Energy drinks and their adverse health effects: A systematic review of the current evidence.

http://informahealthcare.com/pgm ISSN: 0032-5481 (print), 1941-9260 (electronic) Postgrad Med, 2015; 127(3): 308–322 DOI: 10.1080/00325481.2015.1001712

CLINICAL FEATURE REVIEW

Energy drinks and their adverse health effects: A systematic review of the current evidence Fahad Ali1, Hiba Rehman2, Zaruhi Babayan3, Dwight Stapleton4 & Divya-Devi Joshi5

Postgraduate Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 05/10/15 For personal use only.

1

Internal Medicine, Guthrie Medical Group, Robert Packer Hospital, Sayre, PA, USA, 2Hematology Oncology, Aga Khan University Hospital, Karachi, Pakistan, 3Director Cardiac CT, Cardiology, Guthrie medical Group, P.C., Sayre, PA, USA, 4Department of Medicine, Guthrie Medical Group, P.C., Sayre, PA, USA, and 5Miller Children’s and Women’s Hospital Long Beach, CA, USA

Abstract

Keywords:

Purpose: With the rising consumption of so-called energy drinks over the last few years, there has been a growing body of literature describing significant adverse health events after the ingestion of these beverages. To gain further insight about the clinical spectrum of these adverse events, we conducted a literature review. Methods: Using PubMed and Google-Scholar, we searched the literature from January 1980 through May 2014 for articles on the adverse health effects of energy drinks. A total of 2097 publications were found. We then excluded molecular and industry-related studies, popular media reports, and case reports of isolated caffeine toxicity, yielding 43 reports. Conclusion: Energy drink consumption is a health issue primarily of the adolescent and young adult male population. It is linked to increased substance abuse and risktaking behaviors. The most common adverse events affect the cardiovascular and neurological systems. The most common ingredient in energy drinks is caffeine, and it is believed that the adverse events are related to its effects, as well as potentiating effects of other stimulants in these drinks. Education, regulation, and further studies are required.

Energy drink, cardiac arrhythmia, caffeine, seizure

Introduction Energy drinks (EDs) were first introduced in Austria in 1987. They are now available in > 140 countries as part of a multibillion dollar industry. The most popular brands in the United States are Red Bull, Monster, Rockstar, Full Throttle, and Amp. These drinks are marketed to young people as a means to improve athletic performance, concentration, energy, and weight loss [1], and to decrease the after-effects of alcohol [2]. In the United States, these drinks are currently classified as dietary supplements. The most common ingredients are caffeine, taurine, guarana, glucuronolactone, ginseng, vitamin B complex, and many others [1,3,4]. Many of these agents have not been well studied. They are mostly stimulants and are not regulated by the US Food and Drug Administration (FDA). Doses of individual ingredients vary by brand and often exceed recommended dietary intake levels [5]. Caffeine doses, for example, range from 50 to 505 mg per serving [6], compared with 34 mg in a can of Coke. Energy drinks are primarily consumed by adolescents and young adults. According to self-reports, 30% to 50% of children, adolescents, and young adults consume EDs more than once a month [1]. A survey by the Centers for Disease Control and Prevention reports that the daily consumption of these drinks among high school students is close to that of soda drinks (5% vs 7.1%) [7]. It is important to note that

History Received 1 October 2014 Accepted 9 October 2014 Published online 6 January 2015

this data is self-reported, suggesting a high likelihood of underreporting. Although there has been a decrease in the consumption of soft drinks and fruit drinks, sales of EDs in the US have increased by 240% between 2004 and 2009 [8]. Meanwhile, a 2013 report from the Substance Abuse and Mental Health Services Administration revealed that ED-related emergency department visits in the United States doubled from 2007 to 2011, climbing from 10,068 to 20,783 [3]. Over the last few years, there has been a growing body of literature about significant adverse health events after the ingestion of EDs. To gain further insight into the clinical spectrum of these adverse events, we conducted a literature review.

Methods Using PubMed and Google-Scholar, we searched the English-language literature from January 1980 through May 2014 for articles on the adverse health effects of EDs. A total of 2097 publications were found. We then excluded molecular and industry-related studies, popular media reports, and case reports of isolated caffeine toxicity, yielding 43 reports (Figure 1). Two reviewers participated in the literature search independently. Manual cross-checking was performed and

Correspondence: Fahad Ali, MD, Resident Physician, 1 Guthrie Square, Sayre PA 18840, USA. Tel: +1 570 887 3106. E-mail: [email protected] 2015 Informa UK Ltd.

Energy drinks and their adverse health effects

DOI: 10.1080/00325481.2015.1001712

On initial search 2097 related studies were found


Excluded publications (2054): epidemiological, molecular, duplicate studies, studies related to manufacturing of energy drink, etc.

43 cases meeting the criteria

Figure 1. Data collection algorithm.

duplicates were excluded. Only the articles published in scientific journals were included. The bibliographies of articles from the search were searched for pertinent publications and web resources. The title, abstract, or text of the articles was searched using the terms energy drink, energy shots, energy tonics, caffeinated drinks, and caffeinated sports drinks alone and in various combinations. The 2097 pertinent publications were further screened for studies pertaining to the health effects of EDs using the following inclusion criteria: 1.

