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1 Review Article J Clin Nutr 2015;7(2):42-48 pissn ㆍ eissn 중환자영양집중지원에서정주용글루타민의역할 박효정 삼성서울병원약제부 Pharmaceutical Services, Samsung Medical Center, Seoul, Korea Glutamine is the most abundant amino acid, composed of more than 50 percent of free amino acid in the human body. It had been regarded as a conditional essential amino acid and its concentration is markedly reduced in critically ill patients with trauma, burn, or sepsis. From the early 1990s, many parenteral glutamine studies on critical illness have reported the benefits in mortality, infection, and length of stay. However, its clinical efficacy was based on out-of-date, smaller, single-center studies. Clinical effects of parenteral glutamine have shown no benefits or even harms in recent clinical trials and meta-analysis. Furthermore, it has challenged the hypothesis that low plasma glutamine concentration was associated with poor outcomes in critically ill patients. Although many studies showing the efficacy of glutamine have been reported, parenteral glutamine supplementation may be harmful in patients with multiorgan failure or baseline kidney dysfunction. Further studies should be conducted to identify the use of glutamine supplementation in combination with parenteral and enteral nutrition or enteral/oral nutrition alone, specific adult or pediatric patients, the appropriate time and doses for administration of glutamine, cost-benefit analysis, and the exact mechanisms of action. Key Words: Glutamine, Parenteral nutrition, Intensive care units 서 론 글루타민 (glutamine, C 5H 10N 2O 3) 은심각한스트레스상태즉외상, 화상패혈증등의중환자에서체내생산가능한양이필요한양보다일시적으로증가하여조건부아미노산으로알려져있다. 따라서글루타민은심각한스트레스상태의중환자에 Received Aug 3, 2015; Revised Aug 21, 2015; Accepted Aug 22, 2015 Correspondence to Pharmaceutical Services, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: , Fax: , hyoj.park@samsung.com Conflict of interest: None. 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. 서요구량이증가하는조건부아미노산이다. 1 일시적으로부족한글루타민을외부에서인위적으로공급하는것은산화스트레스반응 (oxidative stress reaction) 조절에긍정적인효과를기대할수있으며치사율과감염, 재원기간의감소와같은임상효과를향상시킬것으로간주되어왔다. 그러나최근여러다기관무작위통제글루타민임상시험에서기존의긍정적인치료효과에반대되는임상효과가부정적이거나관련이없다는연구결과들이보고되고있다. 글루타민을사용한임상연구의대부분이정주용글루타민투여후의연구이므로, 2 본종설에서는정주용글루타민투여에대하여지금까지제시된가이드라인, 메타분석, 중환자에서의영양집중지원시정주용글루타민사용과관련된최신다기관연구를검토하여앞으로의정주용글루타민사용에대하여제언하고자한다. c 2015, The Korean Society for Parenteral and Enteral Nutrition. All Rights Reserved.

