Updates in the management of postoperative pancreatic fistula

Abstract

Postoperative pancreatic fistula (POPF) remains a common and dreaded complication after pancreatic resections and is associated with increased morbidity and mortality. Over the years, several different strategies have been investigated to prevent and mitigate POPF. However, when a POPF occurs, a consensus on the optimal management strategy of grade B and grade C POPF is still lacking, and the current management strategy is often based on local expertise and driven by patient’s condition. Nevertheless, whereas the incidence of POPF after pancreatic surgery has remained stable, the overall mortality related to this complication has decreased over the years. This reflects an improvement in the management of this complication, which has become increasingly conservative. The aim of this review is to provide an updated evidence-based overview on the management strategies of POPF for surgeons and physicians in the clinical practice.

Introduction

Highlights

• Postoperative pancreatic fistula (POPF) remains one of the most frequent and dangerous complications after partial pancreatectomy and is associated with increased morbidity and mortality.

• Management strategies of POPFs have long been poorly standardized and are often based on surgeon’s expertise and driven by patient’s status.

• This narrative review aims to provide an updated evidence-based overview on the current practice management strategies of POPF, including the optimal drainage of the remnant pancreas, nutritional support, use of somatostatin analogues, threshold for using antibiotic, and indications for reoperation.

Postoperative pancreatic fistula (POPF) remains one of the most frequent and dangerous complications after partial pancreatectomy and is associated with increased morbidity and mortality^1–3.

The benchmark from the International Study Group of Pancreatic Surgery (ISGPS) Evidence Map of Pancreatic Surgery shows a grade B and C POPF rate of 14% (99% CI: 12–17%) in 99 randomized controlled trials (RCTs) after PD and 23% (99% CI: 17–30%) after DP⁴.

The highest rate of POPF follows central pancreatectomy, ranging from 20 to 60% depending on the series, because of the presence of two pancreatic remnants and thus of two potential sites for POPF development⁵.

Whereas the incidence of POPF after pancreatic surgery has remained stable, the overall mortality related to this condition has decreased over the years. This reflects an improvement in POPF management, which has become increasingly conservative.

The consensus definition of POPF, formulated in 2005 and updated in 2016 by the ISGPS, standardized for the first time the classification of POPFs grading the severity according to the clinical impact on the patient’s postoperative course⁶.

Several elements have been recognized as risk factors for POPF development, including pancreatic parenchymal texture, disease pathology, pancreatic duct size, and intraoperative blood loss⁷.

Unlike its prevention and mitigations strategies, management strategies of POPFs have long been poorly standardized and are often based on surgeon’s expertise and driven by patient’s status^2,7–14.

A consensus on the optimal treatment strategy of POPF, which include the optimal drainage of the remnant pancreas, nutritional support, use of somatostatin analogues, threshold for using antibiotic and indications for reoperation, is still debated and varies from institutions¹⁵.

This is particularly important because a poor management of this complications may not only negatively affect the quality of life in these patients, but also delay or limit the administration of adjuvant treatments, affecting the overall survival^16,17.

The aim of this narrative review is to provide an updated evidence-based overview on the current practice management strategies of POPF.

Definition, diagnosis, and grading

POPF develops as a consequence of pancreatic juice leakage from an impaired sealing of the pancreatic anastomosis (in the case of PD or middle pancreatectomy), at the site of the pancreatic stump (for distal pancreatectomy) or surgically exfoliated surface (e.g. enucleation).

From a clinical standpoint, it can be asymptomatic, but it can lead to the development of further sequelae as abdominal collections, bleeding, sepsis and, ultimately, postoperative mortality¹⁸.

According to the 2005 ISGPF, the necessary criterion for the diagnosis of POPF is the detection on any measurable volume of drain (intraoperatively placed) fluid on or after postoperative day 3 with amylase level >3 times the upper limit of normal amylase for each specific institution¹⁹.