309

studies; observational studies and surveys; letters to the editor; short communications; images; features; news in scientific journals, newspapers, or online resources; popular media reports; animal studies and small sample size studies on humans; and studies that are either not directly related to the health effects of EDs or are related to the composition of or manufacturing of EDs. Some articles also mentioned cases that could not be reported or published due to the lack of consent of the subjects, and therefore such cases are not included in our review. Cases related to isolated caffeine toxicity were excluded, as we only focused on cases related to ED consumption [10]. We extracted data related to age, sex, ethnicity, geographic location, season and year of the event, clinical presentation, consumed beverage, co-ingested agents, the scenario in which the agents were consumed, past medical histories, clinical signs and symptoms, vital signs, investigations performed and their results, pharmacological modalities used for treatment, drug and social history, family history, outcomes, length of stay in the health care facility, and follow-up outcomes if available in the publication (Table 1). Using these variables, the cases were subclassified based on the major organ systems affected (Figure 2). According to the Dietary Supplement and Nonprescription Drug Consumer Protection Act, a serious adverse event is defined as an adverse health-related event that is associated with the use of a dietary supplement and that results in death, a life-threatening experience, inpatient hospitalization, a persistent or significant disability or incapacity, a congenital anomaly or birth defect, or a condition that requires medical or surgical intervention to prevent one of those outcomes [11]. Our definition of ED-related adverse events includes both serious and nonserious adverse events.

Results

The publication is in a scientific journal and not a media report. 2. The publication describes the case of an adverse event that is related to energy drink consumption in any quantity. 3. The publication describes ‡ 1 clinical, laboratory, radiological, or electrophysiological finding supporting the clinical scenario, such as electrocardiogram, troponin, isoenzyme of creatine kinase with muscle and brain units, transthoracic echocardiography, telemetry, cardiac catheterization, toxicology screening, serum coagulation profiles, electroencephalogram, or psychiatric evaluation.

The majority of studies were individual outcome reports; the types and amounts of EDs involved were often unclear, and the health effects of the various stimulants as well as their interrelations are poorly understood. Few studies compare the effects of whole drinks versus those of the individual ingredients, and dosages vary widely in the different reviews [5]. In addition, most studies had few participants and the followup range was short. Although the articles reviewed had these limitations, certain trends clearly emerge, as discussed in the following subsections.

We also included a single patient experiment demonstrating the prolongation of the QTc interval by 25 ms from baseline when two 16-oz EDs were consumed over a 45-minute interval, as this publication met our criteria of inclusion [9]. Studies not meeting the above criteria were excluded from the review and analysis, but some of the pertaining studies are used as references and discussed in the discussion section of this article. The excluded publications are epidemiological studies; knowledge, attitude, and practice studies; interventional

Energy drinks are consumed by 30% to 50% of children and young adults [3]. They are more popular among males than females [9]. We did not find a link between other socioeconomic factors and ED consumption. When asked what was the main reason for consuming EDs, 57% of consumers cited the desire to “increase energy [10].” As for amounts consumed, 58% of young adults admitted to drinking an average of 2.6 EDs per day over the last 30 days [12]. Although EDs were first introduced in 1987, 63% of adverse event reports were published after 2010, with a peak

Socioeconomic distribution and demographics

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Table 1. Summary of the data provided by the reports found in the literature. Age, sex, race 24, M, Afro-American


16, M, South East Asian

24, M, race not described

Presentation

Pertinent findings in history

Smokes Palpitations, 5 cig/week chest pain started 1-2 hours after the ED intake mixed with vodka None Intermittent palpitations for 1 week

Palpitations, chest pain, and shortness of breath

None

Consumed beverage and co-ingestants

Physical exam findings

Investigations

ECG

1 can; 3 bottles of vodka

Not described

Troponin Normal. LHC = LM, LCX, and LAD thrombus

J point elevation in II, III, aVF, V2–V6; later developed ST elevation in lateral leads

3 cans of ED/day for 2 weeks

Persistently elevated BP around 140–160/80–95, resting sinus tachycardia of 110

Sinus tachycardia

ED: name and quantity not mentioned

Afebrile, tachycardia HR 150s

ECG, CBC, serum Cr and electrolytes, urinalysis, urine VMA levels, TSH and lipid profile were checked and were within normal limits Troponins were mildly increased, BNP was 8000 pg/ mL, CXR showed b/ l pulmonary fluffly infiltrates, CMR imaging, moderate to severe hypokinesis of the basal segments of the LV with apical sparing and globally increased myocardial wall thickness (reflecting the presence of edema) was observed without any late gadolinium enhancement

Sinus tachycardia, 150/ min; nonspecific T- wave inversions in leads I and aVL

Abbreviations: ABG = Arterial blood gas; ACEi = Angiotensin-converting enzyme inhibitor; ACLS = Advanced cardiac life support; APTT = Activated partial thromboplastin time; ASA = Acetylsalicylic acid; aVF = Augmented limb lead F; aVL = Augmented limb lead L; BP = Blood pressure; BUN = Blood urea nitrogen; CABG = Coronary artery bypass grafting; CAD = Coronary artery disease; resonance; CPK = Creatine phosphokinase; Cr = Creatinine; c/s = Culture and sensitivity; CT = Computed tomography; EEG = Electroencephalogram; EF = Ejection fraction; EP = Electrophysiology; FFP = Fresh frozen plasma; FT4 = Free thyroxine; HR = Heart rate; HTN = Hypertension; Hx = History; IABP: Intra-aortic balloon pump; ICD = Implantable cardioverter-defibrillator; LAD = Left anterior descending; LAMA = Left Against Medical Advice ; LCX = Left circumflex; LFT = Liver function test; Syndrome 1; LQTS = Long QT syndrome; LV = Left ventricle; Mg = Magnesium; MI = Myocardial infarction; MMSE = Mini-mental status examination; PMH = Past medical history; RBC = Red blood cells; RVR = Rapid ventricular response; SaO2 = Oxygen saturation; SVT = Supra ventricular tachycardia; V-fib = Ventricular fibrillation; VMA = Vanillylmandelic acid; V-tach = Ventricular tachycardia.


