Pernille Haraldsen

Incidence, management and recurrence rate of acute pancreatitis.

Background: Acute pancreatitis is a common condition that is still associated with substantial morbidity and mortality rates. Management, outcome and recurrence rate in acute pancreatitis in a clinical setting using a conservative management approach are described. Methods: A total of 1376 consecutive cases representing 2211 hospitalizations due to acute pancreatitis treated at the Dept. of Surgery, Lund University Hospital, Lund, were reviewed retrospectively. Management, outcome and recurrence rate were recorded. Results: Incidence, including recurrences, was 300 per million per year; 21% of patients had recurrent (≥2) attacks. In relapsing disease, two‐thirds of patients had the first attack within 3 months. Mortality decreased over the period studied, but overall it was 4.2%; mortality in relapsing attacks was 2.5%, related to multiple organ dysfunction (MODS) in 67% and occurring within the first week in 36%. Conclusions: Despite a conservative approach in the management of acute pancreatitis, mortality is still substantial, frequently occurs early after admission, is associated with MODS and is also seen in relapsing disease. Early cholecystectomy and bile duct clearance could decrease recurrent attacks of biliary pancreatitis.

Antioxidant and Calcium Channel Blockers Counteract Endothelial Barrier Injury Induced by Acute Pancreatitis in Rats

BACKGROUND Multiple organ failure is the major mortality-related complication in severe acute pancreatitis. Endothelial barrier injury may be involved in its pathophysiology. METHODS The present study evaluated alterations in endothelial barrier integrity in different organs/tissues 12 h after induction of acute pancreatitis by intraductal infusions of bile. Potential effects of oxygen free radicals and calcium influx were evaluated by pretreatment with an antioxidant, N-acetyl-L-cysteine, and calcium channel antagonists, verapamil and diltiazem. RESULTS Tissue edema, reflected by an increase in tissue water content, was noted in the stomach, proximal small intestine, cecum, spleen, pancreas, kidneys, liver, lungs, heart, and brain in rats with pancreatitis. Also, an increased endothelial barrier permeability, as evidenced by the leakage of radiolabeled human serum albumin from blood to tissues, occurred in the stomach, proximal small intestine, colon, peritoneum, spleen, pancreas, kidneys, liver, lungs, and heart, accompanied by altered liver functions, increased levels of pancreatic enzymes, compromised renal function, and delayed intestinal motility. N-acetyl-L-cysteine prevented tissue edema and endothelial permeability changes in most organs/tissues, whereas the effects of verapamil and diltiazem were less marked. The preventive effects occurred in an organ-dependent manner. CONCLUSIONS Endothelial barrier injury is found in all investigated organs/tissues in acute experimental pancreatitis. Oxygen free radicals and calcium influx may play a role in the development of these changes.

Treatment with lexipafant ameliorates the severity of pancreatic microvascular endothelial barrier dysfunction in rats with acute hemorrhagic pancreatitis

SummaryConclusion: Treatment with lexipafant reduced the severity of pancreatitis-associated endothelial barrier compromise, also associated with a decrease in systemic concentrations of interleukin (IL) 1. Thus, the present findings imply that platelet-activating factor (PAF) may play an important role in the pathogenesis of pancreatic endothelial dysfunction by signaling and triggering the production and release of certain cytokines.Background: Pancreatic capillary endothelial barrier dysfunction is an initial and characteristic feature of acute pancreatic injury and pancreatitis. PAF, a proinflammatory mediator and an intercellular signaling substance, has been considered to be involved in the inflammatory reaction and the systemic endothelial dysfunction of acute pancreatitis.Methods: The development of pancreatic capillary endothelial barrier dysfunction was monitored by tissue edema and exudation of plasma albumin into the interstitium, 3 and 12 h after induction of acute pancreatitis by intraductal infusion of 5% sodium taurodeoxycholate in rats. Pancreatic leukocyte recruitment was reflected by measuring myeloperoxidase activity. Serum levels of IL-1β and IL-6 were determined by an enzyme-linked immunosorbent assay (ELISA).Results: Pretreatment with lexipafant, a potent PAF receptor antagonist, significantly reduced the pancreatitis-induced increase in pancreatic endothelial barrier dysfunction, pancreatic leukocyte recruitment, and serum levels of IL-1β, although a difference persisted between animals with sham operation and pancreatitis.

Multimodal management - of value in fulminant acute pancreatitis?

Background: The multiple organ dysfunction syndrome (MODS) is the major cause of morbidity and mortality associated with acute pancreatitis. Presently, therapy is merely organ supportive as no effective therapy against underlying causative pathophysiological mechanisms exists. Aims: To evaluate the effect of treatment with a platelet-activating factor inhibitor (PAFI), a monoclonal antibody against platelet endothelial cell adhesion molecule 1 (PECAM-1-MAb) and an oxygen free radical scavenger (N-acetylcystein; NAC), alone or in combination, on systemic organ dysfunction in experimental acute pancreatitis. Methods: Severe acute pancreatitis was induced in rats by the intraductal administration of taurodeoxycholate. Treatment was given after 1 or 3 h, and evaluations were performed 6 h after induction. Organ dysfunction was evaluated by means of endothelial integrity impairment expressed as endothelial barrier leakage index. Results: Severe acute pancreatitis caused a significant impairment in endothelial integrity in all organs studied and decreased levels of protease inhibitors compared to controls. The endothelial barrier impairment was significantly ameliorated by all treatment modalities, either given early or later. Combinations of NAC and the PECAM-1-MAb or the PECAM-1-MAb and the PAFI were the only schedules to restore endothelial barrier integrity to normal levels in most of the organs studied. Conclusion: Combination therapy with NAC and PECAM-1-MAb and/or PAFI may offer effective, causative-directed supplements to organ-supportive therapy of MODS in severe acute pancreatitis.

