Circulation 107,515 • Volume 28, No. 1 • Spring-Summer 2013   Issue PDF

The Safety of Hydroxyethyl Starch (HES) – Products Now in Doubt

Ehab Farag, MD, FRCA; D. John Doyle, MD, PhD

To the Editor

Hydroxyethyl starch (HES) products are commonly employed for volume resuscitation in the perioperative period as well as in ICU patients being treated for sepsis and other conditions. The rationale for their clinical use is that they are low-cost colloids that are highly effective for increasing intravascular volume for sustained periods.1,2 Additionally, they are believed to have anti-inflammatory properties as well as other desirable characteristics, such as having a smaller impact on tissue edema compared to commonly used crystalloids.3 As a consequence, HES products have seen a great upswing in popularity in recent years, a fact no doubt also supported by a growing number of publications offering a favorable assessment of HES products.

The purpose of this short commentary is to draw attention to some recent safety concerns for HES products. While worries about the possibility of impaired blood clotting have been a concern for some time (vide infra), more recent studies suggest that HES products are also associated with acute renal injury as well as other adverse events, including an increase in mortality. The pathophysiology may be related to the fact that HES products, while undoubtedly effective at increasing plasma volume, do not stay localized to the circulation but end up instead as deposits in renal, hepatic, splenic, endothelial, and other tissues.4 In addition, as discussed later, HES molecules may interact with the endothelial glycocalyx in an unfavorable manner.

Evidence of the potential harm of HES products was in part diluted by a number of relatively favorable studies authored by Boldt et al., a great many of which turned out to involve scientific misconduct.5,6 This and other considerations have led to investigators to reconsider the role of HES products, as outlined below.

A consensus statement of the European Society of Intensive Care Medicine task force on colloid use in critically ill patients, has now recommended against the use of 6% HES 130/0.4 in ICU patients.7 Similarly, a 2011 Cochrane review cautioned against the routine administration of HES products.8 A systematic review by Hartog et al.9 concluded 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.” The recently published 7000 patient Crystalloid versus Hydroxyethyl Starch Trial (CHEST)10 showed that while there was no significant difference in 90-day mortality, patients randomized to HES 130/.4 had more renal injury and requirement for renal-replacement therapy than those receiving saline. Finally, a 2013 meta-analysis published in JAMA.11 noted that after 7 tainted HES studies by Boldt et al. were removed from consideration, “Hydroxyethyl starch was associated with a significant increased risk of mortality and acute kidney injury” and warned that the “use of hydroxyethyl starch for acute volume resuscitation is not warranted due to serious safety concerns.”

Although it has been known for some time that HES products can affect coagulation via adverse effects on both von Willebrand factor and platelet aggregation,12 it is now also known that HES 130/.4 administration results in a weaker, smaller clot.13 These facts may explain the increased transfusion rate in HES 130/.4 treated individuals with blunt trauma compared to those treated with normal saline.14

Finally, we would like to comment on the importance of the endothelial glycocalyx in understanding the effects of fluid administration. The endothelial glycocalyx covers the endothelial cells present in the lumen of normal blood vessels, playing a central role in its barrier properties. In conjunction with bound fluid and plasma proteins the glycocalyx forms an “endothelial surface layer,” typically 500 to 1000 nm thick. The bound proteins provide the endothelial surface layer with its own colloid osmotic force, with the consequence that Starling’s classic model (of semi-permeable capillaries subject to hydrostatic and oncotic pressure differences) is now considered to be an oversimplification.15,16

The glycocalyx harbors a wide variety of anticoagulant proteins like antithrombin, components of the protein C system, and tissue factor pathway inhibitors.17 The glycocalyx also plays a vital role in nitric oxide release in endothelial cells as well as modulating the immune response by preventing the adhesion of leucocytes and platelets to the endothelial cells.17,18 Damage of the glycocalyx can lead to protein extravasation and tissue edema as well as impair the processes mentioned above. Continuing research on the properties of the glycocalyx and endothelial surface layer is expected to yield a better understanding of the biology of vascular permeability, inflammatory processes, blood pressure regulation, and blood coagulation, as well as clinical conditions like ARDS, sepsis and ischemia/reperfusion injury.

