Patient selection for urgent endoscopic retrograde cholangio-pancreatography by endoscopic ultrasound in predicted severe acute biliary pancreatitis (APEC-2): a multicentre prospective study.

OBJECTIVE: Routine urgent endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic biliary sphincterotomy (ES) does not improve outcome in patients with predicted severe acute biliary pancreatitis. Improved patient selection for ERCP by means of endoscopic ultrasonography (EUS) for stone/sludge detection may challenge these findings. DESIGN: A multicentre, prospective cohort study included patients with predicted severe acute biliary pancreatitis without cholangitis. Patients underwent urgent EUS, followed by ERCP with ES in case of common bile duct stones/sludge, within 24 hours after hospital presentation and within 72 hours after symptom onset. The primary endpoint was a composite of major complications or mortality within 6 months after inclusion. The historical control group was the conservative treatment arm (n=113) of the randomised APEC trial (Acute biliary Pancreatitis: urgent ERCP with sphincterotomy versus conservative treatment, patient inclusion 2013-2017) applying the same study design. RESULTS: Overall, 83 patients underwent urgent EUS at a median of 21 hours (IQR 17-23) after hospital presentation and at a median of 29 hours (IQR 23-41) after start of symptoms. Gallstones/sludge in the bile ducts were detected by EUS in 48/83 patients (58%), all of whom underwent immediate ERCP with ES. The primary endpoint occurred in 34/83 patients (41%) in the urgent EUS-guided ERCP group. This was not different from the 44% rate (50/113 patients) in the historical conservative treatment group (risk ratio (RR) 0.93, 95% CI 0.67 to 1.29; p=0.65). Sensitivity analysis to correct for baseline differences using a logistic regression model also showed no significant beneficial effect of the intervention on the primary outcome (adjusted OR 1.03, 95% CI 0.56 to 1.90, p=0.92). CONCLUSION: In patients with predicted severe acute biliary pancreatitis without cholangitis, urgent EUS-guided ERCP with ES did not reduce the composite endpoint of major complications or mortality, as compared with conservative treatment in a historical control group. TRIAL REGISTRATION NUMBER: ISRCTN15545919.

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.).

Aggressive fluid hydration plus non-steroidal anti-inflammatory drugs versus non-steroidal anti-inflammatory drugs alone for post-endoscopic retrograde cholangiopancreatography pancreatitis (FLUYT): a multicentre, open-label, randomised, controlled trial.

BACKGROUND: Pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). Prophylactic rectal administration of non-steroidal anti-inflammatory drugs (NSAIDs) is considered as standard of care to reduce the risk of post-ERCP pancreatitis. It has been suggested that aggressive hydration might further reduce this risk. Guidelines already recommend aggressive hydration in patients who are unable to receive rectal NSAIDs, although it is laborious and time consuming. We aimed to evaluate the added value of aggressive hydration in patients receiving prophylactic rectal NSAIDs. METHODS: FLUYT, a multicentre, open-label, randomised, controlled trial done across 22 Dutch hospitals, included patients aged between 18 and 85 years with moderate to high risk of post-ERCP pancreatitis. Patients were randomly assigned (1:1) by a web-based module with varying block sizes to a combination of aggressive hydration and rectal NSAIDs (100 mg diclofenac or indomethacin; aggressive hydration group) or rectal NSAIDs (100 mg diclofenac or indomethacin) alone (control group). Randomisation was stratified according to treatment centre. Aggressive hydration comprised 20 mL/kg intravenous Ringer's lactate solution within 60 min from the start of ERCP, followed by 3 mL/kg per h for 8 h. The control group received normal intravenous saline with a maximum of 1·5 mL/kg per h and 3 L per 24 h. The primary endpoint was post-ERCP pancreatitis and was analysed on a modified intention-to-treat basis (including all patients who underwent randomisation and an ERCP and for whom data regarding the primary outcome were available). The trial is registered with the ISRCTN registry, ISRCTN13659155. FINDINGS: Between June 5, 2015, and June 6, 2019, 826 patients were randomly assigned, of whom 388 in the aggressive hydration group and 425 in the control group were included in the modified intention-to-treat analysis. Post-ERCP pancreatitis occurred in 30 (8%) patients in the aggressive hydration group and in 39 (9%) patients in the control group (relative risk 0·84, 95% CI 0·53-1·33, p=0·53). There were no differences in serious adverse events, including hydration-related complications (relative risk 0·99, 95% CI 0·59-1·64; p=1·00), ERCP-related complications (0·90, 0·62-1·31; p=0·62), intensive care unit admission (0·37, 0·07-1·80; p=0·22), and 30-day mortality (0·95, 0·50-1·83; p=1·00). INTERPRETATION: Aggressive periprocedural hydration did not reduce the incidence of post-ERCP pancreatitis in patients with moderate to high risk of developing this complication who routinely received prophylactic rectal NSAIDs. Therefore, the burden of laborious and time-consuming aggressive periprocedural hydration to further reduce the risk of post-ERCP pancreatitis is not justified. FUNDING: Netherlands Organisation for Health Research and Development and Radboud University Medical Center.

