Current Treatment Options in Gastroenterology DOI 10.1007/s11938-014-0018-7

Pancreas (T Stevens, Section Editor)

Evidence-Based Management of Necrotizing Pancreatitis Diana A. Whitehead, MD Timothy B. Gardner, MD MS* Address *Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, USA Email: [email protected]

* Springer Science+Business Media, LLC 2014

Keywords Therapeutic endoscopy I Pancreatitis I Pancreatic fluid collection I Necrotizing pancreatitis I Walled off necrosis I Acute fluid collection I Acute necrotic collection I Pancreatic pseudocyst I Endoscopic ultrasound

Opinion statement Pancreatic necrosis may result as a complication of acute pancreatitis, often causing significant morbidity and mortality. There are many recommendations concerning the management of pancreatic necrosis, including non-operative management with supportive care and antibiotics, computed tomography (CT)-guided percutaneous drainage, endoscopic transluminal drainage, and operative necrosectomy. Historically, pancreatic necrosis has been treated surgically. However, surgical management of pancreatic necrosis is associated with high mortality (6–28 %) and morbidity (19–62 %). Thus, endoscopic therapy has emerged as a relatively new minimally invasive technique for treating infected and/or symptomatic pancreatic necrosis in the last decade. Although there have been two randomized trials comparing endoscopic transluminal drainage versus operative necrosectomy, there is little data regarding timing, indication, and outcomes of these procedures.

Introduction In the last decade, the paradigm of treating pancreatic collections (PCs) and walled off necrosis (WON) has shifted from early surgical intervention to delaying treatment to permit collection maturity. New tools such as linear-array endoscopic ultrasound (EUS) allow for transluminal access and video-assisted retroperitoneal debridement (VARD) and sinus tract surgery allow for retroperitoneal access [1–4]. Although there are no standard guidelines for the treatment of PC and WON, the evidence for the efficacy of interventions was reviewed recently by an

international consensus of leading surgeons, interventional endoscopists, interventional endoscopists, and pancreatologists [5••]. The group concluded that minimally invasive modalities, especially endoscopic transluminal necrosectomy, should now be the procedure of choice for management of WON in certain clinical settings. Although it is also agreed that the care of patients with WON should ideally include a team of intensivists, therapeutic endoscopists, interventional radiologists, and surgeons, there still exists a wide variation in clinical

Pancreas (T Stevens, Section Editor) practice. More often, the approach used to treat WON is determined by institutional preference, availability of equipment, and clinical expertise. Although the first endoscopic debridement of WON was described in 1996, the technique has yet to be adapted universally as the standard of practice. There are still unanswered questions regarding timing and indications for intervention. In addition, there have been only two randomized controlled trials comparing endoscopic intervention of WON with surgical

intervention. To help streamline the standard of care for PC, a team of specialists with interest in pancreatic disease revised the original Atlanta Classification of acute pancreatitis in 2012 [6••, 7]. This article reviews the evidence behind endoscopic management of pancreatic necrosis, specifically highlighting patient selection, timing and indication, endoscopic methods of drainage, complications, and the future direction of endoscopic management.

Types of pancreatic collections PCs can develop in the setting of acute and chronic pancreatitis, abdominal trauma, and/or as a complication of surgery. It is no longer acceptable to use the universal term “pseudocyst” to describe the entire spectrum of PCs. In 1992, the original Atlanta Classification provided standardized definitions of PCs based on the presence or absence of necrosis and time from injury; the guidelines were revised in 2012 [8]. PCs can develop secondary to pancreatic injury and leakage of pancreatic enzymes from a disrupted duct or liquefaction of pancreatic necrosis. These types of collections can result from interstitial or necrotizing pancreatitis. There are four main types of PC, which include acute fluid collections (AFCs), acute necrotic collections (ANCs), pseudocysts, and WON [9, 10]. (Table 1) AFCs develop less than 4 weeks after an episode of interstitial pancreatitis. They are found in the pancreatic parenchyma or peripancreatic tissue and usually resolve without requiring intervention [11, 12]. When a fluid collection develops in the context of pancreatic necrosis, it is known as an ANC. ANCs can be detected radiographically on contrast-enhanced computed tomography (CECT) by the presence of non-enhancing intrapancreatic or extrapancreatic parenchyma. If an AFC does not resolve in 4 weeks and develops an encapsulated wall that lacks solid debris, it is characterized as a pseudocyst. Pseudocysts are usually extrapancreatic, but occasionally can be intrapancreatic as a result of a disrupted pancreatic duct. WON occurs after 4 weeks, contains solid debris, and occurs only in the context of necrotizing

