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1 Journal of Breast Cancer ISSN J Breast Cancer 2008; September 11 (3): ORIGINAL ARTICLE 피부보존유방절제술및즉각적인유방복원수술이후발생하는폐혈전색전증에대한 Enoxaparin 의예방적투여효과 정민성ㆍ윤호성ㆍ손병호 1 ㆍ이정선 1 ㆍ김희정 1 ㆍ박은하 1 ㆍ안세현 1 ㆍ이택종 2 ㆍ엄진섭 2 ㆍ최혜숙 3 ㆍ곽범석 4 한양대학교의과대학외과학교실, 울산대학교의과대학서울아산병원 1 외과학교실 2 성형외과학교실, 3 동국대학교의과대학포항병원호흡기내과학교실, 4 일산병원외과학교실 The Efficacy of Enoxaparin for the Prevention of a Pulmonary Thromboembolism in a Skin-sparing Mastectomy with Immediate Reconstruction in Breast Cancer Min Sung Chung, Ho Sung Yoon, Byung Ho Son 1, Jung Sun Lee 1, Hee Jeong Kim 1, Eun Hwa Park 1, Sei Hyun Ahn 1, Tack Jong Lee 2, Jin Sup Eom 2, Hye Sook Choi 3, Beom Seok Kwak 4 Department of Surgery, College of Medicine, Hanyang University, Seoul; Departments of 1 Surgery and 2 Plastic Surgery, University of Ulsan, College of Medicine and Asan Medical Center, Seoul; 3 Department of Pulmonology, College of Medicine Dongguk University Pohang Hospital, Pohang; 4 Department of Surgery, College of Medicine Dongguk University International Hospital, Goyang, Korea 책임저자 : 손병호 서울시송파구풍납 2 동 388-1, 울산대학교서울아산병원외과 Tel: , Fax: brdrson@korea.com 접수일 : 2008 년 5 월 27 일게재승인일 : 2008 년 8 월 29 일 Purpose: Performance of a skin-sparing mastectomy with immediate reconstruction provides psychological satisfaction and good cosmetic outcome for patients with breast cancer. However, this is a lengthy procedure to perform, and there is increased risk of pulmonary thromboembolism (PTE). The purpose of this study was to evaluate the efficiency of the use of low molecular weight heparins (enoxaparin) for prophylaxis against a pulmomary thromboembolism followed by mastectomy with an immediate transverse rectus abdominis myocutaneous flap (TRAM) in breast cancer. Methods: A total of 123 patients underwent a skin-sparing mastectomy with an immediate TRAM. The non-enoxaparin group wore compression stockings for PTE prophylaxis and the enoxaparin group received enoxaparin (40 mg SC injection, once daily starting 2 hr before surgery and continuing for 6 days postoperatively) in conjunction with the use of compression stockings. Lung perfusion, inhalation scans, and serum D-dimer assays were performed on postoperative day 3. If findings were clinically suspicious or intermediate to high probability of a PTE in a lungs scan, embolism computed tomography was performed. Patients were prospectively investigated according to the clinicopathological data. We compared the incidence of PTE and hemorrhagic complications between the two groups. Results: There were no significant clinicopathological differences between the two groups. Eleven patients developed a PTE (nine patients in the non-enoxaparin group and two patients in the enoxaparin group). The prevalence rate of