Focused Issue J Korean Diabetes 2018;19: Vol.19, No.4, 2018 ISSN 중환자실환자의혈당모니터링과인슐린치료 1,2 인제

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1 Focused Issue J Korean Diabetes 2018;19: Vol.19, No.4, 2018 ISSN 중환자실환자의혈당모니터링과인슐린치료 1,2 인제대학교의과대학내과학교실내분비대사내과 1, 인제대학교의과대학심혈관대사질환센터 2 Advances in Glucose Monitoring and Insulin Therapy in Intensive Care Unit Patients Tae Nyun Kim 1,2 1 Division of Endocrinology and Metabolism, Department of Internal Medicine, 2 Cardiovascular and Metabolic Disease Center, Inje University College of Medicine, Busan, Korea Abstract Since the multicenter Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study was published, the pursuit of tight glycemic control (TGC) among intensive care unit (ICU) patients has been seen as counterproductive and moderate glycemic control has become standard practice in ICUs. However, thus far, there is good evidence that hypoglycemia and hyperglycemia are associated with worse outcomes in ICU patients. Recently, the importance of improving time in band and reducing hypoglycemic episodes and glycemic variability has been more recognized. Compared to intermittent monitoring systems, continuous glucose monitoring (CGM) can have greater clinical benefit in terms of the prevention of severe hyperglycemia and hypoglycemia by enabling insulin infusions to be adjusted more rapidly and accurately. In this review, modern methods for glucose control in the ICU are presented, as well as future perspectives including the development of CGM and semiautomated glucose control, such as closed-loop systems. Keywords: Glucose, Hyperglycemia, Hypoglycemia, Insulin, Intensive care units Corresponding author: Tae Nyun Kim Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University Haeundae Paik Hospital, 875 Haeun-daero, Haeundae-gu, Busan 48108, Korea, kimtn031@gmail.com Received: Nov. 13, 2018; Accepted: Nov. 23, 2018 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. Copyright c 2018 Korean Diabetes Association 224 The Journal of Korean Diabetes

2 김태년 서론 고혈당은중환자집중치료실 (intensive care units, ICUs) 에입원하는급성기중환자에서흔히나타나는문제이며, 특히고혈당은당뇨병병력과관계없이다양한환자군에서좋지않은예후와관련이있다 [1-3]. 실제로혈당을정상에가깝도록적극적으로조절하면중환자의사망률을개선할수있을지에대한본격적인연구가시작된것은불과 20년정도에지나지않는다. 엄격한혈당조절 (tight glycemic control, TGC) 에대한논란의시작은 Van den Berghe 그룹에서 2001년 New England Journal of Medicine (NEJM) 에외과계중환자실을중심으로한연구 [4] 결과를발표하면서부터일것이다. 