CURB-65, PSI, and APACHE II to assess mortality risk in patients with severe sepsis and community acquired pneumonia in PROWESS.

BACKGROUND: Patients with community-acquired pneumonia (CAP) comprised 35.6% of the overall phase 3 Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study and 33.1% of the placebo arm. We investigated the use of CURB-65, the Pneumonia Severity Index (PSI), and Acute Physiology and Chronic Health Evaluation II (APACHE II) prediction scores to identify the CAP population from the PROWESS placebo arm at the greatest mortality risk. METHODS: Patients were classified as having CAP if the lung was the primary infection site and the patient originated from home. The abilities of CURB-65, PSI, and APACHE II scores to determine the 28-day and in-hospital mortality were compared using receiver operator characteristic (ROC) curves and the associated areas under the curve. RESULTS: PROWESS enrolled 278 patients with CAP in the placebo arm. The areas under the ROC curves for PSI = 5, CURB-65 ≥ 3, and APACHE II ≥ 25 for predicting 28-day (c = 0.65, 0.66, and 0.64, respectively) and in-hospital mortality (c = 0.65, 0.65, and 0.64, respectively) were not statistically different from each other. The 28-day mortality of patients with a PSI score of 5, CURB-65 ≥ 3, and APACHE II ≥ 25 was 41.6%, 37.9%, and 43.5%, respectively. CONCLUSIONS: Despite early diagnosis and appropriate antibiotic therapy, conventionally treated CAP with PSI = 5, CURB-65 3, or APACHE II 25 has an unacceptably high mortality. In this study, PSI, CURB-65, and APACHE II scoring systems perform similarly in predicting the 28-day and in-hospital mortality; however, differences in the categorization of severe CAP were observed and there was a significant mortality in patients with a CURB-65 <3 and PSI <5.

A retrospective observational study of drotrecogin alfa (activated) in adults with severe sepsis: comparison with a controlled clinical trial.

OBJECTIVE: To compare characteristics and outcomes of patients treated with drotrecogin alfa (activated) (DrotAA) in clinical practice to those treated in a phase III randomized controlled trial (PROWESS). DESIGN: Observational data were collected retrospectively from patients who received DrotAA as part of physician-directed treatment. SETTING: Intensive care units of five teaching institutions. PATIENTS: Patients were > or = 18 yrs old, had severe sepsis (confirmed/suspected infection with one or more sepsis-induced organ dysfunctions), and received DrotAA. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Baseline demographics, severity of illness, time from organ dysfunction onset to DrotAA treatment, daily assessment of organ dysfunction, serious bleeding events, and in-hospital mortality were reported. Timing from severe sepsis documentation to start of DrotAA infusion was categorized: day 0 (same calendar day); day 1 (next calendar day); and day > or = 2 (second calendar day or later). Clinical practice patients (n = 274) were younger, had more comorbidities, had higher severity of illness (as measured by organ dysfunction or greater vasopressor/ventilator use), and received DrotAA later than PROWESS patients (all p < .05). Overall hospital mortality for clinical practice patients was 42%, compared with 37% for DrotAA-treated PROWESS patients with Acute Physiology and Chronic Health Evaluation II score > or = 25. Mortality for day 0, day 1, and day > or = 2 groups was 33%, 40%, and 52%, respectively. In PROWESS, the vast majority were treated on day 0 or day 1. Serious bleeding events during infusion were noted in 4.0% of clinical practice patients compared with 2.2% of PROWESS DrotAA-treated patients with Acute Physiology and Chronic Health Evaluation II score > or = 25. CONCLUSIONS: Patients treated in clinical practice differed from those in PROWESS. Patients were younger, had more comorbidities, had greater severity of illness, and had longer mean time from severe sepsis onset to the start of DrotAA. Hospital mortality for patients treated within 1 day of severe sepsis onset was similar to DrotAA-treated PROWESS patients. While the low number of serious bleeding events precludes a definitive assessment, the observed incidence of serious bleeding events in clinical practice patients was numerically higher than in DrotAA-treated PROWESS patients.

Growth hormone replacement therapy in adults with growth hormone deficiency improves maximal oxygen consumption independently of dosing regimen or physical activity.