DOI: 10.1080/00325481.2015.1001712


TTE

Toxicology screens

Treatment

Outcome

Length of stay

Geographic location

Follow-up

311

Classification

Apical hypokinesis

Not described

CABGIABP was Discharged used after LHC as patient went into CHF; patient was d/c on Coumadin

Not described USA, NY

Not described

Coronary thrombosis

Not described

Not described

EDs were stopped

Symptoms resolved and BP and HR normalized

Managed as outpatient

Pakistan

Symptoms resolved and BP and HR normalized within 2 weeks

HTN, tachycardia

TTE, hypokinesia of all basal left ventricular segments except apex and EF of 35%

Negative

ASA, heparin, Lasix, nitroglycerine

Discharged

14 days

United States

Cardiomyopathy 2 months later repeat TTE revealed normalization of LV function with EF of 55% and the absence of regional wall motion abnormalities, and a new CMR demonstrated complete normalization of ventricular function and wall motion and thickness (the latter consistent with resolution of edema) and the absence of any late gadolinium enhancement; labs for pheochromocytoma were negative; all medications were stopped because of patient preference and lack of clear ongoing clinical indication

ADHD = Attention-deficit hyperactivity disorder; AICD = Automatic implantable cardioverter-defibrillator; ALT = Alanine aminotransferase; b/l = Bilateral; AST = Aspartate aminotransferase; BMI = Body mass index; BMP = Basic metabolic profile; BNP = B-type Natriuretic Peptide; CBC = Complete blood count; CCB = Calcium-channel blocker; CHF = Congestive heart failure; CMP = Cardiomyopathy; CMR = Cardiac magnetic CVA = Cardiovascular accident; d/c = Discontinued; ECG = Electrocardiogram; Echo = Echocardiogram; ED = Energy drink; GC-MS = Gas chromatography and mass spectrometry; Hct = Hematocrit; HCV = Hepatitis C virus; HIV = Human immunodeficiency virus; ICU = Intensive care unit; IgE = Immunoglobulin E; INR = International normalized ratio; JVD = Jugular venous distention; K = Potassium; LHC = Left heart catheterization; LM = Left Main; LOC = Loss of consciousness; LP = Lumbar puncture; LQT1 (G179S-KCNQ1) = Long QT MRI = Magnetic resonance imaging; N/A = Not available; NSR = Normal sinus rhythm; OCD = Obsessive-compulsive disorder; PLT = Platelets; T = Temperature; TEE = Transesophageal echocardiography; TSH = Thyroid-stimulating hormone; TTE = Transthoracic echocardiography; UA = Urinalysis;

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Table 1. Summary of the data provided by the reports found in the literature.


Age, sex, race

Presentation




Investigations

ECG

Troponin-I was elevated 34.67 mg/mL (normal range < 0.07), LHC was normal, mild LV systolic impairment, D-dimers were normal, CXR and thrombophilia screen were normal Autopsy

2-mm ST elevation in leads I, II, aVL and V4 to V6, 2-mm ST depression in leads V1 and V2; consistent with a diagnosis of posterolateral MI

19, M, race Chest pain not described and shortness of breath

Nonsmoker, occasionally drinks alcohol

2–3 drinks daily for 1 week

Physical examination was unremarkable

25, F, race V-fib arrest, not described shocked 12 times but no return of spontaneous circulation 13, M, race Syncope not described

Mitral valve prolapse

55 mL of ED/ Energy Blast

Brought in with cardiac arrest

Palpitations for several weeks after drinking ED

250 mL of an ED before the event

Irregularly irreg- TTE, ECG, TSH, A-fib with rate between ular rapid pulse FT4, troponin I, lipid 130 and 160 between 100 and profile 180/min, RR 45 breaths/min, BP 132/68

6 pack/yr smoking history; socially drinks alcohol

7–8 cans of ED on the day of the event

Unremarkable

None

1 ED/day

Irregularly irreg- ECG, TTE, TSH, ular rapid pulse electrolytes HR 120–150

28, M, race Patient was not described participating in a motor vehicle race and in the morning had noticed mild dull chest pain for few hours relieved with rest; a couple of hours later followed by V-fib cardiac arrest; he had 7-8 cans of ED since morning 14, M, Palpitations Caucasian started 2 hours after running a race

ECG, CXR, CT chest and head, troponin, electrolytes (low K was found, K = 3.0), troponin = 0.24, elevated N < 0.05)

NSR and ST elevation in anteroseptal leads with reciprocal inferior leads; ST depression

A-fib with occasional aflutter

Abbreviations: ABG = Arterial blood gas; ACEi = Angiotensin-converting enzyme inhibitor; ACLS = Advanced cardiac life support; ADHD = APTT = Activated partial thromboplastin time; ASA = Acetylsalicylic acid; aVF = Augmented limb lead F; aVL = Augmented limb lead BP = blood pressure; BUN = blood urea nitrogen; CABGIABP = Coronary artery bypass grafting intra-aortic balloon pump; CAD = Coronary CMR = Cardiac magnetic resonance; CPK = creatine phosphokinase; Cr = Creatinine; c/s = Culture and sensitivity; CT = Computed tomography; EEG = Electroencephalogram; EF = Ejection fraction; EP = Electrophysiology; FFP = Fresh frozen plasma; FT4 = Free thyroxine; GC-MS = Gas HTN = Hypertension; Hx = History; ICD = Implantable cardioverter-defibrillator; ICU = Intensive care unit; IgE = Immunoglobulin E; INR = Advice ; LCX = Left circumflex; LFT = Liver function test; LHC = Left heart catheterization; LM = Left Main; LOC = Loss of consciousness; MI = Myocardial infarction; MMSE = Mini-mental status examination; MRI = Magnetic resonance imaging; N/A = Not available; NSR = Normal response; SaO2 = Oxygen saturation; SVT = Supra ventricular tachycardia; T = Temperature; TEE = Transesophageal echocardiography; VMA = Vanillylmandelic acid; V-tach = Ventricular tachycardia.


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TTE


Normal

With in normal limits

Toxicology screens Negative

Treatment

Outcome

ASA, Plavix, ACEi, and betablocker

Supportive therapy; discharged home on aspirin, clopidogrel, an ACE inhibitor and a betablocker

Negative except ACLS high levels of caffeine (19 mg/ L) in aortic blood on GC-MS

Died

Negative

Discharged

Flecainide initially and at the time of discharged was switched to amiodarone 200 mg b.i.d.

Length of stay 5 days

United Kingdom

Follow-up

Classification

Follow-up at 2 months; stopped ED consumption and had no further problems

Coronary vasospasm causing myocardial ischemia

Australia

48 hours

Spain

Australia

Negative TTE showed mild LV enlargement and lownormal systolic function with a hypokinetic anteroseptal segment

Discharged ASA, Plavix, heparin, tenecteplase, Lopressor, K replacement; same day was transferred to higher center for LHC which did not show any obstructive lesion; also underwent hypothermia protocol for 24 hrs

6 days

Normal

Discharged One dose of digoxin, partial loading at 75 mg/ kg, with which patient immediately responded to NSR

Not described

Not described

Geographic location

United States

313

Arrhythmia

Stopped EDs; at 6 months follow-up patient remained asymptomatic and was at baseline activities; therefore, amiodarone was stopped; at 1 yr follow-up, patient remained asymptomatic and was participating in sports D/C on ASA, atenolol, perindopril, Aldactone; 2 months later remained asymptomatic and repeat TTE showed preserved global left ventricular function with a limited residual area of akinesia of the anteroseptal wall; 6 months later stress echo was done and was negative for ischemic findings; patient was continued on ASA, perindopril, and atenolol At 1-month follow-up remained asymptomatic and healthy

Arrhythmia

Arrhythmia, coronary vasospasm

Arrhythmia

Attention-deficit hyperactivity disorder; AICD = Automatic implantable cardioverter-defibrillator; ALT = Alanine aminotransferase; L b/l = Bilateral; AST = Aspartate aminotransferase; BMI = Body mass index; BMP = Basic metabolic profile; BNP = B-type Natriuretic Peptide; artery disease; CBC = Complete blood count; CCB = Calcium-channel blocker; CHF = Congestive heart failure; CMP = Cardiomyopathy; CVA = Cardiovascular accident; d/c = Discontinued; ECG = Electrocardiogram; Echo = Echocardiogram; ED = Energy drink; chromatography and mass spectrometry; Hct = Hematocrit; HCV = Hepatitis C virus; HIV = Human immunodeficiency virus; HR = Heart rate; International normalized ratio; JVD = Jugular venous distention; K = Potassium; LAD = Left anterior descending; LAMA = Left Against Medical LP = Lumbar puncture; LQT1 (G179S-KCNQ1) = Long QT Syndrome 1; LQTS = Long QT syndrome; LV = Left ventricle; Mg = Magnesium; sinus rhythm; OCD = Obsessive-compulsive disorder; PLT = Platelets; PMH = Past medical history; RBC = Red blood cells; RVR = Rapid ventricular TSH = Thyroid-stimulating hormone; TTE = Transthoracic echocardiography; UA = Urinalysis; V-fib = Ventricular fibrillation;

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Age, sex, race

Presentation

41, F, race Psychomotor not described agitation, hypervigilance, verbal and physical aggression, impulsive outbursts 38, F, race Psychomotor not described agitation, increased alertness, insomnia 25, M, race Psychomotor not described unease, hypervigilance, verbal aggression Orthostatic intolerance and transient loss of consciousness 39, M, race Symptomatic not described hypokalemia

54, M, Caucasian

Chest pain, shortness of breath, fatigue

26,M, Caucasian

Chest pain

26, M, Caucasian

Chest pain

25, M, race Seizure not described Tonic clonic seizure Tonic clonic seizure Tonic clonic seizure




Personality disor- Few bottles of der type B taurine-containing energy drink

BP 140/117, HR 86

Bipolar disorder, Taurine-containing energy drinks 5– borderline personality disorder, 10 times/day Hx of drug abuse

BP 110/76

Schizophrenia

Taurine-containing energy drinks 5– 10 times/day

Not significant PMH

Red Bull 4–5 cans/ day 80 mg caffeine and 1000 mg taurine

Tourette syndrome, OCD, anxiety, depression, alcohol misuse, mild asthma, haloperidol, diazepam, alprazolam, salbutamol HTN, obesity

24 cans of Red Bull drink, 25 bottles of homeopathic preparation Nervatona Calm; codeine

Investigations

ECG, EEG, MRI BP 100/60 at rest, 80/50 on standing, HR 88 at rest, 128 on standing Severe symmetrical quadriplegia

4–5 Red Bulls per night

BP 190/110, HR TTE, CT scan chest 110

Bicuspid aortic valve

5–6 high-energy drinks per night

BP 145 systolic

Echo, CT chest

Family Hx of HTN, MI

Several energy drinks

BP 145/95

Echo

Not described

Rock Star, 2 bottles of 24 oz

BP 150 systolic, CBC, UA, CT head, HR 120 MRI head, EEG

Complex migraine, seizures Migraines, past history of seizure

Energy drinks, not sure about the drinks, 24 oz Monster, 24 oz; diet pill

BP 189 systolic, MRI, EEG HR 133

Seizure

Monster, 24 oz

BP147 systolic, HR 99

ECG

Normal

UA, MRI, EEG, CBC, BMP MRI, EEG



DOI: 10.1080/00325481.2015.1001712

TTE

Toxicology screens

Treatment

Outcome

Length of stay


Marijuana

Discontinuation of Red Bull

Follow-up

Classification

Israel

Psychomotor agitation

Israel

Psychomotor agitation

Israel

Psychomotor agitation At 1-yr follow-up the patient remained stable.

Symptomatic orthostatic hypotension

Remission of episodes of hypotension and LOC

Italy

LAMA

Australia

Hypokalemia

Reconstructive surgery of ascending aorta with flap resection and interposition of vascular prosthesis Aortic root replacement and resection of dissecting flap with vascular graft Resection of dissecting aorta and vascular graft No antiepileptic medication

Discharge

10 days

Serbia

Aortic dissection

Discharge

8 days

Serbia

Aortic dissection

Discharge

9 days

Serbia

Aortic dissection

Discharge

Not described

United States

Negative

No antiepileptic medication

Discharge

Negative


Discharge

Negative


Discharge

Subacute aortic dissection type 1

Aortic dissec- Negative tion type 2 Aortic dissection.

Geographic location

Negative Negative

315

United States

United States

No seizure in 6 months on avoidance of drink No seizure in 6 months on avoidance of drink No seizure in 4 months on avoidance of drink No seizure in 2 months on avoidance of drink

Seizure Seizure Seizure Seizure


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Age, sex, race

Presentation

23, F, Japanese

Urticaria, anaphylaxis Tonic clonic seizure


20, M, race not described 43, M, race not described

Tonic clonic seizure Paranoia, religious delusions, and agitation



Rhinitis, allergy to buckwheat No significant PMH No significant PMH Schizophrenia, alcohol dependence; drug Hx: haloperidol Possible myopericarditis

ED, 100 mL (Richman 3000) Red Bull, 4–6 cans daily EDs, 5-hour ED; 1 cup coffee 10 cans of ED daily, each has 160 mg of caffeine

17, M, Caucasian

angina

85, F, race not described

Pretibial petechiae and large ecchymoses

23, M, Caucasian

Found unresponsive, PMH: mumps, rubella, and varideclared dead on cella during arrival childhood; Family Hx: heart disease in 2 grandparents, cancer in 1 Worsening dyspnea Previously fit and palpitations and well

58, M, race not described

3–4 Red Bull, 2– 3 Monster

Atrial fibrillation, Energy drug mitral valve bioprosthesis; drug Hx: digoxin, CCB, diuretics, warfarin Ripped Fuel, thermogenic protein drink.


Normal BP 99/57, HR 120 Agitated, delusions

Investigations

ECG

Skin prick test, intradermal test EEG, MRI head CT head, CBC, CMP

Mild distress, BP ECG, echo, CXR, 98/56, HR 104 CBC, electrolytes (hypokalemia), troponin (0104), CPK (190)

ST elevation in 2,3, aVF ST depression

Total complement, Petechiae at extremities and C3, C4, anti-PLT mouth and con- antibodies, autoimjunctival mucosa mune workup, HIV, HCV

BP 126/72, HR 76

Autopsy: features of heart muscle necrosis

1000 mL of highly caffeinated commercially available beverage for 6 months

TSH

Atrial fibrillation with RVR (169 bpm)

5–6 ED that day

ECG, echo, cardiac catheter and EP study

Normal without signs of ischemia or QTc prolongation


Sudden collapse, presented unresponsive

Working overtime in a furniture factory

24, M, Caucasian

1 hour history of crushing chest pain, nausea, and vomiting

Overweight BMI 20 cans of ED XL 40, mild HTN over the previous night


Generalized itching, urticaria, dyspnea, and dizziness

100-mL ED

Anxious, diaphoretic, slight basal rales on lung exam, no JVD, BP 90/60 LFTs, CBC, renal function, serum electrolytes, IgE elevated 685



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TTE

Toxicology screens

Outcome

Length of stay

Geographic location

Discharge

Japan Italy

Negative

Levetiracetam

Discharge

Caffeine and metabolites

Ativan

Discharge

Haloperidol

Discharge

Morphine 2 mg IV, morphine 4 mg IV; started on aspirin 325 Q8h; rapid improvement without intervention; diltiazem and oral nitrate was added on hospital day 2 Withdrawal of energy drug together with an immunosuppressive dose of Solu-Medrol (1 mg/kg/day)

USA 3 hours after pre- 3 days sentation ECGs were normalizing, CPK and troponins started trending down, repeat echo showed improved LV systolic function with EF 65% Return of PLTs Not described;- Italy to normal value < 2 weeks for PLTs to return to normal values

Mild decrease of Positive for opiLV systolic func- ates (received in ED) tion EF 50% Postgraduate Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 05/10/15 For personal use only.

