Abstract Critical assessment of the hepatic reserve is essential prior to liver resection especially in patients with chronic liver disease. Development of liver dysfunction post resection can result in a signifi cant increase in associated complications resulting in prolonged length of hospital stay and increased hospital costs. In addition, the development of liver failure is almost universally fatal unless the patient can undergo liver transplantation. Several scoring systems have been identifi ed which assess the degree of liver disease including the Child-Turcotte-Pugh scoring system (CTP) and the Model for End Stage Liver Disease (MELD). Both of these scoring systems have been used to predict mortality post liver resection. Based on the current available literature, MELD appears to be the best predictor of postoperative liver dysfunction/failure in patients with cirrhosis, and patients with MELD scores 9 should not be considered for hepatic resection. Other factors not included in MELD such as platelet count, presence of portal hypertension, extent of liver resection (and the resulting residual liver volume) and the presence of ascites should also be considered when selecting patients with chronic liver disease to undergo liver resection. Keywords Hepatectomy • Liver resection • MELD • Child-Pugh Score • Liver failure • Cirrhosis Introduction Recent surgical advances in liver resection s have improved the safety and complication rates from this complex operation, and a hepatectomy is now a well-accepted treatment for patients with both benign and malignant liver tumor s and metastatic T. W. Reichman (*) • H. Bohorquez Multi-Organ Transplant Institute, Department of Surgery , Ochsner Medical Center , 1514 Jefferson Highway , New Orleans , LA 70121 , USA e-mail: [email protected] 190 cancers to the liver. The presence of an adequate, healthy remnant liver is essential in order to prevent postoperative liver dysfunction and/or liver failure after liver resection and is especially critical in patients with known chronic liver disease. In the case of hepatocellular cancer ( HCC ), >80 % of the patients diagnosed have chronic liver disease [ 1 ]. With donor shortages across the globe, not all patients with chronic liver disease can undergo transplantation for HCC [ 2 ]. Appropriate assessment of the hepatic reserve is essential to avoiding post-operative liver dysfunction and liver failure. Liver Failure Following Liver Resection Progression of liver dysfunction to liver failure is almost universally fatal unless the patient can undergo liver transplant ation . Post- hepatectomy liver failure was recently defi ned by the International Study Group of Liver Surgery (ISGLS) as the inability of the liver to maintain its synthetic, excretory, and detoxifying functions, which is manifested by an increased INR and hyperbilirubinemia on or after postoperative day 5 [ 3 ]. The reported rate of liver failure varies between 1.2 and 32 % depending on the study population [ 3 ]. Liver dysfunction post liver resection ultimately results in increased length of stay and increased hospital costs. Recently, post operative liver dysfunction was also linked to post resection disease-free survival in patients undergoing resection for HCC [ 4 ]. Evaluation of the Degree of Chronic Liver Disease It is well established that there is an increased risk performing surgery on patients with chronic liver disease and cirrhosis . This increased risk derives from both factors associated with chronic liver disease (e.g. portal hypertension, ascites , thrombocytopenia, and coagulopathy) and also the potential exacerbation of liver dysfunction secondary to general anesthesia and a laparotomy incision. Based on several studies, mortality can be as high as 70–80 % in patients with advanced cirrhosis [ 5 , 6 ]. Based on this knowledge, it is not surprising that there is also an increased risk in performing liver resections on patients with chronic liver disease. Accurate assessment of the functional reserve is critical prior to liver resection especially in patients with chronic liver disease. Two well-known scoring systems are the Model for End Stage Liver Disease ( MELD ) and the Child-Turcotte-Pugh (CTP) scoring system. The accuracy of these tests in predicting hepatic dysfunction post liver resection is still debated. The CTP score was initially reported in 1964 as a way to assess liver function in patients with chronic liver disease and was later modifi ed by Pugh in 1973 [ 7 , 8 ]. The current scoring system utilizes the serum bilirubin, serum albumin, prothromin T.W. Reichman and H. Bohorquez 191 time (PT)/ international normalized ratio (INR), degree of ascites and degree of hepatic encephalopathy assigning 1–3 points for each variable. Patients are divided into three classes based on total points with 6, 7–9, and 10 points representing Child’s class A, B, and C, respectively. Unlike the CTP score which contain variables that are somewhat subjective, the MELD score, a linear regression model based on patient’s serum creatinine, total bilirubin and INR, was initially designed to predict mortality in cirrhotic patients who were undergoing transjugular intrahepatic portosystemic shunts ( TIPS ) [ 9 ]. Subsequently, the model has been validated prospectively as a prognostic tool in patients awaiting liver transplant ation [ 10 ]. This model also effectively predicts mortality in patients who underwent nontransplant surgery [ 11 ]. Search Strategy A literature search of the English language publications from 1990 to 2014 was used to identify published data on the use of Child Class and/or MELD score as a predictor of hepatic reserve prior to liver resection using the PICO outline (Table 16.1 ). The databases searched included PubMed, Science Citation Index/ Social Sciences Citation index, Embase, and Cochran Evidence Based Medicine . Keywords used for the search included “MELD score,” Child score/classifi cation,” “Child- Pugh score/classifi cation,” “Child-Turcotte-Pugh score/classifi cation,” “ cirrhosis ,” AND “liver resection ,” OR “ hepatectomy .” Articles were classifi ed using the GRADE system. Liver Resections and the Childs-Turcotte-Pugh Score CTP score has been applied to liver resection in an attempt to predict hepatic reserve and mortality post liver resection . It is fairly well established that patients with Class C cirrhosis poorly tolerate resection. An early study by Nagasue et al. documented their experience with 63 