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.
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.
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.
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.
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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Ahn HJ, Kim JA, Lee AR, Yang M, Jung HJ, Heo B. The risk of acute kidney injury from fluid restriction and hydroxyethyl starch in thoracic surgery. Anesth Analg. 2016;122:186–93.
Alexander B, Odake K, Lawlor D, Swanger M. Coagulation, hemostasis, and plasma expanders: a quarter century enigma. Fed Proc. 1975;34:1429–40.
Akkucuk FG, Kanbak M, Ayhan B, Celebioglu B, Aypar U. The effect of HES (130/0.4) usage as the priming solution on renal function in children undergoing cardiac surgery. Ren Fail. 2013;35:210–15.
Annane D, Siami S, Jaber S, Martin C, Elatrous S, Declère AD, et al. Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial. JAMA. 2013;310:1809–17.
Baykara N, Akalin H, Arslantas MK, Hanci V, Caglayan C, Kahveci F, et al. Epidemiology of sepsis in intensive care units in Turkey: a multicenter, point-prevalence study. Crit Care. 2018;22:93.
Bellmann R, Feistritzer C, Wiedermann CJ. Effect of molecular weight and substitution on tissue uptake of hydroxyethyl starch: a meta-analysis of clinical studies. Clin Pharmacokinet. 2012;51:225–36.
Bion J, Bellomo R, Myburgh J, Perner A, Reinhart K, Finfer S. Hydroxyethyl starch: putting patient safety first. Intensive Care Med. 2014;40:256–9.
Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358:125–39.
Chappell D, Jacob M. Hydroxyethyl starch - the importance of being earnest. Scand J Trauma Resusc Emerg Med. 2013a;21:61.
Chappell D, Jacob M. Twisting and ignoring facts on hydroxyethyl starch is not very helpful. Scand J Trauma Resusc Emerg Med. 2013b;21:85.
Cittanova ML, Leblanc I, Legendre C, Mouquet C, Riou B, Coriat P. Effect of hydroxyethyl starch in brain-dead kidney donors on renal function in kidney-transplant recipients. Lancet. 1996;348:1620–2.
De Hert S, De Baerdemaeker L. Why hydroxyethyl starch solutions should NOT be banned from the operating room. Anaesthesiol Intensive Ther. 2014;46:336–41.
Durukan AB, Gürbüz HA, Durukan E, Salman N, Tavlaşoğlu M, Serter FT, et al. An evaluation of 6% hydroxyethyl starch 130/0.4 use in fluid therapy following coronary artery surgery. Türk Göğüs Kalp Damar Cerrahis Dergisi 2013;21:276–83.
EMA, 2013. PRAC recommends suspending marketing authorisations for infusion solutions containing hydroxyethyl-starch. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/06/WC500144446.pdf (accessed May 2018).
EMA, 2018a. Hydroxyethyl starch solutions: CMDh introduces new measures to protect patients. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Hydroxyethyl_starch_107i/Position_provided_by_CMDh/WC500251178.pdf (accessed July 2018).
EMA, 2018b. PRAC recommends suspending hydroxyethyl-starch solutions for infusion from the market. Available from: http://www.ema.europa.eu/docs/en¬_GB/document_library/Press_release/2018/01/WC500162361.pdf (accessed May 2018).
EMA, 2018c. Hydroxyethyl starch solutions for infusion to be suspended – CMDh endorses PRAC recommendation. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Hydroxyethyl_starch_107i/Position_provided_by_CMDh/WC500242407.pdf (accessed May 2018).
Ertmer C, Annane D, Van Der Linden P. Is the literature inconclusive about the harm from HES? Yes. Intensive Care Med. 2017;43:1520-2.
Ertmer C, Zwißler B, Van Aken H, Christ M, Spöhr F, Schneider A, et al. Fluid therapy and outcome: a prospective observational study in 65 German intensive care units between 2010 and 2011. Ann Intensive Care. 2018;8:27.
FDA, 2013. FDA Safety Communication: Boxed Warning on increased mortality and severe renal injury, and additional warning on risk of bleeding, for use of hydroxyethyl starch solutions in some settings. Available at: http://www.fffenterprises.com/assets/downloads/Article-FDASafetyCommunicationBoxedWarning6-13.pdf (accessed July 2018).
Gattas DJ, Dan A, Myburgh J, Billot L, Lo S, Finfer S, et al. Fluid resuscitation with 6% hydroxyethyl starch (130/0.4 and 130/0.42) in acutely ill patients: systematic review of effects on mortality and treatment with renal replacement therapy. Intensive Care Med. 2013;39:558–68.
Gillies MA, Habicher M, Jhanji S, Sander M, Mythen M, Hamilton M, et al. Incidence of postoperative death and acute kidney injury associated with i.v. 6% hydroxyethyl starch use: systematic review and meta-analysis. Br J Anaesth. 2014;112:25–34.
Greenberg S, Tung A. But is it safe? Hydroxyethyl starch in perioperative care. Anesth Analg. 2015;120:519–21.
Guidet B, Martinet O, Boulain T, Philippart F, Poussel JF, Maizel J, et al. 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;16(3):R94.
Guo SB, Chen YX, Yu XZ. Clinical characteristics and current interventions in shock patients in Chinese emergency departments: a multicenter prospective cohort study. Chin Med J (Engl) 2017;130:1146–54.
Gurbuz HA, Durukan AB, Salman N, Tavlasoglu M, Durukan E, Ucar Hİ, Yorgancioglu C. Hydroxyethyl starch 6%, 130/0.4 vs. a balanced crystalloid solution in cardiopulmonary bypass priming: a randomized, prospective study. J Cardiothorac Surg. 2013:8;8:71.
Haase N, Perner A, Hennings LI, Siegemund M, Lauridsen B, Wetterslev M, 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.
Hartog CS, Skupin H, Natanson C, Sun J, Reinhart K. Systematic analysis of hydroxyethyl starch (HES) reviews: proliferation of low-quality reviews overwhelms the results of well-performed meta-analyses. Intensive Care Med. 2012;38:1258–71.
Hartog CS, Welte T, Schlattmann P, Reinhart K. Fluid replacement with hydroxyethyl starch in critical care – a reassessment. Dtsch Arztebl Int. 2013;110:443–50.
Hartog CS, Natanson C, Sun J, Klein HG, Reinhart K. Concerns over use of hydroxyethyl starch solutions. BMJ. 2014;349:5981.
Hartog C, Reinhart K. The dilemma for using hydroxyethyl starch solutions for perioperative fluid management. In: Farag E, Kurz A, Editors. Perioperative Fluid Management. Switzerland: Springer International Publishing; 2016;pp235–56.
Irwin MG, Gan TJ. Volume therapy with hydroxyethyl starches: are we throwing the anesthesia baby out with the intensive care unit bathwater? Anesth Analg. 2014;119:737–9.
James MF, Michell WL, Joubert IA, Nicol AJ, Navsaria PH, Gillespie RS. Resuscitation with hydroxyethyl starch improves renal function and lactate clearance in penetrating trauma in a randomized controlled study: the FIRST trial (Fluids in Resuscitation of Severe Trauma). Br J Anaesth. 2011;107:693–702.
Kammerer T, Brettner F, Hilferink S, Hulde N, Klug F, Pagel J, Karl A, Crispin A, Hofmann-Kiefer K, Conzen P, Rehm M. No differences in renal function between balanced 6% hydroxyethyl starch (130/0.4) and 5% albumin for volume replacement therapy in patients undergoing cystectomy: a randomized controlled trial. Anesthesiology. 2018 Jan;128:67–78.
Kashy BK, Podolyak A, Makarova N, Dalton JE, Sessler DI, Kurz A. Effect of hydroxyethyl starch on postoperative kidney function in patients having noncardiac surgery. Anesthesiology. 2014;121:730–9.
Lagny MG, Roediger L, Koch JN, Dubois F, Senard M, Donneau AF, et al. Hydroxyethyl starch 130/0.4 and the risk of acute kidney injury after cardiopulmonary bypass: a single-center retrospective study. J Cardiothorac Vasc Anesth. 2016;30:869–75.
Legendre C, Thervet E, Page B, Percheron A, Noel LH, Kreis H. Hydroxyethylstarch and osmotic-nephrosis-like lesions in kidney transplantation. Lancet. 1993;342:248–9.
Letter to the EMA, 2017. Letter to the EMA urging a ban of hydroxyethyl starch solutions in Europe. Available at https://www.citizen.org/sites/default/files/2359.pdf (accessed May 2018).
Meybohm P, Van Aken H, De Gasperi A, De Hert S, Della Rocca G, Girbes AR, et al. Re-evaluating currently available data and suggestions for planning randomised controlled studies regarding the use of hydroxyethyl starch in critically ill patients – a multidisciplinary statement. Crit Care. 2013;17:R166.
Miller TE, Bunke M, Nisbet P, Brudney CS. Fluid resuscitation practice patterns in intensive care units of the USA: a cross-sectional survey of critical care physicians. Perioper Med (Lond). 2016;5:15.
Mutter TC, Ruth CA, Dart AB. Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function. Cochrane Database Syst Rev. 2013:CD007594.
Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012;367:1901–11.
Parker NE, Porter JB, Williams HJ, Leftley N. Pruritus after administration of hetastarch. Br Med J (Clin Res Ed). 1982;284:385–6.
Patel A, Laffan MA, Waheed U, Brett SJ. Randomised trials of human albumin for adults with sepsis: systematic review and meta-analysis with trial sequential analysis of all-cause mortality. BMJ. 2014;349:g4561.
Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Aneman A, et al. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012;367:124–34.
Petition to FDA, 2017. Petition to ban HES solutions in the U.S. Available at https://www.citizen.org/sites/default/files/2358.pdf (accessed May 2018).
Navickis RJ, Haynes GR, Wilkes MM. Effect of hydroxyethyl starch on bleeding after cardiopulmonary bypass: a meta-analysis of randomized trials. J Thorac Cardiovasc Surg. 2012;144:223–30.
Raghunathan K, Miller TE, Shaw AD. Intravenous starches: is suspension the best solution? Anesth Analg. 2014;119:731–6.
Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43:304–77.
Rochwerg B, Alhazzani W, Gibson A, Ribic CM, Sindi A, Heels-Ansdell D, et al. Fluid type and the use of renal replacement therapy in sepsis: a systematic review and network meta-analysis. Intensive Care Med. 2015;41:1561–71.
Schortgen F, Lacherade JC, Bruneel F, Cattaneo I, Hemery F, Lemaire F, et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet. 2001;357:911–6.
Serpa Neto A, Veelo DP, Peireira VG, de Assuncao MS, Manetta JA, Esposito DC, et al. Fluid resuscitation with hydroxyethyl starches in patients with sepsis is associated with an increased incidence of acute kidney injury and use of renal replacement therapy: a systematic review and meta-analysis of the literature. J Crit Care. 2014;29:181–7.
Strauss RG. Review of the effects of hydroxyethyl starch on the blood coagulation system. Transfusion. 1981;21:299–302.
Strauss RG, Stump DC, Henriksen RA, Saunders R. Effects of hydroxyethyl starch on fibrinogen, fibrin clot formation, and fibrinolysis. Transfusion. 1985;25:230–4.
Tufan ZK, Eser FC, Vudali E, Batirel A, Kayaaslan B, Bastug AT, et al. The knowledge of the physicians about sepsis bundles is suboptimal: a multicenter survey. J Clin Diagn Res. 2015;9:OC13–16.
Wiedermann CJ, Joannidis M. Accumulation of hydroxyethyl starch in human and animal tissues: a systematic review. Intensive Care Med. 2014;40:160–70.
Westphal M, James MF, Kozek-Langenecker S, Stocker R, Guidet B, Van Aken H. Hydroxyethyl starches: different products–different effects. Anesthesiology 2009;111:187–202.
Wilkes MM, Navickis RJ. Postoperative renal replacement therapy after hydroxyethyl starch infusion: a meta-analysis of randomised trials. Netherlands J Crit Care. 2014;18:4–9.
Zarychanski R, Abou-Setta AM, Turgeon AF, Houston BL, McIntyre L, Marshall JC, 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;309:678–88.
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