Disturbances of the microcirculation in acute pancreatitis

BACKGROUND: Severe acute pancreatitis is characterized by pancreatic necrosis, resulting in local and systemic inflammation. Pancreatitis affects both the systemic and pancreatic vasculature. This review focuses on the underlying processes involved in the changes of microvascular anatomy following acute pancreatitis. METHODS: A Medline/PubMed search (January 1966 to December 2005) with manual cross-referencing was conducted. All relevant articles investigating the pancreatic microcirculatory anatomy and the effect of pancreatitis on the microcirculation were included. RESULTS: The pancreas is susceptible to ischaemic insult, which can exacerbate acute pancreatitis. There is also increasing evidence of pancreatic and systemic microvascular disturbances in the pathogenesis of pancreatitis, including vasoconstriction, shunting, inadequate perfusion, and increased blood viscosity and coagulation. These processes may be caused or exacerbated by ischaemia-reperfusion injury and the development of oxygen-derived free radicals. CONCLUSION: Acute pancreatitis impairs the pancreatic and systemic microcirculation, which is a key pathological process in the development of severe necrotizing disease.     

Inflammatory response on the pancreatic acinar cell injury.

Acute pancreatitis is an inflammatory disorder, and inflammation not only affects the pathogenesis but also the course of the disease. Acinar cell injury early in acute pancreatitis leads to a local inflammatory reaction; if marked this leads to a systemic inflammatory response syndrome (SIRS). An excessive SIRS leads to distant organ damage and multiple organ dysfunction syndrome (MODS). MODS associated with acute pancreatitis is the primary cause of morbidity and mortality in this condition. Recent studies by us and other investigators have established the critical role played by inflammatory mediators such as TNF-alpha, IL-1beta, IL-6, IL-8, CINC/GRO-alpha, MCP-1, PAF, IL-10, CD40L, C5a, ICAM-1, MIP1-alpha, RANTES, substance P, and hydrogen sulfide in acute pancreatitis and the resultant MODS. This review intends to present an overview of the inflammatory response that takes place following pancreatic acinar cell injury.     

Hyperbaric Oxygen and N-Acetylcysteine Treatment in L-Arginine-Induced Acute Pancreatitis in Rats

ABSTRACT

Background: This study was designed to evaluate the combined effects of hyperbaric oxygen (HBO) and N-acetylcysteine (NAC) on acute necrotizing pancreatitis in rats. Methods: Experiments were performed in 50 male Wistar rats, which were divided into five groups (N = 10 for each group). The first group received normal saline (0.9% NaCl) intraperitoneal and served as the control group. In the second group, acute pancreatitis was induced by 3.2-g/kg body weight L-arginine intraperitoneal twice at an interval of 1 hr, which has been shown previously to produce severe necrotizing acute pancreatitis. In the third group, NAC treatment (1000 mg/kg) was given after 1 hr of the induction of acute pancreatitis twice 24 hr apart. In the fourth group, animals received HBO, 6 hr after the induction of pancreatitis twice 12 hr apart. In the fifth group, animals received together NAC as in Group 3 and HBO treatment as in Group 4. Groups 1, 2, and 3 were left under normal atmospheric pressures. Twelve hours after last treatment, the animals were killed by exsanguinations. Blood samples were studied for amylase, calcium, and lactate dehydrogenase (LDH), pancreatic histology, pancreatic tissue malondialdehyde, superoxide dismutase, and glutathione levels. Results: Acute pancreatitis is reduced by the treatment of NAC, HBO, NAC + HBO. HBO + NAC groups performed statistically the best in preventing L-arginine-induced acute necrotising pancreatitis. Conclusions: NAC especially combined with HBO, decreases oxidative stress parameters, serum amylase, calcium, and LDH levels, as well as histopathologic score.     

