Author Affiliations: Department of Surgery, Faculty of Medicine and University Hospital Hradec Králové, Sokolská 581, 500 05 Hradec Králové, Czech Republic (Cecka F, Jon B, Šubrt Z and Ferko A); Department of Field Surgery, Military Health Science Faculty, Hradec Králové, Defence University Brno, Trebešská 1575, 500 01 Hradec Králové, Czech Republic (Šubrt Z)

Corresponding Author: Filip Cecka, MD, PhD, Department of Surgery, Faculty of Medicine and University Hospital Hradec Králové, Sokolská 581, 500 05 Hradec Králové, Czech Republic (Tel: 420-737-163931; Fax: 420-495-832026; Email: filip.cecka@seznam.cz)

 

© 2013, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(13)60084-3

 

 

Contributors: CF proposed the study and wrote the first draft. JB and ŠZ analyzed the data. FA provided advice on medical aspects. All authors contributed to the design and interpretation of the study. CF is the guarantor.

Funding: This work was supported by grants from the project for conceptual development of research organization 00179906 and IGA NS 9998-4 from the Ministry of Health, Czech Republic.

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

BACKGROUND: Postoperative pancreatic fistula is the main cause of morbidity after pancreatic resection. This study aimed to quantify the clinical and economic consequences of pancreatic fistula in a medium-volume pancreatic surgery center.

 

METHODS: Hospital records from patients who had undergone elective pancreatic resection in our department were identified. Pancreatic fistula was defined according to the International Study Group on Pancreatic Fistula (ISGPF). The consequences of pancreatic fistula were determined by treatment cost, hospital stay, and out-patient follow-up until the pancreatic fistula was completely healed. All costs of the treatment are calculated in Euros. The cost increase index was calculated for pancreatic fistula of grades A, B, and C as multiples of the total cost for the no fistula group.

 

RESULTS: In 54 months, 102 patients underwent elective pancreatic resections. Forty patients (39.2%) developed pancreatic fistula, and 54 patients (52.9%) had one or more complications. The median length of hospital stay for the no fistula, grades A, B, and C fistula groups was 12.5, 14, 20, and 59 days, respectively. The hospital stay of patients with fistula of grades B and C was significantly longer than that of patients with no fistula (P<0.001). The median total cost of the treatment was 4952, 4679, 8239, and 30 820 Euros in the no fistula, grades A, B, and C fistula groups, respectively.

 

CONCLUSIONS: The grading recommended by the ISGPF is useful for comparing the clinical severity of fistula and for analyzing the clinical and economic consequences of pancreatic fistula. Pancreatic fistula prolongs the hospital stay and increases the cost of treatment in proportion to the severity of the fistula.

 

(Hepatobiliary Pancreat Dis Int 2013;12:533-539)

 

KEY WORDS: pancreatic resection; pancreatic fistula; cost analysis

Pancreatic resection is the only potentially curative modality for pancreatic neoplasm.^{[1, 2]} The mortality associated with this procedure has decreased rapidly in the past decades because of refinement of operative techniques, introduction of new surgical devices, and improvement in postoperative care, including new interventional radiology techniques.^[3-5] However, the morbidity associated with pancreatic resection remains high.^{[6, 7]} The morbidity is due to postoperative pancreatic fistula, which is regarded as the most ominous complication after pancreatic resection.^[8,9] Its reported incidence varies from 10% to >30%.^[8-11] This wide variability is largely due to different definitions of pancreatic fistula.^[12] The definitions are usually based on amylase concentration of drainage fluid, volume, and duration of the drainage. When various definitions of pancreatic fistula are applied to identical groups of patients, the incidence of pancreatic fistula can range from 10% to 29% according to which definition is applied.^[12]

 

A new universal definition of pancreatic fistula was published in 2005.^[13] According to the International Study Group on Pancreatic Fistula (ISGPF), pancreatic fistula is defined as output via an operatively placed drain (or a subsequently placed percutaneous drain) of any measurable volume of drain fluid on or after postoperative day 3, with an amylase content greater than three times the upper normal serum value.^[13] The fistula is then graded according to the clinical impact as A, B, or C. The ISGPF definition has been widely accepted.^[14]

 

Previous studies^{[14, 15]} reported that postoperative pancreatic fistula prolongs the hospital stay and increases the cost of treatment. Furthermore, pancreatic fistula often requires readmission, radiology-guided percutaneous drainage, prolonged parenteral antibiotic therapy, radiological surveillance, and reoperations. The goal of this study was to quantify the consequences of pancreatic fistula in terms of the cost of treatment, medical resources utilization, and the length of hospital stay in a medium-volume pancreatic surgery center. We hypothesized that pancreatic fistula increases the cost of the treatment and prolongs the hospital stay in proportion to the severity of the fistula.

