25 February 2021: Clinical Research
Preoperative Computed Tomography Imaging of the Pancreas Identifying Predictive Factors for the Progression of Grade A, or Biochemical Leak, to Grade B Postoperative Pancreatic Fistula Following Pancreaticoduodenectomy: A Retrospective Study
Feng-Hao Liu12ABCDEF, Xiao-Zhong Jiang12ABCE*, Bin Huang1AEF, Yu Yu1DFDOI: 10.12659/MSM.928489
Med Sci Monit 2021; 27:e928489
Abstract
BACKGROUND: This retrospective study aimed to identify the predictive factors for the progression of grade A, or early biochemical leak, to grade B postoperative pancreatic fistula (POPF) following pancreaticoduodenectomy using preoperative computed tomography (CT) imaging of the pancreas.
MATERIAL AND METHODS: A total of 156 patients were analyzed retrospectively. Biochemical leakage occurred in 60 patients, who were divided into POPF progression and non-POPF progression groups. Perioperative parameters were collected. Univariate analysis and multivariate logistic regression analysis were done. For the parameters with statistical significance, the area under the curve (AUC) was calculated if possible and the predictive value was assessed.
RESULTS: Univariate analysis showed that main pancreatic duct diameter, postoperative complications (except POPF), prothrombin time (PT) and serum albumin on postoperative day 3, and pancreatic CT value were risk factors of POPF (P<0.05). Multivariate analysis showed that serum albumin and PT on postoperative day 3 and pancreatic CT value were independent risk factors of POPF (P<0.05). Lower postoperative albumin, lower pancreatic CT value, and longer PT were associated with a higher risk of POPF (P<0.05). The AUC of CT value was 0.808. CT value thresholds of 42.5 Hounsfield units (HU) and 41.5 HU were tied for the highest predictive performance, with Youden indices of 0.486 for both, and sensitivity of 79% and 71%, and specificity of 69% and 78%, respectively.
CONCLUSIONS: Preoperative laboratory investigations and CT imaging of the pancreas may identify factors associated with early biochemical leakage progressing to grade B POPF following pancreaticoduodenectomy.
Keywords: Cone-Beam Computed Tomography, Pancreatic Fistula, Pancreaticoduodenectomy, Postoperative Complications, Area Under Curve, Disease Progression, Logistic Models, Pancreas, Pancreatectomy, Pancreatic Ducts, Postoperative Period, Preoperative Care, ROC Curve, Risk Factors, Tomography, X-Ray Computed
Background
Pancreaticoduodenectomy is considered one of the most complex and challenging operations owing to the massive dissection and resection required [1–3]. However, this surgery is currently regarded as safe and reliable for the treatment of pancreatic tumors and chronic pancreatitis [4]. Experienced surgeons know how to choose the correct method of resection and reconstruction. Standardized resection procedures are well established and can be carried out in high-volume institutions with a morbidity and mortality rate of less than 5% [5]. One of the most important and harmful complications of the resection is postoperative pancreatic fistula (POPF) [6,7], which has an incidence rate of 3% to 30% [8].
According to the definition and grading of the International Study Group in Pancreatic Surgery (ISGPS), grade A POPF, also called biochemical leak, is not considered a true pancreatic fistula or an actual complication; rather, POPF associated with the incidence of clinically relevant pancreatic fistula is regarded as grade B or C [9,10]. More attention should be given to the possibility of patients with biochemical leaks progressing to grade B pancreatic fistula after surgery [11]. Some researchers suggested that data from computed tomography (CT) imaging before surgery might provide useful information about the risk of POPF [12–14]. Therefore, in this retrospective study, we aimed to identify the predictive factors for the progression of grade A, or early biochemical leak, to grade B postoperative pancreatic fistula (POPF) following pancreaticoduodenectomy using preoperative CT imaging of the pancreas.
