Hanyang Medical Reviews Vol. 31 No. 4, 2011 246 미숙아의영양관리 장윤실성균관대학교의과대학삼성서울병원소아청소년과 Yun Sil Chang, M.D., Ph.D. Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 책임저자주소 : 135-710, 서울시강남구일원로 81 삼성서울병원소아청소년과 Tel: 02-3410-3539, Fax: 02-3410-0043 E-mail: yschang@skku.edu feeding strategies are reviewed to provide neonatal clinicians with current guidelines for nutritional care that can improve neurodevelopmental outcomes in preterm infants during and after treatment in the neonatal intensive care unit. Key Words: Infant, Premature; Nutritional Status; Growth; Intensive Care, Neonatal; Feeding Methods 투고일자 : 2011 년 9 월 5 일, 심사일자 : 2011 년 9 월 7 일, 게재확정일자 : 2011 년 10 월 7 일 서론 Abstract In the early postnatal period, prematurely born infants, especially those born at the earliest limits of viability, face a nutritional crisis. A lack of essential nutrients may result in substantial developmental morbidity. In particular, because this period is crucial to proper neurodevelopment, a central concern must be providing essential nutrition for proper neurodevelopment, and the prevention of long-term neurodeficits. Therefore, providing appropriate nutrition for growth and development is one of the most essential concerns in the care of preterm infants. The optimal goal for providing nutrition in the preterm infant is to achieve a postnatal growth rate approximating that of the normal fetus at the same gestational age. However, extra-uterine growth restriction develops during the course of care for most very low birth weight infants admitted to the neonatal intensive care unit. Herein, the optimal nutrient requirements and most recently recommended total parenteral and enteral 최근국내외로극소및초극소저체중출생아를비롯한전반적인미숙아의생존율이급격하게향상되고있다. 이는주산의학과신생아집중치료술의발달로여러치료법이향상되고수액및전해질요법의세심한관리와함께영양과성장을개선시키기위한노력에기인한다하겠다 [1]. 미숙아의출생후성장은동일주수에해당하는자궁내태아와유사한성장을목표로한다 [2]. 그러나일반적으로미숙아의생리적한계점으로인하여재태주수와출생체중이낮을수록필요한권장영양량을모두공급하기어렵고, 또한기존의권장영양량을모두공급하여도출생후성장지연에빠지기쉬운문제점이있다 [3]. 특히출생체중 1,500 g 이하의극소저체중출생아인경우출생직후영양학적으로의학적응급상태에놓이는만큼, 질과양양면이고려된영양공급이신생아집중치료에있어매우중요하다. 상당수의극소저체중출생아들이신생아집중치료후교정연령 36주에성장부전상태에놓이게되는데 [4] 이는재태주수와출생체중이작을수록더욱심하다. 더욱중요한것은이러한영양공급부전에의한성장부진이추후장기적신경발달에있어서좋지않은예후와밀접하게연관된다는점이다 [5]. 이에미숙아들에있어양호한성장을위한적절한영양공급은장기신경학적예후에있어서도매우중요한
247 바본론에서는미숙아의영양공급의관점에서정맥영양 (parenteral nutrition) 과장관영양 (enteral nutrition) 으로나누어주영양소에대한요구도충족을위한공급원칙을중심으로기술하고자한다. 본론 1. 정맥영양 (parenteral nutrition) 미숙아위장관의생리적미성숙과, 운동성저하, 소화효소를비롯한호르몬불균형등으로인해출생직후장관영양으로모든영양필요량을공급하는것은불가능하여, 생후초기에정맥영양이반드시필요한경우가많다. 특히극소및초극소미숙아들은태아에서자궁외환경으로전이되는출생직후, 태반영양공급이갑자기끊어짐에따라외부정맥영양에전적으로의존하게되는영양학적인응급상황 (nutritional emergency) 에놓이게되므로가능한한빨리정맥영양공급이이루어져야한다. 미숙아정맥영양에있어실제로투여시필요한수액량과에너지, 그리고주영양소증가목표제시가필요한데 Table 1은 2005년도유럽에서발표된미숙아정맥영양의수액과주영양소에대한권장량이다 [6]. 1) 단백질과아미노산만삭신생아의일반적인이화작용을예방하기위해서는 1.5-2 g/kg/day의단백질공급이필요하나, 초극소미숙아들의성장을태아시기의단백축적율과동일하게하기위한단백질필요량은 3.8-4.0 g/kg/day에달한다 [7-9]. 과거에는고요소혈증과대사성산증을우려하여생후초기단백질공급을제한하였으나, 이는주로초기아미노산수액 제제의불완전성에기인하였던것으로최근에는개선된아미노산제제로비교적높은농도의단백질공급을출생초기에공급하는것이일반적으로권장되고있다. 미숙아에서출생첫날 1 g/kg/day 또는 3 g/kg/day의단백질공급에따라군을나누어비교하였을때, 대사성산증이나 blood urea nitrogen (BUN) 수치가두군간에차이가없었으며, 3 g/kg/day의단백질을공급한미숙아들과임신제 2기, 또는 3기의태아에서채취한혈액에서의필수그리고비필수아미노산농도가비교적같은구성을보이고, 1 g/kg/day 의단백을공급받은미숙아군보다 2배이상의높은농도를보이는등생후초기증가된단백질공급의타당성에대한연구가발표되었다 [9]. 임상에서단백질공급모니터링지표로 BUN을이용하고있으나, 실제아미노산공급량과 BUN 과는직접적인상관관계를보이지않는다는보고도있어아미노산의초과독성에대한모니터링을위한적절한방법을찾기어려운실정이다 [10]. 현재까지는미숙아들에서생후초기수일에걸쳐서천천히단백질공급량을늘려가는방법이많이추천되고있으나이또한단백질에대한내성을향상시킨다는명확한증거는없다. 단백질의필요량은개개인의아미노산필요량에, 특히생체에서합성불가능한필수아미노산의필요정도에따라달라지는데, 초극소미숙아들의혈장내아미노산구성에대한충분한정보는아직미흡하다. 미숙아에서필수아미노산중 threonine 과 lysine은부족시단백합성이제한될수있는매우필수적인요소이고 [9], 조건부필수아미노산으로분류되고있는 cysteine, tyrosine은액체에잘녹지않는문제점이있으며, 특히 cysteine은수액제제에서불안정한성분이어서보편적으로사용하는단백질수액제제에거의포함되어있지않다 [11-13]. 글루타민역시회전이빠른세포에서중요한에너지원으로사용되고, 핵산과단백질의중요한전구체로 Table 1. Fluid and Macronutrient Guidelines for Parenterally Fed Premature Infants by the European Society of Paediatric Gastroenterology, Hepatology and Nutrition and European Society for Clinical Nutrition and Metabolism in 2005 Goal, per kg/day When to start Fluid, ml BW <1.5 kg 160-180 immediately with 80-90 ml/kg per day BW >1.5 kg 140-160 immediately with 60-80 ml/kg per day Energy, kcal 110-120 Protein, g 1.5-4.0 postnatal day 1 Lipids, g up to 3-4 postnatal days 1-3 Carbohydrates, g up to 11.5-18.0 (8.0-12.5 mg/kg per min) immediately with 5.8-11.5 g/kg per day (4-8 mg/kg per min)
248 Hanyang Medical Reviews Vol. 31, No. 4, 2011 써미숙아에게중요한조건부필수아미노산이지만, 이또한수액제에서는불안정한문제가있다 [14]. 2) 포도당, 탄수화물포도당은신생아의뇌대사에이용되는유일한물질로써이를충족하기위한포도당생성속도는만삭아에서 3-5 mg/kg/min[15], 초극소미숙아에서는더높아서 8-9 mg/ kg/min 으로알려져있다 [16]. 미숙아에서정상혈당농도를유지하고당의필요량을충족시키기위한정맥영양으로의당공급량은생후첫날 6 mg/kg/min으로시작하여단계적으로 10-12 mg/kg/min 까지증가시키는지침이권장되고있다 [1]. 초극소미숙아들에서적어도혈당은 40 mg/dl 이상으로유지하여저혈당을방지해야하나오히려이들에서는고혈당이더흔한부작용으로약 20-85% 에서나타나고고혈당이되는경우에정맥으로공급되는포도당농도를낮추게되므로이로인한당의공급에제한이초래되는경우가많다 [17]. 고혈당은보통혈장에서포도당수치가 150 mg/dl 이상인경우라고알려져있으나보통 200 mg/ dl 이하인경우에는특별한치료를요하지않는다 [18]. 초극소미숙아에서고혈당이흔한이유는말초에서의당이용을촉진하고, 간의당생성을억제하여조절하는기능을수행하는인슐린의저항성에기인한다. 고혈당은당의공급을억제하여충분한칼로리공급을받지못하게할뿐만아니라, 혈액의삼투압을높여고장성당뇨와탈수, 전해질불균형을초래하고, 뇌실내출혈을야기하는것으로알려져있으나 [19,20], 실제임상에서삼투압에의미있는영향을주는혈당수치는 360 mg/dl 이상이라는보고도있어 [21] 이에대해아직논란이많다. 고혈당에대한조절방법은당의공급을제한하거나, 어느정도범위까지의고혈당을허용하거나, 추가로인슐린치료를시작하는방법이사용되고있다. 극소미숙아들에서인슐린을병합하여사용하는것이효과적으로당의농도를낮추면서칼로리를보장함으로써몸무게를증진시키는것에효과적이라는보고가있으나 [22,23], 한편으로초극소미숙아들에서단백질동화작용에별효과가없었다는보고도있다 [24]. 무엇보다도최근극소저체중출생아에서시도된초기인슐린치료가고혈당증을낮추어이들의생존율을향상시킬수있는가하는국제적인무작위전향적연구가시도되었으나 [25], 오히려초기인슐린치료군에서저혈당의빈도가높고 28일 째사망률이올라가는예측치못한결과로인해조기중단되었다. 따라서극소미숙아들에서인슐린의일상적인사용은권유되지않는다 [26]. 한편고용량의정맥영양단백질을공급한경우, 저용량의단백질을공급한경우보다측정되는인슐린의양이약 2배정도로증가하기에 [9] 정맥영양에있어아미노산을충분히공급하면인슐린호르몬의분비를증가시키고따라서당의농도를낮출수있다는기대가있다. 3) 지방아직도태아의성장과발달에필요한지방의정상요구량에대한연구가충분히이루어져있지않은상태이나필수지방산이장기간공급되지않는다면신경수초형성이부적절하게이루어져신경세포의발달및시냅스형성과기능장애를초래하므로가급적출생초기공급이필요하다 [27]. 정맥영양의경우현재시판되는제품들의필수지방산의구성비율이다르나총 0.5 g/kg/day 이상을공급하는경우필수지방산필요량은충족이가능하며 [28], 출생후외부에서 4일이상지방이공급되지않는경우필수지방산의결핍이초래되기에, 이를예방하기위해서는적어도 0.5-1 g/kg/day 이상의지방이공급되어야한다 [29]. 한편정맥내지방공급은당생성을유도하는간의지방산의산화과정에관여하는보조인자들과효소들을촉진함으로써결과적으로초기의당신생에기여하여고혈당발생과연관이있다 [30]. 현재까지는지방불내성, 고혈당증, 면역기능저하, 빌리루빈대사저하, 폐기능저하등의가능성을우려하여, 초기에그리고빠른속도로지방을공급하는것을꺼려왔었으나최근에는조기지방공급이미숙아의만성폐질환위험증가와는관련없음또한보고되고있다 [31]. 조기에정맥을통한지방주입이단기간의성장촉진과예후의개선에매우효과적이라고결론을내리기는어려우나, 생후첫날부터지방을공급하는것에대한명확한금기또한없다. 따라서최근에는정맥영양에서지방은총칼로리의 25-40% 정도를구성하도록하고, 지방수액제제로 10% 보다는 20% 를사용하여 24시간에걸쳐서천천히투입하며, 첫수일내에 0.5 g/kg/day으로시작, 증량하여 3-4 g/kg/day 이상을초과하지않도록하고, 트리글리세리드혈장수치를모니터링하여 200 mg/dl 이하를유지토록권고하고있다 [1].
249 4) 기반시설과바람직한지원실제적으로신생아의정맥영양이잘수행되기위해서는미숙아에서정맥영양에의한효과및부작용을정확히알고있는의료진에의해처방되는것이중요하다. 그뿐만아니라정맥영양수액제를무균적상태에서제조하고저장할수있도록잘준비된병원과약국시설등이필요하고, 중심정맥의정확한위치를확인할수있는이동식 X-ray 장치등과정맥영양의부작용을빠르고정확히모니터할수있는혈액검사실가동등의기반시설들이필수적이다. 무엇보다도미숙아의영양및임상상태의변화에따라매일매일처방을조정할수있어야하며이를위해신생아의사를보조하는약사, 또는영양사등의영양보조팀이함께운영될수있다면신생아중환자실입원중미숙아환자개인별로좀더많은영양및단백질공급을공급하여성장증가를유도할수있는개별화된영양치료를시행하는데있어서매우이상적일수있다. 이러한노력들은궁극적으로미숙아환자들의유병과사망을줄이고병원재원일수를줄일수있기에충분한투자가고려되어야한다. Table 2. Fluid and Macronutrient Guidelines for Enterally Fed Pre mature Infants by ESPGHAN in 2010 Goal (per kg/day) Goal (per 100 kcal) Fluid, ml 135-200 not applicable Energy, kcal 110-135 not applicable Protein, g BW <1 kg 4.0-4.5 3.6-4.1 BW >1 kg 3.5-4.0 3.2-3.6 Lipids, g 4.8-6.6 4.4-6.0 Carbohydrates, g 11.6-13.2 10.5-12.0 Modified from Ref. 37 with permission from Wolters Kluwer Health 촉진하며, 장기적으로수유곤란을줄이고, 괴사성장염또한줄이는것이보고되었다 [35,36]. 초극소미숙아에서장관영양을시작하고진행하는것에대한명확한기준에대해서는아직논란이있으나장관영양영양필요량에있어총에너지뿐만아니라충분한단백질공급이미숙아성장의질적인면에서매우중요하다고강조되고있다. Table 2 는유럽에서최근에발표한미숙아장관영양에있어필요한수액과주영양소의필요요구량에대한권장기준이다 [37]. 2. 장관영양 (enteral nutrition) 태아는산모의자궁내에서양수를삼키면서장의성숙과발달이이루어진다. 태아는하루 150 cc/kg 정도의양수를삼키면서단백질공급량의 25% 를충족하는데만약이과정이이루어지지않게된다면장이위축되게된다 [32]. 24주에서 32주사이태아의장에는소화효소와위산이존재하며, lactase도비록만삭아보다적은양이나분비가능하다. 따라서조기에출생한미숙아들에게장관영양을진행하여도어느정도소화와흡수가가능하며, 장관영양이장기간이루어지지않으면위장관위축이초래된다는것이비교적잘알려져있다 [33]. 소량의장관영양이위장관에영양학적인자극을주고, 총정맥영양만으로는부족한복합적인영양분을공급하며, 정맥영양이장기화되는것을예방할수있기때문에, 적극적인초기영양공급에있어조기장관영양도입은간과할수없는중요한요소이다 [1,34]. 현재까지미숙아에서초기에장관영양시작을주저하였던가장큰이유는미숙아괴사성장염의위험이증가하는것에대한두려움에기인하였다. 그러나, 모유특히초유를공급하였을때, 조기장관영양이장의위축을예방하고, 장성숙을 1) 최소경관수유 (Minimal enteral feeding) 보편적으로미숙아들에게 5-25 cc/kg/day 정도소량의모유또는분유로위장관영양을시도하는것을 minimal enteral feeding (MEF) 이라한다. 이는위장관의기능을촉진하는면에서 priming feeding 또는장관의성장에긍정적인영향을고려하여 trophic feeding 혹은, 영양공급의 1차적인주된비중이아닌면에서 non nutritive feeding 이라고도부르기도한다 [38]. 이에대한여러동물실험에서짧은기간이라도조기장관영양을공급하였을때, 공급하지않은신생동물들과비교하여, 장점막질량이현저히증가되고, 장점막의성장발달, 운동성뿐만아니라간과췌장의대사에관여하는위장관호르몬이의미있게증가됨이관찰되었다 [36]. 또한장관영양을하루에 12 cc/ kg 정도로소량진행하여도 6일이상이되면위의호르몬농도가의미있게증가하는소견또한보고되었다 [38]. 여러임상연구들에서도조기에 MEF를시행한미숙아군에서완전장관영양도달시기가더빠르고, 몸무게가더빠르게증가하며, 수유곤란이적고광선치료의필요가줄고, 혈중 gastrin 농도가증가하고, 소장의기능과구조적성숙
250 Hanyang Medical Reviews Vol. 31, No. 4, 2011 이촉진되고, 재원기간이줄어드는결과들이보고되었다 [39,40]. 이는국내단일기관연구에서도동일한결과를보인바있다 [41,42]. 2) 모유수유분유에비하여모유수유는미숙아들에서감염과알러지의유발, 괴사성장염의발생률을의미있게낮추는것으로알려져있다 [43]. 대부분의신생아집중치료실에서는첫수유로모유를가장선호하고있으나, 모유만으로는미숙아의영양요구량을충족시켜이상적인성장을유도하기위한칼로리단백질, 나트륨과칼슘, 인등의무기질의공급은불충분하다. 이러한제한점을극복하기위하여미숙아모유수유시부족한성분들을보충하여제공할수있는모유강화제들이개발되어널리사용되고있다 [44,45]. 모유강화제는미숙아들이정상적으로성장하는데에필요한영양공급과함께전적인모유수유가가능하도록설계된특수영양식으로, 탄수화물은정제유당과덱스트린으로구성하여소화가용이하도록하고, 유청단백질대카세인의비율이모유와유사한수준으로맞추어져구성되어있다. medium chain triglyceride (MCT) 와 b-palmitate로흡수율증진을유도하고, 칼슘, 인, 나트륨, 칼륨, 망간, 구리등과지용성비타민 (Vitamin D, E, K) 을보강, 강화하도록조제되었다 [44,46]. 미숙아에서권장되는모유수유의지침으로는신선하거나, 48시간이내에유축하여냉장시킨모유또는냉동모유로출생첫날부터 MEF를시작하여환자의종합적인상태를모니터링하면서수유정도를관찰하여, 점진적으로증량하는것을원칙으로한다. 점차수유량을증량하여 100 cc/ kg/day 이상수유가능하게되면, 모유강화제를시작하고, 몸무게는 15 g/kg/day, 키는 1 cm/week 정도증가하며, 소변의칼슘배설량은 6 mg/kg/day 이하, 인은 4 mg/kg/day 이하의소변배설량을보이는것이이상적이다 [47]. 미숙아의몸무게가성장하여 1,800-2,000 g 정도될때까지혹은직접수유에도달하는시점까지모유강화제를지속하는것이권장된다. 3) 특수조제유미숙아들에게사용되는미숙아분유는주로유당의양을줄이고 glucose polymer를늘리고지방성분으로 MCT를 첨가하고단백질의양을늘리고칼슘과인, 비타민의함량을늘여서미숙아영양권장량에부합하도록제조되고있다. 또한장의흡수부전이의심되는경우에는단백의성분을콩단백또는가수분해또는완전아미노산베이스로, 탄수화물은유당을제한한특수분유들을일시적으로사용해볼수있다. 이전에는미숙아분유사용은신생아집중치료실퇴원전까지국한하고퇴원후에는만삭아분유로바꾸어주었으나, 특히극소미숙아들의경우퇴원당시만삭몸무게에이르지못하고따라잡기성장을위한영양요구량이높아퇴원후만삭아분유만으로는이들의따라잡기성장을충족시키기어려운점이부각되었다. 따라서극소저체중출생아인경우미숙아분유및모유강화제의사용필요성이지속적으로제기되고있으며, 퇴원후이들수유가만삭아분유수유보다퇴원후성장과신경학적발달에있어긍정적이라는결과들이보고되고있다 [48,49]. 따라서최근에극소저체중출생아의경우에는미숙아분유와만삭아분유사이의성분으로조성된미숙아퇴원분유 (preterm discharge formula) 를퇴원후수개월간사용하고, 모유수유를할경우모유강화제를사용하는것이권장되고있다. 결론미숙아의영양공급은자궁내태아성장과같은이상적인성장을유도하기위해서이나극소, 초극소미숙아들에있어서이를충족시키기는매우어렵다. 따라서완전한영양공급과수유지침을개발하기위해서는아직도더많은연구와개선이필요한상태이다. 신생아중환자실입원중또는퇴원후미숙아영양에대해서는적절한영양공급방법의효과와부작용에대한숙지와함께정맥영양및보조가가능한기반시설또한필수적이다. 체계화된정맥영양및장관영양공급은환자개개인에따른개별적정화가필요하고이를통해단기간의성장호전에대한효과와함께장기적으로양호한신경발달도기대할수있는지속적인노력과관심이필요하다.
