Effect of preoperative biliary drainage on surgical outcome after pancreatoduodenectomy

Effect of preoperative biliary drainage on surgical outcome after pancreatoduodenectomy

The American Journal of Surgery 181 (2001) 52–59 Scientific papers Effect of preoperative biliary drainage on surgical outcome after pancreatoduoden...

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The American Journal of Surgery 181 (2001) 52–59

Scientific papers

Effect of preoperative biliary drainage on surgical outcome after pancreatoduodenectomy Marcus E. Martignoni, M.D.*, Markus Wagner, M.D.*, Lukas Kra¨henbu¨hl, M.D., Claudio A. Redaelli, M.D., Helmut Friess, M.D., Markus W. Bu¨chler, M.D.† Department of Visceral and Transplantation Surgery, University of Bern, Inselspital, CH-3010 Bern, Switzerland Received June 7, 2000; revised manuscript August 9, 2000

Abstract Background: The role of preoperative biliary drainage in patients with biliary obstruction undergoing pancreatoduodenectomy remains controversial. Several authors failed to show any effect of preoperative biliary drainage, whereas others even reported an increased morbidity following pancreatoduodenectomy. Methods: Retrospective analysis was performed in a consecutive series of 257 patients undergoing pancreatoduodenectomy between November 1993 and November 1999. Results: Ninety-nine patients (38%) underwent preoperative biliary drainage for a median time period of 10 days (range 1 to 41) prior to resection. Cumulative postoperative morbidity was 47% (120 patients), the reoperation rate was 4.3% (11 patients), and mortality was 2.3% (6 patients). There was no difference in total morbidity, infectious complications, reoperation rate, mortality, or long-term survival between patients with or without preoperative biliary drainage. Conclusions: Preoperative biliary instrumentation and biliary drainage do not affect early or late outcome in patients undergoing pancreatoduodenectomy. © 2001 Excerpta Medica, Inc. All rights reserved. Keywords: Pancreatic cancer; Pancreatoduodenectomy; Mortality; Morbidity; Preoperative biliary drainage; Cholestasis

During the last decades, mortality after major pancreatic resection has decreased considerably to actual rates of fewer than 5% in high-volume centers [1,2]. These improvements are partially based on more sophisticated selection of patients as well as on advances in surgical technique and intensive care management. Moreover, randomized prospective trials have shown that the administration of octreotide, started perioperatively and tapered over the initial postoperative days, in combination with meticulous surgery contributes to a significant reduction of postoperative pancreatic fistulas after pancreatic resection [3,4]. However, despite these marked achievements, pancreatoduodenectomy is still associated with a considerable rate of postoperative morbidity, even in high-volume centers [1,2]. A number of risk factors potentially associated with increased morbidity after pancreatic resection in jaundiced * The first two authors contributed equally to the manuscript. † Corresponding author. Tel.: ⫹41 31 632 24 04; fax: ⫹41 31 382 4772. E-mail address: [email protected]

patients have been described, such as advanced age, increased creatinine, hypoalbuminemia, and hyperbilirubinemia [1,5– 8]. Yet the precise impact of any of these risk factors remains to be fully explored. Due to the considerable morbidity envisioned with surgery for malignant biliary tract obstruction, several authors have proposed preoperative biliary drainage to improve surgical outcome in the past [9,10]. To date, several studies have examined the usefulness of preoperative percutaneous or endoscopic biliary drainage in patients with malignant biliary obstruction. However, all of the retrospective trials have failed to show any advantage for preoperative release of jaundice, with the exception of one rather small series [11–20]. Similarly, three prospective randomized trials did not show any reduction in postoperative morbidity or mortality after preoperative percutaneous biliary drainage, although this intervention carries its own risks such as infectious complications, bleeding as well as biliary fistula formation, and total hospital stay was significantly longer in the drainage groups [8,21,22]. In contrast to studies using percutaneous biliary drain-

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age, two prospective randomized trials showed contradictory results for preoperative endoscopic biliary drainage [23,24]. Whereas Lygidakis et al [23] reported a significantly reduced incidence of postoperative infectious and bleeding complications, Lai et al [24] could not observe any beneficial effects of endoscopic stenting prior to surgery. Moreover, many retrospective and all prospective studies included a heterogeneous group of patients undergoing a variety of surgical procedures, some of them even palliative, to investigate the impact of preoperative biliary drainage on surgical outcome [11–24]. Furthermore, a recent study, which considered a variety of interventional and surgical biliary drainage procedures prior to pancreatoduodenectomy, even found increased incidence of infectious complications after pancreatic head resection [18]. Therefore, especially the value of preoperative biliary drainage as a routine procedure to release obstructive jaundice in candidates undergoing pancreatoduodenectomy remains controversial. This prompted us to analyze our own results in an actual and nonselected consecutive series of patients undergoing pancreatoduodenectomy with or without obstructive jaundice in order to determine the association between preoperative biliary drainage and postoperative morbidity and mortality.

