541997
research-article2014
AOPXXX10.1177/1060028014541997Annals of PharmacotherapyGreene et al
Case Report
Energy Drink–Induced Acute Kidney Injury
Annals of Pharmacotherapy 2014, Vol. 48(10) 1366–1370 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028014541997 aop.sagepub.com
Elisa Greene, PharmD1, Kristy Oman, PharmD1, and Mary Lefler, PharmD1
Abstract Objective:To report a case of acute renal failure possibly induced by Red Bull. Case Summary: A 40-year-old man presented with various complaints, including a recent hypoglycemic episode. Assessment revealed that serum creatinine was elevated at 5.5 mg/dL, from a baseline of 0.9 mg/dL. An interview revealed a 2- to 3-week history of daily ingestion of 100 to 120 oz of Red Bull energy drink. Resolution of renal dysfunction occurred within 2 days of discontinuation of Red Bull and persisted through 10 months of follow-up. Rechallenge was not attempted. Discussion: Energy-drinkinduced renal failure has been reported infrequently. We identified 2 case reports via a search of MEDLINE, one of which occurred in combination with alcohol and the other of which was not available in English. According to the Food and Drug Administration’s (FDA’s) Center for Food Safety and Applied Nutrition Adverse Event Reporting System, between 2004 and 2012, the FDA has received 166 reports of adverse events associated with energy drink consumption. Only 3 of the 166 (0.18%) described renal failure, and none were reported with Red Bull specifically. A defined mechanism for injury is unknown. Assessment of the Naranjo adverse drug reaction probability scale indicates a probable relationship between the development of acute renal failure and Red Bull ingestion in our patient. Conclusions: Acute kidney injury has rarely been reported with energy drink consumption. Our report describes the first English language report of acute renal failure occurring in the context of ingestion of large quantities of energy drink without concomitant alcohol. Keywords energy drinks, acute kidney injury, adverse events, Red Bull, renal dysfunction, acute renal failure Energy drinks were introduced in the United States in 1997.1 Manufacturers have enticed consumers by connecting improved performance, increased arousal and decreased reaction time, enhanced metabolism, and improvement in overall performance to energy drink consumption.2,3 Sales and demand for energy drinks have been strong. In between the years 2006 and 2007 alone, 200 new brands of energy drinks were launched.4 Market growth has shown that Americans have increased consumption from 2.3 billion energy drinks in 2006 to 6 billion in 2010.1 Although consumption continues to increase, little attention has been given to adverse events associated with these drinks. We describe a case of acute kidney injury associated with excessive energy drink consumption that resolved on its discontinuation.
Case Report A 40-year-old Caucasian man presented to the primary care clinic with a 2 week history of complaints of difficulty staying awake, stiffness, and shortness of breath while sleeping. He also reported a recent hypoglycemic episode with blood glucose of 35 mg/dL documented on a home glucometer
approximately 2 weeks prior to the visit, decreased appetite, mild nausea, and abdominal pain. According to the patient, the hypoglycemic event was precipitated by a viral illness and low oral intake. No vomiting or diarrhea was reported. He called the paramedics but was not taken to the emergency department because the hypoglycemic episode resolved rapidly on eating a peanut butter sandwich and drinking a soda. Past medical history was significant for diabetes mellitus type 2, hypertension, anxiety, depression, alcohol abuse, posttraumatic stress disorder, chronic obstructive pulmonary disease, obstructive sleep apnea, gout, and hypertriglyceridemia-induced pancreatitis. He reported 3 months of abstinence from alcohol prior to the date of this visit. Current medications were gemfibrozil 600 mg daily, lamotrigine 100 mg daily, lisinopril 20 mg daily, hydrochlorothiazide 12.5 mg daily, colchicine 0.6 mg as needed for gout, ibuprofen 400 mg as needed for pain, 1
Belmont University College of Pharmacy, Nashville, TN, USA
Corresponding Author: Elisa Greene, Belmont University College of Pharmacy, 1900 Belmont Blvd, Nashville, TN 37212, USA. Email: [email protected]
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Greene et al Table 1. Laboratory Evaluations. Reference Time Point 14 Months prior to presentation Day 1 Day 4 Day 5, evening Day 7 Day 15 10 Months after presentation
Estimated CrCl (mL/min)
SCr (mg/dL)
BUN (mg/dL)
Glucose (mg/dL)
24 0.8 214 17 5.5 108 130 Last ingestion of Red Bull prior to discontinuation (exact time unknown) 87 42 1.1 178 80 33 1.2 287 12 255 106 0.9 106 0.9 — —
Abbreviations: CrCl, creatinine clearance; SCr, serum creatinine; BUN, blood urea nitrogen.
