Introduction

Pancreaticoduodenectomy (PD) is now the cornerstone for treatment of pancreatic head and periampullary pathologies.1 Recent advances in surgical technologies and techniques together with better surgical experience helped lowering the mortality rates in high-volume centers; however, delayed gastric emptying (DGE) and postoperative pancreatic fistula (POPF) remain the leading morbidities.2

DGE is a common complication after PD with reported incidence reaching up to 44 %.3 – 6 It is not a life-threatening condition, but it is associated with delayed oral intake, prolonged hospital stay, affecting quality of life, and increased total cost of hospitalization. Several measures have been described to decrease the incidence of DGE as preoperative use of erythromycin, left gastric preservation, and enteral feeding.5

In 2007, the International Study Group of Pancreatic Surgeons (ISGPS) standardized a definition and a grading for DGE which helped to eliminate the confusion about the true incidence and risk factors associated with DGE.7 – 9 Although this grading clearly defines the severity of DGE, it does not take in consideration the etiology of DGE and if it is secondary to a present postoperative complication.

The aim of this study is to analyze the risk factors for the occurrence, predictors of severity of DGE, and the impact of the etiology of DGE on the surgical outcomes (Table 1).

Table 1 Risk factors and outcome of DGE
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Patients and Methods

This is a retrospective analysis of 588 consecutive cases of PD done for any indication at Gastroenterology Surgical Center, Mansoura University, Egypt, in the period from January 2001 to October 2014. The study was approved by the institute’s ethical committee. Patient’s data were collected prospectively in a web-based data sheet. Informed consents were obtained from all patients.

Patient Evaluation

The diagnosis and resectability were confirmed in all patients by triphasic abdominal CT scan and magnetic resonance cholangiopancreatography (MRCP). Patients presenting with cholangitis, high serum bilirubin levels, or suspected delay in the surgical schedule underwent preoperative biliary drainage by the means of endoscopic stenting.

Operative Technique

All patients underwent laparotomy through a rooftop incision (bilateral subcostal incision). After assessment of resectability by exclusion of liver metastasis and superior mesenteric vein or portal vein invasion, a subtotal stomach preserving PD (SSPPD) was done. The resected specimen included the gall bladder, distal common bile duct, antrum of the stomach, duodenum, pancreatic head, and the proximal 10 cm of the jejunum. All patients underwent regional lymphadenectomy, which included resection of nodes within the outlines of the hepatoduodenal ligament, right side of the superior mesenteric vessels, and inferior vena cava.

Pancreatic Reconstruction

In cases with pancreatico-gastric anastomosis, an end to side pancreatico-gastrostomy (PG) was done using the invagination technique by continuous absorbable sutures in two layers without the use of pancreatic stents. While for those with a pancreatico-jejunal anastomosis, either a simple or isolated loop pancreatico-jejunostomy (PJ) was performed using the duct to mucosa or invagination technique with no pancreatic stents.

Gastro-Jejunal and Hepatico-Jejunal Reconstruction

The hepatico-jejunal anastomosis (HJ) was retro-colic in all cases using absorbable sutures in single layer (posterior continuous and anterior interrupted). The gastro-jejunal anastomosis was performed either antecolic or retrocolic, either end to side or side to side according to the surgeon’s preference using absorbable sutures in two layers.

In the antecolic reconstruction, HJ (retrocolic) was done first, followed by an antecolic GJ either end to side or side to side according to the surgeon’s preference using absorbable sutures in two layers. For the retrocolic reconstruction, a retrocolic GJ was performed first, followed by an end to side hepaticojejunostomy (retrocolic).

In our series, antecolic reconstruction was performed in all cases with PJ. While in cases with PG, the gastro-jejunostomy (GJ) and the hepatico-jejunostomy (HJ) were performed in either an antecolic or a retrocolic fashion according to the surgeon’s preference.

After completion of reconstruction, an abdominal drain is placed in the hepato-renal pouch near the pancreatic and biliary anastomosis.

Postoperative Management

All patients were maintained on postoperative intravenous antibiotics and proton pump inhibitors. Octereotides were given to patients with soft pancreas or small pancreatic ducts (100 μg SC every 8 h, started intra-operatively). Nasogastric tube (NGT) was removed when the amount of suction was below 500 ml/day after which the patient was started on clear fluids and progressed to solid diet over the following days. The abdominal drain was removed after the solid diet is achieved with no signs of pancreatic fistula or intra-abdominal collections.

Definition of the Postoperative Complications

According to the ISGPS definition, DGE was classified into three grades7: grade A, need for NGT intubation for 4 days or NGT reinsertion after postoperative day (POD) 3, or inability to tolerate a solid diet by POD 7; grade B need for NGT intubation for 8 days or NGT reinsertion after POD 7, or inability to tolerate a solid diet by POD 14; and grade C need for NGT intubation for 15 days or NGT reinsertion after POD 14, or inability to tolerate a solid diet by POD 21.

According to the presence of postoperative complications including pancreatic leakage, biliary leakage, pancreatitis, and abdominal collection, DGE is classified into primary DGE (not associated with postoperative complications) and secondary DGE (associated with postoperative complications).

Pancreatic fistula (PF) was defined as amylase values of drained fluid greater than three times the upper limit of normal serum amylase values measured on or after POD 3.8 Three grades of PF were defined by the ISGPS, grade A PF described as transient, and asymptomatic fistula evident only from elevated drain amylase values, while grades B and C PF are clinically obvious fistulas that require adequate therapeutic management.

Assessments

The primary outcome was DGE rate. According to the ISGPS definition, DGE was classified into three grades7 as mentioned before.

Secondary outcomes were operative time, operative time needed for reconstruction, length of postoperative hospital stay, and postoperative morbidities including pancreatic fistula (POPF), pancreatitis, and biliary leakage.9

Primary DGE is made by exclusion of any intra-abdominal complications linked to secondary DGE, and the necessary investigations in patients with primary DGE were performed including abdominal U/S and abdominal CT scan even if the patient did not have signs of intra-abdominal collections (e.g., tachycardia, fever, and leukocytosis) to rule out subtle contained leak especially from the pancreatic anastomosis.

Follow-Up

Follow-up was carried out 1 week postoperatively, 3 months, 6 months, and then after 1 year.

Statistical Analysis

Statistical analysis of the variables was performed using SPSS software, version 17. Categorical variables were described using frequency distributions. Continuous variables were calculated and were reported as mean ± standard deviation (SD). Independent sample t test was used to detect differences in the means of continuous variables, and chi-square test was used in cases with low expected frequencies. One-way analysis of variance (ANOVA) was used when comparing continued variable among three groups. P values <0.05 were considered to be significant. Variables with P < 0.05 were entered into a logistic regression model to determine independent risk factors of postoperative PF (Table 2). The independent risk factors of the variables were expressed as odds ratios (OR) with their 95 % confidence intervals (CI).

Table 2 Multivariate logistic regression for risk factors of DGE
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Results

Of the 588 patients included in the study, the mean age was 52.79 ± 10.8 years; 352 (59.9 %) were males, while 236 (40.1 %) were females. All patients underwent PD at Gastroenterology Surgical Center, Mansoura University, Egypt, in the period from January 2001 to October 2014. One hundred fifty-nine (27 %) patients had a preoperative BMI of more than 25, and 314 (53.4 %) had preoperative endoscopic biliary drainage.

Regarding the pancreatic reconstruction, PG was done in 474 (80.6 %) patients, simple loop PJ was performed in 68 (11.6 %) patients, and isolated loop PJ in 46 (7.8 %) patients. While for the GJ and HJ, antecolic reconstruction was carried out in 450 (76.5 %) patients versus 138 (28.5 %) patients that had the retrocolic reconstruction.

