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In summary, contrary to conventional wisdom, caffeine use at high altitude seems to be not only safe but likely beneficial. Fears of dehydration from caffeine are exaggerated. Its effect on ventilation and cerebral circulation and its action as a psychostimulant are likely to be helpful at altitude. Whether caffeine may prevent or ameliorateAMS deserves study. Caffeine may also help exercise performance at high altitude. Importantly, habitual caffeine users should not discontinue caffeine because of travel to altitude; the symptoms of withdrawal are very similar to acute mountain sickness and can be misdiagnosed as AMS. The issue of altitude, coronary artery disease, and caffeine in exercising patients deserves further study.
Caffeine at High Altitude: Java at Base Camp
Peter H. Hackett
Asurvey of high altitude destination resort web sites
finds that most recommend avoiding caffeine at high
altitude. Reducing or avoiding caffeine at high altitude is also
a common admonition in visitors’ guides in Colorado and
other places. Why does caffeine use at high altitude have a bad
reputation? Is it a carry-over from a minority opinion on its
use in general (Lovett, 2005)? Does scientific evidence support
this? Does caffeine affect acclimatization, the development of
high altitude headache and acute mountain sickness, or ex-
ercise performance at altitude? A review of the scant literature
suggests that, if anything, caffeine is likely to be helpful at
altitude, rather than detrimental.
Caffeine is a xanthine alkaloid, an adenosine receptor
blocker and psychoactive stimulant. The German Friedrich
Runge discovered caffeine in 1819. He coined the term kaffein,
a chemical compound in coffee, which in English became
caffeine. Caffeine is found in varying quantities in some
plants, where it acts as a natural pesticide. Humans ingest
extracts from the cherries of the coffee plant and the leaves of
the tea bush, as well as from various foods and drinks con-
taining products derived from the kola nut and cacao plant.
Humans have apparently ingested caffeine since the Stone
Age. Beverages containing caffeine, such as coffee, tea, soft
drinks, and energy drinks, are popular today, making caffeine
the world’s most widely consumed psychoactive substance; it
is legal and unregulated in nearly all jurisdictions. Through-
out the world, it is estimated that 80% of adults consume
caffeine daily, and 90% in North America.
Pharmacodynamics and Metabolism of Caffeine
at High Altitude
Is the biology of caffeine the same at low and high altitude?
A change in the pharmacodynamics of caffeine could alter its
effects. In healthy adults at sea level, caffeine’s half-life is
approximately 4.9 h. (In women taking oral contraceptives,
this increases to 5 to 10 h, and in pregnant women the half-life
is roughly 9 to 11 h.) Caffeine is metabolized in the liver by the
cytochrome P450 oxidase enzyme system, specifically
CYP1A2. Ju
¨rgens and colleagues bAU6
(2002) studied CYP enzyme
activity at baseline and 24 and 96 h after a stay at 4559m in 12
subjects. They found no significant change in the metabolic
ratio of caffeine and only minor changes in other substance
metabolic ratios; they concluded that altitude hypoxia had
no clinically significant effects on CYP enzymes in humans.
Kamimori and colleagues bAU7
(1995a) studied micro swine after
21-day exposure to 4600 m. Caffeine clearance nearly doubled
and, consistent with Ju
¨rgens and colleagues, there was no
change in the ratio of primary metabolites. They concluded
that the increase in caffeine clearance was owing to increased
hepatic blood flow. These same investigators (Kamimori et al.,
1995b) then studied the issue in eight males after 16 days at
4300 m. Compared to sea level, the half-life of caffeine de-
creased from 6.7 to 4.7 h, the area under the curve (AUC)
decreased by 32%, and clearance increased 36%. They also
reported an increase in the AUC ratio of metabolites to caf-
feine, suggesting that either metabolite formation or elimi-
nation was increased at high altitude. These studies taken
together indicate that high altitude hypoxia appears to hasten
the clearance of caffeine and decrease the area under the
curve, in part because of increased hepatic blood flow and,
perhaps, a change in metabolism. Caffeine may thus be ex-
pected to have a shorter duration of action at high altitude
compared to low altitude.
The metabolites of caffeine contribute to caffeine’s effects.
Paraxanthine is responsible for an increase in the lipolysis
process, which releases glycerol and fatty acids into the blood
to be used as fuel by the muscles. Theobromine is a vasodi-
lator that increases the amount of oxygen and nutrient flow to
Institute for Altitude Medicine, Telluride, CO.
Volume 11, Number 1, 2010
ªMary Ann Liebert, Inc.
DOI: 10.1089=ham.2009.1077
HAM-2009-1077-Hackett_1P.3D 02/08/10 2:35pm Page 1
Type: review-article
the brain and muscles. Theophylline is a smooth-muscle rela-
xant that chiefly affects bronchioles and acts as a chronotrope
and inotrope to increase heart rate and efficiency. All three of
these compounds are much weaker than caffeine. In addition,
infusions from coffee and tea plants contain other substances
with biological actions, such as theobromine in chocolate and
polyphenols in tea and coffee. Infact, research suggests that the
polyphenols in coffee can counteract some of the effects of
caffeine, making caffeinetablets, for example, a superior choice
to coffee for exercise improvement.
Clinical Effects
Does caffeine lead to dehydration?
One reason tourist literature recommends avoidance of
caffeine is because of its feared diuretic effect. The layperson
seems to exaggerate the importance of dehydration at high
altitude, and there is a mistaken belief that dehydration can
lead to AMS. While symptoms of dehydration are similar to
AMS, no compelling evidence suggests that dehydration
contributes to AMS. Nonetheless, conventional wisdom is
what it is, and many apparently think that caffeine should be
avoided for fear of dehydration leading to AMS. Caffeine, in
fact, does have diuretic properties, but only in sufficient doses
in subjects without tolerance for it. Regular users develop a
strong tolerance to this effect, and studies in athletes and
nonathletes at low altitude have generally failed to support
the common notion that ordinary consumption of caffeinated
beverages contributes significantly to dehydration (Arm-
strong et al., 2005; Millard-Stafford et al., 2007). Supporting
this, a clinical study conducted at Everest base camp (5345 m)
in 13 subjects used a crossover experimental design with two
24-h dietary interventions (Scott et al., 2004). Ingested fluid
volume was the same, but for one intervention the fluid was
mostly black tea. No other source of caffeine was allowed.
Urine volume was identical in the tea and no-tea groups, as
were other markers of hydration status. However, the tea
drinkers reported less fatigue. Unfortunately, neither ingested
dose nor blood levels of caffeine were measured. The authors
emphasized that even in an environment of cold and altitude,
where diuresis is stimulated, caffeinated tea did not increase
diuresis, while it did improve mood. (Scott et al., 2004).
Does caffeine depress ventilation?
One measure of a drug’s safety at altitude is its effect on
ventilation. Clearly, caffeine stimulates ventilation rather than
depresses it, and therefore caffeine might actually be helpful.
