Intensive Care Medicine

, Volume 35, Issue 8, pp 1337–1342 | Cite as

CONTRA: Hydroxyethyl starch solutions are unsafe in critically ill patients

  • Christiane Hartog
  • Konrad Reinhart
Special Article



To describe the risk–benefit profile of hydroxyethyl starch (HES).


Narrative review.


(1) Efficacy: no single clinical study or systemic review has shown that administration of any HES solution confers a clinically relevant benefit compared to crystalloids in critically ill patients or surgical patients in need of volume replacement. Contrary to beliefs expecting a ratio of 4:1 or more for crystalloid to colloid volume need, recent studies of goal-directed resuscitation observed much lower ratios of between 1 and 1.6. (2) Safety: HES administration is associated with coagulopathy, nephrotoxicity, pruritus and increased long-term mortality. Clinical studies claiming that modern HES 130/0.4 is safe have serious methodological drawbacks and do not adequately address the safety concerns.


Given the complete lack of superiority in clinical utility studies and the wide spectrum of severe side effects, the use of HES in the ICU should be stopped. The belief that four times as much crystalloid as colloid fluid volume is needed for successful resuscitation is being seriously questioned.


Colloids Crystalloids Hydroxyethyl starch Efficacy Safety Critically ill 



No funding was obtained in support of this analysis. The authors have in the past received unrestricted funding from B. Braun, Melsungen, for the conduct of the VISEP study.

Conflict of interest statement

The authors report no current conflict of interest.