quetiapine 50 mg daily, and sertraline 200 mg daily. Colchicine was most recently used during his last gout attack, which occurred 116 days prior to the date of presentation. The patient admitted to only occasional doses of ibuprofen and denied active use at the time of this visit. Metformin 1000 mg twice daily and glipizide 5 mg twice daily had been discontinued 2 weeks prior at the time of the hypoglycemic episode. The patient denied taking any of his medications on the day of this visit. Physical examination revealed a blood pressure of 113/57 mm Hg, heart rate of 109 bpm, respiratory rate of 18 to 20 breaths/min, temperature of 97.5°F, and O2 saturation of 92% on room air. Height was recorded as 5 feet 3 inches, and weight as 192 lbs (87.3 kg). On examination, the patient appeared hyperkinetic with a mild tic and mild agitation. Hepatomegaly and mild inspiratory wheeze with labored breathing at rest were also noted. All other parameters were within normal limits or consistent with baseline. In office urinalysis revealed trace blood and leucocytes, 1+ glucose and protein, with all other values within normal limits. Fasting blood glucose level was 117 mg/dL. A “breathing treatment” (specific medication and response not documented) was given and followup scheduled for the following week. Blood was collected and sent out for laboratory analysis. Laboratory results were reported the following day and revealed several abnormalities, including a blood urea nitrogen (BUN) of 108 mg/dL (7-20 mg/dL), serum creatinine (SCr) 5.5 mg/dL (0.8-1.4 mg/dL), sodium 130 mmol/ mL (136-145 mmol/L), potassium 5.6 mmol/L (3.7-5.2 mmol/L), chloride 89 mmol/L (96-106 mmol/L), and carbon dioxide 19 mmol/L (20-29 mmol/L). Creatinine clearance of 17 mL/min was estimated using adjusted body weight and the Cockroft-Gault formula. Previous laboratory analysis 14 months prior had revealed a BUN of 24 mg/ dL and SCr of 0.8 mg/dL. At that time, sodium remained slightly low at 133 mmol/L, whereas glucose and albumin were elevated at 214 mg/dL and 5.1 g/dL, respectively. All other parameters were within normal limits at baseline. The most recent hemoglobin A1C (A1C), 3 months prior to presentation, was 6.6%.
When the patient returned for follow-up 5 days later, blood pressure and temperature remained normal, heart rate remained elevated at 99 bpm, and random blood glucose was elevated at 232 mg/dL. Of note, he was fasting the morning of this visit. On questioning by the pharmacist at this visit, the patient described normal urine output and admitted drinking at least 5 to 6 “largest size, 20-oz” Red Bull energy drinks daily for “several” weeks. The last ingestion was on the day prior to this visit (Table 1). At that time, it was determined that after the patient became abstinent from alcohol, he had switched to drinking large amounts of Red Bull. The recent hypoglycemia episode combined with elevated BUN and SCr suggested subacute renal failure, possibly induced by the Red Bull ingestion. The patient was instructed to stop drinking Red Bull, discontinue his gemfibrozil, and take half his usual doses of lamotrigine, lisinopril, and hydrochlorothiazide. Repeat labs were drawn that evening and follow-up, including a planned renal ultrasound, was arranged for the following week. Lab work collected on the evening of this office visit revealed the following: lipase 36 U/L, hemoglobin (Hgb) 10.6, glucose 178 mg/dL, BUN 42 mg/dL, sodium 134 mmol/L, potassium 5.2 mmol/L, and chloride 95 mmol/L. All other labs were within normal limits. SCr had fallen to 1.1 mg/dL, with an estimated creatinine clearance of 87.1 mL/min. The urine obtained for a urinalysis was accidentally discarded; therefore, these results were not available. The patient returned 2 days later (7 days after initial presentation) for follow-up labs. Results showed improvement, although potassium remained elevated at 5.5 mmol/L; BUN improved, but remained elevated at 33 mg/dL; and glucose was elevated at 287 mg/dL (Table 1). All other results from the comprehensive metabolic panel and urine chemistry assessment were normal. At that time, it was determined that these results, taken with the fractional excretion of sodium of 1.12%, suggested neither a prerenal nor postrenal cause definitively, but that his renal failure was nearly resolved. Renal ultrasound was cancelled. Two weeks following initial presentation, all noted electrolyte and renal function abnormalities had resolved (Table 1).
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Annals of Pharmacotherapy 48(10)
Table 2. Ingredient Comparison.7,8 Product
Volume
Caffeine Content
Red Bull
8.4 oz 20 oz
80 mg 190.5 mg
6 oz
107-151 mg
Brewed coffee
Other Ingredients Vitamins B3, B5, B6, B12; sucrose; glucose; taurine; and glucuronolactone None known
The patient reported severe headaches for 1 week on discontinuation of Red Bull. He resumed lisinopril and hydrochlorothiazide therapy at previously prescribed doses at this time and reported that he had stopped lamotrigine entirely. This was not resumed for reasons of patient preference. Based on an A1C of 6.8% at an 8-week follow-up visit, diabetes was controlled without medications at that time, which was attributed to a 25 lb weight loss occurring over the previous year. Metformin was reinitiated at 500 mg daily 5 months later, when A1C increased to 7.9%. After 10 months of follow-up, renal function remained normal (Table 1), and the patient remained abstinent from both Red Bull and alcohol.
