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Caffeine Alters Skeletal Muscle Contraction by Opening of Calcium Ion Channels
Abstract
The aim of this study was to investigate the effect of caffeine on the amplitude and rate of skeletal muscle contraction using frog sciatic nerve-gastrocnemius muscle model. Caffeine is a xanthine alkaloid whose use is widely unregulated. It is taken as a central nervous system stimulant in various foods and drinks. The effect of caffeine on skeletal muscle contraction and a possible elucidation of its mechanism of action were investigated. The sciatic nerve-gastrocnemius muscle preparation of the frog mounted on a kymograph was utilized. Varying doses of caffeine was added to the organ bath at 5, 10, 15, 20 and 25 mg/mL and its effect on skeletal muscle contraction was studied. The effects of caffeine preceded by administration of acetylcholine, atropine, nifedipine, magnesium chloride and calcium gluconate at 25 mg/mL were also studied. A dose dependent increase in skeletal muscle contraction (25.25±0.48, 49.00 ±1.23, 52.38±2.58, 59.25±1.11 and 68.50±0.87 mV; p<0.05) was observed on administration of increasing doses (5, 10, 15, 20 and 25 mg/mL, respectively) of caffeine respectively. While a significant reduction (0.90±0.04 mV) and increase (77.50±1.56 mV) in strength of contraction was observed on administration of nifedipine and calcium gluconate respectively. Administration of magnesium chloride caused a significant decrease in the strength of contraction (28.25±5.01) as compared to control. However, there was no significant difference in the contraction period and relaxation period between the treatment groups. The findings imply that caffeine increases skeletal muscle contraction and suggests it exerts the effect through increasing calcium ion release.
... This apparent ergogenic effect may have to do with calcium (Ca 2+ ) ion channels of skeletal muscles. CAF showed a greater force and duration of muscle contraction in dissected gastrocnemius muscle of a frog 19 . Ca 2+ ion channels stayed open longer, causing an increase in cytosolic Ca 2+ concentrations from Ca 2+ being released by the sarcoplasmic reticulum (SR) 2 . ...
Caffeine (CAF) is known for its central nervous system (CNS) stimulating function by acting as an adenosine receptor antagonist, but it also has some ergogenic effects. That is, CAF has implications in enhancing physical performance and endurance 10. CAF has been shown to alter skeletal muscle contractions by opening of calcium ion channels 19. There is also some evidence that suggests that CAF affects rate of relaxation of the skeletal muscles 2. To further understand how caffeine affects humans in our daily living activities, the effects of CAF on dynamic and static balance were investigated. With the consumption of CAF, it can be assumed that there will be improvement in balance and motor control due to increase in force and duration of skeletal muscle contraction in the muscles being used for balance.
... The persons were asked to avoid caffeine consumption for 24 h before the experiment and avoid participation in any sports activity one day before the testing. The direct ergogenic effect of caffeine on the skeletal muscle's force and duration of contraction has been shown (Olorunschola & Achie, 2011;Tarnopolsky, 2008). The study was performed at participants' workplace. ...
The daily work tasks of dentists are associated with repeated movements and static load during the treatment of patients. Dentists’ profession includes manual dexterity and maintaining the occupational posture for a long time. Previously it has been noted that dentists have increased muscle stress in neck, shoulder and lower back regions. The aim of the present study was to compare the muscle tone and motor performance characteristics of neck and shoulder region in dentists and representatives of other professions who do not have similar static load of long-time duration (as controls). Twenty women aged 34–55 years participated in the study: ten dentists with the age (mean and SE) of 40.2 ± 3.9 years and ten controls (bookkeepers, security guards, office workers, printing house workers, laundry and dry cleaning workers) with the age of 40.9 ± 2.4 years; working period was on the average 14 years in both groups. The tone characteristics of m. trapezius and m. extensor carpi radialis were investigated by device Myoton-2 (Müomeetria Ltd, Estonia) at rest and at maximal voluntary contraction (MVC) in sitting position at the workplace of participants. The cervical range of motion (CROM) and the handgrip strength were measured. Significantly higher (P < 0.05) tone and elasticity characteristics of m. extensor carpi radialis and lower (P < 0.05) tone and elasticity characteristics of m. trapezius at rest were noted in dentists compared to controls. At MVC, no significant differences were found in the studied characteristics between body sides in the measured groups. Dentists had lower (P < 0.05) CROM of flexion and rotation than controls. In dentists emerged significant difference in muscle elasticity characteristics for the right body side, this is related with stretching for dentistry instruments.
... The persons were asked to avoid caffeine consumption for 24 h before the experiment and avoid participation in any sports activity one day before the testing. The direct ergogenic effect of caffeine on the skeletal muscle's force and duration of contraction has been shown (Tarnopolsky, 2008;Olorunschola & Achie, 2011). The study was performed at participants' workplace. ...
The daily work tasks of dentists are associated with repeated movements and static load during the treatment of patients. Dentists’ profession includes manual dexterity and maintaining the occupational posture for a long time. Previously it has been noted that dentists have increased muscle stress in neck, shoulder and lower back regions. The aim of the present study was to compare the muscle tone and motor performance characteristics of neck and shoulder region in dentists and representatives of other professions who do not have similar static load of long-time duration (as controls). Twenty women aged 34–55 years participated in the study: ten dentists with the age (mean and SE) of 40.2 ± 3.9 years and ten controls (bookkeepers, security guards, office workers, printing house workers, laundry and dry cleaning workers) with the age of 40.9 ± 2.4 years; working period was on the average 14 years in both groups. The tone characteristics of m. trapezius and m. extensor carpi radialis were investigated by device Myoton-2 (Müomeetria Ltd, Estonia) at rest and at maximal voluntary contraction (MVC) in sitting position at the workplace of participants. The cervical range of motion (CROM) and the handgrip strength were measured. Significantly higher (P < 0.05) tone and elasticity characteristics of m. extensor carpi radialis and lower (P < 0.05) tone and elasticity characteristics of m. trapezius at rest were noted in dentists compared to controls. At MVC, no significant differences were found in the studied characteristics between body sides in the measured groups. Dentists had lower (P < 0.05) CROM of flexion and rotation than controls. In dentists emerged significant difference in muscle elasticity characteristics for the right body side, this is related with stretching for dentistry instruments.
... The persons were asked to refrain from caffeine for 24 h before the experiment and avoid participation in any sports activity one day before the testing. The direct ergogenic effect of caffeine on the skeletal muscle has been shown (Tarnopolsky, 2008), and it has also been demonstrated that caffeine causes dose-dependent increases in the force and duration of the contraction of the skeletal muscle (accompanied by an increased release of calcium ions from the sarcoplasmatic reticulum) (Olorunschola and Achie, 2011). ...
The association between muscle tone and postural sway characteristics during standing was investigated in 27 healthy men aged 17–31 years. Frequency of muscle oscillations as an indicator of the tone, logarithmic decrement of the dampening of muscle oscillations as an indicator of the elasticity, and stiffness of the medial gastrocnemius (MG) muscle were measured bilaterally using a hand-held Myoton-3 device (Estonia). Postural sway of the centre of foot pressure during 30 s quiet bipedal standing was recorded using a Kistler force plate. As compared to the lying position, at standing on stable ground (SG) as well as on unstable ground (USG) (balance pad) the frequency of muscle oscillations was greater (162% and 166%, respectively) and so was stiffness (199% and 203%, respectively) but no significant differences for the logarithmic decrement of the dampening of muscle oscillations were noted. A greater coefficient of variation at standing on SG and USG as compared to the lying position for frequency of muscle oscillations (403% and 471%, respectively), for stiffness (177% and 187%, respectively), and for the logarithmic decrement of the dampening of muscle oscillations (120% and 122%, respectively) was found. Muscle tone and elasticity characteristics correlated positively with sway characteristics (radius and area of the centre of pressure) at USG standing. The change of posture from the supine to the standing position was accompanied by a marked increase in MG muscle tone and stiffness, but elasticity did not change. Coefficients of variation for the measured characteristics are suggested as new criteria for muscle function in relation to postural stability.
... These data are consistent with the previous demonstration of decreased magnitude of caffeineinduced contractions in six-week disused muscular fibers [30]. Caffeine causes gain of force and duration of skeletal muscle contraction by the release of ion calcium from the sarcoplasmic reticulum via physical coupling/conformational changes in the voltage-sensitive dihydropyridine receptor [19] and augment in myofilament sensitivity to the ion calcium [34]. We speculated that the change in the sensitivity of myofibrils to calcium observed at six weeks [30] may already be present after only two weeks of disuse. ...
This study analyzed the sensorial, structural and functional response of rats subjected to paw immobilization.
Animal pelvis, hip, knee and ankle were immobilized using waterproof tape during two weeks for assessment of sensorial response to thermal (hot plate test) and mechanical stimuli (Von Frey test), motor system structure (histology and radiography) and muscle function (soleus contractility).
Disuse animals became more responsive to thermal stimuli (49%), although less responsive to mechanical challenge (58%). Disuse animals showed local injuries such as reduction in muscle fiber diameter (16.7% in gastrocnemius, 5.7% in soleus), contractile activity (55% of the control maximal tonic contraction) and tibia cortical thickness (9.3%), besides increased nitrite:protein ratio, suggestive of protein degradation. Disuse also evoked systemic adaptations that include increase in serum lactate dehydrogenase (36.1%) and alkaline phosphatase (400%), but reduction in calcium (8.4%) and total serum protein (5.5%), especially albumin (34.2%).
Two weeks of functional paw disuse leads to local and systemic harmful adaptive changes in sensorial and structural systems. This study brings new insights into nervous and motor system mechanism associated with therapeutic limb immobilization in muscle and skeletal pathological conditions.
Copyright © 2015. Published by Elsevier Inc.
Mitochondria are central pieces of machinery of energy production within the cells. Mitochondrial deficits may be functional and structural or a result from aberrations in mitochondrial DNA (mtDNA), which is associated with several metabolic and chronic impairments. Improvement of mitochondrial function may be achieved by a verity of natural and chemical agents. Thereby, pathways or agents that regulate mitochondrial function are therapeutic targets for these diseases. Caffeine was shown to induce mitochondrial function and biogenesis. Depending on caffeine concentration and the target organ, this compound plays both inhibitory and stimulating roles on mitochondrial function. Here, we present a brief introduction to caffeine and its pharmacological activities. Besides, the involvement of mitochondria in some physiological actions at the presence of caffeine is discussed, with specific emphasis on caffeine effects on neurodegenerative diseases.
Abstarct
Objective
To clarify the acute effect of caffeine on postexercise memory and learning performance.
Methods
Eight male slow‐to‐normal caffeine metabolizers, unhabituated to caffeine, were recruited into this randomized, double blind, placebo controlled, cross over study. Caffeine (150 mg) or the placebo was consumed one hour prior to two 30 min submaximal cycling sessions. Blood was collected at the beginning, after 20 and 35 min of exercise and 30 min postexercise. Mature brain‐derived neurotrophic factor (BDNF) and proBDNF concentrations were determined. Auditory memory was assessed immediately, 30 min and 24 h postexercise.
Results
Participants averaged lower scores in every measure of learning and memory after ingesting caffeine compared to the placebo. Although the mean did not differ significantly for all measures, significant differences were found between the caffeine and placebo groups for the three indices; learning over time, short‐term index and retroactive interference. The ratio of serum mBDNF:proBDNF increased with exercise across all time points. No significant difference in the mBDNF:proBDNF ratio was observed between treatment groups.
Conclusion
The consumption of caffeine prior to exercise may impair an unhabituated individual's capacity to learn and recall auditory information postexercise. However it is yet to be elucidated whether this is through caffeine's modulating effects on brain BDNF.
We studied the properties of calcium-induced calcium release (CICR) and its regulation by inhibitors (caffeine, ryanodine, ruthenium red and procaine) in a multicellular atrial preparation that lacks T-tubules. CICR was elicited by application of brief (2-3 sec) calcium pulses (pCa 6.0-6.5). The transient contractions induced by these brief pulses were used to monitor the release of calcium from the sarcoplasmic reticulum in saponin-permeabilized chick atrial fibers. Prolonged (3-10 sec) calcium pulses produced contractions with a phasic CICR-mediated component followed by a tonic component due to direct activation of the myofilaments by calcium. Ryanodine (1 microM) suppressed the phasic but not the tonic contraction. CICR-mediated contractions are suppressed not only by ryanodine (IC50 = 23 nM), but also by ruthenium red (270 nM), procaine (8.1 mM) and millimolar caffeine. Ryanodine inhibits contractions mediated by CICR in a use-dependent manner, due to a strong requirement to act on the activated state of the calcium release channels. However, the blocking action of ryanodine does not require the presence of elevated myoplasmic calcium. A transient contraction occurs upon removal of procaine, which we attribute to unblocking of calcium release channels. Our previous studies of Ins(1,4,5)P3- and caffeine-induced calcium release together with the present work with CICR allow us to propose a model of SR calcium release mechanisms in avian atrial muscle in which corbular sarcoplasmic reticulum may participate.
