Showing papers by "Gordon R. Bernard published in 2003"

Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS).

Abstract: ContextGoal-directed delivery of sedative and analgesic medications is recommended as standard care in intensive care units (ICUs) because of the impact these medications have on ventilator weaning and ICU length of stay, but few of the available sedation scales have been appropriately tested for reliability and validity.ObjectiveTo test the reliability and validity of the Richmond Agitation-Sedation Scale (RASS).DesignProspective cohort study.SettingAdult medical and coronary ICUs of a university-based medical center.ParticipantsThirty-eight medical ICU patients enrolled for reliability testing (46% receiving mechanical ventilation) from July 21, 1999, to September 7, 1999, and an independent cohort of 275 patients receiving mechanical ventilation were enrolled for validity testing from February 1, 2000, to May 3, 2001.Main Outcome MeasuresInterrater reliability of the RASS, Glasgow Coma Scale (GCS), and Ramsay Scale (RS); validity of the RASS correlated with reference standard ratings, assessments of content of consciousness, GCS scores, doses of sedatives and analgesics, and bispectral electroencephalography.ResultsIn 290-paired observations by nurses, results of both the RASS and RS demonstrated excellent interrater reliability (weighted κ, 0.91 and 0.94, respectively), which were both superior to the GCS (weighted κ, 0.64; P<.001 for both comparisons). Criterion validity was tested in 411-paired observations in the first 96 patients of the validation cohort, in whom the RASS showed significant differences between levels of consciousness (P<.001 for all) and correctly identified fluctuations within patients over time (P<.001). In addition, 5 methods were used to test the construct validity of the RASS, including correlation with an attention screening examination (r = 0.78, P<.001), GCS scores (r = 0.91, P<.001), quantity of different psychoactive medication dosages 8 hours prior to assessment (eg, lorazepam: r = − 0.31, P<.001), successful extubation (P = .07), and bispectral electroencephalography (r = 0.63, P<.001). Face validity was demonstrated via a survey of 26 critical care nurses, which the results showed that 92% agreed or strongly agreed with the RASS scoring scheme, and 81% agreed or strongly agreed that the instrument provided a consensus for goal-directed delivery of medications.ConclusionsThe RASS demonstrated excellent interrater reliability and criterion, construct, and face validity. This is the first sedation scale to be validated for its ability to detect changes in sedation status over consecutive days of ICU care, against constructs of level of consciousness and delirium, and correlated with the administered dose of sedative and analgesic medications.

Effects of drotrecogin alfa (activated) on organ dysfunction in the PROWESS trial.

Abstract: Objective To assess morbidity in patients with severe sepsis managed with and without drotrecogin alfa (activated). Design Analysis of secondary end points in a prospective, randomized, double-blind, placebo-controlled, multicenter, phase 3 trial (PROWESS). Setting A total of 164 medical institutions in 11 countries. Patients A total of 1,690 consecutive adult patients with severe sepsis. Interventions A 96-hr infusion of drotrecogin alfa (activated) (human recombinant activated protein C) or placebo. Measurements and main results Sequential Organ Failure Assessment (SOFA) scores for cardiovascular, respiratory, renal, hematologic, and hepatic organ systems were measured for 28 days. Mean cardiovascular SOFA scores were significantly lower for patients treated with drotrecogin alfa (activated) compared with placebo patients over this time period (p = .022). Drotrecogin alfa (activated)-treated patients also showed significantly faster resolution of cardiovascular (p = .009) and respiratory (p = .009) dysfunction and significantly slower onset of hematologic organ dysfunction (p = .041) compared with placebo patients for days 1 to 7. No significant differences in morbidity were observed between treatment groups among 28-day survivors. Conclusion Drotrecogin alfa (activated) demonstrated significant improvements in organ function compared with placebo in a large phase 3 clinical trial that has shown a mortality benefit in patients with severe sepsis.

Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis.

Abstract: Objective: To assess the effects of drotrecogin alfa (activated) therapy, a recombinant human activated protein C, across clinically relevant subpopulations in a randomized, phase 3, placebo-controlled study of patients with severe sepsis (recombinant human activated protein C worldwide evaluation in severe sepsis [PROWESS]). Design: Univariate and multivariable analysis of prospectively defined subgroups from the PROWESS study. Setting. A total of 164 medical centers in 11 countries. Patients. A total of 1,690 patients with severe sepsis. Measurements and Main Results., We report observed 28-day mortality rates for drotrecogin alfa (activated) and placebo patients for subgroups prospectively defined by demographic data, surgical status, type and site of infection, and clinical and biochemical measures of disease severity. We performed subgroup analyses to explore the consistency of the mortality benefit observed in the overall population and performed tests for both quantitative and qualitative interactions. To examine the magnitude of the treatment benefit with drotrecogin alfa (activated) across the underlying predicted risk of mortality spectrum, we used stepwise logistic regression on PROWESS placebo patients to generate a predicted risk of mortality model that simultaneously included many clinical and biochemical markers of mortality risk. Because drotrecogin alfa (activated) has anticoagulant properties, we also present analyses of bleeding and thrombotic events. Actual mortality rates were lower with drotrecogin alfa (activated) compared with placebo for nearly all prospectively defined subgroups. Both univariate and multivariable regression analyses showed a consistent relative risk reduction in 28-day mortality rates for drotrecogin alfa (activated). Larger absolute risk reductions were found with drotrecogin alfa (activated) in patients with a higher baseline predicted risk of mortality, and actual mortality rates were lower with drotrecogin alfa (activated) in all subgroups defined by disease severity measures where a greater than or equal to20% placebo mortality was observed. Although discriminatory power was limited by few observed events, the increased absolute risk of experiencing a serious bleeding event with treatment did not seem to vary according to the baseline predicted risk of mortality. Conclusions. The administration of drotrecogin alfa (activated) to patients with severe sepsis was associated with a significant survival benefit that tended to increase with higher baseline likelihood of death. Current data suggest that the increased risk of bleeding does not vary according to likelihood of death.

