic if substantial ingestion has occurred within the previous few hours.
• Following a large ingestion or in patients who have serious signs or symptoms, one to two extra doses of activated charcoal (0.5-1 g/kg) are recommended at 2- to 4-hour intervals.

ANTIDOTES

There is no specific antidote for caffeine poisoning.

ADJUNCTIVE TREATMENT

Persistent Vomiting Refractory to Initial Antiemetic

• Suggested antiemetic adult regimen is intravenous metoclopramide 0.5 to 1 mg/kg plus intravenous diphenhydramine 25 to 50 mg combined with intravenous prochlorperazine 10 mg or droperidol 2.5 mg.
• Intravenous ondansetron 8 mg infused over 15 minutes is an alternative in refractory cases.

Psychomotor Agitation

• A benzodiazepine familiar to the provider should be administered.
  • Diazepam. Adult dose is 5 to 10 mg intravenously, pediatric dose is 0.2 to 0.5 mg/kg intravenously, repeated at 10-minute intervals, titrating to effect, or
  • Lorazepam. Adult dose is 2 to 4 mg intravenously, pediatric dose is 0.05 mg/kg, intravenously, repeated at 10-minute intervals, titrating to effect.
• The airway should be monitored closely.

Tachydysrhythmia

• Overview. A variety of standard therapies for tachydysrhythmia have been used (esmolol, lidocaine, phenytoin, and procainamide), depending on rhythm.
• Esmolol. The loading dose is an intravenous bolus of 500 µg/kg infused over 1 minute followed by an infusion of 50 µg/kg/min for 4 minutes. If the response is inadequate, the loading dose is repeated and the infusion increased to 100 µg/kg/min for 4 minutes. Titration is continued until the heart rate is controlled or toxicity (hypotension) develops.
• Unopposed alpha-receptor stimulation is a theoretical concern during beta-blockade. If heart rate or blood pressure increase precipitously during infusion, alpha-receptor stimulation may be the cause.
• Hypokalemia is common, and potassium should be replaced as needed.

Serious Complications of Intoxication

Hemodialysis is recommended when serious effects such as dysrhythmia, seizures, and hypotension complicate intoxication. It is rarely needed.

Section Outline:

• DIRECTING PATIENT COURSE
  • Admission Considerations
• DECONTAMINATION
  • Out of Hospital
  • In Hospital
• ANTIDOTES
• ADJUNCTIVE TREATMENT
  • Persistent Vomiting Refractory to Initial Antiemetic
  • Psychomotor Agitation
  • Tachydysrhythmia
  • Serious Complications of Intoxication

PATIENT MONITORING

Symptomatic patients require continuous monitoring of respiratory and cardiac status and potassium levels until signs and symptoms of toxicity resolve.

EXPECTED COURSE AND PROGNOSIS

Signs and symptoms typically occur within 2 to 4 hours and peak within a few hours. If treated with appropriate supportive care, nearly all patients recover without sequelae.

DISCHARGE CRITERIA/INSTRUCTIONS

• From the emergency department. The asymptomatic patient can be discharged after gastrointestinal decontamination and 4- to 6-hour observation or after signs and symptoms have resolved, following psychiatric evaluation, if needed.
• From the hospital. The patient can be discharged after signs and symptoms of caffeine intoxication have resolved and following psychiatric evaluation, if needed.

Section Outline:

• PATIENT MONITORING
• EXPECTED COURSE AND PROGNOSIS
• DISCHARGE CRITERIA/INSTRUCTIONS

DIAGNOSIS

• Waiting for the results of toxicologic screening should not delay instituting aggressive supportive care.
• Caffeine withdrawal symptoms may occur following chronic exposure, but would not be expected following an acute overdose.

TREATMENT

There should be no delay in consulting nephrology or transporting patients with life-threatening effects to a facility capable of performing hemodialysis

Section Outline:

• DIAGNOSIS
• TREATMENT

Poisoning by psychotropic agents: psychostimulants.

See Also: SECTION III, Activated Charcoal chapter.

RECOMMENDED READING

Aaronson LS, Macnee CL. Tobacco, alcohol, and caffeine use during pregnancy. J Obstet Gynecol 1989;18:279-287.

Benowitz NL, Osterloh J, Goldschlager N. Massive catecholamine release from caffeine poisoning. JAMA 1982;248:1097-1098.

Author: Edwin K. Kuffner

Reviewer: Katherine M. Hurlbut