title: Effect of molecular weight and substitution on tissue uptake of hydroxyethyl starch: a meta-analysis of clinical studies.
abstract: BACKGROUND
  Intravenously infused hydroxyethyl starch (HES) can be found in urine, plasma and tissues. HES remaining in plasma and tissues is thought to increase the risk of clinical complications. HES solutions of lower molecular weight and substitution have been developed to increase urinary excretion and reduce plasma persistence. However, their effect on tissue uptake of HES has not been investigated in human subjects.
  
  
  OBJECTIVE
  Our objective was to test the hypothesis that lower molecular weight and substitution decrease tissue uptake of HES.
  
  
  METHODS
  Computer searches were performed of MEDLINE; EMBASE; the Cochrane Library; meeting abstract databases in surgery, anaesthesiology and intensive care; ClinicalTrials.gov; and Google. Supplementary sources were reference lists and electronic tables of journal contents. No time period or language restrictions were imposed.
  
  
  METHODS
  Clinical studies were eligible for inclusion in the meta-analysis, if data were reported both for cumulative urinary excretion of HES over 24 hours after infusion and for plasma HES concentration at 24 hours.
  
  
  METHODS
  Data were extracted on 24-hour urinary excretion of HES, 24-hour HES plasma concentration, plasma volume, HES molecular weight and substitution, study design, type and demographics of subjects, indication for fluid infusion, and HES infusion regimen. Tissue uptake of HES was computed as the difference between the infused dose and the sum of urinary excretion and residual plasma HES at 24 hours.
  
  
  RESULTS
  Twenty-five clinical studies totalling 287 subjects were included. Tissue uptake of low-molecular-weight HES (≤200 kD) was 42.3% (95% confidence interval [CI] 39.6, 45.0) compared with 24.6% (CI 17.8, 31.4) for high-molecular-weight HES (p < 0.001). Similarly, tissue uptake of lower-substitution HES (≤0.5) was 42.4% (CI 39.5, 45.3) versus 26.6% (CI 19.6, 33.6) for higher-substitution HES (p < 0.001). Among the three most often investigated single HES solutions, tissue uptake of 130/0.4 (42.6%; CI 35.0, 50.2) and HES 200/0.5 (43.3%; CI 39.4, 47.2) closely coincided, whereas uptake of HES 450/0.7 (22.2%; CI 14.8, 29.6) was lower (p = 0.001 and p < 0.001, respectively).
  
  
  CONCLUSIONS
  This meta-analysis did not support the hypothesis that lower molecular weight and substitution decrease tissue uptake of HES. Further clinical studies of HES tissue uptake are needed.
authors.affiliation: Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Romuald
authors.initials: R
authors.lastname: Bellmann
authors.forename: Clemens
authors.initials: C
authors.lastname: Feistritzer
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Wiedermann
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D006801:Humans; D006895:Hydroxyethyl Starch Derivatives / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008970:Molecular Weight; D010952:Plasma Substitutes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D006895:Hydroxyethyl Starch Derivatives; D010952:Plasma Substitutes