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    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

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Long-term Outcomes of Direct Endoscopic Necrosectomy for Complicated or Symptomatic Walled-Off Necrosis: A Korean Multicenter Study

Yeon Suk Kim1 , Jae Hee Cho2 , Dong Hui Cho3 , Se Woo Park4 , Sung-Hoon Moon5 , Jin-Seok Park6 , Yun Nah Lee7 , and Sang Soo Lee3

1Division of Gastroenterology, Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, 2Division of Gastroenterology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 3Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 4Division of Gastroenterology, Department of Internal Medicine, Hallym University Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong, 5Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, 6Digestive Disease Center, Department of Internal Medicine, Inha University School of Medicine, Incheon, and 7Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University School of Medicine, Bucheon, Korea

Correspondence to:Jae Hee Cho
ORCID https://orcid.org/0000-0003-4174-0091
E-mail jhcho9328@yuhs.ac

Sang Soo Lee
ORCID https://orcid.org/0000-0002-3785-2341
E-mail ssleedr@amc.seoul.kr

Received: September 30, 2020; Revised: December 28, 2020; Accepted: January 8, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut and Liver 2021; 15(6): 930-939

Published online November 15, 2021 https://doi.org/10.5009/gnl20304

Copyright © Gut and Liver.

Background/Aims: The endoscopic step-up approach is accepted as the preferred treatment for complicated or symptomatic walled-off necrosis (WON). Direct endoscopic necrosectomy (DEN) is an effective therapeutic option, but few reports describe long-term follow-up in this patient population. Thus, we aim to assess the long-term outcomes of DEN following severe necrotizing pancreatitis.
Methods: The data of all acute pancreatitis patients who underwent DEN following endoscopic transmural drainage from six referral centers between 2007 and 2017 were retrospectively collected.
Results: Sixty patients (76.7% male, mean age 48.3 years) underwent a median of 4 sessions of DEN starting at a median of 45.5 days after the onset of acute pancreatitis. Clinical success was achieved in 51 patients (85%), with a 35% complication rate and a 5% mortality rate. Using multivariate analysis, the risk factor associated with DEN failure or major DEN complications requiring intervention or surgery was an identified bacterial/fungal WON infection (odds ratio, 19.3; 95% confidence interval, 1.5 to 261.7). During the median follow-up period of 27 months, complicated WON recurrence was observed in 5.3% of patients, and long-term complications occurred in 24.6% of patients (four exocrine insufficiency, nine newly developed diabetes mellitus, one recurrent small bowel obstruction, one chylous ascites).
Conclusions: Considering that long-term complications are similar to those observed after pancreatectomy, DEN should be performed meticulously while minimizing damage to the viable pancreatic parenchyma with adequate antibiotic escalation.

Keywords: Acute pancreatitis, Infected necrosis, Necrosectomy, Endoscopy, Antibiotics

Acute necrotizing pancreatitis is a potentially lethal disease, and its incidence is currently increasing. Because infected necrotizing pancreatitis is associated with a mortality of 20% to 30%, an expert multidisciplinary team approach is required to improve clinical outcomes.1-5 Over the past decade, much progress has been made in improving the management of acute necrotizing pancreatitis.6,7 A surgical step-up approach consisting of percutaneous catheter drainage followed by minimally invasive surgical necrosectomy has replaced open necrosectomy as the standard treatment.8-10 Endoscopic treatment has also been highlighted because it is potentially less invasive and can also be performed in a step-up manner.11-13 Endoscopic transmural drainage (ETD) is usually the first procedure to be performed, followed up by direct endoscopic necrosectomy (DEN) if required for improving clinical outcomes. In a Dutch randomized trial, the risk of developing a pancreatic fistula and the length of hospital stay were lower in the endoscopy group when compared to the surgical group. However, endoscopy did not demonstrate superior therapeutic outcomes in terms of mortality and major complications.14 Contrary to these data, a U.S. randomized trial indicated that an endoscopic transluminal approach reduced major complications, lowered costs, and increased the patients’ quality-of-life when compared to minimally invasive surgery.15,16 Controversy remains as to whether an endoscopic step-up approach should be used as the preferred therapeutic modality for infected necrotizing pancreatitis. Furthermore, sufficient information from long-term follow-up after DEN does not currently exist. Therefore, we aimed to assess the long-term outcomes of DEN following ETD as part of an endoscopic step-up approach in patients with severe acute necrotizing pancreatitis.

1. Patient information

The Korean Pancreatobiliary Association conducted a nationwide multicenter retrospective study by accumulating information on severe acute necrotizing pancreatitis patients who underwent DEN across six referral centers in Korea between January 2007 and December 2017. After standardized data collection forms were sent to each center, each institution retrospectively reviewed their database and collected the clinical data. The participating institutions were Asan Medical Center (Seoul), Gachon University Gil Medical Center (Incheon), Hallym University Dongtan Sacred Heart Hospital (Hwaseong), Hallym University Sacred Heart Hospital (Anyang), Inha University hospital (Incheon), and Soonchunhyang University Bucheon Hospital (Bucheon) in the Republic of Korea. Institutional review board approval was obtained for each participant in this study. The informed consent was waived. A total of 60 patients were ultimately included in this study.

2. Procedures

The indications for endoscopic intervention were determined for each patient. Inclusion criteria were symptomatic or complicated walled-off necrosis (WON), such as suspected/identified infection, and biliary/gastric outlet obstruction following severe necrotizing pancreatitis. The standard technique used for the endoscopic step-up approach is described as follows. Endoscopic ultrasound-guided transmural drainage was performed using either one or two 7-F double-pigtail plastic stents (DPPS) or self-expandable metallic stent (SEMS). Based on clinical decisions, an additional nasocystic drainage catheter was placed into the WON cavity if necessary. Types of SEMS used were as follows: tubular fully covered SEMS including 26 Soo stents (Standard Sci Tech Inc., Seoul, Korea), seven AL stents (Standard Sci Tech Inc.) and two Nagi stents (Taewoong Medical, Goyang, Korea), or lumen-apposing metallic stent of six SPAXUS stents (Taewoong Medical). If there was no clinical improvement following ETD, a DEN was performed. In most cases, an established fistula tract was dilated using a large balloon (maximal diameter, 12 to 20 mm) several days after placement of stent or drainage catheter. A conventional forward-viewing endoscope or water jet scope (GIF-Q260J; Olympus, Tokyo, Japan) was subsequently advanced into the WON cavity and mechanical debridement of the necrotic tissue was performed using snares, forceps, and stone removal baskets accompanied by forceful irrigation using normal saline. In anticipation of a subsequent DEN, the fistula to the necrotic cavity is maintained by placing a DPPS or nasocystic drainage catheter. Repeated DEN sessions were carried out until clinical improvement was achieved, regardless of whether the necrotic debris in the WON was completely removed. At the final DEN session, a DPPS might be placed depending on each institution’s protocol. Depending on the patient’s condition, additional intervention measures, including transpapillary pancreatic duct (PD) stenting, percutaneous drainage, and surgery were performed as necessary. Additionally, in order to diagnose WON infection, microbial culture was conducted with pus aspirated in the ETD procedure. If the patient's condition did not improve, additional culture tests were performed in pus and necrotic tissue during DEN.

3. Outcomes

The primary outcome was to assess the long-term clinical outcomes, such as recurrence of the symptomatic/complicated WON and late complications following DEN. The definition of symptomatic/complicated WON is as follows: (1) clinical suspicion or documented infected WON with clinical deterioration; (2) symptomatic sterile WON including intractable pain, persistent unwellness, ongoing gastrointestinal obstruction despite medical treatment; (3) abdominal compartment syndrome or disconnected PD syndrome with WON. In terms of long-term results, the recurrence of WON was defined as the case of WON redevelopment after 6 months of last DEN session in a patient who had completed treatment. New onset diabetes mellitus was defined as requiring insulin or oral antidiabetic drugs for at least 6 months after DEN and not present prior to the onset of pancreatitis. Exocrine insufficiency was defined as the development of clinical symptoms of steatorrhea and weight loss in patients not previously taking oral pancreatic enzyme supplements. The secondary outcomes were to evaluate the initial treatment success and early complication rates associated with DEN. Clinical success of the DEN was defined as improvement of WON on computed tomography (CT) scan in association with clinical resolution of symptoms at 6-month follow-up period.17 DEN failure was defined as the need for rescue surgery or death during index admission as well as readmission for management of recurred pancreatitis or WON within 6 months.

Other DEN-related complications are defined as follows; “massive bleeding” is the bleeding within the intraabdominal cavity or gastrointestinal tract requiring radiologic interventional procedure, “visceral perforation” is the perforation of visceral organ with intraabdominal free air, “duodenal or colonic fistula” is the formation of a fistula between the small bowel or colon and pancreas confirmed on imaging or endoscopy.

