Caffeine for Apnea of Prematurity: Too Much or Too Little of a Good Thing

Caffeine has become one of the most prescribed drugs in neonatal medicine.1Al-Turkait A. Szatkowski L. Choonara I. Ojha S. Review of drug utilization studies in neonatal units: a global perspective.Int J Environ Res Public Health. 2020; 17: 5669Crossref PubMed Scopus (14) Google Scholar, 2Al-Turkait A. Szatkowski L. Choonara I. Ojha S. Drug utilisation in neonatal units in England and Wales: a national cohort study.Eur J Clin Pharmacol. 2022; 78: 669-677Crossref PubMed Scopus (7) Google Scholar, 3Stark A. Smith P.B. Hornik C.P. Zimmerman K.O. Hornik C.D. Pradeep S. et al.Medication use in the neonatal intensive care unit and changes from 2010 to 2018.J Pediatr. 2022; 240: 66-71Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar The effects of this medication on mortality, neonatal morbidities, and child development have been rigorously studied in the Caffeine for Apnea of Prematurity (CAP) trial.4Schmidt B. Roberts R.S. Davis P. Doyle L.W. Barrington K.J. Ohlsson A. et al.Caffeine for apnea of prematurity trial groupCaffeine therapy for apnea of prematurity.N Engl J Med. 2006; 354: 2112-2121Crossref PubMed Scopus (860) Google Scholar, 5Schmidt B. Roberts R.S. Davis P. Doyle L.W. Barrington K.J. Ohlsson A. et al.Caffeine for apnea of prematurity trial groupLong-term effects of caffeine therapy for apnea of prematurity.N Engl J Med. 2007; 357: 1893-1902Crossref PubMed Scopus (728) Google Scholar, 6Schmidt B. Anderson P.J. Doyle L.W. Dewey D. Grunau R.E. Asztalos E.V. et al.Caffeine for apnea of prematurity (CAP) trial investigatorsSurvival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity.JAMA. 2012; 307: 275-282Crossref PubMed Scopus (289) Google Scholar, 7Schmidt B. Roberts R.S. Anderson P.J. Asztalos E.V. Costantini L. Davis P.G. et al.Caffeine for apnea of prematurity (CAP) trial groupAcademic 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.JAMA Pediatr. 2017; 171: 564-572Crossref PubMed Scopus (141) Google Scholar The World Health Organization (WHO) has included caffeine citrate in its short core list of essential medicines for neonates.8Model List of Essential Medicines for Newborn (< 1 month). Accessed June 19, 2023. https://list.essentialmeds.org/?section=&indication=&year=&age=newborn&sex=Google Scholar However, caffeine remains unavailable or unaffordable in many middle-and-low-income countries.9Nabwera H.M. Ekhaguere O.A. Kirpalani H. Burgoine K. Ezeaka C.V. Otieno W. et al.Caffeine for the care of preterm infants in sub-Saharan Africa: a missed opportunity?.BMJ Glob Health. 2021; 6e007682Crossref PubMed Scopus (2) Google Scholar At the same time, regional and national guidelines are promoting potentially unsafe therapeutic drift in some high-income countries.10Queensland HealthCaffeine citrate.2019https://www.health.qld.gov.au/__data/assets/pdf_file/0033/846843/nmq-caffeine-citrate.pdfDate accessed: January 25, 2023Google Scholar,11National Institute for Heath and Care Excellence (NICE)Specialist neonatal respiratory care for babies born preterm. NG 124, 2019https://www.nice.org.uk/guidance/ng124Date accessed: January 25, 2023Google Scholar This development is concerning for the health of preterm infants everywhere. What are the indications for caffeine? What are standard doses of caffeine, and what are their benefits? Are higher doses potentially risky? When should clinicians start and stop caffeine therapy? Are theophylline and aminophylline appropriate replacement drugs in regions where caffeine is not available or affordable? This article provides evidence-based and concise answers to these questions. Caffeine is the respiratory stimulant of choice12Aranda J.V. Beharry K.D. Pharmacokinetics, pharmacodynamics and metabolism of caffeine in newborns.Semin Fetal Neonatal Med. 2020; 25101183Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar to treat or prevent apnea of prematurity and reduce extubation failure.13Henderson-Smart D.J. De Paoli A.G. Methylxanthine treatment for apnoea in preterm infants.Cochrane Database Syst Rev. 2010; : CD000140PubMed Google Scholar, 14Henderson-Smart D.J. De Paoli A.G. Prophylactic methylxanthine for prevention of apnoea in preterm infants.Cochrane Database Syst Rev. 2010; 2010: CD000432PubMed Google Scholar, 15Ferguson K.N. Roberts C.T. Manley B.J. Davis P.G. Interventions to improve rates of successful extubation in preterm infants: a systematic review and meta-analysis.JAMA Pediatr. 