Robin Timmer

A Step-up Approach or Open Necrosectomy for Necrotizing Pancreatitis

BACKGROUND Necrotizing pancreatitis with infected necrotic tissue is associated with a high rate of complications and death. Standard treatment is open necrosectomy. The outcome may be improved by a minimally invasive step-up approach. METHODS In this multicenter study, we randomly assigned 88 patients with necrotizing pancreatitis and suspected or confirmed infected necrotic tissue to undergo primary open necrosectomy or a step-up approach to treatment. The step-up approach consisted of percutaneous drainage followed, if necessary, by minimally invasive retroperitoneal necrosectomy. The primary end point was a composite of major complications (new-onset multiple-organ failure or multiple systemic complications, perforation of a visceral organ or enterocutaneous fistula, or bleeding) or death. RESULTS The primary end point occurred in 31 of 45 patients (69%) assigned to open necrosectomy and in 17 of 43 patients (40%) assigned to the step-up approach (risk ratio with the step-up approach, 0.57; 95% confidence interval, 0.38 to 0.87; P=0.006). Of the patients assigned to the step-up approach, 35% were treated with percutaneous drainage only. New-onset multiple-organ failure occurred less often in patients assigned to the step-up approach than in those assigned to open necrosectomy (12% vs. 40%, P=0.002). The rate of death did not differ significantly between groups (19% vs. 16%, P=0.70). Patients assigned to the step-up approach had a lower rate of incisional hernias (7% vs. 24%, P=0.03) and new-onset diabetes (16% vs. 38%, P=0.02). CONCLUSIONS A minimally invasive step-up approach, as compared with open necrosectomy, reduced the rate of the composite end point of major complications or death among patients with necrotizing pancreatitis and infected necrotic tissue. (Current Controlled Trials number, ISRCTN13975868.)

Endoscopic Transgastric vs Surgical Necrosectomy for Infected Necrotizing Pancreatitis: A Randomized Trial

CONTEXT Most patients with infected necrotizing pancreatitis require necrosectomy. Surgical necrosectomy induces a proinflammatory response and is associated with a high complication rate. Endoscopic transgastric necrosectomy, a form of natural orifice transluminal endoscopic surgery, may reduce the proinflammatory response and reduce complications. OBJECTIVE To compare the proinflammatory response and clinical outcome of endoscopic transgastric and surgical necrosectomy. DESIGN, SETTING, AND PATIENTS Randomized controlled assessor-blinded clinical trial in 3 academic hospitals and 1 regional teaching hospital in The Netherlands between August 20, 2008, and March 3, 2010. Patients had signs of infected necrotizing pancreatitis and an indication for intervention. INTERVENTIONS Random allocation to endoscopic transgastric or surgical necrosectomy. Endoscopic necrosectomy consisted of transgastric puncture, balloon dilatation, retroperitoneal drainage, and necrosectomy. Surgical necrosectomy consisted of video-assisted retroperitoneal debridement or, if not feasible, laparotomy. MAIN OUTCOME MEASURES The primary end point was the postprocedural proinflammatory response as measured by serum interleukin 6 (IL-6) levels. Secondary clinical end points included a predefined composite end point of major complications (new-onset multiple organ failure, intra-abdominal bleeding, enterocutaneous fistula, or pancreatic fistula) or death. RESULTS We randomized 22 patients, 2 of whom did not undergo necrosectomy following percutaneous catheter drainage and could not be analyzed for the primary end point. Endoscopic transgastric necrosectomy reduced the postprocedural IL-6 levels compared with surgical necrosectomy (P = .004). The composite clinical end point occurred less often after endoscopic necrosectomy (20% vs 80%; risk difference [RD], 0.60; 95% CI, 0.16-0.80; P = .03). Endoscopic necrosectomy did not cause new-onset multiple organ failure (0% vs 50%, RD, 0.50; 95% CI, 0.12-0.76; P = .03) and reduced the number of pancreatic fistulas (10% vs 70%; RD, 0.60; 95% CI, 0.17-0.81; P = .02). CONCLUSION In patients with infected necrotizing pancreatitis, endoscopic necrosectomy reduced the proinflammatory response as well as the composite clinical end point compared with surgical necrosectomy. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN07091918.

