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Caffeine for asthma (Review)

  Welsh EJ, Bara A, Barley E, Cates CJ  

  Welsh EJ, Bara A, Barley E, Cates CJ.  

Caffeine for asthma.
Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD001112.
DOI: 10.1002/14651858.CD001112.pub2.

  [Link]  

 
Caffeine for asthma (Review)
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TABLE OF CONTENTS
HEADER......................................................................................................................................................................................................... 1
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
BACKGROUND.............................................................................................................................................................................................. 3
OBJECTIVES.................................................................................................................................................................................................. 3
METHODS..................................................................................................................................................................................................... 3
RESULTS........................................................................................................................................................................................................ 4
Figure 1.................................................................................................................................................................................................. 6
Figure 2.................................................................................................................................................................................................. 8
DISCUSSION.................................................................................................................................................................................................. 8
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 10
ACKNOWLEDGEMENTS................................................................................................................................................................................ 10
REFERENCES................................................................................................................................................................................................ 11
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 12
DATA AND ANALYSES.................................................................................................................................................................................... 18
Analysis 1.1. Comparison 1 All caffeine doses versus placebo, Outcome 1 FEV1 outcomes at 'short' time frame.......................... 20
Analysis 1.2. Comparison 1 All caffeine doses versus placebo, Outcome 2 FEV1 outcomes at 'medium' time frame..................... 20
Analysis 1.3. Comparison 1 All caffeine doses versus placebo, Outcome 3 FEV1 outcomes at 'long' time frame........................... 21
Analysis 1.4. Comparison 1 All caffeine doses versus placebo, Outcome 4 FEF 25-75 outcomes at 'short' time frame.................. 21
Analysis 1.5. Comparison 1 All caffeine doses versus placebo, Outcome 5 FEF 25-75 outcomes at 'medium' time frame............. 21
Analysis 1.6. Comparison 1 All caffeine doses versus placebo, Outcome 6 FEF 25-75 outcomes at 'long' time frame.................... 22
Analysis 1.7. Comparison 1 All caffeine doses versus placebo, Outcome 7 Gaw/VL outcomes at 'short' time frame...................... 22
Analysis 1.8. Comparison 1 All caffeine doses versus placebo, Outcome 8 FEV1 outcomes at 2 hours........................................... 23
Analysis 1.9. Comparison 1 All caffeine doses versus placebo, Outcome 9 FEV1 outcomes at 2 hours (High dose)........................ 23
ADDITIONAL TABLES.................................................................................................................................................................................... 24
APPENDICES................................................................................................................................................................................................. 25
FEEDBACK..................................................................................................................................................................................................... 26
WHAT'S NEW................................................................................................................................................................................................. 27
HISTORY........................................................................................................................................................................................................ 27
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 27
DECLARATIONS OF INTEREST..................................................................................................................................................................... 27
SOURCES OF SUPPORT............................................................................................................................................................................... 28
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 28
INDEX TERMS............................................................................................................................................................................................... 28

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[Intervention Review]

Caffeine for asthma

Emma J Welsh1, Anna Bara2, Elizabeth Barley3, Christopher J Cates1

1Population Health Sciences and Education, St George's, University of London, London, UK. 2Medical Research Unit, Clinical Trials Unit,
London, UK. 3Florence Nightingale School of Nursing and Midwifery, King's College London, London, UK

Contact address: Emma J Welsh, Population Health Sciences and Education, St George's, University of London, Cranmer Terrace,
London, SW17 0RE, UK. ewelsh@[Link].

Editorial group: Cochrane Airways Group

Publication status and date: Stable (no update expected for reasons given in 'What's new'), published in Issue 8, 2012.

Citation: Welsh EJ, Bara A, Barley E, Cates CJ. Caffeine for asthma. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.:
CD001112. DOI: 10.1002/14651858.CD001112.pub2.

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

Background
Caffeine has a variety of pharmacological effects; it is a weak bronchodilator and it also reduces respiratory muscle fatigue. It is chemically
related to the drug theophylline which is used to treat asthma. It has been suggested that caffeine may reduce asthma symptoms and
interest has been expressed in its potential role as an asthma treatment. A number of studies have explored the effects of caffeine in asthma;
this is the first review to systematically examine and summarise the evidence.

Objectives
To assess the effects of caffeine on lung function and identify whether there is a need to control for caffeine consumption prior to either
lung function or exhaled nitric oxide testing.

Search methods
We searched the Cochrane Airways Group trials register and the reference lists of articles (August 2011), an updated search in June 2011
yielded one potentially relevant article which has been added to 'studies awaiting classification'. We also contacted study authors.

Selection criteria
We included randomised trials (RCTs) of oral caffeine compared to placebo or coffee compared to decaffeinated coffee in adults with
asthma.

Data collection and analysis

Two review authors independently carried out trial selection, quality assessment and data extraction.

Main results
We included seven trials involving a total of 75 people with mild to moderate asthma. The studies were all of cross-over design.

Six trials involving 55 people showed that in comparison with placebo, caffeine, even at a 'low dose' (less than 5 mg/kg body
weight), appears to improve lung function for up to two hours after consumption. Forced expiratory volume in one second (FEV1) showed
a small improvement up to two hours after caffeine ingestion (standardised mean difference 0.72; 95% confidence interval 0.25 to 1.20),
which translates into a 5% mean difference in FEV1. However in two studies the mean differences in FEV1 were 12% and 18% after caffeine.
Mid-expiratory flow rates also showed a small improvement with caffeine and this was sustained up to four hours.

One trial involving 20 people examined the effect of drinking coffee versus a decaffeinated variety on the exhaled nitric oxide levels in
patients with asthma and concluded that there was no significant effect on this outcome.

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Authors' conclusions
Caffeine appears to improve airways function modestly, for up to four hours, in people with asthma. People may need to avoid caffeine
for at least four hours prior to lung function testing, as caffeine ingestion could cause misinterpretation of the results. Drinking caffeinated
coffee before taking exhaled nitric oxide measurements does not appear to affect the results of the test, but more studies are needed to
confirm this.

PLAIN LANGUAGE SUMMARY

The effect of caffeine in people with asthma

Caffeine is found in coffee, tea, cola drinks and cocoa. Caffeine is a drug that is very similar to theophylline. Theophylline is a bronchodilator
drug that is taken to open up the airways in the lungs and therefore relieve the symptoms of asthma, such as wheezing, coughing and
breathlessness. Scientists are interested in finding out whether caffeine has the same effect on the lungs as theophylline.

There are two major reasons why it is important to know if caffeine is a bronchodilator. The first is because it may be beneficial for
asthmatics to take caffeine in order to relieve the symptoms of asthma. The second is because consuming caffeine may affect the results
of important tests that determine how bad someone's asthma is.

If caffeine acts as a bronchodilator and widens the airways, then a patient who has consumed caffeine before taking the test would show
a better result in a lung function test than they would have if they had not consumed any caffeine. The potential problem with this is that
if the test results are better than expected doctors may prescribe a lower dose or a weaker drug than is really necessary, which can lead
to problems with asthma management.

This review carefully examines all the available high-quality clinical trials on caffeine in asthma. This review was conducted to discover if
people should avoid consuming caffeine before taking lung function tests.

This review found that even small amounts of caffeine can improve lung function for up to four hours. Therefore caffeine can affect the
result of a lung function test (e.g. spirometry) and so caffeine should be avoided before taking a lung function test if possible, and previous
caffeine consumption should be recorded.

It is not known if taking caffeine leads to improvements in symptoms. It may be that in order to improve the symptoms of asthma, caffeine
is needed in such large amounts that the drug's adverse effects would become a problem, so more research is needed.

Another clinical trial looked at the effect of caffeine on exhaled nitric oxide levels and found that there is no significant effect, so it appears
unlikely that patients would need to avoid caffeine before taking this type of test. However, this is the result of just a single study so more
research is needed to clarify this.

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BACKGROUND 4. To test whether there is a need to control for caffeine

consumption prior to lung function testing and testing exhaled
Caffeine has been widely consumed throughout the world for nitric oxide (FeNO).
centuries. It is used for both non-medical and medical purposes. It 5. To examine the need for further research into the effects of
is ubiquitous, being found in coffee, tea, cola-flavoured soft drinks caffeine in asthma.
and compounds containing cocoa. Caffeine and its derivatives have
therapeutic uses and are contained in medicines such as analgesics METHODS
and cold remedies.
Criteria for considering studies for this review
The general pharmacological effects of caffeine have been
extensively investigated and are described in several reviews Types of studies
(e.g. Curatolo 1983; Stephenson 1977). Early studies reported We included randomised trials (RCTs) only.
that caffeine improved mental performance and increased motor
activity (Cheney 1935) and this has been confirmed in other Types of participants
studies. Caffeine ingestion has also been shown to elevate
oxygen consumption (Grollman 1930), increase respiratory rates We included adults (older than 18 years) with previously
in disease-free patients (Robertson 1978) and increase ventilation documented asthma of any level of severity.
in patients with coronary obstructive pulmonary disease (COPD)
Types of interventions
(Woodcock 1981).
We included the following comparisons:
Caffeine belongs to a group of chemicals called methylxanthines,
along with the bronchodilator drug theophylline. As a class, 1. oral caffeine versus placebo; and
these drugs have a history of use in respiratory disorders. The 2. coffee versus decaffeinated coffee.
mechanism of action of the methylxanthines is uncertain, but is
possibly due to their inhibition of the enzyme phosphodiesterase. Types of outcome measures
Phosphodiesterase hydrolyses cyclic adenosine monophosphate
We did not use outcome measures to decide if a study was eligible
(cAMP) which is a messenger within the cell that regulates many
for inclusion in the review.
functions including the contraction and relaxation of smooth
muscle. Methylxanthines are also competitive antagonists for We did not include challenge test data in this review.
adenosine receptors. One of the effects of adenosine, a chemical
regulator, is that of bronchoconstriction. Methylxanthines are Primary outcomes
known to be weak bronchodilators and they also interact with
1. Lung function outcomes used were: forced expiratory volume
respiratory muscles to reduce respiratory muscle fatigue. Some
in one second (FEV1), maximum mid-expiratory flow (FEF25-75)
believe the latter to be more important than the former in the
and specific airway conductance (Gaw/VL)
treatment of respiratory diseases.
2. Exhaled nitric oxide concentration (FeNO)
Thus, interest has been expressed in the potential role of caffeine
as a treatment in respiratory disease (Pagano 1988). As early as Secondary outcomes
1859, Salter (in Becker 1984) recommended coffee as one of the 1. Forced vital capacity (FVC)
best remedies for asthma. A study of the general Italian population
2. Maximal expiratory flow rates at 25% and 50% of vital capacity
in 1983 by Pagano 1988 found an inverse relationship between
(Vmax50 and Vmax25 respectively)
the prevalence of bronchial asthma and the amount of coffee
consumed. From this, the authors suggested that caffeine may 3. Exercise-induced bronchoconstriction
reduce asthma symptoms. 4. PC20
5. Carbachol challenge
Why it is important to do this review 6. Pulse
Despite the amount of information regarding caffeine and its 7. Blood pressure
potential effectiveness in obstructive airways diseases, no reviews 8. Symptoms
have been conducted that examine the evidence in a systematic 9. Serum caffeine levels
fashion. The results from such a review could have important
[Link] effects and adverse effects.
implications for research and clinical practice.
Search methods for identification of studies
OBJECTIVES
Electronic searches
1. To identify all published randomised controlled trials of caffeine
in the management of asthma. We identified trials using the Cochrane Airways Group Specialised
2. To assess the methodological quality of these randomised Register of trials (CAGR), which is derived from systematic searches
controlled trials. of bibliographic databases including the Cochrane Central Register
of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED
3. To estimate the overall effect of caffeine upon lung function and and PsycINFO, and handsearching of respiratory journals and
exhaled nitric oxide (FeNO). meeting abstracts (see Appendix 1). We searched all records in the
Specialised Register coded as 'asthma' using the following terms:

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caffeine* or *caffeine or coffee or tea or chocolate or cola. For each domain we judged the risk of bias as being high, low
or unclear risk of bias in line with recommendations from the
We did not exclude trials on the basis of language. We searched the Cochrane Handbook for Systematic Reviews of Interventions (Higgins
CAGR up to August 2011. 2008).
Searching other resources Measures of treatment effect
We reviewed reference lists of all primary studies and review We reported individual and pooled statistics as odds ratios
articles for additional references. (OR) with 95% confidence intervals (95% CI). We used weighted
mean difference (MD) when identical units of measurement were
We contacted authors of identified trials and asked them to identify
reported. To allow the combination of studies where different
other published and unpublished studies.
units (e.g. actual values, change scores, % predicted values) were
reported for a particular pulmonary function test (e.g. FEV1 or
Data collection and analysis
FEF25-75), we performed analyses using the standardised mean
Selection of studies difference (SMD).
Two of us (AB, EB) independently reviewed the title, abstract and Unit of analysis issues
key words of the references obtained from the literature search.
For the 2009 and 2011 update this was done by EJW and CC. We Outcomes were measured and reported at a variety of different
excluded all studies that were not randomised trials or that clearly time points and following different doses of caffeine. For the
did not fit the inclusion criteria. Two of us reviewed the full text purposes of this review and meta-analysis, we grouped data for
of the remaining articles. Complete agreement was achieved at all each outcome according to time of measurement. We divided data
stages. into three time frames labelled as follows: 'short' (less than or equal
to two hours); 'medium' (greater than two hours and less than or
Data extraction and management equal to four hours); and 'long' (greater than four hours). In the 2009
review a comparison of all doses at two hours was included; where
We contacted trial authors in an effort to obtain raw and missing
no data at two hours were given we used the nearest data point and
data for the original review. Two of us (AB, EB) independently
recorded the time in Table 1.
extracted means and standard deviations or standard errors. We
converted standard errors to standard deviations. Two research Dealing with missing data
staff from the Division of Physiological Medicine, St. George's
Hospital Medical School (Sally Spencer and Catherine O'Leary) Since the trials were run over a few hours there were few dropouts.
extracted data visually from graphs. There was little variation in the Out of a total of 75 patients only six dropped out.
data extracted by the four review authors. We used the mean figures
Data synthesis
from the four independently extracted sets in this review.
We analysed continuous data using the inverse-variance fixed-
Only data from cross-over studies were available for inclusion in effect method in RevMan 5.1.
this review. Since caffeine is a short-acting agent and most studies
reported washout periods, 'carryover' and 'period' effects were not Subgroup analysis and investigation of heterogeneity
considered to affect the results in an important way. They were
treated as parallel designs in the analyses for the original review, For each outcome in each time frame, we performed subgroup
but for the 2009 update we have used paired t-test results with analyses to test for differences between 'high' and 'low' doses of
Generic Inverse Variance pooling. In addition, since no results were caffeine. Using the median value to divide the data, we defined
reported from parallel-group studies, there was no need to provide doses as: 'high' (greater than 5 mg/kg (mg per kg of body weight));
subgroup analyses on the basis of design. or 'low' (lower than 5 mg/kg).

We entered extracted data into the Cochrane Collaboration RESULTS

software program (RevMan 5.1).
Description of studies
In one paper (Bukowskyj 1987) the mean value provided in the table Results of the search
and that in the corresponding figure were inconsistent (value for %
change FEF25-75 at 0.5 hours); this was assumed to be a misprint An all years literature search to 2011 returned 23 references. We
and therefore omitted from the meta-analysis. discarded 13 on the basis of the title, abstract or title and abstract.
We obtained full papers for the remaining 10 references. We
Assessment of risk of bias in included studies identified 17 additional references by searching the bibliographies
For this 2009 update, two of us (EW and CC) updated the risk of bias of the retrieved studies.
according to four domains: Seven trials fulfilled the inclusion criteria and were included in
1. allocation generation and concealment; this review. Complete agreement was achieved between the review
authors.
2. blinding;
3. handling of missing data; and Included studies
4. selective reporting bias. Six studies were included in the original review and an update
search conducted in August 2009 identified one additional study

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which met the inclusion criteria (Taylor 2004). All studies are plus caffeine = one study, caffeine versus decaffeinated coffee =
outlined in the Characteristics of included studies table. one study). Two studies contributed to the 'low' dose comparison:
Bukowskyj 1987 (5 mg/kg) and Colacone 1990 (5 mg/kg). Four
Six studies tested for the effects of caffeine on pulmonary function, studies contributed to the 'high' dose comparison: Crivelli 1986 (6
although the main aim of these studies differed. Three studies of mg/kg), Duffy 1991 (10 mg/kg), Gong 1986 (7.2 mg/kg) and Kivity
these six additionally tested the influence of caffeine on bronchial 1990 (7 mg/kg).
provocation challenge tests, one using histamine (Colacone 1990),
one carbachol (Crivelli 1986) and one using eucapnic voluntary One study, Taylor 2004, assessed drinking a cup of coffee
hyperventilation (EVH) (Duffy 1991). We did not include challenge (intervention group) versus decaffeinated coffee (placebo group)
test data in this review. One study also tested the effect of caffeine prepared using a standard quantity (15 g) of either caffeine-
on exercise-induced bronchoconstriction (Kivity 1990). One study containing coffee or decaffeinated coffee.
also compared caffeine to aminophylline (Gong 1986), but these
data were not analysed as it was considered to be beyond the scope Outcomes
of this review. Pulmonary function tests were the only outcomes suitable for entry
into the meta-analysis.
One study (Taylor 2004) assessed the effects of coffee on exhaled
nitric oxide (FeNO). See Characteristics of included studies for details of secondary
outcomes of trials.
Participants
There were 55 (39 male) adult participants in the six included Excluded studies
studies testing for pulmonary function in the original review. These From examination of the full papers of the of the potentially eligible
patients were all described as having stable, mild to moderate references, we excluded two studies (Becker 1984; Henderson
asthma. Further details of baseline lung function are found in Table 1993). One potentially eligible reference was returned from the
1. bibliographic search and this was excluded on retrieval of the full
paper (Simmons 1983). See Characteristics of excluded studies.
There were 20 adult participants (gender not specified) in the study
testing for exhaled nitric oxide included in the 2009 update. The Risk of bias in included studies
severity of their asthma was not described, but there were 10
steroid-naive and 10 steroid-treated patients. Complete agreement was reached by the review authors for both
assessments. See Characteristics of included studies for 'Risk of
Interventions bias' tables for individual studies and Figure 1 for an overview.
Caffeine and matched placebos were administered orally (as a
solution = three studies, capsule = two studies, decaffeinated coffee
 

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Figure 1.   'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