2017; 171: 165-174Crossref PubMed Scopus (88) Google Scholar The largest placebo-controlled randomized trial of caffeine recruited 2006 infants with birth weights of 500 to 1250 g during the first 10 days of life and followed study participants to age 11 years.4Schmidt B. Roberts R.S. Davis P. Doyle L.W. Barrington K.J. Ohlsson A. et al.Caffeine for apnea of prematurity trial groupCaffeine therapy for apnea of prematurity.N Engl J Med. 2006; 354: 2112-2121Crossref PubMed Scopus (860) Google Scholar, 5Schmidt B. Roberts R.S. Davis P. Doyle L.W. Barrington K.J. Ohlsson A. et al.Caffeine for apnea of prematurity trial groupLong-term effects of caffeine therapy for apnea of prematurity.N Engl J Med. 2007; 357: 1893-1902Crossref PubMed Scopus (728) Google Scholar, 6Schmidt B. Anderson P.J. Doyle L.W. Dewey D. Grunau R.E. Asztalos E.V. et al.Caffeine for apnea of prematurity (CAP) trial investigatorsSurvival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity.JAMA. 2012; 307: 275-282Crossref PubMed Scopus (289) Google Scholar, 7Schmidt B. Roberts R.S. Anderson P.J. Asztalos E.V. Costantini L. Davis P.G. et al.Caffeine for apnea of prematurity (CAP) trial groupAcademic 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.JAMA Pediatr. 2017; 171: 564-572Crossref PubMed Scopus (141) Google Scholar Clinicians in the CAP trial enrolled 41% of the study participants to treat documented apnea, 23% to prevent apnea, and 36% to facilitate the removal of an endotracheal tube.4Schmidt B. Roberts R.S. Davis P. Doyle L.W. Barrington K.J. Ohlsson A. et al.Caffeine for apnea of prematurity trial groupCaffeine therapy for apnea of prematurity.N Engl J Med. 2006; 354: 2112-2121Crossref PubMed Scopus (860) Google Scholar A post hoc subgroup analysis of the CAP trial data did not suggest a differential treatment effect of caffeine by these 3 clinical indications.16Davis P.G. Schmidt B. Roberts R.S. Doyle L.W. Asztalos E. Haslam R. et al.Caffeine for apnea of prematurity trial: benefits may vary in subgroups.J Pediatr. 2010; 156: 382-387Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar Preterm infants who cannot manifest apnea because they are mechanically ventilated should become candidates for caffeine therapy when they are ready to be weaned off the ventilator.17Amaro C.M. Bello J.A. Jain D. Ramnath A. D'Ugard C. Vanbuskirk S. et al.Early caffeine and weaning from mechanical ventilation in preterm infants: a randomized, placebo-controlled trial.J Pediatr. 2018; 196: 52-57Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Several investigators are searching for neuroprotective effects of caffeine in the laboratory as well as in late preterm and term infants with hypoxic ischemic encephalopathy.18Di Martino E. Bocchetta E. Tsuji S. Mukai T. Harris R.A. Blomgren K. et al.Defining a time window for neuroprotection and glia modulation by caffeine after neonatal hypoxia-Ischaemia.Mol Neurobiol. 2020; 57: 2194-2205Crossref PubMed Scopus (18) Google Scholar,19Caffeine for Hypoxic-Ischemic Encephalopathyhttps://clinicaltrials.gov/ct2/show/NCT03913221Date accessed: February 14, 2023Google Scholar In addition, it has been hypothesized that early caffeine therapy may reduce the risk of acute kidney injury in preterm infants.20Harer M.W. Askenazi D.J. Boohaker L.J. Carmody J.B. Griffin R.L. Guillet R. et al.Association between early caffeine citrate administration and risk of acute kidney injury in preterm neonates: results from the AWAKEN study.JAMA Pediatr. 2018; 172e180322Crossref PubMed Scopus (49) Google Scholar,21Harer M.W. Rothwell A.C. Richard L.J. Adegboro C.O. McAdams R.M. Renal tissue oxygenation after caffeine administration in preterm neonates.Pediatr Res. 2021; 90: 1171-1176Crossref PubMed Scopus (2) Google Scholar However, the currently available evidence does not support any other indication for caffeine than as a respiratory stimulant.22Fleiss B. Gressens P. Neuroprotection of the preterm brain.Handb Clin Neurol. 