Supplementary tables

Suppl. Table 1 PubMed search strategy

Search # / Query / Items found
#4 Combined final search / #1 AND #2 AND #3 / 700
#3
Publication types / “case reports” OR “classical article” OR “clinical conference” OR “clinical trial” OR “comparative study” OR “congresses” OR “controlled clinical trial” OR “English abstract” OR “evaluation studies” OR “in vitro” OR “journal article” OR “letter” OR “meta analysis” OR “multicenter study” OR “randomized controlled trial” OR “study characteristics” OR “technical report” OR “twin study” OR “validation studies” / 22,655,554
#2
Storage terms / “storage” OR" uptake" OR “lysosomal” OR “tissue” OR “stored” OR “accumulate” OR “accumulation” OR “deposit” OR “deposition” OR “osmotic nephrosis” / 1,979,598
#1
HES terms / “hydroxyethyl starch” OR “hydroxy ethyl starch” OR “hydroxy ethylstarch” OR “hydroxyethylstarch” OR “tetrastarch” OR “hexastarch”) OR hetastarch [MH] / 3,348

[MH], PubMed search tag denoting a Medical Subject Heading (MeSH) term, which automatically searches for that term and synonyms.

The searches were performed on 21 May 2013 and updated on 31 August 2013 and were not restricted by date or language.

Suppl. Table 2 Eligibility criteria applied during screening of titles/abstracts

Inclusion criteria / Exclusion criteria
Describes a study of HES administration in humans or animals / Not a study of HES administration in humans or animals HES administration mentioned only briefly (not a focus of the study) or not at all
Reports original data on whether or not HES accumulates in cells/tissues/organs / Does not report original data on whether or not HES accumulates in cells/tissues/organs Article reports only on other aspects of HES therapy (e.g., pharmacokinetics, effects on coagulation parameters, cellular activation/function, cryopreservation)
The article is a review, editorial, commentary, etc.

Suppl. Table 3 Animal studies of HES storage

Reference / n / Design / Species / Solution / Tissue distribution
Thompson et al 1970 [2] / 63 / NCS / rat and dog / HES 435 / Kidney: At 5 days, granules of water-soluble HES present in glomerular and tubular spaces. At 18 days, HES observed in macrophages and parenchymal cells. At 30-60 days, no histological evidence of HES or dextran in tissues
Lindblad and Falk 1976 [3] / 16 / NCS / rabbit / 6% HES 450/0.7 vs. 6% dextran 70 / Liver: Vascular abnormalities observed 5 months after HES. No pathology observed in rabbits that received dextran
Sadek et al 1989 [8] / 20 / NCS / rabbit / Labelled HES (MW 450 kDa) / Lymph: HES showed greater uptake into lymph nodes than dextran or human serum albumin
Parth et al 1992 [11] / 10 / NCS / Lewis rats, weight ~200 g / 10% HES 200/0.5 vs. 0.9% NaCl solution / Total organ morphology was not affected. Storage could be observed in most organs
Liver: Parenchymal cells – empty vacuoles. Spindle-shaped cells – granular structure and small intracytoplasmic vacuoles
Kidney: Only a few vacuolized cells could be observed
Skin: Cells with granular appearance could rarely be seen; mainly found in upper dermis
Lymph nodes: Intracellular storage observed in large reticular cells with varied sized vacuoles
Lung: Vacuolized cells with granular structures in alveolar epithelium, alveolar walls and interlobular septa
Hosgood et al 1993 [13] / 10 / NCS / dogs (6 female; 4 male) weight range 16.4-20.5 kg, mean 17.2 kg / DEF-HES vs. HES / Skin: DEF-HES but not HES grafts had perivascular aggregates of foamy macrophages in dermis and deep subcutaneous tissue
Standl et al 1993 [22] / 18 / RCT / dog / 6% HES 200/0.5 vs. polymerized hemoglobin / Kidney: Vacuolization of renal tubules in the HES 200/0.5 but not the polymerized hemoglobin group
Liver: No severe histological changes in either group
Ständer et al 2002 [30] / 9 / OS / rat and sheep / HES 70/0.02, HES 200/0.02, HES 200/0.5 and HES 450/0.02 / Liver, skin, spleen, lung and kidney: Storage vacuoles observed
Nerve: Deposits of HES in cutaneous fibres
Leuschner et al 2003 [31] / 48 / NCS / rats, aged 46-48 days, weight 167-205 g / Radiolabelled (14C) 10% HES 130/0.4 vs. 10% HES 200/0.5 / Mean total body HES radioactivity: HES 130/0.4 vs. HES 200/0.5 at: 3 days = 4.3% vs. 7.7%; 10 days = 2.0% vs. 4.0%; 24 days 1.4% vs. 2.9%; 52 days = 0.6% vs. 2.4%.
Liver: Organ with highest level of HES radioactivity. Significant difference between HES 130/0.4 vs. HES 200/0.5
Kidney: Evidence of radioactivity accumulation but to lower levels than liver/whole body
Spleen/Lymph: Lower accumulation of radioactive HES
Eisenbach et al 2007 [38] / 40 / RCT / pigs aged 12 weeks; weight 24-27 kg / Control vs. 6% HES 200/0.62 vs. 6% HES 200/0.5 vs. 6% HES 100/0.5 / Kidney: Storage of all three HES types; trend towards higher accumulation of HES 100/0.5 (not significant)
Liver: Storage of all three HES types; no significant difference due to high variations
Lung, spleen and lymph node: Lower accumulation of all three HES types compared with kidney and liver; lower retention of HES 200/0.5; no difference between HES 200/0.62 and HES 100/0.5
Brandt et al 2009 [43] / 48 / RCT / pigs; median weight 41 kg; experimental sepsis: endotoxin/fecal peritonitis/ control / 5 mL·kg-1·h-1 HES 130/0.4 + 15 mL·kg-1·h-1 RL vs. 10 mL·kg-1·h-1 RL / Kidney: Severe damage caused in 85% of high volume + endotoxin animals compared with only 30-40% in moderate volume
Liver: Histological abnormalities seen in all groups
Lung: Colloid plaques observed in all animals; most frequent in high-volume (84%) group compared with moderate-volume (59%) group
Hüter et al 2009 [45] / 12 / RCT / female pigs; mean weight 44.0 ± 4.6 kg / 10% HES 200/0.5 vs. 6% HES 130/0.42 vs. RL / Kidney: Osmotic nephrosis-like lesions of the tubuli present in all groups but lower in RL group. Macrophage infiltration higher in HES 200/0.5. Significant increase in interstitial cell proliferation in HES 200/0.5 group

Abbreviations: DEF-HES, deferoxamine-hydroxyethyl starch; HES, hydroxyethyl starch; NCS, nonrandomized controlled study; OS, observational study; RCT, randomized controlled trial; RL, Ringer’s lactate.

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