대한혈관외과학회지 : 제 25 권제 1 호 Vol. 25, No. 1, May 2009 심포지엄 외과적환자에서정맥혈전증의유병률과예방 조선대학교의과대학외과학교실 장정환 VTE Prevalence and Prophylaxis in Surgical Patients Jeong Hwan Chang, M.D. Department of Surgery, College of Medicine, Chosun University, Gwangju, Korea DEFINITION OF VENOUS THROMBOEMBOLISM 1) 심부정맥혈전증 (Deep Vein Thrombosis, DVT) 하지에흔하게생기는질환중의하나로증상이없는경우도있고하지의통증과함께부종을나타내는경우도있다. 심부정맥혈전증발생에대한정확한우리나라의통계는없지만서구의경우인구 1,000명당 1명에서발생하는것으로알려져있고, 그합병증으로는폐색전증 (pulmonary embolism, PE) 그리고혈전후하지증후군 (postthrombotic leg syndrome, PLS) 이있다. 미국의경우 1986년 NIH 조사자료를보면해마다 300,000에서 600,000명이이질환으로입원하고이환자들중 50,000 명이폐합병증으로사망하는것으로알려져있다 (1). 2006년재출간된 international union of angiology의자료에의하면 (27) 북미와유럽에서는매년 100,000명당 160 명의 DVT 환자가발생하고, 증상이있긴하나치명적이지는않은폐색전증 (pulmonary embolism) 은 100,000명당 20명, 그리고부검에서확인된폐색전증은 100,000명당 50명으로보고하였다. 2) 비증상심부정맥혈전증 (Asymptomatic DVT) 환자는증상이없지만, I-fibinogen을이용한 scan, 초음파상행적정맥조영술을이용한방법에서심부정맥혈전증을확인하는경우이다 (2,3). 책임저자 : 장정환, 광주시동구서석동 588 501-717, 조선대학교의과대학외과학교실 Tel: 062-220-3109, Fax: 062-228-3441 E-mail: jhchang@chosun.ac.kr 3) 증상이있는심부정맥혈전증 (Symptomatic DVT) 하지또는상지의주요혈관이폐쇄되어발생한다. 주로, 하지의통증, 부종, 심한경우 plegmasia alba dolens 또는 plegmasia cerulea dolens가발생한다. 4) 폐색전증 (Pulmonary Embolism, PE) 대부분의환자약 90% 에서무증상의 DVT 환자에서발생하며 (4) 급사, 호흡곤란, 실신, 흉통등을호소한다. 예방적인처치가안된경우더욱발생빈도가높다고알려져있으며병원내사망률과연관하여그빈도가점차증가한다고한다 (5). 5) 정맥혈전증 (Venous Thromboembolism, VTE) 심부정맥혈전증과폐색전증을포함한광범위한정맥내혈전증을일컫는다. 외과적치료를받는환자는특히나외과적처치자체가조직에손상을주고혈액응고인자의감작을증진시키고오랫동안침상에누워있기때문에심부정맥혈전증의발생빈도가높다. 정맥혈의정체, 혈액구성성분의변화, 혈관내막의손상으로알려진 3인자, 즉 Virchow s triad가 19세기초가설을이룬후정맥혈전증에서발생되는병리적현상은점차현실로규명이되었고, 최근기존의가설과유사하지만이질환에는최소 2가지개념이관련된다고한다 (27). 즉위험인자 (Table 1) 와그기저에있는혈전성향증 (thrombophilia) 이다. 따라서예방적처치를시행받지않은경우정형외과관련수술에서는 45 70%, 일반외과수술에서는 15 30% 에서발병할수있다 (6). 심부정맥혈전증환자의 2/3가무증상이며폐색전증환자의대부분이무증상인경우가많기때문에진단이대부분환자의자각적인호소에의 73
74 대한혈관외과학회지 : 제 25 권제 1 호 2009 Table 1. Risk factors for venous thromboembolism (8) Age Exponential increase in risk with age. In the general population: <40 years - annual risk 1/10,000 60 69 years - annual risk 1/1,000 >80 years - annual risk 1/100 Obesity 3배 risk if obese (body mass index 30 kg/m 2 ) May reflect immobility and coagulation activation Varicose veins 1.5배 risk after major general / orthopedic surgery But low risk after varicose vein surgery Previous VTE Recurrence rate 5% / year, increased by surgery Thrombophilias Low coagulation inhibitors (antithrombin, protein C or S) Activated protein C resistance (e.g. factor V Leiden) High coagulation factors (I, II, VIII, IX, XI) Antiphospholipid syndrome High homocysteine Other thrombotic states Malignancy 7배 risk in the general population Heart failure Recent myocardial infarction / stroke Severe infection Inflammatory bowel disease, nephrotic