2019; 162: 315-328Crossref PubMed Scopus (19) Google Scholar In the CAP trial, a standard loading dose of 20 mg/kg caffeine citrate was used. Daily maintenance doses started at 5 mg/kg and could be increased up to 10 mg/kg.4Schmidt B. Roberts R.S. Davis P. Doyle L.W. Barrington K.J. Ohlsson A. et al.Caffeine for apnea of prematurity trial groupCaffeine therapy for apnea of prematurity.N Engl J Med. 2006; 354: 2112-2121Crossref PubMed Scopus (860) Google Scholar Increased maintenance doses were prescribed for 60% of the CAP trial participants (unpublished data). Caffeine accelerated both the removal of endotracheal tubes and the discontinuation of any application of positive airway pressure by approximately 1 week for each (Figure).4Schmidt B. Roberts R.S. Davis P. Doyle L.W. Barrington K.J. Ohlsson A. et al.Caffeine for apnea of prematurity trial groupCaffeine therapy for apnea of prematurity.N Engl J Med. 2006; 354: 2112-2121Crossref PubMed Scopus (860) Google Scholar In addition, caffeine reduced the risks of bronchopulmonary dysplasia, severe retinopathy of prematurity, and survival with disability at 18-21 months.4Schmidt B. Roberts R.S. Davis P. Doyle L.W. Barrington K.J. Ohlsson A. et al.Caffeine for apnea of prematurity trial groupCaffeine therapy for apnea of prematurity.N Engl J Med. 2006; 354: 2112-2121Crossref PubMed Scopus (860) Google Scholar,5Schmidt B. Roberts R.S. Davis P. Doyle L.W. Barrington K.J. Ohlsson A. et al.Caffeine for apnea of prematurity trial groupLong-term effects of caffeine therapy for apnea of prematurity.N Engl J Med. 2007; 357: 1893-1902Crossref PubMed Scopus (728) Google Scholar The rates of motor impairment were improved by caffeine into middle school age.5Schmidt B. Roberts R.S. Davis P. Doyle L.W. Barrington K.J. Ohlsson A. et al.Caffeine for apnea of prematurity trial groupLong-term effects of caffeine therapy for apnea of prematurity.N Engl J Med. 2007; 357: 1893-1902Crossref PubMed Scopus (728) Google Scholar, 6Schmidt B. Anderson P.J. Doyle L.W. Dewey D. Grunau R.E. Asztalos E.V. et al.Caffeine for apnea of prematurity (CAP) trial investigatorsSurvival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity.JAMA. 2012; 307: 275-282Crossref PubMed Scopus (289) Google Scholar, 7Schmidt B. Roberts R.S. Anderson P.J. Asztalos E.V. Costantini L. Davis P.G. et al.Caffeine for apnea of prematurity (CAP) trial groupAcademic 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.JAMA Pediatr. 2017; 171: 564-572Crossref PubMed Scopus (141) Google Scholar,23Doyle L.W. Schmidt B. Anderson P.J. Davis P.G. Moddemann D. Grunau R.E. et al.Reduction in developmental coordination disorder with neonatal caffeine therapy.J Pediatr. 2014; 165: 356-359.e2Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Although motor impairment was defined and measured differently at 18 months, 5 years, and 11 years, the size of the relative treatment benefit was remarkably similar at all ages (Table I). Post hoc analyses suggested that at least 25% and possibly 100% of the beneficial effect of neonatal caffeine therapy on motor function 11 years later could be explained by earlier discontinuation of devices that deliver positive airway pressure to treat apnea of prematurity.7Schmidt B. Roberts R.S. Anderson P.J. Asztalos E.V. Costantini L. Davis P.G. et al.Caffeine for apnea of prematurity (CAP) trial groupAcademic 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.JAMA Pediatr. 2017; 171: 564-572Crossref PubMed Scopus (141) Google Scholar Lasting motor benefits of caffeine are, therefore, at least partly attributable to the drug's action as a respiratory stimulant and hence less need for exposure to noxious mechanical respiratory support options.24Jobe A.H. Caffeine: a lung drug for all very low birth weight preterm infants?.Am J Respir Crit Care Med. 2017; 196: 1241-1243Crossref PubMed Scopus (14) Google ScholarTable ICaffeine benefits on motor outcomesMotor outcomeCaffeinePlaceboAdjusted∗Adjusted for center. OR (95% CI)P valueCerebral palsy at 18 mo4.4%7.3%0.58 (0.39-0.87).009DCD at 5 y11.3%15.2%0.70 (0.51-0.95).024Motor impairment at 11 y19.7%27.5%0.66 (0.48-0.90).009CI, confidence interval; DCD, developmental co-ordination disorder; OR, odds ratio.