title: Critical illness is associated with low circulating concentrations of insulin-like growth factors-I and -II, alterations in insulin-like growth factor binding proteins, and induction of an insulin-like growth factor binding protein 3 protease.
abstract: OBJECTIVE
  To describe the sequential changes in the circulating concentrations of insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding proteins in critically ill patients. To determine whether critical illness is associated with induction of a specific protease directed against insulin-like growth factor binding protein 3 and to relate these changes to outcome.
  
  
  METHODS
  Prospective, descriptive study.
  
  
  METHODS
  Intensive care unit (ICU) of a university hospital.
  
  
  METHODS
  Eighteen heterogeneous critically ill patients, requiring ventilatory support.
  
  
  METHODS
  Serial daily blood samples were collected until death or discharge from the ICU. In five patients, samples were also obtained on the ward before discharge from the hospital.
  
  
  RESULTS
  Serum concentrations of insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding proteins 1, 2, and 3 were measured by radioimmunoassay. After 5 days, insulin-like growth factor binding protein 3 concentrations were measured on alternate days. Alterations in binding of insulin-like growth factor-I to insulin-like growth factor binding protein 3 and the presence of protease activity directed against insulin-like growth factor binding protein 3 were investigated by Western ligand blotting. Circulating concentrations of insulin-like growth factor-I and insulin-like growth factor-II were low and remained low throughout the 7-day study period. Insulin-like growth factor binding protein 1 concentrations were initially increased to within the fasting range, but subsequently decreased. There was considerable variability in insulin-like growth factor binding protein 2 concentrations, but generally, concentrations were at the upper end of the normal range throughout. Insulin-like growth factor binding protein 3 concentrations were consistently low and Western ligand blotting at the nadir of the insulin-like growth factor-I concentration demonstrated the presence of a protease directed against insulin-like growth factor binding protein 3. The last recorded concentrations of insulin-like growth factor-I and insulin-like growth factor binding protein 3 were higher in survivors than in nonsurvivors (p < .05). Two patients were also studied for a prolonged period. In one patient, a survivor, insulin-like growth factor-I and insulin-like growth factor binding protein 3 were low initially, but later increased in association with recovery and cessation of protease activity over a period of 33 days. In another patient, a nonsurvivor, insulin-like growth factor-I and insulin-like growth factor binding protein 3 remained low and protease activity persisted until the patient died 38 days after admission to the ICU.
  
  
  CONCLUSIONS
  Critical illness is associated with low circulating concentrations of insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding protein 3 and these low values are associated with induction of protease activity specifically directed against insulin-like growth factor binding protein 3. In survivors, recovery is associated with increasing insulin-like growth factor-I and insulin-like growth factor binding protein 3 concentrations and cessation of protease activity. The therapeutic effects of exogenous growth factors are likely to be influenced by these changes.
authors.affiliation: Department of Intensive Care, St. Bartholomew's Hospital, London, UK.
authors.forename: A C
authors.initials: AC
authors.lastname: Timmins
authors.forename: A M
authors.initials: AM
authors.lastname: Cotterill
authors.forename: S C
authors.initials: SC
authors.lastname: Hughes
authors.forename: J M
authors.initials: JM
authors.lastname: Holly
authors.forename: R J
authors.initials: RJ
authors.lastname: Ross
authors.forename: W
authors.initials: W
authors.lastname: Blum
authors.forename: C J
authors.initials: CJ
authors.lastname: Hinds
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016638:Critical Illness; D010450:Endopeptidases / Q000097:blood*; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D007362:Intensive Care Units; D008111:Liver Function Tests; D008875:Middle Aged; D011446:Prospective Studies; D011863:Radioimmunoassay
chemical_list: D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D010450:Endopeptidases; C080473:insulin-like growth factor binding protein-3 protease