Perioperative Management of Hepatic Resection Toward Zero Mortality and Morbidity: Analysis of 793 Consecutive Cases in a Single Institution

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1 ORIGINAL SCIENTIFIC ARTICLES Perioperative Management of Hepatic Resection Toward Zero Mortality and Morbidity: Analysis of 793 Consecutive Cases in a Single Institution Toshiya Kamiyama, MD, Kazuaki Nakanishi, MD, Hideki Yokoo, MD, Hirofumi Kamachi, MD, Munenori Tahara, MD, Kenichiro Yamashita, MD, Masahiko Taniguchi, MD, Tsuyoshi Shimamura, MD, Michiaki Matsushita, MD, Satoru Todo, MD, FACS BACKGROUND: STUDY DESIGN: RESULTS: CONCLUSIONS: The mortality rates associated with hepatectomy are still not zero. Our aim was to define the risk factors for complications and to evaluate our perioperative management. Between 2001 and 2008, 793 consecutive patients (547 men and 246 women; mean age SD, years) underwent hepatectomy without gastrointestinal resection and choledocojejunostomy at our center. Of these patients, 354 (44.6%) were positive for the hepatitis B virus surface antigen and/or the hepatitis C virus antibody. We categorized 783 (98.7%) patients as Child-Pugh class A. Major resection (sectionectomy, hemihepatectomy, and extended hemihepatectomy), was performed in 535 patients (67.5%) and re-resection in 81 patients (10.2%). The median operative time was minutes and median blood loss was 360 ml. The rate of red blood cell transfusion was 6.8%. The morbidity rate was 15.6%. Reoperations were performed in 19 patients (2.4%). The mean postoperative hospital stay was days. The in-hospital mortality rate was 0.1% (1 of 793 patients; caused by hepatic failure). The independent relative risk for morbidity was influenced by an operative time of more than 360 minutes, blood loss of more than 400 ml, and serum albumin levels of less than 3.5 g/dl, as determined using multivariate logistic regression analysis. Shorter operative times and reduced blood loss were obtained by improving the surgical technique and using new surgical devices and intraoperative management, including anesthesia. Additionally, decision making using our algorithm and perioperative management according to CDC guidelines reduced the morbidity and mortality associated with hepatectomy. (J Am Coll Surg 2010;211: by the American College of Surgeons) Liver resection is indicated for hepatocellular carcinoma (HCC), metastatic liver tumor, biliary malignancy, living donor liver transplantation, and other liver tumors. Liver resection for HCC has the highest local controllability of all local treatments and promotes a good survival rate. 1,2 Because approximately 90% of patients with HCC have been infected with the hepatitis B and/or hepatitis C viruses, and therefore have chronic hepatitis or cirrhosis, 3 the functional reserve of the liver decreases in almost all patients with Disclosure information: Nothing to disclose. Received March 3, 2010; Revised June 3, 2010; Accepted June 3, From the Departments of General Surgery (Kamiyama, Yokoo, Kamachi, Tahara, Yamashita, Shimamura, Todo) and Organ Transplantation and Regenerative Medicine (Nakanishi, Taniguchi), Hokkaido University Graduate School of Medicine; and the Department of Health Sciences, School of Medicine, Hokkaido University (Matsushita), Sapporo, Japan. Correspondence address: Toshiya Kamiyama, MD, Department of General Surgery, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo Japan. t-kamiya@med.hokudai.ac.jp HCC. Cirrhotic patients have elevated portal venous pressures, decreased reticuloendothelial system function, and impaired regeneration and coagulopathy. 4 Therefore, liver resection in cirrhotic patients is associated with high mortality rates (8.9% to 19.6%). 5 Conversely, recent advances in surgical techniques and pre- and postoperative care, including the decision criteria for hepatectomy 6,7 and indications for liver resection, have been applied to extended hepatectomy for hilar bile duct carcinoma, 8 living donor liver transplantation, 9 and colorectal metastasis. 10 The morbidity and mortality rates of these operations are decreasing, but are still not zero. 11,12 In cirrhotic patients with decreased reticuloendothelial system function, infections associated with the operation occur easily and increase the probability of liver failure; 13 therefore, infection control is very important for hepatectomy. The guidelines for the prevention of surgical site infection from the CDC 14 are useful for prevention of infections associated with operations. We have given pre- and 2010 by the American College of Surgeons ISSN /10/$36.00 Published by Elsevier Inc. 443 doi: /j.jamcollsurg