A porcine model for acute ischaemic right ventricular dysfunction

OBJECTIVES To establish an experimental model for acute ischaemic isolated right ventricular dysfunction and the subsequent haemodynamic changes. METHODS An open-chest porcine model with ischaemic dysfunction of the right ventricle induced by ligation of the three main branches supporting the right ventricular free wall. Invasive monitoring of mean arterial blood pressure (MAP), central venous pressure (CVP), left atrial pressure (LAP) and right ventricular pressure (RVP); ultrasonic measurement of cardiac output (CO) and calculation of haemodynamic parameters such as stroke volume (SV), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR) and right ventricular stroke work (RVSW) using standard formulae. RESULTS The ischaemic challenge to the right ventricle resulted in a significant (≥30%) reduction in RVSW associated with an increase (6-25%) in CVP and reduction (8-18%) in pulmonary artery pressure (PAP) despite unchanged PVR, all reflecting the failing right ventricle. There was also a significant drop in CO (14-22%) despite unchanged LAP indicating lessened transpulmonary delivery of left ventricular preload due to the failing right ventricle causing the haemodynamic compromise rather than left ventricular failure. Supraventricular and ventricular arrhythmias occurred in three and two out of seven pigs, respectively-all of which except one were successfully resuscitated with cardioversion and/or defibrillation. CONCLUSIONS This novel open-chest porcine model of induced ischaemia of the right ventricular free wall resulted in significant haemodynamic compromise confirmed using standard haemodynamic measurements making it useful for further research on acute, ischaemic isolated right ventricular failure.

Sevoflurane anesthesia during acute right ventricular ischemia in pigs preserves cardiac function better than propofol anesthesia.

Background: The intention of the present study was to evaluate possible cardioprotective properties of inhalation anesthesia with sevoflurane. Methods and Materials: A porcine, open-chest model of right ventricular ischemia was used in 7 pigs receiving inhalation anesthesia with sevoflurane. The model was earlier developed and published by our group, using pigs receiving intravenous anesthesia with propofol. They served as controls. The animals were observed for three hours after the induction of right ventricular ischemia by ligation of the main branches supplying the right ventricular free wall. Results: In the sevoflurane group, the cardiac output recovered 2 hours after the induction of ischemia and intact right ventricular stroke work was observed. In the propofol group, no such recovery occurred. The release of troponin T was significantly lower than in the sevoflurane group. Conclusions: Inhalation anesthesia with sevoflurane seems superior to intravenous anesthesia with propofol in acute right ventricular ischemic dysfunction.

Pancreatitis-associated pulmonary injury - effects of Lexipafant, a PAF-antagonist

Objective. Pulmonary injury is an important determinant of outcome in severe acute pancreatitis. The aim of this experimental study was to investigate the potential effect of lexipafant, a platelet-activating factor (PAF) antagonist, on pancreatitis-associated pulmonary injury in experimental acute pancreatitis. Material and methods. Acute pancreatitis was induced by intraductal infusion of 5% sodium taurodeoxycholate in rats that were given the PAF antagonist lexipafant either before (pretreatment) or after (treatment) induction of pancreatitis. Pulmonary endothelial barrier permeability, oedema, protease inhibitor levels, pulmonary ultrastructure and membrane system integrity and levels of interleukin-1 and -6 were evaluated. Results. Pulmonary injury was characterized by increased pulmonary endothelial barrier permeability, alveolar oedema and hypoxaemia, which were noted 12 h after the induction of pancreatitis. Pretreatment with lexipafant counteracted the increase in endothelial permeability and par...

Potential mechanisms responsible for zymosan-associated endothelial injury in rats

OBJECTIVE To assess alterations in endothelial barrier integrity and potential factors involved in zymosan-associated endothelial injury. DESIGN Experimental study. SETTING University hospital, Sweden. ANIMALS 42 adult male Sprague-Dawley rats. INTERVENTIONS One hour before an intraperitoneal injection of paraffin or zymosan (0.25 mg/g body weight), 1.0 ml of a solution of saline, N-acetyl-L-cysteine, dimethyl sulphoxide, indomethacin, verapamil, or allopurinol was given intravenously. MAIN OUTCOME MEASURES Measurement of tissue water content, tissue intravascular plasma volume, interstitial fluid volume, and extravascular 125I-labelled human serum albumin distribution as well as plasma concentrations of albumin, alpha1-macroglobulin, alpha2-antiplasmin, and antithrombin III, 24 hours after the intraperitoneal injection. RESULTS Endothelial permeability significantly increased in abdominal organs and the gastrointestinal tract, and plasma antiplasmin concentrations decreased. Pretreatment with N-acetyl-L-cysteine, dimethyl sulphoxide, or indomethacin protected against zymosan-induced endothelial barrier injury and the decline in protease inhibitors in plasma to varying degrees, while pretreatment with verapamil or allopurinol had a limited effect. CONCLUSION Oxygen free radicals, prostaglandin, and proteases may have roles in the pathogenesis of zymosan-induced endothelial barrier injuries, implying that several mediators probably are interacting.