a PTE was 17.3% and 3.2% for each group, respectively (p= 0.01). One patient in the non-enoxaparin group required a second operation for bleeding control and three patients in the enoxaparin group needed transfusions. There were minor hemorrhagic complications in the enoxaparin group that improved after supportive management. Conclusion: Although there were minor hemorrhagic complications, enoxaparin is safe and effective in a preventing PTE in patients that undergo immediate reconstruction after a skin-sparing mastectomy. Key Words : Breast cancer, Pulmonary thromboembolism, Skin sparing mastectomy, Immediate reconstruction, Enoxaprin 중심단어 : 유방암, 폐혈전색전증, 피부보존유방절제술, 즉각적유방복원술, 에녹사파린 125

2 126 Min Sung Chung, et al. 서론폐혈전색전증과심부정맥혈전증과같은정맥혈전색전증은암환자에서흔하게나타날수있는합병증이다. 암환자에서는종양자체에서전혈액응고인자 (procoagulant factor) 등의사이토카인 (cytokine) 들이분비되고신생혈관들이생성되며종양에의한직접적인내피세포의손상이나압박, 그리고암세포에의한혈소판응집과유착등에의해응고기전이대부분항진되어있어일반환자들에비해정맥혈전색전증의위험이 4배이상높다고보고되고있다.(1-3) 또한정맥혈전색전증의위험인자인수술, 운동제한, 항암화학치료, 항호르몬치료, 정맥혈전색전증의과거력, 비만, 에스트로젠복용력, 고령그리고중심정맥삽관등을동반할경우에는암환자에서정맥혈전색전증의위험성은더욱높아지게된다.(2) 암과관련된수술을받을경우정맥혈전색전증의발생위험은더욱증가하게되어아무런예방조치없이수술을받을경우에는많게는 50% 에서정맥혈전색전증이생길수있으며암관련수술이아닌수술에서도암환자에서는수술후정맥혈전색전증이 2배높게보고되었다.(4,5) American College of Chest Physicians (ACCP) 를비롯한여러정맥혈전색전증의예방에대한권고안에서는정맥혈전색전증에대해중등도이상의위험성을가지거나모든암환자의수술에서는항응고제투여의금기사항이없다면예방적으로항응고제를투여하고선택적으로물리적예방법을사용할것을권고하고있다.(4,6,7) 예방적항응고제로와파린, 저용량헤파린, 저분자량헤파린이사용되는데이중에녹사파린 (enoxaparin) 은저분자량헤파린으로여러임상연구를통해정맥색전혈전증의예방에효과가입증되었고기존의헤파린에비해예방효과는유사하면서투여가간편하고혈액검사측정을할필요가없으며간혹나타날수있는헤파린에의한혈소판감소증과같은합병증의위험도적은것으로알려져있다.(8,9) 유방암에의해서도혈액과다응고 (hypercoagulability) 상태가유도된다는것은이미알려진사실이며유방암환자에서의심부정맥혈전증이나심각한폐혈전색전증을경험한적이있다고하는외과의사들은많으나이에대한대규모의연구나체계적인보고가이루어진것은매우적다.(10) 그리고현재까지유방암으로수술을받는환자에서정맥혈전색전증의예방에관한무작위전향적인연구가이루어진것은없다. 최근유방암환자에서많이시행되고있는피부보존유방절제술및자가조직을이용한즉각적인유방복원수술은안전하면서도수술후에환자에게심리적, 미용적인측면에서이득을주는수술로자리를잡아감에따라그빈도가증가하고있다.(9) 피부보존유방절제술및자가조직을이용한즉각적인유방복원수술 은기본적으로암수술이면서수술소요시간이길고수술후에도일정기간동안침상안정을해야한다는점에서수술후에폐혈전색전증과같은정맥혈전색전증의합병증을일으킬위험성이높은고위험군에속한다고할수있다. 저자들은이전의연구에서유방절제술및즉각적인유방복원수술후에증상을동반한폐혈전색전증 7예 (3.2%; 7/216) 에대해보고하였고,(11) 이후전향적인연구를통하여서무증상인경우를포함하여높은빈도 (16.7%; 9/54) 의폐혈전색전증이발생한것을보고하였다.(12) 하지만현재유방암과관련수술에대한예방적인항응고제투여에대한연구는매우드물고보다위험성이높은피부보존유방절제술및자가조직을이용한즉각적인유방복원수술에서예방적인항응고제의효과와안전성에대한연구는없었다. 이에본연구에서는유방절제술및즉각적인유방복원수술후폐혈전색전증에대한예방으로저분자량헤파린인에녹사파린을사용했을때의효과와안전성에대해알아보고자하였다. 방법 2005년 1월부터 2006년 6월까지서울아산병원유방암클리닉에서임상적으로 0기에서 II 기의조기유방암으로진단받고피부보존유방절제술및즉각적인횡복직근피판을이용한유방복원술 (transverse rectus abdominis myocutaneous flap, TRAM) 을시행받은환자는모두 123 명이었고, 이중 2005년 1월부터 5월까지에녹사파린을투여하지않고수술을받은환자는 52명, 2006년 1월부터 6월까지에녹사파린을투여한환자는 63 명이었다. 수술시간의차이를고려하여유리피판횡복직근피판을이용한환자와양측유방을수술한환자는제외하였고한쪽유방에대해유경 (pedicle) 횡복직근피판술을시행한환자만을대상으로하여에녹사파린을투여하지않은군 (non-enoxaparin group) 52명과예방적으로에녹사파린을투여한군 (enoxaparin group) 63명을비교분석하였다. 에녹사파린을투여한군중에혈액응고질환, 최근에심혈관계의혈전성질환을앓은병력, 최근에헤파린을사용한병력이있거나, 헤파린에대한과민반응, 기존에간질환이나신질환과같은금기사항을가진환자는없었다. 예방적으로에녹사파린투여한군에서는에녹사파린 (Clexane, Sanofi Aventis, Paris, France) 40 mg을수술 2시간전에피하주사하였고수술후 6일동안매일 1회씩피하주사하였다. 모든환자들은수술전후에허벅지까지고탄력압박스타킹을착용하였고복부창상과횡복직근피판의안정을고려하여수술후 2일까지는침상안정을하였다. 간헐적공기압박기 (intermittent pneumatic compression device, IPC) 가있는수술

