Focused Issue J Korean Diabetes 2015;16: Vol.16, No.1, 2015 ISSN 중환자에서의혈당조절의목표 김현민, 김재택중앙대학교

Size: px

Start display at page:

Download "Focused Issue J Korean Diabetes 2015;16: Vol.16, No.1, 2015 ISSN 중환자에서의혈당조절의목표 김현민, 김재택중앙대학교"

수영 조
5 years ago
Views:

1 J Korean Diabetes 2015;16:18-24 Vol.16, No.1, 2015 ISSN 김현민, 김재택중앙대학교의과대학내분비대사내과 Glycemic Targets for the Critically Ill Patient Hyun Min Kim, Jaetaek Kim Division of Endocrinology and Metabolism, Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea Abstract Critically ill patients often experience hyperglycemia, which may be associated with increased morbidity and mortality. In 2001, van den Berghe et al. suggested significant benefit of normalization of blood glucose level in critically ill patients using intensive intravenous insulin therapy. Subsequent multicenter randomized studies, however, demonstrated adverse effects of tight glucose control. Therefore, while the need for glucose control in critically ill patients is generally accepted, the treatment thresholds for initiation of insulin therapy or target glucose values are still undetermined. Furthermore, occurrence of a hypoglycemic event during intensive insulin therapy is known to be an independent predictor of clinical outcome, and glycemic variability is an important variable of glucose management in the critically ill patients. Novel technological approaches such as a continuous glucose monitoring system (CGMS) might help to overcome some problems of tight glucose control by reducing the risk of hypoglycemia and minimizing glycemic variability. Keywords: Critical illness, Hyperglycemia, Intensive care units 서론 중환자에게서고혈당은흔히관찰되며, 당뇨병을진단받 은적이없는경우에도동반되는경우가많다 [1]. 고혈당은좋지않은예후와관련된다는사실이잘알려졌고, 정상에가까운적극적인혈당조절을통해중환자의사망률을감소 Corresponding author: Jaetaek Kim Division of Endocrinology and Metabolism, Department of Internal Medicine, Chung-Ang University College of Medicine, 84 Heukseok-ro, Dongjak-gu, Seoul , Korea, jtkim@cau.ac.kr 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 2015 Korean Diabetes Association 18 The Journal of Korean Diabetes

