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Completed Systematic Reviews




Glasgow Coma Scale for Field Triage of Trauma: A Systematic Review [Entered Retrospectively]


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Statistics: 32 Studies, 2 Key Questions, 3 Extraction Forms,
Date Published: May 19, 2017 06:13PM
Description: Objectives. To assess the predictive utility, reliability, and ease of use of the total Glasgow Coma Scale (tGCS) versus the motor component of the Glasgow Coma Scale (mGCS) for field triage of trauma, as well as comparative effects on clinical decisionmaking and clinical outcomes. Data Sources. MEDLINE®, CINAHL, PsycINFO, HAPI (Health & Psychosocial Instruments), and the Cochrane Databases (January 1995 through June, 2016). Additional studies were identified from reference lists and technical experts. Study Selection. Studies on the predictive utility of the tGCS versus the mGCS or Simplified Motor Scale (SMS) (a simplified version of the mGCS), randomized trials and cohort studies on effects of the tGCS versus the mGCS on rates of over- or under-triage, and studies on interrater reliability and ease of use of the tGCS, mGCS, and/or SMS. Data Extraction. One investigator abstracted details about study characteristics and results; a second investigator checked data for accuracy. Two investigators independently applied prespecified criteria to rate study quality. Data on discrimination of tGCS versus mGCS and tGCS versus SMS were pooled using a random effects model. The strength of evidence was determined based on the overall risk of bias, consistency, directness, precision, and reporting bias. Results. 33 studies met inclusion criteria; 24 studies addressed predictive utility and 10 addressed interrater reliability or ease of use. No study assessed comparative effects on over- or under-triage or clinical outcomes. For in-hospital mortality, the tGCS is associated with slightly greater discrimination than the mGCS (pooled mean difference in area under the receiver operating characteristic curve [AUROC] 0.015, 95% confidence interval [CI] 0.009 to 0.022, I2=85%, 12 studies; strength of evidence [SOE]: Moderate) or the SMS (pooled mean difference in AUROC 0.030, 95% CI 0.024 to 0.036, I2=0%, 5 studies; SOE: Moderate). This means that for every 100 trauma patients, the tGCS is able to correctly discriminate 1 to 3 more cases of in-hospital mortality from cases without in-hospital mortality than the mGCS or the SMS . The tGCS is also associated with greater discrimination than the mGCS or SMS for receipt of neurosurgical interventions, severe brain injury, and emergency intubation (differences in AUROC ranged from 0.03 to 0.05; SOE: Moderate). Differences in discrimination between the mGCS versus the SMS were small (differences in the AUROC ranged from 0.000 to 0.01; SOE: Moderate). Findings were robust in sensitivity and subgroup analyses based on age, type of trauma, study years, assessment setting (out-of-hospital vs. emergency department), risk of bias assessment, and other factors. Differences between the tGCS, mGCS, and SMS in diagnostic accuracy (sensitivity, specificity) based on standard thresholds (scores of ≤15, ≤5, and ≤1) were small, based on limited evidence (SOE: Low). The interrater reliability of tGCS and mGCS appears to be high, but evidence was insufficient to determine if there were differences between scales (SOE: Insufficient). Three studies found the tGCS associated with a lower proportion of correct scores than the mGCS (differences in proportion of correct scores ranged from 6% to 27%), though the difference was statistically significant in only one study (SOE: Low). Limitations. Evidence on comparative predictive utility was primarily restricted to effects on discrimination. All studies on predictive utility were retrospective and the mGCS and SMS were taken from the tGCS rather than independently assessed. Most studies had methodological limitations. We restricted inclusion to English-language studies and were limited in our ability to assess publication bias. Studies on ease of use focused on scoring of video or written patient scenarios; field studies and studies on other measures of ease of use such as time required and assessor satisfaction were not available. Conclusions. The tGCS is associated with slightly greater discrimination than the mGCS or SMS for in-hospital mortality, receipt of neurosurgical interventions, severe brain injury, and emergency intubation. The clinical significance of small differences in discrimination is likely to be small, and could be offset by factors such as convenience and ease of use. Research is needed to understand how use of the tGCS versus the mGCS or SMS impacts clinical outcomes and risk of over- or under-triage.
Contributor(s): Roger Chou, M.D. Annette M. Totten, Ph.D. Miranda Pappas, M.A. Nancy Carney, Ph.D. Spencer Dandy, B.S. Sara Grusing, B.A. Rochelle Fu, Ph.D. Ngoc Wasson, M.P.H. Craig Newgard, M.D., M.P.H., F.A.C.E.P.
DOI: DOI pending.
Funding Source: Agency for Healthcare Research and Quality. (Prepared by the Pacific Northwest Evidence-based Practice Center under Contract No. 290-2015-00009-I.) AHRQ Publication No.16(17)-EHC041-EF.
Methodology Description: Data Sources. MEDLINE®, CINAHL, PsycINFO, HAPI (Health & Psychosocial Instruments), and the Cochrane Databases (January 1995 through June, 2016). Additional studies were identified from reference lists and technical experts. Study Selection. Studies on the predictive utility of the tGCS versus the mGCS or Simplified Motor Scale (SMS) (a simplified version of the mGCS), randomized trials and cohort studies on effects of the tGCS versus the mGCS on rates of over- or under-triage, and studies on interrater reliability and ease of use of the tGCS, mGCS, and/or SMS. Data Extraction. One investigator abstracted details about study characteristics and results; a second investigator checked data for accuracy. Two investigators independently applied prespecified criteria to rate study quality. Data on discrimination of tGCS versus mGCS and tGCS versus SMS were pooled using a random effects model. The strength of evidence was determined based on the overall risk of bias, consistency, directness, precision, and reporting bias.