Treatment

Concentric hypertrophy with normal EF 55% with moderate right-side chamber dilation (12 hours after presentation)

10 days

None 6 months after discontinuing the caffeine beverage, he was asymptomatic 5 days in ICU After 4–5 days Hypothermia the patient protocol within 3 hours of arrest showed progresalong with hepa- sive neurological improvement rin drip empirically for 48 hours Digoxin, ramipril, warfarin

Oral challenge test, basophil activation test

No seizure at 1 month follow-up No seizure at 2-month follow-up

Classification Urticaria and anaphylaxin Tonic-clonic seizure Tonic-clonic seizure

United States

Died

Urine tox originally negative but subsequently positive for ephedrine

Dilated left ventricle with a diastolic diameter of 62 mm and reduced EF 45% Negative Negative for structural abnormalities, valvular abnormalities or ventricular hypertrophy

United States

Follow-up

317

United Kingdom

United States

South Korea

At 1-month follow- Acute coronary up, patient taken off vasospasm diltiazem

Thrombocy1 year after onset the patient remained topenia stable

Follow-up microscopic exam: myocyte necrosis, focal endocardial and focal epicardial fibrosis

Sudden cardiac death secondary to myocardial necrosis

Follow-up TTE confirmed LV dimensions had normalized with EF 65% Discharged to rehabilitation with AICD for secondary prevention of sudden cardiac death

Tachycardiainduced cardiomyopathy Ventricular fibrillation cardiac arrest

Taurine-related anaphylaxin



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between 2011 and 2013, demonstrating the novelty of this phenomenon and reflecting the increasing incidence of EDrelated adverse events. Indeed, ED-related emergency room visits in the United States have seen a dramatic 10-fold increase, from 1128 in 2005 to 13,114 in 2009 [3], and doubling between 2007 and 2011, going from 10,068 to 20,783 [3]. A cross-sectional survey reported that almost one third of ED consumers experienced some type of ED-related adverse event [10]. Almost half the cases of ED-related toxicity were due to unintentional exposure in children aged < 6 years [13]. Of the emergency room visits for ED-related causes, 45% occurred in 18- to 25-year-olds and 32% in 26to 39-year-olds [3]. Overall, more emergency room visits involving EDs were made by males (64%) than by females [3], epidemiologically making ED-related adverse events a problem of the young male. Co-ingestion Co-ingestion with other agents was common. In fact, it is now normal to combine EDs with alcohol. Emergency room visits by males were more often linked to co-ingestion with alcohol or drugs, whereas in females co-ingestion with other pharmaceuticals was more common [3]. Co-ingestion with alcohol is a growing trend and is associated with increased risk-taking. Studies describe a significant association with substance abuse such as cannabis, tobacco, binge drinking, and nonmedicinal use of prescription drugs, leading to increased risky behaviors as well as injuries [14]. Effects of caffeine Caffeine is by far the main active ingredient in EDs, and consumption in large amounts causes the effects of acute caffeine intoxication: tachycardia, vomiting, arrhythmias, seizures, disruption of sleep patterns, and exacerbation of psychiatric disease [10,14]. Caffeine metabolism is extremely variable and depends on age, sex, daily exposure to caffeine, inducers or inhibitors of cytochrome P450 1A2 (the primary caffeine metabolizing enzyme in the liver), rapidity of consumption, and physical activity [15]. Younger people might be quite caffeine naive. Higher caffeine doses, repeated dosing, and habitual caffeine intake generally result in prolongation of its half-life and reduced clearance of caffeine and its metabolite, increasing the potential for caffeine toxicity [15]. Caffeine reaches maximum plasma concentration in a mean time of 45 minutes and has an average half-life of 5 hours [16], which would explain why ED-related adverse events usually occur a few hours after the consumption of the drink. Much is known about the physiological effects of caffeine ingestion, but significantly less about the other stimulants in EDs. Positron emission tomography scans after caffeine consumption have demonstrated a statistically significant drop in myocardial blood flow during exercise. Myocardial perfusion reserve decreased by 14% in controls and by up to 25% in subjects with coronary artery disease [17]. A similar study demonstrated a 22% drop in myocardial blood flow reserve with exercise after a caffeine load.