Based on the 2016 ISGPS update, three different grades of pancreatic juice leakage can be identified, with different clinical impact⁶:

Biochemical leak

It is an asymptomatic pancreatic leak, which does not affect the normal postoperative course (previous Grade A POPF, according to the 2005 classification) and does not require any treatment or invasive procedure. The drains can be left in place even after discharge for up to 3 weeks.

The macroscopic appearance of the drain material can vary from amaranth to greenish/yellowish infected fluid, to limpid pancreatic juice.

Grade B

Involves therapeutic intervention such as an endoscopic or radiological drainage of collections or angiographic procedures to enhance the fistula healing. The drains are left in situ over 3 weeks or, if needed, they might be replaced under radiologic guidance. Patients with grade B POPF can present with a variety of nonspecific symptoms including abdominal pain, fever, and increased inflammations index and requires only antibiotic therapy. Whenever a single or multiorgan failure occurs the fistula shifts to a grade C POPF.

Grade C

This grade is framed as a severe POPF. Patients with a grade C have developed single or multiple organ failure as a direct result of the POPF and might require surgical reoperation to manage the

clinical status. This is a life-threatening condition and is associated with a mortality up to 39%²⁰.

If the 2016 updated ISGPS definition has the merit of replacing grade A POPF by introducing the concept of biochemical leak (BL), however, grade B definition still combines a heterogeneous group of clinical conditions.

For these reasons, a stricter distinction of grade B POPF in three different sub-categories has been proposed: B1, maintenance of abdominal drain more than 3 weeks; B2, use of antibiotics or other specific medical treatment for POPF; and B3, use of interventional procedures for the POPF treatment²¹.

Nappo et al.²², in a retrospective study including 716 patients, shows that this subclassification allows to better discriminate the severity of postoperative course, especially after PD, supporting its adoption in the new ISGPS classification.

Clinical presentation

From a clinical standpoint, patient with POPF can present asymptomatic or with wide range of nonspecific symptoms. The development of a POPF should be suspected any time that a patient who underwent pancreatic resection presents a deviation from the normal postoperative course.

Parallel to the transformation of the drainage material from serous to dark brown or corpuscular, patients can present with unspecific symptoms like abdominal pain, delayed gastric emptying (DGE), impaired bowel function. Fever and increased C-reactive protein (CRP) levels and white blood cells count may be suggestive of an undrained peripancreatic fluid collection related to POPF.

Notably, in most cases, POPF develops within few days after the surgery; however, in few cases patients present with a latent POPF, which initially lacks amylase-rich drain effluent but eventually shows the clinical and radiological findings indicative of POPF²³.

The early recognition of this complication is fundamental for its successful management. Latent POPFs represent a rare but treacherous presentation, a close observation in the early postoperative period is fundamental because a timely treatment of this condition is the key element to avoid life-threatening sequalae.

A standardized postoperative patient monitoring to early detect any deviation from the normal postoperative course is the first step in the management of a POPF and to improve patient’s outcome. However, in the current clinical practice, guidelines on effective postoperative patient monitoring, are lacking.

Smits et al.²⁴ developed a best-practice algorithm based on national (Dutch) and international consensus on early detection and step-up management of pancreatic fistula to prevent further clinical deterioration. More recently, in the PORSH-trial, the Dutch group demonstrated that the application of a standardized detection and management algorithm for POPF in the postoperative period could nearly half the mortality at 90 days after PD²⁵.

Management

Nonoperative management

Antibiotic therapy

Microbial growth in POPF is strongly associated with poor outcome after pancreatic surgery and marks a turning point in the development of POPF into life-threatening intra-abdominal infection, sepsis, and erosive bleeding resulting in postpancreatectomy hemorrhage (PPH), increasing morbidity and mortality^26–28.

Manipulation of the bile duct and multiple enteric anastomoses, together with the physiologic alterations occurring during PD (fluid shifts, blood loss, and systemic vasodilation), play a role in this process, representing the source of microorganism’s contamination.

Moreover, preoperative biliary procedures, which introduce bacteria into a normally sterile biliary tree and the resulting intraoperative biliary contamination are associated with and increased infection risk also for multidrug resistant (MDR) bacteria^17,29,30.

Several studies have shown the correlation between bacteriobilia found on intraoperative bile culture and not just postoperative surgical site infection (SSI) but also with organ space infection and sepsis^29,31,32.

In light of this, intraoperative bile sampling during PD allows the identification of potentially pathogenic microorganisms, enabling the clinician to target postoperative antibiotic treatment to cover also MDR bacteria.

This is especially important considering that frequently postoperative infectious complications after pancreatic surgery are sustained from a polymicrobial flora, with a median of three species of microorganisms isolated in the of POPF fluid^17,33.

A proper preoperative prophylaxis strategy has been proven effective in reducing CR-POPF and multiple resulting sequelae^3,33,34. This strategy should include surveillance preoperative rectal swabs to check for the presence of resistant bacteria and an antimicrobial therapy with antienterococcal activity should be chosen in stent-bearing patients^32,35.

Some authors have postulated that prolonged antibiotic prophylaxis may reduce postoperative infectious complications after PD³⁶. A recent metanalysis including 10 studies evaluating the effect of prolonged antibiotics after pancreatoduodenectomy showed that prolonged antibiotic prophylaxis is associated with fewer organ/space infection in patients who undergo preoperative biliary drainage³⁷. However, the authors did not observe a difference in POPF rate between patients receiving perioperative versus prolonged prophylaxis (OR 1.35, 95% CI: 0.94–1.93)³⁷.

Conversely, Ocuin et al.³⁸, in a recent single-center study, observed that extended antibiotic therapy (10 days of broad-spectrum antibiotics) is associated with a lower rate of POPF after pancreatoduodenectomy in patients with a fistula risk score ≥3.

Postoperatively, the threshold to start antibiotic treatment is still debated and mainly driven by patient’s conditions. In the clinical practice antibiotic therapy should be started whenever the patient should manifest signs of infection and should be targeted on the basis of cultural isolation data available from both intraoperative bile culture and drain effluent.

However, since cultural data may not be immediately available in the early postoperative period, a step- up strategy, starting with a broad-spectrum antibiotic subsequently shifted to targeted therapy once the results and the antibiogram are available, should be adopted.

Drainages management

Intraoperative drains placement after pancreatic resections as well as the timing of their removal is still a matter of debate.

The rationale behind prophylactic drains placement is early recognition and mitigation of postoperative complications, such as postpancreatectomy hemorrhage, POPF, and biliary leaks.

Moreover, drains allow to measure amylase levels on the drain effluent, which, together with the macroscopic appearance, is the key element to guide the timing of removal^39,40.

However, concerns also have been raised that drains placement presents its own risks, including serving as a potential pathway for retrograde infection which may shift a self-limiting postoperative fluid collection into an abscess, and they may cause trauma from suction, potentially eroding into anastomoses leading to fistula or hematoma development, increasing morbidity and hospitalization⁴¹.

Owing this and the implementation of POPF predictive scores, some authors have postulated that intra-abdominal drains can be avoided in selected cases after PD and DP in patient at low risk of developing POPF according to the fistula risk score (FRS)^7,39.

To date, drains placement is recommended, and postoperative drain management policy should be driven by the amylase levels on the effluent together with the macroscopic appearance and the volume output.

Regarding the type of drains, open passive (e.g. Penrose drains) and closed-suction drains system (e.g. Jackson-Pratt drain) seems to be comparable in terms of postoperative morbidity, mortality, and in preventing bacterial contamination⁴².

Other than the ‘diagnostic’ purpose, intraoperatively placed drains may also have a ‘therapeutic’ function, due the possibility to progressively mobilize them in order to promote the spontaneous healing process of the fistula, supporting the success of nonoperative management.

In specific cases, drainage mobilization could also help evacuating any surrounding collection that was not captured in the initial position, potentially contributing reducing the rate of late POPF and intra- abdominal collections.

