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쇽혹은우심실부전을보이는중증폐혈전색전증에서혈전용해요법과항응고요법의효과 울산대학교의과대학서울아산병원호흡기내과, 심장내과 1 한송이, 송재관 1, 이상도, 임채만, 고윤석, 박찬선, 오연목, 심태선, 김우성, 김동순, 김원동, 홍상범 Comparison of Effect Between Thrombolysis and Anticoagulation in Major Pulmonary Thromboembolism Song Yi Han, Jae Kwan Song, Sang Do Lee, Chae-Man Lim, Younsuck Koh, Chan Sun Park, Yeon Mok Oh, Tae Sun Shim, Woo Sung Kim, Dong Soon Kim, Won Dong Kim, Sang-Bum Hong Divisions of Pulmonary and Critical Care Medicine and Cardiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea Background : Major pulmonary thromboembolism is defined as right ventricular (RV) dysfunction, with or without shock, accompanied by significant morbidity and mortality. In this study, those with major pulmonary thromboembolism were divided into the shock and RV dysfunction only groups, and then investigated the mortality and complications in thrombolysis or anticoagulation, respectively. Methods : In a retrospective study, between January 1995 and December 2004, 60 eligible patients with a major pulmonary thromboembolism, admitted in Asan Medical Center, were included. Results : A total of 57 patients were treated with medical therapy. Thrombolysis was performed in 13 patients (23%) and anticoagulation in 44 (77%). There were no differences in the APACHEⅡ and SOFA scores between the two groups. 6 (46%) and 11 (25%) patients died in the thrombolysis and anticoagulation groups, respectively (p=0.176). In the 19 patients (33%) showing shock, thrombolysis was performed in 9 (47%) and anticoagulation in 10 (53%). 4 (44%) of the 9 patients treated with thrombolytic agents and 3 (30%) of the 10 treated with anticoagulants died (p=0.650). In the 38 patients (67%) showing RV dysfunction only, thrombolysis was performed in 4 (11%) and anticoagulation in 34 (89%). 2 (50%) of the 4 patients treated with thrombolytics and 8 (24%) of the 34 treated with anticoagulants died (p=0.279). Three patients (23%) who underwent thrombolysis had a major bleeding episode, compared with 2 (5%) who were treated with anticoagulants (p=0.072). Conclusion: The results of our study showed that thrombolysis did not lower mortality and tended to increase major bleeding compared with anticoagulation in both the shock and RV dysfunction only groups. Further evaluation of the efficacy and safety of thrombolytic therapy for major thromboembolism appears warranted in Korea. (Tuberc Respir Dis 2005; 59: 487-496) Key words : Major pulmonary thromboembolism, Thrombolysis, Anticoagulation RV dysfunction, Shock 서 미국에서한해에급성폐혈전색전증의발생율은 10만명당 23명이며 1, 3개월사망률이 15.3% 로보고되고있다 2. 