07-이두효

대한응급의학회지제 26 권제 1 호 Volume 26, Number 1, February, 2015 원 저 Resuscitation 심정지후저체온치료를시행한환자군에서혈액응고검사를이용한신경학적예후의예측 가톨릭대학교의과대학응급의학교실 이두효 오주석 김성욱 최경호 박규남 The Relation between Coagulation Profile Test and Outcome in Survivors who were Treated with Therapeutic Hypothermia after Cardiopulmonary Resuscitation Doo Hyo Lee, M.D., Joo Suk Oh, M.D., Ph.D., Sung Wook Kim, M.D., Kyung Ho Choi, M.D., Ph.D., Kyu Nam Park, M.D., Ph.D. Purpose: The purpose of this study is to clarify the clinical significance of coagulation factor as a prognostic tool in patients with cardiac arrest treated with therapeutic hypothermia (TH). Methods: We designed a retrospective case review study in one university hospital. All adult patients who suffered cardiac arrest from December 2011 to February 2014 were considered for inclusion in the study. Patients who did not undergo TH were excluded from the analysis. Patients with any hematologic disorder were also excluded. Patients were divided into two groups, the good outcome group and the poor outcome group depending on the final cerebral performance category (CPC). Serum D-dimer, FDP, PT, aptt, anti-thrombin III, fibrinogen, Troponin T, CK-MB, Troponin-I, DIC score, NSE, and S-100 were taken within one hour after ROSC. Logistic regression was used for multivariable analysis. Results: A total of 92 patients were included; 22 in the good outcome group, 70 in the poor outcome group. The median serum PT, aptt, FDP, fibrinogen, and D-dimer levels were grossly elevated in the poor outcome group. Only serum PT, D-dimer level showed significant association with poor outcome (PT: OR=1.577; 95% CI=1.08-17.49, D- dimer: OR=1.577; 95% CI=1.06-2.33). The area under the receiver operating characteristic (AUC) of PT, D-dimer, and S-100 for prediction of poor outcome was 0.822 (95% CI=0.72-0.89), 0.68 (95% CI=0.57-0.77), and 0.811 (95% CI=0.70-0.89), respectively. Other factors were not associated with prognosis. Conclusion: Increased PT and D-dimer levels are significantly associated with poor outcome. PT and D-dimer values have potential for use as new prognostic predictors along with the current prognostic factor, S-100 protein. Key Words: Hypothermia, Sudden cardiac death, Prognosis, Blood coagulation factor Department of Emergency Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea Article Summary What is already known in the previous study Coagulopathy is a common complication of post-cardiac arrest syndrome. While undergoing therapeutic hypothermia, hypothermic coagulopathy can be combined, and it may worsen the prognosis. Previous study showed that high DIC score is associated with poor prognosis, regardless of implementation of therapeutic hypothermia. What is new in the current study PT and D-dimer are independent prognostic factor in postcardiac arrest patients undergoing therapeutic hypothermia. 