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1 대한내과학회지 : 제 73 권제 3 호 2007 종 설 괴사췌장염의내과치료 울산대학교의과대학서울아산병원내과 이성구 =Abstract= Medical treatments of necrotizing pancreatitis Sung Koo Lee, M.D. Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea Pancreatic necrosis is associated with complications and mortality if the necrotic tissue becomes infected. The development of necrosis is associated with hypovolemia, vascular spasm and hemoconcentration. Control of hypovolemia, use of antibiotics, nutritional support and endoscopic treatments are the nonsurgical options in the mamagement of necrotizing pancreatitis. The proper use of antibiotics in acute pancreatitis remains controversial, however, current evidence favors the use of prophylactic antibiotics in necrotizing pancreatitis. Enteral feeding is usually well tolerated, however, total parenteral nutrition may be necessary. Several studies have demonstrated that enteral feeding via a nasojejunal tube infused distal to the ligament of Treitz is associated with a decreased rate of complications, including infection, when compared to total parenteral nutrition. Infected pancreatic necrosis can be managed by percutaneous or endoscopic dranage. The choice of drainage routes depends on the disease status, availability of the interventional radiologist or gastroenterologist. For improvement of outcomes and reducing complications in the management of necrotizing pancreatitis, proper patient selection and technical expertise are required.(korean J Med 73: , 2007) Key Words : Necrotizing pancreatitis, Medical treatments 서론중증급성췌장염환자의전반적인사망률은대략 30% 이고, 췌장염발생후 1~2주에생기는조기사망은 inflammatory mediators 와 cytokine에의해야기되는다장기기능부전 (mutisystem organ failure, MOF) 에기인하며 1), 후기사망은국소또는전신적인감염에기인한다. 췌실질에미만또는국소영역에생길수있는췌장괴사는췌장염발생후첫수일에생길수있는중요한합병증으로췌장의염증, 혈량저하증 (hypovolemia), 저혈압, 혈관수축, 혈액농축등과연관된다고한다 2). 급성괴사췌장염이무균적으로유지되는경우전반적인 사망률은약 10% 이나감염괴사가있는경우사망률은 3배가된다고알려져있다 3). 급성괴사췌장염의초기치료로는집중적인내과치료와예방적항생제의사용을통한감염의예방등이며후기치료로는국소감염 ( 췌장감염 ) 의치료와적극적인괴사조직의제거 (debridement) 등이있다. 급성괴사췌장염환자의 30~70% 에서감염괴사가생기며, 급성췌장염에의한사망의 80% 이상을차지한다고한다 4). 감염괴사의위험도는췌장괴사의양에따라증가하며급성췌장염의시작부터경과시간에따라증가하여 3주에최고조를이룬다 1, 4). 무균췌장괴사의경우최소 3~4주동안내과치료가필요한데만일임상증상의호전이없으면유도하경피흡인

2 -The Korean Journal of Medicine : Vol. 73, No. 3, 으로감염을확인해야한다. 3~4주후에조직화된괴사로 (organized necrosis) 변하는데기본적으로괴사를함유하며섬유성피막 (fibrous capsule) 으로둘러싸인다. 최근한보고에서는급성췌장염기간중췌장괴사가늦게나타날수있으며임상소견에따라추적 CT 의필요성에대해보고한바있다 5). 감염괴사의치료법에는외과적괴사조직제거와방사선학치료, 내시경치료, 항생제를포함하는내과치료로대별할수있는데주로비수술적인내과치료에대해기술하고자한다. 수액공급혈량저하증은췌장의미세순환을저해하며췌장괴사의발생과관련이깊은데 6) 혈양저하가소화관의허혈을초래하고이는장투과성을증가시켜세균및세균독소투과가증가되어췌장괴사의이차감염에도관여하게되기때문으로알려져있다 7). 실험연구에서도능동적인조기수액공급이췌장의산소공급을유지하며췌장괴사를최소화하고사망률을줄였다는보고가있다 8, 9). 