국내에서는결핵및호흡기학회에서총 808명의환자들을대상으로시행한급성폐혈전색전 Address for correspondence : Sang-Bum Hong, M.D. Address: Division of Pulmonary and Critical Care Medicine, University of Ulsan College of Medicine, Asan Medical Center 388-1 Pungnap-2 Dong, Songpa-gu, Seoul, 138-736, Korea Phone : 02-3010-3893 Fax : 02-3010-6968 E-mail : sbhong@amc.seoul.kr Received : Jul. 22. 2005 Accepted : Sep. 14. 2005 론 증의전국실태조사보고에서서구와유사한 16.9% 의사망률을보고하였다 3. 급성폐혈전색전증에서쇽이나우심실부전이동반되는경우사망률이증가하며, 이를중증폐혈전색전증 (major pulmonary thromboembolism) 으로정의한다 4-7. 중증폐혈전색전증에대한메타분석에서는혈전용해요법이환자들의사망률을감소시켰다고보고하였으나좀더연구가필요한것으로제시하였고, 이연구에서는쇽과우심실부전단독인경우로구분을하지않았다 8. 특히우심실부전단독에서는혈전용해요법의효과에대해논란이있다. Konstantinides 등은우심실부전단독을보이는환자들에서혈전용해요법을시행하였을때항응고요법에비해 30일생존율이 487

SY Han et al. : Thrombolysis and anticoagulation in major pulmonary thromboembolism 높았음을보고하였으나 9, Hamel 등은이러한환자들에서혈전용해요법이항응고요법에비해사망률을줄이지못한다고보고하였다 10. 그러므로중증폐혈전색전증을쇽과우심실부전단독인경우로구분해서혈전용해요법치료를분석하는것이필요할것이다. 그리고혈전용해요법은출혈부작용이항응고요법에비해높게보고되고있으나 9-11 이에대한국내연구는적었다. 혈전증의원인은인종별차이가있어 12-14, 치료및부작용에서도서구와차이가있을가능성이있다. 하지만우리나라에서중증폐혈전색전증환자를쇽과우심실부전으로구분하여혈전용해요법을시행했을때치료효과및합병증에대해분석한연구는없었다. 그리고쇽을보이지만출혈부작용가능성이높아서혈전용해요법을시행하지못했던환자들의예후에대해서도보고된바가적다. 이에저자들은서울아산병원에입원했던중증폐혈전색전증환자들을대상으로혈압이정상인우심실부전환자군과쇽을보이는환자군에서각각혈전용해요법과항응고요법을시행했을때치료효과와부작용을알아보고자하였다. 폐환기스캔에서높은가능성 (high probability) 을보이거나, 2) 흉부나선형 CT상폐혈전이확인된경우, 3) 심초음파상직접폐혈전이확인된경우나 4) 폐혈관조영술을통해확인되었을때로하였다. 약물요법을받지않은환자는제외하였으며, 폐혈전색전증의심후 24시간이내에혈전용해제와항응고제를사용한경우를혈전용해요법군으로, 항응고제만사용한경우를항응고요법군으로정의하였다. 환자들은또한혈압에따라쇽을보이는군과혈압이정상이면서우심실부전이나폐고혈압을보이는우심실부전군으로구분하였다. 치료결정에서쇽이나우심실부전이있지만항응고요법을시행받은것은혈전용해요법의금기가있어서였거나임상의의판단에의해서였다. 혈전용해요법의금기는 2개월내뇌졸중이있었거나두개강내수술을받았을때, 10일이내에수술받은기왕력, 현성출혈이있었을때, 출혈경향이있었던경우로정의하였고, 이외의경우는임상의의판단으로정의하였다. 항응고요법을시행받은쇽군에서이후의치료는역시임상의의판단에의해결정되었다. 대상및방법 2. 방법 1. 대상 1995년 1월부터 2004년 12월까지서울아산병원에입원하여폐혈전색전증으로진단받은환자 141명중중증폐혈전색전증의기준을만족시키는 60명을대상으로의무기록을조사하였다. 중증폐혈전색전증은 1) 수축기혈압이 90mmHg 이하거나기저혈압보다 40mmHg 의감소를보이는경우, 2) 심폐소생술이요구되는순환허탈 (circulatory collapse) 이있을때, 3) 심초음파상우심실부전 (par adoxical septal motion 또는 RV dilatation>30mm, 또는 RV/LV end-diastolic diameter ratio >1) 을보이거나, 4) 심초음파또는우심카테터상중등도이상의폐고혈압을보이는경우 ( 수축기폐동맥압 50 mmhg) 로정의하였다. 폐혈전색전증의진단은임상적으로급성폐혈전색전증이의심되면서 1) 폐관류와 의무기록을통해증상및진찰소견, 흉부방사선, 심전도, 심초음파및동맥혈가스검사소견을조사하였다. 폐관류스캔은 10 mci의 Tc 99m MAA로, 폐환기스캔은 10 mci의 pertechnegas로시행되었고, 전면, 후면, 양측사위면이촬영되었다. 폐동맥압은도플러심초음파를통해 TR Vmax를이용하여간접적으로계산하거나, Swan-Ganz 카테터또는심혈관조영술을통해측정하였다. 심부정맥혈전증의여부는도플러초음파나, 방사성동위원소정맥조영술을통해확인되었다. 혈전용해요법군과항응고요법군간에중증도를비교하기위해서순환허탈유무, 중환자실입원여부, APACHEⅡ 점수, SOFA 점수, 기계환기및이탈여부를조사하였다. 사망은진단후 28일내발생한폐혈전색전관련사망으로정의하였다. 중요출혈부작용 (major bleeding) 488

