Overdose caffeine games

At the ED, she presented an episode of presyncope followed by agitation. ECG showed polymorphic broad complex QRS tachycardia and arterial blood gas revealed metabolic acidaemia with severe hypokalemia. The dysrhythmia was successfully treated with intravenous propranolol. Acid—base and hydroelectrolytic disorders were also corrected. A persistent sinus tachycardia was observed in the first 2 days in the ward and 5 days later she was discharged asymptomatic with internal medicine follow-up.

This case illustrates the life-threatening consequences, such as malignant cardiac arrhythmias, of severe caffeine poisoning, which is a rare event. A year-old woman with no significant medical and family history presented to the local emergency department ED referring malaise, anxiety, dizziness and nausea. Symptoms like chest pain, syncope, palpitations or fever were denied.

After observation, the patient had an episode of presyncope followed by agitation and vomiting. Her pupils were equally round and reactive to light, and no muscle weakness or sensory deficits were found. The ECG showed a polymorphic broad QRS tachycardia and the arterial blood gas revealed metabolic acidaemia with severe hypokalemia. The patient switched the dose dispensers shown in figure 1.

Two view angle of dose dispensers; A dose dispenser for the proteic supplement; B dose dispenser for the anhydrous caffeine. Electrocardiogram figures 2 and 3 showing a broad QRS polymorphic tachycardia. Arterial blood gas showed a metabolic acidosis with pH of 7. Prominent laboratory findings included mild leucocytosis of Magnesium and calcium serum values were within normal range as well as thyroid, renal and liver function tests.

Urinalysis was positive for ketones and glucose and negative for cocaine and opioid drugs. Unfortunately, a blood sample for caffeine analysis was not taken. No activated charcoal was administered as the medical team was unaware of a dietary product ingestion during the initial evaluation. The patient remained in our intermediate care unit for 2 days, with normal level of consciousness maintained, normalisation of arterial blood gas values and no recurrence of presyncope episodes. The patient remained clinically stable and 5 days later was discharged asymptomatic referred to internal medicine follow-up.

The patient performed a treadmill exercise stress test by Bruce Protocol with adequate chronotropic response, normotensive profile and negative result for myocardial ischaemia. Six months after the episode, at follow-up evaluation, the patient remained asymptomatic.

Caffeine 1,3,7-trimethylxanthine is a natural product commonly found in foodstuffs, beverages and medicinal products. However, in recent years, larger amounts of caffeine have been added to energy drinks or taken as dietary supplements, such as anhydrous caffeine, for increasing endurance, concentration and athletic performance. Normally, mild stimulation is obtained with a caffeine dosage of 0. Therefore, there is a significant variability regarding ingested amounts and their toxic effects.

Caffeine is structurally similar to adenosine and acts as a competitive antagonist on adenosine receptors. However, they have a specific role in the brain and heart. By blocking the adenosine receptors, at high doses, caffeine interacts with the sympathetic nervous system inducing prolonged and intensified beta-receptor activation with positive inotropic and chronotropic effects which can trigger arrhytmia. Symptoms of caffeine intoxication may include headache, fever, nausea, vomiting, tachycardia, dizziness, tinnitus, anxiety, irritability, insomnia and seizures.

Common cardiovascular effects are described as hypertension followed by hypotension and cardiac dysrhythmias, including supraventricular and ventricular tachyarrhythmias. Arrhythmias are considered the most common cause of caffeine-related death. The determination of blood caffeine concentration might be useful in confirming the diagnosis. Morita et al suggests that the plasma lactate concentration allows establishing the severity level of the caffeine intoxication.

This phenomenon can be explained by the excessive sympathetic stimulation caused by caffeine overdose, and therefore, glycogenolysis and lipolysis are increased with a consequently pyruvate level raise. If pyruvate does not enter the aerobic pathway, it is converted to lactate instead, which causes hyperlactacidaemia. Treatment of caffeine toxicity can vary on case-to-case basis.

It can take up to 10 hours to completely clear caffeine from your bloodstream. Extremely high daily intakes of 1, mg or more per day have been reported to cause nervousness, jitteriness and similar symptoms in most people, whereas even a moderate intake may lead to similar effects in caffeine-sensitive individuals 9, The Food and Drug Administration says mg per day is too much.

