Epidemiology, treatment and outcomes of infected pancreatic necrosis in France: a bicenter study.

INTRODUCTION: Acute necrotizing pancreatitis (ANP) mortality increases when pancreatic necrosis is infected (IPN). Current treatment of IPN relies on prolonged antibiotic therapies associated with a step-up strategy of drainage. The objective of this study was to analyze IPN treatment outcomes in two referral centers in France. METHODS: Data of consecutive patients with documented IPN hospitalized in two expert centers in France between 2014 and 2019 were retrospectively reviewed. The composite primary outcome was the proportion of unsuccessful management outcome, defined as new emergency drainage to treat sepsis with organ failure, an unplanned new antibiotic course, an unplanned prolongation of antibiotic course and/or death by septic shock, within three months following the diagnosis of ANP. RESULTS: All in all, 187 patients (138 males; 74.0%), with documented IPN were included. The most frequently identified microorganism was Escherichia coli (26.2%). Ninety-eight patients (52.4%) were admitted to an intensive care unit or resuscitation ward within the first two days of ANP care. Overall, 126 patients (67.4%) endured an unsuccessful outcome: new emergency drainage to treat acute sepsis (62.0%), unplanned new antibiotic course (47.1%), unplanned prolongation of antibiotic course (44.9%) and/or death by septic shock complicating IPN (8.0%). CONCLUSION: The unfavorable evolution in two thirds of patients shows that determination of optimal drainage timing and choice of antibiotic therapy remain major challenges in 2024.

Early systemic anticoagulation reduces hospital readmission in acute necrotizing pancreatitis patients: A retrospective cohort study.

BACKGROUND: Early systemic anticoagulation (SAC) is a common practice in acute necrotizing pancreatitis (ANP), and its impact on in-hospital clinical outcomes had been assessed. However, whether it affects long-term outcomes is unknown. This study aimed to evaluate the effect of SAC on 90-day readmission and other long-term outcomes in ANP patients. METHODS: During January 2013 and December 2018, ANP patients admitted within 7 days from the onset of abdominal pain were screened. The primary outcome was 90-day readmission after discharge. Cox proportional-hazards regression model and mediation analysis were used to define the relationship between early SAC and 90-day readmission. RESULTS: A total of 241 ANP patients were enrolled, of whom 143 received early SAC during their hospitalization and 98 did not. Patients who received early SAC experienced a lower incidence of splanchnic venous thrombosis (SVT) [risk ratio (RR) = 0.40, 95% CI: 0.26-0.60, P < 0.01] and lower 90-day readmission with an RR of 0.61 (95% CI: 0.41-0.91, P = 0.02) than those who did not. For the quality of life, patients who received early SAC had a significantly higher score in the subscale of vitality (P = 0.03) while the other subscales were all comparable between the two groups. Multivariable Cox regression model showed that early SAC was an independent protective factor for 90-day readmission after adjusting for potential confounders with a hazard ratio of 0.57 (95% CI: 0.34-0.96, P = 0.04). Mediation analysis showed that SVT mediated 37.0% of the early SAC-90-day readmission causality. CONCLUSIONS: The application of early SAC may reduce the risk of 90-day readmission in the survivors of ANP patients, and reduced SVT incidence might be the primary contributor.

Bile acid metabolomics identifies chenodeoxycholic acid as a therapeutic agent for pancreatic necrosis.

Bile acids are altered and associated with prognosis in patients with acute pancreatitis (AP). Here, we conduct targeted metabolomic analyses to detect bile acids changes in patients during the acute (n = 326) and the recovery (n = 133) phases of AP, as well as in healthy controls (n = 60). Chenodeoxycholic acid (CDCA) decreases in the acute phase, increases in the recovery phase, and is associated with pancreatic necrosis. CDCA and its derivative obeticholic acid exhibit a protective effect against acinar cell injury in vitro and pancreatic necrosis in murine models, and RNA sequencing reveals that the oxidative phosphorylation pathway is mainly involved. Moreover, we find that overexpression of farnesoid X receptor (FXR, CDCA receptor) inhibits pancreatic necrosis, and interfering expression of FXR exhibits an opposite phenotype in mice. Our results possibly suggest that targeting CDCA is a potential strategy for the treatment of acinar cell necrosis in AP, but further verification is needed.