 
Allocation presumably be able to detect if they had ingested any caffeine
due to side effects. Five studies were judged to have a low risk
All the papers stated that the trials were randomised. One trial
of bias with respect to blinding (Bukowskyj 1987; Colacone 1990;
reported computerised sequence generation which was judged to
Duffy 1991; Gong 1986; Kivity 1990). None of the papers described
have a low risk of bias (Gong 1986), while the remaining six trials
blinding of the investigator administering the caffeine or placebo to
were unclear. Two trials reported adequate allocation concealment
the patient or the investigator taking the outcome readings.
(Bukowskyj 1987; Colacone 1990) while the remaining five were
unclear. Incomplete outcome data
Blinding Since the trials took place over relatively short time frames there
were few dropouts and only one missing data point throughout
All the studies were described as double-blind. Blinding of the
all the studies. All trials were judged to be of low risk of bias with
patient is important so that they put the same effort into lung
respect to dealing with incomplete data.
function testing regardless of intervention, however they would

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Other potential sources of bias the 'short' and one study at the 'medium' time frame. No FEV1 data
were reported at the 'long' time frame. For FEF25-75, one study on
All the included studies used a cross-over design. In all cases the
16 participants only contributed data at the 'short' and 'medium'
cross-over rule was time. The time period between study days was
time frames. One study provided data for Gaw/VL at the 'short' time
not always stated but, where details were provided, ranged from
frame only.
consecutive days to within two weeks. To control for the effects of
circadian rhythms, tests took place at the same time on each day Lung function was found to improve following a 'high' dose of
in all studies. Few studies comment on the existence or effect of caffeine compared to placebo for all measured outcomes. This
outlying values. effect was clear at the 'short' time frame only for FEV1 and FEF25-75.
A clear improvement in Gaw/VL was also seen at the 'short' time
Effects of interventions frame.
Outcomes relating to lung function
Two other studies (Crivelli 1986; Duffy 1991) tested the effect of
The description of the analysis will follow the list of comparisons 'high' dose caffeine at the 'short' time frame on FEV1, but no data
used in this Cochrane Review and will concentrate on caffeine were extracted for inclusion into the meta-analysis in the original
versus placebo results. Subgroup analyses will highlight the 'low' review. However, in correspondence, both authors reported no
dose versus 'high' dose and time of final assessment comparisons. significant difference in bronchodilation between caffeine and
placebo ingestion. For the 2009 update, data were extracted from
Results: Crivelli 1986 from the original patient data provided into FEV1
outcomes at two hours.
• Forced expiratory volume in one second (FEV1):
'short' (standardised mean difference (SMD) 0.72; 95% Subgroup analysis: FEV1 outcomes at two hours
confidence interval (CI) 0.25 to 1.20; six studies on 78
participants), 'medium' (mean difference (MD) 12.66; 95% CI In order to draw an overall conclusion we felt that it would be
-0.34 to 25.67; two studies on 34 participants), 'long' (MD 11.00; helpful to have a comparison with as many studies side by side
95% CI -6.49 to 28.49; one study on 16 participants). as possible (2009 update). Peak FEV1 readings were recorded at
• Maximum mid-expiratory flow (FEF25-75): 'short' (MD 25.14; around two hours, so this was chosen as the best time point (see
95% CI 11.92 to 38.37; two studies on 34 participants), Table 1). Crivelli 1986 reported a reading of FEV1 at 45 minutes
'medium' (MD 32.72; 95% CI 16.26 to 49.17; two studies on 34 rather than two hours and these data were included in the meta-
participants), 'long' (MD 26.00; 95% CI 5.02 to 46.98; one study analysis. Data were extracted from the patient data provided in
on 16 participants). Crivelli 1986. Five studies on 88 participants gave FEV1 readings at
'high' doses and one study on 20 participants gave an additional
• Specific airway conductance (Gaw/VL): 'short' (MD 30.30; 95% CI
reading at 'low' dose (Analysis 1.8). The forest plot shows improved
1.08 to 59.52; one study on 18 participants).
FEV1 when patients had consumed caffeine at high dose prior to
An improvement was seen for all outcomes after ingesting caffeine testing (SMD 0.76; 95% CI 0.32 to 1.20). There was no heterogeneity
compared to placebo at all recorded time frames. This effect was in the result (I2 = 0) indicating a good agreement in the outcome
statistically significant in all cases except for FEV1 at the 'medium' data between studies.
and 'long' time frames where the confidence intervals crossed the
For this update we entered the paired t-test results into the review
line of no effect.
using Generic Inverse Variance pooling for the two-hour FEV1
Subgroup analysis: 'low' dose outcome. The confidence intervals for each trial were fairly similar
to those found previously, when the results had not been analysed
Two studies on 36 participants reported FEV1 outcomes at 'low' with paired t-tests. This provides reassurance that the previous
dose. Data for the three time frame comparisons came from the conclusions of the review are valid.
following number of studies: 'short' = two studies, 'medium' =
one study, 'long' = one study. For FEF25-75 only one study on 16 When analysed as % change in FEV1 the pooled result of three
participants contributed data at all time frames. There were no data trials on 26 participants showed a significant benefit with caffeine
for Gaw/VL at this dose. at higher dose (MD 5.47%; 95% CI 1.43 to 9.52, Analysis 1.9) (see
Figure 2). There was significant heterogeneity in this result (I2 =
All lung function parameters tended to improve post caffeine 61%), but this appears to come from Crivelli 1986; the participants
ingestion compared to placebo. For FEV1, this effect was clear only in this trial were asymptomatic and not on treatment for asthma, so
at the 'short' time frame. For FEF25-75, the difference was clear at would have little potential to increase their FEV1 following caffeine.
all times. If the results of the two other trials (Bukowskyj 1987; Gong 1986)
are combined this gives a larger mean difference with caffeine of
Subgroup analysis: 'high' dose
around 15% difference in FEV1 (MD 14.54%; 95% CI 5.35 to 23.72).
Four studies on 42 participants reported FEV1 outcomes at 'high'
dose. Data were available for the meta-analysis from two studies at
 

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Figure 2.   Forest plot of comparison: 1 All caffeine doses (highest dose from each study) versus placebo, outcome:
1.10 FEV1 outcomes at 2 hours (High dose).

 
Serum caffeine levels Outcomes relating to exhaled nitric oxide
The papers differed in their reporting of serum caffeine levels. After The impact of caffeine on FeNO was assessed in one study on 20
a dose of caffeine (5 mg/kg), Bukowskyj 1987 reported a peak serum participants (Taylor 2004). This small study reported no significant
level of 8.7 (SD = 1.7) μg/mL one hour after ingestion. Colacone 1990 difference in exhaled nitric oxide (data reported in the text as non-
used the same dose and reported a mean (but not peak) level at 1 significant (P = 0.38) and presented graphically). Findings were not
hour 45 minutes of 5.4 (SD = 1.23) μg/mL. Duffy 1991 reported that significantly different in subgroups for those treated with inhaled
peak serum levels of caffeine (mean 18.8; 95% CI 12.4 to 25.2 mg/ steroids and those not treated with steroids.
L at 45 minutes) were observed 45 to 60 minutes after ingestion of
caffeine (10 mg/kg). DISCUSSION

