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From the *Laboratory of Experimental Surgery and Surgical Research and Thoracic and Cardiac Surgery Clinic, School of Medicine, Democritus University of Thrace, Alexandroupolis, Greece; Laboratory of Forensic Medicine and Toxicology, Medical School, and Laboratory of Analytical Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Address correspondence and reprint requests to Petros Ypsilantis, DVM, PhD, Laboratory of Experimental Surgery and Surgical Research, School of Medicine, University General Hospital of Alexandroupolis, Dragana, 68 100 Alexandroupolis, Greece. Address e-mail to pipsil{at}med.duth.gr.
Propofol is commonly used for the sedation of critically ill patients undergoing mechanical ventilation. These patients may develop tolerance during long-term administration. Here, we describe the development of tolerance to propofol’s sedative effect in rabbits during prolonged mechanical ventilation. Six healthy male New Zealand White rabbits were endotracheally intubated and received propofol by continuous IV infusion to maintain sedation for 48 h. The propofol infusion rate (IR) was adjusted to maintain the desired level of sedation. Assessments of the sedation level were made every 30 min or earlier if there were signs of awakening. Propofol concentrations were measured in arterial plasma after every other IR adjustment, provided there was an adequate level of sedation, using high performance liquid chromatography, and calculations of systemic clearance rates were made. The mortality rate was 100% with a survival period of 30.8 ± 6.0 h (mean ± sd). The course of IR adjustments followed a 5-phase pattern: 1) steady IR (mean ± sd duration; 1.2 ± 0.6 h), 2) increasing IR (9.4 ± 5.5 h), 3) steady high-IR (2.3 ± 1.2 h), 4) decreasing IR (13.7 ± 1.9 h), and 5) steady low-IR (5.0 ± 2.7 h). The course of propofol concentrations during the experiment in relation to propofol IR followed a 3-phase pattern: 1) steady concentration with increasing IRs (6.0 ± 2.7 h), 2) increasing concentrations with increasing IR (5.8 ± 2.5 h), and 3) increasing concentrations with decreasing IR (18.8 ± 3.3 h). Propofol systemic clearance rates were progressively increased for 6.0 ± 2.7 h and then gradually decreased for 24.6 ± 4.7 h. In conclusion, all rabbits developed tolerance to propofol’s sedative effect within the first hours of administration related to changes to the drug’s metabolic clearance.
This article has been cited by other articles:
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  P. Ypsilantis, M. Politou, D. Mikroulis, M. Pitiakoudis, M. Lambropoulou, C. Tsigalou, V. Didilis, G. Bougioukas, N. Papadopoulos, C. Manolas, et al. Organ Toxicity and Mortality in Propofol-Sedated Rabbits Under Prolonged Mechanical Ventilation Anesth. Analg., July 1, 2007; 105(1): 155 - 166. [Abstract] [Full Text] [PDF]
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