2 김현민외 시켰다는초기연구를바탕으로철저한혈당조절의필요성이강조되어왔다 [2]. 그러나이후연구에서는적극적혈당조절이사망률에차이를가져오지않았으며특히중증저혈당이의미있게증가하는결과를보여주었다 [3,4]. 본고찰에서는집중치료실에서적극적인인슐린치료에관한연구결과를소개하고, 일반적으로권고되는혈당조절의목표와고혈당, 저혈당, 혈당변동성각각의혈당조절의요소가갖는임상적의미를검토하고자한다. 또한저혈당의위험을낮추고혈당변동성을최소화하면서안전하게고혈당을조절할수있는신의료기술의적용에대해간단히소개하겠다. 근거중심의관련연구 중환자실에서의고혈당관리의중요성을밝힌가장초기의대규모연구는 van den Berghe 등 [2] 의 Leuven 연구이다. 이는 1,548명의외과계중환자실환자들을대상으로한단일기관의연구로 60% 이상이심장수술을받은환자들이었다. 혈당을정상혈당범위인 80~110 mg/dl를목표로조절한군과 180~200 mg/dl 까지허용한대조군을비교하였으며, 혈당은동맥혈을통해지속적으로측정했고, 중심정맥을통해지속적인정맥인슐린주입요법을시행하였다. 이연구에서는철저한혈당조절이사망률을의미있게감소시켰을뿐아니라패혈증의발생, 응급투석, 기계호흡기 간, 수혈등관련이병률 (morbidity) 에서도호전을보였다. 같은연구진들은내과계중환자실환자 1,200명을대상으로도연구를시행하였으며, 원내사망률에서는큰차이가없었으나 3일이상중환자실재원이필요했던경우에는철저한혈당조절이사망률및재원기간을단축시켰다 [5]. 하지만이후발표된여러연구에서는철저한혈당조절의효과를입증하지못하였다. Volume Substitution and Insulin Therapy in Severe Sepsis 연구는 17개의기관에서 488명의환자들을대상으로이루어진전향적연구이나, 재원 28일과 90일후사망률에차이가없었고, 적극적인혈당조절군에서저혈당의발생이의미있게증가되어조기에종료되었다 [3]. Glucontrol 연구도철저한혈당조절군에서사망률의감소없이저혈당발생이높아져조기종료되었다 [6]. 2009년에발표된 Normoglycemia in Intensive Care Evaluation: Survival Using Glucose Algorithm Regulation (NICE-SUGAR) 연구는중환자실에입원하여 3일이상중환자실치료가예상되는 6,100여명의환자를대상으로하였으며, 목표혈당이 81~108 mg/dl인적극적인혈당조절군과 180 mg/dl 미만을목표로하는고식적치료군으로나누어사망률을비교하였다. 90일이내사망률은적극적인혈당조절군에서오히려 14% 더높게나타났으며, 외과계와내과계환자사이에차이는없었다. 40 mg/dl 이하의중증저혈당은적극적혈당조절군에서 10배이상많이나타났다 [4]. 이후체계적고찰연구에서는 110 mg/dl 미 Table 1. Summary of current professional society guideline for glycemic control in critical illness Organization Year Patient population Treatment threshold for initiation of intensive insulin therapy (mg/dl) Target glucose level (mg/dl) Korean Diabetes Association [11] 2011 Critical ill patients ~180 American Diabetes Association [10] 2015 ICU patients ~180 Surviving Sepsis Campaign [12] 2013 ICU patients American Heart Association [13] 2012 ICU patients with acute 180 < 180 coronary syndromes American College of Physicians [14] 2014 ICU patients 140~200 ICU, intensive care unit. 19

