title: Impact of hyperglycemia on neuropathological alterations during critical illness.
abstract: BACKGROUND
  Although preventing excessive hyperglycemia during critical illness may provide clinical neuroprotection, it remains debated whether normoglycemia is without risk for the brain.
  
  
  OBJECTIVE
  To address this question, we compared the neuropathological alterations in microglia, astrocytes, and neurons, with uncontrolled hyperglycemia, moderately controlled hyperglycemia, and normoglycemia during human critical illness. We further investigated the time course in an animal model.
  
  
  METHODS
  We analyzed brain specimens from patients who died in the intensive care unit and from critically ill rabbits randomized to hyper- or normoglycemia. PATIENTS/OTHER PARTICIPANTS: We compared 10 critically ill patients randomized to normoglycemia (104 ±9 mg/dl) or moderate hyperglycemia (173 ±32 mg/dl), and five patients with uncontrolled hyperglycemia (254 ±83 mg/dl) with 16 controls (out of hospital sudden deaths). Critically ill rabbits were randomized to hyperglycemia (315 ±32 mg/dl) or normoglycemia (85 ±13 mg/dl) and studied after 3 and 7 d.
  
  
  METHODS
  Insulin was infused to control blood glucose.
  
  
  RESULTS
  Patients with uncontrolled hyperglycemia showed 3.7-6-fold increased microglial activation, 54-95% reduced number and activation of astrocytes, more than 9-fold increased neuronal and glial apoptosis, and a 1.5-2-fold increase in damaged neurons in hippocampus and frontal cortex (all P ≤ 0.05). Most of these abnormalities were attenuated with moderate hyperglycemia and virtually absent with normoglycemia. Frontal cortex of hyperglycemic rabbits that had been critically ill for 3 d only revealed microglial activation, followed after 7 d by astrocyte and neuronal abnormalities similar to those observed in patients, all prevented by normoglycemia.
  
  
  CONCLUSIONS
  Preventing hyperglycemia with insulin during critical illness reduced neuropathological abnormalities, with microglial activation being the earliest preventable event. Whether these pathological findings associate with neurological outcome remains unknown.
authors.affiliation: Laboratory of Intensive Care Medicine, Katholieke Universiteit Leuven, Herestraat 49, B 3000 Leuven, Belgium.
authors.forename: Romain
authors.initials: R
authors.lastname: Sonneville
authors.forename: Heleen M
authors.initials: HM
authors.lastname: den Hertog
authors.forename: Fabian
authors.initials: F
authors.lastname: Güiza
authors.forename: Jan
authors.initials: J
authors.lastname: Gunst
authors.forename: Inge
authors.initials: I
authors.lastname: Derese
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Wouters
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Brouland
authors.forename: Andrea
authors.initials: A
authors.lastname: Polito
authors.forename: Françoise
authors.initials: F
authors.lastname: Gray
authors.forename: Fabrice
authors.initials: F
authors.lastname: Chrétien
authors.forename: Philippe
authors.initials: P
authors.lastname: Charlier
authors.forename: Djillali
authors.initials: D
authors.lastname: Annane
authors.forename: Tarek
authors.initials: T
authors.lastname: Sharshar
authors.forename: Greet
authors.initials: G
authors.lastname: Van den Berghe
authors.forename: Ilse
authors.initials: I
authors.lastname: Vanhorebeek
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001927:Brain Diseases / Q000401:mortality / Q000473:pathology / Q000517:prevention & control; D016638:Critical Illness / Q000401:mortality*; D004195:Disease Models, Animal; D005260:Female; D005625:Frontal Lobe / Q000473:pathology; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology*; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D011817:Rabbits; D012307:Risk Factors
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin