j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e6
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Hypercoagulability after energy drink consumption Matthew J. Pommerening, MD, Jessica C. Cardenas, PhD, Zayde A. Radwan, MD, Charles E. Wade, PhD, John B. Holcomb, MD, and Bryan A. Cotton, MD, MPH* Department of Surgery and the Center for Translational Injury Research, The University of Texas Health Science Center, Houston, Texas
article info
abstract
Article history:
Background: Energy drink consumption in the United States has more than doubled over the
Received 3 January 2015
last decade and has been implicated in cardiac arrhythmias, myocardial infarction, and
Received in revised form
even sudden cardiac death. We hypothesized that energy drink consumption may increase
6 May 2015
the risk of adverse cardiovascular events by increasing platelet aggregation, thereby
Accepted 11 June 2015
resulting in a relatively hypercoagulable state and increased risk of thrombosis.
Available online xxx
Methods: Thirty-two healthy volunteers aged 18e40 y were given 16 oz of bottled water or a standardized, sugar-free energy drink on two separate occasions, 1-wk apart. Beverages
Keywords:
were consumed after an overnight fast over a 30-min period. Coagulation parameters and
Energy drink
platelet function were measured before and 60 min after consumption using thrombe-
Coagulation
lastography and impedance aggregometry.
Hypercoagulability
Results: No statistically significant differences in coagulation were detected using kaolin or
Platelet aggregation
rapid thrombelastography. In addition, no differences in platelet aggregation were detected
Thrombosis
using ristocetin, collagen, thrombin receptoreactivating peptide, or adenosine diphosphate einduced multiple impedance aggregometry. However, compared to water controls, energy drink consumption resulted in a significant increase in platelet aggregation via arachidonic acideinduced activation (area under the aggregation curve, 72.4 U versus 66.3 U; P ¼ 0.018). Conclusions: Energy drinks are associated with increased platelet activity via arachidonic acideinduced platelet aggregation within 1 h of consumption. Although larger clinical studies are needed to further address the safety and health concerns of these drinks, the increased platelet response may provide a mechanism by which energy drinks increase the risk of adverse cardiovascular events. ª 2015 Elsevier Inc. All rights reserved.
1.
Background
In the last two decades, energy drinks have become increasingly popular in the United States. In 2007, just 10 y after the introduction of Red Bull to the United States, the energy drink market expanded to over 500 brands, comprising over 62% of the national beverage market. Sales have increased at an
exponential rate, and as of 2013, Americans spend nearly $20 billion consuming 0.05). Additionally, for each of the parameters measured, the delta change in coagulation values after energy drink consumption was not significantly different from the delta change in coagulation measured after consumption of water controls.
3.2.
3.
Before
Rapid TEG
There were no changes in coagulation parameters by rTEG before and after water controls for activated clotting time (174.0 versus 177.2 s; P ¼ 0.73), k-value (1.9 versus 1.9 min; P ¼ 0.97), alpha angle (66.3 versus 66.6 ; P ¼ 0.45), MA (61.3 versus 61.8 mm; P ¼ 0.11), G-value (8.1 versus 8.3 d/cm2; P ¼ 0.10), or LY30 (1.3% versus 1.2%; P ¼ 0.43). Similarly, there were no significant changes in rTEG coagulation parameters before and after energy drink consumption (Table 3), and the
Table 3 e rTEG values before and after energy drink consumption. rTEG Table 1 e Targets and receptors involved in platelet aggregation measured by Multiplate. Platelet activator ADP Arachidonic acid (AA) Collagen TRAP-6 Ristocetin
Target/receptor pathway P2Y12 COX pathway GPIa/IIa, GPVI PAR GPIba
ACT, s k-value, min Alpha, MA, mm G-value, dynes/cm2 LY30, %
Before 173.7 1.80 66.70 61.66 8.14 1.68
(13.55) (0.33) (3.66) (3.57) (1.24) (2.02)
After 179.08 1.83 66.46 61.46 8.09 1.24
(15.41) (0.29) (3.16) (3.63) (1.31) (1.39)
ACT ¼ activated clotting time. Values are reported as means and standard deviations.
P value 0.110 0.440 0.554 0.619 0.686 0.787
4
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e6
delta changes in coagulation values after energy drink consumption were not significantly different from those measured after water controls (all P > 0.05).