3 만을목표로하여적극적인인슐린치료를시행하는것은패혈증을감소시켰으나, 전체적인사망률을줄이지는못하였으며, 다만외과계중환자실환자의경우에만사망률을감소시키는것을확인하였다. 그러나저혈당의발생은 5배가량높았다 [7]. NICE-SUGAR 연구를포함한최근의고찰연구에서도마찬가지로적극적인혈당조절은사망률을의미있게줄이지못하였고, 저혈당의발생은 6배증가시켰다 [8]. mg/dl를넘는환자들에게서사망률은 42.5% 까지증가하였으며, 평균혈당은원내사망률의독립적인관련인자였다 [22]. 앞에서살펴본연구들중중환자에게서혈당조절의효과를입증했던 Leuven 연구에서대조군의혈당의상한치는 180~200 mg/dl였다 [2,5]. 따라서중환자에서적어도혈당을 180 mg/dl 이상으로허용하지는않도록적극적인노력이필요함은명백하다. 혈당조절의목표 2. 저혈당 Leuven 연구이후중환자에서정상혈당을목표로철저한혈당조절이권고되었으나 [9], 이후대규모연구와체계적고찰연구에서일관적인결과를보여주지못함에따라적절한혈당치의기준에대해서는아직은논란의여지가있다. 최근미국당뇨병학회의권고안에서는중증저혈당의위험도를줄일수있도록 180 mg/dl 이상인경우인슐린치료를시작하고, 목표혈당은 140~180 mg/dl로조절하도록하였으며 [10], 주요학회의권고안은 Table 1과같다 [10-14]. 또한중환자에서혈당조절의목표를세울때에중요한점은, 단순히혈당만을낮추는것만이아니라, 저혈당, 그리고혈당변동성이라는각각의요소를모두고려해야한다는것이다 [15]. 1. 고혈당고혈당은다형핵백혈구의기능을저하시키고 [16], 세포자체의살균작용을저해하며 [17], 이로인해감염의위험을높인다 [18]. 또한미토콘드리아단백질에손상을일으키고 [19], 면역력을감소시키며 [20], 혈관내피세포의산화질소생성을억제하고, 말초순환장애를일으킬수있다 [21]. 고혈당이사망률및이환율을증가시킬수있음은잘알려져있다. 1,826명의중환자를대상으로한관찰연구에서는평균혈당이증가할수록원내사망률이증가하는것을보고하였다. 평균혈당이 80~99 mg/dl로유지된환자들에게서사망률은 9.6% 로가장낮았고, 평균혈당이 300 중환자실에서혈당이 40 mg/dl 미만으로감소하는중증저혈당의빈도는 5.1% 에서 19% 까지보고된다 [23]. 내과계중환자나패혈증을동반한경우에더흔하게나타나며 [24], 여성, 당뇨병의과거력, 간기능및신기능장애, 인슐린주사경로의변경 ( 정맥주입요법에서피하요법 ), 영양요법의변경, 승압제의투여, 스테로이드중단혹은감량등이저혈당발생의위험인자로알려져있다 [25]. 저혈당발생은철저한혈당조절을시도한임상연구에서확실히더증가했다. NICE-SUGAR 연구에서중등도의저혈당 (40~70 mg/dl) 은전체의 45% 의환자에게서발생하였는데, 그중 85% 가적극적인혈당조절군이었고, 40 mg/ dl 미만의중증저혈당은총 3.7% 에서발생하였는데대부분이적극적인혈당조절군이었다. 또한모든환자에게서저혈당이없었던경우사망률이 23.5%, 중등도의저혈당이있었던경우 28.5%, 중증저혈당이있었던경우 35% 로나타났으며, 저혈당의발생자체는사망률을 1.41배높이는것으로나타났다 [4]. 이와는달리 Leuven 연구에서는적극적인혈당조절군에서도 40 mg/dl 미만의중증저혈당의발생이 5.1% 로다른연구들과비교하여현저히낮았다 [2]. 단일기관에서지속적인혈당모니터링기술, 프로토콜화된정맥영양요법및환자와간호사의비율이 1:1이었던점등이저혈당의위험을낮출수있었고, 저혈당의낮은발생률이긍정적인결과를가져왔을가능성이있다. 고혈당을낮추고자하는노력은필연적으로저혈당의위험을증가시킨다. 중환자에게서저혈당이발생하여경련등 20

