The results of this study suggest that, in general, the proposed chairside hand-mixing methodology is as effective as the commercially available Onpharma mixing system in buffering local anesthetics with sodium bicarbonate—specifically for lidocaine, for which the Onpharma device is indicated, but also with similar results following buffering of any of the other local anesthetics tested. It is possible, too, that this hand-mixing technique is a more financially economical option.
Malamed et al6 found that raising the pH level of a cartridge of 2% lidocaine with 1:100,000 epinephrine anesthetic closer to physiologic pH level (7.3) required 0.18 mL of the Onset Sodium Bicarbonate Injection, 8.4% USP Neutralizing Additive when utilizing the Onset mixing device. Therefore, the investigators delivered 0.18 mL of 8.4% sodium bicarbonate into the anesthetic cartridge while removing the same amount of anesthetic, resulting in a mixed ratio of 9:1. According to the Henderson-Hasselbalch equation, the ratio of uncharged (active) anesthetic molecules to charged (inactive) anesthetic molecules changes during this buffering process from 11,000:1 at a pH value of 3.5 to 3:1 at a pH level of 7.3. While this same study did not investigate articaine, it is reasonable that this solution may be less stable following a 9:1 mixing ratio because there is twice as much drug compared with lidocaine (4% solution versus 2% solution). As the authors recorded pH value changes in all seven of the solutions beyond 24 hours (Table 3), the Articadent® solutions and Citanest® with epinephrine 1:200,000 began to form a precipitate by day 3, perhaps due to too much of the uncharged base form being created. Further studies should focus on the proper ratio of local anesthetic and 8.4% sodium bicarbonate for 4% solutions because there could be clinical implications, and perhaps solutions of higher concentrations such as those containing articaine and prilocaine would be more desirable if buffered at a more diluted ratio. By day 7, all samples had formed a layer of precipitate on the surface, which required mixing before pH levels could be recorded.
Another consequence of buffering local anesthetics with sodium bicarbonate, which relates to stability of the solution, is the production of carbon dioxide (CO2) as a byproduct. Catchlove13 first demonstrated that CO2 in a lidocaine solution has an independent anesthetic effect and that both chemicals have similar effects on peripheral nerves. He suggested that in situations in which a solution contains both lidocaine and CO2, the CO2 may cause the more immediate form of analgesia because it diffuses rapidly through the nerve sheath and probably reaches the axon before the local anesthetic. While this initial effect may be beneficial, as a gas, however, buffered anesthetics in a glass carpule may be considered unstable. Without the timely injection of the buffered mixture, the unreleased gas may be further responsible for the recognized precipitate over time. Tissue damage from such an unstable mixture and precipitate could also be of clinical concern.
Onpharma instructs that buffered solutions be used immediately; premixing and storage is not recommended. Bartfield and colleagues14 studied whether there were differences in pain at injection, pH levels, and percentage lidocaine between lidocaine and sodium bicarbonate-buffered lidocaine. They recorded data immediately after mixing, at 1 day, and again at 7 days. Besides an approximately 10% decrease in lidocaine concentration, the authors found no statistically significant difference in pain at injection or pH values from freshly mixed to 7 days. All buffered solutions were significantly less painful than unbuffered lidocaine. Robinson et al15 studied the stability of sodium bicarbonate-buffered local anesthetic solutions containing epinephrine. The pH of the buffered solutions decreased slightly over the 24-hour period following buffering, however, the epinephrine concentration significantly decreased in all the buffered solutions. In the buffered lidocaine and buffered bupivacaine groups, the epinephrine concentrations decreased by 100%. It was the authors’ conclusion that buffered local anesthetic solutions containing epinephrine should not be premixed and stored prior to clinical use.
In the present authors’ study, the pH values of the buffered local anesthetic solutions increased at 3 days and in most cases increased further by day 7. The average pH value of the buffered solutions at 3 days was 7.63 ± 0.29 after hand mixing and 7.56 ± 0.11 after using the Onpharma mixing system. At 7 days, the average pH value of the buffered solutions was 8.06 ± 0.34 after hand-mixing and 7.82 ± 0.27 after using the Onpharma mixing system. The present study did not include concentration testing for lidocaine or epinephrine. Based on the studies by Bartfield et al14 and Robinson et al,15 it is reasonable to presume lidocaine concentrations remained stable and epinephrine concentrations decreased.
In trying to control for potential confounders, pH testing of both sodium bicarbonate formulations was performed (Table 4) without any statistically significant difference being recorded (8.12 ± 0.13 versus 8.11 ± 0.11 for the 50-mL vial of 8.4% sodium bicarbonate injection, USP and the 8.4% Onset Sodium Bicarbonate Injection, 8.4% USP Neutralizing Additive Solution, respectively). These near-identical results helped control for at least one variable in this in vitro study; however, the authors do acknowledge other study limitations. Primarily, this was a laboratory investigation and, as such, clinical implications can be suggested only as a direction of research for future clinical trials. The total of 28 samples were rigorously controlled for any aseptic, temperature, humidity, or ultraviolet light-exposure excursion; however, this study is based on just these 28 samples using a single laboratory site.