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Changes in Propofol Concentration in a Propofol-Lidocaine 9:1 Volume Mixture

2000; Lippincott Williams & Wilkins; Volume: 9; Issue: 4 Linguagem: Inglês

10.1097/00000539-200004000-00039

1526-7598

Yoko Masaki, Makoto Tanaka, Toshiaki Nishikawa,

Dental Anxiety and Anesthesia Techniques

Propofol (2,6-diisopropylphenol) is widely used for the induction and maintenance of anesthesia as well as for sedation of intensive care patients. However, a 30%–70% incidence of pain associated with IV injection is one important source of patient dissatisfaction (1). Although several methods for alleviating pain have been described (2), the addition of lidocaine is one of the most common methods in clinical practice. The manufacturer of propofol recommends administration of the propofol-lidocaine mixture immediately after preparation, without specifying any safety period. To date, the only published study regarding the compatibility of propofol and lidocaine dealt with changes in the microscopic appearance of emulsion after mixing and in the zeta potential of various combination doses (4). More importantly, the chemical stability of the propofol-lidocaine mixture has never been addressed. The characteristics of a colorless, liquid, separate layer that appears on the surface of the emulsion after the addition of lidocaine to propofol (5) suggest that it is propofol, per se. Accordingly, the purpose of our study was to test a hypothesis that propofol is dissociated as a immiscible layer after the addition of lidocaine and, as a consequence, propofol concentrations decrease in a time-dependent manner in the propofol-lidocaine mixture. We made serial determinations of propofol concentrations by gas chromatography (GC) for 24 h after the preparation of a clinically relevant combination dose of propofol and lidocaine. Methods Propofol and lidocaine were used in this study. After mixing 9 mL of propofol and 1 mL of lidocaine, the samples (0.8 mL) were divided into 11 glass vials and stored at room temperature (23°C). To detect the oil droplet on the surface of the mixture macroscopically, the vials were rotated gently and were centrifuged at 170 g for 1 min. After centrifugation, 100 μL of mixture was sampled to determine concentrations of propofol and lidocaine. Macroscopic changes and the drug concentrations were measured at 0, 10, 20, and 30 min, every 1 h for 6 h, and at 24 h. Propofol (1%), with no addition of lidocaine, was used as a control. To determine whether centrifugation procedure affects drug concentrations, propofol and lidocaine concentrations were separately measured without centrifugation at 6 and 24 h. Simultaneous analyses of propofol and lidocaine concentrations were performed by GC with thymol as the internal standard. To examine the oily layer, 2,6-diisopropylphenol was used as a standard. The GC apparatus (Model GC-6A; Shimadzu, Kyoto, Japan) with a flame ionization detector consisted of a packed column (glass 2 m, 3.2 mm internal diameter) and was connected with a SIC chromatocorder 12 (SIC instruments, Tokyo, Japan). The column was packed with chromosorb WAW DMCS 60/80 mesh coated with OV-17, 2% by weight (GL Science, Tokyo, Japan). The flow rates of nitrogen and hydrogen gases were 55 and 60 mL/min, respectively. Injector and detector temperature was 250°C. The oven temperature was held at 150°C for 2.5 min and was increased at 20°C/min for 7.5 min. In these conditions, thymol, propofol, and lidocaine elute at 1.49, 1.95, and 7.07 min, respectively. The extraction procedure was performed by modification of a single extraction procedure, as described by Guitton et al. (6). Briefly, a 100-μL sample and a 100-μL thymol (10 mg/mL) were made alkaline with 100 μL of 1N NaOH and were mixed with 1.0 mL distilled water and 3 mL of chloroform-ethyl acetate (70:30, vol/vol) on a vortex mixer for 5 min. After centrifugation at 400 g for 5 min at 10°C, 1 mL of organic layer was transferred to glass vials and dried under a nitrogen stream. After adding 100 μL af acetone, 0.5 μL was injected into the column of the GC system. The propofol and lidocaine calibration standards (9, 2 mg/mL, respectively) were analyzed by using the commercial formulation of 1% propofol and 2% lidocaine, and a response factor of calibration was obtained. The expected propofol concentrations at baseline with and without lidocaine were 0.9 and 1.0 mg/100 μL, respectively. With these methods, the minimum detectable concentration of propofol is 10-6 mg/100 μL. Within-run coefficient of variation is <0.5%, while coefficient of variation for the interday precision is <0.3%. All preparations were performed at room temperature, unless otherwise stated. All data were expressed as mean ± SD. Propofol and lidocaine concentrations over time were analyzed by repeated-measures analysis of variance and, if a significant difference was detected, followed by paired Student’s t-tests as a post hoc testing to analyze differences between at baseline and at each time interval. Differences in propofol values with and without lidocaine were analyzed by using unpaired Student’s t-tests. A P value <0.05 was considered to be statistically significant. Results A 9:1 volume mixture of 1% propofol and 2% lidocaine was macroscopically stable, i.e., neither precipitation nor oily droplets were observed for 1 h after the addition of lidocaine. Small, colorless, oily droplets were first seen on the surface of the mixture 2 h after the addition of lidocaine and became larger time-dependently. At 24 h, individual oil droplets aggregated into a single, large surface layer. No precipitation was observed in the bottom of the vials after centrifugation at any interval during the study. No evidence of macroscopic change in propofol emulsion without lidocaine was noted for 24 