Accumulation of hydroxyethyl starch in human and animal tissues: a systematic review

Abstract

Purpose: To systematically review clinical and preclinical data on hydroxyethyl starch (HES) tissue storage.

Methods: MEDLINE (PubMed) was searched and abstracts were screened using defined criteria to identify articles containing original data on HES tissue accumulation.

Results: Forty-eight studies were included: 37 human studies with a total of 635 patients and 11 animal studies. The most frequent indication for fluid infusion was surgery accounting for 282 patients (45.9%). HES localization in skin was shown by 17 studies, in kidney by 12, in liver by 8, and in bone marrow by 5. Additional sites of HES deposition were lymph nodes, spleen, lung, pancreas, intestine, muscle, trophoblast, and placental stroma. Among major organs the highest measured tissue concentration of HES was in the kidney. HES uptake into intracellular vacuoles was observed by 30 min after infusion. Storage was cumulative, increasing in proportion to dose, although in 15% of patients storage and associated symptoms were demonstrated at the lowest cumulative doses (0.4 g kg(-1)). Some HES deposits were extremely long-lasting, persisting for 8 years or more in skin and 10 years in kidney. Pruritus associated with HES storage was described in 17 studies and renal dysfunction in ten studies. In one included randomized trial, HES infusion produced osmotic nephrosis-like lesions indicative of HES storage (p = 0.01) and also increased the need for renal replacement therapy (odds ratio, 9.50; 95% confidence interval, 1.09-82.7; p = 0.02). The tissue distribution of HES was generally similar in animals and humans.

Conclusions: Tissue storage of HES is widespread, rapid, cumulative, frequently long-lasting, and potentially harmful.

Fig. 1

Process of study selection

Fig. 2

Percentages of patients with moderate to heavy vacuolization of dermal histiocytes as a function of cumulative HES dose in a study of 115 patients receiving assorted HES solutions for otologic disorder, surgery, and other indications [29]. HES hydroxyethyl starch

Fig. 3

Electron micrograph of osmotic nephrosis persisting 6 months after the development of acute kidney injury in a patient with septic shock who had received 6 % HES 130/0.4 at a cumulative dose of 4.9 g kg⁻¹ [44]. Severe renal insufficiency continued ≥3 years after HES 130/0.4 exposure. HES hydroxyethyl starch

Fig. 4

Severe hyperplasia and hypertrophy of foamy portal macrophages and Kupffer cells and swelling of hepatocytes (top) and heavy infiltration of bone marrow with foamy cell degenerated macrophages, which accounted for approximately 50 % of nucleated cells, and marked depletion of fat cells (bottom) in a trauma patient who developed persistent thrombocytopenia and liver dysfunction and died after a 17.1 g kg⁻¹ cumulative dose of 6 % HES 130/0.4 and 6 and 10 % HES 200/0.5 [37]. HES hydroxyethyl starch