title: Hydroxyethyl starch for fluid resuscitation in critically ill patients.
abstract: BACKGROUND
  Intravenous fluid therapy is one of the most frequent interventions provided to patients in the intensive care unit; however, the type of fluid (i.e., crystalloid or colloid) used for resuscitation remains controversial. The most common type of colloid administered to resuscitate critically ill patients is hydroxyethyl starch (HES); however, its safety and efficacy have not been rigorously evaluated in large pragmatic randomized trials, and emerging data have accumulated to question its potential for toxic adverse effects.
  
  
  OBJECTIVE
  To evaluate the efficacy and safety of HES for fluid resuscitation in critically ill patients with a focus on survival and kidney function.
  
  
  METHODS
  Multicentre (32 sites in Australia and New Zealand) blinded randomized controlled parallel-group trial.
  
  
  METHODS
  Seven thousand eligible adult patients (age - ≥ 18 yr) admitted to an intensive care unit and judged by their treating clinician to require fluid resuscitation were included in the study. Study treatment allocation used encrypted Web-based randomization stratified by site and an admission diagnosis of trauma.
  
  
  METHODS
  Randomized patients were assigned to receive either 6% HES with a molecular weight of 130 kD and molar substitution ratio of 0.4 (130/0.4; Voluven(®), Fresenius Kabi) in 0.9% sodium chloride or 0.9% sodium chloride (saline) in indistinguishable Free flex 500 mL bags until intensive care unit (ICU) discharge, death, or 90 days after randomization. According to registration guidelines, the study fluid was administered to a maximum dose of 50 mL kg(-1) body weight per day and followed, if necessary, by open-label saline during the remaining 24-hr period.
  
  
  METHODS
  The primary efficacy outcome was death within 90 days after randomization. The key secondary outcomes were incidence of acute kidney injury (AKI), defined by the RIFLE (Risk, Injury, Failure, Loss, Endstage) criteria; treatment with renal replacement therapy(RRT); development of new organ dysfunction, defined by the sequential organ failure assessment score; duration of mechanical ventilation; duration of RRT; cause-specific mortality; and adverse events. Tertiary outcomes were ICU and hospital lengths of stay and ICU and hospital mortality. The primary outcome was evaluated across six a prior idefined subgroups: urine output criteria for AKI; presence of sepsis; presence of trauma, with or without traumatic brain injury; acute physiology and chronic health evaluation (APACHE) score C ≥ 25; and receipt of HES prior to randomization.
  
  
  RESULTS
  The HES and saline groups had similar characteristics at baseline. The average age was 63 yr, 60.4% of patients were male, and 42.7% were admitted to the ICU after surgery (54.7% after elective surgery). The median [interquartile range] APACHE II score was 17[12.0-23.0] with a score C ≥ 25 in 18.2%. Sepsis and trauma were primary diagnoses in 28.8% and 7.9% of patients, respectively. Mechanical ventilation was received by 64.5% of patients, vasopressor therapy by 45.8%, and HES fluid prior to randomization by 15.1%. Enrolment occurred approximately 11 hr after ICU admission. During the first four days after randomization, the mean (standard deviation) study fluid received by the HES group was less when compared with the saline group [526 (425) mL day(-1) vs 616 (488) mL day(-1), respectively; P < 0.001]. Mortality at 90 days was 18.0% in patients receiving HES (597/3,315) and 17.0% in those receiving saline (566/3,336) (relative risk [RR] for HES, 1.06; 95% confidence interval (CI), 0.96 to 1.18; P = 0.26). There was no significant difference in 90-day mortality across the six a priori defined subgroups. Renal replacement therapy was received in 7.0% of patients in the HES group (235/3,352) and 5.8% of patients in the saline group (196/3,376) (RR for HES, 1.21; 95% CI, 1.00 to 1.45; P = 0.04). In the HES and saline groups, RIFLE - Injury occurred in 34.6% and 38.0% of patients,respectively (P = 0.005), and RIFLE - Failure occurred in 10.4% and 9.2% of patients, respectively (P = 0.12). There were no differences in mortality in ICU, in hospital, or at 28 days. Hydroxyethyl starch was associated with a decrease in new cardiovascular organ failure compared with saline (36.5% vs 39.9%, respectively; RR 0.91; 95% CI, 0.84 to 0.99; P = 0.03) and an increase in new hepatic organ failure compared with saline (1.9% vs 1.2%, respectively; RR 15.6; 95% CI, 1.03 to 2.36; P = 0.03). There were no differences between HES and saline for days in ICU or hospital or for duration of mechanical ventilation or RRT. Hydroxyethyl starch was associated with more adverse events compared with saline (5.3% vs 2.8%, respectively; RR 1.86; 95% CI, 1.46 to 2.38; P < 0.001). Adverse events were predominantly accounted for by pruritis and skin rash.
  
  
  CONCLUSIONS
  In critically ill patients receiving fluid resuscitation, there was no significant difference in 90-day mortality between 6% HES (130/0.4) or saline. Even so, more patients who received resuscitation with HES were treated with RRT and experienced adverse events.
authors.affiliation: Division of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, 3C1.12 Walter C. Mackenzie Centre, 8440-122 ST NW, Edmonton, AB, T6G 2B7, Canada. bagshaw@ualberta.ca
authors.forename: Sean M
authors.initials: SM
authors.lastname: Bagshaw
authors.forename: Lakhmir S
authors.initials: LS
authors.lastname: Chawla
mesh_terms: D016638:Critical Illness / Q000628:therapy*; D005260:Female; D005440:Fluid Therapy / Q000379:methods*; D006801:Humans; D006895:Hydroxyethyl Starch Derivatives / Q000627:therapeutic use*; D008297:Male
chemical_list: D006895:Hydroxyethyl Starch Derivatives