syndrome Polycythaemia, paraproteinaemia Bechet s disease, paroxysmal nocturnal haemoglobinuria Hormone therapy Oral combined contraceptives, HRT, raloxifene, tamoxifen 3배 risk High-dose progestogens 6배 risk Pregnancy, puerperium 10배 risk Immobility Bed rest >3 days, plaster cast, paralysis 10배 risk; increases with duration Hospitalization Acute trauma, acute illness, surgery 10배 risk Anesthesia 2배 general vs spinal/epidural 존하고있고, 진단이되지않은환자에서갑자기치명적인폐색전증이발생할수있으며추후, 심부정맥혈전증과연관된후기합병증 (Post thrombotic syndrome, PTL), 재발성심부정맥혈전증등이생길수있기때문에결국에는예방적인접근이질환의발병을억제하고합병증을예방하는최선의방법이다할수있다. GENERAL RISK FACTORS FOR VENOUS THROMBOEMBOLISM 외상에인한환자, 45분이상의수술을받은환자 (27) 또는급성질환으로병원에찾아오는사람들에게정맥성혈전증의발생가능성은누구에게나있다. 다음의 3 가지가개인적인위험인자를확인해볼수있는방법이다. 1 정맥성혈전증의개인적인위험도 (Table 1) 2 정맥성혈전증의과거병력 3 외상, 수술의종류또는내과적질환의종류 1) Prevalence in general and vascular surgical patients Clagett 등 (28) 은혈전증에대한예방적처치를시행받지않은일반외과수술환자에서하지심부정맥혈전증발병율는 6.9%, 폐색전증은 1.6%, 치명적인폐색전증은 0.87% 로보고하였다. 이비율은물론수술의규모, 시간, 마취의형태그리고수술후환자의상태에따라변할수있겠다. 수술의종류와시간, 환자의연령과위험도를고려하여발생도를비교해보면 Table 2와같다 (27). 혈관외과적수술, 복강경수술에따른발생률을정리하면다음과같다 (Table 3)(27). METHODS OF PROPHYLAXIS 1) 일반적인방법 (1) Mobilization and leg exercise: 하지의고정은 DVT 발생률을 10배가량증가시킨다 (9). 따라서침상안정인환자에서하지의운동은정맥혈의저류를예방하므로 DVT 발생을감소시킨다. (2) Hydration, hemodilution: 혈액의농도농축은혈액
Jeong-Hwan Chang:VTE; Prevalence and Prophylaxis 75 Table 2. Prevalence categories in according to risks of general surgical patients Category General Surgery Prevalence of DVT Fatal PE High risk Major general surgery, age >60 10 30% >1% Major general surgery, age 40 60 and cancer 또는 History of DVT, PE Thombophilia Moderate Major general surgery, age 40 60 1 10% 0.1 1% Without other risk Minor surgery, age >60 Low Minor surgery, age 40 60 with history of DVT/PE 또는 estrogen therapy <1% <0.1% Surgery, age <40, no other risk factor Minor Surgery age 40 60, no other risk factor Major surgery; any intra-abdominal operation and all other operation lasting more than 45 min. Table 3. Prevalence of symptomatic and asymptomatic DVT in vascular and laproscopic surgery Types of surgery Symptomatic DVT Asymptomatic DVT Vascular surgery 4 6% Abdominal aortic vascular 0.9% Peripheral vascular 0.7% Laparoscopic surgery 0 2% 의점성을증가시키고혈류을감소시켜하지의심부정맥에혈전증을유발할수있다. 그러므로침상에안정인환자에게는충분한수액공급이필수적이다. 2) 기계적인방법 하지에저류되는정맥혈을기계적인방법으로감소시키고, 혈류속도를증가시키는방법이다. (1) Graduated elastic compression stocking (GECS): GECS는무증상의 DVT와증상이있는 PE 환자에게효과가있다 (11,12). 특히무릎상방으로착용하는 stocking 이 DVT 예방에더효과적일수있다. 환자마다체형이일정하지않고각개인의체간의길이가일정치않기때문에 15 20% 의환자에서는 GECS을효과적으로이용할수없기도하다 (13). Table 4에서는 GECS의금기와주의점을정리하였다. GECS 방법과약물을이용한방법또는 IPC 방법을함께했을때의효과를비교해보면 Amaragiri 등 (14) 은외과적환자에서무증상 DVT 환자발생을줄여주는데효과적이다고하였다. (2) Intermittent pneumatic compression (IPC) devices: 분당약 10초동안 35 40 mmhg의압력을종아리나허벅지에전달해주는방법이다. 