The Scandinavian Starch for Severe Sepsis/Septic Shock (6S) trial [3] was powered to detect potential differences in mortality in patients with severe sepsis resuscitated with either 6 % HES 130/0.42 or Ringer’s acetate. The 6S trial had a simple pragmatic design aiming at reflecting clinical practice and included 798 patients in 26 Scandinavian ICUs. At 90 days patients in the HES group had increased mortality (Table 9.1). Also, more patients in the HES group received renal replacement therapy and blood products, and they had more bleeding events as compared to those in the Ringer’s group.

The 6S trial was shortly followed by the larger Crystalloid vs. Hydroxyethyl Starch Trial (CHEST) [4]. Also pragmatic, CHEST randomized 7,000 general ICU patients to resuscitation using either 6 % HES 130/0.4 or normal saline. The trial confirmed kidney impairment with HES as increased use of RRT (Table 9.1) and showed a higher incidence of adverse events, mainly pruritus, and use of blood products with HES vs. saline. Deaths at day 90 did not differ statistically significant between the intervention groups (Table 9.1), but the trial had lower mortality rate than expected and hence lower power.

The results of the Colloids Compared to Crystalloids in Fluid Resuscitation of Critically Ill Patients (CRISTAL) trial differed from those in the above trials [5]. In a 9-year period, 2,857 ICU patients with shock were randomized to open-label resuscitation with colloids (mainly HES) vs. crystalloids (mainly saline). The primary outcome measure, a 28-day mortality, did not differ between the groups, and RRT was used at equal rates in the two intervention groups. However, 90-day mortality, which was a post hoc added secondary outcome, was lower in the colloid group. In contrast to the trials mentioned above, CRISTAL had high risk of bias in several domains including open-label design, uncertain allocation concealment, and marked baseline imbalance [13]. The use of different fluids in both intervention groups further hampers the interpretation of the results.

The Fluids in Resuscitation of Severe Trauma (FIRST) trial randomized trauma patients for resuscitation with 6 % HES 130/0.4 vs. normal saline, but was stopped early after the inclusion of 115 patients due to low inclusion rates [14]. The investigators reported faster lactate clearance and decreased kidney impairment in the subgroup of patients with penetrating trauma receiving HES, but more blood products were given to the patients with blunt trauma receiving HES. The trial was criticized for selective outcome reporting [15], and subsequent reporting of mortality (intention-to-treat) revealed a marked increased risk of death at 30 days with HES, but the low sample size precludes firm conclusions from these data (Table 9.1).