Table 1. Classification of pancreatic fluid collections Acute fluid collection (AFC) Pancreatic pseudocyst Acute necrotic collection (ANC) Walled-off necrosis (WON)

Fluid collection that develops less than 4 weeks after initial injury, contains no solid debris, and has no encapsulated wall Collection that arises from a mature acute fluid collection and is surrounded by a well-defined wall and contains essentially no solid debris Collection that arises in the context of pancreatic or peripancreatic necrosis that develops less than 4 weeks after the initial injury Mature collection of solid and liquid debris that arises from an acute necrotic collection and has a well-encapsulated wall

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pancreatitis (Figs. 1 and 2). It is also important to ensure that the PC is preceded by an episode of acute pancreatitis and to rule out cystic pancreatic neoplasms such as mucinous cystic neoplasm (MCN), intraductal papillary MCN (IPMN), and solid pseudopapillary tumor [13]. To further characterize PCs, several imaging modalities are available including CECT, magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP), and EUS. CECT remains the most commonly used imaging modality in the setting of acute pancreatitis. The most important role for CECT is to diagnose pancreatic necrosis as well as other complications including venous thrombosis and pseudoaneurysms. It is important to note that pancreatic necrosis may take several days to develop; therefore, it is possible to miss necrosis if imaging is performed at admission. The disadvantages of CECT include radiation exposure, potential contrast-induced nephropathy, and unreliability in detecting the underlying amount of necrotic debris in WON [14]. MRI/MRCP may be used for detection of pancreatic necrosis. The major advantage of MRI/MRCP is its ability to detect pancreatic necrosis based on fat-suppressed T1-weighted images. Other advantages of MRI/MRCP include lack of radiation, no need for contrast, and greater sensitivity in detecting non-liquid (debris) in pancreatic and peripancreatic collections. Some of the disadvantages of using MRI/MRCP are possible variation in availability and scanner quality as well as patient intolerance due to claustrophobia or metallic implants. Both T2weighted MRI and EUS seem to be superior to CECT for detecting non-liquid necrosis and debris within PCs. Although MRI/MRCP is solely diagnostic, EUS allows for the possibility of intervention. The disadvantages of EUS include its reliance on operator performance and its limited availability [15–17]. Thus, these imaging modalities can help distinguish the type of PC and identify patients in whom endoscopic therapy should be considered [18, 19••]. In the following sections, the management of pancreatic necrosis is discussed.

Indication and timing of drainage The clinical course of necrotizing pancreatitis can be divided into two phases. The first phase, within the first 1–2 weeks after presentation, is characterized by the potential development of the systemic inflammatory response syndrome (SIRS) and organ failure. Aggressive therapeutic interventions such as necrosectomy during this period are almost always contraindicated unless the patient develops Figure 1. Walled-off necrosis with both liquid and solid debris (arrows) within the collection.

Pancreas (T Stevens, Section Editor) Figure 2. Peripancreatic necrosis with multiple fat-attenuation debris noted in the collection (arrows).

abdominal compartment syndrome or bowel ischemia requiring laparoscopy. The later phase of the disease (usually after the first 2 weeks) typically features resolution of SIRS and/or organ failure. It is during this time that infected necrosis usually develops [19••, 20]. Infected necrosis usually presents with fevers, and may also be accompanied by worsening abdominal pain, lethargy, or other clinical deterioration. While definitive sampling is not generally recommended by current guidelines, multiple sampling techniques such as percutaneous, open operative, and endoscopic sampling can be used to make the diagnosis. The treatment of infected necrosis has undergone fundamental changes in recent years. Historically, most patients with infected necrosis underwent open operative necrosectomy. However, it is now acceptable for infected necrosis to be first treated conservatively with antibiotics and exquisite supportive care. The main indication for intervention should be clinical decompensation while on maximum medical therapy. Several large studies have confirmed that patients who are clinically stable and have infected necrosis can be treated with antibiotics and supportive care alone [21–24]. Other indications include gastric outlet obstruction, pain, or persistent unwellness [25]. For patients undergoing intervention for infected necrosis, there is convincing evidence that delaying intervention is better than early intervention; i.e., it should be postponed until the necrosis is walled off or encapsulated. Attempts at debridement of infected necrosis before 4 weeks have been shown to have increased morbidity. For example, a recent randomized trial demonstrated that early necrosectomy (within the first 2–3 days after onset of acute pancreatitis) was associated with higher morbidity and mortality than delayed intervention after at least 12 days [25]. In another study, a retrospective series from the Mayo Clinic Rochester (Rochester, MN, USA), 138 patients with pancreatic necrosis, acute pseudocyst, or chronic pseudocyst underwent endoscopic therapy. Resolution was significantly more frequent in the patient with chronic pseudocyst (59/64, 92 %) than acute pseudocyst (23/31, 74 %, p=0.02) or necrosis (31/43, 72 %, p= 0.006) [26]. Therefore, it is imperative to wait for encapsulation or “walling off” for the success of endoscopic therapy. In addition, with the advent of minimally invasive endoscopic techniques, surgical debridement can often be avoided completed, which further decreased complications [27, 28]. A recent randomized trial by the Dutch Acute Pancreatitis study group showed that a step-up approach of percutaneous catheter drainage with

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subsequent minimally invasive surgical necrosectomy (by endoscopic, sinus tract endoscopy, VARD) is superior to primary open necrosectomy [29]. The step-up approach reduced multiple organ failure and long-term complications such as diabetes and the need for pancreatic enzymes. In addition, minimally invasive techniques have a lower complication rate than the open surgical necrosectomy rate [30–33].

Endoscopic drainage methods Endoscopic drainage of PCs was initially performed by the transpapillary approach using ERCP or “blind” transmural drainage using needle knife puncture of luminal bulges. After the advent of EUS, transmural drainage was made easier and safer, including access of collections without a luminal bulge [34, 35]. Treatment of WON via endoscopic debridement was first described by Dr. Todd Baron via creation of an endoscopic cystenterostomy and insertion of a nasocystic catheter to provide irrigation [36]. Although the first transluminal direct endoscopic necrosectomy (DEN) for WON was not reported until 2000, there have been several case series and two randomized control studies showing the superiority of endoscopic transgastric necrosectomy in patients with infected necrosis when compared with surgical necrosectomy [37–40]. Prior to undergoing endoscopic drainage/debridement of PCs, the following should be considered by the treating endoscopist:

& & & & & &

Ensure that the collection is inflammatory and arising from acute or chronic pancreatitis and not a pre-malignant pancreatic cystic neoplasm such as MCN, IPMN, or solid pseudopapillary neoplasm. Confirm that the patient does not have a contraindication to the procedure such as coagulopathy. Verify that the procedure is in the realm of the endoscopist’s skill set and that the facility has the expertise to support the patient if a complication develops. Clearly review the risk and benefits of the procedure with the patient and obtain written informed consent. Ensure there is an anesthesia team available to perform endotracheal intubation as generally all patients should be intubated for airway protection. Confirm that the patient is hemodynamically stable to allow for prone patient positioning, thereby decreasing the risk of reflux and tracheal aspiration.