Urgent endoscopic retrograde cholangiopancreatography with sphincterotomy versus conservative treatment in predicted severe acute gallstone pancreatitis (APEC): a multicentre randomised controlled trial.

BACKGROUND: It remains unclear whether urgent endoscopic retrograde cholangiopancreatography (ERCP) with biliary sphincterotomy improves the outcome of patients with gallstone pancreatitis without concomitant cholangitis. We did a randomised trial to compare urgent ERCP with sphincterotomy versus conservative treatment in patients with predicted severe acute gallstone pancreatitis. METHODS: In this multicentre, parallel-group, assessor-masked, randomised controlled superiority trial, patients with predicted severe (Acute Physiology and Chronic Health Evaluation II score ≥8, Imrie score ≥3, or C-reactive protein concentration >150 mg/L) gallstone pancreatitis without cholangitis were assessed for eligibility in 26 hospitals in the Netherlands. Patients were randomly assigned (1:1) by a web-based randomisation module with randomly varying block sizes to urgent ERCP with sphincterotomy (within 24 h after hospital presentation) or conservative treatment. The primary endpoint was a composite of mortality or major complications (new-onset persistent organ failure, cholangitis, bacteraemia, pneumonia, pancreatic necrosis, or pancreatic insufficiency) within 6 months of randomisation. Analysis was by intention to treat. This trial is registered with the ISRCTN registry, ISRCTN97372133. FINDINGS: Between Feb 28, 2013, and March 1, 2017, 232 patients were randomly assigned to urgent ERCP with sphincterotomy (n=118) or conservative treatment (n=114). One patient from each group was excluded from the final analysis because of cholangitis (urgent ERCP group) and chronic pancreatitis (conservative treatment group) at admission. The primary endpoint occurred in 45 (38%) of 117 patients in the urgent ERCP group and in 50 (44%) of 113 patients in the conservative treatment group (risk ratio [RR] 0·87, 95% CI 0·64-1·18; p=0·37). No relevant differences in the individual components of the primary endpoint were recorded between groups, apart from the occurrence of cholangitis (two [2%] of 117 in the urgent ERCP group vs 11 [10%] of 113 in the conservative treatment group; RR 0·18, 95% CI 0·04-0·78; p=0·010). Adverse events were reported in 87 (74%) of 118 patients in the urgent ERCP group versus 91 (80%) of 114 patients in the conservative treatment group. INTERPRETATION: In patients with predicted severe gallstone pancreatitis but without cholangitis, urgent ERCP with sphincterotomy did not reduce the composite endpoint of major complications or mortality, compared with conservative treatment. Our findings support a conservative strategy in patients with predicted severe acute gallstone pancreatitis with an ERCP indicated only in patients with cholangitis or persistent cholestasis. FUNDING: The Netherlands Organization for Health Research and Development, Fonds NutsOhra, and the Dutch Patient Organization for Pancreatic Diseases.