Although no studies have addressed whether caffeine facili-
tates acclimatization to altitude, there are good physiologic
studies suggesting that it might. Caffeine has long been docu-
mented as a respiratory stimulant. D’Urzo and colleagues
(1990) found that caffeine increased hypoxic ventilatory re-
sponse (HVR, þ135%), hypercapnic ventilatory response
(HCVR, þ28%), and the ventilatory response to exercise
(þ14%). In addition, caffeine increased both resting ventila-
tion (41%) and metabolic rate. However, they administered a
large dose of 650 mg and to only 7 subjects. It is likely that
smaller doses would have similar but less robust effects on
ventilation. Although caffeine had only a small effect on re-
spiratory muscle fatigue at sea level (Lanigan et al., 1993), its
effect could be more pronounced at altitude, where ventila-
tion is markedly increased from sea level and muscle fatigue is
relatively more important. Caffeine has been used for decades
in neonates for treatment of apnea (Comer et al., 2001; Char-
don et al., 2004). At 4 mg=kg=day, it apparently works by in-
creasing the effectiveness of chemoreceptor activity. Caffeine
also stimulates ventilation in athletes with exercise-induced
hypoxemia. Chapman and Stager (2008) administered 7 mg=
kg to 7 adults and, although ventilation increased at all levels
of exercise, there was no change in desaturation or in HVR
and HCVR with caffeine, in contrast to the work of D’Urzo.
Whether caffeine might increase ventilation sufficiently to
speed acclimatization to altitude and thus prevent or ame-
liorate AMS is untested, but deserves investigation.
What effect might caffeine have on the cerebral cir-
culation at high altitude?
Hypoxia increases brain adenosine, which increases cere-
bral blood flow through A2A and A2B receptors located on
vascular smooth muscle. By counteracting adenosine, caffeine
reduces resting cerebral blood flow between 22% and 30%
at sea level acutely, and less so in those with chronic use
(Addicott et al., 2009). Caffeine also decreases the ratio of
(cerebral blood flow to cerebral metabolic rate
for oxygen) (Chen and Parrish, 2009). Many recent studies
have investigated the effect of caffeine on BOLD responses
(blood oxygen dependent MRI) (Rack-Gomer et al., 2009) and
functional MRI responses and CBF changes (Haase et al., 2005;
Sigmon et al., 2009), and one animal study has suggested an
effect on cerebrospinal fluid formation (Han et al., 2009). All
these documented actions are theoretically beneficial for the
high altitude brain, since vasodilation and overperfusion
would be minimized without sacrificing oxygenation and
metabolism. None of these studies, however, has addressed
these issues during acute or chronic hypoxia. Research de-
signed to answer the question of the effects of caffeine on brain
physiology at altitude would be enlightening.
Could caffeine help prevent or treat AMS?
Similar to caffeine’s successful use for headaches at low
altitude, owing to its cerebral vasoconstriction properties, it is
likely that caffeine will help prevent or treat altitude head-
aches and therefore AMS because of its ability to reduce cer-
ebrovasodilation in response to hypoxia. In addition to the
AU10 cCaffeine Content of Select Common Food and Drugs
Product Serving size
Caffeine per
serving (mg)
Caffeine tablets 1 tablet 100–200
Excedrin tablet 1 tablet 65
Dark chocolate bar
(45% cacao content)
1 bar (43 g) 31
Light chocolate bar
(11% cacao content)
1 bar (43 g) 10
Percolated coffee 207 mL (7 oz) 80–135
Drip coffee 207 mL (7 oz) 115–175
Decaffeinated coffee 207 mL (7 oz) 5–15
Espresso 44–60 mL (1.5–2 oz) 100
Tall coffee 360 mL (12 oz) 240
Black tea 177 mL (6 oz) 50
Green tea 177 mL (6 oz) 30
Coca-Cola 355 mL (12 oz) 34
Red Bull 250 mL (8.2 oz) 80
HAM-2009-1077-Hackett_1P.3D 02/08/10 2:35pm Page 2
studies cited above, research has suggested that another aden-
osine blocker closely related to caffeine, theophylline, may
indeed help to prevent AMS, improve sleep at high altitude,
and reduce episodes of oxygen desaturation (Fischer et al.,
2000; Fischer et al., 2004; Ku
¨pper et al., 2008). To the extent that
these effects are owing to mechanisms in common with caf-
feine, then caffeine would also help prevent AMS. These
studies did not control for caffeine habituation. Thus, whether
these possible benefits would apply to both caffeine-habituated
and caffeine-naive persons is unknown, but a trial of caffeine
for AMS prevention in both populations would be worthwhile.
What effect might caffeine have on sleep at altitude?
Disrupted sleep is a very common complaint in newcomers
to high altitude. Caffeine promotes wakefulness and can in-
terfere with sleep at low altitude, and it likely does the same at
high altitude. It is interesting that theophylline promotes sleep
at high altitude, but this agent apparently does not encourage
wakefulness as does caffeine. To the extent that caffeine may
help prevent AMS, it could improve sleep. But until further in-
formationis available, theclinician might bewise to recommend
avoiding caffeine in the late afternoon or evening, especially in
nonhabitual users, to avoid caffeine-induced insomnia, which
could aggravate altitude-associated insomnia.
Could caffeine counteract high altitude lassitude?
Caffeine is a psychostimulant, also related to its adenosine
receptor-blocking properties (Barry et al., 2005; McClellan
et al., 2007). Since altitude exposure commonly causes fatigue
or lassitude, caffeine could be an antidote for this effect. In the
Everest tea study
AU6 c(Scott et al., 2006), there was indeed a de-
crease in fatigue with tea drinking. Whether the mechanism is
a general increase in alertness, documented with caffeine at
low altitude, or a specific interruption in pathologic processes
at altitude, the net effect may be to counteract the neurocog-
nitive effects of hypoxia. At low altitude, 200 mg of caffeine
was found comparable to 200 mg of modafinil in alleviating
the nocturnal decline in cognitive performance (Dagan and
Doljansky, 2006). A number of studies have shown compa-
rable effectiveness between caffeine (600 mg), dextroamphet-
amine (20 mg), and modafinil (200mg), with some differences
in duration, side effects, and different effects on specific cog-
nitive functions (Huck et al., 2008; Killgore et al., 2008; Kill-
gore et al., 2009). Although amphetamine, a dopamine
agonist, was shown to improve cognition and mood at high
altitude (Dillet al., 1940), there has been a surprising lack of
attention since then to the issue of neurocognitive decline and
possible neurocognitive enhancers at high altitude. Indeed,
mountaineers clearly suffer risks from these deficits, and a
systematic study of caffeine and other stimulant drugs to
counteract altitude hypoxia is long overdue.
Does caffeine impair exercise?