Methods All patients undergoing pancreatic head resection were selected from a prospectively collected statistical database. Registered data consisted of patient demographics, preoperative risk assessment according to the ASA classification scoring system in combination with preoperative spirometry and ergometry in most patients, preoperative biliary drainage procedures, standard hematological and biochemical laboratory tests, pathologic diagnosis, type of surgery performed and intraoperative findings, blood loss and transfusion of red blood cells, postoperative morbidity and mortality, postoperative intensive care unit (ICU) and hospital stay, and survival after discharge [25]. All patients received a complete physical examination before surgery. Routine laboratory tests consisted of hematological, liver and renal function tests and determination of the tumor markers CEA and CA19-9. Basic diagnostic imaging included a chest radiograph and a computed tomography (CT) scan in all patients as well as magnetic resonance imaging (MRI) in selected cases. Patients with jaundice (bilirubin ⬎100 ␮mol/L) or suspicion of obstruction of the common bile duct underwent endoscopic retrograde cholangiopancreatography (ERCP). If biliary obstruction was detected, a biliary plastic stent was inserted into the common bile duct if technically feasible. Otherwise, an endoscopic nasobiliary tube was placed or the patient underwent percutaneous transhepatic external biliary drainage.

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Surgical technique All patients received a prophylactic antibiotic regimen consisting of 4 g of piperacillin (Pipril, Lederle, Switzerland) and 1 g ornidazol (Tiberal, Roche Pharma AG, Switzerland). In addition, Octreotide (Sandostatin, Novartis, Switzerland) was administered to all patients receiving a pancreatic resection, starting perioperatively and continuing for 7 days at doses varying between 100 ␮g and 200 ␮g given subcutaneously three times a day [3]. The abdominal cavity was explored through a midline incision to exclude metastatic lesions or major infiltration of adjacent structures. If no contraindications for resection were found, patients underwent either pylorus-preserving or classic pancreatoduodenectomy, as described previously [2]. Resection encompassed removal of the gallbladder and the common bile duct together with all adjacent lymphatic tissue and en bloc resection of the pancreatic head together with the duodenum and the distal stomach in patients undergoing classic pancreatoduodenectomy. Reconstruction consisted of an interrupted two-layer end-to-side pancreatojejunostomy, an end-to-side hepatico-jejunostomy 10 to 15 cm distal to the pancreatic anastomosis, and an end-to-side gastro-jejunostomy some 40 cm distal to the bilio-digestive anastomosis followed by a Braun jejuno-jejunostomy. For pylorus-preserving Whipple resection, the intestinal anastomosis consisted of an end-to-side duodeno-jejunostomy. Both operations were carried out in combination with a standardized lymph node dissection of the celiac trunk, the hepatoduodenal ligament, the superior mesenteric vein, and the right side of the superior mesenteric artery, as well as the lymphatic tissue behind the pancreatic head. Postoperative management Tumor stage was determined according to the UICC (Union Internationale Contre le Cancer) classification and the TNM system. The secretion volume from the gastric tube and the volume of the abdominal drainage were measured daily and the amylase concentration of the latter was determined every second day to detect low-output pancreatic fistulae. All patients underwent routine received a gastrointestinal contrast study with water-soluble contrast medium to exclude leakage of the gastrointestinal anastomosis and to verify upper gastrointestinal passage 5 days after surgery prior to the onset of oral food intake. According to generally accepted principles of surgical and supportive care, the standard postoperative treatment included hemodynamic monitoring with a central venous catheter, urinary catheter, fluid balance, and adequate parenteral replacement of electrolytes. The nasogastric tube was removed when less than 300 mL fluid volume was secreted per day. Perioperative antibiotics and postoperative analgesics (intravenously, peridural) were administered according to the protocol or as needed, respectively. Patients were given nothing by mouth for the first 48 hours after surgery. Thereafter, pa-

