Randomized controlled trials are not designed to prove the safety of third-generation hydroxyethyl starch for resuscitation: results from a systematic review

Introduction

Hydroxyethyl starch (HES) is widely used for volume therapy in intensive care. In critically ill and sepsis patients, HES use was dose-dependently associated with increased renal failure, tissue storage with organ failure, and increased long-term mortality. There are other safety concerns with regard to coagulopathy, pruritus, and mortality. However, third-generation HES 130/0.4 is considered to have an improved risk profile. Therefore, we wanted to assess whether published studies on HES 130/0.4 resuscitation are sufficiently well designed to draw conclusions about the safety of this compound.

Methods

We derived clinically relevant outcome parameters to analyze safety outcomes from the literature and provided exemplary power calculations. Randomized controlled trials (RCT) on fluid resuscitation with HES 130/0.4 were systematically searched and analyzed for clinical condition, sample size, study duration, cumulative dose, control fluids, endpoints, and colloid-crystalloid volume ratios in studies with a goal-directed fluid regimen. Due to the heterogeneity of included studies, all analyses were descriptive (SPSS 17.0).

Results

A total of 56 RCTs were included. Only two studies included severe sepsis patients, 80% were from the elective surgical setting and one study from the emergency surgical setting. In general, studies were underpowered (median sample size 25 patients in HES 130/0.4 groups, range 10 to 90 patients); of short duration (median study period 12 hours, range 0.5 to 144 hours) and with low cumulative HES doses (median 2,465 ml, range 328 to 6,229 ml). Sepsis studies (n = 2) included 18 patients (median, range 10 to 26 patients), study period was 96 hours (median, range 72 to 120 hours) and total fluid volumes was 3,000 ml in one study. Sixty percent of control fluids were synthetic colloids (other starches, gelatins, or dextran) that carry a similar risk profile. Primary endpoints with power calculation (in 87% of studies) were mostly unspecific or clinically irrelevant. Only one sepsis study provided a primary endpoint, which was extravascular lung water. This did not differ in comparison with the albumin 20% control group.

Conclusions

There is no reliable evidence from published clinical data that third-generation HES 130/0.4 is safe in septic patients or in the emergency or elective surgical setting.