Is the literature inconclusive about the harm from HES? No
Colloid solutions may be more effective than crystalloid solutions in expanding the intravascular space, which may result in improved hemodynamics and reduced tissue edema. Whether this is clinically important is unknown. Despite lack of evidence of overall benefit in terms of clinical or patient-important outcome measures, hydroxyethyl starch (HES), an artificial colloid solution, has been used in a variety of clinical settings to treat hypovolemia including during surgery, after trauma and burns, in sepsis, and in critically ill patients. As we will outline below, HES has clear side effects based on well-described pathophysiologic pathways resulting in worse outcome in critically ill patients.
Acute kidney injury
Hydroxyethyl starch has been shown to increase the risk of acute kidney injury (AKI) and need for renal replacement therapy (RRT) as compared to other fluid solutions in different clinical settings . The effects are independent of molecular weight, molar substitution, C2/C6 ratio, and dose of HES. Increased use of RRT with HES vs other fluids has been shown in surgical and non-surgical intensive care patients, and in patients with sepsis [2, 3, 4, 5]. Because most of these data are from trials done in ICU, the effects of HES on kidney function in the intraoperative period have yet to be settled.
The nephrotoxic pathway of HES is likely secondary to renal tissue uptake and storage because HES cannot be degraded once it leaves the circulation [6, 7]. Moreover, HES is by no means confined to the intravascular compartment. Up to 50 % of administered volumes cannot be accounted for in blood or urine at 24 h after infusion meaning that this amount resides in other compartments where it cannot be degraded . In the kidney, HES may induce osmotic nephrotic lesions  and tubular obstruction by hyperviscous urine and inflammation . HES-related inflammation has also been observed in other organs months after intravenous infusion, including liver and bone marrow .
In general, the data on HES and clinical bleeding are less robust than those on AKI. However, recent trials have shown increased risk of bleeding with the use of HES as compared to crystalloid solutions in patients with sepsis  and those undergoing major surgery [10, 11]. In a meta-analysis of patients undergoing cardiac surgery, HES solutions were associated with increased postoperative blood loss and rates of reoperation for bleeding compared to albumin . Other meta-analyses including data on HES and bleeding have been published by authors with ties to the industry . Their results have favored HES, but the authors have been criticized for biased inclusion of control groups and data imputation. HES-induced bleeding is likely the result of direct effects on hemostasis through impaired fibrinogen/fibrin polymerization resulting in weaker and smaller blood clots .
Increased risk of death
After inclusion of data from large high-quality trials [2, 15], the updated Cochrane meta-analysis of colloids vs crystalloids in critically ill patients showed increased mortality with HES . Additional meta-analyses confirmed this finding using different methodologies and in different settings underlining the robustness of the data [3, 17].
Misleading trial results
The evidence from high-quality meta-analyses shows that fluid therapy with HES vs crystalloids increases the rate of AKI and mortality in critically ill patients. Thus, the European Medicines Agency (EMA) has made the legally binding decision (EMA/809470/2013) that HES cannot be used in these patients nor in those with sepsis or burn-related injury. Although currently data are insufficient to identify a difference in outcomes of perioperative fluid therapy in non-cardiac surgery, the use of HES also appears to be associated with increased risk of bleeding in patients with sepsis and those undergoing surgery as compared with the use of crystalloid or albumin solutions.
The literature about harm of HES is conclusive and the mechanisms of toxicity have been identified. The harmful effects of HES appear to be common to all HES classes and dose dependent. No safe dose of HES has been defined [1, 17]. Since there are no data from trials with adequate methodology and power showing clinically important benefits from using HES in any clinical setting, the EMA has requested the marketing authorization holders of HES-containing medicinal products to perform postauthorization safety studies. Results of these studies will determine if the use of HES will have to be further restricted.
- 1.Mutter TC, Ruth CA, Dart AB (2013) Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function. Cochrane Database Syst Rev 7:CD007594Google Scholar
- 5.Wilkes MM, Navickis R (2014) Postoperative renal replacement therapy after hydroxyethyl starch infusion: a meta-analysis of randomised trials. Neth J Crit Care 18:4–9Google Scholar
- 16.Perel P, Roberts I, Ker K (2013) Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev 2:CD000567Google Scholar