251 References 1. Hay WW, Jr. Strategies for feeding the preterm infant. Neonatology 2008;94:245-54. 2. American Academy of Pediatrics Committee on Nutrition. Nutritional needs of low-birth-weight infants. Pediatrics 1985;75:976-86. 3. Denne SC, Poindexter BB. Evidence supporting early nutritional support with parenteral amino acid infusion. Semin Perinatol 2007;31:56-60. 4. Fanaroff AA, Stoll BJ, Wright LL, Carlo WA, Ehrenkranz RA, Stark AR, et al. Trends in neonatal morbidity and mortality for very low birth weight infants. Am J Obstet Gynecol 2007;196:147 e1-8. 5. Stephens BE, Walden RV, Gargus RA, Tucker R, McKinley L, Mance M, et al. First-week protein and energy intakes are associated with 18-month developmental outcomes in extremely low birth weight infants. Pediatrics 2009;123:1337-43. 6. Koletzko B, Goulet O, Hunt J, Krohn K, Shamir R. 1. Guidelines on Paediatric Parenteral Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), Supported by the European Society of Paediatric Research (ESPR). J Pediatr Gastroenterol Nutr 2005;41 Suppl 2:S1-87. 7. Rivera A, Jr., Bell EF, Bier DM. Effect of intravenous amino acids on protein metabolism of preterm infants during the first three days of life. Pediatr Res 1993;33:106-11. 8. Thureen PJ, Anderson AH, Baron KA, Melara DL, Hay WW, Jr., Fennessey PV. Protein balance in the first week of life in ventilated neonates receiving parenteral nutrition. Am J Clin Nutr 1998;68:1128-35. 9. Thureen PJ, Melara D, Fennessey PV, Hay WW, Jr. Effect of low versus high intravenous amino acid intake on very low birth weight infants in the early neonatal period. Pediatr Res 2003;53:24-32. 10. Ridout E, Melara D, Rottinghaus S, Thureen PJ. Blood urea nitrogen concentration as a marker of amino-acid intolerance in neonates with birthweight less than 1250 g. J Perinatol 2005;25:130-3. 11. Roberts SA, Ball RO, Filler RM, Moore AM, Pencharz PB. Phenylalanine and tyrosine metabolism in neonates receiving parenteral nutrition differing in pattern of amino acids. Pediatr Res 1998;44:907-14. 12. Wykes LJ, House JD, Ball RO, Pencharz PB. Aromatic amino acid metabolism of neonatal piglets receiving TPN: effect of tyrosine precursors. Am J Physiol 1994;267:E672-9. 13. Zlotkin SH, Bryan MH, Anderson GH. Cysteine supplementation to cysteine-free intravenous feeding regimens in newborn infants. Am J Clin Nutr 1981;34:914-23. 14. Parimi PS, Kalhan SC. Glutamine supplementation in the newborn infant. Semin Fetal Neonatal Med 2007;12:19-25. 15. Denne SC, Kalhan SC. Glucose carbon recycling and oxidation in human newborns. Am J Physiol 1986;251:E71-7. 16. Hertz DE, Karn CA, Liu YM, Liechty EA, Denne SC. Intravenous glucose suppresses glucose production but not proteolysis in extremely premature newborns. J Clin Invest 1993;92:1752-8. 17. Cowett RM, Farrag HM. Selected principles of perinatalneonatal glucose metabolism. Semin Neonatol 2004;9:37-47. 18. Hey E. Hyperglycaemia and the very preterm baby. Semin Fetal Neonatal Med 2005;10:377-87. 19. Stonestreet BS, Rubin L, Pollak A, Cowett RM, Oh W. Renal functions of low birth weight infants with hyperglycemia and glucosuria produced by glucose infusions. Pediatrics 1980;66:561-7. 20. Hays SP, Smith EO, Sunehag AL. Hyperglycemia is a risk factor for early death and morbidity in extremely low birthweight infants. Pediatrics 2006;118:1811-8. 21. Kairamkonda VR, Khashu M. Controversies in the management of hyperglycemia in the ELBW infant. Indian Pediatr 2008;45:29-38. 22. Binder ND, Raschko PK, Benda GI, Reynolds JW. Insulin infusion with parenteral nutrition in extremely low birth