Discussion Energy drinks are defined as soft drinks that contain caffeine and may include an assortment of other ingredients, such as herbs, amino acids, vitamins, sugar, and sugar derivates.2,5 Energy drinks such as Red Bull are commonly consumed by young men and are associated with a number of adverse effects discussed in the following paragraphs.6 Caffeine, the primary psychoactive agent in energy drinks, is considered the most commonly used drug in the world.2,3 The caffeine content of energy drinks varies depending on package size and the presence of the caffeine-containing plant, guarana. According to the product Web site, a single 8.4 fl oz can of Red Bull contains 80 mg of caffeine, which the site claims is approximately equal to that in 1 cup of coffee.7 However, as Table 2 illustrates, the caffeine content in 1 brewed coffee typically exceeds this level. Drinking 6 of the 20-oz Red Bull drinks per day, as our patient reported, would provide approximately 1143 mg of caffeine per day. Caffeine content may vary significantly depending on coffee preparation and brewing methods; however, the average cup of coffee contains between 107 and 151 mg of caffeine.8 Drinking approximately 10 cups of an average strength brewed coffee would provide the equivalent amount of caffeine to what our patient consumed. Adverse effects of energy drinks are often attributed to the high caffeine content or the effects of their combination with alcohol, which often occurs. However, to the authors’ knowledge, there is no reported case of renal failure after drinking coffee, so it is plausible that caffeine itself is not the sole contributor to injury. The sustained ingestion of significant quantities over several weeks, speed of ingestion
(ie, repeatedly getting a bolus of caffeine each time) or other ingredients in Red Bull somehow may have contributed. Other medications were considered as possible inducers of renal injury but were determined to be unlikely primary causes. Ibuprofen was consumed only occasionally. Lisinopril was being consumed at the appropriate prescribed dose and had been stable for over a year prior to the incident. These agents were both resumed at the same dose after the event, with no relapse in kidney function. Lamotrigine was discontinued permanently after the event; however, a MEDLINE search revealed no reports of lamotrigine-induced kidney injury. There was no evidence to suggest any other medications were likely causes, and they were resumed with no recurrence of kidney injury after the event. Diabetes was determined to be an unlikely cause because of the well-controlled A1C and return of kidney function without a change in diabetic control. Two weeks prior to presentation, the patient had experienced a viral illness with poor oral intake. He reported no vomiting or diarrhea; however, he could have potentially become dehydrated during this time. This illness alone was considered an unlikely primary cause but could have added to the effects of the energy drink. One would have expected the large quantity of sugar ingested in the Red Bull to worsen the patient’s diabetes control. It is possible that reduced oral intake associated with the viral illness may have contributed to the previous hypoglycemic event and balanced out the effect of the Red Bull ingestion. It does not appear that he experienced other adverse effects from this large amount of carbohydrate because his A1C 8 weeks after the presentation remained steady at 6.8%. Home glucose log levels are not available; however, he did report blood glucose values being “all over the place.” This could be attributed to the carbohydrate component in Red Bull. According to the RIFLE and KDIGO criteria, our patient experienced “acute kidney failure” or “stage 3 acute kidney injury,” based on his SCr having increased more than 3 times the baseline level or ≥4 mg/dL.9 The Food and Drug Administration’s (FDA’s) Center for Food Safety and Applied Nutrition (CFSAN) Adverse Event Reporting System (CAERS) was searched for voluntary and mandatory reports with the keywords 5-Hour Energy, Monster Energy, and Rockstar Energy (January 1, 2004, to October 23, 2012). The CFSAN CAERS was also searched for voluntary reports on Red Bull Energy Drink (January 1, 2004, to October 23, 2012). Articles were identified through a MEDLINE/PubMed search using the MeSH terms acute kidney injury, energy drinks, taurine, caffeine, Red Bull, and toxicity. The bibliographies of all retrieved articles were reviewed for possible references not identified in the original search. The purpose of the search was to identify abstracts, studies, review articles, and case reports pertaining to the keywords listed above. All foreign language articles were excluded, except as noted below.
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Greene et al Two case reports of energy drink–associated kidney injury have been published. In 2011, Schöffl et al10 reported a case of acute renal failure, which occurred in a 17-yearold boy who consumed 3 L of energy drink in combination with 1 L of vodka, yielding approximately 780 mg of caffeine and 4600 mg of taurine. Labs revealed an increase in SCr from 1.0 to 6.9 mg/dL, and urine sediment indicated that acute tubular necrosis was present.10 His renal function returned to normal over the course of a 10-day hospital stay, which included dialysis, and remained normal at a 3-week follow-up.10 A previous case, published in 2006, was cited in the above-mentioned publication. Unfortunately, the publication was only available in Swedish. Schöffl et al10 related that this case also described acute kidney failure with tubular necrosis and rhabdomyolysis after ingestion of 750 mL of energy drink. Excessive intake of taurine was hypothesized by the authors as involved in the development of kidney injury because of its ability to alter renal blood flow and regulate osmolarity in the renal medulla, although this role is not clearly established.11 Another foreign language publication described a case of kidney injury in a patient taking guarana and nonsteroidal anti-inflammatory drugs.12 It is possible that the combination of caffeine in the Red Bull and normal, occasional doses of ibuprofen may have led to the injury in our patient.12 Several articles address potential adverse effects associated with energy drinks and their components. Energy drinks are reported to cause insomnia, shakiness, palpitations, headache, gastrointestinal upset, chest pain, and seizures.13 Increased blood glucose levels, increased platelet aggregation, and decreased endothelial function have also been reported.6 Red Bull contains caffeine, taurine, glucuronolactone, B vitamins (B3, B5, B6, and B12), sucrose, and glucose.7 The effects of caffeine are well described, and taurine has not been directly linked to any specific effects in healthy patients. Simple sugar intake may cause a temporary “high” followed by a “crash” and is associated with dental caries, obesity, and diabetes.2 Consumption of 300 mg of niacin (vitamin B3 and 50 mg of pyridoxine (vitamin B6), respectively, have been implicated in causing liver and nerve injury.3 There are no known reports of kidney injury related to B vitamins, sucrose, glucose, or glucuronolactone. Taurine is the only ingredient with any hypothesized link to renal injury. Other energy drinks may contain guarana, ginseng, ginkgo biloba, and bitter orange, which are associated with similar effects.2,3 These additives have also been linked to potential myocardial infarction, stroke, mania, bleeding, hypertension, and drug interactions.2,3 These effects may be magnified by a combination with alcohol.2,3 Although our patient had a history of alcohol abuse, all evidence indicated consistent abstinence from alcohol at the time of these events. Between 2004 and 2012, the FDA received 166 reports of adverse events for energy drinks. Of the 166, only 3
Table 3. Summary of FDA Reports of Adverse Events Related to Energy Drinks (Pertinent to Renal Failure).14,15 Total Number of Reports in FDA Database
Number of Reports Suggesting Renal Dysfunction
Monster 5-hour Energy
40 92
0 3
Red Bull Rockstar
21 13
0 0
Product
Comments Minimal detail available
Abbreviation: FDA, Food and Drug Administration.
