RANDOMIZED CONTROLLED TRIAL
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Hydroxyethyl starch in sepsis.

BACKGROUND: Hydroxyethyl starch (HES) is a colloid that has been widely used for fluid resuscitation for decades. The newest generation of HES, tetrastarch, was believed to provide an efficient volume expansion without causing the side effects observed with former HES solutions. However, this belief was based on physiological models and small studies rather than on firm clinical evidence. Our aim was to assess the safety and efficacy of tetrastarch in a randomised clinical trial and in a systematic review.

METHODS: We first conducted a blinded, clinical trial, in which we randomly assigned patients with severe sepsis in the intensive care unit to fluid resuscitation with either 6% HES 130/0.42 (Tetraspan) or Ringer's acetate. The primary outcome measure was death or dialysis-dependency at 90 days after randomisation. Secondary outcomes described kidney function and serious adverse reactions. Secondly, we systematically identified all randomised clinical trials comparing tetrastarch with either crystalloid or albumin in patients with sepsis and pooled their results in meta-analyses and trial sequential analyses.

RESULTS: Of the 804 patients who underwent randomisation, 798 were included in the modified-intention-to-treat population. At 90 days after randomisation, 201 of 398 patients (51%) assigned to HES 130/0.42 had died, as compared with 172 of 400 patients (43%) assigned to Ringer's acetate (relative risk 1.17, p=0.03); 1 patient in each group was dialysis-dependent at 90 days. In the 90 day observation period, 87 patients (22%) assigned to HES received renal replacement therapy vs. 65 patients (16%) assigned to Ringer's acetate (relative risk 1.35, p=0.04), and 38 patients (10%) vs. 25 patients (6%) had severe bleeding (relative risk 1.52, p=0.09). Post-hoc sensitivity analysis showed a strongly significant increased risk of any bleeding with HES vs. Ringer's acetate (relative risk 1.56, p=0.003). In the systematic review, we identified nine trials that randomised 3,456 patients with sepsis. In meta-analyses, tetrastarch vs. crystalloid or albumin lead to increased use of renal replacement therapy (relative risk 1.36, p=0.009) and red blood cells (relative risk 1.29, p=0.0002) and to more serious adverse events (relative risk 1.30, p=0.03). Trials with low risk of bias suggested 11% increased risk of death. After adjusting the results with trial sequential analysis signals for harm persisted.

CONCLUSION: Our randomised clinical trial is one of several high-quality trials in critically ill patients with and without sepsis that now provide evidence that the use of tetrastarch impairs kidney function and haemostasis and may even increase mortality. Whether the results can be extrapolated to other types of patients is unclear, but so far no group of patients with an overall benefit of HES beyond surrogate markers has been identified. In line with this, the European Medicines Agency's Pharmacovigilance Risk Assessment Committee now recommends that the marketing authorisations of all HES solutions are suspended in the European Union.

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