Efficacy of somatostatin and its analogues in the treatment of acute pancreatitis: clinical retrospective study

Acute pancreatitis is an acute inflammatory disease of the pancreas, with variable involvement of other regional tissues or remote organ systems. Acute pancreatitis is mild in 80% of cases; virtually all patients with this form of disease will survive, because it's associated with minimal organ dysfunction and uneventful recovery; the severe pancreatitis develops in 20% of cases and is associated with higher morbidity and mortality. It's most important to identify the severity of disease at the moment of hospital admission; many scoring systems have been developed to serve as early prognostic signs: Ranson's criteria, Imrie's criteria, Apache II score, Balthazar's TC score. Recently, new drugs have been proposed in the treatment of acute pancreatitis, as, for example, calcitonine, glucagon, systemic antioxidants, antagonists of the receptors of interleukines, antiproteases (aprotinin and gabexate-mesilate) and the inhibitors of pancreatic secretions (somatostatin and its analogues). However, many controversies still exist concerning the real efficacy of these drugs in the treatment of acute pancreatitis, particularly regarding the inhibitors of pancreatic secretions: recently, some studies showed that somatostatin is able to actually reduce the local complication of the disease and the development of severe forms of acute pancreatitis; on the other hand, other studies failed to show real advantages of somatostatin reducing morbidity and mortality for pancreatitis. The aim of present study is a retrospective analysis of patients affected by acute pancreatitis in order to evaluate efficacy of somatostatin and its analogues. All patients subdivided in two groups: group A, patients treated with conventional therapy plus somatostatin and/or octreotide (SS/LS), and group B, patients treated only with conventional therapy. Results seem to show that somatostatin does not positively affect morbidity and mortality in patients with acute pancreatitis. The Authors conclude that, at present; somatostatin cannot be considered surely effective in preventing complications and mortality in acute pancreatitis. Further studies are still necessary to verify the effectiveness of somatostatin and its analogues in the therapy of acute pancreatitis.     

Macrophage ablation attenuates adenoviral vector-induced pancreatitis

BACKGROUND: The objective of these studies is to determine the effects of macrophage ablation on the course of acute viral pancreatitis. Macrophages secrete proinflammatory cytokines triggering local pancreatic and systemic inflammation in the acute phase of virus-induced pancreatitis. We hypothesized that ablation of macrophages should attenuate the host inflammatory response in a mouse model of adenovirus-induced pancreatitis. METHODS: Liposome-encapsulated dichloromethylene-diphosphonate, a macrophage-depleting agent, was used before direct pancreatic injection of a recombinant adenovirus expressing a marker gene in C57Bl/6 and IL-6 knockout (KO) mice. RESULTS: C57Bl/6 mice depleted of macrophages had diminished pancreatic inflammation in the first 24 hours after vector administration. IL-6 KO mice depleted of macrophages had more severe inflammation than similarly treated C57Bl/6 mice. C57Bl/6 mice depleted of macrophages, and IL-6 KO mice had prolonged transgene expression and diminished cytotoxic T lymphocyte responses to adenoviral vector. Mortality was highest in IL-6 KO mice depleted of macrophages. Depletion of macrophages also prevented detectable serum IL-6, IL-10, or IL-12 levels in C57Bl/6 mice. CONCLUSIONS: The data suggest that macrophages play a role in the acute inflammatory response to viral vector-induced pancreatitis and that IL-6 may be protective. Understanding of the mechanisms that initiate the host immune cascade will allow more effective use of adenoviral vector-based pancreatic gene delivery.     

