Effect of Pre-operative Biliary Drainage on Surgical Outcomes after Pancreaticoduodenectomy in Patients with Common Bile Duct Cancer

Effect of Pre-operative Biliary Drainage on Surgical Outcomes after Pancreaticoduodenectomy in Patients

with Common Bile Duct Cancer

Introduction: Biliary drainage is tried before surgery because it is thought that obstructive jaundice is associated with post-operative mortality and morbidity. However, there are no confirmed criteria about the optimal operation time after drainage. We attempted to determine the appropriate pre-operative bilirubin level after drainage which should be achieved before pancreaticoduodenectomy is done for extrahepatic bile duct cancer.

Methods: We reviewed 100 patients (69 males and 31 females with a mean age of 61.3 ± 9.4 years) who underwent pancreaticoduodenectomy after a pre-operative biliary drainage procedure for distal common bile duct cancer by one surgeon at the Asan Medical Center in Seoul Korea between 1994 and 2005.

Results: We compared the group with pre-operative bilirubin levels < 5.0 mg/dl (N = 14) with the group with a bilirubin levels ≥ 5.0 mg/dl (N = 86). In the bilirubin < 5.0 group, the pre- operative hemoglobin level was lower (p = 0.001), the pre-operative creatinine level was higher (p = 0.000), pre-operative cholangitis was more frequent (p = 0.034), and the bilirubin level at the time of admission was also higher (p = 0.000). The bilirubin < 5.0 group showed no post- operative morbidity, while there was a 25.6% morbidity rate in the bilirubin ≥ 5.0 group (p = 0.032).

Conclusion: The pre-operative bilirubin < 5.0 and ≥ 5.0 groups had a clear difference in post- operative morbidity. Therefore, we suggest waiting until the pre-operative bilirubin level decreases to < 5.0 mg/dl after biliary drainage.

Effect of Pre-operative Biliary Drainage on Surgical Outcomes after Pancreaticoduodenectomy in Patients with Common Bile Duct Cancer

Key Words : drainage, bilirubin, common bile duct neoplasm, pancreaticoduodenectomy

Introduction

Jaundice is the most common chief complaint in many biliary diseases such as periampullary cancer, primary biliary cirrhosis, and hilar and intrahepatic

cholangiocellular carcinomas.

Atkinson et al.

s u g g e s t e d t h a t p e r c u t a n e o u s t r a n s h e p a t i c cholangiography (PTC) is useful in differentiating between intra- and extra-hepatic obstruction or primary biliary cirrhosis. Moreover, in the case of obstructive jaundice, PTC can provide information

Received: 2009. 5. 13.

Accepted: 2009. 6. 11.

1 Department of Surgery, Ajou University School of Medicine, Suwon, Korea

2 Department of surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea

Jae Myeong Lee, M.D.1, Young Joo Lee, M.D.2, Chan Wook Kim, M.D.2, Ki Miung Moon, M.D.2, Myung Wook Kim, M.D.1

Corresponding author Young Joo Lee

Department of surgery, University of Ulsan College of Medicine,

Asan Medical Center, Seoul, Korea TEL : +82-2-3010-3507 FAX : +82-2-474-9027 E-mail : yjlee@amc.seoul.kr

※ This article was presented as a poster

presentation at 60th Annual Meeting of

the Korean Surgical Society, 12 - 14,

November, 2008, COEX, SEOUL.

Patient selection

We reviewed the medical records of 148 patients who underwent surgery for distal common bile duct (CBD) cancer by one surgeon at the Asan Medical Center between December 1994 and November 2005. We selected 103 patients who had undergone a standard Whipple’s procedure or a pylorus-preserving PD. We excluded 3 patients who had not had a pre-operative BD procedure. Thus, we reviewed the medical records of 100 patients who had a PD after a pre-operative BD procedure. The study population consisted of 69 males and 31 females with a mean age of 61.3±9.4 years (40- 84 years).

Surgery

We selected only patients who had undergone surgery by one surgeon to exclude the potential bias of surgeons’

skills. A standard Whipple’s procedure was performed in 18 cases and a pylorus-preserving PD was performed in 82 cases. The skin incisions were inverted T incisions. All methods of anastomosis involving the pancreas were pancreatico-jejunostomies (PJs) in 2 layers using prolene 4-0 or 5-0. All PDs were performed with a radical

Methods

regarding the site and nature of extrahepatic obstructive lesions. Because it is thought that obstructive jaundice is associated with post-operative mortality and morbidity,

percutaneous biliary drainage using a PTC catheter (PTBD) has been attempted.

Other methods, such as endoscopic nasobiliary drainage (ENDB), endoscopic retrograde biliary drainage (ERBD), and metallic stents to decrease obstructive jaundice before surgery, have also been developed.