Early closure of a multicenter randomized clinical trial of endoscopic stenting versus surgery for stage IV left-sided colorectal cancer

BACKGROUND AND STUDY AIMS The introduction of self-expandable metal stents has offered a promising alternative for palliation of malignant left-sided colonic obstruction. This randomized clinical trial aimed to assess whether a nonsurgical policy, with endoluminal stenting, is superior to surgical treatment in patients with stage IV left-sided colorectal cancer and imminent obstruction. PATIENTS AND METHODS Patients with incurable left-sided colorectal cancer who fulfilled the study criteria were randomly assigned to nonsurgical or surgical treatment. The primary outcome measure was survival in good health out of hospital (World Health Organization performance scores 0 or 1). RESULTS A high number of serious adverse events in the nonsurgical arm led to premature closure of the trial. Ten patients were allocated to surgical treatment and 11 patients to nonsurgical palliation. The median survival in good health out of hospital during the first year was 56 days (interquartile range 7.5 - 338.5 days) in the surgical arm vs. 38 days (interquartile range 5.25 - 288.75 days) in the nonsurgical arm (P = 0.68). Eleven adverse events (six perforations) occurred in the nonsurgical arm vs. one adverse event in the surgical arm (P < 0.001). Of the six perforations, two were stent-related because they occurred at the proximal edge of the stent by erosion through a normal colon wall; one was probably stent-related (it was located in the region of the proximal half of the stent); one was a colon blowout; and two were late tumor perforations in patients on chemotherapy. CONCLUSIONS The unexpected high rate of perforation in the nonsurgical arm might be specifically WallFlex-related or enteral stent-related in patients on chemotherapy and warrants attention.

Esophageal pH-Impedance Monitoring in Patients With Therapy-Resistant Reflux Symptoms: 'On' or 'Off' Proton Pump Inhibitor?

BACKGROUND:In patients with proton pump inhibitor (PPI)-resistant symptoms, ambulatory 24-h pH-impedance monitoring can be used to assess whether a relationship exists between symptoms and reflux episodes. Until now, it is unclear whether combined pH-impedance monitoring in these patients should be performed on or off PPI.METHODS:Thirty patients with symptoms of heartburn, chest pain, and/or regurgitation despite PPI twice daily underwent ambulatory 24-h pH-impedance monitoring twice, once on PPI and once after cessation of the PPI for 7 days. The order of the measurements was randomized. Reflux episodes were identified and classified as acid, weakly acidic, or weakly alkaline reflux. In addition, the symptom association probability (SAP) was calculated for each measurement.RESULTS:The total number of reflux episodes and proximal extent were not affected by PPI therapy. On PPI, there were fewer acid reflux episodes (49 ± 34 off PPI vs 20 ± 25 on PPI) while more weakly acidic reflux episodes were identified (24 ± 17 off PPI vs 48 ± 31 on PPI). Symptom association analysis identified 15 and 11 patients with a positive SAP in the measurement off and on PPI, respectively, the difference in yield of the SAP not being statistically significant. Eight of the 19 patients who had no symptoms or a negative SAP during measurement on PPI had a positive SAP off PPI therapy. In contrast, only 4 patients with a positive SAP on PPI were missed in the measurement off PPI therapy.CONCLUSIONS:In order to demonstrate or exclude GERD in patients with PPI-resistant symptoms, ambulatory 24-h pH-impedance monitoring should preferably be performed after cessation of PPI therapy because this approach seems to offer the best chance to assess a relationship between symptoms and reflux episodes.

