Received Drotrecogin Alfa Research Articles

A Multicenter Evaluation of the Safety of Drotrecogin Alfa (Activated) in Patients with Baseline Bleeding Precautions

We recently reported an increased incidence of serious bleeding events and mortality in patients with baseline bleeding precautions treated with drotrecogin alfa (activated) compared to patients without such precautions. Whether these observations were specific to our single medical campus is unclear. All patients who received drotrecogin alfa (activated) for the treatment of severe sepsis from January 2006 through September 2009 within the South Central Veterans Affairs Health Care Network were retrospectively reviewed using a regional clinical database. Demographic information, bleeding precautions that were exclusion criteria of the PROWESS trial, and 30-day post-discharge incidences of serious bleeding events and mortality were collected. Seventy-nine patients from 5 medical centers were included. Serious bleeding events occurred in 4 of 24 patients (16.7%) with any bleeding precaution vs 1 of 55 patients (1.8%) without a bleeding precaution (P=0.03). All patients (5) who experienced a serious bleeding event died compared to 39 of 74 patients (52.7%) who did not (P=0.06). Seventeen of 24 patients (70.8%) with bleeding precautions died vs 27 of 55 patients (49.1%) without bleeding precautions (P=0.07). The number of serious bleeding events did not allow meaningful multivariate analyses. The mean number of failing organs was an independent predictor of 30-day post-discharge mortality (OR 1.63 for each organ failed, 95% CI 1.05- 2.6). The findings of this study were consistent with our prior observations and suggest the risk for serious bleeding events with drotrecogin alfa (activated) may outweigh any potential benefit in patients with baseline bleeding precautions.

Clinical response to unintentionally rapid infusion of drotrecogin alfa (activated)

The case of a patient with severe sepsis who received a bolus dose of 184 microg/kg of drotrecogin alfa (activated) over one hour is reported. An 84-year-old woman who had undergone right total knee replacement was admitted to the hospital from a rehabilitation facility with an initial diagnosis of mental status changes and a suspected urinary tract infection. Examination of the patient's incision from her recent knee surgery revealed a discharge, and a culture was obtained. The patient was diagnosed with sepsis, intubated, and transferred to the intensive care unit. Multiple antibiotics were administered, but the patient's condition continued to deteriorate. In addition, the patient developed acute renal failure, required a ventilator, had cyanotic limbs, and had partially compensated metabolic acidosis. On hospital day 7, drotrecogin alfa (activated) was initiated. She inadvertently received an infusion of 184 microg/kg of drotrecogin alfa over 1 hour. Nine hours later, she received drotrecogin alfa 24 microg/kg/hr for 95 hours. The patient's clinical status was improved after the initial infusion. Peripheral limb cyanosis was markedly decreased, with pink, warm extremities. In addition, the patient's clinical laboratory test values improved after administration of drotrecogin alfa. However, the patient was unable to recover fully from the acute kidney failure and was discharged to hospice care. A drotrecogin alfa dose of 184 microg/kg i.v. was erroneously administered over 1 hour to a patient with sepsis. Nine hours later, a drotrecogin alfa infusion of 24 microg/kg/hr was started and continued for 95 hours. The patient improved clinically and had no apparent adverse events.

Novel H1N1 influenza and Panton-Valentine leukocidin Staphylococcus aureus necrotizing pneumonia

The association between seasonal influenza and staphylococcal pneumonia has long been recognized (Chickering and Park, 1919; Roberts et al, 2008), and both meticillin-resistant Staphylococcus aureus and Panton-Valentine leukocidin S. aureus have been associated with seasonal influenza pandemics (Roberts et al, 2008; Kearns et al, 2009; Murray et al, 2010).

A prospective, observational study of Xigris Use in the United States (XEUS)

Background Use of pharmacologic agents in clinical practice may differ from the manner in which they were studied in rigorous randomized clinical trials. This was a prospective, observational, noninterventional study to determine the profile of patients receiving drotrecogin alfa (activated) in clinical practice, provide additional outcome and safety data, and allow for a comparison to patients studied in the phase 3 Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial. Methods A total of 548 adult patients with severe sepsis were enrolled from 61 nonteaching or academically affiliated hospitals in the United States. Patients received drotrecogin alfa (activated) as part of physician-directed therapy for severe sepsis. Results The Xigris Use in the United States (XEUS) patients were younger (58 vs 63 years of age), had more comorbidities, and more sepsis-induced organ dysfunction at baseline compared to high-risk (Acute Physiology and Chronic Health Evaluation II score ≥ 25) PROWESS patients who received drotrecogin alfa (activated), (cardiovascular, 85.0% vs 79.7%; hematologic, 22.3% vs 16.4%; and renal, 57.9% vs 50.7%) (all P < .05). The XEUS patients had a higher mortality rate compared to high-risk PROWESS patients receiving drotrecogin alfa (activated) (36.7% vs 30.9%; P = .062) but a similar safety profile (infusion period serious bleeding, 2.7% vs 2.2%; P = .579; 28-day serious bleeding, 3.1% vs 3.9%; P = .520). The rate of intracranial hemorrhage in XEUS was 0.2%. Conclusions Patients receiving drotrecogin alfa (activated) in clinical practice were more acutely ill, had a higher mortality rate, but a similar safety profile with respect to serious bleeding events compared to the PROWESS trial.

Use of activated protein C has no avail in the early phase of acute pancreatitis

Objectives. Sepsis and acute pancreatitis have similar pathogenetic mechanisms that have been implicated in the progression of multiple organ failure. Drotrecogin alfa, an analogue of endogenous protein C, reduces mortality in clinical sepsis. Our objective was to evaluate the early therapeutic effects of activated protein C (APC) in a rat model of acute necrotizing pancreatitis. Subjects and method. Acute necrotizing pancreatitis was induced by intraductal injection of 5% Na taurocholate. Hourly bolus injections of saline or recombinant human APC (drotrecogin alfa) was commenced via femoral venous catheter four hours after the induction of acute pancreatitis. The experiment was terminated nine hours after pancratitis induction. Animals in group one (n=20) had a sham operation while animals in group two (n=20) received saline and animals in group three (n=20) received drotrecogin alfa boluses after acute pancreatitis induction. Pancreatic tissue for histopathologic scores and myeloperoxidase, glutathione reductase, glutathione peroxidase, and catalase activites were collected, and blood for serum amylase, urea, creatinine, and inleukin-6 measurements was withdrawn. Results. Serum amylase activity was significantly lower in the APC treated group than the untreated group (17,435±432 U/L vs. 27,426±118 U/L, respectively). While the serum interleukin-6 concentration in the APC untreated group was significantly lower than the treated group (970±323 pg/mL vs. 330±368 pg/mL, respectively). Conclusion. In the early phase of acute pancreatitis, drotrecogin alfa treatment did not result in a significant improvement in oxidative and inflammatory parameters or renal functions.

Bleeding Complications with Drotrecogin Alfa Activated (Xigris®): A Retrospective Review of 31 Operative and 68 Non-Operative Patients with Severe Sepsis

We reviewed 100 consecutive patients who received Drotrecogin alfa (activated) (DAA) (Xigris, Eli Lilly, Indianapolis, IN) for the treatment of severe sepsis and compared the incidence of bleeding complications in surgical (n = 30) and nonsurgical cohorts (n = 70). Thirty patients who received DAA therapy for severe sepsis underwent one or more contemporaneous surgical procedures. These were compared with 70 DAA patients who did not undergo surgery. During the course of DAA administration, transfusion of greater than three units of blood, an intracranial hemorrhage, or other bleeding serious adverse event were qualified as bleeding complications. Overall, we identified seven patients who fulfilled the designated bleeding complication criteria, four in the surgical cohort, and three in the nonsurgical cohort. There was no significant difference in the rate of bleeding complications between surgical and nonsurgical cohorts (P = 0.1063). Moreover, there were no mortalities ascribed to bleeding and there were no intracranial hemorrhage events. All bleeding complications were due to a drop in hemoglobin or platelets only, and were treated with transfusion. Our experience demonstrates that there is an equivalent risk of bleeding for surgical patients treated with DAA compared with nonsurgical patients. Additionally, all bleeding complications were amenable to simple transfusion.

Heparin prophylaxis did not increase mortality and was beneficial in adults with sepsis receiving drotrecogin alfa

Source Citation Levi M, Levy M, Williams MD, et al. Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated). Am J Respir Crit Care Med. 2007;176:483-90. 17556722

Filter survival time and requirement of blood products in patients with severe sepsis receiving drotrecogin alfa (activated) and requiring renal replacement therapy

IntroductionDrotrecogin alfa (activated) (DrotAA) is licensed in the United States and the European Union for the treatment of severe sepsis with multiple organ failure. Patients with severe sepsis on renal replacement therapy (RRT), who typically receive additional anticoagulation to prevent circuit clotting, may be at higher risk of bleeding when DrotAA is administered in addition to standard anticoagulation. However, the effects of DrotAA on filter duration in the absence of additional anticoagulation have not been established. The aim of this study was to analyse the filter survival time (FST), and to quantify the requirement of packed red cells (PRC) and blood products during DrotAA infusion.MethodsThis was a single-centre, retrospective observational study conducted in an adult intensive care unit (ICU). Thirty-five patients with severe sepsis who had received both RRT and DrotAA were identified, and all relevant clinical and laboratory data were retrieved from the departmental electronic patient record. We compared haemofilter parameters, requirement of blood products and haemodynamic data recorded during RRT and the infusion of DrotAA with those recorded on RRT with standard anticoagulation after the DrotAA infusion had been completed (post-DrotAA).ResultsThe proportion of filter changes due to filter clotting was similar during DrotAA infusion and with conventional anticoagulation post-DrotAA infusion. There was no difference in the FST and filter parameters during DrotAA in the presence or absence of additional anticoagulation with heparin or epoprostenol. A similar proportion of patients required red cell transfusion, although a greater proportion of patients received platelet and fresh frozen plasma during DrotAA infusion compared with the post-DrotAA period with no difference between medical and surgical patients.ConclusionsAdditional anticoagulation during DrotAA infusion does not appear to improve FST. The use of DrotAA in patients with severe sepsis requiring RRT is safe and is not associated with an increased need for PRC transfusion or major bleeding events.

Drotrecogin alfa (activated)

Although the PROWESS trial demonstrated a mortality benefit, subsequent studies in different patient populations have not reproduced the effect. As a result, concerns have been expressed about the clinical effectiveness of drotrecogin alfa (activated). Therefore the aim of this audit was to review the clinical impact of drotrecogin alfa (activated) when used outside clinical trials. A retrospective review of ICU charts and medical records of patients who had received drotrecogin alfa (activated) in the five largest users of drotrecogin alfa (activated) in England. Patients characteristics details at ICU admission and vital status at hospital discharge were recorded. The severity of illness was assessed by the APACHE II score (using first 24 h admission data) and the number of organ dysfunctions. Adverse incidents were recorded and any sequence effect explored. In all, 351 patients received drotrecogin alfa (activated) between December 2002 and November 2005. Of those, 201 (57.2%) were male, and 177 (50.4%) were admitted after recent surgery. The patients' average age was 61.8 yr. The mean admission APACHE II score was 23.3 and the average number of dysfunctional organs on admission was 3.3. The hospital mortality was 46.7% (164 deaths). The expected number of deaths calculated by using the APACHE II risk of death was 173 (49.3%) and by number of sepsis induced organ failures 210 (59.7%). Overall, there were 33 (9.4%) adverse incidents. Expected mortality derived from both the APACHE II score and organ dysfunctions suggests that drotrecogin alfa (activated) does reduce mortality. Serious adverse incidents occurred in 5.1% patients; however, the direct contributing effect of drotrecogin alfa (activated) cannot be established from this type of audit.

