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1 SMN SURGICAL METABOLISM AND NUTRITION Vol. 9, No. 1, June, 2018 pissn , eissn REVIEW ARTICLE 정맥글루타민보충의적정성여부 신동우 한림대학교의과대학동탄성심병원외과 Parenteral Glutamine Supplementation, Is It Optimal or Not? Dong Woo Shin, M.D. Department of Surgery, Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong, Korea Glutamine is a conditionally essential amino acid in the body because it falls into a shortage of supply during the catabolic state. Glutamine plays a key role in the gut function, immune system, and other essential processes in the body. A number of small randomized controlled trials have demonstrated positive clinical outcomes of a glutamine treatment, such as the ICU length of stay, and hospital mortality with glutamine supplementation. On the other hand, recent reports of large scale randomized controlled trials assessing the efficacy of glutamine supplementation demonstrated some negative effects and the main conclusions were a trend toward an increased 28-day mortality and significantly increased hospital stay and 6-month mortality in those who received glutamine. With such results, many academic societies have recommended that IV and enteral glutamine should not be used in a critical care setting based on the moderate quality of evidence available. The indiscriminate use of glutamine supplementation in critically ill patients with any type of organ failure can have deleterious effects. Nevertheless, more sophisticated and well-controlled larger studies will be needed to confirm how these moderate quality results are corrected and suggest the optimal usage of glutamine. More recent clinical trials have focused on specific populations and demonstrated benefits in burn and elective surgery patients with glutamine supplementation. The poor correlation between the plasma glutamine concentration and tissue concentration evoke scattered knowledge about glutamine treatments. A better understanding of the glutamine metabolism and proper guidelines for supplementation are expected. (Surg Metab Nutr 2018;9:5-10) Key Words: Glutamine, Supplementation, Immunity, Metabolism 서론 글루타민은인체내가장풍부하게존재하는아미노산의한종류이다.