종설접수번호 :09-029(2 차 -0710) 경동맥스텐트삽입술시술전평가와시술전후관리 원광대학교의과대학원광대학교병원신경과, 인하대학교의과대학인하대학교병원신경과 a 하연수박희권 a Pre-Procedural Evaluation and Peri-Procedural Management in Carotid Artery Stenting Yeon Soo Ha, MD, Hee-Kwon Park, MD a Department of Neurology, Wonkwang University Hospital, Wonkwang University School of Medicine, Iksan, Korea Department of Neurology a, Inha University Hospital, Inha University School of Medicine, Incheon, Korea Carotid-artery stenting (CAS) is as an alternative to surgical endarterectomy for severe carotid-artery stenosis. CAS is advantageous over carotid endarterectomy in that it is less invasive and could shorten the hospital stay. A preprocedural evaluation is necessary to assess the patient s anatomic status or clinical risk factors to determine whether they are a good candidate for CAS. Proper evaluation and management can reduce CAS-associated complications such as embolism and cerebral hyperperfusion syndrome. The frequent use of statins appears to improve the outcome of CAS. Using the appropriate stent type and a protection device could also reduce the complication rate. Given the changes in cerebral hemodynamics following CAS, adequately controlling the blood pressure in individual patients can enhance the efficacy of this treatment. However, there is currently limited data regarding the preprocedural evaluation and periprocedural management for CAS. The evidence and the clinical status related to the preprocedural evaluation and periprocedural management of CAS are presented herein. J Korean Neurol Assoc 32(2):59-71, 2014 Key Words: Carotid-artery stenosis, Stroke, Carotid-artery stenting, Evaluation, Management 서 론 인구고령화에의한뇌혈관질환의증가와진단기술의발달로경동맥질환의유병률이날로증가하고있다. 경동맥죽상경화증 (carotid atherosclerosis) 은허혈뇌졸중의주된위험인자중하나로전체뇌졸중의약 15-20% 가경동맥죽상경화증으로인한협착에의해서발생한다고알려져있다. 1 수많은연구에도불구하고유증상경동맥협착증과무증상경동맥협착증에대한최적관리방법에대해서는여전히논란의여지가있다. 경동맥죽상경화증의혈관중재술에관련하여국내에서는뇌졸중임상연구센터의뇌졸중진료지침 (2009년개정 ) 이있으며외국에서는미국 Received July 4, 2013 Revised December 19, 2013 Accepted December 19, 2013 *Hee-Kwon Park, MD Department of Neurology, Inha University Hospital, Inha University School of Medicine, 27 Inhang-ro, Jung-gu, Incheon 400-711, Korea Tel: +82-63-859-1410 Fax: +82-63-842-7379 E-mail: next4099@naver.com 뇌졸중학회와유럽뇌졸중학회에서보고된진료지침이있다. 대부분의진료지침에따르면증상을동반한 70% 이상심한경동맥협착증이발견되면증상발생 2주이내에경동맥내막절제술을먼저추천하며대체치료로경동맥스텐트삽입술을권고하고있다. 2-4 무증상환자의경우에는심한협착일경우환자에따라경동맥내막절제술을하거나또는약물치료를권장하며경동맥스텐트삽입술에대해서는논란이있다. 2 경동맥스텐트삽입술은경동맥내막절제술에비해덜침습적이고입원기간이짧다는장점이있는반면, 고령환자의경우에시술과관련된합병증이내막절제술에비하여높다는보고도있다 (per 1-year increase; hazard ratio [HR] 1.19, 95% confidence interval [CI] 1.05-1.35; p=0.007). 2,5 이전까지보고된전향무작위연구의결과를정리하면시술전후발생하는뇌졸중과사망률은내막절제술에비해스텐트삽입술에서더높다 (Table 1). 6-9 하지만최근연구에서시술또는시술후 4년까지추적관찰한결과시술전후뇌졸중과사망발생빈도가두군에서비슷하였다 (Fig. 1). 10 저자의경험에따르면국내환자의경우에수술보다는시술을선호하는경우가많아 J Korean Neurol Assoc Volume 32 No. 2, 2014 59
