Rhabdomyolysis induced by excessive coffee drinking

Introduction

Rhabdomyolysis is defined as muscle necrosis with release of muscle cell constituents into the bloodstream and a rise in plasma creatine kinase (CK) level to greater than five times the upper limit of normal. ¹ Patients with rhabdomyolysis usually present with muscle pain, limb weakness, swelling of the affected muscles, and tea-colored urine. In severe cases, rhabdomyolysis can result in life-threatening hyperkalemia and myoglobin-induced acute kidney injury. The etiologies of rhabdomyolysis are heterogeneous and can be categorized into physical and nonphysical causes of muscular injury. The physical causes include trauma, compression, strenuous exercise, electrical current, and hyperthermia, while the nonphysical causes comprise endogenous factors—congenital myopathies, electrolyte disturbances, and endocrine diseases—and exogenous toxins—venom, infections, and drugs, such as statins, colchicine, alcohol, heroin, and cocaine. ² Caffeine, a common constituent of energy drinks, is rarely acknowledged as a potential cause of rhabdomyolysis. In this report, we present a 44-year-old woman who rapidly developed rhabdomyolysis following excessive caffeine ingestion for the purpose of nocturnal mental alertness.

Case report

A 44-year-old woman presented to our emergent department (ED) with nausea, vomiting, chest tightness, muscle twitching, palpitations, and tea-colored urine 6 h after ingestion of 4 cups of black coffee (approximately 1000 mL) to keep her awake at night. She denied any past medical history or medications. On initial examination, she had a regular, rapid heartbeat of 110 beats per minute, blood pressure of 136/92 mmHg, respiration rate of 20 breaths per minute, body temperature of 36.2°C, and oxygen saturation of 99% on room air. Her cardiac and pulmonary exams were normal and there was no icterus, jugular venous distension, hepatomegaly, splenomegaly, or extremity edema. Relevant laboratory studies included sodium 138 mmol/L (reference range 136–145 mmol/L), potassium 4.4 mmol/L (reference range 3.5–5.1 mmol/L), chloride 104 mmol/L (reference range 98–107 mmol/L), magnesium 2.1 mg/dL (reference range 1.7–2.5 mg/dL), calcium 8.6 mg/dL (reference range 8.6–10.2 mg/dL), inorganic phosphate 3.0 mg/dL (reference range 2.7–4.5 mg/dL), uric acid 5.1 mg/dL (reference range 3.4–7.0 mg/dL), blood urea nitrogen 7 mg/dL (reference range 6–20 mg/dL), creatinine 0.7 mg/dL (reference range 0.7–1.2 mg/dL), CK 274 U/L (reference range 26–308 U/L), CK-MB 19 U/L (reference range 0–25 U/L), aspartate aminotransferase (AST) 45 U/L (reference range 0–40 U/L), and alanine aminotransferase (ALT) 108 U/L (reference range 0–41 U/L). Urinalysis revealed occult blood 3+, pH 6.0, red blood cells approximately 0–2/high-power field, and positive myoglobin. Electrocardiography showed sinus tachycardia. Toxicology screening of salicylates, cocaine, and phenylephrine was all negative.

After 4 h of observation and intravenous saline in the ED, her CK and CK-MB increased to 7315 and 266 U/L, respectively, with troponin I < 0.01 ng/mL. Ten hours after drinking black coffee, her plasma caffeine concentration was still 4 μg/mL (reference range 0.2–13.1 μg/mL), suggesting caffeine overdose (average half-life of caffeine was 5 h, hence the initial plasma caffeine concentration was estimated to be 16 μg/mL). The patient was treated with 4–5 L of intravenous saline and alkalization with sodium bicarbonate. Her plasma CK level decreased to 3638 U/L after 30 h of hospitalization (Figure 1). After 5 days of supportive care, she had fully recovered without any recurrence of elevated CK or neuromuscular sequelae. Her plasma AST and ALT levels also returned to normal within 2 weeks.

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Figure 1.

Serial plasma CK level after excessive caffeine ingestion. CK: creatine kinase.

Discussion

Caffeine is a major constituent of coffee and its content varies widely depending on the type of coffee bean. In general, one small cup of coffee (177 mL) provides 100 mg of caffeine. ³ The ordinary consumption of 2–3 cups of coffee, containing 250 mg of caffeine, usually does not cause adverse health effects. ⁴ Caffeine overdose is usually associated with a plasma level greater than 30 mg/L or daily intake greater than 6 mg/kg body weight. ^5,6 The reported lethal dose in human is 150–200 mg/kg body weight or 5–10 g of total ingested caffeine. ⁷ It should be noted that the rate of caffeine metabolism is highly variable and its half-life ranges from 3 to 7 h. ⁶ Furthermore, the development of caffeine toxicity is also dependent on individual sensitivity. This patient’s CK level was normal 6 h after coffee drinking because plasma CK usually begins to rise 2–12 h following the onset of muscle injury. ⁸ She developed rhabdomyolysis without any identifiable causes besides the ingestion of large amounts of black coffee (estimated caffeine about 565 mg and 14 mg/kg body weight) over a few hours at night. Considering the clinical features and time of blood drawn after the patient’s reported ingestion, caffeine overdose is likely to be high. Other chemicals in coffee, to the best of our knowledge, are not associated with rhabdomyolysis. ⁹

Besides coffee, caffeine is also present in various foods and drinks, such as tea (120–420 mg caffeine/L), soft drinks (e.g. cola, 100 mg caffeine/L), energy drinks (e.g. Red bull, 320 mg caffeine/L), chocolate, and over-the-counter caffeine pills (approximately 100 mg/tablet) for enhancing mental alertness. Caffeine acts as a central nervous system stimulant to reduce the sensation of physical fatigue and enhance alertness. It is a natural alkaloid methylxanthine that is metabolized in the liver by polymorphic cytochrome P450 into paraxanthine, theobromine, and theophylline. ^10,11 These metabolites together with caffeine competitively bind to the adenosine receptor to increase catecholamine release. ¹² At higher doses, caffeine inhibits enzymatic activity of phosphodiesterases and increases intracellular concentrations of cyclic adenosine monophosphate, which results in the relaxation of smooth muscles but excitation of skeletal muscles, cardiac myocytes, and neurons. ¹³ Some reports have suggested that caffeine potentiates calcium release from the sarcoplasmic reticulum and causes twitching and tetanic contractions of skeletal muscle. Other manifestations of caffeine toxicity include effects on neuropsychology (psychomotor agitation, restlessness, anxiety, confusion, and seizures), the cardiovascular system (tachyarrhythmias and hypotension), and systemic metabolism (hypokalemia and hyperglycemia). ^{5,7,14 –16} Patients with low body mass (e.g. children and young females with eating disorders) or concurrent use of medications with inhibitory effects on the cytochrome P450 enzyme CYP1A2 (e.g. some quinolone antibiotics) may be more susceptible to caffeine toxicity.

To date, there have only been six reported cases of caffeine-induced rhabdomyolysis (Table 1). ^{15 –19} Most cases were attributed to suicide attempts or accidental overuse of caffeine tablets. The lowest dose of caffeine ingestion in these cases was 20 mg/kg body weight. ¹⁷ The longest duration of rising plasma CK levels was 6 days, indicating that the effects of caffeine may persist for a few days. ¹⁵ Acute kidney injury occurred in four of six patients and was correlated with extremely high plasma CK levels. Of note, most measured plasma caffeine levels were normal, probably due to delayed sampling and the rapid metabolism of caffeine.

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Table 1.

Reports of rhabdomyolysis related to caffeine overdose.

	Wrenn and Oschner 15	Michaelis et al. 17	Kamijo et al. 18	Emohare and Ratnam 16	Chakraborty and Rajeswaran 19	Present patient (2012)
Source of caffeine	Over-the-counter stimulant	Over-the-counter painkiller	Oolong tea	Over-the-counter stimulants	Over-the-counter stimulant	Black coffee
Estimated caffeine intake	3.57 g	1.45 g (20 mg/kg)	3 g (59 mg/kg) daily	17.5 g (233 mg/kg)	15 g	565 mg (14 mg/kg)
Peak plasma CK level	8200 U/L (estimated)	1920 U/L	227,200 U/L	28,352 U/L	10,324 U/L	7315 U/L
Time to peak CK level	Unknown	10–15 h	About 1 day	48 h	Unknown	10 h
Duration of elevated CK	6 days	>40 h	Unknown	Unknown	48 h	55 h
Highest plasma level of caffeine	Unknown	About 26 μg/mL	Undetectable (delayed sampling)	Theophylline 5 mmol/L	Unknown	4 μg/mL (delayed sampling)
Other complications	Acute kidney injury	Subclinical	Acute kidney injury	Cardiac arrest Hypokalemia Acute kidney injury	Hypokalemia Acute kidney injury	None
Associated conditions	Suicide attempt	Suicide attempt	Schizophrenia Water intoxication	Suicide attempt Gunshot trauma	Suicide attempt	None

CK: creatine kinase.

The treatment of rhabdomyolysis due to caffeine toxicity includes discontinuation of caffeine consumption, volume resuscitation, and alkalinization of urine. Activated charcoal has been used successfully and should be reserved for alert patients with recent ingestion and significant toxicity. ²⁰ In severe cases, caffeine can be eliminated by hemodialysis because of its low molecular weight, plasma protein binding, and volume of distribution. ²¹

In all, caffeine-induced rhabdomyolysis may occur more frequently in future as caffeine-containing beverages and over-the-counter preparations become increasingly popular and easily-available. Excessive caffeine ingestion related to large amounts of coffee or other beverages should be considered in the differential diagnosis of rhabdomyolysis.