title: Organ toxicity and mortality in propofol-sedated rabbits under prolonged mechanical ventilation.
abstract: BACKGROUND
  Prolonged administration of propofol at large doses has been implicated in propofol infusion syndrome in intensive care unit patients. In this study we investigated organ toxicity and mortality of propofol sedation at large doses in prolonged mechanically ventilated rabbits and determined the role of propofol's lipid vehicle.
  
  
  METHODS
  Eighteen healthy male rabbits were endotracheally intubated and sedated with propofol 2% (Group P), sevoflurane (Group S) or sevoflurane while receiving Intralipid 10% (Group SI). Sedation lasted 48 h or until death (Group P) or the maximum surviving period of Group P (Groups S and SI). The initial propofol infusion rate (20 mg x kg(-1) x h(-1)) or sevoflurane concentration (1.5%) was adjusted, if needed, to maintain a standard level of sedation. Blood biochemical analysis was performed in serial blood samples and histologic examination in the heart, lungs, liver, gallbladder, kidneys, urinary bladder, and quadriceps femoris muscle at autopsy.
  
  
  RESULTS
  The mortality rate was 100% (surviving period, 26-38 h) for Group P, whereas 0% for Groups S and SI. The initial propofol infusion rate had to be increased up to 65.7 +/- 4.6 mg x kg(-1) x h(-1) and sevoflurane concentration up to 4%. Serum liver function indices, lipids and creatine kinase were significantly increased (P < 0.05) in Groups P and SI and lactate was increased only in Group P, whereas amylase was increased in all groups. In Group P, histologic examination revealed myocarditis, pulmonary edema with interstitial pneumonia, hepatitis, steatosis, and focal liver necrosis, cholangitis, gallbladder necrosis, acute tubular necrosis of the kidneys, focal loss of the urinary bladder epithelium, and rhabdomyolysis of skeletal muscles; in Group S, low-grade bronchitis and incipient inflammation of the liver and the kidneys; and in Group SI, low-grade bronchitis, liver steatosis and hepatitis, and incipient inflammation of the gallbladder, kidneys, and urinary bladder.
  
  
  CONCLUSIONS
  Continuous infusion of 2% propofol at large doses for the sedation of rabbits undergoing prolonged mechanical ventilation induced fatal multiorgan dysfunction syndrome similar to the propofol infusion syndrome seen in humans. Our novel findings including lung, liver, gallbladder, and urinary bladder injury were also noted. The role of propofol's lipid vehicle in the manifestation of the syndrome was minor. Sevoflurane proved to be a safe alternative medication for prolonged sedation.
authors.affiliation: Laboratory of Experimental Surgery and Surgical Research, School of Medicine, Democritus University of Thrace, Alexandroupolis, Greece. pipsil@med.duth.gr
authors.forename: Petros
authors.initials: P
authors.lastname: Ypsilantis
authors.forename: Maria
authors.initials: M
authors.lastname: Politou
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Mikroulis
authors.forename: Michail
authors.initials: M
authors.lastname: Pitiakoudis
authors.forename: Maria
authors.initials: M
authors.lastname: Lambropoulou
authors.forename: Christina
authors.initials: C
authors.lastname: Tsigalou
authors.forename: Vasilios
authors.initials: V
authors.lastname: Didilis
authors.forename: Georgios
authors.initials: G
authors.lastname: Bougioukas
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Papadopoulos
authors.forename: Constantinos
authors.initials: C
authors.lastname: Manolas
authors.forename: Constantinos
authors.initials: C
authors.lastname: Simopoulos
mesh_terms: D000818:Animals; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D009102:Multiple Organ Failure / Q000139:chemically induced / Q000401:mortality*; D015742:Propofol / Q000008:administration & dosage / Q000633:toxicity*; D011817:Rabbits; D012121:Respiration, Artificial / Q000379:methods; D013997:Time Factors
chemical_list: D006993:Hypnotics and Sedatives; D015742:Propofol