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Project: Systematic review of acute adverse effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children

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Title Systematic review of acute adverse effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children
Description To date, one of the most heavily cited assessments of caffeine safety in the peer-reviewed literature is that issued by Health Canada (Nawrot et al., 2003). Since then, >10,000 papers have been published related to caffeine, including hundreds of reviews on specific human health effects; however, to date, none have compared the wide range of topics evaluated by Nawrot et al. (2003). Thus, as an update to this foundational publication, we conducted a systematic review of data on potential adverse effects of caffeine published from 2001 to June 2015. Subject matter experts and research team participants developed five PECO (population, exposure, comparator, and outcome) questions to address five types of outcomes (acute toxicity, cardiovascular toxicity, bone and calcium effects, behavior, and development and reproduction) in four healthy populations (adults, pregnant women, adolescents, and children) relative to caffeine intake doses determined not to be associated with adverse effects by Health Canada (comparators: 400 mg/day for adults [10 g for lethality], 300 mg/day for pregnant women, and 2.5 mg/kg/day for children and adolescents). The a priori search strategy identified >5000 articles that were screened, with 381 meeting inclusion/exclusion criteria for the five outcomes (pharmacokinetics was addressed contextually, adding 46 more studies). Data were extracted by the research team and rated for risk of bias and indirectness (internal and external validity). Selected no- and low-effect intakes were assessed relative to the population-specific comparator. Conclusions were drawn for the body of evidence for each outcome, as well as endpoints within an outcome, using a weight of evidence approach. When the total body of evidence was evaluated and when study quality, consistency, level of adversity, and magnitude of response were considered, the evidence generally supports that consumption of up to 400 mg caffeine/day in healthy adults is not associated with overt, adverse cardiovascular effects, behavioral effects, reproductive and developmental effects, acute effects, or bone status. Evidence also supports consumption of up to 300 mg caffeine/day in healthy pregnant women as an intake that is generally not associated with adverse reproductive and developmental effects. Limited data were identified for child and adolescent populations; the available evidence suggests that 2.5 mg caffeine/kg body weight/day remains an appropriate recommendation. The results of this systematic review support a shift in caffeine research to focus on characterizing effects in sensitive populations and establishing better quantitative characterization of interindividual variability (e.g., epigenetic trends), subpopulations (e.g., unhealthy populations, individuals with preexisting conditions), conditions (e.g., coexposures), and outcomes (e.g., exacerbation of risk-taking behavior) that could render individuals to be at greater risk relative to healthy adults and healthy pregnant women. This review, being one of the first to apply systematic review methodologies to toxicological assessments, also highlights the need for refined guidance and frameworks unique to the conduct of systematic review in this field.
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Methodology Problem formulation was based on providing an update of Nawrot et al. (2003), “Effects of caffeine on human health,” [PMID 12519715]. No comprehensive studies of similar scope have been published in the peer-reviewed literature, and thus the overall objective is to conduct an update to Nawrot et al. that applies the rigor of a systematic review. This review is one of five systematic reviews being conducted simultaneously (other endpoints include acute toxicity and adverse effects on reproduction/development, cardiovascular, and bone and calcium balance outcomes. Exposure and comparators were thus based on levels determined by Nawrot et al., (2003). Searches: The searches were conducted using: PubMed, EMBASE, and the Cochrane Database of Systematic Review. The restrictions will be articles published in English between 2001 and June 8, 2015. EMBASE searches were exclusive of MEDLINE and restricted to selected journals (430 journals were selected based on relevance). The Cochrane library was searched between Jan 2001 and June 2015 for review articles. Search strategies were informed and reviewed by a librarian. Types of studies included: All study types (excluding case studies) characterizing a quantitative exposure to caffeine and an adverse bone and calcium balance endpoint will be included. Both exposure and response must be evaluated at the individual level. Reviews will not be included in the systematic assessment (unless original data, such as a meta analysis, were conducted), but selected reviews will be consulted for context. Include: studies reporting parameters or effects associated with adverse effects within a benefit/therapy study. Exclude: Studies assessing only beneficial or therapeutic endpoints or outcomes following exposure to caffeine. Participants/ population: Populations: healthy adults, healthy pregnant women, healthy adolescents (aged 12-19), healthy children (aged 3-12). Exposure: = 400 mg/day, 300 mg/day, 2.5 mg/kg-bw day*, respectively (by population). Comparator: < 400 mg/day, 300 mg/day, 2.5 mg/kg-bw day*, respectively (by population). *Applies to both adolescents and children. Include: Studies evaluating a healthy population; this will include athletes, military, and pregnant women, unless otherwise noted as unhealthy. Healthy in this context was defined as subjects who were not specifically described as hospitalized, diagnosed with disease, and/or receiving medical treatment for a disease at the time of the study. Include: Studies that evaluate the effects of caffeine exposure in humans. This included studies in which healthy individuals were included as a control group (or similar) as part of a study on unhealthy populations (only information from the healthy individuals would be carried forward). Include: crossover balance studies could with a control period rather than a control group. Exclude: Studies evaluating unhealthy populations with no healthy control arm; this includes asthmatics and smoking populations. Exclude: Studies that describe effects of caffeine exposure in animal species or in vitro studies. Exclude: Case studies with no comparison group.
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Funding Source This Systematic Review of acute adverse effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children was sponsored by the North American Branch of the International Life Sciences Institute (ILSI) Caffeine Working Group. Unrestricted grants from the American Beverage Association (ABA) and the National Coffee Association (NCA) were also received.
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Key Questions

