title: Flutamide fails to reduce resuscitation requirements in a porcine ischemia-reperfusion model.
abstract: BACKGROUND
  Hemorrhagic shock and subsequent resuscitation can lead to ischemia-reperfusion injury, followed by multiorgan failure and death. Flutamide, a vasoactive nonsteroidal antiandrogen compound, is thought to improve tissue and organ perfusion. We tested whether administration of flutamide-cyclodextrin (FLU-CYD) alters physiologic parameters or resuscitation requirements in a porcine model of severe acidosis and shock secondary to combined hemorrhage + ischemia-reperfusion injury.
  
  
  METHODS
  Fifteen male pigs underwent a 35% blood-volume hemorrhage. Ischemia was induced by cross-clamping the supraceliac aorta for 50 min followed by reperfusion and resuscitation. FLU-CYD complex was administered during aortic clamping. Fluid resuscitation and epinephrine were titrated by protocol to maintain mean arterial pressure ≥40 mm Hg for 6 h. Sequential laboratory results were obtained and serum levels of FLU and 2-hydroxy-flutamide (FLUOH) were measured by mass spectrometry.
  
  
  RESULTS
  Mean requirements for injured control swine were 14.6 (± 1.21 standard error of the mean [SEM]) L crystalloid saline and 0.59 (± 0.29 SEM) g epinephrine, compared with 16.30 (± 1.33 SEM) L and 0.54 (± 0.16 SEM) g, respectively, in the FLU-CYD group (both P > 0.05). There were no significant differences in central hemodynamics between control and experimental groups. No significant differences for pH, bicarbonate, fibrinogen, or international normalized ratio were evident. FLU-CYD resuscitation was associated with a significant increase in lactate levels compared with controls (10.1 versus 5.7 mmol/L, P < 0.05). Histologic injury was significantly increased in the livers of FLU-CYD compared with sham (P = 0.022). High serum levels of FLU and the active metabolite FLUOH were measurable throughout the resuscitation period.
  
  
  CONCLUSIONS
  Flutamide failed to show any benefit to resuscitation in a model of severe injury and was associated with increased acidosis, hemodilution, and liver injury compared with standard crystalloid resuscitation.
authors.affiliation: Department of Surgery, Madigan Healthcare System, Tacoma, Washington 98431, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Satterly
authors.forename: Matthew
authors.initials: M
authors.lastname: Martin
authors.forename: Mark
authors.initials: M
authors.lastname: Wingerd
authors.forename: James
authors.initials: J
authors.lastname: Hempel
authors.forename: Zach
authors.initials: Z
authors.lastname: Hoffer
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Stallings
mesh_terms: D000138:Acidosis / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D000077324:Crystalloid Solutions; D003505:Cyclodextrins / Q000494:pharmacology; D004195:Disease Models, Animal; D005485:Flutamide / Q000494:pharmacology*; D006438:Hemodilution / Q000379:methods; D007552:Isotonic Solutions / Q000494:pharmacology; D019344:Lactic Acid / Q000097:blood; D008297:Male; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D012151:Resuscitation / Q000379:methods; D012771:Shock, Hemorrhagic / Q000150:complications* / Q000503:physiopathology; D034421:Sus scrofa; D017211:Treatment Failure
chemical_list: D000726:Androgen Antagonists; D000077324:Crystalloid Solutions; D003505:Cyclodextrins; D007552:Isotonic Solutions; D019344:Lactic Acid; D005485:Flutamide
keywords: Acidosis; Flutamide; Hemorrhage; Ischemia-reperfusion; Lactic acid; Resuscitation; Trauma