Material and Methods
PATIENT ENROLLMENT:
A total of 156 consecutive patients underwent pancreaticoduodenectomy from 2015 to 2019 for periampullary diseases at the Second Hospital of Yibin City. There were 104 men and 52 women, with an average age of 62±7 years (range, 37–77 years). Among the 156 patients, 60 experienced postoperative biochemical leakage, of which 24 progressed to grade B pancreatic fistula, without grade C pancreatic fistula. All enrolled patients received surgical treatment, and all operations were performed by the same surgical team to minimize differences in surgical experience and technique. After surgery, routine therapy was applied, such as short-term feeding restriction, parenteral nutrition support, symptomatic therapy, and postoperative drainage tube unblocking. The results of postoperative pathological examination were used to determine whether the patients’ tumors were benign or malignant.
STUDY DSESIGN:
This investigation was a clinical retrospective study. Patients who had biochemical leaks were divided into 2 groups: the POPF progression group and the non-POPF progression group. All related preoperative, intraoperative, and postoperative parameters were collected and recorded to identify the risk factors of progression from biochemical leak to grade B pancreatic fistula.
SURGICAL TECHNIQUE:
All patients underwent conventional Whipple surgery after tracheal intubation and general anesthesia. Pancreaticoduodenectomy and lymph node dissection were performed. The Child’s method was used to reconstruct the digestive tract. End-to-side anastomosis of the pancreatic duct and jejunum mucosa was performed in all patients. The pancreatic stump was meshed with 4-0 Prolene suture at a distance of 0.5 to 1.0 cm from the pancreatic section. A continuous suture was applied from the posterior margin tissue to the jejunum line of the mesangial limbus serosa. Then, the seromuscular layer of the jejunum was cut at the corresponding pancreatic stump and pulled to both sides to expose an area with the size equivalent to the pancreatic stump. Thus, an area of the jejunum mucosa layer, with a size equivalent to the pancreatic stump, was exposed and a small hole was opened, with the diameter equal to that of the pancreatic duct. According to the diameter of the pancreatic duct, a supportive drainage tube of appropriate size was placed and sutured in the duct. The pancreatic duct and the posterior wall of the jejunal mucosa were sutured continuously for 3 to 4 stitches, and then the supportive tube of the pancreatic duct was inserted into the jejunum. The distal end of the supportive tube passed through the anastomosis between the duct and the jejunum. Then, the pancreatic duct and the anterior wall of the jejunum mucosa were sutured continuously with 3 to 4 stitches and the anterior margin of the pancreatic stump was sutured continuously with the serosamus layer of the jejunum at a distance of 0.5 to 1.0 cm from the pancreatic section.
DEFINITIONS:
The International Study Group on Pancreatic Fistula (ISGPF) developed the definition and grading of POPF, which has been commonly accepted and used by clinicians. Biochemical leakage is defined as a drain output of any measurable volume of fluid with an amylase level >3 times the upper limit of the normal serum amylase range. Grade B POPF is defined more strictly. Biochemical leakage combined with any of the following 5 conditions is defined as grade B POPF: (1) peritoneal drainage tubes indwelling >3 weeks; (2) clinical changes in postoperative management; (3) the pancreatic fistula requires repositioning by endoscopic or percutaneous procedures; (4) bleeding requires postoperative treatment of angiography; or (5) the pancreatic fistula causes infection, without organ failure [9].
Some research groups have extensively analyzed CT images of the pancreas and have identified many variables that are significantly associated with POPF [12–14]. The diameter of the main pancreatic duct (MPD) and the CT value of the pancreatic body are the independent components derived from CT images. In our study, the diameter of the MPD and the CT value of the pancreatic body were independently measured by the same radiologist before surgery. The diameter of the MPD was measured at the section where maximal ductal dilatation was noted on CT. When measuring the CT value of the pancreatic body, the radiologist avoided all pancreatic tumors, calcifications, ducts, blood vessels, and non-pancreatic tissue. The CT value was measured 3 times for each patient, and the average of the results was taken as the final CT value of the patient’s pancreatic body.
STATISTICAL ANALYSIS:
SPSS v.25.0 for Microsoft Windows (IBM) statistical software package was used to conduct all statistical analyses. The data were expressed as the mean and standard deviation for continuous variables or median (interquartile range) for the frequency of categorical variables. Univariable analyses were performed by
Results
A total of 156 patients underwent pancreaticoduodenectomy. After the surgery, 60 patients had biochemical leak, and, of them, 24 patients experienced significant POPF (grade B). The median age of the 60 patients was 62 years (range, 49–74 years) and 31 were men (51.7%). The non-POPF progression group received routine therapy including short-term feeding restriction, parenteral nutrition support, liver protection, postoperative drainage tube unblocking, and symptomatic therapy. The POPF progression group received an intensive treatment including rational use of antibiotics, extended drainage time, percutaneous peritoneal drainage, and angiographic procedures to detect bleeding. All patients (n=60) were discharged from the hospital.
According to the results of the univariate analyses, the risk factors associated with progression from biochemical leak to grade B fistula were MPD diameter, postoperative complications (except POPF), prothrombin time (PT) on postoperative day 3, serum albumin on postoperative day 3, and the preoperative CT value of the pancreatic body (
A receiver operating characteristic (ROC) curve was drawn to detect the relationship between a preoperative pancreas plain CT value and grade B POPF (Figure 1). When the area under the curve (AUC) ≥0.5 and <1, the larger the AUC was, the greater the predictive value was. When AUC <0.5, it did not have predictive value. Generally, when the AUC ≥0.5 and <0.7, it had low predictive value; when the AUC ≥0.7 and <0.9, it had medium predictive value; and when the AUC <0.9, it had high predictive value. The AUC of preoperative pancreatic plain CT values was 0.808, with medium predictive value. Table 3 shows that with the increase of the cutoff CT value, the true positive rate gradually increased and the false negative rate decreased, and the true negative rate decreased and the false positive rate increased. Cutoff CT values of 42.5 Hounsfield units (HU) and 41.5 HU achieved 79.2% and 70.8% sensitivity and 69.4% and 77.8% specificity, respectively. These 2 cutoffs were tied for the highest predictive performance, with a Youden index of 0.486.
Discussion
The results of this research show that the albumin level on day 3 after pancreaticoduodenectomy was an independent predictor of prognosis after the surgery, and the albumin level on day 3 after the surgery might predict whether or not biochemical leakage progressed to grade B pancreatic fistula after surgery. As the albumin level decreased after surgery, the risk of developing into grade B pancreatic fistula POPF increased (OR=0.607, 95% CI=0.396–0.930,
In the present study, the PT value (OR=2.955, 95% CI=1.100–7.941,
At present, and based on extensive research, the texture of the pancreas is considered to be an independent predictor of postoperative pancreatic fistula. If the texture is softer, the patient is at higher risk of POPF [20]. However, this factor could not be tested in the preoperative comprehensive discussion and patient consultation. At the same time, different surgeons make their own subjective judgments about the texture of the pancreas by touching it with their fingers. In recent years, some studies have confirmed that that preoperative CT scans have the value of predicting POPF [21,22], and some research suggested that the number of CT scans of the pancreas was related to the density of the pancreas and suggested pancreatic fibrosis [23,24]. In addition, Kusafuka et al reported that a pancreas-visceral fat CT value ratio ≥ – 0.40 and a serrated-type pancreas might indicate a high risk of POPF [14]. To standardize the judgement of pancreatic texture, the preoperative plain CT scan was chosen as the index in this study. The risk of progressing to grade B pancreatic fistula was predicted by measuring the number of preoperative CT scans. Our results showed that the pancreatic CT value was also an independent predictor of progressing to grade B pancreatic fistula, and for the patients with postoperative biochemical leak, the lower preoperative CT number they had, the more easily they would develop to grade B pancreatic fistula. Meanwhile, the ROC of the number of preoperative pancreas plain CT scans was generated according to whether the biochemical leak would develop to grade B pancreatic fistula or not. It was discovered that 0.7 ≤AUC <0.9 had a medium value of prediction. When the CT number was 41.5 HU or 42.5 HU, the correct index was the most effective. However, the sample size was small in this study. Further research is needed to determine whether the preoperative CT number can be regarded as the judging index.
At present, a thinner pancreatic duct is recognized as an independent predictor of the prognosis of pancreaticoduodenectomy. The reason may be that the dilated pancreatic duct is related to pancreatic fibrosis. The fibrosis hardens the pancreas and thickens the pancreatic duct, resulting in a low incidence of fistulas after pancreaticoduodenectomy [25]. The thin pancreatic duct is not conducive to anastomosis and drainage of pancreatic juice, which increases the risk of POPF. Tomohisa Yamamoto et al [26] believe that a soft pancreatic texture and a pancreatic duct ≤3 mm in diameter are independent predictors of prognosis after pancreaticoduodenectomy, stating that the soft pancreas and narrow diameter of the duct indicates that pancreatic exocrine function is close to normal. Further, the secretion of pancreatic juice increases after pancreatectomy, while the risk of pancreatic fistula increases as well. Unfortunately, the results of our present study did not confirm that a pancreatic duct diameter ≤3 mm was an independent predictor of POPF prognosis. This may have resulted from the placement of pancreatic duct stents in most patients during the operation of the end-to-side anastomosis of the pancreatic duct and mucous membrane. The placement of pancreatic duct stents in our study, to a certain extent, alleviated the problem of obstructed drainage caused by the narrow diameter of the pancreatic duct.
Six patients experienced other complications after pancreaticoduodenectomy. Five patients were in the POPF progression group; 4 patients had early abdominal hemorrhage and 1 had abdominal infection. One patient had early abdominal hemorrhage in the non-POPF progression group. Zhang et al [27] reported that POPF is closely related to other main complications such as peritoneal abscess, sepsis, postponement of stomach emptying, and hemorrhage. We considered that postoperative early abdominal hemorrhage might be associated with incomplete hemostasis during surgery, blood coagulation dysfunction, and bleeding at the anastomotic stoma. We also considered that abdominal infection was associated with pancreas fistulas and biliary fistulas. Nevertheless, the results of the analysis were not statistically significant. To a large extent, this was due to insufficient specimens. The patients who were enrolled in the present study underwent surgery with the routine Whipple procedure and underwent excision of the pancreas duodenum and lymph node dissection. Digestive tract reconstruction was conducted based on the Child’s procedure. End-to-side anastomosis of the pancreatic duct and jejunum mucosa was performed in all patients. The surgery was completed with the cooperation of 2 teams led by 2 experienced surgeons, and so the suturing of the pancreas was not analyzed. Although there are many standardized anastomosis techniques available at present, there is no evidence that one anastomosis technique is better than another [28]. Also, the variable of operation time was analyzed, and the results showed no statistical significance. Kinaci et al [29] reported that there is no correlation between the operation time and prediction of POPF. However, Kim et al [30] suggested that an operation time of more than 300 min is an independent risk factor for grade B.
There are some limitations in this study. First, the sample size was small and patients with pancreatic fistula progressing to grade C from grade B were not enrolled, and therefore not discussed. Second, this was a retrospective, single-center study, and there may be selection bias of patients for pancreaticoduodenectomy. Third, the study investigators were the surgeons, which could have introduced bias. Finally, the postoperative pancreatic fistula risk score for patients were not performed in this study. Therefore, further studies with larger sample size, multiple centers, and postoperative pancreatic fistula risk scores are required to identify predictive factors for the progression of grade A, or biochemical leak, to grade B postoperative pancreatic fistula following pancreaticoduodenectomy.
Conclusions
In summary, the postoperative PT and albumin on day 3 after surgery can predict the progression to grade B pancreas fistula, according to our results. In the early period after surgery, more attention should be given to patients with abnormal coagulation function and low serum albumin, relevant indicators should be reviewed regularly, and corresponding symptomatic treatment could be given. The preoperative pancreas plain CT scan should be analyzed, and the CT number value should be studied instead of the texture of the pancreas. Such standardized judgement of pancreatic texture could be effective in predicting grade B POPF. When the CT number is 41.5 HU to 42.5 HU according to the generated ROC, biochemical leak has a high risk of developing into grade B pancreas fistula. Therefore, preoperative laboratory investigations and CT imaging of the pancreas may identify factors associated with grade A, or early biochemical leak, progressing to grade B POPF following pancreaticoduodenectomy.
Tables
Table 1. Univariate analysis of risk factors for progression from biochemical leak to grade B pancreatic fistula. Table 2. Multivariate logistic regression analysis of factors for progression from biochemical leak to grade B pancreatic fistula. Table 3. Preoperative computed tomography (CT) value of the pancreatic body in the sensitivity and specificity for identifying progression from biochemical leak to grade B pancreatic fistula.References
1. Gianotti L, Besselink MG, Sandini M, Nutritional support and therapy in pancreatic surgery: A position paper of the International Study Group on Pancreatic Surgery (ISGPS): Surgery, 2018; 164; 1035-48
2. Ke Z, Cui J, Hu N, Risk factors for postoperative pancreatic fistula: Analysis of 170 consecutive cases of pancreaticoduodenectomy based on the updated ISGPS classification and grading system: Medicine (Baltimore), 2018; 97; e12151
3. Karim SAM, Abdulla KS, Abdulkarim QH, Rahim FH, The outcomes and complications of pancreaticoduodenectomy (Whipple procedure) : Cross sectional study: Int J Surg, 2018; 52; 383-87
4. Sun X, Zhang Q, Zhang J, Meta-analysis of invagination and duct-to-mucosa pancreaticojejunostomy after pancreaticoduodenectomy: An update: Int J Surg, 2016; 36; 240-47
5. Hackert T, Hinz U, Pausch T, Postoperative pancreatic fistula: We need to redefine grades B and C: Surgery, 2016; 159; 872-77
6. Xia T, Zhou JY, Mou YP, Risk factors for postoperative pancreatic fistula after laparoscopic distal pancreatectomy using stapler closure technique from one single surgeon: PLoS One, 2017; 12; e0172857
7. Dugalic VD, Knezevic DM, Obradovic VN, Drain amylase value as an early predictor of pancreatic fistula after cephalic duodenopancreatectomy: World J Gastroenterol, 2014; 20; 8691-99
8. Liang X, Shi LG, Hao J, Risk factors and managements of hemorrhage associated with pancreatic fistula after pancreaticoduodenectomy: Hepatobiliary Pancreat Dis Int, 2017; 16; 537-44
9. Bassi C, Marchegiani G, Dervenis C, The 2016 update of the International Study Group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 Years After: Surgery, 2017; 161; 584-91
10. Pulvirenti A, Ramera M, Bassi C, Modifications in the International Study Group for Pancreatic Surgery (ISGPS) definition of postoperative pancreatic fistula: Transl Gastroenterol Hepatol, 2017; 2; 107
11. Ji WC, Liu HRisk factors for biochemical leak progressing to grade B pancreatic fistula after pancreaticoduodenectomy early: Zhonghua Wai Ke Za Zhi, 2019; 57; 654-59 [in Chinese]
12. Roberts KJ, Karkhanis S, Pitchaimuthu M, Comparison of preoperative CT-based imaging parameters to predict postoperative pancreatic fistula: Clin Radiol, 2016; 71; 986-92
13. Utsumi M, Aoki H, Nagahisa S, Preoperative predictive factors of pancreatic fistula after pancreaticoduodenectomy: Usefulness of the CONUT score: Ann Surg Treat Res, 2020; 99(1); 18-25
14. Kusafuka T, Kato H, Iizawa Y, Pancreas-visceral fat CT value ratio and serrated pancreatic contour are strong predictors of postoperative pancreatic fistula after pancreaticojejunostomy: BMC Surg, 2020; 20(1); 129
15. Gruppo M, Angriman I, Martella B, Perioperative albumin ratio is associated with post-operative pancreatic fistula: ANZ J Surg, 2018; 88; E602-5
16. Fujiwara Y, Shiba H, Shirai Y, Perioperative serum albumin correlates with postoperative pancreatic fistula after pancreaticoduodenectomy: Anticancer Res, 2015; 35; 499-503
17. Xia W, Zhou Y, Lin Y, A predictive risk scoring system for clinically relevant pancreatic fistula after pancreaticoduodenectomy: Med Sci Monit, 2018; 24; 5719-28
18. Bassi C, Falconi M, Salvia R, Management of complications after pancreaticoduodenectomy in a high volume centre: Results on 150 consecutive patients: Dig Surg, 2001; 18; 453-58
