The use of drotrecogin alfa recombinant activated protein C for severe sepsis in the critically burned patient: A new treatment approach

Burns ◽  
2006 ◽  
Vol 32 (6) ◽  
pp. 783-787 ◽  
Author(s):  
Jennifer Weintraub ◽  
Thomas Satterwhite ◽  
Maria Allo
Keyword(s):  
Severe Sepsis ◽  
Protein C ◽  
Drotrecogin Alfa ◽  
Treatment Approach ◽  
Activated Protein C ◽  
Burned Patient ◽  
New Treatment

New and Emerging Therapies for Sepsis

2002 ◽  
Vol 36 (4) ◽  
pp. 648-654 ◽  
Author(s):  
Daniel P Healy
Keyword(s):  
Severe Sepsis ◽  
Inflammatory Response ◽  
Protein C ◽  
Drotrecogin Alfa ◽  
Activated Protein C ◽  
Antibody Fragment ◽  
Phase Iii ◽  
Human Form ◽  
Risk Of Death ◽  
Phase Iii Trials

OBJECTIVE: To review the recent advances related to the pathophysiology of sepsis and the rationale for recombinant human-activated protein C (drotrecogin alfa) and other antisepsis agents currently in Phase III trials. DATA SOURCES: A MEDLINE (1990–December 2001) search was performed to identify pertinent literature on the pathophysiology of sepsis and treatment strategies. The search was supplemented with AdisInsight (Adis International) using the search terms sepsis, severe sepsis, or septic shock combined with agents in Phase II or higher clinical development. Abstracts presented at infectious diseases and critical care meetings were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Clinical efficacy studies were selected for drotrecogin alfa and other Phase III investigational agents. DATA SYNTHESIS: Our current understanding of the pathophysiology of sepsis underscores the contribution of increased coagulation and diminished fibrinolytic activity working in conjunction with an excessive and dysregulated inflammatory response. The loss of homeostatic balance among these systems results in a systemic inflammatory response with generalized coagulopathy, microvascular thrombosis, and, ultimately, acute organ failure and death. As a result of these advances, several compounds are now in various phases of development. A recombinant human form of endogenous activated protein C (drotrecogin alfa) was recently approved by the Food and Drug Administration for severe sepsis in adults who have a high risk of death. It possesses anticoagulant, profibrinolytic, and antiinflammatory properties. Other compounds currently in Phase III trials include tissue-factor pathway inhibitor, tumor-necrosis factor antibody fragment, platelet-activating factor acetylhydrolase, antithrombin III, and pyridoxylated hemoglobin polyoxyethylene. CONCLUSIONS: With the recent approval of drotrecogin alfa, there is renewed optimism that we can effectively reduce sepsis-associated mortality.

scholarly journals Testing of anti-activated protein C antibodies in four drotrecogin alfa (activated) severe sepsis studies

Critical Care ◽  
2008 ◽  
Vol 12 (Suppl 2) ◽  
pp. P203 ◽  
Author(s):  
S Yan ◽  
J Brandt ◽  
G Vail ◽  
S Um ◽  
J Bourdage ◽  
...  
Keyword(s):  
Severe Sepsis ◽  
Protein C ◽  
Drotrecogin Alfa ◽  
Activated Protein C ◽  
Drotrecogin Alfa Activated

Role of Activated Protein C in the Pathophysiology of Severe Sepsis

2003 ◽  
Vol 12 (6) ◽  
pp. 518-524 ◽  
Author(s):  
Patricia Dettenmeier ◽  
Bridget Swindell ◽  
Mary Stroud ◽  
Nancy Arkins ◽  
April Howard
Keyword(s):  
Severe Sepsis ◽  
Protein C ◽  
Drotrecogin Alfa ◽  
Activated Protein C ◽  
Therapeutic Agents ◽  
Multiple Organ ◽  
Phase 3 ◽  
The Past ◽  
Drotrecogin Alfa Activated