Taylor 2004 reported that at 60 minutes, serum caffeine levels The available evidence of the effect of caffeine compared to
were higher after ingesting regular caffeine-containing coffee than placebo on lung function and exhaled nitric oxide from randomised
after decaffeinated coffee at 60 minutes (3.9 versus 0.4 mg/mL controlled trials is summarised in this systematic review.
respectively). Statistical tests of significance were only reported for
within-group differences. Summary of main results
For all dose strengths, caffeine compared to placebo was found
Side effects and adverse effects
to significantly improve lung function measured in terms of FEV1,
Five of the studies commented on side effects, including heart FEF25-75 and Gaw/VL for up to two hours post ingestion. This effect
rate and blood pressure changes although none contributed data was sustained for FEF25-75 for over four hours. Improvement was
that could be entered in a meta-analysis. No side effects were also seen in FEV1 up to this time, however this effect did not reach
reported after 'low' doses of caffeine. After ingestion of a 'high' statistical significance. No data were available for Gaw/VL after two
dose of caffeine two patients reported mild tremor (Kivity 1990), hours. Bronchodilation was also seen after ingesting caffeine even
three patients reported nervousness and gastrointestinal upset following a 'low' dose (5 mg/kg). For FEV1, the difference between
(Gong 1986), and one patient withdrew from the study because of the caffeine and placebo groups was not significant after two hours.
nervousness and agitation (Duffy 1991), which was presumed to be In contrast, for FEF25-75 the effect was clear at all times, even
due to the caffeine. Only one study (Gong 1986) reported significant over four hours. A clear increase following a 'high' dose of caffeine
changes in heart rate (a decrease up to 9%) and blood pressure (an (> 5 mg/kg) compared to placebo was seen in FEV1, FEF25-75
increase up to 12%). and Gaw/VL at up to two hours only. Gaw/VL outcomes were not
recorded beyond two hours. At two hours, at all doses, there was
an improvement in lung function after ingesting caffeine, and when
Caffeine for asthma (Review) 8
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reported as % increase in FEV1 this showed an average difference The findings of any review are only applicable to the characteristics
of 5% change (MD 5.47%; 95% CI 1.43 to 9.52). However when the of the participants taking part in the included studies. Although
study on patients who were asymptomatic and on no treatment a standardised definition was not used across the studies,
(Crivelli 1986) was excluded, the change in FEV1 was higher after participants were described as having mild or moderate asthma,
caffeine (MD 14.54%; 95% CI 5.35 to 23.72). therefore results may not be generalisable to those with more
severe asthma. Most subjects were described as having stable
The size of improvements in lung function were small and at the or asymptomatic asthma, but how this was assessed was not
margins of what would normally be considered clinical significance described. Similarly, patients' treatment regimens varied greatly
(FEV1: maximum 13.7% change from baseline (Gong 1986) or across the trials and the effect of this was not studied.
maximum 330 mL absolute change for caffeine versus placebo
(Kivity 1990)). Only one study (Gong 1986) explicitly recorded It could be argued that insufficient data were presented on side
the patients' perception: four of the nine participants reported effects resulting from caffeine, however the studies were designed
improved breathing following ingestion of a 'high' dose of caffeine; not to asses the long-term effects of caffeine, but instead to assess
the same information was not provided for the placebo group. the short-term impact of ingesting caffeine on lung function and
exhaled nitric oxide tests. The side effects of caffeine are similar to
Concerns have been raised as to whether caffeine interferes those of theophylline (tachycardia, palpitation, nausea and other
with the measurement of exhaled nitric oxide levels, based on gastrointestinal disturbances, headache, central nervous system
a randomised study in non-asthmatic healthy volunteers (Bruce stimulation, insomnia).
2002). The only randomised study to date in a small sample of
people with mild asthma did not identify a significant difference The issue arising from this review is not whether caffeine should
between a cup of coffee made with 15 g of grounds and a similar cup or should not be used as a bronchodilator in preference for
made with decaffeinated coffee (Taylor 2004). Additional studies theophylline or whether the side effects are sufficient to override
would help to determine whether this finding is valid. this benefit. Instead the issue is whether or not the amount of
caffeine ingested in a cup of coffee (or two) is sufficient to alter
Overall completeness and applicability of evidence the result of a lung function test. This may be important if coffee
drinkers show better results in lung function tests than they would
Comparison of the findings across studies was complicated by the
achieve if they did not drink coffee. The evidence presented here
use of five different doses of caffeine, different outcome measures
shows that taking a 'normal' amount of caffeine, equivalent to one
recorded at different times, and different methods of reporting
to five cups of coffee, is enough to alter the results of a lung function
outcomes. To permit the aggregation of data we grouped the
test. Therefore patients should be advised not to drink coffee
trials according to dose and time. Similarly, we made analyses
for four hours before taking a lung function test. Drinking coffee
using the SMD where the combined trials used different units of
before taking a FeNO test does not affect the results according to
measurement for the same variable. Despite this, few data were
the single-study data presented here, although further data are
available to be combined in the meta-analysis.
necessary to clarify. The long-term impact of drinking coffee was
The dose of caffeine tested varied greatly between studies, from 5 not studied in these trials or reviewed here.
to 10 mg/kg. In an effort to make this more meaningful in dietary
terms, most authors related doses to cups of coffee. However, the Quality of the evidence
average amount of caffeine per cup is quoted as between 30 to 150 Interpretation of the results of this review must include
mg, although 150 mg was most commonly stated. Consequently, consideration of methodological limitations. All of the studies
the number of cups of coffee required to produce bronchodilation employed a cross-over design. Although the method of allocation
is reported from one to five cups. was in all cases reported to be randomised, none of the authors
assessed order effects, and only two authors explicitly stated
One method of standardising the dose ingested between studies
that the patients could not discern which treatment they had
would be to examine the peak serum levels. The reported peak
received (Bukowskyj 1987; Gong 1986). Sample sizes were small
serum levels vary greatly: from 5.4 mg/L (Colacone 1990) to 18.8
and the existence or effect of outlying values were rarely discussed.
mg/L (Duffy 1991). Interestingly, the study reporting serum caffeine
Outlying values are important in small studies using cross-over
level of 18.8 mg/L after a dose of caffeine (10 mg/kg) found
designs, as each subject provides a large proportion of the data.
no increase in FEV1, although a later protective effect against
bronchoconstriction post broncho provocation challenge test was This review was restricted to an analysis of clinically relevant data
found (Duffy 1991). These data were not presented in a way that in terms of a patient response and excluded the scientific issue of
would enable extraction for entry into the meta-analysis. Peak whether caffeine affects airway response to bronchoconstricting
serum levels of caffeine tended to occur at 45 or 60 minutes agents.
post caffeine intake. However, a clear difference between caffeine
and placebo was seen even four hours post ingestion (Bukowskyj Potential biases in the review process
1987). Few studies reported measurements beyond four hours post
dosing. However, serum caffeine was detected in some patients at The possibility of publication bias (non-publication of negative
baseline. It is not known whether this would affect the potential studies) should be considered given that only small differences in
for bronchodilation, especially where lung function outcomes were bronchodilator effect were found between caffeine and placebo.
reported in terms of change from baseline. Even consideration of However, we used a comprehensive search strategy and searched
the peak serum levels would not fully compensate for this. for unpublished trials in an attempt to minimise this bias.

Caffeine for asthma (Review) 9

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Agreements and disagreements with other studies or products would be needed to achieve a beneficial bronchodilatory
reviews effect and that possible undesirable side effects may outweigh the
benefits.
There are no other published reviews.
Implications for research
AUTHORS' CONCLUSIONS
That caffeine has a bronchodilatory effect in asthma is clear from
Implications for practice existing research. Future studies could address the following.
Caffeine, even at 'low' doses, has been found to improve lung 1. Patients' perception of the effect of caffeine on their asthma and
function for at least four hours after ingestion. One trial using quality of life, as this has not been systematically studied.
the most sensitive outcome measurements (FEF25-75) showed 2. The maximum length of time at which bronchodilation is
that effects are sustained for over four hours post ingestion. It sustained, as this cannot be determined from existing trials.
is therefore recommended that patients be advised to withhold
3. Effects on patients with different levels of asthma severity, since
caffeine for at least four hours prior to lung function testing.
existing trials have only studied people with mild to moderate
Alternatively lung function tests results should be considered in
asthma.
light of caffeine ingested within four hours of the start of the test, as
coffee drinkers may present with a better lung function test result 4. The response to caffeine of people with well-controlled
than if they had not consumed so much caffeine. Caffeine does not asthmatics on anti-inflammatory agents. Asthmatics using
appear to have a significant effect on exhaled nitric oxide levels. inhaled steroids may be less responsive and this needs further
evaluation.
With regard to advice to patients, caffeine ingestion may improve 5. Differences in the bronchodilator effects of caffeine between
lung function in the short term. However, these trial data do habitual consumers and non-consumers.
not indicate whether the effect reaches a threshold for clinical 6. Whether caffeine ingestion alters management decisions in
significance in terms of an improvement of symptoms or quality of asthma (based on lung function measurements).
life. This was not the purpose of trials examined in this review. It
is not known if tolerance to the bronchodilatory effects of caffeine ACKNOWLEDGEMENTS
develops in habitual consumers, which is a concern given that
tolerance has been found in studies of sleep and renal function We would like to thank Steve Milan and Jane Dennis for all their
(Curatolo 1983). The amount of dietary caffeine required and help, Brian Rowe and Paul Jones for their editorial input, and
the true benefit of dietary caffeine intake would be difficult to Sally Spencer and Catherine O'Leary for their assistance with the
calculate due to the varying levels of caffeine within different foods data extraction. We would also like to thank all the authors who
and beverages. It appears that a substantial intake of caffeinated responded to our enquiries: Dr E. Simons, Dr M. Bukowskyj, Dr A.
Colacone, Dr S. Kivity, Dr H. Gong and Dr F. O'Connell.

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REFERENCES
 
References to studies included in this review References to studies awaiting assessment
Bukowskyj 1987 {published data only} Yurach 2011 {published data only}
Bukowskyj M, Nakatsu K. The bronchodilator effect of caffeine Yurach MT, Davis BE, Cockcroft DW. The effect of caffeinated
in adult asthmatics. American Review of Respiratory Disease coffee on airway response to methacholine and exhaled nitric
1987;135(1):173-5. oxide. Respiratory Medicine 2011;105:1606-10.

