Abstract
Objectives: Despite improvements in surgical techniques, instruments and perioperative management, postoperative pancreatic fistula (POPF) remains a serious complication after pancreaticoduodenectomy. The aim of the present study was to characterize a high-risk group for POPF after pancreaticoduodenectomy using perioperative clinical variables of patients. Patients and Methods: This retrospective study comprised of 247 patients who had undergone pancreaticoduodenectomy between May 2000 and May 2013. Perioperative risk factors pertinent to development of POPF were investigated using univariate and multivariate analyses. Results: POPF developed in 43 out of 247 patients (17.4 %). In univariate analysis, male gender (p=0.005), higher postoperative serum amylase (p=0.025) and lower postoperative serum albumin (p=0.041) were significant risk factors for POPF. In multivariate analysis, male gender (p=0.008) and lower postoperative serum albumin (p=0.010) were found to be independent risk factors. Conclusion: Male gender and postoperative lower serum albumin were associated with the development of POPF after pancreaticoduodenectomy.
Pancreaticoduodenectomy is one of the accepted operative methods for patients with pancreatic cancer, bile tract cancer and other benign diseases worldwide. Pancreaticoduo-denectomy was first successfully performed as a two-stage procedure in 1912 (1) and as a one-stage procedure in 1914 (2). Despite improved indication for surgery, surgical techniques, instruments and perioperative management, in-hospital mortality rate after pancreaticoduodenectomy remains high (1-4%) (3, 4). New strategies are needed to further reduce the substantial incidence of postoperative complications and the significant postoperative mortality rate.
Postoperative pancreatic fistula (POPF) is the most frequent serious complication after pancreaticoduodenectomy (5, 6) and has been reported to be associated with a high incidence of postoperative mortality and prolonged postoperative hospital stay by causing intra-abdominal abscess, intra-abdominal bleeding and sepsis (6, 7). Risk factors for POPF are multifactorial, such as soft pancreatic parenchyma and narrow main pancreatic duct (8-10). Therefore, risk stratification of POPF after pancreaticoduodenectomy may help postoperative management.
Prediction of surgical risks by evaluation of postoperative nutritional or inflammatory status can be useful to prevent POPF. Ryan et al. reported that lower postoperative serum albumin may be a risk factor of postoperative complications in patients undergoing esophagectomy (11). Preoperative elevation of blood urea nitrogen (BUN) and preoperative low serum albumin have been associated with increased risk of morbidity and mortality in patients undergoing pancreaticoduodenectomy (12).
We hypothesized that postoperative nutritional or inflammatory status might be related to the development of POPF after pancreaticoduodenectomy. In the present study we retrospectively investigated perioperative clinical variables to identify predictors of POPF.
Patients and Methods
Patients and patients' management. Between May 2000 and May 2013, 247 patients underwent pancreaticoduodenectomy for various primary diseases in the Department of Surgery, Jikei University Hospital, Tokyo, Japan (151 male and 96 female; mean age, 65.7 years; range, 15-83 years) for this study. The procedures included pancreaticoduodenectomy (PD) (n=234) and pylorus-preserving duodenopancreatectomy (PpPD) (n=13). Basically, reconstruction of digestive tracts was performed using the modified Child's method with a retro-colic gastrojejunostomy. Pancreaticojejunostomy was performed by both duct to mucosa and the pull-through adhesive anastomosis using the modified Kakita's method with restrictive use of external pancreatic duct stenting.
Patients' characteristics.
Pancreatic fistula was defined by the guideline of the International Study Group on Pancreatic Fistula (ISGPF) (13). Pancreatic fistula was classified into three categories by ISGPF as follows: transient pancreatic fistula (no clinical impact) (grade A); requiring a change in management or adjustment in the clinical pathway (grade B); needing a major change in clinical management or deviation from the normal clinical pathway (grade C). In the present study, grade B and C were defined as “postoperative pancreatic fistula (POPF)”. Hemogram and chemistry profile were routinely measured for each patient preoperatively and on postoperative day (POD) 1.
Absolute white blood cell (WBC), neutrophil, lymphocyte and monocyte counts, as well as serum total bilirubin, albumin and CRP were routinely determined in peripheral venous samples. Use of blood products and dose were determined by the preference of attending surgeons based on guidelines for administration of blood products by the Japanese Ministry of Health and Welfare settled in 1999 (14), as well as intraoperative blood loss, postoperative hemoglobin, serum albumin and prothrombin time.
At first, to assess the risk factors for POPF, we investigated the relation between clinical variables and POPF after pancreaticoduodenectomy by univariate and multivariate analyses. The following 22 factors were included for analysis: age, gender, diagnosis, duration of operation, intraoperative blood loss, perioperative transfusion of red blood cell (RCC) or fresh-frozen plasma (FFP), concomitant resection of the portal vein or other organs, co-existent disease of cardiovascular nature, coexistent disease of diabetes mellitus, body mass index (BMI), pre- and postoperative neutrophil counts, lymphocyte and monocyte counts, pre- and postoperative serum amylase, pre- and postoperative serum albumin, as well as pre- and postoperative serum CRP.
Pathological diagnosis and incidence of grade B or C POPF.
This study was approved by the Ethics Committee of the Jikei University School of Medicine (# 21-121).