Sepsis is a complex syndrome that can lead to multiple organ failure and death. Severe sepsis has been associated with mortality rates ranging from 28% to 50% and is the most common cause of death in the noncardiac intensive care unit. Despite advances in both antibiotic therapy and supportive care, the mortality rate due to severe sepsis has remained fundamentally unchanged in the past several decades. With increased understanding of the pathophysiology of sepsis, particularly the intricate interplay between activation of coagulation and inflammation, novel therapeutic agents that may improve clinical outcomes are being researched and developed. The epidemiology, pathophysiology, and treatment of severe sepsis are reviewed. Also discussed are the recently published results from a multicenter, randomized, placebo-controlled phase 3 clinical trial of drotrecogin alfa (activated), a recombinant form of human activated protein C, in patients with severe sepsis. The nursing implications of this new approved therapy are discussed.

Drotrecogin Alfa (Xigris) Induced Coagulopathy as Measured by Routine Lab Tests in a Community Hospital Setting.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4129-4129
Author(s):  
Archana Maini ◽  
Chudaratna Madangopal ◽  
Kishor Sheth
Keyword(s):  
Severe Sepsis ◽  
Platelet Count ◽  
Protein C ◽  
Drotrecogin Alfa ◽  
Community Hospital ◽  
Activated Protein C ◽  
Adult Patients ◽  
Apache Ii ◽  
Drug Infusion ◽  
Post Infusion

Abstract Drotrecogin alfa - Recombinant Human Activated Protein C (Xigris) is FDA approved for the reduction of mortality in adult patients with severe sepsis who have a high risk of death as determined by APACHE II. Patients with sepsis have decreased circulating levels of protein C and that is associated with increased mortality. Drotrecogin alfa presumably has three main mechanisms of action: anticoagulant, anti-inflammatory and pro-fibrinolytic. In the protein C pathway, protein C circulates as a zymogen which is converted to activated protein C (APC) when thrombin complexes with thrombomodulin, further augmented by Endothelial Protein C Receptor (EPCR). This APC, alongwith protein S, inactivates Factors Va and VIIIa, thereby limiting thrombin generation. Endogenous protein C activation is blunted in severe sepsis due to down-regulation of thrombomodulin and EPCR. PROWESS study was the first phase III landmark study to demonstrate an absolute 6.1% reduction in 28 day all cause mortality. The only significant toxicity was a 3.5% bleeding risk, especially with laboratory parameters of aPTT>120 secs, INR>3 and platelet count < 30,000/microliter as well as gastrointestinal ulceration and traumatic injury. Since then several other studies have been conducted with slightly varying results and as many as 19 different systemic biomarkers of thrombosis, coagulation, fibrinolysis and inflammation have been used. But practically, in the ICU setting, the anticoagulant activity of Drotrecogin alfa may be demonstrated by the prolongation of aPTT and PT during the drug infusion. No significant difference has been found in platelet counts in the major studies. The hematocrit is insignificantly changed in the absence of a bleeding complication. We report here a retrospective review of 10 adult patients with sepsis from our ICU who met the criteria to get drotrecogin alfa based on APACHE II. Their PT, INR, aPTT, Hb, Hct and platelet counts were recorded prior to drug infusion not exceeding 24 hours pre infusion. These counts were again looked at post infusion. The highest post infusion coagulation profile was selected and concordant Hb and Hct were recorded. We found the following mean changes in the selected parameters: Increase in aPTT of 58% (20.32 sec); increase in PT of 15% (2.61 sec); decrease in platelet count of 16% (26,000/microliter); decrease in Hb of 13% (1.44 gm/dl); decrease in Hct of 13% (4.09 %). Despite the seeming worsening of coagulopathy and some drop in Hb, Hct and platelets, patients did not have any major bleeding episodes attributable to Drotrecogin alfa. Out of our 10 patients, 7 have expired and 3 have survived for a mean of 130 days (range 118 days to 141 days) till today. Thus in our small retrospective sample, Drotrecogin alfa was found to be a safe and effective drug, based on routine blood tests and clinical observation alone in the ICU of a community hospital.

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