책임저자 : 오주석경기도의정부시천보로 271 가톨릭대학교의과대학의정부성모병원응급의학과 Tel: 031) 820-3898, Fax: 031) 820-3439 E-mail: erkeeper@catholic.ac.kr 접수일 : 2014년 8월 14일, 1차교정일 : 2014년 8월 18일게재승인일 : 2014년 10월 6일 44 서론심정지후증후군은높은사망률과나쁜신경학적예후를가지는경우가대부분이다 1). 주요한원인중하나는심

이두효외 : 심정지후저체온치료를시행한환자군에서혈액응고검사를이용한신경학적예후의예측 / 45 정지후발생하는허혈과자발순환회복후에발생하는재관류손상에의한다양한혈액학적변화이다 1). 심정지가발생한환자들에게서신장과폐모세혈관에미세혈전이발생한다는것을발견한뒤많은동물연구에서심폐소생술이후혈액응고반응이현저히증가한다는사실을알게되었고이러한혈액응고반응을조절하는내인성섬유소용해반응이심정지후자발순환이지연된환자에게서는효과적으로조절되지않는다고보고하였다 2-4). 그러나최근연구결과에따르면심정지가일어난후이러한비정상적인혈액응고반응에맞서과다섬유소용해반응이일어나며심폐소생술을시행한뒤성공적으로순환이돌아오지않은환자군에서돌아온환자군에비해이러한반응이더강하게일어나는것으로밝혀졌다 5). 심정지후증후군환자의신경학적예후를평가하는혈액학적지표로는 neuron specific enolase (NSE), S- 100 등이연구된바있으나예후예측의기준이되는절단값에대해서는논란의여지가있으며민감도, 특이도, 양성예측치등의검사신뢰도가불충분하다 6,7). 비교적정확하게평가하는도구로는 MRI, SEP 등이있으나이는검사방법이복잡하고안정되지않은환자에게시행하기는어려우며, 초기에시행하는것은의미가없고 3일정도경과한후에야의미있는결과를얻을수있다 8,9). 한편, 혈액응고검사는간단하고빠른결과를얻을수있으며심정지후자발순환을회복한환자의예후와관련이있을것으로생각되나, 심정지후저체온치료를시행한환자를대상으로이를규명하고자한연구는매우적으며 DIC profile과병원내사망이나신경학적예후와의관계를분석한연구가있었으나이는저체온치료의적용유무와관계없이시행한연구이다 10,11). 본연구에서는심정지후자발순환이회복되어저체온치료를받은환자들을대상으로자발순환직후 1시간이내에측정한다양한혈액학적지표와신경학적예후와의관련성여부를확인하고자한다. 대상과방법본연구는가톨릭의과대학임상연구심사위원회 (IRB) 의승인 (UC13RISI0052) 을받고이루어졌다. 1. 연구설계본연구는본원에서시행된후향적관찰연구이다. 2011 년 12월부터 2014년 2월까지응급의료센터에재원하거나내원한병원내및병원외심정지환자중자발순환이회복되고저체온치료를시행한환자들을대상으로하였다. 단, 자발순환이회복되었으나 24시간이내에사망한환 자, 보호자의요청으로저체온치료를중단한환자, 기존에혈액학적질환을가진환자, 임신한환자및경구피임약을복용중인환자는제외하였다. 2. 저체온치료본연구의대상자에게시행한저체온치료를포함한소생후치료의전반적인프로토콜은 2010년미국심장협회의심폐소생술가이드라인을따랐다 12). 32~34 C 의목표체온에도달하기위해 4 C 생리식염수의주입및얼음팩대기등의방법과함께온도조절패드 (Artic Sun Energy Transfer Pads TM, Medivance Corp, Louisville, USA) 를이용하여저체온을유도하였다. 34 C 에도달하면목표체온에도달한것으로간주하고 24시간동안저체온을유지하였다. 24시간이지난이후에는시간당 0.25 C 의속도로재가온을실시하였다. 저체온치료를실시하는동안의떨림의방지를위하여 Rocuronium을, 진정을위하여 Midazolam을지속적으로투여하였으며중심체온이 35 C와 36 C 에도달하였을때중단하였다. 3. 자료수집자료의수집은대상환자의의무기록을바탕으로후향적으로검토하였다. 대상환자의성별, 연령, 항혈소판제제의복용여부, 심정지의목격여부, 목격자심폐소생술시행여부, 심정지발생으로부터심폐소생술을시작하기까지걸린시간, 심정지로부터자발순환회복까지걸린시간, 초기심전도리듬이제세동가능한지의여부, ST분절상승심근경색여부, 혈액응고에영향을미치는기저질환의유무, 퇴원시신경학적예후등을조사하였다. 퇴원시신경학적예후판정은 Cerebral performance category scale (CPC) 로평가하였고 CPC 1, 2는좋은예후군으로, CPC 3~5는나쁜예후군으로정의하였다. 초기혈액학적지표와신경학적예후와의관련성을알아보기위해연구에포함된환자로부터자발순환이돌아온시점으로부터 1시간이내에혈액채취가이루어졌고채취한혈액샘플의 D-dimer, FDP, Prothrombin time (PT), activated Partial thromboplastin time (aptt), anti-thrombin III, fibrinogen, CK-MB, Troponin-T, Troponin-I (Lifesign MI Troponin I Test, 절단값 1.5 ng/ml), NSE와 S-100의값을측정하였고중증도평가를위해 PT (seconds), Platelet count, Fibrinogen, D- dimer의값을이용하여 International Society on Thrombosis and Hemostasis (ISTH) Disseminated intravascular coagulation (DIC) score 를산출하였다.