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M.E. Martignoni et al. / The American Journal of Surgery 181 (2001) 52–59 Table 2 Patient characteristics (median ⫾ range)

Table 1 Surgical and medical morbidity Morbidity

Total (n ⫽ 257)

No biliary drain (n ⫽ 158)

Biliary drainage (n ⫽ 99)

P value

Demographics

Surgical DGE Wound sepsis Bleeding Pancreatic fistula Other fistula Abscess Other Medical Pulmonary Cardiocirculatory Renal Sepsis Neural Other Relaparotomy Cumulative morbidity Mortality

91 (35%) 64 (25%) 14 (5.5%) 11 (4.3%) 6 (2.3%) 5 (2.0%) 4 (1.6%) 7 (2.7%) 60 (23%) 24 (9.3%) 14 (5.5%) 10 (3.9%) 9 (3.5%) 7 (2.7%) 12 (4.7%) 11 (4.3%) 120 (47%) 6 (2.3%)

51 (32%) 35 (22%) 8 (5.1%) 6 (3.8%) 5 (3.2%) 3 (1.9%) 4 (2.5%) 3 (1.9%) 35 (22%) 13 (8.2%) 7 (4.4%) 9 (5.7%) 4 (2.5%) 4 (2.5%) 9 (5.7%) 7 (4.4%) 71 (45%) 3 (1.9%)

40 (40%) 29 (29%) 6 (6.1%) 5 (5.1%) 1 (1.0%) 2 (2.0%) 0 4 (4.0%) 25 (25%) 11 (11%) 7 (7.1%) 1 (1.0%) 5 (5.1%) 3 (3.0%) 3 (3.0%) 4 (4.0%) 49 (50%) 3 (3.0%)

n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s.

Male 140 (54%) 86 (54%) 52 (53%) Female 119 (46%) 72 (46%) 47 (47%) Age (years) 67 (18–87) 64 (18–87) 69 (41–86) ASA I–II 193 (75%) 129 (82%) 64 (65%) III–IV 64 (25%) 29 (18%) 35 (35%) Diabetes 46 (18%) 27 (17%) 19 (19%) Hypertension 25 (9.7%) 13 (8.2%) 12 (12%) Cardiac disease 41 (16%) 28 (18%) 13 (13%) COPD 13 (5.1%) 4 (2.5%) 9 (9%) Alcohol abuse 29 (11%) 16 (10%) 13 (13%) Bilirubin (␮mol/L) 33 (3–558) 14 (3–558) 145 (6–489) Albumin (g/L) 33 (11–48) 35 (11–48) 32 (13–44) Creatinin (␮mol/L) 80 (41–189) 78 (41–189) 82 (53–154)

DGE ⫽ delayed gastric emptying (inability to tolerate oral food intake for more than 10 days after surgery); n.s. ⫽ not significant.

tients were allowed a maximum of 300 mL fluid consumption per day until routine contrast stomach radiographs were performed. Either oral food intake or parenteral alimentation was then started where appropriate. Some of the patients received early enteral nutrition through a feeding jejunostomy tube. Follow-up after discharge was checked every 6 months and included estimation of tumor recurrence and long-term survival. Definition of complications Surgical complications included delayed gastric emptying (DGE), wound sepsis, bleeding, pancreatic and other fistulae, intraperitoneal and wound abscess. Medical complications were categorized as pulmonary, cardiocirculatory, renal, or neural morbidity and sepsis, independent of the operation (Table 1). DGE was defined as a delay in oral food intake for more than 10 days after surgery. All patients with DGE received parenteral nutrition or enteral nutrition through a tube jejunostomy until solid oral food intake was tolerated. A pancreatic fistula was defined if there was more than 30 mL secretion of amylase-rich fluid (amylase concentration more than 5,000 IU) over the abdominal drainage for more than 10 days. Postoperative bleeding was defined as the occurrence of blood loss either through the abdominal drains or by hematemesis in combination with a decrease in systemic hemoglobin content of more than 20 g/L to a value of under 80 g/L within 24 hours, requiring at least 2 units of blood to prevent further blood loss. All items of interest as well as all complications or adverse reactions were documented in the patient record form.

Total (n ⫽ 257)

No biliary drain (n ⫽ 158)

Biliary drainage (n ⫽ 99)

P value n.s. n.s. n.s. 0.02 0.02 n.s. n.s. n.s. 0.036 n.s. ⬍0.001 n.s. n.s.