Spontaneous local increases in the concentration of intracellular calcium, called "calcium sparks," were detected in quiescent
rat heart cells with a laser scanning confocal microscope and the fluorescent calcium indicator fluo-3. Estimates of calcium
flux associated with the sparks suggest that calcium sparks result from spontaneous openings of single sarcoplasmic reticulum
(SR) calcium-release channels, a finding supported by ryanodine-dependent changes of spark kinetics. At resting intracellular
calcium concentrations, these SR calcium-release channels had a low rate of opening (approximately 0.0001 per second). An
increase in the calcium content of the SR, however, was associated with a fourfold increase in opening rate and resulted in
some sparks triggering propagating waves of increased intracellular calcium concentration. The calcium spark is the consequence
of elementary events underlying excitation-contraction coupling and provides an explanation for both spontaneous and triggered
changes in the intracellular calcium concentration in the mammalian heart.
Although reports of caffeine withdrawal in the medical literature date back more than 170 years, the most rigorous experimental investigations of the phenomenon have been conducted only recently.
The purpose of this paper is to provide a comprehensive review and analysis of the literature regarding human caffeine withdrawal to empirically validate specific symptoms and signs, and to appraise important features of the syndrome.
A literature search identified 57 experimental and 9 survey studies on caffeine withdrawal that met inclusion criteria. The methodological features of each study were examined to assess the validity of the effects.
Of 49 symptom categories identified, the following 10 fulfilled validity criteria: headache, fatigue, decreased energy/activeness, decreased alertness, drowsiness, decreased contentedness, depressed mood, difficulty concentrating, irritability, and foggy/not clearheaded. In addition, flu-like symptoms, nausea/vomiting, and muscle pain/stiffness were judged likely to represent valid symptom categories. In experimental studies, the incidence of headache was 50% and the incidence of clinically significant distress or functional impairment was 13%. Typically, onset of symptoms occurred 12-24 h after abstinence, with peak intensity at 20-51 h, and for a duration of 2-9 days. In general, the incidence or severity of symptoms increased with increases in daily dose; abstinence from doses as low as 100 mg/day produced symptoms. Research is reviewed indicating that expectancies are not a prime determinant of caffeine withdrawal and that avoidance of withdrawal symptoms plays a central role in habitual caffeine consumption.
The caffeine-withdrawal syndrome has been well characterized and there is sufficient empirical evidence to warrant inclusion of caffeine withdrawal as a disorder in the DSM and revision of diagnostic criteria in the ICD.
Caffeine is a competitive antagonist at adenosine receptors. Receptor up-regulation during chronic drug treatment has been proposed to be the mechanism of tolerance to the behavioral stimulant effects of caffeine. This study reassessed the role of adenosine receptors in caffeine tolerance. Separate groups of rats were given scheduled access to drinking bottles containing plain tap water or a 0.1% solution of caffeine. Daily drug intake averaged 60-75 mg/kg and resulted in complete tolerance to caffeine-induced stimulation of locomotor activity, which could not be surmounted by increasing the dose of caffeine. 5'-N-ethylcarboxamidoadenosine (0.001-1.0 mg/kg) dose dependently decreased the locomotor activity of caffeine-tolerant rats and their water-treated controls but was 8-fold more potent in the latter group. Caffeine (1.0-10 mg/kg) injected concurrently with 5-N-ethylcarboxamidoadenosine antagonized the decreases in locomotor activity comparably in both groups. Apparent pA2 values for tolerant and control rats also were comparable: 5.05 and 5.11. Thus, the adenosine-antagonist activity of caffeine was undiminished in tolerant rats. The effects of chronic caffeine administration on parameters of adenosine receptor binding and function were measured in cerebral cortex. There were no differences between brain tissue from control and caffeine-treated rats in number and affinity of adenosine binding sites or in receptor-mediated increases (A2 adenosine receptor) and decreases (A1 adenosine receptor) in cAMP accumulation. These results are consistent with theoretical arguments that changes in receptor density should not affect the potency of a competitive antagonist. Experimental evidence and theoretical considerations indicate that up-regulation of adenosine receptors is not the mechanism of tolerance to caffeine-induced stimulation of locomotor activity.