3.3.
Platelet aggregation
Platelet function was measured using impedance aggregometry for both water controls and energy drinks. No associated changes in platelet aggregation (AUC) were detected after water consumption for ADP (57.21 versus 58.72 U; P ¼ 0.357), arachidonic acid (67.13 versus 68.53 U; P ¼ 0.457), collagen (41.40 versus 42.47 U; P ¼ 0.292), TRAP (101.75 versus 98.33 U; P ¼ 0.530), or ristocetin (57.82 versus 55.00 U; P ¼ 0.625). Platelet aggregation before and after energy drink consumption is shown in Table 4. Similar to the water controls, no significant changes in platelet aggregation were observed after consumption of energy drinks for samples activated with ADP, collagen, TRAP, or ristocetin. However, compared to water controls, energy drink consumption was associated with a significant increase in platelet aggregation after arachidonic acideinduced platelet activation (AUC, 72.43 versus 66.29 U; P ¼ 0.018). In addition, the increase in platelet aggregation after energy drink consumption was significantly greater than after water controls (delta AUC, 6.14 versus 1.40 U; P ¼ 0.012). Peak platelet aggregation (122.58 versus 111.59 AU; P ¼ 0.026) and the velocity of platelet aggregation (17.72 versus 16.03 AU/min; P ¼ 0.008) were also significantly increased with arachidonic acideinduced activation after energy drink consumption (Figure).
4.
Discussion
As energy drink consumption in the United States has exponentially increased over the last two decades, concerns have been raised regarding their safety and potential role in adverse cardiovascular events and death. We found that consumption of a single, sugar-free energy drink was associated with a significant increase in platelet aggregation within 90 min in otherwise healthy volunteers. Platelet function was increased via arachidonic acideinduced platelet activation; however, this did not translate to measurable hypercoagulable changes in the rate of clot formation or overall clot strength measured by TEG. While more clinical data are needed, these findings suggest that health concerns associated with energy drinks may be related to hypercoagulable changes in platelet function occurring in the same pathway
Table 4 e Platelet aggregation before and after energy drink consumption. Multiplate ADP Arachidonic acid Collagen TRAP-6 Ristocetin
Before 58.28 (21.95) 66.29 (35.50) 41.71 (22.93) 104.91 (20.03) 59.6 (33.58)
After 63.39 72.43 46.14 107.91 53.9
(23.5) (28.69) (24.32) (12.29) (34.9)
P value 0.106 0.018 0.167 0.563 0.647
Values indicate AUC, reported in units, and are reported as means and standard deviations.
Figure e Platelet function before and after energy drink consumption. AUC, reported in arbitrary units (U), expresses overall platelet activity. The AUC is an expression of both peak aggregation, measured in AU, and the velocity or rate of platelet aggregation. (Color version of figure is available online.)
targeted by aspirin to reduce thrombosis risk and adverse cardiovascular events. Because so-called “energy” products are relatively new to the market, few studies have examined, in detail, the shortand long-term health consequences of energy drink consumption. The predominance of literature pertaining to energy drinks has focused on social and behavioral studies examining demographics, consumption patterns, and behavioral effects [18e23]. Others have explored the claims of increased endurance and performance enhancement with conflicting results [24]. In athletes, energy drinks have shown to improve lap times in cyclists but have not shown an effect on high-intensity run times to exhaustion in university athletes or an improvement in sprint times in women sprinters [25e27]. Energy drinks also have been linked to improvements in mood, decreased perception of stress and pain, and improved cognition in college students [24,28]. The quality of evidence of the studies investigating health and safety outcomes is limited by sample size, methodology, and heterogeneity. Of the existing studies, energy drinks have been shown to cause a modest increase systolic and mean arterial blood pressure and also an increased stroke volume in athletes who consumed energy drinks with taurine [3,29]. Findings of changes in the heart rate are inconsistent, with some studies showing an increase and others no change; however, it does appear there is a decrease in heart rate variability [29e31]. No studies have shown electrocardiogram changes with energy drink consumption; however, it is recommended that people with heart arrhythmias and heart failure not drink these drinks [3,32,33]. Associations of energy drinks with adverse cardiovascular events is limited to case reports and anecdotal evidence, citing cases such as atrial fibrillation in adolescents and cardiac arrest in young males during sporting events [4e6]. To our knowledge, only one prior study has looked at the effects of energy drinks on the coagulation system and found similar results. Using optical light aggregometry, Worthley et al. [29] also found that platelet aggregation was increased after consumption of energy drinks when compared with
