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DOI: 10.1542/neo.8-5-e214 2007;8;e214 Neoreviews Girija Natarajan, Mirjana Lulic-Botica and J.V. Aranda Pharmacology Review: Clinical Pharmacology of Caffeine in the Newborn http://neoreviews.aappublications.org/content/8/5/e214 located on the World Wide Web at: The online version of this article, along with updated information and services, is ISSN: 1526-9906. 60007. Copyright © 2007 by the American Academy of Pediatrics. All rights reserved. Online the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, it has been published continuously since . Neoreviews is owned, published, and trademarked by Neoreviews is the official journal of the American Academy of Pediatrics. A monthly publication, at University of Michigan on October 18, 2014 http://neoreviews.aappublications.org/ Downloaded from at University of Michigan on October 18, 2014 http://neoreviews.aappublications.org/ Downloaded from

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DOI: 10.1542/neo.8-5-e2142007;8;e214Neoreviews 

Girija Natarajan, Mirjana Lulic-Botica and J.V. ArandaPharmacology Review: Clinical Pharmacology of Caffeine in the Newborn

http://neoreviews.aappublications.org/content/8/5/e214located on the World Wide Web at:

The online version of this article, along with updated information and services, is

ISSN: 1526-9906. 60007. Copyright © 2007 by the American Academy of Pediatrics. All rights reserved. Online the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,it has been published continuously since . Neoreviews is owned, published, and trademarked by Neoreviews is the official journal of the American Academy of Pediatrics. A monthly publication,

at University of Michigan on October 18, 2014http://neoreviews.aappublications.org/Downloaded from at University of Michigan on October 18, 2014http://neoreviews.aappublications.org/Downloaded from

Page 2: Pharmacology Review: Clinical Pharmacology of Caffeine in the Newborn

Author Disclosure

Drs Natarajan, Lulic-Botica, and

Aranda did not disclose any financial

relationships relevant to this article.

Clinical Pharmacology ofCaffeine in the NewbornGirija Natarajan, MD,* Mirjana Lulic-Botica, RPh,* J.V. Aranda, MD, PhD*

AbstractCaffeine is used commonly in the neonatal intensive care unit to treatapnea of prematurity. This review describes the mechanism of action,pharmacokinetics, and therapeutic role of caffeine. Published data on itsefficacy and safety document that caffeine can reduce the frequency ofapneic episodes and appears safe in the short term.

IntroductionCaffeine, a trimethylxanthine, iswidely used as first-line drug therapyin apnea of prematurity. Its pharma-cologic effect in apnea includes stim-ulation of the medullary respiratorycenter, increased sensitivity to car-bon dioxide, and enhanced dia-phragmatic contractility. (1) Otherdemonstrated effects include stimu-lation of the central nervous and car-diovascular systems, enhanced cate-cholamine secretion, an increase inthe basal metabolic rate, and alter-ation in glucose homeostasis. (2)Cardiac output and heart rate areincreased, while peripheral vascularresistance is lowered. Caffeine exertsmost of its effects by blocking aden-osine receptors A1 and A2a, increas-ing cyclic 3,5 adenosine monophos-phate (AMP) by inhibition ofphosphodiesterase, and translocatingintracellular calcium. (3) Prostaglan-din antagonist activity and, in animalmodels, upregulation of gamma-aminobutyric acid A receptor sub-units in the brainstem also have beensuggested. (4)(5)

PharmacokineticsCaffeine is one of the drugs used inthe neonatal intensive care unit forwhich extensive pharmacokineticdata are available, particularly in thepreterm neonate. (6)(7) Biotransfor-mation of caffeine occurs in the livervia microsomal cytochrome P450mono-oxygenases (CYP1A2) and viathe soluble enzyme xanthine oxidase.The predominant process of caffeinemetabolism in the preterm infant isN7-demethylation, which matures atabout 4 months of age. (8) N3- andN7-demethylation increase expo-nentially with postnatal age, regard-less of birthweight or gestational age.(8)(9) The female neonate demon-strates a higher rate of caffeine me-tabolism than the male. (8) In animalexperiments, caffeine causes a dose-dependent elevation of hepaticCYP1A1 and 2 activities in microso-mal preparations and CYP1A1 and 2mRNA concentrations over a doseregimen of 50 to 150 mg/kg per dayfor 3 days. (10) Through its induc-tive effects on N-demethylation andC-8 oxidation, it appears to increaseits own metabolism. (11)

Pharmacokinetic studies in pre-term neonates have established thatthe half-life of caffeine is prolongedto 102.9�17.9 hours and remainsprolonged for as long as 38 weeks’

*Divisions of Neonatology, Clinical Pharmacologyand Toxicology, The Pediatric PharmacologyResearch Unit Network (PPRU) at Wayne StateUniversity, Children’s Hospital of Michigan, Detroit,Mich.

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gestation, which reflects a matura-tional deficit of hepatic biotransfor-mation. (6) Plasma half-life and elim-ination rates reach adult levels at 3 to4.5 months of age. (7) Caffeine half-life may be prolonged further in in-fants who have cholestatic jaundiceand exclusively breastfed infants.(12) Caffeine is eliminated primarilyby renal excretion in the first postna-tal weeks. Population pharmacoki-netic studies have established thatpostconceptional age and parenteralnutrition influence caffeine clearancein neonates; neonates of low gesta-tion receiving parenteral nutrition,therefore, may need closer monitor-ing of caffeine concentrations. (13)

Therapeutic Drug MonitoringTherapeutic concentrations of caf-feine vary widely from 8 to 40 mg/L,with some overlap with subtherapeu-tic concentrations. (14) The recom-mended dose regimen includes aloading dose of 20 to 40 mg/kgcaffeine citrate, which corresponds to10 to 20 mg/kg caffeine base, fol-lowed by a maintenance dose of 5 to8 mg/kg per dose of caffeine citratestarting 24 hours later. (15) Standarddoses of 5 mg/kg per day following aloading dose of 20 mg/kg shouldachieve therapeutic levels in morethan 70% of neonates. (16) The drughas a wide therapeutic margin, withserious toxicity reported only atplasma concentrations higher than40 to 50 mg/L, if at all. (15)

A higher dose regimen (loadingdose of 50 mg/kg caffeine citrateadministered as two separate doses1 hour apart and maintenance doseof 12 mg/kg once daily to produce adesired plasma concentration of30 mg/L [range, 26 to 40 mg/L])has been shown to reduce the num-ber of apneic episodes by more than50% within 24 hours of treatmentcompared with a one-third reductionwith the standard dose. (17) A rapid

improvement in apnea within 8hours also was apparent in the infantstreated with the higher dose regimenwithout any adverse effects. (17) Inthis particular study, 69% of infantsreceiving standard doses achievedplasma concentrations between 13and 20 mg/L, and 73% of the higherdose group achieved concentrationsin the range of 26 to 40 mg/L.

Another population pharmacoki-netic study compared daily doses ofcaffeine citrate of 30, 15, and3 mg/kg for 7 days following load-ing doses of 60, 30, and 6 mg/kg in119 preterm infants who had apnea.(18) Mean serum concentrations af-ter the final dose were 69, 35.8, and7.4 mg/L in the treatment groups,and no adverse effects were reported.A dose of 20 mg/kg caffeine citrateresulted in reduced extubation fail-ure compared with a dose of5 mg/kg in another study withoutany adverse effects during a 12-month follow-up period. (19)

In a single report of a toxic over-dose of 160 mg/kg in a 31-weekgestation 1,860-g infant, the serumconcentration was 217.5 mg/L 36.5hours after dosing. Toxic manifesta-tions included hypertonia, sweating,tachycardia, cardiac failure, pulmo-nary edema, metabolic acidosis, hy-perglycemia, and creatine kinase ele-vation. (20) Monitoring of plasmaconcentrations generally is recom-mended if there is lack of clinicalresponse or suspected toxicity. (21)Periodic routine drug monitoringalso is performed at some centers,although the value of this practice isuncertain.