 

 

Hospital records of patients who had undergone elective pancreatic resection at the University Hospital Hradec Králové, Czech Republic from January 2008 to June 2012 were identified from our prospectively entered pancreatic surgery database. Patients with non-elective pancreatic resection and multivisceral pancreatic resection were excluded from the study because urgent resection and multivisceral resection may increase the morbidity and the rate of pancreatic fistula.^{[16, 17]} Both open and laparoscopic pancreatic resections were included in the study.

 

After pancreaticoduodenectomy, a pancreaticojejuno anastomosis was made in a duct-to-mucosa end-to-side manner and in two layers with interrupted stitches in all patients. Ductal stents were not used, and pancreaticogastrostomy was not performed. Open distal pancreatectomy was performed in a uniform fashion, followed by a sharp transection with a blade. If the main pancreatic duct was visible, it was occluded with a stitch. Finally, the pancreatic remnant was secured with sutures. No staplers were used for the transection of the pancreas in open procedures. Laparoscopic distal pancreatectomy was introduced in our department in 2009. For laparoscopic pancreatic resection, transection was done with a stapler. In the open procedures, three drains were routinely placed in the subhepatic region anterior to the pancreaticojejuno anastomosis, in the left subphrenic area, and in the Douglas space. In laparoscopic distal pancreatectomy, one drain was placed in the left subphrenic area. Prophylactic octreotide was given to all of the patients (100 µg every 8 hours) for 5 days.

 

Postoperative management was standardized for all patients. Outputs from all drains were recorded daily. The amylase concentration was measured on postoperative day 3. If the amylase concentration was above three times of the normal serum value, the drain was kept in place and the measurement was repeated every other day. In clinically suspicious cases, ultrasound or CT scans were performed to assess peripancreatic fluid collection. Undrained collections were drained with CT guidance.

 

Pancreatic fistula was defined according to the ISGPF as output via operatively or postoperatively placed drains of any measurable volume of drain fluid on or after postoperative day 3, with amylase content greater than three times of the upper normal serum value. Three grades of pancreatic fistula were determined according to the clinical severity. The grades were determined only after complete healing of the fistula.^[13]

 

Grade A fistula, also called "transient fistula" has no clinical impact. They require little or no change in the clinical management of the patient. Grade A fistula is not associated with a delay in hospital discharge; however, the patient may be discharged with the drain. The drain is usually removed within 3 weeks. Imaging studies do not reveal worrisome or suspicious peripancreatic collections.

 

Grade B fistula is symptomatic and clinically apparent, and they require changes in clinical management or adjustment of the clinical pathway. The patients with grade B fistula are usually supported by enteral or parenteral nutrition, and the peripancreatic drains are usually kept in place or new drains may be inserted. The patients may experience abdominal pain, fever, and leukocytosis.

 

Grade C fistula is severe and clinically significant, and they require major clinical adjustments. Aggressive intervention is needed for the patients with grade C fistula. The patients are treated with enteral or parenteral nutrition, antibiotics, and somatostatin analogues often in the intensive care unit (ICU). CT scan usually shows worrisome peripancreatic fluid collection that needs percutaneous drainage. Surgical revision may be indicated in some cases.

 

Other postoperative complications have been assessed according to the grading system proposed by DeOliveira et al,^[6] i.e. grade I: any deviation from the normal postoperative course, e.g. wound infection; grade II: pharmacological treatment; grade III: surgical, endoscopic, or radiologic intervention; grade IV: single-organ or multiorgan dysfunction; and grade V: death of patient.

 

The data were prospectively put in the pancreatic surgery database of our department. Preoperative parameters included basic patient demographics (age, gender, and comorbidity) and presenting symptoms. Intraoperative parameters included operative time, perioperative complications, and blood loss. Postoperative events and management included incidence and type of complication, ICU stay, total hospital stay, radiological intervention, reoperation, and mortality.

 

The economic consequences of pancreatic fistula were determined by the cost of the treatment during the hospital stay, and during the out-patient follow-up lasting until the pancreatic fistula was completely healed. The hospital costs covered operating room, pharmacy (medication, fluid management, and nutritional support), radiology (imaging studies and interventional radiology), transfusion (blood products), laboratory examination, ICU, and room costs. The costs are expressed in Euros. Results are expressed as median and interquartile range.

 

Statistical analyses were performed using statistical software NCSS 2007. The cost increase index (CII) was calculated for pancreatic fistula grades A, B, and C as multiples of the total cost for the no fistula group. Fistula grades were compared using the Chi-square test and the Kruskal-Wallis test. Post-hoc comparison of hospital costs for various fistula grades was made using Dunn's test with Bonferonni adjustment. A P value less than 0.05 was considered statistically significant.

 

 

Over 54 months, we performed elective pancreatic resections in 102 patients; all the patients met the criteria for evaluation in the study. Their characteristics and histological findings are summarized in Table 1. Sixty-six patients underwent pancreaticoduodenectomies (30 classical Whipple and 36 Traverso-Longmire) and 36 underwent distal pancreatectomies, open (n=28) or laparoscopic (n=8). In two patients, the laparoscopic procedure was converted to the open procedure. Forty patients (39.2%) developed pancreatic fistula according to the ISGPF definition and 62 (60.8%) had no fistula. The fistula rates are summarized in Table 2. The fistula rates for pancreaticoduodenectomy and distal pancreatectomy were 42.4% and 33.3%, respectively, but there was no significant difference between them (P=0.4). Regarding grades B and C fistula groups, the fistula rates after pancreaticoduodenectomy and distal resection were 31.8% and 11.1%, respectively. Although the fistula which appeared after pancreaticoduodenectomy tended to be more severe, the difference was not statistically significant.

 

Fifty-four patients (52.9%) had one or more complications. Twelve patients (11.8%) had complication grade I, 18 (17.6%) grade II, 13 (12.7%) grade III, and 5 (4.9%) grade IV. Regarding diagnosis, the most common complications, in addition to pancreatic fistula, were of an infectious nature (14.7%), bleeding (9.8%), delayed gastric emptying (6.9%), cardiopulmonary complications (4.9%), bile leak (3.9%) and neurological complications (2.9%). The most common site of infections was the surgical wound (7.8%).

 

Two patients died within 30 days of the procedure. Four other patients died in the postoperative period on the 35th, 40th, 58th and 89th day, respectively. Overall the in-hospital mortality was 5.9%. Four patients died as a result of grade C pancreatic fistula and two patients died of other causes. The mortality of grade C fistula was 50.0% (4/8).

 

We evaluated the clinical parameters associated with pancreatic fistulae and complications. The median ICU stay was 4 days for patients with no fistula, 3 days for patients with grade A fistula, 6 days for grade B fistula, and 24.5 days for grade C fistula. The ICU stay for grade C fistula was significantly longer than that for the other groups (P<0.05). The median lengths of hospital stay for the no fistula and grade A fistula groups were comparable: 12.5 days (10-15) and 14 days (11.5-19.5), respectively. The median lengths of hospital stay for the grade B and C fistula groups were 20 days (16-24) and 59 days (36-73), respectively. The hospital stay of patients with fistula of grades B and C was significantly longer than that of patients with no fistula (P<0.001). The median hospital stay for patients with no complication and no fistula was 11 days. Radiological interventions were performed in ten patients. Interventional angiography with embolization of hepatic artery aneurysm was performed twice in patients with bleeding due to a grade C pancreatic fistula. Drainage of peripancreatic fluid collections under CT guidance was performed in eight patients (7.8%), all of whom had grade B fistula. Reoperations were performed in eight patients (7.8%), 5 out of the 8 were grade C fistula, and the other 3 were due to postoperative bleeding.