Can Caffeine Cause Insomnia? While there are short-term performance benefits to caffeine consumption, overuse can lead to insomnia symptoms 14 or worsen pre-existing insomnia. Consuming caffeine to stay awake at night may lead to sleeplessness, anxiety, frequent nighttime awakenings, and overall poorer sleep quality. Removing it from your day keeps cortisol and melatonin at their natural rhythms, which results in better sleep and less fatigue.

But, caffeine, in general, may worsen symptoms in people already prone to anxiety. Coffee containing caffeine can cause insomnia, nervousness and restlessness, stomach upset, nausea and vomiting, increased heart and breathing rate, and other side effects. The answer: Caffeine lasts in our systems anywhere from 4 to 6 hours on average, and it has a half life of about 5 hours. Studies show that to mg of caffeine about 1 to 2 cups of regular coffee are enough to achieve these results.

When caffeine consumption climbs to to mg per day, people may experience nausea, headaches, sleep difficulties or increased anxiety.

People may have heart palpitations with more than 1, mg. You need to make up for the electrolytes that your body has lost, as well as water. This seems less likely to be necessary, yet there are indeed sustained release caffeine formulations available on the market [ ]. With respect to enhanced elimination the use of intralipid has apparently shown some success while hemodialysis alone or in combination with intralipid also seems successful [ 29 , 30 , 38 , , ].

These same authors have also pointed out that intralipid may cause unintended consequences by interfering with other medications which are administered as a result of caffeine intoxication such as esmolol and especially amiodarone i. It has been used either alone or in combination with hemoperfusion and has proven successful [ 38 , 46 , 47 , , ]. Hemoperfusion alone while not performed as often due to practical limitations has also been used in the past [ 38 , ].

This particular case seemed to garner attention because the amount of caffeine was not considered lethal and the teenager was apparently otherwise healthy and had no reported medical conditions or allergies. The following is a case reconstruction with discussion of what may have led to this outcome.

The coroner also indicated that the young male was otherwise healthy and had no signs of any cardiac abnormalities at autopsy. It is unknown what, if any symptoms the young male experienced before collapsing. Due to privacy laws in the United States only limited information is publicly available. While the exact dose of caffeine ingested by the young male is unknown, an estimate may be obtained based upon the drinks that were reportedly ingested.

Others have reported a range between 0. Although, this variation is not surprising considering coffee is a natural product and thus is prone to variation not only from the raw product but how it is processed, extracted and prepared for consumption [ ]. In any event, such data may at least give a range. Finally, the young male was reported as having consumed an energy drink all at once, the name or brand of which is not available. This is well below the total dose i. While a serum caffeine level of the young male has not been reported one might estimate via two methods, although it should be noted that both are highly speculative.

One method involves a simple calculation derived from Jones [ 14 ], who albeit controversially, uses a variation of this formula to determine the potential dose of caffeine ingested based upon known post-mortem concentrations in a deceased individual by taking the post-mortem concentration multiplied by the known volume of distribution and the bodyweight of the decedent [ 14 , 38 ]. In this case, conversely, the post-mortem concentration of caffeine in serum is unavailable but there is an estimated level of caffeine intake prior to death.

Thus, one will instead take the known volume of distribution of caffeine average of 0. This also assumes that caffeine is completely and equally distributed into total body water which others have indicated is indeed the case [ ]. This concentration is also at zero time and thus does not account for any elimination.

While these figures are again speculative, if accurate these concentrations are not normally known to be toxic let alone lethal in healthy individuals. Another method of estimating the possible plasma concentrations is based upon data from others. However, these concentrations are not in the range normally associated with serious toxicity and lethality. For example, if coronary vasospasm occurs it may lead to myocardial infarction but it may also potentially lead to cardiac arrhythmia and sudden death and thus myocardial infarction may serve as a potential surrogate for risk of arrhythmia due to coronary vasospasm [ 53 , ].

After statistical analyses the authors found there was a significant gene-coffee interaction only amongst the younger participants in the study. The authors also note that other groups have previously suggested that coffee is associated with an increased risk of myocardial infarction among younger individuals [ ].

It is also interesting to note that the risk increased as the dose of coffee increased. However, it seems unlikely that this would fully account for this particular death. Sweden also has one of the highest rates of coffee consumption in the world [ ]. Thus, if this were the only factor necessary for such an event, many more cases would be expected in younger individuals. However, observational and interventional data have failed to find an association between CYP1A2 polymorphism and coffee and caffeine intake [ , ].

