Hjalmar C. van Santvoort

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.

A Conservative and Minimally Invasive Approach to Necrotizing Pancreatitis Improves Outcome

BACKGROUND & AIMS Treatment of patients with necrotizing pancreatitis has become more conservative and less invasive, but there are few data from prospective studies to support the efficacy of this change. We performed a prospective multicenter study of treatment outcomes among patients with necrotizing pancreatitis. METHODS We collected data from 639 consecutive patients with necrotizing pancreatitis, from 2004 to 2008, treated at 21 Dutch hospitals. Data were analyzed for disease severity, interventions (radiologic, endoscopic, surgical), and outcome. RESULTS Overall mortality was 15% (n=93). Organ failure occurred in 240 patients (38%), with 35% mortality. Treatment was conservative in 397 patients (62%), with 7% mortality. An intervention was performed in 242 patients (38%), with 27% mortality; this included early emergency laparotomy in 32 patients (5%), with 78% mortality. Patients with longer times between admission and intervention had lower mortality: 0 to 14 days, 56%; 14 to 29 days, 26%; and >29 days, 15% (P<.001). A total of 208 patients (33%) received interventions for infected necrosis, with 19% mortality. Catheter drainage was most often performed as the first intervention (63% of cases), without additional necrosectomy in 35% of patients. Primary catheter drainage had fewer complications than primary necrosectomy (42% vs 64%, P=.003). Patients with pancreatic parenchymal necrosis (n=324), compared with patients with only peripancreatic necrosis (n=315), had a higher risk of organ failure (50% vs 24%, P<.001) and mortality (20% vs 9%, P<.001). CONCLUSIONS Approximately 62% of patients with necrotizing pancreatitis can be treated without an intervention and with low mortality. In patients with infected necrosis, delayed intervention and catheter drainage as first treatment improves outcome.

Interventions for Necrotizing Pancreatitis Summary of a Multidisciplinary Consensus Conference

Abstract Pancreatic and peripancreatic necrosis may result in significant morbidity and mortality in patients with acute pancreatitis. Many recommendations have been made for management of necrotizing pancreatitis, but no published guidelines have incorporated the many recent developments in minimally invasive techniques for necrosectomy. Hence, a multidisciplinary conference was convened to develop a consensus on interventions for necrotizing pancreatitis. Participants included most international experts from multiple disciplines. The evidence for efficacy of interventions was reviewed, presentations were given by experts, and a consensus was reached on each topic. In summary, intervention is primarily indicated for infected necrosis, less often for symptomatic sterile necrosis, and should ideally be delayed as long as possible, preferably 4 weeks or longer after the onset of disease, for better demarcation and liquefaction of the necrosis. Both the step-up approach using percutaneous drainage followed by minimally invasive video-assisted retroperitoneal debridement and per-oral endoscopic necrosectomy have been shown to have superior outcomes to traditional open necrosectomy with respect to short-term and long-term morbidity and are emerging as treatments of choice. Applicability of these techniques depends on the availability of specialized expertise and a multidisciplinary team dedicated to the management of severe acute pancreatitis and its complications.

Enteral nutrition and the risk of mortality and infectious complications in patients with severe acute pancreatitis: A meta-analysis of randomized trials

OBJECTIVE To compare the effect of enteral vs parenteral nutrition in patients with severe acute pancreatitis for clinically relevant outcomes. DATA SOURCES A computerized literature search was performed in the MEDLINE, EMBASE, and Cochrane databases for articles published from January 1, 1966, until December 15, 2006. STUDY SELECTION From 253 publications screened, 5 randomized controlled trials comparing enteral and parenteral nutrition in patients with predicted severe acute pancreatitis met the inclusion criteria. DATA EXTRACTION Information on study design, patient characteristics, and acute pancreatitis outcomes were independently extracted by two of us using a standardized protocol. DATA SYNTHESIS A meta-analysis of randomized controlled trials was performed using a random-effects model. Enteral feeding reduced the risk of infectious complications (relative risk, 0.47; 95% confidence interval, 0.28-0.77; P < .001), pancreatic infections (0.48; 0.26-0.91; P = .02), and mortality (0.32; 0.11-0.98; P = .03). The risk reduction for organ failure was not statistically significant (0.67; 0.30-1.52; P = .34). CONCLUSIONS Enteral nutrition results in clinically relevant and statistically significant risk reduction for infectious complications, pancreatic infections, and mortality in patients with predicted severe acute pancreatitis.