Perhaps caution regarding caffeine at altitude owes its con-
cern to caffeine’s effect on exercise. A large body of evidence
demonstrates that caffeine can improve exercise performance
at low altitudes. Despite differences in dose, differences with
pure caffeine (caffeine citrate) versus caffeine-containing
foods and liquids, elite versus recreational subjects, and so on,
hundreds of studies support the use of caffeine to improve
performance. The mechanisms are thought to be both central,
with reduced perceived exertion (Demura et al., 2007), and
peripheral, with increased muscular force from changes in
calcium utilization. This issue has received numerous recent
reviews (e.g., Graham, 2001; Burke, 2008; Tarnopolsky, 2008).
Burke states that a moderate dose of 3 mg=kg is adequate for
performance benefits, and perhaps even 1 mg=kg (Kolata,
2009). Would the effect of caffeine on performance be different
at high altitude? Could caffeine help ameliorate the exercise
impairment caused by hypoxia? In contrast to low altitude,
the study of caffeine and exercise at high altitude is limited.
Berglund and Hemmingsson (1982) studied cross-country
skiers and found improved race times with caffeine: faster by
1.7% at 300 m and 3.2% at 2900 m. The latter correspondedto a
decrease of 152 sec in a 21 km race, a substantial improve-
ment. Fulco and colleagues (1994) studied 8 males with sub-
maximal endurance tests to exhaustion, using placebo or
caffeine drinks (4 mg=kg) 1 h before the test. The subjects ex-
ercised at sea level, after 1 h at 4300 m, and after 2 weeks at
4300 m. Caffeine provided little improvement at sea level, but
a 54% improvement with acute hypoxia and 24% improve-
ment with chronic hypoxia. These two studies are insufficient
to allow comparison to the low altitude studies. However, they
do suggest that caffeine might confer more benefit to perfor-
mance at high altitude than at low altitude and certainlydo not
suggest that caffeine might impair exercise.
How does caffeine affect pulmonary circulation
at high altitude?
Caffeine is known to be a competitive inhibitor of the en-
zyme cAMP-phosphodiesterase (cAMP-PDE), which con-
verts cyclic AMP (cAMP) in cells to its noncyclic form, thus
allowing cAMP to build up in cells. This raises the theoretical
question of whether caffeine might influence hypoxic pul-
monary vasoconstriction by promoting relaxation of the pul-
monary arterial smooth-muscle cells. Indeed, a recent study
using pulmonary arterial rings in vitro showed attenuation of
smooth-muscle activity owing to caffeine, which was attrib-
uted to its effect on calcium signaling and ryanodine receptors
Zheng et al., 2008). Although the concentration of caffeine
was far above blood levels of caffeine in usual human use,
there is at least no evidence that caffeine might cause an in-
crease in hypoxic pulmonary vasoconstriction and therefore
no reason to suspect that it might contribute to the develop-
ment of high altitude pulmonary edema.
How does caffeine affect coronary circulation?
Because coffee consumption has been found to blunt
dipyridamole-induced hyperemia through adenosine A2 re-
ceptor antagonism, caffeinated foods or beverages must be
avoided before pharmacologic radionuclide stress perfusion
imaging. Namdar and colleagues (2006) investigated whether
caffeine might impair exercise-induced increases in cardiac
blood flow. They studied the acute effect of 200mg of caffeine
on myocardial blood flow (MBF) at rest and exercise in 10
subjects during normoxia and when breathing 12.5% oxygen,
simulating a 4500 m altitude. Myocardial flow reserve ( MFR)
was calculated as the ratio of hyperemic to resting MBF. Caf-
feine reduced MFR by 22% at normoxia and 39% at hypoxia.
The results were questioned by McLellan (2006), who pointed
out the limitations of the study design owing to possible order
effect. In addition, the clinical implications of the study are
unclear, since acute hypoxia of this magnitude is unrealistic in a
HAM-2009-1077-Hackett_1P.3D 02/08/10 2:36pm Page 3
mountain environment for most visitors to resorts, the skiers
and trekkers. Although mountaineers can get to over 4000 m in
1 day, this is still less stressful than the immediate onset of
comparable hypoxemia. Perhaps more importantly, although
the subjects were habitual coffee drinkers, coffee was withheld
for 36 h before the study. Thus, the subjects had upregulated
adenosine receptors, and the action of acute caffeine may have
been exaggerated and not applicable in a nonwithdrawal state.
One wonders, however, if the combination of coronary artery
disease and caffeine at high altitude would reduce MBF even
more. A more recent study did suggest that this is the case
(Namdar et al., 2009); but until clinical assessment shows de-
creased exercise performance, ECG changes, symptoms, ven-
tricular wall motion, or other negative outcomes, these data
remain interesting but not compelling.
Cessation of Caffeine Intake
Recommending cessation of caffeine intake to those who
habitually use it makes the withdrawal syndrome very likely.
Adenosine receptors are upregulated in habitual caffeine
users. As a result, the increased effects of adenosine owing to
caffeine withdrawal cause cerebral vasodilation with resul-
tant headache and nausea. In addition, the increase in brain
adenosine on ascent to altitude, coupled with increased re-
ceptors owing to habituation, could cause even worse vaso-
dilation than in caffeine-naive persons. Cessation of caffeine
may also cause feelings of fatigue and drowsiness, anxiety,
irritability, inability to concentrate, and diminished motiva-
tion to initiate or to complete daily tasks; in extreme cases it
may cause mild depression. Together, these effects have come
to be known as a "crash," and the symptoms and their timing
(12 to 24 h) mimic acute mountain sickness. Withdrawal
symptoms may last for 1 to 5 days, representing the time
required for the number of adenosine receptors in the brain to
revert to normal levels, uninfluenced by caffeine consump-
tion. Thus, contrary to helping people, the recommendation to
cease caffeine at high altitude is more likely to be harmful. The
most effective treatment of caffeine withdrawal is a combi-
nation of both an analgesic and a small amount of caffeine.
One can only guess at how many cases of caffeine withdrawal
are misdiagnosed as AMS and at what role caffeine with-
drawal might play in promoting AMS.
In summary, contrary to conventional wisdom, caffeine use
at high altitude seems to be not only safe but likely beneficial.
Fears of dehydration from caffeine are exaggerated. Its effect
on ventilation and cerebral circulation and its action as a psy-
chostimulant are likely to be helpful at altitude. Whether caf-
feine may prevent or ameliorate AMS deserves study. Caffeine
may also help exercise performance at high altitude. Impor-
tantly, habitual caffeine users should not discontinue caffeine
because of travel to altitude; the symptoms of withdrawal are
very similar to acute mountain sickness and can be misdiag-
nosed as AMS. The issue of altitude, coronary artery disease,
and caffeine in exercising patients deserves further study.
AU1 cauthor has no conflicts of interest or financial ties to
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Guo L., Zhang R., and Zhu D. (2008). Source of the elevation bAU3
Ca2þevoked by 15-HETE in pulmonary arterial myocytes.