Drug InteractionsBecause cytochrome P450 1A2(CYP1A2) is the major enzyme in-volved in its metabolism, caffeine hasthe potential to interact with drugsthat are substrates for CYP1A2. Ci-metidine and ketoconazole can in-

hibit caffeine metabolism, necessi-tating lower doses of caffeine.Phenytoin and phenobarbital can in-crease caffeine elimination, possiblyrequiring higher doses of caffeine.(22) In adults, estrogen-containingcontraceptives can decrease caffeineclearance by up to 65%, resulting inan extended elimination half-life.(22) Caffeine antagonizes the effectsof adenosine, with a decreased ther-apeutic effect at standard doses.

Comparison WithTheophyllineAlthough very similar in its actions totheophylline, caffeine has several ad-vantages and has become the pre-ferred methylxanthine in the treat-ment of apnea. Its toxicity is lowerand half-life is longer, and there isless need for therapeutic drug moni-toring (Table). A systematic reviewof three trials comparing theophyl-line and caffeine citrate at loadingdoses of 20 to 25 mg/kg, with main-tenance doses of 2.5 to 6 mg/kg,revealed no difference in efficacy ofreduction of apnea. (23) Adverse ef-fects, such as tachycardia and feedingintolerance, were lower with caffeine.In neonates, caffeine is a biotransfor-mation product of theophylline viamethylation; in adults, the principalmetabolic pathway for theophyllineis demethylation and oxidation.

EfficacyApnea of Prematurity

Apnea is a commonly encounteredproblem in the neonatal intensivecare unit, with a reported prevalenceof 35% in infants born at less than 32weeks’ gestation and 84% in ex-tremely low-birthweight neonates.(24) Caffeine currently is consideredthe pharmacologic treatment ofchoice for apnea of prematurity. TheCochrane review of five trials involv-ing 192 preterm infants who had ap-nea indicated that methylxanthine

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therapy is effective in reducing thenumber of apneic spells and the useof mechanical ventilation in the 2 to7 days after starting treatment. (25)Caffeine, which was specifically eval-uated in two trials involving 103 pre-term neonates, had a relative risk oftreatment failure of 0.46 (95% confi-dence interval [CI], 0.27 to 0.78).(26)(27) When used as prophylaxisto prevent apnea in two placebo-controlled studies involving 104 pre-term infants, no differences were ap-parent between the groups in theproportion of infants who had apnea,bradycardia, or hypoxemic episodesor the use of positive-pressure venti-

lation. (28)(29) The sample sizes inthe studies were small, however, andcaffeine was used for a total durationof 96 hours in one study.

Postoperative ApneaThe risk of postoperative apnea fol-lowing general anesthesia, which ispredominantly central, persists forabout 60 weeks after conception.(30) Three trials involving 78 infantsat gestational ages of 40 to 44 weeksfound a significantly lower relativerisk of 0.09 (95% CI, 0.02 to 0.34)when caffeine citrate was used at adose of 5 to 10 mg/kg during orafter induction of anesthesia. (31)

Although probably efficacious, caf-feine is not used routinely as prophy-laxis to prevent postoperative apneadue to concerns of possible adverseeffects and lack of long-term data.

ExtubationThe use of methylxanthines as respi-ratory stimulants when weaning pre-term infants from mechanical venti-lation appears to reduce the failure ofextubation, although controversypersists about the dosing regimen,duration, and long-term effects ofuse in this context. An overall analysisof six published trials showed a de-creased relative risk of 0.47 (95% CI,

Table. Comparison of Caffeine and TheophyllineCaffeine Theophylline

Loading dose (LD) 20 to 40 mg/kg per dose IV/PO 4 to 8 mg/kg per dose IVMaintenance dose

(MD)5 to 8 mg/kg per dose IV/PO caffeine citrate 1.5 to 3 mg/kg per dose IV

Plasma half-life (h) 40 to 230 (mean, 103) 12 to 64 (mean, 30)Therapeutic level

(mcg/mL)5 to 25 7 to 12

Toxic level (mcg/mL) >40 to 50 >20Signs of toxicity Sinus tachycardia, hypertonia, sweating,

cardiac failure, pulmonary edema,metabolic disturbances

Sinus tachycardia, agitation, electrolyteabnormalities, significant diuresis,gastrointestinal bleeding, ventriculartachycardia, seizure

Cerebrospinal fluid(CSF) distribution

Similar to plasma concentrations (reportedcorrelation coefficients of 0.77)

Crosses into the CSF (reportedcorrelation coefficients of 0.54)

