The addition of D10 (5%), epinephrine, or sterile water significantly altered the pH of 2% 2-CP (P < 0.0001)(Fig. 3). Except for plain 2-CP and 2-CP in 1.1% dextrose, and because of the very small standard deviation of all solutions, the differences in pH among all other solutions are statistically significant (P < 0.0001). However, compared with the large change in pH after the addition of the first 0.25 mL NaHCO3, these differences are relatively minor. No precipitation was observed for any of the solutions in the immediate mixing time nor was any seen after a prolonged time period (>24 h).
The primary finding of this investigation is that dextrose-free 2-CP solutions are hyperbaric relative to CSF at 37°C. Therefore, plain 2% and 3% 2-CP become quite useful as hyperbaric intrathecal anesthetics and thus eliminated the need to add dextrose to increase baricity. This relationship is not affected by the addition of either epinephrine or 8.4% sodium bicarbonate. The density of dextrose-free lidocaine is consistent with earlier reports by Horlocker and Wedel (12), and Richardson and Wissler (11). Depending on the definition of hypobaricity, lidocaine is categorized as either hypobaric or isobaric. As hyperbaric solutions are clinically used most in the US, commercially prepared spinal anesthetic solutions are packaged in combination with dextrose. Based on the above findings, our recommendation regarding the use of 2-CP in the setting of a spinal anesthetic is to administer it plain, without the addition of any dextrose.
The density of an anesthetic solution is an important determinant of its spread in the CSF. The baricity of an intrathecal drug is largely responsible for the spread of a sensory block. Baricity is defined as the ratio between the density of the local anesthetic solution and the density of CSF at 37°C. Hyperbaric is a ratio more than 1.0, and hypobaric is a ratio less than 1.0. We use the CSF density range of 1.00028 to 1.00100 g/mL (10), defining the limits in most populations of hypo- and hyperbaricity, respectively. Because there is variation in CSF density among patients, three standard deviations below the mean has been historically used as the upper limit of hypobaricity. Yet the lower limit of hyperbaricity has not been defined. By applying the use of three standard deviations above the mean CSF density, we defined the lower limit of hyperbaricity as 1.00100 g/mL.
Richardson and Wissler (10) found that postmenopausal women (8 patients) have more variability in their CSF density (1.00070 ± 0.00018 g/mL). The upper limit of the CSF density may be as much as 1.00124 g/mL in a few patients (mean + 3 sd). Therefore, it is possible that the baricity of 2% 2-CP may be isobaric in a few patients, namely postmenopausal women, whose CSF density occurs in the outlier range.
Typically, dextrose is the easiest method to increase the density of an anesthetic solution and is necessary to achieve a hyperbaric solution, as most local anesthetics are hypobaric relative to CSF in plain concentrations (11,12). However, adding too much dextrose can decrease the reliability of a block. It has been shown that 0.8% glucose with bupivacaine (density, 1.0045 at 23°C) produced a more consistent block height than 8% glucose added to bupivacaine (density, 1.0203 at 23°C) (13). With similar relative density results in our study, it can be expected that 1.1% dextrose is more than adequate to increase the density compared with 5% dextrose and might produce a more reliable block height when used clinically. Although hyperbaric solutions are used for the majority of spinal anesthetics in the US, isobaric and hypobaric solutions remain useful for selected clinical situations. An easy 1:1 dilution of water with 2-CP produces a hypobaric solution as demonstrated in this study.
In recording the density of local anesthetics, temperature and precision of measurements are essential factors to consider. The density of a solution is inversely related to its temperature (14). Therefore, readings need to be evaluated at physiologic temperature (37.0°C) to make a fair assessment of the density in comparison with CSF. The density of bupivacaine decreases by 0.00007 g/mL with each increase in temperature of 0.20°C (11). In earlier work, Stienstra et al. (15) showed the necessity for precise measurements to 5 significant digits, reporting that differences as small as 0.0006 g/mL can influence the spread of local anesthetics in the spinal canal.
In addition to outpatient surgery, a short duration anesthetic such as 2-CP may also be of value in the obstetrical patient having combined spinal-epidural anesthesia for labor analgesia or a single injection spinal anesthetic for postpartum tubal ligations. In the study by Richardson and Wissler (10), the CSF density in pregnant women was determined to be 1.00030 ± 0.00004 g/mL, which is significantly less than that seen in men and nonpregnant women. Therefore, the use of plain 2-CP in the intrathecal space in the parturient will be even more hyperbaric considering the decreased CSF density.
Both the 2% and 3% concentrations of the current formulation of 2-CP are acidic, with a mean pH of 3.34 ± 0.01 and 3.31 ± 0.02, respectively, comparable to earlier preparations (16–18). However, these prior studies were done with earlier formulations of 2-CP containing either EDTA or bisulfite. Two separate reports were published on the amount of bicarbonate necessary to alkalinize 3% 2-CP to physiologic range (more than 7.0) (17,18). Although bisulfite-containing 3% 2-CP (Nesacaine®-CE) had a slightly higher pH (3.84 – 3.89) than current formulations, alkalinization of the newer product is achieved with less bicarbonate (0.25–0.33 mEq NaHCO3 per 10 mL of anesthetic versus 1.0–1.5 mEq per 30 mL of bisulfite-containing 2-CP). In 1987, bisulfite was replaced with EDTA (Nesacaine®-MPF). The pH of this formulation (2% 2-CP, 3.40; 3% 2-CP, 3.38) was closer to that of the current formulation, and alkalinization to physiologic pH could be accomplished with 0.5 mL per 20 mL (16).
Stevens et al. (19) have shown that the onset time for epidural anesthesia is decreased when the pH of 2-CP is increased closer to physiologic pH by the addition of sodium bicarbonate. The relevance of onset time and pH is unknown with regards to spinal anesthesia. The equilibration of pH between a local anesthetic and CSF is much more rapid with intrathecal injection, most likely negating any benefit of first increasing the pH with sodium bicarbonate. Nonetheless, if desired, the addition of only 0.25–0.33 mL of sodium bicarbonate per 10 mL of local anesthetic is enough to increase the pH of 2% and 3% chloroprocaine to the mean pH of 7.22 ± 0.05 and 7.07 ± 0.02, respectively.
In conclusion, the commercially available preparation of 2-CP (2% or 3%) is a hyperbaric solution. It is feasible to use this solution as a hyperbaric spinal drug as it currently is packaged. The preservative-free solution continues to have an acidic pH, which can be readily alkalinized if necessary. However, the impact of alkalinization in an intrathecal drug is likely to be minimal.
The authors would like to thank Suzanne Noe, Amgen Inc., Bothell, WA, and Sharon Kochik, Benoroya Research Institute, Seattle, WA for their technical assistance.
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© 2004 International Anesthesia Research Society
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