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Metabolic and Cardiovascular Effects of Intramuscular Injec-
tions of Adrenalin and of Amphetamine 1939. November
D.B. Dill, et al. bAU4
Address correspondence to: bAU9
Received November 10, 2009;
accepted in final form December 9, 2009.
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AU1: Update, if necessary.
AU2: Page nos.?
AU3: ‘‘of’’?
AU4: Is this entry to be included in ref. list? If so, pls. complete data?
AU5: Affiliation ok?
AU6: OK?
AU7: 1995a?
AU8: Cite in text.
AU9: Pls. furnish mailing address.
AU10: Cite Table 1 in Text and check table title.
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... Typical caffeine contents of commonly consumed beverages (Hackett, 2010) Caffeine and theine are chemically identical; the only thing that sets them apart is the concentration, lesser in a cup of tea than in a cup of coffee. Tea is the most widely consumed beverage in the world after water. ...
... Caffeine does have diuretic effects, but with normal consumption, even in an environment of cold and altitude where diuresis is stimulated, caffeine did not increase diuresis with no risk for dehydration (Hackett, 2010). A study performed by Scott et al. (2004) showed that there is no evidence that tea acts as a diuretic when drunk by regular tea drinkers at altitude, but it does have a positive effect on mood. ...
... Caffeine may interfere with sleep and promotes wakefulness, so it is recommended avoiding caffeine in the late afternoon or evening, especially in nonhabitual users, to avoid caffeine-induced insomnia, which could aggravate altitudeassociated insomnia (Hackett, 2010). Habitual caffeine users should not discontinue it because of travel to altitude since withdrawal symptoms are very similar to those of AMS (Hackett, 2010). ...
Kurdziel, Marta, Jarosław Wasilewski, Karolina Gierszewska, Anna Kazik, Gracjan Pytel, Jacek Wacławski, Adam Krajewski, Anna Kurek, Lech Poloński, and Mariusz Gąsior. Echocardiographic assessment of right ventricle dimensions and function after exposure to extreme altitude: Is an expedition to 8000 m hazardous for right ventricular function? High Alt Med Biol 00:000-000, 2017.-Although the right ventricle (RV) is under great hypoxic stress at altitude, still little is known what happens to the RV after descent. The aim of this study was to evaluate RV dimensions and function after exposure to extreme altitude. Therefore, echocardiographic examination was performed according to a protocol that focused on the RV in 11 healthy subjects participating in an expedition to K2 (8611 m) or Broad Peak (BP, 8051 m). In comparison to measurements before the expedition, after 7-8 weeks of sojourn above 2300 meters with the aim of climbing K2 and BP, the RV Tei index increased (0.5 ± 0.1 vs. 0.4 ± 0.1; p = 0.028), and RV free wall longitudinal systolic strain (RVFWLSS) decreased (-23.1% ± 2.7% vs. -25.9% ± 2.4%; p = 0.043). Decrease in peak systolic strain and strain rate was observed in the basal and mid segments of the RV free wall (respectively: -24.4% ± 4.4% vs. -30.9% ± 6.5%; -1.4 ± 0.3 s(-1) vs. -1.8 ± 0.3 s(-1); -28.7% ± 3.9% vs. -34% ± 3.3%; -1.5 ± 0.2 s(-1) vs. -1.9 ± 0.3 s(-1); p for all <0.05). The linear RV dimensions, the proximal and distal RV outflow tracks, increased (respectively: 31.3 ± 4 mm vs. 29.2 ± 3 mm, p = 0.025; 27 ± 2.7 mm vs. 24.8 ± 3 mm, p = 0.012). We found that exposure to extreme altitude may cause RV dilatation and a decrease in RV performance. The Tei index and RVFWLSS are sensitive performance indices to detect changes in RV function after the exposure to hypoxic stress. The observed alterations seem to be a manifestation of physiological adaptation to high-altitude condition in healthy individuals.
... Caffeine is a psychoactive drug widely consumed in the world and has a plethora of actions in the central nervous system (CNS) [1]. Nowadays, in addition to traditional beverages such as coffee and tea, caffeine can be found in energy drinks, soft drinks, and chocolates [2,3]. The consumption of these products increased in recent years, including in children and adolescents [4][5][6], and may even exceed the recommended daily intake (2.5 mg/kg for 6-12 years old children) due to advertisements designed to attract these young consumers [7][8][9]. ...
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Caffeine, a stimulant largely consumed around the world, is a non-selective adenosine receptor antagonist, and therefore caffeine actions at synapses usually, but not always, mirror those of adenosine. Importantly, different adenosine receptors with opposing regulatory actions co-exist at synapses. Through both inhibitory and excitatory high-affinity receptors (A1R and A2R, respectively), adenosine affects NMDA receptor (NMDAR) function at the hippocampus, but surprisingly, there is a lack of knowledge on the effects of caffeine upon this ionotropic glutamatergic receptor deeply involved in both positive (plasticity) and negative (excitotoxicity) synaptic actions. We thus aimed to elucidate the effects of caffeine upon NMDAR-mediated excitatory post-synaptic currents (NMDAR-EPSCs), and its implications upon neuronal Ca2+ homeostasis. We found that caffeine (30–200 μM) facilitates NMDAR-EPSCs on pyramidal CA1 neurons from Balbc/ByJ male mice, an action mimicked, as well as occluded, by 1,3-dipropyl-cyclopentylxantine (DPCPX, 50 nM), thus likely mediated by blockade of inhibitory A1Rs. This action of caffeine cannot be attributed to a pre-synaptic facilitation of transmission because caffeine even increased paired-pulse facilitation of NMDA-EPSCs, indicative of an inhibition of neurotransmitter release. Adenosine A2ARs are involved in this likely pre-synaptic action since the effect of caffeine was mimicked by the A2AR antagonist, SCH58261 (50 nM). Furthermore, caffeine increased the frequency of Ca2+ transients in neuronal cell culture, an action mimicked by the A1R antagonist, DPCPX, and prevented by NMDAR blockade with AP5 (50 μM). Altogether, these results show for the first time an influence of caffeine on NMDA receptor activity at the hippocampus, with impact in neuronal Ca2+ homeostasis.
... 12 At normal doses, caffeine has variable effects on learning and memory, but it generally improves reaction time, wakefulness, concentration, and motor coordination. 13,14 The amount of caffeine needed to produce these effects varies from person to person, depending on body size and degree of tolerance. 15,16,17 The desired effects arise approximately one hour after consumption, and the desired effects of a moderate dose usually subside after about three or four hours. ...
