Antioxidant therapy in the management of acute, chronic and post-ERCP pancreatitis： A systematic review

We systematically reviewed the clinical trials which recruited antioxidants in the therapy of pancreatitis and evaluated whether antioxidants improve the outcome of patients with pancreatitis. Electronic bibliographic databases were searched for any studies which investigated the use of antioxidants in the management of acute pancreatitis （AP） or chronic pancreatitis （CP） and in the prevention of post-endoscopic retrograde cholangio-pancreatography （post-ERCP） pancreatitis （PEP） up to February 2009. Twenty-two randomized, placebo-controlled, clinical trials met our criteria and were included in the review. Except for a cocktail of antioxidants which showed improvement in outcomes in three different clinical trials, the results of the administration of other antioxidants in both AP and CP clinical trials were incongruent and heterogeneous.Furthermore, antioxidant therapy including allopurinol and N-acetylcysteine failed to prevent the onset of PEP in almost all trials. In conclusion, the present data do not support a benefit of antioxidant therapy alone or in combination with conventional therapy in the management of AP, CP or PER Further double blind, randomized, placebo-controlled clinical trials with large sample size need to be conducted.     

急性胰腺炎促炎细胞因子和抗炎细胞因子的动态变化及其作用

目的：探讨促炎细胞因子和抗炎细胞因子在急性胰腺炎（AP）发病机制中的作用,方法：应用ELISA法检测48例病人血液中促炎细胞因子（TNF（α、IL-1β、IL-6、IL-8）和抗炎细胞因子（IL－10、IL－1ra)。结果：AP病人血液中促炎细胞因子和抗炎细胞因子在早期持续显著升高（与正常对照组相比P＜0．05）,其后逐渐下降,并与临床症状变化的时相一致。结论：促炎细胞因子和抗炎细胞因子在急性胰腺炎的发生发展过程中可能均具有重要作用。     

Influence of Hydrocortisone, Prednisolone, and NO Association on the Evolution of Acute Pancreatitis

Leukocyte activation, inflammatory up-regulation, and microcirculatory disruption associated with ischemia-reperfusion injury are hallmarks in the pathogenesis of acute pancreatitis (AP). NO donors ensure microvascular integrity, while glucocorticoids act as anti-inflammatory and immune modulator drugs. AP was induced by the biliopancreatic duct outlet exclusion-closed duodenal loops (BPDOE-CDLs) model. Treatment with hydrocortisone (6 mg/kg) or prednisolone (0.5 mg/kg) alone or together with DETA-NO (0.5 mg/kg) was done (a)1 hr pre or (b)1 hr post, or (c) 1 hr pre and 4 hr post ,or (d) 4 hr post triggering AP. NOS inhibition by l-NAME (15 mg/kg) and glucocorticoid receptor blockage by mifepristone (3 mg/kg) was considered. AP severity was assessed by biochemical and histopathological analyses. Treatment with glucocorticoids together with DETA-NO 1 hr pre and 4 hr post BPDOE-CDLs reduced serum amylase, lipase, C-reactive protein, IL-6, IL-10, hsp72, and 8-isoprostane as well as pancreatic and lung myeloperoxidase. Acinar and fat necrosis, hemorrhage, and neutrophil infiltrate were also decreased. Hydrocortisone together with DETA-NO rendered the best results. We conclude that AP severity was significantly diminished by glucocorticoids associated with DETA-NO, with the optimal dose and time point of administration being crucial to provide adequate protection against AP.This work was supported by a research grant to Dr. Laura Iris Cosen-Binker from GlaxoSmithKline S.A.     

Preventing post-endoscopic retrograde cholangiopancreatography pancreatitis: What can be done?

