Antibiotic therapy in acute pancreatitis: From global overuse to evidence based recommendations.

BACKGROUND: Unwarranted administration of antibiotics in acute pancreatitis presents a global challenge. The clinical reasoning behind the misuse is poorly understood. Our aim was to investigate current clinical practices and develop recommendations that guide clinicians in prescribing antibiotic treatment in acute pancreatitis. METHODS: Four methods were used. 1) Systematic data collection was performed to summarize current evidence; 2) a retrospective questionnaire was developed to understand the current global clinical practice; 3) five years of prospectively collected data were analysed to identify the clinical parameters used by medical teams in the decision making process, and finally; 4) the UpToDate Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system was applied to provide evidence based recommendations for healthcare professionals. RESULTS: The systematic literature search revealed no consensus on the start of AB therapy in patients with no bacterial culture test. Retrospective data collection on 9728 patients from 22 countries indicated a wide range (31-82%) of antibiotic use frequency in AP. Analysis of 56 variables from 962 patients showed that clinicians initiate antibiotic therapy based on increased WBC and/or elevated CRP, lipase and amylase levels. The above mentioned four laboratory parameters showed no association with infection in the early phase of acute pancreatitis. Instead, procalcitonin levels proved to be a better biomarker of early infection. Patients with suspected infection because of fever had no benefit from antibiotic therapy. CONCLUSIONS: The authors formulated four consensus statements to urge reduction of unjustified antibiotic treatment in acute pancreatitis and to use procalcitonin rather than WBC or CRP as biomarkers to guide decision-making.

Managing Patients With Concurrent High Risk for Bleeding and Thromboembolic Events.

The number of patients with high bleeding risk (HBR) and high thromboembolic risk (HTR) is increasing. Gastrointestinal bleeding (GIH), acute coronary syndrome (ACS), and pulmonary embolism (PE) are representative conditions due to HBR/HTR. Although these disorders are located at opposite ends of the same disease spectrum, this does not mean a patient with HBR cannot have a concomitant HTR. The clinical manifestation of these two risks mostly results in critically ill patients for whom management means a huge challenge. We have numerous well-structured guidelines about treating GIH, ACS, or PE, but the literature and recommendations about the concomitant onset of these diseases are limited. Expert recommendations suggest an integrative, comprehensive assessment of patient and intervention-related factors to decide on the antithrombotic regimen with the best clinical benefit by assessing thrombotic and bleeding risks. In general, if thrombotic factors predominate, a longer duration, more aggressive antithrombotic regimen should be planned, and if bleeding susceptibility is higher, a shorter duration, de-escalated regimen should be pursued. In this study, we aimed to explore the clinical dilemmas involved by presenting two cases with delicate management.

[Pancreatic cancer or autoimmune pancreatitis: endosonography as a diagnostic reviser]. / Pancreastumor vagy autoimmun pancreatitis: az endoszonográf mint diagnosztikus revizor.

Conventional radiologic imaging (abdominal ultrasound, computer tomography) used in the differential diagnosis of post-hepatic jaundice can frequently provide inaccurate diagnosis. Inflammatory lesions may mimic neoplastic processes and malignancy may be accompanied by perifocal inflammation resulting in histological misdiagnosis. Furthermore, chronic and autoimmune pancreatitis are associated with an increased risk for pancreatic cancer. Radial endosonography has become a markedly important method in the imaging of the pancreas. It has a crucial role in the diagnosis and staging of pancreatic cancer. The authors present three cases where the diagnosis of pancreatic cancer determined by conventional imaging techniques (abdominal ultrasound, computer tomography, endoscopic retrograde cholangiopancreatography) was excluded or confirmed by the radial endosonography. The authors conclude that radial endosonography is an essential complementary method among imaging techniques of the pancreas and in tumor staging. Application of that may prevent unnecessary surgeries, which is obviously useful for patients and cost effective for health care providers.

Prospective, Multicentre, Nationwide Clinical Data from 600 Cases of Acute Pancreatitis.