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Diazepam is commonly used in clinical setting in treatment and management of several conditions such as convulsion, insomnia, anxiety disorder and sleep disorder. Caffeine is widely and regularly consumed for different purposes. A total of thirty (30) wister rats of 120–210 g of either sex were divided into five groups of six mice per group. Rats in all group received diazepam (4 mg/Kg), while group 2, 3, 4 and 5 received concurrent dose of caffeine (2.5, 5, 10 and 20 mg/Kg) intraperitoneally respectively. After 2 minutes of administration of the drugs, sedative and hypnotic study were carried out. There was significant (P<0.05) dose dependent decreased in the time taken for rat in all groups to return the widely parted hind limb to their normal position when compare to the control. There was also significant (P<0.05) dose dependent increased in sleep latency and decreased in duration of sleep in all group administered caffeine. Group 5 rats did not have sleep latency and duration of sleep throughout the 90 minutes period of observation. result from the study showed that caffeine significantly reduced CNS effect of diazepam induced rats which suggests that dose
... 12 At normal doses, caffeine has variable effects on learning and memory, but it generally improves reaction time, wakefulness, concentration, and motor coordination. 13,14 The amount of caffeine needed to produce these effects varies from person to person, depending on body size and degree of tolerance. 15,16,17 The desired effects arise approximately one hour after consumption, and the desired effects of a moderate dose usually subside after about three or four hours. ...
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Introduction/aim: Diazepam is commonly used in clinical setting in treatment and management of several conditions such as convulsion, insomnia, anxiety disorder and sleep disorder. Caffeine is widely and regularly consumed for different purposes. It is a central nervous system stimulant that affects the body in numerous ways. The aim of this study is to investigate the effect of caffeine on diazepam– induced in rat. Method: A total of thirty (30) wister rats of 120–210 g of either sex were divided into five groups of six mice per group. Rats in all group received diazepam (4 mg/Kg), while group 2, 3, 4 and 5 received concurrent dose of caffeine (2.5, 5, 10 and 20 mg/Kg) intraperitoneally respectively. After 2 minutes of administration of the drugs, sedative and hypnotic study were carried out. Result: There was significant (P<0.05) dose dependent decreased in the time taken for rat in all groups to return the widely parted hind limb to their normal position when compare to the control. There was also significant (P<0.05) dose dependent increased in sleep latency and decreased in duration of sleep in all group administered caffeine. Group 5 rats did not have sleep latency and duration of sleep throughout the 90 minutes period of observation. Conclusion: result from the study showed that caffeine significantly reduced CNS effect of diazepam induced rats which suggests that dose adjustment should be considered to patients on diazepam who may have been exposed to caffeine.
... Elsewhere, it has been identified as carrying a higher risk for AMS [6]. Other substances are dexamethasone, ibuprofen, previously ridiculed Gingko biloba, caffeine [7] and many others. While pretreatment with Gingko biloba (EGb761) prevented AMS [8] or reduced its severity [9], other results were indifferent [10,11], with Gertsch [12] starting the experiment at a baseline at 4000 m which appears far too late in the ascent to draw meaningful conclusions. ...
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Few travel health measures are as controversial as the use of coca leaves at high altitude; yet, there appears widespread ignorance among health professionals and the general public about coca, its origins as well as its interesting and often flamboyant history. Equally, the cultural and traditional significance to Andean people is not recognised. The coca leaves contain many alkaloids, one of which, cocaine, has gained notoriety as a narcotic, leading to the mistaken idea that coca equals cocaine. This article contrasts coca with cocaine in an attempt to explain the differences but also the reasons for this widespread misconception. By its very nature, there may never be scientific ‘proof’ that coca leaves do or do not work for travellers at altitude, but at least a solid knowledge of coca, and how it differs from cocaine, provides a platform for informed opinions and appropriate critical views on the current confusing and contradictory legal situation.
... The prominent psychoactive drug, caffeine is mainly used to treat bronchopulmonary dysplasia, apnea [17], Parkinson's disease [18] and cardiovascular complications (e.g. coronary artery disease and stroke) [19], weight gain [20], cerebral palsy, language and cognitive delay [21], orthostatic hypotension [22], fatigue (both from muscle and central) [23,24], drowsiness [25], type 2 diabetes (T2D) [26], liver cirrhosis [27], headaches [28] and acute mountain sickness [29]. The excess consumption of caffeine may increase blood pressure and could lead to vasoconstriction [30], affect gastrointestinal motility and gastric acid secretion [31], bone loss [32], dehydration [33], anxiety and panic disorder [34], low birth weight [35], colorectal cancer [36], intraocular pressure in glaucoma [37], caffeinism and caffeine dependency [38]. ...
Background: The popular drink, coffee (Coffea arabica) is under the great attention of late because of its promising pharmacological potential. Caffeine (the major constituent of coffee) is known for its prominent psychoactive impact. This review aims at highlighting the therapeutic potentials of caffeine and other five coffee components viz. caffeic acid, chlorogenic acids, cafestol, ferulic acid and kahweol and their mechanisms of action. Methods: An up-to-date search was made with selected keywords in PubMed, Science Direct, Web of Science, Scopus, The American Chemical Society and miscellaneous databases (e.g., Google Scholar) for the published literature on the selected topic. Results: A number of pharmacological activities are attributed to these components that include anti-oxidant, antiinflammatory, immunomodulatory, anti-microbial, anti-cancer, cardioprotective and neuroprotective effects. In addition, osteogenesis (kahweol), anti-diabetic (caffeine, chlorogenic acid and ferulic acid) and hepatoprotective (chlorogenic acid) activities have also been reported by some of these components in the scientific literature. Caffeine has also been noted for adverse effect on the development of the brain at early stages and reproductive systems. Conclusion: A more advanced pre-clinical and clinical trials are recommended to investigate the safety profiles of these coffee components before their use as possible therapeutics.
... PPOK paling banyak diderita pada kelompok umur 49-80 tahun dengan presentase 90,24% (37 pasien), selanjutnya pada kelompok umur 17-48 tahun 9,76% (4 pasien). Hasil penelitian sesuai dengan penelitian yang dilakukan yaitu PPOK adalah penyebab utama kematian bagi individu berusia diatas 65 tahun dan menjadikan ancaman serius bagi sebagian penduduk Amerika 14 . Sedangkan menurut (Tabrani, 2010), umur berpengaruh terhadap elastisitas paru, dan penurunan elastisitas paru akan berpengaruh pada terjadinya PPOK. ...
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The prevalence of COPD in Indonesia is increasing. Over the world, COPD is predicted to be the third cause of death in 2020. As the chronic disease, quality of life became one of the outcome treatments of COPD. This research was aimed to validate Indonesian version of St. George's Respiratory Questionnaire (SGRQ) Indonesia. This study used cross sectional design approach from June to July 2016, conducted at Respira Lung Hospital, Yogyakarta. Data was collected from medical record and direct interviews to patients using SGRQ. An inclusion criterion was adult patients with COPD. Some statistical tests were performed to analyze construct validity, known group validity and reliability of Indonesian version of SGRQ. We recruited 41 respondents. The SGRQ meet reliability criteria with the value of Cronbach alpha are > 0.7 for symptom, activity and impact domains. There are 17 questions and 10 questions in symptom, activity and impact domains which do not meet convergent and discriminant validity. The significant difference is found in symptom domain for the 17-48 and 49-80 year age. The SGRQ Indonesian version is not valid enough to be used in clinical practice but still reliable.
