RESUMO
CONTEXT: Gamma-aminobutyric acid receptor agonist medications are the most commonly used sedatives for intensive care unit (ICU) patients, yet preliminary evidence indicates that the alpha(2) agonist dexmedetomidine may have distinct advantages. OBJECTIVE: To compare the efficacy and safety of prolonged sedation with dexmedetomidine vs midazolam for mechanically ventilated patients. DESIGN, SETTING, AND PATIENTS: Prospective, double-blind, randomized trial conducted in 68 centers in 5 countries between March 2005 and August 2007 among 375 medical/surgical ICU patients with expected mechanical ventilation for more than 24 hours. Sedation level and delirium were assessed using the Richmond Agitation-Sedation Scale (RASS) and the Confusion Assessment Method for the ICU. INTERVENTIONS: Dexmedetomidine (0.2-1.4 microg/kg per hour [n = 244]) or midazolam (0.02-0.1 mg/kg per hour [n = 122]) titrated to achieve light sedation (RASS scores between -2 and +1) from enrollment until extubation or 30 days. MAIN OUTCOME MEASURES: Percentage of time within target RASS range. Secondary end points included prevalence and duration of delirium, use of fentanyl and open-label midazolam, and nursing assessments. Additional outcomes included duration of mechanical ventilation, ICU length of stay, and adverse events. RESULTS: There was no difference in percentage of time within the target RASS range (77.3% for dexmedetomidine group vs 75.1% for midazolam group; difference, 2.2% [95% confidence interval {CI}, -3.2% to 7.5%]; P = .18). The prevalence of delirium during treatment was 54% (n = 132/244) in dexmedetomidine-treated patients vs 76.6% (n = 93/122) in midazolam-treated patients (difference, 22.6% [95% CI, 14% to 33%]; P < .001). Median time to extubation was 1.9 days shorter in dexmedetomidine-treated patients (3.7 days [95% CI, 3.1 to 4.0] vs 5.6 days [95% CI, 4.6 to 5.9]; P = .01), and ICU length of stay was similar (5.9 days [95% CI, 5.7 to 7.0] vs 7.6 days [95% CI, 6.7 to 8.6]; P = .24). Dexmedetomidine-treated patients were more likely to develop bradycardia (42.2% [103/244] vs 18.9% [23/122]; P < .001), with a nonsignificant increase in the proportion requiring treatment (4.9% [12/244] vs 0.8% [1/122]; P = .07), but had a lower likelihood of tachycardia (25.4% [62/244] vs 44.3% [54/122]; P < .001) or hypertension requiring treatment (18.9% [46/244] vs 29.5% [36/122]; P = .02). CONCLUSIONS: There was no difference between dexmedetomidine and midazolam in time at targeted sedation level in mechanically ventilated ICU patients. At comparable sedation levels, dexmedetomidine-treated patients spent less time on the ventilator, experienced less delirium, and developed less tachycardia and hypertension. The most notable adverse effect of dexmedetomidine was bradycardia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00216190 Published online February 2, 2009 (doi:10.1001/jama.2009.56).
Assuntos
Agonistas alfa-Adrenérgicos , Sedação Consciente , Estado Terminal , Dexmedetomidina , Moduladores GABAérgicos , Hipnóticos e Sedativos , Midazolam , Respiração Artificial , APACHE , Agonistas alfa-Adrenérgicos/administração & dosagem , Agonistas alfa-Adrenérgicos/efeitos adversos , Idoso , Sedação Consciente/métodos , Delírio/epidemiologia , Dexmedetomidina/administração & dosagem , Dexmedetomidina/efeitos adversos , Método Duplo-Cego , Feminino , Moduladores GABAérgicos/administração & dosagem , Moduladores GABAérgicos/efeitos adversos , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Unidades de Terapia Intensiva , Estimativa de Kaplan-Meier , Tempo de Internação , Masculino , Midazolam/administração & dosagem , Midazolam/efeitos adversos , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
CONTEXT: Ventilator-associated pneumonia (VAP) causes substantial morbidity. A silver-coated endotracheal tube has been designed to reduce VAP incidence by preventing bacterial colonization and biofilm formation. OBJECTIVE: To determine whether a silver-coated endotracheal tube would reduce the incidence of microbiologically confirmed VAP. DESIGN, SETTING, AND PARTICIPANTS: Prospective, randomized, single-blind, controlled study conducted in 54 centers in North America. A total of 9417 adult patients (> or = 18 years) were screened between 2002 and 2006. A total of 2003 patients expected to require mechanical ventilation for 24 hours or longer were randomized. INTERVENTION: Patients were assigned to undergo intubation with 1 of 2 high-volume, low-pressure endotracheal tubes, similar except for a silver coating on the experimental tube. MAIN OUTCOME MEASURES: Primary outcome was VAP incidence based on quantitative bronchoalveolar lavage fluid culture with 10(4) colony-forming units/mL or greater in patients intubated for 24 hours or longer. Other outcomes were VAP incidence in all intubated patients, time to VAP onset, length of intubation and duration of intensive care unit and hospital stay, mortality, and adverse events. RESULTS: Among patients intubated for 24 hours or longer, rates of microbiologically confirmed VAP were 4.8% (37/766 patients; 95% confidence interval [CI], 3.4%-6.6%) in the group receiving the silver-coated tube and 7.5% (56/743; 95% CI, 5.7%-9.7%) (P = .03) in the group receiving the uncoated tube (all intubated patients, 3.8% [37/968; 95% CI, 2.7%-5.2%] and 5.8% [56/964; 95% CI, 4.4%-7.5%] [P = .04]), with a relative risk reduction of 35.9% (95% CI, 3.6%-69.0%; all intubated patients, 34.2% [95% CI, 1.2%-67.9%]). The silver-coated endotracheal tube was associated with delayed occurrence of VAP (P = .005). No statistically significant between-group differences were observed in durations of intubation, intensive care unit stay, and hospital stay; mortality; and frequency and severity of adverse events. CONCLUSION: Patients receiving a silver-coated endotracheal tube had a statistically significant reduction in the incidence of VAP and delayed time to VAP occurrence compared with those receiving a similar, uncoated tube. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00148642.
