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We have demonstrated that pancreatitis-associated ascitic fluid contributes to hepatocyte injury during acute pancreatitis; a phenomenon independent of ascites'' enzymatic content and Kupffer cell-derived cytokines. Our aim is to characterize the mechanisms of pancreatitis-associated ascitic fluid induced hepatocyte death. NIH mice were injected intraperitoneally with pathogen-free pancreatitis-associated ascitic fluid. Twenty-four hours later, serum AST, ALT, LDH, and hepatocyte apoptosis (TUNEL) were measured. Human hepatocytes (CCL-13) were treated with pancreatitis-associated ascitic fluid ±SB203580 or caspase-3 inhibitor-II. Mitochondrial membrane integrity was determined by DiOC6 staining. Apoptosis was measured by TUNEL staining and flow cytometry after dual labeling with Annexin-V/7-AAD. Data are mean ± SEM of triplicates. Pancreatitis-associated ascitic fluid increased serum AST, ALT, LDH, and apoptotic cells in the mouse liver (all P < 0.03 vs. sham). In CCL-13 cells, pancreatitis-associated ascitic fluid induced a time and dose-dependent increase in apoptosis, in addition to p38-MAPK phosphorylation (P = 0.02 vs. control), caspase-3 cleavage (P < 0.03 vs. control) and decreased DiOC6 mitochondrial staining (P < 0.01 vs. control). Both caspase-3 inhibitor-II and SB203580 decreased apoptosis, but the former had no effect on DiOC6 staining. Pancreatitis-associated ascitic fluid induces liver injury and hepatocyte apoptosis by activating p38-MAPK and caspase-3 dependent pro-apoptotic pathways. ( J Gastrointest Surg 2003;7:200–208.) [Copyright &y& Elsevier]

Purpose: In addition to opioid abuse and dependency, opioid use can lead to opioid related adverse drug events (ORADEs). ORADEs are associated with increased length of stay, cost of care, 30-day readmission rate, and inpatient mortality. The addition of scheduled non-opioid analgesic medications has shown to be effective in reducing opioid utilization in post-surgical and trauma populations, but evidence in entire hospital patient populations is limited. The objective of this study was to determine the effects of a multimodal analgesia order set on opioid utilization and adverse drug events in adult hospitalized patients. Methods: This retrospective pre/post implementation analysis was conducted at 3 community hospitals and a level II trauma center between January 2016 and December 2019. Patients included were 18 years of age or older, admitted for greater than 24 hours, and had at least one opioid ordered during hospital admission. The primary outcome of this analysis was the average oral morphine milligram equivalents (MME) used on days 1 through 5 of hospitalization. Secondary outcomes included the percentage of hospitalized patients with an opioid ordered for analgesia who received a scheduled non-opioid analgesic medication, the average number of ORADEs recorded in nursing assessments on hospitalization days 1 through 5, length of stay, and mortality. Multimodal analgesic medications included acetaminophen, gabapentinoids, non-steroidal anti-inflammatory drugs, muscle relaxants, and transdermal lidocaine. Results: The pre- and post-groups included 86 535 patients and 85 194 patients, respectively. The average oral MMEs used on days 1 through 5 were lower in the post-group (P <.0001). Utilization of multimodal analgesia as measured by the percentage of patients with 1 or more scheduled multimodal analgesia agent ordered increased from 33% to 49% at the end of the analysis. Conclusion: Utilization of a multimodal analgesia order set was associated with a decrease in opioid use and an increase in multimodal analgesia use in an entire hospital adult population. [ABSTRACT FROM AUTHOR]

