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Stored RBC metabolism as a function of caffeine levels.
D'Alessandro, A, Fu, X, Reisz, JA, Kanias, T, Page, GP, Stone, M, Kleinman, S, Zimring, JC, Busch, M, ,
Transfusion. 2020;(6):1197-1211
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Abstract
BACKGROUND Coffee consumption is extremely common in the United States. Coffee is rich with caffeine, a psychoactive, purinergic antagonist of adenosine receptors, which regulate red blood cell energy and redox metabolism. Since red blood cell (purine) metabolism is a critical component to the red cell storage lesion, here we set out to investigate whether caffeine levels correlated with alterations of energy and redox metabolism in stored red blood cells. STUDY DESIGN AND METHODS We measured the levels of caffeine and its main metabolites in 599 samples from the REDS-III RBC-Omics (Recipient Epidemiology Donor Evaluation Study III Red Blood Cell-Omics) study via ultra-high-pressure-liquid chromatography coupled to high-resolution mass spectrometry and correlated them to global metabolomic and lipidomic analyses of RBCs stored for 10, 23, and 42 days. RESULTS Caffeine levels positively correlated with increased levels of the main red cell antioxidant, glutathione, and its metabolic intermediates in glutathione-dependent detoxification pathways of oxidized lipids and sugar aldehydes. Caffeine levels were positively correlated with transamination products and substrates, tryptophan, and indole metabolites. Expectedly, since caffeine and its metabolites belong to the family of xanthine purines, all xanthine metabolites were significantly increased in the subjects with the highest levels of caffeine. However, high-energy phosphate compounds ATP and DPG were not affected by caffeine levels, despite decreases in glucose oxidation products-both via glycolysis and the pentose phosphate pathway. CONCLUSION Though preliminary, this study is suggestive of a beneficial correlation between the caffeine levels and improved antioxidant capacity of stored red cells.
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Early Caffeine Administration and Neurodevelopmental Outcomes in Preterm Infants.
Lodha, A, Entz, R, Synnes, A, Creighton, D, Yusuf, K, Lapointe, A, Yang, J, Shah, PS, ,
Pediatrics. 2019;(1)
Abstract
BACKGROUND Although caffeine use for apnea of prematurity is well studied, the long-term safety and benefit of routine early caffeine administration has not been explored. Our objective was to determine the association between early (within 2 days of birth) versus late caffeine exposure and neurodevelopmental outcomes in preterm infants. METHODS Infants of <29 weeks' gestation born between April 2009 and September 2011 and admitted to Canadian Neonatal Network units and then assessed at Canadian Neonatal Follow-up Network centers were studied. Neonates who received caffeine were divided into early- (received within 2 days of birth) and late-caffeine (received after 2 days of birth) groups. The primary outcome was significant neurodevelopmental impairment, defined as cerebral palsy, or a Bayley Scales of Infant and Toddler Development, Third Edition composite score of <70 on any component, hearing aid or cochlear implant, or bilateral visual impairment at 18 to 24 months' corrected age. RESULTS Of 2108 neonates who were eligible, 1545 were in the early-caffeine group and 563 were in the late-caffeine group. Rates of bronchopulmonary dysplasia, patent ductus arteriosus, and severe neurologic injury were lower in the early-caffeine group than in the late-caffeine group. Significant neurodevelopmental impairment (adjusted odds ratio 0.68 [95% confidence interval 0.50-0.94]) and odds of Bayley Scales of Infant and Toddler Development, Third Edition cognitive scores of <85 (adjusted odds ratio 0.67 [95% confidence interval 0.47-0.95]) were lower in the early-caffeine group than in the late-caffeine group. Propensity score-based matched-pair analyses revealed lower odds of cerebral palsy and hearing impairment only. CONCLUSIONS Early caffeine therapy is associated with better neurodevelopmental outcomes compared with late caffeine therapy in preterm infants born at <29 weeks' gestation.
