title: Thromboxane A2-receptor blockade improves cerebral protection for deep hypothermic circulatory arrest.
abstract: OBJECTIVE
  Following the use of deep hypothermic circulatory arrest in cardiac surgery, cerebral blood flow and cerebral oxygen metabolism are impaired. These may result from abnormal cerebral vasospasm. Powerful vasoconstrictors including endothelins and thromboxane A2 could mediate these processes. We investigated possible involvement of these two factors by assessing the effects of (a) phosphoramidon-an inhibitor of endothelin converting enzyme, and (b) vapiprost (GR32191B)-a specific thromboxane A2-receptor antagonist, on the recovery of cerebral blood flow and cerebral oxygen metabolism following deep hypothermic circulatory arrest.
  
  
  METHODS
  A total of 18 1-week-old piglets were randomised into three groups (n = 6 per group). At induction, the control group received saline; group PHOS received phosphoramidon 30 mg kg-1 intravenously. Group VAP received vapiprost 2 mg kg-1 at induction and at 30 min intervals thereafter. All groups underwent cardiopulmonary bypass cooling to 18 degrees C, exposed to 60 min of deep hypothermic circulatory arrest, rewarmed and reperfused for 1 h. Cerebral blood flow was measured with radio-labeled microspheres: cerebral oxygen metabolism was calculated at baseline before deep hypothermic circulatory arrest and at 1 h of reperfusion and rewarming.
  
  
  RESULTS
  In the control group, cerebral blood flow decreased to 40.2 +/- 2.0% of baseline after deep hypothermic circulatory arrest and cerebral oxygen metabolism decreased to 50.0 +/- 5.5% (P < 0.0005). The responses in group PHOS were similar. In group VAP, cerebral blood flow and cerebral oxygen metabolism were 64.3 +/- 10.6 and 80.1 +/- 9.8% of baseline, respectively, after deep hypothermic circulatory arrest. Thus, treatment with vapiprost significantly improved recovery of cerebral blood flow (P = 0.046) and cerebral oxygen metabolism (P = 0.020) following deep hypothermic circulatory arrest. No such improvement was seen after treatment with phosphoramidon.
  
  
  CONCLUSIONS
  Thromboxane A2 mediates impairments in cerebral perfusion and metabolism following deep hypothermic circulatory arrest. These changes were attenuated by blockade of thromboxane A2-receptors using vapiprost. Endothelins are not shown to be involved. Better knowledge of injury mechanisms will enable development of more effective cerebral protection strategies and allow safer application of deep hypothermic circulatory arrest.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Tsui
authors.forename: P M
authors.initials: PM
authors.lastname: Kirshbom
authors.forename: M J
authors.initials: MJ
authors.lastname: Davies
authors.forename: M T
authors.initials: MT
authors.lastname: Jacobs
authors.forename: F H
authors.initials: FH
authors.lastname: Kern
authors.forename: J W
authors.initials: JW
authors.lastname: Gaynor
authors.forename: W J
authors.initials: WJ
authors.lastname: Greeley
authors.forename: R M
authors.initials: RM
authors.lastname: Ungerleider
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D002315:Cardiopulmonary Bypass; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D016001:Confidence Intervals; D004195:Disease Models, Animal; D016232:Endothelins / Q000032:analysis / Q000096:biosynthesis; D006020:Glycopeptides / Q000494:pharmacology*; D006324:Heart Arrest, Induced; D006538:Heptanoic Acids / Q000494:pharmacology*; D007036:Hypothermia, Induced / Q000379:methods; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D010100:Oxygen / Q000097:blood / Q000378:metabolism; D011897:Random Allocation; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D012016:Reference Values; D013552:Swine; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D001713:Biphenyl Compounds; D016232:Endothelins; D006020:Glycopeptides; D006538:Heptanoic Acids; D017482:Receptors, Thromboxane; D008666:Metalloendopeptidases; C060013:vapiprost; D010100:Oxygen; C008890:phosphoramidon