enteral feeding

Scientifically Based Strategies for EnteralFeeding in Premature InfantsLeslie A. Parker, PhD,

ARNP, NNP-BC,*

Josef Neu, MD, Roberto

Murgas Torrazza, MD,

Yuefeng Li, MDx

Author Disclosure

Drs Murgas Torrazza

and Li have disclosed

no financial

relationships relevant

to this article. Dr Neu

has disclosed that he

serves as a consultant

to Abbott Nutrition,

Mead Johnson, Medela,

and Fonterra Foods; he

receives honoraria from

Nestle and Danone; and

he has research grants

with Covidien and

Gerber. Dr Parker has

disclosed that she has

a research grant

1R01NR014019-01A1

from N1NR. This

commentary does

contain a discussion of

an unapproved/

investigative use of

a commercial product/

device.

Educational Gap

Decisions regarding enteral feeding in very low birthweight infants are often not based

on sound scientific evidence.

AbstractFeeding intolerance and necrotizing enterocolitis are relatively common occurrencesin very low birthweight infants in the NICU. Fear of these disorders can signicantlyaffect decisions regarding initiation, advancement, and withholding of enteral feedings.Lack of sufcient enteral feedings and complications related to parenteral nutrition in-crease neonatal morbidity, thereby emphasizing the need for safe evidence-based feed-ing decisions and guidelines. Unfortunately, evidence to guide feeding practices isoften limited, making clinical decisions and the formulation of guidelines difcult. Thisarticle discusses controversies regarding the enteral feeding of very low birthweightinfants and includes current scientic evidence supporting and/or refuting specicfeeding practices.

Objectives After completing this article, readers should be able to:

1. Discuss the risks and benefits of providing enteral nutrition to very low birthweight

infants.

2. Explore current controversies in neonatal feeding practices.

3. Understand evidence supporting and refuting controversial feeding practices.

4. Discuss feeding practices requiring additional evidence to guide clinical decision-

making.

IntroductionProvision of optimal nutrition to very low birthweight (VLBW) infants in the NICU is oneof the most challenging and important aspects of neonatal care. (1) Although the enteralroute is the preferred method of nutritional delivery, the risk of necrotizing enterocolitis(NEC) and feeding intolerance (FI) causes decisions regarding initiation and advance-ment of enteral nutrition to be both difcult and controversial. The ultimate goal of en-teral nutrition is optimal growth and development without increasing complications,including NEC and FI. Unfortunately, decisions regarding enteral nutrition, includingtiming of initiation and rate of advancement, as well as indications for discontinuingand the mechanisms for delivery, are controversial and often based on individual or insti-tutional preference rather than scientic evidence. Thus, to determine best practices forthe NICU, this article summarizes the available evidence regarding enteral nutrition forVLBW infants.

Benefits of Enteral NutritionThe birth of a VLBW infant has been described as a nutritional emergency, and promptattention is essential to avoid complications, including parenteral nutrition (PN)-associ-ated liver disease, osteopenia of prematurity, poor neurologic outcomes, and extrauterinegrowth retardation (EUGR). Although the nutritional goal for premature infants is

*Clinical Assistant Professor, College of Nursing, University of Florida, Gainesville, FL.Associate Editor. Professor of Pediatrics, College of Medicine, University of Florida, Gainesville, FL.College of Medicine, University of Florida, Gainesville, FL.xDepartment of Neonatology, Baoan Maternity and Child Health Hospital of Shenzhen, Guangdong, China.

Article evidence-based medicine

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achievement of intrauterine growth rates, this goal maybe impossible due to limitations in PN, the increasedmetabolic demands of critically ill infants, and the neces-sity of uid restriction. Enteral nutrition decreases theneed for PN and thereby reduces PN-associated compli-cations, including PN-associated liver disease and late-onset sepsis. Although nutrition and growth can besustained with PN, when infants are maintained nil peros (NPO), impaired intestinal growth, mucosal atrophy,intestinal barrier dysfunction, decreased enzymatic activity,and abnormal intestinal bacterial colonization can occur.(2)(3) Intestinal dysfunction may occur quickly, with in-testinal atrophy occurring after only 23 days of NPO statusin animal models. (4)

Despite tremendous progress in neonatology, un-answered questions regarding enteral nutrition in ex-tremely premature infants result in remarkable practicevariation among institutions and individual clinicians.Decisions regarding enteral feeding are often not basedon sound scientic evidence; instead, they are basedon a fear of NEC and FI. Thus, safe, comprehensive,evidence-based feeding guidelines are necessary to avoidcomplications, including poor growth, prolonged hos-pitalization, PN-associated complications, and a delayin achievement of full enteral feedings. In another re-view in this issue, evidence-based nutritional guidelinesare addressed.