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Academic Performance, Motor Function, and Behavior 11 Years After Neonatal Caffeine Citrate Therapy for Apnea of Prematurity: An 11-Year Follow-up of the CAP Randomized Clinical Trial.
Schmidt, B, Roberts, RS, Anderson, PJ, Asztalos, EV, Costantini, L, Davis, PG, Dewey, D, D'Ilario, J, Doyle, LW, Grunau, RE, et al
JAMA pediatrics. 2017;(6):564-572
Abstract
IMPORTANCE Caffeine citrate therapy for apnea of prematurity reduces the rates of bronchopulmonary dysplasia, severe retinopathy, and neurodevelopmental disability at 18 months and may improve motor function at 5 years. OBJECTIVE To evaluate whether neonatal caffeine therapy is associated with improved functional outcomes 11 years later. DESIGN, SETTING, AND PARTICIPANTS A follow-up study was conducted at 14 academic hospitals in Canada, Australia, and the United Kingdom from May 7, 2011, to May 27, 2016, of English- or French-speaking children who had been enrolled in the randomized, placebo-controlled Caffeine for Apnea of Prematurity trial between October 11, 1999, and October 22, 2004. A total of 1202 children with birth weights of 500 to 1250 g were eligible for this study; 920 (76.5%) had adequate data for the main outcome. INTERVENTIONS Caffeine citrate or placebo until drug therapy for apnea of prematurity was no longer needed. MAIN OUTCOMES AND MEASURES Functional impairment was a composite of poor academic performance (defined as at least 1 standard score greater than 2 SD below the mean on the Wide Range Achievement Test-4), motor impairment (defined as a percentile rank of ≤5 on the Movement Assessment Battery for Children-Second Edition), and behavior problems (defined as a Total Problem T score ≥2 SD above the mean on the Child Behavior Checklist). RESULTS Among the 920 children (444 females and 476 males; median age, 11.4 years [interquartile range, 11.1-11.8 years]), the combined rates of functional impairment were not significantly different between the 457 children assigned to receive caffeine compared with the 463 children assigned to receive placebo (145 [31.7%] vs 174 [37.6%]; adjusted odds ratio, 0.78; 95% CI, 0.59-1.02; P = .07). With all available data, including those from up to 24 Swedish trial participants, the rates of poor academic performance on 1 or more of 4 subtests (66 of 458 [14.4%] vs 61 of 462 [13.2%]; adjusted odds ratio, 1.11; 95% CI, 0.77-1.61; P = .58) and behavior problems (52 of 476 [10.9%] vs 40 of 481 [8.3%]; adjusted odds ratio, 1.32; 95% CI, 0.85-2.07; P = .22) were broadly similar between the group that received caffeine and the group that received placebo. However, caffeine therapy was associated with a reduced risk of motor impairment compared with placebo (90 of 457 [19.7%] vs 130 of 473 [27.5%]; adjusted odds ratio, 0.66; 95% CI, 0.48-0.90; P = .009). CONCLUSIONS AND RELEVANCE Caffeine therapy for apnea of prematurity did not significantly reduce the combined rate of academic, motor, and behavioral impairments but was associated with a reduced risk of motor impairment in 11-year-old children with very low birth weight. At the doses used in this trial, neonatal caffeine therapy is effective and safe into middle school age. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00182312; isrctn.org Identifier: ISRCTN44364365.
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Caffeine as symptomatic treatment for Parkinson disease (Café-PD): A randomized trial.