Post-endoscopic retrograde cholangiopancreatographypancreatitis(PEP) is the most common complication of endoscopic retrograde cholangiopancreatography. The incidence of post-endoscopic retrograde cholangiopancreatography(ERCP) pancreatitis varies substantially and is reported around 1%-10%, although there are some reports with an incidence of around 30%. Usually, PEP is a mild or moderate pancreatitis, but in some instances it can be severe and fatal. Generally, it is defined as the onset of new pancreatictype abdominal pain severe enough to require hospital admission or prolonged hospital stay with levels of serum amylase two to three times greater than normal, occurring 24 h after ERCP. Several methods have been adopted for preventing pancreatitis, such as pharmacological or endoscopic approaches. Regarding medical prevention, only non-steroidal anti-inflammatory drugs, namely diclofenac sodium and indomethacin, are recommended, but there are some other drugs which have some potential benefits in reducing the incidence of post-ERCP pancreatitis. Endoscopic preventive measures include cannulation(wire guided) and pancreatic stenting, while the adoption of the early pre-cut technique is still arguable. This review will attempt to present and discuss different ways of preventing post-ERCP pancreatitis.     

Selective biliary cannulation techniques for endoscopic retrograde cholangiopancreatography procedures and prevention of post- endoscopic retrograde cholangiopancreatography pancreatitis

Numerous endoscopic retrograde cholangiopancreatography (ERCP) techniques have been reported to achieve selective biliary cannulation success. For standard biliary cannulation procedures, the wire-guided cannulation technique has been reported to reduce the rate of post-ERCP pancreatitis (PEP) and increase the biliary cannulation success rate, although conflicting reports exist. The pancreatic or double-guidewire technique and several precut techniques have been reported as useful techniques in difficult biliary cannulation cases. Although ERCP is a useful endoscopic procedure, the risk of adverse events, particularly post-ERCP pancreatitis, is inevitable. Previous studies and analyses have revealed the risk factors for PEP. The efficacy of prophylactic pancreatic duct stent placement and the administration of rectal nonsteroidal anti-inflammatory drugs for preventing PEP has also been reported. Herein, we reviewed reports in the literature regarding the current status of selective biliary cannulation techniques and PEP prevention.     

Rectal indomethacin with topical epinephrine versus indomethacin alone for preventing Post-ERCP pancreatitis – A systematic review and meta-analysis

BackgroundRecent studies have compared the utility of rectal indomethacin with topical epinephrine (IE) sprayed on duodenal papilla and rectal indomethacin alone (IS) to prevent post-ERCP pancreatitis (PEP) with conflicting results. We performed a systematic review and meta-analysis to evaluate the benefit of using the combination prophylaxis as oppose to rectal indomethacin alone.MethodsThe following database were searched for our systematic review: PubMed∖Medline, Embase, Cochrane, and Web of Science. We included both randomized controlled trials (RCTs) and cohort studies. Primary outcome was incidence of PEP and secondary outcomes were adverse events and mortality.ResultsA total of 3 studies (all RCTs) with 2244 patients (1132 in IS and 1112 in IE group) were included. The IE group did not demonstrate any significant benefit over IS group in preventing PEP (RR: 1.15, 95% CI 0.62–2.2), mortality (RR: 0.85, 95% CI 0.22–3.24) or overall adverse events (RR: 1.3, 95% CI 0.93–1.7).ConclusionThe combination of rectal indomethacin and topical epinephrine failed to demonstrate any benefit over indomethacin alone in preventing PEP, decreasing mortality and overall adverse events.     

Endoscopic retrograde cholangiopancreatography-induced and non-endoscopic retrograde cholangiopancreatography-induced acute pancreatitis: Two distinct clinical and immunological entities?