Assuntos
Anti-Infecciosos Locais , Biofilmes , Contaminação de Equipamentos/prevenção & controle , Intubação Intratraqueal/instrumentação , Pneumonia Associada à Ventilação Mecânica/prevenção & controle , Compostos de Prata , Adulto , Idoso , Idoso de 80 Anos ou mais , Líquido da Lavagem Broncoalveolar/microbiologia , Feminino , Humanos , Incidência , Intubação Intratraqueal/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pneumonia Associada à Ventilação Mecânica/epidemiologia , Pneumonia Associada à Ventilação Mecânica/microbiologia , Estudos Prospectivos , Respiração Artificial/instrumentação , Fatores de Risco , Método Simples-Cego , Fatores de TempoRESUMO
STUDY OBJECTIVE: To gather additional 28-day all-cause mortality and safety data among adult patients with severe sepsis who were treated with drotrecogin alfa (activated). DESIGN: Prospective, single-arm, multicenter clinical trial. SETTING: Eighty-five study sites in the United States and two in Puerto Rico. PARTICIPANTS: Adult patients (273 patients) with a diagnosis of severe sepsis, which was defined as a systemic inflammatory response due to acute infection and one or more sepsis-induced organ dysfunctions present for = 48 h, as in the recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial. INTERVENTIONS: Drotrecogin alfa (activated) [Xigris; Eli Lilly and Company; Indianapolis, IN], 24 micro g/kg/h, as a continuous IV infusion for a duration of 96 +/- 1 h. MEASUREMENTS AND RESULTS: The primary end point was all-cause mortality, which was assessed 28 days after the start of the infusion of drotrecogin alfa (activated). Serious bleeding was monitored to day 28. Comparisons of mortality were made to treatment groups from two double-blind, placebo-controlled clinical trials (PROWESS United States and the Secretory Phospholipase A2 Inhibitor [sPLA2I] in Severe Sepsis trial) that used similarly defined patient populations from the United States. For the 273 adult patients enrolled in this study, the 28-day all-cause mortality rate was 26.4%. This mortality rate was 6% lower than that observed in the placebo groups in the PROWESS US trial (32.9%) and the sPLA2I trial (33.2%), and was similar to that of the group treated with drotrecogin alfa (activated) in the PROWESS US trial (24.4%). One nonfatal intracranial hemorrhage was reported in the Extended Evaluation of Recombinant Human Activated Protein C United States trial (ENHANCE US) [0.35%]. Serious bleeding events during the infusion period occurred in 11 patients (4.0%) compared to 10 patients (2.8%) in the PROWESS US drotrecogin alfa (activated) treatment group. CONCLUSIONS: Despite the limitations associated with comparisons across trials, this study provides confirmatory evidence of the efficacy and safety of drotrecogin alfa (activated) documented in the PROWESS trial.
Assuntos
Causas de Morte , Proteína C/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Sepse/tratamento farmacológico , Sepse/mortalidade , APACHE , Adulto , Fatores Etários , Idoso , Intervalos de Confiança , Estado Terminal , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Probabilidade , Estudos Prospectivos , Proteína C/efeitos adversos , Proteínas Recombinantes/efeitos adversos , Valores de Referência , Medição de Risco , Sepse/diagnóstico , Índice de Gravidade de Doença , Fatores Sexuais , Método Simples-Cego , Análise de Sobrevida , Resultado do Tratamento , Estados UnidosRESUMO
Drotrecogin alfa (activated) improved survival in patients with severe sepsis in PROWESS, a double-blind, study of 1690 adult patients randomized to drotrecogin alfa (activated) at 24 microg/kg/h (N=850) or placebo (N=840) infused for 96 hours. Pharmacodynamic effects of drotrecogin alfa (activated) were assessed with 15 prospectively defined systemic biomarkers of hemostasis, inflammation and endothelial injury. The last-observation-carried-forward (LOCF) method of imputation for missing observations was the prospectively defined statistical method. The results were also analyzed with only the observed values without imputation for missing data (repeated measures analysis). With both statistical methods, drotrecogin alfa (activated)-treated patients demonstrated antithrombotic (reduced markers of thrombin generation and accelerated normalization of anticoagulant factor, protein C and fibrinolytic factors) and anticoagulant (prolonged PT and APTT) effects compared with placebo. A profibrinolytic (reduction in plasminogen activator inhibitor-1) effect was significant only with the LOCF imputation method in observed case and percent change from baseline analyses. An anti-inflammatory (reduction in interleukin-6) effect was significant only with the LOCF imputation method in change from baseline and percent change from baseline analyses. Drotrecogin alfa (activated) is a new and promising agent for treatment of patients with severe sepsis. The extensive analysis of systemic biomarkers confirms the previously published antithrombotic effects. However, the present results using different statistical methods do not provide a strong basis for systemic anti-inflammatory or pro-fibrinolytic effects. These latter two effects may occur at the local or cellular level. The systemic biomarkers reported here might not be the most appropriate approach to demonstrate these potential effects of drotrecogin alfa (activated).