Volume of distribution(L/kg)

0.8 to 0.9 0.45

Metabolism Excreted unchanged or CYP P450(CYP1A2) liver-methyltransferase pathway

Excreted unchanged or CY P450(CYP1A2) metabolism

Interconversionbetween two

3% to 8% converted to theophylline viaCYP1A2

25% converted to caffeine viamethylation

Routine measurementof bloodconcentrations

Not required Required

Clearance (L/kg perhour)

0.002 to 0.017 0.02 to 0.05

Elimination Neonates younger than 1 month of ageexcrete 86% unchanged in urine; first-order elimination

Neonates excrete approximately 50%of the dose unchanged in urine;first-order kinetics; at highconcentrations (>20 mg/L), thedrug elimination mechanismbecomes saturated, resulting inconcentration-dependent elimination(zero-order kinetics)

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0.32 to 0.70) and an absolute reduc-tion of 27% in the incidence of failedextubation. (32) One of these trialssuggested a preferential beneficial ef-fect in infants born at less than 1 kgbirthweight and extubated withinthe first week after birth. (33) Onlytwo of the trials evaluated caffeine.More recently, a randomized,double-blind clinical trial of threedosing regimens of caffeine citrate(3, 15, and 30 mg/kg) for periextu-bation management of 127 venti-lated preterm infants of less than 32weeks’ gestation showed no statisti-cally significant difference in the inci-dence of extubation failure amongthe dosing groups. (34) However,the infants in the two higher dosinggroups had statistically significantless documented apnea in the imme-diate periextubation period. A largertrial involving 234 neonates born atless than 30 weeks’ gestation re-ported a significant reduction in fail-ure to extubate among infants receiv-ing 20 mg/kg per day caffeine citratecompared with 5 mg/kg per day(15% versus 29.8%; relative risk,0.51; 95% CI, 0.31 to 0.85). (19) Asignificant difference in the durationof mechanical ventilation was ob-served in infants of less than 28weeks’ gestation who received thehigher dose. No differences werenoted in short-term adverse effects orat 12 months follow-up.

Other EffectsLung Function

Caffeine increases the central respira-tory drive, thereby improving oxy-genation and ventilation and de-creasing hypoxic episodes. In thelarge randomized, controlled Caf-feine for Apnea of Prematurity(CAP) trial, the rates of bronchopul-monary dysplasia (BPD), defined asan oxygen need at 36 weeks postcon-ceptional age, were 36.3% in the caf-feine group and 46.9% in the placebo

group, a statistically significant dif-ference. (35) This promising effecton the incidence of BPD has beenattributed to the diuretic, respiratorystimulant, and anti-inflammatory ef-fects of caffeine. (35) Previously,other smaller studies showed a de-crease in airway resistance and im-proved lung mechanics within 1 hourof caffeine therapy in infants who hadBPD. (36) An improvement in respi-ratory system compliance after caf-feine administration also has been re-ported in preterm infants who hadresolving respiratory distress syn-drome. (37) The clinical effect hasbeen validated in an immature ba-boon model treated with surfactant,where early caffeine treatment wasassociated with better lung function,higher compliance, and significantdecreases in ventilator support. (38)In a rat pup model that received neo-natal caffeine, there was a 22% higherminute ventilation response to hy-percapnia in males in the juvenilestage, which persisted until adult-hood. (39) This reported long-termeffect on respiratory control wasspeculated to be due to a persistentchange in adenosinergic neurotrans-mission.

Patent Ductus ArteriosusThe CAP trial involving infantsweighing less than 1,250 g at birthshowed a statistically significant de-crease in the incidence of patent duc-tus arteriosus (30% versus 40%) andin the rates of surgical ligation (4.5%versus 12.6%) in the group treatedwith caffeine citrate (loading dose of20 mg/kg followed by 5 to10 mg/kg maintenance). (35) Thiseffect needs to be clarified in furtherstudies evaluating this specific out-come. However, caffeine is known tohave prostaglandin antagonistic ac-tivity, an effect that is demonstrableat the concentrations achieved in hu-man plasma. (4) In addition, it is a

diuretic and a vasoconstrictor, re-lated to adenosine antagonism, bothpossible mechanisms of a real effecton the ductus.