4 김현민외 심각한합병증이나타났을때는쉽게발견할수있지만, 불안이나발한, 심계항진, 의식저하등과같은증상은집중치료상태에서진정제를지속적으로투여하는상황에서는알아채기가거의불가능하다 [26]. 따라서중환자에게서안전하고효과적인혈당조절을위해서는, 저혈당을빨리알아채고대처할수있는다양한프로토콜이반드시필요하겠다. 3. 혈당변동성최근연구들에따르면, 혈당변동성이큰것은환자의좋지않은예후와관련이있다. 7,049명의중환자를대상으로한연구에서혈당변동성이집중치료실내사망률과원내사망률의독립적인위험인자인것을확인하였다 [27]. 5,728명을대상으로한후향적연구에서는혈당변동성이높으면서평균혈당이높은군에서사망률이가장높았으며, 평균혈당이높더라도혈당변동성이낮을경우에는사망률이크게증가하는것을막을수있었다 [28]. 따라서혈당변동성은매우중요한변수이며, 중환자의혈당조절에있어서반드시고려되어야하는부분이다. 혈당의급격한변화는세포자멸사를유도하고 [29], 산화스트레스를높인다 [30]. 이는혈관내피세포의기능부전을일으키고혈관에손상을야기하며, 혈관수축, 미세혈관혈전및염증반응의증폭에관여한다 [31]. 앞에서살펴보았던지속적인인슐린치료의효과를확인하고자했던과거의연구들은상반되는결과를보였다 [2-6]. 위연구들에서혈당변동성에대한충분한검사가시행되지는못하였으나, 혈당변동성이중요한영향을미쳤을가능성이있겠으며, 이에대한추가적인전향적연구가혈당변동성의중요성을밝히는것에도움이될수있겠다. 을수있는이득을반감시키는것은분명하다. 따라서중환자에게인슐린을투여할때지속적혈당감지시스템 (continuous glucose monitoring system, CGMS) 을도입하는것은저혈당의발생위험을낮추고혈당변동성을감소시킬수있는좋은방안이될수있을것이다. 그러나 124명의중환자를대상으로 80~110 mg/dl의혈당을목표로조절하며 CGMS의유용성을확인한연구에서는, 중증저혈당의발생은의미있게낮추었으나혈당조절정도나사망률에서는차이를보이지않았다 [32]. 간질액내의포도당이아닌혈액내의포도당을측정할수있는센서의상용화등기술적인발전과함께중환자에게서 CGMS의정확도와효과에대한추가적인연구가필요하겠다 [33]. 결론 중환자에게서혈당조절이필요하다는사실은명백하나, 과연얼마까지낮추어야하는지에대해서는아직논란의여지가있다. 여러관찰연구및최근의대규모전향적연구결과를고려하였을때일반적인중환자의경우에는 140~180 mg/dl 정도를목표로조절하며, 180 mg/dl 이상일경우지속적인슐린요법을시작하는것을권고하는것이바람직하다. 그러나지속적인슐린요법을시행하는도중에발생하는중증저혈당은철저한혈당조절로인한이득을상쇄시키고오히려환자의사망률이나이환율에좋지않은영향을미치므로철저한주의를요하며, 혈당변동성자체도예후와관련된다는보고가있어이에대한관리도필요하다. 최근여러병원에서사용중인 CGMS 등신의료기술을중환자에게활용하는것이저혈당의위험을최소화하고혈당변동성을낮추어, 안전하고효과적인혈당조절에도움이될수있을것으로기대된다. 신의료기술의적용 REFERENCES 중환자실환자에게서적극적인혈당조절을하는중에발생한의도치않은저혈당은정상에가까운혈당조절로얻 1. Levetan CS, Passaro M, Jablonski K, Kass M, Ratner RE. Unrecognized diabetes among hospitalized patients. 21

5 Diabetes Care 1998;21: 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: Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, Olthoff D, Jaschinski U, John S, Rossaint R, Welte T, Schaefer M, Kern P, Kuhnt E, Kiehntopf M, Hartog C, Natanson C, Loeffler M, Reinhart K; German Competence Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008;358: 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: 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: Preiser JC, Devos P, Ruiz-Santana S, Mélot C, Annane D, Groeneveld J, Iapichino G, Leverve X, Nitenberg G, Singer P, Wernerman J, Joannidis M, Stecher A, Chioléro R. A prospective randomised multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units: the Glucontrol study. Intensive Care Med 2009;35: Wiener RS, Wiener DC, Larson RJ. Benefits and risks of tight glucose control in critically ill adults: a meta-analysis. JAMA 2008;300: Kansagara D, Fu R, Freeman M, Wolf F, Helfand M. Intensive insulin therapy in hospitalized patients: a systematic review. Ann Intern Med 2011;154: 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: American Diabetes Association. 13. Diabetes Care in the Hospital, Nursing Home, and Skilled Nursing Facility. Diabetes Care 2015;38(Suppl 1):S Korean Diabetes Association: Treatment guideline for diabetes. 4th ed. Seoul: Gold Planning and Development; p Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, Intensive Care Med 2013;39: Writing Committee Members, Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE Jr, Ettinger SM, Fesmire FM, Ganiats TG, Lincoff AM, Peterson ED, Philippides GJ, Theroux P, Wenger NK, Zidar JP, Anderson JL; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-st-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2012;126:875-22

