Enteral Feeding during Indomethacin and Ibuprofen Treatmentof a Patent Ductus Arteriosus

Ronald Clyman, MD1,2, Andrea Wickremasinghe, MD1,2, Nami Jhaveri, MD1,2, Denise C. Hassinger, MD3,

Joshua T. Attridge, MD4, Ulana Sanocka, MD5, Richard Polin, MD5, Maria Gillam-Krakauer, MD6, Jeff Reese, MD6,

Mark Mammel, MD7, Robert Couser, MD7, Neil Mulrooney, MD7, Toby D. Yanowitz, MD8, Matthew Derrick, MD9,

Priya Jegatheesan, MD10, Michele Walsh, MD11, Alan Fujii, MD12, Nicolas Porta, MD13, William A. Carey, MD14,

and Jonathan R. Swanson, MD3, on behalf of the Ductus Arteriosus Feed or Fast with Indomethacin

or Ibuprofen (DAFFII) Investigators*

Objective To test the hypothesis that infants who are just being introduced to enteral feedings will advance to fullenteral nutrition at a faster rate if they receive “trophic” (15 mL/kg/d) enteral feedings while receiving indomethacinor ibuprofen treatment for patent ductus arteriosus.Study design Infants were eligible for the study if they were 231/7-306/7 weeks’ gestation, weighed 401-1250 g atbirth, received maximum enteral volumes#60mL/kg/d, and were about to be treated with indomethacin or ibupro-fen. A standardized “feeding advance regimen” and guidelines for managing feeding intolerance were followed ateach site (N = 13).Results Infants (N = 177, 26.3 � 1.9 weeks’ mean � SD gestation) were randomized at 6.5 � 3.9 days to receive“trophic” feeds (“feeding” group, n = 81: indomethacin 80%, ibuprofen 20%) or no feeds (“fasting [nil per os]” group,n = 96: indomethacin 75%, ibuprofen 25%) during the drug administration period. Maximum daily enteral volumesbefore study entry were 14 � 15 mL/kg/d. After drug treatment, infants randomized to the “feeding” arm requiredfewer days to reach the study’s feeding volume end point (120mL/kg/d). Although the enteral feeding end point wasreached at an earlier postnatal age, the age at which central venous lines were removed did not differ between the 2groups. There were no differences between the 2 groups in the incidence of infection, necrotizing enterocolitis,spontaneous intestinal perforation, or other neonatal morbidities.Conclusion Infants required less time to reach the feeding volume end point if they were given “trophic” enteralfeedings when they received indomethacin or ibuprofen treatments. (J Pediatr 2013;-:---).

The prostaglandin synthase inhibitors indomethacin and ibuprofen are the only drugs licensed in the US for the treatmentof patent ductus arteriosus (PDA) in preterm infants. Unfortunately, both drugs have gastrointestinal side effects: in-domethacin decreases intestinal blood flow, inhibits the normal postprandial hyperemic response,1 and interferes

From the 1Department of Pediatrics and 2CardiovascularResearch Institute, University of California SanFrancisco, San Francisco, CA; 3Department ofPediatrics, Morristown Medical Center, Morristown, NJ;4Department of Pediatrics, University of Virginia,Charlottesville, VA; 5Department of Pediatrics, ColumbiaUniversity Medical Center, New York, NY; 6Departmentof Pediatrics, Vanderbilt University, Nashville, TN;7Department of Pediatrics, Children’s Hospitals andClinics of Minnesota-Minneapolis, Saint Paul, MN;8Department of Pediatrics, University of Pittsburgh,Pittsburgh, PA; 9Department of Pediatrics, NorthshoreUniversity Health System, Evanston, IL; 10Department ofPediatrics, Santa Clara Valley Medical Center, San Jose,CA; 11Department of Pediatrics, Case Western ReserveUniversity, Cleveland, OH; 12Department of Pediatrics,Boston University Medical Center, Boston, MA;13Department of Pediatrics, Northwestern UniversityFeinberg School of Medicine, Chicago, IL; and14Department of Pediatrics, Mayo Clinic, Rochester, MN

*A list of the DAFFII Investigators is available at www.jpeds.com (Appendix).

with gastrointestinal mucosal barrier function.2-6 Although ibuprofen does notappear to have the same effect as indomethacin on intestinal blood flow,7,8 itdoes produce similar alterations in gastrointestinal permeability.9,10 Thus, thereis a concern that the introduction of enteral feedings (which promote intestinalbacterial colonization and increase intestinal oxygen demands) may be hazard-ous when these drugs are used.

Because of this concern, infants enrolled in clinical trials, conducted to licenseindomethacin and ibuprofen for PDA treatment with the US Food and DrugAdministration, were fasted (nil per os [npo]) and received only intravenousnutrition during study drug administration. Currently, 85% of US neonatolo-gists report they withhold enteral feedings when treating infants with indometh-acin or ibuprofen.11

The practice of withholding feedings andmaking infants npomay have its ownunintended consequences. Studies in animals and humans demonstrate thatwithholding enteral nutrition and providing only parenteral nutrition for

Supported by Gerber Foundation, National Institutes ofHealth/National Center for Research Resources-Clinical& Translational Science Institute (UL1 RR024131 andUL1TR000445), and a gift from the Jamie and BobbyGates Foundation. The authors declare no conflicts ofinterest.