Acute pancreatitis(AP) is common gastrointestinal disease of varied aetiology. The most common cause of AP is gallstones, followed by alcohol abuse as an independent risk factor. With the increased need for invasive techniques to treat pancreatic and bile duct pathologies such as endoscopic retrograde cholangiopancreatography(ERCP), AP has emerged as the most frequent complication. While severe AP following ERCP is rare(0.5%), if it does develop it has a greater severity index compared to non-ERCP AP. Development of a mild form of AP after ERCP is not considered a clinically relevant condition. Differences in the clinical presentation and prognosis of the mild and severe forms have been found between non-ERCP AP and postendoscopic pancreatitis(PEP). It has been proposedthat AP and PEP may also have different immunological responses to the initial injury. In this review, we summarise the literature on clinical and inflammatory processes in PEP vs non-ERCP AP.     

ERCP术后急性胰腺炎药物预防临床研究现状

逆行胰胆管造影术后急性胰腺炎(PEP)是逆行胰胆管造影最常见的并发症,发生率1%~40%。药物预防PEP临床研究已取得一定进展,生长抑素、加贝酯等有一定临床疗效,但许多药物临床效果不令人满意。     

The use of antibiotics for acute pancreatitis: Is there a role?

Infections due to pancreatic necrosis and abscesses are observed in one third of patients with severe acute pancreatitis (SAP). Based on results of double-blind, randomized, placebo-controlled trials, antibiotic prophylaxis in SAP is ineffective for reducing the frequency of infected necrosis and to decrease hospital mortality. Antibiotic treatment using carbapenems and quinolones is indicated on demand in patients with SAP and multiorgan failure at admission and in those with hemodynamic shock. Patients with biliary acute pancreatitis (AP) and clinically acute cholecystitis and/or cholangitis benefit from antibiotic treatment. Patients with AP associated with bacteremia, positive bronchoalveolar lavage, and urinary tract infection should receive antibiotics. In necrotizing pancreatitis, evidence-based data do not support late use of antibiotic prophylaxis after onset. Further high-quality, randomized, controlled trials are needed to evaluate antibiotic prophylaxis in the first 24 to 48 hours after SAP onset.     

Pharmacologic prevention of pancreatitis after endoscopic retrograde cholangiopancreatography: Present and future

Despite extensive research over the past 2 decades, effective prevention of post–endoscopic retrograde cholangiopancreatography pancreatitis (PEP) using pharmacologic agents has been elusive. Recently, research that is focused on nonsteroidal anti-inflammatory drugs has provided renewed hope by demonstrating that a medication can indeed prevent PEP. Today, based on high-quality clinical trial data, rectal nonsteroidal anti-inflammatory drugs can be recommended for preventing PEP in high-risk cases,and given the highly favorable risk and cost-benefit ratios, they should be considered for all patients undergoing endoscopic retrograde cholangiopancreatography. Ongoing research will define the optimal dose of rectal indomethacin and whether this medication can eliminate the need for prophylactic pancreatic stent placement in high-risk cases. Additional research is necessary to define the role of other promising pharmacologic agents in clinical practice.     

Rectal INdomethacin,oral TacROlimus,or their combination for the prevention of post-ERCP pancreatitis (INTRO Trial): Protocol for a randomized,controlled, double-blinded trial

BackgroundAcute pancreatitis remains the most common and morbid complication of endoscopic retrograde cholangiopancreatography (ERCP). The use of rectal indomethacin and pancreatic duct stenting has been shown to reduce the incidence and severity of post-ERCP pancreatitis (PEP), but these interventions have limitations. Recent clinical and translational evidence suggests a role for calcineurin inhibitors in the prevention of pancreatitis, with multiple retrospective case series showing a reduction in PEP rates in tacrolimus users.MethodsThe INTRO trial is a multicenter, international, randomized, double-blinded, controlled trial. A total of 4,874 patients undergoing ERCP will be randomized to receive either oral tacrolimus (5 mg) or oral placebo 1–2 h before ERCP, and followed for 30 days post-procedure. Blood and pancreatic aspirate samples will also be collected in a subset of patients to quantify tacrolimus levels. The primary outcome of the study is the incidence of PEP. Secondary endpoints include the severity of PEP, ERCP-related complications, adverse drug events, length of hospital stay, cost-effectiveness, and the pharmacokinetics, pharmacodynamics, and pharmacogenomics of tacrolimus immune modulation in the pancreas.ConclusionsThe INTRO trial will assess the role of calcineurin inhibitors in PEP prophylaxis and develop a foundation for the clinical optimization of this therapeutic strategy from a pharmacologic and economic standpoint. With this clinical trial, we hope to demonstrate a novel approach to PEP prophylaxis using a widely available and well-characterized class of drugs.Trial registrationNCT05252754, registered on February 14, 2022.     

Different profile of cytokine synthesis according to the severity of acute pancreatitis

AIM: To evaluate the cellular synthetic ability of cytokines involved in pro- and anti-inflammatory reactions in patients with AP. METHODS: Sixty-seven patients with AP (16 severe, 51 mild) and 10 controls were included in the study. Cultures of whole blood were performed in samples obtained within the first 72 h from the onset of pain. Serum levels of interleukins (IL) 6, 8, 10, and TNF-α were measured at baseline and in the supernatant of cultures with (functional reserve) or without stimulation with phytohemaglutinin. RESULTS: Basal levels of cytokines were significantly higher in patients with severe AP. A significant increase of all pro-inflammatory cytokines vs basal levels was observed in the supernatant after 24 h of whole blood cultures in patients, but not in controls. In contrast, IL-10 increased significantly in the supernatant of cultures only in patients with mild AP. Cells showed a statistically significant functional reserve for all IL in patients with mild, but only for pro-inflammatory cytokines in patients with severe AP. CONCLUSION: A marked activation of immune system may be observed in patients with AP, being balanced between pro- and anti-inflammatory cytokines in patients with mild but not severe AP. A reduced functional reserve for the synthesis of IL-10 may be observed in patients with severe AP, which might lead to a worst prognosis.     

Does rectal ketoprofen prevent post ERCP pancreatitis?

Background and study aimsEndoscopic retrograde cholangiopancreatography (ERCP) is a commonly used procedure in the management of pancreatic and biliary diseases. Acute pancreatitis is the most common complication following ERCP. Among many medications, nonsteroidal anti-inflammatory drugs (NSAIDs) were subject of numerous trials concerning post ERCP pancreatitis (PEP) prophylaxis. By inhibiting phospholipase A2, these drugs could intervene in the pathogenesis of the disease therefore limiting its occurrence. The use of some rectal NSAIDs agents was shown, to be advantageous in preventing this complication but there were not enough data on ketoprofen. The aim of this study was to assess the efficacy of rectal ketoprofen prophylactic administration in reducing the risk of PEP.Patients and methodsThe study was a non randomized retrospective single center study conducted between 2014 and 2018 on 242 patients divided into control and trial group receiving 100 mg of rectal Ketoprofen 30 mins before ERCP.PEP was defined as a new or exacerbated abdominal pain, in association with an elevation of serum lipase at least three times higher than the normal upper limit within and lasting more than 24 h after the procedure requiring a re-admission or a prolongation of the hospital stay.This endpoint was determined by comparing the number of patients presenting PEP in the NSAIDs group vs. the control group using Fisher exact test, with p < 0.05 representing a significant statistical value.ResultsPancreatitis developed in 6% after ERCP, 5 of them being in the trial group and 9 in the control group. Additionally, statistical calculations showed a non significant difference between the two groups in the prevalence of PEP.ConclusionRectal ketoprofen administration before ERCP does not have any effect in preventing pancreatitis post ERCP.     