이방법은정맥혈의저류를막아줄뿐아니라혈전용해작용을자극하는기 Table 4. Contraindications and cautions for use of GECS Contraindications Cautions ㆍMassive leg edema ㆍSelect correct size ㆍPulmonary edema (e.g. heart ㆍApply carefully, aligning toe failure) hole under toe ㆍSevere peripheral arterial ㆍCheck fitting daily for change disease in leg circumference ㆍSevere peripheral neuropathy ㆍDo not fold down ㆍMajor leg deformity ㆍRemove daily for no more ㆍDermatitis than 30 minutes 전이있다 (15). IPC 방법은 UFH (unfractionated heparin) 과함께사용했을때심장수술과연관된폐색전증의발생률을 4 1.5% (risk reduction 62%) 로감소시켜주는역할을한다고보고되어있다 (16). (3) Mechanical foot pumps: 정형외과수술환자의무증상 DVT 의예방에효과가있다고한다 (17). 이와같은방법들은약물복용과는다르게출혈의위험성을증가시키지않기때문에출혈의소지가있는환자에게적당하다. 단지동맥폐쇄질환이있는환자에게는허혈을유발시킬수있으므로주의가요구된다 (10). 3) 예방적약물요법 (1) Aspirin: 일반적인수술또는정형외과적수술을시행받은환자의 VTE 예방효과를비교군과비교분석한자료를보면 (18,19) 무증상 DVT (26% vs. 35%), 폐색전증 (0.6% vs. 1.6%) 그리고치명적인폐색전증 (0.2% vs. 0.6%) 등의위험도를현저히감소시켜주는것으로되어있다. 이러한자료는 17,444명을대상으로 160 mg씩수술전부터시작하여 35일동안 Aspirin과 placebo를지속투여한 Pulmonary Embolism Prevention (PEP) Trial에서도전체사망률 (3.9% vs. 4.0%) 에는무관하지만증상이있는
76 대한혈관외과학회지 : 제 25 권제 1 호 2009 DVT 또는 PE의발생을감소시키는유사한결과를보였다 (20). Aspirin은고령의환자에서심근경색을예방하는데사용되고있으며 VTE의예방효과를증진시키기도하지만출혈성경향을증가시키기도한다. 이와는다르게정맥혈전증에대한예방과치료지침으로나온 ACCP 가이드라인을보면 aspirin 단독사용을통한혈전증의예방은효과가없다고하였다 (32). (2) Unfractionated heparin (UFH) and low molecular heparin (LMWH): UFH 그리고 LMWH은대부분의외국에서는 VTE의예방목적으로사용되어오고있다. 1980 년대후반 UFH은무증상의 DVT 발생률을 22% 에서 9%, 치명적인 PE을 0.8% 에서 0.3% 로감소시켜준다는것을 meta-analysis를통해확인하였다 (28). VTE 예방의목적으로 heparin은항상피하주사로투여하는데, 적은용량으로사용하는것이 aptt (activated partial thromboplastin time) 에영향을주지않는다. 다기관검사 (multicenter analysis) 결과, LMWH을사용하는경우, 치명적인 PE의발생뿐아니라전체적인외과적수술환자의사망률도감소한다는것을확인하였고, 복부수술환자의무증상 DVT 발생율도감소시키는것으로나타났다. 또한 UFH의 8 12시간효과보다 LMWH의반감기가훨씬길기때문에하루에한차례정도의투여로도예방적효과를유지할수있다 (21,22). 결론적으로저용량의피하주사 UFH의효과는무증상의 DVT, 증상이있는 DVT, PE, 치명적인 PE, 그리고전체적사망률의감소를현저 Table 5. Contraindications and cautions for aspirin and heparins in prophylaxis of VTE Contraindications ㆍUncorrected bleeding disorders, e.g. - haemophilias - oral anticoagulants - platelet count <70 10 9 /L ㆍBleeding or potentially bleeding lesions - oesophageal varices - active peptic ulcer - recent (3 months) GI or intracranial bleed - intracranial aneurysm or angioma ㆍAllergy ㆍHeparin associated thrombocytopenia or thrombosis (heparin) Cautions ㆍAsthma (aspirin) ㆍSevere liver impairment, alcoholism ㆍSevere kidney impairment ㆍMajor trauma or surgery to brain, eye or spinal cord ㆍSpinal or epidural block ㆍAnemia (Hb<10 g/dl) 하게보여주었으나주요출혈의빈도는증가하였으며 (4 6%) 치명적인출혈의빈도는차이가없었다 (23). 피하주사용 LMWH은예방적효과와출혈의위험도는 UFH과유사하였다. UFH와 LMWH의 VTE 예방적목적사용의금기와주의점은 Table 5에정리되어있다. (3) Others medication 1 Dextran: 정맥투여용 dextran은무증상 DVT환자의예방요법으로는 heparin에비해덜효과적이다. 