Caffeine may disrupt the impact of real-time drowsiness on cognitive performance: a double-blind, placebo-controlled small-sample study.

Caffeine is widely used to promote alertness and cognitive performance under challenging conditions, such as sleep loss. Non-digestive modes of delivery typically reduce variability of its effect. In a placebo-controlled, 50-h total sleep deprivation (TSD) protocol we administered four 200 mg doses of caffeine-infused chewing-gum during night-time circadian trough and monitored participants' drowsiness during task performance with infra-red oculography. In addition to the expected reduction of sleepiness, caffeine was found to disrupt its degrading impact on performance errors in tasks ranging from standard cognitive tests to simulated driving. Real-time drowsiness data showed that caffeine produced only a modest reduction in sleepiness (compared to our placebo group) but substantial performance gains in vigilance and procedural decisions, that were largely independent of the actual alertness dynamics achieved. The magnitude of this disrupting effect was greater for more complex cognitive tasks.

Synchronized drowsiness monitoring and simulated driving performance data under 50-hr sleep deprivation: A double-blind placebo-controlled caffeine intervention.

This paper presents the 60-s time-resolution segment from our 50-h total sleep deprivation (TSD) dataset (Aidman et al., 2018) [1] that captures minute-by-minute dynamics of driving performance (lane keeping and speed variability) along with objective, oculography-derived drowsiness estimates synchronised to the same 1-min driving epochs. Eleven participants (5 females, aged 18-28) were randomised into caffeine (administered in four 200 mg doses via chewing gum in the early morning hours) or placebo groups. Every three hours they performed a 40 min simulated drive in a medium fidelity driving simulator, while their drowsiness was continuously measured with a spectacle frame-mounted infra-red alertness monitoring system. The dataset covers 15 driving periods of 40 min each, and thus contains over 600 data points of paired data per participant. The 1-min time resolution enables detailed time-series analyses of both time-since-wake and time-on-task performance dynamics and associated drowsiness levels. It also enables direct examination of the relationships between drowsiness and task performance measures. The question of how these relationships might change under various intervention conditions (caffeine in our case) seems worth further investigation.

Hormonal and cardiovascular response to low-intensity exercise with atropine administration.

The hormonal and cardiovascular responses to atropine and low-intensity exercise were examined in 7 young men. Subjects completed 3 trials in a single blind crossover design. During the first trial (T1), subjects received 2.0 mg of atropine intramuscularly at rest. Subsequently in trial 2 (T2), subjects received a saline placebo before 90 minutes of intermittent exercise, and during trial 3 (T3), they received atropine before 90 min of intermittent exercise [3 x (25-minute cycle/5-minute rest) @ 40% VO2 peak]. Venous blood samples and physiological data were collected before, during, and post exercise. Growth hormone (GH) was significantly increased in T2 but unchanged in T1 and T3. Cortisol (CORT) was unchanged in T1 and T2, but in T3 significantly increased (p <0.05) from 45 to 90 minutes compared to T2. Plasma luteinizing hormone (LH) was unaffected in all trials. Plasma prolactin (PRO) significantly increased in T3 from 45 to 90 minutes in comparison to T2. Norepinephrine (NE) was unaffected in T1, but significantly increased in both T2 and T3 (5 to 90 minutes). NE in T3 was also significantly higher compared to T2 (30 to 90 minutes). The heart rate (HR) and rate pressure product (RPP) significantly increased in all trials (15 to 90 minutes) and T3 was significantly elevated in comparison to T2. The administration of atropine before 90 minutes of low-intensity exercise significantly increased cortisol, prolactin, and norepinephrine, decreased growth hormone, and significantly increased cardiovascular stress.

Both atenolol and propranolol blunt the fibrinolytic response to exercise but not resting fibrinolytic potential.

This randomized, double-blind trial found that tissue plasminogen activator activity increased and plasminogen activator inhibitor-1 activity decreased significantly more with exercise during placebo treatment than during treatment with beta blockade. These results suggest that beta blockade blunts the fibrinolytic response to maximal exercise.

The influence of the menstrual cycle on triazolam and indocyanine green pharmacokinetics.

