Intravenous Administration Of Caffeine Research Articles

Respiratory Safety Pharmacological Testing with Single Intravenous Administration of Caffeine in Sprague-Dawley Rats.

As caffeine consumption continues to increase, both positive and negative effects are becoming evident. Caffeine directly affects the cardiovascular system, including heart function and rate. Thus, understanding the current respiratory safety pharmacological responses is of utmost importance. To elucidate the respiratory safety pharmacological characteristics of caffeine, male Sprague-Dawley rats, aged 6 weeks, were intravenously administered doses of 0, 2, 6, and 20 mg/kg of caffeine. Respiratory rate, tidal volume, and minute volume were subsequently measured. In this study, we observed a significant increase in respiratory rate and minute volume, but a remarkable reduction in tidal volume following the intravenous administration of caffeine at doses exceeding 6 mg/kg. These changes were evident within the timeframe of 0.25 to 1.5 h. The data we have collected can serve as valuable foundational scientific information for future research on caffeine, encompassing absorption, distribution, metabolism, excretion, and pharmacological core-battery experiments.

A Narrative Review on Prevention and Treatment Strategies of Post Spinal Anesthesia Headache

Background: Post spinal anesthesia headache (PSAH) is a headache occurring after spinal anesthesia induction due to Dura and arachnoid puncture and has a significant effect on the patients’ post operative well being. Methods: We run a cross sectional descriptive study on patient under spinal anesthesia that suffer from post spinal anesthesia headache parallel with a review on observational and experimental studies in the medical databases of PubMed, Scopus, Embase, Cochrane for preparing a strategy in prevention and treatment of post spinal anesthesia headache. Aim of this study was adapting different treatment method and prevention system of Post Spinal Anesthesia Headache (PSAH) according to our facilities base on our observation and experiences. Results: The overall incidence of post-Spinal Anesthesia headache has a very wide range. Its incidence obtained 17.3% by spinal needle 25G Quincke in our observation. Under hydration and tension headaches could be a factor influencing the incidence of PSAH. Intravenous administration of caffeine may be effective for prophylaxis of PSAH. Pregabalin has also been shown to alleviate PSAH. Drugs that have been used to treat PSAH include caffeine, NSAIDs, vasopressin, hydrocortisone, dexamethasone, theophylline, sumatriptan, gabapentin and adrenocorticotropic hormone (ACTH). Conclusion: A combination of keeping patients normovulemic during the spinal anesthesia induction and prophylaxis prescription of caffeine and Dexamethone before and; Aminophylline and NSAIDS after the procedure could have a main role in keeping and treatment of the patient from PSAH.

Effects of caffeine administration on sedation and respiratory parameters in patients recovering from anesthesia.

Caffeine has been shown to enhance the speed of recovery from general anesthesia in murine models, though data in human patients is lacking. This is a retrospective review of intravenous caffeine administration (median dose 150 [125, 250] mg) to 151 heavily sedated patients in the post-anesthesia recovery area, to determine the association between caffeine administration and changes in sedation score, respiratory rate, and oxyhemoglobin saturation. Richmond Agitation-Sedation Scale (RASS) score, respiratory rate, and oxyhemoglobin saturation values were obtained during the 90-minute period prior to and following caffeine administration. Generalized estimating equations (GEE) with explanatory variables of time, caffeine, and the time-by-caffeine interaction were created to assess changes in the variables of interest after caffeine administration. Following the administration of caffeine, the RASS scores increased (estimate = 0.57, SE = 0.14, p < 0.001) but a trend over time or in the interaction effect was not observed, suggesting that the changes in RASS were not solely due to the recovery from anesthesia over time. No association was found between caffeine administration and changes in respiratory parameters. No adverse cardiac events were observed. Our data suggests that intravenous caffeine may enhance the speed of recovery following general anesthesia, though future prospective trials are necessary to define the optimal dose and timing of administration.

Effects of intravenous caffeine on fractional flow reserve measurements in coronary artery disease

BackgroundIntravenous adenosine is used to minimise the coronary micro-resistance to achieve maximal hyperaemia along with nitrates for optimal fractional flow reserve (FFR) measurements. We hypothesise that caffeine, being a competitive...

Caffeine Increases Cerebral Cortical Activity in Preterm Infants

Caffeine improves the rate of survival without neurodevelopmental disability in preterm infants. The mechanisms underlying neuroprotection are incompletely understood. In 51 preterm infants studied by amplitude-integrated electroencephalography from 2 hours before to 2 hours after intravenous caffeine administration, we found that caffeine increases amplitudes and periods of continuity.

Acute hemodynamic effects of caffeine administration in premature infants

Administration of caffeine citrate (caffeine) has been a central component of the treatment of apnea of prematurity. However, given its multiple pharmacologic effects, caffeine might be expected to produce hemodynamic changes in heart rate, stroke volume, cardiac output and vascular resistance. In this prospective observational study, we report the hemodynamic effects of intravenous caffeine administration in a population of premature infants who received caffeine to correct or prevent apnea of prematurity. Hemodynamic effects of caffeine were determined in 31 infants. Stroke volume was measured via echocardiogram, using velocity time integral at the aortic root diameter. Statistically univariate analyses were performed parametrically using paired t-test and nonparametrically (sign test). Multivariate linear regression models were used to identify subgroup covariate effects. After intravenous caffeine, cardiac index increased in 31 of 31 trials, by an average of 14.6+/-16.3% (s.d.); stroke volume increased in 24 of 31 trials, by 7.8+/-12.2%; heart rate increased in 28 of 31 trials by 7.7+/-7.2 beats per min; and blood pressure increased in 25 of 31 trials, by 4.1+/-5.8 mm Hg (all P<0.001). Multivariate linear regression revealed no significant effect of dose, birth weight, gestational age or postnatal age. Intravenous caffeine consistently increases cardiac output and blood pressure in relatively stable premature infants, when given to treat or prevent apnea of prematurity. We speculate that there may be a role for caffeine in the hemodynamic treatment of hypotensive/hypoperfused infants.

Effects of intravenous administration of caffeine on physiologic variables in exercising horses

To investigate the effect of acute administration of caffeine on the athletic performance of Arabian horses. 12 healthy adult Arabian horses that were trained for exercise on a treadmill. By use of a crossover study design, horses received each of the following treatments: IV administration of caffeine (5 mg/kg) and IV administration of approximately the same volume of saline (0.9% NaCl) solution. Order of treatment was randomized, and there was a 10-day interval between treatments. Thirty minutes after treatments, horses underwent an incremental exercise test (IET) on a treadmill. Blood samples were collected 15 seconds before the end of each velocity step of the IET for determination of blood lactate, blood glucose, plasma cortisol, and plasma insulin concentrations. Heart rate and hematologic variables were also analyzed. Velocities achieved when heart rates were 180 and 200 beats/min increased significantly in caffeine-treated horses, compared with control horses. Velocities corresponding to blood lactate concentrations of 4 and 2 mmol/L decreased significantly in caffeine-treated horses, compared with control horses. In comparison between groups, insulinemia was greater in control horses and glycemia was greater in caffeine-treated horses. Plasma cortisol concentration was significantly lowered by treatment with caffeine. IV administration of caffeine at 5 mg/kg improved the performance of Arabian horses during intense exercise of short duration and diminished the oxidative metabolism of glucose.

Pharmacokinetics of intravenously administered caffeine in healthy alpacas (Lama pacos) and llamas (Lama glama)

To determine the pharmacokinetic disposition of IV administered caffeine in healthy Lama spp camelids. 4 adult male alpacas and 4 adult female llamas. Caffeine (3 mg/kg) was administered as an IV bolus. Plasma caffeine concentrations were determined by use of high-performance liquid chromatography in 6 animals and by use of liquid chromatography-mass spectrometry in 2 llamas. Median elimination half-life was 11 hours (range, 9.3 to 29.8 hours) in alpacas and 16 hours (range, 5.4 to 17 hours) in llamas. The volume of distribution at steady state was 0.60 L/kg (range, 0.45 to 0.93 L/kg) in alpacas and 0.75 L/kg (range, 0.68 to 1.15 L/kg) in llamas. Total plasma clearance was 44 mL/h/kg (range, 24 to 56 mL/h/kg) in alpacas and 42 mL/h/kg (range, 30 to 109 mL/h/kg) in llamas. High-performance liquid chromatography and liquid chromatography-mass spectrometry were suitable methods for determination of plasma caffeine concentrations in alpacas and llamas. Plasma caffeine concentration-time curves were best described by a 2-compartment model. Elimination half-lives, plasma clearance, volume of distribution at steady state, and mean residence time were not significantly different between alpacas and llamas. Intravenous administration of caffeine at a dose of 3 mg/kg did not induce clinical signs of excitement.