Additionally, there is a rather large body of evidence demonstrating an overall lack of risk for sudden death, arrhythmia and myocardial infarction in the population as a whole even with rather high intakes of caffeine [ ].

Such environmental factors may substantially mask the role of genetics [ 73 ]. However, data indicate that by the time an individual reaches the age of 16 years, the pharmacokinetic profile of caffeine is similar to that of adults [ [] , [] , [] , [] , [] ]. Upon reaching puberty i. Some have found that adolescents i. While some individuals such as the coroner in this case have speculated that the rapid consumption of caffeine was a factor a recent study has found this unlikely to be the case [ 57 ].

While a pharmacokinetic explanation alone does not appear sufficient to explain this particular case there are also other considerations. For example, there are data demonstrating that some individuals possess a polymorphism associated with decreased catechol-o-methyltransferase COMT activity and that this decrease is associated with an increased risk of acute coronary events linked with coffee intake [ ].

This is important to consider in the context of caffeine as it is known to increase catecholamine levels as one potential mechanism. There are also known mutations for the adenosine receptor gene specifically the A2A receptor which may also cause an increased sensitivity by some. Although, it is important to note that such mutations have only been linked to differences in sensitivity to the psychological effects of caffeine rather than cardiovascular [ 19 , ]. However, mutations in the adenosine receptor have been linked to infarct size in patients with ischemic cardiomyopathy indicating a possible role in the response of the heart to ischemia or injury [ ].

This is an area worth further exploration. Aside from those discussed previously, other mechanisms could be involved. For example, caffeine has been shown to act as an inhibitor of the Human Ether-a-go-go hERG potassium channel which is found in different tissues including the heart [ , ]. The blockage of this channel has been implicated in the cause of cardiac arrhythmia in certain circumstances by causing QT prolongation [ ]. However, as with many other molecular targets, hERG requires rather high concentrations for significant interaction with caffeine.

Furthermore, caffeine may begin to have a small effect upon intracellular calcium release at these concentrations i. Additionally, as some authors have found, the inhibition of hERG can be dramatically increased when two compounds with inhibitory effects are combined [ ].

Thus, it is also possible that one of the constituents in the energy drink may have such activity and also contributed to the death by lowering the threshold for inhibition.

While this study had several limitations e. However, further study addressing the limitations of this study is needed to confirm these findings. An examination of other cases may offer clues in the case of the young male. Several other case reports have been published concerning caffeinated energy drinks where the patient similarly consumed several drinks and ultimately experienced either myocardial infarction i.

In this particular case however, toxicity may have been related to her lower bodyweight i. Considering that a majority of deceased individuals with long QT syndrome i. Sudden cardiac death SCD is a sudden and unexpected death resulting from rapidly occurring cardiac arrest outside the reach of a hospital or emergency room [ ].

Incidence rates vary according to definitions, data sources and methods, demonstrating a range of Seemingly corroborating such data, in prospective studies using standardized definitions in the United States, Netherlands, Ireland and China, SCD had an incidence rate of 40— per , person-years with China displaying the lowest rate [ ].

Some of the potential causes include coronary heart disease CHD which accounts for the majority of cases in those over the age of 35, while valvular heart disease, cardiomyopathies, myocarditis, and primary arrhythmia syndromes account for most of the remainder [ , ]. In individuals between the ages of 1 to 35 years, cardiomyopathies e. In many cases, causes are inherited or have an underlying genetic basis [ , ]. Interestingly, the results of a population-based, prospective study conducted in New Zealand and Australia from through found the annual incidence of SCD amongst children and young adults aged 1 to 35 to be 1.

Those ages 16 to 20 had the highest incidence of unexplained SCD at 0. The authors also note that unexplained SCD is often attributed to cardiac arrhythmia due to ion-channel dysfunction that is not detectable in conventional autopsies [ ].

Also relevant to this case is the lack of any apparent cardiac abnormalities i. It is unknown whether detailed histologic examination took place at autopsy in this case which may also reveal abnormalities not apparent from macroscopic examination [ ]. Assuming that other potential causes such as over the counter medications, dietary supplements or prescription medications were already ruled out as contributors in this case, one is ultimately left with some likely genetic predisposition or perhaps a combination of them or possibly a pre-existing structural heart disease not revealed with macroscopic examination [ ].

Unless genetic analyses and histologic examination were completed it ultimately leaves only speculation as to whether there was a single cause or if there was a confluence of factors that ultimately caused his death.