3 Thromboprophylaxis in a Skin-sparing Mastectomy with Immediate Reconstruction in Breast Cancer 127 실에서수술을받은환자에서는수술중에압박기를착용하였다. 폐혈전색전증증상이없는환자들은수술후 3일째폐환기 / 관류스캔과혈중 D-dimer 수치를측정하였다. 수술후회복기간중호흡곤란, 흉통등의폐혈전색전증증상을보인환자들은즉각적으로흉부전산화단층촬영과환기 / 관류스캔을검사하였고, 혈중 D-dimer 수치를측정하였다. 폐색전증의진단은폐스캔검사에서환기는정상이면서두구역 (segment) 이상에서관류결손이있을때를고위험 (high probability) 으로분류하였으며, 이때시행한흉부전산화단층촬영에서폐동맥내혈전이보이는경우를폐혈전색전증이라고진단하였다. 폐스캔검사에서 intermediate probability로진단된환자에서는흉부전산화단층촬영을시행하여정상인경우는관찰하였고, 의심스러운경우는 1주일뒤에추적검사를시행하였다 (Fig 1). 폐혈전색전증이진단된환자에서는증상의여부에관계없이저분자량헤파린을투여하면서와파린 (wafarin, Coumadin Je Il Pharm, Seoul, Korea) 10 mg으로 International Normalizatiom Ratio (INR) 을조절하면서전환하였고퇴원후 6개월동안투약하였다. 예방적으로저분자량헤파린을투여하던환자는지속적으로사용하다가와파린으로전환하여동일하게치료하였다. 본연구에서저자들은피부보존유방절제술및횡복직근피판술을이용한즉각적유방복원술환자군에서에녹사파린을예방적으로사용한군과사용하지않은군에서의환자의나이, 체질량지수 (body mass index, BMI), 수술시간, D-dimer 수치, 알려진폐혈전색전술의위험인자및병리소견을비교하였고양군에서흉부전산화단층촬영에서진단된폐혈전색전증환자의발생 Surgery Normal or Low p. Intermediate p. High p. Observation Lung scan/d-dimer Normal Observation Embolism CT Suspicious Follow up Compression stocking PTE Sx(+)/IF No Sx POD #3 PTE LMWH Wafarin Fig 1. Design of the study. PTE=pulmonary thromboembolism; Sx=symptom; POD=postoperative day; p.=probability; LMWH= low-molecular-weight heparin. 빈도의차이와수혈여부, 재수술, 수술후 1일째배액량, 배액관제거일등을 t-test, chi-square test를이용하여비교분석하였다. 결 대상환자들은모두여성이었고전체환자의평균연령은 41.2± 7.4 (23-63) 세였다. 에녹사파린비투여군과에녹사파린투여군각각의평균연령은 42.4±6.3세와 40.2±8.1 세로양군간의연령에따른통계학적인차이는없었다. 체질량지수는평균 22.78± 2.89 ( ) kg/m 2 이었고양군간의차이는없었다 (p= 0.77). 폐혈전색전증의위험인자인당뇨, 고혈압, 흡연력, 음주력, 호르몬치료경력을가진환자는비투여군에서는 8명, 투여군에서는 5명이있었다. 수술후 D-dimer 수치와병리학적소견에서는모두통계학적으로유의한차이가없었다. 평균수술시간은에녹사파린투여군에서 524.0±77.0분으로비투여군의 488.4± 52.4분에비해유의하게길었다 (p=0.02) (Table 1). 에녹사파린비투여군에서폐스캔검사상에서 intermediate probability 인환자가 9명 (17.3%) 이었고, high probability` 인환자는 6명 (11.5%) 이었다. 이들중폐전산화단층촬영을통해폐혈전색전증으로진단된환자는 9명 (17.3%) 이었다. 이중 2명의환자에서는호흡곤란등의증세가있었고나머지에서는증상이없었다. 진단된환자중폐혈전색전증의위험인자가있는환자는 2명이었다. 에녹사파린투여군에서는 intermediate probability 인환자가 7명 (11.1%) 이었고, high probability ` 인환자는 2명 (3.2%) 이었으며, 폐전산화단층촬영에서는폐스캔에서 high probability ` 로진단된 2명 (3.2%) 에서만폐혈전색전증으로진단되었다. 그리고진단된 2명은검사이전에각각호흡곤란 과 Table 1. Clinicopathologic characteristics of patients Nonenoxaparin group (N=52) Enoxaparin group (N=63) p- value Mean age (yr) 42.4± ± Mean BMI (kg/m 2 ) 22.8± ± Mean operative time (min) 488.4± ± Mean D-dimer level (μg/ml) 2.3± ± Mean tumor size (mm) 18.8± ± No. of LN metastais 0.8± ± Stage 0 17 (32.7%) 7 (11.3%) I 17 (32.7%) 30 (48.4%) II 14 (26.9%) 19 (30.6%) III 4 (7.7%) 6 (9.7%) BMI=body mass index; LN=lymph node.