OBJECTIVE: The aim of this study was to analyse the clinical characteristics of acute pancreatitis (AP) in a prospectively collected, large, multicentre cohort and to validate the major recommendations in the IAP/APA evidence-based guidelines for the management of AP. DESIGN: Eighty-six different clinical parameters were collected using an electronic clinical research form designed by the Hungarian Pancreatic Study Group. PATIENTS: 600 adult patients diagnosed with AP were prospectively enrolled from 17 Hungarian centres over a two-year period from 1 January 2013. MAIN RESULTS: With respect to aetiology, biliary and alcoholic pancreatitis represented the two most common forms of AP. The prevalence of biliary AP was higher in women, whereas alcoholic AP was more common in men. Hyperlipidaemia was a risk factor for severity, lack of serum enzyme elevation posed a risk for severe AP, and lack of abdominal pain at admission demonstrated a risk for mortality. Abdominal tenderness developed in all the patients with severe AP, while lack of abdominal tenderness was a favourable sign for mortality. Importantly, lung injury at admission was associated with mortality. With regard to laboratory parameters, white blood cell count and CRP were the two most sensitive indicators for severe AP. The most common local complication was peripancreatic fluid, whereas the most common distant organ failure in severe AP was lung injury. Deviation from the recommendations in the IAP/APA evidence-based guidelines on fluid replacement, enteral nutrition and timing of interventions increased severity and mortality. CONCLUSIONS: Analysis of a large, nationwide, prospective cohort of AP cases allowed for the identification of important determinants of severity and mortality. Evidence-based guidelines should be observed rigorously to improve outcomes in AP.

Plasma levels of IL-6 correlate with hemodynamic abnormalities in acute pancreatitis in rabbits.

OBJECTIVE: To examine the relationship between plasma cytokine levels and cardiac and hemodynamic function. DESIGN: Measurement of cytokines and the systolic (left ventricular dimensions, heart rate, and cardiac output) and diastolic (early and late transmitral peak flow velocity: E and A-waves and their ratio) functions of the left ventricle (assessed by echocardiography) in rabbits. SETTING AND INTERVENTIONS: Laboratory and echocardiographic analyses were performed at baseline and at 1, 3, 6, 12, and 24 h after acute necrotizing pancreatitis induction (Group ANP), in rabbits after somatostatin pretreatment (Group S-ANP) and in sham-operated controls (Group C). MEASUREMENTS AND RESULTS: Left ventricular dilatation occurred at 6 h and cardiac output was increased 3 h after induction of acute necrotizing pancreatitis. Somatostatin pretreatment mitigated the left ventricular enlargement and filling abnormalities. Plasma level of IL-6 was increased significantly 3 h after pancreatitis induction, but to a lesser extent in Group S-ANP, while somatostatin prevented TNFalpha release (IL-6: Group ANP: 0, 0, 518+/-139, 956+/-125, 373+/-48, and 122+/-37 pg/ml; Group S-ANP: 0, 0, 191+/-68, 261+/-49, 23+/-13, and 0 pg/ml; TNFalpha: Group ANP: 88+/-42, 371+/-40, 2963+/-291, 276+/-30, 197+/-106, and 23+/-14 U/l; Group S-ANP: 91+/-34, 41+/-25, 68+/-42, 25+/-9, 0, and 0 U/ml). The increase in plasma level of IL-6 correlated significantly with left ventricular end-diastolic diameter and volume, cardiac output, and diastolic dysfunction. CONCLUSIONS: Plasma levels of IL-6, but not TNFalpha correlate with cardiac output and left ventricular filling characteristics in acute pancreatitis. Somatostatin pretreatment improves the cardiac and hemodynamic changes, probably through the decrease in cytokine release.

L-arginine-induced experimental pancreatitis.

Despite medical treatment, the lethality of severe acute pancreatitis is still high (20-30%). Therefore, it is very important to find good animal models to characterise the events of this severe disease. In 1984, Mizunuma et al. developed a new type of experimental necrotizing pancreatitis by intraperitoneal administration of a high dose of L-arginine in rats. This non-invasive model is highly reproducible and produces selective, dose-dependent acinar cell necrosis. Not only is this a good model to study the pathomechanisms of acute necrotizing pancreatitis, but it is also excellent to observe and influence the time course changes of the disease. By writing this review we illuminate some new aspects of cell physiology and pathology of acute necrotizing pancreatitis. Unfortunately, the reviews about acute experimental pancreatitis usually did not discuss this model. Therefore, the aim of this manuscript was to summarise the observations and address some challenges for the future in L-arginine-induced pancreatitis.

