Showing papers by "Gordon R. Bernard published in 2014"

Rosuvastatin for Sepsis-Associated Acute Respiratory Distress Syndrome

Abstract: Background In the acute respiratory distress syndrome (ARDS), inflammation in the lungs and other organs can cause life-threatening organ failure. Inhibitors of 3-hydroxy3-methylglutaryl coenzyme A reductase (statins) can modulate inflammatory responses. Previous observational studies suggested that statins improved clinical outcomes in patients with sepsis. We hypothesized that rosuvastatin therapy would improve clinical outcomes in critically ill patients with sepsis-associated ARDS. Methods We conducted a multicenter trial in which patients with sepsis-associated ARDS were randomly assigned to receive either enteral rosuvastatin or placebo in a doubleblind manner. The primary outcome was mortality before hospital discharge home or until study day 60 if the patient was still in a health care facility. Secondary outcomes included the number of ventilator-free days (days that patients were alive and breathing spontaneously) to day 28 and organ-failure–free days to day 14. Results The study was stopped because of futility after 745 of an estimated 1000 patients had been enrolled. There was no significant difference between study groups in 60-day in-hospital mortality (28.5% with rosuvastatin and 24.9% with placebo, P = 0 .21) or in mean (±SD) ventilator-free days (15.1±10.8 with rosuvastatin and 15.1±11.0 with placebo, P = 0 .96). The groups were well matched with respect to demographic and key physiological variables. Rosuvastatin therapy, as compared with placebo, was assoc iated with fewer days free of renal failure to day 14 (10.1±5.3 vs. 11.0±4.7, P = 0 .01) and fewer days free of hepatic failure to day 14 (10.8±5.0 vs. 11.8±4.3, P = 0 .003). Rosuvas tatin was not associated with an increased incidence of serum creatine kinase levels that were more than 10 times the upper limit of the normal range. Conclusions Rosuvastatin therapy did not improve clinical outcomes in patients with sepsis a ssociated ARDS and may have contributed to hepatic and renal organ dysfunction. (Funded by the National Heart, Lung, and Blood Institute and the Investigator-Sponsored Study Program of AstraZeneca; ClinicalTrials.gov number, NCT00979121.)

Delirium in the ICU and subsequent long-term disability among survivors of mechanical ventilation.

Abstract: Objective:Survivors of critical illness are frequently left with long-lasting disability. The association between delirium and disability in critically ill patients has not been described. We hypothesized that the duration of delirium in the ICU would be associated with subsequent disability and wor

Simplified severe sepsis protocol: a randomized controlled trial of modified early goal-directed therapy in Zambia.

Abstract: In the United States, 750,000 people die each year from sepsis.(1) Although available data are limited, the number of sepsis-related deaths is likely much higher in sub-Saharan Africa, where more than half of all deaths are attributed to infections.(2) Cohort studies from the region have found sepsis to be the third leading cause of death among HIV-infected adults, after tuberculosis and cryptococcal meningitis,(3) and an unpublished audit at the University Teaching Hospital in Zambia showed sepsis to be the leading cause of death among hospitalized medical patients. However, optimal management strategies for septic patients in Africa remain controversial.(4-7) Protocol-based management of sepsis has had wide uptake in North America and Europe.(8,9) Studies of early goal directed therapy have demonstrated that aggressive intravenous (IV) fluid administration, hemodynamic support, and blood transfusion can significantly reduce mortality due to sepsis. Central venous pressure or serum-lactate-guided approaches have generally resulted in patients receiving between 4 and 5 liters of fluid in the first 6 hours of admission.(10,11) In sub-Saharan Africa, however, uptake has been generally non-existent due to resource limitations.(12) Central venous catheters and lactic acid tests are not widely available, and the use of IV fluids for volume resuscitation has been much more conservative than guidelines recommend.(13,14) There are also questions regarding the generalizability of existing evidence to the sub-Saharan African setting, considering the under-representation of resource-limited study sites and HIV/AIDS patients in most sepsis trials.(15) Furthermore, the limited existing evidence from the region is conflicting regarding the potential benefits and harms of aggressive fluid resuscitation.(4,6) We hypothesized that a novel simplified treatment protocol, based on existing early goal directed therapy protocols, would reduce mortality compared with usual care in African patients with severe sepsis. The simplified severe sepsis protocol (SSSP) intervention consisted of early goal-directed fluid administration, plus dopamine and/or blood transfusion when indicated. Patients in both arms received close nurse monitoring with early blood cultures and antibiotics.