Cardiac EffectsCaffeine has a positive inotropic andchronotropic effect on the heart.Tachycardia is a well-known adverseeffect of methylxanthine use. (2)Heart rate variability also has beennoted in infants after receiving meth-ylxanthine, with the effect beingmore pronounced in the sickest in-fants. (40)

Central Nervous SystemEffects

Caffeine is a generalized central ner-vous system excitant, causing in-creased transmission of impulsesacross neurons and synapses andstimulation of the motor end-plate.The acute neurologic effects of caf-feine include jitteriness, tremor, hy-pertonia, and rhabdomyolysis, al-though these occur at higher plasmaconcentrations. (2) The effect of caf-feine on cerebral blood flow has beena focus of investigation, primarily be-cause of the concern of hemorrhageor periventricular leukomalacia inpreterm neonates. A significant de-crease in blood flow velocity in theinternal carotid artery (22%) and an-terior cerebral artery (14%) was ob-served in 16 preterm neonates fol-lowing an oral “pure” caffeine doseof 25 mg/kg without a concomitantdecrease in cardiac output. (41) Oth-ers have shown no effect on cerebralhemodynamics at lower loading dosesand at a maintenance dose of 2.5 mg/kg caffeine base. (42)(43)(44)

Oxygen Consumption, WeightGain, and Growth

An increase in oxygen consumptionand energy expenditure has been re-ported in preterm neonates after 48hours of caffeine therapy, which per-

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sisted through 4 weeks. (45)Caffeine-treated infants in the studyrequired lower environmental tem-peratures to maintain normothermia.(45) The CAP trial validated a re-duced weight gain in the caffeine co-hort, with the greatest differencenoted after 2 weeks (mean difference�23 g), (35) an effect known previ-ously in adults and animals. (46)(47)Long-term effects on growth are un-known.

Renal FunctionThe diuretic effect of caffeine, fol-lowing an increase in renal bloodflow and glomerular filtration, is wellknown in adults and experimentalanimals. (2) Caffeine has no effect onserum sodium, potassium, calcium,and phosphorus concentrations; uri-nary calcium excretion increases andserum creatinine decreases signifi-cantly in preterm neonates. (48) Atthe clinically used doses, however,effects on renal function in neonatesare minimal. (2)

Glucose HomeostasisIn the neonate, caffeine, like theoph-ylline, may increase blood glucoseconcentrations acutely due to in-creased glycogenolysis, although thisis seen infrequently in the usual clin-ical situation.

Gastrointestinal EffectsCaffeine increases gastric secretionand reduces lower gastroesophagealsphincter pressure. An increased du-ration of acid gastroesophageal refluxhas been reported on esophageal pHmonitoring in neonates receivingcaffeine treatment during the latepostprandial time (more than 2 hafter the beginning of a meal). (49)Other studies have reported a similarincrease in reflux time in about 50%of infants treated with caffeine,which resolved 2 weeks after stop-ping therapy and improved with cisa-

pride. (50)(51) The increase in epi-sodes of reflux was independent ofplasma xanthine concentrations ordrug efficacy. (52) The mechanismof lower esophageal sphincter relax-ation appears to be via an enhance-ment of cyclic AMP levels. (53)

SafetyFetuses and newborns are exposed tocaffeine via maternal intake ofcaffeine-containing foods and bever-ages. This widespread and extensiveexposure to caffeine must be consid-ered in the evaluation of the long-term effects of caffeine in the new-born and young infants.

The CAP trial demonstrated noapparent short-term toxicity relatedto caffeine, although long-term neu-rodevelopmental outcomes areawaited. In particular, the incidenceof necrotizing enterocolitis did notdiffer between the caffeine and pla-cebo groups. (35) A previous smallertrial involving 85 neonates had raisedconcerns about a possible associationwith necrotizing enterocolitis, as haddata indicating a reduction in mes-enteric blood flow velocities fol-lowing caffeine administration.(26)(41)(54)

The rates of ultrasonographicsigns of brain injury did not differbetween the caffeine-treated and pla-cebo groups in the CAP trial. (35)Currently, the data on long-term ef-fects in preterm neonates are scarceand inconclusive. A study involving73 very low-birthweight neonates,some of whom also had germinal ma-trix or intraventricular hemorrhage,demonstrated no adverse effects ofneonatal caffeine use on the 18-month Bayley mental developmentscore. (55) In fact, infants who had ahistory of neonatal methylxanthinetherapy scored better at 18 monthsthan infants not treated, regardless ofhemorrhage status, although thesample size was small. Gunn and as-

sociates (56) had earlier reported nodifferences in growth and develop-ment at 12 months of age in 21 verylow-birthweight infants treated withmethylxanthines compared with 21untreated infants.