  1. 1.
    Perel P, Roberts I (2007) Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev (Online):CD000567Google Scholar
  2. 2.
    Wills BA, Nguyen MD, Ha TL, Dong TH, Tran TN, Le TT, Tran VD, Nguyen TH, Nguyen VC, Stepniewska K, White NJ, Farrar JJ (2005) Comparison of three fluid solutions for resuscitation in dengue shock syndrome. N Engl J Med 353:877–889PubMedCrossRefGoogle Scholar
  3. 3.
    Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R (2004) A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 350:2247–2256PubMedCrossRefGoogle Scholar
  4. 4.
    Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, Olthoff D, Jaschinski U, John S, Rossaint R, Welte T, Schaefer M, Kern P, Kuhnt E, Kiehntopf M, Hartog C, Natanson C, Loeffler M, Reinhart K (2008) Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 358:125–139PubMedCrossRefGoogle Scholar
  5. 5.
    Wilkes MM, Navickis RJ, Sibbald WJ (2001) Albumin versus hydroxyethyl starch in cardiopulmonary bypass surgery: a meta-analysis of postoperative bleeding. Ann Thorac Surg 72:527–533 discussion 534PubMedCrossRefGoogle Scholar
  6. 6.
    Schortgen F, Lacherade JC, Bruneel F, Cattaneo I, Hemery F, Lemaire F, Brochard L (2001) Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet 357:911–916PubMedCrossRefGoogle Scholar
  7. 7.
    Pillebout E, Nochy D, Hill G, Conti F, Antoine C, Calmus Y, Glotz D (2005) Renal histopathological lesions after orthotopic liver transplantation (OLT). Am J Transplant 5:1120–1129PubMedCrossRefGoogle Scholar
  8. 8.
    Bork K (2005) Pruritus precipitated by hydroxyethyl starch: a review. Br J Dermatol 152:3–12PubMedCrossRefGoogle Scholar
  9. 9.
    Sedrakyan A, Gondek K, Paltiel D, Elefteriades JA (2003) Volume expansion with albumin decreases mortality after coronary artery bypass graft surgery. Chest 123:1853–1857PubMedCrossRefGoogle Scholar
  10. 10.
    Auwerda JJ, Leebeek FW, Wilson JH, van Diggelen OP, Lam KH, Sonneveld P (2006) Acquired lysosomal storage caused by frequent plasmapheresis procedures with hydroxyethyl starch. Transfusion 46:1705–1711PubMedCrossRefGoogle Scholar
  11. 11.
    FDA, Center for Biologics Evaluation and Research (2007) Product approval information––new drug applications. NDA review memo (mid-cycle) Accessed 10 Sept 2008
  12. 12.
    Rudolf J (2002) Hydroxyethyl starch for hypervolemic hemodilution in patients with acute ischemic stroke: a randomized, placebo-controlled phase II safety study. Cerebrovasc Dis 14:33–41PubMedCrossRefGoogle Scholar
  13. 13.
    Aichner FT, Fazekas F, Brainin M, Polz W, Mamoli B, Zeiler K (1998) Hypervolemic hemodilution in acute ischemic stroke: the multicenter Austrian hemodilution stroke trial (MAHST). Stroke 29:743–749PubMedGoogle Scholar
  14. 14.
    Klemm E, Bepperling F, Burschka MA, Mosges R (2007) Hemodilution therapy with hydroxyethyl starch solution (130/0.4) in unilateral idiopathic sudden sensorineural hearing loss: a dose-finding, double-blind, placebo-controlled, international multicenter trial with 210 patients. Otol Neurotol 28:157–170PubMedCrossRefGoogle Scholar
  15. 15.
    Ganzevoort W, Rep A, Bonsel GJ, Fetter WP, van Sonderen L, De Vries JI, Wolf H (2005) A randomised controlled trial comparing two temporising management strategies, one with and one without plasma volume expansion, for severe and early onset pre-eclampsia. BJOG 112:1358–1368PubMedCrossRefGoogle Scholar
  16. 16.
    Ernest D, Belzberg AS, Dodek PM (1999) Distribution of normal saline and 5% albumin infusions in septic patients. Crit Care Med 27:46–50PubMedCrossRefGoogle Scholar
  17. 17.
    Waxman AB, Ward N, Thompson T, Lilly CM, Lisbon A, Hill N, Nasraway SA, Heard S, Corwin H, Levy M (2005) Roundtable debate: controversies in the management of the septic patient––desperately seeking consensus. Crit Care 9:1CrossRefGoogle Scholar
  18. 18.