The aim of this study was to investigate the effects of the menstrual cycle phase on the pharmacokinetics of two high-clearance agents, triazolam and indocyanine green (ICG). Eleven nonsmoking, healthy, eumenorrheic women were enrolled in this study. Triazolam (0.25 mg) was administered orally, and indocyanine green was administered as an i.v. bolus (0.5 mg/kg) during the follicular, ovulatory, and luteal phases of a single menstrual cycle. Blood samples were collected over 10 hours for triazolam and over 30 minutes for ICG. Triazolam and indocyanine green concentrations were quantitated by electron capture gas chromatography and spectrophotometry, respectively. Noncompartmental analysis was used to determine relevant pharmacokinetics parameters, which were statistically assessed using two-way ANOVA (p < 0.05). No statistical differences for triazolam were observed. Vd/F was lower in the luteal phase (107 L) as compared to the follicular (138 L) and ovulatory (133 L) phases. Clearance of triazolam was comparable in the follicular (583 ml/min), ovulatory (565 ml/min), and luteal (538 ml/min) phases. ICG also revealed no significant differences across the phases. These results suggest that the phases of the menstrual cycle do not influence triazolam or ICG pharmacokinetics.

Effect of three caffeine doses on plasma catecholamines and alertness during prolonged wakefulness.

OBJECTIVE: Determine the relationship between caffeine, catecholamines, and alertness during prolonged wakefulness. METHODS: Following 49 h of prolonged wakefulness, each of 50 healthy males (18-32 years) orally ingested either a placebo or one of three doses of caffeine, 2.1 (low), 4.3 (medium), or 8.6 mg kg-1 body weight (high), in a randomized double-blind design. Wakefulness continued for an additional 12 h during which venous blood samples were collected for catecholamine and caffeine analysis [determined using high-performance liquid chromatography (HPLC)]. A sleep latency test, the Stanford sleepiness scale, and a choice reaction time test were administered periodically during the post-dosing period and served as measures of alertness (physiological, subjective, and behavioral, respectively). RESULTS: Caffeine had no significant effect on noradrenaline, but adrenaline was significantly increased between 1 h and 4 h post-dosing in the high dose group compared with a placebo group. Following caffeine administration, responses to sleep latency, sleepiness scores, and reaction time scores showed dose-related changes that were exhibited by significant correlation coefficients. CONCLUSION: The results indicate that high doses of caffeine have a significant and beneficial effect on alertness during prolonged wakefulness.

Hemostatic responses to maximal exercise in oral contraceptive users.

OBJECTIVE: This study examined the effect of exercise on markers of fibrinolysis and coagulation in users and nonusers of oral contraceptives. STUDY DESIGN: Fourteen oral contraceptive users and 14 nonusers performed a maximal exercise test on a cycle ergometer. Blood samples were collected before and immediately after the completion of the test. A repeated-measures analysis of variance was used for statistical analysis with values considered significant at P =.05. RESULTS: Acute maximal exercise resulted in significant increases in tissue plasminogen activator activity in both groups. There was a trend toward a smaller increase in tissue plasminogen activator activity in oral contraceptive users, but the difference between groups was not statistically significant. Plasminogen activator inhibitor 1 activity was reduced with exercise in both groups but with a significantly greater decrease observed in the nonusers (P <.0001). Prothrombin fragment 1+2 was significantly higher (P <.0001) in the oral contraceptive group but did not change with exercise. Epinephrine levels before and after exercise were similar between the 2 groups, but postexercise norepinephrine concentrations were significantly lower (P =.026) in the oral contraceptive users. CONCLUSION: These data suggest that oral contraceptive use blunts the fibrinolytic response to exercise. This, together with increased coagulation activation in oral contraceptive users, may alter the hemostatic balance during exercise.

The effect of the menstrual cycle on the pharmacokinetics of caffeine in normal, healthy eumenorrheic females.

OBJECTIVE: Hormonal fluctuations of estrogen and progesterone in eumenorrheic women may be capable of altering the pharmacokinetics of certain agents. The objective of this study was to determine the effect of the luteal, ovulatory and follicular phases of the menstrual cycle on the pharmacokinetics of caffeine, a low clearance, flow-independent drug. METHODS: Subjects were ten healthy, non-smoking, eumenorrheic females who were not pregnant and had not used oral contraceptives for a minimum of 3 months prior to the study. Blood samples were collected during one menstrual cycle for the determination of estradiol and progesterone concentrations during the follicular (days 2-6 post-onset of menses), ovulatory (days 13-16 post-onset of menses) and luteal (days 22-26 post-onset of menses) phases. Caffeine was administered over a single menstrual cycle during the follicular, ovulatory and luteal phases. Each subject was administered a single oral dose of caffeine (300 mg) in 100 ml of lemonade during each phase of the menstrual cycle. A venous catheter was used to collect blood samples at pre-dose and at the following time points: 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 and 24 h. Plasma caffeine concentrations were determined using a validated ultraviolet high-performance liquid chromatography method. RESULTS: There were no significant (P < 0.05) differences in the pharmacokinetic parameters of caffeine across the menstrual cycle phases. The average area under the plasma concentration-time curve (AUCinf) was 93.01 mg 1(-1) x h and the absorption rate constant (ka) was 2.88 h(-1) during the ovulatory phase, 83.0 mg 1(-1) h and 2.06 h(-1), respectively, during the luteal phase and 84.7 mg 1(-1) x h and 1.84 h(-1), respectively, during the follicular phase. CONCLUSIONS: These findings suggest that the menstrual cycle does not significantly alter the pharmacokinetics of caffeine.

Improvement in hypoxemia at 4600 meters of simulated altitude with carbohydrate ingestion.

BACKGROUND: Carbohydrate ingestion increases the relative production of carbon dioxide which results in an increase in ventilation in normal individuals. An increase in ventilation at altitude can result in improvement of altitude-induced hypoxemia. HYPOTHESIS: Carbohydrate ingestion will increase the arterial blood oxygen tension and oxyhemoglobin saturation during acute high altitude simulation. METHODS: There were 15 healthy volunteers, aged 18-33 yr, who were given a 4 kcal x kg(-1) oral carbohydrate beverage administered 2.5 h into an exposure to 15,000 ft (4600 m) of simulated altitude (5.5 h after the last meal). Altitude was simulated by having subjects breath a 12% oxygen/balance nitrogen mixture while remaining at sea level. Arterial blood gas samples were drawn at baseline and at regular intervals up to 210 min after carbohydrate ingestion. Subjects were evaluated for AMS by use of the Environmental Symptoms Questionnaire (ESQ) and a weighted average of cerebral symptom score (AMS-C). RESULTS: Baseline PaO2 increased significantly (p < 0.01) from 43.0 +/- 3.0 mmHg at 4600 m before carbohydrate ingestion to 46.8 +/- 6.2 mmHg at 60 min after carbohydrate ingestion. Arterial oxygen saturation rose significantly (p < 0.01) from a baseline of 79.5% +/- 5.1 to 83.8% +/- 6.42 at 60 min. CONCLUSIONS: Carbohydrate consumption significantly increased oxygen tension and oxyhemoglobin saturation in arterial blood of normal subjects during simulated altitude. Effects reached statistical significance across all subjects at 60 min. There was no significant difference in arterial oxygen levels or arterial oxygen saturation in subjects who developed AMS vs. those who did not develop AMS.

Gender effect on beta-endorphin response to exercise.

