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Department of Anesthesiology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan
Address correspondence and reprint requests to Michiaki Yamakage, MD, PhD, Department of Anesthesiology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan. Address e-mail to yamakage{at}sapmed.ac.jp.
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Abstract |
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Introduction |
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Since 1995, propofol in an emulsion of 50% medium-chain triglyceride (MCT) and 50% LCT (propofol MCT/LCT) (Propofol Lipuro® 1%; B. Braun Melsungen AG, Melsungen, Germany) has been used clinically, especially in Europe and Japan (13). Although changing the composition of the carrier fat emulsion does not have an impact on the pharmacokinetics and efficacy of propofol (14), propofol MCT/LCT provides better patient acceptance by decreasing the incidence of moderate and severe pain on injection (14–17). This could be because that propofol MCT/LCT has a significantly smaller concentration of free propofol (14 µg/mL) than that in propofol LCT (13,16). It has also been shown that the use of lidocaine resulted in a significant reduction in the incidence and intensity of pain on injection of propofol MCT/LCT (13,15). To understand how these techniques reduce pain on injection, it is important to investigate their effects on the concentrations of free propofol in aqueous phases.
A high-performance liquid chromatography (HPLC) technique (18) was used in the present study to determine the concentrations of free propofol in aqueous phases of propofol LCT and propofol MCT/LCT after changing pH or temperature and after mixing with lidocaine.
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Methods |
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In the first series of experiments, 1.5 mL of 2% lidocaine [pH 6.40 ± 0.01 (mean ± sd, n = 5)] was added to and mixed with 15 mL of propofol LCT or propofol MCT/LCT (pH 7.51 ± 0.03 and 7.43 ± 0.02, respectively). The pH of the mixed propofol products (6.00 ± 0.01 and 5.97 ± 0.00, respectively) was decreased significantly. In the second series of experiments, the pH of each propofol product was changed by adding 10% (vol/vol) 5% dextrose in Ringer’s acetate solution (pH 5.30 ± 0.01). The pH of propofol LCT and propofol MCT/LCT was significantly decreased to 6.29 ± 0.02 and 6.64 ± 0.01, respectively. pH was measured at 20°C. In the last series of experiments, in which temperature was changed (4°, 20°, and 36°C), propofol products per se were used for dialysis. The pH of the propofol products propofol LCT and propofol MCT/LCT was 7.36 ± 0.01 and 7.50 ± 0.00 at 4°C, and 7.49 ± 0.03 and 7.64 ± 0.04 at 36°C, respectively.
We prepared each five samples for each experiment to measure pH and the concentration of free propofol. The volumes of lidocaine and Ringer’s acetated solution and the temperature changes in propofol products tested in this study were decided based on the optimal doses and changes to reduce the pain on injection reported in previous studies (5–12).
The propofol preparations were dialyzed using a Dialysis-Cup (cut-off molecular weight: approximately 3500–4000) in a set of 3 chambers. A solution of 2.5% (wt/vol) glycerol in water was used as a receptor medium. In the first and second series of experiments, 10% (vol/vol) 2% lidocaine and 10% (vol/vol) 5% dextrose in Ringer’s acetate solution were respectively added to the glycerol solution to adjust the osmolarity for membrane transition, and dialysis was performed at 20°C for 24 h. In the last series of experiments, dialysis was performed for 24 h at different environmental temperatures by the use of temperature-controlled incubators, MIR-553 (SANYO Electric Co., Osaka, Japan) for 4° and 20°C and LH-20 (NAGANO SCIENCE Co., Osaka, Japan) for 36°C. In a preliminary study, the propofol content in the receptor medium was found to be saturated after 16 h incubation (data not shown, n = 3 each).
The receptor medium was analyzed using HPLC according to Bailey et al.’s technique (18). Briefly, samples were analyzed by HPLC using a Nucleosil 120 (C18, 3 µm, 120 x 4.6 mm) column at a column temperature of 40°C and with detection at a wavelength of 220 nm. Mobile phase A consisted of a mixture of acetonitrile (50% vol/vol). Flow rate was 1.5 mL/min. Magnitude of the limit of detection and precision of the dosages were 0.50 and 0.01 µg/mL, respectively.
Values were expressed as mean ± sd. Differences in measured concentrations between the two groups and among the three groups were compared using the unpaired two-tailed t-test and one-way analysis of variance with Fisher’s a posteriori post hoc test, respectively. In all comparisons, P < 0.05 was considered significant.
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Results |
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Even though the pH of both lidocaine-mixed propofol products, propofol LCT and propofol MCT/LCT, were significantly decreased, the concentration of free propofol in propofol LCT did not change (14.70 ± 0.09 µg/mL) and that in propofol MCT/LCT decreased (9.43 ± 0.33 µg/mL) by 9%.
When the pH was changed by adding dextrose in Ringer’s acetate solution, the concentrations of free propofol in propofol LCT and propofol MCT/LCT were significantly decreased (13.25 ± 0.54 and 8.34 ± 0.48 µg/mL, respectively) by 10% and 20%, respectively.
