Propofol versus Propofol/Remifentanil for Deep Sedation in Prolonged Mechanically Ventilated Rabbits: Dose Requirements and Tolerance Development Preliminary Results
This project was designed to compare the dose requirements and the development of tolerance on the sedative/analgesic effect of propofol versus propofol plus remifentanil administered in rabbits under prolonged mechanical ventilation (PMV).
Eight male, clinically healthy New Zealand White rabbits were intubated under xylazine-ketamine-isoflurane anesthesia. After isoflurane discontinuation, the animals received either propofol (group P, n=4) or propofol plus remifentanil (group P/R, n=4) by continuous intravenous infusion for a maximum period of 38 hours. Arterial pressure (AP), heart rate (HR), respiratory rate (RR), electrocardiograph (ECG) and spO2 were continuously measured while arterial blood gases were analysed periodically. Initial doses were adjusted in order to achieve adequate level of sedation and analgesia based on reflexes, HR, arterial pressure and attempt for spontaneous breathing. Tolerance on the sedative/analgesic effect of the agents was indicated by the increase of their initial dose (ID). Statistics; data were expressed as means ± SD and were subjected to repeated measures ANOVA. The means were tested using the Student's t-test. Statistical significance if P<0.05.
The mortality rate was 100%. The animals survived for 36.3 ± 2.0 h (group P) or 36.8 ± 0.9 h (group P/R). Propofol ID was 0.33 ± 0.03 mg/kg/min (group P) or 0.36 ± 0.05 mg/kg/min (group P/R) and was increased up to 1.15 ± 0.12 mg/kg/min (group P) or 0.63 ± 0.05 mg/kg/min (group P/R). Maximal propofol dose in group P (264 ± 30 % of ID) was significantly higher than that in group P/R (95 ± 20% of ID) (P<0.001). The time from onset of infusion to 25, 50 and 100% ID increase was significantly lower in group P compared to group P/R (P<0.05) (1.8 ± 1.4 h vs 5.0 ± 0.4 h, 2.5 ± 1.7 h vs 7.3 ± 1.4 h, 3.0 ± 1.7 h vs 10.5 ± 0.4 h, respectively). Remifentanil ID was 0.19 ± 0.03 μg/kg/min and was increased up to 0.41± 0.02 μg/kg/min (120 ± 6 % of ID). A 25, 50 and 100% ID dose increase was noted at 6.0 ± 0.6 h, 8.3 ± 2.6 h and 10.0 ± 1.7 h from onset of infusion, respectively. In both groups, after a period of maximal dosing (propofol; 12.3 ± 0.9 h in group P, 13.5 ± 0.6 h in group P/R, remifentanil; 14 ± 1.2 h), adequate sedation/analgesia was achieved by administration of progressively decreasing doses down to 187 ± 72% of propofol ID in group P, 123 ± 43% of propofol ID in group P/R and 184 ± 58% of remifentanil ID.
In conclusion, both propofol and remifentanil lead to tolerance with regard to their sedative and analgesic effect in PMV rabbits within the first few hours. Although the concurrent administration of propofol with remifentanil does not affect the ID of propofol, it reduces the rate and delays the occurrence of its tolerance.