patients (46 Class B and 17 Class C cirrhotics). In their series, they had a 17.6 % overall peri-operative mortality (30 days from surgery ) for their class C patients and a 23.5 % in-hospital death rate [ 12 ]. Table 16.1 PICO table for assessment of hepatic reserve prior to liver resection P (Patients) I (Intervention) C (Comparator group) O (Outcomes measured) Patients with cirrhosis undergoing hepatic resection Use of MELD scoring system preoperatively to assess hepatic reserve Use of the ChildTurcotte-Pugh classifi cation to assess hepatic reserve prior to liver resection Incidence of liver dysfunction/ failure post liver resection resulting in increased length of stay, hospital cost, morbidity, and mortality 16 Which Is the Better Predictor of Hepatic Reserve Prior to Liver Resection… 192 Few studies also focus on class B cirrhotics with even fewer giving a detailed analysis of peri-operative morbidity . Two studies were identifi ed which focused on outcomes following resection of class B cirrhotics. The fi rst series by Nakahara et al. examined 119 patients with HCC who underwent resection that were identifi ed as class B cirrhotics [ 13 ]. Of these patients, >75 % of them underwent a limited resection (less then a segmentectomy). In this series, the in-hospital mortality was 5 %, with two patients suffering from liver failure in the immediate postoperative setting. Multivariate analysis revealed risk factors for poor outcome which included elevated bilirubin (>1.5 mg/dl) and the presence of ascites [ 13 ]. Similarly, Kuroda et al . studied 150 class B cirrhotics. Although the risk of immediate post-operative liver failure appears to be low in these patients, many patients ultimately die of liver failure (15 %) [ 14 ]. Based on these studies, limited resection can be performed on patients with CTP Class B cirrhosis with caution but major resections should be avoided. One would predict that class A cirrhotics would have less post-operative liver dysfunction and liver failure based on the fact that Class A patients by defi nition have minimal symptoms (if any) of chronic liver disease. The majority of large published studies focus on patients with class A cirrhosis and HCC . However, studies have clear bias and show improvement in outcomes over time but little change in the number of patients with cirrhosis [ 15 ]. Even for patients with class A cirrhosis, the range of liver function appears to vary widely as judged by ICG retention studies performed on Class A patients [ 16 ]. In a series of 625 patients resected for HCC, CTP was not found to be an independent predictor of perioperative morbidity [ 17 ]. In contrast, Nagasue et al. reported their outcomes of 229 patients and found that CTP was predictive of post-operative complications. In this series, only patient with cirrhosis were at risk for developing post-operative liver failure [ 18 ]. In a large European study, all patient resected were considered Class A but they noted a 32 % incidence of post-operative liver failure in patients with stage 4 fi brosis (cirrhosis) [ 19 ]. The extent of liver resection is obviously an important predictor of post- operative liver dysfunction and liver failure . Two studies were identifi ed which focused on major hepatic resection s and CTP classifi cation. Yang et al. specifi cally examined outcomes of patients with cirrhosis following major hepatic resection [ 20 ]. In this series, 270 patients had class A cirrhosis versus 35 with class B cirrhosis. Risk factors for preoperative morbidity were the presence of portal hypertension, Child class B, and platelet count <100 × 10 9 /l. However, independent risk factors for postoperative hepatic dysfunction were a prothrombin time >14 s and a platelet count <100 × 10 9 /l, not CTP score. In addition, four patients died of post-operative liver failure of which two were Class A cirrhotics. Similarly, Zhou et al. examined their experience after major hepatectomy in 81 patients of which 6 (7.4 %) had class B cirrhosis and only one patient suffered perioperative hepatic failure [ 21 ]. Based on the current available literature, Class C cirrhosis should be an absolute contraindication to resection . On the other hand, resection in Class A and B cirrhosis is not an absolute contraindication, but these patients should be selected carefully in order to minimize post-operative complications. In addition, the magnitude T.W. Reichman and H. Bohorquez 193 of resection required for cure should be carefully considered when selecting suitable patients for hepatic resection . Liver Resections and the Meld Score MELD has been applied to cirrhotic patients who underwent liver resection for hepatocellular carcinoma ( HCC ) for more than a decade. Marrero et al. in a subgroup of ten patients fi rst reported that MELD score correlates with post-operative survival in patients who underwent liver resection for HCC and found that a MELD score >10 was indicative of poor prognosis [ 22 ]. Similarly, Teh et al . retrospectively analyzed 82 cirrhotic patients who underwent liver resection for HCC [ 23 ]. A MELD score 9 was an independent predictor of perioperative mortality (0 % in patients with MELD score 8 vs. 29 % with MELD score 9). In another study with 154 liver resections, Cuchetti et al. demonstrated that MELD score not only predicts accurately postoperative liver failure , complications, and survival but that is also helpful stratifying the risk [ 24 ]. When the patients were analyzed in three groups according to their MELD score, <9, 9–10 and 11, postoperative liver failure occurred in 0, 3.6 and 37.5 % respectively. A MELD score cut-off of <9 for mortality- morbidity for liver resections in cirrhotic patients has been confi rmed by others [ 25 – 27 ]. AASLD and EASL guidelines recommend liver resection for HCC patients with solitary tumors and well-preserved liver function defi ned as normal bilirubin, platelets >100,000/mm 3 and hepatic pressure <10 mmHg [ 28 , 29 ]. Cuchetti reviewed this concept in 241 cirrhotic patients that underwent liver resections and were divided in two groups according to the presence or absence of portal hypertension [ 30 ]. The study showed lower survival in those patients with portal hypertension because of greater liver impairment; however, after propensity score matching of 78 patients, the overall survival was similar in patients with and without portal hypertension. In this subgroup of patients, the only predictors of postoperative liver failure