Levels of the chemokines growth-related oncogene alpha and epithelial neutrophil-activating protein 78 are raised in patients with severe acute pancreatitis

BACKGROUND: Multiple organ dysfunction syndrome secondary to systemic leucocyte activation is the major cause of death following an attack of acute pancreatitis. Although plasma levels of interleukin (IL) 8 are known to be raised in acute pancreatitis, levels of other CXC chemokines such as growth-related oncogene (GRO) alpha and epithelial neutrophil-activating protein (ENA) 78, which are also potent neutrophil chemoattractants and activators, have not been measured.METHODS: Timed plasma samples were obtained from 51 patients with acute pancreatitis, 27 with a severe attack and 24 with mild disease according to the Atlanta classification. Samples were analysed to determine levels of C-reactive protein (CRP), IL-8, GRO-alpha and ENA-78.RESULTS: Plasma levels of IL-8, GRO-alpha and ENA-78 were increased in patients with severe as opposed to mild acute pancreatitis as early as 24 h following disease onset. Using cut-off levels of 7 pg/ml for IL-8, 70 pg/ml for GRO-alpha and 930 pg/ml for ENA-78, peak levels within the first 24 h of admission had an accuracy of 81, 71 and 87 per cent respectively in predicting the severity of an attack of acute pancreatitis.CONCLUSION: In patients with severe acute pancreatitis plasma levels of GRO-alpha and ENA-78 were raised in addition to those of IL-8, suggesting that all three chemokines are involved in the inflammatory response in this condition.     

Pancreatitis and nutrition. Significance of the gastrointestinal tract and nutrition for septic complications

Septic complications are an important factor for the morbidity and mortality of acute pancreatitis. The gut has been identified as a source of infection early in the course of the disease allowing intestinal bacteria to translocate into pancreatic necrosis and other organs. Bacterial translocation is promoted by an impaired intestinal mucosal barrier which can be attributed to the reduced oxygen and substrate supply of the intestine during the early systemic response to the pancreatic injury. A rat model of severe acute pancreatitis has been used to confirm the hypothesis that an impaired mucosal barrier can be stabilized by supplying certain nutritients, vitamins and trace elements. Following a discussion of the many aspects of bacterial translocation and gut derived sepsis, the role of the gut and nutrition for the development of septic complications in acute pancreatitis is summarized as follows: Early in the course of acute pancreatitis the gut is a target organ of the primary systemic inflammatory response (SIRS) to pancreatic injury. SIRS-induced gut barrier dysfunction promoting bacterial translocation makes the gut the motor for secondary (septic) complications. As a septic focus the gut becomes a target for therapeutic measures aimed at stabilizing the impaired gut barrier. Nutritive factors demonstrated to improve impaired gut barrier function include early enteral feeding and specific factors like glutamine which are essential for enterocytes and colonocytes in stress. Experimental data are presented to underline the significance of these nutritive factors and subsequent randomized multicenter trials performed to verify the positive experimental results are introduced. The effect of other nutritive factors (e.g. omega-3-fatty acids) has not yet been systemically investigated. Thus, experimental and clinical studies need to be performed for evaluating their effect on bacterial translocation and the disease course in acute pancreatitis.     

Management of Severe Acute Pancreatitis

Severe acute pancreatitis (SAP) develops in about 25% of patients with acute pancreatitis. Severity of acute pancreatitis is linked to the presence of systemic organ dysfunctions and/or necrotizing pancreatitis. Risk factors independently determining the outcome of SAP are early multiorgan failure (MOF), infection of necrosis, and extended necrosis (>50%). Morbidity of SAP is biphasic, in the first week it is strongly related to systemic inflammatory response syndrome while, sepsis due to infected pancreatic necrosis leading to MOF syndrome occurs in the later course after the first week. Contrast-enhanced computed tomography provides the highest diagnostic accuracy for necrotizing pancreatitis when performed after the first week of disease. Patients who suffer early organ dysfunctions or are at risk for developing a severe disease require early intensive care treatment. Antibiotic prophylaxis has not been shown as an effective preventive treatment. Early enteral feeding is based on a high level of evidence, resulting in a reduction of local and systemic infection. Patients suffering infected necrosis causing clinical sepsis are candidates for intervention. Hospital mortality of SAP after interventional or surgical debridement has decreased to below 20% in high-volume centers.     

Cytokine storm in acute pancreatitis

Efforts to unravel the events in the evolution of tissue damage in acute pancreatitis have shown a number of inflammatory mediators to be involved. The pathways of damage are similar, whatever the etiology of pancreatitis, with three phases of progression: local acinar injury, systemic response, and generalized sepsis. The proinflammatory response is countered by an anti-inflammatory response, and an imbalance between these two systems leads to localized tissue destruction and distant organ damage. Cytokines lie at the heart of the problem and are involved in all aspects of the cascade leading to systemic inflammatory response syndrome and multiple organ dysfunction syndrome. This review discusses the present knowledge about the role of various mediators in this process, their genetic control, and the effects of their modulation. The major proinflammatory mediators are tumor necrosis factor, interleukins 1, 6, and 8, platelet activation factor, and the chemokines. The major anti-inflammatory factors include interleukin 10, and interleukin 1 receptor antagonist. Emerging knowledge of new mediators as well as future strategy of damage control is discussed. Received: February 19, 2002 / Accepted: March 8, 2002 Offprint requests to: A.N. Kingsnorth     

The Impact of Obesity on the Course and Outcome of Acute Pancreatitis

Obesity has reached epidemic proportions in many countries and is an established risk factor in many chronic illnesses, but its role in acute illness is less clear. Pancreatologists have long recognized obesity as a risk factor for a poor outcome in severe acute pancreatitis. There are now several studies that have identified obesity as a primary risk factor for developing local complications (abscess, pseudocyst, necrosis), organ failure, and death. Indeed, meta-analysis of these studies gives a relative risk of 4.3 for local complications, 2.0 for systemic complications, and 2.1 for death. This has led to proposed modifications of acute pancreatitis scoring systems to include obesity as an independent primary predictive factor of severe disease. Obesity is associated with a low-grade inflammatory state, which may predispose obese patients to such complications. Furthermore, visceral obesity and visceral adipose tissue may be particularly important in underlying the pathophysiology of these observations.     

A historic perspective on the contributions of surgeons to the understanding of acute pancreatitis

BACKGROUND: Acute pancreatitis is a disease with a broad spectrum of presentation, severity, and treatment. Current management involves a multidisplinary team of surgeons, gastroenterologists, and interventional radiologists whose varied clinical skills contribute to the evolving diagnostic and therapeutic strategies for this disease. However, critical aspects of therapy have remained the responsibility of the general surgeon. The purpose of this review is to examine the many contributions of surgeons in acute pancreatitis. DATA SOURCES: A review of the literature taken from PubMed on seminal articles published by surgeons on the subject of acute pancreatitis. CONCLUSIONS: Surgeons have made significant contributions to the understanding of the pathophysiology and evolution of therapy of acute pancreatitis. The specialty should continue to take a leadership role to improve outcomes.     

Inhaled nitric oxide in the peroperative period and recovery

OBJECTIVE: To analyse the current knowledge concerning use of inhaled NO (iNO) in anaesthesia and intensive care. DATA SOURCE: References were obtained from Medline, recent review articles, the library of the department and personal files. STUDY SELECTION: All categories of articles on this topic have been selected. DATA EXTRACTION: Articles have been analysed for history, biochemistry, pharmacology, toxicity and clinical use of iNO. DATA SYNTHESIS: Nitric oxide (NO) is a potent endothelium-dependent vasodilator. Because of its selective action on pulmonary circulation and the lack of effect on the systemic circulation due to its inactivation by haemoglobin, iNO has been presented as a new therapeutic agent in most diseases with pulmonary hypertension. During heart transplantation or surgical correction of congenital heart disease, iNO decreases pulmonary hypertension and improves altered right ventricular function. Studies included however small numbers of patients. Preliminary pharmacological studies demonstrated that iNO was able to decrease pulmonary hypertension and improve systemic oxygenation in adult respiratory distress syndrome. To date, none of the three multicentric studies performed was able to show any significant effect on duration of mechanical ventilation, morbidity or mortality. Finally, the sole demonstrated indication for iNO which remains is the persistent pulmonary hypertension of the newborn. Two multicentric studies have evidenced an improvement in systemic oxygenation and a reduced need for extracorporeal membrane oxygenation. In these two studies global mortality was however unchanged. CONCLUSION: Persistent pulmonary hypertension is the sole demonstrated indication for iNO. Inhaled nitric oxide may be efficient in pulmonary hypertension, right ventricular dysfunction and severe hypoxemia. Inhaled nitric oxide must be considered as a rescue therapy or needs to be part of research protocols.     