4 128 Min Sung Chung, et al. Table 2. The incidence of PTE with diagnostic method Table 3. PTE diagnosis PTE diagnosed by Nonenoxaparin group (N=52) 과심계항진을호소하였던환자였으며이중한명은고혈압으로치료받고있는환자였다 (Table 2). 양군간에발생한폐혈전색전증의빈도는각각 9명 (17.3%) 과 2명 (3.2%) 으로통계학적으로의미있는차이로에녹사파린을투여한군에서낮게나타났다 (Table 3). 수술후 1일째배액량은투여군에서유의하게많이배액되었고 (200.92±66.05 ml vs ±79.68 ml; p<0.001), 배액관을모두제거하는데소요한시간도투여군에서더오래걸렸다 (8.65±1.98 vs 9.43±2.3; p=0.06). 수술후낮은혈색소농도로수혈을받은환자는비투여군에서는없었고투여군에서는 3명 (4.8%) 이있었으나 2명에서는 1단위만수혈하였고 1명에서는 2단위의수혈을하였으나출혈이심하지않았고모두에서에녹사파린을중단하지않았다. 수술후출혈로지혈을위해재수술을시행한환자는비투여군에서 1명 (1.9%) 이있었다. 폐혈전색전증으로진단된환자들가운데사망한환자는없었으며치료후모두에서심각한합병증없이호전되었다 (Table 4). 고 Non-enoxaparin group (N=52) 본연구는저자들의선행연구를기반으로하여유방암에서정맥혈전색전증에대한고위험인자를가지게되는유방절제술및즉각적인유방복원수술을받는환자들을대상으로하여예방적 찰 Enoxaparin group (N=63) Enoxaparin group (N=63) Lung scan Normal 26 (50%) 37 (58.7%) Low probability 11 (21.2%) 17 (27.0%) Intermediate probability 9 (17.3%) 7 (11.1%) High probability 6 (11.5%) 2 (3.2%) Total 52 (100%) 63 (100%) Embolism CT Normal 6 (40%) 7 (77.8%) PTE 9 (60%) 2 (22.2%) Total 15 (28.8%) 9 (14.3%) CT=computed tomography; PTE=pulmonary thromboembolism. p- value Embolism CT 9 (17.3%) 2 (3.2%) 0.01 Lung scan or embolism CT 11 (21.2%) 2 (3.2%) PTE=pulmonary thromboembolism; CT=computed tomography. Table 4. Mean drainage volume, postoperative days of drain removed and the incidence of transfusion and re operation after the surgery Nonenoxaparin group (N=52) Enoxaparin group (N=63) p- value *Mean drainage ± ±79.68 <0.001 volume (ml) Drain remove (POD) 8.65± ± Transfusion 0 (0%) 3 (4.8%) 0.12 Re operation 1 (1.9%) 0 (0%) 0.2 POD=postoperative day. *Mean drainage volume of postoperative day #1. Table 5. PTE incidence between IPC use IPC No IPC p-value No enoxaparin group 6/35 (17.1%) 3/17 (17.6%) Enoxaparin group 1/33 (3%) 1/30 (3.3%) PTE=pulmonary thromboembolism; IPC=intermittent pneumatic compression decive use during operation. 항응고제의효과와안전성에대한최초의연구이고본연구를통해서고위험군의환자에서저분자량헤파린인에녹사파린이폐혈전색전증의예방에효과적임을알게되었다 (p=0.01). 암환자에서암관련수술을받는경우에는정맥혈전색전증의위험성은증가하게되는데암이아닌비슷한종류의수술을받는환자에비해심부정맥혈전증의위험이최소 2배이상높고, 심각한폐혈전색전증은 3배이상높다고알려져있다.(13) 또한암관련수술환자에서정맥혈전색전증에대한예방적조치가없는경우에는 20-40% 에서심부정맥혈전증이정맥조영술에서확인되었고, 이들중에정맥혈전색전증의위험인자가동반된경우에는 40-60% 까지빈도가증가한다고하였다.(4) 비록무증상인심부정맥혈전증과증상있는정맥혈전색전증의빈도가대부분의연구보고에서 5:1 에서 10:1의비율로나타났고,(14) 본연구에서도예방적처치를시행하지않았던군에서증상이없는폐혈전색전증환자들과증상이있는폐혈전색전증환자들의비율은 3.5:1 의비율을보였지만 (7:2 명 ), 무증상의심부정맥혈전증은언제든지임상적으로심각한정맥혈전색전증로발전할수있기때문에많은경우의암관련수술에서는정맥혈전색전증에대한적극적인예방을권고하고있다. 일반적인암과이에관련한수술에대한정맥혈전색전증의보고와는달리유방암과유방암수술후에발생하는정맥혈전색전증에대한보고는많지않다. European Organization for Research and Treatment of Cancer (EORTC) 의 adjuvant breast cancer therapy 연구에서는유방절제술이나유방보존수술을