6 김현민외 Qaseem A, Chou R, Humphrey LL, Shekelle P; Clinical Guidelines Committee of the American College of Physicians. Inpatient glycemic control: best practice advice from the Clinical Guidelines Committee of the American College of Physicians. Am J Med Qual 2014;29: Todi S. Glycemic control in critically ill: A moving target. Indian J Crit Care Med 2014;18: Rassias AJ, Marrin CA, Arruda J, Whalen PK, Beach M, Yeager MP. Insulin infusion improves neutrophil function in diabetic cardiac surgery patients. Anesth Analg 1999;88: Nielson CP, Hindson DA. Inhibition of polymorphonuclear leukocyte respiratory burst by elevated glucose concentrations in vitro. Diabetes 1989;38: Rayfield EJ, Ault MJ, Keusch GT, Brothers MJ, Nechemias C, Smith H. Infection and diabetes: the case for glucose control. Am J Med 1982;72: Van den Berghe G. How does blood glucose control with insulin save lives in intensive care? J Clin Invest 2004;114: Amour J, Brzezinska AK, Jager Z, Sullivan C, Weihrauch D, Du J, Vladic N, Shi Y, Warltier DC, Pratt PF Jr, Kersten JR. Hyperglycemia adversely modulates endothelial nitric oxide synthase during anesthetic preconditioning through tetrahydrobiopterin- and heat shock protein 90-mediated mechanisms. Anesthesiology 2010;112: Nazir FS, Alem M, Small M, Connell JM, Lees KR, Walters MR, Cleland SJ. Blunted response to systemic nitric oxide synthase inhibition in the cerebral circulation of patients with Type 2 diabetes. Diabet Med 2006;23: Krinsley JS. Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients. Mayo Clin Proc 2003;78: Weston A, Caldera K, Doron S. Surgical care improvement project in the value-based purchasing era: more harm than good? Clin Infect Dis 2013;56: Bagshaw SM, Egi M, George C, Bellomo R; Australia New Zealand Intensive Care Society Database Management Committee. Early blood glucose control and mortality in critically ill patients in Australia. Crit Care Med 2009;37: Arabi YM, Tamim HM, Rishu AH. Hypoglycemia with intensive insulin therapy in critically ill patients: predisposing factors and association with mortality. Crit Care Med 2009;37: Boord JB, Graber AL, Christman JW, Powers AC. Practical management of diabetes in critically ill patients. Am J Respir Crit Care Med 2001;164: Egi M, Bellomo R, Stachowski E, French CJ, Hart G. Variability of blood glucose concentration and shortterm mortality in critically ill patients. Anesthesiology 2006;105: Hermanides J, Vriesendorp TM, Bosman RJ, Zandstra DF, Hoekstra JB, Devries JH. Glucose variability is associated with intensive care unit mortality. Crit Care Med 2010;38: Risso A, Mercuri F, Quagliaro L, Damante G, Ceriello A. Intermittent high glucose enhances apoptosis in human umbilical vein endothelial cells in culture. Am J Physiol Endocrinol Metab 2001;281:E Schiekofer S, Andrassy M, Chen J, Rudofsky G, Schneider J, Wendt T, Stefan N, Humpert P, Fritsche A, Stumvoll M, Schleicher E, Häring HU, Nawroth PP, Bierhaus A. Acute hyperglycemia causes intracellular formation of CML and activation of ras, p42/44 MAPK, and nuclear factor kappab in PBMCs. Diabetes 2003;52: Monnier L, Mas E, Ginet C, Michel F, Villon L, Cristol JP, Colette C. Activation of oxidative stress by acute 23

7 glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA 2006;295: Holzinger U, Warszawska J, Kitzberger R, Wewalka M, Miehsler W, Herkner H, Madl C. Real-time continuous glucose monitoring in critically ill patients: a prospective randomized trial. Diabetes Care 2010;33: Haluzik M, Mraz M, Kopecky P, Lips M, Svacina S. Glucose control in the ICU: is there a time for more ambitious targets again? J Diabetes Sci Technol 2014;8:

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract