Upregulated but insufficient generation of activated protein C is associated with development of multiorgan failure in severe acute pancreatitis (original) (raw)
Related papers
Use of activated protein C has no avail in the early phase of acute pancreatitis
HPB, 2008
Objectives. Sepsis and acute pancreatitis have similar pathogenetic mechanisms that have been implicated in the progression of multiple organ failure. Drotrecogin alfa, an analogue of endogenous protein C, reduces mortality in clinical sepsis. Our objective was to evaluate the early therapeutic effects of activated protein C (APC) in a rat model of acute necrotizing pancreatitis. Subjects and method. Acute necrotizing pancreatitis was induced by intraductal injection of 5% Na taurocholate. Hourly bolus injections of saline or recombinant human APC (drotrecogin alfa) was commenced via femoral venous catheter four hours after the induction of acute pancreatitis. The experiment was terminated nine hours after pancratitis induction. Animals in group one (n 020) had a sham operation while animals in group two (n 020) received saline and animals in group three (n020) received drotrecogin alfa boluses after acute pancreatitis induction. Pancreatic tissue for histopathologic scores and myeloperoxidase, glutathione reductase, glutathione peroxidase, and catalase activites were collected, and blood for serum amylase, urea, creatinine, and inleukin-6 measurements was withdrawn. Results. Serum amylase activity was significantly lower in the APC treated group than the untreated group (17,4359432 U/L vs. 27,4269 118 U/L, respectively). While the serum interleukin-6 concentration in the APC untreated group was significantly lower than the treated group (9709323 pg/mL vs. 3309368 pg/mL, respectively). Conclusion. In the early phase of acute pancreatitis, drotrecogin alfa treatment did not result in a significant improvement in oxidative and inflammatory parameters or renal functions.
The effect of activated protein C on experimental acute necrotizing pancreatitis
Critical Care, 2005
Introduction Community-acquired pneumonia remains a common condition worldwide. It is associated with significant morbidity and mortality. The aim of this study was to evaluate conditions that could predict a poor outcome. Design Retrospective analyse of 69 patients admitted to the ICU from 1996 to 2003. Demographic data included age, sex and medical history. Etiologic agents, multiorgan dysfunction, nosocomial infections, SAPS II and PORT scores were recorded for each patient. For statistical analysis we used a t test, chi-square test and Mann-Whitney U test on SPSS ® . A value of P less than 0.05 was considered significant. Results Forty-seven patients were male and 22 patients were female. Mean age was 52 years. Sixty-seven percent had serious pre-morbid conditions including pulmonary disease (34.8%), cardiac problems (36.2%), diabetes (13%) and chronic liver disease (5.8%); 40.6% were smokers, drug abusers or alcohol dependents. Sixtyeight patients required invasive mechanical ventilation. The average length of ventilation was 13.5 days, median 8 days. The mean SAPS II score was 40.14 and the mean PORT score was 141. The mortality rate was 27.5% (SAPS II estimated mortality, 35%). Complications reported were ARDS (40.6%), septic shock (34.8%), acute renal failure (2.9%), cardiac arrest (8.7%) and nosocomial infeccions (46.4%). Mortality rates were higher for previous hepatic (75%) and metabolic (33%) diseases. We found a close association between crude mortality and SAPS II score (P = 0.003) and development of complications (P = 0.0028). Respiratory dysfunction (P = 0.006) and septic shock (P = 0.022) were most significantly related to mortality. No significant differences were founded regarding age, comorbidities, PORT score, etiologic agents, nosocomial infections and length of invasive mechanical ventilation. Conclusions Previous hepatic chronic disease was strictly related to higher mortality as well as isolation of MRSA. ARDS and septic shock predicted a poor outcome. SAPS II score was the best severity indicator of mortality.
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.], 2012
The severity of organ failure caused by acute pancreatitis (AP) is the most important determinant of mortality in the disease. Recombinant human activated protein C (Drotrecogin Alfa; Xigris, APC, rhAPC) is the first drug to show a decrease in all-cause mortality due to multiple organ failure caused by sepsis. As the systemic inflammatory response syndrome (SIRS) that causes organ failure in early AP is similar to that caused by severe sepsis, the use of rhAPC in the management of AP has been investigated in experimental and clinical studies which are collated in this review.
2016
Context Microvascular thrombosis is a critical event in severe acute pancreatitis. Human recombinant activated protein C (Xigris®, Eli Lilly, Indianapolis, IN, USA) modulates the interplay between pro-inflammatory and pro-coagulant pathways and maintains microvascular patency. However, the anticoagulant properties of Xigris ® may precipitate bleeding from the inflamed pancreas. Objective This study tests the hypothesis that Xigris ® can ameliorate experimental acute pancreatitis without causing pancreatic haemorrhage. Methods Sprague Dawley rats were allocated as follows: Group 1: control (n=7); Group 2: acute pancreatitis (n=6); Group 3: administration of Xigris ® 500 µg/kg body weight before induction of acute pancreatitis (n=6); and Group 4: Administration of Xigris ® 500 µg/kg body weight 30 minutes after induction of acute pancreatitis (n=6). Acute pancreatitis was induced by intraperitoneal administration of L-arginine 300 mg/100 g body weight. Animals were sacrificed at 48 ho...