252 Hanyang Medical Reviews Vol. 31, No. 4, 2011 weight infants with hyperglycemia. J Pediatr 1989;114:273-80. 23. Ditzenberger GR, Collins SD, Binder N. Continuous insulin intravenous infusion therapy for VLBW infants. J Perinat Neonatal Nurs 1999;13:70-82. 24. Poindexter BB, Karn CA, Denne SC. Exogenous insulin reduces proteolysis and protein synthesis in extremely low birth weight infants. J Pediatr 1998;132:948-53. 25. Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, Vanhole C, Palmer CR, van Weissenbruch M, et al. Early insulin therapy in very-low-birth-weight infants. N Engl J Med 2008;359:1873-84. 26. Sinclair JC, Bottino M, Cowett RM. Interventions for prevention of neonatal hyperglycemia in very low birth weight infants. Cochrane Database Syst Rev 2011:CD007615. 27. Carlson SE. Docosahexaenoic acid and arachidonic acid in infant development. Semin Neonatol 2001;6:437-49. 28. Carlson SE, Werkman SH, Tolley EA. Effect of long-chain n-3 fatty acid supplementation on visual acuity and growth of preterm infants with and without bronchopulmonary dysplasia. Am J Clin Nutr 1996;63:687-97. 29. Carlson SE, Werkman SH, Rhodes PG, Tolley EA. Visualacuity development in healthy preterm infants: effect of marine-oil supplementation. Am J Clin Nutr 1993;58:35-42. 30. Sunehag AL. The role of parenteral lipids in supporting gluconeogenesis in very premature infants. Pediatr Res 2003;54:480-6. 31. Simmer K, Rao SC. Early introduction of lipids to parenterally-fed preterm infants. Cochrane Database Syst Rev 2005:CD005256. 32. Newell SJ. Enteral feeding of the micropremie. Clin Perinatol 2000;27:221-34, viii. 33. Simon J N. Gastrointestinal function and its ontogeny: how should we feed the preterm infant? Semin Neonatol 1996;1:59-66. 34. Hay WW, Jr. Nutritional needs of the extremely low-birthweight infant. Semin Perinatol 1991;15:482-92. 35. Stoddart RW, Widdowson EM. Changes in the organs of pigs in response to feeding for the first 24 h after birth. III. Fluorescence histochemistry of the carbohydrates of the intestine. Biol Neonate 1976;29:18-27. 36. Heird WC, Schwarz SM, Hansen IH. Colostrum-induced enteric mucosal growth in beagle puppies. Pediatr Res 1984;18:512-5. 37. Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Dar maun D, Decsi T, et al. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr 2010;50:85-91. 38. Lucas A, Bloom SR, Aynsley-Green A. Gut hormones and minimal enteral feeding. Acta Paediatr Scand 1986;75:719-23. 39. Tyson JE, Kennedy KA. Minimal enteral nutrition for promoting feeding tolerance and preventing morbidity in parenterally fed infants. Cochrane Database Syst Rev 2000:CD000504. 40. Tyson JE, Kennedy KA. Trophic feedings for parenterally fed infants. Cochrane Database Syst Rev 2005: CD000504. 41. Jeon GW, Park SE, Choi CW, Hwang JH, Chang YS, Park WS. The effects of early eteral feeding in extremely low birth-weight infants. Korean J Pediatr 2005;48:711-5. 42. Lee HY, Lee GY, Kim MJ, Jeon GW, Shim JW, Chang YS, et al. The effect of early enteral trophic feeding within 24 hours after birth in extremely low birth weight infants of 26 weeks and less, and birth weight below 1,000 g. J Korean Soc Neonatol 2007;14:59-65. 43. Kosloske AM. Breast milk decreases the risk of neonatal necrotizing enterocolitis. Adv Nutr Res 2001;10:123-37. 44. Schanler RJ. Human milk fortification for premature infants. Am J Clin Nutr 1996;64:249-50. 45. Lucas A, Fewtrell MS, Morley R, Lucas PJ, Baker BA, Lister G, et al. Randomized outcome trial of human milk fortification and developmental outcome in preterm infants. Am J Clin Nutr 1996;64:142-51. 46. Corvaglia L, Aceti A, Paoletti V, Mariani E, Patrono D, Ancora G, et al. Standard fortification of preterm human milk fails to meet recommended protein intake: bedside
253 evaluation by Near-Infrared-Reflectance-Analysis. Early Hum Dev 2010;86:237-40. 47. Lawrence RA. Breastfeeding in the premature infant. J Arab Neonatal Forum 2005;2:43-9. 48. Carver JD, Wu PY, Hall RT, Ziegler EE, Sosa R, Jacobs J, et al. Growth of preterm infants fed nutrient-enriched or term formula after hospital discharge. Pediatrics 2001;107:683-9. 49. Jeon GW, Jung YJ, Koh SY, Lee YK, Kim KA, Shin SM, et al. Preterm infants fed nutrient-enriched formula until 6 months show improved growth and development. Pediatr Int 2011;53:683-8.