Low molecular weight hydroxyethyl starches (HES) are widely used in clinical practice as parenteral replacement fluids. Hypoalbuminemia occurs generally after HES infusion by haemodilution. The effect of haemodilution on coagulation is well studied, but no report describes these effects on drug protein binding [1,2]. Albumin is one of the major proteins responsible for hormone and drug binding in plasma. A reduction in binding from 95 to 90% represents a 100% increase in unbound fraction of drug, the moiety responsible for the pharmacological effect . Many drugs used in the intensive care unit are highly bound, such as sedative agents, antibiotics or diuretics. Therefore, we have investigated the effects of haemodilution with HES on drug protein binding in critically ill patients, by measuring the free fraction of a highly bound drug to albumin, ex vivo supplemented in the serum.
We studied 77 consecutive patients in an adult tertiary intensive care unit. Forty patients were hypoproteinemic (< 45 g L−1) after HES 6% infusion (HES group) and 37 were normoproteinic (> 60 g L−1) without HES infusion (‘no HES’ group). Patients with proteinemia > 80 g L−1, burn injury, pregnancy, acute physiology and chronic health evaluation (APACHE) II score > 40 and severe hepatic dysfunction (defined as a prothrombin time > 30 s and bilirubin > 100 mmol L−1), or who had received valproic acid were excluded. A venous blood sample was taken for each patient as part of routine sampling. Serum was separated by centrifugation and frozen at −20°C until assayed approximately two weeks later. Serum aliquots were supplemented with valproic acid. A concentration of 60 μg L−1 of valproic acid was our target. The samples were vortexed and incubated at 37°C for 30 min, as we have previously shown that equilibrium is achieved within this time. Protein-free ultrafiltrate was prepared in a Centrifree Micropartition unit, MPS (Amicon, Denver, MA, USA) with a membrane filter with a molecular weight cut-off of 30 000 Da (Ultrafree-Cl filters, Millipore) at 5000 g for 20 min at 25°C. The free concentration of valproic acid was then measured by a fluorescence polarization immunoassay (TDx, Abbott Laboratories, Abbott Park, IL, USA). The free fraction is the ratio of free concentration to total concentration. Oncotic pressure was measured by a membrane oncometer (Osmomat 050, Gonotec). The concentration of serum albumin was determined by immunoturbidimetry (Roche). The concentration of total plasma protein was measured by the Biuret determination.
The two groups were comparable in age, sex and APACHE II score. Fifty-nine patients received at least one highly bound protein drug (> 85%). There were 46 medical and 31 surgical patients. HES quantity infused was 858 ± 442 mL and 12 patients, in the HES group, received human albumin with a mean quantity infused of 28 ± 11 g. The free fraction of valproic acid was significantly higher in the hypoalbuminemia group (Table 1).
Our investigations indicate that hypoalbuminemia after HES infusion in critically ill patients is associated with an increase of free fraction level of highly bound drugs to serum protein. Valproic acid is an acidic drug that is highly bound to albumin (90%). The free fraction variations are well known, in relation to age, gender, disease or drug association [4–6]. No difference was found between the two groups regarding factors influencing plasma protein binding. The ex vivo supplementation of the drug permits control of its concentration. However, this could be not reflected exactly with in vivo drug binding.
In conclusion, hydroxyethyl starches are responsible, through hypoalbuminemia, for an increase in the free fraction of highly bound drugs to serum protein. In vivo studies are required to confirm this result and to evaluate therapeutic implications.
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