Registered with ClinicalTrials.gov: NCT00728117.

0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc.

All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.01.057

BPD Bronchopulmonary dysplasia

NEC Necrotizing enterocolitis

npo Nil per os

PDA Patent ductus arteriosus

1

Table I. Feeding advance regimen

(A) Day offeeding

mL/kg/d

(B) Birth weight401-700 g

(C) Birth weight701-1000 g

(D) Birth weight1001–1250 g

1 “trophic” = 15 “trophic” = 15 “trophic” = 152 “trophic” = 15 “trophic” = 15 “trophic” = 153 “trophic” = 15 “trophic” = 15 304 “trophic” = 15 30 455 “trophic” = 15 45 606 30 60 807 45 80 1008 60 100 120*9 80 120*10 10011 120*

*Primary feeding end point is achieved on the day infant takes 120 mL/kg/d.

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periods as short as 72 hours can cause duodenal mucosal at-rophy, impaired intestinal function, abnormal gut perme-ability,12-17 subsequent feeding intolerance,18 and longerhospital stays.19 The longer it takes to attain full enteral nu-trition, the longer infants need intravenous nutrition andthemore likely they are to develop septicemia and cholestasis.Therefore, withholding feedings for several days during treat-ment with indomethacin or ibuprofen may be detrimental tothe infant and lead to subsequent feeding intolerance.

Currently, there are no published controlled randomizedtrials addressing whether it is better to feed or fast an infantduring indomethacin or ibuprofen treatment. Several studieshave shown that small amounts of enteral nutrition havetrophic effects that can minimize some of the intestinal prob-lems caused by total parenteral nutrition.16,20 We hypothe-sized that infants who are to be treated with indomethacinor ibuprofen and who are just being introduced to enteralfeedings will advance to full enteral nutrition at a faster rateif they receive “trophic” enteral feedings while receiving thedrug treatment. We conducted a randomized controlled trialto test this hypothesis.

Methods

This prospective randomized study was conducted betweenOctober 2008 and June 2012 at 13 sites after obtaining insti-tutional review board approval. Written informed parentalconsent was obtained before enrollment. Infants were eligiblefor the study if they were: (1) delivered between 231/7-306/7

weeks’ gestation; (2) weighed 401-1250 g at birth; (3) werejust beginning enteral feedings (receiving #60 mL/kg/d);and (4) were about to receive pharmacologic treatment toclose their PDA. The decision to treat the PDA was madeby the infants’ clinical care teams. Infants were excludedfrom the trial if they had previously received enteral feedingsvolumes >60 mL/kg/d or if there were contraindications forthe use of indomethacin or ibuprofen, contraindications forfeedings, chromosomal anomalies, congenital or acquiredgastrointestinal anomalies, prior episodes of necrotizingenterocolitis (NEC) or intestinal perforation, or inotropicsupport for hypotension at the time of entry. The presenceof an umbilical artery or vein catheter was not a reason forexclusion.

Our intention was to examine the effects of the feeding in-tervention on the entire population of indomethacin andibuprofen-treated infants as well as on the infants in each in-dividual drug treatment subgroup. To distribute the drugtreatment equally among the study populations, each studysite’s research pharmacist initially randomized the infants toeither indomethacin or ibuprofen. After the drug treatmentassignment, infants were randomized to the study’s feedingintervention: either “feeding” or “fasting (npo)” during the“study drug administration period” (definition given later).Block randomization at each site was stratified by birth weight(401-700 g, 701-1000 g, and 1001-1250 g) and by center.

The drug assignment was masked from the clinical staff inthe beginning of the trial; however, this could not be achieved

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as the study progressed due to drug availability that forcedboth the indomethacin and the ibuprofen arms of the studyto be closed at different points in time. As a result, 58% of theinfants were treated with either open-label indomethacin oribuprofen. Throughout the trial, infants received only thedrug they were initially assigned if they required retreatmentof their PDA. When indomethacin was the study drug, in-fants received 4 doses per treatment course (0.2, 0.1, 0.1,and 0.1 mg/kg/dose at 0, 12, 24 and 48 hours, respectively,if they were #1000 g at birth and <7 days old, or 0.2 mg/kg/dose for each of the 4 doses if they were >1000 g at birthor$7 days old). When ibuprofen was the study drug, infantsreceived the same 3 doses of ibuprofen (independent of birthweight or postnatal age): 10, 5, and 5 mg/kg/dose at 0, 24, and48 hours, respectively.All infants had an echocardiogram and Doppler study per-

formed before study entry to document the presence ofa PDA. An echocardiogram and Doppler study were per-formed within 24 hours of the last dose of study drug to de-termine residual ductus patency. Additional courses of studydrug could be administered at the discretion of the attendingneonatologists who also decided if and when the PDA neededto be ligated.

