Long-Term Outcome of Immediate Versus Postponed Intervention in Patients With Infected Necrotizing Pancreatitis (POINTER): Multicenter Randomized Trial.

OBJECTIVE: To compare the long-term outcomes of immediate drainage versus the postponed-drainage approach in patients with infected necrotizing pancreatitis. BACKGROUND: In the randomized POINTER trial, patients assigned to the postponed-drainage approach using antibiotic treatment required fewer interventions, as compared with immediate drainage, and over a third were treated without any intervention. METHODS: Clinical data of those patients alive after the initial 6-month follow-up were re-evaluated. The primary outcome was a composite of death and major complications. RESULTS: Out of 104 patients, 88 were re-evaluated with a median follow-up of 51 months. After the initial 6-month follow-up, the primary outcome occurred in 7 of 47 patients (15%) in the immediate-drainage group and 7 of 41 patients (17%) in the postponed-drainage group (RR 0.87, 95% CI 0.33-2.28; P =0.78). Additional drainage procedures were performed in 7 patients (15%) versus 3 patients (7%) (RR 2.03; 95% CI 0.56-7.37; P =0.34). The median number of additional interventions was 0 (IQR 0-0) in both groups ( P =0.028). In the total follow-up, the median number of interventions was higher in the immediate-drainage group than in the postponed-drainage group (4 vs. 1, P =0.001). Eventually, 14 of 15 patients (93%) in the postponed-drainage group who were successfully treated in the initial 6-month follow-up with antibiotics and without any intervention remained without intervention. At the end of follow-up, pancreatic function and quality of life were similar. CONCLUSIONS: Also, during long-term follow-up, a postponed-drainage approach using antibiotics in patients with infected necrotizing pancreatitis results in fewer interventions as compared with immediate drainage and should therefore be the preferred approach. TRIAL REGISTRATION: ISRCTN33682933.

Prospective multicentre study of indications for surgery in patients with idiopathic acute pancreatitis following endoscopic ultrasonography (PICUS).

BACKGROUND: Cholecystectomy in patients with idiopathic acute pancreatitis (IAP) is controversial. A randomized trial found cholecystectomy to reduce the recurrence rate of IAP but did not include preoperative endoscopic ultrasonography (EUS). As EUS is effective in detecting gallstone disease, cholecystectomy may be indicated only in patients with gallstone disease. This study aimed to determine the diagnostic value of EUS in patients with IAP, and the rate of recurrent pancreatitis in patients in whom EUS could not determine the aetiology (EUS-negative IAP). METHODS: This prospective multicentre cohort study included patients with a first episode of IAP who underwent outpatient EUS. The primary outcome was detection of aetiology by EUS. Secondary outcomes included adverse events after EUS, recurrence of pancreatitis, and quality of life during 1-year follow-up. RESULTS: After screening 957 consecutive patients with acute pancreatitis from 24 centres, 105 patients with IAP were included and underwent EUS. In 34 patients (32 per cent), EUS detected an aetiology: (micro)lithiasis and biliary sludge (23.8 per cent), chronic pancreatitis (6.7 per cent), and neoplasms (2.9 per cent); 2 of the latter patients underwent pancreatoduodenectomy. During 1-year follow-up, the pancreatitis recurrence rate was 17 per cent (12 of 71) among patients with EUS-negative IAP versus 6 per cent (2 of 34) among those with positive EUS. Recurrent pancreatitis was associated with poorer quality of life. CONCLUSION: EUS detected an aetiology in a one-third of patients with a first episode of IAP, requiring mostly cholecystectomy or pancreatoduodenectomy. The role of cholecystectomy in patients with EUS-negative IAP remains uncertain and warrants further study.

Some patients develop acute inflammation of the pancreas without a clear cause. These patients have a high risk of developing more episodes of acute inflammation of the pancreas. Potentially, such inflammation could be caused by tiny gallstones that physicians are not able to detect. If this is true, these patients may also benefit from surgical removal of the gallbladder. However, this is still controversial. Endoscopic ultrasonography is a diagnostic procedure during which a physician looks at the gallbladder and bile ducts in detail via a small ultrasound probe inserted through the mouth. This endoscopic ultrasonography may be able to detect gallstones better than physicians were able to previously. This study tested the value of endoscopic ultrasonography, and the number of patients who developed more episodes of acute inflammation after endoscopic ultrasonography was recorded. Some 106 patients with acute inflammation of the pancreas for the first time without a clear cause participated and were offered endoscopic ultrasonography. The number of times endoscopic ultrasonography found a cause for the acute inflammation was recorded, as well as safety parameters, number of patients who developed more episodes of acute inflammation, and quality of life. After screening 957 patients, 105 ultimately underwent endoscopic ultrasonography. A cause was found in one-third of patients. This was mostly (tiny) gallstones, but chronic inflammation and even tumours were found. These patients were mostly treated surgically for their gallstones and tumours. In the first year after the first acute episode of inflammation, the inflammation came back at least once in almost one in six patients in whom endoscopic ultrasonography did not find a cause. This occurred less in patients in whom a cause was found; the inflammation came back in 1 in 16 of these patients. It was also found that having inflammation coming back negatively affected quality of life. In this study, endoscopic ultrasonography was able to detect a cause in one-third of patients with first-time acute inflammation of the pancreas. In one in four patients, this cause could be treated by a surgical procedure. Whether surgical removal of the gallbladder can be helpful in patients in whom endoscopic ultrasonography is not able to detect an aetiology should be investigated in further studies.

[Milk-alkali syndrome: a careful history is crucial in diagnosing hypercalcemia]. / Melk-alkalisyndroom.

BACKGROUND: Milk-alkali syndrome is a rare cause of hypercalcemia in the Netherlands, due to ingestion of large amounts of calcium and absorbable alkali. CASE DESCRIPTION: A 38-year-old female patient was admitted with severe stomach pain, vomiting and weight loss. Laboratory results showed hypercalcemia and acute kidney injury. We initially suspected that the hypercalcemia was related to primary hyperparathyroidism, a malignancy with bone metastasis or a granulomatous disease. Gastroduodenoscopy, however, revealed a duodenal ulcer, which turned out to be Helicobacter pylori-related. A thorough history revealed that the patient had consumed large amounts of milk and antacids to relieve symptoms of heartburn. In light of this history, milk-alkali syndrome was diagnosed. CONCLUSION: The case aims to underline the importance of a thorough history in patients with hypercalcemia. The use of over-the-counter medications and dairy products should be evaluated in all patients presenting with hypercalcemia.

Short-term and Long-term Outcomes of a Disruption and Disconnection of the Pancreatic Duct in Necrotizing Pancreatitis: A Multicenter Cohort Study in 896 Patients.

INTRODUCTION: Necrotizing pancreatitis may result in a disrupted or disconnected pancreatic duct (DPD) with the potential for long-lasting negative impact on a patient's clinical outcome. There is a lack of detailed data on the full clinical spectrum of DPD, which is critical for the development of better diagnostic and treatment strategies. METHODS: We performed a long-term post hoc analysis of a prospectively collected nationwide cohort of 896 patients with necrotizing pancreatitis (2005-2015). The median follow-up after hospital admission was 75 months (P25-P75: 41-151). Clinical outcomes of patients with and without DPD were compared using regression analyses, adjusted for potential confounders. Predictive features for DPD were explored. RESULTS: DPD was confirmed in 243 (27%) of the 896 patients and resulted in worse clinical outcomes during both the patient's initial admission and follow-up. During hospital admission, DPD was associated with an increased rate of new-onset intensive care unit admission (adjusted odds ratio [aOR] 2.52; 95% confidence interval [CI] 1.62-3.93), new-onset organ failure (aOR 2.26; 95% CI 1.45-3.55), infected necrosis (aOR 4.63; 95% CI 2.87-7.64), and pancreatic interventions (aOR 7.55; 95% CI 4.23-13.96). During long-term follow-up, DPD increased the risk of pancreatic intervention (aOR 9.71; 95% CI 5.37-18.30), recurrent pancreatitis (aOR 2.08; 95% CI 1.32-3.29), chronic pancreatitis (aOR 2.73; 95% CI 1.47-5.15), and endocrine pancreatic insufficiency (aOR 1.63; 95% CI 1.05-2.53). Central or subtotal pancreatic necrosis on computed tomography (OR 9.49; 95% CI 6.31-14.29) and a high level of serum C-reactive protein in the first 48 hours after admission (per 10-point increase, OR 1.02; 95% CI 1.00-1.03) were identified as independent predictors for developing DPD. DISCUSSION: At least 1 of every 4 patients with necrotizing pancreatitis experience DPD, which is associated with detrimental, short-term and long-term interventions, and complications. Central and subtotal pancreatic necrosis and high levels of serum C-reactive protein in the first 48 hours are independent predictors for DPD.

Comparison of lumen-apposing metal stents versus double-pigtail plastic stents for infected necrotising pancreatitis.