CONTEXT: Several studies have demonstrated an improvement in aerobic exercise capacity with 6 months of GH replacement in adults with GH deficiency (GHD). OBJECTIVE: The objective of the study was to determine whether improvements in aerobic exercise capacity with GH treatment in adults with GHD are related to changes in physical activity or affected by the GH dosing regimen. DESIGN: This was a randomized, two-arm, parallel, open-label study. SETTING: The study was conducted at five academic medical centers with exercise physiology laboratories. SUBJECTS: Study subjects were adults (n = 29) with GHD due to hypothalamic-pituitary disease. INTERVENTIONS: The intervention was GH replacement therapy, administered either as a fixed body weight-based dosing regimen as an individualized dose titration regimen for 32 wk. MAIN OUTCOME MEASURES: Maximal oxygen consumption (VO2 max) and oxygen consumption (VO2) at the lactate threshold, ventilatory threshold using a cycle ergometry protocol, and weekly energy expenditure (physical activity questionnaire), assessed at baseline and end point, were measured. RESULTS: In the group as a whole, VO2 max increased significantly (by 9%) from baseline (19.1+/- 0.89 ml/kg.min) to end point (21.6 +/- 1.23 ml/kg.min, P = 0.010). Compared with baseline, VO2 max also changed significantly within the individualized dose titration regimen group (+2.5 +/- 0.98 ml/kg.min, P =0.034) but not within the fixed body weight-based dosing regimen group (+1.2 +/- 0.78 ml/kg.min, P = 0.15), although these changes from baseline were not significantly different between the two groups. VO2 at lactate threshold, VO2 at ventilatory threshold, and weekly energy expenditure also did not change. CONCLUSIONS: GH replacement therapy in GH-deficient adults improved VO2 max similarly with both dosing regimens, without any influence of physical activity. There was no effect on submaximal exercise performance.

Simplified pharmacoeconomics of critical care and severe sepsis.

Understanding pharmacoeconomic evaluation can empower clinicians to be stronger decision makers. However, cost-effectiveness analyses (CEAs) in critical care are sometimes not easy to understand and often not placed in context with other interventions. The purpose of this article is to clarify and simplify the CEA process using examples from critical care and severe sepsis. First discussed is cost-effectiveness as a framework for clinical decision making and how it compares to other types of economic evaluations. Then important considerations when conducting or reviewing CEAs are explored, such as perspective, discounting, sensitivity analysis, and grading of CEAs, as well as shortcomings and resistance to using CEAs. Next, applications of CEA in critical care and severe sepsis are reviewed. Included is the Food and Drug Administration-approved drug for severe sepsis, drotrecogin alfa (activated), as an example of a recently new critical care intervention that resulted in significant interest in understanding cost-effectiveness. Finally, CEAs of other medical and nonmedical interventions are placed in context with CEAs from critical care. Understanding pharmacoeconomic evaluation can empower clinicians to be stronger decision makers. CEAs provide decision makers a quantitative measure of the value of therapeutic options that can guide clinicians toward balancing the cost burdens of therapy with their profound effects and choosing between options that compete for funding.

Differences in follicle-stimulating hormone secretion between 45,X monosomy Turner syndrome and 45,X/46,XX mosaicism are evident at an early age.

CONTEXT: Little information exists regarding FSH values in very young girls with Turner syndrome (TS). OBJECTIVES: The objective of the study was to evaluate the pattern, natural progression, and karyotype-related differences in FSH secretion in young, prepubertal girls with TS. STUDY DESIGN: FSH was measured at study entry and annually for 2 yr. SETTING: The Toddler Turner study was conducted at 11 U.S. pediatric endocrine centers. STUDY PARTICIPANTS: Eighty-eight girls with karyotype-proven TS aged 9 months to 4 yr participated in the study. MAIN OUTCOME MEASURES: By-karyotype differences in FSH concentration and age-related changes in FSH were measured. RESULTS: Mean (+/- SD) FSH was markedly elevated in the 45,X (n = 56: 68.3 +/- 36.0 IU/liter) and Other groups [n = 15 (excluding three subjects with Y-containing karyotypes): 52.7 +/- 50.8 IU/liter] but was minimally elevated in girls with 45,X/46,XX mosaicism (n = 14: 10.1 +/- 13.5 IU/liter, P < 0.005 both comparisons). Over the 2-yr period, FSH declined in the 45,X group (-13.4 IU/liter.yr, P < 0.0001). Nonetheless, only three of 159 FSH values fell within normal range for age at any time during the 2-yr study. FSH decline was similar in the Other group (-14.3 IU/liter.yr, P = 0.0032). In contrast, no significant decrease in FSH with age was observed in the 45,X/46,XX group. CONCLUSIONS: In contrast to the original report of FSH concentrations in individuals with TS, this study demonstrates distinct differences in patterns of FSH secretion between young girls with monosomy TS, who have persistent elevation of FSH to age 6 yr, and those with 45,X/46,XX mosaicism, whose FSH values suggest retained ovarian function in the majority. These findings have implications for patient management and family counseling.