그러나폐색전증의예방에는동등한효과를가지고있다 (24). 그러나이약제는임산부, 신장과심부전이있는환자에게는주의가필요한데 (25) 그이유는정맥내투여후급격한혈관내체액의증가또는아나필락시스 (anaphylaxis) 반응이일어나기때문이다. 따라서최근에는날마다투여하는것보다는수술중한차례의투여가효과적인것으로되어있다 (27). 2 Oral anticoagulants: Warfarin은무증상 DVT환자의예방에효과적인약제이다. 그러나외상과수술후출혈의위험이있기때문에 INR을통한 monitoring이필요한단점이있다 (25). 3 Pentasaccharides: Dl 약제는강력한응고인자 Xa 의선택적억제재로정형외과적수술을받은무증상 DVT 환자의발병감소에 LMWH보다효과가있기는하나증상이있는 DVT, PE 또는사망률감소에는효과가없는것으로나타났다 (26). 4 병용요법과예방적치료기간 : 지금까지조사된병용요법의효과를분석해보면단독적으로사용하는것보다는효과가좋은것으로확인되고있다. 예를들어저용량헤파린의단독사용보다압박용스타킹을병용했을때심부정맥혈전증의발생을 22% 에서 9.5% 로감소시키며 (21,27) 저용량의 LMWH 군을사용한집단과고용량 LMWH과 GEC 그리고 IPC를동시에사용한집단을비교해보면후자에서혈전질환의발생률이감소된다 (5.4% vs 0.6%) 고한다 (31). 이와같은연구의대부분은예방적처치의기간을 5 7일로하고있다 (27). 그러나일부의연구들은사대적으로 DVT 발병의위험도는지속적이기때문에환자가퇴원후에도지속적으로치료를해야한다고주장하였다 (29). 이에 Lausen 등 (30) 은한달이상의예방적인치료가무증상의 DVT 발생을약 50 70% 가량줄일수있다는발표를하였지만아직은일주일이상의예방적치료를전체의외과적인환자에게적용시키기에는연구결과가부족하므로논란의여지가있다. CONCLUSION 외과적인처치가필요한환자이거나수술을받은환자에서정맥성혈전증은주로침상에장기간안정을취해
Jeong-Hwan Chang:VTE; Prevalence and Prophylaxis 77 야하거나환자자신의질환형태 ( 외인성 ) 또는환자가가지고있는소인 ( 내인성 ) 에따라다양한형태로발병을하게된다. 외국의보고로는하지의혈전이있는환자의약 5% 에서혈전이폐색전을유발하여가슴의통증또는호흡곤란을유발하고이러한환자의 1,000명당 6명에서사망이일어난다고보고되어있다 (1,2,3,24,27). 치명적인색전증의합병증을막기위해서는수술후조기운동과규칙적인하지의움직임이필요하며, 움직임이힘든경우보조적인치료방법을이용하고, 혈전증의위험성이높은군에서는상기에서술한여러약제들을복용하여질환의발생을억제하는것이중요하다고생각된다. 이질환은한번발생이되면완벽한치료가어렵고합병증의발생기회가많고또재발이많은만큼치료의의미보다는예방에더중점을두는계획이필요하겠다. REFERENCES 1) National Institutes of Health. Consensus conference on prevention of venous thromboembolism. JAMA 1986;256:744-748. 2) Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomised trials in general, orthopedic and urologic surgery. N Engl J Med 1988;318:1162-1173. 3) Collaborative overviews of randomised trials of antiplatelet therapy-iii. Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. Antiplatelet Trialists' Collaboration. BMJ 1994;308:235-246. 4) Sandler DA, Martin JF. Autopsy proven pulmonary embolism in hospital patients: are we detecting enough deep vein thrombosis? J R Soc Med 1989;82:203-205. 5) Gillies TE, Ruckley CV, Nixon SJ. Still missing the boat with fatal pulmonary embolism. Br J Surg 1996;83:1394-1395. 6) Cardiovascular Disease Educational and Research Trust. European Consensus Conference on Prevention of Venous Thromboembolism. Int Angiol 1992;2:151-159. 7) Heit JA, Silverstein MD, Mohr DN, Petterson TM, Lohse CM, O'Fallon WM, et al. The epidemiology of venous thromboembolism in the community. Thromb Haemost 2001;86:452-463. 8) Scottish Intercollegiate Guidelines Network. Prophylaxis of venous thromboembolism. SIGN publication No. 62, 2002. 9) Van Beek EJ, Buller HR, ten Cate JW. Epidemiology of venous thromboembolism. In: Tooke JE, Lowe GD, editors. A textbook of vascular medicine. London: Arnold; 1996. p. 465-478. 