Tuberculosis and Respiratory Diseases Vol. 59. No. 5, Nov. 2005 은 1) 사망에기여한출혈이나 2) 두개내출혈또는 3) 혈색소가 2 g/dl 이상감소하거나, 농축적혈구수혈이 2단위이상필요한경우로정의하였다. 그외의출혈부작용은경미한출혈부작용 (minor bleeding) 으로정의하였다. 3. 통계혈전용해요법과항응고요법을시행받은환자군들의특성은연속변수에대해서 t-검정을사용하여평균과표준편차로나타내었다. 비연속변수에대해서는카이자승검정을이용하였다. 소집단분석은연속변수에대해서는 Mann-Whitney U 검정을, 비연속변수에서는 Fisher 의정확검정을사용하였다. 통계적유의성은 p < 0.05로하였다. 모든자료의분석에는 SPSS 소프트웨어 (SPSS for windows, version 10.0; SPSS inc; Chicago, IL, USA) 를이용하였다. 결과 법군에서 57세, 항응고요법군에서 62세였고, 남자가각각 7명 (54%) 과 17명 (39%) 으로차이는없었다. 폐혈전색전증의위험인자로는악성종양, 부동상태, 응고장애등이흔한원인이었고, 부동상태는항응고요법군에서더많았다 (p=0.042). 수술의기왕력이있었던환자는총 11명이었고모든환자에서항응고요법이시행되었다 (Table 1). 이중정형외과수술이 7명으로가장많았다. 수술후폐혈전색전증은평균 29일이지나발생하였고수술전예방적항응고제는단지 1명에서사용되었다. 항응고요법군에서는혈전용해요법의금기가있어항응고요법을시행받은경우가 20명 (45%) 이었고이중뇌졸중이 6명 (14%), 10일이내수술받은경우가 8명 (18%), 현성출혈이 4명 (9%), 출혈경향이있었던경우가 2명 (5%) 이었다. 기계환기는혈전용해요법군에서더많이시행되었고 (p=0.043), 총기계환기시간은항응고요법군에서더길었다 (p=0.003). 그외평균혈압, 순환허탈유무, APACHEⅡ 점수, SOFA 점수는두군간에차이가없었다 (Table 2). 1. 환자특성 2. 임상증상, 징후및진단적검사 중증폐혈전색전증의기준을만족시키는 60명중 57명이약물요법으로치료받았고, 이중 13명 (23%) 이혈전용해요법을, 44명 (77%) 이항응고요법을시행받았다 (Figure 1). 진단당시평균연령은혈전용해요 두군모두에서호흡곤란이각각 13명 (100%), 42명 (95%) 으로가장흔한증상이었고, 그외흉통이 7명 (54%), 10명 (23%) (p=0.043), 실신이 3명 (23%), 5명 (11%) 순이었다. 심박수는각각 89 회 / 분과 100 회 / Major PTE* (N=60) Medical treatment (N=57) Nommedical treatment (N=3) 2 명 : surgical embolectomy 1 명 : intraarterial thrombolysis Thrombolysis (N=13) Anticoagulation (N=44) RV dysfunction (N=4) shock (N=9) RV dysfunction (N=34) shock (N=10) Figure 1. Distribution of major pulmonary thromboembolism subjects, inclusive data * PTE : pulmonary thromboembolism, RV : right ventricle 489

SY Han et al. : Thrombolysis and anticoagulation in major pulmonary thromboembolism Table 1. Baseline characteristics of study patients with major pulmonary thromboembolism Thrombolysis (N=13) Anticoagulation (N=44) p-value Age 57.2 ± 19.4 62.2 ± 14.9 0.357 Sex (Men) 7 (54%) 17 (39%) 0.564 Smoking 4 (31%) 13 (30%) 1.000 Immobilization 1 ( 8%) 18 (41%) 0.042 Periods (days) 88 111 ± 339 0.949 Operation 0 11 (25%) 0.053 Malignancy 5 (38%) 11 (25%) 0.483 Coagulative disease 3 (23%) 9 (20%) 1.000 Underlying disease Cardiovascular 3 (23%) 20 (45%) 0.204 Respiratory 2 (15%) 4 ( 9%) 0.611 Gastrointestinal 1 ( 8%) 2 ( 5%) 0.547 Nephrology 0 1 ( 2%) 1.000 Endocrinology 1 ( 8%) 8 (18%) 0.668 Table 2. Severity indices in patients with major pulmonary thromboembolism Thrombolysis (N=13) Anticoagulation (N=44) p-value Mean blood pressure (mmhg) 72.5 ± 39.1 92.5 ± 19.6 0.097 Circulatory collapse 2 (15%) 1 (2%) 0.127 APACHE Ⅱ score* 13.5 ± 9.8 12.7 ± 7.9 0.654 SOFA score 5.2 ± 4.2 3.6 ± 2.9 1.000 Mechanical ventilation 7 (54%) 10 (25%) 0.043 Weaning 2 5 0.495 Total ventilation time (days) 2.1 ± 1.4 14.1 ± 9.6 0.003 * APACHEⅡscore : acute physiology and chronic health evaluationⅡscore SOFA score : sequential organ failure assessment score 분, 징후는빈호흡이 6명 (46%), 31명 (70%) 으로두군간에차이가없었다. Table 3은두군간에혈액검사소견을비교한것으로간효소수치, 동맥혈가스분석수치, 심근효소수치, BNP 등두군간에차이를보이 지않았다. 