134 Byong Sop Lee Glucose Homeostasis in Premature Infants vate) 으로변환되어아세틸조효소 A가된다. 지질인 triglyceride 는글리세롤 (glycerol) 과지방산 (fatty acid) 으로분해되는데글리세롤은인산

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1 Review Article Neonatal Med 2015 August;22(3): pissn eissn Glucose Homeostasis Disorders in Premature Infants Byong Sop Lee, M.D., Ph.D. Division of Neonatology, Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea ABSTRACT An abnormal plasma glucose concentration is one of the most commonly encountered metabolic problems in the intensive care of premature infants. Compared with term infants, glycogen reserves are lower in the preterm neonatal liver. Despite this, preterm infants are at a greater risk of hyperglycemia than term infants are, which is owing to comparable production rate of endogenous glucose and impaired ability to reduce glucose production rate in response to hyperglycemia. Debate continues about the normal plasma glucose concentrations and the guideline for glucose control in pre mature infants. Some randomized controlled trials in very low birth weight infants demonstrated little clinical benefit of tight glycemic control with early insulin therapy and higher calorie intake in terms of mortality, morbidities and growth parameters. Compared with term infants, preterm infants have limited endocrine and metabolic adaptation to hypoglycemia. In any case, hypoglycemia in premature infants should not be considered a physiologic condition. The operational criteria for intervention of hypoglycemia should be different from that in term infants. Continuous non-invasive glucose monitoring is a promising tool considering the principle of minimal handling of extremely premature infants. However, the clinical implication of abnor mal glucose concentrations, previously undetected on intermittent measurements, is unclear. Received: 27 May 2015 Revised: 23 July 2015 Accepted: 28 July 2015 Correspondence to: Byong Sop Lee, M.D., Ph.D. Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic- Ro 43-Gil, Songpa-Gu, Seoul 05505, Korea Tel: Fax: mdleebs@amc.seoul.kr Key Words: Glucose, Hyperglycemia, Hypoglycemia, Insulin, Premature infant 서론 인체가생명을유지하려면 adenosine triphosphate (ATP) 같은에너지저장물질을분해해야한다. 포도당은해당 (glycolysis) 이라는혐기성대사 (anaerobic metabolism) 를통해 2개의 ATP 를생성하고, TCA 회로 (tricarboxylic acid cycle) 과전자전달계 (electron transfer system) 를거치는호기성대사 (aerobic metabolism) 를통해 36 개의 ATP 를생성한다. TCA 회로는세포호흡의중간과정중하나로대사생성물을산화시켜 ATP 에에너지를일부저장하고나머지를 nicotinamide adenine dinucleotide (NAD), flavin adenine dinucleotide (FAD) 등의중간체형태로전자전달계에넘겨주는과정이다. 포도당, 지방, 아미노산대사는 TCA 회로에서통합되며각대사물질은 TCA 회로시작의공통재료인아세틸조효소 A (acetyl-coa) 로변환될수있다 (Figure 1). 즉, 포도당은해당과정을거쳐피루브산 (pyru- Copyright(c) By Korean Society of Neonatology. All right reserved. This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( by-nc/3.0), which permits unrestricted non-commercial use, distribution, and repro duction in any medium, provided the original work is properly cited.