From bench to bedside: a review of the clinical trial development plan of drotrecogin alfa (activated).

OBJECTIVE: To provide a comprehensive overview of the various clinical trials of drotrecogin alfa (activated) (DrotAA) completed by Eli Lilly and Company over the past 10 years. METHODS: Eli Lilly and Company data from phase 1 through phase 4 trials, observational studies, and compassionate-use studies of DrotAA were reviewed. Safety, efficacy, and pharmacokinetic data were included. The review excluded pediatric studies and studies recently concluded where the manuscript was in press. All studies included in the review were approved by the ethical review boards at the participating institutions. RESULTS: Over 9000 adults with severe sepsis have been enrolled in DrotAA clinical trials through December 2005 and the results of the clinical evaluation of DrotAA have been widely disseminated in publications. Analyses of the data indicate that the pharmacokinetics of DrotAA are both linear and dose-proportional. The phase 2 and phase 3 studies of administration of DrotAA to patients with severe sepsis demonstrated a significant reduction in mortality and were associated with a favorable benefit/risk profile. Three of these trials (a phase 2 and two phase 3, PROWESS and ENHANCE) evaluated the effect of DrotAA in adult patients with sepsis associated with acute organ dysfunction (severe sepsis) while another phase 3 trial (ADDRESS) was conducted in the non-indicated population of adult patients with severe sepsis associated with a lower risk of death. A phase 4 trial demonstrated no significant difference in steady-state plasma concentrations or elimination half-life of DrotAA between patients < or =135 kg and >135 kg, indicating that DrotAA should be dosed by actual body weight. DISCUSSION: The challenges and limitations of the clinical development plan for DrotAA are discussed. CONCLUSION: DrotAA is indicated for the reduction of mortality in adult patients with severe sepsis (sepsis associated with acute organ dysfunction) who have a high risk of death. DrotAA is not indicated in adult patients with severe sepsis and low risk of death. The clinical plan for DrotAA continues with a focus on tailored therapy and identifying the most appropriate patients for DrotAA treatment.

Steroid use in PROWESS severe sepsis patients treated with drotrecogin alfa (activated).

INTRODUCTION: In a study conducted by Annane, patients with septic shock and unresponsive to adrenocorticotropic hormone stimulation receiving low-dose steroid therapy had prolonged survival but not significantly improved 28-day mortality. The present study examines intravenous steroid use in PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) patients meeting the Annane enrollment criteria (AEC). METHODS: Adrenocorticotropic hormone stimulation tests were not done in PROWESS. Steroids were allowed but their use was not directed. Patients were identified using AEC (all of: randomization to study drug treatment within 8 hours of shock onset; infection, fever, or hypothermia; tachycardia; systolic blood pressure <90 mmHg on vasopressors; mechanical ventilation; and one of urine <0.5 ml/kg per hour, lactic acidosis, or arterial oxygen tension/inspired fractional oxygen <280). We examined steroid use and mortality data; additional analyses were done outside the 8-hour window. RESULTS: Steroid-treated patients were older, had higher Acute Physiology and Chronic Health Evaluation scores and more organ dysfunctions, and were more commonly receiving mechanical ventilation. Among patients meeting AEC, regardless of steroid treatment (n = 97), mortality in the placebo and drotrecogin alfa (activated) groups was 38% (19/50) and 28% (13/47), respectively (relative risk [RR] = 0.73, 95% confidence interval [CI] 0.41-1.30). When using AEC but excluding the requirement for randomization within 8 hours of shock onset (n = 612), placebo mortality was 38% (118/313) and drotrecogin alfa (activated) mortality was 29% (88/299; RR = 0.78, 95% CI 0.62-0.98). Using AEC but excluding the 8-hour window and with steroids initiated at baseline and/or infusion (n = 228) resulted in mortality for placebo and drotrecogin alfa (activated) groups of 43% (51/118) and 33% (36/110), respectively (RR = 0.76, 95% CI 0.54-1.06). CONCLUSION: Patients with severe sepsis from the PROWESS trial who were likely to respond to low-dose steroids according to the AEC were those patients at a high risk for death. However, when using the AEC, regardless of steroid use, patients exhibited a survival benefit from treatment with drotrecogin alfa (activated).

Application of a population-based severity scoring system to individual patients results in frequent misclassification.