Technique for endoscopic transmural cystgastrostomy and necrosectomy Routine antibiotics are usually given pre-procedurally and are recommended only for those who are not already receiving them. When using EUS, the PC is first located and color doppler guidance is used to identify surrounding vasculature. Endoscopic technique for cystgastrostomy of pancreatic fluid

Pancreas (T Stevens, Section Editor) collection (PFC) and necrosectomy is fairly standardized and the technique is outlined below: [36, 41–44, 45••, 46, 47]

& & & & &

& & & &

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If EUS is not being used, external compression of the gastric or duodenal wall by the collection is determined endoscopically while using the most recent cross-sectional imaging. The site of puncture is determined by choosing the site closest to the collection, preferably not more than 1–2 cm between the lumen and the cavity. Transmural puncture is performed using a 19-gauge FNA (fine-needle aspiration) needle directly into the PC under fluoroscopic guidance. After aspiration of contents, contrast is injected to access and document collection size and determine boundaries and communication with the pancreatic duct. Once the collection is accessed, any standard-size guide wire (although usually a 0.035-inch size) is advanced through the needle under fluoroscopic guidance and the needle subsequently removed using Seldinger technique. Creation of the fistula tract can be performed with needle sheath dilation followed by balloon dilation, dilating catheter dilation or, if there is resistance, a wire-guided needle knife or cystotome. Dilation of the fistula tract to at least 10 mm, and to as large as 20 mm, is performed if endoscopic debridement is planned. If the plan is to simply drain the PC, two to four 10-Fr double-pigtail stents of 2–4 cm in length or a fully covered biliary-type metallic stent are used. If debridement is planned, a gastroscope is driven into the collection and aggressive debridement of fluid and solid content performed using a combination of balloons, snares, baskets, waterjets, and capsuction techniques after creation of a fistula tract. Stents are then left in place to allow further drainage—usually 3–4 10-Fr double-pigtail stents. Most patients with necrotizing pancreatitis will require multiple debridements until WON has resolved—this is usually followed with serial cross-sectional imaging.

Follow-up care Following an uncomplicated procedure, hospital admission is not required and most patients are discharged home on a short course of oral antibiotics. Cross-sectional imaging is usually repeated in 2–4 weeks to ensure resolution [48•]. Patients with WON may require multiple debridements with followup imaging every 1–2 weeks until the solid debris has been eradicated. Once resolution has been confirmed with restoration of pancreatic duct integrity, all stents should ideally be removed (metallic stents) or allowed to migrate

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spontaneously (plastic stents) per current practice guidelines [49]. Patients with disrupted ducts, which serve as the source of the fluid collection, should undergo stenting of the pancreatic duct in order to control the leak [50]. It is also helpful if patients stop taking acid-suppressing medication to allow further debridement and liquefaction of necrosis by gastric acid via the cystenterostomy. If endoscopy failed to resolve the PC, other modalities can be used in combination such as VARD or sinus tract endoscopy (also referred to as minimal access retroperitoneal pancreatic necrosectomy; MARPN) [51].

Complication management Several life-threatening complications can occur, such as bleeding, perforation, infection, and/or air embolism. In the largest multicenter case series, adverse events including perforation, peritonitis, bleeding, and air embolism occurred in 15 and 26 % of patients, respectively [35, 45••]. Therefore, it is imperative to ensure that endoscopists who perform these procedures have the appropriate back-up available at the time of the procedure and immediate post-operative period, including surgeons, interventional radiologists, and intensivists. Most bleeding can be controlled endoscopically with available closure devices, but interventional radiologist support is sometimes necessary [8, 9, 52••, 53–57]. If perforation occurs during transgastric drainage and is confined to the gastric or duodenal wall, it may be successfully managed conservatively with nasogastric tube suction and antibiotics. There is potential for air-embolism during this procedure, so CO2 insufflation is recommended. Although CO2 does not reduce the risk of air embolism, it is cleared rapidly from the blood stream as compared with oxygen [58]. To prevent infection, broad-spectrum antibiotics should be given at least peri-procedurally. Most patients remain on oral antibiotics for at least 1 week following the procedure. Antifungal agents are added only if there are culture data to support their use [59–61].

