Journal of Cancer Research and Therapeutics

ORIGINAL ARTICLE
Year
: 2019  |  Volume : 15  |  Issue : 4  |  Page : 857--863

Pancreatic fistula after pancreaticoduodenectomy: Risk factors and preventive strategies


Jian-Shu Chen1, Gang Liu2, Tian-Ran Li1, Jian-Yu Chen1, Qi-Ming Xu1, Yan-Zhen Guo1, Ming Li1, Li Yang3,  
1 Department of Radiology, The 4th Medical Center of Chinese PLA General Hospital, Beijing, China
2 Department of Radiology, OASIS International Hospital, Beijing, China
3 Department of Radiology, The 1st Medical Center of Chinese PLA General Hospital, Beijing, China

Correspondence Address:
Gang Liu
Department of Radiology, OASIS International Hospital, No. 9 North Jiuxianqiao Road, Chaoyang District, Beijing 100015
China

Abstract

Purpose: Postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD) is a worrisome and life-threatening complication. This study aimed to investigate the risk factors and preventive strategies for POPF after PD. Materials and Methods: We retrospectively reviewed 301 consecutive patients who underwent PD at our hospitals between January 2011 and December 2017. We analyzed the pancreatic fistula rate according to the clinical characteristics, pathologic and laboratory findings, and the anastomotic methods and summarized the prevention measures. Results: Postoperative morbidities included pancreatic leakage in 10.30% (31/301), delayed gastric emptying in 22.92% (69/301), abdominal infection in 6.98% (21/301), post-PD hemorrhage in 4.65% (14/301), and bile leakage in 4.98% (15/301), and the mortality rate was 2.33% (7/301). POPF was the most prominent factor for preoperative morbidity. Significant risk factors for pancreatic fistula were a soft pancreas, small pancreatic duct, tumor location, and interrupted anastomosis. Of these, soft texture, pancreatic duct <4 mm, and end-to-end anastomosis through hand suture closure were independent risk factors on multivariate analysis, while interrupted anastomosis, internal stent, and somatostatin use were risk factors in the high-risk pancreas subgroup. Conclusions: Our study demonstrated that pancreatic fistula is related to a soft texture and small pancreatic duct. The surgeon must consider these risk factors when performing PD. Thus, we propose a risk- and indication-adapted choice of anastomosis or an individualized approach for the pancreatic remnant to reduce the pancreatic fistula rate.



How to cite this article:
Chen JS, Liu G, Li TR, Chen JY, Xu QM, Guo YZ, Li M, Yang L. Pancreatic fistula after pancreaticoduodenectomy: Risk factors and preventive strategies.J Can Res Ther 2019;15:857-863


How to cite this URL:
Chen JS, Liu G, Li TR, Chen JY, Xu QM, Guo YZ, Li M, Yang L. Pancreatic fistula after pancreaticoduodenectomy: Risk factors and preventive strategies. J Can Res Ther [serial online] 2019 [cited 2020 Mar 30 ];15:857-863
Available from: http://www.cancerjournal.net/text.asp?2019/15/4/857/264286


Full Text



 Introduction



Pancreatoduodenectomy (PD) is the gold standard surgical procedure performed for both benign and malignant diseases of the pancreas and periampullary region.[1] The incidence of pancreatic fistulas after PD is reportedly 6%–25%, and the mortality rate remains from 2% to 10% in many hospitals.[2],[3],[4],[5] Pancreaticojejunostomy (PJ) anastomotic leakage is the single most important factor responsible for the considerable morbidity and mortality associated with PD. Pancreatic fistula resulting from inflammation around leakage sites due to static fluid induce abdominal infection, abscess formation, and rupture of pseudoaneurysms or delayed hemorrhage.[4],[5] Patients who underwent PD at our hospitals were retrospectively reviewed to analyze the risk factors for pancreatic fistula and summarize the strategies for preventing postoperative pancreatic fistula (POPF).