ASA ⫽ American Society of Anesthesiologists; COPD ⫽ chronic obstructive pulmonary disease; n.s. ⫽ not significant.

Statistical analysis For qualitative analyses, either a two-sided chi-square test with Yates’ correction for continuity or a Fisher exact test was applied where appropriate, and a Kruskal-Wallis H test or a Mann-Whitney U test was used for quantitative variables. Variables determined to be statistically significant were entered into a stepwise logistic regression model for multivariate analysis to identify independent predictors of outcome. The analysis of survival was calculated according to the Kaplan-Meier method, and the levels of significance were tested with a log-rank test. Results are expressed as the median (range) or the number and percentage of the total number of patients. The statistical package SPSS for Windows (SPSS Inc., Chicago, Illinois) was used for all statistical analyses. A P value ⬍0.05 was considered significant. Results Between November 1993 and November 1999, 257 patients underwent pancreatic head resection and their data were prospectively collected in a statistical database. Patients’ demographics are summarized in Table 2. A total of 65 patients had a history of jaundice with a bilirubin level of ⬎100 ␮mol/L on admission. Biliary instrumentation procedures prior to surgery are depicted in Table 3. A total of 184 patients (72%) underwent diagnostic biliary instrumentation and 99 patients had biliary drainage in addition. Endoscopic insertion of a stent failed in 5 patients with significant obstruction of the common bile duct (success rate 95%). These 5 patients underwent percutaneous transhepatic cholangiography and had percutaneous stent insertion in 4 cases and nasobiliary tube drainage in 1. The median duration between biliary drainage and definitive surgery was 10 days (range 1 to 45), with 54% of patients having drainage for more than 10 days.

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Table 3 Incidence and management of preoperative biliary instrumentation in 257 patients undergoing pancreatic head resection with or without severe jaundice (bilirubin ⬎100 ␮mol/L) Parameters (median ⫾ range)

Total (n ⫽ 257)

No jaundice (n ⫽ 192)

Jaundice (n ⫽ 65)

P value

Diagnostic instrument* ERCP Biliary drainage Endoscopic stent Endosc nasobiliary drain Percutaneous internal stent Percutaneous external drain Biliary instrumentation

86 (34%) 86 (34%) 99 (39%) 85 (33%) 8 (3.1%) 4 (1.6%) 1 (0.4%) 185 (72%)

76 (40%) 76 (40%) 49 (26%) 40 (21%) 6 (3.1%) 2 (1.0%) 1 (0.5%) 125 (65%)

10 (15%) 10 (15%) 50 (77%) 45 (69%) 3 (4.6%) 2 (3.1%) 0 60 (92%)

0.05 0.05 ⬍0.001 ⬍0.001 n.s. n.s. n.s. ⬍0.001

* Biliary instrumentation: PTHC was performed in 5 patients if endoscopic stent insertion was not possible. ERCP ⫽ endoscopic retrograde cholangiopancreatography; PTHC ⫽ percutaneous transhepatic cholangiography; n.s. ⫽ not significant.

Operative findings and length of stay are shown in Table 4. The results of the histopathological examination are summarized in Table 5. UICC classification for the 190 malignancies was: stage I in 32 cases (17%), stage II in 46 cases (24%), stage III in 109 cases (57%), and stage IV in 3 cases (1.6%). There was no significant difference concerning UICC classification between patients with biliary drainage and patients without biliary drainage. In-hospital morbidity and mortality are given in Table 1. A total of 11 patients underwent reoperation. The reason for relaparotomy was intraabdominal bleeding in 5 cases, large bowel fistula in 2 cases, and biliary fistula in 2 cases. One patient developed a persistent gastric outlet obstruction after pylorus-preserving Whipple resection and received distal gastrectomy. The last patient developed pseudo-obstruction of the large bowel and underwent resection of the right colon due to massive distension of the right colon. Six patients died after surgery (2.3%). One patient died due to massive aspiration on day 6, and 1 patient succumbed to acute heart failure 8 days after surgery. A third patient developed adult respiratory distress syndrome and died of multiorgan failure, and a fourth patient died of MRSArelated sepsis. The remaining 2 patients had surgical com-