 

We evaluated the economic consequences of pancreatic fistula of varying degrees of severity. The costs were calculated in Euros. As the two surgical procedures (pancreaticoduodenectomy and distal pancreatectomy) are different, first we calculated the costs of the treatment for both procedures separately. There were no statistical differences between pancreaticoduodenectomy and distal pancreatectomy for either the no fistula group or the grades A and B fistula groups. This is the reason we performed further calculations of both procedures together. The economic parameters are summarized in Table 3. The median of total treatment costs increased between the grades A, B and C fistula groups (P<0.001). Dunn's test with Bonferonni adjustment shows comparison of hospital costs for various fistula grades. We evaluated the costs for grade C fistula in detail; in the group of patients with grade C fistula, the ICU costs represented 72.6% of the total treatment costs, which were more than the ICU costs in any other group and even more than the total hospital costs in the grade B fistula group.

 

The operating room costs for the no fistula, grades A, and B fistula groups were similar. Operating room costs were higher for patients with grade C fistula due to the more frequent reoperations in this group. Our study did not include indirect costs such as lost work time or frequent transportation to and from the medical facility.

 

 

The mortality of pancreatic resections has decreased in the past decades; however, the postoperative morbidity remains high.^[6] The overall morbidity in our series was 52.9%. The most ominous postoperative complication is pancreatic fistula, with a reported incidence of 10% to >30% even in high-volume centers.^[8-11] The large amount of variation in incidence is due mainly to different definitions of pancreatic fistula. The definitions are usually based on amylase concentration of drainage fluid, volume, and duration of the drainage. Lowy et al^[18] was the first to use the term clinically significant fistula. They defined biochemical fistula as secretion with a high amylase concentration that is asymptomatic and resolves spontaneously. The clinical fistula was defined as secretion with a high amylase concentration, leukocytosis, fever, sepsis, and necessity to drain worrisome peripancreatic fluid collections.

 

A broad and general definition of pancreatic fistula was published by the ISGPF in 2005.^[13] This definition is based on the clinical severity of the fistula. It defines three grades of fistula and can be used to correlate their clinical and economic consequences. Our study indicates that grade A fistula has no clinical or economic consequences. However, it is important to identify and report patients with grade A pancreatic fistula so that a uniform definition of pancreatic fistula is maintained and the results of centers performing pancreatic surgery can be compared. The fistula rate depends largely upon the definition of fistula.^[12] Yang et al^[19] performed 31 pancreaticoduodenectomies. The reconstructions were made with "modified Child pancreaticojejunostomy", and the authors claimed to have a zero fistula rate. However, the fistula definition was quite liberal: >50 mL of secretion per day with an amylase concentration of >1000 IU/L. Moreover, the authors did not report the postoperative morbidity. The ISGPF definition is stricter; fistula is defined as any measurable volume of secretion with an amylase concentration greater than three times the upper limit of the serum concentration.

 

Our center is considered to be a medium-volume center; we perform approximately 20 pancreatic resections yearly on average. The fistula rate at our center over the 54-month study period was 39.2%, which is higher than that in other centers. However, this high percentage is due in part to the strict definition of pancreatic fistula by the ISGPF. With this definition, even high-volume centers can have pancreatic fistula rate over 30%.^[20] Of course, high-volume centers and experienced surgeons tend to have a lower pancreatic fistula rate.^[21] There are only a few reports of pancreatic fistula rates in medium- and low-volume centers. Cunningham et al^[22] reported excellent results with a low mortality rate following pancreatic resections at a low-volume center; however, the pancreatic fistula rate was not described.

 

Placement of intra-abdominal drains is a common practice in our department. A drain was always placed near the pancreaticojejuno anastomosis in cases of pancreaticoduodenectomy or near the pancreatic remnant in cases of distal pancreatectomy. However, it did not prevent the formation of an intra-abdominal fluid collection, and CT guided drainage was necessary in 8 patients (7.8%) in our study, which is comparable to the 10% described in another large series.^[23]

 

The incidence of pancreatic fistula after pancreatico­duodenectomy and distal pancreatectomy was similar in several studies.^{[20, 24]} Our data were consistent with those of other studies. The pancreatic fistula rate for open and laparoscopic pancreatectomy was also comparable; although this calculation is underpowered, it is in concordance with a recent review.^[25] Nevertheless, the clinical significance of pancreatic fistula after pancreaticoduodenectomy or distal pancreatectomy could be different. Sauvanet et al^[26] suggested that pancreatic fistula originating from pancreaticoenteric anastomosis seems to have a worse prognosis than those originating from a pancreatic remnant. This may be due to the activation of pancreatic juice by enterokinase, which is a necessary mechanism that stimulates the proteoclastic activity of various pancreatic enzymes.^[27] This process may contribute to the differences between pancreatic fistulae after operations that require enteric reconstructions (pancreaticoduodenectomy and central pancreatic resection) and those that do not (distal pancreatectomy and enucleation). Pratt et al^[20] suggested that clinically relevant fistulae after pancreaticoduodenectomy require more aggressive management in intensive care settings compared to those that occur after distal resections. Surgical exploration, when indicated, is more often urgent. On the other hand, fistulae that occur after distal resections often require prolonged drainage of intra-abdominal collections and multiple hospital readmissions, usually for image-guided percutaneous drainage.