Risks Associated With Feeding VLBW InfantsNecrotizing Enterocolitis

NEC, a potentially devastating disease, affects 7% to 14%of VLBW infants and is characterized by hemorrhagic, is-chemic, and necrotic intestines. (5) NEC has a mortalityrate of 20% to 40% and is associated with complications,including intestinal strictures, short bowel syndrome, andan increased risk of neurodevelopmental delay. (6)(7)The etiology of NEC is poorly understood but seemsmultifactorial and related to gastrointestinal and immunesystem immaturity. Because greater than 90% of infantsdiagnosed with NEC have received enteral nutrition, pre-vention of this disease signicantly inuences feeding de-cisions in VLBW infants. (8)

Feeding IntoleranceVLBW infants frequently experience what is clinically de-scribed as FI due to intestinal immaturity, which includesdecreased gastric emptying (GE) and intestinal motility.Although the denition of FI varies, the term is histori-cally based on the presence of increased gastric residuals(GRs), abdominal distention, and emesis. Symptoms as-sociated with FI are often nondistinguishable from moreserious conditions, including NEC. GE is slower in pre-term infants due to intrinsic immaturities of the gastroin-testinal tract, including immature lower esophageal toneand function, low percentage of gastric (gastrointestinal)electrical slow wave, and slower intestinal transit time. (9)(10) Furthermore, intestinal motor patterns during fast-ing and feeding are immature in preterm infants and arecharacterized by short episodes of quiescence alternatingwith irregular contractions, with no clear migrating mo-tor complexes. (11) Similarly, during fasting, the clusteramplitude and mean duration of duodenum motor activ-ity are less in preterm than in term infants, and cluster fre-quency is higher in preterm infants. (12) Taken together,these intrinsic, physiologic characteristics are responsiblefor delayed GE and potential FI in preterm infants.

Evidence Regarding Enteral Feeding in VLBWInfantsBecause of an increased risk of NEC and FI in VLBW in-fants, clinicians are often hesitant to initiate, advance, andfortify feedings; they also often discontinue feedings ininfants who are undergoing blood transfusions and whoare diagnosed with or being treated for a patent ductus ar-teriosus (PDA). (13)(14) Although decisions regardingenteral feeding in this population must be made cau-tiously, practice guidelines and feeding decisions shouldbe based on current evidence. The following discussion

Abbreviations

COX: cyclooxygenaseELBW: extremely low birthweightEUGR: extrauterine growth retardationFI: feeding intoleranceGE: gastric emptyingGR: gastric residualGRV: gastric residual volumeMEN: minimal enteral nutritionNEC: necrotizing enterocolitisNG: nasogastricNPO: nil per osOG: orogastricPDA: patent ductus arteriosusPN: parenteral nutritionPRBC: packed red blood cellRCT: randomized controlled trialTANEC: transfusion-associated necrotizing enterocolitisVLBW: very low birthweight

evidence-based medicine nutrition

NeoReviews Vol.14 No.7 July 2013 e351


summarizes the current evidence regarding issues pertain-ing to enteral nutrition in VLBW infants. Table 1 summa-rizes the current evidence and unanswered questions foreach issue presented.

Minimal Enteral NutritionMinimal enteral nutrition (MEN), also called trophic ornonnutritive nutrition, is the provision of nutritionally in-signicant amounts of feeding, usually 12 to 24 mL/kgper day, to nourish and stimulate gastrointestinal de-velopment and to prevent intestinal atrophy. (3)(15)MEN has been associated with improved gut motilityand GE, enhanced intestinal structure and function, in-creased activity of digestive enzymes, and promotion ofmature migrating motor activity in preterm pigs. (15)(16) Although the use of MEN is now a well-establishedpractice in the NICU, evidence regarding its clinical ben-et is controversial. MEN reportedly improves weightgain as well as decreases PN complications, days to dis-charge, and time to attain full enteral feedings. (17)

(18) Signicantly, there have been no reports of adverseoutcomes from MEN, especially NEC or FI. However,small study populations, inconsistent FI denitions, andvariations in duration of MEN and type of diet makecomparison of available studies difcult and suggest thatthe results of a recent Cochrane review indicating a lackof benet in administering MEN should be questioned.(19) In addition, research regarding both the benetsand timing of initiation of MEN often fails to either in-clude extremely low birthweight (ELBW) infants or dif-ferentiate between VLBW infants and ELBW infantsdespite their physiologic and developmental differences.

Timing of Initiation of MENDuring gestation, the fetus swallows signicant amountsof amniotic uid, which contains growth factors and cy-tokines essential for intestinal development. When an in-fant is born prematurely, ingestion of amniotic uidceases, and if the infants gastrointestinal tract no longerreceives such enteral stimulation, proper gastrointestinal

Table 1. Evidence Regarding Feeding Strategies

Feeding Strategy Evidence Unanswered Questions

MEN Improves weight gain, decreases time to fullfeedings, decreases PN complications,decreases days to discharge

Influence of diet, optimal duration, anddosage. Risks and benefits in ELBW andclinically unstable infants

Timing of initiation of MEN2 to 4 days after birth

Earlier attainment of full feedings, increasedweight, decreased PN usage

Timing of initiation in ELBW infants.Risk and/or benefits of initiation before2 days