plications: one patient died after reoperation owing to a persistent bile fistula and the last patient developed an intraabdominal abscess and died of multiorgan failure. Postoperative morbidity and mortality in patients with severe obstructive jaundice (bilirubin ⬎100 ␮g/L) are depicted in Table 6. Total morbidity and mortality were not affected by the presence or absence of severe jaundice. In contrast, markedly jaundiced patients had a significantly higher incidence of postoperative bleeding complications, which required reoperation (2 of 132 versus 6 of 60; P ⫽ 0.012). Using first a univariate analysis of variance followed by a stepwise multivariate regression analysis of the parameters depicted in Table 7, neither preoperative biliary drainage nor the presence of severe obstructive jaundice was identified as an independent risk factor for total morbidity, infectious complications or mortality. However, patients with a biliary drainage for more than 10 days had a significantly lower preoperative bilirubin level but a higher incidence of infectious complications after pancreatoduodenectomy than patients with a drainage less than 10 days (23% and 0%, respectively; P ⫽ 0.007). Furthermore, presence of severe obstructive jaundice (bilirubin ⬎100 ␮mol/L) significantly

Table 4 Operative procedure, intraoperative findings and hospital stay (median ⫾ range) Parameters (median ⫾ range) Surgical procedure Classic Whipple Pylorus-preserving Whipple Intraoperative findings Operation time (min) Blood loss (mL) Blood substitution (units) Radical resection Length of stay Intensive care unit stay (days) Hospital stay (days) n.s. ⫽ not significant.

Total (n ⫽ 257) 110 (43%) 149 (58%)

No biliary drain (n ⫽ 158) 63 (40%) 95 (60%)

420 (285–750) 1400 (500–6000) 2 (0–15) 206 (80%)

420 (380–780) 1300 (500–6000) 2 (0–15) 123 (78%)

2 (1–71) 17 (7–118)

2 (1–71) 16 (7–118)

Biliary drainage (n ⫽ 99) 45 (46%) 54 (55%) 432 (285–730) 1500 (500–4300) 2 (0–9) 82 (83%) 2 (1–21) 18 (8–67)

P value

n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s.

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Table 5 Histological findings Characteristics

Chronic pancreatitis Benign tumors Pancreas Ampulla of Vater Distal CBD Duodenum Other Adenocarcinoma Pancreas Ampulla of Vater Distal CBD Duodenum Colon Other Other tumors Neuroendocrine IPMN GIST Other Other lesions

Total (n ⫽ 257) 23 (8.9%) 25 (9.7%) 13 (5.1%) 5 (2.0%) 2 (0.8%) 3 (1.2%) 2 (0.8%) 190 (74%) 133 (52%) 26 (10%) 21 (8.2%) 5 (1.9%) 2 (0.8%) 1 (0.4%) 19 (7.4%) 8 (3.1%) 2 (0.8%) 2 (0.8%) 7 (2.7%) 2 (0.8%)

No biliary drain (n ⫽ 158)

Biliary drainage (n ⫽ 99)

21 (13%) 21 (13%) 9 (5.7%) 5 (3.2%) 2 (1.3%) 3 (1.9%) 2 (1.3%) 96 (61%) 65 (41%) 18 (11%) 7 (4.4%) 3 (1.9%) 2 (1.3%) 1 (0.6%) 18 (11%) 8 (5.1%) 2 (1.3%) 2 (1.3%) 6 (3.8%) 2 (1.3%)

2 (2.1%) 4 (4.0%) 4 (4.0%) 0 0 0 0 92 (93%) 68 (69%) 8 (8.1%) 14 (14%) 2 (2.0%) 0 0 1 (1.0%) 0 0 0 1 0

P value

Parameter ⬍0.001

Gender Age

⬍0.001

Diagnosis of tumor Size of tumor ASA score Diabetes mellitus Weight loss Jaundice Hypertension

⬍0.001

CBD ⫽ common bile duct; IPMN ⫽ intraductal papillary mucinous neoplasm of the pancreas; GIST ⫽ gastrointestinal stroma tumor.

increased the incidence of postoperative bleeding requiring relaparotomy (9.2% versus 2.6%; P ⫽ 0.034). Long-term follow-up in the 191 patients with pancreatic or ampullary cancer who were discharged from the hospital is depicted in Table 8, and survival calculated according to Kaplan-Meier is shown in Fig. 1.

