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829 Gastrointestinal Permeability and Infectious Complications in Acute Pancreatitis; a Prospective Multicenter Study
mortality (1.6% vs 14.4%, p<0.001 χ2). CONCLUSIONS: 1) Azotemia at admission is a significant risk factor for mortality in AP 2) Among all patients, a rise in BUN predicted increased risk of mortality 3) Among patients with azotemia at admission, a reduction in BUN within 48 hours was associated with improved survival.
AGA Abstracts
epithelium using an In Vitro model of the epithelial barrier. Methods: Caco-2 monolayers grown on semipermeable filter supports were stimulated with varying concentrations of endogenous and synthetic glucocorticoids and tight junction function was assessed by measuring transepithelial electrical resistance as well as permeability of fluorophore-coupled tracer compounds. Basic tight junction structure was analyzed by immunofluorescence against ZO-1 and occludin as well as phalloidin staining. Real time rt-PCR was employed to assess transcriptional changes of different claudin genes; in addition, expression of claudin2 and claudin-4 was analyzed by Western blotting. Results: Upon glucocorticoid stimulation, fully differentiated Caco-2 monolayers exhibited a dose dependent significant increase in transepithelial electrical resistance that could be completely reversed by the glucocorticoid receptor antagonist RU-486. Basic tight junction architecture as assessed by localization of ZO-1 and occludin was not altered upon steroid stimulation. Phalloidin staining of the actin cytoskeleton displayed no alterations in these cells. Using real time rt-PCR, we observed a significant down-regulation of the pore forming tight junction component claudin-2, whereas claudin-4 displayed a significant upregulation upon glucocorticoid stimulation on the RNA level. Western blotting confirmed these results on the protein level. Conclusions: Our data suggest that glucocorticoid signaling regulates intestinal barrier function by controlling claudin expression within the intestinal epithelium. We thereby identified a novel mode of action potentially contributing to the well established anti-inflammatory potency of these compounds. The elucidation of the molecular mechanisms involved in this regulation may not only enhance our understanding of glucocorticoid effects on the intestinal epithelium, but also allow for the validation of novel drug targets aiming to enhance or re-establish intestinal barrier function.
831 Prognostic Factors and Outcome of 121 Patients with Non-Surgical Therapy of Necrotizing Pancreatitis: What Is the Impact of An Infection of the Necrosis? Wolfgang Huber, Marion Neudeck, Katja Hauptvogel, Andreas Umgelter, Wolfgang Reindl, Andreas Weber, Jens T. Siveke, Christoph Lampart, Roland M. Schmid
829 Gastrointestinal Permeability and Infectious Complications in Acute Pancreatitis; a Prospective Multicenter Study Marc G. Besselink, Hjalmar C. van Santvoort, Marja A. Boermeester, Kathelijn Fischer, Willem Renooij, Martin B. de Smet, Geert A. Cirkel, Bert van Ramshorst, Bas L. Weusten, Alexander F. Schaapherder, Ben J. Witteman, Rutger J. Ploeg, Harry van Goor, Cees J. van Laarhoven, Camiel Rosman, Menno A. Brink, Erwin van der Harst, Peter J. Wahab, Casper H. van Eijck, Cornelis H. Dejong, Karel J. Van Erpecum, Louis M. Akkermans, Hein G. Gooszen, Members Dutch Acute Pancreatitis Study Group
Background: The mortality of necrotizing pancreatitis (NP) is up to 40%. Several recent studies demonstrated successful conservative (i.e. non-surgical) therapy of NP with sterile necroses. Despite the absence of convincing data, the presence of bacteria or fungi in the necroses usually leads to surgical therapy. Therefore, within the last 13 years our patients were treated conservatively regardless of the presence of an infection of necroses. Aims of the study: To investigate the prognostic factors and the outcome of 121 patients with proven NP admitted to a medical ICU between 1994 and 2006. Methods: systematic evaluation of outcome and risk factors including microbiological data from the aspirates/drainages of pancreatic necroses. Multiple regression analysis with “y = maximal increase in APACHEII score after admission on the ICU”; chi-square-test. Clinical algorithm: antibiotic therapy with imipenem or according to antibiogramm; repeated CT and puncture or drainage in case of clinical deterioration and/or deterioration of laboratory markers of inflammation (leukocytes, CRP, procalcitonin); surgery only in case of complications of the puncture or fluid collections not accessible to radiological drainage (n=3). Results: 1.) Patients characteristics: n=121; 48 female; 73male; age 56.7+-15.6 years, maximum CRP 28.4+-11.7mg/dl, max. APACHE-II-Score 20.0+-11.8, max. lipase 7375+-13193U/L. 40/98 patients (41%) required mechanical ventilation and 29/98 (30%) dialysis. 2.) Prognosis: The only independent risk factors at admission to the ICU for an unfavourable outcome were the level of serum creatinine (p=0.0007) and old age (p=0.035). The following parameters were not predictive: aetiology of pancreatitis, blood/serum levels of lipase, calcium, glucose, leukocytes and hematocrit as well as the presence of Cullen- and/or Grey-Turner-sign. 3.) Mortality: The overall mortality was 14/121 (12%). In 65 patients puncture and/or drainage of the necroses was performed. The mortality of these patients (8/65; 12%) was not different compared to the patients without puncture/drainage (6/56; 11%). In 49/65 (75%) of the patients with puncture bacteria and/or fungi were cultured in the aspirates. The mortality of these patients (6/49; 12%) was not different compared to the patients with sterile necrosis. Conclusions: 1.) The overall mortality of 12% was low with regard to severity of pancreatitis. 2.) Infection of the necroses had no impact on the patients outcome. Therefore, the presence of infected necrosis is no contraindication to conservative management of NP. 3.) The most important predictors for the outcome were serum creatinine levels and old age.
Background: Infectious complications and organ failure are major determinants for mortality in acute pancreatitis. Increase in gastrointestinal permeability is thought to be an early step in the pathophysiological process leading up to these events. To date, no study has reported a relationship between increased gastrointestinal permeability and the risk of infectious complications. Methods: We conducted a prospective study in 159 patients with acute pancreatitis in 14 hospitals in the Netherlands. Within 72 hours after admission a mixture of 4 polyethylene glycols (PEGs) with varying molecular weights: 5g PEG 400, 1.5g PEG 1500, 5g PEG 4000 and 10g PEG 10000 dissolved in 100 ml water was orally administered. PEG 400 can freely pass the intact intestinal mucosal barrier, whereas larger PEGs can only pass if intestinal permeability is compromised. Twenty-four hours urine output was collected and PEG-recovery determined by high performance liquid chromatography. We investigated whether the intestinal permeability, as measured with PEGs, is associated with bacteremia, and infected pancreatic necrosis, organ failure and mortality. Onset of organ failure, bacteremia and infected necrosis is presented in days after admission (mean, ± SD). When there was a significant difference in recovery of PEGs of several molecular weights, only for the largest PEG the p-value is given. Results: Overall mortality rate was 2.5%. Recovery of PEG 10000 in urine was higher in deceased patients (p=0.01). Organ failure at the time of the PEG test (9 patients; 6%) was associated with higher PEG 4000 recovery (p=0.02). The 15 patients who developed organ failure during admission (9.4%; mean 6.3 days ± 9.1 after admission) had higher recovery of PEG 10000 than patients without organ failure during admission (p=0.03). The 22 patients with bacteremia during admission (13.8%; mean 9.0 days ± 10.6 after admission) had higher recovery of PEG 4000 than patients without bacteremia (p=0.001). In patients without organ failure during the PEG test, bacteremia remained associated with higher recovery of PEG 4000 (p=0.005). Twelve patients with infected necrosis during admission (7.5%; mean 38.8 days ± 25.1) had non-significantly higher recovery of PEG 1500 than patients without infected necrosis (p=0.11). Conclusions: Increased intestinal permeability in the first 72 hours of acute pancreatitis is associated with mortality, organ failure (early and late) and bacteremia. Strategies aiming at a reduction of infectious complications by fortifying the gastrointestinal mucosal barrier should start as early as possible in the course of acute pancreatitis.
832 Prospective Randomized Trial Comparing Early Versus Delayed Oral Refeeding in Moderate Acute Pancreatitis Pierre H. Deprez, Andre P. Geubel, Etienne Danse, Yves Horsmans INTRODUCTION: In mild to moderate acute pancreatitis (AP) oral refeeding can be started when pain is controlled and the pancreatic enzymes return to normal (ESPEN guidelines 2002). Unfortunately, not enough information is available on the optimal timing of refeeding. AIMS & METHODS: To compare early vs. delayed oral refeeding in a prospective randomised trial. Inclusion criteria: AP of mild to moderate severity defined as Ranson's score <3, CT scan severity index CTSI <5, necrosis <30% and CRP < 12mg/dl, delay between start of pain and admission less than 48h, inform consent. Timing of refeeding: early (in the 24h after pain disappearance) vs. delayed (after normalisation of pancreatic enzymes or 72h after admission). Progressive intake of 1000, 1400,1800 kcal on 1st, 2nd and 3rd day, respectively. Resting energy expenditure (REE) was measured by indirect calorimetry. Objectives: comparison of length of stay, tolerance and pain relapse, nutritional and inflammatory parameters. Results are expressed as mean ± 95%CI and statistical analysis was done by one-way analysis of variance. RESULTS: 34 pts were included (16 W,18 M; mean age 47±6, BMI 25±2), 14 in the early and 11 in the delayed refeeding group. Results are summarized in table. Mean CRP level at 48h was 8.7±3.1mg/dl, CTSI 2,3±0,4, Ranson's score 1±0,3 and length of stay 149,7±21,9 hours. Delay between start of pain and admission was 15±6h and total duration of pain 71±16 h. There were no differences between groups concerning patients characteristics, etiology (42% biliary, 36% ethanol, 22% misc.), tolerance to refeeding, CRP or pancreatic enzymes rises after refeeding. Daily caloric intake was 851±109 kcal (12.1% proteins, 45% glucids, 30% lipids) increasing from 417 to 818 and 1378 kcal on 1st, 2nd and 3rd days, respectively, sign. below measured REE. Early refeeding however reduced significantly length of stay compared to delayed oral refeeding (P=0,03). Higher CRP levels, CTSI scores were significantly correlated to length of stay. CONCLUSION: Oral early refeeding defined as intake of food in the 24h following disappearance of pain resulted in a significant shortening
830 Correction of Azotemia Is Associated with Reduced Mortality in Acute Pancreatitis Bechien U. Wu, Richard S. Johannes, Xiaowu Sun, Darwin Conwell, Peter A. Banks INTRODUCTION: While an increase in BUN >5mg/dL at 48 hours is one of the Ranson criteria of severity in AP, the impact of correcting azotemia on mortality is unknown. AIMS: 1) To confirm whether azotemia at admission (BUN>25 mg/dL)is a risk factor for in-hospital mortality in AP 2) To determine whether serial BUN measurements can help predict inhospital mortality 3) To assess whether correction of azotemia is associated with reduced mortality. METHODS: A retrospective cohort study was performed on patient data obtained from the Cardinal Health Outcomes Research Database; a large population-based dataset. Cases from 72 participating U.S. hospitals were identified from 2003 thru 2006 by ICD9CM 577.0 (AP). Eligible cases were further restricted to those with ≥3 BUN measurements within 48 hours of admission. Linear regression was used to identify individual patient laboratory trajectories. RESULTS: There were a total of 15,153 AP cases with 173 (1.1%) deaths. Among these, 6,613 patients had ≥ 3 BUN measurements within 48-hours. There were 93 (1.4%) deaths in this cohort of patients. Azotemia at admission was a significant risk factor for mortality (0.8% vs. 4.1%, p<0.001 χ2). Among all patients, an increase in BUN was associated with significantly increased mortality (p<0.001 χ2, see figure). Among the 1,301 patients with azotemia at admission, there were 53 (4.1%) deaths. In these patients, correction of azotemia within the first 48 hours was associated with significantly reduced
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AGA Abstracts
AGA Abstracts