4. Statistical analysis

Differences of continuous variables were compared using the independent t-tests. Categorical variables were compared by the chi-square tests or Fisher exact test. Multivariate logistic regression analysis was performed to evaluate the independent effect of each variable. Odds ratios and confidence intervals were calculated. Statistical analysis was performed using the SPSS software, version 24.0 for Windows (IBM Corp., Armonk, NY, USA). Statistical significance was reached when p-values were below 0.05.

1. Characteristics of patients

A total of 60 patients (76.7% male, mean age 48.3 years) with complicated or symptomatic WON were included from six centers. Twenty of the total 60 patients were treated in the intensive care unit. Continuous renal replacement therapy was administered in 10 patients, and one patient improved after receiving extracorporeal membrane oxygenation. The main causes underlying acute pancreatitis in these patients were alcohol (45%) and the presence of gallstones (25%). The size of the WON (mean of long axis×short axis) was estimated to be 145.9×72.1 mm and the median severity index determined by CT was 6. Coronal CT imaging was used to evaluate the lower margin of the WON, which was found to be an extension to the pelvic cavity in 15 patients and below the kidney in 34 patients. Twenty-one patients had undergone percutaneous catheter drainage. Additionally, the medians of laboratory findings in these patients at the time of DEN were as follows: white blood cell counts 16,380/mm3, amylase 438 U/L, lipase 938 U/L, creatinine 1.03 mg/dL, and C-reactive protein 10.6 mg/dL (Table 1).

Table 1. Characteristics of Patients with Complicated or Symptomatic Walled-Off Necrosis Who Underwent Direct Endoscopic Necrosectomy

PatientsValue (n=60)
Age, yr48.3±14.4
Sex
Male46 (76.7)
Female14 (23.3)
BMI, kg/m224.4±3.71
Smoking23 (38.3)
Alcohol41 (68.3)
Etiology
Alcohol27 (45.0)
Gallstone15 (25.0)
Post-ERCP6 (10.0)
Others*12 (20.0)
Diabetes mellitus
Yes12 (20.0)
No48 (80.0)
Initial management of pancreatitis
ICU care20 (33.3)
CRRT/ECMO10 (16.7)/1 (1.7)
CT severity index score6 (5–7)
Previous placement of PCD21 (35.0)
Main locations of WON
Head7 (11.7)
Body and tail32 (53.3)
Entire pancreas21 (35.0)
Lower margin of WON cavity
Above kidney/below kidney 11 (18.3)/34 (56.7)
Extension to pelvic cavity15 (25.0)
No. of WON cavities
Single28 (46.7)
Multiple32 (53.3)
Size, mm
Long axis145.9±50.6
Short axis72.1±33.1
Laboratory findings at the time of DEN
White blood cell,/mm316,380 (13,047–20,005)
CRP, mg/dL10.6 (0.4–30.7)
Amylase, U/L438 (146–2,667)
Lipase, U/L938 (106–10,886)
Creatinine, mg/dL1.03 (0.71–1.57)

Data are presented as mean±SD, number (%), or median (interquartile range).

BMI, body mass index; ERCP, endoscopic retrograde cholangiopancreatography; ICU, intensive care unit; CRRT, continuous renal replacement therapy; ECMO, extracorporeal membrane oxygenation; CT, computed tomography; PCD, percutaneous catheter drainage; WON, walled-off necrosis; DEN, direct endoscopic necrosectomy; CRP, C-reactive protein.

*Others include hypertriglyceridemia-induced, malignancy, postoperative, and trauma.



2. Initial outcomes of DEN

Initial ETD using DPPS or SEMS were performed after a median duration of 34 days (interquartile range [IQR], 21 to 52.5 days) from the onset of pancreatitis. Of them, transmural SEMS placement was achieved in 41 patients (68.3%). If the patient’s condition did not improve even during ETD, DEN was administered after a median duration of 45.5 days (IQR, 31.25 to 70.75 days) after the index admission. Indication of DEN were as follows; suspected infection (fever and pain) in 40 patients, intractable pain in 18 patients, and gastric outlet obstruction in two patients. With respect to the DEN technique, transgastric (53 cases), transduodenal (five cases), or both (two cases) routes were used, and the multiple gateway technique was performed in 11 patients (18.3%). Carbon dioxide (CO2) gas was used instead of room air for insufflation in 54 patients (90%). A median of 4 necrosectomy sessions (IQR, 2 to 6 sessions) was carried out and the median procedural time of each session was estimated to be 48 minutes (IQR, 37.25 to 64.23 minutes). Endoscopic retrograde cholangiopancreatography was performed in 27 patients and was followed by PD stenting in 17 patients (28.3%). WON infection was identified in 44 patients (73.3%) (Table 2). In terms of short-term outcomes, clinical success was achieved in 51 patients (85%) and DEN complications developed in 21 patients (35%). Among them, major complications such as bleeding requiring intervention (n=9), perforation requiring surgery (n=1), and air embolism (n=1) developed in 10 patients (16.7%). The WON recurrence was developed in four patients within 6 months after discharge, that might be attributed to unsuccessful DENs. Additionally, six patients underwent surgery and three patients succumbed to pancreatitis-related mortality (Fig. 1). Altogether, there were 16 patients (26.7%) who displayed DEN failure or major complications associated with DEN. Multivariate analysis demonstrated that the only significant risk factor for those patients was an identified bacterial/fungal infection of the WON (odds ratio, 19.28; 95% confidence interval, 1.50 to 261.7) (Table 3). Among 44 patients with positive microbial cultures, Candida infection was found in six patients and bacterial infection was noted in 41 patients. The bacterial infections included carbapenem-resistant Acinetobacter baumannii that was identified in five patients, carbapenem-resistant Klebsiella pneumoniae in one patient, extended-spectrum beta-lactamase-producing Klebsiella pneumonia in one patient, methicillin-resistant Staphylococcus aureus in 11 patients, and vancomycin-resistant enterococci in two patients; infection with multidrug-resistant bacteria was found in 17 (28.3%) of 60 patients (Table 4). Furthermore, at the end of the DEN procedure, complete clearance of necrotic tissue in the WON cavity under visualization of DEN was achieved in eight patients (13.3%) (Fig. 2).

Table 2. Procedural Details and Outcomes of Direct Endoscopic Necrosectomy

Direct endoscopic necrosectomyValue
Time from onset of pancreatitis to initial EUS drainage, day34 (21.0–52.5)
Placed drainage method
DPPS and/or nasocystic drainage catheter19 (31.7)
SEMS and/or nasocystic drainage catheter41 (68.3)
Time from onset of pancreatitis to the first DEN, day45.5 (31.25–70.75)
Indications of DEN
Suspected infection40 (66.7)
Intractable pain18 (30.0)
Gastric outlet obstruction2 (3.3)
Diameter of dilation for entry site of DEN, mm
12–1535 (58.3)
16–2025 (41.7)
Route
Transgastric53 (88.3)
Transduodenal5 (8.3)
Both2 (3.3)
Gateway
Single49 (81.7)
Multiple11 (18.3)
No. of DEN4 (2–6)
Procedural time of DEN in each session, min48 (37.25–64.23)
Insufflation during the procedure
Room air6 (10.0)
CO2 gas54 (90.0)
ERCP27 (45.0)
Identified main PD disruption15 (25.0)
Transpapillary PD stent17 (28.3)
Preprocedural intravenous antibiotics60 (100)
Identified infection in WON cavity
Yes44 (73.3)
No16 (26.7)
Clinical outcomes of DEN as part of endoscopic step-up approach
Success51 (85.0)
Failure
Surgery/pancreatitis-related mortality*6 (10.0)/3 (5.0)
WON recurrence within 6 months4 (6.7)
Degree of cavity clearance at the end of DEN
Complete clearance8 (13.3)
Incomplete clearance52 (86.7)
Procedure related complications during the treatment period of DEN21 (35.0)
Massive bleeding requiring radiologic intervention9 (15.0)
Visceral perforation3 (5.0)
Stent migration8 (13.3)
Duodenal or colonic fistula5 (8.3)
Others2 (3.3)

Data are presented as median (interquartile range) or number (%).

EUS, endoscopic ultrasound; DPPS, double-pigtail plastic stents; SEMS, self-expandable metallic stent; DEN, direct endoscopic necrosectomy; CO2, carbon dioxide; ERCP, endoscopic retrograde cholangiopancreatography; PD, pancreatic duct; WON, walled-off necrosis.

*Two cases of mortality developed despite surgical intervention; Others include air embolism, cutaneous fistula.