Xanthine (3,7-dihydro-purine-2,6-dione) is a purine base that can naturally be found in human body tissues and fluids as well as in plants and other organisms. Methylated xanthines (methylxanthines) are phosphodiesterase inhibitors and adenosine receptor antagonists. Methylxanthines have thus different effects: reduce inflammation and immunity, reduce sleepiness, and increase alertness, but also stimulate the heart rate and contraction and dilate the bronchi. The most well-known methylxanthines are caffeine, methylbromine, and theophylline. Large observational studies suggest that caffeine may have long-term health benefits. Coffee and caffeine withdrawal symptoms exist and are often not recognized, especially in treatment settings, where caffeine withdrawal can be confounded with other symptoms. Caffeine intoxication and withdrawal are recognized clinical entities, but caffeine dependence is currently not. Caffeine withdrawal symptoms occur in half of regular coffee drinkers, even at moderate caffeine intake. The most common symptoms are headache, fatigue, and difficulty to concentrate. Health professionals and patients should be better informed about these symptoms and the risk of occurrence of caffeine withdrawal. There is little research on treatments for clinical problems associated with xanthine use or abuse.
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Caffeine is a common substance in the diets of most athletes and it is now appearing in many new products, including energy drinks, sport gels, alcoholic beverages and diet aids. It can be a powerful ergogenic aid at levels that are considerably lower than the acceptable limit of the International Olympic Committee and could be beneficial in training and in competition. Caffeine does not improve maximal oxygen capacity directly, but could permit the athlete to train at a greater power output and/or to train longer. It has also ben shown to increase speed and/or power output in simulated race conditions. These effects have been found in activities that last as little as 60 seconds or as long as 2 hours. There is less information about the effects of caffeine on strength; however, recent work suggests no effect on maximal ability, but enhanced endurance or resistance to fatigue. There is no evidence that caffeine ingestion before exercise leads to dehydration, ion imbalance, or any other adverse effects. The ingestion of caffeine as coffee appears to be ineffective compared to doping with pure caffeine. Related compounds such as theophylline are also potent ergogenic aids. Caffeine may act synergistically with other drugs including ephedrine and anti-inflammatory agents. It appears that male and female athletes have similar caffeine pharmacokinetics, i.e., for a given dose of caffeine, the time course and absolute plasma concentrations of caffeine and its metabolites are the same. In addition, exercise or dehydration does not affect caffeine pharmacokinetics. The limited information available suggests that caffeine non-users and users respond similarly and that withdrawal from caffeine may not be important. The mechanism(s) by which caffeine elicits its ergogenic effects are unknown, but the popular theory that it enhances fat oxidation and spares muscle glycogen has very little support and is an incomplete explanation at best. Caffeine may work, in part, by creating a more favourable intracellular ionic environment in active muscle. This could facilitate force production by each motor unit.
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This investigation determined if 3 levels of controlled caffeine consumption affected fluid-electrolyte balance and renal function differently. Healthy males (mean standard deviation; age, 21.6 +/- 3.3 y) consumed 3 mg caffeine (.) kg(-1) (.) d(-1) on days I to 6 (equilibration phase). On days 7 to 11 (treatment phase), subjects consumed either 0 mg (CO; placebo; n = 20), 3 mg (C3; n = 20), or 6 mg (C6; n = 19) caffeine (.) kg(-1) (.) d(-1) in capsules, with no other dietary caffeine intake. The following variables were unaffected (P > 0.05) by different caffeine doses on days 1, 3, 6, 9, and 11 and were within normal clinical ranges: body mass, urine osmolality, urine specific gravity, urine color, 24-h urine volume, 24-h Na+ and K+ excretion, 24-h creatinine, blood urea nitrogen, serum Na+ and K+, serum osmolality, hematocrit, and total plasma protein. Therefore, C0, C3, and C6 exhibited no evidence of hypohydration. These findings question the widely accepted notion that caffeine consumption acts chronically as a diuretic.
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Caffeine is the most commonly consumed psycho-stimulant in the world. The effects of caffeine on the body have been extensively studied; however, its effect on the structure of the brain has not been investigated to date. In the present study we found that the long-term consumption of caffeine can induce ventriculomegaly; this was observed in 40% of the study rats. In the caffeine-treated rats with ventriculomegaly, there was increased production of CSF, associated with the increased expression of Na(+), K(+)-ATPase and increased cerebral blood flow (CBF). In contrast to the chronic effects, acute treatment with caffeine decreased the production of CSF, suggesting 'effect inversion' associated with caffeine, which was mediated by increased expression of the A1 adenosine receptor, in the choroid plexus of rats chronically treated with caffeine. The involvement of the A1 adenosine receptor in the effect inversion of caffeine was further supported by the induction of ventriculomegaly and Na+, K+-ATPase, in A1 agonist-treated rats. The results of this study show that long-term consumption of caffeine can induce ventriculomegaly, which is mediated in part by increased production of CSF. Moreover, we also showed that adenosine receptor signaling can regulate the production of CSF by controlling the expression of Na(+), K(+)-ATPase and CBF.
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Caffeine is one of the most widely consumed pharmacologically active substances. Its acute effect on myocardial blood flow is widely unknown. Our aim was to assess the acute effect of caffeine in a dose corresponding to two cups of coffee on myocardial blood flow (MBF) in coronary artery disease (CAD). MBF was measured with (15)O-labelled H2O and Positron Emission Tomography (PET) at rest and after supine bicycle exercise in controls (n = 15, mean age 58+/-13 years) and in CAD patients (n = 15, mean age 61+/-9 years). In the latter, regional MBF was assessed in segments subtended by stenotic and remote coronary arteries. All measurements were repeated fifty minutes after oral caffeine ingestion (200 mg). Myocardial perfusion reserve (MPR) was calculated as ratio of MBF during bicycle stress divided by MBF at rest. Resting MBF was not affected by caffeine in both groups. Exercise-induced MBF response decreased significantly after caffeine in controls (2.26+/-0.56 vs. 2.02+/-0.56, P<0.005), remote (2.40+/-0.70 vs. 1.78+/-0.46, P<0.001) and in stenotic segments (1.90+/-0.41 vs. 1.38+/-0.30, P<0.001). Caffeine decreased MPR significantly by 14% in controls (P<0.05 vs. baseline). In CAD patients MPR decreased by 18% (P<0.05 vs. baseline) in remote and by 25% in stenotic segments (P<0.01 vs. baseline). We conclude that caffeine impairs exercise-induced hyperaemic MBF response in patients with CAD to a greater degree than age-matched controls.