Relationship of carotenoid and vitamins A and E with the acute inflammatory response in acute pancreatitis

BACKGROUND: Inflammation and oxidative stress are believed to be important in the development of the systemic complications of acute pancreatitis. The fat-soluble vitamins A and E, and the carotenoids have antioxidant properties. The aim of this study was to assess the effect of acute pancreatitis on serum concentrations of vitamin antioxidants and to relate such changes to the degree of the inflammatory response. METHODS: Thirteen consecutive patients with predicted severe acute pancreatitis were compared with 26 matched healthy controls. Five patients developed severe acute pancreatitis and three of these died. Vitamin antioxidant and C-reactive protein (CRP) levels were measured daily for up to 7 days. RESULTS: Patients had significantly lower levels of antioxidants throughout the course of the study (P < 0.017). In patients there was a significant correlation between peak CRP and trough antioxidant levels (P < 0. 01). In patients with mild acute pancreatitis, the concentrations of retinol and beta-carotene at final review were significantly higher than those in patients with severe acute pancreatitis (P < 0.05). This coincided with a reduction in CRP level. CONCLUSION: In acute pancreatitis, circulating concentrations of vitamin antioxidants are reduced and are inversely related to the rise in CRP level.     

Evolution of nutritional support in acute pancreatitis

BACKGROUND: Acute pancreatitis is a catabolic illness and patients with the severe form have high metabolic and nutrient demands. Artificial nutritional support should therefore be a logical component of treatment. This review examines the evidence in favour of initiating nutritional support in these patients and the effects of such support on the course of the disease. METHODS: Medline and Science Citation Index searches were performed to locate English language publications on nutritional support in acute pancreatitis in the 25 years preceding December 1999. Manual cross-referencing was also carried out. Letters, editorials, older review articles and most case reports were excluded. Results and conclusion: There is no evidence that nutritional support in acute pancreatitis affects the underlying disease process, but it may prevent the associated undernutrition and starvation, supporting the patient while the disease continues and until normal and sufficient eating can be resumed. The safety and feasibility of enteral nutrition in acute pancreatitis have been established; enteral nutrition may even be superior to parenteral nutrition. Some patients, however, cannot tolerate enteral feeding and this route may not be practical in others. Parenteral nutrition still has a role, either on its own or in combination with the oral and enteral routes, depending on the stage of the illness and the clinical situation.     

急性胰腺炎发病机理的研究进展

目的总结急性胰腺炎发病机理的研究进展。方法分析近年来国内、外有关急性胰腺炎发病机理的文献报道。结果实验数据表明，促炎性细胞因子和趋化因子的合成与释放对于局部损伤和炎性介质的全身播散起着重要作用，同时提示免疫系统，包括淋巴细胞和中性粒细胞的活化，在胰腺炎的发展过程中也起一定作用。另外，胰腺在一次发病之后可以完全恢复，也可以纤维化，星状细胞被认为在胰腺成纤维过程中起着极其重要的作用。结论急性胰腺炎的发病机理非常复杂，在疾病发作后能够决定其严重程度的因子仍然未知。     

Prevention of severe change in acute pancreatitis: prediction and prevention.