h. Propofol concentrations in the mixture were unchanged within 30 min, but they decreased linearly and significantly compared with baseline (Time 0, 0.87 ± 0.02 mg/100 μL) in a time-dependent manner from 1 (0.82 ± 0.02 mg/100 μL, P < 0.05) to 24 h (0.38 ± 0.06 mg/100 μL, P < 0.05) after preparation. Because concentrations of propofol without lidocaine were unchanged from baseline (Time 0, 0.96 ± 0.02 mg/100 μL) for 24 h, significant differences in percent concentrations of propofol were seen from 1 to 24 h between with and without lidocaine (Fig. 1). Propofol concentrations with and without centrifugation were 0.64 ± 0.03 and 0.66 ± 0.02 mg/100 μL at 6 h, and 0.38 ± 0.06 and 0.36 ± 0.02 mg/100 μL at 24 h after mixture with lidocaine, respectively; hence, propofol concentrations were unaffected by the centrifugation procedure. However, lidocaine concentrations in the mixture were unaltered (0.18–0.20 mg/100 μL) during the entire study period with or without centrifugation.Figure 1: Propofol concentration (mean ± SD) expressed as a percentage of baseline (Time 0) with (Propofol + Lidocaine) or without (Propofol) lidocaine. *P < 0.05 versus Time 0. †P < 0.05 versus Propofol at the corresponding interval.The oily surface layer of the mixture at 24 h after the addition of lidocaine was injected directly into the column of the GC system without extraction. Its retention time was consistent with 2,6-diisopropylphenol (Fig. 2). Furthermore, the droplet mixed with 2,6-diisopropylphenol showed a single peak at retention time of 1.95 min.Figure 2: Gas chromatograms of 2,6-diisopropylphenol (A), oily, surface layer of the mixture at 24 h after the addition of lidocaine to propofol (B), and 2,6-diisopropylphenol mixed with the surface layer (C).Discussion One of our major findings is the lack of significant changes in propofol and lidocaine concentrations in the propofol-lidocaine mixture within 30 minutes of preparation, whereas a time-dependent decrease in propofol concentrations was seen from 1 to 24 hours after preparation, although lidocaine concentrations were unchanged during this period. In addition, no macroscopic evidence of emulsion instability was present for one hour after the addition of lidocaine. These results suggest that the propofol-lidocaine mixture may be safely administered within 30 minutes of preparation without anticipating clinically important alterations in anesthetic and sedative efficacy of propofol. It should also be emphasized that long-term infusions of propofol-lidocaine mixtures should not be used beyond one hour, such as might be the case in intensive care settings, and that a new mixture should be made if needed. Our results also demonstrated that, after the addition of lidocaine, a significant amount of propofol is dissociated into a colorless, immiscible surface layer on the emulsion. The appearance of such a layer is in accordance with the study by Lilley et al. (4), who documented, but failed to identify, a similar surface layer 75 minutes after the addition of 40 mg lidocaine to 200 mg propofol and 90 minutes after the addition of 50 mg lidocaine. In their study, droplets of 2–3 μm were also observed under the light microscope after the addition of a smaller dose of lidocaine with a concomitant decrease in the absolute value of the zeta potential, an electrostatic repulsive force required to maintain emulsion stability. However, a time-dependent change in the quantity of this oily layer, either microscopically or macroscopically, has not been evaluated. It is clear from our results and from previous studies that the dissociation of propofol into a separate oily layer is a time-dependent reaction, i.e., small, oily droplets under the light microscope are finally aggregated into a separate surface layer visible to the human eye. Of note, droplet diameters greater than 5 μm may pose the risk of pulmonary embolism (7). Even though no complication, including pulmonary embolism after IV administrations of propofol-lidocaine, has been reported, adherence to the manufacturer’s recommendation is further emphasized. Moreover, because larger doses of lidocaine exert greater influences on the zeta potential (4), time courses of droplet sizes under the light microscope after the addition of various doses of lidocaine need to be evaluated to determine optimal safety periods between preparations and IV administrations of such mixtures. It is not clear whether dissociated propofol is originated from the aqueous or lipid phase of emulsion, because propofol in the aqueous phase was not separately determined in our study. Propofol per se is hardly water-soluble, and 0.19% (18.57 μg/mL) is dissolved in the aqueous phase (8), 21% of which migrates into the lipid phase by the addition of lidocaine (5). However, a decrease in the absolute value of the zeta potential after the addition of lidocaine results in emulsion instability and the formation of large droplets (4), suggesting that the dissociated propofol is primarily formed in the lipid phase. Apart from lidocaine, the clinical use of propofol-alfentanil mixture has been used to reduce pain on IV injection as well as to supplement analgesia to propofol-based anesthesia (9–11). Because chemical stability cannot be predicted from macroscopic changes in appearance of the mixture, further laboratory investigations are needed to examine the compatibility of the mixture and the chemical stability of either component before it is recommended for clinical use. In conclusion, a concentration of propofol in a 9:1 volume mixture of 1% propofol and 2% lidocaine remains stable for 30 minutes after preparation. However, the propofol concentration in the mixture continues to decrease linearly in a time-dependent fashion from 1 to 24 hours, with a concomitant dissociation of propofol as a separate, oily surface layer.