Postuma, RB, Anang, J, Pelletier, A, Joseph, L, Moscovich, M, Grimes, D, Furtado, S, Munhoz, RP, Appel-Cresswell, S, Moro, A, et al
Neurology. 2017;(17):1795-1803
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Abstract
OBJECTIVE To assess effects of caffeine on Parkinson disease (PD). METHODS In this multicenter parallel-group controlled trial, patients with PD with 1-8 years disease duration, Hoehn & Yahr stages I-III, on stable symptomatic therapy were randomized to caffeine 200 mg BID vs matching placebo capsules for 6-18 months. The primary research question was whether objective motor scores would differ at 6 months (Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale [MDS-UPDRS]-III, Class I evidence). Secondary outcomes included safety and tolerability, motor symptoms (MDS-UPDRS-II), motor fluctuations, sleep, nonmotor symptoms (MDS-UPDRS-I), cognition (Montreal Cognitive Assessment), and quality of life. RESULTS Sixty patients received caffeine and 61 placebo. Caffeine was well-tolerated with similar prevalence of side effects as placebo. There was no improvement in motor parkinsonism (the primary outcome) with caffeine treatment compared to placebo (difference between groups -0.48 [95% confidence interval -3.21 to 2.25] points on MDS-UPDRS-III). Similarly, on secondary outcomes, there was no change in motor signs or motor symptoms (MDS-UPDRS-II) at any time point, and no difference on quality of life. There was a slight improvement in somnolence over the first 6 months, which attenuated over time. There was a slight increase in dyskinesia with caffeine (MDS-UPDRS-4.1+4.2 = 0.25 points higher), and caffeine was associated with worse cognitive testing scores (average Montreal Cognitive Assessment = 0.66 [0.01, 1.32] worse than placebo). CONCLUSION Caffeine did not provide clinically important improvement of motor manifestations of PD (Class I evidence). Epidemiologic links between caffeine and lower PD risk do not appear to be explained by symptomatic effects. CLINICALTRIALSGOV IDENTIFIER NCT01738178. CLASSIFICATION OF EVIDENCE This study provides Class I evidence that for patients with PD, caffeine does not significantly improve motor manifestations.
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The Real-World Routine Use of Caffeine Citrate in Preterm Infants: A European Postauthorization Safety Study.
Lista, G, Fabbri, L, Polackova, R, Kiechl-Kohlendorfer, U, Papagaroufalis, K, Saenz, P, Ferrari, F, Lasagna, G, Carnielli, VP, ,
Neonatology. 2016;(3):221-7
Abstract
BACKGROUND Caffeine citrate is the treatment of choice for apnea of prematurity (AOP). Regulatory agencies have requested real-world data on drug utilization and safety, a postauthorization safety study, of a pharmaceutical-grade caffeine citrate, Peyona, to confirm its benefit for preterm infants. OBJECTIVES To investigate the clinical use, outcomes, and safety profile of this pharmaceutical-grade caffeine citrate in the routine treatment of preterm infants with a gestational age (GA) <37 weeks. METHODS We conducted a multicenter, noninterventional, prospective study in five European countries. Patients eligible for study enrollment were <37-week GA neonates who received treatment with the pharmaceutical-grade caffeine citrate and whose parents had given informed consent. RESULTS A total of 506 preterm infants were enrolled from 21 institutions. The pharmaceutical-grade caffeine citrate doses were administered intravenously, orally, or via both routes. The main indication of use was AOP treatment (58%) followed by AOP prophylaxis (37%). Median treatment duration was 21 days. The primary cause of study termination was AOP resolution (n = 407; 80%). Hundred and six patients (21%) required supplemental oxygen on day 28; 48 patients (9.5%) had bronchopulmonary dysplasia at 36 weeks' postmenstrual age. Twenty-three adverse drug reactions were observed in 21 neonates (4.2%); the most frequent was tachycardia (2.3%) and only one (seizures) was considered serious. Thirty-one patients (8.1%) had hepatic or renal functional impairment; the side effects were manageable, and these patients also benefitted from treatment. CONCLUSIONS The use of this caffeine citrate is safe for the management of AOP in a real-world setting.
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Association of early caffeine administration and neonatal outcomes in very preterm neonates.