PURPOSE: Twelve healthy men (26.4 yr) and women (26.8 yr) were compared at rest and after cycling for 25 min at 60 and 80% VO2max to determine whether gender and menstrual cycle influenced circulating beta-endorphin concentration (BE). METHODS: VO2max was determined on a cycle ergometer, and subjects completed the exercise in a randomized order. Women were tested in both the luteal (L) and follicular (F) phases of their menstrual cycle, which was confirmed by their blood estrogen levels. All tests were conducted in the morning after a 30-min rest (12-h postabsorptive). An indwelling venous catheter placed in a forearm vein enabled blood sampling at rest, 25 min of cycling, and 25 min of recovery. RESULTS: Resting BE was similar for men before both 60 and 80% intensities of exercise, 5.27 +/- 0.43 and 5.30 +/- 0.33 pmol.mL-1, respectively. BE was not significantly changed at 60% VO2max (6.54 +/- 0.33 pmol.mL-1) but significantly increased at 80% VO2max (11.90 +/- 1.98 pmol.mL-1). Women tended to have slightly lower BE during the L compared with F, but this did not reach significance (L = 4.40 +/- 0.22, F = 4.73 +/- 0.30 pmol.mL-1). Cycling at 60% VO2max did not significantly increase BE in the L (5.41 +/- 0.42 pmol.mL-1) nor the F (5.35 +/- 0.40 pmol.mL-1). Cycling at 80% VO2max increased BE to a similar extent in both the L and F phase, respectively (10.44 and 10.96). Although the BE concentrations tended to be slightly lower in women compared with men at 80% VO2max, this did not reach statistical significance. CONCLUSIONS: These data suggest that women cycling at 80% VO2max will have a similar BE response to men independent of their menstrual cycle. BE in women at rest and who exercise at lower exercise intensities may have slightly lower BE levels then men independent of the time of the women's menstrual cycle.

Plasma catecholamine and ventilatory responses to cycling after propranolol treatment.

The purpose of the present study was to examine the relationship between minute ventilation (VE) and plasma concentrations of epinephrine (EPI) and norepinephrine (NE) during incremental cycling (20 W.2 min-1) performed under conditions of beta-adrenergic blockade (80 mg of propranolol) and placebo in six untrained male subjects. No significant differences existed between treatments in O2 uptake, CO2 output, blood lactate, pH, or VE during the submaximal work stages of incremental exercise common to both treatments (20 - 220 W). During exercise with beta-blockade, EPI, and NE concentrations were both significantly elevated compared with control levels at every submaximal work stage. Significant positive correlations between VE and plasma levels of EPI and NE were found during both beta-blockade (r = 0.98 and 1.00) and control conditions (r = 0.98 and 0.96). Although the high correlations were unchanged during exercise with beta-blockade, the slopes of the regression lines for the VE-EPI and the VE-NE relationships were both significantly reduced compared with control conditions. Beta-blockade resulted in elevated plasma levels of both EPI and NE compared with control conditions without causing a change in exercise VE. These findings suggest that catecholamines may not be important substances in regulating breathing during exercise.

Visual performance with the Aviator Night Vision Imaging System (ANVIS) at a simulated altitude of 4300 meters.

This study determined if visual performance with Aviator Night Vision Imaging System (ANVIS) was degraded by the degree of hypoxia experienced at the maximum flight altitude currently authorized (U.S. Army regulations) without supplemental oxygen. Visual acuity and contrast sensitivity with ANVIS were tested under simulated starlight and full moonlight illumination in a hypobaric chamber: at ground level (93 m), 5 min and 30 min after ascent to 4300 m, and 10 min after return to ground level. Visual acuity was significantly (p < 0.05) degraded by a small amount (0.05 log minimal angle resolvable) after 30 min at 4300 m. Contrast sensitivity was not significantly degraded at any time. No significant difference between males (n = 11) and females (n = 6) on any measure of visual performance was detected. Females did have a significantly lower percent oxygen saturation of hemoglobin compared with males at altitude (72% versus 80% after 30 min). The results suggests that visual acuity ANVIS is degraded slightly after 30 min of exposure to 4300 m, although less than what would be expected with unaided night vision under these conditions.

Dose-dependent caffeine pharmacokinetics during severe sleep deprivation in humans.

Following 49 h of sleep deprivation, 37 healthy males ingested either 2.1, 4.3, or 8.6 mg*kg-1 body weight of caffeine in a randomized double-blind design. Subjects were sleep deprived for additional 12 h and venous blood samples were collected intermittently. Caffeine and primary metabolite concentrations were determined by HPLC. Pharmacokinetics were computed using the Lagran computer program. The ratio of the primary human metabolite, paraxanthine, to caffeine was used to estimate the rate of metabolism. There was a significant (p < 0.05) and disproportional increase in the dose normalized caffeine AUC and a significant decrease in its clearance associated with increasing dose. In addition, the paraxanthine to caffeine ratio significantly decreased with an increase in dose, indicating that the rate of caffeine metabolism decreased. These results demonstrate that under the conditions of severe sleep deprivation caffeine exhibits dose-dependent pharmacokinetics. In addition, these results are consistent with a model of capacity-limited metabolism.

Effects of chronic hypoxia on the pharmacokinetics of caffeine and cardio-green in micro swine.

METHODS: The pharmacokinetics of caffeine and cardio-green (ICG) were examined in four micro swine at sea level (SEA) and following 21 d continuous exposure to 4600 m (ALT) in a hypobaric chamber. Caffeine (84.7 mg) and ICG (10 mg) were administered as separate intravenous boluses and sequential blood samples collected. RESULTS: Caffeine clearance significantly (p < 0.05) increased in ALT (96.8 +/- 20.0 ml.min-1) as compared to SEA (53.6 +/- 24.8 ml.min-1), demonstrating that liver function increased in ALT. There was no significant change in the ratio of primary metabolites to caffeine, suggesting that the increase in clearance was not due to a change in the rate of caffeine metabolism. ICG clearance significantly increased in ALT (179.8 +/- 57.4 ml.min-1) as compared to SEA (84.4 +/- 28.9 ml.min-1) indicating that hepatic blood flow (HBF) increased. CONCLUSION: These results demonstrate that chronic exposure to 4600 m increases the clearance of caffeine and ICG in the micro swine model and suggests that the increase in caffeine clearance is related to HBF.

Effects of altitude (4300 m) on the pharmacokinetics of caffeine and cardio-green in humans.

The effects of chronic exposure to high altitude on the pharmacokinetics of caffeine and cardio-green (ICG) were examined in eight healthy males (23-35 y) at sea level (SEA) and following 16 days residence at 4300 m (ALT). ICG (0.5 mg. kg-1) was administered as an intravenous bolus and caffeine (4 mg. kg-1) in an orally ingested solution. The concentration of ICG, caffeine, and the primary metabolites of caffeine (MET) were determined in serial blood samples and their pharmacokinetics computed. In comparison to SEA, ALT resulted in a significant decrease in a caffeine half-life (t1/2, 4.7 vs 6.7 h) and area under the curve (2.5 vs 3.7 g.l-1.min-1), and increased clearance (117 vs 86 ml.min-1.70 kg-1). In ALT the area under the curve the ICG significantly decreased (85 vs 207 mg.l-1.min-1) and the volume of distribution and clearance increased (5.2 vs 2.4 l and 532 vs 234 ml.min-1 respectively) compared to SEA. There was a significant increase in the AUC ratio of MET to caffeine indicating that either metabolite formation or elimination was increased in ALT. These results demonstrate that in humans, chronic exposure to 4300 m results in the modification of the pharmacokinetics of caffeine and ICG.

Altitude and time of day effects on EEG spectral parameters.

Electroencephalographic (EEG) recordings were obtained from nine male subjects at sea level and again following rapid ascent to high altitude (4300 meters) at 0900, 1600, and 1830 h. Electroencephalographic data were subjected to Fast Fourier Transformation and analyzed for beta, spindle, alpha, theta, delta, and total amplitudes. Total amplitude increased from baseline to altitude while relative theta (absolute theta/total amplitude) decreased from baseline to altitude. Amplitude for absolute and relative spindle and total amplitude increased across the day. The results indicate that altitude exerts an effect on the waking electroencephalogram which can be quantified via spectral analysis.

Caffeine reversal of sleep deprivation effects on alertness and mood.