[1] 글루타민은정상성인의경우체내약 80 g 이상존재하며대부분근육에서만들어져혈중농도가유지되고대사 (metabolism) 에사용되지만패혈증과같은중증질환이나대수술후에발생하는이화성대사상황 (catabolic metabolism) 에서는생산되는양보다대사로소모되는양이더많아져서조건부필수아미노산 (conditionally essential amino acid) 으로알려져있다.[2] 글루타민의역할은아미노산의한종류로서단백질합성에참여하고, 일부 myc 유전자가관여하는암에서대사변화를유발하여지질생성에관여하기도한다.[3] 콩팥에서암모늄생산과관계되어산-염기평형에기여하며, 포도당다음으로세포에너지원으로많이사용되는주요대사물질이다. 특히위장관세포, 림프구, 폐조직세포, 간세포등빠르게분열하는세포에서의에너지원사용이많다.[4] 따라서글루타민은장방어막 (gut-barrier) 에서의중요한역할과 glutathione과같은항산화물의전구체로서체내면역기능은물론 Received June 12, Accepted June 20, Correspondence to: Dong Woo Shin, Department of Surgery, Hallym Univertisy Dongtan Sacred Heart Hospital, 7 Keunjaebong-gil, Hwaseong 18450, Korea Tel: , Fax: , shin519@hallym.or.kr 본논문은 2018 년 3 월제 25 회대한외과대사영양학회학술대회에서발표되었던연제입니다. CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyrights c The Korean Society of Surgical Metabolism and Nutrition

2 6 Surgical Metabolism and Nutrition Vol. 9, No. 1, 2018 이고 heat shock protein의발현과퓨린 (purine) 과같은핵산물질의생산에도관여하는기능을가지고있다.[5] 그외에도 protein kinase 및세포분열을조절하여 mammalian target of rapamycin (mtor) 를활성화하는신호전달물질로서의역할도있고 N-acetylglucosamine과 N-acetylgalactosamine 합성에관여하여장점막의점액 (mucin) 생성에도기여한다고한다.[6] 이렇게글루타민은체내에서다양한필수역할을하기때문에, 혈중글루타민농도는중증질환을겪으면서동반되는이화성대사상태에서부족에빠질수밖에없고, 이를보충하기위한외부공급은적절하다 는가정이필연적이고적정한것으로보인다. 글루타민을따로정제하기는쉽지않다. 육류및콩류를포함하는대부분의단백함유음식에는글루타민이포함되어있는데, 글루타민만따로정제하기위해서는매우특수한기술이필요하며, 정제된글루타민은물에녹지않고불안정하다. 건조파우더형식의 L-glutamine 제제가먼저상품화되어출시되었고, 알라닌 (alanine) 혹은글라이신 (glycine) 과글루타민을 dipeptide 결합시켜수용성을높여경장영양은물론이고정맥영양공급이가능하게된제품은최초로 1990년대후반에개발되었다. 정맥공급용글루타민제제가상품화되어출시된것은 2000년대들어유럽에서먼저사용이가능하였다. 이후아시아를비롯한전세계에보급이되었으나미주에서의사용은많이늦어져서 2010년캐나다에서승인이되었고, 미국은 2011 년 ASPEN Position Paper를통해임상사용승인을요청하는작업이이뤄졌으나 FDA는부분적승인만허용하였다.[7] 정맥주사용글루타민제제에대한미국 FDA의안전성, 유효성평가와제약사간에갈등이생기는과정과글루타민에대한학술적인논란이무관하지않은것은이전소규모임상연구에서감염합병증, 재원기간단축등의이점을보였던결과와달리최근이뤄진대규모무작위임상시험에서글루타민투여군이사망률이더높고, 감염이나재원기간등의임상적이득이더높지않다는보고가이어졌기때문이다. 본종설에서는정맥글루타민보충에대한학술적배경과이와관련한논란을정리하고현시점에서바람직한임상적유용성, 앞으로예상되는연구의방향성을제시하고자한다. 논란의시작 특정한병적상황, 즉중증패혈증이나다발성외상, 외과적인대수술후에혈장이나조직내글루타민의농도는골격근에서의생산된제한적글루타민양만으로는적정수준을유지하 기어렵다.[2,8,9] 혈장이나조직의낮은글루타민농도는임상적으로나쁜예후를보이는것으로알려져있다.[10] 그래서외부에서글루타민을보충하는것이여러면에서이점이있다고보고되어왔다.[9] 글루타민의보충은경구, 경장, 정맥모두가능하지만문헌고찰을통한분석에서정맥보충이경장보충에비해사망률이나재원기간에서더이롭다고나타났다.[11] 같은양의글루타민을공급하더라도정맥공급된경우경장공급보다더높은혈장글루타민농도가확인되며빠르게내장순환계로유입된다.[12] 최근보고된경장글루타민보충에관한메타분석에서도화상환자에게재원기간의감소가있었을뿐, 달리임상적으로유의한이점은보이지않았다.