단순흉부촬영상과심전도검사소견역시두군간에차이가없었다 ( 자료제시안함 ). CT로진단된환자가가장많았으며, 심초음파상두군간에우심실부전과폐고혈압의정도에는차이가없었다 (Table 4). Table 3. Laboratory findings in patients with major pulmonary thromboembolism Thrombolysis (N=13) Anticoagulation (N=44) p-value WBC count ( 10 3 /mm 3 ) 14.7 ± 7.6 10.3 ± 4.6 0.067 Hemoglobin (g/dl) 14.4 ± 2.4 12.7 ± 2.5 0.039 Platelet count ((10 3 /mm 3 ) 184.4 ± 74.0 208.2 ± 95.1 0.410 ph 7.395 ± 0.153 7.435 ± 0.094 0.255 PaCO 2 (mmhg) 32.4 ± 15.7 31.7 ± 7.8 0.826 PaO 2 (mmhg) 53.6 ± 11.1 65.0 ± 28.5 0.165 SaO 2 (%) 90.3 ± 32.2 89.3 ± 8.0 0.907 AST (IU/L) 80.9 ± 126.0 45.1 ± 32.6 0.330 ALT (IU/L) 69.1 ± 103.9 34.2 ± 30.7 0.254 Creatinine (mg/dl) 1.2 ± 0.5 1.0 ± 0.4 0.035 BNP (pg/ml) 544.7 ± 533.1 623.9 ± 863.4 0.887 CK (IU/L) 380.8 ± 779.2 109.9 ± 96.4 0.301 CK-MB (ng/ml) 16.6 ± 39.2 5.2 ± 4.2 0.384 Troponin I (ng/ml) 11.7 ± 35.1 1.1 ± 1.8 0.365 490

Tuberculosis and Respiratory Diseases Vol. 59. No. 5, Nov. 2005 Table 4. Diagnostic methods in patients with major pulmonary thromboembolism Thrombolysis (N=13) Anticoagulation (N=44) p-value Lung scan (high probability) 4 (31%) 24 (55%) 0.207 Spiral CT 11 (85%) 28 (39%) 0.191 Pulmonary angiography 1 ( 8%) 5 (30%) 1.000 Echocardiographic findings PA* pressure (mmhg) 46.1 ± 15.0 60.1 ± 20.0 0.067 RV dilatation 9 (69%) 38 (41%) 0.654 Paradoxical septal motion 6 (46%) 25 (59%) 1.000 Thrombus 1 ( 8%) 5 (11%) 1.000 Search for deep vein thrombosis Doppler US or RI venography 11 (85%) 34 (77%) 0.713 Abnormal findings 6 (46%) 8 (18%) 0.071 D-dimer (μg/ml) 20.9 ± 19.4 8.3 ± 9.7 0.141 * PA : systolic pulmonary artery, RV : right ventricle, US : ultrasonography, RI : radioisotope 3. 치료및예후혈전용해제는 tissue-plasminogen activator(t-pa) 가 10명 (77%), urokinase(uk) 가 3명 (23%) 에서사용되었다. 중증폐혈전색전증에서혈전용해요법군과항응고요법군의 28일사망률은각각 46% (6명), 25% (11명) 로두군간에차이는없었다 (p=0.176). 중요출혈부작용은혈전용해요법군에서 23% (3명), 항응고요법군에서 5% (2명) 로혈전용해요법군에서높은경향을보였다 (p=0.072). 사망관련출혈은각각 2명, 1 명에서발생하였다 (Table 5). 4. 소집단분석 쇽군 19명이쇽군에포함되었고혈전용해요법과항응고요법이각각 9명 (47%) 과 10명 (53%) 에서시행되었다. 혈전용해요법군에비해항응고요법군에서부동상태와수술의기왕력이있는환자가많았고, 그외는 두군간에차이가없었다 (Table 6). 항응고요법의적용은 70% (7/10) 의환자에서혈전용해요법의금기로인해서였으며, 두군간에중증도는항응고요법군에서총기계환기시간이더길었던것외에차이는없었다 (Table 7). 임상증상및징후와혈액검사소견도두군간에차이가없었다. 혈전용해제는 t-pa가 8명, UK는 1명에서사용되었다. 혈전용해요법과항응고요법시 28일사망률은각각 44% (4명), 30% (3명)(p=0.650) 이었고중요출혈부작용은 22% (2명), 0명 (p=0.211) 으로두군간에차이는없었다 (Table 7). 혈전용해제를사용했을때발생한 4명의사망중 3명은폐혈전색전증의악화와관련되어나타났고 1명은혈전용해요법후발생한동맥천자부위출혈때문이었다. 다른 1명에서나타난중요출혈부작용은복부혈종이었고사망에기여하지않은출혈이었다. 경미한출혈은 1명 ( 동맥천자부위삼출 ) 에서있었다. 항응고요법군에서발생한 3명의사망은모두폐색전관련사망이었고출혈부작용 Table 5. Outcome in patients with pulmonary thromboembolism Thrombolysis (N=13) Anticoagulation (N=44) p-value Outcome Recurrence 1 ( 8%) 5 (11%) 1.000 Death 6 (46%) 11 (25%) 0.176 Major bleeding 3 (23%) 2 ( 5%) 0.072 Fatal bleeding 2 1 Intracranial hemorrhage 1 0 Minor bleeding 1 ( 8%) 6 (14%) 0.547 491

