1.
Activated protein C does not alleviate the course of systemic inflammation in the APCAP Trial
Kyhala L, Mentula P, Kylanpaa L, Moilanen E, Puolakkainen P, Pettila V, Repo H
International Journal of Inflammation. 2012;2012:712739.
Abstract
The study aimed to determine the effect of the activated protein C on the course of systemic inflammation in the APCAP (activated protein C in acute pancreatitis) trial where we randomized 32 patients with severe acute pancreatitis to receive either recombinant activated protein C (drotrecogin alfa activated) (n = 16) or placebo (n = 16) for 96 hours. In the present study, we present the time course of the patients' plasma or serum levels of soluble markers (IL-8, IL-6, IL-10, IL-1ra, sE-selectin, PCT) and monocyte and neutrophil cell surface (CD11b, CD14, CD62L, HLA-DR) markers of systemic inflammatory response during the first 14 days after the randomization. The results of the intervention and placebo groups were comparable showing that recombinant APC treatment did not alter the course of systemic inflammation in severe acute pancreatitis. Our finding is in accordance with the clinical findings in the APCAP trial indicating that the intervention did not affect evolution of multiple organ dysfunctions.
2.
Recombinant human activated protein C as a disease modifier in severe acute pancreatitis: systematic review of current evidence
Miranda CJ, Babu BI, Siriwardena AK
Pancreatology. 2012;12((2):):119-23.
Abstract
BACKGROUND The severity of organ failure caused by acute pancreatitis (AP) is the most important determinant of mortality in the disease. Recombinant human activated protein C (Drotrecogin Alfa; Xigris, APC, rhAPC) is the first drug to show a decrease in all-cause mortality due to multiple organ failure caused by sepsis. As the systemic inflammatory response syndrome (SIRS) that causes organ failure in early AP is similar to that caused by severe sepsis, the use of rhAPC in the management of AP has been investigated in experimental and clinical studies which are collated in this review. METHODS A literature review of published material identified from MEDLINE and EMBASE databases, for the period from January 1985 to January 2011, reporting rhAPC usage in AP. RESULTS 3 of 4 experimental studies reported an improvement in outcome in animals with AP given rhAPC. The clinical randomized trial showed no improvement in outcome in the treatment arm. CONCLUSION The experimental evidence of disease amelioration in AP following intervention with rhAPC has not translated to the small clinical RCT. Given that there were only 16 patients in the treatment arm, further clinical evaluation is justified. Copyright Copyright 2012 IAP and EPC. Published by Elsevier B.V. All rights reserved.
3.
APCAP--activated protein C in acute pancreatitis: a double-blind randomized human pilot trial
Pettilä V, Kyhälä L, Kylänpää ML, Leppäniemi A, Tallgren M, Markkola A, Puolakkainen P, Repo H, Kemppainen E
Critical Care (London, England). 2010;14((4):):R139.
Abstract
INTRODUCTION 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. TRIAL REGISTRATION ClinicalTrials. gov NCT01017107.