Clinical Symposium 1 Preoperative risk assessment of patients with chronic liver disease Tae Yeob Kim Department of Internal Medicine, Hanyang University Guri Hospital, Guri, Korea Since the treatment of viral hepatitis and the management of complications in patients with chronic liver disease have developed, the survival rate has improved. Furthermore, comparing to the past, patients with cirrhosis are exposed to higher potential of surgery. However, the morbidity and mortality after surgery are substantially high. Preoperative evaluation can predict development of postoperative mortality and complications. Surgical risk in patients with chronic liver disease correlates with the severity and nature of underlying disease and type of surgery. To date, risk stratification for cirrhotic patients is based on Child-Turcotte-Pugh (CTP) score, the Model for End-Stage Liver Disease (MELD), and the Mayo clinic model. In addition, all patients with known liver disease should be assessed and managed for reversible factors such as electrolyte abnormalities, coagulopathy, and clinical manifestations of portal hypertension. This review will cover preoperative risk assessment of patients with chronic liver disease. Key words: Chronic liver disease, Preoperative evaluation, Surgery, Risk assessement 서론 만성간질환의주된원인중의하나인바이러스간염의치료가발전하고, 질환의합병증에대한치료의발전은만성간질환환자의생존율을향상시켰다. 특히간경변증환자들의생존기간이연장되면서과거에비해수술을시행하는빈도가증가하고있고, 1 10% 의환자에서생애의마지막 2년동안수술을경험하는것으로알려져있다. 2 간질환이있는환자는정상인에비해수술과마취와관련된합병증이발생의빈도가높다. 3 의료진이수술전에수술후사망과합병증발생을예측하고환자상태를관리하는것은수술적치료의적용여부를결정하고수술로인한위험을최소화하는데중요한역할을한다. 이번소고에서는만성간질환환자의수술전위험평가에대해언급하고자한다. 만성간질환환자의수술위험도 수술전수술위험도의평가는수술후의사망과합병증의발생여부로판단하고있다. 수술후환자의사망률은다양하게나타나는데이는기저간질환의중등도, 수술의종류, 응급도, 동반전신질환의유무, 의료수준등여러가지요인들에의해영향을받기때문에예측이쉽지않다. 하지만여러 - 25 -
2012 년대한간학회추계학술대회 연구들의일관된결과는기저간질환의중증도가결과를예측하는가장중요한요소이다. 45 간질환이진행될수록출혈, 감염, 수술후간기능부전이발생위험이높아지므로위험도를세분화하여평가하여야한다. 1. 기저간질환의중등도의평가미국마취과학회 (American Society of Anesthesiologist, ASA) 가채택하여사용하는신체상태분류는수술을준비하는모든환자를대상으로적합성을보기위해제안된방법으로수술의위험도를평가하기위해사용하고있다 (Table 1). 하지만경증과중증의전신질환이있는환자의정의가주관적이고, 문맥압항진증정도와영양상태를반영하기어려운점이있다. Child-Turcott-Pugh (CTP) 점수체계는간질환의중등도를분류하는데현재까지도이용되는계산이간편한방법으로수술전후의이환율과사망률평가에사용되고있다. 2,6,7 1980년대와 1990년대의연구에서간경변증환자들의복부수술후사망률을 CTP A등급 10%, CTP B등급 30%, CTP C등급 76-82% 를보고하였다. 2,8 2000년대이후자료에서간경변증이있는환자에서수술후사망률은 CTP A 등급 10%, CTP B등급 17%, CTP C등급 63% 를보고하였다. 9 최근후향적자료에서간경변증환자에서복부수술후 30일사망률은 CTP A등급 2%, CTP B등급 12%, CTP C등급은 12% 임을보고하였다. 10 2000년대이후의간경변증환자의수술후사망률의개선은수술전후의관리의발전과도관련이있을것으로생각된다. 심장수술을시행한간경변증환자에서 CTP 7점이하인경우에는 CTP 8점이상인환자보다 90일후사망률이의미있게낮았고, 간경변증이없는대조군과차이가없었다. 11 CTP A 등급이라도문맥압항진증이있는경우간절제술후합병증의위험이높았다. 12 CTP 등급이외에여러인자들이수술전후위험을증가시킬수있는데예정수술 (elective surgery) 보다응급수술 (emergency surgery) 의같은등급이라도사망률이높고, 만성폐쇄성폐질환과호흡기수술인경우수술전후의사망의독립적인위험인자이다. 813 일반적으로간경변증환자에서예정수술은 CTP A등급인경우가능하고, CTP B등급의경우수술전충분한준비후에선택적으로시행할수있고, CTP C등급의경우수술의적응증이되지않는다. 14 하지만 CTP등급은같은등급이라도임상양상이다양하게나타날수있고, 간성뇌증과복수의중등도는주관적으로판단이가능하여평가가정확하지않을수있는약점이있다. 15 Model for end-stage liver disease (MELD) 점수는경경정맥간내문맥전신단락술 (transjuglar intra- Table 1. American Society of Anesthesiologists (ASA) classification of preoperative risk 4 ASA Class Systemic disturbance Mortality (%) 1 Healthy patients with no disease outside of the surgical process <0.03 2 Mild to moderate systemic disease caused by the surgical condition or by other 0.2 pathological processes, medically well-controlled 3 Severe disease process which limits activity but is not incapacitating 1.2 4 Severe incapacitating disease process that is a constant threat to life 8 5 Moribund patient not expected to survive 24hr with or without an operation 34 E Suffix to indicate emergency surgery for any class Increased - 26 -
김태엽 Preoperative risk assessment of patients with chronic liver disease hepatic portosystemic shunt) 수술이후생존율을예측하기위해개발되었고, 16 미국에서는간이식우선순위의기준으로채택되었다. 17 MELD점수는혈청빌리루빈수치, 크레아티닌농도, INR에근거한선형회귀모델로 CTP 점수와비교하여객관적이고변수에가중치를부여하고있다. 수술후 30일사망률에서는 MELD점수 20점미만일경우 1% 의증가 20점이상일경우 2% 의증가를보고하여 MELD점수가좋은수술전예측인자임을제시하고있다. 18 여러연구에서 MELD점수의임계값이 8-14점일때복부수술후나쁜결과를예측한다고제시하고있다. 19-22 CTP및 MELD 점수를비교한연구들을보면 MELD점수가 CTP점수보다사망률예측에있어비슷하거나더좋은것으로보고하고있다. 22 국내후향적연구에서도간경변증환자에서수술후사망률의예측에있어서 MELD점수가 CTP점수에유용한예측인자임을제시하고있다. 23 Mayo clinic model은 2007년도에개발이되었는데수술후사망을예측하는데 MELD점수에의한간질환의중등도, 연령, ASA 신체상태분류로평가되는동반질환상태를공식화하여수술후사망률을계산할수있는예측모델 (http://www.mayoclinic.org/meld/mayomodel9.html) 을제공하고있다. 7 국내에서도 ASA 신체상태분류, CTP점수, MELD점수, 고령, 응급수술일경우수술후사망을예측하는독립적인인자이고, Mayo clinic model의유용함을제시하고있다. 24 하지만이러한모델은 1년후사망률의예측에있어서는낮은일치도를보이고있어추가적인검증이필요하다. 24 2. 수술종류수술종류는수술후결과를예측하는중요한결정인자중에하나이다. 심장수술, 개복담낭절제술 (open cholecystectomy) 과같은개복수술, 위절제술, 결장절제술 (colectomy) 와같은수술은수술후이환율과사망률이높다 (Table 2). 복부수술은간의허혈성손상을유발하고문맥압항진증으로인해수술하는동안출혈이위험이높아진다. 심박출량의증가, 내장혈관환장, 전신혈관저항의감소의혈역학적인변화는문맥압항진증이있는환자에서흔하다. 심박출량의증가에도불구하고혈류의단락으로관류 (perfusion) 이감소되어있고 4 또한마취에관련된약제들은간내혈류및간과내장의산소섭취를감소시킨다. 3,25 저혈압, 저산소증, 출혈과혈관수축약물의사용은간에서산소섭취를더욱감소시킨다. 간내혈류와간기능은카테콜아민방출과여러신경호르몬반응에의해악화된다. 4 응급수술을시행하는환자들은간기능부전의상당한위험이있는데이는수술전위험인자들인전해질장애, 응고병증, 복수, 간성뇌증을조절이어려울가능성이있다. 응급수술은예정수술보다이환율과사망률이높은것으로알려져있다. 100명의복부수술을시행한환자를대상으로한연구에서사망한환자의 80% 와합병증이있는생존자의 40% 는응급수술을시행한경우였다. 2 복부수술을시행한 92명의간경변증환자에서응급수술후의사망률은 50% 로예정수술의 18% 보다높았다. 40명의전신마취하에시행한수술에서응급수술후의 3개월사망률은 44% 로예정수술의 21% 보다높았다. 820 응급수술의경우 CTP점수와 MELD 점수는사망률을예측하는데좋은상관관계를보였다. 20-27 -
2012 년대한간학회추계학술대회 Table 2. Surgical severity risk stratification 4 Low risk Moderate risk High risk Eye ENT Dental Sinus/Tonsils Chest tube/thoracentesis Brochoscopy Laryngoscopy Tracheostomy Venous procedures Vein strippng Pacemaker insertion Lymph node biopsy/resection GI endoscopy Laparoscopy GU endoscopy Male GU procedures Female GU procedures D&C Skin lesion excision Superficial tumor excision Other diagnostic/therapeutic procedures Intracranial surgery Laminectomy/Disc surgery Thryoidectomy Other endocrine surgery Head and neck surgery Major blood vessels surgery Peripheral artery surgery Embolectomy Carotid artery surgery Rectal/Anal surgery Herniorrhagphy Bladder procedures Prostate procedures Hystrectomy±oophorectomy Amputations Hand, foot, knee surgery Breast biopsy/mastectomy Lung resection Heart surgery AAA repair Porto-systemic shunt Splenectomy Laparotomy Esophagus/Stomach surgery Liver/Biliary surgery Small bowel/large bowel/pancreas surgery Renal surgery Hip surgery Back fusion Long bone fractures ENT, Ear, nose and throat; GI, Gastrointestinal; GU, Genitourinary; D&C, Dilation and curettage; AAA, Abdominal aortic aneurysm. 3. 기저간질환의종류기저간질환의원인도수술후결과에영향을미친다. 간기능수치의이상을보이는무증상의환자의일부에서는간경변증이동반된경우도있지만황달, 복수, 간성뇌증, 간의합성능력감소등의단순한간수치의상승의경우에는수술후이환율과사망률은정상인과비슷하다. 26 기저간질환의상태에의해예정수술은진행되지않을수있는데금기증은표 3에정리하였다. 4 급성간염은바이러스와약물등의다양한원인에의해서나타난다. 과거의후향적연구들을보면급성간염의원인과관계없이예정수술이후에간부전과사망이위험성이증가한다. 간외담관폐색으로의심하여복강경을시행하여급성바이러스간염으로진단된환자의수술후사망률은 10% 였다. 과거자료와는달리최근에는간외담관폐색이의심되는경우에는자기공명췌담관조영술및내시경적역행성담췌관조영술로진단및치료가가능하여진단적개복술은피해야하며예정수술은급성간염환자에서는금기사항으로간주되고있다. 27 급성간염은대부분시간이경과하면좋아지기때문에예정수술의경우가능하면간기능이회복될때까지연기한다. 14 알코올간경변환자에서질환의중등도가높게되는데이는알코올간염이동반될수있기때문에동반여부를판단해야한다. 알코올간염은수개월이내에대개는좋아지기때문에예정수술의금기이고응급수술을시행할경우수술전후의사망률을증가시킨다. 알코올간염환자에서예정수술은적어도 12주이상금주하고간기능을재평가하여회복이된경우시행하는것을권유한다. 14 또한간세포암종에대해근치적간절제술을시행받은환자에서비알코올성지방간염에기인한 - 28 -
김태엽 Preoperative risk assessment of patients with chronic liver disease Table 3. Contraindications to elective surgery in patients with liver disease 4 Acute hepatitis Alcoholic Autoimmune Uncontrolled Wilson s disease Chronic hepatitis Chronic severe hepatitis Class C cirrhosis Uncontrolled PHT with sequelae Severe coagulopathy1 Systemic liver-related co-morbidities Hypoxia (POPH or HPS) 2 Cardiac volume overload Hepatorenal syndrome 1 Severe coagulopathy defined as platelets < 50,000/mm 3 and prothrombin time prolonged beyond 3 s with no response to vitamin K; 2 POPH: portopulmonary hypertension; HPS: hepatopulmonary syndrome 경우에 C 형간염과알코올간질환보다전체생존율이높았다. 28 폐쇄성황달이있는환자는감염, 스트레스궤양, 범발성혈관내응고증 (disseminated intravascular coagulopathy, DIC), 수술상처파열과신부전을포함한수술전후의합병증위험이증가한다. 수술전후의사망률은 8-28% 로보고되고있으다. 29-31 특히수술후사망률을예측하는인자는초기적혈구용적율이 30% 미만, 혈청빌리루빈 11 mg/dl 이상, 악성종양이있는경우로제시하였는데 3개의인자를모두만족하는경우에는사망률이 60% 까지증가한다. 29 이러한환자들에게서수술전광범위한항생제를사용하여수술후감염을줄일수있고, 내시경또는경피적담도배액술은수술적치료보다선호된다. 14 간질환환자에서수술전내과적관리 기존에간질환이있는환자에서수술전적절한관리는수술후의합병증과사망의위험을줄여준다 (Table 4). 1. 응고병증 (Coagulopathy) 만성간질환이있는환자에서간에서만들어지는여러응고인자의합성이감소하고, 영양결핍과장관내흡수장애로인해비타민 K가결핍되어비타민 K 의존성응고인자활성이감소된다. 혈소판감소는혈소판합성에관여하는트롬보포이에틴 (thrombopoietin, TPO) 생성감소, 문맥압항진증으로인해비장에서혈소판제거, 알코올유도골수억제, DIC, 혈소판기능억제인자, 면역기전등으로나타난다. 심한응고병증혹은혈소판감소증이있는경우수술위험에대한자료는거의없다. 14 혈소판수가 50,000/mm 3 미만일경우혈소판수혈을고려할수있다. 프로트롬빈시간이정상치보다 3초이상증가하거나 INR 1.5를초과할경우에비타민 K 투여로교정이되지않거나응급수술을고려할경우에는신선냉동혈장 (fresh frozen plasma) 을투여할수있다. 14 출혈이조절되지않을때동결침전제제 (cryoprecipitate) 를정맥내로투여한다. 34 프로트롬빈시간을교정할수있는 recombinant factor VIIA의 - 29 -
2012 년대한간학회추계학술대회 Table 4, Preoperative management of the complications of advanced liver disease 33 Clinical manifestation Nutritional status Coagulopathy Ascites Renal dysfunction Portosystemic encephalopathy Pulmonary hepatic vascular disorders Management considerations Maintenance of an adequate protein intake (1-1.5 g/kg per day) Promotion of a balanced diet Vitamin K supplementation (oral or parenteral) Fresh, frozen plasma transfusions Intravenous administration of cryoprecipitate Intravenous administration of recombinant factor VIIa Platelet transfusions Paracentesis with analysis of ascetic fluid for evidence of infection Dietary sodium restriction (<2 g daily) Oral diuretic therapy with spironolactone and/or furosemide Fluid restriction (if sodium concentration is <120 meq/l) Avoidance of excessive saline administration Avoidance of NSAIDs Avoidance of nephrotoxic insult Albumin infusion (with paracentesis volume > 5 liter) Correction of reversible metabolic factors Avoidance of sedatives and opioid narcotics, as far as possible Oral lactulose administration, titrated to ~3-4 bowel movements per day Administration of nonabsorbable antibiotics Decreased protein intake Supportive care Supplemental oxygen 자료들은제시되고있지만, 35 고비용, 일시적효과, 색전증위험의증가로사용에는제한적이다. 35,36 출혈시간이연장되어있는경우에는 diamino-8-d-arginine vasopressin (DDAVP) 로투여할수있다. 이러한응고병증에대한치료에반응이없을경우에는혈장교환 (plasma exchange) 이고려한다. 또한수술중에 4 는적절한수술기법과중심정맥압을낮게유지하여혈액소실을줄이는것이필요하다. 37 2. 복수 (Ascites) 복수는수술후상처파열, 복벽탈장, 폐의팽창감소로인한호흡곤란의위험을증가시킨다. 수술전복수가있는경우저염식과이뇨제를조합하여치료하고혈청크레아티닌과전해질을모니터링 4 이필요하다. 수술전복수조절이되지않을경우대량복수천자 (large volume paracentesis) 를수술전, 수술중에시행할수있고, 천자후순환장애와간신증후군의위험성을낮추기위해복수 1리터당 8-10g의알부민을투여하여혈관내용적을유지한다. 복수의원인감별과감염 4 여부확인하고자발성세균성복막염이있는경우에는적절한항생제로치료해야한다. 수술전경경정맥간내문맥전신단락술은수술후합병증의개선효과가없어유용성의논란의여지가있지만, 38 최근자료에의하면선택적으로고려될수있다. 39-30 -
김태엽 Preoperative risk assessment of patients with chronic liver disease 3. 신부전 (Renal dysfunction) 진행성간질환에서신부전은약물 ( 이뇨제, 비스테로이드성소염제, 신독성약물 ), 알부민보충없이시행된대량복수천자, 감염 ( 자발성세균성복막염, 요로감염 ), 위장관출혈과간신증후군에의해발생한다. 40 수술후신부전의위험성은혈역학적인변화와체액이동, 특히복수를개복시에제거할경우증가한다. 신기능에대해서는수술전후주의깊은모니터링이필요하고, 잠재적으로위험이되는약물등을피해야한다. 대다수의환자는 BUN (blood urea nitrogen) 과크레아티닌으로신기능을평가하지만진행된간질환환자에서는근육량및크레아티닌합성의감소로초기신부전을놓치는경우가있으므로주의해야한다. 41,42 4. 간성뇌증 (Hepatic encephalopathy) 간성뇌증을악화시킬수있는인자들은제거해야한다. 간성뇌증이조절될때까지정규수술은연기해야하는데수술후에탈수, 저칼륨혈증, 감염, 출혈, 향정신성약제와수면제사용을피할수없기때문이다. 미세뇌증에서 14 수술후현성뇌증이발생할수있으나예방치료의역할에대해서는아직알려진바가없다. 간성뇌증의위험을줄이기위해서는적절한수분공급, 칼륨공급, 감염과출혈의조절, 향정신성약제와수면제의사용을최소화해야한다. 락툴로스를사용하고최근선호되는경구용 rifaximin을투여하여혼수를치료할수있다. 43 5. 영양결핍 (Malnutrition) 만성간질환환자에서영양결핍은흔히관찰되고심한경우수술전영양상담을통해교정해야하고, 이는단기사망률과수술후합병증을감소시킨다. 44,45 하지만장기생존율과의관계는불분명하다. 간성뇌증을예방하기위해탄수화물 / 지질함량이많고아미노산함량이적은영양공급이고려되고, 특히알코올환자인경우에는비타민 B1을포함하는것이필요하다. 4 6. 폐와관련된상태 (Pulmonary conditions) 흉수, 간폐증후군 (hepatopulmoanry syndrome), 문맥폐고혈압 (portopulmonary hypertension), 면역매개폐질환, 폐기종등이발생할수있다. 흉수는간경변증환자의 5% 에서나타날수있지만저산소증이심하지않기때문에수술전흉수천자는대개권유하지않는다. 46 간폐증후군은폐혈관확장에의해동맥혈가스교환의장애가발생하고, 문맥폐고혈압은폐동맥수축과재형성이유발되어폐동맥압이증가되어우심부전과저산소증이나타나는질환으로예후는불량하고, 수술전처치에대해서는보존적인방법이외에정립되어있지않다. 7. 질환특이적인자 (Disease-specific factors) 간질환의원인에따라수술전후의처치가달라질수있다. 자가면역성간염질환이있는경우수술전후스트레스용량의하이드로코티손을투여하고, 윌슨병이있는경우사용하는 D-penicillamine은 - 31 -
2012 년대한간학회추계학술대회 콜라겐교차결합을방해하여상처치유를방해하기때문에수술전과수술후 1-2주동안감량해야한다. 4 알코올간질환이있거나최근지속적인알코올섭취환자는수술전에일정기간금주를권하고, 아세트아미노펜유발간독성이발생할위험이높기때문에수술이후진통제의투여는주의해야한다. 33 급성담관염에서는담도배액과항생제투여를하고수술은감염이회복될때까지연기해야한다. 33 8. 이외고려할점수술전빈혈의교정이필요하다. 내당능장애와당뇨병은간질환환자에서흔히발생하고수술전인슐린으로조절하지만간경변환자에서저혈당의위험이있으므로주의해야한다. 비타민 D결핍이동반된경우비타민 D와 calcitriol투여를고려한다. 간경변환자에서수술전정맥류에대한평가는필요하고, 예방요법으로베타차단제를복용하는경우에는수술전후유지할수있다. 간경변환자에서는수술전예방적항생제사용이필요하고, 소화성궤양이있는경우장기간의프로톤펌프억제제의사용을권유할수있다. 4 결론 과거와는달리만성간질환환자에서적절한치료개입이이루어지고있어장기생존이가능하면서수술에노출되는경우가증가하고있다. 하지만만성간질환환자의수술후사망률은질환의중등도와수술종류등에따라상당히높은편이다. 이에수술전에수술후사망과합병증을줄이기위해위험성을정확하게평가하는것이필요하고수술전후적절한내과적관리가요구된다. 참고문헌 1. Friedman LS. Surgery in the patient with liver disease. Trans Am Clin Climatol Assoc 2010;121:192-204. 2. Garrison RN, Cryer HM, Howard DA, Polk HC, Jr. Clarification of risk factors for abdominal operations in patients with hepatic cirrhosis. Ann Surg 1984;199:648-655. 3. Friedman LS, Maddrey WC. Surgery in the patient with liver disease. Med Clin North Am 1987;71:453-476. 4. Millwala F, Nguyen GC, Thuluvath PJ. Outcomes of patients with cirrhosis undergoing non-hepatic surgery: risk assessment and management. World J Gastroenterol 2007;13:4056-4063. 5. Bhangui P, Laurent A, Amathieu R, Azoulay D. Assessment of risk for non-hepatic surgery in cirrhotic patients. J Hepatol 2012;57:874-884. 6. Friedman LS. The risk of surgery in patients with liver disease. Hepatology 1999;29:1617-1623. 7. Teh SH, Nagorney DM, Stevens SR, Offord KP, Therneau TM, Plevak DJ, et al. Risk factors for mortality after surgery in patients with cirrhosis. Gastroenterology 2007;132:1261-1269. 8. Mansour A, Watson W, Shayani V, Pickleman J. Abdominal operations in patients with cirrhosis: still a major surgical challenge. Surgery 1997;122:730-735; discussion 735-736. 9. Neeff H, Mariaskin D, Spangenberg HC, Hopt UT, Makowiec F. Perioperative mortality after non-hepatic general surgery in patients with liver cirrhosis: an analysis of 138 operations in the 2000s using Child and MELD scores. J Gastrointest Surg 2011;15:1-11. - 32 -
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