Cost-effectiveness of drotrecogin alfa (activated) in the treatment of severe sepsis*

Abstract: Objective: To assess the cost-effectiveness of drotrecogin alfa (activated) therapy, which was recently shown to reduce mortality in severe sepsis. Design: Estimates of effectiveness and resource use were based on data collected prospectively as part of a multicenter international trial. Estimates of hospital costs were based on a subset of the patients treated in the United States (33% of all enrolled patients). Lifetime projections were modeled from published sources and tested in sensitivity analyses. Analyses were conducted from the United States societal perspective, limited to healthcare costs, and using a 3% annual discount rate. Setting: A total of 164 medical institutions in 11 countries. Patients: Adults ≥18 yrs of age with severe sepsis. Interventions: Eligible patients were randomly assigned to receive a 96-hr intravenous infusion of drotrecogin alfa (activated) at 24 μg/kg/hr (n = 850) or placebo (n = 840). Measurements and Main Results: Base Case: incremental short-term (days 1-28) healthcare costs per day-28 survivor; Panel on Cost-Effectiveness in Health and Medicine Reference Case: incremental lifetime healthcare costs per quality-adjusted life-year. Over the first 28 days (short-term Base Case), drotrecogin alfa (activated) increased the costs of care by $9,800 and survival by 0.061 lives saved per treated patient. Thus, drotrecogin alfa (activated) cost $160,000 per life saved (with 84.7% probability that ratio is $100,000 per quality-adjusted life-year if survivors lived <4.6 yrs on average. Drotrecogin alfa (activated) cost $27,400 per quality-adjusted life-year when limited to patients with an Acute Physiology and Chronic Health Evaluation II score ≥25 and was cost-ineffective when limited to patients with a score <25. Conclusions: Drotrecogin alfa has a cost-effectiveness profile similar to that of many well-accepted healthcare strategies and below commonly quoted thresholds.

Systemic Host Responses in Severe Sepsis Analyzed by Causative Microorganism and Treatment Effects of Drotrecogin Alfa (Activated)

Abstract: Clinical trials with novel therapeutic agents for severe sepsis have suggested that patients might respond differently depending on causative microorganism. Data from a large, placebo-controlled trial of recombinant human drotrecogin alfa (activated) (DrotAA) were analyzed by type of causative microorganism for treatment-associated differences in mortality, coagulopathy, and inflammatory response. Compared with placebo, mortality rates associated with DrotAA were consistently reduced for each microorganism group (gram-positive bacteria, gram-negative bacteria, mixed bacteria, fungi, other, and unknown microbial etiology), with a stratified relative risk (RR) of 0.80 (95% confidence interval [CI], 0.69-0.94). The greatest reduction in the mortality rate was for Streptococcus pneumoniae infection (RR, 0.56; 95% CI, 0.35-0.88). Levels of coagulation and inflammation biomarkers varied with different pathogens at study entry. Results demonstrate that DrotAA, administered as an adjunct to standard anti-infective therapy, can improve the rate of survival for patients who develop severe sepsis regardless of causative microorganism.

Drotrecogin alfa (activated) in the treatment of severe sepsis patients with multiple-organ dysfunction: data from the PROWESS trial

Abstract: Objective Based on the results of the PROWESS trial the European Agency for the Evaluation of Medicinal Products has recently approved drotrecogin alfa (activated) for treatment of adult patients with severe sepsis and multiple-organ failure We report study's data on efficacy and safety in patients with multiple-organ dysfunction

Safety assessment of drotrecogin alfa (activated) in the treatment of adult patients with severe sepsis