Network meta-analysis of prophylactic pancreatic stents and non-steroidal anti-inflammatory drugs in the prevention of moderate-to-severe post-ERCP pancreatitis

BackgroundThere is an ongoing debate that non-steroidal anti-inflammatory drugs (NSAID) or prophylactic pancreatic stents (PPS) are more beneficial in preventing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). In our present network meta-analysis, we aimed to compare PPSs to rectal NSAIDs in the prevention of moderate and severe PEP in average- and high-risk patients.MethodsWe performed a systematic search for randomized controlled trials (RCT) from MEDLINE (via PubMed), Embase and Cochrane Central databases. RCTs using prophylactic rectal NSAIDs or PPSs in patients subjected to ERCP at average- and high-risk population were included. The main outcome was moderate and severe PEP defined by the Cotton criteria. Pairwise Bayesian network meta-analysis was performed, and interventions were ranked based on surface under cumulative ranking (SUCRA) values.ResultsSeven NSAID RCTs (2593 patients), and 2 PPS RCTs (265 patients) in the average-risk, while 5 NSAID RCTs (1703 patients), and 8 PPS RCTs (974 patients) in the high-risk group were included in the final analysis. Compared to placebo, only PPS placement reduced the risk of moderate and severe PEP in both patient groups (average-risk: RR = 0.07, 95% CI [0.002–0.58], high-risk: RR = 0.20, 95% CI [0.051–0.56]) significantly. Rectal NSAID also reduced the risk, but this effect was not significant (average-risk: RR = 0.58, 95% CI [0.22–1.3], high-risk: RR = 0.58, 95% CI [0.18–2.3]). Based on SUCRA, PPS placement was ranked as the best preventive method.ConclusionProphylactic pancreatic stent placement but not rectal NSAID seems to prevent moderate-to-severe PEP better both, in average- and high-risk patients.     

Indomethacin for post-endoscopic retrograde cholangiopancreatography pancreatitis prophylaxis:Is it the magic bullet?

Acute pancreatitis is a common complication of endoscopic retrograde cholangiopancreatography (ERCP). Pancreatic duct stent insertion after ERCP has been widely accepted as the standard of care for the prevention of this complication in high-risk patients. Unfortunately, the placement of pancreatic stents requires higher level of endoscopic expertise and is not always feasible due to anatomic considerations. Therefore, effective non-invasive pharmacologic prophylaxis remains appealing, particularly if it is inexpensive, easily administered, has a low risk side effect profile and is widely available. There have been multiple studies evaluating potential pharmacologic candidates for post-ERCP pancreatitis (PEP) prophylaxis, most of them yielding disappointing results. A recently published large, multi-center, randomized controlled trial reported that in high risk patients a single dose of rectal indomethacin administered immediately after the ERCP significantly decreased the incidence of PEP compare to placebo.     

Elevated level of interleukin-6 predicts organ failure and severe disease in patients with acute pancreatitis

BACKGROUND AND AIM: Cytokines play an important role in the pathogenesis of acute pancreatitis (AP). The aim of the present paper was to study the profile of anti- and proinflammatory cytokines in AP and to determine their predictive value for severity of AP, organ failure and mortality. METHODS: Consecutive patients with AP were included in the study. Cytokines were measured in those patients who presented within the first 72 h of the onset of AP. Plasma levels of proinflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-Ibeta, IL-6 and anti-inflammatory cytokine IL-10 were measured on days 1, 3, 7 and 14 of AP. RESULTS: Of 108 patients, 30 presented within 72 h of the onset (mean age 40.27 +/- 13.89 years; 22 males). Of the 30 patients, 13 (43.3%) had severe and 17 (56.7%) had mild pancreatitis. Eleven (36.7%) patients developed organ failure and three died. The level of IL-6 on day 3 was significantly higher in severe pancreatitis than in mild pancreatitis (146.29 +/- 57.53 pg/mL vs 91.42 +/- 71.65 pg/mL; P = 0.04) and was significantly higher in patients who developed organ failure compared with those who did not (161.59 +/- 53.46 pg/mL vs 88.16 +/- 65.50 pg/mL; P = 0.004). At a cut-off value of 122 pg/mL on day 3, IL-6 predicted organ failure and severe pancreatitis with a sensitivity and specificity of 81.8% and 77.7%, respectively. TNF-alpha and IL-10 were detectable only in one-third of patients and were not related to the severity of pancreatitis, while Il-1beta was not detectable. CONCLUSION: Elevated levels of IL-6 predicted organ failure and severe pancreatitis and suggested its pathophysiological significance in AP.     

