Update on the management of acute pancreatitis.

PURPOSE OF REVIEW: This review provides insight into the recent advancements in the management of acute pancreatitis. RECENT FINDINGS: Moderate fluid resuscitation and Ringer's lactate has advantages above aggressive fluid resuscitation and normal saline, respectively. A normal "on-demand" diet has a positive effect on recovery from acute pancreatitis and length of hospital stay. A multimodal pain management approach including epidural analgesia might reduce unwarranted effects of opiate use. A more targeted use of antibiotics is starting to emerge. Markers such as procalcitonin may be used to limit unwarranted antibiotic use. Conversely, many patients with infected necrotizing pancreatitis can be treated with only antibiotics, although the optimal choice and duration is unclear. Delay of drainage as much as is possible is advised since it is associated with less procedures. If drainage is required, clinicians have an expanding arsenal of interventional options to their disposal such as the lumen-apposing metal stent for transgastric drainage and (repeated) necrosectomy. Immunomodulation using removal of systemic cytokines or anti-inflammatory drugs is an attractive idea, but up to now the results of clinical trials are disappointing. No additional preventive measures beside non-steroidal anti-inflammatory drugs (NSAIDs) can be recommended for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. SUMMARY: More treatment modalities that are less invasive became available and a trend towards less aggressive treatments (fluids, starvation, interventions, opiates) of acute pancreatitis is again emerging. Despite recent advancements, the pathophysiology of specific subgroup phenotypes is still poorly understood which reflects the disappointing results of pharmacological and immunomodulatory trials.

Overuse and Misuse of Antibiotics and the Clinical Consequence in Necrotizing Pancreatitis: An Observational Multicenter Study.

OBJECTIVE: The use and impact of antibiotics and the impact of causative pathogens on clinical outcomes in a large real-world cohort covering the entire clinical spectrum of necrotizing pancreatitis remain unknown. SUMMARY BACKGROUND DATA: International guidelines recommend broad-spectrum antibiotics in patients with suspected infected necrotizing pancreatitis. This recommendation is not based on high-level evidence and clinical effects are unknown. MATERIALS AND METHODS: This study is a post-hoc analysis of a nationwide prospective cohort of 401 patients with necrotizing pancreatitis in 15 Dutch centers (2010-2019). Across the patient population from the time of admission to 6 months postadmission, multivariable regression analyses were used to analyze (1) microbiological cultures and (2) antibiotic use. RESULTS: Antibiotics were started in 321/401 patients (80%) administered at a median of 5 days (P25-P75: 1-13) after admission. The median duration of antibiotics was 27 days (P25-P75: 15-48). In 221/321 patients (69%) infection was not proven by cultures at the time of initiation of antibiotics. Empirical antibiotics for infected necrosis provided insufficient coverage in 64/128 patients (50%) with a pancreatic culture. Prolonged antibiotic therapy was associated with Enterococcus infection (OR 1.08 [95% CI 1.03-1.16], P =0.01). Enterococcus infection was associated with new/persistent organ failure (OR 3.08 [95% CI 1.35-7.29], P <0.01) and mortality (OR 5.78 [95% CI 1.46-38.73], P =0.03). Yeast was found in 30/147 cultures (20%). DISCUSSION: In this nationwide study of patients with necrotizing pancreatitis, the vast majority received antibiotics, typically administered early in the disease course and without a proven infection. Empirical antibiotics were inappropriate based on pancreatic cultures in half the patients. Future clinical research and practice must consider antibiotic selective pressure due to prolonged therapy and coverage of Enterococcus and yeast. Improved guidelines on antimicrobial diagnostics and therapy could reduce inappropriate antibiotic use and improve clinical outcomes.

Whole-exome Sequencing Identifies SLC52A1 and ZNF106 Variants as Novel Genetic Risk Factors for (Early) Multiple-organ Failure in Acute Pancreatitis.