epithelium using an In Vitro model of the epithelial barrier. Methods: Caco-2 monolayers grown on semipermeable filter supports were stimulated with varying concentrations of endogenous and synthetic glucocorticoids and tight junction function was assessed by measuring transepithelial electrical resistance as well as permeability of fluorophore-coupled tracer compounds. Basic tight junction structure was analyzed by immunofluorescence against ZO-1 and occludin as well as phalloidin staining. Real time rt-PCR was employed to assess transcriptional changes of different claudin genes; in addition, expression of claudin2 and claudin-4 was analyzed by Western blotting. Results: Upon glucocorticoid stimulation, fully differentiated Caco-2 monolayers exhibited a dose dependent significant increase in transepithelial electrical resistance that could be completely reversed by the glucocorticoid receptor antagonist RU-486. Basic tight junction architecture as assessed by localization of ZO-1 and occludin was not altered upon steroid stimulation. Phalloidin staining of the actin cytoskeleton displayed no alterations in these cells. Using real time rt-PCR, we observed a significant down-regulation of the pore forming tight junction component claudin-2, whereas claudin-4 displayed a significant upregulation upon glucocorticoid stimulation on the RNA level. Western blotting confirmed these results on the protein level. Conclusions: Our data suggest that glucocorticoid signaling regulates intestinal barrier function by controlling claudin expression within the intestinal epithelium. We thereby identified a novel mode of action potentially contributing to the well established anti-inflammatory potency of these compounds. The elucidation of the molecular mechanisms involved in this regulation may not only enhance our understanding of glucocorticoid effects on the intestinal epithelium, but also allow for the validation of novel drug targets aiming to enhance or re-establish intestinal barrier function.
831 Prognostic Factors and Outcome of 121 Patients with Non-Surgical Therapy of Necrotizing Pancreatitis: What Is the Impact of An Infection of the Necrosis? Wolfgang Huber, Marion Neudeck, Katja Hauptvogel, Andreas Umgelter, Wolfgang Reindl, Andreas Weber, Jens T. Siveke, Christoph Lampart, Roland M. Schmid
829 Gastrointestinal Permeability and Infectious Complications in Acute Pancreatitis; a Prospective Multicenter Study Marc G. Besselink, Hjalmar C. van Santvoort, Marja A. Boermeester, Kathelijn Fischer, Willem Renooij, Martin B. de Smet, Geert A. Cirkel, Bert van Ramshorst, Bas L. Weusten, Alexander F. Schaapherder, Ben J. Witteman, Rutger J. Ploeg, Harry van Goor, Cees J. van Laarhoven, Camiel Rosman, Menno A. Brink, Erwin van der Harst, Peter J. Wahab, Casper H. van Eijck, Cornelis H. Dejong, Karel J. Van Erpecum, Louis M. Akkermans, Hein G. Gooszen, Members Dutch Acute Pancreatitis Study Group
Background: The mortality of necrotizing pancreatitis (NP) is up to 40%. Several recent studies demonstrated successful conservative (i.e. non-surgical) therapy of NP with sterile necroses. Despite the absence of convincing data, the presence of bacteria or fungi in the necroses usually leads to surgical therapy. Therefore, within the last 13 years our patients were treated conservatively regardless of the presence of an infection of necroses. Aims of the study: To investigate the prognostic factors and the outcome of 121 patients with proven NP admitted to a medical ICU between 1994 and 2006. Methods: systematic evaluation of outcome and risk factors including microbiological data from the aspirates/drainages of pancreatic necroses. Multiple regression analysis with “y = maximal increase in APACHEII score after admission on the ICU”; chi-square-test. Clinical algorithm: antibiotic therapy with imipenem or according to antibiogramm; repeated CT and puncture or drainage in case of clinical deterioration and/or deterioration of laboratory markers of inflammation (leukocytes, CRP, procalcitonin); surgery only in case of complications of the puncture or fluid collections not accessible to radiological drainage (n=3). Results: 1.) Patients characteristics: n=121; 48 female; 73male; age 56.7+-15.6 years, maximum CRP 28.4+-11.7mg/dl, max. APACHE-II-Score 20.0+-11.8, max. lipase 7375+-13193U/L. 40/98 patients (41%) required mechanical ventilation and 29/98 (30%) dialysis. 2.) Prognosis: The only independent risk factors at admission to the ICU for an unfavourable outcome were the level of serum creatinine (p=0.0007) and old age (p=0.035). The following parameters were not predictive: aetiology of pancreatitis, blood/serum levels of lipase, calcium, glucose, leukocytes and hematocrit as well as the presence of Cullen- and/or Grey-Turner-sign. 3.) Mortality: The overall mortality was 14/121 (12%). In 65 patients puncture and/or drainage of the necroses was performed. The mortality of these patients (8/65; 12%) was not different compared to the patients without puncture/drainage (6/56; 11%). In 49/65 (75%) of the patients with puncture bacteria and/or fungi were cultured in the aspirates. The mortality of these patients (6/49; 12%) was not different compared to the patients with sterile necrosis. Conclusions: 1.) The overall mortality of 12% was low with regard to severity of pancreatitis. 2.) Infection of the necroses had no impact on the patients outcome. Therefore, the presence of infected necrosis is no contraindication to conservative management of NP. 3.) The most important predictors for the outcome were serum creatinine levels and old age.
Background: Infectious complications and organ failure are major determinants for mortality in acute pancreatitis. Increase in gastrointestinal permeability is thought to be an early step in the pathophysiological process leading up to these events. To date, no study has reported a relationship between increased gastrointestinal permeability and the risk of infectious complications. Methods: We conducted a prospective study in 159 patients with acute pancreatitis in 14 hospitals in the Netherlands. Within 72 hours after admission a mixture of 4 polyethylene glycols (PEGs) with varying molecular weights: 5g PEG 400, 1.5g PEG 1500, 5g PEG 4000 and 10g PEG 10000 dissolved in 100 ml water was orally administered. PEG 400 can freely pass the intact intestinal mucosal barrier, whereas larger PEGs can only pass if intestinal permeability is compromised. Twenty-four hours urine output was collected and PEG-recovery determined by high performance liquid chromatography. We investigated whether the intestinal permeability, as measured with PEGs, is associated with bacteremia, and infected pancreatic necrosis, organ failure and mortality. Onset of organ failure, bacteremia and infected necrosis is presented in days after admission (mean, ± SD). When there was a significant difference in recovery of PEGs of several molecular weights, only for the largest PEG the p-value is given. Results: Overall mortality rate was 2.5%. Recovery of PEG 10000 in urine was higher in deceased patients (p=0.01). Organ failure at the time of the PEG test (9 patients; 6%) was associated with higher PEG 4000 recovery (p=0.02). The 15 patients who developed organ failure during admission (9.4%; mean 6.3 days ± 9.1 after admission) had higher recovery of PEG 10000 than patients without organ failure during admission (p=0.03). The 22 patients with bacteremia during admission (13.8%; mean 9.0 days ± 10.6 after admission) had higher recovery of PEG 4000 than patients without bacteremia (p=0.001). In patients without organ failure during the PEG test, bacteremia remained associated with higher recovery of PEG 4000 (p=0.005). Twelve patients with infected necrosis during admission (7.5%; mean 38.8 days ± 25.1) had non-significantly higher recovery of PEG 1500 than patients without infected necrosis (p=0.11). Conclusions: Increased intestinal permeability in the first 72 hours of acute pancreatitis is associated with mortality, organ failure (early and late) and bacteremia. Strategies aiming at a reduction of infectious complications by fortifying the gastrointestinal mucosal barrier should start as early as possible in the course of acute pancreatitis.