5 Thromboprophylaxis in a Skin-sparing Mastectomy with Immediate Reconstruction in Breast Cancer 129 Table 6. Risk factors for venous thromboembolism Surgery Trauma (major or lower extremity) Immobility, paresis Malignancy Cancer therapy (hormonal, chemotherapy, or radiotherapy) Previous VTE Increasing age Pregnancy and the postpartum period Estrogen-containing oral contraception or hormone replacement therapy Selective estrogen receptor modulators Acute medical illness Heart or respiratory failure Inflammatory bowel disease Nephrotic syndrome Myeloproliferative disorders Paroxysmal nocturnal hemoglobinuria Obesity Smoking Varicose veins Central venous catheterization Inherited or acquired thrombophilia VTE=venous thromboembolism. 받은 1,332명의환자에서수술후 6주이내에 0.8% 의환자에서정맥혈전색전증이발생하였다.(15,16) 유방절제술을시행한 91 명의환자중 5명 (5%) 에서심부정맥혈전증이발생하였고 2명 (2%) 에서는폐혈전색전증이생겼고 1명이사망한예가보고되기도하였다.(16) Eastern Cooperative Oncology Group (ECOG) 의 adjuvant therapy for breast cancer 연구의보고에의하면수술후보조적치료를받은환자의 5.4% 에서정맥혈전색전증이발생하였고보조치료를받지않은환자에서는 1.6% 에서발생하여유의한차이를보여서 (p<0.001) 수술후보조치료를시행할경우정맥혈전색전증의빈도가높아졌다.(17) Fisher 등 (18) 은유방암수술후보조요법중발생한정맥혈전색전증의빈도를타목시펜을복용하는경우 0.9%, 항암치료를받은경우 2.1%, 타목시펜과항암치료를모두시행한경우에서는 4-13% 발생하였다고보고하였다. 유방암수술후유방복원수술을시행한후에발생한정맥혈전색전증에대한보고는매우적은데유리피판횡복직근피판술을시행한 16 명의환자에서 2명의심부정맥혈전증과 1명의폐혈전색전증에대한보고가있었고횡복직근피판술을시행한 76 명의환자에서회복기간중에 1명의심부정맥혈전증이발생한것을보고한예가있었다.(19) 여러문헌과치료지침에서는이러한암환자에대한적극적인예방적항응고제를투여를권고하고는있는데그이유는첫째, 앞서기술하였듯이정맥혈전색전증은실제로대부분의암환자에서 높은빈도로나타나지만이중어떤환자가증상이있고심각한정맥혈전색전증으로진행될지예측할수가없고진단을위해신체검진이나비침습적인검사를모든환자에서시행하는것은진단에효과적이지않으며경제적인면에서효율적이지못하기때문이다. 둘째, 예방하지않아서증상이있는정맥혈전색전증으로발전할경우에는이에대한진단과치료에따른추가적인위험과비용을부담해야하고정맥혈전색전증이한번발생하면재발의위험성은더높아지게되며본연구에서처럼심각한합병증인폐혈전색전증이생길경우에는환자의생명을직접적으로위협할수도있기때문이다. 셋째, 예방적항응고제는정맥혈전색전증예방에매우효과적인것으로확인되었고이는결국폐혈전색전증을예방하게되며여러연구들을통해예방을통한비용대비효율성이입증이되었기때문이다.(4) ACCP에서는혈전색전증에대한예방적처치가없이수술을받는환자에서정맥혈전색전증의위험도에대해환자의연령, 수술종류, 위험인자 (Table 6) 를기준으로저위험, 중등도위험, 고위험, 최고위험군으로분류하여정맥혈전색전증의발생률을보고하고각각에따른예방처치를권고하였는데고위험군의기준은대수술을받는환자중 60 세이상또는 40-60세환자중추가적인위험인자 ( 암, 선행정맥색전혈전증병력등 ) 가있는경우를말하며최고위험군은수술을받는환자중여러개의위험인자가있는경우, 고관절또는슬관절의관절성형술을받는경우, 그리고중증의외상에의한수술을받는경우에해당한다. ACCP에서는수술환자에서임상적인폐혈전색전증과생명을위협하는심각한폐혈전색전증의빈도를각각저위험군에서는 0.2%, <0.01% 중등도위험군은각각 1-2%, %, 고위험군은각각 2-4%, 0.4-1%, 그리고최고위험군은각각, 4-10%, 0.2-5% 에서발생한다고하였다.(4) 본연구에서는에녹사파린을투여하지않고압박스타킹만착용한경우에증상이있는임상적인폐혈전색전증의빈도는 3.7% 로 ACCP의고위험군에서의빈도와유사한결과를보였다. 각군에따른예방처치는위험인자가없는상황에서소수술을시행하는저위험군에서는특별한예방없이수술후조기운동을, 중증도이상의위험군에서는모두저용량의기존헤파린이나저분자량헤파린과물리적인예방법의병행처지를선택사항으로권장하고있다. ACCP 예방권고의기준으로보면본연구처럼유방암환자에서유방절제술및즉각적인유방복원술을받는환자들은여러위험인자들 ( 암, 수술, 장시간의수술시간, 수술후운동제한 ) 을가지고있는고위험군이상에속하게되므로예방적항응고제투여가적응이된다. National Comprehensive Cancer Network (NCCN) 에서는암환자에대해더포괄적으로예방적항응고제투여지침을권