OBJECTIVE: The aim of this study was to identify genetic variants associated with early multiple organ failure (MOF) in acute pancreatitis. SUMMARY BACKGROUND DATA: MOF is a life-threatening complication of acute pancreatitis, and risk factors are largely unknown, especially in early persistent MOF. Genetic risk factors are thought to enhance severity in complex diseases such as acute pancreatitis. METHODS: A 2-phase study design was conducted. First, we exome sequenced 9 acute pancreatitis patients with early persistent MOF and 9 case-matched patients with mild edematous pancreatitis (phenotypic extremes) from our initial Dutch cohort of 387 patients. Secondly, 48 candidate variants that were overrepresented in MOF patients and 10 additional variants known from literature were genotyped in a replication cohort of 286 Dutch and German patients. RESULTS: Exome sequencing resulted in 161,696 genetic variants, of which the 38,333 non-synonymous variants were selected for downstream analyses. Of these, 153 variants were overrepresented in patients with multiple-organ failure, as compared with patients with mild acute pancreatitis. In total, 58 candidate variants were genotyped in the joined Dutch and German replication cohort. We found the rs12440118 variant of ZNF106 to be overrepresented in patients with MOF (minor allele frequency 20.4% vs 11.6%, Padj=0.026). Additionally, SLC52A1 rs346821 was found to be overrepresented (minor allele frequency 48.0% vs 42.4%, Padj= 0.003) in early MOF. None of the variants known from literature were associated.Conclusions: This study indicates that SLC52A1, a riboflavin plasma membrane transporter, and ZNF106, a zinc finger protein, may be involved in disease progression toward (early) MOF in acute pancreatitis.

Western-type diet influences mortality from necrotising pancreatitis and demonstrates a central role for butyrate.

OBJECTIVE: The gut microbiota are the main source of infections in necrotising pancreatitis. We investigated the effect of disruption of the intestinal microbiota by a Western-type diet on mortality and bacterial dissemination in necrotising pancreatitis and its reversal by butyrate supplementation. DESIGN: C57BL/6 mice were fed either standard chow or a Western-type diet for 4 weeks and were then subjected to taurocholate-induced necrotising pancreatitis. Blood and pancreas were collected for bacteriology and immune analysis. The cecum microbiota composition of mice was analysed using 16S rRNA gene amplicon sequencing and cecal content metabolites were analysed by targeted (ie, butyrate) and untargeted metabolomics. Prevention of necrotising pancreatitis in this model was compared between faecal microbiota transplantation (FMT) from healthy mice, antibiotic decontamination against Gram-negative bacteria and oral or systemic butyrate administration. Additionally, the faecal microbiota of patients with pancreatitis and healthy subjects were analysed. RESULTS: Mortality, systemic inflammation and bacterial dissemination were increased in mice fed Western diet and their gut microbiota were characterised by a loss of diversity, a bloom of Escherichia coli and an altered metabolic profile with butyrate depletion. While antibiotic decontamination decreased mortality, Gram-positive dissemination was increased. Both oral and systemic butyrate supplementation decreased mortality, bacterial dissemination, and reversed the microbiota alterations. Paradoxically, mortality and bacterial dissemination were increased with FMT administration. Finally, patients with acute pancreatitis demonstrated an increase in Proteobacteria and a decrease of butyrate producers compared with healthy subjects. CONCLUSION: Butyrate depletion and its repletion appear to play a central role in disease progression towards necrotising pancreatitis.

Early laboratory biomarkers for severity in acute pancreatitis; A systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: Acute pancreatitis is complicated by local and systemic complications in 20-30% of the patients. Accurate prediction of severity may be important for clinical decision making. Our aim is to identify and compare the accuracy of laboratory biomarkers that predict severity and complications in adult patients. METHODS: Medline, EMBASE, Web of Science and Cochrane Library (1993 to August 2020) were searched for studies with an unselected population of patients with acute pancreatitis, that contains accuracy data for ≥1 laboratory biomarker(s) and/or APACHE-II score for the prediction of a patient outcomes of interest during the first 48 h of admission. The primary outcome is moderate severe or severe acute pancreatitis (MSAP/SAP). Secondary outcomes are severe acute pancreatitis, pancreatic necrosis and organ failure. Risk of bias was assed using QUADAS-2. Biomarkers extracted from ≥3 unique sources, were analyzed using hierarchical summary receiver operating characteristic (HSROC) and bivariate model analysis. RESULTS: In total, 181 studies were included in the qualitative analysis reporting on 29 biomarkers. For the primary outcome at admission, summary sensitivities and specificities were, respectively, 87% (95% CI 69-95%) and 88% (95% CI 80-93%) for IL-6 at a threshold of >50 pg/ml, 72% (95% CI 64-79%) and 76% (95% CI 67-84%) for an APACHE-II score of ≥8, and 53% (95% CI 35-71%) and 82% (95% CI 74-88%) for CRP >150 mg/l. HSROC curve analysis confirmed these results. CONCLUSION: This study indicates superiority of IL-6 for the early prediction of MSAP/SAP and may be used for to guide clinical decision making.