(0.18%) were associated with renal failure, and none of these were reported with Red Bull specifically (Table 3).14,15 Despite the paucity of literature reporting kidney injury associated with energy drinks, a score of 5 from the assessment of the Naranjo adverse drug reaction probability scale was assigned to this incident. This places the reaction in the realm of “probable” adverse drug reaction.16
Conclusions Acute kidney failure is a life-threatening condition that has not been conclusively linked to energy drink consumption. We describe a patient who presented with signs and symptoms consistent with subacute renal failure, which resolved on discontinuing consumption of significant amounts of Red Bull energy drinks. Conclusions may be limited by the unclear exact time of last Red Bull ingestion in relation to improvement in renal function. Although unlikely, chances of a laboratory error or product contamination cannot be entirely dismissed. The history of diabetes mellitus type 2, recent viral illness, possible dehydration, and only occasional use of ibuprofen were unlikely to have precipitated this event but may have added to the insult. The patient had no history of prior renal dysfunction. SCr and laboratory markers returned to baseline within approximately 2 weeks of ceasing Red Bull consumption. Energy drinks contain myriad active ingredients, which, especially in large quantities, have the potential to induce adverse health events. Adverse effects associated with energy drinks are not widely documented, but because of the increasing popularity of these products and the case presented in this discussion, closer attention to and reporting of side effects is warranted. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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Authors’ Note The views expressed in the submitted article are the authors’ own and not an official position of the institution. The authors have not previously presented any portion of this material.
References 1. Sepkowitz KA. Energy drinks and caffeine-related adverse effects. JAMA. 2013;309:243-244. 2. Rath M. Energy drinks: what is all the hype? The dangers of energy drink consumption. J Am Acad Nurse Pract. 2012;24:70-76. 3. Wolk BJ, Ganetsky M, Babu KM. Toxicity of energy drinks. Curr Opin Pediatr. 2012;24:243-251. 4. MacDonald J. The potential adverse health effects of energy drinks. Am Fam Physician. 2013;87:321. 5. Centers for Disease Control and Prevention (CDC).Energy drink consumption and its association with sleep problems among U.S. service members on a combat deployment–Afghanistan, 2010. MMWR Morb Mortal Wkly Rep. 2012;61:895-898. 6. Burrows T, Pursey K, Neve M, Stanwell P. What are the health implications associated with the consumption of energy drinks? A systematic review. Nutr Rev. 2013;71:135-148. 7. Caffeine. Red Bull™. http://energydrink-us.redbull.com/content/caffeine. Accessed April 8, 2014. 8. Bunker ML, McWilliams M. Caffeine content of common beverages. J Am Diet Assoc. 1979;74:28-32. 9. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl. 2012;2
(suppl 1):1-138. http://www.kdigo.org/clinical_practice_ guidelines/pdf/KDIGO%20AKI%20Guideline.pdf.Accessed April 8, 2014. 10. Schöffl I, Kothmann JF, Schöffl V, Rupprecht HD, Rupprecht T. “Vodka Energy”: too much for the adolescent nephron? Pediatrics. 2011;128;e227-e231. 11. Chesney RW, Han X, Patters AB. Taurine and the renal system. J Biomed Sci. 2010;17(suppl 1):S4-S14. 12. Vagasi K, Degrell P, Wittmann I, et al. Acute renal failure caused by plant extract. Orv Hetil. 2007;148:421-424. 13. Nordt SP, Vilke GM, Clark RF, et al. Energy drink use and adverse effects among emergency department patients. J Community Health. 2012;37:976-981. 14. US Department of Health and Human Services, FDA Center for Food Safety and Applied Nutrition Adverse Event Reporting System. Voluntary and mandatory reports on 5-Hour Energy, Monster Energy, and Rockstar energy drink. http://www.fda.gov/downloads/ AboutFDA/CentersOffices/OfficeofFoods/CFSAN/ CFSANFOIAElectronicReadingRoom/UCM328270.pdf. Accessed January 1, 2014. 15. US Department of Health and Human Services, FDA Center for Food Safety and Applied Nutrition Adverse Event Reporting System. Voluntary and mandatory reports on Red Bull energy drink. http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofFoods/CFSAN/ CFSANFOIAElectronicReadingRoom/UCM328525.pdf. Accessed January 1, 2014. 16. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239-245.
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research-article2014
AOPXXX10.1177/1060028014541997Annals of PharmacotherapyGreene et al
Case Report
Energy Drink–Induced Acute Kidney Injury
Annals of Pharmacotherapy 2014, Vol. 48(10) 1366–1370 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028014541997 aop.sagepub.com
Elisa Greene, PharmD1, Kristy Oman, PharmD1, and Mary Lefler, PharmD1
Abstract Objective:To report a case of acute renal failure possibly induced by Red Bull. Case Summary: A 40-year-old man presented with various complaints, including a recent hypoglycemic episode. Assessment revealed that serum creatinine was elevated at 5.5 mg/dL, from a baseline of 0.9 mg/dL. An interview revealed a 2- to 3-week history of daily ingestion of 100 to 120 oz of Red Bull energy drink. Resolution of renal dysfunction occurred within 2 days of discontinuation of Red Bull and persisted through 10 months of follow-up. Rechallenge was not attempted. Discussion: Energy-drinkinduced renal failure has been reported infrequently. We identified 2 case reports via a search of MEDLINE, one of which occurred in combination with alcohol and the other of which was not available in English. According to the Food and Drug Administration’s (FDA’s) Center for Food Safety and Applied Nutrition Adverse Event Reporting System, between 2004 and 2012, the FDA has received 166 reports of adverse events associated with energy drink consumption. Only 3 of the 166 (0.18%) described renal failure, and none were reported with Red Bull specifically. A defined mechanism for injury is unknown. Assessment of the Naranjo adverse drug reaction probability scale indicates a probable relationship between the development of acute renal failure and Red Bull ingestion in our patient. Conclusions: Acute kidney injury has rarely been reported with energy drink consumption. Our report describes the first English language report of acute renal failure occurring in the context of ingestion of large quantities of energy drink without concomitant alcohol. Keywords energy drinks, acute kidney injury, adverse events, Red Bull, renal dysfunction, acute renal failure Energy drinks were introduced in the United States in 1997.1 Manufacturers have enticed consumers by connecting improved performance, increased arousal and decreased reaction time, enhanced metabolism, and improvement in overall performance to energy drink consumption.2,3 Sales and demand for energy drinks have been strong. In between the years 2006 and 2007 alone, 200 new brands of energy drinks were launched.4 Market growth has shown that Americans have increased consumption from 2.3 billion energy drinks in 2006 to 6 billion in 2010.1 Although consumption continues to increase, little attention has been given to adverse events associated with these drinks. We describe a case of acute kidney injury associated with excessive energy drink consumption that resolved on its discontinuation.
Case Report A 40-year-old Caucasian man presented to the primary care clinic with a 2 week history of complaints of difficulty staying awake, stiffness, and shortness of breath while sleeping. He also reported a recent hypoglycemic episode with blood glucose of 35 mg/dL documented on a home glucometer
approximately 2 weeks prior to the visit, decreased appetite, mild nausea, and abdominal pain. According to the patient, the hypoglycemic event was precipitated by a viral illness and low oral intake. No vomiting or diarrhea was reported. He called the paramedics but was not taken to the emergency department because the hypoglycemic episode resolved rapidly on eating a peanut butter sandwich and drinking a soda. Past medical history was significant for diabetes mellitus type 2, hypertension, anxiety, depression, alcohol abuse, posttraumatic stress disorder, chronic obstructive pulmonary disease, obstructive sleep apnea, gout, and hypertriglyceridemia-induced pancreatitis. He reported 3 months of abstinence from alcohol prior to the date of this visit. Current medications were gemfibrozil 600 mg daily, lamotrigine 100 mg daily, lisinopril 20 mg daily, hydrochlorothiazide 12.5 mg daily, colchicine 0.6 mg as needed for gout, ibuprofen 400 mg as needed for pain, 1
Belmont University College of Pharmacy, Nashville, TN, USA
Corresponding Author: Elisa Greene, Belmont University College of Pharmacy, 1900 Belmont Blvd, Nashville, TN 37212, USA. Email: [email protected]
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Greene et al Table 1. Laboratory Evaluations. Reference Time Point 14 Months prior to presentation Day 1 Day 4 Day 5, evening Day 7 Day 15 10 Months after presentation
Estimated CrCl (mL/min)
SCr (mg/dL)
BUN (mg/dL)
Glucose (mg/dL)
24 0.8 214 17 5.5 108 130 Last ingestion of Red Bull prior to discontinuation (exact time unknown) 87 42 1.1 178 80 33 1.2 287 12 255 106 0.9 106 0.9 — —
Abbreviations: CrCl, creatinine clearance; SCr, serum creatinine; BUN, blood urea nitrogen.