were MELD score and the extent of hepatectomy . They concluded that when other prognostic variables were appropriately handled, the presence of portal hypertension had no impact on peri-operative outcomes and that the presence of portal hypertension alone should not be considered a contraindication for hepatic resection . MELD score has been reported to have low prognostic power in non-cirrhotic or well preserve hepatic function patients. Schroeder et al. in a review of 587 hepatectomies found no correlation between MELD score and post-operative outcomes [ 31 ]. However, the majority of the study population (91 %) had minimal or no evidence of liver disease (MELD score 5.7 ± 3.3). A similar smaller study of 46 patients (21 without cirrhosis vs. 25 with cirrhosis) with HCC who underwent liver resection demonstrated that MELD score failed to predict perioperative outcomes in the noncirrhotic patients [ 32 ]. By contrast, in the cirrhotic group, the model was able to predict poor outcomes when MELD was calculated preoperatively and on postoperative day 5 (MELD score >9 and >15, respectively). 16 Which Is the Better Predictor of Hepatic Reserve Prior to Liver Resection… 194 Extent of resection , a major limitation for hepatectomies especially in cirrhotic patients, also correlates with the MELD score. In a report by Cescon et al., 341 cirrhotic patients were retrospectively evaluated to determine the incidence and factors that affect irreversible post-operative liver failure (IPLF). In this study, MELD score and extent of hepatectomy were identifi ed as independent factors of IPLF [ 33 ]. For analysis, patients were stratifi ed according to their MELD score. In patients with MELD <9, IPLF occurred in one patient (0.4 %) with four segments resected; in MELD scores 9–10, IPLF occurred in 1.2 % of patients that underwent resection of less than one segment, in 5.1 % for 1 or 2 segments resected and in 11 % for 3 segments. In patients with a MELD score >10, IPLF occurred in >15 % of the patients regardless of the degree of resection. Interestingly, in the group with MELD scores 9–10, all IPLF cases occurred in patients with a sodium level <140 mEq/L; a level that seems to defi ne high/low risk groups for liver resection . The MELD -Sodium (MELD-Na) model, a revised MELD formula that incorporates serum sodium levels, is superior at predicting outcomes in liver transplant ation especially in those patients with lower MELD scores. Recently, a study successfully applied the MELD-Na score in predicting morbidity and mortality following elective colon cancer surgery irrespective of underlying liver disease [ 34 ]. Studies are needed to defi ne whether this parameter could be applied to patients who underwent liver resection . The MELD score has also been evaluated against other prognostic tests and scores to test their ability to determine the functional hepatic reserve in cirrhotic patients undergoing liver resection . In a study from the University of Toronto, the MELD score was compared against the use of ICG retention at 15 min (ICG15), a dynamic test for hepatic functional reserve [ 35 ]. In this study of 129 patients who underwent liver resection for HCC , ICG15 15 % and MELD score 14 were independent factors to predicts length of stay >10 days. However, MELD score failed to predict liver failure at post-operative day 3 while ICG15 did. Postoperative survival was not analyzed. Likewise, in a prospective study that included 40 patients, ICG15 and MELD score correlated with prognosis; however, ICG15 had a higher sensitivity and specifi city than the MELD score, 85 % and 90 % vs. 60 and 80 %, respectively [ 36 ]. Child-Turcotte-Pugh vs. MELD Score Although the CTP score is easy to use and evaluates major elements of liver function, it has several limitations. Two of the components of the score, ascites and encephalopathy, are subjective measurements; the score factors are weighted equally and use arbitrary cut-off. Therefore, CTP score calculation is not always reliable, and since patients within the same CTP class are not necessarily homogeneous, discrimination of the risk is limited. As a consequence, patients could erroneously be classifi ed and either be exposed unnecessarily to high risk procedures or excluded from benefi cial therapeutic interventions. T.W. Reichman and H. Bohorquez 195 By contrast, MELD score is objective, reproducible, weighs its components differently and does not depend on arbitrary cut-offs providing a very useful tool to predict outcomes in cirrhotic patients. In patients with cirrhosis who underwent liver resection , preoperative MELD score has been able to not only predict outcomes but also to stratify the risk. Moreover, in patients within the same CTP class or same level of portal hypertension, the MELD score was able to successfully discriminate the risk and identify appropriate candidates for liver resection. In addition, delta MELD, variations in MELD score at different points of the perioperative time, is also predictive of morbidity and mortality . MELD score, however, seems to be limited to cirrhotic patients and fails to predict outcomes in non-cirrhotic patients. In this population, a combination of the serum sodium level and/or MELD-Na seems to improve accuracy but further studies are required to validate this observation . There are several limitations to the studies that use CTP and MELD score to stratify patients for liver resection . First, there is a lack of prospective randomized control trials. Second, the majority the patients evaluated in different studies were cirrhotic patients with CTP class A (88–100 %), indicating a selection bias where liver resection is offered to patients with minimal liver disease. Third, minimal information is available comparing these scoring systems in non-cirrhotic patients. Table 16.2 compares major studies examining MELD vs. CTP. A Personal View of the Data The currently available literature has a large selection bias and lacks large amounts of patients with advanced cirrhosis . In our practice, MELD has been found to be the most predictive of hepatic reserve . However, we rarely use the MELD score in isolation to determine a patient’s candidacy for resection . Other factor not accounted for in MELD such as the presence of ascites , evidence of portal hypertension on imaging or endoscopic gastroduodenoscopy (EGD), and the platelet count (<100) are also used in determining the ability of patient to tolerate resection. Detailed volumetric analysis is performed to determine the residual liver volume and also to aid in planning the resection. If the residual volume appears to be marginal, portal vein embolization is performed to increase the remnant volume but also to test the regenerative capacity of the remaining liver. Biopsy of the remnant segment is also performed liberally to determine the degree of fi brosis/cirrhosis. For patients with HCC , if there is any question as to the hepatic reserve of the liver and the patient is within Milan or close to being within Milan, many of these patients are referred for transplant evaluation. 