Postponed or immediate drainage of infected necrotizing pancreatitis (POINTER trial): study protocol for a randomized controlled trial.

BACKGROUND: Infected necrosis complicates 10% of all acute pancreatitis episodes and is associated with 15-20% mortality. The current standard treatment for infected necrotizing pancreatitis is the step-up approach (catheter drainage, followed, if necessary, by minimally invasive necrosectomy). Catheter drainage is preferably postponed until the stage of walled-off necrosis, which usually takes 4 weeks. This delay stems from the time when open necrosectomy was the standard. It is unclear whether such delay is needed for catheter drainage or whether earlier intervention could actually be beneficial in the current step-up approach. The POINTER trial investigates if immediate catheter drainage in patients with infected necrotizing pancreatitis is superior to the current practice of postponed intervention. METHODS: POINTER is a randomized controlled multicenter superiority trial. All patients with necrotizing pancreatitis are screened for eligibility. In total, 104 adult patients with (suspected) infected necrotizing pancreatitis will be randomized to immediate (within 24 h) catheter drainage or current standard care involving postponed catheter drainage. Necrosectomy, if necessary, is preferably postponed until the stage of walled-off necrosis, in both treatment arms. The primary outcome is the Comprehensive Complication Index (CCI), which covers all complications between randomization and 6-month follow up. Secondary outcomes include mortality, complications, number of (repeat) interventions, hospital and intensive care unit (ICU) lengths of stay, quality-adjusted life years (QALYs) and direct and indirect costs. Standard follow-up is at 3 and 6 months after randomization. DISCUSSION: The POINTER trial investigates if immediate catheter drainage in infected necrotizing pancreatitis reduces the composite endpoint of complications, as compared with the current standard treatment strategy involving delay of intervention until the stage of walled-off necrosis. TRIAL REGISTRATION: ISRCTN, 33682933 . Registered on 6 August 2015. Retrospectively registered.

Serum concentrations after switching from originator infliximab to the biosimilar CT-P13 in patients with quiescent inflammatory bowel disease (SECURE): an open-label, multicentre, phase 4 non-inferiority trial.

BACKGROUND: Biological treatment of chronic inflammatory diseases has improved patient outcomes but increased health-care costs. Switching patients from originator infliximab to a biosimilar can reduce costs, but prospective data about pharmacokinetics and potential immunogenicity are scarce. We aimed to show that infliximab serum concentrations with biosimilar CT-P13 are non-inferior to those with originator infliximab after switching from originator infliximab in patients with inflammatory bowel disease. METHODS: SECURE was a prospective, open-label, interventional, non-inferiority, multicentre, phase 4 trial at 13 academic and non-academic sites in Belgium and the Netherlands. Eligible participants were aged 18 years or older, had ulcerative colitis or Crohn's disease, were in clinical remission, and were on continuous treatment with originator infliximab for more than 30 weeks. Patients were switched from originator infliximab to CT-P13 at a dose and infusion duration identical to those of originator infliximab (ie, ∼5 mg/kg every 7-9 weeks). Patients were followed up for 16 weeks after switching, with serum concentrations of infliximab measured at baseline (before the first dose of CT-P13), 8 weeks, and 16 weeks. The primary endpoint was serum concentrations of infliximab 16 weeks after switching, assessed separately in patients with ulcerative colitis and those with Crohn's disease in the per-protocol population, which included all patients with available serum concentrations and without major protocol violations. A non-inferiority margin of 15% was set (the null hypothesis was that the geometric mean of the ratio of serum infliximab concentrations at 16 weeks to those at baseline was 85% or less). Safety analyses were done in the safety population, which included participants who received at least one dose of CT-P13 and attended at least one safety assessment after that dose. This trial is registered at www.ClinicalTrialsRegister.eu, number 2014-004904-31, and is completed. FINDINGS: Between June 5, 2015, and April 6, 2016, 120 consecutive patients with inflammatory bowel disease were recruited: 59 with ulcerative colitis and 61 with Crohn's disease. 46 patients with ulcerative colitis and 42 patients with Crohn's disease comprised the per-protocol population. The geometric mean ratio of serum infliximab concentrations at week 16 (CT-P13) compared with those at baseline (originator) was 110·1% (90% CI 96·0-126·3) in patients with ulcerative colitis and 107·6% (97·4-118·8) in those with Crohn's disease. In both cases, the lower bound of the 90% CI was higher than the prespecified non-inferiority margin of 85%. Six serious adverse events were reported in six patients. Only one of these adverse events, a perianal abscess, was judged to be related to study treatment. INTERPRETATION: Switching to CT-P13 is safe and well tolerated in patients with inflammatory bowel disease in remission. Future trials should assess switching to CT-P13 in patients with active disease. FUNDING: Mundipharma.

Fluid hydration to prevent post-ERCP pancreatitis in average- to high-risk patients receiving prophylactic rectal NSAIDs (FLUYT trial): study protocol for a randomized controlled trial.

BACKGROUND: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is the most common complication of ERCP and may run a severe course. Evidence suggests that vigorous periprocedural hydration can prevent PEP, but studies to date have significant methodological drawbacks. Importantly, evidence for its added value in patients already receiving prophylactic rectal non-steroidal anti-inflammatory drugs (NSAIDs) is lacking and the cost-effectiveness of the approach has not been investigated. We hypothesize that combination therapy of rectal NSAIDs and periprocedural hydration would significantly lower the incidence of post-ERCP pancreatitis compared to rectal NSAIDs alone in moderate- to high-risk patients undergoing ERCP. METHODS: The FLUYT trial is a multicenter, parallel group, open label, superiority randomized controlled trial. A total of 826 moderate- to high-risk patients undergoing ERCP that receive prophylactic rectal NSAIDs will be randomized to a control group (no fluids or normal saline with a maximum of 1.5 mL/kg/h and 3 L/24 h) or intervention group (lactated Ringer's solution with 20 mL/kg over 60 min at start of ERCP, followed by 3 mL/kg/h for 8 h thereafter). The primary endpoint is the incidence of post-ERCP pancreatitis. Secondary endpoints include PEP severity, hydration-related complications, and cost-effectiveness. DISCUSSION: The FLUYT trial design, including hydration schedule, fluid type, and sample size, maximize its power of identifying a potential difference in post-ERCP pancreatitis incidence in patients receiving prophylactic rectal NSAIDs. TRIAL REGISTRATION: EudraCT: 2015-000829-37 . Registered on 18 February 2015. ISRCTN: 13659155 . Registered on 18 May 2015.

Early biliary decompression versus conservative treatment in acute biliary pancreatitis (APEC trial): study protocol for a randomized controlled trial.