Use of drotrecogin alfa (activated) for severe sepsis in New Jersey acute care hospitals

The use of drotrecogin alfa (activated) for the treatment of severe sepsis in acute care hospitals in New Jersey was evaluated. An observational study was conducted to determine the prevalence of severe sepsis and drotrecogin alfa use in hospitalized patients in New Jersey. In November 2003, a survey was mailed to the pharmacy directors of 84 acute care hospitals (teaching, major teaching, nonteaching) in New Jersey to collect information about the monthly use of drotrecogin alfa in 2002 and 2003. Health Care Financing Administration Uniform Bill of 1992 patient discharge data from New Jersey for the same period were analyzed to identify patients with severe sepsis and calculate the rate of drug use for their treatment. The survey received a total response rate of 55%. Among 7292 patients with severe sepsis who were treated in 2002 in participating hospitals, 137 received drotrecogin alfa. From January 2003 to October 2003, the average rate of drotrecogin alfa use in the same hospitals was identical. Drug use in teaching and major teaching hospitals was greater than in nonteaching hospitals. An increase in drotrecogin alfa use in 2003 compared with 2002 was expected; however, a comparison of its use in 2002 and 2003 in New Jersey acute care hospitals found that the rate of drug use remained the same. One tenth of responding hospitals never used drotrecogin alfa during the study period. An observational study showed an apparent underutilization of drotrecogin alfa (activated) for treatment of severe sepsis in acute care hospitals in New Jersey.

ENHANCE: Results of a global open-label trial of drotrecogin alfa (activated) in children with severe sepsis*

To gather additional 28-day all-cause mortality data and safety information for pediatric patients with severe sepsis who received drotrecogin alfa (activated) (DrotAA). Single-arm, open-label, multicentered study conducted in 59 study sites in 15 countries. One-hundred eighty-eight children (term newborn to <18 yrs old) with severe sepsis were consecutively enrolled in the study. Administration of DrotAA, 24 microg/kg/hr for 96 hrs. Four-day and 28-day all-cause mortality, safety information, and protein C levels. : One-hundred eighty-seven patients completed the study. The 4-day mortality rate was 7.0%, and the 28-day mortality rate was 13.4%. At baseline, 57.6% of patients were severely deficient in protein C (a level < or = 40% of normal). There was a statistically significant association between increased 28-day mortality and decreased end-of-infusion protein C levels (p < .001), greater number of baseline organ dysfunctions (p < .001), and greater baseline ventilator use (p = .03). Bleeding was the most significant complication observed. Serious bleeding events (including anemia without a bleeding source) were experienced by 27.7% of patients (n = 52). Six of the serious bleeding events (3.2%) were considered related to administration of DrotAA. During infusion, serious bleeding events with an identified source of bleeding were experienced by 5.9% of patients (n = 11). Central nervous system bleeding was experienced by 2.7% (n = 5). Two of the intracranial hemorrhages were fatal and occurred postinfusion. Without a placebo control, no efficacy conclusions are possible. Subgroups at higher risk of death were identified, and the change in protein C level from baseline was predictive of survival. The most significant complication observed was bleeding. Risk factors for serious bleeding appear to be multiple organ failure, thrombocytopenia, and coagulopathy.

Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: Further evidence for survival and safety and implications for early treatment*

