A novel strategy for transmural stent removal in necrotizing pancreatitis undergoing endoscopic transmural necrosectomy: a nested, case-control study

Abstract

Background

Although metal stents have been widely used in the endoscopic step-up approach for necrotizing pancreatitis (NP), the exact timing of transmural stent removal has not been well studied. Here, we report a novel strategy for stent removal and compare it with the conventional strategy.

Methods

This retrospective, nested, case-control study analyzed all adult NP patients who underwent endoscopic transmural necrosectomy (ETN). Clinical outcomes were compared between case group (a novel strategy in which the stents were removed during the last necrosectomy when the ETN endpoint was achieved) and 1:1 necrosis extent matched control group (the conventional strategy in which the stents were removed after necrosectomy when clinical symptoms were relieved and collection was nearly completely resolved, as confirmed by imaging).

Results

Baseline characteristics was comparable between case group (n=37) and control group (n=37). Three (8.1%) patients in case group and one (2.7%) patient in control group needed additional ETN after stent removal (P >0.05). Nearly all patients (case: 97.3%; control: 94.6%) achieved clinical success. There was no difference in disease-related (case: 40.5%; control: 37.8%) or stent-related (case: 27.0%; control: 16.2%) complications. Case group had a trend of shorter length of stent placement (median: 20.0 days vs. 29.5 days, P >0.05).

Conclusions

Compared to the convention strategy, the novel strategy of transmural stent removal during last necrosectomy avoids one endoscopy procedure and is feasible, with no need for additional ETN after stent removal, similar improvement in clinical outcomes, and no increase in complications. Prospective multicenter studies regarding the timing of transmural stent removal are needed to further validate our conclusions.

Background

Acute pancreatitis (AP) is an inflammatory condition of the pancreas and one of the most common gastrointestinal illnesses. The incidence of AP ranges from 5 to 30 cases per 100,000 with high morbidity and an overall case fatality rate of 5%.^1,2 Most cases of AP (approximately 80%) are mild, self-limited, and follow an uncomplicated course. However, 10–20% of cases may be associated with necrosis of the pancreatic gland, peripancreatic tissue, or both. This subset of patients may face a complex, prolonged clinical course, with associated mortality of up to 20–30% if infected pancreatic necrosis (IPN) develops.³ Over the last decade, approaches to managing necrotizing pancreatitis (NP) have evolved from open surgery to a minimally invasive approach due to the efficacy and lower morbidity and mortality rates of the latter technique.^4,5

As one of minimally invasive approaches, endoscopic step-up approach, with transmural drainage whenever feasible and subsequent necrosectomy as required, was first described in 1996 and has evolved to first-line therapy for symptomatic NP.^6,7 However, there are still some issues that need to be clarified about endoscopic step-up approach, with the efficacy and safety of transmural stents being one.⁸ Transmural stents have evolved over the decades and range from multiple plastic double-pigtail stents, fully covered self-expanding metallic biliary or esophageal stents, and lumen-apposing metal stents (LAMSs). Large-diameter fully covered self-expanding metal stents (FCSEMSs) and LAMSs appeared to provide better egress of necrotic material and were found to be superior for necrotic collection resolution, with fewer bleeding events and a trend toward a lower occlusion and perforation rate but an increased migration rate compared with plastic stents in a meta-analysis of 41 studies involving 2213 patients.⁹ However, a recent randomized trial did not show its superiority to plastic stents.¹⁰ Adversely, stent-related adverse events were higher with LAMSs (32.3%) than with plastic stents (6.9%), which was highly related to the duration of stent placement. Most of the stent-related adverse events were observed ≥ 3 weeks postintervention in the LAMS cohort. After protocol amendment where a computed tomography (CT) scan was obtained at 3 weeks postintervention followed by LAMS removal if walled-off necrosis (WON) had resolved, there was no significant difference in adverse events between cohorts. Thus, the authors advised that patients should undergo follow-up imaging and stent removal at 3 weeks if WON has resolved to minimize adverse events with LAMSs.¹⁰

The exact timing of transmural stent removal has not been well studied. The conventional strategy for stent removal in the published guidelines has been that patients should undergo follow-up imaging and stent removal at 4–8 weeks if WON has resolved.^11,12 Here, we introduced a novel strategy in which the stents were removed during the last necrosectomy when the endpoint of endoscopic transmural necrosectomy (ETN) was achieved, that was, the necrotic tissue was nearly completely removed, and the pink granulation tissue lining the wall was uncovered. Compared to the conventional strategy, the novel strategy avoided one endoscopy procedure. The present study is the first to compare the clinical outcomes of patients with NP who have undergone ETN in which transmural stents are removed by the novel strategy versus the conventional strategy.