 Materials and Methods



Patients

Between January 2011 and December 2017, 301 consecutive patients who underwent radical PD or pylorus-preserving PD at our hospital were enrolled in this study. All of the patients were diagnosed on the basis of pathologic examinations. Serum chemistries and disease-specific tumor markers (carcinoembryonic antigen, CA 19-9, and CA125) were obtained in the preoperative clinic. Imaging studies employed abdominal ultrasonography, total body computed tomography (CT), abdominal magnetic resonance imaging, endoscopic retrograde cholangiopancreatography with brushing for cytology, and endoscopic transduodenal ultrasonography with pancreatic fine-needle biopsy. An endoscopic stent or nasobiliary drainage was positioned whenever required. The study protocol was approved by the Institutional Ethics Committee of the PLA General Hospital, in accordance with the International Conference on Harmonization guidelines for Good Clinical Practice (E6, 1996), Declaration of Helsinki (1975), and its subsequent revisions. All patients received information on the purpose and conduct of this study and provided written informed consent.

Surgery and pancreatic anastomotic techniques

The surgical procedures were performed according to a Whipple-Child operation: En bloc resection of a section of the pancreatic head on the left margin of the mesenteric-portal vein, section of the biliary duct, section of gastric or preservation of the pylorus, and section of the first jejunal loop and cholecystectomy with resection margin frozen examination.[1],[6],[7] Usually, while the tumor infiltrates portal vein is <180° or >180° without thrombosis responding to neoadjuvant chemotherapy, the tumor involving a short segment of the hepatic artery responding to neoadjuvant therapy, the portal vein and/or hepatic artery resection margin being free of cancer, and an R0 resection.

Three kinds of techniques in pancreatic anastomosis after PD were adopted with a little modification in this series according to the previous studies as follows.[8],[9],[10]

Interrupted suture maneuver (end-to-side duct-to-mucosa anastomosis)

With interrupted sutures at the outer layer of the anastomosis using absorbable thread, the so-called interrupted suture maneuver was performed. Briefly, the jejunal limb is brought into the retroperitoneum adjacent to the pancreas. A two-layer anastomosis is constructed with interrupted absorbable suture thread beginning with a posterior row of seromuscular sutures securing the jejunum to the pancreas. The pancreatic duct-to-mucosa anastomosis is performed to an enterotomy in the jejunum with a second circumference initial layer of interrupted sutures. Generous amounts of pancreas and the full thickness of the jejunum are gathered, followed by the completion of an anterior layer of seromuscular sutures, and the anterior aspect of the opened jejunum is anchored to the capsule of the pancreas.

Blumgart's anastomosis (modified duct-to-mucosa pancreatojejunostomy)

One noteworthy variation of the duct-to-mucosa technique is the transpancreatic U-suture technique with a duct-to-mucosa anastomosis described by Blumgart et al., in short, Blumgart's anastomosis, which is similar to end-to-end anastomosis. In this technique, an outer full-thickness layer of polyglactin sutures is first inserted anterior to posterior through the pancreas with a subsequent seromuscular horizontal mattress suture on the jejunum with polydioxanone (PDS) or polypropylene (Prolene), followed again by a full-thickness posterior to anterior bite coming up through the pancreas. Care is taken not to pass the needle through the pancreatic duct. The u-stitches are not tied yet, and a duct-to-mucosa anastomosis is then created with fine PDS interrupted sutures. The seromuscular sutures are then tied, bringing the jejunum into close apposition anteriorly on the pancreas.

End-to-end anastomosis (end-to-end anastomosis and invagination)

Pancreatic remnant is freed for about 1 cm in preparation for the end of the jejunum to invaginate it. A posterior outer layer of a 4-0 polypropylene (Prolene) continuous sutures secures the jejunal seromuscular wall to the posterior pancreatic parenchyma. The cut surface of the jejunum is sewn to the inner margin of the pancreas. An additional anterior layer of continuous sutures is placed to pull the jejunal wall up over the pancreatic parenchyma for approximately 1–2 cm.

Except for patients with a remarkably dilated main pancreatic duct, a stent tube was inserted into the pancreatic duct according to doctor's preference. Silastic flexible drains (Blake® drain, Ethicon, Beijing, China) were placed at the anterior and posterior surfaces of the pancreaticojejunal and choledochojejunal anastomosis.

Preoperative management

For all patients, antibiotics and H2 blockers were continuously administered. Blood tests and the amylase content discharged from the closed-suction drains were examined on days 1, 3, 5, and 7 after resection. Blood glucose level was routinely monitored, and appropriate levels were maintained (72 mg/dL ≤ glucose level <180 mg/dL). All patients underwent US or CT examinations when necessary to assess the presence of abdominal fluid collections. Infectious complications were treated with selected antibiotics according to blood culture and antibiograms. The fluid amylase level from all drains placed near the pancreatic and biliary anastomoses was determined every other day until drain removal. Percutaneous drainage or tube replacement was employed when signs of inadequate drainage were found.

Definition of pancreatic fistula

Patients were categorized as having Grade A, B, or C fistula based on the International Study Group of Pancreatic Fistula definitions.[11] Briefly, POPFs were classified as three grades: Grade A – asymptomatic fistula defined as output containing transient pancreatic amylase on or after the third postoperative day from an operatively positioned drain with a pancreatic amylase level more than three times the upper serum reference value; Grade B – symptomatic fistula requiring therapeutic management and prolonged hospital stay; and Grade C – leaks that require aggressive diagnostic management and therapeutic interventions and were associated with an extended hospital stay.

Statistical analysis

The qualitative Chi-square test and quantitative Mann–Whitney U-test on SPSS 22.0 software (IBM company, Armonk, New York, USA) were used to analyze the data. The risk factors for clinically relevant POPFs were evaluated using logistic regression. P < 0.05 was considered statistically significant.

 Results



Patient characteristics

The patients' demographic characteristics are summarized in [Table 1]. The ages of the 301 patients ranged from 23 to 89 years (60.1 ± 10.2 years; mean ± standard deviation), including 178 men and 123 women with a body mass index (BMI) of 17–40 (median, 28). Regarding pathological diagnoses, 183 (60.8%) participants had carcinoma of the pancreas, 49 (16.2%) patients had diabetes mellitus or other complications preoperatively, and 20 (13%) patients had a history of pancreatitis. None of the enrolled participants had active inflammation.{Table 1}

Operation

Surgery consisted of pylorus-preserving PD in 69 patients (22.9%) and segmental portal vein or hepatic artery resection in 41 patients; 232 patients (77.1%) underwent conventional pancreaticoduodenectomy (PD). Changes in the pattern of practice of pancreatic stump management are shown in [Table 1]. The median operation time was 320 min (range, 150–480 min). Three specialized pancreatic surgeons performed all of the operations [Table 1]. The total incidence of POPF was 10.29% (n = 31), the occurrence of delayed gastric empty was 22.92% (n = 69), the rate of abdominal infection was 6.98% (n = 21), rate of postoperative bleeding was 4.64% (n = 14), incidence of biliary leak was 4.98% (n = 15), rate of mortality was 2.33% (n = 7), and rate of reoperation was 4.98% (n = 15).

Pancreatic fistula and main preoperative morbidity

The overall rate of Grade B or C pancreatic fistula was 10.29%. As shown in [Table 2], the occurrence of POPF correlated significantly with intraabdominal infection, post-PD hemorrhage, reoperation, morbidity (overall, surgical, and severe morbidity), and longer hospital stay [Table 2]. Indications for reoperation in the patients with active bleeding in the early postoperative period included erosion bleeding due to infection or pancreatic fistula in the late stage and intra-abdominal abscess not amenable to sufficient interventional drainage. Postoperative mortality occurred due to septic shock after reoperation for pancreatic fistula or bleeding with erosion and shock in 4 patients.{Table 2}

Risk factor analysis of pancreatic fistula in pancreaticoduodenectomy

Univariate analysis disclosed that pancreatic anastomosis by an interrupted suture maneuver (odds ratio [OR], 2.88; P = 0.014), a high BMI (OR, 1.18 per unit; P = 0.001), biliary neoplasms (OR, 3.00; P = 0.029), and a high-risk pancreas (OR, 3.00; P = 0.011) as risk factors and pancreatic ductal adenocarcinoma (OR = 0.31, P = 0.042) as a protective factor for pancreatic fistula B/C. On multivariate analysis, a soft texture, pancreatic duct <4 mm, and biliary neoplasm were the only independent risk factors [Table 1].