46 / 대한응급의학회지 : 제 26 권제 1 호 2015 4. 통계분석자료가정규분포에근사한지알아보기위하여 Kolmogorov-Smirnov test를이용하여정규성을검정하였다. 범주형변수는백분율로표현하였고 Chi-square 또는 Fisher s exact test을이용하여두군을비교하였다. 정규성검정을한결과에따라정규분포를보이는값은평균값을 t-test를이용하여비교하였고, 비정규분포를보이는값은중앙값 ( 사분위값 ) 으로표현하고 Mann- Whitney test를이용하여비교하였다. 이중신경학적예후와관련된독립적인변수를찾기위해통계적으로유의한변수를모아로지스틱회귀분석을하였다. 또한신경학적예후예측을위한혈액학적지표의판별력을알아보기위해수신기작동특성 (Receiver Operating Characteristics, ROC) 을분석하여곡선아래면적 (Area Under Curve, AUC) 을구하였고, 절단값을정하였다. 통계분석은 SPSS TM software, version 20 (IBM Inc., Chicago, USA) 를사용하였고 p<0.05인경우를통계학적으로유의하게판정하였다. 결과 1. 환자의일반적특성연구대상자 96명중제외조건을만족하는 4명을제외한나머지 92명의환자를최종분석대상으로선정하였다. 분석대상중남자가 59명, 여자가 33명, 평균나이는 58세였다. 심정지가목격된환자는 66명 (77.1%) 이었고목격자심폐소생술을시행한환자는 41명 (43.5%), 제세동이불가 Fig. 1. Diagram showing the inclusion and exclusion criteria of the patients. ROSC: return of spontaneous circulation, CPC: cerebral perfomance scale Table 1. Patient demographics and underlying medical conditions. Good outcome (CPC 1, 2) Poor outcome (CPC 3, 4, 5) n=22 n=70 Sex, male, no. (%) 17 (77.27) 42 (60.0) <0.203 Age, years, mean (SD) 50 (±17.40) 60.38 (±14.44) <0.05 Patients receiving antithrombic therapy, no. (%) 0 (0) 2 (2.85) <0.577 Septicemia, no. (%) 0 (0) 2 (2.85) <0.577 Malignancy, no. (%) 0 (0) 3 (4.28) <0.436 Liver disease, no. (%) 0 (0) 5 (7.1)0 <0.246 CPC: cerebral performance category, SD: standard deviation p

이두효외 : 심정지후저체온치료를시행한환자군에서혈액응고검사를이용한신경학적예후의예측 / 47 능한심전도리듬을보인환자는 71명 (77.2%) 이었으며심정지로부터자발순환회복까지의평균시간은 30.19분이었다. 이중퇴원시좋은신경학적예후를보이는군 (CPC 1, 2) 은 22 (23.9%) 명이었고나쁜신경학적예후를보이는군 (CPC 3~5) 은 70 (76%) 명이었다 (Fig. 1). 나쁜예후군이좋은예후군에비하여환자의평균나이가유의하게높았으나남녀성비, 혈액응고기능에영향을미칠수있는기저요인들은나쁜예후군과좋은예후군간에유의한차이가없었다 (Table 1). 걸리는시간의경우에는각군간에유의한차이가없었다. 혈액학적지표에서는 aptt, D-dimer, FDP가나쁜예후군에서유의하게높았으며 Anti-thrombin III는유의하게낮았다. 기존에알려진예후예측인자인 NSE와 S- 100의경우 S-100은나쁜예후군에서유의하게높았고 NSE는나쁜예후군에서더높은경향을보였으나통계학적으로는유의한차이가없었다. 3. 혈액학적지표와신경학적예후와의관계 (Table 3) 2. 