Lodha, A, Seshia, M, McMillan, DD, Barrington, K, Yang, J, Lee, SK, Shah, PS, ,
JAMA pediatrics. 2015;(1):33-8
Abstract
IMPORTANCE Advantages of caffeine for apnea of prematurity have prompted clinicians to use it prophylactically even before apnea. OBJECTIVE To determine the effect of early initiation of caffeine therapy on neonatal outcomes in very preterm infants born in Canada. DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort study was conducted. Patients included preterm neonates born at less than 31 weeks' gestation admitted to 29 participating Canadian Neonatal Network neonatal intensive care units between January 1, 2010, and December 31, 2012. EXPOSURES Neonates who received caffeine were divided into 2 groups based on the following timing of caffeine initiation: within the first 2 days after birth (early) and on or after the third day following birth (late). MAIN OUTCOME AND MEASURE A composite of death or bronchopulmonary dysplasia. RESULTS Of 5517 eligible neonates, 5101 (92.5%) received caffeine (early: 3806 [74.6%]; late: 1295 [25.4%]). There was no difference in weight or gestational age at birth between the groups. Neonates in the early group had decreased odds of a composite outcome of death or bronchopulmonary dysplasia (adjusted odds ratio [AOR], 0.81; 95% CI, 0.67-0.98) and patent ductus arteriosus (AOR, 0.74; 95% CI, 0.62-0.89). There was no difference between the groups in mortality (AOR, 0.98; 95% CI, 0.70-1.37), necrotizing enterocolitis (AOR, 0.88; 95% CI, 0.65-1.20), severe neurological injury (AOR, 0.80; 95% CI, 0.63-1.01), or severe retinopathy of prematurity (AOR, 0.78; 95% CI, 0.56-1.10). CONCLUSIONS AND RELEVANCE In very preterm neonates, early (prophylactic) caffeine use was associated with a reduction in the rates of death or bronchopulmonary dysplasia and patent ductus arteriosus. No adverse impact on any other outcomes was observed.
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The effect of self-regulated caffeine use on cognition in young adults.
Harvanko, AM, Derbyshire, KL, Schreiber, LR, Grant, JE
Human psychopharmacology. 2015;(2):123-30
Abstract
OBJECTIVE Based on previous observational studies that have suggested self-regulated caffeine use by older adults may enhance reaction time performance and vigilance on cognitive tasks, the current study sought to examine whether this effect held true for young adults as well. METHODS One hundred and four young adults from two major metropolitan areas, ages 18-29 years, not meeting the criteria for a current psychiatric disorder, completed several cognitive tasks related to decision-making (Cambridge Gamble Task), response inhibition and reaction time (stop-signal task), and vigilance and reaction time (Rapid Visual Information Processing). Caffeine usage was self-reported using a reliable quantity and frequency questionnaire. RESULTS Self-reported caffeine usage was not significantly associated with any of the cognitive measures used in this study after controlling for age, gender, cigarette smoking, alcohol use, cannabis use, and gambling frequency. CONCLUSIONS These data suggest that self-regulated caffeine usage may not have a significant impact on reaction time, vigilance, response inhibition, or decision-making in young adults, or that these effects are contingent upon other variables not accounted for in the current study.
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Design and rationale of TROCADERO: A TRial Of Caffeine to Alleviate DyspnEa Related to ticagrelOr.