2 444 Kamiyama et al Perioperative Management of Hepatectomy J Am Coll Surg Abbreviations and Acronyms CUSA Cavitron ultrasonic surgical aspirator HCC hepatocellular carcinoma 99m Tc-GSA technetium 99m diethylenetriaminepentaacetic acid galactosyl human serum albumin HH 15 uptake ratio of heart at 15 minutes to that at 3 minutes ICGR15 indocyanine green retention rate at 15 minutes LHL15 uptake ratio of liver to liver plus heart at 15 minutes PTPE percutaneous transhepatic portal embolization postoperative care according to the guidelines of the CDC for the past 8 years. To further improve the outcomes of liver resection, it is important to identify and prevent the causes of complications. In this study, we reviewed the postoperative courses of patients undergoing liver resection in our hospital, and we sought to define the risk factors for complications and to evaluate our perioperative management. METHODS Patients Between 2001 and 2008, 793 consecutive patients (547 men and 246 women; mean age [ SD], years) underwent hepatectomy without gastrointestinal resection and choledocojejunostomy at our center. Indications for resection are shown in Table 1. Three hundred fifty-four (44.6%) patients were positive for the hepatitis B virus surface antigen and/or hepatitis C virus antibody. Among the 793 patients, 783 (98.7%) were categorized as Child- Pugh class A. Major resection, which included sectionectomy, hemihepatectomy and extended hemihepatectomy, was performed in 535 (67.5%) patients (Table 2) and reresection was done in 81 (10.2%) patients. Left hemihepatectomy, left lateral sectionectomy, and limited resection were laparoscopically performed in 5 patients, 11 patients, and 5 patients, respectively. Evaluated factors The indocyanine green retention rate at 15 minutes (ICGR15) was measured to evaluate the liver functional reserve, regardless of the presence or absence of cirrhosis. Moreover, hepatic receptor imaging with technetium 99m diethylenetriaminepentaacetic acid galactosyl human serum albumin ( 99m Tc-GSA) facilitates the numerical evaluation of the hepatic functional reserve by means of the receptor index (uptake ratio of the liver to the liver plus Table 1. Indications for Hepatectomy and the Surgical Procedures Indication/diagnosis Patients, n % Primary liver tumor Hepatocellular carcinoma Cholangiocellular carcinoma Mixed type Cystic disease Other malignant tumor Metastatic liver tumor Donor for LDLT Benign tumor Hemangioma Other benign tumor Echinococcosis Surgical procedure Limited resection Segmentectomy Sectionactomy Hemihepatectomy or more LDLT, living donor liver transplantation. heart at 15 minutes [LHL15]) and the index of blood clearance (uptake ratio of the heart at 15 minutes to that at 3 minutes [HH15]). LHL15 and HH15 are simplified and universal methods used in 99m Tc-GSA scintigraphy analysis. The correlation of LHL15 and HH15 to ICGR15 using a linear regression model is an easy and convenient method for predicting hepatic functional reserve when using 99m Tc-GSA scintigraphy. The converted ICGR15, as calculated from LHL15 and HH15, categorized by liver damage severity, also complements the weak points of the actual measured ICGR15 and is, therefore, useful to evaluate the hepatic functional reserve. 15 The converted ICGR15 and ICGR15 were used to determine the operative procedure. An algorithm (Hokkaido University Algorithm), incorporating the ICGR15 and remnant liver volume, was used to determine the operative procedure (Fig. 1). Anatomic resection was defined as a resection in which the lesion(s) are completely anatomically removed on the basis of Couinaud s classification, including segmentectomy, sectionectomy, hemihepatectomy, and extended hemihepatectomy, in patients with tolerable functional reserves. Nonanatomic partial resection was defined as a limited resection. Not all patients who undergo hepatic resection have uncontrollable ascites. If the ICGR15 is less than 15% and the resected liver volume is less than 60%, hemihepatectomy or extended hemihepatectomy can be tolerated. However, if the ICGR15 is less than 15% and the resected liver volume is greater than 60%, then percutaneous transhepatic portal embolization (PTPE) is performed before surgery to induce compensatory hypertrophy of the liver

3 Vol. 211, No. 4, October 2010 Kamiyama et al Perioperative Management of Hepatectomy 445 Table 2. Clinical Characteristics of the Patients Clinical characteristic n Gender, male : female 547 : 246 Age (y), 65 : : 250 Operation time (min), 360 : : 359 Blood loss (ml), 400 : : 373 Albumin (g/dl), 3.5 : : 753 Total bilirubin (mg/dl), 0.7: : 335 ICGR15 (%), 15 : : 220 HBV( )HCV( ) : HBV( )HCV( ), HBV( ) HCV( ), HBV( )HCV( ) 439 : 354 Minor resection : major resection 258 : 535 Child-Pugh class A:B 783:10 Re-resection, no : yes 712 : 81 HBV, hepatitis B virus surface antigen; HCV, hepatitis C virus antibody; ICGR 15, indocyanine green retention rate at 15 minutes. remnant after hepatectomy. Between 2001 and 2008, PTPE was performed on 28 patients. For patients with an ICGR15 of 15% to 20%, sectionectomy can be performed; for patients with an ICGR15 of 20% to 25%, segmentectomy can be performed; and for patients with an ICGR15 of 25% to 40%, a limited resection can be performed. If the ICGR15 is more than 40%, hepatectomy is contraindicated. Three-dimensional CT and volumetry To understand the correlation between vessels and the tumor, and for preoperative simulations, we reconstructed 3-dimensional images using multidetector row-ct (MD-CT; Toshiba Aquilion Multi-Slice CT; Toshiba Medical Systems Co Ltd). All datasets acquired using helical scanning were reconstructed to isotropic voxel datasets. Reconstructed data were transferred to a 3-dimensional workstation (Virtual Place Advance; Medical Imaging Laboratory). 16 The volumes of the liver parenchyma and tumors were also measured using Virtual Place Advance and the effective resection of ratio (%) ([volume of liver to be resected tumor volume/total liver volume tumor volume] 100) 17 was calculated. Preoperative care Preparation of the patient was performed according to the 1999 CDC guidelines for prevention of surgical site infections. We administered 2 g cefazolin for antimicrobial prophylaxis no more than 30 minutes before the skin was incised. When the duration of an operation was expected to exceed the time in which therapeutic levels of cefazolin could be maintained, cefazolin was administered every 4 hours after the previous administration. After the operation, 2 g cefazolin was given twice daily for 3 days according to a previous report, 18 although the CDC guidelines recommended maintaining therapeutic levels of the antimicrobial agent in both serum and tissues throughout the operation and until, at most, a few hours after the incision is closed in the operating room. 14 Hepatectomy Transection of the liver parenchyma was performed using the hook spatula of an ultrasonic harmonic scalpel (Ethicon EndoSurgery) and a Salient DS3.0 Monopolar Sealer (DS3.0) (Salient Surgical Technologies) or bipolar cautery with a saline irrigation system. Vessels were carefully exposed with the hook spatula. Vessels less than 2 mm in diameter were coagulated with the DS3.0 or bipolar cautery and cut with the hook spatula. Vessels greater than 2 mm in diameter were ligated. Inflow occlusion was applied in an intermittent manner, with 15 minutes of occlusion alternated with 5 minutes of reperfusion. During transection of the liver parenchyma, the central venous pressure was maintained below 5 cm H 2 O to prevent venous hemorrhage. Intraoperative cholangiography was routinely performed to map the bile duct before resection of the paren- Figure 1. Hokkaido University Algorithm for hepatic resection. This algorithm used the ICGR15 and remnant liver volume to determine the operative procedure. ICGR15, indocyanine green retention rate at 15 minutes; ERR, effective resection of ratio (%) ([volume of liver to be resected tumor volume/total liver volume tumor volume] 100); Hemi or Extended, hemihepatectomy or extended hemihepatectomy; PTPE, percutaneous transhepatic portal embolization.

4 446 Kamiyama et al Perioperative Management of Hepatectomy J Am Coll Surg Figure 2. Median operative time. The median operative time from 2001 to 2008 was minutes. chyma, to confirm the branch of the bile duct to be preserved, and to ensure there was no leakage of bile. Since 2005, if leakage of the contrast medium or an air bubble was observed, a C-tube, which was easily removable, was inserted in the cystic duct to decompress the bile duct. A closed suction drain (Davol ReliaVac) was used as an abdominal drainage tube. This drain was routinely removed 3 days after hepatectomy. However, when the discharge fluid was bloody and/or the bilirubin level of the discharge fluid was more than 5 mg/dl, the drainage tube was left in until the discharge fluid became serous. Postoperative incision care When a surgical incision was primarily closed, the incision was usually covered with a sterile dressing for 48 hours. After 48 hours, the incision was left uncovered. Statistics Logistic regression multivariate analysis was performed to determine the predictive value of the risk factors. Significance was defined as apvalue Statistical analyses were performed using StatView 5.0 for Windows (SAS Institute Inc). Figure 3. Median blood loss. The median blood loss from 2001 to 2008 was 360 ml. RESULTS The median operative time during 2001 to 2008 was minutes, and the median operative time of each year is shown in Figure 2. The median blood loss during 2001 to 2008 was 360 ml and the median operative blood loss during each year is shown in Figure 3. The rate of red blood cell transfusion was 6.8%. The morbidity rate was 15.6%, caused by the rising rates of pleural effusion (5.7%), ascites (2.9%), hemoperitoneum (2.2%), bile leakage and intraabdominal abscess (6.7%), and wound infection (2.4%) (Table 3). Pneumonia, urinary tract infection, cardiac complications, renal insufficiency and failure, deep vein thrombosis, and pulmonary embolism were not included in complications from our series. In total, 53 patients suffered from bile leakage and/or an abscess, and a reoperation was performed on 15 patients, change of drainage tube or echoguided puncture in 25 patients, and conservative therapy in 13 patients. Reoperations caused by postoperative bleeding and bile leakage occurred in 19 patients (2.4%). The mean postoperative hospital stay was days and the in-hospital mortality rate was 0.1% (1 of 793 patients; caused by hepatic failure). Results from multivariate logistic regression analysis evaluating the independent relative risk for morbidity are shown in Table 4. The independent relative risk for morbidity was influenced by an operative time of more than 360 minutes (p ), blood loss of more than 400 ml (p ), and serum albumin levels of less than 3.5 g/dl (p ). DISCUSSION The independent relative risk for morbidity was influenced by an operative time of more than 360 minutes, blood loss of more than 400 ml, and serum albumin levels of less than 3.5 g/dl, as determined using multivariate logistic regression analysis. Although hepatectomy is generally a complex operation, a shorter operative time and reduced blood loss were obtained by improving the surgical technique with new devices and intraoperative management, including anesthesia. In addition to these efforts, decision making using our algorithm and perioperative management according to the CDC guidelines also reduced the morbidity and mortality associated with hepatectomy. The outcomes of our series were equal or superior to the outcomes of a large series including more than 600 patients. 19 The length of postoperative hospital stay (18.4 days) was equal to that in another Japanese center. 18 Recently criteria, including include ICGR15, have become reliable to determine the indication for hepatectomy, 6,7 especially the criteria of Makuuchi, which are widely used in Japan

5 Vol. 211, No. 4, October 2010 Kamiyama et al Perioperative Management of Hepatectomy 447 Table 3. Postoperative Complications Patients Pleural effusion Ascites Bleeding Reoperation after bleeding Bile leakage/ abscess Reoperation after bile leakage/ abscess Wound infection Year n n % n % n % n % n % n % n % Total and determine the operative procedure. Conversely, although the Child-Pugh classification system has been applied worldwide to evaluate the functional reserve of the liver in patients with chronic liver disease, 20 the resectable volume is not determined by this system. Our algorithm, which was classified by ICGR15, had no limitations according to the bilirubin level and regulated the volume of liver to be resected, in contrast with Makuuchi s criteria. In Makuuchi s criteria, patients with a total bilirubin level greater than 1.1 mg/dl undergo a limited resection with enucleation. However, in our series, 78 (64.5%) of 121 patients with a total bilirubin level over 1.1 mg/dl underwent hepatectomy in which the resected liver volume was more than segmentectomy, and the rate of postoperative hepatic failure was only 0.1% (1 of 793). Therefore, our algorithm was supposed to be reasonable for selection of the appropriate operative procedures in patients with impaired liver functional reserves. Moreover, as indications for PTPE were incorporated into Table 4. Logistic Regression Multivariate Analysis of the Risk Factors for Postoperative Complications p Value Odds ratio Risk factor 95% CI Gender, male Age 65 y Operation time 360 min Blood loss 400 ml Albumin 3.5 g/dl Total bilirubin 0.7 mg/dl ICGR15 15% HBV( )HCV( ) Minor resection Child-Pugh class B Re-resection, yes HBV, hepatitis B virus surface antigen; HCV, hepatitis C virus antibody; ICGR15, indocyanine green retention rate at 15 minutes. our algorithm, it was considered more useful in determining the appropriate operative procedure. When the effective resection ratio was more than 60%, PTPE was indicated in patients whose ICGR15 was less than 15%. This indication for PTPE was the same as that described by Imamura and colleagues, 21 although they indicated PTPE for patients in whom the remaining liver volume ratio after hepatectomy was less than 40% using Makuuchi s criteria. 3D-CT achieved a higher spatial and temporal resolution of orthogonal images and produced multiplanar reformation of images. Because 3D-CT clearly revealed the position of the tumor and vessels, almost to a similar extent as observed in vivo, preoperative simulation of the surgical procedure was easier and more accurate. 3D-CT was useful to understand the correlation between vessels and tumor and for preoperative simulations, particularly in patients with large tumors or vascular anomalies. 22 Because the hepatic segment, sector, or lobe in which the tumor to be resected was located, and the hepatic artery and portal vein were well understood by the surgeons, hepatic parenchyma with no inflow was completely resected. We resected hepatic parenchyma using the hook spatula of a harmonic scalpel combined with bipolar cautery and a saline irrigation system or DS3.0. On the basis of our observations, the outer nonsharp radius of the hook spatula is particularly useful for dissecting the soft liver parenchyma because it offers slightly less cutting power than the inner sharp radius or Cavitron ultrasonic surgical aspirator (CUSA). Vessels that were firmer than the liver parenchyma could be easily exposed using the outer nonsharp radius when their diameter was greater than approximately 2 mm. In our opinion, this device is more suitable for liver dissection than CUSA or dissecting forceps, not only for experienced surgeons, but also for inexperienced surgeons. Conversely, bipolar cautery with a saline irrigation system combined

6 448 Kamiyama et al Perioperative Management of Hepatectomy J Am Coll Surg with CUSA 23 or the hook spatula of the harmonic scalpel 24 are useful for dissection of the hepatic parenchyma without inflow occlusion. Because the harmonic scalpel needs an extended period of time to achieve adequate hemostasis, we obtained certain and convenient coagulation using bipolar cautery with a saline irrigation system and DS3.0. DS3.0 uses radiofrequency energy that accumulates at the tip of the device and is transmitted to the liver tissue via the saline solution flowing from the tip at a low rate (1 drop/second) through a channel provided inside the device. Therefore, DS3.0 induces tissue coagulation to a wider area and readily coagulates vessels and Glisson s sheaths with a diameter of less than 2 mm. The combination of the hook spatula of the harmonic scalpel and bipolar cautery with a saline irrigation system or DS3.0 is useful to decrease operative blood loss and shorten the operative time. In this study, we examined the relationship between complications and clinical factors. Multivariate analysis revealed that a longer operative time and increased blood loss were significantly related to postoperative complications. The quantity of blood loss and blood transfusion adversely affect the outcomes of patients. 25,26 Massive blood loss and the associated blood transfusion correlate with morbidity after hepatic resection. 21 An immunosuppressive state is induced by transfusion of red blood cells in patients undergoing an operation, and this state can increase the risk of postoperative infections 27 and tumor recurrence. 28 In our series, the median blood loss from 2001 to 2008 was 360 ml and the transfusion rate was 6.8%, which was equal to data from a previous report. 21 This low amount of blood loss and rate of transfusion were achieved by using a harmonic scalpel and coagulating device (bipolar cautery or DS 3.0), low central venous pressure during the operation, 29 intermittent inflow occlusion, etc. Conversely, it is well established that the longer the wound is open the higher is the risk for surgical site infection. 30 It has been reported that hospitals in the outlier category for surgical site infection have a shorter mean duration of operation, significantly reduced incidence of other complications, and reduced mortality. 31 Although the Hokkaido University Hospital is a teaching hospital and hepatectomy is generally a complex operation, the operative time was gradually shortened by improving the surgical technique with new devices and intraoperative management, including anesthesia. As a result of these efforts, postoperative complications involving surgical site infection were very infrequent. Bile leakage is a major complication after hepatic resection because the presence of bile in a dead space may provide an ideal environment for bacterial growth and become an intra-abdominal abscess. 32 Intraoperative cholangiography was routinely performed to confirm the branch of the bile duct to be preserved and to detect insufficiently closed stumps of the bile ducts as a bile leakage test, although it is reported that there is no advantage in using a bile leakage test during hepatic resection. 18 Since 2005, if leakage of the contrast medium or an air bubble was observed, we used a C-tube, which was easily removable, inserted into the cystic duct to decompress the bile duct. The number of reoperations for bile leakage gradually decreased to between 0 and 1 from 2005 to For this reason, decompression of the bile duct with a C-tube is suggested as an effective technique to prevent a massive bile leakage. Moreover, because operative procedures in which the cut surface exposes the major Glisson s sheath and includes the hepatic hilum are high-risk procedures, 33 decompression using a C-tube is also suggested to be useful for this procedure. In conclusion, a shorter operative time and reduced blood loss were obtained by improving the surgical technique using new devices and intraoperative management, including anesthesia. Moreover, decision making using our algorithm and perioperative management according to the CDC guidelines contributed to a reduction in the morbidity and mortality associated with hepatectomy. Author Contributions Study conception and design: Kamiyama Acquisition of data: Nakanishi, Yokoo, Tahara, Yamashita, Shimamura, Matsushita Analysis and interpretation of data: Kamiyama, Kamachi, Taniguchi Drafting of manuscript: Kamiyama, Todo Critical revision: Todo Acknowledgment: The authors wish to thank the staff of General Surgery, Graduate School of Medicine, Hokkaido University, for their kind cooperation. REFERENCES 1. Arii S, Yamaoka Y, Futagawa S, et al. Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. The Liver Cancer Study Group of Japan. Hepatology 2000;32: Poon RT, Fan ST, Ng IO, et al. Significance of resection margin in hepatectomy for hepatocellular carcinoma: A critical reappraisal. Ann Surg 2000;231: Ikai I, Arii S, Ichida T, et al. Report of the 16th follow-up survey of primary liver cancer. Hepatol Res 2005;32: Tobe T. 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