title: Drotrecogin alfa (recombinant human activated protein C) in severe acute pancreatitis.
abstract: BACKGROUND
  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, 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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Hepatobiliary Unit, Department of Surgery, Manchester Royal Infirmary, Manchester, UK. sjamdar@doctors.org.uk
authors.forename: Saurabh
authors.initials: S
authors.lastname: Jamdar
authors.forename: Ajith K
authors.initials: AK
authors.lastname: Siriwardena
mesh_terms: D000208:Acute Disease; D000890:Anti-Infective Agents / Q000627:therapeutic use*; D003422:Critical Care / Q000379:methods; D006470:Hemorrhage / Q000209:etiology; D006801:Humans; D010195:Pancreatitis / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D011486:Protein C / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D018805:Sepsis / Q000209:etiology / Q000503:physiopathology; D016896:Treatment Outcome
chemical_list: D000890:Anti-Infective Agents; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated