title: Administration of tetrahydrobiopterin improves the microcirculation and outcome in an ovine model of septic shock.
abstract: OBJECTIVE
  Supplementation with tetrahydrobiopterin, a nitric oxide synthase cofactor, may reduce microvascular endothelial dysfunction in severe sepsis. We studied whether tetrahydrobiopterin administration exerts beneficial effects in an ovine septic shock model.
  
  
  METHODS
  Randomized animal study.
  
  
  METHODS
  University hospital animal research laboratory.
  
  
  METHODS
  Fourteen adult female sheep.
  
  
  METHODS
  Fecal peritonitis was induced, and the sheep were randomized to receive tetrahydrobiopterin (n=7), given intravenously as 20 mg/kg boluses at 4 and 12 hrs after sepsis induction, or placebo (n=7). All animals were fluid resuscitated. The experiment was continued until death or for a maximum of 30 hrs.
  
  
  RESULTS
  In addition to standard hemodynamic assessment, the sublingual microcirculation was evaluated using sidestream dark-field videomicroscopy. The first bolus of tetrahydrobiopterin blunted the increase in heart rate and cardiac index seen in the control group without affecting mean arterial pressure, and the second bolus of tetrahydrobiopterin prevented the decreases in cardiac index and mean arterial pressure. The reduction in mixed venous blood oxygen saturation and the increase in blood lactate seen in the control group were also delayed. Tetrahydrobiopterin significantly attenuated the deterioration in perfused small vessel proportion and density, microvascular flow index, and the increase in microvascular heterogeneity observed in the control group. Tetrahydrobiopterin was associated with better preserved lung compliance and PaO2/FIO2 ratio, which were associated with a lower lung wet/dry weight ratio at the end of the study. Median survival time was significantly prolonged in the tetrahydrobiopterin group (25.0 vs. 17.8 hrs, p<.01).
  
  
  CONCLUSIONS
  In this clinically relevant model of sepsis, tetrahydrobiopterin supplementation attenuated the impairment in sublingual microvascular perfusion and permeability, which was accompanied by better preserved gas exchange, renal flow and urine output, and prolonged survival.
authors: Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium.
authors: Xinrong
authors: X
authors: He
authors: Fuhong
authors: F
authors: Su
authors: Dimitrios
authors: D
authors: Velissaris
authors: Diamantino Ribeiro
authors: DR
authors: Salgado
authors: Dalton
authors: D
authors: de Souza Barros
authors: Sophie
authors: S
authors: Lorent
authors: Fabio Silvio
authors: FS
authors: Taccone
authors: Jean-Louis
authors: JL
authors: Vincent
authors: Daniel
authors: D
authors: De Backer
mesh_terms: D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D008833:Microcirculation / Q000187:drug effects*; D009060:Mouth Floor / Q000098:blood supply*; D010538:Peritonitis / Q000188:drug therapy / Q000401:mortality; D011659:Pulmonary Gas Exchange; D011897:Random Allocation; D012756:Sheep; D012772:Shock, Septic / Q000188:drug therapy* / Q000401:mortality
chemical_list: D001708:Biopterins; C003402:sapropterin