Drugs in R & D

, Volume 4, Issue 6, pp 331–338 | Cite as

Tissue Storage of 14C-Labelled Hydroxyethyl Starch (HES) 130/0.4 and HES 200/0.5 after Repeated Intravenous Administration to Rats

  • Jost Leuschner
  • Jens Opitz
  • Andreas Winkler
  • Roland Scharpf
  • Frank Bepperling
Original Research Article


Objective: To investigate the effect of the molar substitution of hydroxyethyl starch (HES) solutions on tissue and organ storage in rats after repeated administration.

Study design: A controlled, multiple-dose study was performed in 48 rats. Daily bolus injections of 0.7 g/kg of 10% HES 130/0.4 or 10% HES 200/0.5 were administered on 18 consecutive days. In order to examine quantitatively the distribution and excretion of both preparations on HES tissue storage, radiolabelled HES was measured 3, 10, 24 and 52 days after the last administration. Tissue storage was expressed as percentage radioactivity of total administered HES dose in the total body, carcass, liver, kidney, spleen, lymph nodes, plasma and urine.

Results: 52 days after the last administration the remaining radioactivity of labelled HES 200/0.5 was nearly 4-fold higher compared with HES 130/0.4 in the total body (2.45% vs 0.65% of the total administered dose). This difference in tissue storage was statistically significant (p ≤ 0.01). A comparable difference was observed for the liver and carcass.

Conclusion: Tissue storage after repeated administration of an HES solution with a low molar substitution (0.4) was significantly lower in the total body as well as in the liver and carcass compared with an HES solution with a medium molar substitution (0.5). However, the potential clinical consequences of these present findings have not yet been determined.


  1. 1.
    Treib J, Baron JF, Grauer MT, et al. An international view of hydroxyethyl starches. Intensive Care Med 1999; 25: 258–68PubMedCrossRefGoogle Scholar
  2. 2.
    Treib J, Haass A, Pindur G, et al. Influence of the C2/C6 hydroxyethylation ratio of hydroxyethyl starch (HES) on hemorheology, coagulation and elimination kinetics. Thromb Haemost 1995; 78: 1452–6Google Scholar
  3. 3.
    Mishler JM. Pharmacology of hydroxyethyl starch. New York: Oxford University Press, 1982Google Scholar
  4. 4.
    Ständer S, Szepfalusi Z, Bohle B, et al. Differential storage of hydroxyethyl starch (HES) in the skin: an immunoelectron-microscopical long-term study. Cell Tissue Res 2001; 304: 261–9PubMedCrossRefGoogle Scholar
  5. 5.
    Reimann S, Szepfalusi Z, Kraft D, et al. Hydroxyethylstärke-Speicherung in der Haut unter besonderer Berücksichtigung des Hydroxyethylstärke-assozierten Juckreizes. Dtsch Med Wochenschr 2000; 125: 280–5PubMedCrossRefGoogle Scholar
  6. 6.
    Gall H, Kaufmann R, von Ehr M, et al. Persistierender Pruritus nach Hydroxyäthylstärke-Infusionen. Hautarzt 1993; 44: 713–6PubMedGoogle Scholar
  7. 7.
    Kiesewetter H, Blume J, Jung F, et al. Haemodilution with medium molecular weight hydroxyethyl starch in patients with peripheral arterial occlusive disease stage IIb. J Intern Med 1990; 227: 107–14PubMedCrossRefGoogle Scholar
  8. 8.
    Hulse JD, Yacobi A. Hetastarch: an overview of the colloid and its metabolism. Drug Intell Clin Pharm 1983; 17: 334–41PubMedGoogle Scholar
  9. 9.
    Waitzinger J, Bepperling F, Papst G, et al. Pharmacokinetics and tolerability of a new hydroxyethyl starch (HES) specification (HES 130/0.4) after single-dose infusion of 6% or 10% solutions in healthy volunteers. Clin Drug Invest 1998; 16: 151–60CrossRefGoogle Scholar
  10. 10.
    Jungheinrich C, Scharpf R, Wargenau M, et al. The pharmacokinetics and tolerability of an intravenous infusion of the new hydroxyethyl starch 130/0.4 (6%, 500ml) in mild-to-severe renal impairment. Anesth Analg 2002; 95: 544–51PubMedGoogle Scholar
  11. 11.
    Waitzinger J, Bepperling F, Pabst G F, et al. Hydroxyethyl starch (HES) [HES 130/0.4], a new specification: pPharmacokinetics and safety of after multiple infusions of 10% solution in healthy volunteers. Drugs R&D 2003; 4: 149–57CrossRefGoogle Scholar
  12. 12.
    Asskali F, Forster H. Zur Kumulation unterschiedlich substituierter Hydroxyethylstärke (HES) nach repetetiver Infusion bei gesunden Versuchsprobanden. Anasthesiol Intensivmed Notfallmed Schmerzther 1999; 34: 537–41PubMedCrossRefGoogle Scholar
  13. 13.
    Dienes HP, Gerharz CD, Wagner R, et al. Accumulation of hydroxyethyl starch (HES) in the liver of patients with renal failure and portal hypertension. J Hepatol 1986; 3: 223–7PubMedCrossRefGoogle Scholar
  14. 14.
    Pfeifer U, Kult J, Forster H. Ascites als Komplikation hepatischer Speicherung von Hydroxyethylstärke (HES) nach Langzeitdialyse. Klin Wochenschr 1984; 62: 862–6PubMedCrossRefGoogle Scholar
  15. 15.
    Jesch F, Hübner G, Zumtobel V, et al. Hydroxyäthylstärke (HÄS 450/0,7) in Plasma und Leber-Konzentrationsverlauf und histologische Veränderungen beim Menschen. Infusionsther Klin Ernahr 1979; 6: 112–7PubMedGoogle Scholar
  16. 16.
    Ständer S, Bone HG, Machens HG, et al. Hydroxyethyl starch does not cross the blood-brain or the placental barrier but the perineurium of peripheral nerves in infused animals. Cell Tissue Res 2002; 310: 279–87PubMedCrossRefGoogle Scholar
  17. 17.
    Metze D, Reimann S, Szepfalusi Z, et al. Persistent pruritus after hydroxyethyl starch infusion therapy: a result of long-term storage in cutaneous nerves. Br J Dermatol 1997; 136: 553–9PubMedCrossRefGoogle Scholar
  18. 18.
    Cox NH, Popple AW. Persistent erythema and pruritus, with a confluent histiocytic skin infiltrate, following the use of a hydroxyethylstarch plasma expander. Br J Dermatol 1996; 134: 353–7PubMedCrossRefGoogle Scholar
  19. 19.
    Jurecka W, Szepfalusi Z, Parth E, et al. Hydroxyethylstarch deposits in human skin: a model for pruritus? Arch Dermatol Res 1993; 285: 13–9PubMedCrossRefGoogle Scholar
  20. 20.
    Heilmann L, Lorch E, Hojnacki B, et al. Die Speicherung von zwei unterschiedlichen Hydroxyäthylstärke-Präparaten in der Plazenta nach Hämodilution bei Patientinnen mit fetaler Mangelentwicklung oder Schwangerschaftshochdrucks. Infusionstherapie 1991; 18: 236–43PubMedGoogle Scholar
  21. 21.
    Van Rijen EA, Ward JJ, Little RA. Effects of colloidal resuscitation fluids on reticuloendothelial function and resistance to infection after hemorrhage. Clin Diagn Lab Immunol 1998; 5: 543–9PubMedGoogle Scholar
  22. 22.
    Shatney CH, Chaudry IH. Hydroxyethylstarch administration does not depress reticuloendothelial function or increase mortality from sepsis. Circ Shock 1984; 13: 21–6PubMedGoogle Scholar
  23. 23.
    Ginz H, Gottschall V, Schwarzkopf G, et al. Exzessive Gewebespeicherung von Kolloiden im retikuloendothelialen System. Anaesthesist 1998; 47: 330–4PubMedCrossRefGoogle Scholar
  24. 24.
    Gröchenig E, Albegger K, Dieterich HJ, et al. Hydroxyethyl-starch-related pruritus: a prospective multicentre investigation of 544 patients. Perfusion 1998; 11: 62–9Google Scholar
  25. 25.
    Speight EL, MacSween RM, Stevens A. Persistent itching due to etherified starch plasma expander. BMJ 1997; 314: 1466–7PubMedCrossRefGoogle Scholar
  26. 26.
    Neff TA, Doelberg M, Jungheinrich C, et al. Repetitive large-dose infusion of the novel hydroxyethyl starch 130/0.4 in patients with severe head injury. Anest Analg 2003; 96: 1453–9CrossRefGoogle Scholar
  27. 27.
    Rudolf J. Hydroxyethyl starch for hypervolemic hemodilution in patients with acute ischemic stroke: a randomized, placebo-controlled phase II safety study. Cerebrovasc Dis 2002; 14: 33–41PubMedCrossRefGoogle Scholar
  28. 28.
    Grauer MT, Baus D, Woessner R, et al. Effects on general safety and coagulation after long-term, high-dose volume therapy with 6% hydroxyethyl starch 130/0.4 in patients with acute ischemic stroke: results of a randomised, placebo-controlled, double-blind study [abstract]. Crit Care 2001; 5 Suppl. 1: P115CrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  • Jost Leuschner
    • 1
  • Jens Opitz
    • 2
  • Andreas Winkler
    • 1
  • Roland Scharpf
    • 2
  • Frank Bepperling
    • 2
  1. 1.LPT Laboratory of Pharmacology and ToxicologyHamburgGermany
  2. 2.Clinical ResearchFresenius Kabi Deutschland GmbHBad HomburgGermany

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