title: Attenuation of propofol tolerance conferred by remifentanil co-administration does not reduce propofol toxicity in rabbits under prolonged mechanical ventilation.
abstract: BACKGROUND
  Prolonged sedation with propofol at high doses may lead to fatal multi-organ dysfunction, know as propofol infusion syndrome. We tested the hypothesis that propofol plus remifentanil co-administration attenuates propofol tolerance to its sedative effect and assessed if such an effect has an impact on propofol toxicity in rabbits under prolonged mechanical ventilation.
  
  
  METHODS
  Eighteen healthy male rabbits were mechanically ventilated and received propofol (group P, n = 6), propofol plus remifentanil (group PR, n = 6), or remifentanil plus sevoflurane (group RS, n = 6) in order to be kept under sedation (group P) or sedation/analgesia (groups PR and RS) for up to 48 h. Initial propofol and remifentanil infusion rates (IRs) were adjusted, if needed, to maintain the desired level of sedation and analgesia, respectively (groups P and PR). In group RS, remifentanil was infused at IRs equivalent to those of group PR. Propofol IRs were recorded, propofol concentrations were measured in the arterial plasma, and blood biochemical parameters and organ histopathology were assessed.
  
  
  RESULTS
  Animals survived for 29-36 h in group P and 22-38 h in group PR (100% mortality rate). Tolerance was developed to propofol's sedative effect. The onset of tolerance was delayed and its magnitude was decreased in group PR compared with group P. Propofol was accumulated in the systemic circulation. Propofol clearance rate was gradually decreased. Arterial lactate, and serum aspartate aminotransferase (AST), lactate dehydrogenase (LDH), bilirubin, cholesterol, triglycerides, and creatine kinase (CK) levels were increased. The heart, lungs, liver, gallbladder, kidneys, urinary bladder, and skeletal muscles were seriously injured in groups P and PR. In group RS, mortality was 0%, while there was only mild injury of the lungs, liver, gallbladder, kidneys, and urinary bladder.
  
  
  CONCLUSIONS
  Although propofol tolerance is attenuated in propofol plus remifentanil receiving rabbits under prolonged mechanical ventilation, fatal multi-organ injury occurs resembling human propofol infusion syndrome.
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: Maria
authors.initials: M
authors.lastname: Lambropoulou
authors.forename: Ioannis
authors.initials: I
authors.lastname: Bougioukas
authors.forename: Georgios
authors.initials: G
authors.lastname: Theodoridis
authors.forename: Christina
authors.initials: C
authors.lastname: Tsigalou
authors.forename: Constantinos
authors.initials: C
authors.lastname: Manolas
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Papadopoulos
authors.forename: Georgios
authors.initials: G
authors.lastname: Bougioukas
authors.forename: Constantinos
authors.initials: C
authors.lastname: Simopoulos
mesh_terms: D018685:Anesthetics, Inhalation / Q000008:administration & dosage; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D000818:Animals; D004347:Drug Interactions; D004361:Drug Tolerance; D005704:Gallbladder / Q000473:pathology; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D008297:Male; D008738:Methyl Ethers / Q000008:administration & dosage; D009102:Multiple Organ Failure / Q000139:chemically induced* / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D010880:Piperidines / Q000494:pharmacology*; D015742:Propofol / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D011817:Rabbits; D000077208:Remifentanil; D000077149:Sevoflurane; D001743:Urinary Bladder / Q000473:pathology
chemical_list: D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D008738:Methyl Ethers; D010880:Piperidines; D000077149:Sevoflurane; D000077208:Remifentanil; D015742:Propofol