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Energy Drinks: Another Cause of QT Prolongation?
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Download the PDF here
Michael D. Winniford
"individuals who are taking QT‐prolonging medications as well as those with coronary or structural heart disease should be advised of this risk……...On the research front, the observation that energy drinks can cause QT prolongation, a well‐established risk factor for sudden death, warrants further investigation."
From Jules: what about HIV+, QT prolongation & certain ARTs like maybe a boosted PI ????
Since the first product appeared on US shelves in 1997, the caffeinated energy drink market has grown dramatically, with an estimated annual revenue of $10 billion in 2018. Advertising for products such as Red Bull, Monster, and Rockstar emphasizes claims of enhanced energy level, mental focus, and physical performance. This marketing strategy resonates with teenagers and young adults, the dominant consumer group for these products. As the energy drink market has grown, so too has awareness of their health risks.1, 2 Between 2004 and 2014, 34 deaths linked to energy drinks were reported to the US Food and Drug Administration, and serious adverse events described in the literature include cardiac arrest, myocardial infarction, atrial fibrillation, and seizures.3 Despite multiple articles in the medical literature and lay press describing the risks of energy drinks, especially when combined with alcohol, growth of this industry shows little sign of slowing.
Although the health risks of energy drinks have been widely recognized, the mechanism responsible for the cardiovascular complications associated with them remains uncertain. The acute hemodynamic effects of energy drinks in healthy volunteers have been well described: a modest increase in systolic and diastolic blood pressure (in the range of 3–5 mm Hg) with little change in heart rate.
Although transient hemodynamic changes of this degree are unlikely to be harmful in the young consumers of energy drinks, the rapid ingestion of a large volume by a susceptible individual may result in potentially more dangerous changes. In this issue of the Journal of the American Heart Association (JAHA), Shah and colleagues4 test the hypothesis that energy drinks can cause QT‐interval prolongation, a well‐recognized risk factor for ventricular arrhythmias. Previous small studies of the electrocardiographic effect of energy drinks, some lacking a placebo control, have reached conflicting conclusions. Using a double‐blinded crossover trial design, the effect of 2 different caffeinated energy drinks and a caffeine‐free placebo drink on the QT interval was assessed in healthy volunteers with a normal QT interval at baseline. Both energy drinks produced an average maximal increase in heart rate–corrected QT interval (QTc) of 18 to 20 ms that persisted up to 4 hours after consumption. In contrast, the placebo drink was followed by only a small transient increase in QTc. Although no subject developed a QTc >500 ms, both energy drinks resulted in QTc prolongation >50 ms in 2 subjects, a range clearly associated with increased risk of arrhythmia. The effect of the energy drinks on blood pressure and heart rate was similar to that observed in previous studies.
In the drug development world, the US Food and Drug Administration would require extensive safety testing before approval of a drug that caused this degree of QT prolongation in a "thorough QT/QTc study." Whether classified as beverages or dietary supplements, energy drinks require no such safety evaluation. It is sufficient to declare that the individual ingredients are "generally recognized as safe." Safety testing is not required to determine whether the combination of several ingredients that are each generally recognized as safe results in a not‐so‐safe concoction.
The electrocardiographic effects of caffeine, the main ingredient in energy drinks, have been extensively studied; there is no convincing evidence that caffeine alone causes QTc prolongation.5, 6 Ginseng, added to many of these products for its purported energy‐boosting properties, has been reported to cause QT prolongation, but in a direct comparison of a ginseng‐containing energy drink with the same amount of ginseng alone, ginseng had no effect on QT interval.7 In the concentration found in energy drinks, none of the other common ingredients, such as taurine, guarana, l‐carnitine, yohimbine, sugars, and B vitamins, is known to cause QT prolongation. Although the observation by Shah et al4 that the 2 different energy drinks had the same effect on QTc suggests that this may be a class effect, there are >100 different products on the market, each with a proprietary combination of ingredients. A conclusion about a possible class effect would at least require knowing about differences in the composition of the 2 products tested.
So, does energy drink–induced QT prolongation pose a serious health risk? The most obvious at‐risk group would be those with a genetic long‐QT syndrome (LQTS); a health risk in this group is supported by 2 case reports and a small clinical trial. A previously healthy 22‐year‐old woman experienced cardiac arrest after drinking 6 cans of energy drink over 4 hours.8 The initial ECG showed torsade de pointes, and her QTc shortly after arrival was prolonged at 526 ms, normalizing to 419 ms over the next few days. Subsequent genetic testing confirmed LQTS‐1. In a similar case, a 13‐year‐old girl who presented with chest pain and palpitations after consuming an energy drink had a prolonged QTc interval on admission (561 ms) that fully normalized by the next day.9 Genetic testing again confirmed LQTS‐1. Finally, in a randomized, placebo‐controlled study of subjects with familial LQTS, the QTc interval increased by >50 ms after energy drink in 3 of 24 patients.10 Perhaps some of the cardiac arrests linked to energy drinks were the result of unmasking a previously undiagnosed genetic ion channelopathy.
Of course, most energy drink consumers do not have a genetic LQTS. Is there evidence that energy drink–induced QT prolongation poses a risk to these individuals? A MEDLINE search finds only a single case of torsade de pointes, the characteristic arrhythmia caused by QT prolongation, linked to energy drink consumption (ie, the young woman with LQTS‐1 described above).8 Torsade de pointes can rapidly progress to ventricular fibrillation, and it is impossible to know whether QT prolongation played a role in any of the unexplained deaths or cardiac arrests linked to energy drinks. But with millions of consumers and >20 000 emergency department visits yearly involving energy drinks, the role of QT prolongation would be more compelling if there were other reports of torsade de pointes.
Concerns about the short‐ and long‐term health risks of energy drinks extend well beyond their effect on ventricular repolarization. These concerns have led to a wide range of recommendations, including stricter requirements for product labeling, restrictions on caffeine content, limitations on the marketing and sale to children and adolescents, and educating parents, teachers, and healthcare providers about the health risks of energy drinks. On the research front, the observation that energy drinks can cause QT prolongation, a well‐established risk factor for sudden death, warrants further investigation. Which ingredient or combination of ingredients is responsible for this effect on repolarization? Do some products pose a greater risk than others? What effect does the addition of alcohol or other drugs have on the electrocardiographic effect of energy drinks? What role does QT prolongation play in the sudden deaths linked to energy drinks? Further research is not needed to support the sensible recommendation that patients with a genetic LQTS should be cautioned about the risks of energy drinks. Likewise, individuals who are taking QT‐prolonging medications as well as those with coronary or structural heart disease should be advised of this risk.
Disclosures
None.
Footnotes
*Correspondence to: Michael D. Winniford, MD, Cardiovascular Division, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216. E‐mail: mwinniford@umc.edu
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Impact of High Volume Energy Drink Consumption on Electrocardiographic and Blood Pressure Parameters: A Randomized Trial
Sachin A. Shah, PharmD et al.
4 Jun 2019
Energy drink consumption has been associated with cardiac arrest, myocardial infarction, spontaneous coronary dissection, and coronary vasospasm.9, 10, 11, 12, 13, 14, 15, 16 This association is strengthened with studies showing increased platelet aggregation, increased systolic blood pressure (SBP), and QTc prolongation.17, 18, 19, 20 QT/QTc interval prolongation is a biologically plausible reason for the sudden cardiac arrest associated with energy drinks and QTc prolongation places patients at increased risk for developing torsades de pointes, which can lead to fatal ventricular arrhythmias.21 Several small studies have demonstrated mild QTc prolongation with energy drink consumption but the data remain controversial because of energy drink dose and study design‐related confounders.19, 20, 22, 23 To validate previous electrocardiographic findings and to assess the differences between energy drink types, we conducted a randomized, double‐masked, placebo‐controlled, crossover study in young healthy volunteers.