1 For [population], is caffeine intake above [exposure dose], compared to intakes [exposure dose] or less, associated with adverse effects on acute toxicity*?
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Associated Extraction Forms

Title Created by Key Questions Addressed Form Notes
Acute Toxicity - Study Design Details Ray DeVirgiliis 1

Associated Studies (each link opens a new tab)

Title Author Year
Autopsy report for a caffeine intoxication case and review of the current literature T. Yamamoto, K. Yoshizawa, S. Kubo, Y. Emoto, K. Hara, B. Waters, T. Umehara, T. Murase and K. Ikematsu 2015
Caffeine-induced hypokalemic paralysis in pregnancy. CC Appel,TD Myles, 2001
Another case of excessive caffeine and hypokalemia in pregnancy. SL Young,ML Hage,J Li, 2001
Caffeine fatalities--four case reports. P Holmgren,L Nordén-Pettersson,J Ahlner, 2004
Massive caffeine overdose requiring vasopressin infusion and hemodialysis. CP Holstege,Y Hunter,AB Baer,J Savory,DE Bruns,JC Boyd, 2003
Coca-Cola and kangaroos. DW Mudge,DW Johnson,
Clinical importance of caffeine dependence and abuse. N Ogawa,H Ueki, 2007
Caffeine poisoning and lactate rise: an overlooked toxic effect? A Schmidt,C Karlson-Stiber, 2008
Cardiac arrest in a young man following excess consumption of caffeinated "energy drinks". AJ Berger,K Alford, 2009
Treatment of cardiovascular collapse from caffeine overdose with lidocaine, phenylephrine, and hemodialysis. R Kapur,MD Smith, 2009
A case of fatal caffeine poisoning. T Rudolph,K Knudsen, 2010
Caffeine fatalities--do sales restrictions prevent intentional intoxications? G Thelander,AK Jönsson,M Personne,GS Forsberg,KM Lundqvist,J Ahlner, 2010
First-Onset Seizure After Use of an Energy Drink [corrected]. KM Babu,MD Zuckerman,JK Cherkes,JB Hack, 2011
A case of caffeine-induced coronary artery vasospasm of a 17-year-old male. RE Wilson,HS Kado,R Samson,AB Miller, 2012
Single tonic-clonic seizure after energy drink abuse. RS Calabrò,D Italiano,G Gervasi,P Bramanti, 2012
A case of acute suicidality following excessive caffeine intake. A Szpak,D Allen, 2012
Caffeinated energy drink intoxication. D Trabulo,S Marques,E Pedroso, 2011
Hypertension in a young boy: an energy drink effect. A Usman,A Jawaid, 2012
Survival of a highly toxic dose of caffeine. G Bioh,MM Gallagher,U Prasad, 2013
Fatal cardiac arrhythmia following voluntary caffeine overdose in an amateur body-builder athlete. M Poussel,A Kimmoun,B Levy,N Gambier,F Dudek,E Puskarczyk,JF Poussel,B Chenuel, 2013
Death of a young man after overuse of energy drink. S Avcı,R Sarıkaya,F Büyükcam, 2013
High-energy drinks may provoke aortic dissection. ZS Jonjev,G Bala, 2013
Caffeine overdose resulting in severe rhabdomyolysis and acute renal failure. C Campana,PL Griffin,EL Simon, 2014
Fatal caffeine overdose: a case report and review of literature. SB Jabbar,MG Hanly, 2013
Does an energy drink cause a transient ischemic attack? S Dikici,A Saritas,S Kilinc,S Guneysu,H Gunes, 2015
Caffeine intoxication successfully treated by hemoperfusion and hemodialysis. S Ishigaki,H Fukasawa,N Kinoshita-Katahashi,H Yasuda,H Kumagai,R Furuya, 2014

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