Feeding RegimenThe only clinical management controlled by the study was thefeeding regimen. Because the time to achieve a specific enteralfeeding volume (120 mL/kg/d) was the primary end point ofthe trial, the feeding regimen needed to be directive ratherthan left to the discretion of the clinicians. Therefore, a stan-dardized “feeding advance regimen” was instituted at each ofthe participating centers before the start of the trial. The feed-ing advance regimen specified the number of days (based onbirth weight) of “trophic” feedings (15 mL/kg/d) that infantshad to tolerate before their enteral volumes could be in-creased (Table I). Criteria defining feeding intolerance andits management were also established (Table II; available atwww.jpeds.com). Breast milk was the primary source ofenteral nutrition. A 20 cal/oz premature formula could besubstituted for breast milk if mother’s milk wasunavailable. Caloric fortification of enteral feedings did not

Clyman et al

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occur until after the infants were tolerating the designatedprimary volume end point for the study (enteral feedings =120 mL/kg/d).

Study InterventionAlthough the feeding intervention was randomized, we couldnot mask which intervention (“feeding” or “fasting [npo]”)the infants received during the “study drug administrationperiod”—the time between the first dose of study drug and24 hours after the last dose of study drug. Infants randomizedto the “feeding” group received “trophic” enteral nutrition(15mL/kg/d) during the “study drug administration period.”Infants, who received additional courses of study drug as partof their initial PDA treatment or later in the hospitalization,received 15 mL/kg/d of enteral nutrition during the “studydrug administration period” of each additional course. In-fants randomized to the “fasting (npo)” group were madenpo during the “study drug administration period” of thefirst and any subsequent treatment courses. Once the “studydrug administration period” was completed, enteral feedingwas returned to the volume and rates of advancement speci-fied by the infant’s standardized feeding advance regimen.

Primary End Point and OutcomesThe primary end point of the study was achieved when a dailyenteral feeding of 120 mL/kg/d was reached. Because thepostnatal age when the primary end point was achieved couldvary, based on the age when feedings initially were started andthe infants’ birth weight–specific, feeding advance regimen,we created a new variable (“ideal number” of days to reach120 mL/kg/d) to reflect the number of days an infant wouldbe expected to take, from the day the “study drug administra-tion period” was completed until the enteral feeding goal of120 mL/kg/d was reached (assuming nothing interruptedthe prescribed feeding advance regimen).

The “ideal number” of days to reach 120mL/kg/d was calcu-lated at the time of study entry, before randomization, and wasbased on the assumption that the infant would be fasted (npo)during the “study drug administration period.” The “idealnumber” of days was defined as the difference between theday of feeding at which the infant started on completion ofthe “study drug administration period” (refer to column A inTable I) and the day of feeding on the “feeding advanceregimen” when 120 mL/kg/d was anticipated to be reached.The maximum enteral volume an infant received before studyentry determined the infant’s starting position on the “feedingadvance regimen” once the “study drug administrationperiod” was completed (refer to column A in Table I). Forexample, a 600-g birth weight infant who had never been fedshould, ideally, have required 11 days to reach 120 mL/kg/d (Table I). If the infant had started enteral feeding andtolerated only 1 day of 15 mL/kg/d before study entry, he orshe would be expected to start at “day 2” of the standardized“feeding advance regimen” once the “study drugadministration period” was completed and would “ideally”require 10 days to reach and tolerate 120 mL/kg/d (assumingno feeding difficulties occurred during the feeding advance).

Enteral Feeding during Indomethacin and Ibuprofen Treatment o

The primary outcome for our study was the difference be-tween the actual number of days required for each infant toreach 120mL/kg/d (from the day the “study drug administra-tion period” was completed) and the “ideal number” of daysto reach 120 mL/kg/d. It should be noted that the lowest dif-ference between the actual and “ideal number” of days thatinfants randomized to the “fasting (npo)” group couldachieve was 0 (when actual = “ideal number”); in contrast,infants randomized to the “feeding” group could have nega-tive differences as some of the days of trophic feedings re-ceived during the “study drug administration period”could be applied to their “feeding advance regimen.” For ex-ample, if the 600-g infant, referred to earlier (who tolerated 1day of 15 mL/kg/d feedings before study entry), was assignedto the “feeding” group and the infant tolerated all 3 days ofthe “trophic” (15 mL/kg/d) feedings during the “studydrug administration period,” he or she could start at “day5” of the standardized “feeding advance regimen” once the“study drug administration period” was completed becausehe or she already received 4 days of 15 mL/kg/d. If no feedingdifficulties occurred, this infant could take only 7 days toreach 120 mL/kg/d and the difference between actual number(7 days) and “ideal number” (10 days, see earlier) to reach120 mL/kg/d would be �3 days.

