Caffeine Toxicity - Bruce Grattan, DO, MS, RD, PGY-1
A 17-year-old male presents to your emergency department brought in by EMS from a local Crossfit Gym with chief complaints of anxiety, dizziness, nausea, and palpitations. He is ill-appearing without evidence of trauma. According to EMS, the patient was just about to participate in his daily workout when he experienced a pre-syncopal episode consisting of dizziness, nausea, and lightheadedness that lasted for approximately one minute, and prompted bystanders to call EMS. On arrival to your department, his GCS is 15 and vitals are as follows: HR 160, RR 24, BP 100/60, temp 37.2C, SpO2 100% on room air, and blood glucose of 150. The patient is extremely anxious, making further history difficult. His pulse is tachycardic and regular without murmurs, rubs, or gallops. His lungs are clear to auscultation bilaterally. His pupils are equal, round, and reactive to light, and there is no muscle weakness or sensory deficits. His abdomen is soft, nontender, and non-distended. You note that his skin is clammy, but there are no rashes or lesions; his axillae are moist. Deep tendon reflexes are 2+ bilaterally. Here is his ECG:
The differential diagnosis would include: thyrotoxicosis, sympathomimetic toxicity, panic disorder, sedative/hypnotic withdrawal, tension pneumothorax, sepsis, dehydration, carotid and aortic dissection, myocardial infarction, esophageal rupture, anemia, atrial fibrillation, carbon monoxide toxicity, cyanide toxicity, delirium tremens, diabetic ketoacidosis, disulfuram toxicity, intracranial hemorrhage, status epilepticus, among others.
Labs showed the following:
WBC: 13.5 (68% neutrophils)
UTox: negative for amphetamines, benzodiazepines, cocaine, marijuana, opiates and PCP
CXR: showed no acute cardiopulmonary process
Bedside echo: structurally normal heart, no pericardial effusion, normal overall squeeze
EKG: polymorphic tachycardia with wide complex QRS
ABG: metabolic acidosis with pH of 7.29, PCO2 30, pO2 117, bicarb 16
Lactate: 5.3 mmol/L (0.5-1.6)
Caffeine is one of the most widely consumed psychoactive compounds with nearly 80% of Americans reporting daily consumption. Caffeine-enhanced products are often marketed for use in enhancing physical and mental performance, leading athletes and those with active lifestyles subject to potentially deleterious effects when taken in excess. In 2012 there were an estimated 5 billion caffeinated energy drinks sold in the U.S.
Why is this relevant to the emergency physician? Between 2007 and 2011, the number of energy drink-related visits to EDs doubled, and in 2011, 1 in 10 of these visits resulted in hospitalization. In 2016 there were 3,702 caffeine-related incidents reported to Poison Control Centers in the U.S. with an equal ratio of pediatric and adult cases. Of these, 846 cases required treatment at a medical facility and there were 16 major outcomes. The Drug Abuse Warning Network (DAWN) found that from 2005 to 2011, the number of ED visits for caffeine increased from 1500 to >20,000 annually. A 2014 study found that nearly 40% of the calls to poison control centers concerning children under the age of 16 were related to energy drink consumption.
America has a long history of caffeine enhanced products. In fact, in 1911 the government initiated a case under the 1906 Pure Food and Drug Act trying to force the Coca-Cola Company to remove caffeine from Coca-Cola, believing that the product was adulterated and misbranded.
Yet over the past decade or so, the amount of caffeine in products has increased. Today’s cup of coffee is not your grandma’s cup of joe. Traditional coffee contains 100mg of caffeine in a 12oz cup. However, we have seen the rise of highly caffeinated products recently, including “black insomnia,” which debuted in October 2017 packing 700mg of caffeine into 12oz. Additionally, the fitness community has seen the introduction of powders and pills containing caffeine marketed as pre-workout products with powders containing 300-500 mg and pills often containing 300mg per pill. By comparison, a typical No-Doze pill contains 200mg of caffeine.
