1. Milton Tenenbein, MD University of Manitoba
Systematic review of the potential adverse effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children: Acute Health Outcome
Milton Tenenbein, MD
University of Manitoba

2. Member of the ILSI North America Caffeine Systematic Review Team
Disclosure
Member of the ILSI North America Caffeine Systematic Review Team
ILSI North America provided an honorarium and travel funds to attend this meeting. 

3. PECO Questions for the Acute Health Outcome
For [population], is caffeine intake above [dose], compared to intakes [dose] or less, associated with adverse acute outcomes?
Population*
Healthy Adults
Exposure
> 400 mg/day
> 10 g
Comparator
≤ 400 mg/day
≤ 10 g
Outcome
Acute, nonlethal effects
Death
Example: For healthy adults, is caffeine intake above 400 mg/day, compared to intakes of 400 mg/day or less, associated with acute adverse outcomes?
* Comparators not identified by Nawrot et al for other populations

4. Characterization of Data for Acute Health Outcome
Data Type
Characterization
Number of studies
26 included; 20 excluded
Study types*
Case reports and case series
Populations
Adults, pregnant women, adolescents
Exposure
Mostly self-reports with poor exposure characterization
Voluntary and intentional consumption
Few repeated exposures
~1/2 specifically evaluated caffeine (powder or tablet); others involved energy drinks or cola
Outcome (Endpoints)
Death, non-fatal effects associated with suicide attempts or high-dose related events (e.g., cardiovascular events; nausea; vomiting; seizures; hypokalemia)
* Study types included only for acute endpoint on basis of rare effects

5. Considerations re: Fatal Doses
For all drugs, published doses are not precise
Data are based on observation, not on the scientific method
Derived from case reports of suicide gestures where the dose history is unreliable
Controlled studies are not possible
These considerations also apply to establishing the adverse effect dose

6. Death
The evidence demonstrates that in adolescents and adults, deaths occurred at doses mostly > 10g/day
Most exposures were suicidal gestures
Adverse effects in non-fatal cases included nausea, vomiting, and cardiovascular events
Exposure characterization was poor
Very low to low level of confidence in the body of evidence
From manuscript:
Following review of data from these six case reports involving assessment of acute toxicity in
adolescents (aged 15–18 years), data support that the comparators of 10 g and 2.5 mg/kg/day for
lethality and nonlethal endpoints, respectively, are acceptable. There is a very low to low level of
confidence in the evidence base (Figure 11; Table 1). Confidence is limited by high risk of bias
and likely publication bias; inherent to the case studies included, reports are limited to those
reporting effects (and not reporting a lack of effects), as well as very low confidence in exposure
estimates.

7. Non-fatal Effects
Most non-fatal effects of caffeine occurred at doses > 400 mg/day
Reporting bias due to nature of study types (case studies associated with effects)
Most exposures were NOT suicidal gestures
Adverse effects typically included nausea, vomiting, hypokalemia, seizure, and cardiovascular events (e.g. tachycardia, palpitations, changes in blood pressure)
Exposure characterization was poor
Very low to low level of confidence in the body of evidence
From manuscript:
Following review of data from these six case reports involving assessment of acute toxicity in
adolescents (aged 15–18 years), data support that the comparators of 10 g and 2.5 mg/kg/day for
lethality and nonlethal endpoints, respectively, are acceptable. There is a very low to low level of
confidence in the evidence base (Figure 11; Table 1). Confidence is limited by high risk of bias
and likely publication bias; inherent to the case studies included, reports are limited to those
reporting effects (and not reporting a lack of effects), as well as very low confidence in exposure
estimates.
Following review of data from these 20 reports involving assessment of acute toxicity in adults,
it was determined that the comparators of 10 g and 400 mg/day for lethality and nonlethal
endpoints, respectively, are acceptable. There was a very low to low level of confidence in the
evidence base. Confidence is limited by high risk of bias (likely publication bias) (Figure 11;
Table 1); inherent to the case studies included, reports are limited to those reporting effects (and
not reporting a lack of effects), as well as very low confidence in exposure estimates.

8. Evaluation of Individual Study Quality (Risk of Bias)
Overall “high” risk of bias for studies in adults; few qualified studies in other populations, none in children
Limited greatly by exposure characterization
Q8: Unintended
Q11: Other, purity
+2: Definitely low
+1: Probably low
-1: Probably high
-2: Definitely high

9. Factors that increased or decreased confidence in the body of evidence by endpoint
No. of Studies
Initial Confidence Rating
Based on study type and study features (OHAT, 2015)
Overall RoB
Domain-based evaluation of risk of bias per the OHAT RoB tool (OHAT, 2015)
Indirectness
Was the study designed to evaluate the PECO?
Magnitude
Strength of effect (when effect observed below the comparator)
Confounding
Were plausible confounders that would change the observed effect accounted for?
Consistency
Were findings consistent in demonstrating effects or lack of effects at or below the comparator
Final Confidence Rating
What is the overall rating when factors that increase or decrease confidence were considered
 Death 14
Very low to low ↓ ↑
Not Evaluated —
↑/-
Other acute effects 18
↑ increased confidence no change to confidence ↓ decreased confidence

10. Weight of Evidence Conclusion: Acute
Adults: When the weight of evidence was considered, 400 mg caffeine/day (2.5 mg/kg/day for adolescents) was not associated with acute adverse effects.
Wide range of adverse effects observed across cases, with overlap
Death has been associated with acute exposures of 10g or more
Only a single report of death following a dose less than 10g
Acute effects may be a result of rapid consumption and do not represent typical consumer behavior
Pregnant Women & Children: insufficient evidence to develop a conclusion
From manuscript:In summary, the SR of 26 studies provided evidence to evaluate potential acute toxicity. Following a weight of evidence review, the comparators of 10 g for lethality and 400 mg/day or 2.5 mg/kg/day for other acute effects, were determined to be acceptable for healthy adults and adolescents, respectively. There is very low to low confidence in this evidence base, due primarily to uncertainty in the estimates of exposure and to the high risk of bias. A higher level of confidence is also precluded by the inherent bias introduced by utilizing case reports (i.e., limitations to reporting of effects versus no effects). Insufficient and/or lack of data precluded conclusions related to acute toxicity for children and pregnant women.

11. Future Research Needs
Improved exposure characterization (i.e., testing of blood concentrations)