title: APCAP--activated protein C in acute pancreatitis: a double-blind randomized human pilot trial.
abstract: BACKGROUND
  Previous human studies have shown low activity of protein C (APC) in severe acute pancreatitis (SAP). This, together with the findings in animal models, suggests that activated protein C (APC) may protect against pancreatic injury and ameliorate the disease. We, therefore, evaluated its effect on multiple organ dysfunction (MOD) measured by the SOFA (Sequential Organ Failure Assessment) and on organ-failure-free days, and the safety of APC in SAP.
  
  
  METHODS
  A prospective double blind randomized pilot study was use. The study occurred in one university hospital tertiary intensive care unit (ICU) with eight beds. The patients were chosen according to the following inclusion criteria: 1) Those admitted to the hospital < 96 h from the onset of pain, 2) Those who had a three-fold increase in serum amylase over normal upper range or/and in whom computed tomography (CT) verification of SAP was noted, 3) Those who had one or more organ dysfunction (OD), and 4) Those in whom less than 48 hours had passed since their first OD. Of a total of 215 adult patients with SAP screened between June 2003 and August 2007, 158 fulfilled the study inclusion criteria. After exclusions 32 patients were randomized to the study. The intervention consisted of APC (N = 16) administered intravenously for 96 hours with a dose of 24 μg/kg/hour or placebo (N = 16) with a similar infusion rate. The sample size for the study was calculated according to the primary end-point: the change in SOFA during study drug infusion (Days 0 and 5). Comparisons between the study groups were performed using patient-related changes and calculation of difference in means (DIM, 95% CIs) and regarding categorical variables with Fisher's exact test. For all comparisons P < 0.05 was considered significant.
  
  
  RESULTS
  No serious bleeding was detected clinically or by CT scans in either group. No significant difference in SOFA score change between the APC and placebo groups was found (difference in means (DIM) +2.3, 95% CI -0.7 to +5.3). Treatment with APC was associated with an increase in serum levels of both total and conjugated bilirubin. No differences in ventilator-free days, in renal replacement therapy-free days, in vasopressor-free days, or in days alive outside the hospital were detected.
  
  
  CONCLUSIONS
  No serious bleeding or differences in the evolution of MOD were detected between APC and the placebo. Instead we found an increase in serum bilirubin in the APC group compared to the placebo group in patients with SAP.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01017107.
authors.affiliation: Department of Anesthesia and Intensive Care Medicine, Helsinki University Central Hospital, Haartmaninkatu 2, Helsinki 00029, Finland. ville.pettila@hus.fi
authors.forename: Ville
authors.initials: V
authors.lastname: Pettilä
authors.forename: Lea
authors.initials: L
authors.lastname: Kyhälä
authors.forename: Marja-Leena
authors.initials: ML
authors.lastname: Kylänpää
authors.forename: Ari
authors.initials: A
authors.lastname: Leppäniemi
authors.forename: Minna
authors.initials: M
authors.lastname: Tallgren
authors.forename: Antti
authors.initials: A
authors.lastname: Markkola
authors.forename: Pauli
authors.initials: P
authors.lastname: Puolakkainen
authors.forename: Heikki
authors.initials: H
authors.lastname: Repo
authors.forename: Esko
authors.initials: E
authors.lastname: Kemppainen
mesh_terms: D000208:Acute Disease; D000328:Adult; D001663:Bilirubin / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000517:prevention & control; D010195:Pancreatitis / Q000000981:diagnostic imaging / Q000188:drug therapy*; D010865:Pilot Projects; D011446:Prospective Studies; D011486:Protein C / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated; D001663:Bilirubin