Colacone 1990 {published data only}  

Colacone A, Bertolo L, Wolkove N, Cohen C, Kreisman H. Effect Additional references
of caffeine on histamine bronchoprovocation in asthma. Thorax Bruce 2002
1990;45(8):630-2.
Bruce C, Yates DH, Thomas PS. Caffeine decreases exhaled nitric
Crivelli 1986 {published data only} oxide. Thorax 2002;57:361-3.
Crivelli M, Wahllander A, Jost G, Preisig R, Bachofen H. Effect Cheney 1935
of dietary caffeine on airway reactivity in asthma. Respiration
Cheney RH. Ventricular response in caffeine-nicotine
1986;50(4):258-64.
antagonism. Journal of Pharmacology and Experimental
Duffy 1991 {published data only} Therapeutics 1935;54(1):42-52.
Duffy P, Phillips YY. Caffeine consumption decreases the Curatolo 1983
response to bronchoprovocation challenge with dry gas
Curatolo PW, Robertson D. The health consequences of caffeine.
hyperventilation. Chest 1991;99(6):1374-7.
Annals of Internal Medicine 1983;98(1):641-53.
Gong 1986 {published data only}
Grollman 1930
Gong H Jr, Simmons MS, Tashkin DP, Hui KK, Lee EY.
Grollman A. The action of alcohol, caffeine, and tobacco,
Bronchodilator effects of caffeine in coffee. A dose-response
on the cardiac output (and its related functions) of normal
study of asthmatic subjects. Chest 1986;89(3):335-42.
man. Journal of Pharmacology and Experimental Therapeutics
Kivity 1990 {published data only} 1930;39(3):313-27.
Kivity S, Aharon YB, Man A, Topilsky M. The effect of caffeine on Higgins 2008
exercise-induced bronchoconstriction. Chest 1990;97(5):1083-5.
Higgins JPT, Green S, editors. Cochrane Handbook for
Taylor 2004 {published data only} Systematic Reviews of Interventions Version 5.0.1 [updated
September 2008]. The Cochrane Collaboration, 2008. Available
Taylor E, Smith AD, Herbison GP, Cowan JO, Taylor DR. Effect
from [Link].
of caffeine on exhaled nitric oxide measurements in asthma
[Abstract]. European Respiratory Journal 2003;22(Suppl Pagano 1988
45):P1165.
Pagano R, Negri E, Decarli A, La Vecchia C. Coffee drinking and
* Taylor ES, Smith AD, Cowan JO, Herbison GP, Taylor DR. Effect prevalence of bronchial asthma. Chest 1988;94(2):386-9.
of caffeine ingestion on exhaled nitric oxide measurements
RevMan 5.1 [Computer program]
in patients with asthma. American Journal of Respiratory and
Critical Care Medicine 2004;169(9):1019-21. Copenhagen, The Nordic Cochrane Centre: The Cochrane
Collaboration. Review Manager (RevMan) Version 5.1.
  Copenhagen, The Nordic Cochrane Centre: The Cochrane
References to studies excluded from this review Collaboration, 2011.
Becker 1984 {published data only} Robertson 1978
Becker AB, Simons KJ, Gillespie CA, Simons FE. The Robertson D, Frolich JC, Carr RK, Watson JT, Hollifield JW,
bronchodilator effects and pharmacokinetics of caffeine in Shand DG, et al. Effects of caffeine on plasma renin activity,
asthma. New England Journal of Medicine 1984;310(12):743-6. catecholamines and blood pressure. New England Journal of
Medicine 1978;298:181-6.
Henderson 1993 {published data only}
Henderson JC, O'Connell F, Fuller RW. Decrease of histamine Stephenson 1977
induced bronchoconstriction by caffeine in mild asthma. Thorax Stephenson PE. Physiologic and psychotropic effects of
1993;48(8):824-6. caffeine on man. Journal of the American Dietetic Association
1977;71:240-7.
Simmons 1983 {published data only}
Simmons M, Gong H, Tashkin DP, Hui K, Lee E. Bronchodilator Woodcock 1981
effects of coffee in asthmatics. Chest 1983;84:332. Woodcock AA, Gross ER, Gellert A, Shah S, Johnson M,
Geddes DM. Effects of dihydrocodeine, alcohol, and caffeine on
 
breathlessness and exercise tolerance in patients with chronic
Caffeine for asthma (Review) 11
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obstructive lung disease and normal blood gases. New England  

Journal of Medicine 1981;305:1611-6. * Indicates the major publication for the study
 
CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

 
Bukowskyj 1987 
Methods Randomised controlled trial

Cross-over design - double-blinded, rule = time (1 week)

Participants Ten patients admitted, 8 (4 male) completed the study

Mean age 64.8 (SD = 8) years

Severity of asthma:

Inclusion criteria: reversible obstructive airway disease, clinically stable, FEV1 < 75% predicted value

Exclusion criteria: congestive heart failure, hepatic disease, ingestion of cimetidine, ingestion of oral
contraceptives

Prescribed medication: 7 patients took oral theophylline and salbutamol; 3 patients took inhaled be-
clomethasone dipropionate; 1 patient took inhaled beclomethasone dipropionate and prednisolone

Control measure: refrained from caffeine, other methylxanthine-containing substances and orally-ad-
ministered beta-agonists for 12 h prior to and throughout 8 h study. Refrained from inhaling beta-ago-
nists for 6 h prior to and throughout the 8 h study period.

Interventions 5 mg/kg caffeine versus placebo as a solution in a juice drink

Outcomes % change FEV1, % change FVC, % change FEF25-75, % change Vmax50, % change Vmax25, FEV1 % pre-
dicted, pulse, blood pressure

Notes Administration of corticosteroids was continued unchanged in those patients receiving long-term ther-
apy with these drugs

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- Unclear risk No details

tion (selection bias)

Allocation concealment Low risk Allocated by pharmacist

(selection bias)

Blinding (performance Low risk Quote: "Double-blinded"

bias and detection bias)
All outcomes Quote: "The medication code was known only to the hospital pharmacists."

Incomplete outcome data Low risk Quote: "The two patients who withdrew did so because they found the repeat-
(attrition bias) ed spirometric tests unacceptably tiring. There was one patient who complet-
All outcomes ed the study except for the last four h of the placebo day when she developed
dyspnoea."

No data used from these patients

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Colacone 1990 
Methods Randomised controlled trial

Cross-over design, rule = time (variable, within 2 weeks)

Participants Ten adults (7 male) completed the study

Mean age 46 (SD = 17) years

Asthma severity: mild. Nine patients had previously documented increased airways reactivity and one
had seasonal asthma Symptom-free

Prescribed medication: 7 patients took inhaled beta-agonist, 5 patients took theophylline, 4 patients
took inhaled corticosteroid and 2 required no medication

Control measures: no caffeine 48 h before study. Fasted for 8 h. Withheld antiasthmatic medications
according to standard guidelines for histamine broncho provocation testing. Beta-agonists and an-
ticholinergic drugs withheld for 8 to 12 h and theophylline for 12 h before testing. Slow-release theo-
phylline and antihistamines withheld 48 h before testing. Steroids continued as normal.

Interventions 5 mg/kg caffeine versus placebo in a juice drink solution indistinguishable in taste and smell
Histamine broncho provocation challenge

Outcomes Change in FEV1, PC20

Notes  

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- Unclear risk No details

tion (selection bias)

Allocation concealment Low risk Allocated by pharmacist

(selection bias)

Blinding (performance Low risk Quote: "Caffeine and corresponding placebo were prepared in solution and
bias and detection bias) coded by the hospital pharmacy."
All outcomes
Quote: "Both solutions were indistinguishable by taste, colour and smell."

Incomplete outcome data Low risk No dropouts

(attrition bias)
All outcomes

 
 
Crivelli 1986 
Methods Randomised controlled trial

Cross-over design rule = time (2 consecutive days)

Participants Seven adults (6 male) completed the study

Age range 27 to 40 years

Asthma severity: asymptomatic

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Crivelli 1986  (Continued)
Included: patients with documented asthmatic airway obstruction

Excluded: pregnant women asthmatic patients with concomitant liver and/or cardiovascular diseases,
and patients treated with drugs affecting the hepatic microsomal enzyme system (barbiturates, pheny-
toin, rifampicin etc.)

Prescribed medication: no bronchodilators, sodium cromoglycate or steroids for at least 2 weeks be-
fore the investigation

Control measures: withheld all caffeine and methyl xanthine-containing foods and beverages at least
12 h prior to the experiment

Interventions 6 mg/kg caffeine versus placebo. Orange juice drink containing caffeine or a placebo drink containing
solvent, i.e. saline.

Carbachol challenge

Outcomes FEV1, SGaw

Notes  

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- Unclear risk No details

tion (selection bias)

Allocation concealment Unclear risk Method of allocation unknown

(selection bias)

Blinding (performance Unclear risk Described as "double-blind" but caffeine or saline given in orange juice so may
bias and detection bias) not have tasted the same
All outcomes

Incomplete outcome data Low risk No dropouts

(attrition bias)
All outcomes

 
 
Duffy 1991 
Methods Randomised controlled trial

Cross-over design - double-blinded, rule = time (not stated)

Participants 12 adults (11 male) admitted, 11 males completed the study

Age range 18 to 42 years

Inclusion criteria: FVC and FEV1 > 80% predicted and at least 10% fall in FEV1 in response to EVH (eu-
capnic voluntary hyperventilation) broncho provocation. Non-smokers.

Exclusion criteria: upper respiratory tract infection or influenza vaccination within 6 weeks before test-
ing, an episode of asthma requiring hospitalisation or steroids within the previous 6 weeks before test-
ing, pregnancy, or other cardiovascular disease apart from asthma

Prescribed medication: no daily asthma medication

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Duffy 1991  (Continued)
Control measures: refrain from caffeine and methylxanthine-containing substances for 12 hours, and
food and cigarettes for 4 hours before testing

Interventions 5 mg/kg, 10 mg/kg, placebo

EVH broncho provocation

Outcomes FEV1, FVC, % dFEV (the percentage fall in FEV1, after EVH)

Notes Quote: 8 of 11 subjects had detectable caffeine levels on the day placebo was given, despite explicit in-
structions for avoidance of xanthine-containing products

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- Unclear risk No details

tion (selection bias)

Allocation concealment Unclear risk Quote: "on three separate test days, each individual received, in random order,
(selection bias) either placebo, 5 mg/kg caffeine or 10 mg/kg caffeine."

Blinding (performance Low risk Quote: "After baseline pulmonary function tests, caffeine was given in a ran-
bias and detection bias) domised, crossover, double blind fashion. Gelatin capsules were administered
All outcomes which contained either 0 mg, 5 mg/kg or 10 mg/kg caffeine."

Incomplete outcome data Low risk Dropout = 1 (female), due to side effects of nervousness and agitation presum-
(attrition bias) ably from the caffeine
All outcomes

 
 
Gong 1986 
Methods Randomised controlled trial. Method of allocation computer program

Cross-over design - double-blinded, rule = time (at least 3 days)

Participants Nine (4 male)

Mean age = 35 (SD = 17) years

Inclusion criteria: stable asthma (ATS criteria), 12 years of mild to moderately severe asthma, allergic in
nature for 7 subjects, no other clinically evident disorders including hepatic disease or hypertension

Exclusion criteria: no subject was receiving immunotherapy

Prescribed medication: 7 = theophylline, 8 = sympathomimetic agents, 3 = inhaled corticosteroids, 1 =

oral corticosteroids, 1 = cromolyn sodium

Control measures: fasted for 4 hours prior to study and withheld the following prior to each day of
study: theophylline compounds (48 h); adrenergic agents, oral (12 h) and inhaled (8 h); corticosteroids,
oral (24 h) and inhaled (12 h); cromolyn sodium (24 h); antihistamines (48 h); caffeine-containing bever-
ages and medications (12 h)

Interventions Decaffeinated coffee (containing ˜13 mg caffeine) plus a capsule containing aminophylline (200 mg)
Decaffeinated coffee (containing ˜13 mg caffeine) plus a placebo (lactose) capsule

Decaffeinated coffee with additional 150 mg caffeine plus a placebo (lactose) capsule
Decaffeinated coffee with additional 300 mg caffeine plus a placebo (lactose) capsule
Decaffeinated coffee with additional 450 mg caffeine plus a placebo (lactose) capsule

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Gong 1986  (Continued)
Outcomes % change FEV1, FVC, FEF25-75, Gaw/VL (results given only for 7.2 mg/kg caffeine versus placebo + 200
mg aminophylline). Sampling of venous blood, whole body plethysmography, spirometry, respiratory
rate, heart rate, sitting blood pressure, and symptoms

Notes  

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- Low risk Randomised by computer program

tion (selection bias)

Allocation concealment Unclear risk No details

(selection bias)

Blinding (performance Low risk Although they went to lengths to blind the patients, there was no indication of
bias and detection bias) method for blinding investigators
All outcomes

Incomplete outcome data Low risk No dropouts

(attrition bias)
All outcomes

 
 
Kivity 1990 
Methods Randomised controlled trial

Cross-over design - double-blinded, rule = time (within 2 weeks)

Participants 13 admitted, 10 adults (7 male) completed the study

Mean age = 19.5 (SD = 1.1) years

Inclusion criteria: documented reversible obstructive airway disease with a 20% improvement in either
FVC or FEV1 after bronchodilator therapy, exercise-induced drop in FEV1 of ≥ 15% from baseline, all pa-
tients clinically stable

Exclusion criteria: any other chronic illness or receiving medication other than for bronchial asthma

Prescribed medication: 2 = slow release theophylline, 10 = inhaled salbutamol. None of the patients
were receiving corticosteroids, cromolyn sodium or ketotifen.

Interventions Opaque placebo capsule or opaque 3.5 mg/kg caffeine capsule or opaque 7 mg/kg caffeine capsule
taken with 100 mL water.
Exercise-induced bronchoconstriction

Outcomes FEV1, pulse, blood pressure

Notes Patients refrained from caffeine for 12 h, from theophylline containing drugs for 48 h, and from inhaled
beta-agonists 8 h prior to the study. The patient did not have caffeinated drinks 24 h prior to the study
day (conflicting information in paper). The patients did not eat during the study.

Risk of bias

Bias Authors' judgement Support for judgement

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Kivity 1990  (Continued)
Random sequence genera- Unclear risk No details
tion (selection bias)

Allocation concealment Unclear risk No details

(selection bias)

Blinding (performance Low risk Quote: "Caffeine and placebo were given through an opaque capsule together
bias and detection bias) with 100 mL of water." Stated double-blind
All outcomes

Incomplete outcome data Low risk Quote: "three patients who withdrew from the study could not comply with
(attrition bias) multiple visits to the clinic". No data used from these patients.
All outcomes

 
 
Taylor 2004 
Methods Randomised, double-blind, cross-over trial

Participants 20 adults (gender not specified) completed the study

Mean age: 37 (range 16 to 73) years

Inclusion criteria: regular coffee drinkers; FeNO > 10 PPB. 10 steroid-naive and 10 treated with ICS
(mean dose 980 μg/d)

Exclusion criteria: oral prednisone, oral theophylline or inhaled long-acting beta-agonist for 1 month
prior to study

Control measures: caffeine withheld for 24 h. Inhaled bronchodilators withheld 6 h.

Interventions Intervention: 15 g caffeine-containing coffee (Illy Espresso Caffe Macinato) prepared in an espresso cof-
fee maker as a 200 mL cup of coffee

Placebo: 15 g decaffeinated coffee (Illy Espresso Decaffeinated Macinato) prepared in an espresso cof-
fee maker as a 200 mL cup of coffee

Outcomes FeNO

Notes  

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- Unclear risk No details

tion (selection bias)

Allocation concealment Unclear risk Stated randomised, no information given on method used
(selection bias)

Blinding (performance Unclear risk Stated double-blind, but patient blinding depends on regular and decaffeinat-
bias and detection bias) ed coffee being indistinguishable by taste. No mention of researcher blinding.
All outcomes

Incomplete outcome data Low risk No dropouts

(attrition bias)

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Taylor 2004  (Continued)
All outcomes

ATS: American Thoracic Society

EVH: eucapnic voluntary hyperventilation
FEF25-75: maximum mid-expiratory flow
FEV1: forced expiratory volume in one second
FVC: forced vital capacity
h: hour
ICS: inhaled corticosteroids
PPB: parts per billion
SD: standard deviationVmax25/Vmax50: maximal expiratory flow rates at 25% and 50% of vital capacity
 
Characteristics of excluded studies [ordered by study ID]
 
Study Reason for exclusion

Becker 1984 Participants are children

Interventions are caffeine versus theophylline

Henderson 1993 Histamine broncho provocation challenge (FEV1 measured after challenge)

Simmons 1983 Not a randomised controlled trial

 
DATA AND ANALYSES
 
Comparison 1.   All caffeine doses versus placebo

Outcome or subgroup title No. of No. of Statistical method Effect size

studies partici-
pants

1 FEV1 outcomes at 'short' time 6 78 Std. Mean Difference (IV, Fixed, 95% 0.72 [0.25, 1.20]
frame CI)

1.1 Low dose 2 36 Std. Mean Difference (IV, Fixed, 95% 0.70 [0.02, 1.38]
CI)

1.2 High dose 4 42 Std. Mean Difference (IV, Fixed, 95% 0.75 [0.08, 1.41]
CI)

2 FEV1 outcomes at 'medium' time 2 34 Mean Difference (IV, Fixed, 95% CI) 12.66 [-0.34, 25.67]
frame

2.1 Low dose 1 16 Mean Difference (IV, Fixed, 95% CI) 11.5 [-7.44, 30.44]

2.2 High dose 1 18 Mean Difference (IV, Fixed, 95% CI) 13.7 [-4.18, 31.58]

3 FEV1 outcomes at 'long' time 1 16 Mean Difference (IV, Fixed, 95% CI) 11.0 [-6.49, 28.49]
frame

3.1 Low dose 1 16 Mean Difference (IV, Fixed, 95% CI) 11.0 [-6.49, 28.49]

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Outcome or subgroup title No. of No. of Statistical method Effect size

studies partici-
pants

3.2 High dose 0 0 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]

4 FEF 25-75 outcomes at 'short' 2 34 Mean Difference (IV, Fixed, 95% CI) 25.14 [11.92, 38.37]
time frame

4.1 Low dose 1 16 Mean Difference (IV, Fixed, 95% CI) 23.33 [6.18, 40.48]

4.2 High dose 1 18 Mean Difference (IV, Fixed, 95% CI) 27.8 [7.03, 48.57]

5 FEF 25-75 outcomes at 'medium' 2 34 Mean Difference (IV, Fixed, 95% CI) 32.72 [16.26, 49.17]
time frame

5.1 Low dose 1 16 Mean Difference (IV, Fixed, 95% CI) 35.5 [15.85, 55.15]

5.2 High dose 1 18 Mean Difference (IV, Fixed, 95% CI) 26.20 [-3.89, 56.29]

6 FEF 25-75 outcomes at 'long' 1 16 Mean Difference (IV, Fixed, 95% CI) 26.0 [5.02, 46.98]
time frame

6.1 Low dose 1 16 Mean Difference (IV, Fixed, 95% CI) 26.0 [5.02, 46.98]

6.2 High dose 0 0 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]

7 Gaw/VL outcomes at 'short' time 1 18 Mean Difference (IV, Fixed, 95% CI) 30.30 [1.08, 59.52]
frame

7.1 Low dose 0 0 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]

7.2 High dose 1 18 Mean Difference (IV, Fixed, 95% CI) 30.30 [1.08, 59.52]

8 FEV1 outcomes at 2 hours 5   Std. Mean Difference (IV, Fixed, 95% Subtotals only
CI)

8.1 Low dose 1 20 Std. Mean Difference (IV, Fixed, 95% 0.40 [-0.49, 1.29]
CI)

8.2 High dose 5 88 Std. Mean Difference (IV, Fixed, 95% 0.76 [0.32, 1.20]
CI)

9 FEV1 outcomes at 2 hours (High 5   Mean Difference (Fixed, 95% CI) Subtotals only
dose)

9.1 % Change in FEV1 3   Mean Difference (Fixed, 95% CI) 5.47 [1.43, 9.52]

9.2 Post-treatment FEV1 litres 1   Mean Difference (Fixed, 95% CI) 0.38 [0.01, 0.75]

9.3 Change in FEV1 litres 1   Mean Difference (Fixed, 95% CI) 0.05 [-0.06, 0.16]

 
 