When the temperature of the propofol products was decreased to 4°C, the concentration of free propofol in propofol LCT (16.60 ± 0.29 µg/mL) significantly increased by 12% and that in propofol MCT/LCT (9.59 ± 0.14 µg/mL) slightly but significantly decreased by 8%. Conversely, the concentrations of free propofol in propofol LCT and propofol MCT/LCT (10.96 ± 0.48 and 8.18 ± 0.21 µg/mL, respectively) were significantly decreased, by 26% and 21%, respectively, by increasing the temperature of the propofol products to 36°C.
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Discussion |
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Because free propofol in an aqueous phase is thought to be the cause of pain on injection of propofol (3), the results of this study showing that the concentration of free propofol is significantly smaller in propofol MCT/LCT than in propofol LCT are consistent with previously reported suggestions that the use of propofol MCT/LCT reduces the incidence and intensity of pain on injection (14–17). This is also supported by results of recent studies showing that the use of Ampofol, 1% propofol with a half concentration of LCT (5%), resulted in an increase in the concentration of free propofol in an aqueous phase and increases in the incidence and intensity of pain on injection (19).
Eriksson et al. (12) reported that the pH of 1% propofol LCT decreased from 7.97–8.02 to 6.32 and that the concentration of free propofol decreased by 21% after mixing with 1% lidocaine, resulting in the reduction of incidence and intensity of pain on injection. Although we observed significant decreases in the pH of both propofol products after mixing with lidocaine in this study, mainly because of its acidity, mixing lidocaine with propofol products in this study had little effect on the concentrations of free propofol in either propofol LCT (reduction by 1%) or propofol MCT/LCT (reduction by 9%). This is thought to be, in part, attributable to the changes in emulsion stability that can occur after the common practice of adding lidocaine to propofol to reduce pain on injection (8,9). It took at least 12 hours to dialyze free propofol appropriately in this study, and the instability of the fat emulsion depends on incubation time with lidocaine (8,9). Further studies are needed to clarify this point. Nevertheless, a significant reduction of incidence and intensity of pain on injection by mixing lidocaine with propofol can be clearly observed in clinical use (5–7). The potential mechanism of propofol-induced pain on injection is thought to be activation of the plasma kallikrein-kinin system via direct contact between aqueous-phase free propofol and free nerve endings of vessels (20). Therefore, the reason why lidocaine works favorably is that it can inhibit pain transmission via the free nerve endings of vessels. This speculation is supported by the fact that IV lidocaine given just before propofol injection is also effective for reducing pain on injection (21,22).
Adding 5% dextrose in acetated Ringer’s solution to the propofol products in this study significantly decreased the pH of the propofol products as did lidocaine. Contrary to the findings in the lidocaine study, the concentrations of free propofol in propofol LCT and propofol MCT/LCT significantly decreased by 10% and 20%, respectively. These data are consistent with data reported previously (12), and this seems to be the reason why mixing 5% dextrose in acetated Ringer’s solution can decrease the incidence and intensity of pain on injection (12). However, there is no evidence that a decrease in pH can affect the instability of propofol emulsion seen in lidocaine (8,9).
Even though there is evidence that the number of patients who experienced pain and the severity of the pain were reduced significantly when propofol was administered at a temperature of 4°C (11), the concentration of free propofol in an aqueous phase in propofol MCT/LCT showed almost no change, but that in propofol LCT slightly increased. This would be because cold injection into a vein inhibits the activity of the kallikrein-kinin system and/or inhibits pain transmission via free nerve endings. Conversely, warming propofol to body temperature significantly decreased the concentration of free propofol in both propofol products in this study. This might be the main reason for the previously reported decrease in incidence and intensity of pain on injection without the addition of other drugs (10). However, a warm environment can induce rapid growth of pathogenic microorganisms contaminating propofol products, especially propofol MCT/LCT without disodium edetate as a bacteriostatic (23,24). Therefore, it is recommended to cool propofol products before use to reduce the incidence and intensity of pain on injection (11) as well as to suppress bacterial growth before injection (25). Furthermore, the changes in concentrations of free propofol seem to have no effect on pharmacokinetics and pharmacodynamics in the range observed in this study (14–17).
In conclusion, neither mixing lidocaine with propofol nor cooling it can decease the concentrations of free propofol in an aqueous phase in propofol products, but the concentrations can be decreased by a decrease in pH or by an increase in temperature. Because mixing lidocaine can induce instability of an emulsion of a propofol product and warming of a propofol product can rapidly induce microbial growth, injection of lidocaine before administration of propofol may reduce the incidence and intensity of pain on injection. The use of propofol MCT/LCT is also recommended for reduction of pain on injection, because the concentrations of free propofol were found to be significantly smaller (by approximately 30%–45%) than those in propofol LCT in this study.
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Footnotes |
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These data will be presented in abstract form at the annual meeting of International Anesthesia and Research Society 79th Clinical and Scientific Congress, Honolulu, Hawaii, March 11–15, 2005.
Accepted for publication December 8, 2004.
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References |
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