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Noncaffeine stimulants Energy drinks might also have a negative impact on endovascular and platelet function, acutely increasing platelet aggregation and causing altered endothelial function [18]. The particular agent producing these effects is yet to be identified [18]. Complex and potentially unknown interactions among various stimulants could potentiate adverse events; guarana extract, for example, another frequent ingredient in EDs, contains caffeine, theobromine, and theophylline [19], thereby potentiating the effect of caffeine. Taurine, another stimulant commonly found in EDs, is the most common free amino acid found in mammalian cardiac muscle (Table 2) [20]. When combined with caffeine, taurine potentiates its effects on the sarcoplasmic reticulum of cardiac myocytes. Both taurine and caffeine have shown in vitro physiological effects on intracellular calcium concentration within vascular smooth muscle. Higher levels of taurine were found in heart tissues of patients with congestive heart failure and experimental models of cardiac hypertrophy [21]. Taurine might also have a positive inotropic effect. These findings support the notion that caffeine and taurine may be acting in synergy to cause these adverse events. Glucuronolactone may contribute to cardiovascular changes including endothelial dysfunction, increased platelet aggregation, and an increase in blood pressure [18]. The interaction of caffeine with other ingredients in EDs is not clear. It is important to recognize that the EDs’ causality of adverse events cannot be established with certainty. This is due to the lack of a standardized definition of use and the lack of knowledge about the effects of the various active ingredients in EDs. However, the temporal relationship between ED ingestion and the reported adverse events, in conjunction with the known physiological effects of the active ingredients, makes these relationships highly likely. As to the nature of the ED-related adverse events, it is not surprising that the majority of the cases reported (53%, n = 23) entailed cardiovascular problems, followed by neurological issues [22-27]. Far less often, we found hemorrhagic complications [28,29], anaphylaxis [30,31], renal and electrolyte abnormalities [32], and 1 case of hepatic injury (Figure 2) [33].

Effects on the cardiovascular system Among the cardiovascular problems, more than a third (35%, n = 8) were related to various types of arrhythmias [34-39]. Caffeine ingested in high quantities is known to have an arrhythmogenic effect. The remaining presentations were rare: 3 reports of coronary vasospasm [40-42], 3 reports of aortic aneurysm dissection [43], 2 reports of cardiac arrests [44,45], 2 reports of QT prolongation [46,47], 2 reports of acute cardiomyopathies [48,49], 1 report of accelerated hypertension [50], 1 report of reversible postural tachycardia syndrome [51], 1 report of acute coronary thrombosis [52], and 1 report of ST-elevation myocardial infarction of unclear mechanism (Figure 3) [53]. The increased platelet


DOI: 10.1080/00325481.2015.1001712

5% 2%

Cardiovascular events

5% Neurological events

7%

Platelet disorders 52% 29%

Anaphylactic reactions Renal and electrolyte disorders Hepatic injury


Figure 2. Energy drink–related adverse events by organ system (n = 43).

aggregation, disturbed endothelial function, and potential for vasospasm in conjunction with hypertension would explain the incidence of cardiac ischemia, cardiac arrests, and cerebrovascular events. Neuropsychiatric outcomes Among the neurological outcomes, the most common presentations were seizures, some of them first-onset (6 cases), followed by neuropsychiatric agitation and aggressive behavior (3 cases) and 1 case of suicidal ideation [22]. Caffeine and taurine are known psychoactive agents, which may lead to modification of neurotransmission, although there is little information in the literature. Psychiatric problems usually only arise after EDs and alcohol. This combination has also led to increased suicidality in an army base study [54]. Hematological effects Three cases with hemorrhagic complications were also described. One patient developed thrombocytopenia that resolved after the cessation of EDs and treatment with steroids. Two cases of perioperative excessive bleeding of unclear etiology were attributed to chronic excessive ED consumption.

Discussion Although a placebo-controlled study found that the ingestion of 1 energy shot can significantly improve important

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aspects of cognitive function for up to 6 hours [55], all other health claims made by the producers of EDs remain unsubstantiated. This particular study was conducted under controlled conditions in partially sleep-deprived healthy volunteers. The majority of adverse events described in the literature, however, are related to indiscriminate use and combination with alcohol and other substances. The real health impact of these popular drinks remains unclear. This is due to the largely unknown effect, dosage, and interactions of the various ingredients found in these drinks. The evidence, however, seems compelling: as ED consumption increased over the last 8 years, ED-related emergency department visits dramatically increased. Because the reports in the literature rely on self-reporting, we believe that the incidence of ED-related adverse events is likely to be underreported and the events are likely to be underdiagnosed. We note the emergence of a specific sociobehavioral profile of the typical person who imbibes excessive amounts of EDs – a young man (generally < 25 years of age) who secondarily engages in substance abuse. It is not surprising that young people would seek an easy source of more energy that would enable them to study harder, study longer, or win at sports. Young people in the United States have been experiencing increasing amounts of stress and expectations both at school or work and at play. The old-fashioned approach of a cup of coffee has given way to the more powerful and expertly marketed ED. These drinks harmlessly promise more energy, an increased ability to experience pleasure and excitement, and a decreased effect of alcohol. A significant number of young people admit to not knowing that EDs differ from sports drinks and soft drinks. Caffeine continues to be the most common ingredient in EDs, and the most frequently ingested drug in the world. It is so common that many people underestimate the health effects that excessive consumption can cause. Caffeine acts through inhibition and activation of various receptors, and thus affects almost all body systems. Better known are the effects of mild consumption, such as increases in blood pressure and heart rate as well as dehydration. Energy drinks increase the potency of caffeine by combining it with other stimulants such as taurine, guarana, glucuronolactone, ginseng, and vitamin B complex. Contrary to the consumers’ expectations, EDs actually have negative effects on overall well-being, causing increased

Table 2. Effects of noncaffeine stimulants in energy drinks. Stimulant Guarana extract Taurine