Fully covered self-expandable metal stents (SEMS), partially covered SEMS and self-expandable plastic stents for the treatment of benign esophageal ruptures and anastomotic leaks

BackgroundBenign esophageal ruptures and anastomotic leaks are life-threatening conditions that are often treated surgically. Recently, placement of partially and fully covered metal or plastic stents has emerged as a minimally invasive treatment option. We aimed to determine the clinical effectiveness of covered stent placement for the treatment of esophageal ruptures and anastomotic leaks with special emphasis on different stent designs.MethodsConsecutive patients who underwent placement of a fully covered self-expandable metal stent (FSEMS), a partially covered SEMS (PSEMS) or a self-expanding plastic stent (SEPS) for a benign esophageal rupture or anastomotic leak after upper gastrointestinal surgery in the period 2007-2010 were included. Data on patient demographics, type of lesion, stent placement and removal, clinical success and complications were collectedResultsA total of 52 patients received 83 esophageal stents (61 PSEMS, 15 FSEMS, 7 SEPS) for an anastomotic leak (n = 32), iatrogenic rupture (n = 13), Boerhaaves syndrome (n = 4) or other cause (n = 3). Endoscopic stent removal was successful in all but eight patients treated with a PSEMS due to tissue ingrowth. Clinical success was achieved in 34 (76%, intention-to-treat: 65%) patients (PSEMS: 73%, FSEMS: 83%, SEPS: 83%) after a median of 1 (range 1-5) stent and a median stenting time of 39 (range 7-120) days. In total, 33 complications in 24 (46%) patients occurred (tissue in- or overgrowth (n = 8), stent migration (n = 10), ruptured stent cover (all Ultraflex; n = 6), food obstruction (n = 3), severe pain (n = 2), esophageal rupture (n = 2), hemorrhage (n = 2)). One (2%) patient died of a stent-related cause.ConclusionsCovered stents placed for a period of 5-6 weeks may well be an alternative to surgery for treating benign esophageal ruptures or anastomotic leaks. As efficacy between PSEMS, FSEMS and SEPS is not different, stent choice should depend on expected risks of stent migration (SEPS and FSEMS) and tissue in- or overgrowth (PSEMS).

Reproducibility of multichannel intraluminal electrical impedance monitoring of gastroesophageal reflux

OBJECTIVE:Esophageal impedance measurement is a novel method for gastroesophageal reflux monitoring. Reproducibility is an important aspect of every biomedical test. The aim of this study was therefore to asses the reproducibility of gastroesophageal reflux monitoring using impedance measurements.METHODS:Impedance and pH signals were recorded in 20 healthy volunteers during 90-min postprandial periods on two separate days. Hourly rates of gas, liquid, and mixed gas-liquid reflux episodes were measured in each recording period as well as percentage of time with pH < 4 and rate of acid reflux episodes. As a quantitative description of inter- and intraindividual variation for each variable, the mean percentage of covariation (100 × SD/mean: %COV) was calculated. As a second measure for reproducibility, Kendalls coefficients of concordance (W values) were calculated.RESULTS:For all variables, interindividual %COV was at least 50% higher than intraindividual %COV. Statistically significant concordances were found for gas reflux (W = 0.81, p = 0.04) and mixed reflux (W = 0.85, p = 0.03) while concordance for liquid reflux tended to be significant (W = 0.75, p = 0.08). This was comparable to the reproducibility of the number of acid reflux episodes and percentage of time with pH < 4 (W = 0.78, p = 0.05 and W = 0.88, p = 0.02, respectively).CONCLUSIONS:Postprandial gastroesophageal reflux data assessed with impedance monitoring are as reproducible as assessed with pH monitoring.

