Pharmacy & Therapeutics- August 2008 - (Page 469) CASE REPORT Low-Dose, Off-Label Drotrecogin Alfa (Xigris) In Severe Sepsis Shan Wang, PharmD, Kristina Dabovic, PharmD, and Ruth S. Spector, MD ABSTRACT Objective: In this article, we describe a successful lowdose, off-label usage of drotrecogin alfa (Xigris), given at 18 mcg/kg per hour, in a patient with severe sepsis who had an Acute Physiology and Chronic Health Evaluation II (APACHE II) score of 26 and multiorgan failure. Patient: A 64-year-old man was admitted to the surgical intensive-care unit of Winthrop University Hospital in Mineola, New York. After undergoing small-bowel resection secondary to obstruction, he became severely septic. Because of his high risk of death (with an APACHE II score of 26 and two organ failures), he was initially treated with drotrecogin alfa 24 mcg/kg per hour, the dose approved by the U.S. Food and Drug Administration (FDA). Within four hours, his activated partial thromboplastin time became significantly prolonged from a baseline of 27.8 to 92.9 seconds, and he had coffeeground nasogastric tube output. In light of signs of bleeding, drotrecogin alfa was temporarily discontinued. After 26 hours without further evidence of bleeding, drotrecogin alfa was administered at a lower dose of 18 mcg/kg per hour. The manufacturer’s recommendation of 96 hours of infusion therapy was completed with the lower dosing. The patient’s condition improved significantly, and eventually he was discharged home. Conclusion: This case report demonstrates an alternative use of drotrecogin alfa at a lower dose of 18 mcg/kg per hour in a severely septic patient who could not tolerate the FDAapproved dose of 24 mcg/kg per hour because of bleeding. Key words: severe sepsis, APACHE II score, multiorgan failure, low-dose drotrecogin alfa released when an infection occurs, and they trigger a systemic response. A cascade of inflammation and activation of the coagulation system is associated with impaired fibrinolysis, which leads to alterations in microvascular circulation.3,6,7 Activated protein C, an endogenous protein that promotes fibrinolysis and inhibits thrombosis as well as inflammation, is one of the important modulators associated with severe sepsis.4–7 In 2001, the FDA approved drotrecogin alfa, a recombinant version of activated human protein C (Xigris, Eli Lilly) for the treatment of severe sepsis. Drotrecogin alfa is the first in a relatively new class of antithrombotic coagulation inhibitors for septic patients who are at high risk of dying (i.e., an APACHE II score of 25 or greater).4,8–10 Activated protein C inhibits factors VIIIa and Va, thereby limiting thrombin formation by promoting fibrinolysis.6,8,9,11 Various dosing regimens of drotrecogin alfa in severe sepsis have been studied in a phase 2 trial. Bernard et al.12 conducted a double-blind, randomized, placebo-controlled, multicenter, dose-ranging (sequential) clinical trial. One hundred thirty-one adults with organ failure and severe sepsis, as defined by systemic inflammatory response syndrome (SIRS) criteria, received intravenous (IV) infusions of drotrecogin alfa at 12, 18, 24, or 30 mcg/kg per hour or placebo for 48 or 96 hours. Significant dose-dependent decreases in both D-dimer and interleukin-6 (IL-6) levels at the end of the infusion were demonstrated in those receiving 18 mcg/kg per hour and 24 mcg/kg per hour.13 In this article, we report a case of survival in a patient with severe sepsis who was treated with low-dose drotrecogin alfa (18 mcg/kg per hour) after he experienced bleeding with the FDA-approved dose (24 mcg/kg per hour). Case Report A 64-year-old man was admitted to Winthrop University Hospital with a ventral hernia and a small-bowel obstruction on August 27, 2006. His medical history was significant for Crohn’s disease, asthma, diverticulitis, intermittent tachycardia, and mitral valve prolapse. Previous surgeries included an open cholecystectomy and bowel resection 12 years earlier. He arrived at the emergency department complaining of “trapped gas” with nausea, vomiting, and pain. He had no complaints of chest pain, shortness of breath, weakness, dysuria, or diarrhea. His rectal temperature was 96.6º F; heart rate, 56 beats/minute; blood pressure, 123/88 mm Hg, respiratory rate, 18 breaths/minute; and oxygen saturation, 97% in room air. The patient underwent an exploratory laparotomy, repair of a ventral hernia, and small-bowel resection with primary anasDisclosure: The authors have no commercial or financial relationships to report in regard to this article. INTRODUCTION Sepsis is defined as a systemic inflammatory syndrome in response to an infection. It is associated with acute organ dysfunction, which can be fatal.1–3 In the U.S., sepsis affects more than 750,000 patients at an estimated annual cost of $17 billion.1,3,4 Despite advances in intensive-care medicine and antimicrobial treatment, sepsis is associated with a mortality rate of 50%.5 The three principal components in sepsis are inflammation, coagulation, and fibrinolysis.4–7 Endotoxins and exotoxins are Dr. Wang is a Clinical Pharmacist in the Department of Pharmacy at Winthrop University Hospital in Mineola, New York. Dr. Dabovic is an Early Clinical Research and Experimental Medicine Fellow at the Ernest Mario School of Pharmacy at Rutgers University in Piscataway, New Jersey. Dr. Spector is a Critical Care Physician in the Department of Surgery, Critical Care Division, at Winthrop University Hospital in Mineola, New York. Accepted for publication July 10, 2008. Vol. 33 No. 8 • August 2008 • P&T® 469
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