Adenosine A1 receptors arewidely distributed through the brainand are highly expressed in the hip-pocampus during development. (57)Adenosine is neuroprotective duringischemia by reducing the release ofglutamate. There have been concernsthat caffeine may worsen certainforms of ischemic brain injurythrough its antagonistic effects onadenosine and may interfere withneural cell proliferation, axonalgrowth, learning, and memory dur-ing development. (57)(58) In exper-imental studies, caffeine inducedneuronal death in neonatal rat brainand cortical cell cultures. (59) Inneonatal mice, therapeutic doses ofaminophylline decreased the rate ofanoxic survival in vivo. (60) In ratpups treated with daily caffeine, im-paired motor skills and changes inlocomotor activity were demon-strated. The effects were dependenton the developmental stages at whichcaffeine was administered and theage at which tests were performed.(61) Impairment of motor skills, al-though transient, appeared early af-ter treatment. (61) In a newbornmouse model, however, caffeine ex-posure did not worsen excitotoxiclesions of the periventricular whitematter mimicking human periven-tricular leukomalacia. (57)

ConclusionsCaffeine is a widely used drug in pre-term neonates who have apnea. Sev-eral clinical trials have demonstratedits efficacy in reducing the frequencyof apneic episodes and need for me-chanical ventilation. There has been aresurgence of interest in the drug,with a large randomized trial show-

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ing a decrease in the incidence ofBPD. Caffeine, at least in the shortterm, appears safe at the currentlyused doses. Further long-term stud-ies on neurodevelopmental outcomeare awaited.

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variability in premature neonates pre andpost methylxanthine administration. Paedi-atr Anaesth. 1996;6:399–40341. Hoecker C, Nelle M, Poeschl J, Beed-gen B, Linderkamp O. Caffeine impairs ce-rebral and intestinal blood flow velocity inpreterm infants. Pediatrics. 2002;109:784–78742. Saliba E, Autret E, Gold F, Bloc D,Porcelet L, Laugier J. Effect of caffeine oncerebral blood flow velocity in preterm in-fants. Biol Neonate. 1989;56:198–20343. Van Bel F, Van de Bor M, Stijnen T,Baan J, Ruys JH. Does caffeine affect cere-bral blood flow in the preterm infant? ActaPaediatr Scand. 1989;78:205–20944. Dani C, Bertine G, Reali MF, et al.Brain hemodynamic changes in preterm in-fants after maintenance dose caffeine andaminophylline treatment. Biol Neonate.2000;78:27–3245. Bauer J, Maier K, Linderkamp O,Hentschel R. Effect of caffeine on oxygenconsumption and metabolic rate in very lowbirth weight infants with idiopathic apnea.Pediatrics. 2001;107:660–66346. Dulloo AG, Geisller CA, Horton T,Collins A, Miller DS. Normal caffeine con-sumption: influence on thermogenesis anddaily energy expenditure in lean and obesehuman volunteers. Am J Clin Nutr. 1989;49:44–5047. Ramssey JJ, Ricki JC, Swick AG, Kem-nitz JW. Energy expenditure, body compo-