Additional work is also needed to determine what molecular target or targets that caffeine is affecting in cases of toxicity. Ideally, an effort would be made to identify cases such as these and after a thorough examination to rule out any other potential causes, genetic analyses would take place to determine if these individuals have any mutations in certain molecular targets or metabolic enzymes that might be relevant to caffeine toxicity e.

This is an area of research that could yield benefit and perhaps identify those in the population that are sensitive to such effects from caffeine. In cases of intentional caffeine overdose, tablets containing caffeine are typically ingested with suicidal intent.

In recognition of this in the country of Sweden, sales of caffeine tablets were limited in quantity i. While the reduction suffered an initial delay, presumably due to leftover products purchased prior to enactment of the purchase restriction, from until there were no fatal intoxications attributed to caffeine [ ]. However, it is important to note as the authors do that individuals may have simply turned to alternative substances to attempt suicide.

Nonetheless, such data appear promising with respect to reducing the likelihood of intentional caffeine intoxication. In the United States caffeine is also included in multi-ingredient formulas used to treat migraine and other conditions, thus individuals may still have access to substances including caffeine in tablet form [ ]. With respect to unintentional overdose, the United States FDA recently and prudently, banned the sale of pure, concentrated caffeine powders which have resulted in inadvertent overdoses [ ].

Some understandable efforts are underway in some areas of the United States to limit the sale of energy drinks to those 18 years of age or older [ ]. However, the regulation of energy drinks based upon caffeine content alone may be problematic, considering the equivalent or even greater content of caffeine available in coffee or espresso-based beverages. A potential solution may be to limit the content of caffeine in such energy drinks as it is already done for soft drinks in the United States and energy drinks in Canada [ ].

Finally, recommendations by manufacturers of energy drinks to the consumer, suggesting they seek medical advice prior to use and avoid over-consumption of the product or consumption with other sources of caffeine may be prudent [ ]. Caffeine is an interesting molecule with diverse physiological effects in humans. The main molecular target considered today is the adenosine receptor but research continues in this area.

Despite having a general understanding of the toxic and lethal doses of caffeine there is clearly a need for more data, especially with respect to determining safe doses in sensitive populations. The diagnosis of caffeine toxicity is based largely upon reported ingestion and symptoms, although serum caffeine concentrations can be obtained through quantitative chemical analysis. Treatment generally involves supportive therapy along with decontamination and increased elimination techniques, although there is no standard treatment regimen.

Looking to steps that other countries have taken in order to reduce the risk of intentional and unintentional caffeine intoxication may provide insight into how the United States and other countries may similarly implement such practices. The author has served as a consultant to companies in the dietary supplement industry who have manufactured products containing caffeine. However, these companies would not be expected to gain financially by the work and have no knowledge of or influence over this work at the time of submission.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. National Center for Biotechnology Information , U. Journal List Toxicol Rep v. Toxicol Rep. Published online Nov 3. Author information Article notes Copyright and License information Disclaimer. Cyril Willson: moc. This article has been cited by other articles in PMC. Abstract Caffeine is a widely recognized psychostimulant compound with a long history of consumption by humans.

Introduction with a brief history of caffeine consumption Caffeine 1,3,7-trimethylxanthine is a psychostimulant purine-like alkaloid, which is found naturally in coffee, tea, cacao beans source for chocolate and cocoa guarana, mate, and kola nuts, though it has been identified in more than 60 plant species [ 1 , 2 ]. Clinical features Caffeine is known to have generally dose-dependent effects with positive or desirable effects at lower doses i.

Paradoxical effects Some of the more paradoxical effects seen e. Potential mechanisms for serious cardiovascular side effects With respect to arrhythmia in cases of caffeine intoxication, ventricular fibrillation is most often determined to be the cause of death [ 26 ], while the most frequently cited mechanisms for arrhythmia include increased catecholamine levels, phosphodiesterase inhibition, increased intracellular calcium and antagonism of anti-arrhythmic adenosine receptors See Mechanism of Action [ 47 ].

Differential diagnosis While there are no definitive symptoms for diagnosis, vomiting or severe recurrent vomiting is often seen. Chronic effects While the above discussion generally involves acute toxicity, chronic toxicity can also occur with caffeine. Pharmacokinetics 3. Absorption Caffeine has rapid and complete i. Open in a separate window. Distribution Caffeine is distributed throughout the body after being absorbed from the gastrointestinal tract the small intestine in particular , entering all tissues via cell membranes i.