Methods

Study design and participants

This was a retrospective, nested, case-control study with an analysis of patients with NP who were hospitalized in the Department of Gastroenterology of the First Affiliated Hospital of Nanchang University, a tertiary care referral center in China, from April 2015 to April 2020. We used data from a prospectively maintained database, which is a data repository for the clinical data of all AP patients admitted to our department, including diagnostic, therapeutic, and follow-up data recorded by a special research assistant.

Adult patients with NP who underwent endoscopic transmural drainage (ETD) and subsequent ETN were eligible. Patients who died or were transferred to open surgery were excluded due to the failure of stent removal and being grouped. All patients were followed up for at least three months after discharge, and patients who were lost to follow-up were excluded. All primary necrotic collections adherent to the stomach or duodenum were drained by ETD and subsequent ETN only. For necrotic collections not in communication with the primary collection, percutaneous drainage (PCD) and/or sinus tract endoscopy was adjunctively used. Patients whose primary collection was drained by both endoscopic and percutaneous approaches were excluded due to the confounding effect on the evaluation of the research results.

Case group (the novel strategy) and 1:1 necrosis extent matched control group (the conventional strategy) was nested in the retrospective cohort, and compared. The AP database was approved by the Ethics Committee of the First Affiliated Hospital of Nanchang University (N0: 2011001). Informed consent for the procedures was obtained from all the patients prior to the procedures. The ethics approval and written informed consent for using the data were waivered by the Ethics Committee of the First Affiliated Hospital of Nanchang University due to the retrospective nature of the study. All methods were performed in accordance with the relevant guidelines and regulations.

Interventions

All management decisions regarding interventions were made in a multidisciplinary team involving pancreatologists, endoscopists, surgeons, interventional radiologists, radiologists, and intensivists using our previously described algorithm.^13,14 Patients enrolled in our study were managed using a strategy based on an endoscopically centered step-up approach. ETD was first optimal for primary necrotic collection adjacent to the stomach or duodenum, with subsequent ETN as required. Adjunctive PCD was typically performed for collections not amenable to endoscopic therapy due to a lack of contact with the gastric or duodenal wall, with subsequent sinus tract endoscopy as required. Open surgery was reserved for failure of the step-up approach or severe complications such as severe abdominal bleeding.

All patients underwent contrast-enhanced CT to determine the location and extent of the necrotic collections before the procedure. All patients were administered broad-spectrum antibiotics during and after the procedure to prevent infection. Patients underwent tracheal intubation and general anesthesia in the left lateral decubitus position. All of the interventions were performed by experienced gastroenterologists. A linear echoendoscope (Olympus GIF-H290, Tokyo, Japan) was used to examine and assess the necrotic collections. The puncture path was oriented according to the principle of making the distance between the digestive wall and the necrotic collections shortest and avoiding blood vessels. Under ultrasound endoscopic guidance, a COOK 19-G needle was used to puncture the necrotic collections, and then the fluid was aspirated for microbiology, biochemical testing and routine examination.

If a patient did not have clinical improvement or resolution of necrotic fluid, ETN was performed as needed after initial ETD, typically within 3 to 5 days after drainage for patients with IPN or organ failure, or later for patients with less acute illness and/or primarily liquified collections. All ETNs in our cohort were delayed up to 4 weeks after AP onset to allow for the development of a wall around the necrosis, which was consistent with the recommendations of the newest guideline.⁸ ETN was repeated as needed based on the clinical course and until there was complete resolution of solid necrosis. The endpoint of ETN was achieved when the necrotic tissue was nearly completely removed and the pink granulation tissue lining the wall was uncovered. There were two strategies for stent removal: In the novel strategy, the stents were removed during the last necrosectomy when the endpoint of ETN was achieved (Case group). In the conventional strategy, a CT scan was performed to assess the resolution of fluid and whether the stents were in place within 4 weeks after stent placement. The stent was removed when clinical symptoms were relieved and fluid was nearly completely resolved (Control group). Compared to the conventional strategy, the novel strategy avoided one endoscopy procedure.

Outcomes of interest and data collection

The primary outcome of interest was the number of additional ETN sessions after stent removal. The secondary outcomes included clinical success and disease- or stent-related complications, as well as the length of hospital stay. Clinical success was defined as nearly completely resolution or <2 cm of collection assessed by image at the three-month follow-up without additional open surgery or death.^13,14 Disease-related complications included new-onset organ failure, transient fever, new-onset infection, abdominal or gastrointestinal bleeding, or gastrointestinal fistula. Stent-related complications included stent occlusion and migration. Other rare complications were not observed in our cohort. Organ failure included respiratory failure, circulatory failure or renal failure, which was defined as a score of 2 or more using the modified Marshall scoring system.^15,16 Transient fever meant low fever (usually <38 ℃), which persisted for 3-5 days without culture positivity. IPN was confirmed by extraluminal gas in the pancreatic and/or peripancreatic tissues on contrast-enhanced CT or positive bacteria and/or fungi on Gram stain or culture of pancreatic and/or peripancreatic tissues obtained from the first drainage procedure or the first necrosectomy.¹⁵ Abdominal or gastrointestinal bleeding was defined as severe bleeding requiring intervention along with decreased hemoglobin, and this complication was examined by imaging. The other detailed records, including baseline characteristics, indications, and interventions, were also analyzed.

Statistical analysis

Quantitative variables are presented as medians (interquartile ranges (IQR)) and were analyzed using the Mann-Whitney U test. Categorical variables are reported as absolute numbers and proportions and were tested by the Chi-square test or Fisher’s exact test. P<0.05 was considered statistically significant. Data were analyzed using SPSS software (v17.0; SPSS Inc., Chicago, IL, USA).

Results

Discussion

An endoscopic step-up approach has evolved to first-line therapy for symptomatic NP.⁸ Although transmural metal stents have been widely used in the endoscopic step-up approach, the exact timing and strategy of stent removal have not been well studied. Here, we report a novel strategy for transmural stent removal in which the stents were removed during the last necrosectomy when the endpoint of ETN was achieved, that was, the necrotic tissue was nearly completely removed, and the pink granulation tissue lining the wall was uncovered. By comparing the clinical outcomes with the conventional strategy, we found that the novel strategy of transmural stent removal was feasible, with no need for more additional ETN after stent removal, similar improvement in clinical outcomes, and no increase in complications.

The duration of transmural stent placement is variable among different stents. Plastic stents can remain in place until collection resolves and are potentially placed indefinitely for the prevention and treatment of pancreatic duct disruption.⁸ However, there are concerns about leaving metal stents in place beyond several weeks due to the increase in reports of stent-related complications. Thus, several guidelines recommend that metal stents of any type should not remain in place long-term.^8,11,12 However, the exact timing recommended by the guidelines varies from four weeks to eight weeks and is undergirded by insufficient evidence.^11,12 Transmural metal stent use was associated with a 5.6% incidence of bleeding, 2.8% incidence of perforation, 9.5% incidence of stent occlusion, and 8.1% incidence of migration in a large-sample meta-analysis, without mention of the timing of stent removal.⁹ Due to the different strategies performed to remove stents in different studies, it was difficult to clarify the relationship between stent-related complications and the timing of stent removal. Recently, a randomized controlled study demonstrated that the incidence of stent-related adverse events was highly related to the duration of placement.¹⁰ In that study, significant stent-related adverse events were observed ≥ 3 weeks postintervention in the LAMS cohort. Interim audits resulted in protocol amendments where CT scans were obtained at 3 weeks postintervention followed by LAMS removal if WON had resolved. After protocol amendment, there was no significant difference in adverse events between LAMSs and plastic stents. Once the WON resolved, the LAMSs impinged on adjacent structures by virtue of its immobility, leading to bleeding and occlusion or becoming deeply embedded in the gut wall.¹⁷

We now propose a novel strategy for stent removal in which the stents were removed during the last necrosectomy when the endpoint of ETN was achieved. Using this novel strategy, the stents was removed as early as possible. Compared with the conventional strategy, the novel strategy showed a similar improvement in clinical outcomes, with no need for more ETN sessions after stent removal (8.1% vs. 2.7%), similar improvement in clinical success (97.3% vs. 94.6%), and no increase in disease-related complications (40.5% vs. 37.8%) or stent-related adverse events (27.0% vs. 16.2%). It is encouraging that compared to the conventional strategy, the novel strategy avoided one endoscopy procedure. Theoretically, the novel strategy may reduce readmissions, hospital costs, and the length of hospital stay accordingly, which should be proven in further study.

Of the 123 patients with NP undergoing ETD and subsequent ETN in our study, the all-cause mortality was 12.2% (15/123), which was somewhat lower than the 15–39% mortality suggested in the overall literature and similar to that reported in recent randomized trials of the endoscopic step-up approach.^4,18−21 In this cohort, all necrotic collection was managed by a multidisciplinary team using a strategy based on the endoscopically centered step-up approach. ETD was first optimal for primary necrotic collection adjacent to the stomach or duodenum, with subsequent ETN as required. Adjunctive PCD was typically performed for collections not amenable to endoscopic therapy, with subsequent sinus tract endoscopy as required. Open surgery was reserved for failure of the step-up approach or severe complications. We believe our low mortality may be related to our emphasis on a multidisciplinary team and our use of a strategy of minimally invasive intervention as the first choice.^13,14 Our endoscopic treatment approach utilized larger drainage stents to provide a larger egress window to the necrotic collection. We delayed endoscopic necrosectomy to at least 4 weeks and chose to perform endoscopic necrosectomy on an “as needed” basis rather than as per a fixed schedule.

A potential strength was that it was a nested, case-control study based on a prospectively maintained database including all patients with NP undergoing ETD and subsequent ETN. Thus, the study represented the entire spectrum of patients rather than a preselected case series and thus reduced selection bias. However, there are some limitations to the current study. Firstly, this was a single-center study, and the outcomes were analyzed retrospectively, which might have induced information bias and confounding bias. Secondly, whether it was necessary to routinely undergo magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP) to confirm the integrity of the pancreatic duct, and place pancreatic duct stent to prevent pancreatic duct disruption was inconclusive. Thus, in our study, only patients who failed to respond to invasive intervention would undergo MRCP or ERCP to confirm the integrity of the pancreatic duct, and place pancreatic duct stent for disruption or stenosis of pancreatic duct. The integrity of the pancreatic duct might be a confounding factor in selecting the timing for removing stents. Last but not least, the 3-month follow-up was relatively short for observing long-term disease-related complications.

Conclusions

In conclusion, our novel strategy for transmural stent removal during the last necrosectomy when the endpoint of necrosectomy is achieved shows feasibility. Compared to the convention strategy, the novel strategy avoids one endoscopy procedure. Prospective multicenter studies regarding the timing of transmural stent removal are needed to further validate our conclusions.

Abbreviations

AP, acute pancreatitis;

IPN, infected pancreatic necrosis;

NP, necrotizing pancreatitis;

LAMS, lumen-apposing metal stent;

FCSEMS, fully covered self-expanding metal stent;

CT, computed tomography;

WON, walled-off necrosis;

ETN, endoscopic transmural necrosectomy;

ETD, endoscopic transmural drainage;

PCD, percutaneous drainage;

IQR, interquartile range;

BMI, body mass index;

SIRS, systemic inflammatory response syndrome;

MRCP, magnetic resonance cholangiopancreatography;

ERCP, endoscopic retrograde cholangiopancreatography;

Declarations

Ethics approval and consent to participate: the AP database was approved by the Ethics Committee of the First Affiliated Hospital of Nanchang University (N0: 2011001). Informed consent for the procedures was obtained from all the patients prior to the procedures. The ethics approval and written informed consent for using the data were waivered by the Ethics Committee of the First Affiliated Hospital of Nanchang University due to the retrospective nature of the study.

Consent for publication: not applicable.

Availability of data and materials: the datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests: the authors declare that they have no competing interests.

Funding: None.

Authors’ contributions: YZ conceived the idea and performed the procedure in our center; LD designed the study, collected and analyzed the data, and wrote the manuscript; LX, WhH and HfX revised the study design; PL, XS and ZjL performed the procedure in our center; YZ, YxC and NhL revised the manuscript. All authors read and approved the final manuscript.

Acknowledgments: None.

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