Sample SizeSample size was determined using the time to reach the pri-mary feeding volume end point (120 mL/kg/d). Our priordata indicated that infants with birth weights #1000 g whohad a PDA requiring drug treatment achieved enteral feed-ings of 120 mL/kg/d at 30� 13 days after birth. We estimatedthat we would need a total of 400 infants to detect a significantdifference (of 4 days) between the “feeding” and “fasting(npo)” groups (with a probability of 80%) if the SD was�13 days. An interim analysis was planned, once 50% ofthe subjects had been enrolled, to calculate the actual SD inour study population and to determine the final number ofsubjects to be enrolled.We planned to complete the study in 3 years. However,

several factors prevented us from completing the study dur-ing this interval: (1) indomethacin and ibuprofen becameunavailable at different points in time; and (2) a significantshift in the approach to PDA treatment made many infantsno longer eligible for the study (there was a shift at most sitesfrom treating infants within the first days after delivery totreating infants later in the neonatal course, by which timemany had already received enteral feedings >60 mL/kg/d).Therefore, after 3.5 years (having enrolled only 45% of theplanned enrollment), we performed an early interim analysisto determine the actual number of patients needed for studyenrollment. We found that the mean � SD age at which ourstudy population was achieving enteral feedings of 120 mL/kg/d was 22.9 � 9.2 days. Based on the SD of �9.2 days,we realized that we had already enrolled a sufficient numberof patients to detect a significant difference of 4 days betweenthe “feeding” and “fasting” groups (with a probability of80%). Therefore, we terminated study enrollment.

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Statistical AnalysesUnivariate analyseswereperformedusing thec2 test for categor-ical variables and Student t test for continuous variables. Al-though this was a randomized controlled trial, some of thedemographic variables were unequally distributed between thefeeding and nonfeeding groups (Tables III and IV; Table IVavailable at www.jpeds.com). Therefore, multivariable analyseswere performed to adjust the study outcomes for any possibledemographic differences. Demographic variables wereincluded in the statistical models if their univariate P valuewas <.10. In addition, because 32% of the infants enrolled inthe trial were twins or triplets (Table III) and 46% of themultiple gestation infants had a sibling enrolled in the trial, weused generalized estimating equations to adjust for anynonindependence of the clustered data that might be affectedby shared genetic or environmental factors. aORs (for binaryoutcomes) and correlation coefficients (for continuousoutcomes) with 95% CIs were calculated using generalizedestimating equations. When models were unable to run usingan exchangeable correlation structure, an independentcorrelation structure was substituted. A P value of <.05 wasconsidered significant. All analyses were performed usingSTATA 11 (StataCorp, College Station, Texas) statisticalsoftware.

Results

Between October 2008 and June 2012, there were 251 infantswho were eligible for the study. Seventy-four were excluded

Table III. Demographics of total populations: univariate ana

Demographic and riskvariables

Total population

DFasting (npo)

(n = 96)Feeding(n = 81)

Study drug: indomethacin, % 75 80 Surfactant,Multiple birth, % 41 21* RSS at 24Rupture of membranes >18 h, % 18 23 VasopressoPreterm labor, % 68 75 ProphylactiMaternal diabetes, % 9 6 HydrocortisChorioamnionitis, % 14 11 UAC presenPreeclampsia, % 21 19 UVC presenBetamethasone (>6 h), % 74 68 RSS at enrBetamethasone (>24 h), % 57 54 No. of contAntenatal antibiotics, % 50 55 1Birth weight, g, mean (SD) 873 (205) 857 (171) 2Birth weight categories, g (%) 3#700 24 20 PDA failed701-1000 45 59 Additional1001-1250 31 21 Ligation du

Gestation, wk, mean (SD) 26.3 (2.0) 26.2 (1.8) Ligation duSGA, % 9 4 Age at first5-min Apgar <4, % 8 12 Maximum

mean (SSex male, % 42 51 Age at studWhite, % 60 47† Milk type:RDS, % 85 94†

Betamethasone (>6 h), receipt of betamethasone >6 h before delivery; SGA, small for gestational ageRDS, respiratory distress syndrome diiagnosed by elevated oxygen requirement during the first 24 hpressure � fraction of inspired oxygen, measured at 24 h after birth; UAC, umbilical artery catheter;treatment ductus arteriosus was still either: (1) moderate-to-large; or (2) initially closed (or small) a*P < .05.†P < .10.

4

because of parental refusal, and 177 subjects were enrolledin the study. Because of drug shortages, only 40 infantswere treated with ibuprofen, and 137 were treated with indo-methacin. There were no significant demographic differencesbetween the “feeding” and “fasting (npo)” arms in the totalstudy population except for the following variables: incidenceof multiple gestation births, presence of umbilical venouscatheter at the time of enrollment, and age when the first en-teral feeding was attempted (Table III).Infants randomized to the “feeding” arm required fewer

days to reach 120 mL/kg/d enteral feedings after the “studydrug administration period” was completed (P = .01). Theyalso reached the study’s feeding volume end point at a youn-ger postnatal age (P = .08) (Tables V and VI; Table VIavailable at www.jpeds.com). There were no differencesbetween the 2 groups during either the feeding advance orthe entire hospitalization in the incidence of infection,NEC, or spontaneous intestinal perforation (Table V).Several demographic variables appeared to be unequally

distributed between the “feeding” and “fasting (npo)” groups(Table III). Therefore, we performed multivariable analysesto adjust the study outcomes for any possible demographicdifferences. In the multivariable statistical models, weincluded all of the demographic variables that differedbetween the 2 groups with a P value <.10. These includedmultiple birth, respiratory distress syndrome, white race,umbilical venous catheter present at enrollment, PDAligation during the hospitalization, and age when first fed(Tables III and VII). When our analyses were adjusted for

lyses

emographic and risk variables

Total population

Fasting (npo)(n = 96)

Feeding(n = 81)

% 85 84h, units, mean (SD) 1.9 (1.1) 2.0 (1.6)rs needed before enrollment, % 6 6c indomethacin before enrollment, % 20 23one before enrollment, % 5 5t at enrollment, % 43 36t at enrollment, % 48 32*ollment, mean (SD) 2.0 (1.9) 2.0 (2.0)iguous initial study drug courses, %

70 7226 274 1

to close after initial drug treatment, % 57 62study drug given during feeding advance, % 10 7ring feeding advance, % 18 21ring hospitalization, % 24 36†

feeding, d, mean (SD) 4.9 (3.8) 3.5 (2.6)*enteral volume before study, mL/kg/d,D)

12.3 (14.3) 15.6 (16.0)

y entry, d, mean (SD) 6.4 (3.8) 6.6 (4.0)breast milk, % 83 84

, birth weight <10th percentile for gestational age22; Age, postnatal age (where day of birth = 0);and characteristic radiographic findings; RSS at 24 h, Respiratory Severity Score: mean airwayUVC, umbilical venous catheter; PDA failed to close after initial treatment, defined as followingnd reopened (and developed a moderate–to-large shunt again).

Clyman et al

Table V. Effect of “feeding” versus “fasting (npo)” onneonatal outcomes: univariate analyses

Total population

Fasting (npo)(n = 96)

Feeding(n = 81)

Feeding-related outcomesAge when taking 120 mL/kg/d, d, mean (SD) 24.0 (9.6) 21.6 (8.7)†

Actual No. of days to reach 120 mL/kg/d,mean (SD)

13.1 (7.8) 10.3 (6.6)*

Difference between actual and ideal No. ofdays to reach 120 mL/kg/d, d, mean (SD)

5.5 (7.1) 3.0 (6.3)*

Feeding advance delayed by feedingintolerance or NEC, %

40 24*

Feeding advance delayed by “other”causes, %

44 59†

NEC/perforation before reaching 120mL/kg/d, %

4 1

NEC/perforation ANY TIME duringhospitalization, %

13 10

Age when central venous line removed, d,mean (SD)

30 (28) 27 (21)

Infection during feeding advance, % 34 26Infection any time during hospitalization, % 45 44

Other morbiditiesICH grade III or IV, % 7 5PVL or hydrocephalus, % 7 6BPD, % 36 56*ROP treated, % 4 12†

Death, % 7 5Death or BPD, % 39 58*Death, NEC, or BPD, % 43 61*

Age, postnatal age (day of birth = 0 days); Infection, any culture positive infection (bacteremia,pneumonia, urinary tract infection, meningitis); ICH, intracranial hemorrhage $grade III; PVL,cystic periventricular leukomalacia diagnosed by ultrasound; BPD, the need for supplementaloxygen to maintain oxygen saturation >90% at 36 wk’ corrected age; ROP, retinopathy of pre-maturity stage 2 with plus disease or stage 3 treated with either laser or bevacizumab; Feedingadvance delayed by “other” causes, percentage of the population who had their feeding ad-vance interrupted or delayed by$1 of the following causes: (a) PDA ligation, (b) sepsis workup,recurrent apneas, respiratory deterioration, (c) hypotension requiring inotropes, or (d) bloodtransfusions.*P < .05.†P < .10.

Table VII. Effect of “feeding” versus “fasting (npo)” onneonatal outcomes: adjusted ORs and correlationcoefficients

Total population (n = 177):feeding vs fasting (npo)

Outcomevariable P value (95% CI)

Feeding-related outcomesAge when taking 120 mL/kg/d, d �3.38 0.009* (�5.90 to �0.86)Actual No. of days to reach 120

mL/kg/d, d�3.64 0.001* (�5.83 to �1.46)

Difference between actual andideal No. of days to reach120 mL/kg/d, d

�3.52 0.001* (�5.56 to �1.48)

Feeding advance delayed byfeeding intolerance or NEC

0.53 0.103 (0.25 to 1.14)

Feeding advance delayed by“other” causes

1.80 0.151 (0.81 to 4.03)

NEC/perforation, before reaching120 mL/kg/d

1.60 0.450 (0.47 to 5.48)

NEC/perforation, ANY TIME duringhospitalization

0.97 0.963 (0.28 to 3.37)

Age when central venous lineremoved, d

�5.23 0.193 (�13.13 to 2.66)

Infection during feeding advance 0.63 0.247 (0.29 to 1.37)Other morbidities

BPD 1.68 0.207 (0.75 to 3.77)ROP treated 2.28 0.277 (0.52 to 10.01)Death 0.66 0.606 (0.14 to 3.16)Death or BPD 1.74 0.167 (0.79 to 3.80)Death, NEC, or BPD 1.79 0.138 (0.83 to 3.88)

Analyses were performed by generalized estimating equations (GEEs) as described in Methods.The ORs (for binary outcomes), correlation coefficients (for continuous outcomes), P values, and95% CIs are reported. Predictive variables used in the models differed between the “feeding”and “fasting (npo)” groups in Table I with P values <.1. These included multiple birth, RDS,white race, UVC present at enrollment, PDA ligation during the hospitalization, and age whenfirst fed. When treated ROP was examined as an outcome, BPD was added to the otherpredictors in the GEE model.*P < .05.