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e6
water controls. The authors demonstrated that platelet aggregation increased via ADPeinduced activation and this occurred in a dose-response fashion, further strengthening the association of energy drinks and platelet activity. Energy drinks were also associated with increased systolic blood pressure and decreased endothelial function, both of which are likely to act in combination with platelet aggregation to increase thrombosis and cardiovascular risk. In the present study, platelet aggregation after energy drink consumption was increased after ADPeinduced activation; however, this only approached a weak statistical association (P ¼ 0.106). In both the Worthley study and ours, energy drinks appear to increase platelet aggregation via two important pathways of platelet activation targeted by the most commonly prescribed drugs aimed at reducing cardiovascular events. Aspirin irreversibly inhibits platelets production of thromboxane A2, a prothrombotic product of arachidonic acid. Clopidogrel inhibits binding of ADP to its platelet P2Y12 receptor, thereby inhibiting ADPemediated activation of the glycoprotein GPIIb/IIIa complex and subsequent platelet aggregation. Aspirin and clopidogrel have both been extensively studied and shown to reduce the risk of adverse cardiovascular events, such as stroke and myocardial infarction [34e38]. Increased platelet activation by either of these pathways may increase the risk of thrombosis and cardiovascular events, particularly in high-risk patients or those with preexisting conditions [39e41]. Currently, trauma centers that use TEG as a point-of-care device use rTEG given that it supplies the physician with a hemostatic profile quicker than standard kaolin TEG. However, kaolin TEG is more sensitive than rTEG, particularly in comparing parameters that measure the initial phases of clot formation and also fibrinolysis. This is due to the addition of tissue factor, an extremely potent initiator of coagulation, in rTEG which stimulates the more rapid formation of a slightly less stable clot. Thus, we included kaolin TEG as we expected it may detect smaller variations in coagulation. The lack of significant hypercoagulable changes on either kaolin or rTEG is not discordant with increased platelet aggregation and does not rule out the possibility of increased thromboembolic risk. In fact, antiplatelet-mediated effects on coagulation are not routinely detected on TEG. This is likely multifactorial, owing to the complexity of the coagulation cascade and the comprehensive nature of TEG in measuring multiple aspects of clot kinetics. For example, the kaolin and tissue factor used in TEG are potent initiators of coagulation that, in addition to platelet activation, also result in significant fibrin generation. Clot strength is largely reflective of the plateletefibrin interaction; therefore, MA and other clot kinetics may be unlikely to be significantly altered by the influence of single pathways. This may explain why we did not detect hypercoagulable changes on TEG despite increased platelet aggregation after energy drink consumption. There are several limitations in this pilot study that are important to consider regarding the implications of our findings. First and foremost, the association of energy drinks and adverse cardiovascular events is merely speculative and, to the best of our knowledge, based only on anecdotal evidence. No causal associations can be made at this time, and energy drinks may in fact have no bearing on mortality or even
5
general health. In addition, our results demonstrate statistically significant changes in platelet function however clinical outcomes were not measured in this study and the clinical significance of this platelet response, if any, is unknown. Finally, coagulation is complex, and even if there are procoagulant effects associated with one or several of the ingredients in energy drinks, thromboembolic risk is multifactorial and likely also related to several host factors and their interaction with those ingredients.
5.
Conclusions
In this study, we demonstrate that energy drinks are associated with increased platelet aggregation via the arachidonic acid pathway within 1 h of consumption. Because this is the same pathway inhibited by aspirin therapy, our findings support a potential mechanism by which energy drink consumption may lead to an increased risk for thromboembolic disease and adverse cardiovascular events. Future work in this area should aim to elucidate the mechanism of energy drink ingredients on platelet function and coagulation pathways and correlate with clinical outcomes. Potential implications for surgery patients include improved understanding of early cardiovascular deaths after trauma in young patients, improved thromboembolism prophylaxis by targeting pathways not addressed with current therapies and, on the opposite end of the spectrum, identifying a potential resource for reversal of traumaeinduced platelet dysfunction and hemorrhage.