Effect of body weight on fixed dose of diclofenac for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis

Objective: The aim of this study was to assess the influence of patient body weight on the clinical effect of 100?mg diclofenac administered as a single dose for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP).

Materials and methods: All patients subjected to endoscopic retrograde cholangiopancreatography (ERCP) from 2009 to 2014 were evaluated for inclusion. In total, 772 patients were included of whom 378 (49%) received diclofenac prophylaxis.

Results: In the diclofenac prophylaxis group, body weight was higher in patients with PEP (mean?±?SD: 82?±?18?kg) than in patients without PEP (74?±?18?kg) (p?=?0.029). In patients not receiving prophylaxis, body weight was not associated with the occurrence of PEP (mean?±?SD: 77?±?18 vs 75?±?18?kg, respectively, p?=?0.450). In an adjusted analysis, higher patient body weight was inversely associated with the clinical effect of 100?mg diclofenac for the prophylaxis of PEP.

Conclusions: High patient body weight was associated with a reduced effect of 100?mg diclofenac for prophylaxis of PEP.     

Updated meta-analysis of pancreatic stent placement in preventing post-endoscopic retrograde cholangiopancreatography pancreatitis

AIM: To investigate the efficacy and safety profile of pancreatic duct (PD) stent placement for prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP).METHODS: We performed a search of MEDLINE, EMBASE, and Cochrane Library to identify randomized controlled clinical trials of prophylactic PD stent placement after ERCP. RevMan 5 software provided by Cochrane was used for the heterogeneity and efficacy analyses, and a meta-analysis was performed for the data that showed homogeneity. Categorical data are presented as relative risks and 95% confidence intervals (CIs), and measurement data are presented as weighted mean differences and 95%CIs.RESULTS: The incidence rates of severe pancreatitis, operation failure, complications and patient pain severity were analyzed. Data on pancreatitis incidence were reported in 14 of 15 trials. There was no significant heterogeneity between the trials (I² = 0%, P = 0.93). In the stent group, 49 of the 1233 patients suffered from PEP, compared to 133 of the 1277 patients in the no-stent group. The results of this meta-analysis indicate that it may be possible to prevent PEP by placing a PD stent.CONCLUSION: PD stent placement can reduce postoperative hyperamylasemia and might be an effective and safe option to prevent PEP if the operation indications are well controlled.     

The Route of Administration of Rabies Vaccines: Comparing the Data

Cell culture rabies vaccines were initially licensed in the 1980s and are essential in the prevention of human rabies. The first post-exposure prophylaxis (PEP) vaccination regimen recommended by the World Health Organization (WHO) was administered intramuscularly over a lengthy three-month period. In efforts to reduce the cost of PEP without impinging on safety, additional research on two strategies was encouraged by the WHO including the development of less expensive production methods for CCVs and the administration of reduced volumes of CCVs via the intradermal (ID) route. Numerous clinical trials have provided sufficient data to support a reduction in the number of doses, a shorter timeline required for PEP, and the approval of the intradermal route of administration for PEP and pre-exposure prophylaxis (PreP). However, the plethora of data that have been published since the development of CCVs can be overwhelming for public health officials wishing to review and make a decision as to the most appropriate PEP and PreP regimen for their region. In this review, we examine three critical benchmarks that can serve as guidance for health officials when reviewing data to implement new PEP and PreP regimens for their region including: evidence of immunogenicity after vaccination; proof of efficacy against development of disease; and confirmation that the regimen being considered elicits a rapid anamnestic response after booster vaccination.