OBJECTIVE: Lumen-apposing metal stents (LAMS) are believed to clinically improve endoscopic transluminal drainage of infected necrosis when compared with double-pigtail plastic stents. However, comparative data from prospective studies are very limited. DESIGN: Patients with infected necrotising pancreatitis, who underwent an endoscopic step-up approach with LAMS within a multicentre prospective cohort study were compared with the data of 51 patients in the randomised TENSION trial who had been assigned to the endoscopic step-up approach with double-pigtail plastic stents. The clinical study protocol was otherwise identical for both groups. Primary end point was the need for endoscopic transluminal necrosectomy. Secondary end points included mortality, major complications, hospital stay and healthcare costs. RESULTS: A total of 53 patients were treated with LAMS in 16 hospitals during 27 months. The need for endoscopic transluminal necrosectomy was 64% (n=34) and was not different from the previous trial using plastic stents (53%, n=27)), also after correction for baseline characteristics (OR 1.21 (95% CI 0.45 to 3.23)). Secondary end points did not differ between groups either, which also included bleeding requiring intervention-5 patients (9%) after LAMS placement vs 11 patients (22%) after placement of plastic stents (relative risk 0.44; 95% CI 0.16 to 1.17). Total healthcare costs were also comparable (mean difference -€6348, bias-corrected and accelerated 95% CI -€26 386 to €10 121). CONCLUSION: Our comparison of two patient groups from two multicentre prospective studies with a similar design suggests that LAMS do not reduce the need for endoscopic transluminal necrosectomy when compared with double-pigtail plastic stents in patients with infected necrotising pancreatitis. Also, the rate of bleeding complications was comparable.

Endoscopic Versus Surgical Step-Up Approach for Infected Necrotizing Pancreatitis (ExTENSION): Long-term Follow-up of a Randomized Trial.

BACKGROUND & AIMS: Previous randomized trials, including the Transluminal Endoscopic Step-Up Approach Versus Minimally Invasive Surgical Step-Up Approach in Patients With Infected Pancreatic Necrosis (TENSION) trial, demonstrated that the endoscopic step-up approach might be preferred over the surgical step-up approach in patients with infected necrotizing pancreatitis based on favorable short-term outcomes. We compared long-term clinical outcomes of both step-up approaches after a period of at least 5 years. METHODS: In this long-term follow-up study, we reevaluated all clinical data on 83 patients (of the originally 98 included patients) from the TENSION trial who were still alive after the initial 6-month follow-up. The primary end point, similar to the TENSION trial, was a composite of death and major complications. Secondary end points included individual major complications, pancreaticocutaneous fistula, reinterventions, pancreatic insufficiency, and quality of life. RESULTS: After a mean follow-up period of 7 years, the primary end point occurred in 27 patients (53%) in the endoscopy group and in 27 patients (57%) in the surgery group (risk ratio [RR], 0.93; 95% confidence interval [CI], 0.65-1.32; P = .688). Fewer pancreaticocutaneous fistulas were identified in the endoscopy group (8% vs 34%; RR, 0.23; 95% CI, 0.08-0.83). After the initial 6-month follow-up, the endoscopy group needed fewer reinterventions than the surgery group (7% vs 24%; RR, 0.29; 95% CI, 0.09-0.99). Pancreatic insufficiency and quality of life did not differ between groups. CONCLUSIONS: At long-term follow-up, the endoscopic step-up approach was not superior to the surgical step-up approach in reducing death or major complications in patients with infected necrotizing pancreatitis. However, patients assigned to the endoscopic approach developed overall fewer pancreaticocutaneous fistulas and needed fewer reinterventions after the initial 6-month follow-up. Netherlands Trial Register no: NL8571.

Immediate versus Postponed Intervention for Infected Necrotizing Pancreatitis.