sition and glucose metabolism in lean andobese rhesus monkeys treated with epineph-rine and caffeine. Am J Clin Nutr. 1998;68:42–5148. Zanardo V, Dani C, Trevisanuto D, etal. Methylxanthines increase renal calciumexcretion in preterm infants. Biol Neonate.1995;68:169–17449. Skopnik H, Koch G, Heimann G. Ef-fect of methylxanthines on periodic respira-tion and acid gastro-esophageal reflux innewborn infants. Monatsschr Kinderheilkd.1990;138:123–12750. Sacre L, Vandenplas Y. Xanthines inapnea of premature infants. Influence ongastroesophageal reflux. Arch Fr Pediatr.1987;44:383–38551. Kentrup H, Baisch HJ, Kusenbach G,Heimann G, Skopnik H. Effect of cisaprideon acid gastroesophageal reflux duringtreatment with caffeine. Biol Neonate. 2000;77:92–9552. Vandenplas Y, De Wolf D, Sacre L.Influence of xanthines on gastroesophagealreflux in infants at risk for sudden infantdeath syndrome. Pediatrics. 1986;77:807–81053. Goyal RK, Rattan S. Mechanism of thelower esophageal sphincter relaxation: ac-tion of prostaglandin E1 and theophylline.J Clin Invest. 1973;52:33754. Lane AJ, Coombs RC, Evans DH,Levin RJ. Effect of caffeine on neonatal

splanchnic blood flow. Arch Dis Child FetalNeonatal Ed. 1999;80:F128–F12955. Ment LR, Scott DT, Ehrenkrantz RA,Duncan CC. Early childhood developmen-tal follow-up of infants with GMH/IVH:effect of methylxanthine therapy. Am J Peri-natol. 1985;2:223–22756. Gunn TR, Metrakos K, Riley P, WillisD, Aranda JV. Sequelae of caffeine treat-ment in preterm infants. J Pediatr. 1979;84:106–10957. Bahi N, Nehlig A, Evrard P, GressensP. Caffeine does not affect excitotoxic brainlesions in newborn mice. Eur J PaediatrNeurol. 2001;5:161–16558. Dux E, Fastborn J, Ungerstedt U, Ru-dolphi K, Fredholm BB. Protective effect ofadenosine and a novel xanthine derivativepropentofylline on the cell damage after bi-lateral carotid occlusion in the gerbil hip-pocampus. Brain Res. 1990;516:248–25659. Kang SH, Lee YA, Won SJ, Rhee KH,Gwag BJ. Caffeine induced neuronal deathin neonatal rat brain and cortical cell cul-tures. Neuroreport. 2002;13:1945–195060. Thurston JH, Hauhart RE, Dirgo JA.Aminophylline increases cerebral metabolicrate and decreases anoxic survival in youngmice. Science. 1978;201:649–65161. Tchekalarova J, Kubova H, Mares P.Postnatal caffeine exposure: effects on mo-tor skills and locomotor activity during onto-genesis. Behav Brain Res. 2005;160:99–106

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NeoReviews Quiz

8. The pharmacologic effects of caffeine in the treatment of apnea of prematurity include stimulation of themedullary respiratory center, increased sensitivity to carbon dioxide, and enhanced diaphragmaticcontractility. Of the following, caffeine exerts most of its effects by:

A. Antagonism of prostaglandin activity.B. Blockage of adenosine receptors.C. Enhancement of catecholamine secretion.D. Stimulation of phosphodiesterase.E. Upregulation of gamma-amino-butyric acid receptors.

9. Caffeine administration in preterm infants warrants careful consideration of its dosage because of theinteractions between caffeine and several other drugs. Of the following, the drug most likely to increasecaffeine elimination, thereby warranting a higher dose of caffeine, is:

A. Cimetidine.B. Estrogen.C. Indomethacin.D. Ketoconazole.E. Phenobarbital.

10. A 12-day-old neonate, whose birthweight was 760 g and estimated gestational age at birth was26 weeks, has recurrent episodes of apnea, bradycardia, and cyanosis. Caffeine is administeredintravenously with a loading dose of 20 mg/kg, followed by a maintenance dose of 5 mg/kg per day. Ofthe following, the most likely adverse effect of caffeine at this dose and assuming plasma concentrationsof caffeine in the therapeutic range in this infant is:

A. Altered renal function.B. Decreased energy expenditure.C. Increased blood glucose concentration.D. Opening of the ductus arteriosus.E. Relaxation of the lower esophageal sphincter.

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DOI: 10.1542/neo.8-5-e2142007;8;e214Neoreviews 

Girija Natarajan, Mirjana Lulic-Botica and J.V. ArandaPharmacology Review: Clinical Pharmacology of Caffeine in the Newborn

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