무작위대조연구에서혈당수치를 81~108 mg/dl 로엄격하게조절하는것이그당시보편적으로행하던혈당조절방법 (conventional glucose control, CGC) 에비해사망률을낮출수있다고보고하면서 TGC는지대한관심을모으게된다. 하지만 2006년 NEJM에같은그룹이발표한내과계중환자들을대상으로한연구 [5] 에서는유의한사망률개선이확인되지않았다. 2009년에는단일기관이아닌대규모다기관무작위대조연구결과가 NEJM에소개되었다 [6]. 42개병원의내과계및외과계중환자실에입원한지 24시간이내인 6,104명의중환자들을대상으로한이연구는무작위로혈당수치목표를 81~108 mg/dl로하는 TGC군과 180 mg/dl 미만으로하는 CGC 군의치료성적을비교했다. 일차평가변수는 90일사망으로정의하였는데 TGC군에서오히려사망률이높게나타났다 (27.5% vs. 24.9%; odds ratio, 1.14; 95% confidence interval, 1.02~1.28). 이러한결과는외과계환자와내과계환자사이에서도유의한차이를보이지않았다. TGC군에서는중증의저혈당이 6.8% 에서나타나 CGC 군의 0.5% 보다 10배이상많이발생하였다. 두군간에 ICU 재원일수와입원기간, 기계환기기간, 신대체요법여부에는유의한차이가없었다 [6]. Van den Berghe 그룹에서는첫번째연구이후중환자 에서혈당목표를정상혈당으로적극적으로조절할것을권고하였으나 [7-9], 이후의연구들에서일관적인결과를보여주지못함에따라현재까지의지침은 Van den Berghe 그룹에서제시한혈당목표 (80~110 mg/dl) 보다상향조정 (140~180 mg/dl) 하여조절할것을제시하고있고, TGC 효과에관한논란은잠시소강상태이나향후에다시재개될것으로보인다 [10-12]. 이전연구들에서 TGC의효과를일관성있게보여주지못한요인으로는설정된혈당의목표에도달하는데있어서각연구기관별능력의차이, TGC군에서의높은저혈당빈도와혈당변동폭등이제기되었다. 또한환자의혈당을감시하는기술적방법의한계 ( 부정확한혈당측정과적은횟수의혈당측정 ) 가 TGC 효과를제대로증명해내지못한중요요인으로지적되고있다. 본글에서는 ICU에서향후 TGC 효과를제대로증명하기위해해결되어야할과제들중에실시간연속혈당측정방법과이러한혈당측정감시시스템을기반으로한인슐린치료방법의문제점과발전방안에대해소개하고자한다. 중환자집중치료실에서의혈당측정의현재 ICU에서적극적인인슐린치료를하기위해서는실시간으로정확한혈당측정이이루어져야한다. 즉, 이상적인혈당측정은비침습적이면서, 신뢰할수있는혈당수치를연속적으로보여주는방법일것이다. 하지만이러한방법을임상적으로널리적용하기에는아직많은장벽이있다 [13,14]. 현재까지가장신뢰할만한혈당수치는환자의정맥또는동맥혈에서채취한혈액을중앙검사실에서검사한결과값일것이다. 하지만매시간인슐린용량을조절해야하는상황에서이러한방법으로는인슐린조절을적극적으로할수없다. 그대안으로휴대용현장검사 (point-of-care, POC) 방법으로정맥혈또는동맥혈에서혈당을감시하거나동맥혈가스분석기인비휴대현장검사용혈액분석장비를이용한방법으로혈당을측정할수있다. 실제로대부분병원의중환자실에서는빠른혈당검사결과를얻기위 225

3 Focused Issue 중환자실환자의혈당모니터링과인슐린치료 해 POC 휴대용혈당측정기또는동맥혈가스분석기로혈당을측정한다. ICU에비치되어있는동맥혈혈액가스분석기로혈당을측정할경우휴대용혈당측정기보다정확한수치를보여줄뿐만아니라, 혈액칼륨농도를제공해주기때문에인슐린용량증가에의한저칼륨혈증발생을대비할수있다 [15,16]. 휴대용현장검사혈당측정기도비휴대용혈액검사기에비해다른측면에서장점을가지고있다. 예를들어, 혈당을빠르게측정하기때문에훨씬자주측정하는데용이할뿐만아니라부피나비용및기기보정횟수 (calibration frequency), 그리고검사에필요한혈액양이소량이라는점에서충분한장점이있다 [17]. 하지만휴대용현장검사가반드시극복해야할부분은혈당수치의정확도를높이는것이다. 외래나일반병동에서검사의주된오류는시험지 (strip) 의잘못된보관이나유효기간이지난시험지사용으로인해측정효소의기능저하로발생하는경우가많다. 중환자실에서의 POC로혈당측정시오류가나타날수있는원인으로는시험지문제뿐만아니라, 중환자실환자의특성이피부의혈액순환이저하되어있고사지의혈색소, 산소포화도, ph도저하되어있는점, 그리고혈당측정에영향을주는약물을사용하는경우가많기때문에중심정맥또는동맥이아닌모세혈관혈액에서검사할경우혈당수치의정확도에문제가발생할가능성이더욱높아진다 [18,19]. TGC를시행한많은연구들에서휴대용 POC 혈당측정기를이용하여인슐린양을조절하였고 Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR) 연구에서도가능한한혈당측정은동맥관 (arterial catheter) 을통한방법으로측정하고모세혈관혈액의사용을자제하도록하였으나, 실제연구에서는 POC, 동맥혈가스분석기, 또는중앙실험실에서기관별로제각각측정을하였다. TGC 의긍정적인효과를보여준 van den Berghe 등 [4] 의첫번째연구에서는혈당측정을동맥혈가스분석기 (ABL700; Radiometer Medical, Copenhagen, Denmark) 를이용하여혈당을정확하게측정하였고이를기준으로인슐린용량을조절하였다. 