좋은예후군과나쁜예후군간의특성및혈액학적지표결과의비교 (Table 2) 목격자심폐소생술을시행하지않았거나, 목격자가없거나, 제세동가능하지않은초기심전도리듬인경우가나쁜예후군에서유의하게많았다. 또한나쁜예후군의경우심정지로부터자발순환회복까지의평균시간이유의하게길었다. 단, 심정지발생으로부터심폐소생술을시작하는데 심폐소생술후성공적으로순환이돌아온환자의혈액응고검사지표와신경학적예후와의독립적인관계를찾기위해 Table 2에서좋은예후군과나쁜예후군간에뚜렷한차이를보였던요인인목격자심페소생술의시행여부, 목격자의유무, 제세동가능하지않은초기심전도리듬, 심정지로부터자발순환회복까지의평균시간, aptt, D- dimer, FDP, Anti-thrombin III, S-100, DIC score 등을포함하여로지스틱회귀분석을하였다. PT의경우유의 Table 2. Study variables. Good outcome (CPC 1, 2) Poor outcome (CPC 3, 4, 5) n=22 n=70 Pre-hospital factor Out-of-hospital cardiac arrest, no. (%) 17 (77.27) 57 (81.42) <0.759 Witnessed cardiac arrest, no. (%) 20 (90.9)0 46 (65.71) <0.05< Bystander chest compression, no. (%) 15 (68.18) 26 (37.14) <0.05< Non-shockable initial rhythm, no. (%) 11 (50.0)0 60 (85.71) <0.05< Time to ROSC, min, mean (SD) 0015 (±11.91) 31 (±20.64) <0.05< Time to BLS, min, median (IQR) 4.09 (0-5.25) 5.5 (0-9.25) <0.483 ST-elevation myocardial infarction, no. (%) 1 (4.54) 05 (07.14) <0.557 Coagulation factor PT, seconds, median (IQR) 12 (10.95-12.92) 14.35 (12.90-18.92) <0.059 aptt, seconds, median (IQR) 26.4 (23-32.1) 35.1 (26.5-51) <0.05< Fibrinogen, mg/dl, median (IQR) 183.1 (159.3-296.7) 229.65 (172.4-306.6) <0.721 D-dimer, ug/ml, median (IQR)* 5.88 (4.35-14.13) 26.88 (7.58-35.2) <0.05< FDP, ug/ml, median (IQR) 19.65 (12.3-32.5) 60.3 (27-80) <0.05< Anti-thrombin III, ug/l, mean (SD) 088.1 (±15.30) 76.25 (±21.71)00. <0.05< Platelet, 10 9 /L, mean (SD) 221.5 (±83.09) 203 (±83.94)0 <0.059 Troponin T, ng/ml, median (IQR) 0.059 (0.021-0.10) 0.052 (0.026-0.14) <0.728 CK-MB, ng/ml, median (IQR) 3.33 (2.2-6.50) 5.195 (2.78-14.64) <0.089 Troponin I, no. (%) 4 (18.18) 11 (15.71) <0.889 DIC score, median (IQR) 4 (4-5) 5 (4-5) <0.05< Prognostic marker NSE, ng/ml, median (IQR) 18.26 (14.02-26.85) 22.43 (16.23-26.92) <0.253 S-100, ug/l, median (IQR) 0.36 (0.1-1.77) 2.34 (1.19-4.98) <0.05< CPC: cerebral performance category, ROSC: return to spontaneous circulation, SD: standard deviation, BLS: basic life support, IQR: interquartile range, PT: prothrombin time, aptt: activated partial thromboplastic time, FDP: fibrin degradation product, DIC: disseminated intravascular coagulation, NSE: Neuron-specific enolase * D-dimer level higher than 35.20 ug/ml was reported as 35.20 ug/ml in study hospital. * CK-MB level higher than 500 ng/ml was reported as 500 ng/ml in study hospital. p

48 / 대한응급의학회지 : 제 26 권제 1 호 2015 수준이 0.05보다약간높았으나예후와의연관성이보여분석에포함시켰다. 그결과제세동이가능하지않은초기심전도리듬은제세동가능한초기심전도리듬에비해나쁜예후를보일확률이 4.361배높았으며 PT의경우 1.0 초증가할때나쁜예후를보일확률이 1.577배증가하는것으로나타났다. D-dimer의경우 1 ug/ml 증가할때나쁜예후를보일확률이 1.053배증가하였으나통계학적으로는유의하지않았다. 4. 혈액응고검사지표의 ROC 분석 (Fig. 2) PT와 D-dimer의 ROC 곡선의 AUC는각각 0.82 (95% 신뢰구간 ; 0.72-0.89), 0.68 (95% 신뢰구간 ; 0.72-0.89) 이었다. 여기에서구해진 PT의절단값 57.1 초는민감도 57.1%, 특이도 100.0% 를보였고 D-dimer 의절단값 14.69 ug/ml는민감도 60.3%, 특이도 81.0% 를보였다. A B C Fig. 2. Comparison of receiving operating characteristic curves of Prothrombin time (A), D-dimer (B), and S-100 (C) for predicting poor outcome (CPC 3, 4, 5). The area under the curves were 0.82 (A, 95% CI, 0.72-0.89; p<0.0001), 0.68 (B, 95% CI, 0.57-0.77; p<0.0037) and 0.811 (C, 95% CI, 0.70-0.89; p<0.0001), respectively. Table 3. Multivariable logistic regression analysis for the determination of potential prognostic factors. Odds ratio Non-shokable initial rhythm 4.361 (1.08-17.49) 0.038 PT (per 1 second) 1.577 (1.06-2.33)0 0.023 D-dimer (per 1 ug/ml) 1.053 (0.99-1.11)0 0.064 PT: prothrombin time p

이두효외 : 심정지후저체온치료를시행한환자군에서혈액응고검사를이용한신경학적예후의예측 / 49 기존에알려진예후예측인자인 S-100의 ROC 곡선의 AUC는 0.811 (95% 신뢰구간 ; 0.70-0.89) 이었으며, 여기에서구해진 S-100의절단값 0.586 ug/l은민감도 82.%, 특이도 73.7% 를보였다. 고찰심정지후성공적으로순환이돌아온환자에게서일어나는병적인현상을 심정지후증후군 이라고하는데이러한현상은허혈-재관류손상에의한것으로알려져있으며패혈증과비슷한양상을보이는 패혈증양 증후군이동반된다 1,13). 패혈증은파종성혈관내응고 (Disseminated intravascular coagulation, DIC) 를초래하므로 DIC의중증도와심정지후증후군환자의예후와의연관성을분석한연구가있었으나본연구에서는심정지기간이길면섬유소과다용해반응이일어난다는점에착안하여혈액응고검사와예후와의연관성을분석하였다 11,14). 