2 134 Byong Sop Lee Glucose Homeostasis in Premature Infants vate) 으로변환되어아세틸조효소 A가된다. 지질인 triglyceride 는글리세롤 (glycerol) 과지방산 (fatty acid) 으로분해되는데글리세롤은인산화과정을거쳐포도당신생합성 (gluconeogenesis) 과정으로넘어가고, 지방산은베타산화 (β-oxidation) 를거쳐아세틸조효소 A 가된다. 아미노산은알라닌 (alanine) 으로대표되는포도당생성 (glucogenic) 아미노산과케톤생성 (ketogenic) 아미노산으로분류되며각각피루브산과아세틸조효소 A가되어 TCA 회로로간다. 포도당등주요영양소대사는각단계효소와효소활성을조절하는내분비호르몬상호간균형에의해조절된다. 안정상태에있는동물은장에서흡수된당분을바로사용하거나간에저장된글리코겐을분해하여 (glycogenolysis) 공급한포도당을대사하여에너지를생산한다. 그러나영양공급이중단되면상황은바뀐다. 간과근육에서는글리코겐분해가더가속화되며추가적인포도당신생합성을위해지방조직에서는글리세롤을, 근육에서는아미노산까지동원한다. 포도당마저부족하면대체에너지원인젖산 (lactate) 이나케톤 (ketone) 을대사하여에너지를생산한다. 혈당은포도당공급및소모량과이를조절하는관련호르몬들, 즉인슐린과길항호르몬인글루카곤, 코르티솔, 성장호르몬, 카테콜아민의상호작용으로결정된다 (Table 1). 인슐린은말초조직의포도당소모를촉진하며간과근육의글리코겐분해를억제한다. 또한포도당신생합성을억제하고간과지방조직에지방저장을촉진한다. 여러길항호르몬의역할은결과적으로혈당을상승시키는것이다. 신생아중환자실에입원하는미숙아는거의대부분인위적인포도당수액공급이필요하다. 미숙아는임신후반기이후태아와같은포도당대사관련효소및호르몬조절기능을가진다. 또한패혈증, 괴사성장염같은질병이나스테로이드등일부치료약물도포도당대사에영향을미친다. 따라서집중치료중인미숙아는저혈당과고혈당이흔히발생한다. 미숙아생후초기의혈중포도당농도이상은뇌의에너지불균형에영향을미칠수있으며혈당과연관된합병증의잠재적위험과연관되어있다. 이번종설은태아와신생아의포도당대사생리를요약하고미숙아에서발생하는저혈당과고혈당의병태생리를중심으로지금까지진행된연구들을간단히정리할것이다. 선천성고인슐린혈증 (hyperinsulinism) 등유전적질환에의한혈당이상질환에대한치료지침은다른저술을참조하기바란다. 태아는포도당공급을모체에의존한다. 태아혈액의포도당은태반을통한중개수용체매개성확산 (fa cilitated, carrier-mediated diffusion) 기전으로모체로부터전달된것이다 1). 임신 3분기부터만삭시기까지제대혈혈당농도는모체혈당농도와직선관계로비례한다 2). 단, 포도당중일부가태반에서대사되므로태아혈당은모체혈당보다 20-30% 정도낮다. 그렇다면태아는포도당을생산할수있을까? 안정된혈당에서사람과양의태아포도당이용률은산모에서제대혈을통해전달되는포도당공급량과거의일치한다 1,2). Hay 등이수행한연구에서암양 (ewe) 을이용한동위원소실험에서포도당수액공급을유지하여정상혈당을유지한임신한양에서는제대혈포도당전달속도 (umbilical glucose uptake rate) 와태아포도당이용속도 (fetal glucose utili zation rate) 가비슷하지만산모를저혈당상태에빠지게한경우제대혈포도당전달속도를초과하는태아포도당이용속도가관찰되었다 3). 이는산모의저혈당시태아가스스로포도당신생합성이가능하다는의미였다. 이런결과는건강한만삭아와자궁내성장지연태아에서도같았다 4,5). 태아는임신초기부터포도당신생합성의주요효소인 pyruvate carboxylase (PC), phosphoenol pyruvate carboxykinase (PEPCK) 와 fructose diphosphatase 가잘발현되어있다 (Figure 1). 다만, 혈당이안정되어있는태아기에는효소들이활성화되지않을뿐이다 6). 포도당신생합성에관여하는주요효소와호르몬은출생전후본격적으로활성화된다. 정리하면건강한산모에서태어난만삭아는출생후에야스스로포도당을생산한다고볼수있다. 이는미숙아도마찬가지이다. 인슐린은임신 13 주부터태아혈액에서발견되지만글리코겐은임신 27 주이후에야태아간에저장된다. 인슐린이글리코겐합성을촉진하려면뇌하수체 -시상하부 -부신축의협조가필요한데충분한스테로이드호르몬은임신 27 주이후에야분비되기때문이다 7). 태아간의글리코겐저장량은임신 36 주부터급격히상승 Table 1. Hormones Associated with Glucose Metabolism and Their Action Hormones Glucose utilization Glycogenolysis Gluconeogenesis Proteolysis Lipolysis Hepatic Ketogenesis Insulin Stimulate Inhibit Inhibit Inhibit Inhibit Inhibit Glucagon Stimulate Stimulate Epinephrine Inhibit Stimulate Stimulate Stimulate Stimulate Norepinephrine Inhibit Stimulate Cortisol Stimulate Stimulate