Caffeine has long been recognized as an addictive substance with numerous toxic effects. Death due to caffeine overdose is rare, due in part to its marked gastric irritation resulting in spontaneous emesis. Caffeine can be found in food, beverages, analgesics, and over-the-counter weight loss products. We report a fatality resulting from the ingestion of mail order diet pills containing caffeine as their only active ingredient. A 22-year-old female arrived in the emergency department in cardiac arrest after ingesting these diet pills. Resuscitation efforts were unsuccessful. A serum toxicology screen revealed the presence of caffeine with a level of 1,560 micrograms/ml (lethal greater than 100 micrograms/ml). To our knowledge this is the highest reported fatal caffeine level. No other drugs were identified on the screen. Based on the absence of pathology on autopsy and the high caffeine level, death was attributed to acute caffeine toxicity. This case illustrates that deaths resulting from caffeine, although rare, continue to occur.
Caffeine consumption causes significant physiologic effects due to its antagonism of adenosine receptors. The A1 adenosine receptor is coupled in an inhibitory manner to adenylate cyclase. To study the effects of chronic caffeine ingestion, rats were provided with 0.1% caffeine drinking solution for 28 d. The A1 adenosine receptor agonist radioligand [3H]phenylisopropyladenosine identifies two affinity states in control rat cerebral cortex membranes with a high affinity dissociation constant (KH) of 0.40 +/- 0.08 nM and low affinity dissociation constant (KL) of 13.7 +/- 3.9 nM, with 33% of the receptors in the high affinity state. In membranes from caffeine-treated animals, all of the A1 receptors are shifted to the high affinity state with a dissociation constant (KD) of 0.59 +/- 0.06 nM. Guanylyl-imidodiphosphate (10(-4) M) decreases binding by 43% in control membrane, with no change in KH or KL, while membrane binding in caffeine-treated animals decreases by 45% with a threefold shift in KD to 1.5 +/- 0.3 nM. Concomitant with the enhanced high affinity A1 receptor state and increased sensitivity to guanine nucleotides, membranes from treated animals show a 35% enhancement in (-)-N6-(R-phenylisopropyl)adenosine-mediated inhibition of adenylate cyclase compared with controls (P less than 0.03). Photoaffinity crosslinking the receptors with [125I]N6-2-(3-iodo-4-aminophenyl)ethyladenosine reveals that A1 receptors from both groups migrate as Mr 38,000 proteins. beta-adrenergic receptor binding with [125I]iodocyanopindolol shows a decrease in the number of beta-receptors from 233 +/- 7 fmol/mg protein in control membranes to 190 +/- 10 fmol/mg protein in treated membranes (P = 0.01). These data indicate that the adenosine receptor antagonist, caffeine, induces a compensatory sensitization of the A1 receptor-adenylate cyclase system and downregulation of beta-adrenergic receptors, and provides a molecular mechanism for the caffeine withdrawal syndrome.
In this study a double-blind design was used to determine the effect of caffeine on time to exhaustion and on associated metabolic and circulatory measures. Eight male subjects ingested either caffeine (5 mg/kg body weight) or a placebo 1 hr prior to exercise at 85-90% of maximum workload. Subjects were encouraged to complete three 30-min intermittent cycling periods at 70 rpm with 5 min rest between each. The exercise was terminated when the subject failed to complete three 30-min periods or failed to maintain 70 rpm for at least 15 s consecutively. Serum free fatty acids, glycerol, blood glucose, lactate, perceived exertion, heart rate, and O2 cost were measured. The time to exhaustion was significantly longer during the caffeine trial than during the placebo trial. Serum free fatty acid levels were significantly different between trials. The decline in blood glucose levels was significantly less during the caffeine trial than during the placebo trial. There were no significant differences between trials for the other measures. It was concluded that caffeine increases time to exhaustion when trained subjects cycled intermittently at high levels of intensity.
A 36-y-o patient with schizophrenia, who had consumed gradually increasing quantities of oolong tea that eventually reached 15 L each day, became delirious and was admitted to a psychiatric hospital. After abstinence from oolong tea his delirium resolved. He was transferred to our hospital when he was discovered to have acute renal failure with hyponatremia (118 mEq/L) and severe rhabdomyolysis (creatine phosphokinase, 227,200 IU/L). On admission rhabdomyolysis had begun to improve despite a worsening of the hyponatremia (113 mEq/L). With aggressive supportive therapy, including hypertonic saline administration and hemodialysis, the patient fully recovered without detectable sequelae. The clinical course suggests that caffeine, which is present in oolong tea, was mainly responsible for the rhabdomyolysis as well as the delirium, although severe hyponatremia has been reported to cause rhabdomyolysis on rare occasions. We hypothesize that caffeine toxicity injured the muscle cells, which were fragile due to the potassium depletion induced by the coexisting hyponatremia, to result in unusually severe rhabdomyolysis. The possibility of severe rhabdomyolysis should be considered in a patient with water intoxication due to massive ingestion of caffeine-containing beverages.
Calcium release channels, known also as ryanodine receptors (RyRs), play an important role in Ca2+ signaling in muscle and nonmuscle cells by releasing Ca2+ from intracellular stores. Mammalian tissues express three different RyR isoforms comprising four 560-kDa (RyR polypeptide) and four 12-kDa (FK506 binding protein) subunits. The large protein complexes conduct monovalent and divalent cations and are capable of multiple interactions with other molecules. The latter include small diffusible endogenous effector molecules including Ca2+, Mg2+, adenine nucleotides, sufhydryl modifying reagents (glutathione, NO, and NO adducts) and lipid intermediates, and proteins such as protein kinases and phosphatases, calmodulin, immunophilins (FK506 binding proteins), and in skeletal muscle the dihydropyridine receptor. Because of their role in regulating intracellular Ca2+ levels and their multiple ligand interactions, RyRs constitute an important, potentially rich pharmacological target for controlling cellular functions. Exogenous effectors found to affect RyR function include ryanoids, toxins, xanthines, anthraquinones, phenol derivatives, adenosine and purinergic agonists and antagonists, NO donors, oxidizing reagents, dantrolene, local anesthetics, and polycationic reagents.
A study was performed involving phonological priming and tip-of-the-tongue states (TOTs) in which participants took either 200 mg of caffeine or placebo. Results show a clear positive priming effect produced for the caffeine group when primed with phonologically related words. When primed with unrelated words, the caffeine subgroup produced a significant increase in the number of TOTs. This contrasting effect provides evidence that the positive priming of caffeine was not a result of caffeine's well-known alertness effects. For placebo, a significant negative effect occurred with the related-word priming condition. The results support the novel hypothesis that the blocking of A, adenosine receptors by caffeine induces an increased short-term plasticity effect within the phonological retrieval system.
Caffeine is a mild central nervous stimulant that occurs naturally in coffee beans, cocoa beans and tea leaves. In large doses, it can be profoundly toxic, resulting in arrhythmia, tachycardia, vomiting, convulsions, coma and death. The average cup of coffee or tea in the United States is reported to contain between 40 and 150 mg caffeine although specialty coffees may contain much higher doses. Over-the-counter supplements that are used to combat fatigue typically contain 100-200 mg caffeine per tablet and doses of 32-200mg are included in a variety of prescription drug mixtures. Fatal caffeine overdoses in adults are relatively rare and require the ingestion of a large quantity of the drug, typically in excess of 5 g. Over a period of approximately 12 months our office reported two cases of fatal caffeine intoxication. In the first case, the femoral blood of a 39-year-old female with a history of intravenous drug use contained 192 mg/L caffeine. In the second case, femoral blood from a 29-year-old male with a history of obesity and diabetes contained 567 mg/L caffeine. In both cases, the cause of death was ruled as caffeine intoxication and the manner of death was accidental.
Methylxanthine therapy reduces the frequency of apnea and the need for mechanical ventilation. Recent research has raised concerns about the safety of methylxanthines in very preterm infants. Possible adverse effects include poor growth, worsening of hypoxic-ischemic brain damage and abnormal childhood behavior. Over 2,000 infants with birth weights 500-1,250 g have been randomized in the international placebo-controlled Caffeine for Apnea of Prematurity (CAP) trial to examine the long-term efficacy and safety of methylxanthine therapy for the management of apnea of prematurity. Additional therapies such as continuous positive airway pressure were used as necessary to control apneic attacks. At 18 months we measure the combined rate of death or survival with one or more of the following impairments: cerebral palsy, cognitive deficit, blindness and deafness. This outcome was chosen because of the need to evaluate the impact of common neonatal therapies beyond discharge from the intensive care unit. However, several potential long-term consequences of methylxanthine therapy may not become apparent until the study cohort reaches pre-school age. We will therefore extend the follow-up to age 5 years. The main outcome at 5 years will be a composite of death or survival with severe disability in at least one of six domains: cognition, neuromotor function, vision, hearing, behavior, and general health. Once this project is completed, caffeine will be one of the most rigorously evaluated neonatal therapies.
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