하연수박희권 Table 1. Carotid endarterectomy and carotid artery stenting periprocedural stroke/death rates from previous randomized control trials (A) Carotid endarterectomy Trial Year N Symptoms Stroke/death rate (%) CAVATAS 2001 253 Mixed (90% Sympt) 9.9 SAPPHIRE 2004 254 Mixed (33% Sympt) 3.6 SPACE 2006 605 Symptomatic 6.3 EVA-3S 2006 257 Symptomatic 3.9 ICSS 2009 858 Symptomatic 3.4 CREST 2010 657 Symptomatic 2.6 CREST 2010 583 Asymptomatic 1.3 (B) Carotid artery stenting Trial Year N Symptoms Stroke/death rate (%) CAVATAS 2001 251 Mixed (90% Sympt) 10.0 SAPPHIRE 2004 254 Mixed (33% Sympt) 4.4 SPACE 2006 605 Symptomatic 7.7 EVA-3S 2006 265 Symptomatic 9.6 ICSS 2009 855 Symptomatic 7.4 CREST 2010 594 Symptomatic 6.0 CREST 2010 664 Asymptomatic 2.5 CAVATAS; carotid and vertebral artery transluminal angioplasty study, SAPPHIRE; stenting and angioplasty with protection in patients at high risk for endarterectomy, SPACE; stent-protected angioplasty versus carotid endarterectomy, EVA-3S; endarterectomy versus angioplasty in patients with symptomatic severe carotid stenosis, ICSS; international carotid stenting study, CREST; carotid revascularization endarterectomy versus stenting trial. 면최소화할수있을것이다. 그러나관련된임상연구결과가부족하여실제임상에서는관상동맥연구결과나전임상연구결과또는임상의의경험을바탕으로경동맥스텐트삽입술을선택하는경우가많아매우혼란스러운상황이다. 이에현재까지보고된근거를중심으로경동맥스텐트삽입술의시술전환자를선정하고평가하는방법과시술후관리및추적관찰을어떻게해야할지에대해서정리해보고자한다. 본 론 1. 시술전평가 Figure 1. The Kaplan-Meier curves for patients undergoing carotid artery stenting and carotid endarterectomy in whom the primary end point did not occur, according to year of follow-up. The primary end point was a composite of stroke, myocardial infarction, or death from any cause during the periprocedural period or ipsilateral stroke within 4 years after randomization. N Engl J Med 2010;363: 11-23. 경동맥내막절제술에비해경동맥스텐트삽입술의빈도가상대적으로증가하는추세이다. 경동맥스텐트삽입술의합병증으로동맥- 동맥색전증 (artery to artery embolism) 에의한뇌경색을들수있다. 시술중발생하는이합병증은예측불가능한경우가많지만시술전평가를통해서적합한환자를선택하고시술전후적절하게처치한다 경동맥협착이발견되었을경우에처음고려해야할점은증상의유무이다. 증상이있는심한경동맥협착인경우혈관재생 (revascularization) 에이견이없으나무증상이면서심한경동맥협착인경우는최근에약물요법이발달하여적극적인혈관재생술에대한논란의여지가있으며관련연구가진행중인상황이다. 11 따라서본논문에서는유증상경동맥협착에대한스텐트삽입술의평가와관리에대해서만논하겠다. 1) 협착의평가저자의경험에의하면일반적으로경동맥협착의증상유무를판단하였다면다음에는상응하는경동맥협착의정도를평가하게된다. 현재안정성을고려하여경동맥초음파검사 (carotid ul- 60 대한신경과학회지제 32 권제 2 호, 2014
경동맥스텐트삽입술시술전평가와시술전후관리 Table 2. Combined criteria for grading internal carotid stenosis Degree of stenosis as defined by NASCET (%) Grading of internal carotid stenosis 10-40 50 60 70 80 90 Occlusion Main criteria 1. B-mode image, diameter Applicable Possibly applicable Imaging of occluded artery 2. Color doppler image Plaque Flow Flow Flow Flow Flow Absence of flow delineation 3. PSV threshold (cm/s) 125 230 NA NA 4a. PSV average (cm/s) 160 210 240 330 370 Variable NA 4b. PSV poststenotic (cm/s) 50 <50 <30 NA 5. Collateral flow (periorbital arteries or Possible Present Present Present circle of willis) Additional criteria 6. Prestenotic flow (diastole) (CCA) Possibly Reduced Reduced Reduced reduced 7. Poststenotic flow disturbances Moderate Pronounced Pronounced Pronounced Variable NA (severity and length) 8. End-diastolic flow velocity in the <100 >100 Variable NA stenosis (cm/s) 9. Carotid ratio ICA/CCA <2 2 2 >4 >4 Variable NA Poststenotic indicates measured distal to turbulences. CCA indicates common carotid artery. ICA; internal carotid artery, NA; not applicable, PSV; peak systolic velocity. Stenosis (%)=(a-b)/a 100 Stenosis (%)=(c-b)/c 100 Figure 2. Angiographic methods for carotid stenosis. trasonography), 전산화단층혈관조영술 (CT angiography) 이나자기공명혈관조영술 (MR angiography) 같은비침습검사를이용해협착정도를평가하는경우가많다. 