3 Neonatal Med 2015 August;22(3): Glucose Glycogen glycogenolysis G6P F6P 3 F1,6BP gluconeogenesis Glyrecol-3P Glycerol Lipid (triglyceride) Fatty acid PEP gluconeogenesis Lactate Pyruvate Alanine Amino acid 2 1 Oxaloacetate Acetyl-CoA electron transport system TCA cycle Ketone bodies 1 pyruvate carboxylase 2 phosphoenolpyruvate carboxykinase 3 fructose diphosphatase Figure 1. Overview of glucose metabolism. Acetyl-CoA is a key metabolic junction, derived from not only glycolysis but also fatty acid oxidation. The key gluconeogenesis enzymes, pyruvate carboxylase (PC), phosphoenolpyruvate carboxykinase (PEPCK), fructose 1,6 bisphosphatase, and glucose-6-phosphatase, are present from early fetal life but are activated only after birth. Under glucose depletion condition, glycerol and glucogenic amino acids such as alanine are supplied by adipose tissue and skeletal muscle, respectively, and are converted to glucose via gluconeogenesis. The production of other substrates such as lactate and ketone bodies are facilitated when glucose is not sufficient for total oxygen uptake in newborn infants. Abbreviations: G6P, glucose 6-phosphate; F6P, fructose 6-phosphate; F1,6BP, fructose 1,6 bisphosphate; PEP, phosphoenolpyruvate; Glycerol-3P, glycerol 3-phospate; TCA, tricyclic acid. 했다가생후 2-3 시간후에는금세고갈되고생후 24 시간이후로는낮다 8). 미숙아는태내에서간에글리코겐을저장할충분한시간이없으므로, 출생후글리코겐분해를통한혈당공급측면에서는만삭아에비해불리하다. 초극소저체중출생아는생후수분만지나도글리코겐분해를통한포도당공급은종료된다. 만삭아와미숙아의포도당생성능력은비슷하다. 포도당대사관점에서출생이란모체로부터의지속적이고안정된포도당공급이갑자기중단되는상황이다. 출생직후, 신생아에서혈중인슐린농도는낮고길항호르몬들농도는높다. 신생아혈당은출생 1시간째가장낮지만수유를전혀하지않아도생후 2-4 시간에는저절로상승하여안정된다 9). 간에서글리코겐분해로포도당을공급하고근육과지방세포에서각각아미노산과글리세롤을동원해서포도당신생합성을시작하기때문이다 10). 신생아의포도당생성속도 (glucose production rate) 는 4-6 mg/kg/min 정도로성인의 2.4 mg/kg/min 속도의약 2-3 배이다 11-13). 그렇다면미숙아는어떨까? 재태주령 28 주미만미숙아에서생후첫날포도당생성속도를측정했더니 6.1 mg/kg/min 으로만삭아와비슷했다 14,15). 이는초극소저체중출생아의포도당생성능력은결코미숙하지않다는의미이다. 신생아포도당생성속도가성인보다빠른이유는뇌가몸에서차지하는비율이상대적으로더크기때문이다. 출생초기신생아뇌에서포도당을소모하는속도는 3.7 mg/kg/min 으로계산되는데이는뇌에서소모하는전체열량의약 70% 정도이다 16). 생후초기에금식중인만삭아에서는글리코겐분해와포도당신생합성이대략절반씩포도당생산에기여한다. 이들에서포도당신생합성에들어가는재료의비율은글리세롤 11-20%, 젖산 18%, 피루브산 31%, alanine 9% 로보고되었다 17,18). 그런데정맥영양을받고있는미숙아에서는어떤비율의영양을받고있느냐에따라각재료가포도당신생합성에기여하는비율이다르다. 평