16 Which Is the Better Predictor of Hepatic Reserve Prior to Liver Resection… 196 Table 16.2 Studies which compare CTP to MELD Study Patients Patients with cirrhosis CTP A/B/C class (%) MELD score Extent of resection Mortality prognostic factor Quality of evidence Teh (2005) 82 100 % 97.5/2.5/0 8 = 37; 9 = 43 range (6–17) <3 seg = 72 % 3 seg = 28 % MELD score (9) Low Cuchetti (2006) 154 100 % 92.9/7.1 9 (range 6–15) Minor = 146 (94.8 %) MELD score (<9, 11) Low Major 8 (5.2 %) Schroeder (2006) 587 N/M 88.2/7.8/0.7 6.51 ± 4.5 range (6–38) 2 seg = 61.4 % CTP score (6.2 ± 1.9) MELD score = not signifi cant Low Total R/L = 31.7 Triseg = 6.5 % Cuchetti (2009) 241 100 % PH = 88.8/11.2/0 PH = 9.5 ± 1.8 1 segment = 81 % MELD score >10 Low noPH = 98/2/0 noPH = 8.4 ± 1.3 Extent of hepatectomy 2 seg = 14.1 % Major hepatectomy 4.9 % Cescon (2009) 466 100 % 94.2/5.8/0 8.9 ± 1.8 <1 Segment = 45 % CTP B MELD <9, 9–10,>10 Low >10 (17 %) 1-segmen = 29.6 % Na <140 mEq/L 2 seg = 2.4 Major hepatectomy 12.4 Extent of hepatectomy CTP Child-Turcotte-Pugh, MELD Model for End Stage Liver Disease, N/M not measured, N/S not specifi ed, PH portal hypertension, noPH no portal hypertension T.W. Reichman and H. Bohorquez 197 Recommendations • The MELD scoring system is the best at predicting preoperative liver dysfunction and liver failure with a MELD score of 9 acting as a cutoff (evidence quality low, weak recommendation) • Other factors such as extent of resection , presence of portal hypertension, absolute platelet count, and the serum sodium should also be taken into account when selecting patients with chronic liver disease for resection (evidence quality low, weak recommendation) References 1. Mittal S, El-Serag HB. Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol. 2013;47(Suppl):S2–6. 2. Smith JM, Biggins SW, Haselby DG, Kim WR, Wedd J, Lamb K, et al. Kidney, pancreas and liver allocation and distribution in the United States. Am J Transplant. 2012;12(12):3191–212. 3. Rahbari NN, Garden OJ, Padbury R, Brooke-Smith M, Crawford M, Adam R, et al. Posthepatectomy liver failure: a defi nition and grading by the International Study Group of Liver Surgery (ISGLS). Surgery. 2011;149(5):713–24. 4. Fukushima K, Fukumoto T, Kuramitsu K, Kido M, Takebe A, Tanaka M, et al. Assessment of ISGLS defi nition of posthepatectomy liver failure and its effect on outcome in patients with hepatocellular carcinoma. J Gastrointest Surg. 2014;18(4):729–36. 5. Garrison RN, Cryer HM, Howard DA, Polk Jr HC. Clarifi cation of risk factors for abdominal operations in patients with hepatic cirrhosis. Ann Surg. 1984;199(6):648–55. 6. Mansour A, Watson W, Shayani V, Pickleman J. Abdominal operations in patients with cirrhosis: still a major surgical challenge. Surgery. 1997;122(4):730–5; discussion 5–6. 7. Child C, Turcotte JG. Surgery and portal hypertension. In: Child C, editor. The liver and portal hypertension. Philadelphia: Saunders; 1964. p. 50–64. 8. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60(8):646–9. 9. Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PC. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology. 2000;31(4):864–71. 10. Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau TM, Kosberg CL, et al. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001;33(2):464–70. 11. Befeler AS, Palmer DE, Hoffman M, Longo W, Solomon H, Di Bisceglie AM. The safety of intra-abdominal surgery in patients with cirrhosis: model for end-stage liver disease score is superior to Child-Turcotte-Pugh classifi cation in predicting outcome. Arch Surg. 2005;140(7):650–4; discussion 5. 12. Nagasue N, Kohno H, Tachibana M, Yamanoi A, Ohmori H, El-Assal ON. Prognostic factors after hepatic resection for hepatocellular carcinoma associated with Child-Turcotte class B and C cirrhosis. Ann Surg. 1999;229(1):84–90. 13. Nakahara H, Itamoto T, Katayama K, Ohdan H, Hino H, Ochi M, et al. Indication of hepatectomy for cirrhotic patients with hepatocellular carcinoma classifi ed as Child-Pugh class B. World J Surg. 2005;29(6):734–8. 16 Which Is the Better Predictor of Hepatic Reserve Prior to Liver Resection… 198 14. Kuroda S, Tashiro H, Kobayashi T, Oshita A, Amano H, Ohdan H. Selection criteria for hepatectomy in patients with hepatocellular carcinoma classifi ed as Child-Pugh class B. World J Surg. 2011;35(4):834–41. 15. Fan ST, Lo CM, Liu CL, Lam CM, Yuen WK, Yeung C, et al. Hepatectomy for hepatocellular carcinoma: toward zero hospital deaths. Ann Surg. 1999;229(3):322–30. 16. Lau H, Man K, Fan ST, Yu WC, Lo CM, Wong J. Evaluation of preoperative hepatic function in patients with hepatocellular carcinoma undergoing hepatectomy. Br J Surg. 1997;84(9):1255–9. 17. Taketomi A, Kitagawa D, Itoh S, Harimoto N, Yamashita Y, Gion T, et al. Trends in morbidity and mortality after hepatic resection for hepatocellular carcinoma: an institute’s experience with 625 patients. J Am Coll Surg. 2007;204(4):580–7. 18. Nagasue N, Kohno H, Chang YC, Taniura H, Yamanoi A, Uchida M, et al. Liver resection for hepatocellular carcinoma. Results of 229 consecutive patients during 11 years. Ann Surg. 1993;217(4):375–84. 19. Farges O, Malassagne B, Flejou JF, Balzan S, Sauvanet A, Belghiti J. Risk of major liver resection in patients with underlying chronic liver disease: a reappraisal. Ann Surg. 1999;229(2):210–5. 20. Yang T, Zhang J, Lu JH, Yang GS, Wu MC, Yu WF. Risk factors infl uencing postoperative outcomes of major hepatic resection of hepatocellular carcinoma for patients with underlying liver diseases. World J Surg. 2011;35(9):2073–82. 21. Zhou L, Rui JA, Wang SB, Chen SG, Qu Q, Chi TY, et al. Outcomes and prognostic factors of cirrhotic patients with hepatocellular carcinoma after radical major hepatectomy. World J Surg. 2007;31(9):1782–7. 22. Marrero JA, Fontana RJ, Barrat A, Askari F, Conjeevaram HS, Su GL, et al. Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort. Hepatology. 2005;41(4):707–16. 23. Teh SH, Christein J, Donohue J, Que F, Kendrick M, Farnell M, et al. Hepatic resection of hepatocellular carcinoma in patients with cirrhosis: Model of End-Stage Liver Disease (MELD) score predicts perioperative mortality. J Gastrointest Surg. 2005;9(9):1207–15; discussion 15. 24. Cucchetti A, Ercolani G, Cescon M, Ravaioli M, Zanello M, Del Gaudio M, et al. Recovery from liver failure after hepatectomy for hepatocellular carcinoma in cirrhosis: meaning of the model for end-stage liver disease. J Am Coll Surg. 2006;203(5):670–6. 25. Delis SG, Bakoyiannis A, Biliatis I, Athanassiou K, Tassopoulos N, Dervenis C. Model for end-stage liver disease (MELD) score, as a prognostic factor for post-operative morbidity and mortality in cirrhotic patients, undergoing hepatectomy for hepatocellular carcinoma. HPB (Oxf). 2009;11(4):351–7. 26. Hsu KY, Chau GY, Lui WY, Tsay SH, King KL, Wu CW. Predicting morbidity and mortality after hepatic resection in patients with hepatocellular carcinoma: the role of Model for EndStage Liver Disease score. World J Surg. 2009;33(11):2412–9. 27. Rahbari NN, Reissfelder C, Koch M, Elbers H, Striebel F, Buchler MW, et al. The predictive value of postoperative clinical risk scores for outcome after hepatic resection: a validation analysis in 807 patients. Ann Surg Oncol. 2011;18(13):3640–9. 28. Bruix J, Sherman M, American Association for the Study of Liver D. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53(3):1020–2. 29. European Association For The Study Of The L, European Organisation For R, Treatment Of C. EASL-EORTC. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56(4):908–43. 30. Cucchetti A, Ercolani G, Vivarelli M, Cescon M, Ravaioli M, Ramacciato G, et al. Is portal hypertension a contraindication to hepatic resection? Ann Surg. 2009;250(6):922–8. 31. Schroeder RA, Marroquin CE, Bute BP, Khuri S, Henderson WG, Kuo PC. Predictive indices of morbidity and mortality after liver resection. Ann Surg. 2006;243(3):373–9. T.W. Reichman and H. Bohorquez 199 32. Teh SH, Sheppard BC, Schwartz J, Orloff SL. Model for End-stage Liver Disease score fails to predict perioperative outcome after hepatic resection for hepatocellular carcinoma in patients without cirrhosis. Am J Surg. 2008;195(5):697–701. 33. Cescon M, Cucchetti A, Grazi GL, Ferrero A, Vigano L, Ercolani G, et al. Indication of the extent of hepatectomy for hepatocellular carcinoma on cirrhosis by a simple algorithm based on preoperative variables. Arch Surg. 2009;144(1):57–63; discussion. 34. Causey MW, Nelson D, Johnson EK, Maykel J, Davis B, Rivadeneira DE, et al. The impact of Model for End-Stage Liver Disease-Na in predicting morbidity and mortality following elective colon cancer surgery irrespective of underlying liver disease. Am J Surg. 2014;207(4):520–6. 35. Greco E, Nanji S, Bromberg IL, Shah S, Wei AC, Moulton CA, et al. Predictors of periopertative morbidity and liver dysfunction after hepatic resection in patients with chronic liver disease. HPB (OXf). 2011;13(8):559–65. 36. Gupta S, Chawla Y, Kaur J, Saxena R, Duseja A, Dhiman RK, et al. Indocyanine green clearance test (using spectrophotometry) and its correlation with model for end stage liver disease (MELD) score in Indian patients with cirrhosis of liver. Trop Gastroenterol. 2012;33(2):129–34. 16 Which Is the Better Predictor of Hepatic Reserve Prior to Liver Resection… © Springer International Publishing Switzerland 2016 201 J.M. Millis, J.B. Matthews (eds.), Diffi cult Decisions in Hepatobiliary and Pancreatic Surgery, Diffi cult Decisions in Surgery: An Evidence-Based Approach, DOI 10.1007/978-3-319-27365-5_17 Chapter 17 Early (<24 h) or Delayed Cholecystectomy for Acute Cholecystitis? Stephan G. Wyers Abstract The optimal timing for operation for acute calculous cholecysitis remains controversial. Two courses of surgical management have traditionally been pursued: (1) early laparoscopic cholecystectomy (within the fi rst 72 h of onset of symptoms) or (2) initial conservative management with administration of intravenous antibiotics until infl ammation resolves followed by delayed laparoscopic cholecystectomy (generally greater than 6 weeks after presentation). There is a growing body of evidence from both retrospective reviews of large clinical databases and prospective randomized controlled trials to recommend early laparoscopic cholecystectomy (ELC) over delayed laparoscopic cholecystectomy (DLC). Keywords Acute cholecystitis • Laparoscopic cholecystectomy • Management • Timing The question of optimal timing of any operation necessarily involves an understanding of the natural history of the disease and reference time points in its clinical course. Acute calculous cholecystitis begins with cystic duct obstruction by a gallstone. Persistence of the obstruction leads to distension of the gallbladder, edema in the gallbladder wall, infl ammation in the gallbladder wall and adjacent tissues. After 72 h the infl amed tissue becomes thickened, more vascular and adherent to surrounding structures making dissection in the hepatocystic triangle more diffi cult. Delaying cholecystectomy for a period of 6 weeks or longer results in the formation of fi brotic adhesions in the hepatocystic triangle distorting the anatomy and complicating dissection. The question of timing of operation also requires agreement about a specifi c clinical event that defi nes the start of the disease process. Various studies use different clinical events, such as the onset of symptoms reported by the patient S. G. Wyers (*) Section of General Surgery , University of Chicago Medicine , MC5031, 5841 S. Maryland Avenue , Chicago , IL 60637 , USA e-mail: [email protected] 202 or admission to the hospital, as surrogate starting points for comparison. This variability complicates comparison of the available studies and limits the ability to make recommendations for optimal timing of laparoscopic cholecystectomy . The rationale for delayed surgery is based on the observation that acute infl ammation may lead to increased risk of surgical complications. This rationale was reinforced in the early years after laparoscopic cholecystectomy was developed. While the benefi ts of laparoscopic cholecystectomy (decreased hospital stay, decreased overall morbidity , earlier return to full activity etc.) were obvious in comparison to open surgery [ 1 ], surgery in the setting of acute infl ammation led to higher rates of conversion to