Hydroxyethyl starch does not cross the blood-brain or the placental barrier but the perineurium of peripheral nerves in infused animals

Therapy with hydroxyethyl starch (HES) is associated with a high incidence of persistent pruritus due to HES storage in cutaneous nerves. Up to now it has been unknown if HES also accumulates in the extracutaneous peripheral or central nervous system. To study this, five rats including one pregnant one were infused with a single dose (34-150 mg) of HES (70/200/450 kDa molecular weight) conjugated with fluorescein isothiocyanate (FITC). In addition, four sheep were infused with a cumulative dosage of 30 g, 120 g, and 420 g HES (200 kDa), respectively. After 7-13 days, biopsies from the adult rats, four fetal rats and sheep were taken from various organs. The specimens were analyzed by light, electron, and confocal laser scanning microscopy. Typical HES storage vacuoles were found in macrophages of the skin, liver, spleen, lung, and kidney. HES storage in healthy animals was not associated with signs of either inflammation or apoptosis contrary to a previously described animal hemorrhagic shock model. Beyond that, fetus biopsies did not show any storage phenomenon, confirming that HES does not cross the placental barrier. Deposits of HES could be detected in Schwann cells of cutaneous nerve fibers as well as in perineural and endoneural cells of sciatic nerve in one rat (HES 450 kDa) and three of four sheep. No HES storage was found in the central nervous system. Our findings clearly demonstrate that storage of HES is detectable only in small peripheral nerves, suggesting a cutaneous origin of the HES-induced pruritus.