대한소화기내시경학회지 2008;37:265-270 Nafamostat Mesilate 전처치를시행한환자에서의내시경역행담췌관조영술후급성췌장염의위험인자 부산대학교의학전문대학원내과학교실 김일두ㆍ강대환ㆍ박진현ㆍ배정호ㆍ김표준ㆍ김용욱최철웅ㆍ엄재섭ㆍ이선미ㆍ김태오ㆍ김광하ㆍ송근암 Risk Factors for Post-ERCP Pancreatitis in Patients Pretreated with Nafamostat Mesilate Il Doo Kim, M.D., Dae Hwan Kang, M.D., Jin Hyun Park, M.D., Jung Ho Bae, M.D., Pyo Jun Kim, M.D., Yong Wook Kim, M.D., Cheol Woong Choi, M.D., Jae Sup Eum, M.D., Sun Mi Lee, M.D., Tae Oh Kim, M.D., Gwang Ha Kim, M.D. and Geun Am Song, M.D. Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea 목적 : 내시경역행담췌관조영술 (ERCP) 은췌장및담도질환의진단과치료에중요한역할을하고있으나시술에따른췌장손상을비롯한다양한합병증을유발할수있다. 이중특히 ERCP 후급성췌장염은때때로사망까지초래할수있어임상에서예방을위한전처치와예측할수있는위험인자를인지하는것이중요하다. 이에 nafamostat mesilate 를예방으로사용하여 ERCP 를시행한환자에서 ERCP 후고아밀라제혈증과급성췌장염의발생률을알아보고발생에관련된요인들을전향분석하여위험인자들을알아보고자하였다. 대상및방법 : 2005 년 4 월부터 2006 년 4 월까지부산대학교병원에서 ERCP 를시행받은 247 명의환자를대상으로하여이들에게예방목적으로투여한 nafamostat mesilate 의 ERCP 후고아밀라제혈증과급성췌장염의발생률을조사하였다. 또한환자와시술에관련된인자들에대하여단변량및다변량분석을시행하여 ERCP 후급성췌장염의발생에영향을미치는위험인자들을분석하였다. 결과 : Nafamostat 를투여받은총 247 명의환자중고아밀라제혈증이 24 명 (9.7%), ERCP 후급성췌장염이 9 명 (3.6%) 에서발생하였다. ERCP 후고아밀라제혈증에서는 20 분이넘는시술시간, 4 회이상의췌관삽관횟수, 이전 ERCP 후급성췌장염의병력, 총담관담석이없는경우등이의미있는위험인자로나타났으며 ERCP 후급성췌장염에서는 60 세미만의나이, 20 분이넘는시술시간, 4 회이상의췌관삽관횟수, 총담관담석이없는경우등이의미있는위험인자로나타났다 (p<0.05). 의미있게나타났던변수들에대하여다변량분석을시행하였을때, 4 회이상의췌관삽관횟수가고아밀라제혈증 (p=0.038, OR 5.165, 95% CI 1.093 24.412) 과 ERCP 후급성췌장염 (p=0.002, OR 33.122, 95% CI 3.526 311.138) 에서모두통계에서유의한차이를보이는위험인자로나타났다. 결론 : ERCP 의전처치로 nafamostat 를사용한경우 ERCP 후고아밀라제혈증은 9.7%, 급성췌장염은 3.6% 에서발생하였다. ERCP 후고아밀라제혈증과급성췌장염의발생은 4 회이상의췌관삽관횟수가독립적인위험인자로나타났다. 색인단어 : 내시경역행담췌관조영술, 급성췌장염, 위험인자, 예방, Nafamostat mesilate 서 론 접수 :2008 년 3 월 1 일, 승인 :2008 년 8 월 12 일연락처 : 강대환, 부산대학교병원소화기내과 (602-739) 부산시서구아미동 1 가 10 전화 : 051-240-7869, 팩스 : 051-244-8180 이메일 : sulsulpul@yahoo.co.kr 본논문은 BK21 연구비지원으로연구되었음. 내시경역행담췌관조영술 (endoscopic retrograde cholangiopancreatography, ERCP) 은담도및췌관조영을할수있을뿐아니라내시경치료가가능하여췌장및담도질환의진단과치료에중요한역할을하고있다. ERCP는시술에따른다양한합병증을유발할수있으 265
266 대한소화기내시경학회지 2008;37:265-270 며, 이중고아밀라제혈증과급성췌장염이흔하여 25 40% 에서고아밀라제혈증, 1.0 5.1% 에서급성췌장염이발생하는것으로보고되고있다. 1-6 급성췌장염은때때로심하며사망까지초래할수있다. ERCP 후급성췌장염을예방하기위해췌장분비억제제인 somatostatin 7 또는 octreotide, 8 Oddi 괄약근수축억제제인 nifedipine, 9 단백분해효소억제제인 gabexate mesilate, 10-12 camostat mesilate, 13 nafamostat mesilate, 14 그리고 inteleukin-10 (IL-10) 15 등의다양한약물전처치가시도되고있다. 이중단백분해효소억제제인 nafamostat mesilate의투여가 ERCP와관련된고아밀라제혈증과급성췌장염의발생을예방할수있는것으로기대되고있으나논란의여지가많다. 이에저자는진단및치료의목적으로 nafamostat mesilate를전처치한후 ERCP를시행한환자에서췌장손상의발생률과 ERCP 후고아밀라제혈증과급성췌장염의발생을유발할수있는위험인자를알아보고자하였다. 1. 대상 대상및방법 2005년 4월부터 2006년 4월까지부산대학교병원에서 nafamostat mesilate (Futhan R ) 를전처치하여 ERCP를시행받은환자중 ERCP 시행전급성췌장염이발생되어있는경우, 만성췌장염이있는경우, 이전에내시경유두괄약근절개술 (endoscopic sphincterotomy, EST) 을시행받은경우, nafamostat 투약에금기가되는경우, 심한전신질환이동반된경우를제외한 247명 ( 평균나이 66.3±11.5세, 남자 123명, 여자 124명 ) 을대상으로하였다. 2. 방법 Nafamostat 20 mg을 5% 포도당주사액 500 ml에혼합하여 ERCP 시행 30분전부터 24시간동안정주하였다. 모든환자는시술전 8시간이상금식하였고 ERCP 시술전전처치로 midazolam (Dormicum R ) 과 pethidine (Pethidine R ) 을정맥주사하였으며시술중연동운동을억제시키기위하여 cimetropium bromide (Algiron R ) 를정맥투여하였다. 시술중조영제로는 ioxitalamate (Telebrix R ) 를사용하였다. 담관삽관과췌관삽관의정의는삽관후조영제를주입한경우로하였고난해한삽관의정의는 5 회이상의삽관시도에도선택적인삽관에실패하고삽관시도이후삽관까지의시간이 10분이상걸린경우로하였으며이경우에는누두절개술을시행하였다. 이들에서성별, 나이, 시술시간, 담관삽관과췌관삽관의횟 수, 난해한삽관, 게실의유무, EST 시행및시행시출혈유무, 누두절개술의시행여부, 시술중발룬및바스켓의사용여부, mechanical lithotripsy의시행여부, ENBD (endoscopic nasobiliary drainage), ERBD (endoscopic retrograde biliary drainage), 담관금속스텐트, 췌관스텐트의시행여부, 이전 ERCP의시행여부및이전 ERCP 후급성췌장염의발생여부, 체질량지수, 이전담낭절제술및위절제술의여부, 총담관담석의유무, 원위부총담관의확장 (1 cm 이상 ) 여부, 이전 ERCP의실패여부, 담도염의유무, 황달의유무등의변수들이 ERCP 후고아밀라제혈증과급성췌장염의발생에영향을미치는지에대하여전향연구를시행하였다. ERCP 시술에따른췌장손상을평가하기위하여혈중아밀라제와리파제의농도를 ERCP 2시간전과시술후 4, 12, 24시간후에측정하였다. 또한췌장과관계되는복통과진통제의사용여부를확인하였다. 고아밀라제혈증은 ERCP 시술후 24시간내에혈중아밀라제농도가정상상한치의 3배이상증가된경우로정의하였고, 12 ERCP 후급성췌장염은혈청아밀라제또는혈청리파아제가정상상한치의 3배이상의증가와함께심한상복부통증을동반한경우로정의하였다. 16 3. 통계분석 결과분석은단변량분석으로카이제곱을사용하였고, p값이 0.05이하인경우의미있는것으로판정하였으며이들항목에대해 logistic regression analysis를이용한다변량분석을시행하였다. 통계적분석은 SPSS 12.0 프로그램을사용하여시행하였다. 결 1. Nafamostat 전처치를시행한 ERCP 후고아밀라제혈증및급성췌장염의발생률 Nafamostat를투여받은총 247명의환자중고아밀라제혈증이 24명 (9.7%), ERCP 후급성췌장염이 9명 (3.6%) 에서발생하였다 (Table 1). 2. ERCP 후급성췌장염에대한위험인자분석 ERCP를시행한적응증은총담관담석이 117예 (47.4%), 담석외의원인 ( 종양, 양성폐색 ) 에의한폐쇄성황달이 70예 (28.3%), 담석이나종양에의한급성담도염이 31예 (12.6%), Oddi 괄약근기능부전이나담석에의한산통이 16예 (6.5%), 기타가 13예 (5.3%) 였다 (Table 1). ERCP에의해고아밀라제혈증이발생한군과발생하지않은군간에위험인자들에대해단변량분석을시행 과
김일두외 : 내시경역행담췌관조영술후급성췌장염의위험인자 267 하였을때 20분이넘는시술시간, 4회이상의췌관삽관횟수, 이전 ERCP 후급성췌장염의병력, 총담관담석이 Table 1. Baseline Characteristics of Patients Gender (M:F) Age (years, mean)±sd Indication of ERCP (%) CBD stone Obstructive jaundice Acute cholangitis Biliary colic Others Post-ERCP hyperamylasemia (%) Post-ERCP pancreatitis (%) Patients (n=247) 123:124 66.3±11.5 117 (47.4) 70 (28.3) 31 (12.6) 16 (6.5) 13 (5.3) 24 (9.7) 9 (3.6) 없는경우등이통계에서의미있는위험인자로나타났다. 또한 ERCP 후급성췌장염이발생한군과발생하지않은군간에위험인자들에대해단변량분석을시행하였을때 60세미만의나이, 20분이넘는시술시간, 4회이상의췌관삽관횟수, 총담관담석이없는경우등이통계적으로의미있는위험인자로나타났다 (Table 2). 단변량분석에서통계적으로의미있게나타났던변수들에대하여각각다변량분석을시행하였을때, 고아밀라제혈증에서는 4회이상의췌관삽관횟수 (p=0.038, OR 5.165, 95% CI 1.093 24.412) 가, ERCP 후급성췌장염에서도역시 4회이상의췌관삽관횟수 (p=0.002, OR 33.122, 95% CI 3.526 311.138) 만이통계에서유의한차이를보이는변수로나타났다. Table 2. Univariate Analysis of Potential Risk Factors for Post-ERCP Hyperamylasemia and Post-ERCP Pancreatitis Variable n Post-ERCP hyper-amylasemia (%) p-value Post-ERCP pancreatitis (%) p-value Female gender Age<60 yrs EST Procedure time >20 min Difficult cannulation Bile duct cannulation 4 times Diverticulum Infundibullotomy Balloon extraction Basket extraction Mechanical lithotripsy ENBD ERBD Biliary metal stent Pancreatic duct cannulation 4 times Prior ERCP Prior post-ercp pancreatitis BMI 25 Prior cholecystectomy No CBD stone Distal CBD dilatation <1 cm Pancreatic duct stent Prior ERCP failure No cholangitis Prior gastrectomy No Jaundice Bleeding after EST 124 65 143 122 37 61 73 19 101 83 8 94 26 16 18 75 10 36 37 116 219 3 5 216 1 177 109 11 (8.9) 9 (13.8) 12 (8.4) 18 (14.8) 5 (13.5) 5 (8.2) 9 (12.3) 5 (26.3) 10 (9.9) 7 (8.4) 1 (12.5) 12 (12.8) 6 (23.0) 8 (44.4) 11 (14.7) 10 (100.0) 2 (5.6) 5 (13.5) 16 (13.8) 21 (9.6) 1 (33.3) 22 (10.2) 17 (9.6) 7 (6.4) 0.652 0.190 0.297 0.008 0.398 0.644 0.511 0.226 0.897 0.487 0.800 0.297 0.053 0.116 0.001 0.083 <0.001 0.362 0.398 0.042 0.850 0.165 0.459 0.512 0.742 0.925 0.120 6 (4.9) 9 (13.8) 5 (3.5) 8 (6.6) 2 (5.4) 1 (1.6) 2 (2.7) 2 (10.5) 4 (4.0) 1 (1.2) 5 (5.3) 3 (11.5) 7 (38.9) 5 (6.7) 5 (50.0) 1 (2.8) 2 (5.4) 8 (6.9) 9 (4.1) 8 (3.7) 5 (2.8) 3 (2.8) 0.314 0.042 0.786 0.016 0.535 0.336 0.538 0.197 0.925 0.118 0.471 0.335 0.055 0.352 <0.001 0.094 <0.001 0.764 0.535 0.010 0.274 0.735 0.660 0.894 0.846 0.275 0.735 ENBD, endoscopic nasobiliary drainage; ERBD, endoscopic retrograde biliary drainage with plastic stent.
268 대한소화기내시경학회지 2008;37:265-270 고 ERCP 후급성췌장염의발생기전은현재까지명확히밝혀져있지않지만, 다음과같은인자들과관련되어있다. 삽관시행중발생하는유두부손상및유두괄약근절개술이나담석제거술도중발생하는손상등의물리적인요인, 조영제에의해발생하는화학적인요인, 조영제등의물질을췌관으로주입할때혹은 Oddi 괄약근내압검사를할때발생하는압력요인, ERCP 시행중췌장효소의활성화에의한효소요인, 미생물요인, EST시발생하는열에의한손상등으로발생한다고알려져있다. 6 급성췌장염은췌장내에서비정상적으로활성화된소화효소에의하여자가소화가발생하고이에따라염증및조직파괴가진행되는것이발생기전으로생각되고있으며선방세포내에서의효소원과립 (zymogen-granule) 과용해소체 (lysosome) 가만나면서단백분해효소인트립신 (trypsin) 이활성화되고, 또세포외기질에서는트립시노겐 (trypsinogen) 이조기활성화되는것이급성췌장염발생초기과정에있어서가장중요한단계들로알려졌다. 17,18 이런결과를기초로하여단백분해효소억제제 (protease inhibitor) 는지난수십년간급성췌장염의치료에대한연구에서중심역할을차지해왔으며, 19-24 그중 gabexate mesilate, camostat mesilate, nafamostat mesilate 가가장많이연구되어져왔다. Nafamostat mesilate (6-amidino- 2-naphthyl p-guanidine benzoate dimethane sulfonate) 는트립신, C1r과 C1s, 보체활성화, 트롬빈 (thrombin), 섬유소용해효소 (plasmin), 칼리크레인 (kallikrein) 등을억제하는것으로알려진분자량 539D의단백분해효소억제제인데, 25 그역가가다른단백분해효소억제제인 gabexate mesilate의 10 100배에이르는것으로알려져있다. 26 하지만급성췌장염의예방에있어서는성공적인동물실험의결과에도불구하고현재까지임상실험에서뚜렷한치료효과는입증되지못하였다. 27-29 본연구에서는 ERCP에의한급성췌장염을예방하기위하여단백분해효소중 nafamostat mesilate를사용하였으며 ERCP 후고아밀라제혈증의발생률은 9.7%, ERCP 후급성췌장염의발생률은 3.6% 였다. ERCP 후고아밀라제혈증은무증상으로대부분 48시간에서는정상화된다. 30 예방목적으로 nafamostat를사용한본연구에서는 ERCP 후고아밀라제혈증의발생률이이전보고의 25 40% 에비해낮게나타났다. 1-6 ERCP 후급성췌장염의발생률은여러연구에서다양하게보고되고있 찰 으며본연구에서는다른연구결과들에서보고된 2% 에서 9% 와비슷한결과를보였다. 1-6 본연구는대조군이없어정확한비교는할수없으나이전의문헌들에서보고된 ERCP 후급성췌장염의발생률이나 gabexate mesilate 등의다른약물에의한전처치가선행된 ERCP 후급성췌장염의발생률과비교해볼때기존의발생률과큰차이는없는것으로생각한다. 급성췌장염의치료로단백분해효소억제제를사용한경우그치료성적은보고자마다서로다른결과를보이고있다. 이는생체내에서단백분해효소억제제의반감기가짧고안정성이감소할뿐아니라, 급성염증과정에의한미세순환의장애및혈관투과성저하로인하여단백분해효소억제제가췌장내에유효한치료농도에도달하지못하고, 급성췌장염이발생한후환자가단백분해효소억제제를투여받을때까지걸리는시간의지연, 그리고일단췌장염이발생하면이에관련된 cytokine cascade의억제의어려움등이그원인으로생각되었다. 31-33 ERCP에의한급성췌장염의발생을예측할수있는임상특성이나시술과관련된인자에대해서는다양한보고가있으며젊은연령, 여성, Oddi 괄약근장애가의심되는경우, 이전 ERCP 후급성췌장염의병력, 반복적으로췌장염이발생한경우, 췌관이조영된경우, 췌관괄약근에대하여절개술을시행한경우, 정상의담도괄약근에대하여풍선확장술을시행한경우, 삽관이어려웠거나실패한경우, 침형절개도를사용하여유두부예비절개술을시행한경우등이위험인자로보고되고있다. 34-39 본연구에서는단변량분석시 20분이넘는시술시간, 4회이상의췌관삽관횟수, 이전 ERCP 후급성췌장염의병력, 총담관담석이없는경우등이 ERCP 후고아밀라제혈증에서의의미있는위험인자로확인되었으며, 60세미만의나이, 20분이넘는시술시간, 4회이상의췌관삽관횟수, 총담관담석이없는경우등이 ERCP 후급성췌장염에서의의미있는위험인자로나타났다. 또한이중 4회이상의췌관삽관횟수만이다변량분석에서의미있는위험인자로확인되었다. 이상의결과로미루어볼때선택적인담관삽관이어려워여러번췌관을삽입한경우와이에따른시술시간의연장이고아밀라제혈증및췌장염과연관이있을것으로생각된다. 잠재적인위험인자로서평가되었던여러요소중시술에관련된누두절개술이나, balloon, basket 사용, EST 시행여부등은시술자의숙련도에의한차이가존재할수있을것으로생각한다.
김일두외 : 내시경역행담췌관조영술후급성췌장염의위험인자 269 결론으로 nafamostat mesilate 전처치를시행한경우 ERCP 후고아밀라제혈증은 9.7%, ERCP 후급성췌장염은 3.6% 에서발생하였으며좀더정확한효과를알기위해서는대규모의전향적대조연구가필요할것으로생각한다. 또한 ERCP 후급성췌장염을가장잘예측할수있는위험인자로는시술중췌관삽관의빈도인것으로생각하며이러한위험인자가있는경우 ERCP 후급성췌장염의예방을위한약물처치및췌관스텐트의유치등의대비가필요할것으로생각한다. ABSTRACT Backgound/Aims: Pancreatitis is the most common and important complication of an endoscopic retrograde cholangiopancreatography (ERCP). The aim of this study was to identify risk factors for post ERCP-pancreatitis in patients pretreated with nafamostat mesilate, a synthetic protease inhibitor. Methods: A total of 247 patients who underwent an ERCP were evaluated prospectively. Potential risk factors of post-ercp pancreatitis in patients pretreated with nafamostat mesilate were evaluated. Results: Twenty-four patients (9.7%) and nine patients (3.6%) developed post-ercp hyperamylasemia and pancreatitis, respectively. As determined by univariate analysis among the potential risk factors, we found a procedure time over 20 minutes, pancreatic duct cannulation over four times, prior post-ercp pancreatitis and the absence of a common bile duct (CBD) stone as risk factors for post-ercp hyperamylasemia. We also found a patient age under 60 years, a procedure time over 20 minutes, pancreatic duct cannulation over four times and the absence of a CBD stone as risk factors for post-ercp pancreatitis (p<0.05). As determined by multivariate analysis, pancreatic cannulation over four times is independently associated with post-ercp hyperamylasemia (p=0.038; OR, 5.165; 95% CI, 1.093 24.412) and post-ercp pancreatitis (p=0.002; OR, 33.122; 95% CI, 3.526 311.138). Conclusions: A repeated pancreatic duct cannulation is the most important risk factor for post-ercp pancreatitis in patients pretreated with nafamostat mesilate. (Korean J Gastrointest Endosc 2008; 37:265-270) Key Words: Post-ERCP pancreatitis, Risk factors, Prevention, Nafamostat mesilate 참고문헌 1. Skude G, Wehlin L, Maruyama T, Ariyama J. Hyperamylasemia after duodenoscopy and retrograde cholangiopancreatography. Gut 1976;17:127-132. 2. Chen YK, Foliene RL, Santoro MJ, Walter MH, Collen MJ. Endoscopic sphinctrotomy-induced pancreatitis: increased risk associated with nondilated bile ducts and sphincter of Oddi dysfunction. Am J Gastorenterol 1994;89:327-333. 3. Sherman S. ERCP and endoscopic sphincteroctomy-induced pancreatitis. Am J Gastroenterol 1994;89:303-305. 4. LaFerla G, Gordon S, Archibald M, Murray WR. Hyperamylasemia and acute pancreatitis following endoscopic retrograde cholangiopancreatography. Pancreas 1986;1:160-163. 5. Freeman ML, Nelson DB, Sherman S, et al. Complications of endoscopic biliary sphincterotomy. N Engl J Med 1996; 335:909-918. 6. Kim JH. Post ERCP pancreatitis. Korean J Gastrointest Endosc 2003;27(abstr):307A-318A. 7. Andriulli A, Levandro G, Niro G, et al. Pharmacologic treatment can prevent pancreatic injury after ERCP: a meta-analysis. Gastrointest Endosc 2000;51:1-7. 8. Binmoeller KF, Harris AG, Dumas R, Grimaldi C, Delmont JP. Does the somatostatin analogue octreotide protect against ERCP induced pancreatitis? Gut 1992;33:1129-1133. 9. Sand J, Nordback I. Prospective randomized trial of the effect of nifedipine on pancreatic irritation after endoscopic retrograde cholangiopancreatography. Digestion 1993;54:105-111. 10. Ohshio G, Saluja AK, Leli U, Sengupta A, Steer ML. Esterase inhibitors prevent lysosomal enzyme redistribution in two noninvasive models of experimental pancreatitis. Gastroenterology 1989;96:853-859. 11. Wisner JR Jr, Renner IG, Grendell JH, Niederau C, Ferrell LD. Gabexate mesilate (FOY) protects against ceruletide-induced acute pancreatitis in the rats. Pancreas 1987;2:181-186. 12. Cavallini G, Tittobello A, Frullori L, Masci E, Mariana A, Di Francesco V. Gabexate for the prevention of pancreatic damage related to endoscopic retrograde cholangiopancreatography. Gabexate in digestive endoscopy--italian Group. N Engl J Med 1996;335:919-923. 13. Yoo KS, Shin WG, Jung JO, et al. Oral camostat for prevention of post-ercp pancreatitis: a pilot study. Gastrointest Endosc 2006;63(abstr):307AB. 14. Yoo KS, Moon JH, Park KH, et al. Nafamostat mesilate for prevention of post-ercp pancreatitis. Gastrointest Endosc 2007;65(abstr):212AB. 15. Devière J, Le Moine O, van Laethem JL, et al. Interlukin 10 reduces the incidence of pancreatitis after therapeutic endoscopic retrograde cholangiopancretography. Gastroenterology
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