Advancement of enteralfeedings (15L20 vs30 mL/kg per day)

Advancement by 30 mL/kg per day isassociated with an earlier attainment of fullfeedings, fewer days of PN, shorter hospitalstay, and improved weight gain

Influence of diet, timing of initiation, andduration of MEN before advancement.Risks and benefits in ELBW infants

Delivery of enteral nutrition(continuous versus bolus)

No difference in time to attain full feedingsor weight gain

Influence on apneic episodes. Effect onweight gain and hospital days in ELBWinfants

Evaluation of gastricresiduals

No documented evidence Usefulness as an indicator of FI or an earlysymptom of NEC

Feeding during bloodtransfusions

Blood transfusions seem to be associated withNEC

Whether feeding during transfusions areassociated with an increased risk ofTANEC

Feeding infants who havea PDA

Infants who have a PDA have decreasedmesenteric blood flow

The risk and benefit of feeding infantsdiagnosed as having a PDA

Feeding duringindomethacin oribuprofen therapy

COX inhibitors decrease mesenteric bloodflow, but normal postprandial blood flowis maintained

The risk and benefit of feeding infants whoare taking COX inhibitors

Fortification of human milk No increase in feeding intolerance or NECwith fortification. Human milkbasedfortifiers may decrease the incidenceof NEC

Influence of human milkbased fortifierson FI

COXcyclooxygenase; ELBWextremely low birthweight; FIfeeding intolerance; MENminimal enteral nutrition; NECnecrotizing enterocolitis;PDApatent ductus arteriosus; PNparenteral nutrition; TANECtransfusion-associated necrotizing enterocolitis.




development and function may be compromised. (20)Thus, provision of human milk (especially colostrum) im-mediately after delivery may be particularly benecial tophysiologic gastrointestinal development due to its simi-larity to amniotic uid. (16) In addition, earlier initiationof enteral feeding after birth could limit the adverse ef-fects of NPO status. Unfortunately, because the majorityof studies investigating the timing MEN initiation useda combination of human milk and formula, the clinicalbenets of using exclusive human milk feedings forMEN are unknown.

Several studies have found that initiation of MEN 2 to4 days after birth is associated with decreased PN, in-creased weight gain, and an earlier attainment of full feed-ings compared with initiation at 5 to 7 days. (19)(21)Although long-term outcomes were not reported inthis study, these early benets could translate into lessEUGR, shorter hospitalizations, and fewer PN complica-tions. The American Society for Parenteral and EnteralNutrition recommends initiation of MEN within the rst2 days in infants weighing greater than 1,000 g. (22) Forvarious reasons, including patient acuity, clinicians oftenuse these recommendations inconsistently, and initiationof enteral feedings may be delayed for up to 10 days afterbirth.

Although research exists regarding initiatingMEN be-tween 2 to 4 days after birth, no studies were found thatevaluated the risks and benets of initiating MEN earlierthan 48 hours after delivery. When considering the valueof continued exposure to nutrients, growth hormones,and other bioactive components present in amniotic uidand human milk, as well as the negative consequences ofNPO status, such a delay may have deleterious conse-quences. It is also possible that current recommendedvolumes of MEN may be insufcient to promote bene-cial clinical outcomes; however, administration of largervolumes could be unrealistic in very premature infantsdue the risk of NEC and FI.

In conclusion, administration of MEN has shown pos-itive clinical outcomes in most small studies conductedthus far and is becoming a well-accepted practice in theNICU. However, unanswered questions, including opti-mal dosage and duration, use of human milk exclusively,risks versus benets in clinically unstable infants, and ben-ets of provision earlier than 48 hours after delivery, po-tentially limit its advantages.

Advancement of Enteral FeedsAfter MEN is provided, feedings are gradually advanceduntil full feedings are attained and PN is discontinued.The daily rate of advancement often varies depending

on institutional and clinician preference, thereby affectingtime to attainment of full enteral feedings and inuencingduration of PN usage. Several randomized controlled tri-als (RCTs) have compared feeding advancement by 15 to20 mL/kg per day with advancement by 30 mL/kg perday and have found that those infants who experienceda faster advancement of feedings reached full feedingsfaster, required fewer days of PN, had a shorter hospitalstay, and regained birthweight more quickly without anincreased risk of either NEC or FI. (23)(24)(25) Thesendings were supported by a recent Cochrane reviewand American Society for Parenteral and Enteral Nutri-tion recommendations that feedings be advanced by30 mL/kg per day in infants weighing greater than1,000 g. (22)(26) Again, discrepancies regarding diet,initiation, and duration of MEN and lack of informationregarding ELBW infants limit our knowledge concerningthe optimal rate for advancement of feedings. In addi-tion, because practice parameters that focus on feedingVLBW infants generally do not differentiate between in-fants born ELBW and VLBW, a more conservative ap-proach to feeding advancement is often used.

Delivery of Enteral NutritionThe most common methods for enteral nutrition deliveryin the NICU are either via continuous or intermittent bo-lus orogastric (OG) or nasogastric (NG) tube. Decisionsregarding administration are also generally based on insti-tutional and clinician preference, not scientic evidence.Potential benets of bolus feedings include improvedfeeding tolerance due to faster GE, enhanced duodenalmotor responses, more normal feedingfasting hormonallevels, and greater muscle protein synthesis. (27) How-ever, a recent Cochrane review reported no differencein time to full feedings or growth when the two modal-ities were compared. (28) Individual studies suggest con-tinuous feedings may increase apnea in VLBW infants(29) and weight gain in infants less than 1,250 g, as wellas result in an earlier discharge for ELBW infants. (30) Inaddition, compared with infants fed via OG tube, thosefed via NG tube are signicantly more likely to experiencelower saturation levels during feeding tube insertion andduring feeding administration. (31)

Evaluation of Gastric ResidualsGR is the volume of milk remaining in the stomach be-fore a feeding and is often considered an indicator of FI,delayed GE, and an early symptom of NEC. (32)(33) Al-though assessment of GRs is generally accepted as rou-tine care, standards for evaluation and management aregenerally lacking. (24)(34) Reports in the literature




indicate a wide variation in practice regarding the pres-ence of large or abnormally colored GRs, and 70% to93% of NICUs use GRs to determine when to alter feed-ing volume or advance feedings. (14) This lack of uni-form standards can lead to EUGR and a discontinuationor delay in advancement of feedings, resulting in prolon-gation of PN. In addition, GR aspiration may not reliablymeasure gastric residual volume (GRV) because accuratemeasurement depends on body position, size of the feed-ing tube, and placement of the OG/NG port in the gas-tric antrum. (35) GRV can be underestimated by 25%,and this variability increases as GRV decreases, which maybe particularly important in VLBW infants whose gastriccontents are small. (36)

Aspiration and evaluation of GR can be associatedwith potentially signicant complications, including dam-age of the fragile gastric mucosa from negative pressurecreated by aspiration of GR and close contact betweenthe tip of the NG/OG tube and the gastric mucosa.In addition, because GRs contain nutrients, gastric acid,and enzymes that might promote intestinal motility andmaturation, discarding GRs may negatively inuence GEand gastrointestinal system maturation. (37) Decisions re-garding when to discard GRs are not based on evidencebut are done according to nurses experience, unit tradi-tion, and physician advice. Indeed, in a small study ofNICU nurses, only 4% consistently replaced GR after as-piration. (38)

Variation in acceptable GR volume restricts its useful-ness as an FI indicator. FI by some authors has been de-ned as a GRV greater than 2 to 3 mL depending onweight, (32)(34) greater or equal to 2 mL/kg, or greaterthan 50% of the previous feeding volume. (39)(40) Al-though some studies suggest that increased GRV maybe an early indicator of NEC, this relationship has notbeen clearly substantiated. Cobb et al (33) reported a sig-nicantly greater maximum GRV in infants during the 6days before the diagnosis of NECcompared with infants who donot have NEC, but the clinical sig-nicance of these ndings is uncer-tain. Similarly, Bertino et al, (32) ina case control study of 34 infants,reported a statistically greater max-imum GRV from birth to onset ofNEC. The amount of GRV consid-ered signicant is also unclear andmay range from greater than 3.5 to4 mL, greater than 1.2 mL, or bebased on a percentage of the pre-vious feeding volume. (41)

Finally, the color of GRs has been evaluated as an in-dicator of NEC, and although several studies have exam-ined this relationship, most have failed to establish a clearconnection. For example, Bertino et al (32) reporteda correlation between bloody residuals and NEC, butthe correlation did not extend to bilious-colored residuals.Similarly, Mihatsch et al (34) found that green GRs (50% of feeding

FIfeeding intolerance; GRgastric residual; GRVgastric residual volume; NECnecrotizingenterocolitis.




with lower hematocrit levels have an increased risk ofTANEC, possibly related to impaired intestinal oxygendelivery due to severe anemia and reperfusion injury.In addition, infants may also be predisposed to TANECdue to bowel ischemia resulting from increased blood vis-cosity, decreased superior mesenteric artery blood ow,and an intestinal immunologic reaction from exposureto biologically active mediators such as free hemoglobin,cytokines, or broken red cell fragments. (45)(46) Trans-fusion of older blood is associated with organ dysfunctionand increased morbidity in adult patients, and dedicateddonor policies (which are used to decrease exposure tomultiple donors) make the transfusion of older blood acommon practice in the NICU. Using older blood fortransfusion exposes the infant to storagemedium, cytokines,red blood cell membrane abnormalities, and additionalchemical changes that are potentially harmful to the intes-tinal mucosa. (47)However, compared with blood less than7 days old, transfusion of blood older than 14 days has notbeen shown to increase the risk of TANEC. (48)

A highly controversial issue surrounding TANEC iswhether feeding before, during, or after a transfusion af-fects its incidence. An RCT by Krimmel et al found noincrease in postprandial mean blood ow velocity intransfused VLBW infants, potentially resulting in intesti-nal hypoperfusion. Two observational studies suggestthat withholding feedings during blood transfusions de-creases the risk of TANEC. (43)(46)(49) El-Dib et al(43) used a case-controlled, retrospective study andfound a reduction in NEC, but not TANEC, after a prac-tice change to withholding feedings during transfusions.Perciaccante and Young found a decrease in TANECfrom 39% to 0% after a change to withholding feedingsbefore, during, and after transfusions. Unfortunately,there are no published RCTs evaluating the associationof feeding during blood transfusions and the incidenceof TANEC. If withholding feedings during PRBC trans-fusions is found benecial, additional research will be re-quired to determine the necessary duration of NPOstatus and the inuence of diet. Although mesentericblood ow after transfusions is not affected by diet, for-mula-fed infants are more likely to develop TANEC. (46)Although many NICUs are changing feeding practices towithhold feedings before or during blood transfusions,there is currently no compelling evidence that withhold-ing feedings affects the incidence of NEC.

Feeding Infants Who Have a PDAA PDA is a common phenomenon in premature infants,occurring in 65% to 80% of infants weighing less than1,000 g. (50) The presence of a clinically signicant

PDA decreases mesenteric blood ow due to diversionof blood away from the systemic circulation, potentiallyincreasing the risk for FI and NEC. Both a reductionin postductal blood ow and the lack of a normal post-prandial intestinal blood ow have been reported in an-imal models, potentially limiting the infants ability tomeet the increased metabolic demands of an active gas-trointestinal system. (51)

Retrospective studies have also reported an associationbetween a PDA diagnosed via echocardiogram and an in-creased incidence of NEC. (52)(53) In addition, delayedtreatment and a persistent PDA have been correlated withan increased risk of NEC in VLBW infants. In contrast,several trials have failed to show an association betweenPDAs and NEC, (54)(55) including a large multicenterstudy of ELBW infants. (56) Because infants diagnosedwith PDAs are generally more immature, clinically less sta-ble, and have often undergone treatment for PDA clo-sure, comparing complication rates can be difcult. (57)

Due to the perceived risk of NEC and FI, clinicians areoften hesitant to feed infants who have a clinically signif-icant PDA; only 30% of NICUs and 29% of US-basedneonatologists continue feeding after a diagnosis, po-tentially delaying full enteral feedings and resulting inless optimal growth. (13)(14) However, this hesitancymay be unwarranted; it has been shown that small feed-ings increase gastrointestinal blood ow, theoreticallyproviding intestinal tract protection. In addition, FI hasnot been shown to increase in infants who have PDAs.Despite these ndings, more research is needed to clar-ify issues regarding the risk and benets of feeding in-fants who have PDAs as well as the impact of initiationtiming, duration of MEN, and rate of advancementand diet.

Feeding During Indomethacin or IbuprofenTherapy

Cyclooxygenase (COX) inhibitors such as indomethacinand ibuprofen are often used in the treatment of PDAs,but due to their negative effect on mesenteric blood ow,they have been theorized to contribute to intestinal injuryand increase the risk of NEC and FI. (1) This perceptionstems from the ndings of retrospective studies, whichhave linked treatment with COX inhibitors to an increasedrisk of NEC, as well as a Cochrane review, which foundthat infants who received a shorter course of indomethacinalso had a lower incidence of NEC. (1)(58) In addition,several early studies indicated an association between in-domethacin for intraventricular hemorrhage prophylaxisand NEC.However, these studies did not consistently dif-ferentiate between spontaneous intestinal perforation and




NEC, and due to the well-established relationship be-tween early indomethacin therapy and spontaneous intes-tinal perforation, the association between indomethacinand NEC may have been overrepresented. (1)(5)

In contrast, numerous investigations have failed tond an association between NEC and treatment withCOX inhibitors even though these treatment groupswere often smaller and less clinically stable. (54)(59)Sharma et al, (31) in a prospective study of 992 infants,found that infants treated with indomethacin actually hada decreased incidence of NEC and suggested a protectiveelement due to indomethacins ability to modulate intes-tinal inammatory mediators.

Although both indomethacin and ibuprofen are usedfor treating PDAs, ibuprofen may be preferable due toits milder effect on mesenteric blood ow. Several stud-ies, including a 2011 Cochrane review, have indicateda decreased risk of NEC in infants treated with ibupro-fen. (60)

In conclusion, investigations regarding feeding infantstreated with COX inhibitors are limited. Although COXinhibitors decrease mesenteric blood ow, they do notprevent normal postprandial increases in intestinal bloodow and are not associated with increased FI. FutureRCTs are needed to investigate specic feeding strategiesfor infants being treated with COX inhibitors.

Fortification of Human MilkConcerns regarding the impact of human milk fortica-tion with bovine-based products on the rate of NECand FI in VLBW infants may inuence clinical decisionsto provide nutritionally necessary fortication. Unfortu-nately, limited information exists regarding the impactof human milk fortication on either NEC or FI. Onestudy by Ewer and Yu, (61) which explored the effectof human milk fortication on GE in preterm infants, re-ported that human milk fortier may slow GE due to anincreased osmolality and change in milk composition.However, several studies (including a systematic review)found no increase in FI or NEC when human milk wasfortied. (31) Sullivan et al (62) reported a signicantlyhigher incidence of NEC in infants receiving a cowsmilkbased fortier compared with a human milkbasedfortier. Actual differences in frequency of NEC weresmall and may have been due to the increased use of hu-man milk rather than fortication.

SummaryDelivery of nutrition to critically ill VLBW infants is oneof the most important challenges in neonatology and

requires the interdisciplinary work of nurses, nurse prac-titioners, physicians, and nutritionists to provide optimalnutrition and to prevent complications. Current practiceis largely based on NICU tradition and individual clinicalpreference rather than sound evidence; in addition, fewhigh-quality RCTs regarding feeding practices in thispopulation are available to determine standards. Thus,for new research to be relevant, it is imperative that cer-tain factors (fortication of human milk, advancement offeedings, denitions of FI and NEC, and timing of initi-ation and duration of MEN) are consistent. Althoughclinical decisions regarding continuing, discontinuing,or advancing enteral feedings must always be based ona thorough assessment of the individual patient, addi-tional research is needed to guide and optimize clinicaldecision-making.

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Know the pathophysiology and preventionof NEC.




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26. Morgan J, Young L, McGuire W. Slow advancement of enteralfeed volumes to prevent necrotising enterocolitis in very low birthweight infants. Cochrane Database Syst Rev. 2011;(3):CD00124127. Gazzaneo MC, Suryawan A, Orellana RA, et al. Intermittentbolus feeding has a greater stimulatory effect on protein synthesis inskeletal muscle than continuous feeding in neonatal pigs. J Nutr.2011;141(12):2152215828. Premji SS, Chessell L. Continuous nasogastric milk feedingversus intermittent bolus milk feeding for premature infants less than1500 grams. Cochrane Database Syst Rev. 2011;(11):CD00181929. Heldt GP. The effect of gavage feeding on the mechanics ofthe lung, chest wall, and diaphragm of preterm infants. Pediatr Res.1988;24(1):555830. Silvestre MA, Morbach CA, Brans YW, Shankaran S. Aprospective randomized trial comparing continuous versus inter-mittent feeding methods in very low birth weight neonates.J Pediatr. 1996;128(6):74875231. Sharma R, Hudak ML, Tepas JJ 3rd, et al. Prenatal or postnatalindomethacin exposure and neonatal gut injury associated withisolated intestinal perforation and necrotizing enterocolitis. J Peri-natol. 2010;30(12):78679332. Bertino E, Giuliani F, Prandi G, Coscia A, Martano C, FabrisC. Necrotizing enterocolitis: risk factor analysis and role of gastricresiduals in very low birth weight infants. J Pediatr GastroenterolNutr. 2009;48(4):43744233. Cobb BA, Carlo WA, Ambalavanan N. Gastric residuals andtheir relationship to necrotizing enterocolitis in very low birthweight infants. Pediatrics. 2004;113(1 pt 1):505334. Mihatsch WA, von Schoenaich P, Fahnenstich H, et al. Thesignicance of gastric residuals in the early enteral feeding advance-ment of extremely low birth weight infants. Pediatrics. 2002;109(3):45745935. Bankhead R, Boullata J, Brantley S, et al; A.S.P.E.N. Board ofDirectors. Enteral nutrition practice recommendations. JPEN JParenter Enteral Nutr. 2009;33(2):12216736. Geraldo V, Pyati S, Joseph T, Pildes RS. Gastric residual (GR):reliability of the measurement. Pediatr Res. 1997;41:15037. Williams TA, Leslie GD. Should gastric aspirate be discarded orretained when gastric residual volume is removed from gastrictubes? Aust Crit Care. 2010;23(4):21521738. Hodges C, Vincent PA. Why do NICU nurses not refeedgastric residuals prior to feeding by gavage? Neonatal Netw. 1993;12(8):374039. Sari FN, Eras Z, Dizdar EA, et al. Do oral probiotics affectgrowth and neurodevelopmental outcomes in very low-birth-weight preterm infants? Am J Perinatol. Sep 2012;29(8):57958640. Dsilna A, Christensson K, Alfredsson L, Lagercrantz H,Blennow M. Continuous feeding promotes gastrointestinal toler-ance and growth in very low birth weight infants. The Journal ofpediatrics. Jul 2005;147(1):434941. Kenton AB, Fernandes CJ, Berseth CL. Gastric residuals inprediction of necrotizing enterocolitis in very low birth weightinfants. Pediatrics. 2004;113(6):1848184942. Shulman RJ, Ou CN, Smith EO. Evaluation of potentialfactors predicting attainment of full gavage feedings in preterminfants. Neonatology. 2011;99(1):384443. El-Dib M, Narang S, Lee E, Massaro AN, Aly H. Red bloodcell transfusion, feeding and necrotizing enterocolitis in preterminfants. J Perinatol. 2011;31(3):183187




44. Mohamed A, Shah PS. Transfusion associated necrotizingenterocolitis: a meta-analysis of observational data. Pediatrics.2012;129(3):52954045. Blau J, Calo JM, Dozor D, Sutton M, Alpan G, La Gamma EF.Transfusion-related acute gut injury: necrotizing enterocolitis invery low birth weight neonates after packed red blood cell trans-fusion. J Pediatr. 2011;158(3):40340946. Krimmel GA, Baker R, Yanowitz TD. Blood transfusion altersthe superior mesenteric artery blood ow velocity response tofeeding in premature infants. Am J Perinatol. 2009;26(2):9910547. Gauvin F, Spinella PC, Lacroix J, et al; Canadian Critical CareTrials Group and the Pediatric Acute Lung Injury and SepsisInvestigators (PALISI) Network. Association between length ofstorage of transfused red blood cells and multiple organ dysfunctionsyndrome in pediatric intensive care patients. Transfusion. 2010;50(9):1902191348. Fergusson D, Hbert PC, Lee SK, et al. Clinical outcomesfollowing institution of universal leukoreduction of blood trans-fusions for premature infants. JAMA. 2003;289(15):1950195649. Perciaccante NY. Necrotizing enterocolitis associated withpacked red blood cell transfusion in premature neonates. E-PAS.2008;2008:S833950. Golombek SG, Sola A, Baquero H, et al; Primer Grupo deConsenso Clnico SIBEN. First SIBEN clinical consensus: diagnosticand therapeutic approach to patent ductus arteriosus in prematurenewborns [in Spanish]. An Pediatr (Barc). 2008;69(5):45448151. McCurnin D, Clyman RI. Effects of a patent ductus arteriosuson postprandial mesenteric perfusion in premature baboons.Pediatrics. 2008;122(6):e1262e126752. Dollberg S, Lusky A, Reichman B. Patent ductus arteriosus,indomethacin and necrotizing enterocolitis in very low birth weightinfants: a population-based study. J Pediatr Gastroenterol Nutr.2005;40(2):184188

53. Sankaran K, Puckett B, Lee DS, et al; Canadian NeonatalNetwork. Variations in incidence of necrotizing enterocolitis inCanadian neonatal intensive care units. J Pediatr GastroenterolNutr. 2004;39(4):36637254. Mirea L, Sankaran K, Seshia M, et al. Treatment of patentductus arteriosus and neonatal mortality/morbidities: adjustmentfor treatment selection bias. J Pediatrics. 2012;161(4):689694.e155. Patole SK, Kumaran V, Travadi JN, Brooks JM, Doherty DA.Does patent ductus arteriosus affect feed tolerance in pretermneonates? Arch Dis Child Fetal Neonatal Ed. 2007;92(1):F53F5556. Madan JC, Kendrick D, Hagadorn JI, Frantz ID III; NationalInstitute of Child Health and Human Development NeonatalResearch Network. Patent ductus arteriosus therapy: impact onneonatal and 18-month outcome. Pediatrics. 2009;123(2):67468157. Saldeno YP, Favareto V, Mirpuri J. Prolonged persistent patentductus arteriosus: potential perdurable anomalies in prematureinfants. J Perinatol. 2012;32(12):95395858. Burrin DG, Stoll B, Jiang R, et al. Minimal enteral nutrientrequirements for intestinal growth in neonatal piglets: how much isenough? Am J Clin Nutr. 2000;71(6):1603161059. Laughon M, Bose C, Clark R Treatment strategies to preventor close a patent ductus arteriosus in preterm infants and outcomes.J Perinatol. 2007;27(3):16417060. Ohlsson A, Shah SS. Ibuprofen for the prevention of patentductus arteriosus in preterm and/or low birth weight infants.Cochrane Database Syst Rev. 2011;(7):CD00421361. Ewer AK, Yu VY. Gastric emptying in pre-term infants: theeffect of breast milk fortier. Acta Paediatr. 1996;85(9):1112111562. Sullivan S, Schanler RJ, Kim JH, et al. An exclusively humanmilk-based diet is associated with a lower rate of necrotizingenterocolitis than a diet of human milk and bovine milk-basedproducts. J Pediatr. 2010;156(4):562567.e1

NeoReviews QuizNew minimum performance level requirementsPer the 2010 revision of the American Medical Association (AMA) Physicians Recognition Award (PRA) and credit system, a minimum performancelevel must be established on enduring material and journal-based CME activities that are certified for AMA PRA Category 1 CreditTM. In order tosuccessfully complete 2013 NeoReviews articles for AMA PRA Category 1 CreditTM, learners must demonstrate a minimum performance level of 60%or higher on this assessment, which measures achievement of the educational purpose and/or objectives of this activity.

In NeoReviews, AMA PRA Category 1 CreditTM can be claimed only if 60% or more of the questions are answered correctly. If you score less than60% on the assessment, you will be given additional opportunities to answer questions until an overall 60% or greater score is achieved.

1. A 1-day-old 29-weeks-gestational-age male who had a birthweight of 1 kg is started on feedings of 2 mL ofhuman milk every 3 hours. This type of feeding is associated with which of the following in preterm animalmodels?

A. Decrease in gut motility.B. Increased activity of digestive enzymes.C. Increased risk of early-onset, but not late-onset, necrotizing enterocolitis (NEC).D. Intestinal atrophy.E. Formation of ileal strictures.

2. The 29-weeks-gestational-age patient in question 1 would be considered as receiving minimal enteralnutrition (MEN). Which of the following is true regarding MEN for premature infants?

A. The use of either human milk or infant formula for MEN likely has equivalent beneficial effects.




B. The initiation of MEN within the first 2 to 4 days after delivery, as opposed to later, may result in decreasedparenteral nutrition use, increased weight gain, and earlier attainment of full enteral feedings.

C. The evidence behind starting MEN within the first hour after delivery is well established, and MEN shouldtherefore be used for all preterm infants with less than 1,500 g birthweight soon after birth.

D. Because colostrum has higher caloric density than regular milk, it should not be used as the initial MEN butwithheld until full enteral feedings are established.

E. Most of the research on MEN for very preterm infants has studied initiation of MEN before 48 hours.Further studies will need to focus on the benefit of initiation of MEN from 3 to 7 days.

3. A 6-day-old 31-weeks-gestational-age female with a birthweight of 1,100 g is receiving approximately 50%parenteral nutrition by umbilical venous catheter and 50% enteral nutrition with maternal human milk. She isreceiving 11 mL of human milk every 3 hours. She has apnea of prematurity but is currently on room air andbeing monitored. Which of the following is true regarding her current nutrition management?

A. Advancing her feedings by 4 mL per feeding daily, as opposed to 2 mL per feeding, is more likely to lead todecreased overall parenteral nutrition use without an increase in risk of NEC.

B. Because parenteral nutrition will provide better nutrition than enteral feedings of human milk or infantformula, the umbilical line should be kept in place for the first 10 days after delivery for parenteralnutrition, regardless of feeding tolerance.

C. The feedings should be changed to continuous feedings at 4 mL per hour to reduce the risk of apnea.D. The optimal approach to feeding this infant is by nasogastric tube, which should be alternated between

each nostril every three to four feedings.E. From the second week on, the patient should receive one half of her feedings with infant formula to

provide adequate protein and calcium intake.

4. During morning rounds, the bedside nurse shows you the gastric residual of a 6-week-old 24-weeks-gestational-age male who is now receiving full enteral feedings by gavage tube. The infant now weighs 1 kg andis receiving 20 mL of human milk every 3 hours. The gastric residual is light green and measures approximately 2mL in volume. Which of the following is true regarding gastric residuals for patients such as this one?

A. Although the research on significance of gastric residuals is ongoing, the lack of harmful effects inchecking residuals makes it the standard of care because it may provide some useful information.

B. Due to the appearance of this residual, it should be discarded, and the patients next feeding should be held.C. The lack of residuals is a strong negative predictive factor for NEC and can be a reassuring sign to continue

feedings even in the presence of other symptoms such as abdominal distension and blood-tinged stools.D. Gastric residuals contain nutrients, gastric acid, and enzymes that may promote motility and maturation.E. This patient should have a sepsis evaluation and be started on antibiotic therapy until culture results are

negative for at least 48 hours.

5. A 4-day-old 26-weeks-gestational-age male has a patent ductus arteriosus diagnosed by echocardiogram,a hematocrit value of 21%, and is intubated on mechanical ventilation requiring the fraction of inspiredoxygen in a gas mixture to be 40%. You are planning to give a packed red blood cell transfusion. Given thecurrent state of evidence, which of the following statements can you confidently state regarding this patientsclinical condition?

A. The presence of a patent ductus arteriosus alone is an absolute contraindication to feeding this patient.B. It is safer to accept this patients current hematocrit level than to provide a transfusion in regard to

avoiding feeding intolerance and other morbidities.C. To promote gut motility and development, the patient should be fed human milk before, during, and

immediately after the transfusion.D. If there is a decision to treat this patients patent ductus arteriosus, indomethacin may be preferable to

ibuprofen because of its potentially milder effect on mesenteric blood flow and reduced risk for NEC.E. Although some studies have linked packed red blood cell transfusions to NEC, further studies are needed to

determine if withholding feedings is beneficial and, if so, to determine the optimal timing of feedingpractice surrounding transfusion.




DOI: 10.1542/neo.14-7-e3502013;14;e350NeoReviews

Leslie A. Parker, Josef Neu, Roberto Murgas Torrazza and Yuefeng LiScientifically Based Strategies for Enteral Feeding in Premature Infants

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DOI: 10.1542/neo.14-7-e3502013;14;e350NeoReviews

Leslie A. Parker, Josef Neu, Roberto Murgas Torrazza and Yuefeng LiScientifically Based Strategies for Enteral Feeding in Premature Infants

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