Mice Fed an Obesogenic Western Diet, Administered Antibiotics, and Subjected to a Sterile Surgical Procedure Develop Lethal Septicemia with Multidrug-Resistant Pathobionts.

Despite antibiotics and sterile technique, postoperative infections remain a real and present danger to patients. Recent estimates suggest that 50% of the pathogens associated with postoperative infections have become resistant to the standard antibiotics used for prophylaxis. Risk factors identified in such cases include obesity and antibiotic exposure. To study the combined effect of obesity and antibiotic exposure on postoperative infection, mice were allowed to gain weight on an obesogenic Western-type diet (WD), administered antibiotics and then subjected to an otherwise recoverable sterile surgical injury (30% hepatectomy). The feeding of a WD alone resulted in a major imbalance of the cecal microbiota characterized by a decrease in diversity, loss of Bacteroidetes, a bloom in Proteobacteria, and the emergence of antibiotic-resistant organisms among the cecal microbiota. When WD-fed mice were administered antibiotics and subjected to 30% liver resection, lethal sepsis, characterized by multiple-organ damage, developed. Notable was the emergence and systemic dissemination of multidrug-resistant (MDR) pathobionts, including carbapenem-resistant, extended-spectrum ß-lactamase-producing Serratia marcescens, which expressed a virulent and immunosuppressive phenotype. Analysis of the distribution of exact sequence variants belonging to the genus Serratia suggested that these strains originated from the cecal mucosa. No mortality or MDR pathogens were observed in identically treated mice fed a standard chow diet. Taken together, these results suggest that consumption of a Western diet and exposure to certain antibiotics may predispose to life-threating postoperative infection associated with MDR organisms present among the gut microbiota.IMPORTANCE Obesity remains a prevalent and independent risk factor for life-threatening infection following major surgery. Here, we demonstrate that when mice are fed an obesogenic Western diet (WD), they become susceptible to lethal sepsis with multiple organ damage after exposure to antibiotics and an otherwise-recoverable surgical injury. Analysis of the gut microbiota in this model demonstrates that WD alone leads to loss of Bacteroidetes, a bloom of Proteobacteria, and evidence of antibiotic resistance development even before antibiotics are administered. After antibiotics and surgery, lethal sepsis with organ damage developed in in mice fed a WD with the appearance of multidrug-resistant pathogens in the liver, spleen, and blood. The importance of these findings lies in exposing how the selective pressures of diet, antibiotic exposure, and surgical injury can converge on the microbiome, resulting in lethal sepsis and organ damage without the introduction of an exogenous pathogen.

Panic features strongly predict the subjective but not the objective benefit of pulmonary vein isolation.

PURPOSE: Clinically observed discrepancies between electrocardiogram findings and subjective report of symptoms related to atrial fibrillation (AF) often remain unexplained. One could hypothesize that after a technically successful ablation, preoperative panic behavior might affect the report of AF-related symptoms. However, research on comorbid panic behavior in patients with AF is limited. METHODS: In this observational prospective cohort study, we investigated psychological characteristics, in particular the prevalence of panic features, among 112 patients with AF and its possible influence on experienced outcome of subsequent ablation treatment. RESULTS: Twelve percent of the AF patients (n = 12) were pre-operatively characterized by panic features. This group experienced higher levels of distress and more limitations in daily life compared to AF patients without panic features, but was not characterized by higher levels of neuroticism. However, AF-ablation resulted in a similar reduction of experienced limitations in daily functioning and levels of distress in both groups. CONCLUSION: Patients with panic features experience more distress and more limitations in daily life from AF, but these complaints are reduced by AF ablation in a similar rate as in patients without panic features. Additional psychological therapy is suggested as a method to further reduce subjective AF disease burden in these patients.