==== Front Ann Saudi MedAnn Saudi MedAnnals of Saudi Medicine0256-49470975-4466King Faisal Specialist Hospital and Research Centre 2792041410.5144/0256-4947.2016.414asm-6-414Original ArticleMorbidity, mortality and predictors of outcome following hepatectomy at a Saudi tertiary care center Al-alem Faisal a*Mattar Rafif Essam a*Fadl Ola Abdelmonem bAlsharabi Abdulsalam aAl-Saif Faisal aHassanain Mazen ac a Department of General Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia b Department of Liver Disease, Research Center, King Saud University, Riyadh, Saudi Arabia c Department of Oncology, McGill University, Montreal, Quebec, CanadaCorrespondence: Dr. Mazen Hassanain, Department of General Surgery, College of Medicine, King Saud University, Riyadh 11466, Saudi Arabia; Department of Oncology, McGill University, Montreal, Quebec, Canada, mhassanain@ksu.edu.sa, ORCID: http://orcid.org/0000-0002-2441-5142* These authors contributed equally to this study. Nov-Dec 2016 36 6 414 421 Copyright © 2016, Annals of Saudi Medicine2016This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.BACKGROUND Hepatic resection is a major surgical procedure. Data on outcomes of hepatectomy in Saudi Arabia are scarce. OBJECTIVE To measure morbidity and mortality and assess predictors of outcome after hepatectomy. DESIGN Descriptive study. SETTING Tertiary care center in Saudi Arabia with well-established hepatobiliary surgery unit. PATIENTS AND METHODS All patients undergoing liver resection in our institute during 2006–2014. Data were analyzed by Kaplan-Meier survival analysis. MAIN OUTCOMES MEASURE(S) Postoperative morbidity and 90-day mortality. Secondary outcomes were risk factors associated with increased morbidity and mortality. RESULTS Data on 77 resections were collected; 56 patients (72.7%) had a malignant etiology, mainly colorectal liver metastases and hepatocellular carcinoma (45.5% and 14.3% respectively). Complications developed following 30 resections (39.0%), with the majority being Clavien grades I–III. In the univariate analysis, predicting factors were the total bilirubin level preoperatively, operative time, extent of resection (i.e., major resection), use of epidural anesthesia, and postoperative liver dysfunction. In the multivariate analysis, the Schindl liver dysfunction score showed the strongest correlation with the development of complications (P=.006). The 90-day postoperative mortality was 5.2% (4/77 patients); 3 patients fulfilled the 50:50 liver dysfunction criteria. Significant predictors were concurrent intra-abdominal surgery, postoperative liver dysfunction, and multiple complications. CONCLUSION Factors that predicted development of complications were elevated total bilirubin level preoperatively, operative time, extent of the resection, use of epidural anesthesia and a postoperative need for blood transfusion. Liver resection is a safe and feasible option at our center. LIMITATIONS The small number of indications for resection and consequent reduction in variety of risk factors limited ability to make inferences. Additionally, only a handful of cases were performed laparoscopically. ==== Body Hepatic resection is a widely used surgical procedure for both oncologic and non-oncologic diseases1,2 such as tumors, intrahepatic duct calculi, hydatid disease, and abscesses. Benign neoplasms include hepatocellular adenoma, hepatic hemangioma, and focal nodular hyperplasia. Resection is a curative option for various malignancies, both primary hepatocellular carcinoma3,4 and metastatic hepatic tumors.5 Specifically, those arising from colorectal cancer are the most amenable to surgical resection. According to Höhn’s classification,6 liver resection is considered major abdominal surgery. This procedure has improved significantly over time, and its outcomes have significantly improved over the last few years.7 This can be attributed to multiple factors, including proper patient selection,8 focused perioperative management,9 the use of portal vein embolization to ensure an adequate future liver remnant,10 a decreased duration of preoperative chemotherapy,11,12 optimized surgical techniques,13 tailored multidisciplinary care,14–17 and improved management plans in the event of complications. 