SY Han et al. : Thrombolysis and anticoagulation in major pulmonary thromboembolism Table 6. Baseline characteristics of study patients in subroups Thrombolysis N=4 RV dysfunction (N=38) Anticoagulation N=34 P value Thrombolysis N=9 Shock (N=19) Anticoagulation N=10 Age 60.2 ± 15.8 60.0 ±14.9 0.505 57.9 ± 18.1 69.6 ±13.5 0.141 Sex (men) 2 (50%) 15 (44%) 1.000 5 (56%) 2 (20%) 0.170 Smoking 2 (50%) 12 (35%) 0.616 2 (22%) 1 (10%) 0.581 (P Yrs) 32.0 ± 39.6 30.0 ±24.0 0.840 17.5 ± 17.7 30.0 ±0 0.480 Immobilization 1 (25%) 11 (32%) 1.000 0 7 (70%) 0.003 Periods (day) 88.0 ± 0 38.4 ±49.9 0.308 224.3 ±545.0 Operation 0 6 (18%) 1.000 0 5 (50%) 0.033 Malignancy 1 (25%) 10 (29%) 1.000 4 (44%) 1 (10%) 0.141 Coagulative disorder 2 (50%) 8 (24%) 0.279 1 (11%) 1 (10%) 1.000 Underlying disease Cardiovascular 1 (25%) 14 (41%) 1.000 2 (22%) 6 (60%) 0.170 Respiratory 1 (25%) 4 (12%) 0.446 1 (11%) 0 0.474 Endocrinology 0 7 (21%) 1.000 1 (11%) 1 (10%) 1.000 P value 은관찰되지않았다. 5. 소집단분석 우심실부전군 38명의환자가우심실부전군에포함되었고혈전용해요법과항응고요법이각각 4명 (12%) 과 34명 (88%) 에서시행되었다. 우심실부전군에서혈전용해요법과항응고요법을시행받은환자들간에기본특성에차이는없었다 (Table 6). 항응고요법군의 38%(13명 ) 가 혈전용해요법의금기때문에항응고제를투여받았고, 59%(20 명 ) 의환자가임상의의판단에의해치료가결정되었다. 혈전용해요법군과항응고요법군사이에임상증상및징후와혈액검사소견은차이가없었고중증도에도차이가없었다 (Table 7). 혈전용해제는 t-pa와 UK가각각 2명에서사용되었다. 우심실부전군에서혈전용해요법과항응고요법시 28일사망률은 50% (2명), 24% (8명)(p=0.279) 였고중요출혈부작용은 25% (1명), 6% (2명)(p=0.291) Table 7. Severity indices and outcome between RV dysfunction and shock group RV dysfunction (N=38) Shock (N=19) Thrombolysis N=4 Anticoagulation N=34 P value Thrombolysis N=9 Anticoagulation N=10 P value Severity indices Mean BP (mmhg) 107.5 ± 13.6 100.7 ± 13.3 0.315 56.9 ± 36.9 63.9 ± 4.5 0.621 Circulatory collapse 0 0 2 (22%) 1 (10%) 0.582 APACHE Ⅱ score * 10.0 ± 4.2 10.2 ± 6.2 0.924 15.1 ± 11.3 21.3 ± 7.1 0.059 SOFA score 2.5 ± 1.9 2.9 ± 2.8 0.942 6.4 ± 4. 5.7 ± 2.6 0.967 MV 1 (25%) 6 (18%) 1.000 6 (67%) 4 (40%) 0.370 Weaning 0 3 1.000 2 2 1.000 TVT (day) 1.5 ± 0 12.3 ± 11.6 0.617 1.5 ± 1.5 16.8 ± 6.1 0.009 Outcome Recurrence 1 (25%) 4 (12%) 0.446 0 1 (10%) 1.000 Death 2 (50%) 8 (24%) 0.279 4 (44%) 3 (30%) 0.650 Major bleeding 1 (25%) 2 (8%) 0.291 2 (22%) 0 0.211 Fatal bleeding 1 1 1 0 Intracranial hemorrhage 1 0 0 0 Minor bleeding 0 2 (6%) 1.000 1 (11%) 0 0.474 * APACHEⅡscore : acute physiology and chronic health evaluationⅡscore, MV : mechanical ventilation, TVT : total ventilation time SOFA score : sequential organ failure assessment score, 492