BACKGROUND: Acute pancreatitis is mostly caused by gallstones or sludge. Early decompression of the biliary tree by endoscopic retrograde cholangiography (ERC) with sphincterotomy may improve outcome in these patients. Whereas current guidelines recommend early ERC in patients with concomitant cholangitis, early ERC is not recommended in patients with mild biliary pancreatitis. Evidence on the role of routine early ERC with endoscopic sphincterotomy in patients without cholangitis but with biliary pancreatitis at high risk for complications is lacking. We hypothesize that early ERC with sphincterotomy improves outcome in these patients. METHODS/DESIGN: The APEC trial is a randomized controlled, parallel group, superiority multicenter trial. Within 24 hours after presentation to the emergency department, patients with biliary pancreatitis without cholangitis and at high risk for complications, based on an Acute Physiology and Chronic Health Evaluation (APACHE-II) score of 8 or greater, Modified Glasgow score of 3 or greater, or serum C-reactive protein above 150 mg/L, will be randomized. In 27 hospitals of the Dutch Pancreatitis Study Group, 232 patients will be allocated to early ERC with sphincterotomy or to conservative treatment. The primary endpoint is a composite of major complications (that is, organ failure, pancreatic necrosis, pneumonia, bacteremia, cholangitis, pancreatic endocrine, or exocrine insufficiency) or death within 180 days after randomization. Secondary endpoints include ERC-related complications, infected necrotizing pancreatitis, length of hospital stay and an economical evaluation. DISCUSSION: The APEC trial investigates whether an early ERC with sphincterotomy reduces the composite endpoint of major complications or death compared with conservative treatment in patients with biliary pancreatitis at high risk of complications. TRIAL REGISTRATION: Current Controlled Trials ISRCTN97372133 (date registration: 17-12-2012).

Development of the Nurses' Observation Scale for Cognitive Abilities (NOSCA).

Background. To assess a patient's cognitive functioning is an important issue because nurses tailor their nursing interventions to the patient's cognitive abilities. Although some observation scales exist concerning one or more cognitive domains, so far, no scale has been available which assesses cognitive functioning in a comprehensive way. Objectives. To develop an observation scale with an accepted level of content validity and which assesses elderly patients' cognitive functioning in a comprehensive way. Methods. Delphi technique, a multidisciplinary panel developed the scale by consensus through four Delphi rounds (>70% agreement). The International Classification of Functioning/ICF was used as theoretical framework. Results. After the first two Delphi rounds, the panel reached consensus about 8 cognitive domains and 17 sub domains. After two other rounds, 39 items were selected, divided over 8 domains and 17 sub domains. Discussion. The Nurses' Observation Scale Cognitive Abilities (NOSCA) was successfully designed. The content validity of the scale is high because the scale sufficiently represents the concept of cognitive functioning: the experts reached a consensus of 70% or higher on all domains and items included; and no domains or items were lacking. As a next step, the psychometric qualities of the NOSCA will have to be tested.

Daily observation of cognitive functioning in hospitalised patients on acute geriatric wards.

BACKGROUND: Daily observation by nurses of the cognitive function of patients is of high ecological validity because cognitive functioning is observed in a natural setting around the clock. AIM: To evaluate why and how geriatric nurses observe the cognitive functioning of their patients. DESIGN: Survey. METHODS: A self-developed questionnaire was administered to a purposeful sample of nurses working on geriatric wards of seven acute care hospitals. The questions were open-ended. Data were analysed through content analysis. RESULTS: The questionnaire was completed by 97 nurses (response rate 77%). Categorisation of the many objectives reported by the nurses revealed four themes: to tailor nursing interventions (51%), to determine discharge arrangements (46%), to support medical diagnosis and therapy (43%) and to map specific elements of functional capacity (34%). Nurses reported also many different domains to observe (mode 2; range 0-7), only 73% of which were actual cognitive domains. The most commonly mentioned cognitive domain was psychomotor behaviour (63%), followed by executive functions (48%), language (37%), attention (33%), thinking (25%) and consciousness (20%). CONCLUSIONS: Geriatric nurses not only made daily observations of their patients' cognitive functioning to support medical diagnoses, but also to guide nursing interventions and determine discharge arrangements. The assessment domains varied fairly widely, because the participants' understanding of the concept cognitive functioning was vague, incomplete and often incorrect. RELEVANCE TO CLINICAL PRACTICE: This is the first study that investigated why geriatric nurses make daily observations of their patients' cognitive functioning. In addition, we explored their understanding of the concept of cognitive functioning. Based on the fact that the content of an assessment is determined by its aim, the objectives to perform daily observations have to be clear and stated explicitly. To observe patients in an unambiguous way, it will be necessarily to develop a validated observation scale.