Mechanism of action and metabolism
Natural alkaloid methylxanthine, similar to theophylline (naturally found in tea) and theobromine (naturally present in chocolate)
Inhibits the adenosine receptor --> CNS activation, release of neurotransmitters (norepinephrine, dopamine, acetylcholine, serotonin, and glutamate)
Norepinephrine stimulates β1 and β2 receptors --> tachycardia, peripheral vasodilation, and hypotension
Hypotension --> Renin excretion --> hypertension, sodium retention, and water retention
Increased renal blood flow --> diuresis, subsequent dehydration, and tachycardia
Caffeine increases lipolysis (--> elevated lactic acid), generates arrhythmias, and alters fine motor coordination
Agonist of ryanodine receptor --> release of calcium from intracellular stores needed for muscle contraction including in the myocardium
Alters ryanodine receptor making it more sensitive to calcium --> less restricted calcium release and more frequent depolarizations
Antagonizes benzodiazepine receptor --> lower seizure threshold
Plasma levels peak in 20-40 minutes; faster if via oral mucosa (gum) or skin (patches)
Metabolized by liver enzymes (CYP450) into paraxanthine (similar effects to caffeine)
Mean half-life is 5 hours; can be influenced by smoking, altitude, oral contraceptive use, obesity, chronic alcohol ingestion and pregnancy
Estrogen status alters the activity of liver enzymes and can increase half-life
Nicotine accelerates metabolism of caffeine
An acute fatal dose of caffeine has been calculated at 10-14 grams or 150-200mg/kg. However, even 1 gram (15mg/kg) has been shown to lead to restlessness, nervousness, tremors, convulsions, irritability, delirium, and emesis. While toxic ingestions can be seen after consuming energy drinks, it rarely occurs as the result of drinking coffee or tea because of the excessive amount of fluid that would have to be ingested to reach toxic caffeine levels. Nausea and vomiting are seen in more than 70% of cases. Electrolyte abnormalities can also result including hypokalemia, hyperglycemia, and metabolic acidosis. These electrolyte disturbances, in combination with hyper-agitated states and seizures, can lead to rhabdomyolysis.
Other energy drink ingredients
Are these effects mediated by caffeine or the other components often found in energy drinks? Most drinks available contain less than 200mg of caffeine per serving which may not sound like much; however, these beverages are consumed far faster than a steaming cup of coffee. These drinks often contain other stimulants and sources of caffeine which are not studied in combination:
Guarana: 3-4% caffeine
Arabica beans: 1-2% caffeine
Ginseng (stimulates the HPA axis and increases the release of ACTH)
Yerba mate (leaves of a shrub in the Holly family)
Taurine (stimulates GABAergic neurons, specifically GABAa receptor à increases stroke volume and blood pressure)
Anhydrous caffeine: one teaspoon is equivalent to 25-28 cups of coffee. Some serving sizes are 1/16th of a teaspoon! According to the FDA website “it is nearly impossible to accurately measure pure powdered caffeine with common kitchen measuring tools and you can easily consume a lethal amount.”
Signs and symptoms
tachycardia or bradycardia, ventricular ectopy, dysrhythmias
altered mental status: agitation, delusional thought, hallucinations, seizures
hypertension or hypotension
hypokalemia, hyponatremia, hypocalcemia, hyperglycemia
fever, nausea, vomiting
Caffeine toxicity is primarily a clinical diagnosis made by obtaining a thorough history and having a high degree of suspicion. There are no specific physical exam findings and patients will often have a normal neurological exam (occasionally ischemia from vasoconstriction can cause a focal neuro deficit). Serum caffeine levels may not be readily available in all hospitals; lethal levels are above 80-100mg/L.
3 B’s: “bolus, benzos, and beta blockade” - Bolus: intravenous fluids to support BP and cardiac output, as well as maintain adequate renal perfusion - Benzodiazepines: to treat agitation/seizures. Phenobarbital (10-20mg/kg IV) can be used in adults if benzodiazepines are not effective. Avoid phenytoin. - Beta blockade: cardio-selective agents such as esmolol or metoprolol. Keep in mind that patients with supraventricular tachycardias may not respond to adenosine due to antagonism from the caffeine molecule.
Additional Measures - Phenylephrine will reduce the tachycardia while supporting the blood pressure - Vasopressin has also been used for inotropic support - Lidocaine/procainamide can be given for arrhythmias - Activated charcoal can be used to both prevent further absorption and enhance elimination - Intra-lipid therapy has been shown to be beneficial
If it is a known caffeine ingestion consider hemodialysis as caffeine is readily dialyzable. The mean plasma protein binding of caffeine (36%), the molecular size (194), and the volume of distribution (0.6–0.8 L/kg) make hemodialysis a possible modality to enhance elimination
Pitfalls to avoid
Phenothiazines such as promethazine should be avoided as this may lower the seizure threshold in a patient already at higher risk
Avoid use of cimetidine as it can inhibit P450 enzymes potentially resulting in half-life prolongation
As with all intentional ingestions one must be mindful of the possibility of other comorbid agents including acetaminophen and aspirin
Monitor for rhabdomyolysis
ICU admission: these patients are at high risk for severe electrolyte disturbances and dysrhythmias. Patients require close monitoring and, frequently, emergent hemodialysis.
These cases are often fatal with only two case reports of a patient surviving a dose larger than 50g.
After stabilization with benzodiazepines and IV fluids the patient explains that he had used a pre-workout anhydrous caffeine powder before his symptoms began. He lost the packaged measuring spoon and added an unknown amount to his water bottle. The patient was treated with beta blockers and supportive care. He was admitted to the ICU, monitored overnight, and discharged the following day. He was counseled to avoid his pre-workout supplements and to use proper measuring devices.
Comment below to share if you have treated a patient with caffeine toxicity and how they were treated!
Edited by Dr. Alexandra Murray, author of a StatPearls article on this same subject; check out her article here!
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