Acknowledgment Funding/support: None. Authors’ contributions: M.J.P., Z.A.R., C.E.W., and B.A.C. designed the study. M.J.P., J.C.C., and Z.A.R. conducted the literature search and collected the data. M.J.P., J.B.H., C.E.W., and B.A.C. analyzed the data. M.J.P., J.C.C., Z.A.R., J.B.H., C.E.W., and B.A.C. interpreted the data. All authors participated in the writing, revising, and editing of the article.
Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in the article.
references
[1] Heckman M, Sherry K, De Mejia EG. Energy drinks: an assessment of their market size, consumer demographics, ingredient profile, functionality, and regulations in the United States. Compr Rev Food Sci Food Saf 2010;9:303. [2] Malinauskas BM, Aeby VG, Overton RF, Carpenter-Aeby T, Barber-Heidal K. A survey of energy drink consumption patterns among college students. Nutr J 2007;6:35. [3] Higgins JP, Tuttle TD, Higgins CL. Energy beverages: content and safety. Mayo Clin Proc 2010;85:1033.
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[4] Berger AJ, Alford K. Cardiac arrest in a young man following excess consumption of caffeinated “energy drinks”. Med J Aust 2009;190:41. [5] Di Rocco JR, During A, Morelli PJ, Heyden M, Biancaniello TA. Atrial fibrillation in healthy adolescents after highly caffeinated beverage consumption: two case reports. J Med Case Rep 2011;5:18. [6] Scott MJ, El-Hassan M, Khan AA. Myocardial infarction in a young adult following the consumption of a caffeinated energy drink. BMJ Case Rep 2011;2011. [7] Energy “drinks” and supplements: investigations of adverse event reports. Silver Spring, Maryland: U.S. Food and Drug Administration; 2012. [8] Voluntary and mandatory reports on 5-hour energy, monster energy, and rockstar energy drink. Center for food safety and applied nutrition adverse event reporting system. Silver Spring, Maryland: U.S. Food and Drug Administration; 2012. [9] Arria AM, O’Brien MC. The “high” risk of energy drinks. JAMA 2011;305:600. [10] Selby R, Geerts W, Ofosu FA, et al. Hypercoagulability after trauma: hemostatic changes and relationship to venous thromboembolism. Thromb Res 2009;124:281. [11] Paffrath T, Wafaisade A, Lefering R, et al. Venous thromboembolism after severe trauma: incidence, risk factors and outcome. Injury 2010;41:97. [12] White AE, Edelman JJ, Lott N, et al. Characterization of the hypercoagulable state following severe orthopedic trauma. J Trauma Acute Care Surg 2014;77:231. [13] Park MS, Owen BA, Ballinger BA, et al. Quantification of hypercoagulable state after blunt trauma: microparticle and thrombin generation are increased relative to injury severity, while standard markers are not. Surgery 2012;151:831. [14] Schreiber MA, Differding J, Thorborg P, Mayberry JC, Mullins RJ. Hypercoagulability is most prevalent early after injury and in female patients. J Trauma 2005;58:475. discussion 480e471. [15] Pommerening MJ, Schwartz DA, Cohen MJ, et al. Hypercoagulability after injury in premenopausal females: a prospective, multicenter study. Surgery 2014;156:439. [16] Brakenridge SC, Henley SS, Kashner TM, et al. Comparing clinical predictors of deep venous thrombosis versus pulmonary embolus after severe injury: a new paradigm for posttraumatic venous thromboembolism? J Trauma Acute Care Surg 2013;74:1231. discussion 1237e1238. [17] Cotton BA, Faz G, Hatch QM, et al. Rapid thrombelastography delivers real-time results that predict transfusion within 1 hour of admission. J Trauma 2011;71:407. discussion 414e407. [18] Miller KE. Energy drinks, race, and problem behaviors among college students. J Adolesc Health 2008;43:490. [19] O’Brien MC, McCoy TP, Rhodes SD, Wagoner A, Wolfson M. Caffeinated cocktails: energy drink consumption, high-risk drinking, and alcohol-related consequences among college students. Acad Emerg Med 2008;15:453. [20] Trapp GS, Allen KL, O’Sullivan T, et al. Energy drink consumption among young Australian adults: associations with alcohol and illicit drug use. Drug Alcohol Depend 2014; 134:30. [21] Aslam HM, Mughal A, Edhi MM, et al. Assessment of pattern for consumption and awareness regarding energy drinks among medical students. Arch Public Health 2013;71:31. [22] Cerimele JM, Stern AP, Jutras-Aswad D. Psychosis following excessive ingestion of energy drinks in a patient with schizophrenia. Am J Psychiatry 2010;167:353.
[23] Chelben J, Piccone-Sapir A, Ianco I, et al. Effects of amino acid energy drinks leading to hospitalization in individuals with mental illness. Gen Hosp Psychiatry 2008;30:187. [24] Pettit ML, DeBarr KA. Perceived stress, energy drink consumption, and academic performance among college students. J Am Coll Health 2011;59:335. [25] Candow DG, Kleisinger AK, Grenier S, Dorsch KD. Effect of sugar-free Red Bull energy drink on high-intensity run timeto-exhaustion in young adults. J Strength Cond Res 2009;23: 1271. [26] Ivy JL, Kammer L, Ding Z, et al. Improved cycling time-trial performance after ingestion of a caffeine energy drink. Int J Sport Nutr Exerc Metab 2009;19:61. [27] Astorino TA, Matera AJ, Basinger J, et al. Effects of red bull energy drink on repeated sprint performance in women athletes. Amino Acids 2012;42:1803. [28] Ragsdale FR, Gronli TD, Batool N, et al. Effect of Red Bull energy drink on cardiovascular and renal function. Amino acids 2010;38:1193. [29] Worthley MI, Prabhu A, De Sciscio P, et al. Detrimental effects of energy drink consumption on platelet and endothelial function. Am J Med 2010;123:184. [30] Steinke L, Lanfear DE, Dhanapal V, Kalus JS. Effect of “energy drink” consumption on hemodynamic and electrocardiographic parameters in healthy young adults. Ann Pharmacother 2009;43:596. [31] Menci D, Righini FM, Cameli M, et al. Acute effects of an energy drink on myocardial function assessed by conventional echo-Doppler analysis and by speckle tracking echocardiography on young healthy subjects. J Amino Acids 2013;2013:646703. [32] Sudano I, Binggeli C, Spieker L, et al. Cardiovascular effects of coffee: is it a risk factor? Prog Cardiovasc Nurs 2005;20:65. [33] Duchan E, Patel ND, Feucht C. Energy drinks: a review of use and safety for athletes. Phys Sportsmed 2010;38:171. [34] Collaborative overview of randomised trials of antiplatelet therapy-I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81. [35] Schwertner HA, McGlasson D, Christopher M, Bush AC. Effects of different aspirin formulations on platelet aggregation times and on plasma salicylate concentrations. Thromb Res 2006;118:529. [36] Verstraete M, Vermylen J. Antithrombotic potential of lowdose aspirin. N Engl J Med 1984;311:1442. [37] Holdright D, Patel D, Cunningham D, et al. Comparison of the effect of heparin and aspirin versus aspirin alone on transient myocardial ischemia and in-hospital prognosis in patients with unstable angina. J Am Coll Cardiol 1994; 24:39. [38] Relman AS. Aspirin for the primary prevention of myocardial infarction. N Engl J Med 1988;318:245. [39] Wennmalm A. Acute myocardial infarction and the arachidonic acid system in the coronary vessels. Clin Physiol 1985;5:311. [40] Ueeda M, Doumei T, Takaya Y, et al. Association of serum levels of arachidonic acid and eicosapentaenoic acid with prevalence of major adverse cardiac events after acute myocardial infarction. Heart Vessels 2011;26:145. [41] Nielsen MS, Schmidt EB, Stegger J, et al. Adipose tissue arachidonic acid content is associated with the risk of myocardial infarction: a Danish case-cohort study. Atherosclerosis 2013;227:386.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Hypercoagulability after energy drink consumption Matthew J. Pommerening, MD, Jessica C. Cardenas, PhD, Zayde A. Radwan, MD, Charles E. Wade, PhD, John B. Holcomb, MD, and Bryan A. Cotton, MD, MPH* Department of Surgery and the Center for Translational Injury Research, The University of Texas Health Science Center, Houston, Texas
article info
abstract
Article history:
Background: Energy drink consumption in the United States has more than doubled over the
Received 3 January 2015
last decade and has been implicated in cardiac arrhythmias, myocardial infarction, and
Received in revised form
even sudden cardiac death. We hypothesized that energy drink consumption may increase
6 May 2015
the risk of adverse cardiovascular events by increasing platelet aggregation, thereby
Accepted 11 June 2015
resulting in a relatively hypercoagulable state and increased risk of thrombosis.