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Systematic review of the adverse reproductive and developmental effects of caffeine consumption in healthy adults and pregnant women


Public Project Complete

Statistics: 58 Studies, 1 Key Question, 1 Extraction Form,
Date Published: May 02, 2017 08:07PM
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.
Contributor(s): None Provided
DOI: DOI pending.
Funding Source: The systematic review of the adverse bone and calcium balance effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children is 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.
Methodology Description: 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. Intervention(s), exposure(s) Exposure to caffeine: = 400 mg/day, 300 mg/day, 2.5 mg/kg-bw day*, respectively (by population). *Applies to both adolescents and children. Include: Studies that provide a quantitative exposure to a caffeine source associated with an adverse effect. Acceptable forms of caffeine are coffee, tea, chocolate, cola-type beverages, energy drinks (e.g. Monster, Red Bull, Rockstar), supplements, medicines, energy shots, caffeinated chewing gum, caffeinated sport gel, and caffeinated sport bars. Include: Studies evaluating the effects of caffeine alone, in one of the aforementioned forms, or in combination with one or more compounds occurring in the approved sources at levels designed to match constituents of valid sources (e.g., caffeine and green tea extract). Exclude: Studies that do not provide a quantitative exposure to an acceptable caffeine source associated with an adverse effect. This includes studies that evaluate only decaffeinated coffee/tea and caffeine placebo exposures (i.e. exposures where participants were expecting caffeine but did not receive the drug), Yerba mate, guarana, damiana and/or contaminants of caffeine or caffeine metabolites. Exclude: Studies that evaluate the effects of caffeine in combination with another pharmacologically active compound in an OTC medicine such as Excedrin (acetaminophen + caffeine) or in a prescribed drug, alcohol, or nicotine. Exclude: Studies less than six months in duration. Six months is the minimum time needed to see bone outcome endpoint effects on most any intervention (this does not include balance studies). Comparator(s)/ control: Comparator: < 400 mg/day, 300 mg/day, 2.5 mg/kg-bw day*, respectively (by population) *Applies to both adolescents and children Outcome(s): Primary outcomes Adverse bone and calcium balance effects include, effects on bone fracture, bone mineral density, calcium absorption and any other adverse bone and calcium balance effects reported (inclusive investigation). Exclude: Studies assessing hypertension and menopausal symptoms (not considered adverse). Studies addressing rare bone disorders like Paget’s disease, Osteoporosis Imperfecta, etc. Secondary outcomes Pharmacokinetic data that could be used to interpret the primary outcome (e.g., contextual information). Risk of bias (quality) assessment: Risk of bias will be evaluated using the U.S. National Toxicology Program: Office of Health Assessment and Translation Risk of Bias Rating Tool for Human and Animal studies (2015). Study reliability will also be characterized using the systematic approach for evaluating and scoring human data proposed by Money et al (2013) [PMID 23579077] Strategy for data synthesis: The body of evidence was evaluated and integrated using the U.S. National Toxicology Program: Office of Health Assessment and Translation Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review an Evidence Integration (2015). The process will involve generation of evidence tables and a qualitative synthesis of the available data. Evidence analysts will use a weight of evidence approach incorporating concepts such as consistency, dose response, imprecision, indirectness, magnitude of effect, confounding, and risk of bias to determine conclusions regarding levels of caffeine associated with acute adverse effects. Analytical tools, such as forest plots and descriptive statistical parameters, were used to aid in the weight of evidence assessment. Based on the availability of data, considerations were also be made regarding the severity of the outcome as well as the event(s) relative to the progression of the outcome.

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Systematic review of the adverse behavioral effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children


Public Project Complete

Statistics: 80 Studies, 1 Key Question, 1 Extraction Form,
Date Published: May 02, 2017 08:07PM
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.
Contributor(s): None Provided
DOI: DOI pending.
Funding Source: This Systematic Review of the adverse behavioral 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.
Methodology Description: 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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Systematic review of acute adverse effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children


Public Project Complete

Statistics: 26 Studies, 1 Key Question, 1 Extraction Form,
Date Published: May 02, 2017 08:07PM
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.
Contributor(s): None Provided
DOI: DOI pending.
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.
Methodology Description: 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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Systematic review of the adverse cardiovascular effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children


Public Project Complete

Statistics: 203 Studies, 1 Key Question, 1 Extraction Form,
Date Published: May 02, 2017 07:56PM
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.
Contributor(s): None Provided
DOI: DOI pending.
Funding Source: This Systematic Review of the adverse cardiovascular 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.
Methodology Description: 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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