Same-admission versus interval cholecystectomy for mild gallstone pancreatitis (PONCHO): a multicentre randomised controlled trial

BACKGROUND In patients with mild gallstone pancreatitis, cholecystectomy during the same hospital admission might reduce the risk of recurrent gallstone-related complications, compared with the more commonly used strategy of interval cholecystectomy. However, evidence to support same-admission cholecystectomy is poor, and concerns exist about an increased risk of cholecystectomy-related complications with this approach. In this study, we aimed to compare same-admission and interval cholecystectomy, with the hypothesis that same-admission cholecystectomy would reduce the risk of recurrent gallstone-related complications without increasing the difficulty of surgery. METHODS For this multicentre, parallel-group, assessor-masked, randomised controlled superiority trial, inpatients recovering from mild gallstone pancreatitis at 23 hospitals in the Netherlands (with hospital discharge foreseen within 48 h) were assessed for eligibility. Adult patients (aged ≥18 years) were eligible for randomisation if they had a serum C-reactive protein concentration less than 100 mg/L, no need for opioid analgesics, and could tolerate a normal oral diet. Patients with American Society of Anesthesiologists (ASA) class III physical status who were older than 75 years of age, all ASA class IV patients, those with chronic pancreatitis, and those with ongoing alcohol misuse were excluded. A central study coordinator randomly assigned eligible patients (1:1) by computer-based randomisation, with varying block sizes of two and four patients, to cholecystectomy within 3 days of randomisation (same-admission cholecystectomy) or to discharge and cholecystectomy 25-30 days after randomisation (interval cholecystectomy). Randomisation was stratified by centre and by whether or not endoscopic sphincterotomy had been done. Neither investigators nor participants were masked to group assignment. The primary endpoint was a composite of readmission for recurrent gallstone-related complications (pancreatitis, cholangitis, cholecystitis, choledocholithiasis needing endoscopic intervention, or gallstone colic) or mortality within 6 months after randomisation, analysed by intention to treat. The trial was designed to reduce the incidence of the primary endpoint from 8% in the interval group to 1% in the same-admission group. Safety endpoints included bile duct leakage and other complications necessitating re-intervention. This trial is registered with Current Controlled Trials, number ISRCTN72764151, and is complete. FINDINGS Between Dec 22, 2010, and Aug 19, 2013, 266 inpatients from 23 hospitals in the Netherlands were randomly assigned to interval cholecystectomy (n=137) or same-admission cholecystectomy (n=129). One patient from each group was excluded from the final analyses, because of an incorrect diagnosis of pancreatitis in one patient (in the interval group) and discontinued follow-up in the other (in the same-admission group). The primary endpoint occurred in 23 (17%) of 136 patients in the interval group and in six (5%) of 128 patients in the same-admission group (risk ratio 0·28, 95% CI 0·12-0·66; p=0·002). Safety endpoints occurred in four patients: one case of bile duct leakage and one case of postoperative bleeding in each group. All of these were serious adverse events and were judged to be treatment related, but none led to death. INTERPRETATION Compared with interval cholecystectomy, same-admission cholecystectomy reduced the rate of recurrent gallstone-related complications in patients with mild gallstone pancreatitis, with a very low risk of cholecystectomy-related complications. FUNDING Dutch Digestive Disease Foundation.

Early Laparoscopic Cholecystectomy Improves Outcomes After Endoscopic Sphincterotomy for Choledochocystolithiasis

BACKGROUND & AIMS Patients with choledochocystolithiasis generally undergo endoscopic sphincterotomy (ES) followed by laparoscopic cholecystectomy (LC). However, many patients receive this surgery 6-8 weeks after ES. There is a high conversion rate of elective LC after ES, and patients can develop recurrent biliary events during the waiting period. We investigated whether the timing of surgery influences outcome. METHODS We performed a randomized trial of patients with choledochocystolithiasis who underwent successful ES. Patients were randomly assigned to groups that received early LC (within 72 hours after ES, n = 49) or delayed LC (after 6-8 weeks, n = 47), based on an expected difference in conversion rate of 25% vs 5%, respectively. Conversion rate, biliary events during follow-up, duration and difficulty of surgeries, postoperative morbidity, and hospital stay were scored. Intention-to-treat analyses were performed. RESULTS Groups were comparable in age, sex, and comorbidity. There was no difference between groups in conversion rate (4.3% in early vs 8.7% in delayed group) nor were there differences in operating times and/or difficulties or hospital stays. During the waiting period for LC, 17 patients in the delayed group (36.2%) developed recurrent biliary events compared with 1 patient in the early group (P < .001). CONCLUSIONS In a randomized trial to evaluate timing of LC after ES, recurrent biliary events occurred in 36.2% of patients whose LC was delayed for 6-8 weeks. Early LC (within 72 hours) appears to be safe and might prevent the majority of biliary events in this period following sphincterotomy.