Effect of caffeine on theophyliine on cerebral blood flow response to brain activation: In vitro and in vivo studies

Despite its wide consumption and well-documented psychoactive effects, little is known regarding the effects of caffeine, an adenosine receptor antagonist, on neurovascular coupling. In the present study, we evaluated the effects of caffeine on intracerebral arterioles in vitro and on the pial circulation in vivo during cortical activation induced by contralateral sciatic nerve stimulation (SNS). In our in vitro studies, we utilized isolated intracerebral arterioles to determine the effects of caffeine (10 or 50uM) on vasodilatation induced by extraluminal application of adenosine. Adenosine caused dose-dependent dilations. Pretreatment with caffeine alone, at either of the concentrations tested, had no effect on resting diameter. The higher concentration (50uM) of caffeine resulted in significant attenuation of adenosine-induced vasodilatation (p<0.05, n=5), whereas 10uM had no effect. We utilized reverse-phase HPLC to quantify in vivo CSF caffeine concentrations. Intravenous administration of 5 mg/kg caffeine led to CSF concentrations of approximately 3uM, whereas higher doses (10 and 40 mg/kg), resulted in CSF caffeine accumulations of more than 10 and 60uM, respectively (n=18). To study the effect of caffeine on neurovascular coupling, we created a close cranial window in anesthetized, ventilated and temperature-regulated rats. Pial arteriolar response to contralateral sciatic nerve stimulation (SNS) was then evaluated before and after intravenous administration of caffeine (5, 10, 20 30 & 40 mg/kg). Contralateral SNS resulted in a 23.8% increase in pial arteriolar diameter in the hindlimb sensory cortex under control conditions. Intravenous administration of caffeine at the lowest dose (5 mg/kg), equivalent to 2 cups of brewed coffee, had no effect on resting arteriolar diameter but slightly suppressed the arteriolar response to somatosensory stimulation. This trend, however, did not reach statistical significance. At all of the higher doses (10, 20, 30 & 40 mg/kg, i.v.), caffeine significantly attenuated the cerebral blood flow responses to contralateral SNS (Figure 1; p<0.05; n=6). Caffeine administration also significantly reduced resting arteriolar diameter. In contrast, hypercarbic vasodilatation was unaffected by caffeine at any of the doses tested. The results of the present study demonstrate that caffeine significantly reduces cerebrovascular responses to both adenosine and to somatosensory stimulation and supports a role of adenosine in the regulation of CBF during functional neuronal activity.

Effect of Caffeine on Cerebral Blood Flow Response to Somatosensory Stimulation

Despite caffeine's wide consumption and well-documented psychoactive effects, little is known regarding the effects of caffeine on neurovascular coupling. In the present study, we evaluated the effects of caffeine, an adenosine receptor antagonist, on intracerebral arterioles in vitro and subsequently, on the pial circulation in vivo during cortical activation induced by contralateral sciatic nerve stimulation (SNS). In our in vitro studies, we utilized isolated intracerebral arterioles to determine the effects of caffeine (10 or 50 micromol/L) on adenosine-induced vasodilatation. At the lower concentration, caffeine was without effect, but at the higher concentration, caffeine produced significant attenuation. In our in vivo studies, we determined the cerebrospinal fluid (CSF) caffeine concentrations at 15, 30, and 60 mins after intravenous administration of 5, 10 and 40 mg/kg. At the latter two concentrations, CSF levels exceeded 10 micromol/L. We then evaluated the pial arteriolar response during cortical activation caused by contralateral SNS after administering caffeine intravenously (0, 5, 10, 20 30, and 40 mg/kg). The pial circulation was observed through a closed cranial window in chloralose-anesthetized Sprague-Dawley rats. The contralateral sciatic nerve was isolated, positioned on silver electrodes and stimulated for 20 secs (0.20 V, 0.5 ms, and 5 Hz). Arteriolar diameter was quantified using an automated video dimension analyzer. Contralateral SNS resulted in a 23.8% +/-3.9% increase in pial arteriolar diameter in the hindlimb sensory cortex under control conditions. Intravenous administration of caffeine at the lowest dose studied (5 mg/kg) had no effect on either resting arteriolar diameter or SNS-induced vasodilatation. However, at higher doses (10, 20, 30, and 40 mg/kg, intravenously), caffeine significantly (P < 0.05; n = 6) attenuated both resting diameter and cerebral blood flow (CBF) responses to somatosensory stimulation. Intravenous administration of theophylline (10, 20, and 40 mg/kg), another adenosine receptor antagonist, also significantly reduced SNS-induced vasodilatation in a dose-dependent manner. Hypercarbic vasodilatation was unaffected by either caffeine or theophylline. The results of the present study show that caffeine significantly reduces cerebrovascular responses to both adenosine and to somatosensory stimulation and supports a role of adenosine in the regulation of CBF during functional neuronal activity.