[Infected pancreatic necrosis: Treatment with antibiotics alone. Would this be the first step of the step-up approach?] / Necrosis pancreática infectada: tratamiento solo con antibióticos. ¿Sería el primer paso del step-up approach?

INTRODUCTION: In 1994, Claudio Bassi reported a case of medical treatment for infected pancreatic necrosis (IPN); then since 1996 numerous articles of case series were published with treatment only with antibiotics with good outcomes. OBJECTIVES: To present our experience in the management of patients with IPN with antibiotics (without drainage). METHODS: We retrospectively reviewed cases with a diagnosis of IPN from January 2018 to October 2020, focusing on those cases that were treated conservatively (hydro-electrolyte, nutritional support and antibiotics). The diagnosis was made by observing gas in the retroperitoneum by CT or by clinical deterioration of the patient with pancreatic necrosis without another focus. Fine needle aspiration was not performed. RESULTS: We identified 25 patients with a diagnosis of IPN; eleven were treated conservatively. According to Atlanta, modified in 2012, 3 were classified severely and the rest moderately severe. All received antibiotics for at least 3 weeks. None required parenteral nutrition. The mean hospital stay was 38 days. Three patients were readmitted. 8 underwent cholecystectomy after having resolved the condition; the rest were already cholecystectomized. There were no deaths in this series. CONCLUSIONS: IPN can be treated conservatively without drainage with good results in selected cases.

Introducción: En 1994, Claudio Bassi relató un caso de tratamiento médico de la necrosis pancreática infectada (NPI); luego desde 1996 se publicaron numerosos artículos de serie de casos con tratamiento solo con antibióticos con buenos resultados. OBJETIVOS: Presentar nuestra experiencia en el manejo de la necrosis pancreática infectada con antibióticos (sin drenaje). Métodos: Revisamos retrospectivamente los pacientes con diagnóstico de NPI desde enero de 2018 a octubre del 2020, enfocándonos en aquellos casos que se trataron de forma conservadora (soporte hidroelectrolítico, nutricional y antibióticos). El diagnóstico se realizó observando gas en el retroperitoneo por TC asociado o no a deterioro clínico del paciente con necrosis pancreática sin otro foco. No se realizó punción aspiración con aguja fina (PAAF). RESULTADOS: Identificamos 25 pacientes con diagnóstico de NPI. Once fueron tratados de forma conservadora. Según la clasificación de Atlanta, modificada en 2012, 3 casos fueron clasificados de forma grave y el resto moderadamente grave. Todos recibieron antibióticos al menos durante 3 semanas. Ninguno requirió nutrición parenteral. El promedio de estancia hospitalaria fue de 38 días. Tres pacientes fueron readmitidos. A 8 se les realizó colecistectomía luego de haber resuelto el cuadro; los restantes ya estaban colecistectomizados. No hubo muertes en esta serie. CONCLUSIONES: La NPI puede ser tratada de forma conservadora sin drenaje con buenos resultados en casos seleccionados.

Clinical characteristics and risk factors for tigecycline-induced pancreatitis in a tertiary hospital: A retrospective study.