섬유소용해반응은혈전이분해되며발생하는국소적인현상이다. 보통이러한현상은정상적인상태에서손상된혈관내피로부터분비되는우로키나아제와조직플라스미노겐활성제 (tissue plasminogen activator, tpa) 로인해야기되고이는 tpa 억제제를이용한생체내정상적인음성되먹임반응으로조절되지만외상이나심정지와같은병적인상태에서는조직의허혈로인하여발생하는 C-단백에의해이러한균형이무너지게되어섬유소과다용해반응이일어난다 15-17). 본연구에서 PT, aptt, D-dimer, FDP 등의혈액응고검사가나쁜예후군에서증가한것은위와같은기전으로설명할수있다 4). 본연구에서도출된결과로는심정지후환자에게서 PT 의 AUC는 S-100의 AUC와비슷하였고 D-dimer의 AUC는 S-100의 AUC보다낮았다. 결과적으로 PT와 D-dimer의진단적가치가 S-100보다월등히우월하지는않은것으로보이며어느정도예후와의연관성은있으나단독으로사용할수는없기때문에다른인자와함께고려해야할것이다. 심정지상황이길어지게되면뇌내혈류의미세혈류의장애가일어나게되는데이는허혈성장애뿐만아니라심정지상황에서발생하는과응고현상으로인한미세혈전의영향도있을수있다 1,4). 이에심정지후자발순환을회복한환자에게혈전용해제를투여하는임상연구가시행되었으나위약효과에비해 30일생존율에는영향을미치지않은것으로나타났다 18). 이미연구된바와같이심정지상황에서는과응고현상뿐만아니라과용혈현상도함께일어나게되기때문에이러한결과에영향을주었을것으로추정된다 5). 본연구에서도 D-dimer 값의증가와함께 PT, aptt 등의혈액응고검사의값이모두증가하는양상을보 였는데대부분의검사가통계학적으로유의하게나쁜예후와관련이있어기존의연구결과와크게다르지않았다 10,11). NSE와 S-100이심정지후소생한환자들의예후를예측하는데도움이되는지표임은이미많은연구를통해알려진사실이다 19). 그러나본연구에서 NSE가예후와통계학적으로의미있는인자가되지않았는데그이유는 NSE 의경우자발순환회복후하루가경과한시점에서의수치가예후와의연관이강하기때문에소생후 1시간이내에채취한혈액샘플로분석한본연구에서는연관성이감소한것으로보인다 20). 추후추가적인연구를통해혈액응고검사의초기값뿐만아니라시간대별데이터분석을통하여 NSE의효용성과비교해볼수있겠다. 본연구는몇가지제한점이있다. 첫째, 단일기관에서시행되어연구대상자의수가불충분하여통계적검증력을충분히확보하지못하였다. 둘째, 본연구는전자의무기록을바탕으로후향적으로검토한연구이기때문에내부적인비틀림이있을수있다. 셋째, 본연구에서분석했던좋은예후군과나쁜예후군의환자군의기본조건이균일하지않아로지스틱회귀분석을실시했으나혈액응고검사가다른예후인자의영향을받았을가능성을배제할수없다. 넷째, 혈액응고인자중 D-dimer의값은본원에서의진단검사기계의한계로인하여그최대값이 35.2 ug/ml로표시가되어 D-dimer가높은환자일수록실제수치와차이가커지게된다. 다섯째, 심정지후순환이돌아온환자의예후에영향을미치는인자는본연구에서조사한인자이외에도더많은인자들이있을수있으며이러한누락된인자들이연구결과에영향을미쳤을가능성이있다. 결 심정지환자중성공적으로자발순환이돌아와저체온치료를받은환자중나쁜예후를가진환자군에서초기혈액학적지표는더심한응고장애를시사하는경향을보였고이중 PT와 D-dimer가나쁜신경학적예후와독립적인관계를보였다. 그러나단독으로예후예측에이용하기에는무리가있어다른예후인자와함께고려해야한다. 향후다기관에서의대규모환자군을대상으로한연구를통해새로운예후예측도구로서의가능성을생각해볼수있다. 론 참고문헌 01. Neumar RW, Nolan JP, Adrie C, Aibiki M, Berg RA, Böttiger BW, et al. Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A

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