Abstract
Hydroxyethyl starch has recently become the subject of renewed interest because of the introduction of a new specification, hydroxyethyl starch 130/0.4, as well as the clinical availability of a solution using a previous hydroxyethyl starch type (hydroxyethyl starch 670/0.75) with a carrier other than 0.9% saline.
Various types of hydroxyethyl starch show different pharmacokinetic behaviour. Since hydroxyethyl starch is a polydisperse solution acting as a colloid, pharmacodynamic action depends on the number of oncotically active molecules, not on the plasma concentration alone; therefore, solutions with a lower in vivo molecular weight contain more molecules at similar plasma concentrations. On the other hand, high plasma concentrations as well as high in vivo molecular weight can affect blood coagulation, especially factor VIII and von Willebrand factor.
Hydroxyethyl starch types with a molar substitution >0.4 accumulate in plasma after repetitive administration, most pronounced with hetastarch (hydroxyethyl starch 670/0.75). Correspondingly, tissue storage as measured by 14C tracer studies in animals showed significantly higher values for hydroxyethyl starch 200/0.5 compared with hydroxyethyl starch 130/0.4 (about 4-fold at the latest timepoint after the last administration), and considerably higher values for hetastarch compared with both hydroxyethyl starch 130/0.4 and 200/0.5.
Hydroxyethyl starch 130/0.4 does not accumulate in plasma after single- and multiple-dose administration in contrast to all other available hydroxyethyl starch specifications. Plasma clearance of hydroxyethyl starch 130/0.4 is at least 20-fold higher than that for hetastarch, and considerably higher than for pentastarch. In patients with renal insufficiency, pharmacokinetic data are only available for hydroxyethyl starch 130/0.4. Cumulative urinary excretion, even in the presence of severe non-anuric renal failure, is higher for hydroxyethyl starch 130/0.4 than values published for older hydroxyethyl starch specifications. Hydroxyethyl starch 130/0.4 may be given to patients with severe renal impairment as long as urine flow is preserved.
The pharmacodynamics with respect to the volume effect does not directly mirror pharmacokinetics in the case of hydroxyethyl starch solutions. Equivalent volume efficacy has been proven for hydroxyethyl starch 130/0.4 compared with 200/0.5. Prolonged persistence of hydroxyethyl starch in plasma and tissues can be avoided by using rapidly metabolisable hydroxyethyl starch types with molar substitution <0.5. Influence on coagulation is minimal with hydroxyethyl starch 130/0.4, and no adverse effects on kidney function have been observed even with large repetitive doses when used according to the product information.
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Notes
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References
Ferber HP, Nitsch E, Förster H. Studies on hydroxyethyl starch (Pt II): changes of the molecular weight distribution for hydroxyethyl starch types 450/0.7, 450/0.5, 450/0.3, 300/0.4, 200/0.7, 200/0.5, 200/0.3 and 200/0.1 after infusion in serum and urine of volunteers. Arzneimittelforschung 1985; 35: 615–22
Jung F, Koscielny J, Mrowietz C, et al. Einfluss der Molekülstruktur von Hydroxyäthylstärke auf die Eliminationskinetik und die Fliessfähigkeit des Blutes bei Probanden. Arzneimittelforschung 1993; 43: 99–105
Lederer K, Huber C, Dunky M, et al. Studies on hydroxyethyl starch (Pt I): molecular characterization by size exclusion chromatography coupled with low-angle laser light scattering. Arzneimittelforschung 1985; 35: 610–4
Lenz K, Schimetta W, Poelz W, et al. Intestinal elimination of hydroxyethyl starch? Intensive Care Med 2000; 26: 733–9
Sommermeyer K, Cech F, Schmidt M, et al. Klinisch verwendete Hydroxyethylstärke: physikalisch-chemische Charakterisierung. Krankenhauspharmazie 1987; 8: 271–8
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%, 500 mL) in mild-to-severe renal impairment. Anesth Analg 2002; 95: 544–51
Mishler JM, Borgerg H, Emerson PM, et al. Hydroxyethyl starch: an agent for hypovolemic shock. J Surg Res 1977; 23: 239–45
Leuschner J, Opitz J, Winkler A, et al. Tissue storage of 14C-labeled hydroxyethyl starch (HES) 130/0.4 and HES 200/0.5 after repeated intravenous administration to rats. Drugs R D 2003; 4: 331–8
Hulse JD, Jacobi A. Hetastarch: an overview of the colloid and its metabolism. Drug Intell Clin Pharm 1983; 17: 334–41
Wilkes NJ, Woolf RL, Powanda MC, et al. Hydroxyethyl starch in balanced electrolyte solution (Hextend): pharmacokinetic and pharmacodynamic proflies in healthy volunteers. Anesth Analg 2002; 94: 538–44
Yacobi A, Stoll RG, Sum CY, et al. Pharmacokinetics of hydroxyethyl starch in normal subjects. J Clin Pharmacol 1982; 22: 206–12
Weidler B, von Bormann B, Sommermeyer K, et al. Pharmakokinetische Merkmale als Kriterien für den klinischen Einsatz von Hydroxyethylstärke. Arzneimittelforschung 1991; 41: 494–8
Köhler H, Zschiedrich H, Linfante A, et al. Die Elimination von Hydroxyaethylstaerke 200/0,5, Dextran 40 und Oxypolygelatine. Klin Wochenschr 1982; 60: 293–301
Waitzinger J, Bepperling F, Pabst 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: 151–60
Boon JC, Jesch F, Ring J, et al. Intravascular persistence of hydroxyethyl starch in man. Eur Surg Res 1976; 8: 497–503
Asskali F, Förster H. Zur Kumulation unterschiedlich substituierter Hydroxyethylstärke (HES) nach repetitiver Infusion bei gesunden Versuchspersonen. Anaesthesiol Intensivmed Unfallmed Notfallmed Schmerzther 1999; 34: 537–41
Asskali F, Warnken U, Förster H. Acetylstärke als Volumenersatz, eine mögliche Alternative zu HES. Dtsch Med Wochenschr 2001; 126: 1–6
Lehmann G, Asskali F, Förster H. Pharmacokinetics of hydroxyethyl starch (70/0.5) following repeated infusions. Transfus Med Hemother 2003; 30: 72–7
Waitzinger J, Bepperling F, Pabst G, et al. 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 2003; 4: 149–57
Költringer P, Pfeiffer KP, Lind P, et al. Hämodilution mit mittelmolekularer Hydroyxyäthylstärke — 6% HAES 200.000/0.60–0.66 — bei Patienten mit peripherer arterieller Verschlusskrankheit. Östereichische Krankenhauspharmazie 1989; 3: 7–12
Treib J, Haass A, Pindur G, et al. Influence of intravascular molecular weight of hydroxyethyl starch on platelets. Eur J Haematol 1996; 56: 168–72
Kroemer H, Haass A, Müller K, et al. Haemodilution therapy in ischaemic stroke: plasma concentrations and plasma viscosity during long-term infusion of dextran 40 or hydroxyethyl starch 200/0.5. Eur J Clin Pharm 1987; 31: 705–10
Jungheinrich C, Sauermann W, Bepperling F, et al. Volume efficacy and reduced influence on measures of coagulation using hydroxyethyl starch 130/0.4 (6%) with an optimised in vivo molecular weight in orthopaedic surgery: a randomised, double-blind study. Drugs R D 2004; 5: 1–9
Treib J, Haass A, Pindur G, et al. HES 200/0.5 is not HES 200/0.5: influence of the C2/C6 hydroxyethylation ratio of hydroxyethyl starch (HES) on hemorheology, coagulation and elimination kinetics. Thromb Haemost 1995; 74: 1452–6
Lang K, Boldt J, Suttner S, et al. Colloids versus crystalloids and tissue oxygen tension in patients undergoing major abdominal surgery. Anesth Analg 2001; 93: 405–9
Standi T, Burmeister MA, Schroeder F, et al. Hydroxyethyl starch (HES) 130/0.4 provides larger and faster increases in tissue oxygen tension in comparison with prehemodilution values than HES 70/0.5 or HES 200/0.5 in volunteers undergoing acute normovolemic hemodilution. Anesth Analg 2003; 96: 936–43
Köhler H, Kirch W, Klein H, et al. Die Volumenwirkung von 6% Hydroxyäthylstärke 450/0.7, 10% Dextran 40 und 3,5% isozyanatvernetzter Gelatine bei Patienten mit terminaler Niereninsuffizienz. Anaesthesist 1978; 27: 421–6
Metcalf W, Papadopulos A, Tufaro R, et al. A clinical physiologic study of hydroxyethyl starch. Surg Gynecol Obstet 1970; 131: 255–67
Kröll W, Gemer P, Colombo T, et al. Einfluss von 6% HES 200/0.6–0.66 auf Plasmavolumen und Blutgerinnung. Infusionstherapie 1992; 19: 171–80
Waitzinger J, Bepperling F, Pabst G, et al. Effect of a new HES specification (6% HES 130/0.4) on blood and plasma volume after bleeding in 12 healthy male volunteers. Clin Drug Invest 1999; 17: 119–25
Jacob M, Rehm M, Orth V, et al. Exakte Messung des Volumeneffektes von 6%iger Hydroxyethylstärke 130/0,4 (Voluven®) während präoperativer akuter normovolämer Hämodilution. Anaesthesist 2003; 52: 896–904
James MF, Latoo MY, Mythen MG, et al. Plasma volume changes associated with two hydroxyethyl starch colloids following acute hypovolemia in volunteers. Anaesthesia 2004; 59: 738–42
Kasper SM, Strömich A, Kampe S, et al. Evaluation of a new hydroxyethyl starch solution (HES 130/0.4) in patients undergoing preoperative autologous blood donation. J Clin Anesth 2001; 13: 486–90
Boldt J, Lehmann A, Römpert R, et al. Volume therapy with a new hydroxyethyl starch in cardiac surgical patients before cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2000; 14: 264–8
Ickx BE, Bepperling F, Melot C, et al. Plasma substitution effects of a new hydroxyethyl starch HES 130/0.4 compared with HES 200/0.5 during and after extended acute normovolemic haemodilution. Br J Anaesth 2003; 91: 196–202
Gallandat Huet RC, Siemons AW, Baus D, et al. A novel hydroxyethyl starch (Voluven®) for effective perioperative plasma volume substitution in cardiac surgery. Can J Anesth 2000; 47: 1207–15
Langeron O, Doelberg M, Ang ET, et al. Voluven, a lower substituted novel hydroxyethyl starch (HES 130/0.4), causes fewer effects on coagulation in major orthopedic surgery than HES 200/0.5. Anesth Analg 2001; 92: 855–62
Cittanova ML, Leblanc I, Legendre C, et al. Effects of hydroxyethyl starch in brain-dead kidney donors on renal function in kidney-transplant recipients. Lancet 1996; 348: 1620–2
Deman A, Peeters P, Sennesael J. Hydroxyethyl starch does not impair immediate renal function in kidney transplant recipients: a retrospective, multicentre analysis. Nephrol Dial Transplant 1999; 14: 1517–20
Kumle B, Boldt J, Piper S, et al. The influence of different intravascular volume replacement regimens on renal function in the elderly. Anesth Anlag 1999; 89: 1124–30
Schortgen F, Lacherade JC, Bruneel F, et al. Effects of hydroxyethyl starch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet 2001; 357: 911–6
Boldt J, Brenner T, Lang J, et al. Kidney-specific proteins in elderly patients undergoing cardiac surgery with cardiopulmonary bypass. Anesth Analg 2003; 97: 1582–9
Winkelmayer WC, Glynn RJ, Levin R, et al. Hydroxyethyl starch and change in renal function in patients undergoing coronary bypass graft surgery. Kidney Int 2003; 64: 1046–9
Boldt J, Priebe HJ. Intravascular volume replacement with synthetic colloids: is there an influence on renal function? Anesth Analg 2003; 96: 376–82
Gosling P, Rittoo D, Manji M, et al. Hydroxyethyl starch as a risk factor for acute renal failure in severe sepsis [letters]. Lancet 2001; 358: 581–3
Dehne MG, Muhling J, Sablontzki A, et al. Hydroxyethyl starch (HES) does not directly affect renal function in patients with no prior renal impairment. J Clin Anesth 2001; 13: 103–11
Neff TA, Doelberg M, Jungheinrich C, et al. Repetitive largedose infusion of the novel hydroxyethyl starch 130/0.4 in patients with severe head injury. Anesth Analg 2003; 96: 1453–9
Boldt J, Haisch G, Suttner S, et al. Effects of a modified, balanced hydroxyethyl starch preparation (Hextend®) on measures of coagulation. Br J Anaesth 2002; 89: 722–8
Haisch G, Boldt J, Krebs C, et al. The influence of intravascular volume therapy with a new hydroxyethyl starch preparation (6% HES 130/0.4) on coagulation in patients undergoing major abdominal surgery. Anesth Analg 2001; 92: 565–71
Haisch G, Boldt J, Krebs C, et al. Influence of a new hydroxyethylstarch preparation (HES 130/0.4) on coagulation in cardiac surgical patients. J Cardiothorac Vasc Anesth 2001; 15: 316–21
Stump DC, Strauss RG, Henriksen RA, et al. Effects of hydroxyethyl starch on blood coagulation, particularly factor VIII. Transfusion 1985; 25: 349–54
Treib J, Haass A, Pindur G, et al. All medium starches are not the same: influence of the degree of hydroxyethyl substitution of hydroxyethyl starch on plasma volume, hemorrheologic conditions, and coagulation. Transfusion 1996; 36: 450–5
Sirtl C, Laubenthal H, Zumtobel V, et al. Tissue deposits of hydroxyethyl starch (HES): dose-dependent and time-related. Br J Anaesth 1999; 82: 510–5
Welters ID, Spangenberg U, Menzebach A, et al. Der Einfluss verschiedener Volumenersatzmittel auf die Funktion von neutrophilen Granulozythen in vitro. Anaesthesist 2000; 49: 196–201
Schmand JF, Ayala A, Morrison MH, et al. Effects of hydroxyethyl starch after trauma-hemorrhagic shock: restoration of macrophage integrity and prevention of increased circulating interleukin-6 levels. Crit Care Med 1995; 23: 806–14
Dieterich HJ, Nohé B, Deschner N. Modulation von Phagozytose und Endothelfunktion. Anaesthesiol Intensivmed Not-fallmed Schmerzther 1998; 33: 270–4
Engel JM, Welters I, Rupp M, et al. Influence of colloid fluids on polymorphonuclear granulocyte function in vivo. Acta Anaesthesiol Scand 2001; 45: 385–9
Guidet B, Podevin P, Robert A, et al. High doses of hydroxyethyl starch and human albumin have similar effects on monocyte function and oncotic pressure. Eur J Clin Invest 1997; 27: 943–7
Ellger B, Freyhoff J, van Aken H, et al. High dose volume replacement using HES 130/0.4 during major surgery does not alter coagulation [abstract]. Eur J Anaesthesiol 2002; 19 Suppl. 24:77
Kasper SM, Meinert P, Kampe S, et al. 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 2003; 99: 42–7
Konrad CJ, Markl TJ, Schuepfer GK, et al. In vitro effects of different medium molecular hydroxyethyl starch solutions and lactated Ringer’s solution on coagulation using SONOCLOT. Anesth Analg 2000; 90: 274–9
Entholzner EK, Mielke LL, Calatzis AN, et al. Coagulation effects of a recently developed hydroxyethyl starch (HES 130/0.4) compared to hydroxyethyl starches with higher molecular weight. Acta Anaesthesiol Scand 2000; 44: 1116–21
Franz A, Bräunlich P, Gamsjäger T, et al. The effects of hydroxyethyl starches of varying molecular weights on platelet function. Anesth Analg 2001; 92: 1402–7
Produktresumé: Swedish summary of product characteristics (SmPC) for Voluven [online]. Available from URL: http://www.mpa.se/spc_pil/pdf/humspc/Voluven%2060mgml%20-solution%20for%20infusion%20.pdf [Accessed 2005 Apr 18]
Acknowledgements
Dr Cornelius Jungheinrich is an employee of Fresenius Kabi, Bad Homburg, Germany.
Dr Thomas Neff participated in a clinical study sponsored by Fresenius Kabi.
Dr Neff did not receive funding for the preparation of this review article.
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Jungheinrich, C., Neff, T.A. Pharmacokinetics of Hydroxyethyl Starch. Clin Pharmacokinet 44, 681–699 (2005). https://doi.org/10.2165/00003088-200544070-00002
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DOI: https://doi.org/10.2165/00003088-200544070-00002