이러한경우검사방법에따라해석하는데주의하여야한다. 예를들면, 경동맥초음파검사에서최대수축속도 (peak systolic velocity) 를이용한 70% 협착은카테터혈관조영술 (catheter based angiography) 에서혈관 지름을이용하여측정한 NASCET 기준 (Fig. 2) 으로 50% 협착에해당한다. 12 그러나실제임상에서는일치하지않는경우가있으며카테터혈관조영술에서의협착평가도완벽하지는않다. 13 아직까지합의된협착평가의기준검사는없는상태이지만최근에미국뇌졸중학회지에발표된경동맥초음파검사에서협착기준을이용하면혈류역학적으로 70% 이상의협착을더욱정확하게평가할수있다 (Table 2). 13 경동맥초음파검사는협착유무를확인할수있는비침습선별검사로다양한변수를이용하면비교적정확하게혈류역학적으로의미있는협착을평가할수있을뿐아니라경동맥협착부위죽상판의불안정성을비교적잘평가할수있어매우유용하다. 13,14 하지만반대측경동맥협착이동반된경우협착의정도가과장될수있어해석할때주의를요한다. 15 경동맥내막절제술전에는석회화와병변혈관주변조직의정보가필요한경우가있는데이런경우에는 CT 혈관조영술이도움이될수있다. MR 혈관조영술은방사선피폭을줄일수있다는장점이있다. 카테터혈관조영술은정확한영상정보를얻을수있으나상대적으로침습적이며진단목적으로시행하지만색전발생위험이높아주의를요한다. 16 따라서협착을평가할수있는검사들의장단점을파악하고가장적합한검사를선택하여시술여부를결정하는것이좋다. 17 2) 수술시기급성뇌경색환자의경동맥내막절제술의경우, 발생 2주이내에시행하도록권고하고있으나 2 스텐트삽입술의적절한시기 J Korean Neurol Assoc Volume 32 No. 2, 2014 61
하연수박희권 Figure 3. Aortic arch types. The vertical distance from the origin of the innominate artery to the top of the arch determines the arch type. This distance is <1 diameter of the left common carotid artery (CCA) in a Type 1 arch, between 1 and 2 CCA diameters in a Type 2 arch, and >2 CCA diameters in a Type 3 arch. J Invasive Cardiol 2008;20:200-204. Table 3. Increased procedural risk and contraindications for carotid artery stenting Increased risk Age 80 yr Symptomatic ICA lesion Severe renal insufficiency Severely diseased and/or steep aortic arch Severely diseased and/or tortuous CCA Severely diseased and/or tortuous distal ICA Long subtotal ICA occlusion (string sign) Poor femoral access Major stroke within 4-6 wk Extensive intracranial microvascular disease Contraindications Intolerance to aspirin and/or clopidogrel Circumferential ICA calcification Intraluminal thrombus Chronic ICA occlusion Intracranial aneurysm or AVM requiring treatment CCA indicates common carotid artery. ICA; internal carotid artery, AVM; arteriovenous malformation. 에대한자료는부족하다. 따라서아직까지는환자개개인의상태에따라시술시기를결정하는것이좋다. 그러나최근연구에서경동맥스텐트삽입술을 2주이내에시행한유증상경동맥협착환자가 2주지나서시행한환자에비해혈관내초음파검사 (intravascular ultrasound) 에서불안정죽상판이더많았다는 (p=0.0048) 18 보고가있어저자는색전에의한합병증을줄이기위해서불안정한죽상판이존재할경우에는안정화시킨후시술하는것을권한다. 양의동반여부, 해부학적위치, 협착원위부의종렬병변 (tandem lesion) 유무, 대동맥궁의형태그리고곁순환의발달상태가주된고려사항이다. 예를들면 80세미만환자에서병변길이가 15 mm 이상인경우 15 mm 미만인경우보다시술후뇌졸중발생률이높다 (odds ratio [OR] 8.77, 95% CI 2.47-31.10; p<0.001). 19 카테터조작중대동맥에서죽종색전 (atheroemboli) 이발생할수있는데 20 대동맥궁의형태가중요하다. 팔머리동맥, 왼쪽총경동맥, 왼쪽쇄골하동맥이대동맥궁에서분지하는형태인 Type 1 arch 는가장흔하고시술할때큰문제가없으나 Type 2 arch 또는 Type 3 arch 형태의대동맥궁인경우기시부굴곡이심하여카테터의접근이어려워시술중과다한카테터조작에의해서죽종색전이발생할위험이높고심한경우스텐트삽입술자체가불가능할수도있다 (Fig. 3). 21 또한원위부종렬병변이동반되어있는경우에는유도철사 (guidewire) 의접근이어려울수있다. 따라서경동맥스텐트삽입술전에환자의시술위험요인을정확하게파악하고시술에임하는것이색전에의한합병증을최소화할수있다 (Table 3). 4) 임상평가시술전에환자의성별, 연령, 허혈증상의유형과심뇌혈관질환의조절상태를파악하면시술의시행여부와위험도를평가하는데도움을준다. 심하지않은협착, 75세미만, 여성, 뇌경색이발생한지 3개월이상, 시각증상, 두개내혈관협착이없는경우에는경동맥협착에의한뇌경색이발생할가능성이낮다. 22 반면당화혈색소 (HbA1c) 가 7% 이상으로조절되지않은당뇨병, 80세이상의고령, 죽상판의궤양, 반대측경동맥의 50% 이상의협착중 2가지이상이있는경우시술전후합병증이발생할위험도가 11% 증가된다 (OR 4.9, 95% CI 2.2-11). 23 기본혈액검사와함께죽상경화증 (atherosclerosis) 과관련된혈중지질과지단백질 (total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, and lipoprotein [a]), 혈청 hscrp를확인하고고혈당, 탈수, 감염같은뇌의곁순환을악화시킬수있는이상이있다면먼저교정한후시술을하는것이바람직하다. 24 그리고경동맥스텐트삽입술의경우에도심장질환이발생할위험이있으므로시술전심전도또는심장초음파검사를하여시술전심장상태를평가하는것이좋다. 2. 시술전후비교검사 3) 해부학적평가다음으로시술과관련된병변의해부학적인구조를파악하여시술여부와방법을결정하여야한다. 협착부위병변의길이, 궤 확산강조영상 (diffusion-weighted imaging, DWI) 은증상이모호하거나없는경우에경동맥협착증상이있는병변인지감별하는데중요한검사일뿐만아니라, 시술후발생한색전에의 62 대한신경과학회지제 32 권제 2 호, 2014
경동맥스텐트삽입술시술전평가와시술전후관리 Table 4. Pre-procedural diagnostic work-up lists in carotid artery stenting Essential factor Blood pressure CBC, BUN, Cr, electrolyte, glucose, PT, PTT Total cholesterol, triglyceride, LDL cholesterol, HDL cholesterol, hscrp EKG Brain MRI (including DWI) Carotid duplex CT angiography or MR angiography (including aortic arch) Optional factor HbA1c (if diabetes patient), Lipoprotein (a), CRP Echocardiography Brain perfusion MR TCD or TCD MES monitoring Catheter-based angiography Acetazolamide SPECT MMSE or SNSB CBC; complete blood count, BUN; blood urea nitrogen, Cr; creatinine, PT; prothrombin time, PTT; partial thromboplastin time, LDL; low density lipoprotein, HDL; high density lipoprotein, hscrp; high-sensitivity CRP, EKG; electrocardiogram, MRI; magnetic resonance imaging, DWI; diffusion weighted imaging, CT; computed tomography, MR; magnetic resonance, HbAlc; glycated haemoglobin, CRP; c-reactive protein, TCD; transcranial doppler ultrasonography, MES; microembolic signal, SPECT; single photon emission computed tomography, MMSE; mini-mental state examination, SNSB;seoul neuropsychological screening battery. 한뇌의허혈병변을찾는데매우유용하다. 25,26 시술중또는시술후일과성허혈발작이나새로운신경계이상이발견되었을경우 DWI를촬영하여색전에의한증상인지감별할수있다. 시술중미세색전 (microembolic signals, MESs) 또는저관류에의한인지기능장애가발생할수있으나반대로만성적인관류저하로인한인지기능장애가있던환자가시술후인지기능이회복된다는연구도있다. 27 시술전후에인지기능의변화유무를평가해야환자의호전또는악화를확인할수있기때문에, 저자는과거력또는병력청취중인지기능장애가의심되거나임상의가필요하다고판단하면시술 1-3일전서울신경심리검사 (SNSB) 또는간이정신상태검사 (MMSE) 를하고시술 4-6개월후재평가를하는것을추천한다. 고령환자에서두개골에초음파가투과되지않아검사가제한적일수있다는단점이있지만두개경유도플러검사는경동맥협착증환자에서미세색전을검출하는데유용하다. 시술전미세색전모니터링 (MESs monitoring) 을통해미세색전의유무를확인함으로써시술중색전이발생할위험을예측하는지표로사용할수있다. 28,29 또한시술전다량의미세색전이보인다면죽상판이불안정함을나타내므로, 30 죽상판을안정화시킬수있는충분한약물치료후재검사를통해미세색전소실을확인한후시술을하거나뇌보호장치 (cerebral protection device) 중 MO.MA (Invatec, Roncadelle, Italy) 같은근위색전방지기구사용을시술할때고려해볼수있다. 뇌혈관의협착으로뇌관류압이감소하고곁순환혈류가충분하지않은부위는뇌혈류를정상으로유지하기위하여말초뇌혈관의확장이일어나는데이때아세트아졸라미드 (acetazolamide, 탈탄산효소억제제 ) 와같은뇌혈관확장제를투여하면정상부위에비해혈관확장이둔화되므로뇌혈관확장예비능을평가할수있다. 31 아세트아졸라미드- 단일광자방출컴퓨터단층촬영 (SPECT) 은뇌허혈부위의범위와뇌예비능을평가하여대상환자를선정하는데도움을줄수있으며시술후에경과를관찰하는데 유용하다. 최근에반대측경동맥폐색을동반한동측경동맥의협착환자를시술전후아세트아졸라미드- 단일광자방출컴퓨터단층촬영을하여시술후양쪽뇌혈류가호전되었음을확인한연구가있었다. 32 하지만시술전어떤환자를대상으로검사해야하는지, 뇌예비능상태에따른예후판정을어떻게해야하는지대해서는아직근거가부족한실정이다. 앞에서살펴보았던경동맥스텐트삽입술을하기에앞서시술전에어떤진단검사를이용하여평가하고비교해야하는지표로정리하면다음과같다 (Table 4). 3. 시술과시술후관리 1) 스텐트의종류와시술후경동맥의자연경과경동맥스텐트삽입술의생리학적인측면과자연경과를이해하는것이시술후환자관리에도움이된다. 현재우리나라에서실제임상에주로쓰이는경동맥스텐트의경우대부분내경직경이 7 mm에서 10 mm 정도이며길이는 4-6 cm 정도이다. 명확한근거는없으나많은경우경동맥의스텐트를설치한이후총경동맥으로스텐트가밀려날위험성을줄이기위해서 (retrograde migration) 대부분의경우원위부는내경동맥, 근위부는총경동맥에설치하게된다. 따라서협착부위와스텐트가놓이는예상위치의길이가 6 cm 이상인경우나총경동맥의스텐트가위치하는부위의혈관내경이 10 mm 이상인경우경동맥스텐트삽입술을신중히시행하거나다른방법을고려해야한다. 경동맥의경우, 관상동맥에비해상대적으로혈관내피의과다형성 (hyperplasia) 비율이낮고합병증도적어서단순금속스텐트 (bare metal stent) 종류를사용하고있다. 관상동맥스텐트에서의결과이기는하지만단순금속스텐트는약물방출스텐트 (drug eluting stent) 에비하여가격이싸고철망구조물 (strut) 이빨리내피혈관세포로덮이므로 2개의항혈소판제를병용투여 J Korean Neurol Assoc Volume 32 No. 2, 2014 63
하연수박희권 A B C D Figure 4. Animal model. (A) Primary lesion, (B) immediately post-angioplasty, (C) neointimal hyperplasia at 3 weeks later, and (D) plaque after 3 month of intervention. Am J Pathol 2003;163:773-778. 해야하는기간이짧아서출혈위험성이높은환자에게권장되고있다. 33 자기팽창스텐트의경우에는설치후직경이점차확대되는데보고에의하면스텐트삽입술후 6개월째평균 48.9% 의단면적증가를보였다. 34 단면적이충분히증가되면재협착가능성은줄어든다. 다만예상되는혈관의원래직경에비하여스텐트직경이지나치게큰경우혈관내벽에스트레스를많이주어내피의과다형성을유도할수도있다. 35 따라서이러한문제를해결하기위해내경동맥의스텐트원위부직경은작고총경동맥의스텐트근위부직경은큰테이퍼드타입 (tapered type) 의스텐트를쓰게된다. 동물모델에따르면시술직후에혈관연축 (vasospasm) 이나스텐트안의혈전 (in-stent thrombosis) 에의한혈관폐색이올수있다. 사람에서는 3-6개월에해당하는시기에스텐트안으로새로운내막이형성되어스텐트의철망구조가혈액과직접적인접촉을하지않게되어스텐트내혈전이발생할위험은줄어든다. 36 1-2년에해당하는시기가되면내막안으로새로운죽상판이형성될수있다 (Fig. 4). 37 단순금속스텐트의경우이러한철망의내피화 (endotheliazation) 에대략 1달정도소요되는것으로알려져있으나경동맥과관련하여명확한임상자료는부족하다. 37 자가팽창스텐트를설치한후 6 개월째혈관내초음파를시행한연구에서는대부분이내피화되었다. 34 2) 시술전후약물요법 CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial) 연구에서는최소시술 48시간전부터 2개의항혈소판제병용투여를시작하였고시술후 1개월까지사용하다가이후한종류의항혈소판제를사용하였다. 10,38 또한뇌졸중임상연구센터의뇌졸중진료지침에따르면경동맥스텐트삽입술직전과시술후최소 1개월동안아스피린과클로피도그렐병용투여를유지를권장하고있다. 39 클로피도그렐을복용하지못하는환자의경우에는티클로피딘 (250 mg 하루 2번 ) 으로교체하여사용할것을권장하고있다. 2 이러한약물치료의이론적근거는위에서설명한철망의내피화와연관되나경동맥에서단순금속스텐트의경우명확한근거는아직부족하다. 스텐트 삽입술후간혹출혈위험성이큰수술을해야되는경우도있다. 이러한경우에경동맥스텐트술은관련자료가불충분하나관상동맥스텐트삽입술은 2-3개월이후, 적어도 1개월이후에받을것을권장한다. 40 다른혈관질환에서스텐트를삽입할때스타틴사용이예후에도움을준다고알려져있다. 경동맥스텐트삽입술을한경우, 장기예후가최근연구에서이전에비하여좋아지고있는데스타틴의사용빈도와연관성이높다고알려져있다. 41,42 일부보고에서는 1998년이전에는경동맥스텐트삽입술이후에 30일까지의뇌졸중위험도가 6.3% 정도였으나 1998년부터 2002년도까지는 5.0% 로 2002년이후로는 3.9% 로계속낮아지고있으며이외에도사망률같은지표도호전되고있으며 42 이러한예후호전이스타틴사용과연관성이있다고추정한다. 실제스타틴을사용할경우사용전에비해색전방지용필터에걸리는색전이감소되었고스타틴을사용한군이그렇지않은군에비해서시술전후뇌졸중과사망률이감소하였는데 (OR 0.327, 95% CI 0.13-0.80, p=0.016), 이러한경향은증상이있는경동맥질환 (OR 0.13, p=0.032) 남자 (OR 0.27, p=0.01) 에서더뚜렷이나타났다. 43 기타 5년간의추적관찰에서도예후가더좋았다. 41 또한스타틴을고용량으로 2번에걸쳐준군 (atorvastatin 80 mg+40 mg) 이그렇지않은군에비하여시술과관련된뇌졸중또는일과성허혈발작을줄일수있다는보고가있었다 (18.4% vs. 35.0%). 44 따라서경동맥스텐트삽입술시행전에고용량의스타틴을투여하고시행후에는뇌경색환자에준해서스타틴을복용할것을권장한다. 고혈압약의경우, 시술전후고혈압약을복용하던환자는그대로유지하는것이유익하다고알려져있지만그근거는부족하다. 2 뇌출혈또는과관류증후군의위험을최소화하기위해서수축기혈압을시술전후또는시술중 180 mmhg 미만으로유지할것으로추천한다. 2 고혈압약를복용하던환자들중에경동맥스텐트삽입술을시행한군에서내막절제술을한경우에비하여고혈압약의사용빈도가줄었다는보고가있으나후속연구가필요하다. 45 마지막으로스텐트와관련되어가장많은논란이되는경우는심방세동이있거나혈전색전증의위험성때문에항응고제를사용해야하는환자에서경동맥스텐트삽입술을시행 64 대한신경과학회지제 32 권제 2 호, 2014
경동맥스텐트삽입술시술전평가와시술전후관리 하는경우이다. 저자는심방세동을동반한경동맥협착환자의경우장기간항응고제와항혈소판제를함께복용하는것을피하기위해수술의위험이높지않거나금기사항이없다면경동맥내막절제술을할것을추천한다. 이에대한자료는매우제한적이고그근거는확실하지않다. 일반적으로혈전색전증의발생위험이높은수술의경우심방세동이있는환자에서 CHADS2 점수가 5 또는 6점이거나 3개월내에뇌경색또는일과성허혈발작이있거나류마티스판막질환이동반된경우에는수술전후에피하또는정맥을통한항응고요법을권고하고있다. 46 3) 경동맥스텐트삽입술과연관된합병증 (1) 과관류증후군 (hyperperfusion syndrome) 시술과관련하여가장심각한합병증인뇌과관류증후군 (cerebral hyperperfusion syndrome, CHS) 은 대사요구량보다관류가더많은상태 또는 시술이전관류량보다 100% 이상증가한경우 로정의한다. 47 1981년 Sundt 등 48 은이러한현상의세증후 (triad) 로두통, 경련, 뇌출혈을열거하였다. 이때두통은대부분병변측이마나눈주위에박동성으로나타난다. 내막절제술환자의 62% 에서두통이, 36% 에서경련이나타나지만일시적인경우가많다. 대부분경동맥협착이 75% 이상진행되어뇌혈관확장예비능에이상이발생한경우생기며 49 기타압력수용체의이상, 시술 / 수술중의허혈손상, 재관류손상같은가설이있다. 50 내막절제술에서는 6일째에가장많이나타나지만스텐트삽입술에서는 12시간이내에가장자주나타난다. 51 과관류증후군의후유증중에서예후에가장큰영향을미치는뇌출혈은내막절제술에서는 0.2-0.7%, 스텐트삽입술에서는 0.6% 정도에서발생한다. 52,53 특히과관류증후군에서뇌출혈이발생한경우는그렇지않은환자에비하여예후가불량하다. 일부의분석에의하면뇌출혈이없는과관류증후군의경우에는 83% 에서양호한예후를보였으나뇌출혈이발생한경우에는사망률이 51% 이었으며 28% 에서영구적인신경계결손이남았다고한다. 54 뇌출혈이동반되지않은경우에는, 국소신경계결손, 두통, 경련같은증상은대부분호전된다고알려져있다. 55 과관류증후군에서의뇌출혈은두가지기전에의해서발생한다. 첫번째는과관류에의한뇌부종에의한것으로내막절제술에서주로발생하며, 두번째는초급성기에전관통동맥 (anterior perforating artery) 의파열에의한기저핵뇌출혈로스텐트삽입술에서흔하다. 56 일반적으로스텐트삽입술에서뇌출혈이초급성기에주로발생하여거미막하출혈이동반되는경우가많다. 뇌관류상태를알려주는검사 (SPECT, 관류MR) 를이용하여이러한과관류의위험성을미리예측할수있다. 이를예방을위해서는명확한임상근거는없으나혈압이정상이더라도시술전기준으로혈압을 10-20% 정 도더줄여야한다. 혈압조절은베타차단제나크로니딘이유리하며하이드랄라진, 앤지오텐신수용체차단제 / 앤지오텐신전환효소억제제, 칼슘통로차단제나질산염 (nitrate) 계열은피하도록권장하나이에대한명확한근거는없다. 57 일반적으로 2주간혈압을주의깊게측정하고두통발생의위험성을사전에교육하는것을권장한다. 기타예방항뇌전증약이나기타에다라본 (edaravone), 디피리다몰 (dipyridamole) 에의한과관류증후군예방효과에대한보고가있으나증례수가적거나또는관련무작위대조군연구가하나이거나경동맥내막절제술의연구여서아직은근거가부족하다. 58,59 자유라디컬을제거하는성분으로항산화효과가있는에다라본을내막절제술시행군 50명에게시술 30분전에 65 mg을정맥내투여하면 SPECT상에서과관류증후군이대조군 (16%) 에비하여치료군 (2%) 에서유의하게낮았다 (p=0.0310). 59 일부에서는과관류증후군예방을위해서풍선성형술에서풍선을작게부풀리거나스텐트삽입술후풍선혈관성형술을하지않는것을권장하기도한다. 또한단계별혈관성형술 (staged angioplasty) 을하여과관류증후군을줄였다는보고도있다. 작은사이즈의풍선성형술만먼저하여뇌혈류를부분적으로증가시킨 1-2달이후경동맥스텐트삽입술을하는것으로단계별혈관성형술을한 9명에서는 SPECT상과관류가없었으나풍선성형술과스텐트삽입술을한번에시행한통상적인그룹에서는 9명중 5명에서과관류가나타났다. 60 과관류증후군의위험인자는과거뇌졸중병변, 내경동맥병변, 심한협착정도 (>90%), 반대측경동맥의폐색이나최근 3개 Table 5. Potential risk factors for cerebral hyperperfusion syndrome Comorbidity/medication Diabetes mellitus Longstanding hypertension Pre-existing hypertensive microangiopathy Minor stroke in the presenting history Age 72 yr Recent (<3 mon) contralateral CEA High-grade carotid artery stenosis Flow related Preoperative Poor collateral flow Contralateral carotid occlusion Incomplete circle of Willis Preoperative hypoperfusion Diminished cerebrovascular reactivity or reserve Intracerebral steal (decrease of CBF after acetazolamide challenge) Perioperative or postoperative Abrupt increased CBF after reperfusion Persistence of hyperperfusion longer than several days postoperative Sustained hypertension after procedure Use of anticoagulants or antiplatelet therapy Periprocedural cerebral infarction CEA; carotid endarterectomy, CBF; cerebral blood flow J Korean Neurol Assoc Volume 32 No. 2, 2014 65
하연수박희권 월이내반대측경동맥시술이나수술병력, 당단백질 IIb/IIIa억제제사용, 고혈압병력, 미세혈관병 (microangiopathy) 이알려져있다. 이외에도당뇨병, 고령, 윌리스고리 (circle of Willis) 의미발달, 시술중시술원위부혈압이 40 mmhg 인경우가알려져있다. 특히, 고령이고곁순환이발달되지않은심한경동맥협착을가진환자에게스텐트삽입술을할경우과관류증후군발병위험이특히높다 (Table 5). 47,50-53,59,61 (2) 혈류역학변화에따른합병증경동맥스텐트삽입술후에발생할수있는저혈압과서맥은경동맥압력수용체 (baroreceptor) 와밀접한연관이있다. 스텐트삽입술후 24시간이내에수축기혈압이이전보다 30 mmhg 이상떨어지는경우가약 75% 발생하며수일내로호전되는경우가대부분이다. 62 시술직후에혈압이급격히떨어질수도있으며장시간에걸쳐경동맥스텐트를설치한경우에혈압이강하된다는보고가있다. 시술중에는주로저혈압은 17-22%, 서맥은 28-71% 에서나타나지만항콜린제 (anticholinergics) 를예방적으로처치하는경우에저혈압은 7%, 빈맥은 1% 이하의빈도로줄일수있다고한다. 63 서맥예방을위해서아트로핀 (atropine sulfate) 을 600 ug-1.2 mg을정맥또는동맥으로주사하며저혈압치료를위해서는베타작용제인이소프레날린 (isoprenaline, 2-4 mg/min, intravenously) 이나도파민을이용할수있다. 