∗ Adjusted for center. Open table in a new tab CI, confidence interval; DCD, developmental co-ordination disorder; OR, odds ratio. The CAP trial dosing regimen of caffeine citrate was subsequently endorsed by the American Academy of Pediatrics and the European Society for Paediatric Research.25Eichenwald E.C. Committee on Fetus and newborn, American academy of pediatricsApnea of prematurity.Pediatrics. 2016; 137Crossref Scopus (125) Google Scholar,26Sweet D.G. Carnielli V.P. Greisen G. Hallman M. Klebermass-Schrehof K. Ozek E. et al.European consensus guidelines on the management of respiratory distress syndrome: 2022 update.Neonatology. 2023; 120: 3-23Crossref PubMed Scopus (31) Google Scholar However, other national and regional guidelines in high-income countries recommend higher maximum loading and/or maintenance doses of caffeine citrate for preterm infants (Table II).10Queensland HealthCaffeine citrate.2019https://www.health.qld.gov.au/__data/assets/pdf_file/0033/846843/nmq-caffeine-citrate.pdfDate accessed: January 25, 2023Google Scholar,11National Institute for Heath and Care Excellence (NICE)Specialist neonatal respiratory care for babies born preterm. NG 124, 2019https://www.nice.org.uk/guidance/ng124Date accessed: January 25, 2023Google Scholar,27Australasian Neonatal Medicines FormularyCaffeine citrate 2022.https://www.anmfonline.org/wp-content/uploads/2022/06/Caffeine_ANMF_v4.0_20220602.pdfDate accessed: February 9, 2023Google Scholar Recent reports from the US and Australia describe great variability in the chosen dosage and confirm that higher than standard doses of caffeine are used regularly in daily practice.28Gray P.H. Chauhan M. Use of caffeine for preterm infants in Australia and New Zealand: a survey.J Paediatr Child Health. 2016; 52: 1121-1122Crossref PubMed Scopus (5) Google Scholar,29Puia-Dumitrescu M. Smith P.B. Zhao J. Soriano A. Payne E.H. Harper B. et al.Dosing and safety of off-label use of caffeine citrate in premature infants.J Pediatr. 2019; 211: 27-32.e1Abstract Full Text Full Text PDF PubMed Scopus (18) Google ScholarTable IIRecommended caffeine citrate doses for preterm infantsGuidelineLoading dose (mg/kg)Lowest maintenance dose (mg/kg/d)Maximum maintenance dose (mg/kg/d)AAP/COFN 201625Eichenwald E.C. Committee on Fetus and newborn, American academy of pediatricsApnea of prematurity.Pediatrics. 2016; 137Crossref Scopus (125) Google Scholar20510European Consensus 202226Sweet D.G. Carnielli V.P. Greisen G. Hallman M. Klebermass-Schrehof K. Ozek E. et al.European consensus guidelines on the management of respiratory distress syndrome: 2022 update.Neonatology. 2023; 120: 3-23Crossref PubMed Scopus (31) Google Scholar20510NICE 201911National Institute for Heath and Care Excellence (NICE)Specialist neonatal respiratory care for babies born preterm. NG 124, 2019https://www.nice.org.uk/guidance/ng124Date accessed: January 25, 2023Google Scholar20520∗“Consider a maintenance dosage higher than 20 mg/kg daily if therapeutic efficacy is not achieved…”.11ANFM 202227Australasian Neonatal Medicines FormularyCaffeine citrate 2022.https://www.anmfonline.org/wp-content/uploads/2022/06/Caffeine_ANMF_v4.0_20220602.pdfDate accessed: February 9, 2023Google Scholar20520Queensland Health 201910Queensland HealthCaffeine citrate.2019https://www.health.qld.gov.au/__data/assets/pdf_file/0033/846843/nmq-caffeine-citrate.pdfDate accessed: January 25, 2023Google Scholar20-80520AAP, American Academy of Pediatrics; COFN, Committee on Fetus and Newborn; NICE, National Institute of Health and Care Excellence; ANFM, Neonatal Medicines a maintenance dosage higher than 20 mg/kg daily if therapeutic efficacy is not Institute for Heath and Care Excellence (NICE)Specialist neonatal respiratory care for babies born preterm. NG 124, 2019https://www.nice.org.uk/guidance/ng124Date accessed: January 25, 2023Google Scholar Open table in a new tab American Academy of Pediatrics; COFN, Committee on Fetus and Newborn; NICE, National Institute of Health and Care Excellence; ANFM, Neonatal Medicines At standard caffeine and J.V. Beharry K.D. Pharmacokinetics, pharmacodynamics and metabolism of caffeine in newborns.Semin Fetal Neonatal Med. 2020; 25101183Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar This is