7 Additionally, more of these procedures are being performed at tertiary centers by specially trained hepatobiliary surgeons who have a higher level of expertise.7 Laparoscopy has also been widely used to decrease the invasiveness of the procedure.18–21 Before 1980, liver resection was associated with a mortality risk above 10%;7 however, this rate has decreased dramatically, and it is reported to be <2.5% and even <1% at specialized centers.22–24 Despite favorable outcomes, hepatic resection remains a complex procedure associated with significant morbidity.25 A number of postoperative complications may occur that should always be anticipated, including hemorrhage, pleural effusion, and sub-phrenic infection, biliary tract injury, liver dysfunction, and biliary tract hemorrhage. The most feared life-threatening complication is post-hepatectomy liver failure (PHLF)26,27 which occurs following about 10% of resections.28,29 PHLF is defined by the International Study Group of Liver Surgery as an increased international normalized ratio and hyperbilirubinemia on or after the fifth postoperative day, thus indicating the inability of the liver to perform its synthetic, excretory, and detoxifying tasks.30 PHLF accompanied by acute renal failure (ARF) may lead to hepatorenal syndrome. ARF is a complication that is usually reversible, mainly by means of dehydration and diuretics.31 Bile leakage is another feared complication that occurs in 4–17% of cases.32 Coagulation disorders can also develop.33,34 Infections are predicted following most procedures, with surgical site infections being common. However, intra-abdominal abscesses, postoperative pneumonia and urinary tract infection are also seen, more so in the elderly.35,36 Our teaching institution, King Saud University Medical City, has a specialized hepato-pancreaticobiliary (HPB) unit that was established in 2006. Our unit consists of three reputable surgeons trained in advanced HPB and transplant procedures, with a focus on hepatobiliary and oncological diseases. We report our rates of morbidity and mortality following hepatectomy, and our analysis of predicting factors. PATIENTS AND METHODS Data were collected from our HPB unit’s database for all hepatectomy cases performed at King Saud University Medical City from 2006–2014. Data were collected from hospital medical records, operative records, pathology reports, radiology software, and outpatient clinics. Variables collected were divided into general demographics, preoperative, intraoperative, and postoperative variables, and outcomes. Liver dysfunction was calculated via two common scores: the Schindl score37 (which is based on total serum bilirubin and lactate, in addition to prothrombin time and encephalopathy), and the 50:50 score38 (which is based on total serum bilirubin and prothrombin time). Primary outcomes were postoperative morbidity (according to the Clavien-Dindo surgical complication score)39 and 90-day mortality. Secondary outcomes were all risk factors associated with postoperative morbidity and mortality. A univatiate analysis was done using chi square for nominal variables and the t test or Mann–Whitney U test for continuous variables not normally distributed. Significant variables were then used in a multivariate analysis. Survival curves were generated to determine disease-specific mortality rates using Kaplan-Meier curves. The log-rank test was used to analyze all collected variables to determine significant risk factors for morbidity after resection and 90-day mortality. Statistical analyses were performed using JMP 11.2.0 software (SAS Institute, Cary, NC). RESULTS Indications Ninety-six liver resections were screened; 19 were excluded due to missing data. Seventy-seven resections were included for further analysis; 56 patients (72.72%) had a malignant etiology, mainly colorectal liver metastases, in 35 patients, and hepatocellular carcinoma in 11 patients (45.45% and 14.29% respectively) (Table 1). Four patients had a second resection for recurrences. All patients underwent preoperative assessment of liver volume, and possibility of portal hypertension as clinically indicated. Baseline characteristics The mean (standard deviation) age of the 77 patients was 49.1 (15.5) years. Our youngest patient was 14 years, whereas the eldest was 74 years. The percentage of our male patients was slightly higher than that of our female patients (53.3% vs. 46.8%). The mean American Society of Anesthesiologists classification was 2. The median preoperative hospitalization period was 4 days (range: 0–25 days, IQR: 2–8 days). The remaining baseline characteristics and preoperative lab values are in Table 2. Fifty-six resections were performed for malignant indications. Thirty-seven were for metastatic lesions (most commonly colorectal liver metastasis, 35 cases), the primary tumor had been resected previously in 29 cases. Extrahepatic synchronous metastasis was documented in 7 patients; 4 of which had pulmonary lesions, the remainders were in peritoneum and colon. Other indications for resection for malignant disease were 11 hepatocellular carcinomas, 2 cases of cholangiocarcinomas, 2 neuroendocrine masses, 1 hepatoblastoma, 1 as part of en bloc resection for colorectal cancer and 1 for a rare hepatic sarcoma. In patients with colorectal liver metastasis (35), 60% received chemotherapy before liver resections (21 cases), with an average of 10 cycles. The median time from the end of chemotherapy to the time of resection was 4.47 months (IQR: 2.53–13.9, range: 1.03–24.2 months). Right portal vein embolization was performed in 6 resections, aiming to improve the future liver residual. Intraoperative variables Of the 77 resections, about two-thirds (45/77, 58.4%) were major (i.e., ≥3 segments). Concurrent intra-abdominal surgery was performed in 8 cases, all for either the colon or rectum, and one patient had a breast mass that was excised simultaneously. Epidural anesthesia was used in slightly less than half of the procedures (34/77, 44.2%). A transfusion was needed intraoperatively for 29 patients (37.7%). Our mean total operative time was 5.3 hours (range: 1.7–10.3 hours). Outcomes Histologically, the average number of resected lesions was 2 (range: 0–20). The median length of total hospital stay was 12 days, although it ranged from 4–80 days. Complications developed following 30 resections (39.0%), with the majority being Clavien grades I–III. The most frequent complications were sepsis (15/77, 19.5%), blood transfusion (10/77, 3.0%), and organ space infection (8/77, 10.4%) (Table 3). Almost half the patients (38/77, 49.4%) exhibited an element of hepatic impairment postoperatively, mostly mild or moderate based on the Schindl liver dysfunction score.37 Interestingly, when calculating liver dysfunction using the 50:50 criteria, only 12/77 patients (15.6%) had liver dysfunction. Factors associated with morbidity in a univariate analysis were only the total bilirubin level preoperatively, operative time, extent of the resection (i.e. major resection), use of epidural anesthesia, and postoperative liver dysfunction (calculated by both the Schindl liver dysfunction score and 50:50 criteria). In a multivariate analysis, the Schindl liver dysfunction score showed the strongest correlation (P=.006) with postoperative morbidity. Details of the outcomes and factors that correlated with morbidity and 90-day postoperative mortality are illustrated in Tables 4 and 5, respectively (All factors shown as Appendices 1 and 2). Factors such as age, gender, body mass index, white blood cell count, hematocrit and several others were not significantly associated with morbidity. The 90-day postoperative mortality was 5.2% (4/77 patients); 3 fulfilled the 50:50 liver dysfunction criteria. Significant predictors were concurrent intra-abdominal surgery, postoperative liver dysfunction, and the development of multiple complications listed in Table 5. Notably, following the 55 resections performed for malignant indications, histology showed a positive margin in 5 patients (9.1%). Overall survival and disease-free survival Patients were followed for a median of 13 months (IQR: 1.49– 22.67, range: 0–56.7 months). Recurrence/progression of the disease was documented after 29/77 resections (37.7%); these were mostly intrahepatic (22/77). Seven recurrences developed in the lung, and 10 in other distant locations. The median time to recurrence/progression was 5.8 months (IQR: 2.0–10.8, range: 0.33–49.07 months). The overall median survival was 13.23 months (IQR: 0.77–22.48, range: 0.13– 49.5 months). Overall and disease-free survival curves are shown in Figures 1 and 2. DISCUSSION Liver resection is a major surgical intervention that is the cornerstone of managing various benign and malignant diseases. In Saudi Arabia, data on the indications and outcomes of this procedure are scarce. Therefore, we performed this study to benchmark our experience and identify predictors of morbidity and mortality at our center. We aimed to optimize our patient care in light of our results. As this paper is a retrospective study it suffers all the limitations that apply to this type of study, including missing data, which is apparent in our paper. However from the collected data, the morbidity and mortality rates reached 39.0% and 5.2% respectively. Compared with data reported by Aloia et al8 in the National Surgical Quality Improvement Project (NSQIP), our rates are within an acceptably close range.40 However, the relatively small sample size of our study limits such a comparison, and ongoing prospective data collection is being carried out for future comparisons and quality improvement. We found that significant predictors of morbidity were the total bilirubin level preoperatively, operative time, extent of resection, use of epidural anesthesia, and postoperative Schindl score for liver dysfunction. In the literature, it is well established that the operative time and blood loss influence morbidity, whereas epidural anesthesia has a protective role.41–43 We think the discrepancies in our data were mainly because of the effect of epidural anesthesia on the operative time, which included within it the anesthesia time. Significant predictors of 90-day mortality were concurrent intra-abdominal surgery, the postoperative Schindl score for liver dysfunction, the 50:50 liver dysfunction criteria, postoperative blood transfusion, and the development of complications. These data correlate with reported findings,30 as liver failure is the most commonly reported cause of postoperative mortality following major liver resection. The majority of our liver resections were performed for an oncological indication, which may explain the significant rate of postoperative liver dysfunction.27 Most of our patients underwent a major liver resection (45 patients, 58.4%), defined as resection of three segments or more. Taking this into consideration when comparing our results to NSQIP data, our morbidity (38.96%) and mortality rates (5.19%) lie in close proximity to their rates for extended resections (31.9% and 5.2% respectively). In our cohort liver dysfunction (49.35%) was the most common complications followed by sepsis (14.98%), and organ space infection (10.39%). In NSQIP data, both organ space collection (4.5–10.9%) and sepsis (5.7–9.6%) were also the most common complications. In conclusion, liver resection is a safe and feasible option at our center. We attained acceptable preliminary results. However, further care should be taken to note the operative time and postoperative liver failure. Laparoscopic liver surgery is a new emerging modality that has a promising future, and it can be utilized at our institution. Factors that predicted development of complications were elevated total bilirubin level preoperatively, operative time, extent of the resection (i.e. major resection), use of epidural anesthesia and a postoperative need for blood transfusion. The development of postoperative liver dysfunction correlated with 90-day mortality in our sample (P<.0001). The relatively small number of indications for resection, which decreases the variety of risk factors and our inability to derive statistical inferences is a major limitation of the study. Additionally, only a handful of cases were performed laparoscopically, which limits the statistical analysis of that form of surgery. Acknowledgments We thank Weam Hussain and Maram AlKhammash of the Liver Disease Research Center at King Saud University for their help and contributions during data collection. Appendix 1 Univariate analysis for correlation with morbidity following liver resection Factor P value Indication (Benign vs. Malignant) .0650 Indication (Type of Malignancy) .4203 Age .9909 Gender .5354 Body Mass Index .2218 White Blood Cell Count .1552 Haematocrit .6881 Platelets .1158 International Normalized Ratio .3221 Partial Thromboplastin Time .7562 Blood Urea Nitrogen .4374 Creatinine .0816 Total Bilirubin .0272 Albumin .2622 Alkaline Phosphatase .8425 Aspartate Aminotransferase .1534 Alanine Aminotransferase .4200 American Society of Anesthesiologists Physical Status Class .5083 Smoking Status .2553 Bronchial Asthma .2180 Diabetes Mellitus .6902 Hypertension .7174 Stroke History .1145 Bleeding Disorder .2682 Previous Coronary Stent .3589 Previous Cardiac Surgery .3589 Sepsis .2597 Preoperative Transfusion .4466 Operative Procedure within 30-days .8581 Number of Hospitalization Days Preoperatively .0915 Radiotherapy .4868 Chemotherapy .4064 Number of Chemotherapy Cycles Preoperatively .7695 Primary disease not resected .9484 Operative Time .0043 Extent of Resection (major) .0487 Epidural Anaesthesia .0208 Concurrent Intra-abdominal Surgery .8498 Intraoperative Transfusion .4665 Fong Score .2692 Number of Resected Lesions .5887 Schindl Liver Dysfunction Score Postoperatively .0261 50:50 Liver Dysfunction Criteria Postoperatively^a^ .0022 a Intra-operative factor; P>.05. Appendix 2 Univariate analysis for variables correlation with 90-day postoperative mortality Baseline Factor P value Indication (Benign vs. Malignant) .7957 Indication (Type of Malignancy) .9941 Age .3614 Gender .9326 Portal Vein Embolization .1924 Body Mass Index .2494 White Blood Cell Count .8543 Haematocrit .3349 Platelets .6055 International Normalized Ratio .2299 Partial Thromboplastin Time .7926 Blood Urea Nitrogen .0854 Creatinine .1393 Total Bilirubin .3084 Albumin .3978 Alkaline Phosphatase .7664 Aspartate Aminotransferase .2535 Alanine Aminotransferase .3012 American Society of Anesthesiologists Physical Status Class .8813 Smoking Status .5990 Bronchial Asthma .6469 Diabetes Mellitus .6659 Hypertension .6417 Stroke History .6965 Bleeding Disorder .8231 Previous Coronary Stent .8231 Previous Cardiac Surgery .7520 Sepsis .6469 Presence of Ascites on CT .5646 Preoperative Transfusion .6940 Operative Procedure within 30-days .2095 Number of Hospitalization Days Preoperatively .3418 Radiotherapy .5990 Chemotherapy .9234 Number of Chemotherapy Cycles Preoperatively .6627 Time Between Chemotherapy and Resection .4750 Primary disease not resected .2042 Intraoperative Factors Operative Time .2336 Extent of Resection (major vs. minor) .0832 Epidural Anaesthesia .0956 Concurrent Intra-abdominal Surgery .0082* Intraoperative Transfusion .4963 Postoperative Factors Schindl Liver Dysfunction Score .0002 50:50 Liver Dysfunction Criteria <.0001 Postoperative Transfusion <.0001 Bleeding Transfusion (>4 units of blood within 72h after surgery) .0030 Acute Renal Insufficiency/Failure <.0001 Respiratory Failure .0001 Return to OR <.0001 Reintubation <.0001 Ventilator Dependence <.0001 Cardiac Arrest <.0001 Coma .0023 Venous Thromboembolism .0021 Pneumonia .8231 Sepsis .0013 Surgical Site Infection .7500 Organ Space Infection .2637 Length of Stay .8066 Figure 1 Kaplan-Meier disease-free survival. Figure 2 Kaplan-Meier overall survival. Table 1 Indications for liver resection (n=77). Indication for liver resection Frequency Percentage Malignant indications (n=56, 72.7%)  Colorectal cancer liver metastasis 35 45.5  Hepatocellular carcinoma 11 14.3  Cholangiocarcinoma 2 2.6  Neuroendocrine tumor 2 2.6  Other malignancies* 6 6.5 Benign indications (n=21, 27.3%)  Hemangioma(s) 7 6.5  Focal nodular hyperplasia 4 5.2  Hydatid cyst 3 3.9  Simple cyst 3 1.3  Hepatocellular adenoma 1 1.3  Traumatic liver injury 1 1.3  Focal steatosis 2 9.1 Total 77 100 * One resection for each of the following was performed: (1) direct invasion