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Analysis 1.1.   Comparison 1 All caffeine doses versus placebo, Outcome 1 FEV1 outcomes at 'short' time frame.
Study or subgroup Caffeine Control Std. Mean Difference Weight Std. Mean Difference
  N Mean(SD) N Mean(SD) Fixed, 95% CI   Fixed, 95% CI
1.1.1 Low dose  
Bukowskyj 1987 8 14 (16.3) 8 2.3 (11) 21.26% 0.8[-0.23,1.83]
Colacone 1990 10 0.1 (0.1) 10 0.1 (0.1) 27.71% 0.63[-0.28,1.53]
Subtotal *** 18   18   48.98% 0.7[0.02,1.38]
Heterogeneity: Tau2=0; Chi2=0.06, df=1(P=0.8); I2=0%  
Test for overall effect: Z=2.03(P=0.04)  
   
1.1.2 High dose  
Crivelli 1986 1 0 (0) 1 0 (0)   Not estimable
Duffy 1991 1 0 (0) 1 0 (0)   Not estimable
Gong 1986 9 15.5 (10.9) 9 2.4 (14.6) 23.01% 0.97[-0.02,1.96]
Kivity 1990 10 3.6 (0.6) 10 3.2 (0.6) 28.01% 0.56[-0.33,1.46]
Subtotal *** 21   21   51.02% 0.75[0.08,1.41]
Heterogeneity: Tau2=0; Chi2=0.35, df=1(P=0.55); I2=0%  
Test for overall effect: Z=2.2(P=0.03)  
   
Total *** 39   39   100% 0.72[0.25,1.2]
Heterogeneity: Tau2=0; Chi2=0.42, df=3(P=0.94); I2=0%  
Test for overall effect: Z=2.99(P=0)  
Test for subgroup differences: Chi2=0.01, df=1 (P=0.93), I2=0%  

Control better -2 -1 0 1 2 Caffeine better

 
 
Analysis 1.2.   Comparison 1 All caffeine doses versus placebo, Outcome 2 FEV1 outcomes at 'medium' time frame.
Study or subgroup Caffeine Control Mean Difference Weight Mean Difference
  N Mean(SD) N Mean(SD) Fixed, 95% CI   Fixed, 95% CI
1.2.1 Low dose  
Bukowskyj 1987 8 14.5 (21) 8 3 (17.5) 47.13% 11.5[-7.44,30.44]
Subtotal *** 8   8   47.13% 11.5[-7.44,30.44]
Heterogeneity: Not applicable  
Test for overall effect: Z=1.19(P=0.23)  
   
1.2.2 High dose  
Gong 1986 9 15.5 (12.6) 9 1.8 (24.3) 52.87% 13.7[-4.18,31.58]
Subtotal *** 9   9   52.87% 13.7[-4.18,31.58]
Heterogeneity: Not applicable  
Test for overall effect: Z=1.5(P=0.13)  
   
Total *** 17   17   100% 12.66[-0.34,25.67]
Heterogeneity: Tau2=0; Chi2=0.03, df=1(P=0.87); I2=0%  
Test for overall effect: Z=1.91(P=0.06)  
Test for subgroup differences: Chi2=0.03, df=1 (P=0.87), I2=0%  

Control better -20 -10 0 10 20 Caffeine better

 
 

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Analysis 1.3.   Comparison 1 All caffeine doses versus placebo, Outcome 3 FEV1 outcomes at 'long' time frame.
Study or subgroup Caffeine Control Mean Difference Weight Mean Difference
  N Mean(SD) N Mean(SD) Fixed, 95% CI   Fixed, 95% CI
1.3.1 Low dose  
Bukowskyj 1987 8 5.5 (21) 8 -5.5 (14) 100% 11[-6.49,28.49]
Subtotal *** 8   8   100% 11[-6.49,28.49]
Heterogeneity: Not applicable  
Test for overall effect: Z=1.23(P=0.22)  
   
1.3.2 High dose  
Subtotal *** 0   0   Not estimable
Heterogeneity: Not applicable  
Test for overall effect: Not applicable  
   
Total *** 8   8   100% 11[-6.49,28.49]
Heterogeneity: Not applicable  
Test for overall effect: Z=1.23(P=0.22)  
Test for subgroup differences: Not applicable  

Control better -40 -20 0 20 40 Caffeine better

 
 
Analysis 1.4.   Comparison 1 All caffeine doses versus placebo, Outcome 4 FEF 25-75 outcomes at 'short' time frame.
Study or subgroup caffeine Control Mean Difference Weight Mean Difference
  N Mean(SD) N Mean(SD) Fixed, 95% CI   Fixed, 95% CI
1.4.1 Low dose  
Bukowskyj 1987 8 17 (11.3) 8 -6.3 (22) 59.47% 23.33[6.18,40.48]
Subtotal *** 8   8   59.47% 23.33[6.18,40.48]
Heterogeneity: Tau2=0; Chi2=0, df=0(P<0.0001); I2=100%  
Test for overall effect: Z=2.67(P=0.01)  
   
1.4.2 High dose  
Gong 1986 9 31.8 (23.6) 9 4 (21.3) 40.53% 27.8[7.03,48.57]
Subtotal *** 9   9   40.53% 27.8[7.03,48.57]
Heterogeneity: Not applicable  
Test for overall effect: Z=2.62(P=0.01)  
   
Total *** 17   17   100% 25.14[11.92,38.37]
Heterogeneity: Tau2=0; Chi2=0.11, df=1(P=0.74); I2=0%  
Test for overall effect: Z=3.73(P=0)  
Test for subgroup differences: Chi2=0.11, df=1 (P=0.74), I2=0%  

Control better -50 -25 0 25 50 Caffeine better

 
 
Analysis 1.5.   Comparison 1 All caffeine doses versus placebo,
Outcome 5 FEF 25-75 outcomes at 'medium' time frame.
Study or subgroup caffeine Control Mean Difference Weight Mean Difference
  N Mean(SD) N Mean(SD) Fixed, 95% CI   Fixed, 95% CI
1.5.1 Low dose  

Control better -50 -25 0 25 50 Caffeine better

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Study or subgroup caffeine Control Mean Difference Weight Mean Difference

  N Mean(SD) N Mean(SD) Fixed, 95% CI   Fixed, 95% CI
Bukowskyj 1987 8 25 (21.5) 8 -10.5 (18.5) 70.09% 35.5[15.85,55.15]
Subtotal *** 8   8   70.09% 35.5[15.85,55.15]
Heterogeneity: Not applicable  
Test for overall effect: Z=3.54(P=0)  
   
1.5.2 High dose  
Gong 1986 9 33.1 (29.1) 9 6.9 (35.7) 29.91% 26.2[-3.89,56.29]
Subtotal *** 9   9   29.91% 26.2[-3.89,56.29]
Heterogeneity: Not applicable  
Test for overall effect: Z=1.71(P=0.09)  
   
Total *** 17   17   100% 32.72[16.26,49.17]
Heterogeneity: Tau2=0; Chi2=0.26, df=1(P=0.61); I2=0%  
Test for overall effect: Z=3.9(P<0.0001)  
Test for subgroup differences: Chi2=0.26, df=1 (P=0.61), I2=0%  

Control better -50 -25 0 25 50 Caffeine better

 
 
Analysis 1.6.   Comparison 1 All caffeine doses versus placebo, Outcome 6 FEF 25-75 outcomes at 'long' time frame.
Study or subgroup Caffeine Control Mean Difference Weight Mean Difference
  N Mean(SD) N Mean(SD) Fixed, 95% CI   Fixed, 95% CI
1.6.1 Low dose  
Bukowskyj 1987 8 9.5 (15.5) 8 -16.5 (26) 100% 26[5.02,46.98]
Subtotal *** 8   8   100% 26[5.02,46.98]
Heterogeneity: Not applicable  
Test for overall effect: Z=2.43(P=0.02)  
   
1.6.2 High dose  
Subtotal *** 0   0   Not estimable
Heterogeneity: Not applicable  
Test for overall effect: Not applicable  
   
Total *** 8   8   100% 26[5.02,46.98]
Heterogeneity: Not applicable  
Test for overall effect: Z=2.43(P=0.02)  
Test for subgroup differences: Not applicable  

Control better -50 -25 0 25 50 Caffeine better

 
 
Analysis 1.7.   Comparison 1 All caffeine doses versus placebo, Outcome 7 Gaw/VL outcomes at 'short' time frame.
Study or subgroup Caffeine Control Mean Difference Weight Mean Difference
  N Mean(SD) N Mean(SD) Fixed, 95% CI   Fixed, 95% CI
1.7.1 Low dose  
Subtotal *** 0   0   Not estimable
Heterogeneity: Not applicable  
Test for overall effect: Not applicable  
   

Control better -50 -25 0 25 50 Caffeine better

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Study or subgroup Caffeine Control Mean Difference Weight Mean Difference

  N Mean(SD) N Mean(SD) Fixed, 95% CI   Fixed, 95% CI
1.7.2 High dose  
Gong 1986 9 37.8 (33.8) 9 7.5 (29.3) 100% 30.3[1.08,59.52]
Subtotal *** 9   9   100% 30.3[1.08,59.52]
Heterogeneity: Tau2=0; Chi2=0, df=0(P<0.0001); I2=100%  
Test for overall effect: Z=2.03(P=0.04)  
   
Total *** 9   9   100% 30.3[1.08,59.52]
Heterogeneity: Tau2=0; Chi2=0, df=0(P<0.0001); I2=100%  
Test for overall effect: Z=2.03(P=0.04)  
Test for subgroup differences: Not applicable  

Control better -50 -25 0 25 50 Caffeine better

 
 