[13] 정맥보충글루타민에대해서는 dipeptide 결합으로수용성을높인 L-alanyl-L-glutamine 제품이전 1990년대초부터동물실험등으로글루타민보충이단백동화대사 (protein anabolic metabolism) 를향상시키고, 장방어막의기능을보존, 면역력유지에도움이된다는보고가많이있었다.[14-17] 2010년전후까지중증내과환자나대수술이후의외과환자를대상으로진행된소규모무작위대조군실험에서도정맥글루타민보충은질소평형의유지, 장방어막기능의유지, 면역지수의유지및병원감염의감소와재원기간감소, 사망률감소같은임상적예후향상에도움이되는것으로보고되었다.[18,19] Wischmeyer 등 [20] 이 2014년발표한정맥글루타민보충에대한체계적고찰에서지적한바에따르면기존연구들이정맥영양이불가피한환자들을주로대상으로하였고 ( 약 85%), 약물로서의글루타민역할이아닌영양공급의보조수단으로공급하였고, 영양요구량에못미치는상황에서정맥영양과함께투여되는방법을주로사용하였으며, 간이나신부전환자들이연구대상에서배제되어진행된경우가대부분이었으며, 공급된글루타민의양이저용량 ( g/kg/day) 이었다고지적하고이로인해사망률, 재원기간, 중환자실재실기간, 감염합병증을줄이는결과를보였다고하였다. Tao 등 [21] 은 2014 년도보고된 53개임상시험을포함하는코크란분석에서중등도근거를가진감염률감소와기계호흡일수의감소를보인다고하였고, 낮은근거도를보이긴하였지만중환자및외과환자의재원일수감소를확인하였다. 사망률과전체적인병원재원일수에는아무런영향을미치지않았는데, 이렇게근거강도가낮은이유는대조군집단의다양성과논문작성과정에서발생한편향성때문이라고보았다. 결국글루타민정맥보충에대한연구들이가지는한계성은첫째, 혈장이나조직내글루타민레벨등의측정을통한글루타민정맥보충을요구하는대상자선정이일관성있게진행되

3 Dong Woo Shin: Parenteral Glutamine Supplementation 7 지않았고, 둘째, 글루타민의정맥보충이전체적인영양공급의부족분을메꾸기위한것인지아니면글루타민이가지는약리적기능을목표로한것인지일차적인연구목표설정이모호하였다. 셋째, 실험대상의설정을중환자, 외과환자등으로특정하였다고하지만이미그안에영양상태, 질병의중증도등의측면에서굉장히다양한양상의환자군을대상으로, 대규모가아닌소규모집단에대한연구를진행함으로써결과의근거강도를낮추는결과를초래하였다고할수있다. 글루타민정맥보충, 논란의정점 논란의시작은근거강도가낮다는점외에는글루타민보충의정당한유효성에대해서는의심받지않았다. 하지만 2013 년 4월 New England Journal of Medicine 368호에실린중환자에대한항산화제와글루타민공급에대한유효성검증실험에서장기부전이있는환자군에서사망률이오히려더증가한다는충격적인결과가보고되었다.[22] 이연구는일명 REDOXS (REducing Deaths due to OXidative Stress) trial이라고도불리며캐나다, 미국, 유럽의 40곳중환자실의다발성장기부전이나기계호흡을하는 1,223명환자가등록되었다. 환자들은무작위로 4군으로나뉘어위약투여군, 정맥및경장글루타민투여군, 비타민과미네랄항산화제투여군, 글루타민과항산화제투여군으로분류되었다. 일차평가지표인 28일사망률과이차평가지표인원내사망률, 6개월사망률모두글루타민투여군에서높았다. 저자들은검토의견에서 중증환자들이초기에혈장글루타민고갈이일어나고혈장글루타민농도가 420 μmol/l 이하인경우사망률이높다 는가정을신뢰하고있었고, 그래서적절한글루타민투여량결정을위해시행한별도의연구에서중증환자의초기혈장글루타민레벨이일정하지않다는단서를이미포착하였다는언급을하고있다. 따라서저자들은결론으로서다발성장기부전을동반한중증환자에게초기에글루타민을투여하는것은바람직하지않으며, 중증질환발병초기에글루타민결핍이오고이들에게글루타민공급이필수적이라는명제에오류가있을수있다고결론을맺고있다. 물론 REDOXS 연구디자인자체에대해서도몇가지편향성오류지적이있다. 75% 이상이내과계중환자였고, 80% 에서 24시간이내의조기경장영양을시도하였지만입원시 35% 환자가신부전을동반할정도로중증도가높았고, 쇼크상태에서충분한칼로리가공급되지않았지만오히려과도한글루타민투여가이뤄졌다는비판이있다. REDOXS 연구가발표되기전 2011년에도 SIGNET (Scottish Intensive care Glutamine or selenium Evaluation Trial) 연구가있었다.[23] 이연구에서도 502명의대규모환자군을글루타민투여군, 셀레늄투여군, 글루타민과셀레늄투여군, 비투여군의 4군으로나누어연구하였고, intention to treat 분석의결과는글루타민투여로감염이나사망률에미치는효과는없었으며, 셀레늄정맥투여군에서새로운감염의감소를보였을뿐이라고글루타민에대해호의적이지않은결과를보고하였다. 