 

Several previous studies^{[28, 29]} analyzed the cost of pancreatic fistula treatment. Holbrook et al^[28] reported that hospital costs increased by 76% due to postoperative complications. However, they did not analyze increases in cost due specifically to pancreatic fistula. Another study included 66 patients who underwent distal pancreatectomy.^[29] Pancreatic fistula was defined as a daily output of at least 30 mL of amylase-rich fluid (three times the serum concentration) from the surgically placed drain on day 5 after surgery. Other pancreatic leak-related complications included a sterile collection, an abscess, and wound disruption. According to the ISGPF definition of pancreatic fistula, those complications would also be considered pancreatic fistula. The authors did not distinguish between transient and clinically relevant pancreatic fistulae. Overall, 33% patients had complications attributed to pancreatic leak. The CII in the pancreatic fistula group was double that of the non-fistula group. The main disadvantage of Rodríguez's study was that it did not use the ISGPF definition of fistula.^[29]

 

Pratt et al^[20] analyzed 256 consecutive pancreatic resections and compared the differences between pancreaticoduodenectomy, distal pancreatectomy, and central resections. The authors used the ISGPF definition of fistula and found that the overall pancreatic fistula rate was 32.4%. The pancreatic fistula rates after pancreaticoduodenectomy and distal pancreatectomy were similar. The pancreatic fistula rate after central pancreatectomy reached 100%. In accordance with the results of Sauvanet et al,^[26] the fistulae that occurred after distal resections were more often biochemical and had no clinical consequences. The authors claimed that the hospital costs were similar between grades B and C fistulae after distal pancreatectomy and the impacts of grades B and C fistulae after distal pancreatectomy were equivalent. However, only three patients had grade C fistula after distal pancreatectomy; this small number could have led to type II error. A similar study was published by the same group in 2007.^[14] It included 176 consecutive pancreaticoduodenectomies; these were the same patients as in the previous study, and thus the results were similar. Recently, a large study^[15] reported the results of 755 patients who underwent pancreaticoduodenectomy over a period of 10 years. The overall pancreatic fistula rate was 19.5%, and the authors reported higher hospital costs for clinically significant pancreatic fistula.

 

The total hospital costs for all of the patients in our study were lower than those in other published studies; this is due to the political and economic differences among individual countries, and to differences in the respective health care systems. Accurate comparisons of the total hospital costs are also difficult because of fluctuating money exchange rates. Our study validated the clinical and economic significance of the ISGPF pancreatic fistula classification in a medium-volume pancreatic surgery center. In our group of patients, the cost of treatment escalated as the fistula severity increased.

 

Calculating the costs of the treatment for both procedures together could be considered a limitation of the study. However, the costs for both procedures were comparable for the no fistula group and for the fistula group as well. The number of patients in our study is lower than in other mentioned studies. Nevertheless, our center is considered medium-volume and one of the aims of the study is to validate the ISGPF definition in a medium-volume pancreatic surgery center.

 

In conclusion, a standardized definition of pancreatic fistula is important for evaluating the rate of this postoperative complication. It allows for comparisons to be made among different centers and even among individual surgeons. The ISGPF definition has been validated in several studies; thus, it should be used in all studies reporting the results of pancreatic surgery. The grading recommended by the ISGPF is useful for comparing the clinical severity of fistula and for analyzing the economic and clinical consequences of pancreatic fistula. Pancreatic fistula prolongs the hospital stay and increases the cost of treatment; these increases are progressively greater with increasing fistula severity. Although the total hospital cost is different in various countries, the increase in the hospital cost index noted in our study is similar to those of previously published studies. Thus, this cost index is applicable to pancreatic surgery centers in other regions and countries.

 

 

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