quetiapine 50 mg daily, and sertraline 200 mg daily. Colchicine was most recently used during his last gout attack, which occurred 116 days prior to the date of presentation. The patient admitted to only occasional doses of ibuprofen and denied active use at the time of this visit. Metformin 1000 mg twice daily and glipizide 5 mg twice daily had been discontinued 2 weeks prior at the time of the hypoglycemic episode. The patient denied taking any of his medications on the day of this visit. Physical examination revealed a blood pressure of 113/57 mm Hg, heart rate of 109 bpm, respiratory rate of 18 to 20 breaths/min, temperature of 97.5°F, and O2 saturation of 92% on room air. Height was recorded as 5 feet 3 inches, and weight as 192 lbs (87.3 kg). On examination, the patient appeared hyperkinetic with a mild tic and mild agitation. Hepatomegaly and mild inspiratory wheeze with labored breathing at rest were also noted. All other parameters were within normal limits or consistent with baseline. In office urinalysis revealed trace blood and leucocytes, 1+ glucose and protein, with all other values within normal limits. Fasting blood glucose level was 117 mg/dL. A “breathing treatment” (specific medication and response not documented) was given and followup scheduled for the following week. Blood was collected and sent out for laboratory analysis. Laboratory results were reported the following day and revealed several abnormalities, including a blood urea nitrogen (BUN) of 108 mg/dL (7-20 mg/dL), serum creatinine (SCr) 5.5 mg/dL (0.8-1.4 mg/dL), sodium 130 mmol/ mL (136-145 mmol/L), potassium 5.6 mmol/L (3.7-5.2 mmol/L), chloride 89 mmol/L (96-106 mmol/L), and carbon dioxide 19 mmol/L (20-29 mmol/L). Creatinine clearance of 17 mL/min was estimated using adjusted body weight and the Cockroft-Gault formula. Previous laboratory analysis 14 months prior had revealed a BUN of 24 mg/ dL and SCr of 0.8 mg/dL. At that time, sodium remained slightly low at 133 mmol/L, whereas glucose and albumin were elevated at 214 mg/dL and 5.1 g/dL, respectively. All other parameters were within normal limits at baseline. The most recent hemoglobin A1C (A1C), 3 months prior to presentation, was 6.6%.
When the patient returned for follow-up 5 days later, blood pressure and temperature remained normal, heart rate remained elevated at 99 bpm, and random blood glucose was elevated at 232 mg/dL. Of note, he was fasting the morning of this visit. On questioning by the pharmacist at this visit, the patient described normal urine output and admitted drinking at least 5 to 6 “largest size, 20-oz” Red Bull energy drinks daily for “several” weeks. The last ingestion was on the day prior to this visit (Table 1). At that time, it was determined that after the patient became abstinent from alcohol, he had switched to drinking large amounts of Red Bull. The recent hypoglycemia episode combined with elevated BUN and SCr suggested subacute renal failure, possibly induced by the Red Bull ingestion. The patient was instructed to stop drinking Red Bull, discontinue his gemfibrozil, and take half his usual doses of lamotrigine, lisinopril, and hydrochlorothiazide. Repeat labs were drawn that evening and follow-up, including a planned renal ultrasound, was arranged for the following week. Lab work collected on the evening of this office visit revealed the following: lipase 36 U/L, hemoglobin (Hgb) 10.6, glucose 178 mg/dL, BUN 42 mg/dL, sodium 134 mmol/L, potassium 5.2 mmol/L, and chloride 95 mmol/L. All other labs were within normal limits. SCr had fallen to 1.1 mg/dL, with an estimated creatinine clearance of 87.1 mL/min. The urine obtained for a urinalysis was accidentally discarded; therefore, these results were not available. The patient returned 2 days later (7 days after initial presentation) for follow-up labs. Results showed improvement, although potassium remained elevated at 5.5 mmol/L; BUN improved, but remained elevated at 33 mg/dL; and glucose was elevated at 287 mg/dL (Table 1). All other results from the comprehensive metabolic panel and urine chemistry assessment were normal. At that time, it was determined that these results, taken with the fractional excretion of sodium of 1.12%, suggested neither a prerenal nor postrenal cause definitively, but that his renal failure was nearly resolved. Renal ultrasound was cancelled. Two weeks following initial presentation, all noted electrolyte and renal function abnormalities had resolved (Table 1).
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Annals of Pharmacotherapy 48(10)
Table 2. Ingredient Comparison.7,8 Product
Volume
Caffeine Content
Red Bull
8.4 oz 20 oz
80 mg 190.5 mg
6 oz
107-151 mg
Brewed coffee
Other Ingredients Vitamins B3, B5, B6, B12; sucrose; glucose; taurine; and glucuronolactone None known
The patient reported severe headaches for 1 week on discontinuation of Red Bull. He resumed lisinopril and hydrochlorothiazide therapy at previously prescribed doses at this time and reported that he had stopped lamotrigine entirely. This was not resumed for reasons of patient preference. Based on an A1C of 6.8% at an 8-week follow-up visit, diabetes was controlled without medications at that time, which was attributed to a 25 lb weight loss occurring over the previous year. Metformin was reinitiated at 500 mg daily 5 months later, when A1C increased to 7.9%. After 10 months of follow-up, renal function remained normal (Table 1), and the patient remained abstinent from both Red Bull and alcohol.