Analysis 1.8.   Comparison 1 All caffeine doses versus placebo, Outcome 8 FEV1 outcomes at 2 hours.
Study or subgroup Caffeine Control Std. Mean Difference Weight Std. Mean Difference
  N Mean(SD) N Mean(SD) Fixed, 95% CI   Fixed, 95% CI
1.8.1 Low dose  
Kivity 1990 10 3.5 (0.6) 10 3.2 (0.6) 100% 0.4[-0.49,1.29]
Subtotal *** 10   10   100% 0.4[-0.49,1.29]
Heterogeneity: Not applicable  
Test for overall effect: Z=0.88(P=0.38)  
   
1.8.2 High dose  
Bukowskyj 1987 8 14 (19) 8 2 (14) 18.54% 0.68[-0.34,1.7]
Colacone 1990 10 0.1 (0.1) 10 0.1 (0.1) 23.52% 0.63[-0.28,1.53]
Crivelli 1986 7 1.7 (4.5) 7 -1.6 (3.2) 15.77% 0.79[-0.32,1.89]
Gong 1986 9 22.5 (13.5) 9 4 (18) 18.77% 1.11[0.1,2.12]
Kivity 1990 10 3.6 (0.5) 10 3.2 (0.6) 23.39% 0.66[-0.25,1.56]
Subtotal *** 44   44   100% 0.76[0.32,1.2]
Heterogeneity: Tau2=0; Chi2=0.62, df=4(P=0.96); I2=0%  
Test for overall effect: Z=3.4(P=0)  
Test for subgroup differences: Chi2=0.51, df=1 (P=0.48), I2=0%  

Caffeine worse -2 -1 0 1 2 Caffeine better

 
 
Analysis 1.9.   Comparison 1 All caffeine doses versus placebo, Outcome 9 FEV1 outcomes at 2 hours (High dose).
Study or subgroup Experi- Control Mean Dif- Mean Difference Weight Mean Difference
mental ference
  N N (SE) IV, Fixed, 95% CI   IV, Fixed, 95% CI
1.9.1 % Change in FEV1  
Bukowskyj 1987 0 0 12 (6) 11.84% 12[0.24,23.76]
Crivelli 1986 0 0 3.3 (2.3) 80.58% 3.29[-1.22,7.8]
Gong 1986 0 0 18.5 (7.5) 7.58% 18.5[3.8,33.2]
Subtotal (95% CI)       100% 5.47[1.43,9.52]
Heterogeneity: Tau2=0; Chi2=5.1, df=2(P=0.08); I2=60.79%  
Test for overall effect: Z=2.65(P=0.01)  
   

Caffeine worse -20 -10 0 10 20 Caffeine better

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Study or subgroup Experi- Control Mean Dif- Mean Difference Weight Mean Difference
mental ference
  N N (SE) IV, Fixed, 95% CI   IV, Fixed, 95% CI
1.9.2 Post-treatment FEV1 litres  
Kivity 1990 0 0 0.4 (0.19) 100% 0.38[0.01,0.75]
Subtotal (95% CI)       100% 0.38[0.01,0.75]
Heterogeneity: Not applicable  
Test for overall effect: Z=2(P=0.05)  
   
1.9.3 Change in FEV1 litres  
Colacone 1990 0 0 0.1 (0.057) 100% 0.05[-0.06,0.16]
Subtotal (95% CI)       100% 0.05[-0.06,0.16]
Heterogeneity: Not applicable  
Test for overall effect: Z=0.88(P=0.38)  

Caffeine worse -20 -10 0 10 20 Caffeine better

 
ADDITIONAL TABLES
 
Table 1.   Characteristics of studies used in meta-analysis 
Study Dose of caffeine Formulation of dose Mean Time of read-
baseline ing

% pre- used in meta-

dicted analysis
FEV1

Bukowskyj 1987 5 mg/kg Aqueous solution 48 2h

Colacone 1990 5 mg/kg Aqueous solution 84 2h

Crivelli 1986 6 mg/kg Aqueous solution -- 45 min

Duffy 1991 5 mg/kg ('low') Capsules 92.9 90 min

10 mg/kg ('high')

Gong 1986 7.2 mg/kg Decaffeinated coffee 56 2h

plus caffeine

Kivity 1990 3.5 mg/kg ('low') Capsules 78.8 2h

7 mg/kg ('high')

Taylor 2004 15 g coffee Coffee of decaffeinated 94 --

coffee

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APPENDICES

Appendix 1. Sources and search methods for the Cochrane Airways Group Specialised Register (CAGR)
Electronic searches: core databases
 
 
Database Frequency of search

MEDLINE (Ovid) Weekly

EMBASE (Ovid) Weekly

CENTRAL (The Cochrane Library) Quarterly

PSYCINFO (Ovid) Monthly

CINAHL (EBSCO) Monthly

AMED (EBSCO) Monthly

Handsearches: core respiratory conference abstracts

 
 
Conference Years searched

American Academy of Allergy, Asthma and Immunology (AAAAI) 2001 onwards

American Thoracic Society (ATS) 2001 onwards

Asia Pacific Society of Respirology (APSR) 2004 onwards

British Thoracic Society Winter Meeting (BTS) 2000 onwards

Chest Meeting 2003 onwards

European Respiratory Society (ERS) 1992, 1994, 2000 onwards

International Primary Care Respiratory Group Congress (IPCRG) 2002 onwards

Thoracic Society of Australia and New Zealand (TSANZ) 1999 onwards

MEDLINE search strategy used to identify trials for the CAGR

Asthma search
1. exp Asthma/

2. asthma$.mp.

3. (antiasthma$ or anti-asthma$).mp.

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4. Respiratory Sounds/

5. wheez$.mp.

6. Bronchial Spasm/

7. bronchospas$.mp.

8. (bronch$ adj3 spasm$).mp.

9. bronchoconstrict$.mp.

10. exp Bronchoconstriction/

11. (bronch$ adj3 constrict$).mp.

12. Bronchial Hyperreactivity/

13. Respiratory Hypersensitivity/

14. ((bronchial$ or respiratory or airway$ or lung$) adj3 (hypersensitiv$ or hyperreactiv$ or allerg$ or insufficiency)).mp.

15. ((dust or mite$) adj3 (allerg$ or hypersensitiv$)).mp.

16. or/1-15

Filter to identify RCTs

1. exp "clinical trial [publication type]"/

2. (randomised or randomised).ab,ti.

3. [Link],ti.

4. [Link].

5. [Link],ti.

6. [Link],ti.

7. [Link],ti.

8. or/1-7

9. Animals/

10. Humans/

11. 9 not (9 and 10)

12. 8 not 11

The MEDLINE strategy and RCT filter are adapted to identify trials in other electronic databases

FEEDBACK

Historical use of caffeine

Summary
Reading the "Background" in the Abstract, it seems that the interest by caffeine as a bronchodilator is new. As a matter of fact, caffeine is
used for asthma since, at least, the last decades of 1800. We can find reference to this drug in Marcel Proust's "A l'Ombre de Jeunes Filles
en Fleur". This author, an asthmatic, refers that when he was very young (he was born in 1871) he used caffeine "that was prescribed for
help me breathing".

Reply
Thank you for this comment.

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Contributors
Roni Marques, chest physician.

WHAT'S NEW
 
Date Event Description

15 June 2012 Review declared as stable This review is no longer being updated. The review remains of
historic interest. Because caffeine has a similar structure to oth-
er bronchodilators, trials have been conducted to examine the
effects on asthma monitoring. However, caffeine is not a recog-
nised treatment for asthma.

15 June 2012 New search has been performed A literature search was conducted and one potentially eligible
study was added to 'studies awaiting classification' but has not
been fully incorporated in to the review.

 
HISTORY
Protocol first published: Issue 3, 1996
Review first published: Issue 2, 1998

 
Date Event Description

11 August 2011 New search has been performed New literature search run. No new eligible studies identified. Mi-
nor copy edits made.

29 September 2009 New citation required but conclusions New authorship of the review.
have not changed

27 August 2009 New search has been performed New search conducted, added new included study (Taylor 2004),
amendments made to Plain Language Summary, reformatted
Results and Discussion and added 'Risk of bias' and 'Summary of
findings' table. Conclusions unchanged.

21 July 2008 Amended Converted to new review format.

7 January 2005 New search has been performed New studies found and included or excluded: 8 January 2005

8 January 2003 New search has been performed New studies sought but none found: 8 January 2003

18 June 2001 New citation required and conclusions Substantive amendment

have changed

 
CONTRIBUTIONS OF AUTHORS
Anna Bara and Elizabeth Barley extracted the data, did the meta-analyses and drafted the original review.

Emma Welsh updated the review, reformatted and redrafted it, added a new included study (Taylor 2004) and added 'Risk of bias' tables.
Chris Cates extracted data for the 'Risk of bias' table, carried out the Generic Inverse Variance analyses and edited the review update.

DECLARATIONS OF INTEREST
None known.

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SOURCES OF SUPPORT

Internal sources
• NHS Research and Development, UK.

External sources
• No sources of support supplied

DIFFERENCES BETWEEN PROTOCOL AND REVIEW
The 2009 update included regular caffeine-containing coffee versus decaffeinated coffee as a comparison type. The 2009 review also
compared lung function at all doses at two hours.

Serum caffeine levels was included as an outcome.

INDEX TERMS

Medical Subject Headings (MeSH)

*Respiratory Function Tests;  Asthma  [diagnosis]  [*drug therapy];  Bronchi  [drug effects];  Bronchodilator Agents  [*pharmacology]; 
Caffeine  [*pharmacology];  Randomized Controlled Trials as Topic

MeSH check words

Adult; Humans

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