BACKGROUND: Infected necrotizing pancreatitis is a potentially lethal disease that is treated with the use of a step-up approach, with catheter drainage often delayed until the infected necrosis is encapsulated. Whether outcomes could be improved by earlier catheter drainage is unknown. METHODS: We conducted a multicenter, randomized superiority trial involving patients with infected necrotizing pancreatitis, in which we compared immediate drainage within 24 hours after randomization once infected necrosis was diagnosed with drainage that was postponed until the stage of walled-off necrosis was reached. The primary end point was the score on the Comprehensive Complication Index, which incorporates all complications over the course of 6 months of follow-up. RESULTS: A total of 104 patients were randomly assigned to immediate drainage (55 patients) or postponed drainage (49 patients). The mean score on the Comprehensive Complication Index (scores range from 0 to 100, with higher scores indicating more severe complications) was 57 in the immediate-drainage group and 58 in the postponed-drainage group (mean difference, -1; 95% confidence interval [CI], -12 to 10; P = 0.90). Mortality was 13% in the immediate-drainage group and 10% in the postponed-drainage group (relative risk, 1.25; 95% CI, 0.42 to 3.68). The mean number of interventions (catheter drainage and necrosectomy) was 4.4 in the immediate-drainage group and 2.6 in the postponed-drainage group (mean difference, 1.8; 95% CI, 0.6 to 3.0). In the postponed-drainage group, 19 patients (39%) were treated conservatively with antibiotics and did not require drainage; 17 of these patients survived. The incidence of adverse events was similar in the two groups. CONCLUSIONS: This trial did not show the superiority of immediate drainage over postponed drainage with regard to complications in patients with infected necrotizing pancreatitis. Patients randomly assigned to the postponed-drainage strategy received fewer invasive interventions. (Funded by Fonds NutsOhra and Amsterdam UMC; POINTER ISRCTN Registry number, ISRCTN33682933.).

Acute pancreatitis in COVID-19 patients: true risk?

BACKGROUND: A relation between coronavirus disease 2019 (COVID-19) and acute pancreatitis has been suggested. However, the incidence and clinical relevance of this relation remain unclear. OBJECTIVE: We aimed to investigate the incidence, severity and clinical impact of acute pancreatitis in patients with COVID-19. METHODS: This is a cross-sectional study of a prospective, observational cohort concerning all COVID-19 patients admitted to two Dutch university hospitals between 4 March 2020 and 26 May 2020. Primary outcome was acute pancreatitis potentially related to COVD-19 infection. Acute pancreatitis was defined according to the revised Atlanta Classification. Potential relation with COVID-19 was defined as the absence of a clear aetiology of acute pancreatitis. RESULTS: Among 433 patients with COVID-19, five (1.2%) had potentially related acute pancreatitis according to the revised Atlanta Classification. These five patients suffered from severe COVID-19 infection; all had (multiple) organ failure and 60% died. None of the patients developed necrotizing pancreatitis. Moreover, development of acute pancreatitis did not lead to major treatment consequences. CONCLUSIONS: In contrast with previous research, our study demonstrated that COVID-19 related acute pancreatitis is rare and of little clinical impact. It is therefore debatable if acute pancreatitis in COVID-19 patients requires specific screening. We hypothesize that acute pancreatitis occurs in patients with severe illness due to COVID-19 infection as a result of transient hypoperfusion and pancreatic ischemia, not as a direct result of the virus.

Diagnosis and treatment of pancreatic duct disruption or disconnection: an international expert survey and case vignette study.

BACKGROUND: Pancreatic duct disruption or disconnection is a potentially severe complication of necrotizing pancreatitis. With no existing treatment guidelines, it is unclear whether there is any consensus among experts in clinical practice. We evaluated current expert opinion regarding the diagnosis and treatment of pancreatic duct disruption and disconnection in an international case vignette study. METHODS: An online case vignette survey was sent to 110 international expert pancreatologists. Expert selection was based on publications in the last 5 years and/or participation in development of IAP/APA and ESGE guidelines on acute pancreatitis. Consensus was defined as agreement by at least 75% of the experts. RESULTS: The response rate was 51% (n = 56). Forty-four experts (79%) obtained a MRI/MRCP and 52 experts (93%) measured amylase levels in percutaneous drain fluid to evaluate pancreatic duct integrity. The majority of experts favored endoscopic transluminal drainage for infected (peri)pancreatic necrosis and pancreatic duct disruption (84%, n = 45) or disconnection (88%, n = 43). Consensus was lacking regarding the treatment of patients with persistent percutaneous drain production, and with persistent sterile necrosis. CONCLUSION: This international survey of experts demonstrates that there are many areas for which no consensus existed, providing clear focus for future investigation.

Clinical outcome of endoscopic treatment for symptomatic sterile walled-off necrosis.