Serum aminotransferase activity as a predictor of clearance of drugs metabolized by CYP isoforms in rats with acute hepatic failure induced by carbon tetrachloride

The values of serum aminotransferase activity (AST) in untreated rats and rats with acute hepatic failure at 24 h after an oral administration of CCl 4 (0.5 ml/kg) were 85±9 IU/l and 4260±620 IU/l (mean±S.D., n=6), respectively. The values of total clearance (CL tot) after intravenous administration of caffeine, tolbutamide, chlorzoxazone or lidocaine (as probe drugs for various CYP isoforms) to CCl 4-treated rats were decreased to about 1/8, 1/3, 1/3 or 1/2 compared with those in untreated rats. Good correlations were observed between mRNA expression and enzyme activity of CYP2C11, CYP2E1, CYP3A2 and CYP1A2 in livers of rats given various doses of CCl 4. There was also a good negative correlation between serum AST activity and hepatic enzyme activity of each CYP. The serum AST activities corresponding to a 50% decrease of CYP2C 11, CYP2E1, CYP3A2 and CYP1A2 activities were about 710, 780, 1030 and 1300 IU/l, respectively. In conclusion, when the serum AST value in CCl 4-treated rats reached about 4000 IU/l, the hepatic CYP activities were one-tenth or less of the control, although the degree of decrease of the CL tot values varied markedly. Nevertheless, the AST value appears to be a promising candidate for an indicator to predict appropriate dose modification of drugs for patients with acute hepatic failure.

Differential Effects of Caffeine on Dopamine and Acetylcholine Transmission in Brain Areas of Drug-naive and Caffeine-pretreated Rats

The effects of caffeine on extracellular dopamine and acetylcholine have been studied in freely moving rats implanted with concentric microdialysis probes in the nucleus accumbens shell and core and in the medial prefrontal cortex. Intravenous administration of caffeine (0.25, 0.5, 1.0, 2.5 and 5.0 mg/kg) dose-dependently increased dopamine and acetylcholine dialysate concentrations in the medial prefrontal cortex, while it did not affect dialysate dopamine in the shell and core of the nucleus accumbens. Intraperitoneal administration of caffeine (1.5, 3, 10, 30 mg/kg) also failed to affect DA in the shell and core of the nucleus accumbens. Such effects were duplicated by intravenous administration of DPCPX, a selective antagonist of adenosine A1 receptors, and of SCH 58261, an antagonist of A2a receptors. The effect of caffeine on prefrontal dopamine and acetylcholine transmission was also studied in rats chronically administered with caffeine (25 mg/kg, twice a day for seven days). At the end of this treatment rats became tolerant to the locomotor stimulating effects of a dose of 1 and 2.5 mg/kg i.v. of caffeine; these doses, however, still increased dialysate acetylcholine but did not affect dopamine in the prefrontal cortex. Therefore, in rats made tolerant to the locomotor stimulant effects of caffeine, tolerance developed to the dopamine stimulant but not to the acetylcholine stimulant effect of caffeine in the prefrontal cortex. The lack of acute stimulation of dopamine release in the nucleus accumbens shell by caffeine is relevant to the issue of its addictive properties and of the role of DA in drug- and substance-addiction. On the other hand, the dissociation between tolerance to the locomotor effects of caffeine and stimulation of acetylcholine release in the prefrontal cortex suggests that this effect might be correlated to the arousing effects of caffeine as distinct from its locomotor stimulant properties.