19. Balachandran P, Sikora SS, Raghavendra Rao RV, Haemorrhagic complications of pancreaticoduodenectomy: ANZ J Surg, 2004; 74; 945-50
20. El Nakeeb A, Salah T, Sultan A, Pancreatic anastomotic leakage after pancreaticoduodenectomy. Risk factors, clinical predictors, and management (single center experience): World J Surg, 2013; 37; 1405-18
21. Roberts KJ, Storey R, Hodson J, Pre-operative prediction of pancreatic fistula: Is it possible?: Pancreatology, 2013; 13; 423-28
22. Frozanpor F, Loizou L, Ansorge C, Correlation between preoperative imaging and intraoperative risk assessment in the prediction of postoperative pancreatic fistula following pancreatoduodenectomy: World J Surg, 2014; 38; 2422-29
23. Hashimoto Y, Sclabas GM, Takahashi N, Dual-phase computed tomography for assessment of pancreatic fibrosis and anastomotic failure risk following pancreatoduodenectomy: J Gastrointest Surg, 2011; 15; 2193-204
24. Kang JH, Park JS, Yu JS, Prediction of pancreatic fistula after pancreatoduodenectomy by preoperative dynamic CT and fecal elastase-1 levels: PLoS One, 2017; 12; e0177052
25. Hong TH, Choi JI, Park MY, Pancreatic hardness: Correlation of surgeon’s palpation, durometer measurement and preoperative magnetic resonance imaging features: World J Gastroenterol, 2017; 23; 2044-51
26. Yamamoto T, Satoi S, Yanagimoto H, Clinical effect of pancreaticojejunostomy with a long-internal stent during pancreaticoduodenectomy in patients with a main pancreatic duct of small diameter: Int J Surg, 2017; 42; 158-63
27. Zhang H, Zhu F, Shen M, Systematic review and meta-analysis comparing three techniques for pancreatic remnant closure following distal pancreatectomy: Br J Surg, 2015; 102; 4-15
28. Bruns H, Kortendieck V, Raab HR, Antolovic D, Intraoperative fluid excess is a risk factor for pancreatic fistula after partial pancreaticoduodenectomy: HPB Surg, 2016; 2016 1601340
29. Kinaci E, Sevinc MM, Ozakay A, Intraoperative acidosis is a new predictor for postoperative pancreatic fistula after pancreaticoduodenectomy: Hepatobiliary Pancreat Dis Int, 2016; 15; 302-9
30. Kim WS, Choi DW, Choi SH, Clinical validation of the ISGPF classification and the risk factors of pancreatic fistula formation following duct-to-mucosa pancreaticojejunostomy by one surgeon at a single center: J Gastrointest Surg, 2011; 15; 2187-92
Tables
In Press
18 Mar 2024 : Clinical Research
Sexual Dysfunction in Women After Tibial Fracture: A Retrospective Comparative StudyMed Sci Monit In Press; DOI: 10.12659/MSM.944136
21 Feb 2024 : Clinical Research
Potential Value of HSP90α in Prognosis of Triple-Negative Breast CancerMed Sci Monit In Press; DOI: 10.12659/MSM.943049
22 Feb 2024 : Review article
Differentiation of Native Vertebral Osteomyelitis: A Comprehensive Review of Imaging Techniques and Future ...Med Sci Monit In Press; DOI: 10.12659/MSM.943168
23 Feb 2024 : Clinical Research
A Study of 60 Patients with Low Back Pain to Compare Outcomes Following Magnetotherapy, Ultrasound, Laser, ...Med Sci Monit In Press; DOI: 10.12659/MSM.943732
Most Viewed Current Articles
16 May 2023 : Clinical Research
Electrophysiological Testing for an Auditory Processing Disorder and Reading Performance in 54 School Stude...DOI :10.12659/MSM.940387
Med Sci Monit 2023; 29:e940387
17 Jan 2024 : Review article
Vaccination Guidelines for Pregnant Women: Addressing COVID-19 and the Omicron VariantDOI :10.12659/MSM.942799
Med Sci Monit 2024; 30:e942799
14 Dec 2022 : Clinical Research
Prevalence and Variability of Allergen-Specific Immunoglobulin E in Patients with Elevated Tryptase LevelsDOI :10.12659/MSM.937990
Med Sci Monit 2022; 28:e937990
01 Jan 2022 : Editorial
Editorial: Current Status of Oral Antiviral Drug Treatments for SARS-CoV-2 Infection in Non-Hospitalized Pa...DOI :10.12659/MSM.935952
Med Sci Monit 2022; 28:e935952