하지만이연구의디자인에서도일차평가지표인입원후 첫 14일동안새로운감염 은이미대다수환자가패혈증의진단이내려진상황에서감별이쉽지않았고, 단백질영양공급이불충분한가운데글루타민의투여량은너무적었고투여기간은너무짧았다. 따라서이연구가가지는의미가축소될수밖에없었다. 후속연구들 2014년 van Zanten 등 [24] 은면역영양소를포함하는고단백경장영양공급군과일반고단백경장영양공급군을비교하는연구결과를 Journal of American Medical Association (JAMA) 에발표한다. 물론본종설논문에서다루기로한정맥글루타민보충과관계없이경장영양에관한내용이지만기존메타분석이나 SIGNET, REDOXS 등의연구에서논의되었던글루타민보충과감염합병증이나사망률과의관련성검증을위해면역영양소에글루타민이포함되어있었다. REDOXS 연구에서는권장되는글루타민 g/kg/d 보다많은양의투여가있었으나이연구에서는 0.28 g/kg/d 정도글루타민경장영양이있었다. 결과는면역양양소를포함하는군에서감염합병증의감소는없었을뿐아니라 6개월보정사망률은오히려증가되었다. 이후시도되는연구들을모두열거할수없으나뚜렷하고일정한경향을보이고있다는점을알수있는데, 장폐색을동반한방사선장염환자들을대상으로정맥글루타민을투여하여면역력을올리고장투과성을낮추는결과,[25] 다발성외상환자에게정맥글루타민을투여한결과고혈당의빈도를낮출수있었다는연구,[26] 소아중환자에게글루타민투여시 heat shock protein 70 농도유지에도움이되었다는연구,[27] 중증화상을입힌 rats에서정맥글루타민투여시 heat shock protein 90 발현을높이고 caspase-3 활성도를낮춰 Peyer s patch apoptosis를완화하고장의 Ig A 유지향상에도움이되었다는동물연구 [28] 등이그것들이다. 즉연구대상을좀더구체화하되글루타민투여의유효성이높다고알려진외과

4 8 Surgical Metabolism and Nutrition Vol. 9, No. 1, 2018 적중증환자, 화상환자등에서어떤메커니즘으로그유효성이발휘되는가를보고있다는점이다. 특히주목을받고있는키워드로 gut barrier, lung, heat shock protein expression, lymphocyte, Ig A level 등에서글루타민보충의유효성을찾는연구가활발히진행되고있고, 진행될예정이다. 글루타민의혈장농도와조직농도 Smedberg와 Wernerman [29] 은 Critical Care 잡지에 2016년기고한글에서글루타민의혈장농도와조직농도의연관성이없음에주목하고, 나쁜예후와관련이있는낮은혈장글루타민의농도는중환자실입원시에만국한된다고정리하고있다. 3일이넘도록중환자실에입원하여있는경우오히려높은혈장농도가나쁜예후와관련이생길수있다는것이다. 중환자실입원당시에낮은혈장글루타민농도가중환자실재실이후의나쁜예후를보일수있는독립적인위험인자로작용한다는것은이미 2012년스웨덴 Wernerman과 Rodas 등 [30] 에의해보고된바있다. Helling 및 Wernerman 그룹에서 2016년간부전과혈장글루타민의관계에대해연구하여보고하였는데, 간부전의급만성경과, 부전의정도, Child-pugh score나 Model for end-stage liver disease (MELD) score에상관없이혈장글루타민의농도는높았고, 왜높은혈장글루타민농도가간부전과밀접한관계를가지는 biomarker로작용할수있는지에대해서는좀더명백한규명이이루어져야한다고하였다.[31] 글루타민투여에관한가이드라인 REDOXS 연구가 2013년 4월발표된후그해 7월 REDOXS 논문의주저자인 Heyland와임상영양사 Dhaliwal은미국정맥경장영양학회지 (Journal of Parenteral and Enteral Nutrition) 에 REDOXS 연구결과로얻어진중환자에서의글루타민보충의역할에대한주석기고 (commentary article) 를싣는다.[32] 즉 REDOXS 연구의결과로얻어진교훈을다시정리한것인데, 약 15% 의환자에서치료시작이전에이미정상범위이상의혈장글루타민농도를나타냈고 2012년 Rodas 등의발표와마찬가지로 930 μmol/l이상의혈장글루타민농도를보인경우높은사망률을보였기때문에 shock이나다발성장기부전을가진환자에게는정맥혹은경장어떤형태로든글루타민보충을하지말아야한다고경고한다. 