BACKGROUND: The majority of patients with symptomatic sterile walled-off necrosis (WON) can be treated conservatively. Although endoscopic transluminal drainage (ETD) is often performed in cases of persistent symptoms, post-procedural iatrogenic infection may occur. This study aimed to evaluate clinical outcomes after ETD of symptomatic sterile WON. METHODS: This was a retrospective, multicenter, open-label case series of 56 patients with necrotizing pancreatitis who underwent ETD for symptomatic sterile WON between July 2001 and August 2018 at two tertiary referral hospitals. Primary end point was clinically relevant post-procedural iatrogenic infection, defined as need for endoscopic transluminal necrosectomy. Secondary end points included mortality, total number of interventions, hospital stay, and resolution of symptoms at 1-year follow-up.  RESULTS : ETD of sterile WON was performed in 56 patients (median age 55 years, 57 % male), who presented with abdominal pain (71 %), gastric outlet obstruction (45 %), jaundice (20 %), and failure to thrive (27 %). A total of 41 patients (73 %) developed clinically relevant post-procedural iatrogenic infection, resulting in a median of 3 (interquartile range [IQR] 2 - 4) endoscopic, radiological, and/or surgical interventions. Mortality rate was 2 %. Median total hospital stay was 12 days (IQR 6 - 17). Resolution of symptoms was reported in 40 of 46 patients (87 %) for whom long-term follow-up data were available (median follow-up 13 months, IQR 6 - 29). CONCLUSIONS: ETD of symptomatic sterile WON resulted in high clinical success. Nonetheless, the majority of patients required additional reinterventions for clinically relevant post-procedural iatrogenic infection.

Acute pancreatitis.

Acute pancreatitis is an unpredictable and potentially lethal disease. The prognosis mainly depends on the development of organ failure and secondary infection of pancreatic or peripancreatic necrosis. In the past 10 years, treatment of acute pancreatitis has moved towards a multidisciplinary, tailored, and minimally invasive approach. Despite improvements in treatment and critical care, severe acute pancreatitis is still associated with high mortality rates. In this Seminar, we outline the latest evidence on diagnostic and therapeutic strategies for acute pancreatitis.

Endoscopic Management of Infected Necrotizing Pancreatitis: an Evidence-Based Approach.

PURPOSE OF REVIEW: Endoscopic management of infected necrotizing pancreatitis has evolved rapidly over the past years and there have been interesting innovations in this field. This review provides an update on the most recently published literature regarding endoscopic management of infected necrotizing pancreatitis. RECENT FINDINGS: A recent randomized trial demonstrated no difference in mortality and major morbidity between endoscopic and surgical step-up treatment of infected necrotizing pancreatitis. However, endoscopic therapy resulted in shorter hospital stay and less pancreatic fistulas. Various innovations have been investigated with the aim to further optimize endoscopic therapy, in particular lumen-apposing metal stents. While major stent-related complications were also reported, findings from recent studies indicated that their use was associated with higher resolution rates of walled-off necrosis compared to double-pigtail stents. Other innovations, such as the multiple gateway technique and dual-modality mode, can be considered for treatment of particular cases. Furthermore, research suggests that irrigation of walled-off necrosis can be performed by using a nasocystic tube and discontinuation of proton-pump inhibitors may be considered. Endoscopic treatment should be the preferred treatment modality in patients with infected necrotizing pancreatitis who are eligible for endoscopic drainage. Although data suggests that lumen-apposing metal stents are superior to double-pigtail stents, prospective multicenter studies focusing on safety as well as long-term follow-up are first needed.

Clinical experience and diagnostic algorithm of vulval Crohn's disease.

BACKGROUND AND AIM: Vulval Crohn's disease (VCD) is a rare extraintestinal cutaneous manifestation of Crohn's disease. No consensus on the diagnostic workup and therapeutic management of this condition has been provided in the current literature. PATIENTS AND METHODS: Retrospective, multicentre descriptive case series of female patients diagnosed and treated with VCD. By chart review, data on initial symptoms, clinical courses, histologic findings and therapeutic management were collected. RESULTS: Fifteen female patients with a median age of 28 years (interquartile range: 28-44 years) suffering from Crohn's disease of the ileum (27%), colon (33%) and ileocolon (40%) were included. VCD manifested most frequently with vulval swelling (93%), pain (80%) and erythema (73%). Histologic analysis demonstrated granulomatous inflammation in 78% and a mixed inflammatory cell infiltrate in 67% of cases. In eight (53%) cases, topical therapy resulted in temporary reduction of vulval symptoms. Combotreatment with immunosuppressive agents and tumour necrosis factor α inhibitors was the most effective second-line therapy: five (33%) patients achieved sustained clinical remission with this therapeutic strategy. CONCLUSION: The diagnostic workup of VCD is challenging and should be approached in a multidisciplinary manner. Histopathologic analysis of the vulva supports the diagnosis. Topical therapy and systemic treatment with immunosuppressive agents and tumour necrosis factor α inhibitors are advised to treat this condition.