Glucuronolactone

Effect Contains caffeine, theobromine, and theophylline When combined with caffeine, taurine potentiates its effects on the sarcoplasmic reticulum of cardiac myocytes May contribute to cardiovascular changes including endothelial dysfunction, increased platelet aggregation, and an increase in blood pressure

Potentiates the effect of caffeine In-vitro physiological effects on intracellular calcium concentration within vascular smooth muscle

Higher levels of taurine were found in heart tissues of patients with congestive heart failure

Might have a positive inotropic effect

May act in synergy with caffeine

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Energy drink related adverse events

Cardio-vascular

Arrhythmias

Myocardial ischemia


Aneurysm/ dissection

Cardiac arrest

Neurological

Seizures

Cerebrovascular accident

Neuro-psychiatric events

Suicidal ideation

Vasospasm Psychosis Coronary thrombosis

Cardiomyopathies

Hypertension

Figure 3. Cardiac and neurological energy drink–related adverse events.

sleepiness or nervousness [56]. Even anecdotal reports of suicidality and psychotic episodes have been reported. The greatest number of adverse events, however, affect the cardiac system, followed by neurological complications. These adverse events are explainable due to the physiological effects of excessive caffeine (mainly on the cardiovascular system and are neuroexcitatory in nature), potentiated by other stimulants in EDs. In the presence of underlying coronary artery disease, combining caffeine consumption with exercise has been found to lead to a significant decrease in myocardial perfusion [17], manifesting as myocardial ischemia, infarction, and arrhythmic activity. Although not necessarily clinically significant in healthy individuals, patients who have some degree of coronary artery disease may manifest with these serious cardiac consequences. The pathophysiology is centered on the effect of caffeine on adenosine. Adenosine acts as an endothelial-dependent vasodilator. Caffeine antagonizes the adenosine receptor, leading to inhibition of vasodilation and decreased blood flow to the myocardium. The second potential pathophysiological mechanism is through inhibition of phosphodiesterase activity, resulting in increased intracellular cyclic adenosine monophosphate, which in turn results in increased inotropic activity [57].

These effects of caffeine may be observed at a serum caffeine level of around 20 mmol/L, which may be achieved after ingestion of 200 mg of caffeine or consuming 2 cups of coffee; 1 to 2 cans of any commonly available ED may provide this much caffeine content [15]. The exact amount of ED consumption leading to these serious health effects is very difficult to ascertain because of the combinations, in different doses, of various stimulants whose health effects and interactions are still unknown. We do know that a safe dose of caffeine is 200 to 300 mg, whereas many EDs have caffeine content in the 500-mg range. The greatest danger arises when EDs are used in combination with alcohol or other drugs [2]. Although some people consume alcohol with EDs to feel less drunk (a common motivation for combining alcohol with illicit stimulants), others report using this combination to facilitate intoxication [58]. The combination of the stimulant caffeine and the depressant alcohol appears to lead to an impaired perception of one’s state of intoxication [2]. Co-ingestion with alcohol leads to increased risk-taking behaviors such as risky driving, riding with an intoxicated driver, being taken advantage of sexually, and injuries. In addition, EDs are frequently consumed when the body is already experiencing an increased circulating adrenaline load such as during a sporting event, on the nightclub scene, during or after physical exertion, sleep deprivation, or work-related stress, potentiating the stimulant effect. Certain conditions likely increase a person’s risk of developing ED-related adverse events, such as young age; caffeine naïvete; preexisting cardiac, vascular, or psychiatric conditions; the use of medications for attention deficit disorder; situational characteristics (excited/stressed mental state, sleep deprivation) [44]; and certain genetic conditions, such as long QT syndrome and the Brugada syndrome.

Conclusion Energy drink consumption is a health issue primarily of the adolescent and young adult male population. Despite the lack of a proven correlation between EDs and the described adverse events, we feel there is sufficient evidence to warrant caution. We believe it is important to educate providers to the potential risks, to increase regulation, and to conduct further studies to prove or refute a causal link. Position statements of the American Academy of Pediatrics and American Medical Association that recommend avoiding the consumption of EDs, particularly in the younger population, should be circulated. Education should occur in the offices of primary care providers during well-child visits, as almost half the cases of ED-related toxicity were due to unintentional exposure in children aged < 6 years [13]. Implementing age limits for such drinks might be beneficial. Legal restrictions on the sale of EDs and educational campaigns have been associated with decreased calls to poison centers for ED toxicity. Primary care providers should also counsel patients at increased risk, and should caution them about consuming EDs in conjunction with alcohol [59]. Routine drug or social histories should include questions about ED consumption. Providers should also consider ED-related


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adverse events in their differential diagnosis, particularly in younger patients who present with the above-described symptoms. Finally, more information is needed about the effects and interactions of the various ingredients in EDs. Placebocontrolled studies need to be conducted with a sufficient sample size to enable establishing the causality between ED consumption and specific adverse health events. More detailed sociodemographic reviews would identify the population groups most likely to consume these drinks, aiding targeted education. Although the increase in ED-related emergency room visits has been a little less dramatic in the last 4 years, it is still rising. It is likely that the increasing consumption of EDs and the resulting adverse events are a problem that is here to stay. Health care providers should be aware of and proactive about this new, growing, and preventable health hazard.

Acknowledgments We thank Hari Prasad MD, Pavan Tenneti MD, Kevin Charles MD and Kris Middaugh for their assistance that greatly improved the manuscript.

Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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