HES colloids have negative charges on the surface of their molecules which render them unattracted to the glycocalyx, which also has negative surface charges.17 As a result they are unable to contribute to the integrity of the endothelium surface layer in a manner like albumin, whose distribution of positive and negative surface charges is more favorable to maintaining the integrity of the endothelial surface layer.19

Neither author has conflicts of interest to declare.

Ehab Farag, MD, FRCA D. John Doyle, MD, PhD Department of General Anesthesiology Cleveland Clinic Cleveland, OH

References

  1. Bunn F, Trivedi D. Colloid solutions for fluid resuscitation. Cochrane Database Syst Rev. 2012; 7:CD001319.
  2. Jungheinrich C, Neff TA. Pharmacokinetics of hydroxyethyl starch. Clin Pharmacokinet. 2005;44 (7):681-699.
  3. Vlachou E, Gosling P, Moiemen NS. Hydroxyethylstarch supplementation in burn resuscitation–a prospective randomised controlled trial. Burns. 2010;36:984-91.
  4. Sirtl C, Laubenthal H, Zumtobel V, Kraft D, Jurecka W. Tissue deposits of hydroxyethyl starch (HES): dose dependent and time-related. Br J Anaesth. 1999; 82(4):510-515.
  5. Hospital presents results of final report: committee completes investigation in the case of Dr Boldt. Akademisches Lehrkrankenhaus der Johannes Gutenberg-Universität Mainz; 2012.
    http://www.klilu.de/content/aktuelles___presse/pressearchiv/2012/hospital_presents_ results_of_final_report_committee_completes_investigation_in_the_case_of_dr_boldt/ index_ger.html. Accessed February 21, 2013.
  6. Editors-in-Chief statement regarding published clinical trials conducted without IRB approval by Joachim Boldt. 2011. http://www.aaeditor.org/EIC.Joint.Statement.on. Retractions.pdf. Accessed February 21, 2013.
  7. Reinhart K, Perner A, Sprung CL, Jaeschke R, Schortgen F, Johan Groeneveld AB, Beale R, Hartog CS; European Society of Intensive Care Medicine. Consensus statement of the ESICM task force on colloid volume therapy in critically ill patients. Intensive Care Med. 2012;38:368-83.
  8. Dart AB, Mutter TC, Ruth CA, Taback SP. Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD007594. DOI: 10.1002/14651858.CD007594.pub2
  9. Hartog CS, Kohl M, Reinhart K. A systematic review of third-generation hydroxyethyl starch (HES 130/0.4) in resuscitation: safety not adequately addressed. Anesth Analg. 2011;112:635-45.
  10. Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, Glass P, Lipman J, Liu B, McArthur C, McGuinness S, Rajbhandari D, Taylor CB, Webb SA; 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;367:1901-11.
  11. Zarychanski R, Abou-Setta AM, Turgeon AF, Houston BL, McIntyre L, Marshall JC, Fergusson DA. 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.
  12. deJonge E, Levi M. Effects of different plasma substitutes on blood coagulation: a comparative review. Crit Care Med. 2001; 29:1261-7.
  13. Hartog CS, Reuter D, Loesche W, Hofmann M, Reinhart K. Influence of hydroxyethyl starch (HES) 130/0.4 on hemostasis as measured by viscoelastic device analysis: a systematic review. Intensive Care Med. 2011;37:1725-37.
  14. 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.
  15. Jacob M, Bruegger D, Rehm M, Welsch U, Conzen P, Becker BF. Contrasting effects of colloid and crystalloid resuscitation fluids on cardiac vascular permeability. Anesthesiology. 2006;104(6):1223-31.
  16. Woodcock TE, Woodcock TM. Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy. Br J Anaesth. 2012;108:384-94.
  17. Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch. 2007;454:345-59.
  18. Chappell D, Dörfler N, Jacob M, Rehm M, Welsch U, Conzen P, Becker BF. Glycocalyx protection reduces leukocyte adhesion after ischemia/reperfusion. Shock. 2010;34:133-9.
  19. Jacob M, Rehm M, Loetsch M, Paul JO, Bruegger D, Welsch U, Conzen P, Becker BF. The endothelial glycocalyx prefers albumin for evoking shear stress-induced, nitric oxide-mediated coronary dilatation. J Vasc Res. 2007;44:435-43.