AIMS: To analyse the clinical characteristics and risk factors for tigecycline-induced pancreatitis (TIP) and evaluate the safety and efficiency of tigecycline use in non-TIP. METHODS: A retrospective case-control study was conducted on adult and juvenile patients administered tigecycline for >3 days. The adults were classified as TIP, non-TIP (pancreatitis with other causes) and non-pancreatitis. Univariate analyses were performed to compare TIP and non-pancreatitis, and multivariate analysis was used to identify risk factors for TIP. The clinical characteristics of TIP, and the safety and efficiency of tigecycline use in non-TIP were evaluated. RESULTS: A total of 3910 patients (3823 adults and 87 juveniles) were enrolled. The adult patients comprised 21 TIP, 82 non-TIP and 3720 non-pancreatitis. The TIP prevalence was 0.56% in adults and 1.15% in juveniles. The mean time from tigecycline use to symptom onset was 7.2 days, and all cases were mild pancreatitis. The mean time from tigecycline withdrawal to symptom relief was 3.6 days. The multivariate analysis identified comorbid renal insufficiency as an independent risk factor for TIP (odds ratio = 3.032). Among the 82 non-TIP patients, 81.7% had severe pancreatitis and 47.6% had necrotizing pancreatitis. The modified computed tomography severity score after tigecycline use was similar to that before tigecycline use, but the pancreatic enzymes and infection indices were significantly decreased. CONCLUSIONS: The prevalence of TIP was low. Comorbid renal insufficiency was as an independent risk factor for TIP. Tigecycline is safe and efficient for treatment of pancreatitis, especially necrotizing pancreatitis, with intra-abdominal infection.

Colonic mucin-2 attenuates acute necrotizing pancreatitis in rats by modulating intestinal homeostasis.

Mucin-2 (MUC2) secreted by goblet cells participates in the intestinal barrier, but its mechanism in acute necrotizing pancreatitis (ANP) remains unclear. In acute pancreatitis (AP) patients, the functions of goblet cells (MUC2, FCGBP, CLCA1, and TFF3) decreased, and MUC2 was negatively correlated with AP severity. ANP rats treated with pilocarpine (PILO) (PILO+ANP rats) to deplete MUC2 showed more serious pancreatic and colonic injuries, goblet cell dysfunction, gut dysbiosis, and bacterial translocation than those of ANP rats. GC-MS analysis of feces showed that PILO+ANP rats had lower levels of butyric acid, isobutyric acid, isovaleric acid, and hexanoic acid than those of ANP rats. The expression of MUC2 was associated with colonic injury and gut dysbiosis. All these phenomena could be relieved, and goblet cell functions were also partially reversed by MUC2 supplementation in ANP rats. TNF-α-treated colonoids had exacerbated goblet cell dysfunction. MUC2 expression was negatively correlated with the levels of pro-inflammatory cytokines (IL-1ß and IL-6) (p < .05) and positively related to the expression of tight junction proteins (Claudin 1, Occludin, and ZO1) (p < .05). Downregulating MUC2 by siRNA increased the levels of the pro-inflammatory cytokines in colonoids. MUC2 might maintain intestinal homeostasis to alleviate ANP.

Vitamin E protects against the modulation of TNF-α-AMPK axis and inhibits pancreas injury in a rat model of L-arginine-induced acute necrotising pancreatitis.

BACKGROUND: Acute pancreatitis (AP) associated with the modulation of TNF-α-AMPK axis in the presence and absence of vitamin E has not been investigated before. MATERIAL AND METHODS: Rats were either injected with L-arginine (2.5 gm/kg) before being sacrificed after 48 h or were pre-treated with vitamin E (60 mg/kg) and continued receiving vitamin E until the end of the experiment. RESULTS: AP was developed as demonstrated by infiltration of inflammatory cells and profound pancreas tissue damage, which were substantially protected by vitamin E. In addition, L-arginine injections significantly (p < .0001) increased the expression of TNF-α mRNA and protein, and decreased phospho-AMPK and IL-10 mRNA and protein that was significantly (p < .0001) protected by vitamin E. Furthermore, vitamin E inhibited L-arginine-induced blood levels of LDH, amylase, and myeloperoxidase. CONCLUSIONS: L-arginine-induced acute pancreatitis modulates TNF-α-AMPK axis, IL-10 and other AP biomarkers, which is protected by vitamin E; thus, may offer therapeutic potential in humans.