장기부전이없고, 경장영양이가능한화상환자나외상환자의경우에는 g/kg/d의글루타민보충이도움이될수있고, 마찬가지로장기부전이없고, 경장영양은어려운경우 0.35 g/kg/d의정맥글루타민보충이가능하다는알고리듬을제시하고있다 (Fig. 1). ASPEN (American Society for Parenteral and Enteral Nutrition) 가이드라인은 2002년처음만들어져배포되었고,[33] 글루타민에관련된내용은굉장히빈약하지만약물영양학적관점에서 branched chain amino acids, 아르기닌, 오메가-3 지방산, 핵산등과함께사용해볼수있지만아직잘밝혀진효과는없다고하였다. 2009년다시개정배포된가이드라인 [34] 에서계획된대수술, 화상, 외상, 두경부암, 기계호흡적용된중환자의경장영양에서아르기닌, 글루타민, 핵산, 오메가-3 지방산, 항산화제등의면역영양소공급이도움이될수있다고근거등급 A, B 정도로제시하였고, 정맥영양공급시에도근거등급 C로낮지만정맥용글루타민보충이감염합병증을낮추고, 중환자실재실기간을감소시키며, 사망률감소에도움이된다고하였다. 2009년당시가이드라인에서밝힌바와같이미국, 캐나다에서정맥용글루타민의상업적사용은불가능한상황이었고, 아직 SIGNET 연구나 REDOXS 연구가발표되기전이었기때문에제시될수있는내용이었다. 가장최근에배포된 2016년도 ASPEN 가이드라인 [35] 에서는경장글루타민이나정맥글루타민모두에서 2009년제시된가이드 Fig. 1. Algorithm for glutamine supplementation by D. Heyland.

5 Dong Woo Shin: Parenteral Glutamine Supplementation 9 라인과사뭇다른내용으로게재되었다. 먼저 2009년언급된경장영양에서글루타민을포함하는면역영양소사용에대해내과계중환자실에서면역영양소의일상적사용 (routine use) 은절대안된다고하고, 다만근거수준은낮지만외상성뇌손상, 외과계중환자실의수술전후환자에게고려해볼수있다고하였다. 중환자실에서의정맥글루타민보충에대해서도마찬가지로중등도근거수준으로일상적사용을금하고있다. 제시된근거로서 REDOXS 연구를소개하고있고, Bistrian [36] 이 Heyland의 REDOXS 연구발표에대한교신기고에서밝혔듯이글루타민이 50% 이상차지하는보충을통해공급아미노산의불균형적인구성비율, 아르기닌이나비필수아미노산의배제, 메치오닌과시스테인과같은주요아미노산의부족한공급등이암모니아대사에나쁜영향을끼쳐사망률증가에기여했다고설명한다. 또한 Rodas 등 [30] 이발표한것처럼글루타민치료시작시모든환자가글루타민결핍에있다는것을입증하지못하였다고하였다. 반면, 유럽의 ESPEN (European Society for Clinical Nutrition and Metabolism) 은 2009년발표된중환자정맥영양에관한가이드라인에서 [37] 중환자실정맥영양이적응되는경우아미노산수액에 L-glutamine g/kg/d ( 혹은 alanyl-glutamine dipeptide로서 g/kg/d) 을포함하여공급하도록권고하고근거등급 A로매겼다. 2017년 ESPEN 에서는임상영양학의용어및그정의를정리한가이드라인, 외과환자의임상영양가이드라인, 염증성장질환의임상영양가이드라인, 암환자의영양실조관련임상영양가이드라인등을동시에발표하였다. 외과환자의임상영양가이드라인에서도 [38] ASPEN의최근경향과달리경장영양이불가능하여정맥영양이불가피한경우정맥글루타민보충을고려할수있다고하였고, 다만 Consensus conference를통해권고등급 B로강등되었다는점을밝히고있다. 최근시행된여러글루타민보충에관한전향적무작위연구가운데유일하게글루타민정맥보충의안전성을언급한 Ziegler 등 [39] 의 2016년발표한연구를근거로들고있다. 이연구에서미국의다기관외과계중환자를대상으로신부전, 간부전, 입원시쇼크상태의환자를제외한환자를대상으로 0.5 g/kg/d alanyl-glutamine dipeptide를공급하였고결과는글루타민정맥보충그룹이나표준정맥영양그룹간에안전성, 감염률이나사망률등지표에서차이가없었다. 결론 기존의중증질환으로인한이화성대사상태에서글루타민이조건부필수아미노산으로작용한다는개념과이를근거로글루타민보충이꼭필요하다는권고사항은더이상유효하지않다. 조직이나혈장에서의글루타민농도의변화와이에관련한정확한대사메커니즘의규명이필요하다. 