However, the recent trend in pre-operative biliary drainage (BD) has revealed the hazards of BD and no reduction in mortality.

It has also been asserted that routine pre-operative external BD increases hospital costs. Sohn et al.

reported that the incidence of pancreatic fistulas and wound complications were increased in patients with pre-operative biliary stenting.

The most important unsolved problem, however, is the tendency to develop cholangitis and clogging of endoprostheses.

Nevertheless, in the case of cholangitis, pre-operative drainage is thought to be essential.

In spite of the numerous reports regarding liver and immune function in patients with jaundice and the pre- operative BD state,

we have not been able to confirm that decreased bilirubin levels are indicative of improved liver function and immunity. Many surgeons have their own criteria or preferences regarding bilirubin levels before surgery after drainage; however, it is not well- established at what point in time it is most appropriate to perform the surgery.

Therefore, we evaluated the influence of pre-operative BD on post-operative morbidity in patients who underwent pancreaticoduodenectomy (PD), and we determined what factors are correlated with post- operative morbidity. In the present study we attempted to determine the appropriate pre-operative bilirubin level after drainage.

Table 1. Surgical morbidity in patients who had undergone PPPD or a standard Whipple’s procedure for distal CBD cancers

Number of patients

( N = 100)

No complications 78 (78%)

Morbidity 22 (22%)

Bleedings 9 (9%)

Bleeding only 4 (4%)

GDA aneurysmal bleeding + wound infection 3 (3%)

Bleeding + CJ leak 1 (1%)

Bleeding + wound dehiscence 1 (1%)

Wound problems 7 (7%)

PJ leaks 3 (3%)

PJ leak only 1 (1%)

PJ leak + wound infection 1 (1%)

PJ leak + abscess + wound dehiscence 1 (1%)

Ileus 1 (1%)

Delayed gastric emptying 1 (1%)

Ischemic colitis 1 (1%)

lymphadenectomy and the specimens were removed en bloc, except in the case where there was a vascular anomaly. All patients received prophylactic antibiotic therapy, which was continued for 3-5 days post- operatively. In patients with pre-operative cholangitis, antibiotic therapy was continued during and after the surgical procedure. An oral diet was begun on the 7

post-operative day after a computed tomography confirmed that there were no intra-abdominal complications.

Definition of post-operative complications

The definition of a PJ leak followed the ISGPF definition;

we only regarded grades B and C as clinically significant PJ leaks. Delayed gastric emptying was defined as an inability to remove the nasogastric tube 10 days post- operatively. Bleeding was defined as intra-abdominal and intestinal bleeding requiring a blood transfusion > 3 units, reoperation, or radiologic or endoscopic intervention.

Wound infections were defined as cases in need of resuturing or reapproximation of the wound, including the fascia. Wound dehiscences were defined as exposure of the intra-abdominal organs through a separated wound.

Intra-abdominal abscesses were defined as a collection of

fluid or an abscess, which was confirmed by radiologic examination.

Statistical analysis

Crosstabs, such as Pearson’s chi-square test, Fisher’s exact test, and linear and linear association, were used to compare groups according to post-operative morbidity or bilirubin level immediately prior to surgery. A probability value < 0.05 was considered significant.

Bilirubin, admit: Total bilirubin level at admission; Bilirubin, preop.:

Total bilirubin level prior to surgery; Decrease in bilirubin: bilirubin, admit. - bilirubin, preop.; Rate of bilirubin decrease: decrease in bilirubin / duration of drainage; Bilirubin, POD#1 : Total bilirubin level on 1

postoperative day; ERBD: endoscopic retrograde biliary drainage; PTBD: percutaneous biliary drainage; ENBD : endoscopic nasobiliary drainage; T- tube: Surgical procedure for T-tube insertion

Table 3. Comparison between groups with and without postoperative complications with a focus on total serum bilirubin levels and biliary drainage methods

No complication Complication P value

(N=78) (N=22)

Bilirubin, admit. (mg/dl) 9.0 (± 7.4) 7.8 (± 6.1) 0.477 Bilirubin, preop. 2.8 (± 2.5) 2.2 (± 1.1) 0.241 Duration of drainage (days) 23.3 (± 9.8) 20.2 (± 10.2) 0.209 Decrease in bilirubin * 6.21 (± 6.17) 5.66 (± 5.59) 0.699 Rate of bilirubin decrease 0.28 (± 0.27) 0.59 (± 1.44) 0.227 (mg/[dl ⅹdays])

Bilirubin, POD#1 2.62 (± 1.75) 2.30 (± 1.04) 0.410 Bilirubin, POD#3 2.32 (± 2.50) 2.23 (± 1.21) 0.873 Preop. cholangitis 20 / 78 (25.6%) 4 / 22 (18.2%) 0.580*

Biliary drainage methods 0.349¶

ENBD 40 (51.3%) 10 (45.5%)

PTBD 31 (39.7%) 7 (31.9%)

ERBD 4 (5.1%) 3 (13.6%)

ENBD + PTBD 1 (1.3%) 0 (0.0%) ERBD + ENBD 1 (1.3%) 0 (0.0%) ERBD + PTBD 0 (0.0%) 1 (4.5%)

T-tube 1 (1.3%) 1 (4.5%)

Table 2. Comparison of clinical characteristics between postoperative complication group and no complication group in patients who had undergone pancreaticoduodenectomy for distal common bile duct cancer

No complication Complication P value

(N=78) (N=22)

Age (years) 62.1 (± 9.0) 58.5 (± 10.3) 0.112

Sex 0.871

Male 53 (76.8%) 16 (23.2%)

Female 25 (80.6%) 6 (19.4%)

Preop. WBC (/㎕) 7658.4 ± 3242.5 7281.8 ± 1823.8 0.600 Preop. Hemoglobin (g/dl) 12.57 ± 1.88 12.41 ± 1.25 0.693 Preop. Albumin (g/dl) 3.39 ± 0.59 3.29 ± 0.59 0.477 Preop. Creatine (mg/dl) 0.90 ± 0.44 0.86 ± 0.19 0.706 OP time (minute) 410.7 ± 91.5 448.2 ± 122.1 0.127 RBC transfusion (unit) 0.34 ± 0.78 0.32 ± 0.14 0.915 FFP transfusion (unit) 0.59 ± 1.51 0.27 ± 1.08 0.375

Results

Among the 100 cases, there were 22 cases of post-

Discussion

There are many opinions about the advantages and disadvantages of pre-operative BD in jaundiced patients.

However, many surgeons do not follow their own preferences regarding BD and the methods for BD because most patients who are referred from an internal medicine department have already undergone such drainage procedures. Some surgeons prefer to maintain their preferences about BD and wait until the total bilirubin level decreases to some level because the claims that assert adverse effects of BD have not been validated. In the present study, we selected PD cases for operative complications (Table 1.). Bleeding was the

most common complication (9 cases), and bleeding complications were sometimes combined with other complications, such as wound complications. A PJ leak was noted in 3 cases. Post-operative paralytic ileus, delayed gastric emptying, and ischemic colitis were observed in 1 case each. There was no hospital mortality.

We compared several factors which were considered to be possible risk factors for post-operative complications, such as pre-operative laboratory findings, operative factors (e.g., operative time), and the need for transfusion (Table 2). The group without complications (N = 78) and the group with complications (N = 22) had no statistical differences with respect to these factors.

Pre-operative BD methods (ENBD, PTBD, ERBD, and T-tube insertion) and the duration of BD were not different between the two groups (p = 0.349; Table 3.).

Moreover, serum total bilirubin levels measured on admission, immediately prior to surgery, and on post- operative days 1 and 3 were not statistically different between the two groups. The decreases in bilirubin values between that obtained at the time of admission and that at the pre-operative time after BD were also not different. The rate of bilirubin decline (decreased bilirubin values [mg/dl] / biliary drainage duration [days]) was slightly longer in the group with complications; however, the difference was not statistically significant (p = 0.227).

We compared the group with a bilirubin level < 5.0 mg/dl immediately prior to surgery (hereafter, Bil. < 5.0; N = 14) and the group with a bilirubin level ≥ 5.0 mg/dl immediately prior to surgery (hereafter Bil. ≥ 5.0; N = 86; Table 4). The pre-operative hemoglobin level was lower in the Bil. < 5.0 group (p = 0.001), and the pre- operative creatinine level was higher in the same group (p = 0.000). Pre-operative cholangitis was more frequent in the Bil. < 5.0 group (p = 0.034). Bilirubin levels at the time of admission were also higher in the Bil. < 5.0 group (p = 0.000). Other clinical characteristics, such as preoperative laboratory findings and operative factors, were not different between the two groups. There were also no differences in BD methods between the two groups (p = 0.431). Post- operative morbidity was observed only in the Bil. ≥ 5.0 mg/dl group, which showed a statistically significant difference (p = 0.032).