Coronary disease Cardiac arrhythmia Other cardiac history Renal dysfunction COPD Other pulmonary history Hemoglobin Quick Alkaline phosphatase Albumin Biliary instrumentation Biliary drainage Time of operation Intraoperative blood loss Intraoperative units given Length of ICU stay Pancreatic fistula Bile leakage

Criteria

Coding Male, female ⬍70 years, ⱖ70 years

Histology Diameter

Percent of predisease weight Bilirubin ⬎100 ␮mol/L Systolic arterial blood pressure ⬎140 mmHg

Creatinin ⬎150 ␮mol/L

g/L % U/L g/L

hours mL

days

⬍2 cm, ⬎2 cm ⬍2, ⬎2 Presence, absence ⬍10%, ⬎10% Presence, absence Presence, absence Presence, absence Presence, absence Presence, absence Presence, absence Presence, absence Presence, absence Normal, abnormal Normal, abnormal Normal, abnormal Normal, abnormal Presence, absence Presence, absence ⬍7, ⬎7 ⬍1500 mL, ⬎1500 mL ⬍2, ⬎2 ⬍2, ⬎2 Presence, absence Presence, absence

ASA ⫽ American Society of Anesthesiologists; COPD ⫽ chronic obstructive pulmonary disease; ICU ⫽ intensive care unit.

Comments

Table 6 Surgical and medical morbidity in patients with severe jaundice (bilirubin ⬎100 ␮mol/L) Morbidity

Total (n ⫽ 65)

No biliary drain (n ⫽ 15)

Biliary drainage (n ⫽ 50)

P value

Surgical Delayed gastric emptying Wound sepsis Bleeding Fistula Other Medical Pulmonary Cardiocirculatory Renal Sepsis Neural Other Relaparotomy Cumulative morbidity Mortality

30 (46%) 17 (26%) 7 (11%) 6 (9.2%) 3 (4.6%) 1 (1.5%) 16 (25%) 7 (11%) 3 (4.6%) 1 (1.5%) 3 (4.6%) 3 (4.6%) 2 (3.1%) 6 (9.2%) 36 (55%) 2 (3.1%)

7 (47%) 3 (20%) 2 (13%) 1 (6.7%) 1 (6.7%) 0 3 (20%) 0 0 0 1 (6.7%) 2 (13%) 0 2 (13%) 8 (53%) 0

23 (46%) 14 (28%) 5 (10%) 5 (10%) 2 (4.0%) 1 (2.0%) 13 (26%) 7 (14%) 3 (6.0%) 1 (2.0%) 2 (4.0%) 1 (2.0%) 2 (4.0%) 4 (8.0%) 28 (56%) 2 (4.0%)

n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s.

n.s. ⫽ not significant.

Table 7 Definition of parameters entered for two-step multivariate regression analysis in order to identify risk factors for morbidity and mortality after pancreatoduodenectomy

In the past, pancreatic surgery in patients with malignant obstruction of the common bile duct has been accompanied by a frightening mortality of 20% to 30% and morbidity rates of 40% to 60% [8]. Since these malignancies Table 8 Follow-up and survival after pancreatoduodenectomy for pancreatic and ampullary cancer Characteristics

Total (n ⫽ 190)

Tumor recurrence 124 (65%) Local 85 (45%) Distant 94 (49%50%) Diseased 86 (45%) Cancer related 85 (45%) Other cause 1 (0.5%) Median survival (months) 18 n.s. ⫽ not significant.

No biliary Biliary drain drainage (n ⫽ 98) (n ⫽ 92)

P value

69 (66%) 50 (51%) 55 (56%) 41 (42%) 41 (42%) 0 18

n.s. n.s. n.s. n.s. n.s. n.s. n.s.

55 (60%) 35 (38%) 39 (42%) 45 (52%) 44 (51%) 1 (1.3%) 18

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Fig. 1. Survival after pancreatoduodenectomy in patients with pancreatic or ampullary adenocarcinoma.