DGE was found in 105 (17.8 %) patients, grade A in 43 (7.3 %) patients, grade B in 53 (9 %) patients, and grade C in 9 (1.5 %) patients.

After univariate analysis, BMI > 25 (P = 0.0001), diabetes mellitus (DM) (P = 0.0001), preoperative biliary drainage (P = 0.005), retrocolic reconstruction (P = 0.0001), pancreatic duct less than 3 mm (P = 0.02), type of pancreatic reconstruction (P = 0.04), postoperative albumin level (P = 0.04), presence of complications (P = 0.0001), postoperative pancreatic fistula (POPF) (P = 0.0001), bile leaks (P = 0.005), presence of pancreatitis (P = 0.0001), wound infection (P = 0.001), and abdominal collections (P = 0.001) were significantly associated with a higher incidence of DGE (Table 1). In multivariate analysis, diabetes mellitus, retrocolic GJ, type of pancreatic anastomosis, presence of complications, and severity of POPF were identified as independent significant risk factors.

Predictors of the Severity of DGE

The incidence of grades B and C DGE was significantly higher in BMI >25, DM, retrocolic reconstruction, POPF, bile leaks, and abdominal collections (Table 3).

Table 3 Predictive factors of severity of DGE
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Primary Versus Secondary DGE

Of the 105 patients complicated by DGE, 33 (31.4 %) patients were diagnosed as primary DGE without any obvious etiology and not associated with any signs of intraabdominal collections, while 72 (68.5 %) patients had DGE secondary to concomitant complications (Table 4). Secondary DGE was associated with wound infection in 18 (25 %) patients, abdominal collections in 50 (69.4 %) patients, POPF in 45 (62.5 %) patients, bile leaks in 16 (22.2 %) patients, and pancreatitis in 6 (8.3 %) patients. There was no statistical significance between primary and secondary DGE regarding the age, sex, BMI, presence of DM, liver status, preoperative biliary drainage, operative duration, blood loss, and rates of nasogastric tube reinsertion. All patients that had primary DGE were not associated with fever tachycardia or leucocytosis.

Table 4 Comparison between primary DGE and secondary DGE
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Types B and C DGE were significantly noticed in secondary DGE (P = 0.04). Nasogastric tube removal and day to start oral intake were significantly earlier in primary DGE (7.84 ± 2.41 vs 10.65 ± 6.32 days, P = 0.01, and 11.21 ± 2.5 vs 14.1 ± 6.79 days, P = 0.02, respectively). Hospital stay was significantly shorter in primary DGE (13.84 ± 11.61 vs 19.6 ± 11.31 days, P = 0.02).

Discussion

Pancreaticoduodenectomy is now considered the only curative procedure in the management of periampulary neoplasms.3 – 8 As a technically demanding, complex procedure, the main concern was always the high incidence of the associated postoperative morbidity and mortality. Upgrades in surgical techniques and evolutions in surgical technologies together with an increase in operative volume and surgeon’s experience in high volume centers reduced the incidence of postoperative complications and improved the overall survival.10 Recently, the hospital mortality rate after PD has dramatically decreased to less than 5 %, while the incidence of postoperative morbidity remains high, from 25 to 60 %.1 – 7 However, even in high volume centers, pancreaticoduodenectomy-specific complications as POPF and DGE remain a particular concern for pancreatic surgeons.11

First described by Warsaw and Torching,12 the incidence of DGE was reported to widely range from 11 to 57 %.3 – 7 , 13 This was attributed mainly to the lack of a standard definition for DGE. However, in 2007, the ISGPS standardized a clinically applicable definition and severity grading of DGE according to the clinical course of the patients.8 After application of the ISGPS criteria to our cohort of patients, the incidence of DGE was 17.8 %, while that for grades B and C were 50.5 and 8.6 %, respectively. This is similar to results reported by Kunstman et al. which were 17.9 % for DGE and 61.9 % for grades B and C DGE.14 However, Sakamoto et al. reported 49 % incidence for DGE and 18.1 % for grades B and C.15 This variation in incidence may be explained by the different institutional practices with tendency to delay the NGT removal and starting the oral feeding in Japanese than Western centers where hospitalization costs and economic disincentives are low.16

The exact etiology and pathogenesis of DGE has been a field of controversy and hypotheses. Although the ISGPS criteria are strict regarding the definition and grading of DGE, it does not address the etiology.

In our study, the incidence and severity of DGE were significantly higher in cases with DM, BMI >25, retrocolic reconstruction, POPF, bile leak, and abdominal collections. Several reports identified certain postoperative complications to be important risk factors for the development of DGE such as POPF, pancreatitis, abdominal collections, and bile leaks.17 – 19 Our results support the correlation between DGE and POPF (p = 0.0001). Also, abdominal collections (p = 0.0001) and bile leaks (p = 0.0001) were independent risk factors. In our series out of 105 patients with DGE, POPF was present in 45 (42.9 %), abdominal collections were present in 50 (47.6 %), and bile leak in 16 (15.2 %).

Regarding preoperative variables, DM (P = 0.0001), BMI > 25 (P = 0.0001), and preoperative biliary drainage (P = 0.005) were significantly associated with DGE. Some data suggest that even mild degrees of hyperglycemia can affect the gastric emptying.20 However, Gangavatiker et al. in a study of 68 patients stated that DM was not significantly correlated to DGE.21 As patients presenting with cholangitis in our series underwent preoperative biliary endoscopic stenting first, the correlation of preoperative biliary drainage with DGE can be attributed to the existing history of cholangitis. Although reports in the literature suggested preoperative cholangitis as a risk factor for DGE,18 Sakamoto et al. in 2011 after standardization of the ISGPS definition of DGE found no significant correlation between DGE and preoperative cholangitis in their study.15

The impact of antecolic versus retrocolic reconstruction on the incidence and severity of DGE has been an area of debate. In our study, of 138 patients with retocolic reconstruction 88 (83.8 %) patients developed DGE versus 16.2 % for patients with antecolic reconstruction (P = 0.0001). This is similar to results published by some pre-ISGPS studies22 , 23; however, Gangavatiker et al. and Kunstman et al. found no significant correlation between DGE and the method of reconstruction weather antecolic or retocolic.14 , 21

Although strongly linked to certain postoperative complications, certain patients develop DGE without any obvious cause, recently called “primary DGE.” Several hypotheses have been postulated in a trial to understand the pathogenesis of primary DGE in such cases. These include antroduodenal ischemia,24 low plasma motilin levels,25 peripancreatic inflammation,26 twist in the gastrojejunostomy, aggressive lymphadenectomy, and pancreatic fibrosis.27 In our study, the 33 patients with primary DGE had oral gastrograffin studies to confirm the patency of the gastrojejunostomy and exclude any torsions. Types B and C DGE were significantly noticed in secondary DGE (P = 0.04). Nasogastric tube removal and day to start oral intake were significantly earlier in primary DGE (7.84 ± 2.41 vs 10.65 ± 6.32 days, P = 0.01, and 11.21 ± 2.5 vs 14.1 ± 6.79 days P = 0.02, respectively). Hospital stay was significantly shorter in primary DGE (13.84 ± 11.61 vs 19.6 ± 11.31 days, P = 0.02). These patients were supported by total or partial parenteral nutrition, and DGE improved without any further treatments. In these patients, exclusion of all causes of secondary DGE was done; however, the etiology of DGE remained unclear.

Conclusion

DGE is strongly linked to the occurrence of other postoperative complications especially pancreatic leakage. However, in some cases, DGE occurs in the absence of any associated complications (primary DGE). Although ISGPS classification helped to standardize the definition and grading of DGE, it does not address the etiology. Primary DGE should therefore be distinguished as a separate entity for better understanding of the pathogenesis and proper management.