A multicenter randomized trial of atorvastatin therapy in intensive care patients with severe sepsis.

RATIONALE: Observational studies link statin therapy with improved outcomes in patients with severe sepsis. OBJECTIVES: To test whether atorvastatin therapy affects biologic and clinical outcomes in critically ill patients with severe sepsis. METHODS: Phase II, multicenter, prospective, randomized, double-blind, placebo-controlled trial stratified by site and prior statin use. A cohort of 250 critically ill patients (123 statins, 127 placebo) with severe sepsis were administrated either atorvastatin (20 mg daily) or matched placebo. MEASUREMENTS AND MAIN RESULTS: There was no difference in IL-6 concentrations (primary end point) between the atorvastatin and placebo groups (P = 0.76) and no interaction between treatment group and time to suggest that the groups behaved differently over time (P = 0.26). Baseline plasma IL-6 was lower among previous statin users (129 [87-191] vs. 244 [187-317] pg/ml; P = 0.01). There was no difference in length of stay, change in Sequential Organ Failure Assessment scores or mortality at intensive care unit discharge, hospital discharge, 28- or 90-day (15% vs. 19%), or adverse effects between the two groups. Cholesterol was lower in patients treated with atorvastatin (2.4 [0.07] vs. 2.6 [0.06] mmol/L; P = 0.006). In the predefined group of 77 prior statin users, those randomized to placebo had a greater 28-day mortality (28% vs. 5%; P = 0.01) compared with those who received atorvastatin. The difference was not statistically significant at 90 days (28% vs. 11%; P = 0.06). CONCLUSIONS: Atorvastatin therapy in severe sepsis did not affect IL-6 levels. Prior statin use was associated with a lower baseline IL-6 concentration and continuation of atorvastatin in this cohort was associated with improved survival. Clinical trial registered with the Australian New Zealand Clinical Trials Registry (ACTRN 12607000028404).

A pilot feasibility trial of allocation of freshest available red blood cells versus standard care in critically ill patients.

BACKGROUND: Prolonged storage of red blood cells (RBCs) may increase posttransfusion adverse events in critically ill patients. We aimed to evaluate in intensive care unit (ICU) patients 1) the feasibility of allocating freshest available compatible RBCs versus standard care and 2) the suitability of this approach in the design of a large randomized controlled trial (RCT). STUDY DESIGN AND METHODS: Eligible patients from two adult ICUs were randomly assigned to receive either the freshest available compatible RBCs or the standard care (the oldest compatible available RBCs) for all transfusions during their ICU stay. Study group allocation was concealed from patients and bedside clinicians, but the transfusion service was unblinded. The study endpoints were the feasibility of the study procedures, including success of the ICU Web randomization, the ICU staff blinding, and the correct delivery of the RBC units by the transfusion service in accordance with the allocated study group. In addition, we measured the difference in age of RBC units between the two groups. RESULTS: During a 3-month period, 177 RBC units were delivered to 51 patients. All study procedures, including randomization, blinding, and delivery of blood in accordance with the study group were successful. The mean (±SD) of the mean age of the RBC received by each patient was lower in the "fresher blood" group compared with the standard care group (12.1 [±3.8] days vs. 23 [±8.4] days; p<0.001). CONCLUSION: Randomized delivery of the freshest available RBCs versus standard care to ICU patients who were prescribed transfusion for clinical reasons is feasible, with a clinically relevant degree of storage duration separation achievable between the two study groups. These findings support the feasibility of a future large pragmatic RCT.

Age of red blood cells and mortality in the critically ill.

INTRODUCTION: In critically ill patients, it is uncertain whether exposure to older red blood cells (RBCs) may contribute to mortality. We therefore aimed to evaluate the association between the age of RBCs and outcome in a large unselected cohort of critically ill patients in Australia and New Zealand. We hypothesized that exposure to even a single unit of older RBCs may be associated with an increased risk of death. METHODS: We conducted a prospective, multicenter observational study in 47 ICUs during a 5-week period between August 2008 and September 2008. We included 757 critically ill adult patients receiving at least one unit of RBCs. To test our hypothesis we compared hospital mortality according to quartiles of exposure to maximum age of RBCs without and with adjustment for possible confounding factors. RESULTS: Compared with other quartiles (mean maximum red cell age 22.7 days; mortality 121/568 (21.3%)), patients treated with exposure to the lowest quartile of oldest RBCs (mean maximum red cell age 7.7 days; hospital mortality 25/189 (13.2%)) had an unadjusted absolute risk reduction in hospital mortality of 8.1% (95% confidence interval = 2.2 to 14.0%). After adjustment for Acute Physiology and Chronic Health Evaluation III score, other blood component transfusions, number of RBC transfusions, pretransfusion hemoglobin concentration, and cardiac surgery, the odds ratio for hospital mortality for patients exposed to the older three quartiles compared with the lowest quartile was 2.01 (95% confidence interval = 1.07 to 3.77). CONCLUSIONS: In critically ill patients, in Australia and New Zealand, exposure to older RBCs is independently associated with an increased risk of death.

Australasian resuscitation of sepsis evaluation (ARISE): A multi-centre, prospective, inception cohort study.

AIM: Determine current resuscitation practices and outcomes in patients presenting to the emergency department (ED) with sepsis and hypoperfusion or septic shock in Australia and New Zealand (ANZ). METHODS: Three-month prospective, multi-centre, observational study of all adult patients with sepsis and hypoperfusion or septic shock in the ED of 32 ANZ tertiary-referral, metropolitan and rural hospitals. RESULTS: 324 patients were enrolled (mean [SD] age 63.4 [19.2] years, APACHE II score 19.0 [8.2], 52.5% male). Pneumonia (n=138/324, 42.6%) and urinary tract infection (n=98/324, 30.2%) were the commonest sources of sepsis. Between ED presentation and 6hours post-enrolment (T6hrs), 44.4% (n=144/324) of patients received an intra-arterial catheter, 37% (n=120/324) a central venous catheter and 0% (n=0/324) a continuous central venous oxygen saturation (ScvO(2)) catheter. Between enrolment and T6hrs, 32.1% (n=104/324) received a vasopressor infusion, 7.4% (n=24/324) a red blood cell transfusion, 2.5% (n=8/324) a dobutamine infusion and 18.5% (n=60/324) invasive mechanical ventilation. Twenty patients (6.2%) were transferred from ED directly to the operating theatre, 36.4% (n=118/324) were admitted directly to ICU, 1.2% (n=4/324) died in the ED and 56.2% (n=182/324) were transferred to the hospital floor. Overall ICU admission rate was 52.4% (n=170/324). ICU and overall in-hospital mortality were 18.8% (n=32/170) and 23.1% (n=75/324) respectively. In-hospital mortality was not different between patients admitted to ICU (24.7%, n=42/170) and the hospital floor (21.4%, n=33/154). CONCLUSIONS: Management of ANZ patients presenting to ED with sepsis does not routinely include protocolised, ScvO(2)-directed resuscitation. In-hospital mortality compares favourably with reported mortality in international sepsis trials and nationwide surveys of resuscitation practices.