To obtain more information about the identified risk factors, we separately analyzed two groups of patients for POPF: high-risk versus low-risk pancreas [Table 3]. A high-risk pancreas was defined as pathology with an OR >1 for the development of pancreatic fistula on univariate analysis [Table 1]. It is noteworthy that this definition is in concordance with the previous risk factor analysis of PD.[12] As shown in [Table 3], only the low-risk group showed a significantly higher pancreatic fistula rate after interrupted anastomosis; when it came to a high-risk pancreas, this elevation was not significant. BMI was an additional risk factor for pancreatic fistula in high-risk patients but had no significant effect in the low-risk group.{Table 3}

 Discussion



Despite marked progress in PD, POPF remains a threatening complication linked with abdominal abscesses and intra-abdominal hemorrhages, delayed hospital time, increased cost, and increased mortality.[13],[14],[15],[16] Therefore, the management of costal stump is controversial, reflecting the complexity of anastomosing a pancreas of different textures to the digestive tract. Many studies evaluating diverse techniques have drawn conflicting conclusions.

The key to excellent outcomes after PD is the reduction of active fistulas. Many investigators have attempted to identify the safest method with the lowest pancreatic fistula rate. By far, duct-to-mucosa pancreaticojejunal anastomosis was previously recommended for patients with a duct size >3 mm, whereas this technique is currently performed regardless of duct size using magnification.[17] Although a prospective study reported by Bassi demonstrated no significant difference in the pancreatic fistula rate between end-to-side and duct-to-mucosa PJ,[18] many authors found that the duct-to-mucosa anastomosis is safer, particularly in patients with wide pancreatic ducts, and usually associated with firm or hard pancreatic tissue.[11],[19],[20],[21] However, based on the current evidence, it is unclear which PJ technique is superior and able to significantly decrease pancreatic fistula rates and related complications.

Many risk factors reported to date associated with pancreatic fistula after PD include age >70 years, male sex, jaundice, malnutrition, low creatinine clearance, and pancreas- and disease-related risk factors, such as pancreatic head or periampullary tumors, pancreatic neuroendocrine tumors, pancreatic fibrosis, pancreatic texture, duct size, and surdgeon experience and volume center for complex surgery.[12],[22],[23],[24],[25] However, the present series, like many others, demonstrated that POPF is mainly associated with pancreatic texture and duct size.[26],[27] This series also identified the indication of biliary carcinoma as a marked risk factor contributing to the soft texture and small pancreatic duct in biliary carcinoma. The development of a pancreaticojejunal fistula is more common in patients with duodenal or ampullary carcinoma than in patients with the diagnosis of pancreatic cancer because the latter are more likely to receive a late diagnosis cancer and develop parenchymal fibrosis and duct dilatation.

Pancreatic duct stenting at the time of anastomosis creation has been proposed as a technique to decrease pancreatic leak and fistula, with the rationale that stenting prevents the accumulation of pancreatic secretions in the pancreatic stump and the pancreatic anastomosis is prevented from directly contacting the pancreatic juice.[28] This was examined in a randomized trial by Winter et al., who randomized 238 patients undergoing PD to internal pancreatic duct stent or no stent with the endpoint of POPF development.[29]