INTRODUCTION: APACHE II (AP2) was developed to allow a systematic examination of intensive care unit outcomes in a risk adjusted manner. AP2 has been widely adopted in clinical trials to assure broad consistency amongst different groups. Although errors in calculating the true AP2 score may not be reducible below 15%, the self-canceling effect of random errors reduces the importance of such errors when applied to large populations. It has been suggested that a threshold AP2 score be used in clinical decision making for individual patients. This study reports the AP2 scoring errors of researchers involved in a large sepsis trial and models the consequences of such an error rate for individual severe sepsis patients. METHODS: Fifty-six researchers with explicit training in data abstraction and completion of the AP2 score received scenarios consisting of composites of real patient histories. Descriptive statistics were calculated for each scenario. The standard deviations were calculated compared with an adjudicated score. Intraclass correlations for inter-observer reliability were performed using Shrout-Fleiss methodology. Theoretical distribution curves were calculated for a broad range of AP2 scores using standard deviations of 6, 9 and 12. For each curve, the misclassification rate was determined using an AP2 score cut-off of >or=25. The percentage of misclassifications for each true AP2 score was then applied to the corresponding AP2 score obtained from the PROGRESS severe sepsis registry. RESULTS: The error rate for the total AP2 score was 86% (individual variables were in the range 10% to 87%). Intraclass correlation for the inter-observer reliability was 0.51. Of the patients from the PROGRESS registry. 50% had AP2 scores in the range 17 to 28. Within this interquartile range, 70% to 85% of all misclassified patients would reside. CONCLUSION: It is more likely that an individual patient will be scored incorrectly than correctly. The data obtained from the scenarios indicated that as the true AP2 score approached an arbitrary cut-off point of 25, the observed misclassification rate increased. Integrating our study of AP2 score errors with the published literature leads us to conclude that the AP2 is an inappropriate sole tool for resource allocation decisions for individual patients.

Obesity does not alter the pharmacokinetics of drotrecogin alfa (activated) in severe sepsis.

BACKGROUND: Drotrecogin alfa (activated) [DrotAA] is approved for the reduction of mortality in adults with severe sepsis (sepsis with acute organ dysfunction) and high risk of death. Patients whose actual body weight was >135 kg were excluded from the Phase III PROWESS trial. OBJECTIVE: To compare exposure to DrotAA in patients with severe sepsis weighing >135 kg with those weighing < or =135 kg in an open-label, Phase IV trial, and quantify the elimination half-life (t1/2) of DrotAA in these patients. METHODS: PROWESS inclusion/exclusion criteria were used, except that patients >135 kg were enrolled. Blood samples were collected for steady-state plasma concentration (Css) analysis of activated protein C once each day and for t1/2 analysis after infusion. Weight-normalized clearance (Clp) and t1/2 estimates for DrotAA were calculated and compared between weight groups. RESULTS: Patient weight range was 59-227 kg. There were 32 patients < or =135 kg and 20 patients >135 kg enrolled. Median Clp was 0.45 L/h/kg (interquartile range [IQR] 0.37-0.54) for patients < or =135 kg and 0.42 L/h/kg (IQR 0.33-0.54) for patients >135 kg (p = 0.692). Median estimates of Css were 51.9 ng/mL (IQR 43.4-62.0) and 56.5 ng/mL (IQR 44.9-71.1; p = 0.570). In patients < or =135 kg, DrotAA had a median t1/2 of 16.7 minutes (IQR 13.9-20.0) compared with 16.0 minutes (IQR 12.9-19.8) in patients >135 kg (p = 0.767), for a composite median t1/2 of 16.3 minutes (IQR 14.2-18.8). CONCLUSIONS: There is no statistically significant difference in Css concentrations or t1/2 of DrotAA between patients weighing < or =135 kg and >135 kg. DrotAA should be dosed by actual body weight.

Hospitalized cancer patients with severe sepsis: analysis of incidence, mortality, and associated costs of care.