Discussion Energy drinks are defined as soft drinks that contain caffeine and may include an assortment of other ingredients, such as herbs, amino acids, vitamins, sugar, and sugar derivates.2,5 Energy drinks such as Red Bull are commonly consumed by young men and are associated with a number of adverse effects discussed in the following paragraphs.6 Caffeine, the primary psychoactive agent in energy drinks, is considered the most commonly used drug in the world.2,3 The caffeine content of energy drinks varies depending on package size and the presence of the caffeine-containing plant, guarana. According to the product Web site, a single 8.4 fl oz can of Red Bull contains 80 mg of caffeine, which the site claims is approximately equal to that in 1 cup of coffee.7 However, as Table 2 illustrates, the caffeine content in 1 brewed coffee typically exceeds this level. Drinking 6 of the 20-oz Red Bull drinks per day, as our patient reported, would provide approximately 1143 mg of caffeine per day. Caffeine content may vary significantly depending on coffee preparation and brewing methods; however, the average cup of coffee contains between 107 and 151 mg of caffeine.8 Drinking approximately 10 cups of an average strength brewed coffee would provide the equivalent amount of caffeine to what our patient consumed. Adverse effects of energy drinks are often attributed to the high caffeine content or the effects of their combination with alcohol, which often occurs. However, to the authors’ knowledge, there is no reported case of renal failure after drinking coffee, so it is plausible that caffeine itself is not the sole contributor to injury. The sustained ingestion of significant quantities over several weeks, speed of ingestion
(ie, repeatedly getting a bolus of caffeine each time) or other ingredients in Red Bull somehow may have contributed. Other medications were considered as possible inducers of renal injury but were determined to be unlikely primary causes. Ibuprofen was consumed only occasionally. Lisinopril was being consumed at the appropriate prescribed dose and had been stable for over a year prior to the incident. These agents were both resumed at the same dose after the event, with no relapse in kidney function. Lamotrigine was discontinued permanently after the event; however, a MEDLINE search revealed no reports of lamotrigine-induced kidney injury. There was no evidence to suggest any other medications were likely causes, and they were resumed with no recurrence of kidney injury after the event. Diabetes was determined to be an unlikely cause because of the well-controlled A1C and return of kidney function without a change in diabetic control. Two weeks prior to presentation, the patient had experienced a viral illness with poor oral intake. He reported no vomiting or diarrhea; however, he could have potentially become dehydrated during this time. This illness alone was considered an unlikely primary cause but could have added to the effects of the energy drink. One would have expected the large quantity of sugar ingested in the Red Bull to worsen the patient’s diabetes control. It is possible that reduced oral intake associated with the viral illness may have contributed to the previous hypoglycemic event and balanced out the effect of the Red Bull ingestion. It does not appear that he experienced other adverse effects from this large amount of carbohydrate because his A1C 8 weeks after the presentation remained steady at 6.8%. Home glucose log levels are not available; however, he did report blood glucose values being “all over the place.” This could be attributed to the carbohydrate component in Red Bull. According to the RIFLE and KDIGO criteria, our patient experienced “acute kidney failure” or “stage 3 acute kidney injury,” based on his SCr having increased more than 3 times the baseline level or ≥4 mg/dL.9 The Food and Drug Administration’s (FDA’s) Center for Food Safety and Applied Nutrition (CFSAN) Adverse Event Reporting System (CAERS) was searched for voluntary and mandatory reports with the keywords 5-Hour Energy, Monster Energy, and Rockstar Energy (January 1, 2004, to October 23, 2012). The CFSAN CAERS was also searched for voluntary reports on Red Bull Energy Drink (January 1, 2004, to October 23, 2012). Articles were identified through a MEDLINE/PubMed search using the MeSH terms acute kidney injury, energy drinks, taurine, caffeine, Red Bull, and toxicity. The bibliographies of all retrieved articles were reviewed for possible references not identified in the original search. The purpose of the search was to identify abstracts, studies, review articles, and case reports pertaining to the keywords listed above. All foreign language articles were excluded, except as noted below.