Tuberculosis and Respiratory Diseases Vol. 59. No. 5, Nov. 2005 에서나타났다 (Table 7). 혈전용해요법시사망한 2명중 1명은폐혈전색전으로인한쇽의진행이원인이었고나머지 1명은혈전용해제사용후발생한뇌출혈이원인이었다. 항응고요법군에서사망한 8명의환자중 7명이조절되지않는폐혈전색전증으로, 1명이항응고요법후발생한객혈로사망하였다. 그외중요출혈부작용이 1명 ( 수혈이필요했던혈변 ), 경미한출혈이 2명 ( 육안적혈뇨, 질출혈 ) 에서나타났다. 고찰본연구는중증폐혈전색전증환자를쇽과우심실부전으로나누어서혈전용해요법과항응고요법을시행했을때예후와부작용에대해조사하였다. 국내에서는폐혈전색전증에대한단일기관연구 15 와전국실태조사가있었지만 3, 중증폐혈전색전증을따로구분하여분석하지않았고, 치료에따른결과가조사되지않았다. 본연구에서중증폐혈전색전증환자의사망률은 30% 였고혈전용해요법군에서 46%, 항응고요법군이 25% 로혈전용해요법시항응고요법에비해사망률의감소를보이지않았다. 세분화하여분석시쇽군에서는혈전용해요법과항응고요법시사망률이각각 44%, 30% 였고우심실부전군역시 50%, 24% 로혈전용해요법이항응고요법에비해사망률을줄이지못했다. 외국에서폐혈전색전증은사망률이 15.3% 으로알려져있고 2, 중증폐혈전색전증에서는본연구와마찬가지로사망률이더높다. Alpert 등은우심실부전이있으나혈압이정상인환자, 쇽을보이는환자에서각각사망률이 6.5%, 25% 라고하였고 16, Blackmon 등은쇽이없었던군과쇽이동반된군에서사망률을 5% 와 35% 로보고하고있다 17. 중증폐혈전색전증에서사망률은우심실부전의정도와관련이있고 4,6, 혈전용해요법은항응고요법에비해첫 24시간내에는혈전을더빨리녹여우심실의부담을줄여주는장점이있다 18. 따라서이론적으로는중증폐혈전색전증환자에서혈전용해요법이예후를향상시킬가능성이있고 Blackmon 등은쇽이있는환자에서 UK가헤파린보다사망률을 8.2% 에서 2.7% 로감소시킨다고보 고하였다 19. 메타분석에서도혈역학적으로불안정한환자에서사망률을줄이는것으로보고되었다 8. 본연구와마찬가지로쇽환자에서혈전용해요법이항응고요법에비해사망률을줄이지못하는것으로보고한연구도있다 20-22. 본연구에서쇽군에서혈전용해요법이사망률을줄이지못했던것에대해몇가지고려해야할점이있다. 첫째로이연구는소규모의후향적연구이며, 두군간에 APACHEⅡ 점수, SOFA 점수등에서차이가없었지만, 혈전용해요법군에서기계환기가더많이사용된것들을볼때이환자들의실제중증도가높았을가능성이있다. 둘째는아시아인에서혈전증의위험인자가서구와다른것처럼치료반응도차이가있을수있다. 서구에서는혈전증의 20-60% 가활성 C단백 (activated protein C, APC) 저항성에의해발생하고 APC 내성의약 90% 는 factor V의점돌연변이 (factor V Leiden) 에의한다. 그러나서구에서와는달리한국및동양에서는 factor V Leiden 은드문것으로보고되어 12, 혈전증의위험인자에는인종간의차이가있는것으로알려져있다 13,14. 외국보고에서는고관절또는슬관절수술후약 4-5주동안예방적항응고제사용을권유하고있으나 23, 국내에서는인공고관절전치환술후심부정맥혈전증의발생빈도는 7.5% 였고임상적징후는발생하지않아특별한처치는필요하지않다는보고도있다 24. 본연구에서혈전용해요법의금기로인해항응고요법을시행되었던환자들을분석해도사망률에차이가없어우리나라에서폐혈전색전증의치료반응에대한대규모전향적연구가필요할것으로사료된다. 우심실부전이있지만혈압이정상인환자에서혈전용해요법을시행하는것은더욱논란의여지가있다. Hamel 등은단기관분석을통해이러한환자들에서혈전용해요법이항응고요법에비해사망률을줄이지못하고오히려출혈부작용을증가시킨다고하였다 10. 하지만 Konstantinides 등은 256명을대상으로한이중맹검연구에서혈전용해제를사용한환자에서 30일생존률이더높다고보고하였다 9. 그러나본연구에서는혈압이정상인우심실부전환자의 89% (34/38) 에서항응고요법이시행되었고, 사망률 493

SY Han et al. : Thrombolysis and anticoagulation in major pulmonary thromboembolism 이 24% 였다. 우심실부전단독인경우혈전용해요법사용이드물어서국내다른기관의조사도필요할것이다. 혈전용해요법시가장문제가되는합병증은뇌출혈과사망관련출혈을포함한중요출혈부작용이다. 현재까지세혈전용해제간에치료효과와합병증의발생에큰차이가없다고알려져있으나, 혈전용해제의종류에따라출혈부작용의발생빈도는보고자마다차이가있다. Hamel 등은 t-pa, UK, SK에서중요출혈부작용이각각 21%, 5%, 9% 라고보고하였고 10, Meneveau 등은 t-pa와 SK 사용시 22%, 7.0% 로보고하였다 25. 본연구에서는혈전용해요법을시행받은환자중 10명에서 t-pa가, 3명에서 UK가사용되었다. 이중중요출혈부작용을일으켰던모든환자에서 t-pa가사용되었다. t-pa는 100mg을 2시간동안지속정주하는것이추천되고있지만, t-pa의용량에는이견이있다. PIOPED 연구에서는 11명의중증폐혈전색전증환자에게 t-pa를 1mg/min 으로 40-80mg 정주하여사용하였을때출혈부작용의빈도가낮았음을보고하였다 18. 그리고중국인중증폐혈전색전증환자 4명에게 t-pa 80mg을몸무게에대한비율로투여하였을때중요출혈부작용이 1예에서발생했지만혈전용해효과에는영향을미치지않음을보여주었다 26. 