commonly occur in elderly patients, the coexistence of concomitant diseases such as malnutrition, history of cardiopulmonary disease, presence of cholangitis, and renal insufficiency may contribute to this high perioperative risk [8,20,26 –28]. Moreover, several studies have shown that obstructive jaundice leads to alteration in glycogen metabolism, impaired mitochondrial and hepatic reticuloendothelial function, decreased cell-mediated immunity, high levels of circulating endotoxins, and depressed synthesis of several hemostasis factors [29 –33]. Together, these alterations can render the patients more susceptible to infections, a well-known event in jaundiced patients undergoing surgery [5]. With the implementation of external transhepatic and thereafter internal endoscopic biliary drainage, several authors have recommended relieving biliary obstruction preoperatively in order to correct the alterations induced by jaundice and to reduce perioperative mortality and morbidity [10,15,20]. To date, numerous studies have been published to characterize the effects of preoperative biliary drainage in patients with resectable as well as unresectable malignant obstruction of the common bile duct. The majority of these studies are retrospective and have failed to show a benefit of preoperative biliary drainage, with the exception of one rather small series [11–15,17,19,20]. Moreover, three prospective randomized trials using preoperative external, transhepatic biliary drainage failed to show any effect on surgical outcome [8,21,22], whereas randomized studies examining endoscopic, internal biliary drainage reported contradictory results. One trial reported decreased postoperative morbidity, whereas the second study showed no benefit [23,24]. Furthermore, several reports have shown that especially percutaneous transhepatic biliary drainage carries its own morbidity [21,22,34]. Therefore, the indication for preoperative release of biliary obstruction has remained controversial.

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One of the reasons why different results have been reported may be that the majority of trials were retrospective and some included heterogeneous groups of patients as well as a variety of different surgical procedures [11–15,17,19, 20]. Thus, unrecognized bias and differences in patient selection may have affected these results. Even the prospective randomized trials included patients who underwent radical resection as well as palliative surgery [8,21,22, 24], with the exception of the study by Lygidakis et al [23]. However, none of these trials recruited a sufficient number of patients to meet standard statistical power requirements [8,21–24]. Furthermore, advances in diagnostic imaging, a better understanding of nutrition, improvements in surgical technique, and perioperative intensive care management may have changed patient selection and operative procedures over time. Moreover, these developments have led to a marked decrease in mortality after pancreatic resection, to rates of under 3% in high-volume centers [1,2]. Another reason that preoperative biliary drainage has failed to benefit severely jaundiced patients in several studies may be that the length of drainage, usually 2 to 3 weeks, was too short. Experimental data in rats with bile duct ligation have shown that alterations in liver function and metabolism normalize in various time frames. Whereas liver function tests and glycogen metabolism recover within 2 to 5 days, other cellular pathways such as beta-oxidation and other mitochondrial functions need 2 to 6 weeks to normalize [30,32,33]. Even bile ductal proliferation and fibrosis may partially reverse 4 to 6 weeks after removal of biliary obstruction [35]. However, these results may not be fully comparable with the situation in humans, since in contrast to studies in rats, most patients develop bile duct stenosis rather than a complete obstruction, and these lesions are built over time. Nevertheless, observations in patients with obstructive jaundice have confirmed that liver metabolism may take several weeks to normalize after release of biliary obstruction [30,36 –38]. Thus it seems possible that normalization of other alterations such as disturbed cell-mediated immunity and hepatic reticuloendothelial function as well as altered endotoxin levels in jaundiced patients will take longer than 2 to 3 weeks after insertion of a biliary drainage [29 –31]. To clarify the role of preoperative biliary drainage with unbiased scientific evidence, large controlled randomized trials from consecutive series of patients undergoing pancreatoduodenectomy for malignant obstructive jaundice would be needed. The most recent randomized study was by Lai et al [24], who recruited a total of 87 patients. The calculated sample size of this study was 80 patients in each treatment group to give a type I error of less than 5% and a type II error of less than 15% with a two-tailed test based on an assumption that mortality was 30% after early surgery and 10% after preoperative endoscopic biliary drainage [24, 38]. However, these mortality rates do not reflect reality any more, since high-volume centers report rates of 5% and lower for elective pancreatoduodenectomy in actual series

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[1,2,18]. If these recent results are taken into account, a randomized trial would require several hundred patients in each treatment group (for example, based on the assumption that mortality is 10% for ␲1 and 5% for ␲2; two-sided test with ␣ error ⬍5% and ␤ error ⬍20%) [38]. Such a trial is hardly feasible in health systems where the consultation of physicians is barely restricted, as is the case for most countries of the Western world. Thus, most patients referred to specialized centers for resection will already have undergone biliary drainage. Although our analysis is not based on a randomized trial, data collection was prospective and only patients undergoing pancreatoduodenectomy were analyzed. Our results demonstrate that preoperative release of obstructive jaundice by endoscopic or percutaneous biliary drainage neither influences postoperative mortality and morbidity when compared with the group of patients who did not receive preoperative biliary drainage nor increases operative time due to more difficult dissections. Furthermore, if only patients with severe jaundice (bilirubin level ⬎100 ␮mol/L) are taken into account, there is again no difference between the two patient groups. Thus, our results are in agreement with most of the previously reported retrospective studies [11–14,17,19,20]. However, in contrast to a recent report from Povoski et al [18] from the Memorial Sloan-Kettering Cancer Center in New York, we could confirm neither an increased incidence of individual infectious complications such as intraabdominal abscess, wound infection, cholangitis, urinary tract infection, catheter infection or postoperative pneumonia, nor a difference in the total incidence of infectious complications. This difference may be explained by the fact that only 5% of our patients (5 out of 99) underwent a second biliary instrumentation prior to surgery, and none had more than two such procedures. In contrast, Povoski et al [18] reported that 43% of patients (54 out of 126) underwent at least a second preoperative biliary instrumentation. In addition, the median period of preoperative biliary drainage prior to resection was 10 days in our study and therefore quite short. This may also explain why preoperative biliary drainage showed no effect when only patients with severe jaundice (bilirubin level ⬎100 ␮mol/L) were taken into account. No patient who underwent pancreatoduodenectomy at our institution had a history of a surgical drainage procedure or presented with severe cholangitis or sepsis on admission. In fact, only 1 patient was admitted to our department with septic fever and a history of cholecysto-jejunostomy due to malignant biliary obstruction. Owing to the infection, this patient was treated with a hepatico-jejunostomy and did not undergo pancreatic resection. In the study from Povoski et al [18] the duration of biliary drainage is not reported. However, taking into account that 13% of patients (16 out of 126) received some form of biliary surgery before undergoing resection and that 43% of patients had more than one biliary instrumentation, it may be assumed that the drainage period was markedly longer compared to our experience.

Furthermore, our own results seem to confirm that the incidence of infectious complications may correlate with the duration of the preoperative biliary drainage. However, a determination of significant risk factors for morbidity and mortality in our series by using a two-step analysis (first univariate analysis of variance followed by a multivariate stepwise regression analysis) found neither a correlation between preoperative biliary instrumentation and morbidity or mortality nor an association between preoperative biliary drainage and postoperative complications. In contrast, presence of severe jaundice (bilirubin level ⬎100 ␮mol/L) was identified as an independent risk factor for surgical complications but no significance was detected for total morbidity, infectious complications, or mortality. Based on the findings of our current study, the after conclusions may be drawn. In the era of MRI and MR cholangiography, routine use of biliary instrumentation in potential candidates for pancreatoduodenectomy does not influence overall morbidity and mortality. In patients with a pancreatic or ampullary mass and obstructive jaundice, routine preoperative biliary drainage is not warranted. Instead, it is imperative that these patients are promptly referred to a surgical department experienced in pancreatic surgery to evaluate the indication for resection. These patients do not benefit from preoperative internal biliary stenting, with the exception of patients with long-standing biliary obstruction and hepatic alterations. Those patients, as well as patients who cannot undergo surgery within 2 to 3 weeks, may benefit from temporary biliary drainage to resolve clinical symptoms or to prevent further deterioration of liver function. However, these patients may be more prone to infectious complications. Actual prospective randomized studies would be needed in order to clarify the indications for preoperative biliary instrumentation and drainage with unbiased scientific evidence. With the marked decrease in mortality after pancreatic resection during the last 2 decades, the required patient numbers would be extremely high. Thus, it is questionable that such trials will ever be realized unless the treating surgeons become involved before placement of a biliary stent has been undertaken. References [1] Yeo CJ, Cameron JL, Sohn TA, et al. Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes. Ann Surg 1997;226:248 –57. [2] Bu¨chler MW, Friess H, Wagner M, et al. Pancreatic fistula after pancreatic head resection: analysis of 331 consecutive patients. Br J Surg 2000;87:883–9. [3] Bu¨chler MW, Friess H, Klempa I, et al. Role of octreotide in the prevention of postoperative complications following pancreatic resection. Am J Surg 1992;163:125–30. [4] Pederzoli P, Bassi C, Falconi M, Camboni MG. Efficacy of octreotide in the prevention of complications of elective pancreatic surgery. Italian Study Group. Br J Surg 1994;81:265–9. [5] Dixon JM, Armstrong CP, Duffy SW, Davies GC. Factors affecting morbidity and mortality after surgery for obstructive jaundice: a review of 373 patients. Gut 1983;24:845–52.

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