현시점에서가장적정한글루타민정맥보충의대상은장기의부전을동반하지않은화상이나외과적대수술을받은, 경장영양이불가능한환자이며, 이들에게적정칼로리와단백질공급을전제로 g/kg/d의글루타민을정맥보충할수있다. REFERENCES 1. Brosnan JT. Interorgan amino acid transport and its regulation. J Nutr 2003;133(6 Suppl 1):2068S-72S. 2. Lacey JM, Wilmore DW. Is glutamine a conditionally essential amino acid? Nutr Rev 1990;48: Gouw AM, Toal GG, Felsher DW. Metabolic vulnerabilities of MYC-induced cancer. Oncotarget 2016;7: Brasse-Lagnel CG, Lavoinne AM, Husson AS. Amino acid regulation of mammalian gene expression in the intestine. Biochimie 2010;92: Wischmeyer PE. Glutamine: mode of action in critical illness. Crit Care Med 2007;35(9 Suppl):S Huang Y, Shao XM, Neu J. Immunonutrients and neonates. Eur J Pediatr 2003;162: Vanek VW, Matarese LE, Robinson M, Sacks GS, Young LS, Kochevar M; Novel Nutrient Task Force, Parenteral Glutamine Workgroup; American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors. A.S.P.E.N. position paper: parenteral nutrition glutamine supplementation. Nutr Clin Pract 2011;26: Roth E. Nonnutritive effects of glutamine. J Nutr 2008;138: 2025S-31S. 9. Wernerman J. Clinical use of glutamine supplementation. J Nutr 2008;138:2040S-4S. 10.Roth E, Funovics J, Mühlbacher F, Schemper M, Mauritz W, Sporn P, et al. Metabolic disorders in severe abdominal sepsis: glutamine deficiency in skeletal muscle. Clin Nutr 1982;1: Novak F, Heyland DK, Avenell A, Drover JW, Su X. Glutamine supplementation in serious illness: a systematic review of the evidence. Crit Care Med 2002;30: Wernerman J. Glutamine supplementation. Ann Intensive Care 2011;1: van Zanten AR, Dhaliwal R, Garrel D, Heyland DK. Enteral glutamine supplementation in critically ill patients: a systematic review and meta-analysis. Crit Care 2015;19: Souba WW, Klimberg VS, Plumley DA, Salloum RM, Flynn TC, Bland KI, et al. The role of glutamine in maintaining a healthy gut and supporting the metabolic response to injury and infection. J Surg Res 1990;48: Ziegler TR, Gatzen C, Wilmore DW. Strategies for attenuating protein-catabolic responses in the critically ill. Annu Rev Med 1994;45: Li J, Kudsk KA, Janu P, Renegar KB. Effect of glutamine- enriched total parenteral nutrition on small intestinal gut-associated lymphoid tissue and upper respiratory tract immunity. Surgery 1997;121:542-9.

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untitled Review Article J Clin Nutr 2015;7(2):42-48 pissn 2289-0203 ㆍ eissn 2383-7101 http://dx.doi.org/10.15747/jcn.2015.7.2.42 중환자영양집중지원에서정주용글루타민의역할 박효정 삼성서울병원약제부 Pharmaceutical Services, Samsung Medical Center,