open operation [ 2 ] and rates of common bile duct injury greater than those in the era of open cholecystectomy for acute cholecystitis [ 3 ]. In the early years of laparoscopic cholecystectomy, acute cholecystitis was considered a relative contraindication [ 4 ]. While later prospective trials showed early laparoscopic cholecystectomy to be as safe as open cholecystectomy for acute cholecystitis [ 5 ], most surgeons continued to opt for initial conservative treatment and delayed laparoscopic cholecystectomy. As late as 2004 surveys of practice patterns in Britain and the United States showed that only 20–30 % of patients with acute cholecystitis were operated on in the early phase [ 6 , 7 ]. While the rate of bile duct injury has decreased with time, it has not fallen to the rates reported in the open era [ 8 ]. Common bile duct injury remains the most signifi cant surgical complication of laparoscopic cholecystectomy. Retrospective Studies The rationale for early laparoscopic cholecystectomy for acute cholecystitis is supported by a growing amount of evidence from retrospective studies. First, early surgery avoids the risks to the patient of gallstone related complications that the wait for a delayed operation assumes. Cheruvu and Eyre-Brook showed that 18.5 % of patients with acute cholecystitis required readmission to the hospital in the fi rst 6 weeks after their initial presentation [ 9 ]. These risks only grow with the longer operation is postponed. A recent Canadian study [ 10 ] followed a cohort of over 10,000 patients who did not undergo cholecystectomy on their fi rst admission for acute cholecystitis. The probability of a gallstone related complication at 6 weeks, 12 weeks, and 1 year after discharge was 14 %, 19 %, and 29 % respectively. Of these 30 % were for biliary tract obstruction or pancreatitis. Second, retrospective studies from large databases have indicated that early laparoscopic cholecystectomy is as safe and effective as delayed surgery. In a retrospective cohort study of over 14,000 patients [ 11 ] early cholecystectomy was associated with a lower risk of common bile duct injury and of common bile duct injury or death than delayed cholecystectomy . The rate of conversion from laparoscopic to open operation was no different in the early group (11 %) and in the delayed group (10 %). Furthermore, hospital stay was 2 days shorter for the early surgery group. Third, retrospective studies suggest that the sooner laparoscopic cholecystectomy is performed during S.G. Wyers 203 the initial hospitalization the more favorable the outcomes . In a recent retrospective analysis from Switzerland of 4,113 patients [ 12 ] immediate surgery was found to have statistically signifi cant advantages in conversion and reoperation rates, postoperative complications, and length of hospital stay compared to delayed cholecystectomy 1–6 days after hospital admission. Brooks et al. reviewed the course of 5,268 patients in the American College of Surgeons National Surgical Quality Improvement Program database [ 13 ]. Patients who underwent operation later in the course of admission (>24 h) had greater risk of open operation and longer postoperative and overall lengths of hospitalization. Prospective Studies A search of the Medline database from 1987 to the present as well as a review of the recent literature produces eight prospective randomized controlled clinical trial s which compare early laparoscopic cholecystectomy (ELC) to delayed laparoscopic cholecystectomy (DLC) in the setting of calculous acute cholecystitis [ 14 – 21 ]. All of prospective surgical trials reviewed here suffer from the inability to blind participants and investigators (Table 17.1 ). The ACDC (Acute Cholecystitis-early laparoscopic surgery versus antibiotic therapy and Delayed elective Cholecystectomy) trial by Gutt et al. [ 14 ] is larger than the remaining studies combined. It specifi cally addresses the question of immediate (<24 h) laparoscopic cholecystectomy vs. delayed (>7 days) laparoscopic cholecystectomy . The variable criteria used by the studies to defi ne the timing of early and delayed cholecystectomy are given in Table 17.2 . Not all of the studies measured the same primary and secondary outcomes . All studies (except Macafee [ 15 ]) reported quantitative outcome data for mortality , morbidity , conversion to open operation and hospital stay. Bile duct injury was Table 17.1 Characteristics of prospective randomized controlled trials comparing Early Laparoscopic Cholecystectomy (ELC) to Delayed Laparoscopic Cholecystectomy (DLC) Authors (Ref.) Year Single or multicenter Number patients total (ELC:DLC) Average age (years) Female (%) Gutt et al. [ 14 ] 2013 Multicenter 618 (304:314) 56.2 58.7 Macafee et al. [ 15 ] a 2009 Single 72 (36:36) 52.5 65.2 Yadav et al. [ 16 ] 2009 Single 50 (25:25) 41 76 Kolla et al. [ 17 ] 2004 Single 40 (20:20) 40 80 Johannson et al.[ 18 ] 2003 Single 145 (74:71) 57 60 Davila et al. [ 19 ] 1999 Single 63 (27:36) 56 71.4 Lai et al. [ 20 ] 1998 Single 104 (53:51) 56 63.5 Lo et al. [ 21 ] 1998 Single 86 (45:41) 60 43.3 a The study by Macafee et al. does not furnish outcomes of interest for this review 17 Early (<24 h) or Delayed Cholecystectomy for Acute Cholecystitis? 204 included in the morbidity for all studies and as a primary outcome in one. Most studies reported outcomes for operative time. Only one [ 14 ] examined hospital cost (Table 17.3 ). Mortality The only deaths reported in the seven trials were in the largest trial [ 14 ]. There was one death in both the ELC (.3 %) and DLC (.3 %) groups. There were no deaths reported in the smaller trials. Common Bile Duct Injury In total in the seven trials above, there were three common bile duct injuries. One was in the ELC group (1/523, .2 %) and two were in the DLC groups (2/533, .4 %). In a recent meta-analysis of these seven trials [ 22 ] these small rates did not achieve statistical signifi cance. Other Morbidity The ACDC trial [ 14 ] showed signifi cantly lower morbidity scores at 75 days and fewer adverse events in the ELC group compared to the DLC group. When combined with the other studies in a meta-analysis there was a trend, albeit not statistically signifi cant, toward decreased morbidity favoring the ELC group [ 22 ]. Conversion to Open Operation The ACDC trial [ 14 ] showed no signifi cant difference between the two groups with respect to conversion to open operation (ELC 30/304, 9.9 %: DLC 33/314, 11.9 % p = .44). A Cochrane