A solitary Peutz-Jeghers type polyp in the jejunum of a 19 year-old male.

A 19-year old male presented with melena and anemia. A duodenoscopy revealed no abnormalities, but a small bowel X-ray series demonstrated a large jejunal polyp. This 4 cm large polyp was visualised during peroperative small bowel endoscopy and was subsequently surgically removed. The polyp had the characteristic histologic appearance of a Peutz-Jeghers type polyp, but the patient had no other signs of Peutz-Jeghers syndrome, such as the characteristic mucocutaneous pigmentation, the presence of multiple polyps or a positive family history. After removal of the polyp, melena did not recur and his hemoglobin concentration normalized. Altogether, the patient does not fulfill the diagnostic criteria for Peutz-Jeghers syndrome and appears to have a solitary jejunal Peutz-Jeghers type polyp. All previously reported patients with such polyps were older than this patient.

Inflammatory bowel disease and liver transplantation for primary sclerosing cholangitis.

OBJECTIVES: To compare the outcome of liver transplantation in primary sclerosing cholangitis (PSC) patients with and without inflammatory bowel disease (IBD), and to analyse the influence of the transplantation on the course of IBD. METHODS: Retrospective analysis of the data regarding PSC, IBD, and liver transplantation in all patients transplanted for PSC. SETTING: Single university transplantation centre. RESULTS: Thirty-one patients were transplanted for PSC, of whom 18 had IBD before liver transplantation. There were no differences in complication rate and outcome between patients with and patients without IBD. Before liver transplantation, the IBD course was active in three patients and quiescent in 14 patients (one patient was not evaluable). After liver transplantation, the course was active in five (one de-novo IBD) patients and quiescent in 13 patients. Exacerbations of IBD occurred in ten patients during treatment with steroids and a calcineurin blocker. Five patients with long-standing and extensive colitis developed colorectal neoplasia after liver transplantation (two colorectal cancer, two extensive dysplasia, one leiomyosarcoma). CONCLUSIONS: Concomitant IBD had no detrimental influence on the outcome of liver transplantation in patients with PSC. The course of IBD was not altered after liver transplantation. Immunosuppression including steroids did not prevent exacerbations of IBD. The development of colorectal neoplasia is a serious threat to patients with IBD and PSC after liver transplantation.

In situ light dosimetry during photodynamic therapy of Barrett's esophagus with 5-aminolevulinic acid.

BACKGROUND AND OBJECTIVES: Previous studies with PhotoDynamic Therapy (PDT) in bladder and bronchi have shown that due to scattering and reflection, the actually delivered fluence rate on the surface in a hollow organ can be significantly higher than expected. In this pilot study, we investigated the differences between the primary calculated and the actual measured fluence rate during PDT of Barrett's Esophagus (BE) using 23 independent clinical measurements in 15 patients. STUDY DESIGN/MATERIALS AND METHODS: A KTP-dye module laser at 630 nm was used as light source. Light delivery was performed using a cylindrical light diffuser inserted in the center of an inflatable transparent balloon with a length corresponding to the length of the Barrett's epithelium. The total light output power of the cylindrical diffuser was calibrated using an integrating sphere to deliver a primary fluence rate of 100 mW cm(-2). Two fiber-optic pseudo sphere isotropic detectors were placed on the balloon and were used to measure fluence rate at the surface of the esophageal wall during PDT. RESULTS AND CONCLUSIONS: The actual fluence rate measured was 1.5-3.9 times higher than the primary fluence rate for 630 nm. In general, the fluence rate amplification factor decreased with increasing redness of the tissue and was less for shorter diffusers. Fluence rate variations in time were observed which coincided with patients coughing, movement, and esophageal spasms. These factors combined with inter patient variability of the fluence rate measured appears to justify the routine application of this technique in PDT of BE.