Bacterial infection of pancreatic necrosis is the most frequent local complication of severe acute pancreatitis and is responsible for the majority of deaths in this disease. The development of systemic complications of severe acute pancreatitis such as septic multiple organ failure is closely related to infected necrosis. In this review, the factors predisposing to a severe course of acute pancreatitis are discussed as are clinical and laboratory markers which allow identification of patients at risk. Prevention of complications of acute pancreatitis is difficult. A variety of drugs including antiproteases and antiinflammatory agents have been shown to be of no benefit with regard to the reduction of severe complications. At present, based on the results of controlled trials, there is the widespread belief that prophylactic antibiotics are capable of reducing the incidence of infected pancreatic necrosis. New approaches for the prevention of systemic complications of severe acute pancreatitis are total enteral nutrition and local arterial infusion of antibiotics and antiproteases into the celiac trunk.     

Adjuvant hyperbaric oxygen therapy in the management of crush injury and traumatic ischemia: an evidence-based approach

Hyperbaric oxygen therapy (HBO) has been recommended as an adjunct treatment in acute traumatic ischemia and crush injury. Several animal models have shown better outcomes when HBO is used in crush injury and compartment syndrome. Animal and in vitro models have suggested that these beneficial effects may be mediated by attenuation of ischemia-reperfusion injury. We did a systematic review of the literature using the Eastern Association for the Surgery of Trauma (EAST) recommendations for evidence-based reviews. An electronic search using Medline, OVID technologies, and the Cochrane database was performed. Only clinical papers published between 1966 and December 2003 with at least five patients that included enough information to evaluate were selected. A group of trauma experts reviewed the selected articles and scored them applying the instrument developed by the EAST practice management guidelines committee. Nine documents fulfilled the inclusion criteria for a total of approximately 150 patients. Most documents were retrospective, uncontrolled, and case series lacking a standardized methodology (class III). There was one prospective controlled randomized trial with some limitations on its design. We determined that eight of nine studies showed a beneficial effect from HBO with only one major complication. We concluded that adjunctive HBO is not likely to be harmful and could be beneficial if administered early. Well designed clinical studies are warranted.     

Management of acute pancreatitis: current knowledge and future perspectives

In recent years, a number of articles have been published on the treatment of acute pancreatitis in experimental models and most of them concerned animals with mild disease. However, it is difficult to translate these results into clinical practice. For example, infliximab, a monoclonal TNF antibody, was experimentally tested in rats and it was found to significantly reduce the pathologic score and serum amylase activity and also to alleviate alveolar edema and acute respiratory distress syndrome; however, no studies are available in clinical human acute pancreatitis. Another substance, such as interleukin 10, was efficacious in decreasing the severity and mortality of lethal pancreatitis in rats, but seems to have no effect on human severe acute pancreatitis. Thus, the main problem in acute pancreatitis, especially in the severe form of the disease, is the difficulty of planning clinical studies capable of giving reliable statistically significant answers regarding the benefits of the various proposed therapeutic agents previously tested in experimental settings.     

Factors involved in the pathogenesis of acute pancreatitis

Pathophysiological and molecular research have marked the understanding of the primary events taking place in triggering acute pancreatitis, although the early diagnosis of pancreas diseases in general, continues to be a source of frustration in modem medicine. This presents the news about pathogenesis (co-localization theory, auto-activation theory of the tripsynogen), location of early events (acinar pancreatic cells which are the "key" involved: muscarinic receptors, acinar membrane, role of ionized calcium, the phenomenon of apoptosis), extracellular events in initiation of acute pancreatitis with the granting of a central place to enzyme activation and systemic inflammatory response. Aspects of early microvascular changes, disturbances of ischemia-reperfusion and systemic microvascular abnormalities are so important that justifies therapeutic concept of microcirculatory protection. Participation of monocyte/macrophage system, excessive activation of leukocytes that involving activation and release of lysosomal enzymes and oxygen free radicals associated with ischemia-reperfusion mechanism are defining for pathogenesis of acute pancreatitis.