for the action of caffeine as a respiratory At higher than standard effects of caffeine become and and in an J.V. Beharry K.D. Pharmacokinetics, pharmacodynamics and metabolism of caffeine in newborns.Semin Fetal Neonatal Med. 2020; 25101183Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar on the exposure caffeine may with other as A and and J.V. Beharry K.D. Pharmacokinetics, pharmacodynamics and metabolism of caffeine in newborns.Semin Fetal Neonatal Med. 2020; 25101183Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar The of a trial that a higher than standard loading dose after birth may be with an increased risk of C. R. A randomized trial of caffeine therapy in preterm Res. 78: PubMed Scopus Google Scholar Although and may have increased the risk of results in this trial, new studies are to confirm or these of randomized have standard doses of caffeine to in both the loading and the maintenance doses prescribed in the CAP P.H. Caffeine citrate for very preterm infants: effects on and Paediatr Child Health. PubMed Scopus Google Scholar, S. I. B. H. caffeine for apnea of prematurity: a randomized J Pediatr. PubMed Scopus Google Scholar, H. A. A randomized trial doses of caffeine for apnoea in J Environ Res Public Health. 2021; PubMed Scopus Google Scholar were to or after caffeine have been for preterm infants all 3 P.H. Caffeine citrate for very preterm infants: effects on and Paediatr Child Health. PubMed Scopus Google Scholar, S. I. B. H. caffeine for apnea of prematurity: a randomized J Pediatr. PubMed Scopus Google Scholar, H. A. A randomized trial doses of caffeine for apnoea in J Environ Res Public Health. 2021; PubMed Scopus Google Scholar evidence does not that higher than standard doses of caffeine are and for the least (Table of higher caffeine citrate loading and maintenance doses than by E.C. Committee on Fetus and newborn, American academy of pediatricsApnea of prematurity.Pediatrics. 2016; 137Crossref Scopus (125) Google be included in this loading and maintenance doses of caffeine citrate in the of the trial to be by and in dose in dose loading dose maintenance dose et P.H. Caffeine citrate for very preterm infants: effects on and Paediatr Child Health. PubMed Scopus Google development at 1 of was as the in this of extubation from mechanical was the for of the infants in this trial to an earlier by the same of for infants in this earlier have been in the later et S. I. B. H. caffeine for apnea of prematurity: a randomized J Pediatr. PubMed Scopus Google et H. A. A randomized trial doses of caffeine for apnoea in J Environ Res Public Health. 2021; PubMed Scopus Google American Academy of Pediatrics; COFN, Committee on Fetus and Newborn; standard be included in this loading and maintenance doses of caffeine citrate in the of the trial to be by Although development at 1 of was as the in this P.H. Caffeine citrate for very preterm infants: effects on and Paediatr Child Health. PubMed Scopus Google Scholar of extubation from mechanical was the for of the infants in this trial to an earlier by the same of P. A. B. P.H. D. et dose caffeine citrate for extubation of preterm infants: a Child Fetal Neonatal PubMed Scopus Google Scholar for infants in this earlier have been in the later P.H. Caffeine citrate for very preterm infants: effects on and Paediatr Child Health. PubMed Scopus Google Scholar Open table in a new tab American Academy of Pediatrics; COFN, Committee on Fetus and Newborn; standard The to with apnea and after preterm birth is at low ages and with E.C. Committee on Fetus and newborn, American academy of pediatricsApnea of prematurity.Pediatrics. 2016; 137Crossref Scopus (125) Google G. of and apnea of prematurity: the and 2021; PubMed Scopus Google Scholar the age at apnea and with age at E.C. Committee on Fetus and newborn, American academy of pediatricsApnea of prematurity.Pediatrics. 