4 136 Byong Sop Lee Glucose Homeostasis in Premature Infants 균재태주령 27 주의초극소저체중출생아에게포도당수액을 3.1 mg/kg/min 속도로주면서동시에아미노산 (3.2 g/kg/d) 과지방 유액 (2.3 g/kg/d) 을함께투여했더니글리세롤이포도당신생합성 에기여하는부분이 64% 로높아졌다 19). 또한지방유액의조성은 포도당대사역학에도영향을미칠수있다. van Kempen 등의연 구에서 60% monounsaturated fatty acid 인 intralipid R 가 60% polyunsaturated fatty acid 인 clinoleic R 이나 glycerol 보다더포 도당신생합성을증가시켰다 20). 미숙아는만삭아보다고혈당위험이크다. 성인에서포도당생성속도는혈당농도에반비례하며포도당을 일정량이상공급하면포도당신생합성은중단된다. 성인의생리적 포도당생성속도를초과하는 3.2 mg/kg/min 속도로포도당을공 급할때성인은포도당생성이완전히억제되는반면, 신생아는 5.6 mg/kg/min 속도에서도포도당신생합성이계속된다. 미숙아 는만삭아와같은포도당공급속도에서포도당생성이억제되는 환자의비율이더적다 21). 인슐린투여에대한포도당생성반응도 신생아와성인이다르다. 성인은인슐린을 2.0 mu/kg/min 의속도 로주입시포도당생성이억제되는반면, 신생아는인슐린투여속 도를 0.2 mu/kg/min 에서단계적으로 4.0 mu/kg/min 까지증량 해도포도당생성은 3 mg/kg/min 미만으로는떨어지지않는다 22). 초미숙아는혈당상승시분비되는인슐린전구물질인 proinsulin 과 C-peptide 의혈중농도가만삭아보다높다. 그러나 pro-insulin 이활성인슐린으로변환되는과정에부분적결함이 있다 23). 최근영장류연구는근육의인슐린자극성 Akt 인산화등 인슐린신호전달체계의결함으로인해미숙아말초조직인슐린 저항성이만삭아에비해높을가능성을시사한다 24). 미숙아는만 삭아에비해고혈당에서글루카곤분비억제가잘되지않는다. 포도당 1 g/kg 를주입하면생후 24 시간이후의만삭아는글루카 곤분비량이 61% 감소하는반면미숙아는 38% 만감소한다 25). 임상적문제를일으키는신생아고혈당의상한선은불분명하다. 고혈당의정의, 측정시기및간격에따라다양하겠지만고혈당 은초극소저체중출생아의약 60-80% 에서관찰될만큼흔하다 26). 아쉽게도신생아고혈당에서는성인당뇨기준과같은국제적으 로합의된정의가없고따라서치료기준도신생아의사들마다다 르다. Avery 교과서는소아기준인 126 mg/dl 이상을, Fanaroff 교과서는 mg/dl 이상을고혈당으로정의한다 27,28). 대사 생리의대가인 Hey 는최대산화능 (maximum oxidation capacity) 에해당하는 12 mmol/l (216 mg/dl) 을신생아고혈당의기준으로제시한다 29). 더높은기준을제시하는연구자도있다. Kairamkonda와 Khashu 는혈당농도가 12 mmol/l 이초과하더라도포도당주입속도가 9 mg/kg/min 미만이고요당이 3+ 미만이라면심지어혈당이 19 mmol/l (340 mg/dl) 라도특별한치료를하지않는소위허용적고혈당증도고려할수있다고제안한다 30). 이런치료방침은미숙아에서고혈당이가진임상적위험은분명하지않은반면, 높은비단백열량공급으로인한성장및발달에대한이점이더클것이라는견해가반영된것으로생각된다. 고혈당이어느농도이상으로얼마동안지속되면미숙아사망률이나기타합병증과신경학적장애가증가하는지는잘연구되지않았다. 다만, 고혈당은성인급성허혈성뇌손상의임상경과를악화시키며 31), 고혈당과고인슐린혈증이성인당뇨환자에서발생하는치매의위험인자라는의견도있다 32). 잘조절되지않는고혈당은당뇨병성망막증의확실한위험요인이고그발생기전의시작은망막혈류와혈중 vascular endothelial growth factor 등의성장인자증가로요약된다 33). 그런데이것은바로미숙아망막증병태생리와같다 34). 물론성인당뇨에비해서현저히짧은기간동안지속되는고혈당이미숙아망막증의위험을증가시키는지는아직불분명하다. 비록최근시행된메타분석에서고혈당지속기간과미숙아망막증사이에통계적경계정도의유의성이있었지만고혈당정도와미숙아망막증의연관성은재태주령, 체중등의변수를보정한경우분명하지않았다 35). 이상의연구들을종합할때, 적어도망막증위험이상대적으로높은미숙아 ( 예, 생존한계재태주령, 높은산소요구량등 ) 는심한고혈당에노출되지않도록주의깊게혈당을모니터링할필요가있다. 요당은초미숙아혈당을잘예측하지못한다. 심한고혈당은혈장삼투압을상승시키고이는뇌부종발생위험을증가시킨다. 심한당뇨로삼투성이뇨 (osmotic diuresis) 까지생기면전해질불균형도따라온다. 원칙적으로요당은신장의포도당재흡수한계를초과하는고혈당이있을때검출되며혈당정도와요당정도는비례한다. 그렇다면미숙아에서시행한소변스틱검사에서요당이검출되면혈당이어느정도되는것일까? 요당정도는혈당농도뿐아니라사구체여과율, 포도당배설분율 (fractional excretion of glucose) 및소변량을변수로결정된다. 생후초기미숙아는만삭아보다사구체여과율이상대적으로낮다. 초미숙아의포도당배설분율은일정하지않은데대략 2-10% 범위이며인공환기치료등환자의임상상태가불안할수록증가한다 36,37). 예를들어혈당이 12 mmol/l (216 mg/dl) 로같아도포

5 Neonatal Med 2015 August;22(3): 도당배설분율에따라요당은 trace 에서 3+ 이상까지측정될수 있다 (Table 2). 반대로, 초미숙아는정상혈당에서도신성당뇨 (renal glycosuria) 가발생할수있다. 다행하게도초미숙아라도 소변의농축능은비교적유지되어 mosm/kg 정도의용 질부하는감당할수있다. 따라서 20 mmol/l (360 mg/dl) 정도 까지높은혈당이라도요당이높아서삼투성이뇨를유발할가능 성은거의없다 36). 정리하자면환자의재태주령이어릴수록, 임상 적으로불안정할수록요당측정값만으로는혈당을짐작하기어려 운경우가많으므로정기적인혈당측정이필요하다. 혈당조절이미숙아사망률과합병증을낮출수있는지는불분명하다. 당뇨환자가사망률과합병증을감소시키려면엄격한혈당조절 을해야한다. 그렇다면중환자도마찬가지일까? van den Berghe 등은대규모전향적연구에서성인외과계중환자를엄격히혈당 조절을했더니대조군에비해사망률과합병증을낮출수있었다 38). 그러나이후진행된다른연구결과는실망스러웠다. NICE- SUGAR 연구를비롯한성인과소아연구에서엄격히혈당을조절 한치료군환자들이더높은혈당을허용하는대조군에비해사망 률이나합병증에차이가없었고저혈당빈도만더높았다 39-42). 생후초기부터인슐린을고농도포도당과병행하면더많은비 단백칼로리를공급할수있다. 또한태아성장관련호르몬으로서 의인슐린의성장촉진효과도기대할수있다. 생후초기부터인 슐린을병합투여하는것이미숙아에게유익할까? 1990 년대초극 소저체중출생아를대상으로시행된연구들에서는첫 2 주간고용 량포도당과인슐린을병합투여한군이포도당속도만조절한군 보다는비단백열량을더많이줄수있었고체중증가속도가더 빨랐다 43,44). 조기인슐린투여가미숙아사망률과합병증감소에 효과적인지에대한관심으로유럽에서시행된 Neonatal Insulin Replacement Therapy in Europe (NIRTURE) trial 은극소저체 중출생아에서조기인슐린투여와고농도포도당투여를병행한 엄격한혈당관리가예후에미치는영향을확인한가장잘된대 규모전향적연구이다 45). 아기들은생후첫주동안 20% 포도당과인슐린지속주입을받으면서혈당을 mg/dl 범위로조절하는조기인슐린군과혈당이 180 mg/dl 이상일때만인슐린을투여받는대조군으로구분되었다. 기존방법보다엄격한혈당관리를위해지속적혈당모니터링방법을도입하였다. 결과는조기인슐린투여군이대조군에비해더많은열량공급과엄격한혈당조절이가능했다. 하지만일차결과변수인교정만삭연령시사망률은차이가없었고오히려조기인슐린투여군이생후 28 일사망률이더높았다. 이연구는중간분석결과조기인슐린군이뇌실내출혈과뇌실질의병변이더많이발견되고사망률이더높은경향이있어종료되었다. 뉴질랜드에서진행했던비슷한연구에서도인슐린을사용한엄격한혈당조절의치료방침이사망률이나합병증을감소시키지못했고저혈당빈도만유의하게증가시켰다 46). 또한인슐린투여군이비록통계적으로는교정연령 36 주의두위가더크고체중이더많이나갔지만임상적으로는큰의미가없는차이였고신장은오히려작았다. 연구들을종합할때, 극소저체중출생아에서생후초기에고용량포도당과인슐린을병행하는치료방침은영양적측면에서유리할것이라는가설에도불구하고저혈당의위험이높아질우려가있으므로추천하기어렵다. 또한사망률이나합병증을감소시킬수있다는증거도부족하다. 미숙아저혈당치료기준은만삭아와다를수있다. 