    Verheij J, van Lingen A, Raijmakers PG, Rijnsburger ER, Veerman DP, Wisselink W, Girbes AR, Groeneveld AB (2006) Effect of fluid loading with saline or colloids on pulmonary permeability, oedema and lung injury score after cardiac and major vascular surgery. Br J Anaesth 96:21–30PubMedCrossRefGoogle Scholar
  19. 19.
    Barron ME, Wilkes MM, Navickis RJ (2004) A systematic review of the comparative safety of colloids. Arch Surg 139:552–563PubMedCrossRefGoogle Scholar
  20. 20.
    Avorn J, Patel M, Levin R, Winkelmayer WC (2003) Hetastarch and bleeding complications after coronary artery surgery. Chest 124:1437–1442PubMedCrossRefGoogle Scholar
  21. 21.
    Jonville-Bera AP, Autret-Leca E, Gruel Y (2001) Acquired type I von Willebrand’s disease associated with highly substituted hydroxyethyl starch. N Engl J Med 345:622–623PubMedCrossRefGoogle Scholar
  22. 22.
    Cittanova ML, Leblanc I, Legendre C, Mouquet C, Riou B, Coriat P (1996) Effect of hydroxyethylstarch in brain-dead kidney donors on renal function in kidney-transplant recipients. Lancet 348:1620–1622PubMedCrossRefGoogle Scholar
  23. 23.
    Legendre C, Thervet E, Page B, Percheron A, Noel LH, Kreis H (1993) Hydroxyethylstarch and osmotic-nephrosis-like lesions in kidney transplantation. Lancet 342:248–249PubMedCrossRefGoogle Scholar
  24. 24.
    Giral M, Bertola JP, Foucher Y, Villers D, Bironneau E, Blanloeil Y, Karam G, Daguin P, Lerat L, Soulillou JP (2007) Effect of brain-dead donor resuscitation on delayed graft function: results of a monocentric analysis. Transplantation 83:1174–1181PubMedCrossRefGoogle Scholar
  25. 25.
    Sakr Y, Payen D, Reinhart K, Sipmann FS, Zavala E, Bewley J, Marx G, Vincent JL (2007) Effects of hydroxyethyl starch administration on renal function in critically ill patients. Br J Anaesth 98:216–224PubMedCrossRefGoogle Scholar
  26. 26.
    Boldt J, Lenz M, Kumle B, Papsdorf M (1998) Volume replacement strategies on intensive care units: results from a postal survey. Intensive Care Med 24:147–151PubMedCrossRefGoogle Scholar
  27. 27.
    Schmidt-Hieber M, Loddenkemper C, Schwartz S, Arntz G, Thiel E, Notter M (2006) Hydrops lysosomalis generalisatus––an underestimated side effect of hydroxyethyl starch therapy? Eur J Haematol 77:83–85PubMedCrossRefGoogle Scholar
  28. 28.
    Christidis C, Mal F, Ramos J, Senejoux A, Callard P, Navarro R, Trinchet JC, Larrey D, Beaugrand M, Guettier C (2001) Worsening of hepatic dysfunction as a consequence of repeated hydroxyethylstarch infusions. J Hepatol 35:726–732PubMedCrossRefGoogle Scholar
  29. 29.
    Auwerda JJ, Wilson JH, Sonneveld P (2002) Foamy macrophage syndrome due to hydroxyethyl starch replacement: a severe side effect in plasmapheresis. Ann Intern Med 137:1013–1014PubMedGoogle Scholar
  30. 30.
    Trowbridge CC, Stammers AH, Wood GC, Murdock JD, Klayman M, Yen BR, Woods E, Gilbert C (2005) Improved outcomes during cardiac surgery: a multifactorial enhancement of cardiopulmonary bypass techniques. J Extra Corpor Technol 37:165–172PubMedGoogle Scholar
  31. 31.
    Tseng MY, Hutchinson PJ, Kirkpatrick PJ (2008) Effects of fluid therapy following aneurysmal subarachnoid haemorrhage: a prospective clinical study. Br J Neurosurg 22:257–268PubMedCrossRefGoogle Scholar
  32. 32.
    Heilmann L, Lorch E, Hojnacki B, Muntefering H, Forster H (1991) Accumulation of two different hydroxyethyl starch preparations in the placenta after hemodilution in patients with fetal intrauterine growth retardation or pregnancy hypertension. Infusionstherapie 18:236–243PubMedGoogle Scholar
  33. 33.
    Stander S, Szepfalusi Z, Bohle B, Stander H, Kraft D, Luger TA, Metze D (2001) Differential storage of hydroxyethyl starch (HES) in the skin: an immunoelectron-microscopical long-term study. Cell Tissue Res 304:261–269PubMedCrossRefGoogle Scholar
  34. 34.
    Neff TA, Doelberg M, Jungheinrich C, Sauerland A, Spahn DR, Stocker R (2003) Repetitive large-dose infusion of the novel hydroxyethyl starch 130/0.4 in patients with severe head injury. Anesth Analg 96:1453–1459PubMedCrossRefGoogle Scholar
  35. 35.