Lindholm, D, Storey, RF, Christersson, C, Halvorsen, S, Grove, EL, Braun, OÖ, Varenhorst, C, James, SK
American heart journal. 2015;(3):465-70
Abstract
BACKGROUND Ticagrelor treatment has the side effect of increased incidence of dyspnea. Adenosine-induced dyspnea is augmented by ticagrelor and can be alleviated with the adenosine antagonist theophylline. Caffeine is a closely related xanthine derivative. OBJECTIVES The primary objective of the TROCADERO is to evaluate the effect of caffeine versus placebo on ticagrelor-associated dyspnea, measured by the visual analog scale area under the curve in patients with ongoing ticagrelor treatment after an acute coronary syndrome event. DESIGN After a run-in period of 1 to 7 days of absence of caffeine intake, acute coronary syndrome patients with ticagrelor-induced dyspnea (planned inclusion 416) are randomized in a blinded fashion to either caffeine 200 mg twice daily or matching placebo with a treatment duration of 1 week. The primary efficacy end point is change in visual analog scale area under the curve for dyspnea, and the primary safety end point is occurrence of high on-treatment platelet reactivity measured by the VerifyNow P2Y12 assay. CONCLUSIONS This trial will determine if adenosine antagonism by caffeine can alleviate ticagrelor-related dyspnea, without impairing the antiplatelet effect of ticagrelor.
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Effect of caffeine on SPECT myocardial perfusion imaging during regadenoson pharmacologic stress: a prospective, randomized, multicenter study.
Tejani, FH, Thompson, RC, Kristy, R, Bukofzer, S
The international journal of cardiovascular imaging. 2014;(5):979-89
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Abstract
A multicenter, double-blind, randomized study was conducted to assess the effect of caffeine on regadenoson stress myocardial perfusion imaging (MPI). Subjects with a high likelihood of coronary artery disease underwent a rest single-photon emission computed tomography MPI on day 1 (MPI-1) and a stress MPI with regadenoson on day 3 (MPI-2). Individuals with ≥1 segment with a reversible defect received double-blind caffeine tablets (200 or 400 mg) or placebo 90 min before a repeat regadenoson stress MPI (MPI-3) on day 5. Overall, 207 subjects completed the study (caffeine 200 mg, n = 70; caffeine 400 mg, n = 71; placebo, n = 66). The mean number of segments with reversible defects decreased from MPI-2 to MPI-3 in the caffeine 200 and 400 mg groups versus no significant change in the placebo group [mean ± standard deviation: -0.61 ± 1.097, -0.62 ± 1.367, and 0.12 ± 0.981, respectively (overall treatment effect, P < 0.001)]. The majority of subjects who received caffeine shifted to a lower ischemia size category from MPI-2 to MPI-3, with no clear pattern observed in subjects who received placebo. For caffeine exposed patients with ≥3 segments with reversible defects at MPI-2, 21/23 had fewer detected at MPI-3. Both the 200 and 400 mg doses of caffeine significantly reduced the number of segments with reversible defects detected by regadenoson stress MPI.
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Reduction in developmental coordination disorder with neonatal caffeine therapy.
Doyle, LW, Schmidt, B, Anderson, PJ, Davis, PG, Moddemann, D, Grunau, RE, O'Brien, K, Sankaran, K, Herlenius, E, Roberts, R, et al
The Journal of pediatrics. 2014;(2):356-359.e2
Abstract
OBJECTIVE To determine the effect of neonatal caffeine treatment on rates of developmental coordination disorder (DCD). STUDY DESIGN Children in the Caffeine for Apnea of Prematurity trial were assessed for motor performance (Movement Assessment Battery for Children [MABC]), clinical signs of cerebral palsy, and Full-Scale IQ at 5 years of age by staff who were unaware of the children's treatment group. DCD was defined as MABC<5th percentile in children with a Full-Scale IQ>69 who did not have a diagnosis of cerebral palsy. RESULTS There were 1433 children with known MABC corrected-age percentile as well as known Full-Scale IQ at 5 years and cerebral palsy status, of whom 735 had been randomly assigned to caffeine and 698 to placebo therapy. The rate of DCD was lower in those treated with caffeine (11.3%) than in the placebo group (15.2%) (OR adjusted for center and baseline covariates, 0.71, 95% CI, 0.52-0.97; P=.032). CONCLUSIONS Neonatal caffeine therapy for apnea of prematurity reduces the rate of DCD at 5 years of age. As more children have DCD than have cerebral palsy, this is an important additional benefit from neonatal caffeine treatment.