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Risk factors for pancreatic fistula following pancreaticoduodenectomy: A retrospective study in a Thai tertiary center

AIM To analyze the risk factors of postoperative pancreatic fistula following pancreaticoduodenectomy in a Thai tertiary care center. METHODS We retrospectively analyzed 179 patients who underwent pancreaticoduodenectomy at our hospital from January 2001 to December 2016. Pancreatic fistula were classified into three categories according to a definition made by an International Study Group on Pancreatic Fistula. The risk factors for pancreatic fistula were analyzed by univariate analysis and multivariate logistic regression analysis. RESULTS Pancreatic fistula were detected in 88/179 patients (49%) who underwent pancreaticoduodenectomy. Fifty-eight pancreatic fistula (65.9%) were grade A, 22 cases (25.0%) were grade B and eight cases (9.1%) were grade C. Clinically relevant pancreatic fistula were detected in 30/179 patients (16.7%). The 30-d mortality rate was 1.67% (3/179 patients). Multivariate logistic regression analysis revealed that soft pancreatic texture (odds ratio = 3.598, 95%CI: 1.77-7.32) was the most significant risk factor for pancreatic fistula. A preoperative serum bilirubin level of > 3 mg/dL was the most significant risk factor for clinically relevant pancreatic fistula according to univariate and multivariate analysis. CONCLUSION Soft pancreatic tissue is the most significant risk factor for postoperative pancreatic fistula. A high preoperative serum bilirubin level (> 3 mg/dL) is the most significant risk factor for clinically relevant pancreatic fistula.

Recently, a soft pancreas and high body mass index (BMI) were reported as the most common risk factors for POPF [9][10][11][12][13] . However, POPF risk factors have not been studied in a Thai population before. The aim of this study was to analyze the risk factors of POPF following PD in a Thai tertiary care center.

Patients
From January 2001 to December 2016, 210 conse cutive patients underwent PD at the Department of Surgery in Ramathibodi Hospital, Bangkok, Thailand and were considered for inclusion in the study. Patients who underwent a concomitant hepatic resection were excluded; in the end, a total of 179 patients were included. Patient data were retrospectively reviewed. These included age, gender, weight, BMI, underlying disease, serum albumin, preoperative total bilirubin levels and preoperative biliary drainage (PBD). In addition, we recorded the use of percutaneous transhepatic biliary drainage or placement of an endoscopic internal biliary stent. We also reviewed the type of operation, pancreatic texture, pancreatic duct size, type of PE anastomosis, use of trans-anastomotic pancreatic duct stent, pathological diagnosis, operative time and operative blood loss. Ethical permission for this study was obtained from the hospital's ethics committee.

Preoperative evaluation
The general condition of patients and any co-morbid conditions were preoperatively assessed by a physician, surgeon and internist. The diagnosis and clinical staging of the disease were reviewed preoperatively by a multidisciplinary team including surgeons, radiologists and gastroenterologists.
Child's technique, starting with a pancreaticojejunostomy (PJ). A PJ can be performed using either a invagination or duct to mucosa technique and this was decided based on the surgeon's preference. A transanastomotic pancreatic duct stent was placed in selected patients, depending on surgeon's preference. The trans-anastomotic pancreatic duct stent was either internal (in the jejunum) or external (partly outside the body). After PJ, biliaryenteric anastomosis was performed followed by a gastro-jejunostomy or duodeno-jejunostomy. A Braun loop jejunojejunostomy was performed in some patients, according to the surgeon's preference. Pancreatic texture was classified into hard, firm or soft consistency based on palpitation by the surgeon. A closed peri-anastomotic drainage system was placed routinely.

Postoperative complications
After surgery, patients were transferred to a critical care unit or intermediate ward. Routine biochemical analyses of patients' blood were performed. An oral diet was started as soon as the output gastric content was < 400 mL and a positive bowel movement occurred. Parenteral nutrition was initiated if the patients did not have a bowel movement or the gastric content was > 400 mL after postoperative day (POD) 3.
POPF was defined according to International Study Group of Pancreatic Fistula (ISGPF) guidelines by amylase levels that were three times higher in the drainage fluid than the serum. POPFs were classified into three categories: (1) Grade A: Transient pancreatic fistula with no clinical impact; (2) grade B: Required a change in management or adjustment of the clinical course; and (3) grade C: Required a major change in clinical management or deviated from the normal clinical course [26] . Combined grade B + C fistulas were defined as "clinically relevant pancreatic fistula" (CRPOPF). DGE was defined as either nasogastric tube insertion after POD 3 or as the inability to tolerate solid food intake by POD 7. Chyle leakage was defined as a milky drain output or triglyceride levels of > 110 mg/dL in the drain fluid on any POD. Postoperative mortality was recorded as the 30-d mortality and in-hospital mortality.