EUS-Guided Endoscopic Transgastric Necrosectomy in Patients with Infected Necrosis in Acute Pancreatitis

Background: Infected pancreatic and peripancreatic necrosis in acute pancreatitis is potentially lethal, with mortality rates up to 35%. Therefore, there is growing interest in minimally invasive treatment options, such as (EUS-guided) endoscopic transgastric necrosectomy. Methods: Retrospective cohort study on EUS-guided endoscopic transgastric necrosectomy in patients with infected necrosis in acute pancreatitis. Results: 8 patients (age 38–75, mean 50 years) with documented infected peripancreatic or pancreatic necrosis were included. Median time to first intervention was 33 days (range 17–62) after onset of symptoms. At the time of first intervention 2 patients had organ failure. All patients were managed on the patient ward. Initial endoscopic drainage was successful in all patients, a median of 4 (range 2–6) subsequent endoscopic necrosectomies were needed to remove all necrotic tissue. Two patients needed additional surgical intervention because of pneumoperitoneum (n = 1) and insufficient endoscopic drainage (n = 1). Six patients recovered, with 1 mild relapse during follow-up (median 12, range 8–60 months). One patient died. Conclusion: EUS-guided endoscopic transgastric necrosectomy of infected necrosis in acute pancreatitis appears to be a feasible and relatively safe treatment option in patients who are not critically ill. Further randomized comparison with the current ‘gold standard’ is warranted to determine the place of this treatment modality.

Air Swallowing, Belching, and Reflux in Patients with Gastroesophageal Reflux Disease

OBJECTIVES:Belching and gastroesophageal reflux share a common physiological mechanism. The aim of this study was to investigate whether air swallowing leads to both belching and reflux.METHODS:Esophageal impedance, pH, and pressure were measured during two 20-min recording periods in 12 controls and 12 patients with gastroesophageal reflux disease (GERD), before and after intragastric inflation of 600 mL of air. This was repeated after a meal. Subsequently, ambulatory 24-h impedance-pH measurement was performed.RESULTS:During the 24-h study, patients showed a higher incidence of air swallows (287 ± 45 vs 176 ± 24, p < 0.05), belches (52.4 ± 6.6 vs 32.7, p < 0.01), and acid reflux (42.3 ± 7.6 vs 19.1 ± 2.8, p < 0.01) than controls. After air infusion the incidence of gas reflux episodes was increased, both in patients (0.58 ± 0.36 vs 3.50 ± 0.61, p < 0.01) and in controls (0.75 ± 0.67 vs 4.08 ± 0.59, p < 0.01). In contrast, the incidence of acid and weakly acidic reflux episodes was not increased after air infusion, neither in patients (acid: 1.25 ± 0.37 vs 1.20 ± 0.33, weakly acidic: 1.08 ± 0.40 vs 0.80 ± 0.23) nor in controls (acid: 0.72 ± 0.34 vs 0.50 ± 0.23, weakly acidic: 0.80 ± 0.35 vs 0.33 ± 0.19). Air infusion increased transient lower esophageal sphincter relaxations (TLESR) frequency in patients and controls, but this was entirely because of an increase in gas reflux-associated TLESRs.CONCLUSIONS:Patients with GERD swallow air more frequently and belch more frequently than healthy subjects. However, air swallowing is not the cause of their increase in reflux.