We have demonstrated that Kupffer cell–derived tumor necrosis factor (TNF) mediates pancreatitis-associated liver injury. The aim of this study was to determine the role of p38 mitogen-activated protein kinase (MAPK), extracellular stress-related kinase 1/2 (ERK1/2), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and nuclear factor–κB (NF-κB) in TNF gene expression within Kupffer cells. TNF and TNF-mRNA were measured in rat livers perfused with elastase. TNF, TNF-mRNA, NF-κB activation, and phosphorylated p38-MAPK, SAPK/JNK, and ERK1/2 were determined in Kupffer cells treated with elastase. Elastase increased TNF and upregulated TNF-mRNA in livers (P<0.03) and Kupffer cells (P<0.001). Phosphorylated p38-MAPK, SAPK/JNK, and ERK1/2 and activated NF-κB were detected in Kupffer cells at 7 minutes; at 60 minutes, TNF-mRNA peaked and NF-κB returned to baseline, whereas all three kinases remained activated. Gadolinium inhibited elastase-induced upregulation of TNF-mRNA (P < 0.001), TNF production (P<0.001), and attenuated SAPK/JNK, as well as ERK1/2, but not p38-MAPK. Both UO126 and SB203580 significantly inhibited elastase-induced upregulation of TNF-mRNA and TNF production (P<0.001), but only UO126 inhibited activation of NF-κB. It was concluded that pretranscriptional regulation of TNF gene expression in Kupffer cells follows an orderly activation of p38-MAPK, ERK1/2, and SAPK/JNK that may not converge on NF-κB. The seemingly limited duration of NF-κB activation may be important in “switching off” the cytokine cascade during acute pancreatitis. ( J Gastrointest Surg 2003;7:20–25.) [Copyright &y& Elsevier]

Introduction. Kupffer-cell-derived cytokines mediate liver injury, yet macrophage pacification does not abolish hepatocyte injury. We undertook this study to examine the role of pancreatitis-associated ascitic fluid (PAAF) in liver injury.Methods. Pathogen-free PAAF was perfused into healthy rat livers in situ for 60 min (n = 5, sham = 5, LPS = 5). AST, ALT, LDH, and TNF were measured in the effluent. Primary cultures of rat Kupffer cells or hepatocytes were treated with PAAF; AST, ALT, LDH, and TNF were measured and cell proliferation was determined by MTT assay. A hepatocyte human cell line (CCL-13) was treated with PAAF and apoptosis was measured by flow cytometry.Results. Liver perfusion with PAAF induced a >15-fold increase in AST/ALT/LDH (P < 0.001 PAAF vs sham), but not in TNF. In vitro, Kupffer cell viability was sharply reduced by PAAF in a dose-dependent manner; however, 5% PAAF (50% viability) did not induce TNF production from Kupffer cells. PAAF induced a multifold increase in AST/ALT/LDH from fresh hepatocytes (P < 0.001 vs control), which was not attenuated by a protease inhibitor. The CCL-13 cell population was reduced to 15 ± 2% of baseline by PAAF (P < 0.001 vs control), whereas elastase, trypsin, or TNF had no effect. PAAF increased the percentage of nonviable CCL-13 cells (78 ± 4% vs 28 ± 1%, P < 0.001 vs control). Neither protease inhibitor nor heat inactivation of PAAF altered this pattern of hepatocyte death.Conclusion. PAAF induces direct hepatocyte injury and death by heat-stable factors other than pancreatic enzymes but not via local production of Kupffer-cell-derived cytokines. [Copyright &y& Elsevier]

Liver injury is a manifestation of the systemic inflammatory response during acute pancreatitis. We have demonstrated that elastase induces macrophage tumor necrosis factor (TNF) production in distant organs, thus mimicking pancreatitis-associated organ injury. The aim of this study was to determine the mechanism by which elastase induces hepatic cytokine production. Rat livers (n = 40) were perfused with elastase ± gadolinium (Gd) to inhibit Kupffer cells. Liver parenchymal enzymes and TNF were measured in the effluent. In vitro, rat hepatocytes or Kupffer cells were treated with elastase (1 U/ml) ± Gd (0.5 mg/ml) or pyrrolidine dithiocarbamate (PDTC; 0.5 mg/ml). TNF protein, TNF messenger RNA, and NF–κB activation were determined. In vivo, Gd blunted the elastase-induced TNF production and decreased AST, ALT, LDH, and nonviable cells (propidium iodide) (P ≤ 0.03 vs. elastase). In vitro, elastase induced TNF production from Kupffer cells (P < 0.001 vs. control) but not from hepatocytes. Gd or PDTC significantly attenuated the elastase-induced TNF production (P < 0.001). Elastase-induced overexpression of TNF messengerRNA and activation of NF-κB was attenuated by Gd. Pancreatic elastase induces a pattern of liver injury similar to that seen during acute pancreatitis by activating cytokine production and gene expression within Kupffer cells via NF-κB. Gd exhibits a protective effect against elastase-induced liver injury by inhibiting activation of NF-κB. ( J Gastrointest Surg 2002;6:474-480.) [ABSTRACT FROM AUTHOR]