Clinical Science, 2003
Immune suppression plays an important role in the pathogenesis of acute pancreatitis. Monocyte expression of HLA (human leucocyte antigen)-DR, a cellular marker of immune suppression, was determined in relation to the development of organ dysfunction in patients with acute pancreatitis. A total of 310 consecutive patients with acute pancreatitis, admitted to a university hospital within 72 h of pain onset, were studied; 194 (63%) had mild disease (group I), 87 (28%) had severe disease without organ dysfunction (group II), and 29 (9%) had severe disease with organ dysfunction (group III). HLA-DR expression, defined both as the proportion of monocytes that were HLA-DR-positive and as monocyte HLA-DR fluorescence intensity, was determined at admission, using whole-blood flow cytometry. Of the patients in group III, 13 (45%) developed organ dysfunction within 24 h of admission. The proportion of HLA-DR-positive monocytes and monocyte HLA-DR density were both related to the severity of p...
Gut, 1996
Background-An excessive leucocyte activation takes place early in severe acute pancreatitis. Furthermore, some indirect evidences suggest a disturbance of the mononuclear phagocytic system in the severe cases. Aims-To compare the early functionalism of leucocytes obtained from patients with mild disease and severe disease, under the hypothesis that an impaired phagocytic function could be associated with the leucocyte activation. Patients and methods-Flow cytometric parameters of leucocyte function, such as phagocytosis, and fluorescence of leucocytes with acridine orange (FLAO) were prospectively measured together with granulocyte elastase plasma concentrations in 21 patients with severe (n=7) and mild (n= 14) acute pancreatitis. Samples were drawn at 24 hours from admission, 48 hours, 72 hours, and on day 5. Results-There was a greater leucocyte activation together with a deficient phagocytosis before 72 hours in severe patients. The results (mean (SEM)) severe v mild were: 440 (115) jiglI v 77 (14) ig/Il for granulocyte elastase, 2.218 (377) v 1.308 (155) for FLAO, 64 (7) v 90 (2), and 55 (9) v 81 (3) for percentages of phagocytising neutrophils and monocytes, respectively. Phagocytic capacity returned to normal later on day 5. Conclusions-The excessive leucocyte activation together with the impaired phagocytosis could be related to the onset of complications in severe acute pancreatitis.
A Comparative Study of the Protein C Pathway in Septic and Nonseptic Patients with Organ Failure
American Journal of Respiratory and Critical Care Medicine, 2007
Rationale: Severe sepsis is associated with an exacerbated procoagulant state with protein C (PC) system impairment. In contrast, the inflammatory and coagulation status of nonseptic patients with organ failure (OF) is less documented. Objectives: To compare coagulation activation, focusing on the PC system, and inflammatory status in septic and nonseptic patients with OF. Methods: Thirty patients with severe sepsis and 30 nonseptic patients were recruited at the onset of OF and compared with 30 matched healthy subjects. We performed an extensive analysis of the PC pathway, including plasma protein measurements and quantification of leukocyte expression of PC system receptors. In addition, we analyzed the inflammatory status, based on inflammation-related gene leukocyte expression. Measurements and Main Results: We observed coagulation activation, reflected by a similar increase in tissue factor mRNA expression, in the two patient groups when compared with the healthy subjects. Soluble thrombomodulin levels were higher in septic patients than in healthy control subjects, whereas PC, protein S, and soluble endothelial cell PC receptor levels were lower. Similar results were obtained in nonseptic patients with OF. Monocyte thrombomodulin overexpression, together with increased circulating levels of activated PC, suggests that the capacity for PC activation is at least partly preserved in both settings. No difference in the inflammatory profile was found between septic and nonseptic patients. Conclusions: The pathogenesis of OF in critical care patients is characterized by an overwhelming systemic inflammatory response and by exacerbated coagulation activation, independently of whether or not infection is the triggering event. Clinical trial registered with www.clinicaltrials.gov (NCT 00361725).
British Journal of Surgery, 2006
Background: Mortality in patients with acute pancreatitis is associated with the number of failing organs and the severity and reversibility of organ dysfunction. The aim of this study was to assess the significance of early systemic inflammatory response syndrome (SIRS) in the development of multiorgan dysfunction syndrome (MODS) and death from acute pancreatitis. and 0 (0-9) respectively; P < 0·001). Thirty-five patients (25·4 per cent) with persistent SIRS died from acute pancreatitis, compared with six patients (8 per cent) with transient SIRS and four (0·7 per cent) without SIRS (P < 0·001). No correlation was observed between CRP level on admission and Marshall score (P = 0·810); however, there was a close correlation between CRP level at 48 h and Marshall score (P < 0·001).
Role of Biomarkers in Diagnosis and Prognostic Evaluation of Acute Pancreatitis
Journal of Biomarkers, 2015
Acute pancreatitis is a potentially life threatening disease. The spectrum of severity of the illness ranges from mild self-limiting disease to a highly fatal severe necrotizing pancreatitis. Despite intensive research and improved patient care, overall mortality still remains high, reaching up to 30–40% in cases with infected pancreatic necrosis. Although little is known about the exact pathogenesis, it has been widely accepted that premature activation of digestive enzymes within the pancreatic acinar cell is the trigger that leads to autodigestion of pancreatic tissue which is followed by infiltration and activation of leukocytes. Extensive research has been done over the past few decades regarding their role in diagnosis and prognostic evaluation of severe acute pancreatitis. Although many standalone biochemical markers have been studied for early assessment of severity, C-reactive protein still remains the most frequently used along with Interleukin-6. In this review we have di...