All the above-mentioned functions are supported by the assumption that once drains are placed intraoperatively, their position remains virtually stable until they are mobilized or removed.

Marchegiani et al.⁴³ showed that postoperative drain dislocation is a frequent event, usually occurring in the early postoperative period (POD 1), with no significant difference in terms of rate of dislocation between PD and DP (29 vs. 39%, respectively).

Interestingly, in this series, dislocation of surgical did not increase postoperative morbidity, including POPFs rate⁴³.

These results are in line with other studies in literature, reinforcing the knowledge that drainless policy might be adopted in selected patients at negligible risk of developing POPF^44–47.

As for the optimal timing of removal, an increasing body of literature underpins the adoption of protocols for early drain removal based on the activity of amylase in the drainage fluid in selected patients at low risk for developing POPF^40,48–50.

However, the definition of ‘early removal’ is heterogeneous among the series, as well as the eligible patients.

An early drain removal policy may be considered in selected patients at low risk of developing POPF based on fistula risk scores, intraoperative pancreas appearance and driven by amylase levels in the early postoperative days.

Indications on drainage placement, especially after DP, continues to be controversial and structured multicenter randomized trials on prophylactic drainage placement versus a no-drain strategy with stratification for fistula risk are needed.

New evidence may emerge from the ongoing PANDORINA trial, a binational multicenter randomized controlled (noninferiority) trial evaluating whether the omission routine intra-abdominal drainage after DP increases postoperative complications⁵¹.

Nutritional support

Nutritional support has been regarded as a key element of conservative therapy of POPF.

Historically, attempts to accelerate POPF closure were made by prolonged fasting, since oral feeding was believed to increase the production of pancreatic juice and trigger the activation of trypsinogen, eventually exacerbating the fistula.

However, patients with grade B and C POPF, are in a catabolic process with a higher basal energy expenditure and an insufficient nutrient intake can worse the clinical course and lead to further complications.

Moreover, patients with high-output POPF (>200 ml in the 24 h) are at risk of fluids and electrolytes imbalance, since the loss of pancreatic juice, which is bicarbonate rich, can lead to metabolic acidosis.

The European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines suggest for patients with a clinically relevant POPF, an energy supply not exceeding 20–25 kcal/kg body weight/day that might be increased up to 25–30 total kcal/kg body weight/day in the case of severe malnutrition. If these target values are not reached, supplementary parenteral nutrition may be given⁵².

The position paper of the ISGPS recommends either enteral nutrition (EN) or fasting with total parenteral nutrition (TPN) for patients with B and C grade POPF, and oral feeding for those with a BL⁵³.

However, the superiority of EN or TPN for fistula healing and the benefit of avoiding oral feeding is still debated and mostly arbitrary, since strong evidence and standardized protocols of nutrition routes are lacking (Table 1A).

Table 1.

Recommendations based on recent literature.

Nonoperative management
A). Nonoperative management
Antibiotic therapy
Preoperative prophylaxis	Preoperative prophylaxis strategy should include surveillance swabs to check for the presence of resistant bacteria and an antimicrobial agent with antienterococcal activity should be chosen in bearing-stent patients
Postoperative treatment	Should be started whenever the patient manifest signs of infection and should be targeted on the basis of cultural isolation data available from both intraoperative bile culture and drain effluent. A step-up strategy (broad- spectrum antibiotic subsequently shifted to targeted therapy once the results and the antibiogram are available) should be adopted
Drainages management
Drainages placement	To date, drains placement is recommended, and postoperative drain management policy should be driven by the amylase levels on the effluent together with the macroscopic appearance and the volume output
Timing for drainages removal	An early drain removal policy may be considered in selected patients at low risk of developing POPF based on fistula risk scores, intraoperative pancreas appearance and driven by amylase levels in the early postoperative days
Nutritional support
Artificial nutrition	The position paper of the ISGPS recommends either EN or fasting with TPN for patients with B and C grade POPF
Nutrition route	To date, there are no evidence supporting the superiority of EN or TPN for fistula healing, as well as the benefit of avoiding oral feeding is still debated and mostly arbitrary, since strong evidence and standardized protocols of nutrition routes are lacking
Somatostatin analogs
	To date, there is no strong evidence supporting postoperative administration of somatostatin/somatostatin analogs to enhance fistula closure and reduction in time to fistula
B). Interventional management
Interventional management
Percutaneous or endoscopic drainage	Endoscopic and percutaneous drainage appear to be equally effective and complementary interventions for POPF-associated collections. A step-up approach should be considered, especially in the setting of refractory POPF
Angiographic embolization	Angiography with embolization should be the initial approach for delayed bleeding if the patients is hemodynamically stable. Different techniques may be used including proximal embolization and vessel occlusion at the site of the bleeding with nonabsorbable materials include PVA particles and metallic coils. If the bleeding site is in a major artery, stent grafting is usually the treatment of choice
Surgical reintervention	Surgical exploration should be considered only in the case of unstable patients with active bleeding or failed control of bleeding after interventional angiography or endoscopy. The choice between pancreas- preserving procedures vs completion pancreatectomy relies on intraoperative findings and patient’s clinical stability

EN, enteral nutrition; ISGPS, International Study Group for Pancreatic Surgery; POPF, postoperative pancreatic fistula; TPN, total parenteral nutrition; PVA, polyvinylic alcohol.

TPN has the advantage of blocking the food-induced pancreatic secretion, however, long-term use of TPN can cause morphological changes in the intestinal mucosa and in the pancreas itself, other than lead to wound infection, sepsis, fluid overload, and metabolic complications⁵⁴.

On the other hand, EN generally not only avoids pancreatic stimulation but also may stimulate the release of specific gut peptides forming a negative feedback control system, and thus inhibiting pancreatic secretion⁵⁴.

In the setting of grade B and C POPF, EN therapy seems to be superior to TPN.

In fact, as shown by Keck et al. in a randomized controlled trial, EN seems to increase by more than twofold the probability of fistula closure (OR 2.571, 95% CI: 1.031–6.41), shorten the time to closure, and is associated with significantly faster recovery, lower rates of nutrition-related complications, and lower cost than TPN⁵⁵.

More recently, Wu et al.⁵⁶ in a noninferiority randomized trial comparing oral versus enteral feeding for patients with POPF after pancreatoduodenectomy, shows that oral feeding did not increase the duration or grade of POPF (88 vs. 89% respectively; difference –1.8%, lower limit of 95% CI –14.4%; P=0.020 for noninferiority), and was associated with reduced duration of stay and hospital costs. These findings support the idea that oral feeding does not exacerbate POPF.

Somatostatin analogs

Somatostatin is a naturally occurring hormone, which has the effect of reducing exocrine pancreatic secretion and increasing the net absorption of water and electrolytes⁵⁷.

Because of these properties, somatostatin has been postulated to be useful in the conservative management of fistula by reducing output and enhancing the closure.

The major disadvantage of somatostatin is the short half-life (1–2 mins) hence, over years, somatostatin synthetic analogues with longer half-life, like octreotide and lanreotide, have been developed.

Several studies and RCTs investigated the impact of preoperative and postoperative somatostatin and somatostatin analogs administration to prevent the occurrence of POPF^58–61.

Bootsma et al.⁶² in a recent Dutch nationwide analysis suggests that administration of lanreotide in patients undergoing open pancreatoduodenectomy is associated with a reduced rate of POPF (OR 0.387; 95% CI: 0.180–0.834, P=0.015) compared to other protocols.

More recently the efficacy of pasireotide, which displays a broader affinity to somatostatin receptor subtypes than octreotide, was noted.

Allen et al.⁶³, in a large RCT, investigated whether pasireotide can be used to prevent POPFs in both PD and DP, demonstrating a significant reduction of POPF after PD and DP in patients receiving preoperative subcutaneous pasireotide.

However, the therapeutic benefit of these drugs in enhancing fistula closure and reduction in time to fistula closure remains unclear.

