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 (14)C 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.

Pharmacokinetics of Hydroxyethyl Starch

Dextran-70 versus albumin as plasma expanders in cirrhotic patients with tense ascites treated with total paracentesis. Results of a randomized study.

Dextran prodrugs — structure and stability in relation to therapeutic activity

Pharmacology of Colloids and Crystalloids

Synthetic plasma volume expanders--their pharmacology, safety and clinical efficacy.

After withdrawal of 400 ml whole blood and subsequent infusion of 500 ml of a colloidal plasma substituent, the intravascular and renal colloid elimination was investigated in 40 test subjects. The individual colloidal solutions could no longer be demonstrated in the intravascular space after the following times: 10% hydroxyethyl starch 200/0.5 (anthrone method) after six weeks, 10% dextran 40 (anthrone method) after two weeks, 6% hydroxyethyl starch 200/0.5 (anthrone method) after four weeks and 5.5% oxypolygelatine (hydroxyproline method) after two days. Colloidal plasma substitutes are polydisperse solutions with various molecular weights and degree of hydroxyethylation and therefore, also have a large number of different elimination constants. With repeated application, the intravascular colloid concentration shifts in favour of the molecules with a longer half life which are difficult to eliminate. The elimination of the clinically employed dextran 40 and oxypolygelatine solution could be best described with an open two-compartment model. As a result of its greater heterogeneity, the elimination of the moderately high molecular weight hydroxyethyl starch 200/0.5 could only be characterized approximately even assuming three elimination constants. In the first four days, the hydroxyethyl starch 200/0.5 was more rapidly eliminated compared to dextran 40. However, subsequently a very much lower elimination from the intravascular space was found for about 3% of the administered hydroxyethyl starch 200/0.5. Oxypolygelatine was eliminated especially rapidly. Accordingly, the greatest renal clearance was found for oxypolygelatine, which showed a close relation to the molecular weight. On the other hand, a rapid elimination simultaneously is followed by a correspondingly lower volume effect.

[The elimination of hydroxyethyl starch 200/0.5, dextran 40 and oxypolygelatine (author's transl)].

The effects of administration of a new, middle-molecular 10% hydroxyethyl starch 200/0.5 (HAES-steril) were compared to 10% dextran 40 (Rheomacrodex) in 20 hypovolaemic volunteers after withdrawal of 400 ml blood. The total increase of blood volume after 500 ml of 10% hydroxyethyl starch 200/0.5 was 10.19 +/- 1.1 ml/kg (754 ml), after 500 ml of 10% dextran 40 14.10 +/- 1.1 ml/kg (1032 ml), which was significantly higher (p less than 0.01) and in correspondence with the known volume expanding properties of 10% dextran 40. The volume effect after administration of both substances was stable, as demonstrated by the ability to compensate the loss of 400 ml blood for more than 8 hours. The maximal increase of the colloid osmotoc pressure after 10% hydroxyethyl starch 200/0.5 was 5.3 +/- 0.2 mm Hg, after 10% dextran 40 7.2 +/- 0.4 mm Hg and paralleled the increase of the blood volume. After 10% hydroxyethyl starch 200/0.5 an increase of serum amylase was observed. This hyperamylasemia is caused by the formation of a high molecular hydroxyethyl starch-amylase complex, which cannot be eliminated easily. Urinary volume and endogenous creatinine clearance were increased by administration of both colloids. After dextran 40 a pronounced increase of the urinary viscosity occurred.

[The effects of 500 ml 10% hydroxyethyl starch 200/0.5 and 10% dextran 40 on blood volume, colloid osmotic pressure and renal function in human volunteers (author's transl)].

Every stress reaction leads to an increased, hormonelly induced mobilisation of fatty acids, the extent of which may be considered as a parameter of the aggression mechanism. In 15 patients with idiopathic trigeminal neuralgia, who were operated under neurolepthypalgesia, the problem of quantitative alterations of the concentration pattern of fatty acids was investigated during the operation. In contrast to some reports of the literature, the increase of the concentration of total fatty acids was due to corresponding increases of all individual fatty acids. By preoperative administration of the beta-adrenergic blocking agent Pindolol the increase of fatty acids was reduced without a qualitative shifting of individual fatty acids.

[Serumconcentrations of non esterified fatty acids during operative stress and blockade of betaadrenergic receptors (author's transl)].

Serumkonzentrationen der einzelnen Nichtesterfettsuren unter operativem Stre und Betarezeptorenblockade

Die Wirkung und Elimination von kolloidalen Plasmaersatzmitteln auf Starkebasis wird im Unterschied zu Dextran- und Gelatinelosungen wesentlich vom Ausmas der Hydroxyathylierung bestimmt. Mit zunehmender Hydroxyathylierung nimmt die hydrolytische Spaltung der Starke durch die S-Amylase ab und damit die intravasale Verweildauer des Kolloids zu. In der vorliegenden Untersuchung interessierte — im Vergleich zu Dextran 40 — die Elimination einer neuen, mittelmolekularen Starke (Mw = 200000) mit relativ niedrigem Hydroxyathylierungsgrad (0,5) sowie ihre Wirkung auf Blutvolumen, kolloidosmotischen Druck, S-Osmolaritat, S-Protein und auf die Nierenfunktion.

R. Clasen

Papers

[The elimination of hydroxyethyl starch 200/0.5, dextran 40 and oxypolygelatine (author's transl)].

[The effects of 500 ml 10% hydroxyethyl starch 200/0.5 and 10% dextran 40 on blood volume, colloid osmotic pressure and renal function in human volunteers (author's transl)].

[Serumconcentrations of non esterified fatty acids during operative stress and blockade of betaadrenergic receptors (author's transl)].

Serumkonzentrationen der einzelnen Nichtesterfettsuren unter operativem Stre und Betarezeptorenblockade

Wirkung und Elimination eines neuen kolloidalen Plasmaersatzmittels— Mittelmolekulare Hydroxyäthylstärke 200/0,5