Available online xxx
Methods: Thirty-two healthy volunteers aged 18e40 y were given 16 oz of bottled water or a standardized, sugar-free energy drink on two separate occasions, 1-wk apart. Beverages
Keywords:
were consumed after an overnight fast over a 30-min period. Coagulation parameters and
Energy drink
platelet function were measured before and 60 min after consumption using thrombe-
Coagulation
lastography and impedance aggregometry.
Hypercoagulability
Results: No statistically significant differences in coagulation were detected using kaolin or
Platelet aggregation
rapid thrombelastography. In addition, no differences in platelet aggregation were detected
Thrombosis
using ristocetin, collagen, thrombin receptoreactivating peptide, or adenosine diphosphate einduced multiple impedance aggregometry. However, compared to water controls, energy drink consumption resulted in a significant increase in platelet aggregation via arachidonic acideinduced activation (area under the aggregation curve, 72.4 U versus 66.3 U; P ¼ 0.018). Conclusions: Energy drinks are associated with increased platelet activity via arachidonic acideinduced platelet aggregation within 1 h of consumption. Although larger clinical studies are needed to further address the safety and health concerns of these drinks, the increased platelet response may provide a mechanism by which energy drinks increase the risk of adverse cardiovascular events. ª 2015 Elsevier Inc. All rights reserved.
1.
Background
In the last two decades, energy drinks have become increasingly popular in the United States. In 2007, just 10 y after the introduction of Red Bull to the United States, the energy drink market expanded to over 500 brands, comprising over 62% of the national beverage market. Sales have increased at an
exponential rate, and as of 2013, Americans spend nearly $20 billion consuming 0.05). Additionally, for each of the parameters measured, the delta change in coagulation values after energy drink consumption was not significantly different from the delta change in coagulation measured after consumption of water controls.
3.2.
3.
Before
Rapid TEG
There were no changes in coagulation parameters by rTEG before and after water controls for activated clotting time (174.0 versus 177.2 s; P ¼ 0.73), k-value (1.9 versus 1.9 min; P ¼ 0.97), alpha angle (66.3 versus 66.6 ; P ¼ 0.45), MA (61.3 versus 61.8 mm; P ¼ 0.11), G-value (8.1 versus 8.3 d/cm2; P ¼ 0.10), or LY30 (1.3% versus 1.2%; P ¼ 0.43). Similarly, there were no significant changes in rTEG coagulation parameters before and after energy drink consumption (Table 3), and the
Table 3 e rTEG values before and after energy drink consumption. rTEG Table 1 e Targets and receptors involved in platelet aggregation measured by Multiplate. Platelet activator ADP Arachidonic acid (AA) Collagen TRAP-6 Ristocetin
Target/receptor pathway P2Y12 COX pathway GPIa/IIa, GPVI PAR GPIba
ACT, s k-value, min Alpha, MA, mm G-value, dynes/cm2 LY30, %
Before 173.7 1.80 66.70 61.66 8.14 1.68
(13.55) (0.33) (3.66) (3.57) (1.24) (2.02)
After 179.08 1.83 66.46 61.46 8.09 1.24
(15.41) (0.29) (3.16) (3.63) (1.31) (1.39)
ACT ¼ activated clotting time. Values are reported as means and standard deviations.
P value 0.110 0.440 0.554 0.619 0.686 0.787
4
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e6
delta changes in coagulation values after energy drink consumption were not significantly different from those measured after water controls (all P > 0.05).
3.3.
Platelet aggregation
Platelet function was measured using impedance aggregometry for both water controls and energy drinks. No associated changes in platelet aggregation (AUC) were detected after water consumption for ADP (57.21 versus 58.72 U; P ¼ 0.357), arachidonic acid (67.13 versus 68.53 U; P ¼ 0.457), collagen (41.40 versus 42.47 U; P ¼ 0.292), TRAP (101.75 versus 98.33 U; P ¼ 0.530), or ristocetin (57.82 versus 55.00 U; P ¼ 0.625). Platelet aggregation before and after energy drink consumption is shown in Table 4. Similar to the water controls, no significant changes in platelet aggregation were observed after consumption of energy drinks for samples activated with ADP, collagen, TRAP, or ristocetin. However, compared to water controls, energy drink consumption was associated with a significant increase in platelet aggregation after arachidonic acideinduced platelet activation (AUC, 72.43 versus 66.29 U; P ¼ 0.018). In addition, the increase in platelet aggregation after energy drink consumption was significantly greater than after water controls (delta AUC, 6.14 versus 1.40 U; P ¼ 0.012). Peak platelet aggregation (122.58 versus 111.59 AU; P ¼ 0.026) and the velocity of platelet aggregation (17.72 versus 16.03 AU/min; P ¼ 0.008) were also significantly increased with arachidonic acideinduced activation after energy drink consumption (Figure).
4.
Discussion
As energy drink consumption in the United States has exponentially increased over the last two decades, concerns have been raised regarding their safety and potential role in adverse cardiovascular events and death. We found that consumption of a single, sugar-free energy drink was associated with a significant increase in platelet aggregation within 90 min in otherwise healthy volunteers. Platelet function was increased via arachidonic acideinduced platelet activation; however, this did not translate to measurable hypercoagulable changes in the rate of clot formation or overall clot strength measured by TEG. While more clinical data are needed, these findings suggest that health concerns associated with energy drinks may be related to hypercoagulable changes in platelet function occurring in the same pathway
Table 4 e Platelet aggregation before and after energy drink consumption. Multiplate ADP Arachidonic acid Collagen TRAP-6 Ristocetin
Before 58.28 (21.95) 66.29 (35.50) 41.71 (22.93) 104.91 (20.03) 59.6 (33.58)
After 63.39 72.43 46.14 107.91 53.9
(23.5) (28.69) (24.32) (12.29) (34.9)
P value 0.106 0.018 0.167 0.563 0.647
Values indicate AUC, reported in units, and are reported as means and standard deviations.
Figure e Platelet function before and after energy drink consumption. AUC, reported in arbitrary units (U), expresses overall platelet activity. The AUC is an expression of both peak aggregation, measured in AU, and the velocity or rate of platelet aggregation. (Color version of figure is available online.)
targeted by aspirin to reduce thrombosis risk and adverse cardiovascular events. Because so-called “energy” products are relatively new to the market, few studies have examined, in detail, the shortand long-term health consequences of energy drink consumption. The predominance of literature pertaining to energy drinks has focused on social and behavioral studies examining demographics, consumption patterns, and behavioral effects [18e23]. Others have explored the claims of increased endurance and performance enhancement with conflicting results [24]. In athletes, energy drinks have shown to improve lap times in cyclists but have not shown an effect on high-intensity run times to exhaustion in university athletes or an improvement in sprint times in women sprinters [25e27]. Energy drinks also have been linked to improvements in mood, decreased perception of stress and pain, and improved cognition in college students [24,28]. The quality of evidence of the studies investigating health and safety outcomes is limited by sample size, methodology, and heterogeneity. Of the existing studies, energy drinks have been shown to cause a modest increase systolic and mean arterial blood pressure and also an increased stroke volume in athletes who consumed energy drinks with taurine [3,29]. Findings of changes in the heart rate are inconsistent, with some studies showing an increase and others no change; however, it does appear there is a decrease in heart rate variability [29e31]. No studies have shown electrocardiogram changes with energy drink consumption; however, it is recommended that people with heart arrhythmias and heart failure not drink these drinks [3,32,33]. Associations of energy drinks with adverse cardiovascular events is limited to case reports and anecdotal evidence, citing cases such as atrial fibrillation in adolescents and cardiac arrest in young males during sporting events [4e6]. To our knowledge, only one prior study has looked at the effects of energy drinks on the coagulation system and found similar results. Using optical light aggregometry, Worthley et al. [29] also found that platelet aggregation was increased after consumption of energy drinks when compared with
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e6