Statistical analysis. Data were expressed as a mean±standard deviation (SD). Univariate analyses were performed using the Mann-Whitney's U-test or Chi-square test. Multivariate analyses were performed using logistic-regression analysis. The software package SPSS (version 20; IBM SPSS statistics®, Tokyo, Japan) was used for statistical analyses. All p-values were considered statistically significant when the association probability was less than 0.05.
Results
Patients' characteristics. Patients' characteristics are listed in Table I. Among the study population, the mean age was 65.7 years. Two hundred twenty-two patients underwent pancreaticoduodenectomy for malignant diseases and 25 patients for benign diseases. The median operating time was 505 min and the median intraoperative blood loss was 880 g. The number of intraoperative transfusion of RCC and FFP product was 4.56 units. The mean preoperative serum albumin and postoperative serum albumin were 3.79 and 2.83 g/dl, respectively. POPF developed in 43 of 247 patients (17.4%).
The pathological diagnosis and incidence of POPF are summarized in Table II. The number of POPF, which underwent pancreaticoduodenectomy for malignant and benign diseases was 40 out of 222 patients (18%) and 3 out of 25 patients (12%), respectively.
Univariate and multivariate analyses of clinical variables in relation to POPF after pancreaticoduodenectomy. Table III lists the relationship between clinical variables and POPF after pancreaticoduodenectomy. In univariate analysis, male gender (p=0.005), serum amylase on POD 1 (p=0.025) and serum albumin on POD 1 (p=0.041) were significantly higher in patients with POPF. In multivariate analysis, male gender (p=0.008, OR=2.979) and serum albumin on POD 1 (p=0.010, OR=2.819) were found to be independent risk factors (Table IV).
Univariate analysis of clinical variables in relation to postoperative pancreatic fistula grade B or C after pancreaticoduodenectomy.
Multivariate analysis of clinical variables in relation to postoperative pancreatic fistula grade B or C after pancreaticoduodenectomy.
Discussion
The major complications, including POPF after pancreaticoduodenectomy, are hospital stay and septic complications. Our data demonstrated a 17.4% incidence of POPF, which was within the incidence range of 5 to 25 % recently reported in large series (5, 6). Several studies have evaluated the risk factors for POPF after pancreaticoduo-denectomy. Gouma et al. (15) reported elevated serum creatinine levels, duration of operation and need for blood transfusion as independent risk factors for major complications after pancreaticoduodenectomy. They also reported that overall mortality after pancreaticoduodenectomy in hospitals which performed less than five pancreaticoduodenactomies per year has been increased.
In this study, male gender and postoperative serum albumin were found as independent factors related to POPF. These findings suggested that postoperative nutritional, inflammatory and immune response after pancreaticoduodenectomy may be related to POPF. Hypoalbuminemia is often linked to poor tissue healing, decreased collagen synthesis in surgical wounds or at anastomoses, delayed return of bowel function and impairment of cell-mediated immune response, such as macrophage activation and granuloma formation (16, 17). Therefore, wound infection, remote infections, such as pneumonia and anastomotic leakage, are commonly observed in hypoalbuminemic patients. In addition, serum albumin concentration reflected to suppress systemic inflammatory responses (18, 19). The postoperative systemic immune response, according to the invasiveness of pancreaticoduodenectomy, includes cytokines, such as tumor necrosis factor alpha (TNFα) and interleukin (IL)-6, which play a key role in catabolic metabolism (20). As a result, an immunnutritional disorder causes a decline in albumin concentration, total lymphocyte count, including helper T cells, interleukins 2 and 3 and T cell blastogenic responses (21-23). Therefore, a compromised immunonutritional status is an important factor that can lead to increased postoperative complications including POPF after PD.
POPF is one of the most significant complications after pancreaticoduodenectomy, which is associated with increased postoperative hospital stay and finite resource utilization. Successful management of POPF after pancreaticoduodenectomy often depends on early detection of POPF and an available external drainage of intra-abdominal fluid collection plays a key role (13, 24). However, in various abdominal surgeries, abbreviation of an external drainage may not be related to increase morbidity. Moreover, the placement of external drain may increase the rate of surgical site infection and intra-abdominal abscess (25, 26). Bassi et al. (26) reported that early removal of external drain after pancreatic resection on POD 3 was related to a decreased rate of pancreatic fistula and abdominal, as well as pulmonary complications, in patients with amylase value in drains < or =5,000 U/L on POD 1. Furthermore, median in-hospital stay was shorter and hospital costs decreased; postoperative mortality was comparable. These results suggest that the placement of external drainage after pancreaticoduodenectomy is not mandatory and, if placed, should be removed as soon as possible. Therefore, an early detection of the low risk group with POPF after pancreaticoduodenectomy is useful.
The results of this study show that postoperative nutritional, inflammatory and immune response(s), as evidenced by serum albumin on POD 1, were independently associated with an increased risk of the development of POPF in patients after pancreaticoduodenectomy. Risk stratification of POPF on POD 1 may improve the management of POPF and prevent more severe complications, such as intra-abdominal abscess, intra-abdominal bleeding and sepsis. Further investigation to clarify the relationship between the postoperative nutritional status and POPF is needed for improving the therapeutic outcome.
Conclusion
Male gender and postoperative lower serum albumin were associated with the development of POPF after pancreaticoduodenectomy. These risk stratifications may help perioperative management of pancreaticoduodenectomy.
Footnotes
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Conflicts of Interests
All Authors declare that there exist no conflicts of interest.
- Received August 5, 2014.
- Revision received September 5, 2014.
- Accepted September 5, 2014.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