To provide further evidence for the efficacy and safety of drotrecogin alfa (activated) treatment in severe sepsis. Single-arm, open-label, trial of drotrecogin alfa (activated) treatment in severe sepsis patients. Enrollment began in March 2001 and day-28 follow-up completed in January 2003. ENHANCE took place in 25 countries at 361 sites. Patients with known or suspected infection, three or four systemic inflammatory response syndrome criteria, and one or more sepsis-induced organ dysfunctions. Of 2,434 adults entered, 2,378 received drotrecogin alfa (activated), and of these, 2,375 completed the protocol. Drotrecogin alfa (activated) was infused at a dose of 24 mug/kg/hr for 96 hrs. The 28-day all-cause mortality approximated that observed in PROWESS (25.3% vs. 24.7%). Although patients in ENHANCE had increased serious bleeding rates compared with patients in the drotrecogin alfa (activated) arm of PROWESS (during infusion, 3.6% vs. 2.4%; postinfusion, 3.2% vs. 1.2%; 28-day, 6.5% vs. 3.5%), increased postinfusion bleeding suggested a higher background bleeding rate. Intracranial hemorrhage was more common in ENHANCE than PROWESS (during infusion, 0.6% vs. 0.2%; 28-day, 1.5% vs. 0.2%). The incidence of fatal intracranial hemorrhage was the same during infusion (0.2%) and higher at 28 days (0.5% vs. 0.2%). ENHANCE patients treated within 0-24 hrs from their first sepsis-induced organ dysfunction had lower observed mortality rate than those treated after 24 hrs (22.9% vs. 27.4%, p = .01). ENHANCE provides supportive evidence for the favorable benefit/risk ratio observed in PROWESS and suggests that more effective use of drotrecogin alfa (activated) might be obtained by initiating therapy earlier.

Challenge and Rechallenge: Drotrecogin alfa (activated)–Induced Prolongation of Activated Partial Thromboplastin Time in a Patient with Severe Sepsis

An 81-year-old woman with ischemic bowel underwent laparotomy with small-bowel resection and developed septic shock. She required broadspectrum antibiotics, norepinephrine, and mechanical ventilation. The patient received drotrecogin alfa (activated) 24 microg/kg/hour for a total of 67.5 hours. Coagulation parameters were monitored during her therapy. Significant increases in activated partial thromboplastin time (aPTT) during infusion led to two temporary discontinuations of the drug. Coagulation parameters decreased when the drug was held and increased with each rechallenge. The patient survived the episode and was discharged on postoperative day 27. Medical records of 26 other patients who received drotrecogin alfa (activated) at our institution from November 2001-August 2003 were reviewed retrospectively for coagulation parameters and bleeding rate. Of the 26 patients, nine (35%) were treatment compliant (>90% of the 96-hr course). Coagulopathy and bleeding resulted in early discontinuation in four (15%) and six (23%) patients, respectively. An increase in aPTT from baseline to during infusion of drotrecogin alfa (activated) was noted in 14 patients with complete data (p=0.56). A decrease in median platelet count from baseline to during infusion was noted in the six patients who bled during therapy (p=0.01). Two of these patients had platelet counts less than 30x10(3)/mm3 during administration. Drotrecogin alfa (activated) should be considered an anticoagulant. In postmarketing reports, clinically significant bleeding occurred more frequently than was noted in a large, randomized, multicenter trial. Patients receiving drotrecogin alfa (activated) should be closely monitored for prolongation of coagulation parameters. Temporary discontinuation of the drug should be considered when international normalized ratio is greater than 3.0, platelet count is less than 15x10(3)/mm3, and aPTT is greater than 100 seconds.

Prognostic Value of Plasma N-Terminal Pro-Brain Natriuretic Peptide in Patients With Severe Sepsis

