Don’t discardyour indomethacinyet

RB Cotton

Departmentof Pediatrics,VanderbiltUniversityMedical Center,Nashville,TN, USA

The beneficialeffectsof surgicalinterventionto closethe ductus arteriosusin prematureinfants with sig-nificant left-to-right shuntingthroughthis vesselweredemonstratedover 20y ago(1). About the sametime,Heymannetal. (2) andFriedmanetal. (3) demonstratedthatclosureof theductuscouldbeachievedpharmaco-logically using the cyclooxygenaseinhibitor indo-methacin.The efficacyof indomethacinin this contextwas substantiatedby a large multicenter randomizedclinical trial that led its investigatorsto recommendindomethacinas the preferabletreatmentfor infantswith symptomaticPDA, reservingsurgical ligation asback-uptreatmentfor indomethacinfailure (4).

Indomethacinhasalsobeenshownto beeffectiveinthepreventionof symptomaticPDA whengivenwithin24h after birth (5). In a review of 9 controlledtrials,prophylactic indomethacinwas found to reduce theincidenceof symptomaticPDA from 40%to 6%amongnewborn premature infants who weighed less than1500g at birth (6). Studies have also shown thatprophylacticindomethacinreducestheneedfor surgicalligation (7) and may reducethe incidenceof severeintraventricularhemorrhage(8).

In spiteof the beneficialeffectsof indomethacininboththetreatmentandpreventionof symptomaticPDA,there are numerousadverseeffects of this drug thatcompetewith its overall effectiveness.Reducedrenalfunctionmanifestby decreasedurineoutput,decreasedserum sodium, and increased serum creatinine isfrequently observedfollowing indomethacinadminis-tration (9). When indomethacin treatment fails toachieveductusclosure,renaldysfunctionmay becomemarkedly aggravatedwhen the adverse effects ofindomethacinarecombinedwith decreasedrenalbloodflow due to the ductusstealof left ventricularoutput.Other adverseeffects include decreasedcerebral(10)and mesenteric(11) blood flow velocity, gastrointest-inal perforation(12), decreasedcardiacfunction (13),impairedsurfactantreleasefrom type II cells (14), anddecreasedplateletfunction (4).

Paradoxically,themostproblematiccomplicationofindomethacinis delayedpermanentductusclosure(theligated ductus rarely reopens). Failure to achievepermanentductusclosurewith indomethacinis espe-cially commonin extremelyimmatureinfantswho arelessthan28 weeksgestationalage.Narayananet al. (7)reportedthat41%of infantstreatedwith indomethacinfor symptomatic PDA and 21% of infants givenprophylactic indomethacin required eventual ductusligation. Arguably, the added morbidity related todelayedclosureand the surgicalprocedureis at least

comparableto, if not greaterthan the indomethacin-associatedmorbidity relatedto changesin cerebrovas-cular andrenalfunction that areusuallytransient.

Recent studies have indicated that another non-steroidal anti-inflammatorydrug, ibuprofen, may bean effectivealternativeto indomethacinwithout manyof the sideeffectsof this drug (15–19).The reportbyDani et al. elsewherein this journal (20) confirm theefficacyof intravenousibuprofenin boththepreventionand treatment of symptomatic PDA in newbornprematureinfants. On the third day after birth, only8%of 40 infantswhohadreceivedibuprofenbeginningwithin 24h following delivery had a significantPDAcomparedwith 53%of 40 infantsin the control group.Ibuprofentreatmentof infantsin thecontrolgroupwhodevelopeda significantPDA by 3 d after birth resultedin ductusclosurein 90%(19/21).Only two infantsfromthe prophylacticgroupandoneinfant from the controlgroupwho hadbeentreatedwith ibuprofendevelopedrecurrentductuspatency.None requiredsurgical liga-tion. Thedesignof this studydid notpermitassessmentof sideeffectsnormally associatedwith indomethacin.However,no significantchangesin renalfunctionwereseenfollowing ibuprofenwhenusedeitherprophylacti-cally or astreatmentfor PDA.