This study assessed the ability of high doses of caffeine to reverse changes in alertness and mood produced by prolonged sleep deprivation. Fifty healthy, nonsmoking males between the ages of 18 and 32 served as volunteers. Following 49 h without sleep, caffeine (0, 150, 300, or 600 mg/70 kg, PO) was administered in a double-blind fashion. Measures of alertness were obtained with sleep onset tests, the Stanford Sleepiness Scale (SSS), and Visual Analog Scales (VAS). Sleep deprivation decreased onset to sleep from a rested average of 19.9 min to 7 min. Following the highest dose of caffeine tested, sleep onset averaged just over 10 min; sleep onset for the placebo group averaged 5 min. Scores on the SSS increased from a rested mean of 1.6-4.8 after sleep deprivation. Caffeine reduced this score to near rested values. Caffeine reversed sleep deprivation-induced changes in three subscales of the POMS (vigor, fatigue, and confusion) and produced values close to fully rested conditions on several VAS. Serum caffeine concentrations peaked 90 min after ingestion and remained elevated for 12 h. This study showed that caffeine was able to produce significant alerting and long-lasting beneficial mood effects in individuals deprived of sleep for 48 h.

Effects of simulated high altitude exposure on long-latency event-related brain potentials and performance.

The N100, P200, N200 and P300 components of the auditory event-related potential were recorded from 10 male subjects at 0900, 1600, and 1830 hours at sea level and again following a rapid ascent to simulated 4300 m altitude. Amplitude and latency of components, ear oximetry, and concurrent performance measures (reaction time and counting errors) were assessed. Amplitude of P300 decreased, while P300 latency and reaction time increased, following ascent to altitude. However, the time course of altitude effects differed for amplitude versus latency. Components N100, P200, N200, and counting errors were unaffected by altitude. The results indicate that central measures of cognitive capacities are differentially sensitive to high altitude. The time course of altitude effects on P300 amplitude versus P300 latency suggests that the two measures reflect different aspects of a response to hypobaric hypoxia exposure.

A comparison of the blood lactate and plasma catecholamine thresholds in untrained male subjects.

The relationships between the plasma epinephrine threshold (TE), the norepinephrine threshold (TNE), and the blood lactate threshold (Tlact) were examined during incremental cycling in 10 untrained male subjects. When oxygen uptake (VO2) measured at each threshold was expressed as a percent of VO2max, the thresholds occurred at 40.8 +/- 2.4%, 45.5 +/- 3.0%, and 46.6 +/- 3.0% for Tlact, TE, and TNE, respectively. The average VO2 and power output values obtained at the lactate and epinephrine thresholds were not found to be significantly different (p < 0.10). However, Tlact and TE occurred simultaneously in six subjects, whereas TE occurred at a higher work stage than Tlact in the other four subjects. The mean VO2 and power output values determined at TNE were found to be significantly greater than the values obtained at Tlact (p < 0.05). These two thresholds occurred together in four subjects, while TNE was observed to occur at a higher work stage than Tlact in the other six subjects. None of the differences between TE and TNE were significantly different. Although plasma norepinephrine concentrations were much greater than those for epinephrine at a given power output, the two catecholamine thresholds occurred simultaneously in seven subjects. The results are not consistent with the hypothesis that the increase in plasma catecholamine levels during incremental exercise is the sole determinant of the lactate threshold. It is also possible that a decrease in muscle pH, due to increased lactic acid, stimulated a reflex increase in sympathetic outflow and a subsequent rise in catecholamine levels.

Effect of high terrestrial altitude and supplemental oxygen on human performance and mood.

Sustained exposure to high terrestrial altitudes is associated with cognitive decrement, mood changes, and acute mountain sickness (AMS). Such impairment in aviators could be a safety hazard. Thirteen male soldiers, ages 19-24, ascended in 10 min from sea level to 4,300 m (simulated), and remained there 2.5 d. Four times per day, subjects completed a test battery consisting of nine cognitive tests, a mood scale, and an AMS questionnaire. During one test session per day, subjects breathed 35% oxygen instead of ambient air. Analysis revealed transient deficits on altitude day 1 for three cognitive tasks. Most tasks displayed a persistent training effect. Sick subjects' moods were more negative and their performance improvement less. On altitude day 1, oxygen administration improved performance on two cognitive tests and one mood subscale. Following rapid ascent to 4,300 m, performance is most affected during the first 8 h. Individuals affected by AMS tend to improve more slowly in performance and have more negative moods than those who feel well.