lexipafant and Multiple-Organ-Failure

The incidence of acute pancreatitis per 100,000 population ranges from 10 to 46. The mortality of acute edematous interstitial pancreatitis is < 1%, while patients suffering from hemorrhagic necrotizing pancreatitis die from their disease in 10-24%. 80% of all cases of acute pancreatitis are etiologically correlated to diseases of the biliary tract or an excess alcohol consumption. As of today, no specific and causal treatment for acute pancreatitis has been established. Early prognostic factors for the evaluation of the clinical course of acute eipancreatitis are three or more indicators of organ failure in the Ranson or Imrie score, the development of extrapancreatic complications or the detection of pancreatic necrosis on contrast-enhanced CT scans. Elevated C-reactive protein (CRP) levels > 130 mg/l can predict a severe course of acute pancreatitis with a high sensitivity. The foundation of medical treatment in acute pancreatitis is the substitution of fluids to counteract hypovolemia. Furthermore, the relief of sometimes severe visceral pain has the highest priority. Infusion of procaine has been found to be ineffective for this purpose. The use of antibiotics should be restricted to patients with pancreatic necrosis. Enteral nutrition has no adverse effect compared to parenteral nutrition and is likely to be beneficial to the course of pancreatitis.

Topics: Acute Disease; Adjuvants, Immunologic; Analgesics; Animals; Anti-Bacterial Agents; APACHE; C-Reactive Protein; Cholangiography; Cholangiopancreatography, Endoscopic Retrograde; Clinical Trials as Topic; Disease Models, Animal; Double-Blind Method; Enteral Nutrition; Humans; Imidazoles; Leucine; Multicenter Studies as Topic; Multiple Organ Failure; Pancreatitis; Pancreatitis, Acute Necrotizing; Placebos; Platelet Activating Factor; Prognosis; Protease Inhibitors; Randomized Controlled Trials as Topic; Retrospective Studies; Tomography, X-Ray Computed

Topics: Animals; Clinical Trials as Topic; Humans; Imidazoles; Leucine; Multiple Organ Failure; Pancreatitis, Acute Necrotizing; Platelet Activating Factor; Severity of Illness Index

Platelet activating factor (PAF) is believed to amplify the activity of key mediators of the systemic inflammatory response syndrome (SIRS) in acute pancreatitis, resulting in multiorgan dysfunction syndrome. We tested the hypothesis that a potent PAF antagonist, lexipafant, could dampen SIRS and reduce organ failure in severe acute pancreatitis.. We conducted a randomised, double blind, placebo controlled, multicentre trial of lexipafant (100 mg/24 hours intravenously for seven days commenced within 72 hours of the onset of symptoms) involving 290 patients with an APACHE II score >6. Power calculations assumed that complications would be reduced from 40% to 24%. Secondary end points studied included severity of organ failure, markers of the inflammatory response, and mortality rate.. Overall, 80/138 (58%) patients in the placebo group and 85/148 (57%) in the lexipafant group developed one or more organ failures. The primary hypothesis was invalidated by the unexpected finding that 44% of patients had organ failure on entry into the study; only 39 (14%) developed new organ failure. Organ failure scores were reduced in the lexipafant group only on day 3: median change -1 (range -4 to +8) versus 0 (-4 to +10) in the placebo group (p=0.04). Systemic sepsis affected fewer patients in the lexipafant group (13/138 v 4/148; p=0.023). Local complications occurred in 41/138 (30%) patients in the placebo group and in 30/148 (20%) in the lexipafant group (20%; p=0.065); pseudocysts developed in 19 (14%) and eight (5%) patients, respectively (p=0.025). Deaths attributable to acute pancreatitis were not significantly different. Interleukin 8, a marker of neutrophil activation, and E-selectin, a marker of endothelial damage, decreased more rapidly in the lexipafant group (both p<0.05); however, absolute values were not different between the two groups.. The high incidence of organ failure within 72 hours of the onset of symptoms undermined the primary hypothesis, and power calculations for future studies in severe acute pancreatitis will need to allow for this. Lexipafant had no effect on new organ failure during treatment. This adequately powered study has shown that antagonism of PAF activity on its own is not sufficient to ameliorate SIRS in severe acute pancreatitis

Topics: Acute Disease; Adult; Aged; Biomarkers; Double-Blind Method; E-Selectin; Female; Humans; Imidazoles; Interleukin-8; Length of Stay; Leucine; Logistic Models; Male; Middle Aged; Multiple Organ Failure; Pancreatitis; Placebos; Platelet Activating Factor; Prospective Studies

To evaluate the safety and efficacy of the platelet-activating factor receptor antagonist BB-882 in the treatment of patients with sepsis.. Double-blind, placebo-controlled, randomized, multi-centered study.. Thirty-four European intensive care units.. One hundred fifty-two patients with clinical suspicion of infection and a mean APACHE II score between 15 and 35 in the 24 hrs before entry into the trial.. Patients received either a loading dose of 4 mg of BB-882 on the first day, followed by an intravenous infusion of 96 mg/24 hrs for up to 120 hrs, or placebo.. Hemodynamic, respiratory and oxygen transport variables, blood lactate concentrations, interleukin-6, interleukin-8, tumor necrosis factor (TNF)-alpha, soluble TNF receptor concentrations, organ failure score, 28-day mortality rate, Acute Physiology And Chronic Health Evaluation (APACHE) II score within 24 hrs of entry.. Sixty-nine patients (42 male, 27 female) received placebo and 83 (59 male, 24 female) received BB-882. Patients ranged in age from 16 to 89 yrs (mean, 60 yrs). No important differences existed between the two groups in terms of gender distribution, age, or initial APACHE II score. Sepsis was identified as Gram-positive in 49 patients, Gram-negative in 40, mixed in 37, and unknown in 26. No important differences were shown in hemodynamic, respiratory, or oxygen transport variables between groups during the study. Organ failure scores were similar in the two groups throughout the study. Cytokine concentrations were not significantly different in the two groups. Within 28 days of entering the study, 75 patients died, including 31 (45%) in the placebo group and 44 (53%) in the treatment group, p = .32. The median time to death in the placebo group was 6.0 days, and in the treatment group, it was 4.5 days (p = .30).. Treatment of sepsis with the platelet-activating factor antagonist BB-882 offers no advantage over placebo on survival, hemodynamic status, respiratory function, or organ failure scores.

Topics: Adult; Aged; Aged, 80 and over; APACHE; Cytokines; Double-Blind Method; Europe; Female; Hemodynamics; Humans; Immunotherapy; Infusions, Intravenous; Lactic Acid; Leucine; Male; Middle Aged; Multiple Organ Failure; Platelet Activating Factor; Platelet Membrane Glycoproteins; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Respiratory Function Tests; Sepsis; Survival Analysis

Many patients with severe acute pancreatitis develop organ system failure during the first few days of illness, and this accounts for the majority of early deaths. No specific therapy is available and treatment remains supportive.. In a randomized controlled trial conducted in 11 hospitals in the West of Scotland, 50 patients with predicted severe acute pancreatitis were selected from 188 screened over a 14-month period. Patients received placebo or lexipafant, a potent platelet-activating factor antagonist, by continuous intravenous infusion at a dose of 100 mg/day for up to 7 days. Early systemic complications were assessed by the measurement of organ failure scores.. There was a significantly greater fall in organ failure score in the treatment group during the 7 days of study (mean and median changes in organ failure score were 0.17 and 0 in the placebo group versus -1.42 and -1 in the treatment group; P = 0.003, Wilcoxon rank sum test), associated with trends towards a reduction in mortality and a reduced incidence of systemic complications.. These results suggest that lexipafant may be a useful adjunct to full supportive care in the early management of patients with severe acute pancreatitis.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Female; Humans; Imidazoles; Infusions, Intravenous; Length of Stay; Leucine; Male; Middle Aged; Multiple Organ Failure; Pancreatitis; Treatment Outcome

Topics: Acute Disease; Acute-Phase Proteins; Animals; Cell Adhesion Molecules; Chemokines; Cytokines; Free Radicals; Humans; Imidazoles; Interleukins; Leucine; Mice; Multiple Organ Failure; Pancreas; Pancreatitis; Platelet Activating Factor; Rabbits; Rats; Selectins; Signal Transduction; Time Factors; Tumor Necrosis Factor-alpha