수액공급은시간당소변량이 0.5~1 ml/kg 이상을유지되도록하는것이이상적이며수액공급의적절성을파악하기위하여혈압, 맥막수, 소변량, 중심정맥압등을정기적으로측정하는것이매우중요하다 10). 감염의치료괴사췌장염환자의약 30~35% 에서감염괴사로진행하며보통발병후 2~3주중에생긴다. 괴사조직의감염은발열, 백혈구수증가, 환자의상태가호전되지않거나악화되는경우의심할수있다. CT 소견에서는괴사조직내에공기음영을볼수있다 11). 급성괴사췌장염환자에서감염괴사가생기면사망률의현저한상승이오므로감염의예방은매우중요하다 4). 급성괴사췌장염의실험동물모델에서감염은일차적으로대장으로부터의세균전파에기인한다고알려져있고 12), 여러동물실험에서경구항생제로장관의세균을제거시키거나 (decontaminate) 췌장조직으로의침투력이높은항생제의정맥투여시췌장의감염과사망률을줄일수있다고하였다 12-14). 전향적연구에서도선택적인장관제균으로치료시급성괴사성췌장염환자에서 gram-negative 췌장감염의빈도와후기사망률 ( 췌장염시작후 2주이후의사망 ) 의의미있는감소를 보였다 15, 16). 선택적인장관제균에사용되는항생제는경구및직장으로투여하여야하기때문에이들처방은상당한간호시간 (nursing time) 이필요하여췌장감염의예방을위해전신적인항생제의투여가더실제적으로볼수있다는견해도있다 17). Imipenem-cilastatin을정맥투여를받은환자에서비록사망률의감소는보이지않았으나, 췌장감염의빈도를낮출수있었다는보고도있다 18). 췌장괴사와중증급성췌장염이환자를대상으로한한후향적연구에서기존의대조군 (historical control) 에비해 imipenem-cilastatin의정맥주사를투여받은경우췌장감염의빈도의감소와사망률의감소추세를보고하였고 19), imipenem-cilstatin의정맥주사는급성괴사성췌장염의진단후가급적이른시간에시작하고최소 2내지 4주간지속해야한다고권고한바있다 17). 무균성및감염성급성췌장염모두발열, 백혈구증가, 심한복통이올수있으므로임상적으로감별하기는어려우나감염성급성괴사췌장염환자의사망률은치료하지않으면 100% 에가깝기때문에그구별은중요하다 3). 췌장의세균상태는 CT 유도하에췌장및췌장주위조직또는액체를세침흡인함으로써알수있으며 20) 흡인하여그램염색, 배양으로췌장감염을안전하고정확히진단할수있다. 이와같은흡인법은안전하고정확하며, 민감도 96%, 특이도 99% 로알려져있고임상적으로악화를보이거나집중적인보존적치료를함에도불구하고악화를보이는급성괴사췌장염환자에서시행할것을권고하고있다 21). 괴사췌장염환자에서항생제의사용에대해서는아직합의가이루어져있지않다. 여러전향적, 무작위, 위약대조연구에서 ( 이중맹점안됨 ) 강력한항생제의투여가감염췌장괴사의빈도를감소시킨다고하나몇몇추가연구에서강력한항생제의사용시진균감염의합병으로사망률이높아질수있다고한다. 괴사췌장염환자모두에게 7~14일간의항생제를기본적으로사용하거나, 장기부전이있을때에만투여또는감염이증명되지않는경우항생제를사용하지않는 center가있는등다양한치료방침을보인다. 최근 Cochrane database의리뷰에서언급된 5개의무작위임상연구에서도항생제사용에대한명확한잇점을제시하지못하고있다 22). 괴사췌장염의임상경과중발열이나백혈구증가와같이감염을의심할만한경우가흔히발생하기때문에다수의경우에서항생제치료가시행되는데예방적항

3 -Sung Koo Lee : Medical treatments of necrotizing pancreatitis - 생제사용의부정적인면으로서는항생제내성균주의출현과진균에의한이차감염의위험성이증가할수있다는것이다. 그러나앞에서언급한 5개의연구에서진균에의한감염의빈도는항생제의투여여부와상관이없었다 6). 항생제의투여도췌장괴사의정도에따라결정되어야할것이라는견해도있다. 영양공급 (Nutritional support) 심하거나합병증이동반된췌장염환자에서영양공급은중요하며상태에맞는영양공급방법에대해서는논란의여지가있다 23). 심한췌장염환자의경우최소한 5~7일간경구영양공급은하지않으며, 관습적으로수일내에 total parenteral nutrition (TPN) 을시행받는다. 최근에경장영양공급 (enteral feeding) 은장관으로부터세균의이동 (bacterial translocation) 을억제함으로써감염괴사를예방할수있다고한다. 또한패혈증과같은부작용의관점에서 TPN 보다안전하고환자도잘견딘다고한다. 급성괴사췌장염환자에서증가된대사요구량을보충하고췌장을쉬게하기위해 TPN이중심정맥카테타를통해흔히투여된다. 그러나이러한치료가급성췌장염의회복을앞당기지는않는다 24). 두가지의무작위전향적연구에서중증급성췌장염환자에서 TPN 또는경장영양공급 ( 방사선조영하에 Treitz인대하방으로유치한경비장관 feeding tube를이용 ) 증상시작후 48시간이내에시행하였다 25, 26). 경장영양공급은환자들이잘받아들였고부작용이없으며, 전반적인합병증과감영성합병증을유의하게감소시켰다고한다. TPN의비용이경장영양공급에비해의미있게많았다고보고되었고 24), 하루에약 15배이상차이가난다고도하였으며경장영양공급후 acute phase response scores와질병의중중도지수의의미있는개선이있었다고도한다 26). 현저한장마비가없는경우, 급성괴사성췌장염환자에서공장영양관 (jejunal feeding tube) 을통한경장고영양공급이선호되는것으로보인다 24). 또한 6개의무작위연구를이용한 meta analysis에서는총 263명의환자를포함하였는데경장영양공급으로임상경과의개선을보였고 27, 28) 감염율 26, 27) 수술치료의감소, 입원기간의단축 27), 비용의절감등 28) 이있었다. 또한장영양공급은장마비가있는환자에서도잘적용되었다 23). 그러나경장영양요법으로충분한칼로리를공급할수없거나, 경장영양경로를유지하기어려운경우는 TPN이필요할수있다 29). 췌장괴사에있어서의중재시술급성괴사췌장염환자의치료에있어서그시기와시술종류에대해서는논란이있다. 무균급성괴사췌장염의사망률은대략 10% 인데, 외과처치가이와같은사망률을낮추는것으로보이지않고있고대부분의연구자들이이들군에서는보존치료를권유하고있다 3). 반면, 감염성급성괴사췌장염의경우중재치료를하지않으면대부분치명적이다 3). 1. 수술에의한괴사조직제거술배액술을하는경우적극적인수술적췌장괴사조직제거 (necrosectomy) 가표준적인치료법이며여러차례의복부수술이필요할수도있다. Necrosectomy는감염성괴사가확진된후곧시행하여야하나수술전세침흡인으로위음성결과가나올수있어임상적으로가능성이높은경우감염이증명되지않는경우도수술을고려할수있다. 2. 괴사조직제거의대체접근법 1) 경피치료 ( 중재방사선학치료 ) 급성괴사췌장염의치료목적으로직경 28 Fr까지의대구경경피도관 (catheter) 를이용한적극적인세척과배액으로성공적으로치료하였다는보고가있다. 내과적으로조절되지않는패혈증을갖는 34명의괴사췌장염환자의췌장액체저류부위에입원후평균 9일간도관을삽입하였다고하며각환자에서평균 3개의독립된도관이필요하였고, 괴사물질을제거하기위해서는 4번의도관교체가필요하였다고하였다 30). 16명 (47%) 의환자에서췌장수술을완전히피할수있었고, 9명의환자에서패혈증이조절되었으며도관유치에따른외부누공 (external fistula) 의치료를위해계획된수술이후에시행되었다고한다. 9명의환자는경피치료가실패후즉각적인수술을요하였고 34명의환자중 4명 (12%) 에서사망하였다고한다. 34명의환자대부분은다장기기능부전이있었고, 감염성괴사를보인환자중에서혈역동학적으로안정된환자를대상으로도도관을이용한적극적인경피배액을시도한보고가있다 31). 여러개의대구경도관의사용과많은양의세척, 결석제거용바스켓을사용하여고형의괴사췌장조직을성공적으로

4 - 대한내과학회지 : 제 73 권제 3 호통권제 565 호 제거하여수술없이괴사의완전한호전이있었다고보고하였는데 31). 이들환자에서췌장염의발병후평균 3.5 주에중재시술을시행하였다. 2) 내시경치료진행성의감염괴사와농양의치료에서수술이표준치료이나높은이환율과사망률, 반복적인개복수술의필요성등에의해내시경치료도발전하게되었다 32). 중증괴사췌장염발병후평균 6.9주에증상이있는무균성또는감염성췌장염에서성공적인내시경배액을하였다는보고도있다 33). 위나십이지장을통해여러개의 10 Fr 내부배액관와 7-Fr의경비췌장배액관을 15 mm 까지확장한경로를통해후복막에내시경을이용하여삽입한다. 이와같은방법으로고형의괴사물질들은장관을통해도관주위로흘러나오게된다. 이와같이췌장괴사, 액체, 췌장주위의조직이피막을형성한후기또는조직화된췌장괴사를 31명중 25명 (81%) 에서수술없이괴사를완전히치료하였다 34). 이들환자에서수술처치가필요한경우는배액실패보다는천공, 출혈등의내시경시술과연관된급성합병증때문이었다. 일부괴사병변을배액하기위해추가적인경피배액이소수의환자에서필요하였다. 췌장괴사의배액방법과시술시점의결정은외과의사, 중재내시경시술자, 중재방사선의사의경험을고려하여야하고팀접근을하여계획을수립하고필요에따라병합시술이필요하기도하다. 무균적췌장괴사의부적절한배액이생명을위협하는감염성괴사에이를수있다. 최근에는위를통한괴사조직제거 (transgastric necrosectomy) 가감염괴사췌장염치료법의하나로이용될수있고내시경치료의성공여부는충분한세척과관류에좌우된다 32, 33, 35). 한편급성괴사췌장염에서췌관의손상이흔히있을수있으며임상적으로심한췌장염환자의경우 44% 에서 ERCP 검사에서췌관누출이발견되었다고한다 36). 이때병행할수있는치료로는담도췌관의스텐트삽입, 액체저류의배액, 필요시수술등이있다. 췌관파열시췌관스텐트의삽입으로저류액체가흡수되고수주내에췌관의파열부분이회복되면스텐트의제거가가능하다. 결론췌장괴사의내과치료에서고려할사항으로는췌장 괴사의존재유무파악과감염유무의판단을어떻게할것인지, 항생제의투여적응증, 항생제의종류의선택, ERCP는언제할것인지, 영양공급의방법으로경정맥으로할것인지경장영양공급을할것인지등이있다. 또한췌장괴사배액술의결정에있어서시술시기, 경피또는내시경배액등치료방법의선택도중요한쟁점이되리라생각한다. 괴사췌장염치료결과의향상을위해서는적절한환자의선택과시술경험이필요하다, 중심단어 : 괴사췌장염, 내과치료 REFERENCES 1) Beger HG, Rau B, Mayer J, Pralle U. Natural course of acute pancreatitis. World J Surg 21: , ) Baillargeon JD, Orav J, Ramagopal V, Tenner SM, Banks PA. Hemoconcentration as an early risk factor for necrotizing pancreatitis. Am J Gastroenterol 93: , ) Idem. Infected necrosis: morbidity and therapeutic consequences. Hepatogastroenterolgy 38: , ) Rau B, Uhl W, Buchler MW, Berger HG. Surgical treatment of infected necrosis. World J Surg 21: , ) Wijffels NA, van Walraven LA, Ophof PJ, Hop WC, van der Harst E, Lange JF. Late development of pancreas necrosis during acute pancreatitis an underestimated phenomenon associated with high morbidity and mortality. Pancreas 34;215: , ) Lee HS. Can early intervention improve patients outcome? Korean J Gastroenterol 49(Suppl):297S- 303S, ) Ammori BJ. Role of the gut in the course of severe acute pancreatitis. Panceas 26: , ) Strate T, Mann O, Kleinhans H, Rusani S, Schneider C, Yekebas E, Freitag M,Standl T, Bloechle C, Izbicki JR. Microcirculatory function and tissue damage is improved after therapeutic injection of bovine hemoglobin in severe acute rodent pancreatitis. Pancreas 30: , ) Klar E, Schratt W, Foitzik T, Buhr H, Herfarth C, Messmer K. Impact of microcirculatory flow pattern changes on the development of acute edematous and necrotizing pancreatitis in rabbit pancreas. Dig Dis Sci 39: , ) Otsuki M, Hirota M, Arata S, Koizumi M, Kawa S, Kamisawa T, Takeda K, Mayumi T,Kitagawa M, Ito

5 - 이성구 : 괴사췌장염의내과치료 - T, Inui K, Shimosegawa T, Tanaka S, Kataoka K, Saisho H, Okazaki K, Kuroda Y, Sawabu N, Takeyama Y; The Research Committee of Intractable Diseases of the Pancreas. The research committee of intractable diseases of the pancreas. Consensus of primary care in acute pancreatitis in Japan. World J Gastroenterol 12: , ) Whitcomb DC. Acute pancreatitis. New Engl J Med 354: , ) Marotta F, Geng TC, Wu CC, Brabi G. Bacterial translocation in the course of acute pancreatitis: beneficial role of nonabsorbable antibiotics and lactitol enemas. Digestion 57: ) Foitzik T, Fernandez-del Castillo C, Ferraro MJ, Tithofer K, Rattner DW, Warshaw AL. Pathogenesis and prevention of early pancreatic infection in experimental acute necrotizing pancreatitis. Ann Surg 222: , ) Mithofer K, Fernandez-del Castillo C, Ferraro MJ, Lewandrowski K, Rattner DW, Warshaw AL. Antibiotic treatment improves survival in experimental acute necrotizing pancreatitis. Gastroenterology 110: , ) Sainio V, Kemppainen E, Puolakkainen P, Taavitsainen M, Kivisaari L, Valtonen V, Haapiainen R, Schröder T, Kivilaakso E. Early antibiotic treatment in acute necritising pancreatitis. Lancet 346: , ) Luiten EJ, Hop WC, Lange JF, Bruining HA. Differential prognosis of gram-negative versus grampositive infected and sterile pancreatic necrosis: results of a randomized trial in patients with severe acute pancreatitis treated with adjuvant selective decontamination. Clin Infect Dis 25: , ) Baron TH, morgan DE. Acute necrotizing pancreatitis. N Engl J Med 340: , ) Pederzoli P, Bassi C, Vesentini S, Campedelli A. A randomized multicenter clinical trial of antibiotic prophylaxis of septic complications in acute necrotizing pancreatitis with imipenem. Surg Gynecol Obstet 176: , ) Ho HS, Frey CE. The role of antibiotic prophylaxis in severe acute pancreatitis. Arch Surg 132: , ) Gerzof SG, Banks PA, Robbins AH, Johnson WC, Spechler SJ, Wetzner SM, Snider JM, Langevin RE, Jay ME. Early diagnosis of pancreatic infection by computed tomography-guided aspiration. Gastroenterology 93: , ) Tenner S, Banks PA. Acute pancreatitis: nonsurgical management. World J Surg 21: , ) Villatoro E, Bassi C, Larvin M, Antibiotic therapy for prophylaxis against infection of pancreatic necrosis in acute pancreatitis. Cochrane Database Syst Rev 18:CD002941, ) Meier R, Beglinger C, Layer P, Gullo L, Keim V, Laugier R, Friess H, SchweitzerM, Macfie J; ESPEN Consensus Group. ESPEN guideline on nutrition in acute pancreatitris: Europian Society of Parenteral and Enteral Nutrition. Clin Nutr 21: , ) McClave SA, Snider H, Owens N, Sexton LK. Clinical nutrition in pancreatitis. Dig Dis Sci 42: , ) Kalfarentzos F, Kehagias J, Mead N, Kokkins K, Gogos CA. Enteral nutrition is superior to parenteral nutrition in severe acute pancreatitis; results of a randomized prospective trial. Br J Surg 84: , ) Windsor AC, Kanwar S, Li AG, Barnes E, Guthrie JA, Spark JI, Welsh F, Guillou PJ, Reynolds JV. Compared with parenteral nutrition, enteral feeding attenuates the acute phase response and improves disease severity in acute pancreatitis. Gut 42: , ) Marik PE, Zaloga GP. Meta-analysis of parenteral nutrition versus enteral nutrition in patient with acute pancreatitis. BMJ 328:1407, ) Mayerle J, Hlouschek V, Lerch MM. Current management of acute pancreatitis. Nat Clin Pract Gastroenetrol Hepatol 2: , ) McClave SA, Dryden GW. Issues of nutritional support for the patients with acute pancreatitis. Semin Gastrointest Dis 13: , ) Freeny PC, Hauptmann E, Althaus SJ, Traverso LW, Sinanan M. Percutaneous CT-guided catheter drainage of infected acute necrotizing pancreatitis: techniques and results. AJR Am J Roentrenol 170: , ) 이 Echenique AM, Sleeman D, Yrizarry J, Scagnelli T, Guerra JJ, Casillas VJ, Huson H, Russell E. Percutaneous catheter directed debridement of infected pancreatic necrosis: results in 20 patients. J Vasc Interv Radiol 9: , ) Raszymski S, Teich N, Borte G, Wittenburg H, Mossner J, Caca K. Percutaneous transgastric irrigation drainage in combination with endoscopic necrosectomy in necrotizing pancreatitis. Gastrointest Endosc 64: , ) Baron TH, Thaggard WG, Morgan DE, Stanley RJ. Endoscopic therapy for organized pancreatic necrosis. Gastroenterology 111: , ) Baron TH, Morgan DE. Organized pancreatic

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황지웅

황지웅 Comparison of Laparoscopy and Exploration in the Distal Pancreatectomy BACKGROUND: To determine the benefits of laparoscopic surgery compared with exploration, the clinical outcomes of open and laparoscopic