2 본론 1. 글루타민의역사글루타민은 1883년, Schulze과 Bosshard가사탕무 (beet) 즙에서분리하여구조를최초로밝혀내었으며, 년 Thierfelder와 Sherwin은인체에서글루타민기능을발견하였다. 20 년후 Krebs 등이간배양모델의체외실험에서글루타민산 (glutamic acid) 과암모니움이온 (ammonium ion) 을반응시켜글루타민합성을성공하였다. 4 글루타민은체내에서중요한역할이있음이계속밝혀져왔으나합성된정주용글루타민은고온살균이후보관할때주변온도나 ph에따라화학적으로매우불안정하였으며, 20 o C에서용매 100 ml에글루타민 3 g만용해되므로임상에서의사용이제한되었다. 그러나 1995년 Fresenius Kabi에서글루타민의용해도과안정성이크게향상시킨글루타민전구체, 글라실글루타민 (L-glycyl-L-glutamine) 을생산하여임상에적용되었으며 1년뒤글라실글루타민보다용해도가 3.5배높은알라닐글루타민 (L-alanyl-L-glutamine) 을생산하였다. 국내에는 2002 년에 Glamin과 2007년에 Dipeptiven이발매되었다. 2. 글루타민의기능글루타민은체내유리된아미노산의 50% 이상을차지하는혈액내가장풍부한아미노산이다. 금식을하거나체내필요량이급격히증가한상태에서글루타민은근육에저장된질소를이동시켜포도당신합성 (gluconeogenesis) 에관여하며글리코겐 (glycogen) 합성에이용되어에너지를만들고 5 인슐린감수성 (insulin sensitivity) 에도영향을미친다. 6,7 또한, 산-염기균형유지에관여하며유리된라디칼제거제 (free radical scavenger) 인글루타치온 (glutathione) 과필수단백질인알지닌 (arginine) 의합성에관여한다. 8 림프구, 대식세포, 장세포등과같이빠르게분화하는세포의연료원으로사용되며장의완전성 (intestinal integrity) 을유지하여장밖으로세균전위 (bacterial translocation) 를예방하고위장관의면역을자극하여소화관위축을예방한다. 9 글루타민은열충격단백 (heat shock protein) 의발현과피리미딘과퓨린의전구체로 DNA와전령 RNA 합성에관여한다. 10 으로정해진다. 혈장으로글루타민을주로방출하는조직은골격근, 폐, 간장, 지방조직이며주로흡수하는조직은창자와간장, 신장이다. 간장과근육이글루타민의혈액내항상성 (homoeostasis) 을유지하는주요조절장기로두장기모두글루타민의방출과흡수에관여하는것으로알려져있으나인간에게필요한글루타민의양은아직까지정확하게확립되어있지않다. 정상성인에서글루타민의체내생산속도는 g/24 h로생각되며중환자의경우에는 g/24 h가추가적으로필요할것으로추정된다. 제약회사에따르면필요시안전하게혈액내글루타민농도를적절하게유지하기위해 1일아미노산공급량의 20% 40% 를알라닐글루타민으로공급할것을권고한다. 4. 중환자에서정주용글루타민공급에대한가이드라인 2009년미국, 유럽, 캐나다에서글루타민사용에대한임상가이드라인을발표하였다 (Table 1). 미국중환자의학회와미국정맥경장영양학회에서공통으로발표한성인중환자의영양지원치료의공급과평가를위한지침 (Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient) 11 에서경장이나정맥영양집중지원을받는중환자는정주용글루타민투여를고려할것을권고하였다. 유럽정맥경장영양학회 12 와캐나다중환자영양그룹 13 에서는중환자에서정맥영양집중지원이필요한경우아미노산공급시알라닐글루타민, g/kg/day를포함하여공급할것을강하게권고하였다. 2011년에발표된미국정맥경장영양학회의정주용글루타민공급에관한성명서 14 에서도정주용글루타민이체내유해하다는증거가없으며관련금기사항도없으므로의료진의전문적인판단에따라사용할수있도록해야한다고권고하였다. 그러나최근 2015년캐나다중환자영양그룹 15 에서는지금까지의정주용글루타민의긍정적사용권고와반대로중환자의정맥영양집중지원시정주용글루타민을공급하지말것을권고하였다. 또한근거가부족하지만, 경장영양집중지원중인중환자에서도정주용글루타민을보조적으로투여하지않도록권고하였다. 3. 글루타민의대사정상인에서기초혈장글루타민교체속도 (basal plasma turnover rate) 는약 5 μmol kg 1 min 1 이며혈액내평균글루타민농도는 0.6 μmol이다. 6 글루타민혈장농도는다양한조직에서혈장으로방출되는속도와흡수되는속도에따라상대적 5. 다기관무작위통제정주용글루타민임상시험 (Multi-Center Randomized Controlled Trial) 1990년대중반부터 2000년대초반까지중환자에서정주용글루타민투여시임상효과가긍정적으로관찰된다는논문들이많이보고되었으나대부분의논문은적은환자수를대상으 Volume 7, Number 2, August