Fentanyl but Not Morphine or Buprenorphine Improves the Severity of Necrotizing Acute Pancreatitis in Rats.

Opioids are widely used for the pain management of acute pancreatitis (AP), but their impact on disease progression is unclear. Therefore, our aim was to study the effects of clinically relevant opioids on the severity of experimental AP. Various doses of fentanyl, morphine, or buprenorphine were administered as pre- and/or post-treatments in rats. Necrotizing AP was induced by the intraperitoneal injection of L-ornithine-HCl or intra-ductal injection of Na-taurocholate, while intraperitoneal caerulein administration caused edematous AP. Disease severity was determined by laboratory and histological measurements. Mu opioid receptor (MOR) expression and function was assessed in control and AP animals. MOR was expressed in both the pancreas and brain. The pancreatic expression and function of MOR were reduced in AP. Fentanyl post-treatment reduced necrotizing AP severity, whereas pre-treatment exacerbated it. Fentanyl did not affect the outcome of edematous AP. Morphine decreased vacuolization in edematous AP, while buprenorphine pre-treatment increased pancreatic edema during AP. The overall effects of morphine on disease severity were negligible. In conclusion, the type, dosing, administration route, and timing of opioid treatment can influence the effects of opioids on AP severity. Fentanyl post-treatment proved to be beneficial in AP. Clinical studies are needed to determine which opioids are best in AP.

Assessment of Prophylactic Carbapenem Antibiotics Administration for Severe Acute Pancreatitis: An Updated Systematic Review and Meta-Analysis.

BACKGROUND: The effectiveness of prophylactic antibiotics in severe acute pancreatitis (SAP) remains a debatable issue. This meta-analysis aimed to determine the efficacy of prophylactic carbapenem antibiotics in SAP. METHODS: This meta-analysis of prophylactic carbapenem antibiotics for SAP was conducted in PubMed, EMBASE, Web of Science, MEDLINE, and Cochrane Library up to February 2021. The related bibliographies were manually searched. The primary outcomes involved infected pancreatic or peripancreatic necrosis, mortality, complications, infections, and organ failure. RESULTS: Seven articles comprised 5 randomized controlled trials and 2 retrospective observational studies, including 3,864 SAP participants. Prophylactic carbapenem antibiotics in SAP were associated with a statistically significant reduction in the incidence of infections (odds ratio [OR]: 0.27; p = 0.03) and complications (OR: 0.48; p = 0.009). Nevertheless, no statistically significant difference was demonstrated in the incidence of infected pancreatic or peripancreatic necrosis (OR: 0.74; p = 0.24), mortality (OR: 0.69; p = 0.17), extrapancreatic infection (OR: 0.64, p = 0.54), pulmonary infection (OR: 1.23; p = 0.69), blood infection (OR: 0.60; p = 0.35), urinary tract infection (OR: 0.97; p = 0.97), pancreatic pseudocyst (OR: 0.59; p = 0.28), fluid collection (OR: 0.91; p = 0.76), organ failure (OR: 0.63; p = 0.19), acute respiratory distress syndrome (OR: 0.80; p = 0.61), surgical intervention (OR: 0.97; p = 0.93), dialysis (OR: 2.34; p = 0.57), use of respirator or ventilator (OR: 1.90; p = 0.40), intensive care unit treatment (OR: 2.97; p = 0.18), and additional antibiotics (OR: 0.59; p = 0.28) between the experimental and control groups. CONCLUSIONS: It is not recommended to administer routine prophylactic carbapenem antibiotics in SAP.

Assessing the Efficacy and Outcomes Following Irrigation with Streptokinase Versus Hydrogen Peroxide in Necrotizing Pancreatitis: A Randomized Pilot Study.