One-year mortality and predictors of death among hospital survivors of acute respiratory distress syndrome

Abstract: Advances in supportive care and ventilator management for acute respiratory distress syndrome (ARDS) have resulted in declines in short-term mortality, but risks of death after survival to hospital discharge have not been well described Our objective was to quantify the difference between short-term and long-term mortality in ARDS and to identify risk factors for death and causes of death at 1 year among hospital survivors This multi-intensive care unit, prospective cohort included patients with ARDS enrolled between January 2006 and February 2010 We determined the clinical characteristics associated with in-hospital and 1-year mortality among hospital survivors and utilized death certificate data to identify causes of death Of 646 patients hospitalized with ARDS, mortality at 1 year was substantially higher (41 %, 95 % CI 37–45 %) than in-hospital mortality (24 %, 95 % CI 21–27 %), P < 00001 Among 493 patients who survived to hospital discharge, the 110 (22 %) who died in the subsequent year were older (P < 0001) and more likely to have been discharged to a nursing home, other hospital, or hospice compared to patients alive at 1 year (P < 0001) Important predictors of death among hospital survivors were comorbidities present at the time of ARDS, and not living at home prior to admission ARDS-related measures of severity of illness did not emerge as independent predictors of mortality in hospital survivors Despite improvements in short-term ARDS outcomes, 1-year mortality is high, mostly because of the large burden of comorbidities, which are prevalent in patients with ARDS

Statins and delirium during critical illness: a multicenter, prospective cohort study.

Abstract: Objective Since statins have pleiotropic effects on inflammation and coagulation that may interrupt delirium pathogenesis, we tested the hypotheses that statin exposure is associated with reduced delirium during critical illness whereas discontinuation of statin therapy is associated with increased delirium.

Evaluating the efficacy and safety of two doses of the polyclonal anti-tumor necrosis factor-α fragment antibody AZD9773 in adult patients with severe sepsis and/or septic shock: randomized, double-blind, placebo-controlled phase IIb study*.

Abstract: OBJECTIVE:: This trial compared the efficacy/safety of two IV doses of AZD9773, a polyclonal antibody to tumor necrosis factor-α, in adult patients with severe sepsis/septic shock. DESIGN:: Multicenter, randomized, double-blind, placebo-controlled phase IIb trial. SETTING:: ICUs in seven countries (Australia, Belgium, Canada, Czech Republic, Finland, France, and Spain). PATIENTS:: Patients 18 years old or older with severe sepsis and/or septic shock. Patients were required to have 1) objective clinical evidence of infection; 2) at least two of four systemic inflammatory response syndrome criteria; and 3) cardiovascular and/or respiratory sepsis-related failure. INTERVENTIONS:: Patients were randomized 1:1:1 to a single loading infusion of AZD9773 250 U/kg followed by 50 U/kg every 12 hours (low dose, n = 100), a single loading infusion of AZD9773 500 U/kg followed by 100 U/kg every 12 hours (high dose, n = 100), or placebo (n = 100) for 5 days. Follow-up assessments were performed up to day 90. MEASUREMENTS AND MAIN RESULTS:: Mean number of ventilator-free days (primary endpoint) did not differ between low-dose (19.7 d) or high-dose AZD9773 (17.3 d) and placebo (18.3 d) (one-sided p = 0.18 and 0.74, respectively). Mortality rates were comparable across treatment groups; relative risk of death versus placebo at day 29 was 0.80 for low-dose AZD9773 (one-sided p = 0.25) and 1.64 for high-dose AZD9773 (p = 0.97). Most patients experienced at least one treatment-emergent adverse event (87.8% in AZD9773-treated patients, 92.9% in placebo patients) although most were mild/moderate in nature. No differences in the incidence of adverse events or laboratory or vital sign abnormalities were observed between groups. CONCLUSIONS:: AZD9773 rapidly and efficiently decreased plasma tumor necrosis factor-α concentration in patients with severe sepsis/septic shock, but this effect did not translate into clinical benefit. Copyright © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.

Vitamin D deficiency and risk of acute lung injury in severe sepsis and severe trauma: a case-control study

Abstract: Background The aim of this study was to determine the association between 25-hydroxyvitamin D (25-OHD) levels at the onset of critical illness and the development of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) in patients with sepsis or trauma.