Metabolism Caffeine is described by a single-compartment model where it follows first-order, linear kinetics [ 70 ], although some have noted that it may follow non-linear kinetics if the dose is high enough and its metabolism is saturated [ 20 , 54 , 65 , 70 ].

Effect is shared with many but not all quinolones. Healthy elderly men. Twelve week use. Four week use. Similar results in six month study. Extracts containing kola nut, grape, green tea and Ginkgo biloba.

Single maximal exercise cycle test in young hockey players. Elimination The vast majority of caffeine is eliminated from plasma via CYP1A2-mediated clearance in which paraxanthine is the main metabolite [ 94 ]. Toxicokinetics While it has been noted that the correlation between the serum concentrations of caffeine and clinical effects are poor, likely due to the substantial inter-individual differences in pharmacokinetics and pharmacodynamics, it is still of some general value [ 28 , 38 , 99 ].

Mechanism of action The main proposed molecular target which caffeine is thought to interact with at physiologically relevant concentrations are the adenosine receptors [ 66 , 67 , 70 , , ].

Mechanisms for specific side effects 5. Hypertension-hypotension While hypertension is typically noted to be due to increased catecholamine release via adenosine antagonism as well as direct vasoconstrictive response due to adenosine antagonism itself after intake of therapeutic amounts, it is interesting that hypotension is frequently noted in cases of severe overdose and perhaps phosphodiesterase inhibition plays a role [ [38] , [39] , [40] , [41] , [42] , 47 , , ].

Questionable role of beta 2-adrenergic agonism in hypotension The role of catecholamines and beta 2-adrenergic agonism in causing hypotension seems questionable.

Difficulties in identifying mechanisms for specific side effects The wide range of potential effects upon catecholamines, calcium-release channels, potassium ion channels, ATPase ion pumps, GABA A receptors, phosphodiesterase and acetylcholine presents difficulties for determining individual roles for some adverse effects in cases of severe intoxication.

Cardiovascular side effects Hypotension should first be treated with isotonic intravenous fluid but if needed, it can be treated with vasopressors such as phenylephrine or epinephrine alternatively while beta-adrenergic antagonists such as esmolol or propanolol have also been used in rarer cases of refractory hypotension [ 38 , 48 ]. No standardized method of treatment Some rather massive overdoses have been successfully treated with isotonic sodium chloride solution, sodium bicarbonate and hemodialysis [ 36 ].

Gastrointestinal side effects The gastrointestinal side effects with caffeine are generally related to recurrent vomiting [ 34 , 38 ]. Psychological side effects and seizures For side effects such as agitation, anxiety and seizures, benzodiazepines are recommended although barbiturates and propofol could also be used as a second-line therapy for seizures that are refractory to benzodiazepines [ 38 , 48 ].

Metabolic side effects and rhabdomyolysis In cases of metabolic acidosis and hypokalemia, sodium bicarbonate and potassium chloride have been used, respectively [ [36] , [37] , [38] ]. Dose ingested While the exact dose of caffeine ingested by the young male is unknown, an estimate may be obtained based upon the drinks that were reportedly ingested.

Role of rapid caffeine consumption While some individuals such as the coroner in this case have speculated that the rapid consumption of caffeine was a factor a recent study has found this unlikely to be the case [ 57 ]. Potential pharmacodynamic explanations While a pharmacokinetic explanation alone does not appear sufficient to explain this particular case there are also other considerations.

Other potential mechanisms of toxicological relevance Aside from those discussed previously, other mechanisms could be involved. Potential clues from previous cases An examination of other cases may offer clues in the case of the young male. Potential connection to sudden cardiac death Sudden cardiac death SCD is a sudden and unexpected death resulting from rapidly occurring cardiac arrest outside the reach of a hospital or emergency room [ ]. Potential solutions In cases of intentional caffeine overdose, tablets containing caffeine are typically ingested with suicidal intent.

Conclusion Caffeine is an interesting molecule with diverse physiological effects in humans. Conflict of interest The author has served as a consultant to companies in the dietary supplement industry who have manufactured products containing caffeine.

Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References 1. Heckman M. Caffeine 1, 3, 7-trimethylxanthine in foods: a comprehensive review on consumption, functionality, safety, and regulatory matters.

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