current concepts of the pathophysiology of acute pancreatitis suggest that disease progression from acinar injury to systemic illness involves a complex interplay between cellular and soluble inflammatory mediators and endothelial beds . to date death from acute pancreatitis remains a major issue , and late deaths are often related to haemorrhage and are associated with unresolved intra - abdominal sepsis . drotrecogin alfa , an analogue of endogenous protein c , has antithrombotic , anti - inflammatory and profibrinolytic properties , and it has been shown to reduce mortality in clinical sepsis . modulation of the coagulation cascade , although probably essential to the mode of action of drotrecogin alfa , can lead to an increased risk of bleeding . the findings of the prowess trial have led to a more widespread use of drotrecogin alfa in sepsis and , critically , in sepsis - related conditions . the present article provides a concise summary of the interaction between the pathophysiology of acute pancreatitis and the modes of action of drotrecogin alfa , placing particular emphasis on the risks related to haemorrhage . attention is further drawn to the reports of use of drotrecogin alfa in severe acute pancreatitis . synthesis of current knowledge on the modes of action and the side - effect profiles of drotrecogin alfa into a practical management algorithm must accept that evidence in this field is changing rapidly . at present there is insufficient evidence to justify the use of drotrecogin alfa in the early stages of this disease . in the later stages , when the probability of infection is proportionately greater , it is probable that intensive care clinicians will turn to drotrecogin alfa , in particular , in the setting of recent - onset organ dysfunction in established severe acute pancreatitis . although this can be justified by extrapolation of the evidence from the prowess trial , practical critical care management in this setting must not overlook the need to rule out infection of necrosis , and must further be cognisant of the specific risks of haemorrhage in patients with prolonged pancreatitis and pancreatic necrosis . the early stages of severe acute pancreatitis are characterised by a profound systemic inflammatory response . current evidence is equivocal regarding the role of infective agents at this stage of the disease process . although there is increased intestinal permeability to macromolecules associated with a fall in endotoxin antibody in severe disease , use of the polymerase chain reaction fails to show early evidence of circulating bacterial genomic products . in contrast , the later stages of severe acute pancreatitis are dominated by the sequelae of peri - pancreatic sepsis . although peri - pancreatic sepsis follows a similar course to other forms of intra - abdominal sepsis , a specific disease - related complication is the high risk of catastrophic intra - abdominal haemorrhage . the pathophysiology of bleeding at this stage of the disease is multifactorial but may be related to the effects of chronic exposure to pancreatic juice in the lesser sac as a consequence of pancreatic ductal blow - out . the search for treatments for severe sepsis has increasingly focused on the interplay between inflammation , microvascular coagulation and endothelial cell injury , and this has led to the development of drotrecogin alfa ( recombinant human activated protein c ) . drotrecogin alfa ( xigris ; eli lilly , indianapolis , in , usa ) is a 55 kda glycoprotein analogue of endogenous protein c that is synthesised and secreted by genetically engineered human cells . endogenous protein c is a vitamin k - dependent glycoprotein synthesised by the liver . under normal physiological conditions the protein c pathway plays an important role in the maintenance of haemostasis and the modulation of inflammation . activation of protein c by thrombin - dependent endothelial binding inhibits thrombin generation and stimulates fibrinolysis . in addition , activated protein c has anti - inflammatory properties related , in part , to inhibition of monocyte tumour necrosis factor alpha production and the modulation of e - selectin expression by endothelial cells . the conversion of protein c to activated protein c is impaired during sepsis , and reduced levels of markers of activated protein c correlate with increased morbidity in patients with sepsis . it has been known for some time that similar changes in protein c activation occur in experimental acute pancreatitis . in 2001 , the prowess trial group reported the phase iii randomised trial of drotrecogin alfa in 1690 patients with severe sepsis . the principal outcome was an absolute reduction of 6.1% in the risk of death at 28 days . in light of this evidence it was perhaps inevitable that drotrecogin alfa would be used more widely   in patients , including those with severe acute pancreatitis . a recent report describes the use of this drug in two