10) Kay TW, Martin FI. Heel ulcers in patients with long-standing diabetes who wear antiembolism stockings. Med J Aust 1986; 145:290-291. 11)Wells PS, Lensing AW, Hirsh J. Graduated compression stockings in the prevention of postoperative venous thromboembolism. A meta-analysis. Arch Intern Med 1994;154:67-72. 12) Wilkins RW, Stanton JR. Elastic stockings in the prevention of pulmonary embolism II. A progress report. N Engl J Med 1953;248:1087-1090. 13) Williams JT, Palfrey SM. Cost effectiveness and efficacy of below knee against above knee graduated compression stockings in the prevention of deep vein thrombosis. Phlebologie 1988; 41:809-811. 14) Amaragiri SV, Lees TA. Elastic compression stockings for prevention of deep vein thrombosis (Cochrane Review). In: The Cochrane Library, Issue 3, 2001. Oxford: Update software. 15) Comerota AJ, Chouhan V, Harada RN, Sun L, Hosking J, Veermansunemi R, et al. The fibrinolytic effects of intermittent pneumatic compression: mechanism of enhanced fibrinolysis. Ann Surg 1997;226:306-313. 16) Ramos R, Salem BI, De Pawlikowski MP, Coordes C, Eisenberg S, Leidenfrost R. The efficacy of pneumatic compression stockings in the prevention of pulmonary embolism after cardiac surgery. Chest 1996;109:82-85. 17) Fordyce MJ, Ling RS. A venous foot pump reduces thrombosis after hip replacement. J Bone Joint Surg Br 1992;74:45-49. 18) Collaborative overviews of randomised trials of antiplatelet therapy-iii. Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. Antiplatelet Trialists' Collaboration. BMJ 1994;308:235-246. 19) Collins R, Baigent C, Sandercock P, Peto RO. Antiplatelet therapy for thromboprophylaxis: the need for careful consideration of the evidence from randomised trials. Antiplatelet Trialists' Collaboration. BMJ 1994;309:1215-1217. 20) Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000;355:1295-1302. 21) Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997;337:688-698. 22) Hirsh J, Warkentin TE, Shaughnessy SG, Anand SS, Halperin JL, Raschke R, et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001;119:64S-94S. 23) Kakkar VV, Corrigan TP, Fossard DP, Sutherland I, Thirwell J. Prevention of fatal postoperative pulmonary embolism by low doses of heparin. Reappraisal of results of international multicentre trial. Lancet 1977;1:567-569. 24) Geerts WH, Heit JA, Clagett GP, Pineo GF, Colwell CW, Anderson FA Jr, et al. Prevention of venous thromboembolism. Chest 2001;119:132S-175S. 25) Imperiale TF, Speroff T. A meta-analysis of methods to prevent venous thromboembolism following total hip replace-
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