Gans et al. in a systematic review of somatostatin and somatostatin analogs for the treatment of pancreatic fistula analyzed seven RCTs. According to the studies included in this review, there is no solid evidence that somatostatin analogues result in a higher closure rate of pancreatic fistula compared with other treatments (OR for fistula closure=1.52, 95% CI: 0.88–2.61)⁶⁴.

To date, there is no strong evidence showing the advantage of postoperative administration of somatostatin/somatostatin analogs to enhance fistula closure and reduction in time to fistula (Table 1A).

Further evidence arising from controlled trials is needed to clear whether new somatostatin analogs may have a therapeutic role in the management of POPF.

Interventional management

Percutaneous or endoscopic drainage

Drainage of the collected pancreatic fluid is mandatory when the patient shows clinical signs of infection not only to mitigate the associated symptoms such as abdominal pain, gastric outlet obstruction and, most importantly, to prevent postoperative hemorrhage (e.g. formation of arterial pseudo-aneurysms secondary to POPF) and septic shock that can lead to life-threatening consequences⁶⁵.

A step-up approach, consisting of percutaneous catheter drainage followed, only in case of failure, by surgical necrosectomy, has replaced surgical debridement as the standard treatment, reducing the risk of further morbidities and subsequent complications⁶⁶.

A percutaneous approach is a viable and safe option as long as the patient is hemodynamically stable and there is a safe access route to the collection.

Drainage placement is performed under ultrasound (US) or CT-scan guidance using the Seldinger technique, which is usually preferable over the trocar technique since allows a highly accurate and safe image-guided needle placement⁶⁷.

The collection is punctured with a small caliber needle, guide-wires are inserted, and the drainage catheter is then advanced over the guidewire and placed into the fluid collection (Figure 1).

Figure 1.

(A) CT-scan shows postpancreaticoduodenectomy fluid collection. (B) A percutaneous. drainage is inserted into the collection using the Seldinger technique under CT-scan.

Several studies have shown that percutaneous drainage is technically safe, with a reported success rate ranging between 85 and 97.6% cases depending on the series and without the need for reoperation^68,69.

However, percutaneous catheters have some downsides, given the need for frequent output monitoring, daily catheter flushing, subsequent catheter exchange due to malfunction or dislodgement and upsize which may lead to local skin irritation and drain track infection⁷⁰.

The use of endoscopic-ultrasound (EUS) guided transmural drainage of POPF-related collections, has increased in frequency due to the favorable outcome in the setting of pseudocysts secondary to acute pancreatitis or infected necrotizing pancreatitis^71–73.

EUS-guided transmural drainage is especially useful to treat refractory POPF after percutaneous drainage and difficult-to-reach collections after DP where the location of the collection within the resection bed may be better accessed from the stomach (i.e. cyst-gastrostomy)^74,75.

In this case, an FNA needle is used to puncture through the gastric wall and access the collection. A guidewire is advanced into the collection cavity under fluoroscopic guidance and the cyst-gastrostomy tract can be dilated using a biliary or esophageal balloon dilator. One or multiple pigtail biliary stents (usually 7F or 10F) are then placed, and debridement may be performed if needed (Figure 2).

Figure 2.

EUS-guided pancreatic fluid collection drainage.

Compared to percutaneous drainage, endoscopic drainage offers several potential benefits.

The real-time high-resolution viewing of the collection, and any associated vasculature, allows for safe access and allow and to debride the necrotic tissue resulting from pancreatic enzymatic digestion.

Furthermore, the lack of an external catheter, lower fluid and electrolyte losses obviates the need for catheter care and is more convenient for patients and caregivers⁷⁶.

On the other hand, endoscopic drainage requires more advanced expertise, compared to percutaneous drainage, and is usually available only in referral centers with advanced interventional endoscopists and require subsequent removal of the stents and could be performed usually at least after 4 weeks from the collection development^77,78.

Several studies have compared the drainage of collections associated with POPF using endoscopic and percutaneous technique.

A recent retrospective study by Efishat et al.⁷⁹ shows that technical success was achieved in almost all patients in both endoscopic and percutaneous groups (100 and 97%) and clinical success was achieved in 67 and 59%, respectively (P=0.63), with no differences in term of recurrence between the two groups.

Endoscopic and percutaneous drainage appear to be equally effective and complementary interventions for POPF-associated collections. The choice between the two routes of drainage should take into account the location of the collection, timing, and the expertise of the interventional endoscopists and a multidisciplinary step-up approach should be considered, especially in the setting of refractory POPF (Table 1B).

Angiographic embolization

Leakage of amylase-rich pancreatic juice can cause vessel erosion resulting in PPH. This a relatively rare complication but it is responsible for up to 38% of deaths⁸⁰.

According to the ISGPS, in contrast with early PPH which develops within 24 h from surgery and is usually due technical failure in achieving adequate hemostasis, late PPH occurs later with a median onset between 13 and 27 days postoperatively and is likely due to vascular erosion caused by intra-abdominal abscesses and POPF, often leading to the formation of a pseudoaneurysm⁸¹.

Delayed hemorrhage, especially from a ruptured pseudoaneurysm, is a rare but rapidly progressing and potentially life-threatening complication following pancreaticoduodenectomies⁸².

Following pancreatic head resections, common sites of bleeding include the peripancreatic vasculature (gastroduodenal artery - GDA stump, common hepatic artery- CHA and its branches, portal vein- PV, superior mesenteric artery- SMA and its branches, splenic artery), resection surfaces, and anastomotic sites (pancreatico-enteric anastomosis, entero-enteric anastomosis, and marginal ulcer)^80,81.

Symptoms and presentation depend on the site of bleeding, varying from signs of upper gastrointestinal bleeding (hematemesis, melena, or blood per nasogastric tube), followed by blood in drainage fluid, drop in hemoglobin and lower gastrointestinal bleeding (e.g. hematochezia). Delayed hemorrhage, especially from a ruptured pseudoaneurysm, is a rare but rapidly progressing and potentially life-threatening complication following pancreaticoduodenectomies.

If the patient is hemodynamically stable, angiography with embolization should be the initial approach for delayed bleeding.

A tri-phasic CT-scan to localize the bleeding may also be performed is the patient is stable; however, vascular spasm may be present and being responsible of false negatives. Failure to identify the bleeding site precludes targeted embolization (TE). In this setting, empiric embolization (EE) should be considered since it has been proven to be a safe and effective option in preventing rebleeding and mortality in patients with angiographically negative delayed PPH⁸³.

Different techniques may be used to stop bleeding, including proximal embolization and vessel occlusion at the site of the bleeding with nonabsorbable materials include polyvinylic alcohol (PVA) particles and metallic coils^84,85.

If the bleeding site is located in a major artery, for example, the superior mesenteric or the hepatic artery, stent grafting is usually the treatment of choice⁸⁶.

Surgical exploration should be considered only in the case of unstable patients with active bleeding or failed control of bleeding after interventional angiography or endoscopy (Table 1B).

Surgical reintervention

Surgical reintervention is considered the last-resort treatment when conservative management fails and is associated with a mortality rate up to 56%⁸⁷.

Clear evidence on indications and proper timing for relaparotomy are still lacking and mostly rely on center and surgeon’s expertise.

Surgical intervention should be considered when the patient deteriorates despite maximal supporting care, for septic intra-abdominal collections inaccessible to percutaneous or endoscopic drainage or for suspected peritonitis by visceral perforation.

Emergency relaparotomy is mandatory in presence of ongoing bleeding after failure or contraindication of radiologic endovascular procedures⁸⁰ (Table 1B).

In this scenario, the key decision is whether preserving the pancreatic remnant or proceed with the completion pancreatectomy (CPLP).

Pancreas-preserving procedures, based on the type on pancreatic resection, comprise drainage of the anastomotic region, repair or redo of the pancreatic anastomosis, oversewing of the stump or duct occlusion with fibrin sealant, salvage pancreatogastrostomy, and the bridge stent technique^88–90.

Although wide external drainage seems to be initially safer and more efficient, it might be an incomplete solution that requires additional re-explorations and prolonged length of stay, eventually leading to a higher mortality⁹¹.

Salvage pancreatogastrostomy has also been proposed as an alternative safe and efficient option to completion pancreatectomy for the treatment of grade C POPF after PD with PJ⁸⁹. However, the feasibility of this approach depends on the adequacy of the pancreatic remnant and requires additional dissection on severely compromised tissues. The bridge stent technique has been described as an alternative approach in the setting of a disrupted PJ anastomosis where a feeding tube stent is placed across a gap between the jejunal enterotomy and the pancreatic duct, and it can be secured at both ends or externalized, depending on the surgical site inflammation⁹⁰.

The choice of the technique mostly relies on intraoperative findings and patient’s clinical stability, since access to the complication site can be problematic due to the significant inflammation from local sepsis and tissue degradation²⁰.

Indications for CPLP are excessive disruption of the anastomosis (more than half the circumference of the suture line), extended necrosis of the pancreatic stump, impossibility to intraoperatively recognize the Wirsung’s duct and splenic artery lesions necessitating its ligation⁹².

Compared with a CPLP, preserving the pancreas is a relatively easier technique, with less blood loss and shorter operative time and avoids the insulin-dependent diabetes that inevitably follows a CPLP⁹³.

On the other hand, pancreas-preserving procedures might not be sufficient and lead to further reinterventions, while CPLP has the advantage of eliminating the source of the leakage and associated inflammation.

Balzano et al.⁹⁴ in a retrospective study compared CPLP and pancreas-preserving procedures in patients undergoing relaparotomy for POPF, showing that mortality rate, blood loss, and transfusion requirement were similar for all techniques but patients undergoing a CPLP required a further relaparotomy less frequently than patients with pancreas preservation (7 vs. 59%, P<0.01), and the ICU stay was reduced after CPLP (P=0.058).

Furthermore, in patients treated with CPLP, the impact of the metabolic consequences related to this procedure can be mitigated by the association of islet autotransplantation (IAT) and, more recently, by the artificial bi-hormonal pump, as shown in the APPEL5 + study⁹⁵.

Considering this and the reassuring results on long-term quality of life (QoL), which have been shown to be comparable in patients undergoing TP and patients at high-risk for POPF (FRS 7– 10) undergoing PD, and the improved perioperative outcomes on short-term mortality and major morbidity, TP with IAT could be considered as an alternative initial approach to a very high-risk PD to avoid POPF-related sequelae^96–100.

Conclusions

POPF is a complex, multivariable phenomenon that continues to challenge pancreatic surgeons starting with its definition, prediction, and detection.

A standardized postoperative patient monitoring protocol early detect any deviation from the normal postoperative course is the first step in the management of a POPF and to improve patient’s outcome.

When a patient develops a POPF, clinicians are faced with multiple, specific, and critical management decisions, particularly in respect to reducing the incidence and burden of B and C grade POPF.

A strong consensus on the optimal management strategy of clinically relevant pancreatic fistula is still lacking and the current management strategy still relies on local expertise and driven by patient’s condition.

Current clinical practice relies mainly on mitigation strategy, proper caloric intake via artificial nutrition, drainage of symptomatic collected pancreatic fluid and surgical reintervention when conservative management fails.

The continuous implementation of centralized, high-volume pancreatic units with appropriate facilities and multidisciplinary experience to treat this complication may significantly contribute to standardize the management and improve the outcomes.

Ethical approval

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Author contribution

M.N.: conceptualization, writing – original draft, and writing – review and editing; G.C. and G.N.: supervision and writing – review and editing; A.Z.: conceptualization, supervision, writing – review and editing.

Conflicts of interest disclosure

The authors declare that they have no financial conflicts of interest with regard to the content of this report.

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Martina Nebbia.

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Provenance and peer review

Invited paper.