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Although the subjective effects of caffeine abstinence, acute and chronic administration, and tolerance are well described, the corresponding neurophysiological effects are not. Caffeine withdrawal, acute caffeine effects, caffeine tolerance, and net beneficial effects of chronic caffeine administration were investigated using cerebral blood flow velocity, quantitative electroencephalography (EEG), and subjective effects. Sixteen regular caffeine users participated in this double-blind, within-subject study during which they received acute caffeine and placebo challenges (1) while maintained on 400 mg caffeine daily for > or =14 days and (2) while maintained on placebo for > or =14 days. Blood flow velocity was determined for the middle (MCA) and anterior (ACA) cerebral arteries using pulsed transcranial Doppler sonography. EEG was recorded from 16 scalp sites. Subjective effects were assessed with questionnaires. Acute caffeine abstinence (evaluated 24 h after placebo substitution) increased mean, systolic, and diastolic velocity in the MCA and ACA and decreased pulsatility index in the MCA. Acute caffeine abstinence increased EEG theta and decreased beta 2 power. Acute caffeine abstinence also increased measures of Tired, Fatigue, Sluggish, and Weary and decreased ratings of Energetic, Friendly, Lively, and Vigor. Acute caffeine effects were demonstrated across a wide range of measures, including cerebral blood flow, EEG, and subjective effects. Tolerance and "complete" tolerance were observed on subjective but not physiological measures. Chronic caffeine effects were demonstrated only on the measure of EEG beta 2 power. Acute caffeine abstinence and administration produced changes in cerebral blood flow velocity, EEG, and subjective effects. Tolerance to subjective but not physiological measures was demonstrated. There was almost no evidence for net effects of chronic caffeine administration on these measures. Overall, these findings provide the most rigorous demonstration to date of physiological effects of caffeine withdrawal.
A wide consumption of caffeine by almost every human culture on earth is discussed. According to a Caffeine researcher Lawrence Armstrong, Caffeine is a substance of dependence, not a drug and addiction. One real risk of taking caffeine is a small elevation in bone fractures among people drinking four or more cups a day. Caffeine causes some degree of calcium loss, with a possible effect on bone density.
Apnoea of prematurity is a common condition in neonates bom at less than 37 weeks’ gestational age; it affects approximately 90% of premature neonates weighing under 1000g at birth, and 25% of infants with a birthweight of less than 2500g. Caffeine, a methylxanthine which occurs naturally in many plants, has been used for over 20 years to treat apnoea of prematurity. In a recent doubleblind, placebo-controlled trial, apnoea was eliminated or reduced by at least 50% in significantly more neonates receiving caffeine citrate as first-line treatment than those receiving placebo. In a nonblind trial, caffeine citrate was more effective at reducing apnoeic episodes when compared with neonates receiving no treatment. Caffeine as first-line treatment demonstrated similar efficacy to theophylline or aminophylline (theophylline ethylenediamine) in 4 small randomised studies. Caffeine citrate was generally well tolerated in short term clinical trials, with very few adverse events reported. Caffeine was associated with fewer adverse events than theophylline in randomised trials. No differences in the incidence of individual adverse events were reported between caffeine citrate and placebo in a double-blind, randomised trial. Long term tolerability data are not yet available. Conclusions: Caffeine citrate was generally well tolerated by neonates in clinical trials and it decreased the incidence of apnoea of prematurity compared with placebo. It has demonstrated similar efficacy to theophylline, but is generally better tolerated and has a wider therapeutic index. Caffeine citrate should, therefore, be considered the drug of choice when pharmacological treatment of apnoea of prematurity is required. Pharmacodynamic Properties Caffeine acts via 3 main mechanisms of action. The mechanism most likely to mediate most of the pharmacological effects of caffeine is antagonism of the actions of adenosine at A1 and A2A receptors in the CNS. Activation of A1 receptors can produce sedation, antinociception, anticonvulsant effects, bradycardia, vasoconstriction, bronchoconstriction, antidiuresis and decreased glomerular filtration, and an increase in insulin sensitivity. Activation of the A2A receptors causes vasodilation, bronchodilation, central respiratory depression and peripheral respiratory stimulation, platelet inhibition, decreased locomotor activity and immunosuppression. At higher concentrations (in the millimolar range), caffeine is a weak inhibitor of phosphodiesterase activity. As millimolar concentrations of caffeine are likely to be toxic in vivo, inhibition of phosphodiesterase is unlikely to mediate most effects of caffeine at therapeutic doses. The third mechanism of action of caffeine is mobilisation of calcium from intracellular storage sites and inhibition of voltage-sensitive calcium channels; as relatively high concentrations of caffeine (≥250 μmol/L) are required for calcium mobilisation, this action may contribute more to the toxic effects of caffeine. Caffeine increases mean respiratory rate and minute volume, stimulates central respiratory centres, increases pulmonary blood flow and increases the sensitivity of central medullary areas to hypercapnia. In premature neonates, caffeine was shown to improve the compliance of the respiratory system, reducing the strength of the Hering Breuer reflex (p < 0.05) and the inspired oxygen requirements over the 7-day study period. Caffeine has stimulant and somnolytic effects in the CNS (probably via blockade of adenosine receptors), and it has a direct effect on the myocardium, increasing ventricular output, stroke volume and mean arterial blood pressure in neonates. In contrast to aminophylline (theophylline ethylenediamine), caffeine has no significant effects on brain haemodynamics in preterm infants. Caffeine can affect the renal system, increasing glomerular flow rate, inducing diuresis, and increasing calcium excretion, urinary flow rate, creatine clearance and water input/output ratio over pretreatment levels. Pharmacokinetic Properties The pharmacokinetics of caffeine are largely independent of the route of administration. In premature neonates, orally administered caffeine citrate is rapidly and completely absorbed. There is almost no first-pass metabolism, and there is almost complete bioavailability of caffeine following oral administration. Following a single oral dose of caffeine citrate 20 mg/kg (a 20 mg/kg dose of caffeine citrate contains 10 mg/kg caffeine base), the mean peak plasma concentration of 12.8 mg/L occurred about 4.6 hours after administration of the dose. Steady-state plasma concentrations ranged from 7.4 to 19.4 mg/L after once daily administration of caffeine base 2.5 mg/kg. The mean terminal half-life of caffeine in neonates ranges from 65 to 102 hours. Caffeine readily passes through most membranes in the body and does not accumulate in tissue. It has an apparent volume of distribution of approximately 0.8 L/kg. Caffeine is metabolised in the liver by cytochrome P450 1A2 (CYP1A2). Metabolism of caffeine is limited in neonates because of their immature hepatic enzyme system; approximately 86% is excreted unchanged in the urine. The terminal half-life of caffeine in infants decreases from birth until reaching adult values at approximately 60 weeks postconceptional age; premature neonates have a significantly longer caffeine half-life than neonates born at term. Therapeutic Efficacy First-Line Therapy: Caffeine citrate has shown efficacy in the treatment of apnoea of prematurity in 1 