Patient characteristics were compared by t-test,
Wilcoxon Mann-Whitney test, χ 2 test and Fisher's exact test. A P-value of < 0.05 was considered statistically significant. Risk factors were analyzed by univariate and multivariate methods using binary logistic regression analysis. Independent risk factors were expressed as odds ratios (ORs) with 95%CI.  Table 1 compares the post-PD complications between POPF and no POPF groups. Age, serum albumin levels, operative blood loss, gender, diabetes mellitus and PBD were not statistically different between the two groups. However, statistically significant differences were observed in BMI, preoperative total serum bilirubin, pancreatic duct diameter, operative time, cardiovascular disease, pancreatic texture and trans-anastomotic stent between the two groups. The POPF group had a higher rate of other complications (5.5% vs 25%, P < 0.001) and a longer LOH (15 d vs 25 d, P < 0.001).

Risk factors for POPF
Univariate and multivariate analyses were used to identify risk factors for POPF (

Effect of POPF grade on patient characteristics and operative outcomes and predictive factors for CR-POPF
Preoperative total bilirubin and pancreatic reconstruction techniques (duct to mucosa vs invagination) were significantly different between grade A POPF and CRPOPF (Table 3). Univariate analysis revealed preoperative total serum bilirubin levels of more than 3 mg/dL as a potential risk factor for grade A POPF (OR 3.749, 95%CI: 1.48-9.51, P = 0.005). Multivariate analysis revealed total serum bilirubin levels of more than 3 mg/dL as the most significant predictive factor for CRPOPF (OR 4.50, 95%CI: 1.54-13.15, P = 0.006) ( Table 4).

DISCUSSION
The most common perioperative complication of PD is    POPF. POPF remains the leading cause of complications such as DGE and postoperative hemorrhage, which increase mortality [1][2][3] and the LOH. Many risk factors for POPF have been reported previously [4][5][6][7][8][9] . In the present study, the incidence of POPF and the 30d mortality rate were similar to previous studies. In addition, we identified soft pancreatic texture as a main risk factor for POPF [8][9][10][11][12] .
Our multivariate analysis showed that a soft pancreas is the most independent predictive factor for POPF. This is in agreement with previous studies [5,[9][10][11][12]27] . There are many reasons why soft pancreatic tissue increases the risk of POPF. First, a soft pancreas makes it more difficult to secure PEA because friable pancreatic tissue cannot hold suture tension. As a result, suture materials cut through the pancreatic parenchyma and anastomosis fails. A soft pancreas is also prone to ischemia when manipulated, which disrupts anastomosis. Finally, a soft pancreas has enriched exocrine function and pancreatic enzymes are released when leakage occurs [9,11,27,28] . The assessment of pancreatic texture is controversial and subjective. Pancreatic texture is commonly assessed intraoperatively by palpation. Callery et al [11] reported the clinical risk score for POPF based on pancreatic texture, pancreatic duct diameter and intraoperative blood loss. They classified the pancreatic texture as firm or soft [11] . Some studies have classified pancreatic texture as hard, firm or soft, but the distinction between a hard and firm pancreas remains unclear [1,5] .
Recently, Ansorge et al [29] reported similar risk factors for POPF. They classified the pancreatic texture into four grades, including very hard (severe chronic pancreatitis), hard (fibrotic or atrophic obstructed pancreatic gland), soft (unaffected compact gland), and very soft (unaffected fatty pancreas). They found that 44/100 patients had a hard pancreas. The rate of POPF in the very hard/hard groups was significantly different to that in the soft/very soft groups [29] . There is a newly developed tissue strain imaging technology reflecting tissue fibrosis or stiffness and is integrated into a conventional ultrasound system called acoustic radiation force impulse (ARFI). Lee et al [30] and Harada et al [30] reported the high accuracy of ARFI for prediction of the stiffness of pancreas preoperatively. The relationship between soft and fatty pancreatic tissue has been well studied [28][29]32] . A fatty pancreas refers to the increasing infiltration of adipose tissue into the pancreas [28] . Ansorge et al [29] found that the softness of pancreatic tissue was strongly associated with fat levels in the tissue. This was supported by previous reports that a fatty pancreas is a risk factor for POPF [13,28,32] . Taken together, these findings suggest that the infiltration of adipose tissue into the pancreas is associated with soft pancreatic texture.
The assessment of pancreatic texture is difficult and subjective. Currently, there are no standard procedures for the intraoperative assessment of pancreatic texture. Pancreatic texture has commonly been assessed intraoperatively by palpation [5,11,29] . In the present study, we also assessed pancreatic texture by palpation. This subjective assessment of pancreatic texture could have differed from surgeon to surgeon. Unfortunately, it was not possible to assess pancreatic texture during the preoperative evaluation. Tranchart et al [33] used computed tomography to predict the occurrence of severe pancreatic fistula following PD. They found that a visceral fat area of more than 84 cm 3 was associated with a fatty pancreas (58.4% vs 48.1%, P = 0.005) and was a risk factor for CRPOPF (OR 8.16 95%CI: 2.23, P = 0.002). They suggested preoperative assessment of body fat distribution as a means of evaluating fat levels in the pancreas and predicting the occurrence of CRPOPF [33] . In our study, the incidence of CRPOPF is high when compared to previous studies [5,6,11,12] . This could be explained by the lower population of pancreatic cancer in this study that the pancreatic cancer is more likely to obstruct the pancreatic duct and therefore increase fibrosis of the pancreas [11] .
Obstructive jaundice was previously regarded as the main factor increasing perioperative morbidity and mortality. The pathophysiology of obstructive jaundice includes increasing endotoxin concentrations in the portal circulation, altered Kupffer cell function affecting the reticuloendothelial system in the liver, over-activation of inflammatory cascades, decreased cellular immunity and renal dysfunction. These manifestations influence the nutritional status of patients. PBD decreased postoperative septic complications in mice by improving liver function, nutritional status, cell-mediated immune function, systemic endotoxemia, cytokine release and the overall immune response [34] . Regarding periampullary obstruction, endoscopic drainage approach today represents the procedure of choice with high succession rate [35,36] .
In this study, a preoperative serum bilirubin level of more than 3 mg/dL was a risk factor for CRPOPF. Kimura et al [3] reported that serum bilirubin of more than 2.0 mg/dL was a significant preoperative risk factor for higher 30-d and in-hospital mortality rates following PD [3] . Gebauer et al [37] found that patients with POPF who underwent repeated surgery had higher in-hospital mortality (0.6 vs 0.7, P = 0.002) and total serum bilirubin levels (0.7 vs 1.1, P = 0.003) than POPF patients that did not undergo reoperation). In a previous study, multivariate binary logistic regression model analysis revealed that a serum bilirubin level of > 2.0 mg/dL is an independent risk factor for reoperation (OR 25.053, 95%CI: 3.486180.069) [37] . Some previous studies have identified higher serum bilirubin levels in CRPOPF patients, but these differences were not statistically significant. For example, El Nakeeb et al [12] reported a preoperative bilirubin level of 4.6 mg/dL in patients with grade A POPF and 9.7 mg/dL in patients with CRPOPF, but this difference was not significant. This was supported by Braga et al [38] , who detected higher total serum bilirubin in patients with grade Ⅲ-Ⅳ complications than patients with grade 0-Ⅱ complications (3.5 mg/dL vs 1.6 mg/dL). Again, this difference was not statistically significant. Fujii et al [39] found that endoscopic internal drainage posed a higher risk for POPF than endoscopic nasobiliary drainage.
In a recent systematic review, Scheufele et al [40] reported that POPF rates do not differ between PBD and no drainage groups. However, a higher infectious complications rate was detected in the PBD group. Most of the studies included in this review were retrospective studies, and the most frequent complications were wound-related [40] . A few randomized control trial studies have now been performed by a Dutch group. In these studies, the POPF rate did not differ between PBD and surgery first groups following PD. However, the population in the POPF group was only 16%, which may not have been high enough to obtain sufficient statistical power [31] . Current evidence does not recommend routine PBD because the rate of infectious (usually wound-related) complications is higher. However, a randomized control trial of a large population is needed to clarify this in the case of CRPOPF.
In this study, 66.8% of patients underwent PBD, which is higher than previous reports [39][40][41] . This could be explained by the fact that Thailand is a low to midincome country, therefore patients with periampullary tumor and pancreatic cancer usually present with severe obstructive jaundice and have poor nutritional status. Serum bilirubin levels were higher than 15 mg/dL and serum albumin levels were less than 30 mg/dL in most patients. In addition, high-volume centers have patient congestion, limited resources and long waiting lists for operations.
This study was limited by the small study population. A larger population study might have revealed more significant risk factors of POPF.
In conclusion, we have identified a soft pancreas as an independent risk factor of POPF. A fatty pancreas is strongly associated with a soft pancreas and can be measured to predict CRPOPF. Preoperative detection of a fatty pancreas by CT and newly developed ultrasound technology is a potential method for predicting a soft pancreas preoperatively. However, this needs to be confirmed by large population studies. At the moment, PBD is not routinely recommended because the rate of infectious complications is higher. Further studies are required to clarify the link between preoperative obstructive jaundice and CRPOPF.

Research background
Many risk factors have been reported for postoperative pancreatic fistula (POPF), including obesity, soft pancreatic texture, small pancreatic duct and low volume center. Some studies have investigated ways to improve the surgical outcome and reduce POPF, including the placement of an external and internal trans-anastomotic pancreatic duct, pancreatogastrostomy, omental rollup around pancreaticoenteric (PE) anastomosis, application of fibrin sealants around PE anastomosis and prophylaxis with somatostatin analogs. However, the outcomes of these different methods remain controversial. Recently, a soft pancreas and high body mass index (BMI) were reported as the most common risk factors for POPF. However, POPF risk factors have not been studied in a Thai population before. The aim of this study was to analyze the risk factors of POPF following PD in a Thai tertiary care center.

Research motivation
The most common perioperative complication of pancreaticoduodenectomy is POPF. POPF remains the leading cause of complications such as DGE and postoperative hemorrhage, which increase mortality and the LOH. Many risk factors for POPF have been reported previously.