Participants were randomized into 1 of 3 intervention phases using a computer‐generated code from http://www.randomization.com. Participants received two 16‐oz bottles of a commercially available caffeinated energy drink brand (drink A), another brand of a caffeinated energy drink (drink B), or a placebo‐drink (placebo) on 3 separate days with a minimum 6‐day washout period in‐between. The beverages were consumed within a 60‐minute period but no faster than 1 bottle in 30 minutes. Based on the package labeling, both drink A and drink B contained caffeine (304–320 mg/32‐fl oz), taurine, glucuronolactone, and vitamins along with other proprietary ingredients.24 Some differences between the 2 energy drink brands include the presence of carnitine, guarana, and panax ginseng. The placebo drink contained carbonated water, lime juice, and cherry flavoring. All drinks were packaged in identical, masked containers prepared within 24 hours of administration and stored in a refrigerator before administration.
Conclusions
Caffeinated energy drinks significantly prolong the QTc interval and raise brachial and central blood pressure post‐acute exposure. Further investigation is warranted on whether an individual ingredient or a unique combination leads to the observed electrophysiological and hemodynamic changes. The impact of long‐term energy drinks consumption remains unknown.
Discussion
To our knowledge, this is the largest, controlled study, indicating acute‐consumption of 32 oz of a caffeinated energy drink significantly prolongs the QTc interval when compared with placebo. According to the Food and Drug Administration, QTc prolongation is a well‐established risk factor for arrhythmias, with a prolongation over 10 ms prompting further investigation.26, 27 Clinically, a QT/QTc interval >500 ms or a change >30 ms warrants careful monitoring.28 Drugs such as ranolazine and terfenadine carry warnings, or have been removed from the market because of prolongation of the mean QT/QTc by 6 ms.29, 30
Three smaller studies have evaluated the impact of consuming 32 oz of energy drinks on heart rhythm variables.19, 25, 31 In a non‐controlled study (n=14) by Kozik et al, 57% of the healthy participants had a QTc >500 ms after consuming 32 oz of the energy drink.31 In a small (n=18) randomized, caffeine‐controlled clinical trial, 32 oz of an energy drink resulted in a significantly higher QTc at 2 hours when compared with the caffeinated control (+0.4±18.4 ms versus −10.4±14.8 ms, respectively; P=0.02).19 In another similar placebo‐controlled trial (n=27), the QTc interval was transiently higher (6 ms) at 2 hours after 32‐oz energy drink consumption when compared with placebo (+3.4±10.7 and −3.2±11.8 ms, respectively; P=0.030).25 The results of our study confirm these previous findings and suggest that the QTc changes are generally sustained over the 4 hour monitoring period versus being a transient effect after 32‐oz energy drink consumption.
The results are inconsistent in other studies where energy drink volumes under 32 oz were investigated. Brothers et al (n=15) reported no changes in the QTc over 6.5 hours post‐consumption of a 24‐oz energy drink.22 Tauseef et al found QTc prolongation of 13 ms after 500 mL (16.9 ounce) energy drink consumption.20 An Australian study enrolled patients with congenital long QT‐syndrome (n=24) and found no statistically significant changes within 90 minutes after consumption of 500 mL (16.9 ounce) of an energy drink. However, 3 patients did have a QTc increase >50 ms when compared with baseline.23 One parallel designed study assessed the impact of consuming 460 mL of 3 different types of caffeinated energy drinks on ECG parameters with no clinically significant changes.32
In this study, both energy drinks had a similar effect on electrocardiographic parameters. Common ingredients contained in this study's products included a combination of caffeine, taurine, glucuronolactone, and B‐vitamins. Caffeine at doses under 400 mg is not expected to induce any electrocardiographic changes.33 Taurine is an endogenous molecule and supplementation is believed to be anti‐arrhythmic rather than pro‐arrhythmic.34, 35 In animal models evaluating short QT syndrome, a taurine‐magnesium coordination compound has been shown to prolong the QT interval in a dose‐dependent manner.36 Data on glucuronolactone and B‐vitamins are limited but they are typically regarded as safe.37 Although the preponderance of data suggest these ingredients may be safe individually, their use in combination requires evaluation.
There was an ≈5 and 4 mm Hg increase in SBP and DBP, respectively after energy drink consumption relative to placebo. A previous meta‐analysis of 15 studies including >300 participants similarly suggested a 4‐ and 3‐mm Hg change in SBP and DBP independent of dose.18 An emerging predictor of cardiovascular risk is cSBP.38 In this study, cSBP was significantly elevated after energy drink consumption but the long‐term consequences remain unknown.
While blood pressure changes can be attributed primarily to the caffeine, other ingredients in energy drinks may pose some hemodynamic activity.37 Taurine has been shown to lower blood pressure in prehypertensive patients, indicating the need for investigating simultaneous caffeine and taurine intake.39
Caffeine and ephedra‐containing supplements were withdrawn from market after discovery of adverse QTc interval effects.40 Additionally, a sustained elevation in SBP of 2 mm Hg is associated with a 7% increased risk of mortality from ischemic heart disease and a 10% increased risk of stroke mortality.41 The cardiovascular effects seen in this study warrant concern as the observation of increased cardiovascular adverse effects and fatalities related to energy drinks remains an important public health issue.42
Several factors may limit the generalizability of this study. We did not investigate the effects of different doses and the volume of drink consumed (two 16‐ounce cans over 60 minutes) in this study may not be representative of real‐world consumption patterns. However, 24‐oz variants of certain energy drink brands are readily available, facilitating consumption of larger volumes of energy drink in one sitting. In a survey of 2040 respondents, 16% reported having once consumed >2 energy drinks in a day.43 We assessed the effects of acute consumption of an energy drink <4 hours, which does not lend insight to long‐term effects nor the effects of chronic consumption. Additionally, we assessed energy drink consumption alone, and it is not uncommon for energy drinks to be consumed in combination with other substances such as alcohol.44, 45 While all products were packaged identically, it is possible that some participants were able to identify the energy drink or placebo drinks based on taste or pharmacodynamic response. Our study included only healthy individuals between the ages of 18 to 40 years and results may not be applicable to populations with concomitant comorbidities or those who are not within the studied age range. We did not independently test the concentrations of the ingredients in the energy drinks but relied on publicly available data.
Significant prolongation in the QT interval was also evident within the first hour after energy drink consumption but these are thought to be HR related changes. There appears to be a mild PR shortening effect and is currently thought to be clinically non‐significant. Most previous studies used the Bazett's correction formula, but it is known to under correct at low heart rates.46 Conversely, the Fridericia formula has been shown to be an acceptable alternate correction formula when compared with the Bazett's.47 Our results are significant regardless of the heart rate correction formula used (Bazett's or Fridericia's). However, it is important to note that QTc prolongation does not necessitate onset of torsades de pointes and is simply a risk factor. While our study incorporates many aspects of a "Thorough QT/QTc Study", assay‐sensitivity could not be assessed due to the lack of a positive‐control (eg, moxifloxacin).27
Individuals with acquired or congenital long QT syndrome and those with hypertension should be more vigilant and limit their energy drink intake. Based on currently available data, the class of energy drinks, rather than one particular product, warrants use with caution.
Conclusions
Caffeinated energy drinks significantly prolong the QTc interval and raise brachial and central blood pressure post‐acute exposure. Further investigation is warranted on whether an individual ingredient or a unique combination leads to the observed electrophysiological and hemodynamic changes. The impact of long‐term energy drinks consumption remains unknown.
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