title: Profound hypothermia protects neurons and astrocytes, and preserves cognitive functions in a Swine model of lethal hemorrhage.
abstract: BACKGROUND
  Lethal injuries can be repaired under asanguineous hypothermic arrest (suspended animation) with excellent survival. This experiment was designed to test the impact of this strategy on neuronal and astroglial damage in a swine model of lethal hemorrhage. Furthermore, our goal was to correlate the histological changes in the brain with neurological outcome, and the levels of circulating brain specific markers.
  
  
  METHODS
  Uncontrolled hemorrhage was induced in 32 female swine (80-120 lbs) by creating an iliac artery and vein injury, followed 30 min later by laceration of the thoracic aorta. Through a thoracotomy approach, organ preservation fluid was infused into the aorta using a roller pump. Experimental groups included normothermic controls (no cooling, NC), and groups where hypothermia was induced at three different rates: 0.5 degrees C/min (slow, SC), 1 degrees C/min (medium, MC), or 2 degrees C/min (fast, FC). Profound hypothermia (core temperature of 10 degrees C) was maintained for 60 min for repair of vascular injuries, after which the animals were re-warmed (0.5 degrees C/min) and resuscitated on cardiopulmonary bypass (CPB). Circulating levels of neuron specific enolase (NSE) and S-100beta were serially measured as markers of damage to neurons and astrocytes, respectively. Light microscopy and quantitative immunohistochemical techniques were used to evaluate hippocampal CA1 area and caudate putamen for neuronal injury and astrogliosis (astrocyte hyperplasia/hypertrophy). Surviving animals were observed for 6 weeks and neurological status was documented on an objective scale, and cognitive functions were evaluated using a technique based upon the concept of operant conditioning.
  
  
  RESULTS
  Normothermic arrest resulted in clinical brain death in all of the animals. None of the surviving hypothermic animals displayed any neurological deficits or cognitive impairment. On histological examination, normothermic animals were found to have ischemic changes in the neurons and astrocytes (hypertrophy). In contrast, all of the hypothermic animals had histologically normal brains. The circulating levels of brain specific proteins did not correlate with the degree of brain damage. The changes in NSE levels were not statistically significant, whereas S-100beta increased in the circulation after CPB, largely independent of the temperature modulation.
  
  
  CONCLUSIONS
  Profound hypothermia can preserve viability of neurons and astrocytes during prolonged periods of cerebral hypoxia. This approach is associated with excellent cognitive and neurological outcome following severe shock. Circulating markers of central nervous system injury did not correlate with the actual degree of brain damage in this model.
authors.affiliation: Trauma Research and Readiness Institute for Surgery, Bethesda, Maryland, USA. halam@usuhs.mil
authors.forename: Hasan B
authors.initials: HB
authors.lastname: Alam
authors.forename: Zhang
authors.initials: Z
authors.lastname: Chen
authors.forename: Naresh
authors.initials: N
authors.lastname: Ahuja
authors.forename: Huazhen
authors.initials: H
authors.lastname: Chen
authors.forename: Richard
authors.initials: R
authors.lastname: Conran
authors.forename: Eduardo C
authors.initials: EC
authors.lastname: Ayuste
authors.forename: Kevin
authors.initials: K
authors.lastname: Toruno
authors.forename: Nanna
authors.initials: N
authors.lastname: Ariaban
authors.forename: Peter
authors.initials: P
authors.lastname: Rhee
authors.forename: Amal
authors.initials: A
authors.lastname: Nadel
authors.forename: Elena
authors.initials: E
authors.lastname: Koustova
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology; D002315:Cardiopulmonary Bypass; D002470:Cell Survival; D003071:Cognition; D005260:Female; D006324:Heart Arrest, Induced; D006470:Hemorrhage / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology / Q000601:surgery*; D006624:Hippocampus / Q000473:pathology; D006984:Hypertrophy; D007036:Hypothermia, Induced / Q000379:methods*; D007150:Immunohistochemistry; D009420:Nervous System / Q000503:physiopathology; D009474:Neurons / Q000473:pathology; D020033:Protein Isoforms / Q000097:blood; D009418:S100 Proteins / Q000097:blood; D012720:Severity of Illness Index; D013552:Swine
chemical_list: D020033:Protein Isoforms; D009418:S100 Proteins