Insulin is necessary for the hypertrophic effect of cholecystokinin-octapeptide following acute necrotizing experimental pancreatitis.

AIM: In previous experiments we have demonstrated that by administering low doses of cholecystokinin-octapeptide (CCK-8), the process of regeneration following L-arginine (Arg)-induced pancreatitis is accelerated. In rats that were also diabetic (induced by streptozotocin, STZ), pancreatic regeneration was not observed. The aim of this study was to deduce whether the administration of exogenous insulin could in fact restore the hypertrophic effect of CCK-8 in diabetic-pancreatitic rats. METHODS: Male Wistar rats were used for the experiments. Diabetes mellitus was induced by administering 60 mg/kg body mass of STZ intraperitoneally (i.p.), then, on d 8, pancreatitis was induced by 200 mg/100 g body mass Arg i.p. twice at an interval of 1 h. The animals were injected subcutaneously twice daily (at 7 a.m. and 7 p.m.) with 1 ?g/kg of CCK-8 and/or 2 IU mixed insulin (300 g/L short-action and 700 g/L intermediate-action insulin) for 14 d after pancreatitis induction. Following this the animals were killed and the serum amylase, glucose and insulin levels as well as the plasma glucagon levels, the pancreatic mass/body mass ratio (pm/bm), the pancreatic contents of DNA, protein, amylase, lipase and trypsinogen were measured. Pancreatic tissue samples were examined by light microscopy on paraffin-embedded sections. RESULTS: In the diabetic-pancreatitic rats treatment with insulin and CCK-8 significantly elevated pw/bm and the pancreatic contents of protein, amylase and lipase vs the rats receiving only CCK-8 treatment. CCK-8 administered in combination with insulin also elevated the number of acinar cells with mitotic activities, whereas CCK-8 alone had no effect on laboratory parameters or the mitotic activities in diabetic-pancreatitic rats. CONCLUSION: Despite the hypertrophic effect of CCK-8 being absent following acute pancreatitis in diabetic-rats, the simultaneous administration of exogenous insulin restored this effect. Our results clearly demonstrate that insulin is necessary for the hypertrophic effect of low-doses of CCK-8 following acute pancreatitis.

Effects of octreotide on acute necrotizing pancreatitis in rabbits.

AIM: To assess the role of oxygen-derived free radicals and cytokines in the pathogenesis of taurocholic acid-induced acute pancreatitis, and to evaluate the preventive effects of octreotide towards the development of acute pancreatitis. METHODS: Acute pancreatitis was induced in male New Zealand white rabbits by retrograde injection of 0.8 mL/kg.b.m. of 50 g/L sodium taurocholate (NaTC) in the pancreatic duct. Sham-operated animals served as control. Octreotide 1 mg/kg.b.m. was administered subcutaneously before the induction of pancreatitis. Blood was taken from the jugular vein before and at 1, 3, 6, 12 and 24 h after pancreatitis induction. Serum activities of amylase, IL-6 and TNF-alpha and levels of malonyl dialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GPx), catalase and superoxide dismutase (Mn-, Cu-, and Zn-SOD) in pancreatic tissue were measured. RESULTS: Serum TNF-alpha and IL-6 levels increased significantly 3 h after the onset of pancreatitis, and then returned to control level. The tissue concentration of MDA was significantly elevated at 24 h, while the GSH level and GP-x, catalase, Mn-SOD, Cu-, Zn-SOD activities were all significantly decreased in animals with pancreatitis as compared to the control. Octreotide pretreatment significantly reversed the changes in cytokines and reactive oxygen metabolites. Octreotide treatment did not alter the serum amylase activity and did not have any beneficial effects on the development of histopathological changes. CONCLUSION: Oxygen-derived free radicals and proinflammatory cytokines are generated at an early stage of NaTc-induced acute pancreatitis in rabbits. Prophylactic octreotide treatment can prevent release of cytokines and generation of reactive oxygen metabolites, but does not have any beneficial effects on the development of necrotizing pancreatitis.