title: Molecular weight and molar substitution are more important in HES-induced renal impairment than concentration after hemorrhagic and septic shock.
abstract: BACKGROUND
  Clinical studies have raised concerns about the safety of 6% hydroxyethylstarch (HES) 130/0.42, but the pathomechanisms of this renal impairment remain unknown. To evaluate the effects of different HES concentrations, molar substitutions and molecular weights in HES-induced renal impairment, we used a porcine two-hit model that combined haemorrhagic and septic shock.
  
  
  METHODS
  We conducted a prospective, randomised, double-blinded, controlled study in a university animal laboratory. Thirty anaesthetised and ventilated pigs were randomised to receive volume replacement therapy using 6% HES130/0.42, 6% HES200/0.5, 10% HES130/0.42 or 10% HES200/0.5, all dissolved in 0.9% NaCl rather than 0.9% NaCl alone. First, we bled the animals until they reached half of their baseline mean arterial pressure (MAP) for 45 minutes followed by fluid resuscitation. As a second hit, sepsis was induced using an Escherichia coli-laden clot 6 hours after haemorrhagic shock. Volume resuscitation started with a delay of two hours and a central venous pressure goal of 12 mmHg.
  
  
  RESULTS
  At the end of the study, the groups showed no difference in cardiac output or MAP, but the volume balance (mL/kg BW) was significantly higher in the 0.9% NaCl group (346±90; P≤0.05) than in the other groups (6% HES130, 125±26; 6% HES200, 105±15; 10% HES130, 114±17; 10% HES200, 96±23). Creatinine clearance (mL/min) was significantly lower in the 6% HES200 (26±33) and 10% HES200 (15±18) groups compared to the 0.9% NaCl group (104±46; P≤0.05) but not in the HES 130 formulations (6% HES130: 64±51; 10% HES130: 58±38) at the end of the study.
  
  
  CONCLUSIONS
  In this porcine two-hit shock model, treatment with 0.9% NaCl, HES 130/0.42 or HES 200/0.5 led to a similar maintenance of haemodynamic values. Despite this similar maintenance of the haemodynamic values, volume replacement with 6% and 10% HES 200/0.5 led to an accumulation of HES, higher colloid osmotic pressure and significantly reduced renal function after haemorrhagic and septic shock. These facts support the presumption that not the concentration but the degree of substitution and the molecular weight play a decisive role in HES-induced renal impairment.
authors.affiliation: Department of Intensive Care and Intermediate Care, RWTH University Hospital Aachen, Aachen, Germany - tsimon@ukaachen.de.
authors.forename: T P
authors.initials: TP
authors.lastname: Simon
authors.forename: C
authors.initials: C
authors.lastname: Thiele
authors.forename: T
authors.initials: T
authors.lastname: Schuerholz
authors.forename: M
authors.initials: M
authors.lastname: Fries
authors.forename: F
authors.initials: F
authors.lastname: Stadermann
authors.forename: G
authors.initials: G
authors.lastname: Haase
authors.forename: K U
authors.initials: KU
authors.lastname: Amann
authors.forename: G
authors.initials: G
authors.lastname: Marx
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006895:Hydroxyethyl Starch Derivatives / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D007674:Kidney Diseases / Q000139:chemically induced*; D007677:Kidney Function Tests; D008970:Molecular Weight; D010952:Plasma Substitutes / Q000009:adverse effects* / Q000737:chemistry* / Q000627:therapeutic use; D012771:Shock, Hemorrhagic / Q000188:drug therapy*; D012772:Shock, Septic / Q000188:drug therapy*; D013552:Swine
chemical_list: D006895:Hydroxyethyl Starch Derivatives; D010952:Plasma Substitutes; C517718:hydroxyethylstarch 200