Understanding the harms of HES: a review of the evidence to date

  • Ünal MN, Reinhart K. Turk J

Vigorous debate followed the decision last year by the European Medicines Agency (EMA) to allow the continued marketing of hydroxyethyl starch (HES), even though under stringent new restrictions. This review of the adverse effects of HES provides a timely contribution to the discussion.

Despite clear guidelines, the choice of IV fluid continues to be largely dependent on physician preference. This is particularly the case for synthetic colloids, such as hydroxyethyl starch (HES), with the potential consequences for patient harm. Research from different countries suggests that many physicians have continued to use HES in settings banned by European and US regulatory bodies and national and international guidelines (Bion et al., 2014; Miller et al., 2016; Guo et al. 2017; Rhodes et al., 2017). 

Following a recent study reporting high mortality rates in Turkish ICUs due to sepsis (55.7%) and septic shock (70.4%) (Baykara et al., 2018) and poor awareness of optimal IV fluid therapy (Tufan et al., 2015), Drs Ünal and Reinhart have produced a review of the use of HSE in fluid resuscitation. This includes the revised guidance issued in 2018 by the European Medicines Agency (EMA), which included stringent new measures to protect patients (EMA, 2018a). The authors argue that the resultant increase in cost, time and labour to fulfil the requirements is clinically and economically unjustifiable. 

They demonstrate overwhelming, high-quality evidence for the harms of HES in critically ill patients, and find no clear evidence for a benefit of HES over other fluids in any setting, including in surgical patients. The authors therefore recommend the avoidance of HES in favour of safer alternatives (crystalloid and albumin) for resuscitation therapy in all settings.

How the controversy over HES has evolved in recent years

In 2013, the US Food and Drug Administration (FDA) recommended a ban on the use of HES in critically ill patients (FDA, 2013) following the publication of research trials and meta-analyses showing an increased risk of mortality and renal failure (Brunkhorst et al., 2008; Myburgh et al, 2012; Perner et al., 2012; Gattas et al., 2013; Mutter et al., 2013; Zarychanski et al., 2013; Patel et al., 2014; Serpa Neto et al., 2014; Rochwerg et al., 2015). The expert debate that followed led to robust restrictions on the use of HES by the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) (EMA, 2013).

In 2017, new research showed that many clinicians appeared to be unaware of, or ignored, these restrictions on the use of HES. Considering patients’ lives to be at risk, a US consumer advocacy organisation petitioned the FDA and EMA to ban HES solutions completely from the market (Petition to FDA, 2017; Letter to the EMA, 2017).

In 2018, the EMA’s PRAC responded by suspending marketing authorisation for all HES products in the EU (EMA, 2018b). This decision was endorsed by the EMA’s Coordination Group for Mutual Recognition and Decentralised Procedures in Humans (CMDh) (EMA, 2018c). Following representation from several leading medical experts, PRAC confirmed its decision to ban HES entirely. In contrast, however, the CMDh decided that HES could still be prescribed, provided additional, stringent, new measures were followed (EMA, 2018a), including a controlled access programme for hospitals with accredited training in the use of HES fluid therapy.

Review of HES research in critical illness 

Approval of the first HES solution by the FDA in 1972 was based on non-controlled studies (n = 315) with an observation period of less than 24 hours (Hartog et al., 2014; Hartog & Reinhart, 2016). Soon after, there were repeated reports of adverse effects with HES (Alexander et al., 1975; Strauss, 1981; Strauss et al., 1985). These included impairment of coagulation, leading to increased bleeding, pruritus, impaired renal function and tissue accumulation of HES (Parker et al., 1982; Legendre et al., 1993; Cittanova et al., 1996; Bellmann et al., 2012; Wiedermann & Joannidis, 2014). However, despite further adverse reports, it was not until 2001 that the first randomised controlled trial (RCT) of HES was published. The trial found an increased risk of acute kidney injury (AKI) for HES versus gelatin in patients with sepsis (Schortgen et al., 2001). In 2007, a modified HES with lower molecular weight and alleged fewer adverse effects (Westphal et al., 2009) was approved by the FDA. Within a few years, however, three large RCTs reported an increased risk of AKI, renal replacement therapy (RRT) and mortality in patients with sepsis and ICU patients treated with HES versus crystalloids (Brunkhorst et al., 2008; Myburgh et al., 2012; Perner et al., 2012). Although, about the same time, three other RCTS reported no adverse effects, these latter studies suffered from serious methodological limitations (James et al., 2011; Guidet et al., 2012; Annane et al., 2017). Indeed, subsequent systematic reviews and meta-analyses also found significantly higher adverse effects with HES compared with other IV fluids (Gattas et al., 2013; Haase et al., 2013; Mutter et al., 2013; Zarychanski et al., 2013; Patel et al., 2014; Serpa Neto et al., 2014; Rochwerg et al., 2015) (Figure 1).

In conclusion, there is overwhelming evidence for the association of HES solutions with adverse effects, such as AKI, RRT and mortality, in ICU and critically ill patients. Based on the extensive evidence available, the authors support the banning of HES in sepsis and ICU care.

Adverse effects of HES in critically ill patients

Figure 1. Adverse effects of HES in critically ill patients.

Review of HES in surgery 

Advocates for the use of HES in surgery do not consider adverse effects in critically ill patients to be relevant to surgical patients (Irwin & Gan, 2014). They consider them to be due to HES administration after the initial stabilisation phase (Chappell & Jacob, 2013a; Meybohm et al., 2013; De Hert & De Baerdemaeker, 2014; Ertmer et al., 2017). Despite a lack of evidence, they support the use of HES for initial haemodynamic resuscitation (for example within 6 hours from onset of shock) during surgery (Chappell & Jacob, 2013a; Chappell & Jacob, 2013b; Irwin & Gan, 2014).

However, the use of HES in elective surgical patients is not supported by high-quality evidence of its safety in perioperative settings (Figure 2). The lack of large high-quality RCTs with long-term follow up and large systematic reviews and meta-analyses precludes any firm conclusions about the safety of HES in surgical patients (Hartog et al., 2012; Hartog et al., 2013; Raghunathan et al., 2014; Greenberg & Tung, 2015). 

Although one meta-analysis of 19 RCTs found no differences in study outcomes between HES and other fluids(Gillies et al., 2014), and a retrospective study (n = 1,442) (Ahn et al., 2016) found increased incidence of AKI only in patients with decreased renal function, the authors of both studies advised against using HES during surgery. This was on the basis of a lack of evidence of any benefit from using HES, proven adverse effects in the critically ill, and because AKI and the need for critical care often arise in patients undergoing major surgery (Gillies et al., 2014; Ahn et al., 2016). In conclusion, Drs Unal and Reinhart recommended the use of safer and proven alternatives (crystalloids, albumin) to HES in the surgical setting.

Adverse effects of the use of HES in patients undergoing surgery

Figure 2. Adverse effects of the use of HES in patients undergoing surgery.

Explore the Fluid Management Knowledge Centre to catch-up on the debate surrounding hydroxyethyl starch use as we take you on an interactive journey through its changing fortunes. Do you think current restrictions will be enough to change clinical practice? Take a look at the time-line of the debate about whether or not hydroxyethyl starch should be banned outright or its use severely restricted and find out the detail of the events and studies that have shaped the ongoing debate.


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