Early endoscopic retrograde cholangiopancreatography versus conservative management in acute biliary pancreatitis without cholangitis: a meta-analysis of randomized trials

Background:Early endoscopic retrograde cholangiopancreatography (ERCP) should be performed in all patients with acute biliary pancreatitis (ABP) and coexisting acute cholangitis. In patients without cholangitis and predicted mild ABP it is generally accepted that early ERCP should not be performed. Nevertheless, there is a controversy regarding the role of early ERCP in the treatment of patients with predicted severe ABP without cholangitis. We reviewed randomized trials on early ERCP versus conservative management in patients with ABP without acute cholangitis. Methods:Relevant publications in 3 electronic databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials) were systematically reviewed and meta-analyzed. Results:Seven randomized trials on ERCP in acute pancreatitis were found, of which 3 including a total of 450 patients (230 in the invasive arm and 220 in the control arm) qualified for a meta-analysis according to predefined criteria. In all patients with ABP (predicted mild and severe), early ERCP was associated with a nonsignificant reduction in overall complications [risk ratio (RR) 0.76; 95% confidence interval (CI) 0.41–1.04; P = 0.38] and a nonsignificant increase in mortality (RR 1.13; 95% CI 0.23–5.63; P = 0.88). Subgroup analysis based on predicted severity did not affect these outcomes (overall complications: predicted mild: RR 0.86; 95% CI 0.62–1.19; P = 0.36; predicted severe: RR 0.82; 95% CI 0.32–2.10; P = 0.68; mortality: predicted mild: RR 1.90; 95% CI 0.25–14.55; P = 0.53; predicted severe: RR 1.28; 95% CI 0.20–8.06; P = 0.80). Conclusion:In this meta-analysis, early ERCP in patients with predicted mild and predicted severe ABP without acute cholangitis did not lead to a significant reduction in the risk of overall complications and mortality.

Timing of Cholecystectomy After Mild Biliary Pancreatitis A Systematic Review

Objectives:To determine the risk of recurrent biliary events in the period after mild biliary pancreatitis but before interval cholecystectomy and to determine the safety of cholecystectomy during the index admission. Background:Although current guidelines recommend performing cholecystectomy early after mild biliary pancreatitis, consensus on the definition of early (ie, during index admission or within the first weeks after hospital discharge) is lacking. Methods:We performed a systematic search in PubMed, Embase, and Cochrane for studies published from January 1992 to July 2010. Included were cohort studies of patients with mild biliary pancreatitis reporting on the timing of cholecystectomy, number of readmissions for recurrent biliary events before cholecystectomy, operative complications (eg, bile duct injury, bleeding), and mortality. Study quality and risks of bias were assessed. Results:After screening 2413 studies, 8 cohort studies and 1 randomized trial describing 998 patients were included. Cholecystectomy was performed during index admission in 483 patients (48%) without any reported readmissions. Interval cholecystectomy was performed in 515 patients (52%) after 40 days (median; interquartile range: 19–58 days). Before interval cholecystectomy, 95 patients (18%) were readmitted for recurrent biliary events (0% vs 18%, P < 0.0001). These included recurrent biliary pancreatitis (n = 43, 8%), acute cholecystitis (n = 17), and biliary colics (n = 35). Patients who had an endoscopic retrograde cholangiopancreatography had fewer recurrent biliary events (10% vs 24%, P = 0.001), especially less recurrent biliary pancreatitis (1% vs 9%). There were no differences in operative complications, conversion rate (7%), and mortality (0%) between index and interval cholecystectomy. Because baseline characteristics were only reported in 26% of patients, study populations could not be compared. Conclusions:Interval cholecystectomy after mild biliary pancreatitis is associated with a high risk of readmission for recurrent biliary events, especially recurrent biliary pancreatitis. Cholecystectomy during index admission for mild biliary pancreatitis appears safe, but selection bias could not be excluded.

Intestinal barrier dysfunction in a randomized trial of a specific probiotic composition in acute pancreatitis

Objectives:To determine the relation between intestinal barrier dysfunction, bacterial translocation, and clinical outcome in patients with predicted severe acute pancreatitis and the influence of probiotics on these processes. Summary of Background data:Randomized, placebo-controlled, multicenter trial on probiotic prophylaxis (Ecologic 641) in patients with predicted severe acute pancreatitis (PROPATRIA). Methods:Excretion of intestinal fatty acid binding protein (IFABP, a parameter for enterocyte damage), recovery of polyethylene glycols (PEGs, a parameter for intestinal permeability), and excretion of nitric oxide (NOx, a parameter for bacterial translocation) were assessed in urine of 141 patients collected 24 to 48 h after start of probiotic or placebo treatment and 7 days thereafter. Results:IFABP concentrations in the first 72 hours were higher in patients who developed bacteremia (P = 0.03), infected necrosis (P = 0.01), and organ failure (P = 0.008). PEG recovery was higher in patients who developed bacteremia (PEG 4000, P = 0.001), organ failure (PEG 4000, P < 0.0001), or died (PEG 4000, P = 0.009). Probiotic prophylaxis was associated with an increase in IFABP (median 362 vs. 199 pg/mL; P = 0.02), most evidently in patients with organ failure (P = 0.001), and did not influence intestinal permeability. Overall, probiotics decreased NOx (P = 0.05) but, in patients with organ failure, increased NOx (P = 0.001). Conclusions:Bacteremia, infected necrosis, organ failure, and mortality were all associated with intestinal barrier dysfunction early in the course of acute pancreatitis. Overall, prophylaxis with this specific combination of probiotic strains reduced bacterial translocation, but was associated with increased bacterial translocation and enterocyte damage in patients with organ failure.

Blood urea nitrogen in the early assessment of acute pancreatitis: an international validation study.

BACKGROUND Objective assessment of acute pancreatitis (AP) is critical to help guide resuscitation efforts. Herein we (1) validate serial blood urea nitrogen (BUN) measurement for early prediction of mortality and (2) develop an objective BUN-based approach to early assessment in AP. METHODS We performed a secondary analysis of 3 prospective AP cohort studies: Brigham and Womens Hospital (BWH), June 2005 through May 2009; the Dutch Pancreatitis Study Group (DPSG), March 2004 through March 2007; and the University of Pittsburgh Medical Center (UPMC), June 2003 through September 2007. Meta-analysis and stratified multivariate logistic regression adjusted for age, sex, and creatinine levels were calculated to determine risk of mortality associated with elevated BUN level at admission and rise in BUN level at 24 hours. The accuracy of the BUN measurements was determined by area under the receiver operating characteristic curve (AUC) analysis compared with serum creatinine measurement and APACHE II score. A BUN-based assessment algorithm was derived on BWH data and validated on the DPSG and UPMC cohorts. RESULTS A total of 1043 AP cases were included in analysis. In pooled analysis, a BUN level of 20 mg/dL or higher was associated with an odds ratio (OR) of 4.6 (95% confidence interval [CI], 2.5-8.3) for mortality. Any rise in BUN level at 24 hours was associated with an OR of 4.3 (95% CI, 2.3-7.9) for death. Accuracy of serial BUN measurement (AUC, 0.82-0.91) was comparable to that of the APACHE II score (AUC, 0.72-0.92) in each of the cohorts. A BUN-based assessment algorithm identified patients at increased risk for mortality during the initial 24 hours of hospitalization. CONCLUSIONS We have confirmed the accuracy of BUN measurement for early prediction of mortality in AP and developed an algorithm that may assist physicians in their early resuscitation efforts.

Early endoscopic retrograde cholangiopancreatography in predicted severe acute biliary pancreatitis: A prospective multicenter study

Summary Background Data:The role of early endoscopic retrograde cholangiopancreatography (ERCP) in acute biliary pancreatitis (ABP) remains controversial. Previous studies have included only a relatively small number of patients with predicted severe ABP. We investigated the clinical effects of early ERCP in these patients. Methods:We performed a prospective, observational multicenter study in 8 university medical centers and 7 major teaching hospitals. One hundred fifty-three patients with predicted severe ABP without cholangitis enrolled in a randomized multicenter trial on probiotic prophylaxis in acute pancreatitis were prospectively followed. Conservative treatment or ERCP within 72 hours after symptom onset (at discretion of the treating physician) were compared for complications and mortality. Patients without and with cholestasis (bilirubin: >2.3 mg/dL [40 &mgr;mol/L] and/or dilated common bile duct) were analyzed separately. Results:Of the 153 patients, 81 (53%) underwent ERCP and 72 (47%) conservative treatment. Groups were highly comparable at baseline. Seventy-eight patients (51%) had cholestasis. In patients with cholestasis, ERCP (52/78 patients: 67%), as compared with conservative treatment, was associated with fewer complications (25% vs. 54%, P = 0.020, multivariate adjusted odds ratio [OR]: 0.35, 95% confidence interval [CI]: 0.13–0.99, P= 0.049). This included fewer patients with >30% pancreatic necrosis (8% vs. 31%, P = 0.010). Mortality was nonsignificantly lower after ERCP (6% vs. 15%, P = 0.213, multivariate adjusted OR: 0.44, 95% CI: 0.08–2.28, P = 0.330). In patients without cholestasis, ERCP (29/75 patients: 39%) was not associated with reduced complications (45% vs. 41%, P = 0.814, multivariate adjusted OR: 1.36; 95% CI: 0.49–3.76; P = 0.554) or mortality (14% vs. 17%, P = 0.754, multivariate adjusted OR: 0.78; 95% CI: 0.19–3.12, P = 0.734). Conclusions:Early ERCP is associated with fewer complications in predicted severe ABP if cholestasis is present.

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.