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these possible demographic variations, the difference infeeding outcomes between the 2 study groups became evenmore significant: infants randomized to the “feeding” armrequired fewer days to reach 120 mL/kg/d enteral feedingsafter the “study drug administration period” (P = .001),and reached the study’s feeding volume end point ata younger postnatal age (P = .009) (Table VII).

The significant differences between the “feeding” and“fasting (npo)” groups were also found when the largestdrug subgroup (indomethacin) was examined by itself ina multivariable post hoc analysis. The differences between“feeding” and “fasting (npo)” groups in the indomethacinsubgroup were age when taking 120 mL/kg/d = �4.17 days(�6.98 to �1.36, P = .004), number of days to reach 120mL/kg/d after completing the “study drug administration pe-riod” =�3.61 days (�5.87 to�1.35, P = .002), and differencebetween the actual and ideal number of days to reach 120mL/kg/d = �3.62 days (�5.80 to �1.44, P = .001).

Several other neonatal morbidities were examined in thestudy population. Although there appeared to be significantdifferences between the “feeding” and “fasting (npo)” groupsin the incidence of bronchopulmonary dysplasia (BPD),

Enteral Feeding during Indomethacin and Ibuprofen Treatment o

death or BPD, and death, NEC, or BPD in the univariateanalysis, these differences were no longer present when theanalyses were adjusted for the demographic differences be-tween the 2 groups as described earlier (Tables V and VII).

Discussion

We found that infants who were in the beginning stages ofenteral feeding required 3-4 fewer days to reach 120 mL/kg/d enteral feedings if they were given small “trophic” feedingsduring the time they received indomethacin or ibuprofen. Al-though we observed no increase in the incidence of feeding-related morbidities, our study was only powered to detecta 1.6-fold increase in the incidence of infection and a 2.4-fold increase in NEC. Smaller increases in morbidity couldhave been missed; however, neither the OR for infection(0.63) nor the OR for NEC (during the hospitalization: OR0.97), suggest a trend toward increased morbidity in the“feeding” group (Table VII). Our findings are similar toa recent case–control study that suggested that feedinginfants during indomethacin treatment appears to have nodetrimental effects and may decrease the time needed forinfants to achieve full enteral feedings.21

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We wanted to determine if “trophic” feedings during the“study drug administration period” decreased the time toreach 120 mL/kg/d by decreasing the number of infantswho developed episodes of feeding intolerance during thefeeding advance. Although this was a randomized controlledtrial, we could not blind the “feeding” intervention. To min-imize any bias in determining when episodes of feeding intol-erance might occur, we developed a standardized feedingadvance regimen and a feeding intolerance guideline(Tables I and II) that were adhered to by all of the centers.Decisions about feeding intolerance were left to theprimary care team, rather than to the study physicians.Although it appeared as if fewer infants in the “feeding”arm had their daily feeding advance delayed due to feedingintolerance or NEC, this finding did not achieve statisticalsignificance when the analysis was adjusted fordemographic differences between the treatment groups(Tables V and VII). In addition, although 33% of the totalpopulation had their feeding advance delayed by episodesof feeding intolerance, a greater number of infants hadtheir feedings interrupted by causes unrelated to feedingintolerance (Table V): 51% of the delays were due to $1 ofthese “other” causes: (1) PDA ligation (16%); (2) sepsisworkup, recurrent apneas, respiratory deterioration (32%);(3) hypotension requiring inotropes (6%); or (4) bloodtransfusions (22%). Therefore, it is unlikely thata difference in the incidence of feeding intolerance wasresponsible for the “feeding” group’s more rapid advanceto the 120 mL/kg/d end point. The shorter time for theinfants in the “feeding” group to reach the study end pointwas due to the trophic feedings, received during the “studydrug administration period,” that were credited toward therequired number of “trophic” feeding days mandated bythe “feeding advance regimen” (Table I).

Although infants in the “feeding” arm reached the enteralfeeding end point and stopped total parenteral nutrition ata significantly earlier age, there was no significant decreasein the age when their central intravenous line was removed.Factors other than nutrition also contribute to the need forcentral venous access and probably account for the wide var-iability in the duration of central line access and the absenceof a significant effect (Table VII).

We conclude that infants, who are just starting enteralfeedings, will advance to full enteral nutrition at an earlierage if they receive “trophic” enteral feedings while receivingdrug treatment for a PDA. n

Submitted for publication Nov 12, 2012; last revision received Jan 10, 2013;

accepted Jan 25, 2013.

Reprint requests: Ronald Clyman, MD, Box 0544, HSW 1408, University of

California, San Francisco, 513 Parnassus Ave, San Francisco, CA 94143-0544.