2016; 137Crossref Scopus (125) Google G. of and apnea of prematurity: the and 2021; PubMed Scopus Google Scholar This as well as variability at ages that to start and stop caffeine therapy be In the CAP trial, caffeine therapy was at a of 3 days and at a age of B. Roberts R.S. Davis P. Doyle L.W. Barrington K.J. Ohlsson A. et al.Caffeine for apnea of prematurity trial groupCaffeine therapy for apnea of prematurity.N Engl J Med. 2006; 354: 2112-2121Crossref PubMed Scopus (860) Google Scholar has been a in years caffeine the first days of and as early as in the A. R. A. D. K. A. et al.Early caffeine administration and in preterm 2019; PubMed Scopus Google Scholar, L. S. J. D. H. et cohort study of use of caffeine in preterm infants and between early caffeine use and neonatal Child Fetal Neonatal 2023; PubMed Scopus (2) Google Scholar, S. P. National on caffeine use in neonatal units the 2022; PubMed Scopus Google Scholar is appropriate to the results of the CAP trial to very early with the infants should be for caffeine therapy after birth if are and positive airway pressure without an endotracheal (2) are weaning from mechanical ventilation a trial of or have documented B. Davis P.G. Roberts R.S. of caffeine therapy in very low birth weight infants.J Pediatr. 2014; Full Text Full Text PDF PubMed Scopus Google Scholar ages at discontinuation of caffeine therapy should vary to the age of the and the clinical of application of positive airway pressure to prevent or treat apnea should be first because it is than caffeine Although many clinicians use a without apnea after of caffeine therapy as a for the may need to be on the age at birth and the and of E.C. Committee on Fetus and newborn, American academy of pediatricsApnea of prematurity.Pediatrics. 2016; 137Crossref Scopus (125) Google Scholar are in to the effects of caffeine therapy the first to accessed: February 2023Google accessed: February 2023Google Scholar The has that caffeine citrate is an essential for List of Essential Medicines for Newborn (< 1 month). Accessed June 19, 2023. https://list.essentialmeds.org/?section=&indication=&year=&age=newborn&sex=Google Scholar In other respiratory as theophylline and aminophylline are not included in the core list for for caffeine has theophylline and Caffeine has is and therapeutic drug is if standard doses are J.V. Beharry K.D. Pharmacokinetics, pharmacodynamics and metabolism of caffeine in newborns.Semin Fetal Neonatal Med. 2020; 25101183Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar In addition, after the in the CAP trial with up to 11 years, caffeine has become one of the studied medicines in B. Roberts R.S. Davis P. Doyle L.W. Barrington K.J. Ohlsson A. et al.Caffeine for apnea of prematurity trial groupCaffeine therapy for apnea of prematurity.N Engl J Med. 2006; 354: 2112-2121Crossref PubMed Scopus (860) Google Scholar, 5Schmidt B. Roberts R.S. Davis P. Doyle L.W. Barrington K.J. Ohlsson A. et al.Caffeine for apnea of prematurity trial groupLong-term effects of caffeine therapy for apnea of prematurity.N Engl J Med. 2007; 357: 1893-1902Crossref PubMed Scopus (728) Google Scholar, 6Schmidt B. Anderson P.J. Doyle L.W. Dewey D. Grunau R.E. Asztalos E.V. et al.Caffeine for apnea of prematurity (CAP) trial investigatorsSurvival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity.JAMA. 2012; 307: 275-282Crossref PubMed Scopus (289) Google Scholar, 7Schmidt B. Roberts R.S. Anderson P.J. Asztalos E.V. Costantini L. Davis P.G. et al.Caffeine for apnea of prematurity (CAP) trial groupAcademic 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.JAMA Pediatr. 2017; 171: 564-572Crossref PubMed Scopus (141) Google Scholar However, caffeine is available H.M. Ekhaguere O.A. Kirpalani H. Burgoine K. Ezeaka C.V. Otieno W. et al.Caffeine for the care of preterm infants in sub-Saharan Africa: a missed opportunity?.BMJ Glob Health. 2021; 6e007682Crossref PubMed Scopus (2) Google Scholar to a of in middle-and-low-income the of caffeine citrate vary and some of the higher are for their (Table of caffeine citrate in middle-and-low-income of 1 20 of caffeine citrate between and January in to for US of 1 20 of caffeine citrate between and January to for Open table in a new tab US Caffeine citrate is an essential respiratory stimulant for infants with apnea of When used for this standard doses of caffeine are and into middle school studies are to evidence the results of clinical should not the currently available should that all preterm infants with apnea have to and caffeine

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