Repeated administration of HES 130/0.42 shows no accumulation and fewer tendencies to time-dependent changes in pharmacokinetic parameters than HES 200/0.5. The improved reproducibility may improve drug safety, particularly as the accumulation of residual starch with HES 200/0.5 does not contribute to the colloid's volume effect, but may rather increase the risk of undesired reactions.
Background: For the purpose of haemodilution different medium substituted hydroxyethyl starches (HES) are available. These plasma substitutes can be further characterized by their average molecular weight (Mw) into medium Mw (HES 200/0.5) and low Mw (HES 70/0.5) starches. Patients and Methods: Pharmacokinetic data were collected in a trial with a design similar to clinical use. 8 healthy volunteers were given 50 g HES on 5 consecutive days (=250 g) to estimate the in vivo changes of the chemical structures of HES (70/0.5). Results: Calculated half-life of serum elimination were 6–10 h which was representative for medium substituted HES and the chosen infusion scheme. The mild accumulation of HES (70/0.5) should be without clinical relevance. The in vivo Mw is equivalent to the in vitro Mw of the infused HES (70/0.5). The in vivo Mw is about 60,000 Dalton for most medium substituted HES. Nevertheless, regarding molar substitution and pattern of substitution (C2:C6) there are some differences between applied HES (70/0.5) and HES recovered in urine. These changes also indicate a shift in the chemical properties of infused HES in the organism. Only 60% of infused HES were recovered in urine. The destination of the remaining 40% (∼100 g in this clinical trial) is still unexplained. A fractional amount might be stored in the reticuloendothelial system. Concerning the measured data of medium substituted HES (70/0.5) it stands to reason that differences in the approximate substituted HES (200/0.5) with a higher molecular weight are without clinical relevance. Conclusion: The in vivo Mw is independent of the in vitro Mw of the applied HES. Pharmacokinetic data suggest that HES (70/0.5) is a good option for the purpose of haemodilution.
Being equivalent with pentastarch and HES 130/0.4/9 : 1 in terms of colloid osmotic and haemodilution effect, HES 130/0.42/6 : 1 shows the fastest clearance from the circulation.
In the study presented the effects of in vitro hemodilution with HES on coagulation are compared with the effects of in vivo hemodilution using thrombelastography (TEG). The in vivo hemodilution was performed by the i. v. infusion of 1000 ml 6 % solution of hydroxyethyl starch HES (2 formulations with HES 130/0.4 and one formulation with HES 200/0.5) in healthy volunteers during 30 min. The in vitro hemodilution was performed with blood samples taken from the volunteers before the infusion was started. These samples were diluted with HES-solution until the same hemoglobin concentration measured at the end of the infusion was attained. The in vivo TEG-parameters remained in the reference range of the method, however all in vitro TEG-parameters are out of the range of normal values. The isolated interpretation of the in vitro data shows an impairment of blood coagulation. The shortening of the reaction time as an indicator for the initiation of blood clotting points to activated coagulation by in vivo hemodilution with HES, whereas in vitro the prolongation of the reaction time is indicative for retardation of clotting. The evaluation of the TEG-parameters and of other clotting parameters determined prior to the beginning of the infusion, at the end of the infusion and four hours after termination of the infusion of HES 130/0.4 and of HES 200/0.5 to healthy volunteers show alterations of blood coagulation parameters caused mainly by dilutional effects. The more pronounced alterations found in vitro cannot be interpreted as impairment of haemostasis in vivo. On the other hand, the likewise haemodilution in vitro causes an impairment of coagulation. Therefore, the effects of in vitro hemodilution with HES on coagulation differ qualitatively and quantitatively from the effects of in vivo hemodilution.
The intravascular changes of the in vivo molecular weight of HES 70/0.5 were investigated on healthy volunteers. A repeated daily infusion of 835 ml of 6% HES solution (50 g HES 70/0.5; Rheohes) during four hours on five consecutive days was performed. The analysis of the distribution of the molecular masses in serum and urine was performed by SEC-HPLC with MALLS/RI detection. The in vivo average molecular weight (Mw) of HES was found to be 58,000 Da at the end of the infusion. This was lower than the Mw of 66,000 Da as measured initially in the HES solution. In the time following the infusion Mw increased steadily up to 64,000 Da because of renal elimination of low molecular HES. However, in the morning before the start of the next infusion of HES, the average molecular weight Mw of HES was even higher up to 71,000 Da. In the first collected portion of urine (i.e. up to 8 h after beginning the infusion) the average molecular weight of HES was as low as 17,000 Da. During the next hours (i.e. in the second collection period lasting from 8 up to 24 h after start of the HES infusion) Mw of HES increased up to 28,000 Da. The top fraction of the first period showed molecular masses of 27,000 Da, in the second collection period top fraction of molecular masses measured 40,000 Da. According to the presented data it is concluded that the renal threshold for medium substituted HES is independent of the initial Mw and related primarily to the molar substitution of the HES used. This renal threshold for medium substituted HES is determined to be at 40,000 Da. The in vivo Mw of HES is variable and related to the sampling time and predicted predominantly by the molar substitution of the HES used. The in vivo Mw, therefore, is not suited for characterisation of HES.
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