Outcomes and literature review In 1992, Wiersema reported the first EUS-guided drainage of PFCs [61, 62]. Subsequently, there have been several studies investigating minimally invasive treatment of pancreatic necrosis. Specifically, the largest case series demonstrated successful resolution in approximately 90 % of cases [35, 45••]. The only randomized, prospective study [PANTER (PAncreatitis, Necrosectomy versus sTEp up appRoach) trial] comparing minimally invasive techniques with open necrosectomy is a study completed by the Dutch Acute Pancreatitis Study Group [63••, 64]. In this multicenter study, 88 patients with infected necrosis were randomized to open necrosectomy or a step-up approach of percutaneous drainage followed by, if necessary, minimally invasive retroperitoneal necrosectomy. Patients who underwent a “step-up approach” had less new-onset multisystem organ failure, major complications, or death than the open necrosectomy group (40 vs. 69 %, p=0.006). Long-term morbidity included incisional hernia (7 vs. 24 %), new-onset diabetes mellitus (16 vs. 38 %), and pancreatic enzymes use

Pancreas (T Stevens, Section Editor) (7 vs. 33 %). Notably, 35 % of patients in the step-up group did not require necrosectomy. The same group recently published the PENGUIN (Pancreatitis, Endoscopic Transgastric vs Primary Necrosectomy in Patients With Infected Necrosis) trial, a multicenter randomized controlled trial comparing endoscopic necrosectomy with surgical necrosectomy (VARD or, if not feasible, open necrosectomy) [52••]. Twenty patients completed randomization with ten in each group (this was an initial report—enrollment is currently ongoing in 2014). This study showed superiority of endoscopic necrosectomy over surgical necrosectomy as endoscopic necrosectomy reduced the post-procedural pro-inflammatory response as measured by serum interleukin-6 (IL-6) levels and a predefined composite endpoint of major complication. New-onset organ failure occurred significantly less frequently with endoscopic necrosectomy (0 vs. 50 %, p=0.03), as did pancreatic fistulas (10 vs. 70 %, p=0.02). There was also a non-significant trend towards lower mortality with endoscopic necrosectomy compared with surgery (10 vs. 40 %).

Current controversies/future considerations Although endoscopic techniques have revolutionized the way we treat infected pancreatic necrosis, there are still several unanswered questions. Further comparative effectiveness trials between endoscopic necrosectomy and other minimally invasive techniques are needed [65, 66]. In addition, the following areas need to be further explored to ensure optimal management of pancreatic necrosis:

&

& & &

How to best mange disconnected duct syndrome (i.e., transmural stent left indefinitely vs. transpapillary pancreatic duct stenting vs. transpapillary pancreatic duct stenting vs. catheter clamping and removal after prolonged drainage vs. surgical approaches) [67, 68]. The extent to which facilities and/or providers need to be credentialed to perform these procedures. The improvements in devices necessary for endoscopic debridement. A randomized controlled trial comparing plastic versus metal stents in drainage of PFCs [69].

Summary The performance of EUS-guided PC drainage and debridement for pancreatic necrosis has increased dramatically in the last three decades. The paradigm has now shifted in the treatment of WON from open surgical debridement to noninvasive techniques. Current evidence favors supportive treatment with antibiotics as first-line therapy for infected pancreatic necrosis. If antibiotics do not resolve the problem, minimally invasive techniques such as endoscopic necrosectomy or percutaneous catheter drainage followed by minimally invasive necrosectomy are the preferred routes for intervention. While endoscopic necrosectomy is preferred over open surgical debridement, further prospective

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randomized controlled trials need to be conducted to validate its effectiveness, cost, and safety when compared with other minimally invasive techniques.

Compliance with Ethics Guidelines Conflict of Interest Diana A. Whitehead declares that she has no conflict of interest. Timothy B. Gardner declares that he has no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

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