Table 3. Risk Factors Associated with the Clinical Outcomes of Direct Endoscopic Necrosectomy

Risk factorDEN failure* or with major complications (n=16)Successful DEN (n=44)p-valueOR (95% CI)p-value§
Age, mean±SD, yr43.9±14.249.8±14.60.0160.99 (0.94–1.04)0.679
Sex (male/female)14/232/120.314
BMI, mean±SD, kg/m224.8±2.824.2±4.00.564
Identified WON infection (yes/no)15/129/150.04619.28 (1.50–261.70)0.023
CRRT (yes/no)10/64/400.0172.00 (0.33–12.0)0.449
Additional PCD (yes/no)9/712/320.0643.30 (0.71–15.34)0.128
Initial drainage method
(plastic/metal stent)
3/1316/280.228
Gateway (single/multiple)12/437/70.462
Transpapillary PD stent (yes/no)2/1415/290.1200.22 (0.35–1.35)0.218
Pelvic extension of necrotic cavity (yes/no)7/98/360.0883.17 (0.51–19.74)0.315
No. of cavity (multiple/single)11/521/230.242
Largest diameter of necrotic cavity (≥15 cm/<15 cm)5/1127/270.764

DEN, direct endoscopic necrosectomy; OR, odds ratio; CI, confidence interval; BMI, body mass index; WON, walled-off necrosis; CRRT, continuous renal replacement therapy; PCD, percutaneous catheter drainage; PD, pancreatic duct.

*Rescue surgery or death during index admission, readmission within 6 months; Massive bleeding or perforation requiring radiological/surgical intervention or air embolism; Univariate analysis; §Multivariate analysis.



Table 4. Type and Frequency of Grown Organisms in Positive Aspirate/Tissue Cultures

VariableIsolates, No. (%)
Total patients (monomicrobial/polymicrobial infection)44 (35/9)
Total microorganisms64
Gram negative
Klebsiella pneumoniae6 (9.4)
Pseudomonas aeruginosa2 (3.1)
Enterobacter aerogenes5 (7.8)
Escherichia coli1 (1.6)
Acinetobacter baumannii9 (14.1)
Citrobacter species2 (3.1)
Aeromonas hydrophilia1 (1.6)
Stenotrophomonas maltophilia6 (9.4)
Morganella morganii1 (1.6)
Gram positive
Enterococci species7 (10.9)
Staphylococcus aureus15 (23.4)
Coagulase-negative Staphylococci2 (3.1)
Streptococcus species1 (1.6)
Fungus
Candida albicans5 (7.8)
Candida glabrata1 (1.6)
Multidrug-resistant bacteria20
ESBL-producing Klebsiella pneumoniae1 (5.0)
Carbapenem-resistant Klebsiella pneumoniae1 (5.0)
Carbapenem-resistant Acinetobacter baumannii5 (7.8)
Methicillin-resistant Staphylococcus aureus11 (55.0)
Vancomycin-resistant enterococci2 (10.0)

ESBL, extended spectrum-beta lactamase.



Figure 1.Flowchart showing the treatment courses of the study patients.
WON, walled-off necrosis; DEN, direct endoscopic necrosectomy; PCD, percutaneous catheter drainage; FU, follow-up. *Air embolism and bleeding occurred simultaneously in one patient.

Figure 2.Intracavitary image of a walled- off necrosis with (A) complete or (B) incomplete removal of necrotic debris in the last session of direct endoscopic necrosectomy.

3. Long-term follow-up after DEN

Complete follow-up data were obtained for 57 patients, after excluding patients that displayed early mortality in the study group. The median follow-up period was 27 months (IQR, 7.8 to 48.4 months). The recurrence of symptomatic/complicated WON was observed in three patients (5.3%) after 6 months of last session of DEN, and the median time to recurrence after completion of DEN was 193 days, 375 days and 433 days (Fig. 1). The cause of recurrence was alcohol in one and unknown in two patients. Long-term complications occurred in 14 patients (24.6%) and included four cases of pancreatic exocrine insufficiency, nine cases of newly developed diabetes mellitus, one case of recurrent small bowel obstruction, and one case of chylous ascites (Table 5). Moreover, when the long-term outcomes and recurrences were compared according to the degree of DEN, there is no difference of those between visual estimation of complete and incomplete clearance of necrotic tissue in WON cavity at end session of DEN (p<0.99) (Table 6). In addition, three patients died due to causes unrelated to the DEN or pancreatitis: one succumbed to lung cancer after 63 months, one to alcoholic ketoacidosis after 26 months, and another patient died due to pancreatic cancer after 16 months.

Table 5. Long-term Follow-up of 57 Patients after Direct Endoscopic Necrosectomy

OutcomeValue
FU duration after completion of endoscopic necrosectomy, median (IQR), mo27 (7.8–48.4)
Recurrence of complicated/symptomatic WON, No. (%)3 (5.3)
Recurrence time after completion of endoscopic necrosectomy, median (range), day378 (193–433)
Long-term complication, No. (%)14 (24.6)
Pancreatic exocrine insufficiency4 (7.0)
Newly developed DM9 (15.8)
Others*2 (3.5)
Death, No. (%)3 (5.3)

FU, follow-up; IQR interquartile range; WON, walled-off necrosis; DM, diabetes mellitus.

*Others include chylous ascites and recurrent small bowel obstruction; Alcoholic ketoacidosis, pancreatic cancer, and lung cancer.



Table 6. The Relationship between WON Recurrence (<6 Months vs ≥6 Months) or Long-term Complications and the Degree of Clearance of Intracavitary Necrotic Tissue at the Last Session of DEN

Degree of clearance of intracavitary necrotic tissue at the end session of DENp-value
Complete clearance of intracavitary
necrotic tissue (n=8)
Incomplete clearance of intracavitary
necrotic tissue (n=49)
DEN failure of complicated/symptomatic WON recurrence within 6 months after discharge (yes/no)0/84/45<0.99
Long-term WON recurrence more than 6 months after discharge (yes/no)1/72/470.37
Long-term complications including newly developed DM, pancreatic exocrine insufficiency, others (yes/no)*2/612/37<0.99

WON, walled-off necrosis; DEN, direct endoscopic necrosectomy; DM, diabetes mellitus.

*Others include chylous ascites and recurrent small bowel obstruction.


With the evolution of endotherapy in recent years, endoscopic step-up approaches have gained popularity for the treatment of complicated or symptomatic WON. Various methods have been suggested, including step-up approaches in which DPPS or metal stents (e.g., tubular SEMS or lumen-apposing metallic stent) are placed to drain the fluids and then if necessary, the remaining necrosis is removed by DEN. In general, the indications for intervention in the WON are as follows: (1) clinical suspicion or identified infection of the WON with clinical deterioration; (2) ongoing organ failure in the several weeks following onset of acute pancreatitis; (3) symptomatic sterile WON including intractable pain, persistent discomfort, and ongoing gastrointestinal and biliary obstruction; or (4) disconnected PD syndrome.18 In this study, the major indication resulting in DEN is suspected infection of the WON in 40 patients (66.7%). However, 44 patients (73%) who underwent DEN had bacterial or fungal infection. In the 15 patients who reported intractable pain and the one patient with gastric outlet obstruction, infections were also identified. Additionally, of the 40 patients with suspected infections, pathogens were not confirmed in 12 patients. This is believed to result from preprocedural antibiotic use prior to the endoscopic treatment (Table 2). Currently, much debate surrounds the routine use of antibiotics in severe necrotizing pancreatitis, however antibiotic escalation could be beneficial for those requiring DEN because our study indicated that identified infection was the only significant risk factor associated with DEN failure and major complications. Furthermore, considering the high incidence of multidrug-resistant infection, appropriate antimicrobial therapy should be chosen in accordance with results from sensitive pathogen identifying tests.19 We expect that this approach will result in a better DEN outcome.

Furthermore, we investigated whether long-term recurrence or complications may occur following DEN. Although long-term follow-up results were inadequate in previous studies, the 6-month follow-up data from the MISER trial15 suggested that new onset diabetes developed in six patients (27.3%) and pancreatic insufficiency was diagnosed in 29 patients (85.3%) following the endoscopic step-up approach for necrotizing pancreatitis. In the long-term follow-up data from the PANTER trial,10 which compared minimal versus open surgical necrosectomy, the step-up group had a lower proportion of incisional hernias (23% vs 53%), pancreatic exocrine insufficiency (29% vs 56%), and endocrine insufficiency (40% vs 64%) after a mean follow-up of 86 months following discharge after the index admission. Additionally, the GEPARD study20 observed that the DEN group had overall long-term clinical success in 84% of the patients. WON recurrence developed in 11% of the patients and new onset diabetes was diagnosed in 20% of the patients after a mean follow-up period of 43 months. In the present study, symptomatic/complicated WON recurrence was confirmed in 5.3% of the patients and long-term complications developed in 22.8% of the patients after a median follow-up period of 27 months. Specifically, new onset diabetes and exocrine insufficiency developed in 15.8% and 7.0% of the patients, respectively. This was comparable to the results of GEPARD study. Interestingly, we found DEN-related typical long-term complications of chylous ascites and intestinal obstruction that may have occurred during pancreatic surgery. Thus, it is necessary to take measures to minimize damage of viable pancreatic tissue as much as possible during DEN.

Multiple methods have been used to increase the effectiveness of necrosectomy, but many questions remain surrounding the uncertainty of optimal timing, number of sessions, interval between sessions, and the degree of completeness of DEN.1,6,21,22 To date, the endpoint of DEN has not been definitively established. These decisions should be based on patient’s clinical course, the indication for intervention and endoscopist expertise and preference. Asian consensus statement suggested that the clearance of necrotic debris and pink granulation tissue lining the wall in the WON cavity were important parameters of successful DEN.23 However, it is also unclear whether necrosectomy should be carried out for complete debridement of necrotic tissue within the WON in every case because complete debridement may itself result in extensive injury of viable pancreatic parenchyma and possible damage to surrounding hidden blood vessels. If the patient's symptoms improve, it may be helpful to treat the underlying infection while maintaining transmural DPPS drainage without completely elimination of the necrotic tissues. In this study, complete clearance of necrotic debris in the WON cavity at the last session of DEN was only achieved in eight patients (13.3%) under direct visualization. If the clinical resolution was achieved by a combination of appropriate antibiotic escalation with repeated DENs, the degree of necrotic tissue clearance in the WON at the last DEN session had no significant effects on symptomatic/complicated WON recurrence and long-term complications. In order to obtain better clinical outcomes, it is therefore recommended not only to perform microbial culture of both aspirated pus and necrotic tissue, but also to minimize unnecessary pancreatic injury during DEN.

There are several limitations to this study. First, the retrospective design and limited sample size have inherent limitations. This study was designed as a multicenter study to overcome size limitations, but each institution lacked consensus for the indication, timing, and DEN methods used. Furthermore, it would be ideal to have specific techniques and procedural elements for a successful DEN, but since various methods are used and inconsistent in almost all procedural details, a unified procedural technique cannot be presented. For instance, consensus has not been reached regarding the effectiveness of hydroperoxide or antibiotics lavage, access technique, amount of debridement, benefit of saline irrigation via nasobiliary tube, and use of preprocedural antibiotics or proton pump inhibitor during DEN. Secondly, for the evaluation of long-term complications, we defined exocrine and endocrine insufficiency based on the need for pancreatic enzyme replacement therapy and antidiabetics/insulin. This entails a risk of underestimating the number of patients with these insufficiencies, whereas direct pancreatic function testing or measurement of glycated hemoglobin or C-peptide might have resulted in a more accurate evaluation. Thirdly, although various types of plastic stents and SEMS were used in this study, we could not identify the benefits of each stent type due to small sample size. Moreover, in Korea, of the currently available lumen-apposing metallic stents, only SPAXUS stent (Taewoong Medical) can be used, so the effectiveness of the 16 mm diameter Hot Axios (Boston Scientific) that has been used worldwide17 could not been verified. However, the results are considered to be meaningful, because incidental SEMS migrations is not uncommon during repeated endoscopic retrievals of necrotic tissue through the lumen of the SEMS. Finally, no standardized follow-up protocol was used for data collection and there were no objective criteria for visual assessing degree of necrotic debridement in the WON cavity. CT scans are an effective method for determining the size reduction of WON, so when determining the endpoint of DEN, it should be compared with the visual assessment of necrotic debris in the WON cavity. Unfortunately, no data has been collected in this study.

In conclusion, as a targeted and minimally invasive approach, DEN is regarded as an efficacious and reproducible technique for the treatment of complicated or symptomatic WON with an acceptable safety profile. Considering that long-term complications are similar to those observed after pancreatectomy, DEN should be performed meticulously so as to minimize damage to the pancreatic parenchyma and should be combined with antibiotics possessing adequate coverage against identified pathogens. Additional multicenter prospective studies are needed to validate the conclusions of our study.


No potential conflict of interest relevant to this article was reported.


Conception and design of the study: J.H.C., S.S.L. Generation, collection, assembly, analysis and/or interpretation of data: Y.S.K., J.H.C., D.H.C., S.W.P., S.H.M., J.S.P., Y.N.L. Drafting or revision of the manuscript: Y.S.K., J.H.C. Approval of the final version of the manuscript: J.H.C., S.S.L.

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Article

Original Article

Gut and Liver 2021; 15(6): 930-939

Published online November 15, 2021 https://doi.org/10.5009/gnl20304

Copyright © Gut and Liver.

Long-term Outcomes of Direct Endoscopic Necrosectomy for Complicated or Symptomatic Walled-Off Necrosis: A Korean Multicenter Study

Yeon Suk Kim1 , Jae Hee Cho2 , Dong Hui Cho3 , Se Woo Park4 , Sung-Hoon Moon5 , Jin-Seok Park6 , Yun Nah Lee7 , and Sang Soo Lee3

1Division of Gastroenterology, Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, 2Division of Gastroenterology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 3Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 4Division of Gastroenterology, Department of Internal Medicine, Hallym University Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong, 5Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, 6Digestive Disease Center, Department of Internal Medicine, Inha University School of Medicine, Incheon, and 7Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University School of Medicine, Bucheon, Korea

Correspondence to:Jae Hee Cho
ORCID https://orcid.org/0000-0003-4174-0091
E-mail jhcho9328@yuhs.ac

Sang Soo Lee
ORCID https://orcid.org/0000-0002-3785-2341
E-mail ssleedr@amc.seoul.kr

Received: September 30, 2020; Revised: December 28, 2020; Accepted: January 8, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/Aims: The endoscopic step-up approach is accepted as the preferred treatment for complicated or symptomatic walled-off necrosis (WON). Direct endoscopic necrosectomy (DEN) is an effective therapeutic option, but few reports describe long-term follow-up in this patient population. Thus, we aim to assess the long-term outcomes of DEN following severe necrotizing pancreatitis.
Methods: The data of all acute pancreatitis patients who underwent DEN following endoscopic transmural drainage from six referral centers between 2007 and 2017 were retrospectively collected.
Results: Sixty patients (76.7% male, mean age 48.3 years) underwent a median of 4 sessions of DEN starting at a median of 45.5 days after the onset of acute pancreatitis. Clinical success was achieved in 51 patients (85%), with a 35% complication rate and a 5% mortality rate. Using multivariate analysis, the risk factor associated with DEN failure or major DEN complications requiring intervention or surgery was an identified bacterial/fungal WON infection (odds ratio, 19.3; 95% confidence interval, 1.5 to 261.7). During the median follow-up period of 27 months, complicated WON recurrence was observed in 5.3% of patients, and long-term complications occurred in 24.6% of patients (four exocrine insufficiency, nine newly developed diabetes mellitus, one recurrent small bowel obstruction, one chylous ascites).
Conclusions: Considering that long-term complications are similar to those observed after pancreatectomy, DEN should be performed meticulously while minimizing damage to the viable pancreatic parenchyma with adequate antibiotic escalation.

Keywords: Acute pancreatitis, Infected necrosis, Necrosectomy, Endoscopy, Antibiotics

INTRODUCTION

Acute necrotizing pancreatitis is a potentially lethal disease, and its incidence is currently increasing. Because infected necrotizing pancreatitis is associated with a mortality of 20% to 30%, an expert multidisciplinary team approach is required to improve clinical outcomes.1-5 Over the past decade, much progress has been made in improving the management of acute necrotizing pancreatitis.6,7 A surgical step-up approach consisting of percutaneous catheter drainage followed by minimally invasive surgical necrosectomy has replaced open necrosectomy as the standard treatment.8-10 Endoscopic treatment has also been highlighted because it is potentially less invasive and can also be performed in a step-up manner.11-13 Endoscopic transmural drainage (ETD) is usually the first procedure to be performed, followed up by direct endoscopic necrosectomy (DEN) if required for improving clinical outcomes. In a Dutch randomized trial, the risk of developing a pancreatic fistula and the length of hospital stay were lower in the endoscopy group when compared to the surgical group. However, endoscopy did not demonstrate superior therapeutic outcomes in terms of mortality and major complications.14 Contrary to these data, a U.S. randomized trial indicated that an endoscopic transluminal approach reduced major complications, lowered costs, and increased the patients’ quality-of-life when compared to minimally invasive surgery.15,16 Controversy remains as to whether an endoscopic step-up approach should be used as the preferred therapeutic modality for infected necrotizing pancreatitis. Furthermore, sufficient information from long-term follow-up after DEN does not currently exist. Therefore, we aimed to assess the long-term outcomes of DEN following ETD as part of an endoscopic step-up approach in patients with severe acute necrotizing pancreatitis.

MATERIALS AND METHODS

1. Patient information

The Korean Pancreatobiliary Association conducted a nationwide multicenter retrospective study by accumulating information on severe acute necrotizing pancreatitis patients who underwent DEN across six referral centers in Korea between January 2007 and December 2017. After standardized data collection forms were sent to each center, each institution retrospectively reviewed their database and collected the clinical data. The participating institutions were Asan Medical Center (Seoul), Gachon University Gil Medical Center (Incheon), Hallym University Dongtan Sacred Heart Hospital (Hwaseong), Hallym University Sacred Heart Hospital (Anyang), Inha University hospital (Incheon), and Soonchunhyang University Bucheon Hospital (Bucheon) in the Republic of Korea. Institutional review board approval was obtained for each participant in this study. The informed consent was waived. A total of 60 patients were ultimately included in this study.

2. Procedures

The indications for endoscopic intervention were determined for each patient. Inclusion criteria were symptomatic or complicated walled-off necrosis (WON), such as suspected/identified infection, and biliary/gastric outlet obstruction following severe necrotizing pancreatitis. The standard technique used for the endoscopic step-up approach is described as follows. Endoscopic ultrasound-guided transmural drainage was performed using either one or two 7-F double-pigtail plastic stents (DPPS) or self-expandable metallic stent (SEMS). Based on clinical decisions, an additional nasocystic drainage catheter was placed into the WON cavity if necessary. Types of SEMS used were as follows: tubular fully covered SEMS including 26 Soo stents (Standard Sci Tech Inc., Seoul, Korea), seven AL stents (Standard Sci Tech Inc.) and two Nagi stents (Taewoong Medical, Goyang, Korea), or lumen-apposing metallic stent of six SPAXUS stents (Taewoong Medical). If there was no clinical improvement following ETD, a DEN was performed. In most cases, an established fistula tract was dilated using a large balloon (maximal diameter, 12 to 20 mm) several days after placement of stent or drainage catheter. A conventional forward-viewing endoscope or water jet scope (GIF-Q260J; Olympus, Tokyo, Japan) was subsequently advanced into the WON cavity and mechanical debridement of the necrotic tissue was performed using snares, forceps, and stone removal baskets accompanied by forceful irrigation using normal saline. In anticipation of a subsequent DEN, the fistula to the necrotic cavity is maintained by placing a DPPS or nasocystic drainage catheter. Repeated DEN sessions were carried out until clinical improvement was achieved, regardless of whether the necrotic debris in the WON was completely removed. At the final DEN session, a DPPS might be placed depending on each institution’s protocol. Depending on the patient’s condition, additional intervention measures, including transpapillary pancreatic duct (PD) stenting, percutaneous drainage, and surgery were performed as necessary. Additionally, in order to diagnose WON infection, microbial culture was conducted with pus aspirated in the ETD procedure. If the patient's condition did not improve, additional culture tests were performed in pus and necrotic tissue during DEN.

3. Outcomes

The primary outcome was to assess the long-term clinical outcomes, such as recurrence of the symptomatic/complicated WON and late complications following DEN. The definition of symptomatic/complicated WON is as follows: (1) clinical suspicion or documented infected WON with clinical deterioration; (2) symptomatic sterile WON including intractable pain, persistent unwellness, ongoing gastrointestinal obstruction despite medical treatment; (3) abdominal compartment syndrome or disconnected PD syndrome with WON. In terms of long-term results, the recurrence of WON was defined as the case of WON redevelopment after 6 months of last DEN session in a patient who had completed treatment. New onset diabetes mellitus was defined as requiring insulin or oral antidiabetic drugs for at least 6 months after DEN and not present prior to the onset of pancreatitis. Exocrine insufficiency was defined as the development of clinical symptoms of steatorrhea and weight loss in patients not previously taking oral pancreatic enzyme supplements. The secondary outcomes were to evaluate the initial treatment success and early complication rates associated with DEN. Clinical success of the DEN was defined as improvement of WON on computed tomography (CT) scan in association with clinical resolution of symptoms at 6-month follow-up period.17 DEN failure was defined as the need for rescue surgery or death during index admission as well as readmission for management of recurred pancreatitis or WON within 6 months.

Other DEN-related complications are defined as follows; “massive bleeding” is the bleeding within the intraabdominal cavity or gastrointestinal tract requiring radiologic interventional procedure, “visceral perforation” is the perforation of visceral organ with intraabdominal free air, “duodenal or colonic fistula” is the formation of a fistula between the small bowel or colon and pancreas confirmed on imaging or endoscopy.

4. Statistical analysis

Differences of continuous variables were compared using the independent t-tests. Categorical variables were compared by the chi-square tests or Fisher exact test. Multivariate logistic regression analysis was performed to evaluate the independent effect of each variable. Odds ratios and confidence intervals were calculated. Statistical analysis was performed using the SPSS software, version 24.0 for Windows (IBM Corp., Armonk, NY, USA). Statistical significance was reached when p-values were below 0.05.

RESULTS

1. Characteristics of patients

A total of 60 patients (76.7% male, mean age 48.3 years) with complicated or symptomatic WON were included from six centers. Twenty of the total 60 patients were treated in the intensive care unit. Continuous renal replacement therapy was administered in 10 patients, and one patient improved after receiving extracorporeal membrane oxygenation. The main causes underlying acute pancreatitis in these patients were alcohol (45%) and the presence of gallstones (25%). The size of the WON (mean of long axis×short axis) was estimated to be 145.9×72.1 mm and the median severity index determined by CT was 6. Coronal CT imaging was used to evaluate the lower margin of the WON, which was found to be an extension to the pelvic cavity in 15 patients and below the kidney in 34 patients. Twenty-one patients had undergone percutaneous catheter drainage. Additionally, the medians of laboratory findings in these patients at the time of DEN were as follows: white blood cell counts 16,380/mm3, amylase 438 U/L, lipase 938 U/L, creatinine 1.03 mg/dL, and C-reactive protein 10.6 mg/dL (Table 1).

Table 1 . Characteristics of Patients with Complicated or Symptomatic Walled-Off Necrosis Who Underwent Direct Endoscopic Necrosectomy.

PatientsValue (n=60)
Age, yr48.3±14.4
Sex
Male46 (76.7)
Female14 (23.3)
BMI, kg/m224.4±3.71
Smoking23 (38.3)
Alcohol41 (68.3)
Etiology
Alcohol27 (45.0)
Gallstone15 (25.0)
Post-ERCP6 (10.0)
Others*12 (20.0)
Diabetes mellitus
Yes12 (20.0)
No48 (80.0)
Initial management of pancreatitis
ICU care20 (33.3)
CRRT/ECMO10 (16.7)/1 (1.7)
CT severity index score6 (5–7)
Previous placement of PCD21 (35.0)
Main locations of WON
Head7 (11.7)
Body and tail32 (53.3)
Entire pancreas21 (35.0)
Lower margin of WON cavity
Above kidney/below kidney 11 (18.3)/34 (56.7)
Extension to pelvic cavity15 (25.0)
No. of WON cavities
Single28 (46.7)
Multiple32 (53.3)
Size, mm
Long axis145.9±50.6
Short axis72.1±33.1
Laboratory findings at the time of DEN
White blood cell,/mm316,380 (13,047–20,005)
CRP, mg/dL10.6 (0.4–30.7)
Amylase, U/L438 (146–2,667)
Lipase, U/L938 (106–10,886)
Creatinine, mg/dL1.03 (0.71–1.57)

Data are presented as mean±SD, number (%), or median (interquartile range)..

BMI, body mass index; ERCP, endoscopic retrograde cholangiopancreatography; ICU, intensive care unit; CRRT, continuous renal replacement therapy; ECMO, extracorporeal membrane oxygenation; CT, computed tomography; PCD, percutaneous catheter drainage; WON, walled-off necrosis; DEN, direct endoscopic necrosectomy; CRP, C-reactive protein..

*Others include hypertriglyceridemia-induced, malignancy, postoperative, and trauma..



2. Initial outcomes of DEN

Initial ETD using DPPS or SEMS were performed after a median duration of 34 days (interquartile range [IQR], 21 to 52.5 days) from the onset of pancreatitis. Of them, transmural SEMS placement was achieved in 41 patients (68.3%). If the patient’s condition did not improve even during ETD, DEN was administered after a median duration of 45.5 days (IQR, 31.25 to 70.75 days) after the index admission. Indication of DEN were as follows; suspected infection (fever and pain) in 40 patients, intractable pain in 18 patients, and gastric outlet obstruction in two patients. With respect to the DEN technique, transgastric (53 cases), transduodenal (five cases), or both (two cases) routes were used, and the multiple gateway technique was performed in 11 patients (18.3%). Carbon dioxide (CO2) gas was used instead of room air for insufflation in 54 patients (90%). A median of 4 necrosectomy sessions (IQR, 2 to 6 sessions) was carried out and the median procedural time of each session was estimated to be 48 minutes (IQR, 37.25 to 64.23 minutes). Endoscopic retrograde cholangiopancreatography was performed in 27 patients and was followed by PD stenting in 17 patients (28.3%). WON infection was identified in 44 patients (73.3%) (Table 2). In terms of short-term outcomes, clinical success was achieved in 51 patients (85%) and DEN complications developed in 21 patients (35%). Among them, major complications such as bleeding requiring intervention (n=9), perforation requiring surgery (n=1), and air embolism (n=1) developed in 10 patients (16.7%). The WON recurrence was developed in four patients within 6 months after discharge, that might be attributed to unsuccessful DENs. Additionally, six patients underwent surgery and three patients succumbed to pancreatitis-related mortality (Fig. 1). Altogether, there were 16 patients (26.7%) who displayed DEN failure or major complications associated with DEN. Multivariate analysis demonstrated that the only significant risk factor for those patients was an identified bacterial/fungal infection of the WON (odds ratio, 19.28; 95% confidence interval, 1.50 to 261.7) (Table 3). Among 44 patients with positive microbial cultures, Candida infection was found in six patients and bacterial infection was noted in 41 patients. The bacterial infections included carbapenem-resistant Acinetobacter baumannii that was identified in five patients, carbapenem-resistant Klebsiella pneumoniae in one patient, extended-spectrum beta-lactamase-producing Klebsiella pneumonia in one patient, methicillin-resistant Staphylococcus aureus in 11 patients, and vancomycin-resistant enterococci in two patients; infection with multidrug-resistant bacteria was found in 17 (28.3%) of 60 patients (Table 4). Furthermore, at the end of the DEN procedure, complete clearance of necrotic tissue in the WON cavity under visualization of DEN was achieved in eight patients (13.3%) (Fig. 2).

Table 2 . Procedural Details and Outcomes of Direct Endoscopic Necrosectomy.

Direct endoscopic necrosectomyValue
Time from onset of pancreatitis to initial EUS drainage, day34 (21.0–52.5)
Placed drainage method
DPPS and/or nasocystic drainage catheter19 (31.7)
SEMS and/or nasocystic drainage catheter41 (68.3)
Time from onset of pancreatitis to the first DEN, day45.5 (31.25–70.75)
Indications of DEN
Suspected infection40 (66.7)
Intractable pain18 (30.0)
Gastric outlet obstruction2 (3.3)
Diameter of dilation for entry site of DEN, mm
12–1535 (58.3)
16–2025 (41.7)
Route
Transgastric53 (88.3)
Transduodenal5 (8.3)
Both2 (3.3)
Gateway
Single49 (81.7)
Multiple11 (18.3)
No. of DEN4 (2–6)
Procedural time of DEN in each session, min48 (37.25–64.23)
Insufflation during the procedure
Room air6 (10.0)
CO2 gas54 (90.0)
ERCP27 (45.0)
Identified main PD disruption15 (25.0)
Transpapillary PD stent17 (28.3)
Preprocedural intravenous antibiotics60 (100)
Identified infection in WON cavity
Yes44 (73.3)
No16 (26.7)
Clinical outcomes of DEN as part of endoscopic step-up approach
Success51 (85.0)
Failure
Surgery/pancreatitis-related mortality*6 (10.0)/3 (5.0)
WON recurrence within 6 months4 (6.7)
Degree of cavity clearance at the end of DEN
Complete clearance8 (13.3)
Incomplete clearance52 (86.7)
Procedure related complications during the treatment period of DEN21 (35.0)
Massive bleeding requiring radiologic intervention9 (15.0)
Visceral perforation3 (5.0)
Stent migration8 (13.3)
Duodenal or colonic fistula5 (8.3)
Others2 (3.3)

Data are presented as median (interquartile range) or number (%)..

EUS, endoscopic ultrasound; DPPS, double-pigtail plastic stents; SEMS, self-expandable metallic stent; DEN, direct endoscopic necrosectomy; CO2, carbon dioxide; ERCP, endoscopic retrograde cholangiopancreatography; PD, pancreatic duct; WON, walled-off necrosis..

*Two cases of mortality developed despite surgical intervention; Others include air embolism, cutaneous fistula..



Table 3 . Risk Factors Associated with the Clinical Outcomes of Direct Endoscopic Necrosectomy.

Risk factorDEN failure* or with major complications (n=16)Successful DEN (n=44)p-valueOR (95% CI)p-value§
Age, mean±SD, yr43.9±14.249.8±14.60.0160.99 (0.94–1.04)0.679
Sex (male/female)14/232/120.314
BMI, mean±SD, kg/m224.8±2.824.2±4.00.564
Identified WON infection (yes/no)15/129/150.04619.28 (1.50–261.70)0.023
CRRT (yes/no)10/64/400.0172.00 (0.33–12.0)0.449
Additional PCD (yes/no)9/712/320.0643.30 (0.71–15.34)0.128
Initial drainage method
(plastic/metal stent)
3/1316/280.228
Gateway (single/multiple)12/437/70.462
Transpapillary PD stent (yes/no)2/1415/290.1200.22 (0.35–1.35)0.218
Pelvic extension of necrotic cavity (yes/no)7/98/360.0883.17 (0.51–19.74)0.315
No. of cavity (multiple/single)11/521/230.242
Largest diameter of necrotic cavity (≥15 cm/<15 cm)5/1127/270.764

DEN, direct endoscopic necrosectomy; OR, odds ratio; CI, confidence interval; BMI, body mass index; WON, walled-off necrosis; CRRT, continuous renal replacement therapy; PCD, percutaneous catheter drainage; PD, pancreatic duct..

*Rescue surgery or death during index admission, readmission within 6 months; Massive bleeding or perforation requiring radiological/surgical intervention or air embolism; Univariate analysis; §Multivariate analysis..



Table 4 . Type and Frequency of Grown Organisms in Positive Aspirate/Tissue Cultures.

VariableIsolates, No. (%)
Total patients (monomicrobial/polymicrobial infection)44 (35/9)
Total microorganisms64
Gram negative
Klebsiella pneumoniae6 (9.4)
Pseudomonas aeruginosa2 (3.1)
Enterobacter aerogenes5 (7.8)
Escherichia coli1 (1.6)
Acinetobacter baumannii9 (14.1)
Citrobacter species2 (3.1)
Aeromonas hydrophilia1 (1.6)
Stenotrophomonas maltophilia6 (9.4)
Morganella morganii1 (1.6)
Gram positive
Enterococci species7 (10.9)
Staphylococcus aureus15 (23.4)
Coagulase-negative Staphylococci2 (3.1)
Streptococcus species1 (1.6)
Fungus
Candida albicans5 (7.8)
Candida glabrata1 (1.6)
Multidrug-resistant bacteria20
ESBL-producing Klebsiella pneumoniae1 (5.0)
Carbapenem-resistant Klebsiella pneumoniae1 (5.0)
Carbapenem-resistant Acinetobacter baumannii5 (7.8)
Methicillin-resistant Staphylococcus aureus11 (55.0)
Vancomycin-resistant enterococci2 (10.0)

ESBL, extended spectrum-beta lactamase..



Figure 1. Flowchart showing the treatment courses of the study patients.
WON, walled-off necrosis; DEN, direct endoscopic necrosectomy; PCD, percutaneous catheter drainage; FU, follow-up. *Air embolism and bleeding occurred simultaneously in one patient.

Figure 2. Intracavitary image of a walled- off necrosis with (A) complete or (B) incomplete removal of necrotic debris in the last session of direct endoscopic necrosectomy.

3. Long-term follow-up after DEN

Complete follow-up data were obtained for 57 patients, after excluding patients that displayed early mortality in the study group. The median follow-up period was 27 months (IQR, 7.8 to 48.4 months). The recurrence of symptomatic/complicated WON was observed in three patients (5.3%) after 6 months of last session of DEN, and the median time to recurrence after completion of DEN was 193 days, 375 days and 433 days (Fig. 1). The cause of recurrence was alcohol in one and unknown in two patients. Long-term complications occurred in 14 patients (24.6%) and included four cases of pancreatic exocrine insufficiency, nine cases of newly developed diabetes mellitus, one case of recurrent small bowel obstruction, and one case of chylous ascites (Table 5). Moreover, when the long-term outcomes and recurrences were compared according to the degree of DEN, there is no difference of those between visual estimation of complete and incomplete clearance of necrotic tissue in WON cavity at end session of DEN (p<0.99) (Table 6). In addition, three patients died due to causes unrelated to the DEN or pancreatitis: one succumbed to lung cancer after 63 months, one to alcoholic ketoacidosis after 26 months, and another patient died due to pancreatic cancer after 16 months.

Table 5 . Long-term Follow-up of 57 Patients after Direct Endoscopic Necrosectomy.

OutcomeValue
FU duration after completion of endoscopic necrosectomy, median (IQR), mo27 (7.8–48.4)
Recurrence of complicated/symptomatic WON, No. (%)3 (5.3)
Recurrence time after completion of endoscopic necrosectomy, median (range), day378 (193–433)
Long-term complication, No. (%)14 (24.6)
Pancreatic exocrine insufficiency4 (7.0)
Newly developed DM9 (15.8)
Others*2 (3.5)
Death, No. (%)3 (5.3)

FU, follow-up; IQR interquartile range; WON, walled-off necrosis; DM, diabetes mellitus..

*Others include chylous ascites and recurrent small bowel obstruction; Alcoholic ketoacidosis, pancreatic cancer, and lung cancer..



Table 6 . The Relationship between WON Recurrence (<6 Months vs ≥6 Months) or Long-term Complications and the Degree of Clearance of Intracavitary Necrotic Tissue at the Last Session of DEN.

Degree of clearance of intracavitary necrotic tissue at the end session of DENp-value
Complete clearance of intracavitary
necrotic tissue (n=8)
Incomplete clearance of intracavitary
necrotic tissue (n=49)
DEN failure of complicated/symptomatic WON recurrence within 6 months after discharge (yes/no)0/84/45<0.99
Long-term WON recurrence more than 6 months after discharge (yes/no)1/72/470.37
Long-term complications including newly developed DM, pancreatic exocrine insufficiency, others (yes/no)*2/612/37<0.99

WON, walled-off necrosis; DEN, direct endoscopic necrosectomy; DM, diabetes mellitus..

*Others include chylous ascites and recurrent small bowel obstruction..


DISCUSSION

With the evolution of endotherapy in recent years, endoscopic step-up approaches have gained popularity for the treatment of complicated or symptomatic WON. Various methods have been suggested, including step-up approaches in which DPPS or metal stents (e.g., tubular SEMS or lumen-apposing metallic stent) are placed to drain the fluids and then if necessary, the remaining necrosis is removed by DEN. In general, the indications for intervention in the WON are as follows: (1) clinical suspicion or identified infection of the WON with clinical deterioration; (2) ongoing organ failure in the several weeks following onset of acute pancreatitis; (3) symptomatic sterile WON including intractable pain, persistent discomfort, and ongoing gastrointestinal and biliary obstruction; or (4) disconnected PD syndrome.18 In this study, the major indication resulting in DEN is suspected infection of the WON in 40 patients (66.7%). However, 44 patients (73%) who underwent DEN had bacterial or fungal infection. In the 15 patients who reported intractable pain and the one patient with gastric outlet obstruction, infections were also identified. Additionally, of the 40 patients with suspected infections, pathogens were not confirmed in 12 patients. This is believed to result from preprocedural antibiotic use prior to the endoscopic treatment (Table 2). Currently, much debate surrounds the routine use of antibiotics in severe necrotizing pancreatitis, however antibiotic escalation could be beneficial for those requiring DEN because our study indicated that identified infection was the only significant risk factor associated with DEN failure and major complications. Furthermore, considering the high incidence of multidrug-resistant infection, appropriate antimicrobial therapy should be chosen in accordance with results from sensitive pathogen identifying tests.19 We expect that this approach will result in a better DEN outcome.

Furthermore, we investigated whether long-term recurrence or complications may occur following DEN. Although long-term follow-up results were inadequate in previous studies, the 6-month follow-up data from the MISER trial15 suggested that new onset diabetes developed in six patients (27.3%) and pancreatic insufficiency was diagnosed in 29 patients (85.3%) following the endoscopic step-up approach for necrotizing pancreatitis. In the long-term follow-up data from the PANTER trial,10 which compared minimal versus open surgical necrosectomy, the step-up group had a lower proportion of incisional hernias (23% vs 53%), pancreatic exocrine insufficiency (29% vs 56%), and endocrine insufficiency (40% vs 64%) after a mean follow-up of 86 months following discharge after the index admission. Additionally, the GEPARD study20 observed that the DEN group had overall long-term clinical success in 84% of the patients. WON recurrence developed in 11% of the patients and new onset diabetes was diagnosed in 20% of the patients after a mean follow-up period of 43 months. In the present study, symptomatic/complicated WON recurrence was confirmed in 5.3% of the patients and long-term complications developed in 22.8% of the patients after a median follow-up period of 27 months. Specifically, new onset diabetes and exocrine insufficiency developed in 15.8% and 7.0% of the patients, respectively. This was comparable to the results of GEPARD study. Interestingly, we found DEN-related typical long-term complications of chylous ascites and intestinal obstruction that may have occurred during pancreatic surgery. Thus, it is necessary to take measures to minimize damage of viable pancreatic tissue as much as possible during DEN.

Multiple methods have been used to increase the effectiveness of necrosectomy, but many questions remain surrounding the uncertainty of optimal timing, number of sessions, interval between sessions, and the degree of completeness of DEN.1,6,21,22 To date, the endpoint of DEN has not been definitively established. These decisions should be based on patient’s clinical course, the indication for intervention and endoscopist expertise and preference. Asian consensus statement suggested that the clearance of necrotic debris and pink granulation tissue lining the wall in the WON cavity were important parameters of successful DEN.23 However, it is also unclear whether necrosectomy should be carried out for complete debridement of necrotic tissue within the WON in every case because complete debridement may itself result in extensive injury of viable pancreatic parenchyma and possible damage to surrounding hidden blood vessels. If the patient's symptoms improve, it may be helpful to treat the underlying infection while maintaining transmural DPPS drainage without completely elimination of the necrotic tissues. In this study, complete clearance of necrotic debris in the WON cavity at the last session of DEN was only achieved in eight patients (13.3%) under direct visualization. If the clinical resolution was achieved by a combination of appropriate antibiotic escalation with repeated DENs, the degree of necrotic tissue clearance in the WON at the last DEN session had no significant effects on symptomatic/complicated WON recurrence and long-term complications. In order to obtain better clinical outcomes, it is therefore recommended not only to perform microbial culture of both aspirated pus and necrotic tissue, but also to minimize unnecessary pancreatic injury during DEN.

There are several limitations to this study. First, the retrospective design and limited sample size have inherent limitations. This study was designed as a multicenter study to overcome size limitations, but each institution lacked consensus for the indication, timing, and DEN methods used. Furthermore, it would be ideal to have specific techniques and procedural elements for a successful DEN, but since various methods are used and inconsistent in almost all procedural details, a unified procedural technique cannot be presented. For instance, consensus has not been reached regarding the effectiveness of hydroperoxide or antibiotics lavage, access technique, amount of debridement, benefit of saline irrigation via nasobiliary tube, and use of preprocedural antibiotics or proton pump inhibitor during DEN. Secondly, for the evaluation of long-term complications, we defined exocrine and endocrine insufficiency based on the need for pancreatic enzyme replacement therapy and antidiabetics/insulin. This entails a risk of underestimating the number of patients with these insufficiencies, whereas direct pancreatic function testing or measurement of glycated hemoglobin or C-peptide might have resulted in a more accurate evaluation. Thirdly, although various types of plastic stents and SEMS were used in this study, we could not identify the benefits of each stent type due to small sample size. Moreover, in Korea, of the currently available lumen-apposing metallic stents, only SPAXUS stent (Taewoong Medical) can be used, so the effectiveness of the 16 mm diameter Hot Axios (Boston Scientific) that has been used worldwide17 could not been verified. However, the results are considered to be meaningful, because incidental SEMS migrations is not uncommon during repeated endoscopic retrievals of necrotic tissue through the lumen of the SEMS. Finally, no standardized follow-up protocol was used for data collection and there were no objective criteria for visual assessing degree of necrotic debridement in the WON cavity. CT scans are an effective method for determining the size reduction of WON, so when determining the endpoint of DEN, it should be compared with the visual assessment of necrotic debris in the WON cavity. Unfortunately, no data has been collected in this study.

In conclusion, as a targeted and minimally invasive approach, DEN is regarded as an efficacious and reproducible technique for the treatment of complicated or symptomatic WON with an acceptable safety profile. Considering that long-term complications are similar to those observed after pancreatectomy, DEN should be performed meticulously so as to minimize damage to the pancreatic parenchyma and should be combined with antibiotics possessing adequate coverage against identified pathogens. Additional multicenter prospective studies are needed to validate the conclusions of our study.

CONFLICTS OF INTEREST


No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS


Conception and design of the study: J.H.C., S.S.L. Generation, collection, assembly, analysis and/or interpretation of data: Y.S.K., J.H.C., D.H.C., S.W.P., S.H.M., J.S.P., Y.N.L. Drafting or revision of the manuscript: Y.S.K., J.H.C. Approval of the final version of the manuscript: J.H.C., S.S.L.

Fig 1.

Figure 1.Flowchart showing the treatment courses of the study patients.
WON, walled-off necrosis; DEN, direct endoscopic necrosectomy; PCD, percutaneous catheter drainage; FU, follow-up. *Air embolism and bleeding occurred simultaneously in one patient.
Gut and Liver 2021; 15: 930-939https://doi.org/10.5009/gnl20304

Fig 2.

Figure 2.Intracavitary image of a walled- off necrosis with (A) complete or (B) incomplete removal of necrotic debris in the last session of direct endoscopic necrosectomy.
Gut and Liver 2021; 15: 930-939https://doi.org/10.5009/gnl20304

Table 1 Characteristics of Patients with Complicated or Symptomatic Walled-Off Necrosis Who Underwent Direct Endoscopic Necrosectomy

PatientsValue (n=60)
Age, yr48.3±14.4
Sex
Male46 (76.7)
Female14 (23.3)
BMI, kg/m224.4±3.71
Smoking23 (38.3)
Alcohol41 (68.3)
Etiology
Alcohol27 (45.0)
Gallstone15 (25.0)
Post-ERCP6 (10.0)
Others*12 (20.0)
Diabetes mellitus
Yes12 (20.0)
No48 (80.0)
Initial management of pancreatitis
ICU care20 (33.3)
CRRT/ECMO10 (16.7)/1 (1.7)
CT severity index score6 (5–7)
Previous placement of PCD21 (35.0)
Main locations of WON
Head7 (11.7)
Body and tail32 (53.3)
Entire pancreas21 (35.0)
Lower margin of WON cavity
Above kidney/below kidney 11 (18.3)/34 (56.7)
Extension to pelvic cavity15 (25.0)
No. of WON cavities
Single28 (46.7)
Multiple32 (53.3)
Size, mm
Long axis145.9±50.6
Short axis72.1±33.1
Laboratory findings at the time of DEN
White blood cell,/mm316,380 (13,047–20,005)
CRP, mg/dL10.6 (0.4–30.7)
Amylase, U/L438 (146–2,667)
Lipase, U/L938 (106–10,886)
Creatinine, mg/dL1.03 (0.71–1.57)

Data are presented as mean±SD, number (%), or median (interquartile range).

BMI, body mass index; ERCP, endoscopic retrograde cholangiopancreatography; ICU, intensive care unit; CRRT, continuous renal replacement therapy; ECMO, extracorporeal membrane oxygenation; CT, computed tomography; PCD, percutaneous catheter drainage; WON, walled-off necrosis; DEN, direct endoscopic necrosectomy; CRP, C-reactive protein.

*Others include hypertriglyceridemia-induced, malignancy, postoperative, and trauma.


Table 2 Procedural Details and Outcomes of Direct Endoscopic Necrosectomy

Direct endoscopic necrosectomyValue
Time from onset of pancreatitis to initial EUS drainage, day34 (21.0–52.5)
Placed drainage method
DPPS and/or nasocystic drainage catheter19 (31.7)
SEMS and/or nasocystic drainage catheter41 (68.3)
Time from onset of pancreatitis to the first DEN, day45.5 (31.25–70.75)
Indications of DEN
Suspected infection40 (66.7)
Intractable pain18 (30.0)
Gastric outlet obstruction2 (3.3)
Diameter of dilation for entry site of DEN, mm
12–1535 (58.3)
16–2025 (41.7)
Route
Transgastric53 (88.3)
Transduodenal5 (8.3)
Both2 (3.3)
Gateway
Single49 (81.7)
Multiple11 (18.3)
No. of DEN4 (2–6)
Procedural time of DEN in each session, min48 (37.25–64.23)
Insufflation during the procedure
Room air6 (10.0)
CO2 gas54 (90.0)
ERCP27 (45.0)
Identified main PD disruption15 (25.0)
Transpapillary PD stent17 (28.3)
Preprocedural intravenous antibiotics60 (100)
Identified infection in WON cavity
Yes44 (73.3)
No16 (26.7)
Clinical outcomes of DEN as part of endoscopic step-up approach
Success51 (85.0)
Failure
Surgery/pancreatitis-related mortality*6 (10.0)/3 (5.0)
WON recurrence within 6 months4 (6.7)
Degree of cavity clearance at the end of DEN
Complete clearance8 (13.3)
Incomplete clearance52 (86.7)
Procedure related complications during the treatment period of DEN21 (35.0)
Massive bleeding requiring radiologic intervention9 (15.0)
Visceral perforation3 (5.0)
Stent migration8 (13.3)
Duodenal or colonic fistula5 (8.3)
Others2 (3.3)

Data are presented as median (interquartile range) or number (%).

EUS, endoscopic ultrasound; DPPS, double-pigtail plastic stents; SEMS, self-expandable metallic stent; DEN, direct endoscopic necrosectomy; CO2, carbon dioxide; ERCP, endoscopic retrograde cholangiopancreatography; PD, pancreatic duct; WON, walled-off necrosis.

*Two cases of mortality developed despite surgical intervention; Others include air embolism, cutaneous fistula.


Table 3 Risk Factors Associated with the Clinical Outcomes of Direct Endoscopic Necrosectomy

Risk factorDEN failure* or with major complications (n=16)Successful DEN (n=44)p-valueOR (95% CI)p-value§
Age, mean±SD, yr43.9±14.249.8±14.60.0160.99 (0.94–1.04)0.679
Sex (male/female)14/232/120.314
BMI, mean±SD, kg/m224.8±2.824.2±4.00.564
Identified WON infection (yes/no)15/129/150.04619.28 (1.50–261.70)0.023
CRRT (yes/no)10/64/400.0172.00 (0.33–12.0)0.449
Additional PCD (yes/no)9/712/320.0643.30 (0.71–15.34)0.128
Initial drainage method
(plastic/metal stent)
3/1316/280.228
Gateway (single/multiple)12/437/70.462
Transpapillary PD stent (yes/no)2/1415/290.1200.22 (0.35–1.35)0.218
Pelvic extension of necrotic cavity (yes/no)7/98/360.0883.17 (0.51–19.74)0.315
No. of cavity (multiple/single)11/521/230.242
Largest diameter of necrotic cavity (≥15 cm/<15 cm)5/1127/270.764

DEN, direct endoscopic necrosectomy; OR, odds ratio; CI, confidence interval; BMI, body mass index; WON, walled-off necrosis; CRRT, continuous renal replacement therapy; PCD, percutaneous catheter drainage; PD, pancreatic duct.

*Rescue surgery or death during index admission, readmission within 6 months; Massive bleeding or perforation requiring radiological/surgical intervention or air embolism; Univariate analysis; §Multivariate analysis.


Table 4 Type and Frequency of Grown Organisms in Positive Aspirate/Tissue Cultures

VariableIsolates, No. (%)
Total patients (monomicrobial/polymicrobial infection)44 (35/9)
Total microorganisms64
Gram negative
Klebsiella pneumoniae6 (9.4)
Pseudomonas aeruginosa2 (3.1)
Enterobacter aerogenes5 (7.8)
Escherichia coli1 (1.6)
Acinetobacter baumannii9 (14.1)
Citrobacter species2 (3.1)
Aeromonas hydrophilia1 (1.6)
Stenotrophomonas maltophilia6 (9.4)
Morganella morganii1 (1.6)
Gram positive
Enterococci species7 (10.9)
Staphylococcus aureus15 (23.4)
Coagulase-negative Staphylococci2 (3.1)
Streptococcus species1 (1.6)
Fungus
Candida albicans5 (7.8)
Candida glabrata1 (1.6)
Multidrug-resistant bacteria20
ESBL-producing Klebsiella pneumoniae1 (5.0)
Carbapenem-resistant Klebsiella pneumoniae1 (5.0)
Carbapenem-resistant Acinetobacter baumannii5 (7.8)
Methicillin-resistant Staphylococcus aureus11 (55.0)
Vancomycin-resistant enterococci2 (10.0)

ESBL, extended spectrum-beta lactamase.


Table 5 Long-term Follow-up of 57 Patients after Direct Endoscopic Necrosectomy

OutcomeValue
FU duration after completion of endoscopic necrosectomy, median (IQR), mo27 (7.8–48.4)
Recurrence of complicated/symptomatic WON, No. (%)3 (5.3)
Recurrence time after completion of endoscopic necrosectomy, median (range), day378 (193–433)
Long-term complication, No. (%)14 (24.6)
Pancreatic exocrine insufficiency4 (7.0)
Newly developed DM9 (15.8)
Others*2 (3.5)
Death, No. (%)3 (5.3)

FU, follow-up; IQR interquartile range; WON, walled-off necrosis; DM, diabetes mellitus.

*Others include chylous ascites and recurrent small bowel obstruction; Alcoholic ketoacidosis, pancreatic cancer, and lung cancer.


Table 6 The Relationship between WON Recurrence (<6 Months vs ≥6 Months) or Long-term Complications and the Degree of Clearance of Intracavitary Necrotic Tissue at the Last Session of DEN

Degree of clearance of intracavitary necrotic tissue at the end session of DENp-value
Complete clearance of intracavitary
necrotic tissue (n=8)
Incomplete clearance of intracavitary
necrotic tissue (n=49)
DEN failure of complicated/symptomatic WON recurrence within 6 months after discharge (yes/no)0/84/45<0.99
Long-term WON recurrence more than 6 months after discharge (yes/no)1/72/470.37
Long-term complications including newly developed DM, pancreatic exocrine insufficiency, others (yes/no)*2/612/37<0.99

WON, walled-off necrosis; DEN, direct endoscopic necrosectomy; DM, diabetes mellitus.

*Others include chylous ascites and recurrent small bowel obstruction.


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Gut and Liver

Vol.15 No.6
November, 2021

pISSN 1976-2283
eISSN 2005-1212

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