Myth: fluids, bed rest, and caffeine are effective in preventing and treating patients with post-lumbar puncture headache.

Myth: fluids, bed rest, and caffeine are effective in preventing and treating patients with post-lumbar puncture headache.

Prophylactic Intravenous Administration of Caffeine and Recovery After Ambulatory Surgical Procedures

To determine whether prophylactic intravenous administration of caffeine, to daily caffeine users, decreases the frequency of postoperative headache and shortens recovery time.The study was a prospective, randomized, double-blind investigation with predetermined sample size and statistical power.After Mayo Institutional Review Board approval and informed consent were obtained, 300 adult ambulatory surgical patients were enrolled in this study, which included randomization to receive either placebo or caffeine (200 mg intravenously) in the postanesthesia care unit. While recuperating, patients were allowed their choice of postoperative beverages. Before dismissal, patients completed a questionnaire providing details about intake of caffeine and tobacco, history of headache, and demographic data. Patients were considered "at risk" for symptoms of caffeine withdrawal if they did not drink a caffeinated beverage after the surgical procedure.Completed questionnaires were obtained from 234 patients. Patients at risk for symptoms of caffeine withdrawal were less likely to have a postoperative headache if they received caffeine intravenously rather than placebo-10% versus 23% (P < 0.05). Time until recovery was not significantly different between caffeine and placebo study groups.We conclude that prophylactic intravenous administration of caffeine was beneficial for those patients at risk for symptoms of caffeine withdrawal. For patients who consume caffeinated beverages on a daily basis, we recommend prophylactic administration of caffeine on the day of an ambulatory surgical procedure and anesthesia.

Relationship between caffeine-induced ocular hypertension and ultrastructure changes of non-pigmented ciliary epithelial cells in rats.

The purpose of this study was to morphologically assess a possible mechanism for caffeine-induced ocular hypertension. Taking into consideration the relationship between the secretion of aqueous humor and the ultrastructure of the ciliary body, the time course of the morphological features in the ciliary epithelium when caffeine was administered intravenously to male Wistar rats was investigated by electron-microscopy. These morphological findings were also compared with the changes in the intraocular pressure (IOP). A significant increase in IOP was noted 15 min and 1 hr after a single dosing of caffeine alone. This change disappeared in all animals within 2 hr after dosing. The IOP in the animals receiving caffeine and the beta-blocker befunolol, which lowers the IOP by inhibiting aqueous humor secretion, decreased significantly from 15 min after dosing, and this change persisted 2 hr after dosing. In electron-microscopy 15 min and/or 1 hr after dosing with caffeine, a slight dilatation in the lateral intercellular spaces near the basement membrane of the non-pigmented ciliary epithelium was observed and the interdigitations between the non-pigmented epithelial cells were intact. Reversal of these changes was observed 2 hr after dosing. On the other hand, the lateral intercellular spaces between the non-pigmented epithelial cells were markedly dilated and the interdigitations were disorganized following dosing with caffeine alone and in combination with befunolol. These results described here indicate that the intravenous administration of caffeine causes ocular hypertension and also changes in the non-pigmented ciliary epithelium, suggesting an enhancement of aqueous humor transportation. This paradigm in the rat is considered to be useful to further assess caffeine-induced ocular hypertension and for use as an animal model in glaucoma research associated with an aqueous humor secretion.

Application of microdialysis for study of caffeine distribution into brain and cerebrospinal fluid in rats.

The usefulness of microdialysis was examined for the chronological determination of caffeine concentration in the brain and cerebrospinal fluids (CSF) following intravenous administration of caffeine in rats. The recovery percent of caffeine by microdialysis, the concentration ratio of caffeine in the dialysate against that in the brain tissue or CSF was determined. The recovery percent was proved to be constant at 5 different steady-state plasma concentrations of caffeine (0.1-280 nmol/ml) and in different collecting periods of dialysate ranging from 30 s to 10 min. The mean recovery percent in the brain and CSF were 10.9 and 13.1%, respectively. Thus, microdialysis was proved useful for determination of drug concentration in the tissue and biological fluids with time resolution of more than 30 s. The microdialysis method was then applied for the chronological determination of caffeine concentration in the brain and CSF following intravenous bolus administration. The estimated caffeine concentration in the brain and CSF was the same as those obtained by direct determination in isolated brain and CSF, respectively. Transfer of caffeine from plasma to brain and CSF were further pharmacokinetically analyzed using a modified 2-compartment model. In this kinetic model, the transfer of caffeine between the CSF and brain was neglected, since the mutual transfer of caffeine was not detected in in vivo experiments. Calculated curves were well fitted on observed caffeine concentrations in the plasma, brain and CSF.

