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Evolution of Evidence for use of HES in Sepsis & Septic Shock

Updated: Apr 9, 2023

Semisynthetic colloid solutions (gelatins, dextrans, and hydroxyethyl starches (HES)) were developed to replace human albumin due to its expense and limited availability. Gelatins are prepared by hydrolysis of bovine collagen, dextrans are biosynthesized from sucrose by bacteria, and HES are synthesized from the maize-derived D-glucose polymer amylopectin. The volume expansion of these colloids is determined by their molecular weight and chemical properties. Multiple side effects have been observed with these agents, mainly increased risk of acute kidney injury (AKI) with HES and gelatin, allergic reactions with gelatins and dextrans, and bleeding with dextrans and HES. HES is the only semisynthetic colloid for which large trials enrolling septic patients have been conducted.

The 2004 Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) trial included 537 patients with severe sepsis and compared Ringer's lactate to 10% HES 200/0.5. The trial was stopped early due to an increased rate of AKI (34.9% versus 22.8%, p=0.002) and a trend toward increased 90-day mortality (41.0% versus 33.9%, p=0.09) with HES [1]. The rate of death at 90 days was significantly increased among patients who received a higher dose of HES compared with those who received a lower dose (57.6% vs. 30.9%, P<0.001).

A lower molecular weight and molar substitution of HES was reported to improve the safety profile for starches. 6% HES 130/0.4 was compared to 0.9% sodium chloride among 196 septic patients in the CRYSTMAS study. Respectively, the mortality rate was 31.0% versus 25.3%, and the AKI rate was 24.5% versus 20.0%, neither showing statistical significance [2].

The Scandinavian Starch for Severe Sepsis/Septic Shock (6S) trial included 804 patients with severe sepsis and compared resuscitation with 6% HES 130/0.4 versus Ringer's acetate. Renal replacement therapy (22% versus 16%, p=0.04) and 90-day mortality (51% versus 43%, p=0.03) were significantly higher with HES [3].

The Crystalloid versus Hydroxyethyl Starch Trial (CHEST) randomized 7,000 critically ill adults (1,937 with sepsis) to 6% HES 130/0.4 or 0.9% sodium chloride. The HES group required increased renal replacement therapy (7.0% versus 5.8%, p=0.04) but had similar 90-day mortality (18.0% versus 17.0%) [4].

A meta-analysis of nine RCTs in septic patients showed a higher risk of renal replacement therapy with the use of HES 130/0.38−0.45 (RR, 1.36; 95% CI, 1.08–1.72), and a higher risk of death in a pre-defined analysis of the low risk of bias trials (RR, 1.11; 95% CI, 1.0–1.2) [5]. A subsequent meta-analysis confirmed an association between HES and both AKI and mortality [6].

A network meta-analysis of patients with sepsis or septic shock also demonstrated a higher risk of death (OR, 1.09; 95% CI, 1.02–1.17) and the need for RRT (OR, 1.32; 95% CI, 1.15–1.50) with starches in a direct comparison with crystalloids [7].

In the 2016 Surviving Sepsis Campaign guidelines, a strong recommendation was issued against using hydroxyethyl starch (HES) and remained the same in the 2021 guidelines. Given the risk of higher RRT and the potential of increased mortality, HES should not be an option for intensivists in resuscitating septic patients.

Surviving Sepsis Campaign (SSC) recommendations

For adults with sepsis or septic shock, we recommend against using starches for resuscitation.

HES Use in Sepsis
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1. Brunkhorst FM, et al. German Competence Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008 Jan 10;358(2):125-39. doi: 10.1056/NEJMoa070716. PMID: 18184958.

2. Guidet B, et al. H. Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: the CRYSTMAS study. Crit Care. 2012 May 24;16(3):R94. doi: 10.1186/cc11358. PMID: 22624531; PMCID: PMC3580640.

3. Perner A, et al; 6S Trial Group; Scandinavian Critical Care Trials Group. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med. 2012 Jul 12;367(2):124-34. doi: 10.1056/NEJMoa1204242. Epub 2012 Jun 27. Erratum in: N Engl J Med. 2012 Aug 2;367(5):481. PMID: 22738085.

4. Myburgh JA, Finfer S, Bellomo R, et al; CHEST Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012;367(20):1901-191123075127

5. Haase N et al. Hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin in patients with sepsis: systematic review with meta-analysis and trial sequential analysis. BMJ. 2013;346:f839. Published 2013 Feb 15. doi:10.1136/bmj.f839.

6. Rochwerg B, et al. Fluids in Sepsis and Septic Shock Group. Fluid resuscitation in sepsis: a systematic review and network meta-analysis. Ann Intern Med. 2014 Sep 2;161(5):347-55. doi: 10.7326/M14-0178. PMID: 25047428.

7. Zarychanski R, et al. Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic review and meta-analysis. JAMA. 2013 Feb 20;309(7):678-88. doi: 10.1001/jama.2013.430. Erratum in: JAMA. 2013 Mar 27;309(12):1229. PMID: 23423413.


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