Increased plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) have been identified as predictors of cardiac dysfunction and prognosis in congestive heart failure and ischemic heart disease. In severe sepsis patients, however, no information is available yet about the prognostic value of natriuretic peptides. Therefore, the aim of the present study was to determine the role of the N-terminal prohormone forms of ANP (NT-proANP) and BNP (NT-proBNP) in the context of outcome of septic patients. Furthermore, the effect of treatment with recombinant human activated protein C [drotrecogin alfa (activated)] on plasma levels of natriuretic peptides in severe sepsis was evaluated. Fifty-seven patients with severe sepsis were included. Levels of NT-proANP and NT-proBNP were measured on the second day of sepsis by ELISA. Septic patients with NT-proBNP levels >1400 pmol/L were 3.9 times more likely (relative risk [RR], 3.9; 95% CI, 1.6 to 9.7) to die from sepsis than patients with lower NT-proBNP values (P<0.01). NT-proANP levels, however, were not predictive of survival in our patient population. A highly significant correlation was found between troponin I levels and plasma concentrations of NT-proBNP in septic patients (r=0.68, P<0.0001). In addition, troponin I significantly accounted for the variation in NT-proBNP levels (P<0.0001), suggesting an important role for NT-proBNP in the context of cardiac injury and dysfunction in septic patients. Twenty-three septic patients who received treatment with drotrecogin alfa (activated) presented with significantly lower concentrations of NT-proANP, NT-proBNP, and troponin I compared with patients not receiving drotrecogin alfa (activated). NT-proBNP may serve as useful laboratory marker to predict survival in patients presenting with severe sepsis.

Predictors of Hospital Mortality for Patients with Severe Sepsis Treated with Drotrecogin alfa (activated)

To identify predictors of hospital mortality among patients with severe sepsis who were treated with drotrecogin alfa (activated). Prospective observational cohort study. A 1400-bed academic medical center. One hundred two patients treated with drotrecogin alfa (activated) for severe sepsis. To identify potential risk factors for hospital mortality, the main outcome evaluated, all patients who received drotrecogin alfa (activated) were segregated according to hospital survival. The following characteristics were recorded: age, sex, weight, surgical or nonsurgical, Acute Physiology and Chronic Health Evaluation (APACHE) II score, number of acquired organ-system derangements, mechanical ventilation, use of vasopressors or dobutamine, patient location 24 hours before receiving drotrecogin alfa (activated), source of infection, microbiologically positive culture, and other process-of-care variables. Of the 102 patients, 43 (42.2%) died during their hospitalization. Potential predictors of hospital mortality identified by univariate analysis included greater APACHE II scores, administration of vasopressin or dobutamine, number of acquired organ-system derangements, time to treatment with drotrecogin alfa (activated), intravenous fluid administered before receiving vasopressors or drotrecogin alfa (activated), number of red blood cell transfusions, and administration of inappropriate initial antimicrobial treatment. Multivariate analysis revealed that vasopressin administration (odds ratio [OR] 3.72, 95% confidence interval [CI] 1.95-7.10), number of acquired organ-system derangements (OR 2.30, 95% CI 1.59-3.31), and administration of inappropriate initial antimicrobial treatment (OR 15.5, 95% CI 6.78-35.6) were independently associated with hospital mortality. Number of acquired organ-system derangements, vasopressin administration, and treatment with an inappropriate initial antimicrobial regimen are independently associated with an increased risk of hospital mortality among patients treated with drotrecogin alfa (activated) for severe sepsis. These findings suggest that other specific medical interventions may increase survival in this patient population.

13. Assessment of Severe Sepsis in Children: Experiences from Pediatric Patients Receiving Drotrecogin Alfa (Activated)

13. Assessment of Severe Sepsis in Children: Experiences from Pediatric Patients Receiving Drotrecogin Alfa (Activated)

New additions to the intensive care armamentarium.