water controls. The authors demonstrated that platelet aggregation increased via ADPeinduced activation and this occurred in a dose-response fashion, further strengthening the association of energy drinks and platelet activity. Energy drinks were also associated with increased systolic blood pressure and decreased endothelial function, both of which are likely to act in combination with platelet aggregation to increase thrombosis and cardiovascular risk. In the present study, platelet aggregation after energy drink consumption was increased after ADPeinduced activation; however, this only approached a weak statistical association (P ¼ 0.106). In both the Worthley study and ours, energy drinks appear to increase platelet aggregation via two important pathways of platelet activation targeted by the most commonly prescribed drugs aimed at reducing cardiovascular events. Aspirin irreversibly inhibits platelets production of thromboxane A2, a prothrombotic product of arachidonic acid. Clopidogrel inhibits binding of ADP to its platelet P2Y12 receptor, thereby inhibiting ADPemediated activation of the glycoprotein GPIIb/IIIa complex and subsequent platelet aggregation. Aspirin and clopidogrel have both been extensively studied and shown to reduce the risk of adverse cardiovascular events, such as stroke and myocardial infarction [34e38]. Increased platelet activation by either of these pathways may increase the risk of thrombosis and cardiovascular events, particularly in high-risk patients or those with preexisting conditions [39e41]. Currently, trauma centers that use TEG as a point-of-care device use rTEG given that it supplies the physician with a hemostatic profile quicker than standard kaolin TEG. However, kaolin TEG is more sensitive than rTEG, particularly in comparing parameters that measure the initial phases of clot formation and also fibrinolysis. This is due to the addition of tissue factor, an extremely potent initiator of coagulation, in rTEG which stimulates the more rapid formation of a slightly less stable clot. Thus, we included kaolin TEG as we expected it may detect smaller variations in coagulation. The lack of significant hypercoagulable changes on either kaolin or rTEG is not discordant with increased platelet aggregation and does not rule out the possibility of increased thromboembolic risk. In fact, antiplatelet-mediated effects on coagulation are not routinely detected on TEG. This is likely multifactorial, owing to the complexity of the coagulation cascade and the comprehensive nature of TEG in measuring multiple aspects of clot kinetics. For example, the kaolin and tissue factor used in TEG are potent initiators of coagulation that, in addition to platelet activation, also result in significant fibrin generation. Clot strength is largely reflective of the plateletefibrin interaction; therefore, MA and other clot kinetics may be unlikely to be significantly altered by the influence of single pathways. This may explain why we did not detect hypercoagulable changes on TEG despite increased platelet aggregation after energy drink consumption. There are several limitations in this pilot study that are important to consider regarding the implications of our findings. First and foremost, the association of energy drinks and adverse cardiovascular events is merely speculative and, to the best of our knowledge, based only on anecdotal evidence. No causal associations can be made at this time, and energy drinks may in fact have no bearing on mortality or even
5
general health. In addition, our results demonstrate statistically significant changes in platelet function however clinical outcomes were not measured in this study and the clinical significance of this platelet response, if any, is unknown. Finally, coagulation is complex, and even if there are procoagulant effects associated with one or several of the ingredients in energy drinks, thromboembolic risk is multifactorial and likely also related to several host factors and their interaction with those ingredients.
5.
Conclusions
In this study, we demonstrate that energy drinks are associated with increased platelet aggregation via the arachidonic acid pathway within 1 h of consumption. Because this is the same pathway inhibited by aspirin therapy, our findings support a potential mechanism by which energy drink consumption may lead to an increased risk for thromboembolic disease and adverse cardiovascular events. Future work in this area should aim to elucidate the mechanism of energy drink ingredients on platelet function and coagulation pathways and correlate with clinical outcomes. Potential implications for surgery patients include improved understanding of early cardiovascular deaths after trauma in young patients, improved thromboembolism prophylaxis by targeting pathways not addressed with current therapies and, on the opposite end of the spectrum, identifying a potential resource for reversal of traumaeinduced platelet dysfunction and hemorrhage.
Acknowledgment Funding/support: None. Authors’ contributions: M.J.P., Z.A.R., C.E.W., and B.A.C. designed the study. M.J.P., J.C.C., and Z.A.R. conducted the literature search and collected the data. M.J.P., J.B.H., C.E.W., and B.A.C. analyzed the data. M.J.P., J.C.C., Z.A.R., J.B.H., C.E.W., and B.A.C. interpreted the data. All authors participated in the writing, revising, and editing of the article.
Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in the article.
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