A systematic review of third-generation hydroxyethyl starch (HES 130/0.4) in resuscitation: safety not adequately addressed

Abstract

Background: Hydroxyethyl starches (HES) are widely used for intravascular volume therapy in surgical, emergency, and intensive care patients. There are safety concerns with regard to coagulopathy, renal failure, pruritus, tissue storage, and mortality. Third-generation HES 130/0.4 is considered to have an improved risk profile. A common rationale for the use of HES is the belief that 3 to 4 times more crystalloid than colloid volume is needed to achieve similar hemodynamic end points. Our goal was to assess whether published studies on HES 130/0.4 resuscitation are sufficiently well designed to draw conclusions about the safety of this compound. In addition, we wanted to assess crystalloid-to-colloid fluid ratios in studies with goal-directed fluid regimen.

Methods: Systematic review of randomized controlled trials in which HES 130/0.4 is used for resuscitation.

Results: We identified 56 randomized controlled trials (RCTs) with HES 130/0.4 in. acute hypovolemia, mainly from the elective surgical setting (n = 45). Surgical studies were small-sized (median 25 patients in the HES groups, range 10 to 90) and of short duration (median 12 hours, range 0.5 to 144 hours). The median cumulative HES dose was 2465 mL (range 328 to 6229 mL), corresponding to 35 mL/kg in a 70-kg patient, the daily dose limit being 50 mL/kg. End points mostly addressed variable surrogate outcomes. Sixty percent of control fluids were other HES solutions, gelatins, or dextran, which have a similar risk profile. Without exception, these studies were not designed for clinically important safety outcomes, primarily because they were too small, used mostly inadequate control fluids, and had inappropriately short observation periods. Therefore, and also because of heterogeneity of patient groups and outcome definitions, results from these studies cannot be pooled. These studies do not allow any conclusion about the safety of HES 130/0.4. There is a common belief that 3 to 4 times more crystalloid than colloid volume is necessary to achieve similar hemodynamic effects. We found a considerably lower ratio in surgical studies (mean 1.8, SD 0.1).

Conclusions: In summary, the extent of fluid load reduction that can be achieved by HES 130/0.4 is overestimated. Use of older HES solutions may be associated with serious side effects, and clinicians should be aware that there is no convincing evidence that third-generation HES 130/0.4 is safe in surgical, emergency, or intensive care patients despite publication of numerous clinical studies.