E-mail: clymanr@peds.ucsf.edu

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Clyman et al

Appendix

DAFFII Investigators include: University of California SanFrancisco, San Francisco, California (n = 22): (Study Coordi-nating Center) Ronald Clyman, MD, Andrea Wickrema-singhe, MD, Nami Jhaveri, MD, Scott Fields, PharmD,NCRC nurses, and (Data Safety Monitoring Committee) Jef-frey Fineman, MD, Yao Sun, MD, Philip Moore, MD; Mor-ristown Medical Center, Morristown, New Jersey (n = 25):Denise C. Hassinger, MD, Jonathan R. Swanson, MD, andCaryn Peters, RN; University of Virginia, Charlottesville, Vir-ginia (n = 23): Joshua T. Attridge, MD, Amy E. Blackman,RN, and Jonathan R. Swanson, MD; Columbia UniversityMedical Center, New York, New York (n = 21): Richard Po-lin, MD, Ulana Sanocka, MD, Teresa Bowman, RN, ErinAmadori, RN, Glen Bona, RN, and Marilyn Weindler, RN;Vanderbilt University, Nashville, Tennessee (n = 19): Jeff Re-ese, MD, Maria Gillam-Krakauer, MD, and Amy Law-Beller,RN; Children’s Hospitals and Clinics of Minnesota-

Minneapolis/Saint Paul, Minnesota (n = 18) (n = 11 and n= 7, respectively): Mark Mammel, MD, Patricia Meyers,RN, Robert Couser, MD, Neil Mulrooney, MD, Molly Max-well, RN, and Cathy Worwa, RN; University of Pittsburgh,Pittsburgh, Pennsylvania (n = 11): Toby D. Yanowitz, MD,and Robyn Baker, RN; Northshore University Health System,Evanston, Illinois (n = 11): Matthew Derrick, MD, and SueWolf, RN; Santa Clara Valley Medical Center, San Jose, Cal-ifornia (n = 9): Priya Jegatheesan, MD, Brian Scottoline, MD,and Dongli Song, MD; Case Western Reserve University,Cleveland, Ohio (n = 6): Michele Walsh, MD, Jalal Abu-Shaweesh, MD, Bonnie Siner, RN, Joyce Gallagher, RN,and Nancy Newman, RN; Boston University Medical Center,Boston, Massachusetts (n = 5): Alan Fujii, MD; NorthwesternUniversity Feinberg School of Medicine, Chicago, Illinois (n= 4): Nicolas Porta, MD, Marissa deUngria, MD, MalikaShah, MD, and Karin Hamann, RN; Mayo Clinic, Rochester,Minnsota (n = 3): William A. Carey, MD, and Gretchen A.Voge, MD.

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Enteral Feeding during Indomethacin and Ibuprofen Treatment of a Patent Ductus Arteriosus 6.e1

Table II. Criteria and management of feeding intolerance

Signs of feeding intolerance

ManagementzGastric aspirate before the feedingOther signs of

feeding intolerance†

1a*. if both #2 mL and #1/3 of previousfeed volume

None Refeed aspirate as part of total volume, continue feeding.

1b*. if #2 mL but >1/3 of previous feed volumeorif >2 mL but <1/3 of previous feed volume

None Check infant, then may refeed aspirate as part of total volume,and continue feeding.

Or may hold feeding and resume in 3 h.2. if >2 mL and >1/3 of previous feed volume None Stop feeding and recheck gastric aspirate in 3 h.

Resume feeding when conditions revert to step 1.3. Regardless Present Stop feeding, perform appropriate evaluationx and

resume when infant stable and conditions revert to step 1.

*If continuous nasogastric or orogastric feedings are used, check for residuals every 3-4 h. Tolerate residuals of #2 mL or <2 h of feeds (whichever is greater).†Other signs will include one or more of the following: blood-stained gastric aspirate; vomiting $1/3 of the previous feed volume; abdominal distention, discoloration, or tenderness; visible bowelloops; bloody stool; kidney/ureter/bladder radiograph showing signs of intestinal dilatation; metabolic acidosis or new thrombocytopenia; evidence that the child is not well (apnea [new onset orincreasing frequency]), respiratory distress, lethargy, poor perfusion, temperature instability, etc.zRecommendations: If residuals are bile stained or >1/3 feed volume, consider checking feeding tube placement, placing the infant prone or right side down; consider glycerin suppository if >18 hsince last stool; if recurrent episodes occur after a recent feeding advance, consider returning to the previously tolerated feeding volume.xEvaluation of significant feeding intolerance to be performed by the primary clinical team according to the standard practice (eg, physical examination, radiography, complete blood cell count,cultures, etc).