    Kasper SM, Meinert P, Kampe S, Gorg C, Geisen C, Mehlhorn U, Diefenbach C (2003) Large-dose hydroxyethyl starch 130/0.4 does not increase blood loss and transfusion requirements in coronary artery bypass surgery compared with hydroxyethyl starch 200/0.5 at recommended doses. Anesthesiology 99:42–47PubMedCrossRefGoogle Scholar
  36. 36.
    Kozek-Langenecker SA, Jungheinrich C, Sauermann W, Van der Linden P (2008) The effects of hydroxyethyl starch 130/0.4 (6%) on blood loss and use of blood products in major surgery: a pooled analysis of randomized clinical trials. Anesth Analg 107:382–390PubMedCrossRefGoogle Scholar
  37. 37.
    Boldt J, Brenner T, Lehmann A, Lang J, Kumle B, Werling C (2003) Influence of two different volume replacement regimens on renal function in elderly patients undergoing cardiac surgery: comparison of a new starch preparation with gelatin. Intensive Care Med 29:763–769PubMedGoogle Scholar
  38. 38.
    Jungheinrich C, Scharpf R, Wargenau M, Bepperling F, Baron JF (2002) The pharmacokinetics and tolerability of an intravenous infusion of the new hydroxyethyl starch 130/0.4 (6%, 500 mL) in mild-to-severe renal impairment. Anesth Analg 95:544–551PubMedCrossRefGoogle Scholar
  39. 39.
    Blasco V, Leone M, Antonini F, Geissler A, Albanese J, Martin C (2008) Comparison of the novel hydroxyethylstarch 130/0.4 and hydroxyethylstarch 200/0.6 in brain-dead donor resuscitation on renal function after transplantation. Br J Anaesth 100:504–508PubMedCrossRefGoogle Scholar
  40. 40.
    Leuschner J, Opitz J, Winkler A, Scharpf R, Bepperling F (2003) Tissue storage of 14C-labelled hydroxyethyl starch (HES) 130/0.4 and HES 200/0.5 after repeated intravenous administration to rats. Drugs R D 4:331–338PubMedCrossRefGoogle Scholar
  41. 41.
    Waitzinger J, Bepperling F, Pabst G, Opitz J (2003) Hydroxyethyl starch (HES) [130/0.4], a new HES specification: pharmacokinetics and safety after multiple infusions of 10% solution in healthy volunteers. Drugs R D 4:149–157PubMedCrossRefGoogle Scholar
  42. 42.
    Boldt J, Scholhorn T, Mayer J, Piper S, Suttner S (2006) The value of an albumin-based intravascular volume replacement strategy in elderly patients undergoing major abdominal surgery. Anesth Analg 103:191–199PubMedCrossRefGoogle Scholar
  43. 43.
    Boldt J, Brosch C, Ducke M, Papsdorf M, Lehmann A (2007) Influence of volume therapy with a modern hydroxyethylstarch preparation on kidney function in cardiac surgery patients with compromised renal function: a comparison with human albumin. Critical Care Med 35:2740–2746CrossRefGoogle Scholar
  44. 44.
    Boldt J, Ducke M, Kumle B, Papsdorf M, Zurmeyer EL (2004) Influence of different volume replacement strategies on inflammation and endothelial activation in the elderly undergoing major abdominal surgery. Intensive Care Med 30:416–422PubMedCrossRefGoogle Scholar
  45. 45.
    Fenger-Eriksen C, Hartig Rasmussen C, Kappel Jensen T, Anker-Moller E, Heslop J, Frokiaer J, Tonnesen E (2005) Renal effects of hypotensive anaesthesia in combination with acute normovolaemic haemodilution with hydroxyethyl starch 130/0.4 or isotonic saline. Acta Anaesthesiol Scand 49:969–974PubMedCrossRefGoogle Scholar
  46. 46.
    Palumbo D, Servillo G, D’Amato L, Volpe ML, Capogrosso G, De Robertis E, Piazza O, Tufano R (2006) The effects of hydroxyethyl starch solution in critically ill patients. Minerva Anestesiol 72:655–664PubMedGoogle Scholar
  47. 47.
    Lang K, Boldt J, Suttner S, Haisch G (2001) Colloids versus crystalloids and tissue oxygen tension in patients undergoing major abdominal surgery. Anesth Analg 93:405–409PubMedCrossRefGoogle Scholar
  48. 48.
    Lang K, Suttner S, Boldt J, Kumle B, Nagel D (2003) Volume replacement with HES 130/0.4 may reduce the inflammatory response in patients undergoing major abdominal surgery. Can J Anaesth 50:1009–1016PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Department of Anaesthesiology and Intensive Care MedicineFriedrich Schiller UniversityJenaGermany

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