3 Table 1. Summary of published clinical guidelines on parenteral nutrition glutamine supplementation in critically Ill patients Clinical guidelines Guideline statement Grade 2009 Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: SCCM and ASPEN 2009 ESPEN Guidelines on Parenteral Nutrition: Intensive care 2009 Canadian Clinical Practice Guidelines for Nutrition Support in the Mechanically Ventilated, Critically Ill Adult, 9.4 Composition of PN: Glutamine (CCCN) 2011 ASPEN Position Paper: Parenteral Nutrition Glutamine Supplementation 2015 Canadian Clinical Practice Guidelines for Nutrition Support in the Mechanically Ventilated, Critically Ill Adult, 9.4a Composition of PN: Glutamine (CCCN) When PN is used in the critical care setting, consideration should be given to supplementation with parenteral glutamine. There are insufficient data to generate recommendations for intravenous glutamine in critically ill patients receiving enteral nutrition. When PN is indicated in ICU patients the amino acid solution should contain g/kg/day of L-glutamine (e.g., g/kg/day alanyl-glutamine dipeptide). Based on 4 level 1 studies and 13 level 2 studies, when parenteral nutrition is prescribed to critically ill patients, parenteral supplementation with glutamine, where available, is strongly recommended. There are insufficient data to generate recommendations for intravenous glutamine in critically ill patients receiving enteral nutrition. To date, there is no evidence that parenteral glutamine is harmful. There are no absolute contraindications to the use of parenteral glutamine. A FDA-approved parenteral glutamine dipeptide solution should be made available for use based on the professional judgment of prescribers. Based on 31 studies (10 level 1 studies and 21 level 2 studies), when parenteral nutrition is prescribed to critically ill patients, we recommend parenteral supplementation with glutamine NOT be used. There are insufficient data on the use of intravenous glutamine in critically ill patients receiving enteral nutrition but given the safety concerns we also recommend intravenous glutamine not be used in enterally fed critically ill patients. Grade: C Grade: A Strongly recommended insufficient data NOT recommended SCCM = Society of Critical Care Medicine; ASPEN = American Society for Parenteral and Enteral Nutrition; PN = parenteral nutrition; ESPEN = Europian Society for Parenteral and Enteral Nutrition; ICU = intensive care unit; CCCN = Canadian Critical Care Nutrition group; FDA = Food and Drug Administration. Table 2. Parenteral glutamine multicenter randomized controlled trials in intensive care unit (ICU) Study References Study design Patients Intervention Gln. outcome Scandinavian Acta anaesthesiol glutamine trial 17 Scand 2011 Scottish Intensive care Glutamine or selenium Evaluative Trial 18 Double blinded, RCT 11 Centers BMJ 2011 Double blinded, factorial, RCT 10 Centers REducing Deaths due to NEJM 2013 Double blinded, factorial, RCT OXidative Stress ICU Metaplus 21 JAMA 2014 Double blinded, RCT 14 ICU EN±PN APACHE II 10 n=413 EN±PN Isonitrogenous, isocaloric (12.5 g nitrogen, 2,000 kcal) n=502 EN±PN n=1,223 EN (25 kcal/kg/day) n=301 IV Gln. (0.283 g/kg/day) Saline Within 72 h ICU discharge IV Gln. (20.2 g/day) or selenium (500 μg/day), or both/standard For up to 7 days IV+PO Gln. or IV+PO selenium (500 μg/day), or both/standard For 28 days/icu death EN Gln.+W3 +selenium+antioxidant Standard Within 48 h >72 h ICU mortality (only per protocol; not ITT) No effect on 6 month mortality No effect on new infection in 1st 14 days/mortality/los 28 days mortality 6 month mortality RCT = randomized controlled trials; EN = enteral nutrition; PN = parenteral nutrition; APACHE II = Acute Physiology and Chronic Health Evaluation II; IV = intravenous; Gln. = glutamine; ICU = intensive care unit; ITT = intention to treat; PO = per oros. 44 Journal of Clinical Nutrition

4 로한단일기관연구로한계가있었다. 16 이논문들에서중환자는혈액내글루타민농도가일시적으로낮아져추가로글루타민을외부에서공급하면큰부작용이나위험없이재원기간을단축시키거나감염률을감소시킬것이라는가정을기반으로하고있다. 그러나최근다기관무작위통제임상시험에서정주용글루타민이임상적효과가없거나오히려치사율을증가시킨다는결과를보고하고있다. 또한중환자에서혈액내글루타민농도가낮아져일시적인부족상태라는가설이혈액내글루타민농도를분석하였을때일치하지않다는보고들이있다. 최근보고된 4개의대규모다기관무작위통제임상시험을고찰하고자한다 (Table 2) ) Scandinavian glutamine trial 17 스웨덴의 9곳, 핀란드와노르웨이에서각각 1곳을포함한 11 개센터가참여한이중맹검무작위통제임상시험 (randomized controlled trial, RCT) 이다. 2003년부터 2008년까지시행하였으며 APACHE II 점수 10 이상의성인중환자를대상으로입원후 72시간내에정주용글루타민 g/kg/day나식염수를무작위배정하여중환자실퇴실시점까지투여하였다. 처음에는 1,000명의환자를목표로연구를시작하였으나 4년간 413명만이등록되어시험대상자모집이너무지연되어임상시험이중단되었다. 프로토콜에따른분석 (per-protocol analysis) 에서는중환자실치사율의감소가관찰되었으나처리의향분석 (intent- to-treat) 에서는통계적인의의가없었다. 6개월후치사율도정주용글루타민투여군과비투여군간의차이가없었다. 2) Scottish Intensive care Glutamine or selenium Evaluative Trial, SIGNET 18 다기관, 2 2 요인설계 (factorial design), 이중맹검임상시험으로 2004년부터 2008년까지경장또는정맥영양집중지원으로동일열량 (2,000 kcal/day) 과동일질소량 (12.5 g) 을공급받은중환자성인 502명을대상으로임상시험을시행하였다. 정주용글루타민 20.2 g/day 단독투여군, 또는정주용셀레니움 500 μg/day 단독투여군, 또는정주용글루타민과정주용셀레니움동시투여군, 또는모두투여하지않은군으로임상시험군을총네그룹으로나누어 7일간투여하였다. 시험대상자에서신대체요법을시행하지않고사구체여과율 (glomerular filtration rate), 10 ml/min 미만환자는제외하였다. 셀레니움단독투여군에서첫 14일간새로운감염발생의감소 (odds ratio [OR], 0.53; 95% confidence interval [CI], ) 가관찰되었을뿐정주용글루타민단독투여군이나글루타민과셀 레니움동시투여군에서는 14일째감염발생이나병원재원기간, 치사율에서긍정적인효과를관찰하지못하였다. 3) REducing Deaths due to OXidative Stress, REDOXS study 19 북미와유럽의 40개중환자실 1,223명이참여한다기관, 2 2 요인설계, 이중맹검임상시험이다. 2년간의글루타민과셀레니움의최대용량결정임상시험과단일기관에서의예비실험후 2005년에서 2011년, 7년간진행되었다. 경장또는정맥영양집중지원을받은성인중환자를대상으로하여정주용글루타민 0.35 g/kg과경장용글루타민 30 g/day를투여한글루타민투여군또는정주용셀레니움 500 μg/day와경장용셀레니움 30 μg, 아연 20 mg, 베타카로틴 10 mg, 비타민 E 500 mg, 비타민 C 1,500 mg을투여한항산화제투여군, 글루타민과항산화제동시투여군, 또는모두투여하지않은대조군으로나누어중환자실입실 24시간이내에임상시험에등록하여최대 28일또는중환자실퇴실또는사망시점까지연구를시행하였다. 정주용글루타민투여군에서병원치사율 (37.2% vs. 31.0%; P=0.02) 과 6개월치사율 (43.7% vs. 37.2%; P=0.02) 이모두통계적으로유의하게높았다. 대상환자의대부분이 2개이상의기관기능부전 (organ failure) 을가지고있었으며특히중환자실입원시기저질환에신장애가있는환자군에서 28일치사율이높았다 (OR, 3.91; 95% CI, ). 20 4) MetaPlus study 21 네델란드, 일본, 프랑스, 벨기에의 14개중환자실에서 301명의성인환자를대상으로 2010년에서 2012년까지진행된이중맹검 RCT로동일열량 (25 kcal/kg/day) 경장유동식을공급하고면역조절영양소 (immune-modulating nutrients) 를포함한시험군과포함하지않은대조군의 14일내새로발생한감염빈도를비교하였다. 면역조절영양소에는글루타민, 알지닌, 핵산, 오메가-3 지방산, 셀레니움등이포함되었다. 두군간 14일내새로발생한감염발생빈도의차이는없었으나오히려 6개월치사율이면역조절영양소를투여한군에서높았다 (hazard ratio, 1.57; 95% CI, ; P=0.04). 6. 중환자에서의혈액내글루타민농도중환자에서낮은혈액내글루타민농도는병원사망률을높이고치료효과를감소시킬것으로생각되어, 글루타민을외부에서추가공급하는방법을연구해왔다. 그러나최근낮은혈액내글루타민농도와 APACHE II 점수와연관성이없어글루타민농도와환자의중증도여부가관련 Volume 7, Number 2, August

5 성이없으며, 중환자에서혈액내글루타민농도가일관성있게저하되어있지않고매우다양한농도로관찰되는것이보고되었다. 22 통상적으로정상혈액내글루타민농도는 μmol/l이며 420 μmol/l 미만, 930 μmol/l 이상의글루타민농도를비정상으로판단한다. 16 REDOXS 연구에서 1,223명의성인중환자중 66명의시험대상자에서만시험참여전기준혈액내글루타민농도를측정한결과, 혈액내글루타민농도가낮을것이라는예상과다르게 31% 의시험대상자에서만글루타민농도가낮게관찰되었다. 또한 Rodas 등 8 은혈액내글루타민농도 400 μmol/l 미만과 930 μmol/l 초과시중환자의치사율이증가하여혈액내글루타민농도증가에따라치사율이 U자형태 (U shape) 로증가되는것을확인하였다. 그러나다른연구에서는혈액내글루타민농도의변화가치사율변화와연관성이없었다 명의중환자를대상으로정주용글루타민, 0.28 g/kg/day를공급하였을때체내글루타민생산이감소되지않았으며 24 중환자실퇴실직후혈액내글루타민농도의정상유무와병원치사율과는통계적으로연관이없었으나퇴실시높은글루타민농도의환자군에서 1년후치사율이통계적으로유의하게높았다 중환자에서정주용글루타민투여효과메타분석최근정주용글루타민효과에대한메타분석은 2013년 Bollhalder 등, 년 Wischmeyer 등, 년캐나다중환자영양그룹 15 이보고하였다. 2002년 Novak 등 27 의 14개 RCT의메타분석에서정주용글루타민추가투여는수술환자에서감염관련부작용을낮추고병원재원기간을감소시키며, 중환자에서부작용과치사율을낮추었으며정주용글루타민용량이많을수록임상효과가더욱증가하는것으로보고하였다. 2013년 Bollhalder 등 26 은 40개 RCT를대상으로한메타분석에서정주용글루타민의공급이기존메타분석들과다르게중환자에서치사율감소를확인할수없었으며감염합병증과병원재원기간을단축하는결과를보였으나연구들이오래되고소규모이며정주용글루타민사용용량이균일하지않아정주용글루타민투여로인한임상효과는확실하지않다고보고하였다. 2015년캐나다중환자캐나다중환자영양그룹 15 에서정주용글루타민을사용할경우중환자재원일수와병원재원일수의감소, 기계환기의감소가관찰되었으나통계적이질성 (statistical heterogeneity) 으로한계가있음을보고하였다. 또한정주용글루타민의사용이치사율과감염발생에미치는효과는없었으 며 REDOXS 연구결과를바탕으로 2개이상의기관기능부전이나쇼크상태의중환자에서정주과경장영양집중지원시정주용글루타민사용을추천하지않았다. 본메타분석에는총 31 개연구를포함하였으나 6개만다기관연구였으며나머지는모두단일기관연구인한계가있다. 병원재원일수감소관련메타분석에서는 1997년 Griffiths와 1999년 Powell-Tuck에의한단일기관연구의가중치가 60% 나차지하였으며평가된 15개논문중, 2개만다기관에서이뤄진 RCT였다. 다기관임상연구에서는병원재원일수감소도통계적으로유의하게관찰되지않아 2014년 Wischmeyer 등 2 의메타분석과동일한경향을나타내었다. 결론 중환자에서추가적인정주용글루타민투여는체내사용량이증가되어감소된혈액내글루타민농도를정상화하여감염발생과재원일수단축등의긍정적인임상효과가예상되었다. 과거정주용글루타민의임상효과는통계적유의성은부족하지만적어도인체에유해하지않다는주장이우세하였다그러나정주용글루타민투여와관련된과거가이드라인과메타분석은대부분소규모환자를대상으로한단일기관연구의한계가있었다. 최근발표된혈액내글루타민농도관련연구들에서는중환자의혈액내글루타민농도가감소되었을것이라는가설을확인할수없어글루타민이조건부아미노산이라는임상적의미가부족하게되었다. 심지어혈액내글루타민농도와임상효과는관련이없거나, 혈액내글루타민농도가정상치를벗어날경우치사율이증가된다는보고들이발표되어실제환자를치료하는임상에서는중환자에서정주용글루타민공급이혼란스러운상태이다. 최근 2011년이후발표된, Scandinavian glutamine trial, SIGNET, REDOXS 연구는정주용글루타민의추가투여가중환자의치사율과관련이없거나치사율을증가시키는부정적효과가있음을보고하였다. 이연구들는 2003년부터시작하여약 10여년간진행된대규모다기관, 다국적 RCT로, 앞으로수년간이연구들의결과를부정할수있는연구수행은어려울것으로예상된다. 현재까지보고된정주용글루타민투여에대한가이드라인, 메타분석, 다기관 RCT의결과를바탕으로중환자에서정주용글루타민추가공급로인한긍정적인임상효과를기대하기는어렵다. 특히대규모환자를대상으로한 REDOXS 연구결과를바탕으로기저질환으로신장애가있거나 2개이상의장기기능 46 Journal of Clinical Nutrition

6 부전이관찰되거나쇼크상태의중환자는정주용글루타민을일상적으로추가공급하는것은권고되지않는다. 추후정주용글루타민투여가필요한환자군에대한명확한정의와경장영양집중지원에서의정주용글루타민의역할, 글루타민투여시점과투여용량, 정확한작용기전, 정주용글루타민투여에대한비용효과분석에대한연구가필요하다. REFERENCES 1. Hankard R, Mauras N, Hammond D, Haymond M, Darmaun D. Is glutamine a 'conditionally essential' amino acid in Duchenne muscular dystrophy? Clin Nutr 1999;18(6): Wischmeyer PE, Dhaliwal R, McCall M, Ziegler TR, Heyland DK. Parenteral glutamine supplementation in critical illness: a systematic review. Crit Care 2014;18(2):R Meister A. Metabolism of glutamine. Physiol Rev 1956;36(1): Cynober LA. Metabolic and therapeutic aspects of amino acids in clinical nutrition. 2nd ed. Boca Raton:CRC Press; Valerio A, D'Antona G, Nisoli E. Branched-chain amino acids, mitochondrial biogenesis, and healthspan: an evolutionary perspective. Aging (Albany NY) 2011;3(5): Stumvoll M, Perriello G, Meyer C, Gerich J. Role of glutamine in human carbohydrate metabolism in kidney and other tissues. Kidney Int 1999;55(3): Bakalar B, Duska F, Pachl J, Fric M, Otahal M, Pazout J, et al. Parenterally administered dipeptide alanyl-glutamine prevents worsening of insulin sensitivity in multiple-trauma patients. Crit Care Med 2006;34(2): Rodas PC, Rooyackers O, Hebert C, Norberg Å, Wernerman J. Glutamine and glutathione at ICU admission in relation to outcome. Clin Sci (Lond) 2012;122(12): Wang X, Pierre JF, Heneghan AF, Busch RA, Kudsk KA. Glutamine improves innate immunity and prevents bacterial enteroinvasion during parenteral nutrition. JPEN J Parenter Enteral Nutr 2015;39(6): Jordan I, Balaguer M, Esteban ME, Cambra FJ, Felipe A, Hernández L, et al. Glutamine effects on heat shock protein 70 and interleukines 6 and 10: Randomized trial of glutamine supplementation versus standard parenteral nutrition in critically ill children. Clin Nutr doi: /j.clnu [Epub ahead of print] 11. McClave SA, Martindale RG, Vanek VW, McCarthy M, Roberts P, Taylor B, et al; A.S.P.E.N. Board of Directors; American College of Critical Care Medicine; Society of Critical Care Medicine. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr 2009;33(3): Singer P, Berger MM, Van den Berghe G, Biolo G, Calder P, Forbes A, et al. ESPEN Guidelines on Parenteral Nutrition: intensive care. Clin Nutr 2009;28(4): Composition of Parenteral Nutrition: Glutamine Supplementation [Internet] Jan 31. Available from: criticalcarenutrition.com/docs/cpg/9.4pnglu_final.pdf. 14. 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(4): a Composition of Parenteral Nutrition: Glutamine Supplementation [Internet]. Canadian Clinical Practice Guidelines; 2015 May. Available from: docs/cpgs%202015/9.4a% pdf. 16. van Zanten AR. Glutamine and antioxidants: status of their use in critical illness. Curr Opin Clin Nutr Metab Care 2015;18(2): Wernerman J, Kirketeig T, Andersson B, Berthelson H, Ersson A, Friberg H, et al; Scandinavian Critical Care Trials Group. Scandinavian glutamine trial: a pragmatic multi-centre randomised clinical trial of intensive care unit patients. Acta Anaesthesiol Scand 2011;55(7): Andrews PJ, Avenell A, Noble DW, Campbell MK, Croal BL, Simpson WG, et al; Scottish Intensive care Glutamine or selenium Evaluative Trial Trials Group. Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients. BMJ 2011;342:d Heyland D, Muscedere J, Wischmeyer PE, Cook D, Jones G, Albert M, et al; Canadian Critical Care Trials Group. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med 2013;368(16): Heyland DK, Elke G, Cook D, Berger MM, Wischmeyer PE, Albert M, et al; Canadian Critical Care Trials Group. Glutamine and antioxidants in the critically ill patient: a post hoc analysis of a large-scale randomized trial. JPEN J Parenter Enteral Nutr 2015;39(4): Van Zanten AR, Sztark F, Kaisers UX, Zielmann S, Felbinger TW, Sablotzki AR, et al. High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition and nosocomial infections in the ICU: a randomized clinical trial. JAMA 2014;312(5): Park HJ, Park SJ, Lee YM, Park CM, Seo JM. Efficacy of parenteral nutrition with intravenous l-alanyl-l-glutamine (dipeptiven inj) in intensive care unit patients. J Korean Soc Parenter Enter Nutr 2013;5(2): Hirose T, Shimizu K, Ogura H, Tasaki O, Hamasaki T, Yamano S, et al. Altered balance of the aminogram in patients with sepsis - the relation to mortality. Clin Nutr 2014;33(1): Volume 7, Number 2, August

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untitled SMN SURGICAL METABOLISM AND NUTRITION Vol. 9, No. 1, June, 2018 pissn 2233-5765, eissn 2465-8383 https://doi.org/10.18858/smn.2018.9.1.5 REVIEW ARTICLE 정맥글루타민보충의적정성여부 신동우 한림대학교의과대학동탄성심병원외과 Parenteral Glutamine