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, Australasian Neonatal Medicines Formulary.∗ “Consider a maintenance dosage higher than 20 mg/kg daily if therapeutic efficacy is not achieved…”.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 Open table in a new tab AAP, American Academy of Pediatrics; COFN, Committee on Fetus and Newborn; NICE, National Institute of Health and Care Excellence; ANFM, Australasian Neonatal Medicines Formulary. At standard doses, caffeine competitively inhibits A1 and A2A adenosine receptors.12Aranda 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 mechanism is responsible for the intended pharmacodynamic action of caffeine as a respiratory stimulant. At higher than standard doses, “the pharmacologic effects of caffeine become more complex and worrisome,” and unpredictable in an individual infant.12Aranda 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 Depending on the exposure level, caffeine may interact with other molecular targets such as γ-Aminobutyric Acid (GABA) A and cholinergic receptors, calcium release channels, and phosphodiesterase.12Aranda 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 authors of a single center trial reported that a higher than standard loading dose soon after birth may be associated with an increased risk of cerebellar hemorrhage.30McPherson C. Neil J.J. Tjoeng T.H. Pineda R. Inder T.E. A pilot randomized trial of high-dose caffeine therapy in preterm infants.Pediatr Res. 2015; 78: 198-204Crossref PubMed Scopus (82) Google Scholar Although multiple outcomes and extensive hypothesis testing may have increased the risk of false-positive results in this trial, new research studies are needed to confirm or reject these findings of potential harm. Three randomized trials have compared standard doses of caffeine to regimens in which both the loading and the maintenance doses exceeded those prescribed in the CAP trial.31Gray P.H. Flenady V.J. Charles B.G. Steer P.A. Caffeine Collaborative Study GroupCaffeine citrate for very preterm infants: effects on development, temperament and behaviour.J Paediatr Child Health. 2011; 47: 167-172Crossref PubMed Scopus (54) Google Scholar, 32Mohammed S. Nour I. Shabaan A.E. Shouman B. Abdel-Hady H. Nasef N. High versus low-dose caffeine for apnea of prematurity: a randomized controlled trial.Eur J Pediatr. 2015; 174: 949-956Crossref PubMed Scopus (72) Google Scholar, 33Mohd Kori A.M. Van Rostenberghe H. Ibrahim N.R. Yaacob N.M. Nasir A. A randomized controlled trial comparing two doses of caffeine for apnoea in prematurity.Int J Environ Res Public Health. 2021; 18: 4509Crossref PubMed Scopus (6) Google Scholar Primary outcomes were either failure to extubate or apnea. These short-term endpoints after high-dose caffeine have been reported for only 220 preterm infants across all 3 trials.31Gray P.H. Flenady V.J. Charles B.G. Steer P.A. Caffeine Collaborative Study GroupCaffeine citrate for very preterm infants: effects on development, temperament and behaviour.J Paediatr Child Health. 2011; 47: 167-172Crossref PubMed Scopus (54) Google Scholar, 32Mohammed S. Nour I. Shabaan A.E. Shouman B. Abdel-Hady H. Nasef N. High versus low-dose caffeine for apnea of prematurity: a randomized controlled trial.Eur J Pediatr. 2015; 174: 949-956Crossref PubMed Scopus (72) Google Scholar, 33Mohd Kori A.M. Van Rostenberghe H. Ibrahim N.R. Yaacob N.M. Nasir A. A randomized controlled trial comparing two doses of caffeine for apnoea in prematurity.Int J Environ Res Public Health. 2021; 18: 4509Crossref PubMed Scopus (6) Google Scholar Their limited evidence does not provide sufficient reassurance that higher than standard doses of caffeine are effective and safe, especially for the least mature patients (Table III).Table IIIRandomized trials of higher caffeine citrate loading and maintenance doses than recommended by AAP/COFN25Eichenwald E.C. Committee on Fetus and newborn, American academy of pediatricsApnea of prematurity.Pediatrics. 2016; 137Crossref Scopus (125) Google Scholar,∗To be included in this table, loading and maintenance doses of caffeine citrate in the comparison “low dose” group of the trial had to be those recommended by AAP/COFN.StudyCountry and enrolment periodNo. in high dose groupMean GA (SD) in high dose groupHigh loading dose (mg/kg)High maintenance dose (mg/kg/d)Primary outcomeGray et al, 201131Gray P.H. Flenady V.J. Charles B.G. Steer P.A. Caffeine Collaborative Study GroupCaffeine citrate for very preterm infants: effects on development, temperament and behaviour.J Paediatr Child Health. 2011; 47: 167-172Crossref PubMed Scopus (54) Google ScholarAustralia 1996-9912027.3 (1.4)8020Extubation failure†Although “cognitive development at 1 year of age” was listed as the main outcome measure in this report,31 “failure of extubation from mechanical ventilation” was the primary outcome measure for 83% of the infants in this trial cohort, according to an earlier publication by the same team of investigators.34 Outcomes for infants in this earlier report have been duplicated in the later report.31Mohammed et al, 201532Mohammed S. Nour I. Shabaan A.E. Shouman B. Abdel-Hady H. Nasef N. High versus low-dose caffeine for apnea of prematurity: a randomized controlled trial.Eur J Pediatr. 2015; 174: 949-956Crossref PubMed Scopus (72) Google ScholarEgypt 2011-126029.4 (2.0)4020Extubation failureMohd Kori et al, 202133Mohd Kori A.M. Van Rostenberghe H. Ibrahim N.R. Yaacob N.M. Nasir A. A randomized controlled trial comparing two doses of caffeine for apnoea in prematurity.Int J Environ Res Public Health. 2021; 18: 4509Crossref PubMed Scopus (6) Google ScholarMalaysia 2019-204030.0 (2.8)4020ApneaAAP, American Academy of Pediatrics; COFN, Committee on Fetus and Newborn; GA, gestational age; SD, standard deviation.∗ To be included in this table, loading and maintenance doses of caffeine citrate in the comparison “low dose” group of the trial had to be those recommended by AAP/COFN.† Although “cognitive development at 1 year of age” was listed as the main outcome measure in this report,31Gray P.H. Flenady V.J. Charles B.G. Steer P.A. Caffeine Collaborative Study GroupCaffeine citrate for very preterm infants: effects on development, temperament and behaviour.J Paediatr Child Health. 2011; 47: 167-172Crossref PubMed Scopus (54) Google Scholar “failure of extubation from mechanical ventilation” was the primary outcome measure for 83% of the infants in this trial cohort, according to an earlier publication by the same team of investigators.34Steer P. Flenady V. Shearman A. Charles B. Gray P.H. Henderson-Smart D. et al.High dose caffeine citrate for extubation of preterm infants: a randomised controlled trial.Arch Dis Child Fetal Neonatal Ed. 2004; 89: F499-F503Crossref PubMed Scopus (122) Google Scholar Outcomes for infants in this earlier report have been duplicated in the later report.31Gray P.H. Flenady V.J. Charles B.G. Steer P.A. Caffeine Collaborative Study GroupCaffeine citrate for very preterm infants: effects on development, temperament and behaviour.J Paediatr Child Health. 2011; 47: 167-172Crossref PubMed Scopus (54) Google Scholar Open table in a new tab AAP, American Academy of Pediatrics; COFN, Committee on Fetus and Newborn; GA, gestational age; SD, standard deviation. The propensity to present with apnea and periodic breathing after preterm birth is universal at extremely low gestational ages and progressively decreases with increasing gestational age.25Eichenwald E.C. Committee on Fetus and newborn, American academy of pediatricsApnea of prematurity.Pediatrics. 2016; 137Crossref Scopus (125) Google Scholar,35Erickson G. Dobson N.R. Hunt C.E. Immature control of breathing and apnea of prematurity: the known and unknown.J Perinatol. 2021; 41: 2111-2123Crossref PubMed Scopus (20) Google Scholar Similarly, the postmenstrual age at which apnea and periodic breathing resolve increases with decreasing gestational age at birth.25Eichenwald E.C. Committee on Fetus and newborn, American academy of pediatricsApnea of prematurity.Pediatrics. 2016; 137Crossref Scopus (125) Google Scholar,35Erickson G. Dobson N.R. Hunt C.E. Immature control of breathing and apnea of prematurity: the known and unknown.J Perinatol. 2021; 41: 2111-2123Crossref PubMed Scopus (20) Google Scholar This natural history as well as between-patient variability at comparable gestational ages mandate that decisions to start and stop caffeine therapy be individualized. In the CAP trial, caffeine therapy was initiated at a median of 3 days (IQR, 2-5) and permanently discontinued at a median postmenstrual age of 34.4 weeks (IQR, 33.0-35.9).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 There has been a trend in recent years toward starting caffeine within the first 1-2 days of life, and as early as in the delivery room.36Lodha A. Entz R. Synnes A. Creighton D. Yusuf K. Lapointe A. et al.Early caffeine administration and neurodevelopmental outcomes in preterm infants.Pediatrics. 2019; 143e20181348Crossref PubMed Scopus (52) Google Scholar, 37Szatkowski L. Fateh S. Abramson J. Kwok T.C. Sharkey D. Budge H. et al.Observational cohort study of use of caffeine in preterm infants and association between early caffeine use and neonatal outcomes.Arch Dis Child Fetal Neonatal Ed. 2023; (fetalneonatal-2022-324919)https://doi.org/10.1136/archdischild-2022-324919Crossref PubMed Scopus (2) Google Scholar, 38Grainge S. Nair V. Kannan Loganathan P. National survey on caffeine use in neonatal units across the United Kingdom.Acta Paediatr. 2022; https://doi.org/10.1111/apa.16635Crossref PubMed Scopus (4) Google Scholar It is probably appropriate to generalize the results of the CAP trial to very early use, but with the following caveats: very-low-birth-weight infants should only be considered for caffeine therapy soon after birth if they: (1) are extremely immature and receive positive airway pressure without an endotracheal tube; (2) are weaning from mechanical ventilation toward a trial of extubation; or (3) have documented apnea.39Schmidt B. Davis P.G. Roberts R.S. Timing of caffeine therapy in very low birth weight infants.J Pediatr. 2014; 164: 957-958Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Postmenstrual ages at discontinuation of caffeine therapy should vary according to the gestational age of the infant and the observed clinical resolution of immature breathing patterns. Any application of positive airway pressure to prevent or treat apnea should be stopped first because it is more invasive than oral caffeine therapy. Although many clinicians use a 5-to-7-day monitoring period without apnea after cessation of caffeine therapy as a prerequisite for discharge, the “specific event-free period may need to be individualized … depending on the gestational age at birth and the nature and severity of recorded events”.25Eichenwald E.C. Committee on Fetus and newborn, American academy of pediatricsApnea of prematurity.Pediatrics. 2016; 137Crossref Scopus (125) Google Scholar Randomized trials are in progress to evaluate the effects of prolonged caffeine therapy beyond the first discharge to home.40https://clinicaltrials.gov/ct2/show/NCT03340727Date accessed: February 26, 2023Google Scholar,41https://clinicaltrials.gov/ct2/show/NCT03321734Date accessed: February 26, 2023Google Scholar The WHO has concluded that caffeine citrate is an essential medicine for newborn infants.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 In contrast, other respiratory stimulants such as theophylline and aminophylline are not included in the WHO core list for neonates, for good reasons: caffeine has important pharmacokinetic advantages over theophylline and aminophylline. Caffeine has reliable enteral absorption, is administered only once per day, and therapeutic drug monitoring is unnecessary if standard doses are prescribed.12Aranda 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 rigorous evaluation in the CAP trial with follow up to 11 years, caffeine has become one of the best studied medicines in neonatology.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 However, caffeine is neither universally available nor affordable.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 According to a recent informal survey of colleagues in several middle-and-low-income countries, the purchase costs of caffeine citrate vary greatly and some of the higher purchase prices are prohibitive for their local payers (Table IV).Table IVCost of caffeine citrate in selected middle-and-low-income countriesCountryManufacturerLocal cost∗Cost of 1 mL vial containing 20 mg of caffeine citrate between December 17, 2022, and January 16, 2023.Cost in USD†Conversion to USD performed using https://fiscaldata.treasury.gov/datasets/treasury-reporting-rates-exchange/treasury-reporting-rates-of-exchange for December 31, 2022.BrazilChiesi125.4 BRL23.75ChinaChiesiMultiple local143.7 CNY33-34 CNY20.844.8-4.9EgyptSingle local (Inspire Pharmaceuticals)10 EGP0.4IndiaMultiple local264-280 INR3.2-3.4PakistanChiesi2000 PKR8.8ThailandChiesi950 THB27.5BRL, Brazilian real; CNY, Chinese yuan; EGP, Egyptian pound; INR, Indian rupee; PKR, Pakistani rupee; THB, Thai Baht; USD, US dollar.∗ Cost of 1 mL vial containing 20 mg of caffeine citrate between December 17, 2022, and January 16, 2023.† Conversion to USD performed using https://fiscaldata.treasury.gov/datasets/treasury-reporting-rates-exchange/treasury-reporting-rates-of-exchange for December 31, 2022. Open table in a new tab BRL, Brazilian real; CNY, Chinese yuan; EGP, Egyptian pound; INR, Indian rupee; PKR, Pakistani rupee; THB, Thai Baht; USD, US dollar. Caffeine citrate is an essential respiratory stimulant for infants with apnea of prematurity. When used for this indication, standard doses of caffeine are effective and safe into middle school age. Further rigorous research studies are required to close existing evidence gaps. Pending the results of such future investigations, clinical guideline developers should not venture beyond the currently available best evidence. Policy makers should ensure that all preterm infants with apnea have access to safely manufactured and affordable caffeine citrate.