본연구에서는혈전용해요법군에서항응고요법군에비해출혈부작용이높은경향을보여향후국내에서도혈전용해요법의출혈부작용및 t-pa의용량에대한연구가진행되어야할것이다. 최근에는중증폐혈전색전증환자에서혈전용해요법치료여부결정시혈전용해요법의금기가상대적인것으로개개인에따른치료가제안되기도한다 17. 출혈의위험성이덜하고폐혈전색전증의위험이더높은경우에는혈전용해요법을시행할수있고 27, 출혈위험성이높은환자에서는혈전용해요법을최대한지연시키면서기다려볼수있다 7. 본연구에서도혈전용해요법의금기가있었던대부분의환자들에서항응고요법이시행되었고, 혈전용해요법군과비교했을때사망률이높지않았다. 이는금기로인해혈전용해요법을시행하지못할때항응고요법으로경과관찰을할수있음을지지하는결과를보였다. 본연구는단일기관의소규모후향적연구여서약물요법의선택이무작위가아닌제한점이있다. 또한쇽군에서색전제거술등이시행되지않았던이유에대해서는알수가없었다. 하지만, 중증폐혈전색전증의기준을만족시키는환자에서대규모의무작위대조시험은시행하기어렵다는점을고려해보면이연구결과가중증폐혈전색전증의치료에도움을줄수있는연구일것이다. 결론적으로쇽과우심실부전을보이는중증폐혈전색전증환자에서혈전용해요법과항응고요법으로치료했을때, 두군모두에서혈전용해요법이항응고요법에비해사망률을감소시키지못했으며출혈부작용은높은경향을보였다. 중증폐혈전색전증은사망률이높은질환이며본연구에서치료결과가외국보고와차이가있어, 향후국내에서도대규모전향적연구가필요할것으로사료된다. 요약연구배경 : 우심실부전또는쇽을보였던중증폐색전증에서혈전용해요법혹은항응고요법을시행했을때예후의차이에대해조사해보고자하였다. 방법 : 1995년 1월부터 2004년 12월까지서울아산병원에입원했던폐색전증환자중에서우심실부전혹은쇽이있었던총 60명의환자를대상으로의무기록분석을통해서후향적으로조사하였다. 결과 : 총 57명의환자가혈전용해요법또는항응고요법을시행받았으며, 이중혈전용해제는 13명 (23%) 에서, 항응고제는 44명 (77%) 에서사용되었다. 혈전용해요법군과항응고요법군에서 APACHEⅡ 점수나 SOFA 점수에차이는없었고사망률은각각 46% (6/13), 16% (7/44) 였다 (p=0.054). 쇽이있는 19명 (33%) 의환자중혈전용해요법은 9명 (47%), 항응고요법은 10명 (53%) 에서시행되었고사망률은각각 44% (4/9), 30% (3/10) 로차이가없었다 (p=0.650). 38명 (67%) 의우심실부전군에서혈전용해요법은 4명 (11%), 항응 494

Tuberculosis and Respiratory Diseases Vol. 59. No. 5, Nov. 2005 고요법은 34명 (89%) 에서시행되었고사망률은 50% (2/4), 24% (8/34) 로차이가없었다 (p=0.279). 중요출혈부작용은혈전용해요법군과항응고요법군에서 23% (3/13), 5% (2/44) 로혈전용해요법이높은경향을보였다 (p=0.072). 결론 : 중증폐혈전색전증환자에서쇽군과우심실부전군을각각혈전용해요법과항응고요법으로치료했을때, 두군모두에서혈전용해요법이항응고요법에비해사망률을감소시키지못했으며, 출혈부작용은높은경향을보였다. 그러므로우리나라에서전향적대규모연구가필요할것으로사료된다. 참고문헌 1. Anderson FA Jr, Wheeler HB, Goldberg RJ, Hosmer DW, Patwardhan NA, Jovanovic B, et al. A popula tion-based perspective of the hospital incidence and case-fatality rates of deep-vein thrombosis and pul monary embolism: the Worcester DVT study. Arch Intern Med 1991;151:933-8. 2. Goldhaber SZ, Visani L, de Rosa M. Acute pulmonary embolism: clinical outcomes in the International Coo perative Pulmonary Embolism Registry (ICOPER). Lancet 1999;353:1386-9. 3. Scientific Committee for National Survey of Acute Pulmonary Thromboembolism, Korea Academy of Tuberculosis and Respiratory Disease. The National survey of acute pulmonary thromboembolism in Korea. Tuberc Respir Dis 2003;54:5-14. 4. Konstantinides S, Geibel A, Kasper W. Predictors of in-hospital mortality in patients with acute massive pulmonary embolism: results of the Management and Prognosis of Pulmonary Embolism Registry. Circulation 1996;94(Suppl I):I572. 5. Hall RJ, Sutton GC, Kerr IH. Long-term prognosis of treated acute massive pulmonary embolism. Br Heart J 1977;39:1128-34. 6. Kasper W, Konstantinides S, Geibel A, Tiede N, Krause T, Just H. Prognostic significance of right ventricular afterload stress detected by echocardiography in patients with clinically suspected pulmonary embolism. Heart 1997;77:346-9. 