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Greene et al Two case reports of energy drink–associated kidney injury have been published. In 2011, Schöffl et al10 reported a case of acute renal failure, which occurred in a 17-yearold boy who consumed 3 L of energy drink in combination with 1 L of vodka, yielding approximately 780 mg of caffeine and 4600 mg of taurine. Labs revealed an increase in SCr from 1.0 to 6.9 mg/dL, and urine sediment indicated that acute tubular necrosis was present.10 His renal function returned to normal over the course of a 10-day hospital stay, which included dialysis, and remained normal at a 3-week follow-up.10 A previous case, published in 2006, was cited in the above-mentioned publication. Unfortunately, the publication was only available in Swedish. Schöffl et al10 related that this case also described acute kidney failure with tubular necrosis and rhabdomyolysis after ingestion of 750 mL of energy drink. Excessive intake of taurine was hypothesized by the authors as involved in the development of kidney injury because of its ability to alter renal blood flow and regulate osmolarity in the renal medulla, although this role is not clearly established.11 Another foreign language publication described a case of kidney injury in a patient taking guarana and nonsteroidal anti-inflammatory drugs.12 It is possible that the combination of caffeine in the Red Bull and normal, occasional doses of ibuprofen may have led to the injury in our patient.12 Several articles address potential adverse effects associated with energy drinks and their components. Energy drinks are reported to cause insomnia, shakiness, palpitations, headache, gastrointestinal upset, chest pain, and seizures.13 Increased blood glucose levels, increased platelet aggregation, and decreased endothelial function have also been reported.6 Red Bull contains caffeine, taurine, glucuronolactone, B vitamins (B3, B5, B6, and B12), sucrose, and glucose.7 The effects of caffeine are well described, and taurine has not been directly linked to any specific effects in healthy patients. Simple sugar intake may cause a temporary “high” followed by a “crash” and is associated with dental caries, obesity, and diabetes.2 Consumption of 300 mg of niacin (vitamin B3 and 50 mg of pyridoxine (vitamin B6), respectively, have been implicated in causing liver and nerve injury.3 There are no known reports of kidney injury related to B vitamins, sucrose, glucose, or glucuronolactone. Taurine is the only ingredient with any hypothesized link to renal injury. Other energy drinks may contain guarana, ginseng, ginkgo biloba, and bitter orange, which are associated with similar effects.2,3 These additives have also been linked to potential myocardial infarction, stroke, mania, bleeding, hypertension, and drug interactions.2,3 These effects may be magnified by a combination with alcohol.2,3 Although our patient had a history of alcohol abuse, all evidence indicated consistent abstinence from alcohol at the time of these events. Between 2004 and 2012, the FDA received 166 reports of adverse events for energy drinks. Of the 166, only 3
Table 3. Summary of FDA Reports of Adverse Events Related to Energy Drinks (Pertinent to Renal Failure).14,15 Total Number of Reports in FDA Database
Number of Reports Suggesting Renal Dysfunction
Monster 5-hour Energy
40 92
0 3
Red Bull Rockstar
21 13
0 0
Product
Comments Minimal detail available
Abbreviation: FDA, Food and Drug Administration.
(0.18%) were associated with renal failure, and none of these were reported with Red Bull specifically (Table 3).14,15 Despite the paucity of literature reporting kidney injury associated with energy drinks, a score of 5 from the assessment of the Naranjo adverse drug reaction probability scale was assigned to this incident. This places the reaction in the realm of “probable” adverse drug reaction.16
Conclusions Acute kidney failure is a life-threatening condition that has not been conclusively linked to energy drink consumption. We describe a patient who presented with signs and symptoms consistent with subacute renal failure, which resolved on discontinuing consumption of significant amounts of Red Bull energy drinks. Conclusions may be limited by the unclear exact time of last Red Bull ingestion in relation to improvement in renal function. Although unlikely, chances of a laboratory error or product contamination cannot be entirely dismissed. The history of diabetes mellitus type 2, recent viral illness, possible dehydration, and only occasional use of ibuprofen were unlikely to have precipitated this event but may have added to the insult. The patient had no history of prior renal dysfunction. SCr and laboratory markers returned to baseline within approximately 2 weeks of ceasing Red Bull consumption. Energy drinks contain myriad active ingredients, which, especially in large quantities, have the potential to induce adverse health events. Adverse effects associated with energy drinks are not widely documented, but because of the increasing popularity of these products and the case presented in this discussion, closer attention to and reporting of side effects is warranted. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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Annals of Pharmacotherapy 48(10)
Authors’ Note The views expressed in the submitted article are the authors’ own and not an official position of the institution. The authors have not previously presented any portion of this material.
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(suppl 1):1-138. http://www.kdigo.org/clinical_practice_ guidelines/pdf/KDIGO%20AKI%20Guideline.pdf.Accessed April 8, 2014. 10. Schöffl I, Kothmann JF, Schöffl V, Rupprecht HD, Rupprecht T. “Vodka Energy”: too much for the adolescent nephron? Pediatrics. 2011;128;e227-e231. 11. Chesney RW, Han X, Patters AB. Taurine and the renal system. J Biomed Sci. 2010;17(suppl 1):S4-S14. 12. Vagasi K, Degrell P, Wittmann I, et al. Acute renal failure caused by plant extract. Orv Hetil. 2007;148:421-424. 13. Nordt SP, Vilke GM, Clark RF, et al. Energy drink use and adverse effects among emergency department patients. J Community Health. 2012;37:976-981. 14. US Department of Health and Human Services, FDA Center for Food Safety and Applied Nutrition Adverse Event Reporting System. Voluntary and mandatory reports on 5-Hour Energy, Monster Energy, and Rockstar energy drink. http://www.fda.gov/downloads/ AboutFDA/CentersOffices/OfficeofFoods/CFSAN/ CFSANFOIAElectronicReadingRoom/UCM328270.pdf. Accessed January 1, 2014. 15. US Department of Health and Human Services, FDA Center for Food Safety and Applied Nutrition Adverse Event Reporting System. Voluntary and mandatory reports on Red Bull energy drink. http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofFoods/CFSAN/ CFSANFOIAElectronicReadingRoom/UCM328525.pdf. Accessed January 1, 2014. 16. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239-245.
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