만삭으로태어난신생아에서출생직후측정되는저혈당은정상적이고일시적인생리적적응과정이다. 만삭아의약 10% 에서출생첫 3시간이내혈당이 35 mg/dl 미만으로측정되며이런신생아들이대사적, 신경학적으로향후문제가된다는증거는없다 45). 따라서미국소아과학회는증상이없는만삭아는혈당선별검사를하지말고후기조산아, 부당경량아, 당뇨병산모아기등위험군만선별혈당검사를받도록권장한다 46) (Figure 2). 반면, 초미숙아는대부분포도당수액치료가필요하므로생후초기 생리적 저혈당을정의하기어렵다. 또한재태주령, 출생후측정시점, 혈당측정빈도등여러요인에따라저혈당빈도와위험도가 Table 2. Serum Glucose, Fractional Excretion of Glucose, and Urine Glucose in Preterm Infants Weighing 1.0 kg of Weight with a Glomerular Filtration Rate of 1.5 ml/kg/min and Urine Output of 3 ml/kg/h; a Hypothetical Situation Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Serum glucose (mmol/l) Fractional excretion of glucose (%) 2% 5% 10% 2% 5% 10% Urine glucose (mmol/d) Urine glucose (mmol/l) Urine glucostix Trace Trace/

6 138 Byong Sop Lee Glucose Homeostasis in Premature Infants Birth to 4 h of age Initial feed < 1h Screen glucose 30 min after 1 st feed Initial screen < 25 mg/dl Feed and check in 1h 다를수밖에없다. 극소저체중출생아에서저혈당빈도를지속적 혈당모니터링으로측정한 NIRTURE 연구에서첫 2 주동안 40 mg/dl 미만이측정된환자의빈도는통상적인포도당생성속도로 치료한대조군에서약 12% 였다 45). 증상이있는신생아저혈당이뇌에미치는영향은뇌파상급성 뇌기능저하와자기공명영상의다양한뇌병변으로확인된다 49,50). 그러나신생아저혈당이장기적신경발달에미치는영향은저혈당 발생과연관된여러위험인자들이교란변수로작용하고저혈당의 지속시간에대한정보가부족한이유로인해정확한인과관계규 명이어렵다. Boluyt 등은체계적문헌고찰에서방법적으로적합 한연구는단두개밖에찾지못했다고하였다 51). 이들이언급한 연구중하나인 Lucas 등의연구에서는미숙아 661 명에서첫 2 개 월간 5 일이상 2.6 mmol/l (47 mg/dl) 미만저혈당이기록된환 자들이저혈당이없는환자들에비해 18 개월의베일리발달지수 가감소하고뇌성마비와발달지연위험도가 3.5 배나증가한다고 하였다 52). 이 47 mg/dl 이라는수치는 Fanaroff 교과서 (45 mg/ dl) 와 Avery 교과서 (50 mg/dl) 에서제시된저혈당기준과대체 로부합한다 25,26). 4 to 24 h of age Continue feeds q 2-3h Screen glucose prior to each feed Screen < 35 mg/dl Feed and check in 1h <25 mg/dl mg/dl <35 mg/dl mg/dl IV glucose Refeed/IV glucose as needed IV glucose Refeed/IV glucose as needed Figure 2. AAP guidelines for screening and management of postnatal asymptomatic hypoglycemia in late preterm infants, term infants, small for gestational age infants, and infants who were born to mothers with diabetes/large for gestational age infants. For symptomatic infants with a serum glucose level < 40 mg/dl, intravenous glucose administration is recommended. Modified from Adamkin DH. Pediatrics 2011;127:575-9[48]. 미숙아는저혈당에대한보상능력이만삭아에비해취약하다. 저혈당에대한보상기전은혈당상승이나에너지대사에만국 한된것은아니다. 