Many advances have improved the care of critically ill patients, but only a few have been through the use of pharmaceutical agents. Recently, the US Food and Drug Administration (FDA) approved drotrecogin alfa (activated), or recombinant human activated protein C, for the treatment of patients with a high risk of death from severe sepsis. Drotrecogin alfa (activated) has antiinflammatory, antithrombotic and fibrinolytic properties. When given as a continuous intravenous infusion, recombinant human activated protein C decreases absolute mortality of severely septic patients by 6.1%, resulting in a 19.4% relative reduction in mortality. The absolute reduction in mortality increases to 13% if the population treated is restricted to patients with an APACHE II score greater than 24, as suggested by the FDA. The most frequent and serious side effect is bleeding. Severe bleeds increased from 2% in patients given placebo to 3.5% in patients receiving drotrecogin alfa (activated). The risk of bleeding was only increased during the actual infusion time of the drug, and the bleeding risk returned to placebo levels 24 hours after the infusion was discontinued. Patients treated in the intensive care unit frequently develop anemia, usually severe enough to require at least one transfusion of red blood cells. With the recent discovery of the harmful effects of allogeneic red blood cell transfusions and the increasing shortage of available red blood cell products, emphasis has been placed on minimizing transfusions. Patients who receive exogenous recombinant human erythropoietin maintain higher hemoglobin levels, in spite of requiring fewer transfusions during their stay in the intensive care unit. Recombinant human erythropoietin appears to be effective whether it is given as 300 units/kg of body weight subcutaneously every other day or as 40,000 units subcutaneously every week. Differences in hemoglobin values were not apparent until at least one week of therapy, but they continued to diverge after that initial week. Furthermore, the incidence of adverse events was similar to that of patients receiving placebo and there was no difference in mortality, suggesting that avoidance of blood transfusions did not translate into increased survival. Thus, recombinant human erythropoietin appears to be both safe and effective in treating the anemia found in critically ill patients, but it is less clear that such treatment is cost effective, especially in the higher dose regimens. Hypotension in patients with septic shock is often difficult to correct. Despite enormous dosages of catecholamines, many of these patients continue to have inadequate blood pressures. Inadequate levels of vasopressin have been identified in patients with septic shock, as well as in other patients with hypotension secondary to refractory vasodilatation. Vasopressin is a peptide hormone secreted from the posterior pituitary in response to hyperosmolality, hypovolemia or hypotension. Levels of vasopressin initially rise in patients with septic shock, but as hypotension persists, vasopressin levels fall below normal. Administration of exogenous vasopressin in physiologic dosages significantly increases blood pressure in patients with shock associated with sepsis and other vasodilatory states. This rise in blood pressure is often significant enough that endogenous catecholamines can be decreased and frequently discontinued entirely. Early withdrawal of the vasopressin replacement infusion results in recurrent hypotension. Unfortunately, randomized, blinded, placebo-controlled trials showing improvement in long-term outcomes such as mortality and length of stay are still lacking.

Impact of drotrecogin alfa (activated) on resource use and implications for reimbursement.

Selecting therapies in health care requires rigorous review of clinical and economic data. The financial implications of new clinical treatment options are an important component. The preferred method for evaluating the costs and effects of therapies is cost-effectiveness analysis along with an estimation of utility associated with the life-years gained. Preliminary reports suggest patients receiving drotrecogin alfa (activated) for severe sepsis have a faster resolution of cardiovascular and pulmonary dysfunction with minimal additional financial burden despite additional survivors. Furthermore, the reported cost/quality-adjusted life-year of $48,800 is consistent with many other common life-saving measures. Recently approved new technology payments for hospitals treating patients with drotrecogin alfa (activated) minimize financial impact. Clinicians and administrators should work collaboratively to optimize the therapy of patients with severe sepsis, minimize the financial impact on the health care system, and maximize the utility of drotrecogin alfa (activated).

Management challenge with drotrecogin alfa (activated).

Clinical trial results for drotrecogin alfa (activated) are discussed in terms of potential effect on morbidity and total cost of care. Interdisciplinary collaboration is crucial for improving care in health systems; teamwork has been shown to improve outcomes in intensive care and reduce costs. The treatment of sepsis is costly and resource intensive. With existing treatments, drugs account for a lower percentage of the total cost than does care in the intensive care unit. Study results indicate that drotrecogin alfa (activated) reduces mortality in severe sepsis without a major morbidity penalty in 28 days. No difference was found in total resource use over 28 days between patients who received the drug and those who received placebo, even though more patients who received drotrecogin alfa (activated) survived and thus required treatment. Estimated costs per life-year saved fall within the cost-effective range. When drotrecogin alfa (activated) becomes available for clinical use, pharmacists must systematically assess this new therapeutic tool in terms of health value.