Abstract: Drotrecogin alfa (activated; recombinant activated protein C) was shown to reduce 28-day all-cause mortality in patients with severe sepsis and to have an acceptable safety profile in 1690 patients studied in the F1K-MC-EVAD (PROWESS) trial. We analyzed all available data on the safety of treatment with drotrecogin alfa (activated) in 2786 adult patients with severe sepsis enrolled in all phase 2 and 3 clinical trials, and in an estimated 3991 patients receiving the drug in commercial use. Mortality and safety analyses were performed on all available data from adult severe sepsis patients enrolled in seven clinical trials as of 12 April 2002. Trial-specific safety data and spontaneously reported serious adverse events from commercial use were extracted from a pharmacovigilance database. The 28-day mortality rate for all adult patients who received active treatment in all clinical trials was 25.3% (704/2786). Serious bleeding events during the infusion period and 28-day study period occurred in 2.8% (79/2786) and 5.3% (148/2786) of patients, respectively. Of bleeding events during the infusion period, 43% (34/79) were procedure-related. Fatal serious bleeding events during the infusion period occurred in 0.4% (12/2786) of cases. Intracranial hemorrhage (ICH) events during the infusion period and 28-day study period occurred in 0.6% (16/2786) and 1.1% (32/2786) of patients, respectively. Ten out of the 16 ICH events occurring during the study drug infusion period were associated with severe thrombocytopenia (≤ 30,000/mm3) and/or meningitis. Serious bleeding and ICH events spontaneously reported from commercial use (n = 3991) occurred in 0.9% and 0.2% of patients, respectively. Drotrecogin alfa (activated) significantly reduces mortality in severe sepsis. The efficacy and safety profiles of drotrecogin alfa (activated) have remained consistent over the conduct of multiple clinical trials. The most important serious adverse event associated with drotrecogin alfa (activated) treatment is bleeding. Additional clinical experience indicates that invasive procedures are associated with a substantial percentage of serious bleeding events, particularly those occurring at the start of infusion of the drug. Severe thrombocytopenia (for all serious bleeding events, including ICH) and meningitis (for ICH only) may be risk factors for serious bleeding. However, patients with severe thrombocytopenia and/or meningitis may be at greater risk for bleeding or ICH in the absence of drug therapy.

Drotrecogin Alfa (Activated) Treatment of Older Patients with Severe Sepsis

Abstract: The incidence of severe sepsis increases dramatically with advanced age, with a mortality rate that approaches 50%. The main purpose of this investigation was to determine both short- and long-term survival outcomes among 386 patients aged >or=75 years who were enrolled in the Protein C Worldwide Evaluation of Severe Sepsis (PROWESS) trial. Subjects who were treated with drotrecogin alfa (activated; DAA) had absolute risk reductions in 28-day and in-hospital mortality of 15.5% and 15.6%, respectively (P=.002 for both), compared with placebo recipients. The relative risk (RR) for 28-day mortality was 0.68 (95% confidence interval [CI], 0.54-0.87), and the in-hospital RR was 0.70 (95% CI, 0.56-0.88). Resource use and patient disposition for DAA-treated patients compared favorably with those for placebo recipients. In addition, long-term follow-up data were available for 375 subjects (97.2%), and survival rates for DAA recipients were significantly higher over a 2-year period (P=.02). The incidences of serious adverse bleeding during the 28-day study period in the DAA and placebo groups were 3.9% and 2.2%, respectively (P=.34). There was no interaction between age and bleeding rates (P=.97). In conclusion, older patients with severe sepsis have higher short- and long-term survival rates when treated with DAA than when treated with placebo but an increased risk of serious bleeding that is not aged related.

Drotrecogin alfa (activated) (recombinant human activated protein C) for the treatment of severe sepsis.

Abstract: Objective To review the data supporting drotrecogin alfa (activated) for severe sepsis treatment Data sources Published research and data from the Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial Data extraction and synthesis The coagulation cascade and intense inflammation play a central role in the development of organ failure due to severe sepsis Drotrecogin alfa (activated) has anti-inflammatory, antithrombotic, profibrinolytic, and other properties that may explain the beneficial results seen in both animal models and humans with severe sepsis Drotrecogin alfa (activated) produces a robust reduction in the mortality rate of patients with severe sepsis that is evident across nearly every subgroup examined in the phase III clinical trial and has an acceptable safety profile with bleeding during infusion as the only significant risk associated with therapy The relative risk reductions for mortality seen in Gram-negative, Gram-positive, pneumonia, abdominal sources, shock, and nonshock are similar to the intent-to-treat population, 194% Treatment also increases days alive and free from mechanical ventilation and shock Conclusions Coagulopathy and systemic inflammation are almost universal in patients with severe sepsis Treatment of this disorder with drotrecogin alfa (activated) directly addresses these derangements and substantially reduces morbidity and mortality rates with potential for bleeding during infusion as the only known risk

CommLog/spl copy/: A communication log system for clinical trials

Abstract: Thanks to the advent of information technologies, the emergence of commercial products for electronic clinical trials has improved many aspects of conducting clinical trials. While there are many new options available to facilitate the collection of patient data, little advancements have been made in the way in which information generated from the coordination of a clinical trial is managed. The coordination of a clinical trial has proven to have a significant impact on the quality and economy of clinical trials. The Vanderbilt Coordinating Center has designed and implemented a communication log system (CommLog/spl copy/) to streamline the coordination of clinical trials in order to improve the quality and economy of clinical trials. The CommLog/spl copy/ has been operational for several industry-sponsored phase II/III clinical trails and has provided a knowledge base for the studies and repository for useful study information.