Thestudyby Danietal. hasseverallimitations.Sincethe meanbirthweightsof the study groupswere over1200g, the results may not apply to extremelyimmature infants 24–26wk gestationalage in whomindomethacinfailureandindomethacin-associatedrenalfailure are such vexing problems. The number ofpatientsenrolledin thestudywassufficientto establishefficacy of ibuprofen to prevent symptomaticPDA.However,amuchlargertrial wouldberequiredto enrollthehundredsof patientsnecessaryto detectdifferencesbetweentheprophylacticandrescuegroupsin regardtoadverseoutcomessuchasneedfor ductusligation andthe incidenceIVH. Nor can inferencesbe madeabouttherelativesafetyof ibuprofencomparedto indometha-cin, since this study did not include an indomethacingroup.

Themain limitation on theusefulnessof indometha-cin is not the effect of this drug on renal function andcerebrovascularfunction, but the poor successrate ofthis drugin achievingpermanentductusclosurein veryimmatureinfants.Theefficacyof ibuprofenin regardtoavoidingtheneedfor eventualligation of theductusinextremelyimmatureinfantshasnotyetbeenadequatelyaddressed.Publishedstudiesto datehavenot includedsufficientnumbersof patientswho arelessthan28 wkgestationalageto drawvalid conclusionsin this regard.

1278 Commentaries ACTA PÆDIATR89 (2000)

However, based on work by the Clyman groupimplicatingtheinvolvementof endogenousnitric oxidein ductuspatency(20,21),onewouldnotexpectthattheuseof a different cyclooxygenaseinhibitor is likely todecreasethenumberof indomethacinfailures.

Nevertheless,this study and others on the samesubjectprovide good evidencethat ibuprofenmay bepreferable to indomethacin in the prevention andtreatmentof symptomaticPDA. However,before theuseof ibuprofencanbeacceptedasthestandardof carefor thiscondition,asufficientlylargemulticentertrial isneededto establishan acceptableequivalencebetweenthe drugsin regardto efficacy.Eventhoughibuprofenappearsto berelatively freeof thecerebrovascularandrenaleffectsof indomethacin,it is importantto establishthat failure to achievepermanentclosureis no worsewith ibuprofenthanwith indomethacin.

When renal insufficiency accompaniesa failedattemptto closethe ductususing indomethacin,somephysiciansmight be tempted to use ibuprofen in arepeatedattemptto achievepharmacologicinductionofductusclosure.Thesafetyandefficacyof inbuprofeninthis clinical context have not been demonstrated.Inaddition,a failed repeatedattemptat pharmacologicalclosurewould furthercompromisethepatient’sclinicalstatus by postponing definitive closure by surgicalligation.

At the presenttime, the intravenouspreparationofibuprofen is unavailable in the United States.Thebioavailability of oral ibuprofen in the newbornprematureinfant is unknown. Oral ibuprofen shouldnotbeusedasasubstitutefor intravenousindomethacinin the managementof symptomaticPDA, either asprimary treatmentor prophylaxis,or asa backupdrugwhenadditionaltreatmentwith indomethacinis contra-indicatedby renalfailure.

References1. Cotton RB, StahlmanMT, BenderHW, GrahamTP, Catterton

WZ, Kovar I. Randomizedtrial of early closure of sympto-matic patent ductus arteriosus in small preterm infants. JPediatr1978;93: 647–51

2. HeymannMA, Rudolph AM, Silverman NH. Closure of theductusarteriosusin prematureinfants by inhibition of prosta-glandinsynthesis.N Engl J Med 1976;295:530–3

3. FriedmanWF, HirschklauMJ, Printz MP, Pitlick PT, Kirkpa-trick SE. Pharmacologicclosureof patentductusarteriosusinthe prematureinfant. N Engl J Med 1976;295:526–9

4. GersonyWM, PeckhamGJ, Ellison RC, Miettinen OS, NadasAS. Effects of indomethacinin prematureinfants with patentductus arteriosus:results of a national collaborativestudy. JPediatr1983;102:895–906

5. Krueger E, Mellander M, Bratton D, Cotton R. Preventionofsymptomaticpatent ductus arteriosuswith a single dose ofindomethacin.J Pediatr1987;111:749–54

6. ClymanRI, CampbellD. Indomethacintherapyfor patentduc-tus arteriosus:When is prophylaxisnot prophylactic?J Pediatr1987;111:718–22