patients with severe acute pancreatitis . there was one death but the authors conclude that the cases indicate the efficacy of drotrecogin alfa in severe acute pancreatitis . these reports highlight an acute dilemma in contemporary critical care practice : there is a clear dearth of specific treatment for severe acute pancreatitis , yet although drotrecogin alfa holds promise in sepsis , is it safe for use in severe acute pancreatitis ? in the absence of specific clinical trial evidence , pragmatic answers can be found in the details of the prowess trial . patients were included only if they had new - onset organ dysfunction ( sepsis - induced dysfunction of at least one organ or system that lasted no longer than 24 hours ) . although pancreatitis was a listed exclusion criterion for the prowess trial , 3.4% of patients receiving the drug had pancreatitis listed as a prior or pre - existing condition . it is highly relevant that the main cause of sepsis in patients in the prowess trial was of lung origin . a ' serious bleeding event ' occurred in 30 patients ( 3.5% ) receiving drotrecogin alfa as compared with 17 patients ( 2% ) receiving placebo . the prowess trial authors state that serious bleeding occurred primarily in patients with an identifiable predisposition to bleeding . synthesis of these findings into a practical management algorithm must accept that evidence in this field is changing rapidly . recognising that patients with severe acute pancreatitis are currently being treated with drotrecogin alfa , however , a practical position for current management would be that , despite the experimental evidence of protein c activation in the early stage of experimental acute pancreatitis , there is insufficient evidence to justify the use of drotrecogin alfa in the early stages of this disease . in the later stages , when the probability of infection is proportionately greater , it is probable that intensive care clinicians will turn to drotrecogin alfa . in the setting of recent - onset organ dysfunction in established severe acute pancreatitis there is ample evidence that infection of pancreatic necrosis is a major source of deterioration , and the availability of new drugs must not blind clinicians to the need to search for , find 2 and treat infected pancreatic necrosis . this need is made more imperative by the risk of bleeding in untreated peri - pancreatic sepsis . in conclusion , drotrecogin alfa appears to represent a genuine advance in the treatment of human sepsis but , in the face of critical illness in severe acute pancreatitis , a vogue for the use of new medications must not replace the need to detect and treat infected pancreatic necrosis .
introductioncurrent concepts of the pathophysiology of acute pancreatitis suggest that disease progression from acinar injury to systemic illness involves a complex interplay between cellular and soluble inflammatory mediators and endothelial beds . to date 
 , there is no specific pharmacologic intervention for acute pancreatitis . 
 death from acute pancreatitis remains a major issue , and late deaths are often related to haemorrhage and are associated with unresolved intra - abdominal sepsis . 
 drotrecogin alfa , an analogue of endogenous protein c , has antithrombotic , anti - inflammatory and profibrinolytic properties , and it has been shown to reduce mortality in clinical sepsis . 
 modulation of the coagulation cascade , although probably essential to the mode of action of drotrecogin alfa , can lead to an increased risk of bleeding.objectivethe findings of the prowess trial have led to a more widespread use of drotrecogin alfa in sepsis and , critically , in sepsis - related conditions . 
 the present article provides a concise summary of the interaction between the pathophysiology of acute pancreatitis and the modes of action of drotrecogin alfa , placing particular emphasis on the risks related to haemorrhage . 
 attention is further drawn to the reports of use of drotrecogin alfa in severe acute pancreatitis.conclusionsynthesis of current knowledge on the modes of action and the side - effect profiles of drotrecogin alfa into a practical management algorithm must accept that evidence in this field is changing rapidly . 
 at present there is insufficient evidence to justify the use of drotrecogin alfa in the early stages of this disease . in the later stages , 
 when the probability of infection is proportionately greater , it is probable that intensive care clinicians will turn to drotrecogin alfa , in particular , in the setting of recent - onset organ dysfunction in established severe acute pancreatitis . 
 although this can be justified by extrapolation of the evidence from the prowess trial , practical critical care management in this setting must not overlook the need to rule out infection of necrosis , and must further be cognisant of the specific risks of haemorrhage in patients with prolonged pancreatitis and pancreatic necrosis .