The Effect of Caffeine on Renal Vein Renin Concentration in Patients With Renal Arterial Disease

The aim of this study was to investigate whether caffeine stimulates selectively renal vein renin levels at the side of unilateral stenosis in patients with renovascular hypertension. In this study seven of the involved patients had renal arterial stenosis and four had no stenosis. Four of the seven patients with a stenosis had retrospectively-proven renovascular hypertension. Renal vein renin sampling was performed before and after intravenous administration of caffeine. Caffeine did not induce any consistent effect on plasma renin activity in the renal veins, either on the stenotic side or on the contralateral side in patients with renovascular hypertension. There were no consistent caffeine mediated changes in systemic plasma renin activity.

Effect of paraxanthine on FFA mobilization after intravenous caffeine administration in humans

Because it has previously been shown that it takes much more caffeine to cause fat mobilization in vitro than in vivo, it has been suggested that there may be an active metabolite working with caffeine causing an increase in lipolysis in vivo. To determine the relationship between the appearance of paraxanthine (caffeine's major dimethylxanthine metabolite) and free fatty acid (FFA) mobilization after intravenous caffeine administration, 10 men were studied at rest after receiving a dose of 4 mg/kg lean body mass. Venous blood samples were obtained before dosing and at minutes 5, 10, 15, 30, 45, 60, 90, 120, 150, and 180. Serum levels of FFA, glycerol, caffeine, and paraxanthine were determined in duplicate. Concentrations of FFA and glycerol were corrected for plasma volume changes. A high negative correlation was seen between decreases in caffeine and increases in FFA (r = -0.90) and a high positive correlation was seen between the appearance of paraxanthine and FFA (r = 0.93). It was concluded that paraxanthine may play a role in increased lipolysis after caffeine administration in humans.

Comparative effects of acute and chronic administration of caffeine on local cerebral glucose utilization in the conscious rat

The quantitative 2-[ 14C]deoxyglucose autoradiographic method was used to compare the effects of acute and chronic administration of caffeine on rat brain energy metabolism. The acute intravenous administration of caffeine (10 mg/kg) to naive rats induced widespread increases in glucose utilization in 20 of 62 structures, maily in striatal and related areas as well as in the 2 raphe nuclei and the locus coeruleus. After 2 weeks' chronic intraperitoneal injection of caffeine (10 mg/kg), increases in glucose utilization were seen in 6 of 62 structures: the substantia nigra, pars compacta, dorsal raphe, locus coeruleus and the 3 parts of the caudate nucleus. An acute caffeine injection (10 mg/kg) to these chronically caffeine-treated rats induced a further increase in glucose utilization in 9 additional structures but there was no significant difference in the effects of an acute administration of caffeine whether the rats had been chronically pretreated with caffeine or saline. The results of the present study show that brain energy metabolism seems to be subject to only partial tolerance to central stimulation by caffeine.

Relationship between total body clearance of caffeine and urine flow rate in elderly men.

The total body clearance (CL), renal clearance (CLR), and nonrenal clearance (CLNR) of caffeine from plasma were determined following the intravenous administration of caffeine (4 mg kg-1) to ten healthy men (aged 66-86 years) on three separate occasions. Positive correlations were observed between CL and urine flow rate (UFR), between CLR and UFR, and between CLNR and UFR (r = 0.8947, p = 0.0002; r = 0.8832, p = 0.0003; and r = 0.8920, p = 0.0002, respectively). Previous studies have established similar relationships between CLR and UFR for caffeine and its initial dimethylxanthine metabolites; theophylline, theobromine, and paraxanthine. A relationship between CL and UFR has not been reported previously.