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Table IV. Demographics of ibuprofen, indomethacin, and total populations: univariate analyses

Demographic and risk variables

Ibuprofen population Indomethacin population Total population

Fasting (npo)(n = 24)

Feeding(n = 16)

Fasting (npo)(n = 72)

Feeding(n = 65)

Fasting (npo)(n = 96)

Feeding(n = 81)

Study drug: indomethacin, % 0 0 100 100 75 80Multiple birth, % 38 25 42 20* 41 21*Rupture of membranes >18 h, % 22 19 17 24 18 23Preterm labor, % 75 63 65 78† 68 75Maternal diabetes, % 8 0 10 8 9 6Chorioamnionitis, % 25 13 10 11 14 11Preeclampsia, % 29 38 18 14 21 19Betamethasone (>6 h), % 83 53* 70 71 74 68Betamethasone (>24 h), % 63 40 55 57 57 54Antenatal antibiotics, % 63 50 46 56 50 55Birth weight, g, mean (SD) 875 (186) 818 (164) 872 (212) 867 (173) 873 (205) 857 (171)Birth weight categories, g (%)#700 17 31 26 17 24 20701-1000 54 50 42 62 45 591001-1250 29 19 32 22 31 21

Gestation, wk, mean (SD) 26.5 (1.9) 26.3 (1.8) 26.2 (2.1) 26.2 (1.8) 26.3 (2.0) 26.2 (1.8)SGA, % 13 6 8 3 9 45-min Apgar <4, % 8 13 8 12 8 12Male sex, % 42 25 42 57† 42 51White, % 63 44 59 48 60 47†

RDS, % 75 100* 89 92 85 94†

Surfactant, % 88 100 85 80 85 84RSS at 24 h, units, mean (SD) 1.8 (1.0) 2.6 (2.7) 1.9 (1.1) 1.9 (1.2) 1.9 (1.1) 2.0 (1.6)Vasopressors needed before enrollment, % 8 0 6 8 6 6Prophylactic indomethacin before enrollment, % 4 13 25 26 20 23Hydrocortisone before enrollment, % 4 0 6 6 5 5UAC present at enrollment, % 46 56 42 31 43 36UVC present at enrollment, % 50 50 47 28* 48 32*RSS at enrollment, mean (SD) 1.6 (0.9) 1.9 (1.3) 2.1 (2.1) 2.1 (2.1) 2.0 (1.9) 2.0 (2.0)No. of contiguous initial study drug courses, %1 63 56 72 75 70 722 29 38 25 25 26 273 8 6 3 0 4 1

PDA failed to close after initial drug treatment, % 54 75 59 58 57 62Additional study drug given during feeding advance, % 13 19 10 5 10 7Ligation during feeding advance, % 29 31 14 19 18 21Ligation during hospitalization, % 33 38 21 36† 24 36†

Age at first feeding, d, mean (SD) 4.7 (3.8) 3.8 (1.7) 4.9 (3.8) 3.5 (2.7)* 4.9 (3.8) 3.5 (2.6)*Maximum enteral volume before study, mL/kg/d, mean (SD) 11.4 (12.5) 9.3 (11.3) 12.6 (14.9) 17.1 (16.7)† 12.3 (14.3) 15.6 (16.0)Age at study entry, d, mean (SD) 5.3 (2.8) 5.5 (2.6) 6.7 (4.1) 6.9 (4.2) 6.4 (3.8) 6.6 (4.0)Milk type: breast milk, % 92 75 81 86 83 84

See abbreviations in Table III.*P < .05.†P < .10.

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Table VI. Effect of “feeding” versus “fasting (npo)” on neonatal outcomes: univariate analyses

Ibuprofen population Indomethacin population Total population

Fasting (npo)(n = 24)

Feeding(n = 16)

Fasting (npo)(n = 72)

Feeding(n = 65)

Fasting (npo)(n = 96)

Feeding(n = 81)

Feeding-related outcomesAge when taking 120 mL/kg/d, d, mean (SD) 25.8 (10.1) 24.7 (9.6) 23.4 (9.4) 20.8 (8.3)† 24.0 (9.6) 21.6 (8.7)†

Actual No. of days to reach 120 mL/kg/d, mean (SD) 15.4 (8.1) 13.4 (8.4) 12.3 (7.6) 9.5 (5.9)* 13.1 (7.8) 10.3 (6.6)*Difference between actual and ideal No. of days to reach

120 mL/kg/d, d, mean (SD)7.5 (7.4) 4.9 (8.7) 4.7 (6.9) 2.5 (5.5)* 5.5 (7.1) 3.0 (6.3)*

Feeding advance delayed by feeding intolerance or NEC, % 46 38 38 21* 40 24*Feeding advance delayed by “other” causes, % 54 56 41 59* 44 59†

NEC/perforation before reaching 120 mL/kg/d, % 4 6 4 0† 4 1NEC/perforation ANY TIME during hospitalization, % 8 25 14 6 13 10Age when central venous line removed, d, mean (SD) 30.1 (13) 26.2 (18) 30 (32) 27 (21) 30 (28) 27 (21)Infection during feeding advance, % 42 13* 31 29 34 26Infection any time during hospitalization, % 54 31 42 48 45 44

Other morbiditiesICH grade III or IV, % 8 6 7 5 7 5PVL or hydrocephalus, % 13 6 6 6 7 6BPD, % 43 50 33 57* 36 56*ROP treated, % 9 13 3 11† 4 12†

Death, % 4 6 8 5 7 5Death or BPD, % 43 50 38 59* 39 58*Death, NEC, or BPD, % 52 63 40 61* 43 61*

See abbreviations in Table V.*P < .05.†P < .10.

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