하지만현실적으로이러한방법으로혈당을 측정하는것을유지하기란매우어려운일이다. Van den Berghe 등 [5] 의두번째연구에서도동맥혈가스분석기로혈당을측정하였으나, 동맥혈측정이어려울경우에는 POC 방법으로모세혈관혈액을이용하여혈당을측정하였다. 인슐린용량결정시휴대용 POC 측정법과동맥혈가스분석기또는중앙실험실측정치와비교한연구에서 POC 혈당측정기로측정하였을경우인슐린용량조절의잦은오류가발생하였음을보고한바있다 [20]. 또한다른연구에서는 1 휴대용 POC 혈당기기로모세혈관혈액, 2 POC 혈당측정기로동맥혈, 3 동맥가스분석기로동맥혈혈당을측정한것을중앙실험실에서측정한혈당을기준치로하여비교한연구가있었다 [21]. 이연구에서는동맥가스분석기로동맥혈혈당을측정한혈당수치 (3 방법 ) 가 POC 혈당기기로측정한 1과 2방법보다오히려낮게측정되었다. 결국이러한혈당측정수치의차이는인슐린용량조절에도영향을주므로 TOC의부정적인결과를초래한원인으로작용했음을의심하게할뿐만아니라실제임상에서혈당조절을위한인슐린주입프로토콜의적용시혈당이예상대로조절되지않는문제로나타나게된다. 현재까지중환자실사용이허가가난 POC 혈당측정제품도동맥혈과정맥혈에서가능하며모세혈관의혈액용으로는승인받지못했다. 미국식품의약국 (U.S. Food and Drug Administration) 에서도예전에비해혈당측정기의승인가이드라인을좀더엄격하게하고있으나 [17], 실제임상에서요구되는수준까지는따라가지못하고있는상황이다. 중환자집중치료실에서의혈당측정의미래 미래에 ICU 환자의혈당은실시간및자동적으로연속해서측정하는방법으로전환될가능성이높아지고있다 [22,23]. 이러한실시간연속혈당측정은목표혈당의낮은수치와높은수치사이에서벗어날조짐이있을경우미리알려주거나이미안전하지않은혈당수치에도달한경우경고신호를주게된다 [24,25]. 인간의생리적현상은일시적이아닌연속적인선상에서이루어지는만큼, 간헐적으로 226

4 김태년 혈당측정하는것에비해연속적으로측정할경우고혈당과저혈당의빈도를낮추어줄수있고혈당의변동폭도줄여줄수있을것이다 [26-28]. 또한간호업무량을경감시킬수도있을것이다. 그러나연속혈당측정법이중환자의생존기간, 중환자실입원기간, 합병증, 그리고기관유지장치의필요성에차이를줄수있을것인가에대한질문에답을찾기위한연구는아직부족한상황이다 [29]. 최근까지십여종이넘는연속혈당측정장치가개발되었고유럽과미국에서승인을받기위한연구가진행되었다. 각각의연속혈당측정기는다양한방법적인측면에서차별점이있다. 정맥혈, 동맥혈, 또는간질액등혈당을획득하는샘플의위치, 센서의위치, 혈당을측정하는방법 ( 전기화학 / 효소법, 분광분석등 ), 측정빈도등이각각다르다. 결국모든연속혈당측정기는각각의방법적인차이와한계로인해다른문제점이발생하게되는데기기별로잦은보정이필요한경우가있고, 혈관내에카테터를이용하여샘플을채취하는경우는혈관의폐색또는혈전의문제등이생길위험이높아진다. 현재까지연속혈당측정기를평가하는연구들이혈당측정의정확도측면에주로초점을맞추어진행되었다면, 향후에는새로운연속혈당측정기가어떠한임상적이득을주는지를확인하는연구들이진행되어야할것이다. 중환자집중치료실에서의정맥인슐린치료 자동화 (automation) 는여러산업의전반에걸쳐생산성과품질의향상에기여하고있으며널리활용되고있다. 하지만의료계에서는다른산업계와비교해볼때매우느리게적용되고있다. ICU에서의혈당조절은이러한자동화방식을적용하는데의료계에서가장이상적인분야일것이다. 이미이러한방향으로여러기술들이축적되고있으나자동혈당조절장치가실제많은기관에적용되기까지는아직넘어야할많은장벽이있다. 현재로서는이러한기기의안전성에대한우려와기기사용에대한규제로인해상업적인개발에한계가있는상황이다. 전통적인방식의인슐린용량조절프로토콜은자주또 는간헐적으로측정한혈당수치에기초하여인슐린용량을조절할수있도록만들어져있다. 여러 TGC를이용한연구에서사용한프로토콜들중에각기관에맞는양식으로수정하여사용하는데, 이중에서많은기관에서응용하여사용하고있는예일대학교 (Yale University) 의 Yale New Haven Hospital에서만들어진프로토콜은 3가지주요데이터인 1 현재의혈당수치, 2 이전의혈당수치, 3 현재주입되고있는인슐린용량에기초하여만들어졌다 [30]. 이프로토콜은다시말하면, 현재혈당에만기초한것이아니라, 혈당변화속도까지감안한것이라하겠다. 하지만이러한전통적인문서 (paper) 기반프로토콜의가장큰단점은기관마다만들어놓고는잘사용하지않고있다는점이다. 이를해결하기위해서는병원내의처방전달시스템과연계된프로토콜이필요할것이다. 자동혈당측정이개발되면서이를기반으로하는컴퓨터 (computer) 기반인슐린주입알고리듬이개발되고있다. 많은 ICU에서사용하고있지는않지만, Stochastic TARgeted (STAR), LOGIC-Insulin, enhanced model predictive control (empc), Glucose Regulation for Intensive care Patients (GRIP), Glucosafe, 그리고 Contrôle Glycémique Assisté par Ordinateur (CGAO) 가각각의연구를거쳐일부기관에서사용중에있다 [31-36]. 이들시스템이다소복잡하지만, 문서기반프로토콜에비해혈당변동성을줄여주고연속혈당측정장치와연동하여자동, 실시간으로혈당을조절할수있는기능을갖출수있다는점이장점이다. 연속혈당측정과컴퓨터기반의인슐린조절프로토콜이확립된다면자동혈당조절시스템, 즉 closed-loop 시스템의개념으로조절할수있게되는데, 이러한시스템은새로운개념이아니라이미 40년전에 Biostator라는인공췌장 (artificial pancreas) 시스템으로임상시험을진행한바가있다 [37]. 최근에개발된 closedloop 혈당조절장치라고불릴만한기기들은과거의기기들에비해점점더소형화되면서정확도도향상되고있다. 이러한새로운장치로중환자실환자들을대상으로한연구에서전통적인비자동화방법에비해저혈당을개선하고목 227

5 Focused Issue 중환자실환자의혈당모니터링과인슐린치료 표혈당내에유지하는시간의비율 (time in band) 을향상시켰음을보여주고있다 [38-40]. 각각의연속혈당측정법과인슐린주입프로토콜이소개가되고있지만혈당조절의정확성과질적측면을평가하는기준이명확하지않아이를표준화하는것이선행되어야하겠다. 또한연속혈당측정과이를이용한자동인슐린주입장치가기존의간헐적혈당측정방법으로인슐린을주입하는방식에비해이환율과사망률개선에영향을주는지확인하는대규모무작위대조연구가필요하겠다. 결론 ICU 환자들에서고혈당과저혈당모두나쁜예후와관련이있음은명백하게밝혀져있다. 하지만 NICE-SUGAR 연구결과이후엄격한혈당조절에관한논의는멈추어져있는듯하다. 물론, 그동안노출된 TGC의문제점을개선하기위한노력은계속되고있다. 특히, 연속혈당측정법과인슐린주입프로토콜이진화하고있다. 연속혈당측정법은목표혈당내로유지하는시간비율을증가시키고, 혈당변동성을낮추고, 의료진의업무량을줄여주는장점을보여주었고, 인슐린주입프로토콜은전통적인방식인문서기반에서컴퓨터로자동계산되는방식으로발전하였고, 최근에는연속혈당측정과연계한 close-loop 시스템방식까지개발되었다. 앞으로는연속혈당측정법과이를이용한인슐린주입시스템으로 TGC를하였을때기존의간헐적혈당측정방식으로혈당을조절한것에비해향상된임상적인성과및비용효과적임을증명해내야한다. 아직해결해야할많은장벽이있으나, 혈당측정법과알고리듬및인슐린주입장치의발전으로그동안멈추어져있는 TGC에관한논의는향후계속될것으로보인다. REFERENCES 1. Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke 2001;32: Weir CJ, Murray GD, Dyker AG, Lees KR. Is hyperglycaemia an independent predictor of poor outcome after acute stroke? Results of a long-term follow up study. BMJ 1997;314: Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab 2002;87: van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345: Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354: NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Bellomo R, Cook D, Dodek P, Henderson WR, Hébert PC, Heritier S, Heyland DK, McArthur C, McDonald E, Mitchell I, Myburgh JA, Norton R, Potter J, Robinson BG, Ronco JJ. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009;360: ACE/ADA Task Force on Inpatient Diabetes. American College of Endocrinology and American Diabetes Association Consensus statement on inpatient diabetes and glycemic control. Diabetes Care 2006;29: Garber AJ, Moghissi ES, Bransome ED Jr, Clark NG, Clement S, Cobin RH, Furnary AP, Hirsch IB, Levy P, Roberts R, Van den Berghe G, Zamudio V; American College of Endocrinology Task Force on Inpatient Diabetes Metabolic Control. American College of Endocrinology position statement on inpatient diabetes 228

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R