일부동물실험과신생아연구에서저혈당시뇌 혈류증가와혈중카테콜아민상승이관찰되었다 53,54). 다만재태주령 31 주미만미숙아는 <30 mg/dl 의저혈당에서도혈중에피네프린농도의상승이없는경우가많았다 54). 정상신생아는혈당이낮더라도대체재료인케톤이나젖산을동원할수있다. 특히케톤공급은모유수유를하는신생아가분유수유아에비해유리하다 55-57) 미숙아도포도당이부족할때다른대체재료로에너지를보충할수있을까? Hawdon 등은생후첫주간신생아에서혈당변화와함께케톤, 해당경로와관련된여러대사물질의농도변화를살펴보았다 56). 미숙아는만삭아에서생후 2-3 일째나타나는혈중케톤상승이분명하지않았다. 또한저혈당에반비례하는혈중케톤농도상승이잘관찰되지않았다. 다만연구에포함된미숙아는총정맥영양이아니라수유만하거나포도당공급만받고있었으므로결과해석에주의가필요하다. 이상의연구들은미숙아가만삭아에비해저혈당시대사적보상기전이취약하고따라서뇌손상의위험이더높을가능성을시사한다. 따라서향후미숙아저혈당과신경학적예후의연관성에대한신뢰할만한연구결과가나오기전까지미숙아의저혈당기준은생후초기의만삭아기준에비하여약간높게잡는것이안전해보인다. 물론그기준은간편하여통상적으로널리사용되는전혈에대한포도당산화효소 (glucose oxidase) 법으로측정한값이아닌혈장포도당농도이다. 미숙아저혈당은신속한교정이필요하다. 미숙아에서포도당스트립검사에서저혈당이발견되면먼저혈장포도당농도를측정해야한다. 패혈증, 뇌출혈, 괴사성장염등이합병된상황은아닌지진찰과검사를통해밝혀야한다. 특히저혈당위험이높은부당경량아는약 50% 까지도일시적이나마고인슐린혈증이동반된다 58). 저혈당이고인슐린혈증에의한것이라면케톤과자유지방산생성도억제되므로미숙아는뇌대사측면에서더위험한상황에노출된다. 극소저체중출생아는저혈당이확인되면바로포도당수액치료를시작해야한다. 먼저적어도생리적포도당생성속도 (6-8 mg/ kg/min) 에해당하는속도로공급되고있는지확인한다. 이속도에서도저혈당이지속되면 1-2 mg/kg/min 씩일정시간간격으로증량해서혈당을정상범위까지올려야한다. 저혈당증상이있다고판단되거나빠른혈당회복이필요하다면일회투여 (200 mg/kg, 2 ml/kg of 10% 포도당용액 ) 를약 1분에걸쳐할수있다. 일회투여후반드시포도당주입속도를올려야안정된범위에서혈당을유지시키고반동성저혈압 (rebound hypoglycemia) 을예방할수있다. 간혹정맥주입로확보를하지못해제대

7 Neonatal Med 2015 August;22(3): 동맥도관으로줄수밖에없다면주의해야한다. 복강동맥 (celiac axis) 근처로포도당이주입되면췌장으로포도당이흘러들어가 오히려인슐린분비를증가시킬수있기때문이다. 신생아에서지 속적으로높은속도 (>12-15 mg/kg/min) 의포도당주입이필요 하다면고인슐린혈증감별을위한검사와 diazoxide 등인슐린억 제치료를해야한다. 향후지속적혈당모니터링이신생아에서도보편화될것이다. 성인당뇨환자에서사용이증가하고있는지속적간질포도당 모니터링측정기 (continuous interstitial glucose monitoring sensor) 가극소저체중출생아를포함한신생아에서도혈당을정 확하게반영할수있다는것이확인되었다 45,59). 이기기는간헐적 인측정시놓칠수있는혈당이상을발견하고그중증도와지속 기간을더정확히파악할수있는장점이있다. 다만상대적으로 생후첫날, 특히첫 2 시간이내는이후측정치에비하여비교적오 차가큰편이다 59). 임상도입시예상되는가장큰문제는자주측 정되는비정상측정치에대한중재여부이다. 저혈당위험이있는 재태주령 32 주이상의신생아에서지속적혈당모니터링을했더 니간헐적혈당측정방법에비해저혈당 (<2.6 mmol/l, <47 mg/ dl) 이있는아기가약 1.5 배더많았고완전수유를하는건강한 아기들에서도 30 분이상지속되는저혈당이 10% 에서나타났다 59). 또한초미숙아로태어나퇴원을앞두고있는건강한초미숙아 에서도 45 mg/dl 이하저혈당이 10%, 140 mg/dl 이상의고혈당 이 23% 나발견되었다 60). 지속적혈당모니터링검사에서더자주 발견되는비정상혈당치가어느기간이상지속되면치료가필요 한지, 또한이런치료가향후신경학적예후를더호전시킬수있 는지에대하여는추가연구가필요하다. 결론 미숙아는만삭아보다혈당이상의위험이높고이에대한대사 적대처능력이불완전하다. 신경학적예후와관련된신생아의정 상혈당범위에대한정보가부족한상황에서엄격한혈당조절로 미숙아사망률과합병증을감소시킬수있는지불분명하다. 태내 의포도당대사와정맥투여라는신생아집중치료의환경을고려 할때미숙아저혈당은생후어느시기라도생리적상황으로해석 되어서는안되고적극적으로교정하여야한다. 