7. NarayananM, CooperB, Weiss H, Clyman RI. Prophylacticindomethacin:factorsdeterminingpermanentductusarteriosusclosure.J Pediatr 2000;136:330–7

8. Ment LR, Oh W, EhrenkranzRA, Philip AG, Vohr B, AllanW, et al. Low-doseindomethacinandpreventionof intraventri-cular hemorrhage:a multicenter randomizedtrial [see com-ments].Pediatrics1994;93: 543–50

9. CifuentesRF, Olley PM, Balfe JW, RaddeIC, Soldin SJ.Indo-methacinand renal function in prematureinfants with persis-tent patentductusarteriosus.J Pediatr1979;95: 583–7

10. Patel J, Roberts I, Azzopardi D, Hamilton P, EdwardsDA.Randomizeddouble-blindcontrolledtrial comparingthe effectsof ibuprofenwith indomethacinon cerebralhemodynamicsinpreterminfantswith patentductusarteriosus.PediatrRes2000;47: 36–42

11. Van Bel F, Van ZoerenD, SchipperJ, Guit GL, BaanJ. Effectof indomethacinon superiormesentericarteryblood flow velo-city in preterminfants.J Pediatr1990;116:965–70

12. Kuhl G, Wille L, Bolkenius M, SeyberthHW. Intestinal per-foration associatedwith indomethacintreatmentin prematureinfants.Eur J Pediatr1985;143:213–6

13. Appleton RS, GrahamTP Jr, Cotton RB, MoreauGA, BoucekRJJr. Decreasedearly diastolicfunction after indomethacinad-ministrationin prematureinfants.J Pediatr1988;112:447–51

14. OyarzunMJ, ClementsJA. Control of lung surfactantby venti-lation, adrenergicmediators,and prostaglandinsin the rabbit.Am RevRespirDis 1978;117:879–91

15. PatelJ, Marks KA, RobertsI, AzzopardiD, EdwardsAD. Ibu-profentreatmentof patentductusarteriosus.Lancet1995;346:255

16. Varvarigou A, Bardin CL, Beharry K, ChemtobS, Papageor-giou A, ArandaJV. Early ibuprofenadministrationto preventpatentductusarteriosusin prematurenewborninfants. JAMA1996;275:539–44

17. Van Overmeire B, Follens I, Hartmann S, Creten W, VanAcker KJ. Treatmentof patentductusarteriosuswith ibupro-fen. Arch Dis Child 1997;76: F179–84

18. MoscaF, Bray M, LattanzioM, FumagalliM, TosettoC. Com-parativeevaluationof the effectsof indomethacinand ibupro-fen on cerebralperfusionandoxygenationin prematureinfantswith patentductusarteriosus.J Pediatr1997;131:549–54

19. PezzatiM, Vangi V, Biagiotti R, Bertini G, Cianciulli D, Ru-baltelli FF. Effects of indomethacinand ibuprofen on mesen-teric andrenalblood flow in preterminfantswith patentductusarteriosus.J Pediatr1999;135:733–8

20. Dani C, Bertini G, Reali MF, Murru P, Fabris,Vangi V, Rubal-telli FF. Prophylaxisof patentductus arterioususwith ibupro-fen in preterminfants.Acta Paediatr2000;89: 1369–74

21. ClymanRI, WalehN, Black SM, RiemerRK, MaurayF, ChenY. Regulationof ductusarteriosuspatencyby nitric oxide infetal lambs:the role of gestation,oxygentension,andvasava-sorum.PediatrRes1998;43: 633–44

22. Clyman RI, Seidner SR, Koch CJ. Combined prostaglandin(PG) andnitric oxide (NO) inhibition producespermanentclo-sureof PDA in pretermbaboons.PediatrRes1999; 45: 190AAbstract

Robert B Cotton, Departmentof Pediatrics, Schoolof Medicine-Vanderbilt University, Nashville TN 37232-2370,USA (Tel. �1615 322 3475, fax. �1 615 343 1763, e-mail. Robert.cotton@mcmail.vanderbilt.edu)

ÐÐÐÐÐÐÐÐÐÐÐÐ

ACTA PÆDIATR89 (2000) Commentaries 1279