63 77 세이상의고령, 관상동맥질환, 경동맥팽대부병변과석회화된죽상판의존재가저혈압과서맥의위험인자로알려져있다. 64 이러한혈류역학적인불안정성은시술의합병증인뇌경색, 심근경색, 사망을초래할수있다. 64 경동맥스텐트삽입술이후에혈압이일시적으로떨어지는경우가흔하나, 오히려혈압이상승한다는보고도있어아직뚜렷한원인이밝혀지지않았다. 65,66 (3) 기타합병증경동맥스텐트삽입술후에발생하는다른합병증으로는색전증과경동맥폐색이있다. 42 색전증이이중가장큰비중을차지하며비교적흔하고뇌경색의원인이되기도한다. ICSS (the International Carotid Stenting Study) 의 MRI 후속연구에서경동맥스텐트삽입술을시행한환자의 50% 가시술후시행한 DWI 에서 1개이상새로운허혈병변이있었다. 67 또한경동맥내막절제술을시행한환자와비교할때스텐트삽입술을시행한환자에서 DWI에새로운병변이더많이보였고병변의크기는더작으며병변이주로피질과인접한백질부위에분포하였다. 68 시술과관련된색전증의발생시기는경동맥부위의시술중이나혈관조영술중또는대동맥이나색전방지기구설치중에발생할수있으나, 주로카테터를경동맥에위치시키고풍선확장, 스텐트설치시에발생한다. 69 색전증의위험인자로는죽상판의성상같은해부학적위험인자가있는데죽상판의초음파적성질 (echogenicity, heterogeneity) 과협착정도, 협착부위의길이또는죽상판의크기와석회화, 죽상판의궤양, 혈전의존재가있다. 이러한색전위험을평가하기위하여초음파로죽상판의성상을그레이척도 (gray scale median, GSM) 로평가하기도하며자기공명영상을이용한죽상판의위험도를평가하려는시도도있다. 70,71 시술과관련된색전증의기타위험인자로는전신에염증반응이있거나말초혈관이나관상동맥질환을위해개발된도구를사용하거나열린구조 (open cell) 스텐트와철망외공간 (stent-free-cell) 영역이클수록위험도가더증가되며 72-74 시술자의경험정도도색전증발생과연관되어있다. 6,75 항혈소판제의경우아스피린과헤파린을단독으로사용하는경우보다는 2가지항혈소판제를병용하는경우에색전증발생이적다고알려져있다. 76 이전보고에의 A B External Carotid Artery and Balloon Internal Carotid Artery and Microwire Common Carotid Artery and Balloon Aorta Figure 5. (A) Filer protection device. (B) MO.MA device is an endovascular cerebral occlusion system designed to achieve proximal protection from cerebral embolization. Catheter Cardiovasc Interv 2010. 66 대한신경과학회지제 32 권제 2 호, 2014
경동맥스텐트삽입술시술전평가와시술전후관리 A B 있다 (Fig. 6). 36,89 이중원위부혈관연축이나동맥박리는색전방지기구에의한경우가많으며 0.7% 이상에서발생된다. 78 이를예방하기위해서는저자의경험에의하면시술중에지속적으로혈류나혈관상태를확인하고카테터를위치시킬때외경동맥에와이어를설치하며굴곡이심한부위에서는경동맥스텐트삽입술을피하는것이좋다. 24시간내급성경동맥폐색의위험인자로는시술부위의혈류역학문제, 죽상판이스텐트내강안으로돌출 (protrusion), 시술전항혈소판제미복용이있다. Figure 6. (A) Immediately after stent insertion and balloon dilatation in-stent thrombus. (B) Stent-related carotid dissection. 하면시술중에발생하여색전방지기구에걸리는색전은 4-5,043 µm로다양하고 73,77 색전의수도 12개-3만개이상으로매우다양하다. 78-80 색전은여러성분이포함되어있으며 (fibrin, cholesterol cleft, red clot, white clot, cell aggraregate, organized thrombus, gas and etc), 대부분경동맥죽상판에서기원한것으로생각한다. 79,81 색전방지기구에걸리는거대색전 (macroembolism) 은고혈압, 고지혈증, 9 mm 이상의스텐트시술을받은환자에서흔하게나타나며이러한색전이발견된경우시술전후로신경계증상이자주발생된다. 82 DWI나두개경유도플러모니터링에서보이는대부분의병변은미세색전 (microembolism) 이다. 80 이러한미세색전증은내막절제술보다스텐트삽입술에서많이발생하는데 DWI 에서대부분 2-3 mm의작은병변이며대부분은신경계증상과는무관하였다. 83,84 다만미세색전증도잠재적뇌경색의위험인자임을생각하면이에대한적절한보호장비가필요하다. 84 색전증을막기위한시술방법으로는필터, 혈류역류, 풍선을이용한폐색법이있다. 실제필터색전방지기구 (Fig. 5-A) 의경우 50% 정도의뇌경색합병증감소효과가있다는보고가있다. 85-87 이들중 MO.MA 기구는주로풍선혈관성형술과스텐트설치시에총경동맥과외경동맥각각을풍선을이용하여혈류를차단하고역류시키는방식을사용하며이론상미세색전증도예방할수있으나일시적으로뇌혈류를차단하는단점도있으므로뇌혈류의곁순환이좋은경우에만제한적으로사용되고있으며더욱많은임상연구가필요하다 (Fig. 5-B). 88 색전방지기구사이의색전억제효과에대한비교자료는아직부족한상태이다. 86,87 또한주요합병증으로경동맥폐색이발생하는경우가있는데이원인으로는혈관연축, 동맥박리, 필터색전방지기구 (filter-protection system) 의색전, 스텐트내혈전증 (in-stent thrombosis) 이 4) 시술후재협착과추적관찰 SAPPHIRE (Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy) 연구에의하면경동맥협착이심한환자의경우, 시술또는수술후다시재개통술을 1년이내에하는비율이스텐트삽입술의경우 0.6% 이며내막절제술의경우 4.0% 라고한다. 7 이외의임상연구에서도경동맥스텐트삽입술이후에재협착비율이장기간에걸쳐 2-7% 로알려져있다 90,91 재협착에대한 10년이상의장기예후에대한보고는아직없다. 그러나 EVA-3S (endarterectomy versus angioplasty in patients with symptomatic severe carotid stenosis) 연구에서 2-3 년을추적관찰했을때스텐트삽입술군이내막절제술군에비해 70% 이상재협착의빈도는비슷하였으나 50% 이상재협착빈도는 2.5배이상더많았다. 92 또한 4-5년을추적관찰한 CAVATAS (carotid and vertebral artery transluminal angioplasty study) 연구에서는 70% 이상의재협착도스텐트삽입술군에서유의하게높았으나두연구모두뇌경색의재발률은큰차이가없었다. 93 따라서이의해석에주의를요한다. 일반적으로내막절제술이나스텐트삽입술시행후 30일이지나서부터두군간의예후의차이는없거나적은것으로보이나이에대해서는추가자료가필요하다. 스텐트삽입술후재협착의치료는경동맥에서도많은예가보고되었다. 94 스텐트안의재협착은대부분풍선혈관성형술로치료하고있으며이는처음경동맥스텐트삽입술과비교하여안정성이동등하거나양호한것으로알려져있다. 95 기타내막절제술을하거나스텐트안에다시스텐트를설치하는경우도있다. 96,97 현재시술후에어떠한검사를언제까지추적관찰해야좋은지에대한자료는부족한상태이다. 가장정확한방법은고식적혈관조영술을정기적으로하는것이나침습적인면과경제적인면을고려할때실제임상에서활용하기는어렵다. 이에 CT 혈관조영술이나경동맥초음파를이용하여추적관찰하는경우가많은데철망으로만들어진스텐트가감싸고있는혈관의내강을봐야한다는물리적제약으로정확한혈관내의재협착정도나또는경미한재협착정도를측정하는것은매우힘들다. 저 J Korean Neurol Assoc Volume 32 No. 2, 2014 67
하연수박희권 Table 6. Suggested the thresholds of velocity criteria at ultrasound for intra-stent restenosis in predicting differential degree of stenosis at angiography (A) Setacci, et al. suggested restenosis criteria in the stented carotid artery % Stenosis PSV (cm/s) EDV (cm/s) ICA/CCA <30 104 30 to 50 105-174 50 to 70 175-299 70 300 140 3.8 PSV; peak systolic velocity, ICA; internal carotid artery, CCA; common carotid artery, EDV; end diastolic velocity. (B) Lal, et al. suggested restenosis criteria in the stented carotid artery % Stenosis PSV (cm/s) EDV (cm/s) ICA/CCA 0 to 19 <150 <2.15 20 to 49 150-219 50 to 79 220-339 2.7 80 to 99 340 4.15 PSV; peak systolic velocity, ICA; internal carotid artery, CCA; common carotid artery, EDV; end diastolic velocity. 자의경우, 환자가특별한증상을호소하지않는다면퇴원전에 CT 혈관조영술로급성기스텐트내혈전생성이나경동맥폐색등을감별하고, 3-6개월후로는매년경동맥초음파로추적관찰하고있다. 실제임상연구에서는경동맥초음파를이용한연구가많은데재협착의진단기준에맞추어재협착유무를판단할수있다. 98,99 현재까지제시된초음파를통한스텐트삽입술후재협착기준은서로상이하여일치된적정기준치가없는상태이다 (Table 6). 98,99 향후스텐트삽입술을받은환자를추적관찰하여적합한재협착의기준이제시되어야할것이다. 100 스텐트삽입술후장기예후에대해서는아직도모르는부분이많다. 최근 2013년유럽뇌졸중학회에서보고된 ICSS연구의중간보고에따르면경동맥스텐트삽입술군과경동맥내막절제술군을추적관찰한결과, 4-5년후양쪽군에서중앙수정 Rankin 척도점수가 1점으로통계적차이가없었던것으로보아장기적으로두치교법간에합병증발생이차이가없을것으로생각한다. ICSS와 CREST 연구는현재최소 10년이상의장기추적관찰연구가진행중으로이에대한결과가나올때까지지켜봐야할것이다. 결론 대부분의신경과의사는스텐트삽입술에직접참여하기보다는시술전후처치를하고시술후추적관찰을한다. 그러므로시술과관련된스텐트와색전방지기구의종류, 협착의모양이나길이에따른시술방법의차이나위험도에대한정보가부족한실정이다. 경동맥스텐트삽입술과관련된합병증을줄이기위해서는적합한환자를선정하고각각의환자의상태를세밀 하게파악하며시술방법과기구에대해충분히이해하고시술전후적절한처치를해야하겠다. REFERENCES 1. Henry M, Polydorou A, Klonaris C, Henry I, Polydorou AD, Hugel M. Carotid angioplasty and stenting under protection. State of the art. Minerva Cardioangiol 2007;55:19-56. 2. Brott TG, Halperin JL, Abbara S, Bacharach JM, Barr JD, Bush RL, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/ SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery. Developed in collaboration with the American Academy of Neurology and Society of Cardiovascular Computed Tomography. Stroke 2011;42:e464-540. 3. Clinical Research Center for Stroke. Clinical Practive Guideline for Stroke. 1st ed. Seoul: Clinical Research Center for Stroke, 2009;263-271. 4. European Stroke Organisation, Tendera M, Aboyans V, Bartelink ML, Baumgartner I, Clement D, et al. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). European Heart J2011;32:2851-2906. 5. Chiam PT, Roubin GS, Panagopoulos G, Iyer SS, Green RM, Brennan 68 대한신경과학회지제 32 권제 2 호, 2014
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