Pharmacy & Therapeutics- August 2008 - (Page 470) CASE REPORT: Low-Dose Drotrecogin Alfa in Sepsis tomosis. He was given 2 g of IV cefoxitin (Mefoxin, Merck) and 500 mg of IV metronidazole for surgical prophylaxis. He became hemodynamically unstable during the surgery and was intubated and transferred to surgical intensive care. Vasopressin, norepinephrine, and phenylephrine were required to maintain adequate mean arterial pressure (MAP). On the second hospital day, the patient was returned to the operating room for a partial omentectomy and reinforcement of small-bowel anastomosis after abdominal compartment syndrome was diagnosed. Postoperatively, he exhibited signs of severe sepsis with a calculated APACHE II score of 26 and multiorgan (cardiovascular and respiratory) failure. MAP was 59 mm Hg, partial pressure of oxygen (PO2) was 51, and the arterial pH was 7.23. The patient’s temperature was 101.1º F, his white blood cell count was 1.1 x 103/mm3, and his hematocrit was stable (27.6%). Upon evaluation of the hospital’s sepsis protocol, he was considered a candidate for drotrecogin alfa. He was started on the FDA-approved dose of 24 mcg/kg per hour at 5 a.m. on hospital day 2, 12 hours after surgery. Four hours later, the patient’s prothrombin time (PT) and activated partial thromboplastin time (aPTT) were prolonged significantly, 16.9 and 92.9 seconds, respectively, from a baseline value of 11 and 27.8 seconds, respectively (Figures 1 and 2). Coffee-ground nasogastric tube output was observed. Drotrecogin alfa was discontinued at this point because of signs of bleeding. On the third hospital day, given the patient’s high risk of death, the intensivist restarted drotrecogin alfa at a lower dose of 18 mcg/kg per hour after finding no evidence of continued bleeding. The patient was also given meropenem (Merrem, AstraZeneca) and vancomycin IV (Vancocin, Viro Pharma) for broad infection coverage. On the fourth day, drotrecogin alfa was withheld for one hour so that a central line could be inserted; therapy was resumed after this procedure. The patient’s hospital course was further complicated with anemia, rhabdomyolysis, metabolic acidosis, hypoadrenia, hypokalemia, thrombocytopenia, and myocardial injury. On the fifth day, positive cultures for Escherichia coli in the blood and Streptococcus pneumoniae in the sputum were noted. On hospital day 6, the patient underwent a tracheostomy, exploratory laparotomy, and complex abdomen wall closure with an application of banked human tissue (AlloDerm, LifeCell) graft and V.A.C. abdominal dressing (KCI Corp.). Drotrecogin alfa was placed on hold for two hours before the procedure and was restarted one hour later according to the hospital protocol. On day 7, the patient completed the recommended 96 hours of drotrecogin alfa therapy without experiencing significant side effects. He ultimately improved clinically, and he was discharged home. Platelets (Figure 3) and International Normalized Ratio (Figure 4) were noted every day while drotrecogin alfa therapy was being administered. 24 mcg/kg/hour 105 95 85 aPTT sec 75 65 55 45 35 25 8: 18 17 :1 22 7 :4 1 3: 0 6: 2 50 9: 14 36 : 17 31 :1 5 3: 11 45 :3 14 0 :4 18 8 :5 22 7 :4 3: 5 11 43 :2 17 5 :0 20 8 :2 3: 6 10 55 :2 17 9 :5 3 0: 0 3: 9 5 7: 0 11 27 :5 15 5 :4 0 18 mcg/kg/hour 102.2 92.9 Bleeding occurred 57.3 27.8 Drotrecogin alfa given HD 1 HD 2 HD 3 HD 4 HD 5 HD 6 HD 7 Figure 1 Hematological parameters: activated partial thromboplastin time (aPTT). HD = hospital day. 24 mcg/kg/hour 20.5 18.5 17 PT sec 16.5 14.5 12.5 10.5 11 Bleeding occurred 19.6 19.5 18 mcg/kg/hour 15.3 Drotrecogin alfa given Figure 2 Hematological parameters: prothrombin time (PT). HD = hospital day. 170 150 130 153 Platelets 110 90 70 50 30 10 8: 18 17 : 22 17 :4 1 3: 0 6: 2 50 9: 14 36 : 17 31 :1 5 3: 11 45 :3 14 0 : 18 48 :5 22 7 :4 3: 5 11 43 :2 17 5 :0 20 8 :2 3: 6 10 55 : 17 29 :5 3 0: 0 3: 9 5 7: 0 11 27 :5 15 5 :4 0 Figure 3 Hematological parameters: platelet levels. HD = hospital day. macological therapy for severe sepsis and septic shock. Those patients with APACHE II scores of 25 or higher appear to benefit from drotrecogin alfa in terms of 28-day survival.4,7,8,9,10 In PROWESS, patients received an infusion of drotrecogin alfa 24 mcg/kg per hour over 96 hours or placebo within 48 hours after the onset of the first sepsis-induced organ dysfunction. DISCUSSION PROWESS (Recombinant Activated Human Protein C Worldwide Evaluation in Severe Sepsis) was the first successful clinical trial showing beneficial outcomes with a novel phar- 470 P&T® • August 2008 • Vol. 33 No. 8 8: 18 17 :1 22 7 :4 3: 1 0 6: 2 5 9: 0 36 14 :3 17 1 :1 5 3: 11 45 :3 14 0 :4 18 8 : 2 2 57 :4 5 3: 11 43 :2 17 5 : 20 0 8 :2 3: 6 10 55 :2 17 9 :5 3 0: 0 3: 9 50 7: 11 27 :5 15 5 :4 0 HD 1 HD 2 HD 3 HD 4 HD 5 HD 6 HD 7 24 mcg/kg/hour 18 mcg/kg/hour 128 Drotrecogin alfa given Bleeding occurred 55 17 HD 1 HD 2 HD 3 HD 4 HD 5 HD 6 HD 7
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