6 130 Min Sung Chung, et al. 고하고있는데이는입원하고있는모든성인암환자중에서항응고제투여에대한금기사항이없는이상예방적항응고제와선택적으로물리적예방장치들을사용하고항응고제를사용할수없는환자에서는물리적예방장치들을사용할것을권유하고있다.(7) 수술전후혈전색전증의예방은물리적인방법과약물을이용한방법이있다. 물리적인방법으로는조기에운동을시행하는것과압박스타킹이나간헐적공기압박장치의착용하는방법이있다. 메타분석에서압박스타킹의착용은중등도의위험성을가진환자의 2/3 에서효과적으로정맥혈전색전증을예방한다고하였다.(20) 그러나고위험군환자에서는물리적인예방법단독으로는예방적항응고제보다효과적이지못하고항응고제투여가금기인환자에서는대안으로사용할수있겠다.(21) 물리적예방법과항응고제의병용에대해서는일부연구에서는예방에보다효과적이라고하였으나아직이에대해서는불분명하다. 본연구에서는모든환자에서수술당일부터입원기간동안허벅지까지오는압박스타킹을예방적으로착용하였고간헐적공기압박장치가구비된수술실에서수술을받은환자들은수술중에는기구를착용하였다. 에녹사파린비투여군과투여군각각에서수술중간헐적공기압박장치의착용유무에따른폐혈전색전증의발생빈도의차이는없었다 (p=0.95, 0.96) (Table 5). 약물을이용한방법으로는예방적항응고제로기존의헤파린 (unfractionated heparin, UFH) 과저분자량헤파린인 dalteparin, enoxaprin, tinazaparin 등이있고 anti-factor Xa inhibitor인 fondaparionux가있다. 모두에서유사한정맥혈전색전증의예방효과를가지고있으나저분자량헤파린이기존의헤파린에비해하루한번만피하주사하면되므로투여가간편하고 INR 을측정할필요가없으며, 드물지만기존의헤파린에서생길수있는헤파린에의한혈소판감소증같은합병증의위험이적고일부환자에서는외래를통하거나집에서혼자투여할수도있기때문에현재많이사용되어지고있으며많은연구들을통해효과와안전성이입증되었다.(8) 이중복부와골반의암수술을받는고위험군의환자를대상으로한전향적무작위연구인 ENO- XACAN I study에서기존의헤파린과저분자량헤파린인에녹사파린를비교하였는데두약제는효과와안전성에서유사하였고저분자량헤파린이보다간편하여효율적인것으로보고하였다.(22) 본연구에서도에녹사파린을예방적항응고제를사용하였고대부분 7-10일간투여를권고하고있으므로본연구에서도수술당일을포함하여 7일간투여하였다. 하지만에녹사파린의투여기간에대해서는 ENOXACAN II study를통해기존의수술후 1주일투여와수술후 4주간의연장투여를비교하였는데고위험군의환자에서에녹사파린을 4주간투여한군에서 1주간투여한군에비해출혈의위험없이정맥혈전색전증의위험이 60% 감소한다는보고를통해입원뿐만아니라퇴원후에도연장적으로사용할것을권고하였다.(23) 유방암수술시예방적항응고제투여와관련된문헌으로는 Lee 등 (24) 이 75 명의환자에서나트륨헤파린, 칼슘헤파린그리고압박스타킹만을착용한세군으로나누어시행한연구가있었다. 헤파린을사용한 50 명중 10 명에서는출혈의부작용이있었으므로정맥형전색전증에대한위험군환자에서만헤파린의예방적사용할것을주장하였다. 후향적인연구로는예방적으로저용량의헤파린을사용한뒤유방절제술을받은 50 명의환자와대조군을비교한연구에서예방적헤파린을사용한군에서수술후총배액량이유의하게증가와긴재원기간을보고한바가있다.(25) 이는모두기존의헤파린을사용한연구였고 Bakker와 Roumen (26) 은 186 명의환자에서예방적으로저분자량헤파린을투여하고 206 예의유방부분절제술을시행했는데 23 예 (11.2%) 에서출혈성합병증이있었고저분자량헤파린의수술직전투여와수술전날투여에출혈의차이는통계적으로의미가없었다고하였다. 이연구에서는유방부분절제술만을시행하였는데유방의부분절제술은혈관이없는면을따라박리하는수술이아니므로이러한높은출혈결과를보였다고설명하였다. 반면유방부분절제술과유사한유방축소수술에있어서는예방적헤파린투여와혈종과는상관관계가없다는보고도있었다.(27) 본연구에서에녹사파린을사용하면서나타난특별한부작용은없었으나에녹사파린을투여한군에서수술소요시간이보다길었는데이는역설적이지만오히려위험인자인수술시간이길어졌음에도폐혈전색전증의빈도가적게나타난것으로에녹사파린의예방적효과를입증한다고볼수도있겠다. 예방적항응고제를투여한군에서심각한출혈은없었고모두대증적인치료로호전되었다. 투여군중에서수혈이필요했던환자는 3명이었고출혈로인해재수술이필요한환자는없었다. 오히려예방적항응고제를투여하지않은군에서 1명이출혈로인해재수술을받았다. 하지만수술후 1일째배액량은에녹사파린투여군에서통계적으로의미있게많았고배액관을모두제거하는데걸린시간도예방적항응고제를사용한군에서더오래걸렸으나통계적으로는유의하지않았다. 유방암으로수술이필요한모든환자들이동일하게정맥혈전색전증에대한위험을갖는다고볼수없고유방암과비교적짧은전신마취및수술시간이고려할때유방암으로수술받는모든경우에예방적항응고제가반드시필요하다고할수는없겠다. 하지만이외에추가적인위험인자를가지고있는환자들에서는항응고제와선택적으로물리적인예방법을병용하는것이바람직하겠다. 기존에정맥혈전색전증의병력이있거나고령의환자들이나유전적과다응고질환이있는유방암환자의수술에서는예방적

7 Thromboprophylaxis in a Skin-sparing Mastectomy with Immediate Reconstruction in Breast Cancer 131 항응고제의투여를고려하는것이좋겠다. 그리고본연구의경우같이장기간의수술시간과수술후운동제한이필요한유방절제술및즉각적인유방복원수술을시행받거나본연구에는포함되지않았으나유방암수술후항암화학요법이나항호르몬치료를시행한이후에자가조직복원을시행하는경우에도정맥혈전색전증의위험인자들을모두가지고있으므로이와같은경우에는적극적인예방을시행해야할것이다. 결론저자들의연구에서저분자량헤파린인에녹사파린의예방적인투여는유방암으로피부보존유방절제술및즉각적인유방복원술이필요한환자에서발생할수있는심각한합병증인폐혈전색전증을효과적이고비교적안전하게예방하였다. 참고문헌 1. Lee AY. Cancer and thromboembolic disease: pathogenic mechanisms. Cancer Treat Rev 2002;28: Prandoni P, Falanga A, Piccioli A. Cancer and venous thromboembolism. Lancet Oncol 2005;6: Bick RL. Cancer-associated thrombosis. N Engl J Med 2003;349: Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, et al. Prevention of venous thromboembolism: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004;126:S Rickles FR, Levine MN. Epidemiology of thrombosis in cancer. Acta Haematol 2001;106: Lyman GH, Khorana AA, Falanga A, Clarke-Pearson D, Flowers C, Jahanzeb M, et al. American society of clinical oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007;25: Venous thromboembolic disease clinical practice guidelines in oncology-v National Comprehensive Cancer Network: http: // accessed June 26, Mismetti P, Laporte S, Darmon JY, Buchmuller A, Decousus H. Meta-analysis of low molecular weight heparin in the prevention of venous thromboembolism in general surgery. Br J Surg 2001;88: Yoon HS. Nationwide breast cancer data of 2002 in Korea. J Breast Cancer 2004;7: Patiar S, Kirwan CC, McDowell G, Bundred NJ, McCollum CN, Byrne GJ. Prevention of venous thromboembolism in surgical patients with breast cancer. Br J Surg 2007;94: Son BH, Kwak BS, Kim JK, Kim HJ, Hong SJ, Lee JS, et al. Symptomatic pulmonary thromboembolism following skin-sparing mastectomy with Immediate TRAM reconstruction in breast cancer patients. J Korean Surg Soc 2006;70: Lee JS, Son BH, Choi HS, Jung MS, Hong SJ, Kim JK, et al. Pulmonary thromboembolism following mastectomy with immediate TRAM in the patients with breast cancer: a prospective study. J Breast Cancer 2006;9: White RH, Zhou H, Romano PS. Incidence of symptomatic venous throm boembolism after different elective or urgent surgical procedures. Thromb Haemost 2003;90: Ibrahim EH, Iregui M, Prentice D, Sherman G, Kollef MH, Shannon W. Deep vein thrombosis during prolonged mechanical ventilation despite prophylaxis. Crit Care Med 2002;30: Clahsen PC, van de Velde CJ, Julien JP, Floiras JL, Mignolet FY. Thromboembolic complications after perioperative chemotherapy in women with early breast cancer: a European organization for research and treatment of cancer breast cancer cooperative group study. J Clin Oncol 1994;12: Wedgwood KR, Benson EA. Non-tumour morbidity and mortality after modified radical mastectomy. Ann R Coll Surg Engl 1992; 74: Saphner T, Tormey DC, Gray R. Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer. J Clin Oncol 1991;9: Fisher B, Dignam J, Wolmark N, DeCillis A, Emir B, Wickerham DL, et al. Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 1997;89: Olsson EH, Tukiainen E. Three-year evaluation of late breast reconstruction with a free transverse rectus abdominis musculocutaneous flap in a county hospital in Sweden: a retrospective study. Scand J Plast Reconstr Surg Hand Surg 2005;39: Wells PS, Lensing AW, Hirsh J. Graduated compression stockings in the prevention of postoperative venous thromboembolism. A metaanalysis. Arch Intern Med 1994;154: Clarke-Pearson DL, Dodge RK, Synan I, McClelland RC, Maxwell GL. Venous thromboembolism prophylaxis: patients at high risk to

8 132 Min Sung Chung, et al. fail intermittent pneumatic compression. Obstet Gynecol 2003;101: Agnelli G, Bolis G, Capussotti L, Scarpa RM, Tonelli F, Bonizzoni E, et al. A clinical outcome-based prospective study on venous thromboembolism after cancer surgery: project. Ann Surg 2006;243: Bergqvist D, Agnelli G, Cohen AT, Eldor A, Nilsson PE, Le Moigne- Amrani A, et al. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med 2002;346: Lee RE, Ho KN, Karran SJ, Taylor I. Haemorrhagic effects of sodium heparin and calcium heparin prophylaxis in patients undergoing mastectomy. J R Coll Surg Edinb 1989;34: Steele RJ, Richmond JD, Lee D, Chetty U, Davies GC. The effect of low-dose subcutaneous heparin on wound haemorrhage, a controlled study of mastectomy patients. Br J Clin Pract 1983;37: Bakker XR, Roumen RM. Bleeding after excision of breast lumps. Eur J Surg 2002;168: Hussien M, Lee S, Malyon A, Norrie J, Webster M. The impact of intraoperative hypotension on the development of wound haematoma after breast reduction. Br J Plast Surg 2001;54:

부인과수술을하는 high-risk* patients 을위한혈전예방을위해서는, especially for malignancy, 아래의예방책중에서선택을한다 : 수술전 Pneumatic compression devices 을사용하고퇴원할때까지계속사용한다. 미분획헤파린 (5,

부인과수술을하는 high-risk* patients 을위한혈전예방을위해서는, especially for malignancy, 아래의예방책중에서선택을한다 : 수술전 Pneumatic compression devices 을사용하고퇴원할때까지계속사용한다. 미분획헤파린 (5, Guideline Title DVT 와 PE 예방. Bibliographic Source(s) American College of Obstetricians and Gynecologists (ACOG). Prevention of deep vein thrombosis and pulmonary embolism. Washington (DC): American College