7. Grifoni S, Olivotto I, Cecchini P, Pieralli F, Camati A, Santoro G, et al. Short-term clinical outcome of patients with pulmonary embolism, normal blood pressure and echocardiographic right ventricular dysfunction. Cir culation 2000;101:2817-22. 8. Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thr ombolysis compared with heparin for the initial treat ment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation 2004;110: 744-9. 9. Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002;347:1143-50. 10. Harmel E, Pacouret G, Vincentelli D, Forissier JF, Peycher P, Pottier JM, et al. Thrombolysis or heparin therapy in massive pulmonary embolism with right ventricular dilation: results from a 128-patient mo nocenter registry. Chest 2001;120:120-5. 11. Agnelli G, Becattini C, Kirschstein T. Thrombolysis vs heparin in the treatment of pulmonary embolism: a clinical outcome-based meta-analysis. Arch Intern Med 2002;162:2537-41. 12. Kim TW, Kim WK, Zang DY, Lee JH, Kim SB, Kim SW, et al. The prevalence of Leiden(1961G A. mutation in the factor V gene in Korean patients suspected to have thrombosis. Korean J Thromb Hemost 1997;4: 27-31. 13. Chan LC, Bourke C, Lam CK, Liu HW, Brookes S, Pasi J, et al. Lack of activation protein C resistance in healthy Hong Kong Chinese blood donors: correla tion with absence of Arg506-Gln mutation of factor V gene. Thromb Haemost 1996;75:522-3. 14. Takamiya O, Ishida F, Kodaira H, Kitano K. APCresistance and Mnl I genotype(gln 506. coagulation factor V are rare in Japanese population. Thromb Haemost 1995;74:996. 15. Bak SM, Lee SH, Sin C, Cho JY, Shim JJ, In KH, et al. Clinical study of pulmonary thromboembolism. Tuberc Respir Dis 2001;50:106-16. 16. Alpert JS, Smith R, Carlson J, Ockene IS, Dexter L, Dalen JF. Mortality in patients treated for pulmonary embolism. JAMA 1976;236:1477-80. 17. Urokinase pulmonary embolism trial: phase 1 results: a cooperative study. JAMA 1970;214:2163-72. 18. Arcasoy SM, Kreit JW. Thrombolytic therapy of pul monary embolism: a comprehensive review of current evidence. Chest 1999;115:1695-707. 19. The urokinase pulmonary embolism trial: a national cooperative study. Circulation 1973;47(Suppl 2):II1-108. 20. The PIOPED investigators. Tissue plasminogen activator for the treatment of acute pulmonary embolism. Chest 1990;97:528-33. 21. Levine M, Hirsh J, Weitz J, Cruickshank M, Neemeh J, Gent M, et al. A randomized trial of single bolus dosage regimen of recombinant tissue plasminogen 495

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