최소침습치료라 는초미숙아진료의원칙에따라서지속적혈당모니터링의사용 이보편화될것이며이는최적혈당범위를결정하기위한대규모 연구에도유용할것이다. REFERENCES 1) Hauguel S, Desmaizieres V, Challier JC. Glucose uptake, utilization, and transfer by the human placenta as functions of maternal glucose concentration. Pediatr Res 1986;20: ) Ashmead GG, Kalhan SC, Lazebnik N, Nuamah IF. Maternalfetal substrate relationships in the third trimester in human pregnancy. Gynecol Obstet Invest 1993;35: ) Hay WW, Jr., Sparks JW, Quissell BJ, Battaglia FC, Meschia G. Simultaneous measurements of umbilical uptake, fetal utilization rate, and fetal turnover rate of glucose. Am J Physiol 1981;240:E ) Kalhan SC, D'Angelo LJ, Savin SM, Adam PaJ. Glucose production in pregnant women at term gestation. J Clin Invest 1979; 63: ) Marconi AM, Cetin I, Davoli E, Baggiani AM, Fanelli R, Fennessey PV, et al. An evaluation of fetal glucogenesis in intrauterine growth-retarded pregnancies. Metabolism 1993; 42: ) Girard J. Gluconeogenesis in late fetal and early neonatal life. Biol Neonate 1986;50: ) Mena P, Llanos A, Uauy R. Insulin homeostasis in the extremely low birth weight infant Semin Perinatol 2001;6: ) Shelley HJ, Neligan GA. Neonatal hypoglycaemia. Br Med Bull 1966;22: ) Heck LJ, Erenberg A. Serum glucose levels in term neonates during the first 48 hours of life. J Pediatr 1987;110: ) Mitanchez D. Glucose regulation in preterm newborn infants. Horm Res 2007;68: ) Denne SC, Kalhan SC. Glucose carbon recycling and oxidation in human newborns. Am J Physiol 1986;251:E ) Kalhan SC, Savin SM, Adam PA. Measurement of glucose turnover in the human newborn with glucose-1-13c. J Clin Endocrinol Metab 1976;43: ) Reinauer H, Gries FA, Hubinger A, Knode O, Severing K, Susanto F. Determination of glucose turnover and glucose oxidation rates in man with stable isotope tracers. J Clin Chem Clin Biochem 1990;28: ) Sunehag A, Ewald U, Larsson A, Gustafsson J. Glucose production rate in extremely immature neonates (<28 weeks) studied by use of deuterated glucose. Pediatr Res 1993;33: ) Thureen PJ. Early aggressive nutrition in the neonate. Neoreviews 1999;20:e ) Settergren G, Lindblad BS, Persson B. Cerebral blood flow and

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