INTRODUCTION: Infection is an important complication in cancer patients, which frequently leads to or prolongs hospitalization, and can also lead to acute organ dysfunction (severe sepsis) and eventually death. While cancer patients are known to be at higher risk for infection and subsequent complications, there is no national estimate of the magnitude of this problem. Our objective was to identify cancer patients with severe sepsis and to project these numbers to national levels. METHODS: Data for all 1999 hospitalizations from six states (Florida, Massachusetts, New Jersey, New York, Virginia, and Washington) were merged with US Census data, Centers for Disease Control vital statistics and National Cancer Institute, Surveillance, Epidemiology, and End Results initiative cancer prevalence data. Malignant neoplasms were identified by International Classification of Disease (ninth revision, clinical modification) (ICD-9-CM) codes (140-208), and infection and acute organ failure were identified from ICD-9-CM codes following Angus and colleagues. Cases were identified as a function of age and were projected to national levels. RESULTS: There were 606,176 cancer hospitalizations identified, with severe sepsis present in 29,795 (4.9%). Projecting national estimates for the US population, cancer patients account for 126,209 severe sepsis cases annually, or 16.4 cases per 1000 people with cancer per year. The inhospital mortality for cancer patients with severe sepsis was 37.8%. Compared with the overall population, cancer patients are much more likely to be hospitalized (relative risk, 2.77; 95% confidence interval, 2.77-2.78) and to be hospitalized with severe sepsis (relative risk, 3.96; 95% confidence interval, 3.94-3.99). Overall, severe sepsis is associated with 8.5% (46,729) of all cancer deaths at a cost of 3.4 billion dollars per year. CONCLUSION: Severe sepsis is a common, deadly, and costly complication in cancer patients.

Benefit/risk profile of drotrecogin alfa (activated) in surgical patients with severe sepsis.

BACKGROUND: The Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial examined the safety and efficacy of drotrecogin alfa (activated) (Xigris) in adult patients with severe sepsis. A clinical evaluation committee examined clinical data for each patient enrolled in PROWESS. However, there were no surgeons on the committee, and thus questions remained regarding the safety and efficacy of drotrecogin alfa (activated) in surgical patients. METHODS: Masked to treatment, a Surgical Evaluation Committee adjudicated the presence and type of operation, timing of surgery, infection, and adequacy of source control of surgical patients included in PROWESS. RESULTS: Twenty-eight percent of PROWESS cases were confirmed as surgical. The absolute risk reduction for mortality in all surgical patients was 3.2% and 9.1% for patients undergoing intraabdominal procedures. Serious bleeding during the infusion and 28-day period was similar between surgical and nonsurgical patients. CONCLUSIONS: Consistent with the overall PROWESS results, drotrecogin alfa (activated) has a favorable benefit/risk profile in surgical patients.

Static and dynamic assessment of biomarkers in surgical patients with severe sepsis.

BACKGROUND: Severe sepsis, defined as a systemic inflammatory response to infection associated with acute organ dysfunction, is common among surgical patients and is a major cause of morbidity and mortality. Severe sepsis has been associated with changes in inflammatory and hemostatic biomarkers. In patients undergoing surgical procedures there may be additional stimulation of cytokine release and activation of the coagulation system. The purpose of this study was to characterize the baseline differences in biomarkers between surgical and non-surgical patients. In addition, we assessed the dynamic changes in biomarkers and coagulation parameters in surgical patients with severe sepsis enrolled in PROWESS and treated with placebo or drotrecogin alfa (activated). METHODS: A blinded PROWESS surgical evaluation committee (SEC) verified patients as having undergone a relevant operative procedure within 30 days of enrollment for inclusion in the surgical cohort of PROWESS. At baseline and on study days 1-7, biomarkers and coagulation parameters available for analysis were D-dimer, interleukin-6 (IL-6), protein C activity, protein S activity, anti-thrombin III (ATIII), activated partial thromboplastin time (aPTT), and prothrombin time (PT). Platelet count was determined at baseline only. Baseline values were compared between SEC-defined surgical and all other non-surgical patients, and between pre- and post-operative surgical patients from the PROWESS trial. Changes from baseline were compared between drotrecogin alfa (activated)-treated and placebo-treated surgical patients. Statistical analyses were performed using ANOVA on the ranked values. RESULTS: The SEC verified 474 (28%) of the 1,690 PROWESS patients as surgical. Median D-dimer, IL-6, aPTT and PT values were significantly higher at baseline for surgical patients than non-surgical patients (p < 0.001). Surgical patients had significantly lower median protein C, protein S, and ATIII activity at baseline than non-surgical patients (p < 0.001). Surgical patients treated with drotrecogin alfa (activated) showed a significant decrease in D-dimer levels on study days 1-5 (p < 0.05), and a more rapid increase in Protein C levels on study days 1-4 (p < 0.05) compared to placebo. CONCLUSIONS: Surgical patients with severe sepsis appear to have a higher severity of illness at baseline as demonstrated by derangements in biomarkers and coagulation markers compared to non-surgical patients. Surgical patients treated with drotrecogin alfa (activated)showed reduced D-dimer concentrations and a more rapid increase in protein C concentrations during the infusion period.