Table 4. Comparison between patients with a preoperative total bilirubin level ≥ 5.0 mg/dl and < 5.0 mg/dl

Bilirubin < 5.0 Bilirubin ≥ 5.0 P value

( N = 14) (N = 86)

Age (years) 63.3 ± 6.9 60.9 ± 9.7 0.394

Preop. WBC 8971.4 ± 3741.9 7344.7 ± 2797.8 0.057 Preop. Hb. 11.68 ± 3.47 12.68 ± 1.25 0.001 Preop. Albumin 2.91 ± 0.69 3.45 ± 0.55 0.308 Preop. Creatinine 1.07 ± 0.94 0.86 ± 0.19 0.000 RBC transfusion 0.57 ± 1.02 0.30 ± 0.55 0.308 FFP transfusion 0.77 ± 1.88 0.48 ± 1.35 0.144 Preop. cholangitis 7/14 (50.0 %) 17/86 (19.8 %) 0.034 Bilirubin, admission 17.76 ± 6.92 7.31 ± 6.05 0.000

Drainage methods 0.431

ENBD 6 (42.9%) 44 (51.2%)

PTBD 8 (57.1%) 30 (34.9%)

ERBD 0 (0.0%) 7 (8.1%)

ENBD + PTBD 0 (0.0%) 1 (1.2%) ERBD + ENBD 0 (0.0%) 1 (1.2%) ERBD + PTBD 0 (0.0%) 1 (1.2%)

T-tube 0 (0.0%) 2 (2.3%)

Postop. morbidity 0/14 (0.0 %) 22/86 (25.6 %) 0.032

Conclusion

Pre-operative BD methods, the duration of BD, decreased bilirubin values obtained at the time of admission and pre-operatively after BD, and the rate of bilirubin decline did not affect postoperative morbidity after PD. However, separating the patients into two groups based on a bilirubin level of 5.0 mg/dl immediately prior to surgery showed a significant difference in post-operative morbidity. Therefore, we suggest that for patients with bilirubin levels > 5.0 mg/dl, the surgeon waits until the pre-operative bilirubin level decreases to < 5.0 mg/dl after biliary drainage.

distal CBD cancers performed by only one surgeon to rule out bias involving surgeons’ skills and operative methods. As mentioned in the Materials and Methods section, there were only 3 patients who did not undergo pre-operative BD.

To evaluate bilirubin-related factors and post- operative morbidity, we compared total serum bilirubin levels between the group with no post-operative morbidity and the group with morbidity at several time points (day of admission, prior to surgery, and post- operative days 1 and 3). The BD methods, duration of drainage, the level to which bilirubin decreased during drainage, and the rate of bilirubin decrease were also compared. There were no significant bilirubin-related risk factors for post-operative morbidities. These results support the reports that claim no relationship exists between pre-operative BD and increased post- operative complications.

Most, if not all surgeons, have their own opinions about operative time in patients who have jaundice or pre-operative cholangitis. Some surgeons prefer a bilirubin level < 2.0 mg/dl before surgery. Nimura and Makuuchi recommended a routine pre-operative BD until the bilirubin level is < 3 mg/dl to minimize complications.

Thomas et al.

suggested that groups with pre-operative bilirubin levels < 5 mg/dl and >5 mg/dl were not significantly different with r e s p e c t t o s u r g i c a l c o m p l i c a t i o n s, g e n e r a l complications, and mortality. However, on logistic regression, the pre-operative serum bilirubin level was an independent factor predicting mortality (p = 0.02). Su et al.

also reported that a total bilirubin ≥ 10 mg/dl was a significant factor affecting survival after resection for cholangiocarcinoma.

In our study, we selected a bilirubin level of 5.0 mg/dl as the cut-off point because in our institute we prefer that surgery is done only after the bilirubin is <

5.0 mg/dl. There were no meaningful risk factors for post-operative morbidity, including pre-operative cholangitis (Tables 2 and 3). However, pre-operative cholangitis is a well-known risk factor for post- operative morbidity and mortality.

In comparing the Bil. < 5.0 and ≥ 5.0 groups, pre-operative cholangitis was more frequent in the Bil. < 5.0 group

than the Bil. ≥ 5.0 group (50.0% vs. 19.8%, p = 0.034). The pre-operative creatinine level, and possible untoward factors of post-operative morbidity if the creatinine level was elevated, were lower in the Bil < 5.0 group. On the other hand, the pre-operative hemoglobin level, regarded as an affirmative factor if elevated, was lower in the Bil <

5.0 group. Despite such influences, the Bil. < 5.0 group had no post-operative morbidity.

This study had several limitations. First, the present study was a retrospective, rather than a randomized study. Second, the number of patients in the Bil. < 5.0 group was small (N = 14). Third, in the logistic regression analysis of risk factors for post-operative morbidity, the pre-operative bilirubin level did not influence morbidity (p = 0.241, Table 3.). Even with these limitations, there was a clear difference in post-operative morbidity between the Bil. < 5.0 and

≥ 5.0 groups (p = 0.032). Therefore, we suggest waiting until the bilirubin level decreases to < 5.0 mg/dl after BD before proceeding with surgery.

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