832 Prospective Randomized Trial Comparing Early Versus Delayed Oral Refeeding in Moderate Acute Pancreatitis Pierre H. Deprez, Andre P. Geubel, Etienne Danse, Yves Horsmans INTRODUCTION: In mild to moderate acute pancreatitis (AP) oral refeeding can be started when pain is controlled and the pancreatic enzymes return to normal (ESPEN guidelines 2002). Unfortunately, not enough information is available on the optimal timing of refeeding. AIMS & METHODS: To compare early vs. delayed oral refeeding in a prospective randomised trial. Inclusion criteria: AP of mild to moderate severity defined as Ranson's score <3, CT scan severity index CTSI <5, necrosis <30% and CRP < 12mg/dl, delay between start of pain and admission less than 48h, inform consent. Timing of refeeding: early (in the 24h after pain disappearance) vs. delayed (after normalisation of pancreatic enzymes or 72h after admission). Progressive intake of 1000, 1400,1800 kcal on 1st, 2nd and 3rd day, respectively. Resting energy expenditure (REE) was measured by indirect calorimetry. Objectives: comparison of length of stay, tolerance and pain relapse, nutritional and inflammatory parameters. Results are expressed as mean ± 95%CI and statistical analysis was done by one-way analysis of variance. RESULTS: 34 pts were included (16 W,18 M; mean age 47±6, BMI 25±2), 14 in the early and 11 in the delayed refeeding group. Results are summarized in table. Mean CRP level at 48h was 8.7±3.1mg/dl, CTSI 2,3±0,4, Ranson's score 1±0,3 and length of stay 149,7±21,9 hours. Delay between start of pain and admission was 15±6h and total duration of pain 71±16 h. There were no differences between groups concerning patients characteristics, etiology (42% biliary, 36% ethanol, 22% misc.), tolerance to refeeding, CRP or pancreatic enzymes rises after refeeding. Daily caloric intake was 851±109 kcal (12.1% proteins, 45% glucids, 30% lipids) increasing from 417 to 818 and 1378 kcal on 1st, 2nd and 3rd days, respectively, sign. below measured REE. Early refeeding however reduced significantly length of stay compared to delayed oral refeeding (P=0,03). Higher CRP levels, CTSI scores were significantly correlated to length of stay. CONCLUSION: Oral early refeeding defined as intake of food in the 24h following disappearance of pain resulted in a significant shortening
830 Correction of Azotemia Is Associated with Reduced Mortality in Acute Pancreatitis Bechien U. Wu, Richard S. Johannes, Xiaowu Sun, Darwin Conwell, Peter A. Banks INTRODUCTION: While an increase in BUN >5mg/dL at 48 hours is one of the Ranson criteria of severity in AP, the impact of correcting azotemia on mortality is unknown. AIMS: 1) To confirm whether azotemia at admission (BUN>25 mg/dL)is a risk factor for in-hospital mortality in AP 2) To determine whether serial BUN measurements can help predict inhospital mortality 3) To assess whether correction of azotemia is associated with reduced mortality. METHODS: A retrospective cohort study was performed on patient data obtained from the Cardinal Health Outcomes Research Database; a large population-based dataset. Cases from 72 participating U.S. hospitals were identified from 2003 thru 2006 by ICD9CM 577.0 (AP). Eligible cases were further restricted to those with ≥3 BUN measurements within 48 hours of admission. Linear regression was used to identify individual patient laboratory trajectories. RESULTS: There were a total of 15,153 AP cases with 173 (1.1%) deaths. Among these, 6,613 patients had ≥ 3 BUN measurements within 48-hours. There were 93 (1.4%) deaths in this cohort of patients. Azotemia at admission was a significant risk factor for mortality (0.8% vs. 4.1%, p<0.001 χ2). Among all patients, an increase in BUN was associated with significantly increased mortality (p<0.001 χ2, see figure). Among the 1,301 patients with azotemia at admission, there were 53 (4.1%) deaths. In these patients, correction of azotemia within the first 48 hours was associated with significantly reduced
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AGA Abstracts