of colorectal cancer into the liver, (2) breast cancer liver metastasis, (3) monophasic synovial sarcoma liver metastasis, (4) hepatoblastoma (5) sarcomatoid tumor and (6) part of extended cholecystectomy for gallbladder cancer. Table 2 Baseline characteristics (n=77). Age, years (median, range) 49 (14–74) Sex  Male 41 (53.3)  Female 36 (46.8) Body Mass Index (mean, range) 25.9 (17.7–51.7) ASA Class  Class 1 7 (9.1)  Class 2 32 (41.6)  Class 3 12 (15.6)  Class 4 1 (1.3)  Class 5 or 6 0 (0) Smokers 5 (6.49) Bronchial asthma 4 (5.19) Diabetes mellitus 15 (19.48) Hypertension 15 (19.48) History of stroke 3 (3.9) Bleeding disorder 1 (0.13) Hepatitis B or C 7 (9.09) Ascites on CT 5 (6.49) Preoperative transfusion 3 (3.9) Previous operation within 30 days 7 (9.09) Preoperative hospitalization, days (median, range) 4 (0–25) Preoperative radiation 5 (6.49) White blood cell count, ×109/L, (median, range) 6.9 (1.5–20.8) Hematocrit level, % (median, range) 35 (21.9–47.4) Platelet count, ×103/μL, (median, range) 247 (53–728) International normalized ratio, (median, range) 1.1 (0.9–1.76) Partial thromboplastin time, s, (median, range) 36.1 (29–90.2) Blood urea nitrogen level, mmol/L, (median, range) 4 (0.8–8.7) Creatinine level, μmol/L, (median, range) 70 (34–182) Total bilirubin level, μmol/L, (median, range) 9 (3–70) Albumin level, g/L, (median, range) 32 (17–43) Alkaline phosphatase level, U/L, (median, range) 101 (54–533) Aspartate Aminotransferase Level, U/L, (median, range) 35 (8–596) Alanine Aminotransferase Level, U/L – median (range) 60.5 (25–512) Values are numbers (percentages), unless indicated otherwise. ASA, American Society of Anesthesiologists; CT, computed tomography Table 3 Postoperative outcomes (n=77). Overall complications 30 (39.0) Pneumonia 1 (1.3) Acute renal insufficiency/failure 5 (6.5) Sepsis/septic shock 15 (19.5) Surgical site infection 2 (2.6) Organ space infection 8 (10.4) Transfusion 10 (13.0) Venous thromboembolism 2 (2.6) Respiratory failure 5 (6.5) Return to operation room 3 (3.9) Reintubation 6 (7.8) Ventilator dependence/failure to wean >48h 4 (5.2) Cardiac arrest 3 (3.9) Coma 2 (2.6) Other 16 (20.8) Liver dysfunction (50:50 rule) 12 (15.6) Liver dysfunction (Schindl score)  All liver dysfunction (Schindl score ≥ 1) 38 (49.4)  0 (none) 0 (0)  1–2 (mild dysfunction) 16 (20.8)  3–4 (moderate dysfunction) 18 (23.4)  ≥5 (severe dysfunction) 4 (5.2) Missing values 39 Length of stay, days (median, range) 12 (4–80) 90-day mortality 4 (5.2) Clavian-Dindo Complication Classification  All complications (Clavian-Dindo score ≥ 1) 30 (39.0)  0 (no complications) 35 (45.5)  1 6 (7.8)  2 10 (13.0)  3 6 (7.8)  4 4 (5.2)  5 4 (5.2) Missing values 12 All values are number (percent) unless otherwise indicated. Table 4 Univariate analysis for variables correlating with morbidity following liver resection (statistically significant factors shown, P<.05). Factors P Baseline factors  Total bilirubin .0272 Intraoperative factors  Operative time .0043  Extent of resection (major) .0487  Epidural anaesthesia .0208  Schindl liver dysfunction score postoperatively .0261  50:50 liver dysfunction criteria postoperatively .0022 Statistically nonsignificant factors shown in Appendix 1. Table 5 Univariate analysis for variables correlating with 90-day postoperative mortality following liver resection (statistically significant factors shown, P<.05). Factors P Intraoperative factors  Concurrent intra-abdominal surgery .0082 Postoperative factors  Schindl liver dysfunction score .0002  50:50 liver dysfunction criteria <.0001  Postoperative transfusion <.0001  Bleeding transfusion (>4 units of blood within 72h after surgery) .0030  Acute renal insufficiency/failure <.0001  Respiratory failure .0001  Return to OR <.0001  Reintubation <.0001  Ventilator dependence <.0001  Cardiac arrest <.0001  Coma .0023  Venous thromboembolism .0021  Sepsis .0013 Statistically nonsignificant factors shown in Appendix 2. ==== Refs REFERENCES 1 Khatri VP Petrelli NJ Belghiti J Extending the frontiers of surgical therapy for hepatic colorectal metastases: is there a limit? 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