randomised, double-blind, placebo-controlled trial in 82 evaluable premature neonates. The frequency of apnoeic episodes was reduced by ≥50% or eliminated in significantly more neonates receiving caffeine citrate than placebo. In another study (n = 18), apnoeic episodes were significantly less frequent in neonates receiving caffeine citrate compared with neonates receiving no treatment. Caffeine has demonstrated similar efficacy to theophylline or aminophylline in 4 small randomised studies. Second-Line Therapy: Caffeine has shown efficacy in the treatment of apnoea which did not respond to theophylline treatment in 2 small, nonblind, noncomparative studies. Over 80% of the 27 neonates responded to caffeine with a reduction in the frequency of apnoeic episodes. Prophylactic Use: Mixed results have been obtained from 3 trials assessing caffeine citrate as a prophylactic agent for the prevention of apnoeic episodes in premature neonates. A double-blind, placebo-controlled study (n = 50) did not show any benefit of caffeine citrate treatment in preventing hypoxaemic or bradycardic episodes in premature neonates. However, a smaller (n = 37) nonblind study showed caffeine citrate to be significantly more effective than no treatment in preventing apnoea. A third trial (n = 180) found no difference in the frequency of apnoeic or bradycardic episodes between caffeine citrate and aminophylline groups over a 10-day period (there was no placebo group in this study). Tolerability Caffeine citrate has, generally, been well tolerated in clinical trials of premature neonates, with very few adverse events reported. No differences in the incidence of individual adverse events were reported between caffeine citrate and placebo treatment groups in a double-blind trial. The discontinuation rate due to adverse events was 4.4% for caffeine citrate and 2.7% for placebo groups. Caffeine was associated with fewer adverse events than theophylline in randomised trials. Caffeine toxicity has not been reported at the therapeutic plasma concentrations required to treat apnoea of prematurity. Caffeine is a CNS and cardiovascular stimulant and has been associated with irritability, restlessness, jitteriness, tachycardia and other cardiovascular effects, although these events have generally been absent from randomised trials of caffeine in premature neonates with apnoea. The long term outcomes of caffeine treatment in neonates have yet to be determined, but evidence from nonblind studies suggests that growth and neurological development are not affected. In cases of accidental caffeine overdose recovery was usually complete. Dosage and Administration The recommended dosage regimen of caffeine citrate for the short term treatment of apnoea of prematurity in previously untreated infants between 28 and <33 weeks’ gestational age is 20 mg/kg infused intravenously over 30 minutes using a syringe infusion pump, followed by maintenance therapy of 5 mg/kg once daily given orally or by intravenous infusion. Serum concentrations of caffeine should be monitored periodically; the therapeutic range is 8 to 20 mg/L. Caffeine clearance and half-life change rapidly in the postnatal period and it may be necessary to adjust dosage regimens as infants increase in age.
Prolonged sleep loss impairs alertness, vigilance and some higher-order cognitive and affective capacities. Some deficits can be temporarily reversed by stimulant medications including caffeine, dextroamphetamine, and modafinil. To date, only one study has directly compared the effectiveness of these three compounds and specified the doses at which all were equally effective in restoring alertness and vigilance following 64 h of wakefulness. The present study compared the effectiveness of these same three stimulants/doses following a less extreme period of sleep loss (i.e., 44 h). Fifty-three healthy adults received a single dose of modafinil 400 mg (n = 11), dextroamphetamine 20 mg (n = 16), caffeine 600 mg (n = 12), or placebo (n = 14) after 44 h of continuous wakefulness. After 61 h of being awake, participants obtained 12 h of recovery sleep. Psychomotor vigilance was assessed bi-hourly during waking and following recovery sleep. Relative to placebo, all three stimulants were equally effective in restoring psychomotor vigilance test speed and reducing lapses, although the duration of action was shortest for caffeine and longest for dextroamphetamine. At these doses, caffeine was associated with the highest percentage of subjectively reported side-effects while modafinil did not differ significantly from placebo. Subsequent recovery sleep was adversely affected in the dextroamphetamine group, but none of the stimulants had deleterious effects on postrecovery performance. Decisions regarding stimulant selection should be made with consideration of how factors such as duration of action, potential side-effects, and subsequent disruption of recovery sleep may interact with the demands of a particular operational environment.
In resting-state functional magnetic resonance imaging (fMRI), correlations between spontaneous low-frequency fluctuations in the blood oxygenation level dependent (BOLD) signal are used to assess functional connectivity between different brain regions. Changes in resting-state BOLD connectivity measures are typically interpreted as changes in coherent neural activity across spatially distinct brain regions. However, this interpretation can be complicated by the complex dependence of the BOLD signal on both neural and vascular factors. For example, prior studies have shown that vasoactive agents that alter baseline cerebral blood flow, such as caffeine and carbon dioxide, can significantly alter the amplitude and dynamics of the task-related BOLD response. In this study, we examined the effect of caffeine (200 mg dose) on resting-state BOLD connectivity in the motor cortex across a sample of healthy young subjects (N=9). We found that caffeine significantly (p<0.05) reduced measures of resting-state BOLD connectivity in the motor cortex. Baseline cerebral blood flow and spectral energy in the low-frequency BOLD fluctuations were also significantly decreased by caffeine. These results suggest that caffeine usage should be carefully considered in the design and interpretation of resting-state BOLD fMRI studies.
Stimulant medications appear effective at restoring simple alertness and psychomotor vigilance in sleep deprived individuals, but it is not clear whether these medications are effective at restoring higher order complex cognitive capacities such as planning, sequencing, and decision making. After 44 hours awake, participants received a double-blind dose of one of 3 stimulant medications or placebo. After 45-50 hours awake, participants were tested on computerized versions of the 5-Ring Tower of Hanoi (TOH), the Tower of London (TOL), and the Wisconsin Card Sorting Test (WCST). In-residence sleep-laboratory facility at the Walter Reed Army Institute of Research. Fifty-four healthy adults (29 men, 25 women), ranging in age from 18 to 36 years. Interventions: Participants were randomly assigned to 1 of 3 stimulant medication groups, including caffeine, 600 mg (n=12), modafinil, 400 mg (n=12), dextroamphetamine, 20 mg (n=16), or placebo (n=14). At the doses tested, modafinil and dextroamphetamine groups completed the TOL task in significantly fewer moves than the placebo group, and the modafinil group demonstrated greater deliberation before making moves. In contrast, subjects receiving caffeine completed the TOH in fewer moves than all 3 of the other groups, although speed of completion was not influenced by the stimulants. Finally, the modafinil group outperformed all other groups on indices of perseverative responding and perseverative errors from the WCST. Although comparisons across tasks cannot be made due to the different times of administration, within-task comparisons suggest that, at the doses tested here, each stimulant may produce differential advantages depending on the cognitive demands of the task.