Patients were stratified by the texture of the pancreatic remnant (soft vs. normal/hard), and 6-cm pediatric feeding tubes were used as stents. Among the hard pancreas group, 1.7% of the stent patients and 4.8% of the nonstent patients developed POPF (P = 0.4), while among the soft pancreas group, 21.1% of the stent patients and 10.7% of the nonstent patients developed POPF (P = 0.1); the authors concluded that internal pancreatic duct stenting does not alter the POPF rate. Pancreatic duct drainage with external stents has also been studied. In a study from Hong Kong in 2007, Poon et al. prospectively randomized 120 patients undergoing PD with PJ duct-to-mucosa anastomosis to an external stent or not group.[30] Patients in the stented group had a significantly lower pancreatic fistula rate compared with the no stent group (6.7% vs. 20%, P = 0.032); on multivariate analysis, the absence of stenting was a significant risk factor for POPF. The authors hypothesized that the use of external drains more completely diverts pancreatic secretions away from the PJ anastomosis with a decreased risk of leak formation. The present study demonstrated that external pancreatic duct stenting has no beneficial effect on the occurrence of POPF, but it significantly decreases the occurrence of POPF in the high-risk subgroup. Therefore, the placement of an external pancreatic duct stent is mandatory in the high-risk subgroup.

The inhibitory peptide hormone (somatostatin) decreases the output of secretions from the GI tract and has been widely used in pancreatic surgery in an attempt to decrease POPF with the hypothesis that decreased pancreatic juice secretion will allow for improved healing of pancreatic ductal anastomoses and consequently decreased leak rates.[31],[32] However, multiple randomized prospective trials show mixed results. Two prospective trials identified that octreotide does not reduce the incidence of POPF and suggested that omission of this treatment may lead to a cost savings for hospitals.[32],[33] Suc et al. conducted a multi-center prospective randomized trial of 230 patients undergoing pancreatectomy, with 122 patients randomized to octreotide and 108 randomized to the control arm; the primary endpoint was all intra-abdominal complications.[34],[35] Intra-abdominal complications were seen in 22% of octreotide patients versus 32% of placebo patients; however, this result was not statistically significant, and the authors concluded that octreotide cannot be routinely used to decrease intra-abdominal complications in pancreatectomy patients. The present retrospective series also demonstrated that somatostatin was not an independent risk factor in a multivariate analysis; however, in the high-risk group, the results demonstrated that the use of somatostatin significantly decreased the occurrence of POPF. Therefore, the use of somatostatin should be adopted in high-risk patients [Figure 1].{Figure 1}

Many surgeons have investigated the safest and easiest surgical techniques with the lowest PF rate. On the basis of our analysis, we propose an individualized approach to PJ in PD [Figure 1] to meet the aforementioned challenges. It is usually possible to assign patients to a high-risk or low-risk category in terms of the risk of pancreatic fistula. This can be done preoperatively and confirmed intraoperatively on the basis of pancreatic texture as already shown for pancreatic head resection.[13] To reduce the risk of pancreatic leakage, selection of the proper PJ according to pancreatic texture and duct size is mandatory. In this series, if end-to-end invagination anastomosis is not technically feasible, for example, due to a very thick pancreas, a small jejunum, or transection close to the pancreatic head, anastomotic methods may be chosen depending on risk category: For a healthy and soft pancreas, we propose end-to-end anastomosis for a thin pancreatic stump, whereas if the jejunum cannot invaginate the thick stump, Blumgart anastomosis is an optional technique. This might also be done in cases of a hard and fibrotic gland; however, no other anastomosis methods showed a significant difference in the occurrence of POPF, and the use of somatostatin and external pancreatic stent were not required in low-risk patients.

 Conclusions



In summary, our study demonstrated that pancreatic fistula is related to a soft texture and a small pancreatic duct. In the high-risk subgroup, the surgeon must take these risk factors into consideration when performing a PD and select the individual PJ according to the pancreatic texture and duct size. Thus, we propose a risk-adapted, indication-adapted choice of anastomosis method and treatment for the pancreatic remnant to reduce the pancreatic fistula rate.

Acknowledgment

The study is supported by the National Natural Science Foundation of China, No. 81271607; the Key Medicine and Health Funding Project of the Nanjing Military Region of Chinese PLA, No. 11Z035; China Postdoctoral Science Foundation, No. 2015M572810.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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