BACKGROUND: Percutaneous catheter drainage (PCD's) are prone to blockage because of necrosum. To improve the efficacy of PCD, necrolytic agents have been used. The present study compared the use of Streptokinase with H2O2 in saline irrigation. MATERIALS AND METHODS: This is a single-center randomized pilot study (from July 2018 to Dec 2019). Patients with infected pancreatic necrosis not showing response to PCD and saline irrigation were included in the study. Patients received either Streptokinase (Streptokinase group 50,000 IU in 100 ml normal saline) or 3% H2O2 (3% H2O2 in 100 ml normal saline in 1:10 dilution). Primary endpoints were the need for surgery and mortality while secondary endpoints were hospital stay and complications attributable to necrolytic agents. RESULTS: There were 30 patients in the study, 15 in each arm. Organ failure was seen in 23 (76.6%), single organ failure was present in 11 (47%), and multi-organ failure in 12 (53%). Bleeding complications (20% in H2O2 vs 6.6% in Streptokinase), need for surgery (73% in H2O2 vs 33.3% in Streptokinase) and mortality (60% in H2O2 vs 33% in Streptokinase) were higher in H2O2 group but the difference was not significant statistically. Post-irrigation hospital stay was lesser in the Streptokinase group compared to H2O2 group but the difference did not reach statistical significance (14.1 ± 7.7 vs 19.2 ± 11.7, p = 0.09) CONCLUSIONS: Streptokinase irrigation led to a trend for reduced need for necrosectomy and mortality. H2O2 group had more bleeding complications. Post-irrigation hospital stay was lesser in Streptokinase group.

Kynurenic Acid and Its Analogue SZR-72 Ameliorate the Severity of Experimental Acute Necrotizing Pancreatitis.

The pathophysiology of acute pancreatitis (AP) is not well understood, and the disease does not have specific therapy. Tryptophan metabolite L-kynurenic acid (KYNA) and its synthetic analogue SZR-72 are antagonists of the N-methyl-D-aspartate receptor (NMDAR) and have immune modulatory roles in several inflammatory diseases. Our aims were to investigate the effects of KYNA and SZR-72 on experimental AP and to reveal their possible mode of action. AP was induced by intraperitoneal (i.p.) injection of L-ornithine-HCl (LO) in SPRD rats. Animals were pretreated with 75-300 mg/kg KYNA or SZR-72. Control animals were injected with physiological saline instead of LO, KYNA and/or SZR-72. Laboratory and histological parameters, as well as pancreatic and systemic circulation were measured to evaluate AP severity. Pancreatic heat shock protein-72 and IL-1ß were measured by western blot and ELISA, respectively. Pancreatic expression of NMDAR1 was investigated by RT-PCR and immunohistochemistry. Viability of isolated pancreatic acinar cells in response to LO, KYNA, SZR-72 and/or NMDA administration was assessed by propidium-iodide assay. The effects of LO and/or SZR-72 on neutrophil granulocyte function was also studied. Almost all investigated laboratory and histological parameters of AP were significantly reduced by administration of 300 mg/kg KYNA or SZR-72, whereas the 150 mg/kg or 75 mg/kg doses were less or not effective, respectively. The decreased pancreatic microcirculation was also improved in the AP groups treated with 300 mg/kg KYNA or SZR-72. Interestingly, pancreatic heat shock protein-72 expression was significantly increased by administration of SZR-72, KYNA and/or LO. mRNA and protein expression of NMDAR1 was detected in pancreatic tissue. LO treatment caused acinar cell toxicity which was reversed by 250 µM KYNA or SZR-72. Treatment of acini with NMDA (25, 250, 2000 µM) did not influence the effects of KYNA or SZR-72. Moreover, SZR-72 reduced LO-induced H2O2 production of neutrophil granulocytes. KYNA and SZR-72 have dose-dependent protective effects on LO-induced AP or acinar toxicity which seem to be independent of pancreatic NMDA receptors. Furthermore, SZR-72 treatment suppressed AP-induced activation of neutrophil granulocytes. This study suggests that administration of KYNA and its derivative could be beneficial in AP.