Organ Toxicity and Mortality in Propofol-Sedated Rabbits Under Prolonged Mechanical Ventilation Petros Ypsilantis, DVM, PhD*# Maria Politou, MD*# Dimitrios Mikroulis, MD, PhD† Michail Pitiakoudis, MD, PhD* Maria Lambropoulou, MD, PhD‡ Christina Tsigalou, MD§ Vasilios Didilis, MD, PhD† Georgios Bougioukas, MD, PhD† Nikolaos Papadopoulos, MD, PhD‡ Constantinos Manolas, MD, PhD Constantinos Simopoulos, MD, PhD* BACKGROUND: Prolonged administration of propofol at large doses has been impli- cated 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  kg -1  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  kg -1  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 pneumo- nia, hepatitis, steatosis, and focal liver necrosis, cholangitis, gallbladder necro- sis, 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. (Anesth Analg 2007;105:155–66) The hypnotic drug propofol (2,6-diisopropylphenol) has been routinely used in the intensive care unit (ICU) for the sedation of critically ill patients. Al- though it has been considered a safe sedative in adults, the administration of propofol in children at large doses for more than 48 h has been implicated in the, usually fatal, propofol infusion syndrome (PRIS) (1–3). Propofol is thus no longer approved for pro- longed sedation of pediatric patients (4). PRIS has also been described in critically ill adults undergoing large- dose propofol sedation for more than 48 h (3,5–7). The main features of PRIS are cardiac failure, rhabdomy- olysis, severe metabolic acidosis, and renal failure (3), and it has been described from a limited number of case reports based mainly on clinical signs and blood biochemistry, whereas less on histopathologic find- ings after biopsy or necropsy. Propofol is commercially formulated in an oil-in- water emulsion. Long-term propofol infusions have been associated with serum lipid increases, which may lead to lipid deposition (8). Lipemia itself can impair mitochondrial oxygen uptake and precipitate problems of oxygen utilization which are considered key pathogenic mechanisms of PRIS (3). Different propofol formulations (1%, 2%, and 6%) have been From the *Laboratory of Experimental Surgery and Surgical Research, †Cardiothoracic Surgery Clinic, ‡Laboratory of Histology and Embryology, and First Clinic of Surgery, School of Medicine, Democritus University of Thrace, Alexandroupolis, Greece; and §Laboratory of Biochemistry, University General Hospital of Alex- androupolis, Alexandroupolis, Greece. #These authors contributed equally to this work. Accepted for publication March 19, 2007. Supported by Laboratory of Experimental Surgery and Surgical Research, School of Medicine, Democritus University of Thrace, Alexandroupolis, Greece. Address correspondence and reprint requests to Petros Ypsilantis, DVM, PhD, Laboratory of Experimental Surgery and Surgical Re- search, University General Hospital of Alexandroupolis, Dragana 68100 Alexandroupolis, Greece. Address e-mail to pipsil@med.duth.gr. Copyright © 2007 International Anesthesia Research Society DOI: 10.1213/01.ane.0000265544.44948.0b Vol. 105, No. 1, July 2007 155