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1 대한내과학회지 : 제 79 권제 5 호 2010 중증패혈증및패혈증쇼크환자에게서파종성혈관내응고의빈도및예후 한림대학교의과대학성심병원호흡기내과 김용민 권영석 김주석 김성열 장길수 이석원 안영환박성훈 황용일 장승훈 정기석 김동규 Incidence and prognosis of disseminated intravascular coagulation in patients with severe sepsis or septic shock Yong-Min Kim, M.D., Young-Seok Kwon, M.D., Ju-Seok Kim, M.D., Seong-Yeol Kim, M.D., Gil-Su Jang, M.D., Seok Won Lee, M.D., Young-Hwan An, M.D., Sunghoon Park, M.D., Yong Il Hwang, M.D., Seung Hun Jang, M.D., Ki-Suck Jung, M.D., and Dong-Gyu Kim, M.D. Department of Pulmonary, Allergy and Critical Care Medicine, Hallym University Sacred Heart Hospital, Anyang, Korea Background/Aims: We investigated the incidence and prognosis of disseminated intravascular coagulation (DIC) using DIC scoring system in patients with severe sepsis or septic shock. Methods: Patients admitted to the intensive care unit (ICU) in a tertiary hospital for severe sepsis or septic shock were enrolled from Mar to Feb Using the International Society on Thrombosis and Haemostasis (ISTH) criteria, we calculated DIC score at three time points (Day 0, Day 1, and Day 2). Results: Among 111 patients with severe sepsis or septic shock, 89 (severe sepsis, 8; septic shock, 81) were enrolled. Mean DIC score at ICU admission was 3.3±1.3 and the incidence of overt DIC (DIC score 5) during the first 48 hours was 33.8% (27/89). Sequential Organ Failure Assessment (SOFA) score was well correlated with DIC score and was higher in patients with overt DIC than in those without. The ICU, hospital and 28-day death rates in patients with overt DIC were 63.0%, 66.7%, and 63.0%, respectively, which were significantly higher than in those without overt DIC. In multivariate analysis, Simplified Acute Physiology Score (SAPS) II was significantly associated with hospital death (p=02), and the occurrence of overt DIC showed a borderline significance (p=53). Conclusions: Using the ISTH criteria for DIC, the incidence of overt DIC was 33.8% in patients with severe sepsis or septic shock. The occurrence of overt DIC was associated with a higher organ failure score and hospital outcomes. (Korean J Med 79: , 2010) Key Words: Disseminated intravascular coagulation; Organ failure; Sepsis Received: Revised: Accepted: Correspondence to Dong-Gyu Kim, M.D., Division of Pulmonary, Allergy and Critical care Medicine, Hallym University Sacred Heart Hospital, 896 Pyeongchon-dong, Dongan-gu, Anyang , Korea dongyu@hallym.or.kr

2 - Yong-Min Kim, et al. Disseminated intravascular coagulation in severe sepsis or septic shock - 서 론 대상및방법 파종성혈관내응고 (disseminated intravascular coagulation, DIC) 는혈액응고체계가활성화되면서미세혈관혈전증이발생하는질환이다. 이는혈액응고인자의과다한소모로인해출혈성경향을보이고, 결국엔다기관기능부전 (multi-organ failure) 에이르게되어높은사망률을보일수있다 1,2). 패혈증혹은패혈증쇼크에서는여러가지내독소및조직인자에의해서혈액응고체계가활성화될수있는데, 이로인해 DIC가발생하고다기관기능부전에이를수있다 3-5). 현재중환자치료의많은발전에도불구하고중증패혈증환자의사망률은아직까지 30~50% 에이르고있다 6,7). 감염에대한인체내에서의염증반증 (inflammatory response) 과응고인자 (coagulation system) 의활성화는밀접하게연관되어있다. Tumor necrosis factor α, interleukin-1β, interleukin-6 등의염증성사이토카인들은응고체계를활성화시키고, 섬유소용해 (fibrinolysis) 작용을억제시키기도하지만, 반대로응고인자의활성화가여러가지염증성경로를활성화시키기도한다. 이로인해결국혈관손상이일어나게되고, 다기관기능부전이발생하게된다 8-10). 중환자실에서사용되고있는중증도지표인 Simplified Acute Physiology Score II (SAPS II) 와 Sequential Organ Failure Assessment (SOFA) 는여러연구를통해그타당성이입증되었으나, 이들점수체계에서혈액응고장애가차지하는비중은높지않다. 특히중증도가높은환자들에게서이들점수체계만으로는 DIC의발생이예후에미치는영향을파악하기는어렵다. 아직까지 DIC를진단할수있는표준화된실험실진단법은없다. 2001년에 The International Society of Thrombosis and Haemostasis (ISTH) 에의해서 DIC의진단을위한점수체계가고안되었는데, 이후로이점수체계가 DIC의진단에민감도와특이도가높다는연구도발표되었다 11,12). 패혈증환자에게서는 DIC의발생률이 7~16% 정도되고, 패혈증쇼크에서는많게는 73% 까지이를수있다 13-16). 패혈증에서의높은사망률에도불구하고, 아직우리나라에서는패혈증및패혈증쇼크환자에서 DIC의발생률에대한연구는없다. 본연구에서는 3차기관의내과중환자실에입원한중증패혈증및패혈증쇼크환자를대상으로 DIC의발생률을확인하고이들과장기부전점수체계인 SOFA score 및사망률과의관련성을알아보고자하였다. 1. 연구대상 2008년 3월부터 2009년 2월까지한림대학교성심병원내과중환자실에입원한중증패혈증및패혈증쇼크환자를대상으로하였다. 18세이상의환자를대상으로하였고, 항응고치료를받는환자, 간부전 (child class C) 이나혈액암환자, 입원시심폐소생술을받거나적극적인치료를거부하는환자는본연구에서제외하였다. 본연구는 1년동안의전향적인연구로한림대학교성심병원임상연구심의위원회의승인을받았고, 본연구에참여하는환자에대해서는환자또는보호자에게동의서를받았다. 2. 연구방법연구자들은본연구에등록된환자들을대상으로나이, 성별및패혈증의원인을조사하였고, 입원시여러가지생화학검사및 lactic acid 수치와 SAPS II를구하였다. 추가로, 혈액응고검사를통하여입원당시 (Day 0), 입원 24시간 (Day 1), 입원 48시간 (Day 2) 의 DIC score 를구하였고, 각각의동일시점에서의 SOFA score 를계산하여 DIC score 와비교하였다. 중증패혈증및패혈증쇼크의정의는 2008년 Surviving Sepsis Campaign 의지침을근거로진단하였다 17). DIC score 는 2001년 Taylor 등에의해제안된 ISTH criteria를이용하였고, 여기에는혈소판 (platelet), 섬유소관련인자 (fibrin-related marker), 프로트롬빈시간 (prothrombin time), 섬유소원 (fibrinogen) 의 4개요소로구성되어있다 ( 표 1) 12). 본연구에서섬유소관련인자로는 D-dimer 를이용하였고, Bakhtiari 등의연구에서와같이정상범위는 0점 (<0.5 μg/ml), 정상범위의 10배이내인경우엔 1점 (0.5~5 μg/ml), 10배이상인경우엔 2점을주었다 (>5 μ g/ml). 총 8점의점수중에서 5점이상인경우를현성 DIC (overt DIC) 로진단하였다 11). DIC score 와여러가지생화학검사및 SAPS II, SOFA 점수간의관련성을조사하였고, 현성 DIC의발생에관련된인자를조사하였다. 중증패혈증및패혈증쇼크환자에서현성 DIC의발생빈도를조사하였고, 쇼크의회복여부, 중환자실사망, 병원사망, 28일사망을조사하여현성 DIC 군을비현성 DIC (non-overt DIC) 군과비교하였다. 3. 통계통계적분석에는 Microsoft Office Excel 2007과 SPSS 13.0 package (SPSS Inc. Chicago, IL, USA) 를이용하였다. 수치는

3 - 대한내과학회지 : 제 79 권제 5 호통권제 603 호 Table 1. International Society of Thrombosis and Haemostasis disseminated intravascular coagulation scoring system 11,12) Platelets >100,000 <100,000 <50,000 D-dimer (fibrin-related marker) <0.5 μg/ml 0.5~5 μg/ml >5 μg/ml Prolonged prothrombin time >3 sec 3~6 sec >6 sec Fibrinogen > g/l < g/l If score 5, compatible with overt DIC DIC, disseminated intravascular coagulation. 평균 ± 표준편차로표시하였고, 빈도는 % 로표시하였다. 연속형변수는 Student s t-test 혹은 Mann-Whitney U test를이용하였고, 명목형변수는 chi-square test 혹은 Fisher s exact test 를이용하여비교하였다. 단변량분석에서 p<5인변수를이용해다변량분석 ( 로지스틱회귀분석 ) 을시행하였고, 병원사망과의관련인자를조사하였다. Correlation coefficient를구하여변수간의관련성을조사하였고, receiver operating characteristics (ROC) curves를이용하여사망률예측에있어서의 ISTH criteria의유용성을알아보았다. 결과 1. 환자의특징및 DIC score 의분포연구기간동안한림대학교성심병원내과중환자실에 111 명의중증패혈증및패혈증쇼크환자가입원하였고, 제외기준에포함된 22명 ( 항응고치료, 4명 ; 간부전 [child class C], 5명 ; 혈액암, 3명 ; 심폐소생술, 5명 ; 치료거부, 5명 ) 을제외한총 89명의환자가선정기준에해당되었다. 이중중증패혈증은 8명, 패혈증쇼크은 81명이었다. 환자들의평균나이는 69.3±13.9세였고, 남자가 52명 (58.4%) 이었다. 환자들의입원시 SAPS II의평균점수는 53.8±15.3이었고, 패혈증의원인으로는폐렴 49명 (55.1%), 요로감염 13명 (14.6%), 간담도계감염 10명 (11.2%), 소화기감염 8명 (9.0%), 중심정맥관감염 3명 (3.4%), 피부및연조직감염 2명 (2.2%), 기타원인이 4명 (4.5%) 이었다. 입원시 DIC score 는평균값이 3.3±1.3이었고, DIC score 5 점인현성 DIC에해당하는환자의비율은 Day 0, Day 1, Day 2에서각각 18% (16/89), 30.7% (23/75), 22.4% (13/58) 를차지하였고 ( 그림 1), 입원 48시간동안한번이상 DIC score 5점인경우는 27명 (33.8%) 이었다. 중증패혈증에서는현성 DIC의발생빈도가 12.5% (1/8) 이었고, 패혈증쇼크에서는 47.2% (26/81) 로훨씬높았으나두군간에통계적차이는없었다. Patient number DIC score Figure 1. Distribution of DIC scores according to the ISTH (International Society on Thrombosis and Haemostasis) criteria in patients with severe sepsis or septic shock. 2. 현성 DIC 의관련된인자및 SOFA 점수와의관계 입원시의활력징후, 생화학검사, 중증도지표와의관련성을조사한결과백혈구 (p=30), hematocrit (p=03), 혈소판 (p<01), blood urea nitrogen (p=23), lactic acid (p=10), SOFA 점수 (p=01), SAPS II (p=43) 가현성 DIC의발생과의미있는관련성을보여주었고 ( 표 2), 로지스틱회귀분석을이용한다변량분석에서는혈소판 (Odds ratio [OR], 0.965; 95% confidence interval [CI], 0.947~0.982; p<01) 과 lactic acid (OR, 1.395; 95% CI, 04~1.938; p=43) 가현성 DIC의발생과의미있는관련성을보였다. DIC score 와 SOFA score 의상관관계분석에서는 Day 0, Day 1, Day 2 모두에서관련성을보여주었고 (r=0.384, p=09; r=0.538, p<01; r=0.543, p<01, respectively; 그림 2), 세시점에서현성 DIC 군이비현성 DIC 군보다평균 SOFA score 가유의하게높았다 (11.4±3.4 vs. 9.3±2.8, p=09; 12.1±3.6 vs. 7.3±3.0, p<01; 12.2±4.2 vs. 6.4±3.2, p<01, respectively). 3. DIC score 와병원예후 생존군과사망군사이의비교에서는 DIC score 와 SOFA score 모두세시점 (Day 0, Day 1 and Day 2) 에서의미있는차이를 Day 0 Day 1 Day

4 - 김용민외 11 인. 중증패혈증환자에게서파종성혈관내응고 - Table 2. Baseline characteristics of the patients with and without overt DIC Overt DIC (n=27) No overt DIC (n=62) p-value Age, years 66.3±12.3 7± Sex (male) 14 (51.9%) 38 (61.3%) 06 Severe sepsis/septic shock 1/7 26/55 26 Co-morbid illnesses Diabetes 8 (29.6%) 19 (3%) Hypertension 6 (22.2%) 17 (27.4%) 07 COPD/BA 3 (11.1%) 8 (12.9%) 13 Chronic kidney disease 1 (3.7%) 5 (8.1%) 51 Coronary artery disease 1 (3.7%) 4 (6.5%) 05 Cancer 8 (29.6%) 11 (17.7%) 08 Site of infection Pneumonia 12 (44.4%) 37 (59.7%) Urinary tract 4 (14.8%) 9 (14.5%) Hepatobiliary 3 (11.1%) 7 (11.3%) Systolic blood pressure, mm Hg 79.9± ± Heart rate (beats/min) 116.4± ± WBC, /mm 3 11,000 (5,000~18,900) 16,400 (10,675~22,100) 30 Hematocrit, % 28.5± ± Platelets, /mm 3 6 K (2 K~92.0 K) K (97.0 K~238.3 K) <01 Blood urea nitrogen, mg/dl 38.7 (24.0~5) 26.2 (16.3~38.5) 23 Creatinine, mg/dl 1.7 (~3.4) 1.1 (~2.025) 92 Bilirubin, mg/dl 1.2 (~3.4) 0.9 (~1.3) 88 Albumin, mg/dl 2.8± 3.0± C-reactive protein, mg/dl (11~274.0) (82.6~269.0) ph 7.32± ± Lactic acid, ug/l 4.9 (3.1~6.2) 2.7 (2.0~5.1) 10 SOFA score 11.2± ± SAPS II 58.7± ± DIC score 5.7± ±0.7 <01 DIC, disseminated intravascular coagulation; COPD, chronic obstructive pulmonary disease; BA, bronchial asthma; WBC, White Blood Cell; SOFA, sequential organ failure assessment score; SAPS II, simplified acute physiologic score II. 보여주었다 ( 그림 3). 쇼크의회복및병원사망과 28일사망을비교한결과에서는현성 DIC 군에서쇼크의회복이유의하게낮았고, 중환자실사망, 병원사망, 28일사망률도비현성 DIC 군보다유의하게높았다 ( 표 3). Surviving sepsis campaign 의초기치료지침 (resuscitation bundle) 에따라첫 6시간에치료목표 (i.e., central venous pressure 8~12 mm Hg, mean arterial pressure 65 mm Hg, urine output 0.5 ml/kg/hr, and ScvO 2 70% or SvO 2 65%) 에도달한 17) 환자의비율은현성 DIC 군 에서 37.0% (10/27), 비현성 DIC 군에서 50% (31/62) 로, 두군간의유의한통계적인차이가없었고, 생존군과사망군사이에서도유의한차이를보이지않았다. 생존군과사망군사이의단변량분석에서는간담도계패혈증 (p=38), hematocrit (p=10), 혈소판 (p<01), SOFA score (p=01), SAPS II (p<01), 현성 DIC (04) 가병원사망과의미있는차이를보여주었다. 이변수들을이용해다변량분석을시행한결과, SAPS II (OR, 64; 95% CI,

5 - The Korean Journal of Medicine: Vol. 79, No. 5, A B C Figure 2. Correlations between DIC and SOFA scores. The DIC scores were relatively well correlated with the SOFA scores on Days 0 (A), 1 (B), and 2 (C) (r=0.384, p=09; r=0.538, p<01; r=0.543, p<01, respectively) ISTH score 3 2 SOFA 6 4 Survivors Survivors 1 Non-survivors 2 Non-survivors 0 A Day 0 Day 1 Day 2 B 0 Day 0 Day 1 Day 2 Figure 3. Comparison of DIC and SOFA scores between survivors and non-survivors. The DIC scores were significantly higher in survivors than in non-survivors on Days 0, 1, and 2 (p=04, p<01, and p=01, respectively) (A). The SOFA scores were significantly higher in survivors than in non-survivors on Days 0, 1, and 2 (p=01, p<01, and p=01, respectively) (B). Table 3. Comparison of the hospital outcomes between patients with and without overt DIC Overt DIC (n=27) Non-overt DIC (n=62) p-value Shock recovery 12 (44.4%) 46 (74.2%) 07 ICU death 17 (63.0%) 21 (33.9%) 11 Hospital death 18 (66.7%) 21 (33.9%) day death 17 (63.0%) 20 (32.3%) 07 DIC, disseminated intravascular coagulation; ICU, intensive care unit. 24~1.105; p=02) 와간담도계패혈증 (OR, 0.72; 95% CI, 06~0.920; p=43) 이의미있는관련성을보여주었고, 현성 DIC (OR, 3.121, 95% CI, 0.996~9.874; p=53) 는경계선상의관련성을보여주었다. Receiver operating characteristic (ROC) curve를이용해분석한결과, 쇼크의회복에있어서 DIC score는 AUC (area under the curve) 값이세시점에서각각 (p=05), (p=10), (p=03) 으로전반적으로높은수치를보여주었다 ( 표 4). 중환자실사망및병원사망과 28일사망에 대한예측에서도 AUC 값이대부분 0.7 이상으로높은수행능력을보여주었고, 특히 Day 0 보다는 Day 1과 Day 2에서의 AUC 값이높게나타났다 ( 그림 4). 고찰 DIC는중증의패혈증이나심한외상에서발생할수있는현상으로혈액응고체계의활성화에의해섬유소와미세혈관혈전증이발생하게되고, 이로인해세포및조직에손상을

6 - Yong-Min Kim, et al. Disseminated intravascular coagulation in severe sepsis or septic shock - Table 4. Univariate analyses of predictors of hospital death Survivors (n=50) Non-survivors (n=39) p-value Age, years 68.9± ± Sex (male) 27 (54.0%) 25 (64.1%) 16 Severe sepsis/septic shock 7/43 1/38 75 Co-morbid illness Diabetes 14 (28.0%) 13 (33.3%) Hypertension 14 (28.0%) 9 (23.1%) COPD/BA 5 (1%) 6 (15.4%) Chronic kidney disease 1 (2.0%) 5 (12.8%) 82 Coronary artery disease 4 (8.0%) 1 (2.6%) Cancer 9 (18.0%) 10 (25.6%) Site of infection Pneumonia 24 (48.0%) 25 (64.1%) Urinary tract 9 (18.0%) 4 (10.3%) Hepatobiliary 9 (18.0%) 1 (2.6%) 38 Systolic blood pressure, mm Hg 83.1± ± Heart rate, beats/min 107.3± WBC, /mm 3 15,400 (8,650~21,525) 13,900 (7,500~20,400) 55 Hematocrit, % 33.6± ± Platelets, /mm 3 13K (84.0K~228.8K) 10K (56.0K~192.5K) <01 Blood urea nitrogen, mg/dl 26.2 (14.6~4) 35.5 (21.5~46.2) Creatinine, mg/dl 1.2 (0.9~2.3) 1.5 (~2.9) Bilirubin, mg/dl 0.9 (0.5~1.7) (~1.6) Albumin, mg/dl 3.0± ± C-reactive protein, mg/dl 17 (117.0~24) (81.2~274.0) 26 ph 7.34± ± Lactic acid, ug/l 3.0 (1.9~5.0) 3.6 (2.4~6.2) 75 SOFA score 8.7±3.1 1± SAPS II 48.4± ±13.8 <01 Overt DIC 9 (18.0%) 18 (46.2%) 04 COPD, chronic obstructive pulmonary disease; BA, bronchial asthma; WBC, White Blood Cell; SOFA, sequential organ failure assessment score; SAPS II, simplified acute physiologic score II; DIC, disseminated intravascular coagulation. 가져오게되어다기관기능부전에이르게된다 1,2). 패혈증은중환자실의주된사망원인으로패혈증에서의 DIC 발생률은 7~16% 정도이고, 패혈증쇼크에서는 73% 까지이를수있다는보고가있다 13-16). 패혈증에서는다기관기능부전이발생할수있는데정확한병태생리에대한이해가아직부족하지만혈액응고체계의활성화가중요한기전으로작용할것으로보고있다. 우리나라에서는패혈증쇼크에서 DIC의발생률을조사한연구는거의없다. 또한, DIC의임상적인중요성에 대해서는많은이해가이루어졌지만, 정확한진단법에대해서는아직확립된것이없다. 1990년대일본의 Japnase Ministry of Health and Welfare (JMHW) 에의해서 DIC criteria가제안된바있지만임상적으로유용성에떨어진다는단점이있어많이이용되지는않았다 18,19). 2001년에는 International Society on Thrombosis and Heamostasis (ISTH) 의 DIC 그룹이 JMHW 의기준을수정하여 ISTH criteria를발표하였다 12). 이그룹에서는 DIC를 여러원인에의해발생될수있고, 한곳에국

7 - 대한내과학회지 : 제 79 권제 5 호통권제 603 호 Sensitivity Sensitivity A B 1 - Specificity 1 - Specificity Sensitivity Sensitivity C 1 - Specificity D 1 - Specificity Figure 4. Receiver operating characteristic (ROC) curves for the DIC score for predicting hospital outcome. The values of the area under the curves (AUC) for predicting shock recovery on Days 0 (-), 1 ( ), and 2 (- -) were 0.770, 0.746, and 0.787, respectively (A). The AUC values for predicting ICU death were 0.702, 0.732, and 0.753, respectively (B). The AUC values for predicting hospital death were 92, 0.726, and 0.767, respectively (C). The AUC values for predicting 28-day death were 0.718, 0.753, and 0.780, respectively (D). 한되지않는혈관내응고체계의활성화 로정의하면서, 진단을위해서는패혈증과같은 DIC가발생하기쉬운기저질환이있어야한다고주장하였다. 또, 혈액응고의활성도를직접측정하는것보다는일반적인혈액응고검사가응고인자의소모및생성장애를반영하는데더좋을수있다고주장하였다. 이들의 ISTH criteria에서는총 8점에서 5점이상인경우에현성 DIC로진단할수있는데, 최근 Bakhtiari 등에의한전향적연구에서는 DIC score 5 점인경우민감도가 91%, 특이도가 97% 로그임상적유용성이크다는결과를발표하였다 11). 하지만최근 Gando 등의 JAAM (Japanese Association for Acute Medicine) DIC 연구그룹에서는 DIC의발생에 SIRS (systemic inflammatory response syndrome) 의역할이중요함을강조하였고, 이를진단기준에포함시켜새로운 scoring system (JAAM scoring system) 을만들었다. 이들은 274명의중환자를대상으로 JAAM scoring system과기존의 JMHW 와 ISTH criteria를비교하였는데 JAAM scoring system을이용한경우 DIC의진단률이 67.4% 로다른두가지 (40.3% and 28.2%) 보다높았다고보고하였다. 본연구에서는 Taylor 등에의한 ISTH criteria를이용하여중증패혈증및패혈증쇼크환자에서 DIC의빈도를알아보았다. 본연구의결과를보면현성 DIC의진단기준에해당되는환자는 Day 0, Day 1, Day 2에서각각 18.0%. 30.7%, 22.4% 였고, 입원초기 48시간동안의현성 DIC의발생률은 33.8% 였다. 다기관기능부전을나타내는 SOFA score와의상관관계에서도 DIC score 가세시점에서유의한관련성을보여주었는데, 특히현성 DIC 군에서높은 SOFA score 를보여주었다. 이는이전의연구들에부합되는결과이고, 패혈증에서발생하는다기관기능부전이 DIC의발생과관련성이있음을시사한다고볼수있다 20). 다변량분석에서는혈소판과 lactic acid가현성 DIC의발생과유의한관련성을보였는데, lactic acid의증가가패혈증에서저산소증에의한조직손상과관련이있고, DIC에서는미세혈관혈전증에의한다기관

8 - 김용민외 11 인. 중증패혈증환자에게서파종성혈관내응고 - 기능부전이발생한다는점을고려한다면현성 DIC가 lactic acid 증가와관련성이있다는점이설명될수있을것으로본다. 혈소판은 DIC score 안에포함되는변수로, 다변량분석에서현성 DIC와유의한관련성을보인것은자연스런결과라고할수있겠다. 병원사망에서는간담도패혈증과입원시의 SAPS II 점수가유의한관련성을보였고, 현성 DIC는경계선상의유의성을보였다. 본연구에서간담도패혈증환자가낮은사망률과관련이있는것은입원시중증도가낮은것과관련이있을것으로보이고, 현성 DIC의발생이병원사망에대해비록경계선상의유의성을보였으나, 더광범위한환자를대상으로연구를시행한다면유의한결과를기대할수있을것으로본다. 병원예후의예측에대한 ROC curves 분석에서는 DIC score 가쇼크의회복과중환자실사망, 병원사망, 28 일사망등을예측하는데좋은수행능력을지녔음을보여주었고, 이는 SOFA score와비슷하였다 (data not shown). 따라서본연구의결과에따르면 ISTH criteria가환자의장기부전의진행및병원예후를예측하는데유용할수있다는점을확인할수있었다. 본연구에서다른항응고인자에대한조사는이루어지지않았지만 Bakhtiari 등의연구를보면 DIC score 가증가할수록 antithrombin과 protein C activity가감소하는경향을보여주었고, 28일사망률도증가하는양상을보여주었다 11). 다기관기능부전의측면에서도 Taylor 등의 ISTH 그룹은 DIC score 자체가다기관기능부전을나타내는점수체계의일부분이될수있다고말하였는데, Angstwurm 등의연구를보면 DIC score 가증가할수록 APACHE II score 와 organ dysfunction score 가증가하는경향을보여주고있어서, DIC score 와다기관기능부전점수체계사이에상당한관련성이있음을알수있었다 20). Taylor 등의 ISTH 그룹은, DIC scoring system이 DIC의진단뿐만아니라환자의중증도를반영할수있다면, DIC 혹은패혈증치료에있어서혈액응고체계 (coagulation system) 를표적으로하는임상연구와치료약개발에큰도움이될수있을것이라고주장한바있다 12). 2001년 Bernard 등에의해서는중증패혈증환자에서 drotrecogin alfa (recombinant human activated protein C, rhapc) 의치료효과를조사한연구가있었다 8). 1,690명의환자에대해무작위대조군연구를시행하였는데 4일간의 drotrecogin alfa (rhapc) 치료로출혈의빈도는높았지만, rhapc 치료군에서 D-dimer 및 interleukin-6 level 이감소하였고, 사망률이의미있게감소하였다는결과 를보여주었다. 이후 Abraham 등에의해는위험도가낮은 (APACHE II<25 or one organ failure) 패혈증환자에서 rhapc 가치료효과가없고, 오히려심각한출혈의발생을높일수있다는결과를발표하여, 현재는 APACHE II 25이거나다기관기능부전을보이는환자에게제한적으로사용이권고되고있다 21). 추가적으로 Dhainaut 등이위의 Bernard 등의연구자료를이용하여사후분석을시행하였는데, 흥미로운점은 29% 의환자에서 ISTH criteria의현성 DIC에해당하였고, 이들에서의 rhapc 치료에의한사망률감소가그렇지않은군 ( 비현성 DIC) 에서의사망률감소보다더컸다는연구결과를보여주었다 (38% vs. 18%) 22). 따라서앞으로도이른시점에 DIC를진단하고치료한다면패혈증을포함한많은중증의환자들에서생존률을향상시키는데적지않은도움을줄수있을것으로본다. 본연구의단점으로는우선일개의대학병원에서이루어진소규모의연구라는점이다. 따라서확인하지못한편이 (bias) 가있을것으로판단되고, 본연구에서의현성 DIC의빈도와예후가일개병원의결과임에주의해야할것이다. 둘째, 결측치자료가있다는점이다. Day 1과 Day 2에 DIC score 를측정하지못한환자가각각 15.7% 와 34.8% 였다. 셋째, 본연구에서는 protein C 활성도및 antithrombin III 등다른응고인자들에대한검사가이루어지지않았다. 앞으로의연구에서는이러한인자들에대한조사도같이이루어져야할것으로보인다. 또한, APACHE II 점수체계에대한조사도이루어진다면패혈증환자에서 drotrecogin alfa (rhapc) 의치료가가능한군에대한결과도얻을수있을것으로본다. 하지만지금까지국내에서패혈증환자의 DIC 발생에대한연구는없었기에본연구가지니는의미는크다고본다. 앞으로 drotrecogin alfa (rhapc) 와같은응고체계에대한표적치료연구가활성화된다면 DIC가발생한패혈증환자들의생존율향상을기대해볼수도있을것으로생각된다. 따라서앞으로는좀더광범위한자료를이용한대규모연구가필요할것으로본다. 요약목적 : 본연구는파종성혈관내응고 (disseminated intravascular coagulation, DIC) 에대한점수체계를이용하여중증패혈증및패혈증쇼크환자에게서파종성혈관내응고의발생률과예후를확인하고자하였다. 방법 : 2008년 3월부터 2009년 2월까지중증패혈증및패

9 - The Korean Journal of Medicine: Vol. 79, No. 5, 혈증쇼크으로일개 3차의료기관의내과중환자실에입원한환자들을대상으로하였다. DIC 점수체계는 ISTH (International Society on Thrombosis and Haemostasis) 를이용하였으며, 연구기간동안각각 Day 0, Day 1, Day 2의세시점에서계산하였다. 결과 : 총 111명의환자중에서제외기준에해당하는 22명을제외하고, 89명의환자가연구에포함되었다. 환자의평균 DIC score 는 3.3±1.3였으며, 입원초기 48시간동안에현성 DIC (overt DIC; DIC score 5) 의발생빈도는 33.8% (27/89) 였다. Sequential Organ Failure Assessment (SOFA) score는 DIC score 와유의한상관관계를보여주었고, 현성 DIC 군에서다른환자군보다높은점수를보여주었다 (p<5). 중환자실사망과병원사망, 28일사망률은현성 DIC 군에서각각 63.0%, 66.7%, 63.0% 이었고, 이는현성 DIC에해당되지않은환자에비해통계적으로유의하게높았다. 다변량분석에서는 Simplified Acute Physiology Score (SAPS) II가병원사망과유의한관련성을보여주었고 (p=02), 현성 DIC의발생은경계선상의관련성을보여주었다 (p=43). 결론 : DIC 진단을위해 ISTH criteria를사용한경우, 중증패혈증및패혈증쇼크환자에서현성 DIC의빈도는 33.8% 이었고, 현성 DIC의발생은높은장기부전점수및병원사 망률과관련이있었다. 중심단어 : 파종성혈관내응고 ; 장기부전 ; 패혈증 REFERENCES 1) Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 341: , ) Levi M, ten Cate H, van der Poll T, van Deventer SJ. Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA 270: , ) Levi M, van der Poll T, ten Cate H, van Deventer SJ. The cytokine-mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia. Eur J Clin Invest 27:3-9, ) Taylor FB, Kinasewitz G. Activated protein C in sepsis. J Thromb Haemost 2: , ) Vervloet MG, Thijs LG, Hack CE. Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. Semin Thromb Hemost 24:33-44, ) From the Centers for Disease Contro: increase in National Hospital Discharge Survey rates for septicemia-united States, JAMA 263: , ) Angus DC, Birmingham MC, Balk RA, Scannon PJ, Collins D, Kruse JA, Graham DR, Dedhia HV, Homann S, MacIntyre N. E5 murine monoclonal antiendotoxin antibody in gram-negative sepsis: a randomized controlled trial: E5 study investigators. JAMA 283: , ) Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344: , ) Conkling PR, Greenberg CS, Weinberg JB. Tumor necrosis factor induces tissue factor-like activity in human leukemia cell line U937 and peripheral blood monocytes. Blood 72: , ) Esmon CT, Taylor FB Jr, Snow TR. Inflammation and coagulation: linked processes potentially regulated through a common pathway mediated by protein C. Thromb Haemost 66: , ) Bakhtiari K, Meijers JC, de Jonge E, Levi M. Prospective validation of the International Society of Thrombosis and Haemostasis scoring system for disseminated intravascular coagulation. Crit Care Med 32: , ) Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 86: , ) Abraham E, Wunderink R, Silverman H, Perl TM, Nasraway S, Levy H, Bone R, Wenzel RP, Balk R, Allred R. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. JAMA 273: , ) Bone RC, Balk RA, Fein AM, Perl TM, Wenzel RP, Reines HD, Quenzer RW, Iberti TJ, Macintyre N, Schein RM. A second large controlled clinical study of E5, a monoclonal antibody to endotoxin: results of a prospective, multicenter, randomized, controlled trial. The E5 Sepsis Study Group. Crit Care Med 23: , ) Fisher CJ Jr, Dhainaut JF, Opal SM, Pribble JP, Balk RA, Slotman GJ, Iberti TJ, Rackow EC, Shapiro MJ, Greenman RL. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhil-1ra Sepsis Syndrome Study Group. JAMA 271: , ) Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA 273: , ) Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri

10 - Yong-Min Kim, et al. Disseminated intravascular coagulation in severe sepsis or septic shock - M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: Crit Care Med 36: , ) Gando S, Kameue T, Nanzaki S, Nakanishi Y. Disseminated intravascular coagulation is a frequent complication of systemic inflammatory response syndrome. Thromb Haemost 75: , ) Wada H, Gabazza EC, Asakura H, Koike K, Okamoto K, Maruyama I, Shiku H, Nobori T. Comparison of diagnostic criteria for disseminated intravascular coagulation (DIC): diagnostic criteria of the International society of thrombosis and hemostasis and of the Japanese ministry of health and welfare for overt DIC. Am J Hematol 74:17-22, ) Angstwurm MW, Dempfle CE, Spannagl M. New disseminated intravascular coagulation score: a useful tool to predict mortality in comparison with Acute Physiology and Chronic Health Evaluation II and Logistic Organ Dysfunction scores. Crit Care Med 34: , ) Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, Francois B, Guy JS, Bruckmann M, Rea-Neto A, Rossaint R, Perrotin D, Sablotzki A, Arkins N, Utterback BG, Macias WL. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 353: , ) Dhainaut JF, Yan SB, Joyce DE, Pettilä V, Basson B, Brandt JT, Sundin DP, Levi M. Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation. J Thromb Haemost 2: ,

012임수진

012임수진 Received : 2012. 11. 27 Reviewed : 2012. 12. 10 Accepted : 2012. 12. 12 A Clinical Study on Effect of Electro-acupuncture Treatment for Low Back Pain and Radicular Pain in Patients Diagnosed with Lumbar