meta-analysis of Table 17.2 Timing of Early Laparoscopic Cholecystectomy (ELC) and Timing of Delayed Laparoscopic Cholecystectomy (DLC) Study Year Timing of ELC Timing of DLC Gutt 2013 <24 h from admission 7–45 days Macafee 2009 <4 days from admission 3 months Yadav 2009 <4 days 6–8 weeks Kolla 2004 <4 days 6–12 weeks Johannson 2003 <7 days 6–8 weeks Davila 1999 <4 days 8 weeks Lai 1998 <7 days 6–8 weeks Lo 1998 <7 days 13 weeks Table 17.3 Outcomes measured in the prospective randomized trials of ELC vs. DLC Study Mortality Morbidity CBD injury Conversion to open Operative time Failure of conservative therapy Hospital stay Hospital costs Gutt x x x x x x x Yadav x x x x x Kolla x x x x x Johannson x x x x x Davila x x x x Lai x x x x x Lo x x x x x S.G. Wyers 205 fi ve of the six smaller trials also showed no signifi cant difference in conversion rates between ELC and DLC [ 23 ]. Operation Time There was considerable heterogeneity in the six smaller trials. A meta-analysis of the six smaller studies showed a trend toward longer operating times in the ELC group [ 23 ]. This trend was not statistically signifi cant. Failure of Conservative Therapy (DLC) In the ACDC trial [ 14 ] change of antibiotics was necessary in 31 of 314 (9.9 %) patients; and, of these 31 patients premature surgery was necessary in 17 (54.8 %). Hospital Length of Stay All seven of the trials showed signifi cant reduction in total length of stay in the hospital. In the ACDC trial [ 14 ] the mean length of stay was 4.6 days less in the ELC group. This was a 50 % reduction in hospital stay. Hospital Cost In the ACDC trial [ 14 ] the reduced hospital stay for the ELC group (<24 h) translated directly into reduced cost (approximately 3000€/case). This was the only prospective trial to evaluate cost. Return to Work and Normal Activity Only one trial examined return to work and normal activity. The study by Lo et al. [ 21 ] showed that patients in the ELC group had shorter average total recuperation periods (7 days) and shorter average periods of time off work (11 days). Summary and Recommendations Early (<24 h) laparoscopic cholecystectomy has signifi cant medical and socioeconomic benefi ts and is the recommended approach for low risk patients with acute cholecystitis . Recommendation Grade 1C. Both ELC and DLC have very low rates of mortality and common bile duct injury and, as a result, the prospective studies cited here are insuffi ciently powered to show superiority with regard to these outcomes . Given these low rates it has been estimated that prospective studies would require thousands to tens of thousands of patients in each arm in order to show signifi cant differences in bile duct injury and mortality. The overall morbidity of ELC compared to DLC is not greater and in the ACDC trial is shown to be signifi cantly less than DLC. The prospective studies demonstrate that ELC dramatically reduces the length of hospital stay and total hospital cost . For a disease as common as acute cholecystitis ELC offers signifi cant reduction in direct hospital costs and improvement in hospital effi ciency. Though only one trial demonstrated earlier return to work and normal activity with ELC, it stands to reason that the patients who avoid DLC have a shorter time to resolution of their illness overall given that morbidity does not increase with ELC. Further prospective studies may improve the strength of this recommendation. 17 Early (<24 h) or Delayed Cholecystectomy for Acute Cholecystitis? 206 A Personal View of the Data It has been my practice to operate within 24 h on all patients with acute cholecystitis whose symptoms are of less than 72 h duration and who are candidates for general anesthesia. A more diffi cult decision is the management of patients whose symptoms have been present for more than 3–4 days prior to admission. (Most of the prospective studies cited above used symptoms of greater than 7 days duration prior to admission as an exclusion criterion.) For this group of patients a more nuanced approach is in order. The presence of other known high risk factors (male sex, a palpable infl ammatory mass on physical exam, extensive upper abdominal surgery , morbid obesity or fi ndings on imaging) would warrant a conservative approach in my view. The Tokyo Guidelines for the surgical management of acute cholecystitis is based on a clinical grading scale of the severity of the acute cholecystitis and endorses this nuanced approach in this group with Grade II (moderate) acute cholecystitis [ 24 ]. The studies reviewed above argue strongly that a policy of early laparoscopic cholecystectomy should be adopted more broadly in acute cholecystitis . This should be undertaken with renewed dedication to what Strasberg has called a “culture of safety” [ 25 ]. Whether operating for biliary colic or acute cholecystitis, I dissect the hepatocystic triangle to “the critical view of safety” which has been well defi ned in the literature [ 26 ]. If infl ammation prohibits dissection to the “critical view of safety”, cholangiography under fl uoroscopy is my next step. If this fails to clarify the anatomy or reveals an injury I convert to open operation. Conversion to open operation should never be viewed as a complication but rather a triumph of good judgment over technical ability. Given the marked improvement in laparoscopic cameras, angled lenses, and monitors in the past 25 years, visualization does not necessarily improve with conversion – except in one very important respect; there is improved ability to appreciate three dimensional anatomic relationships. Way reviewed common bile duct injuries by experienced surgeons and attributed them to cognitive visual spatial errors [ 27 ]. Most bile duct injuries are not recognized in the operating room; therefore, most are due to misidentifi cation. In a diffi cult laparoscopic or open case I don’t hesitate to get a “second set of eyes” from an experienced colleague if one is available. Conversion to open operation allows direct palpation to assist the dissection in densely infl amed tissue. After conversion I will use these advantages to dissect to a critical view of safety. Only if this is unsuccessful do I use “top down” or “fundus fi rst” approach. This also entails risk since the normal plane between the liver and gallbladder is frequently obliterated by the infl ammation. Getting into the hepatic parenchyma from this approach can produce signifi cant hemorrhage. This is the setup for coupling a bile duct injury with a vascular injury. Much better options to avoid this most severe combination of injures would be placement of an open cholecystostomy tube or partial cholecystectomy with extraction of stones and placement of a drain. Other than the high risk situations described above, I reserve delayed laparoscopic cholecystectomy for patients whose comorbidities place them at high risk for S.G. Wyers 207 general anesthesia (e.g. ASA class 4 or 5) or whose symptoms are of greater than 7 days duration. In addition to intravenous antibiotics percutaneous cholecystomy tubes may be used in this group of patients. While there are still clinical situations which warrant delayed laparoscopic cholecystectomy , in my experience, this often results in the performance of a diffi cult operation 6 weeks later in a patient who is better prepared for the operating room. References 1. The Southern Surgeons Club. A prospective analysis of 1518 laparoscopic cholecystectomies. The Southern Surgeons Club. N Engl J Med. 1991;324(16):1073–8. 2. Cheema S, Brannigan AE, Johnson S, Delaney PV, Grace PA. Timing of laparoscopic cholecystectomy in acute cholecystitis. Ir J Med Sci. 2003;172(3):128–31. 3. Richardson MC, Bell G, Fullarton GM. Incidence and nature of bile duct injuries following laparoscopic cholecystectomy an audit of 5913 cases. West of Scotland Laparoscopic Cholecystectomy Audit Group. Br J Surg. 1996;83(10):1356–60. 4. Wilson P, Leese T, Morgan WP, Kelly JF, Brigg JK. Elective laparoscopic cholecystectomy for “all comers”. Lancet. 1991;338(8770):795–7. 5. Kiviluoto J, Siren P, Luukkonen P, Kivilaakso E. Randomised trial of laparoscopic versus open cholecystectomy for acute and gangrenous cholecystitis. Lancet. 1998;351(9099):321–5. 6. Livingston EH, Rege RV. A nationwide study of conversion from laparoscopic to open cholecystectomy. Am J Surg. 2004;188(3):205–11. 7. Senapati PS, Bhattarcharya D, Harinath G, Ammori BJ. A survey of the timing and approach to the surgical management of cholelithiasis in patients with acute biliary pancreatitis and acute cholecystitis in the UK. Ann R Coll Surg Engl. 2003;85(3):306–12. 8. Dolan JP, Diggs BS, Sheppard BC, Hunter JG. Ten-year trend in the national volume of bile duct injuries requiring operative repair. Surg Endosc. 2005;19(7):967–73. 9. Cheruvu CV, Eyre-Brooke IA. Consequences of a prolonged wait before gallbladder surgery. Ann R Coll Surg Engl. 2002;84(1):20–2. 10. deMestral C, Rotstein OD, Laupacis A, Hoch JS, Zagorski B, Nathens AB. A population- based analysis of the clinical course of 10,304 patients with acute cholecystitis, discharged without cholecystectomy. J Trauma Acute Care Surg. 2013;74(1):26–30; discussion 30–1. 11. deMestral C, Rotstein OD, Laupacis A, Hoch JS, Zagorski B, Alali AS, Nathens AB. Comparative outcomes of early and delayed cholecystectomy for acute cholecystitis: a population-based propensity score analysis. Ann Surg. 2014;259(1):10–5. 12. Banz V, Gsponer T, Candinas D, Guller U. Population based analysis of 4113 patients with acute cholecystitis: defi ning the optimal time point for laparoscopic cholecystectomy. Ann Surg. 2011;254(6):964–70. 13. Brooks KR, Scarborough JE, Vaslef SN, Shapiro ML. No need to wait: an analysis of the timing of cholecystectomy during admission for acute cholecystitis using the American College of Surgeons National Quality Improvement Program database. J Trauma Acute Care Surg. 2013;74(1):167–73. 14. Gutt CN, Enke J, Koninger J, Harnoss JC, Weigand K, Kipfmuller, Schunter O, Gotze T, Golling MT, Menges M, Klar E, Feilhauer K, Zoller WG, Ridwelski K, Ackmann S, Baron A, Schon MR, Seitz HK, Daniel D, Stremmel W, Buchler MW. Acute Cholecystitis: early versus delayed cholecystectomy, a multicenter randomized trial (ACDC study NCT00447304). Ann Surg. 2013;258(3):385–93. 15. Macafee DA, Humes DJ, Bouliotis G, Beckingham IJ, Whynes DK, Lobo DN. Prospective randomized trial using cost-utility analysis of early versus delayed laproscopic cholecystectomy for acute gallbladder disease. Br J Surg. 2009;96(9):1031–40. 17 Early (<24 h) or Delayed Cholecystectomy for Acute Cholecystitis? 208 16. Yadav RP, Adhikary S, Agrawal CS, Bhattarai B, Gupta RK, Ghimire A. A comparative study of early vs. delayed laparoscopic cholecystectomy in acute cholecystitis. Kathmandu Univ Med J (KUMJ). 2009;7(25):16–20. 17. Kolla SB, Aggarwal S, Kumar A, Kumar R, Chumber S, Parshad R, et al. Early v. delayed laparoscopic cholecystectomy for acute cholecystitis. Surg Endosc. 2004;18:1323–7. 18. Johannson M, Thune A, Blomquist LN, Lundell L. Management of acute cholecystitis in the laparoscopic era: results of a prospective, randomized clinical trial. J Gastrointest Surg. 2003;7(5):642–5. 19. Davila D, Manares C, Picho ML, Albors P, Cardenas E, Fuster E, et al. Experience in treatment (early vs. delayed) of acute cholecystitis via laparoscopy. Cir Esp. 1999;66 Suppl 1:233. 20. Lai PBS, Kwong KH, Leung KL. Randomized trial of early versus delayed laparoscopic cholecystectomy for acute cholecystitis. Br J Surg. 1998;85(6):764–7. 21. Lo C, Liu C, Fan S, Lai ECS, Wong J. Prospective randomized trial of early versus delayed laparoscopic cholecystectomy for acute cholecystitis. Ann Surg. 1998;227(4):461–7. 22. Zhou MW, Gu XD, Xiang JB, Chen ZY. Comparison of clinical safety and outcomes of early versus delayed laparoscopic cholecystectomy for acute cholecystitis: a meta-analysis. Sci World J. 2014:274516. 23. Gurusamy KS, Davidson C, Gluud C, Davidson BR. Early versus delayed laparoscopic cholecystectomy for people with acute cholecystitis. Cochrane Database Syst Rev. 2013;6, CD005440. 24. Yamashita Y, Takada T, Strasberg SM, Pitt HA, Gouma DJ, Buchler MW, Gomi H, Dervenis C, Windsor JA, Kim SW, deSantibanes E, Padbury R, Chen XP, Chan AC, Fan ST, Jagannath P, Mayumi T, Yoshida M, Miura F, Tsuyuguchi T, Itoi T, Supe AN, Tokyo Guidelines Revision Committee. J Hepatobiliary Pancreatol Sci. 2013;20(1):89–96. 25. Strasberg SM. Biliary injury in laparoscopic surgery: part 2. Changing the culture of cholecystectomy. J Am Coll Surg. 2005;201(4):604–11. 26. Strasberg SM, Brunt LM. Rationale and use of the critical view of safety in laparoscopic cholecystectomy. J Am Coll Surg. 2010;211(1):132–8. 27. Way LW, Stewart L, Gantert W, Liu K, Lee CM, Whang K, Hunter JG. Causes and prevention of laparoscopic bile duct injuries: analysis of 252 cases from a human factors and cognitive psychology perspective. Ann Surg. 2003;237(4):460–9.
Information about diseases