Introduction

The origins of local anesthesia date back to the Inca civilization, whose members observed that chewing coca leaves altered sensitivity in the mouth. Although the active ingredient in cocaine was isolated in the 19th century, it was not until the 20th century that it began to be used clinically, administered as a local anesthetic via syringe. In the 1950s, compounds such as procaine, tetracaine, and chloroprocaine were developed, but their use was limited due to the various adverse effects they produced. In 1943, Löfgren and Lundqvist discovered lidocaine, an aminoamide derivative of 2,6-xylidine, which remains the most widely used local anesthetic to this day due to its low toxicity.1

The efficacy of local anesthetics depends on the following factors: Lipid solubility, protein binding, pKa, intrinsic vasodilator activity, and the diffusion of the anesthetics through the membranes of the area to be anesthetized.

pKa is defined as the pH at which 50% of the solution is ionized; this determines the onset of action of the anesthetic.2

The most used local anesthetics in hand surgery are lidocaine, mepivacaine, bupivacaine, and prilocaine; all of which belong to the amide group. In Colombia, lidocaine and bupivacaine are the most frequently used. Lidocaine has a rapid onset of action (2–4 minutes) and an intermediate duration (40–60 minutes), while bupivacaine has an intermediate onset of action (>10 minutes) and a long duration (>60 minutes). These anesthetics have an acidic pH between 5.5 and 7, so when injected, they produce a burning sensation. However, tissue fluids have a strong buffering capacity, allowing the pH at the injection site to quickly return to its normal value of 7.4.2

Local anesthetic solutions containing vasoconstrictors such as epinephrine are acidified by manufacturers through the addition of sodium metabisulfite to delay the oxidation of the vasoconstrictor and prolong the drug’s duration of action. When they do not contain vasoconstrictors and are intended to be mixed with a vasoconstrictor such as epinephrine, their pH can range from 4.5 to 5.3 It is important to note that, worldwide, the practice of mixing bupivacaine and lidocaine to prolong the duration of action of the anesthetics persists.2

In hand surgery, one of the best-known local anesthesia techniques is the Wide-Awake Local Anesthesia without a Tourniquet (WALANT), which has gained popularity due to its many advantages. It allows for pain-free surgery with adequate bleeding control while the patient remains awake, at a low cost, and thus places less of a burden on the healthcare system.4,5

The traditional WALANT approach uses a 1% lidocaine solution with epinephrine 1:100,000 and sodium bicarbonate to reduce pain at the time of administration and ensure greater patient comfort (1 mL mixed with 9 mL of local anesthetic, for a total of 10 mL).6

A 1% lidocaine solution with epinephrine 1:100,000 has a pH of 4.2, an acidity that contributes to pain at the time of injection.7 In this regard, the international standard recommendation is to buffer the solution by adding 8.4% bicarbonate, in a 10:1 ratio, as this raises the pH to 7.4 and reduces pain.8 In this regard, a Cochrane review concluded that patients prefer lidocaine with bicarbonate to lidocaine alone, and that this preference is more pronounced when the solution contains epinephrine.9

Vycomb & Sahhar,10 as well as Thomson & Lalonde11 prefer bupivacaine over lidocaine due to its longer duration of action, which improves pain control, as the effect can last up to 15 hours, while the return to normal sensation may take up to 30 hours. It is important to note that adding epinephrine to bupivacaine may increase the duration of pain relief by only an additional 1.5 hours.7 Therefore, the patient should be informed that the sensation of pain will return before the paresthesia completely resolve. In contrast, with lidocaine, pain and sensation return simultaneously.7 Furthermore, it has been demonstrated that in procedures using the WALANT approach with up to 22 mg/kg of lidocaine with epinephrine 1:100,000, there are no cases of systemic toxicity.12

Given this context, the objective of this study was to analyze the local anesthetics most commonly used in Colombia for hand surgery, as well as their combinations with other local anesthetics, vasoconstrictors, and buffers based on their pH, in order to determine which combination is most effective for achieving a pH as close as possible to the physiological level. To this end, the onset of action, the reduction in pain at the time of solution infiltration, and the duration of anesthesia in the postoperative period were evaluated. Thus, the study sought to establish how certain biochemical and pharmacological principles that govern the action of drugs used in local anesthesia, such as pH and precipitation, can affect pharmacokinetics and pharmacodynamics when used alone or in combination with other local anesthetics in different solutions.

Methodology

In the second half of 2022, the local anesthetic solutions available in Colombia were identified, and it was found that the most used in hand surgery are: plain lidocaine at 1% and 2%, lidocaine at 1% and 2% with epinephrine, and bupivacaine at 0.5% with adjuvants such as sodium bicarbonate and epinephrine (Figure 1). The pH of the pure initial solutions was measured directly from their original packaging (all from new vials), and the proposed mixtures were subsequently prepared. The measurements were performed in the chemistry laboratory at El Bosque University in Bogotá, Colombia, in the presence of the institution’s pharmaceutical chemist (A.V.), using an Ohaus benchtop pH meter (Figure 2) while adhering to all biosafety protocols.

Figure 1. Solutions used for pH measurement.

Source: Image obtained during the study.

Figure 2. Ohaus benchtop pH meter.

Source: Image taken during the study.

A total of 14 mixtures were prepared, and measurements were taken using a micropipette. The pH was measured on three occasions, during which the temperature was also recorded to reduce bias.

Between each measurement, the pH meter was calibrated, and the electrodes were rinsed with distilled water and dried with special paper to minimize the risk of contamination.

Ethical Considerations

The study was based on laboratory pH measurements and did not require interaction with patients.

Results

Our measurements yielded the following results, which are summarized in Table 1:

• Mixtures 1 and 2: Consisting of 1% lidocaine with epinephrine plus 1 mL of bicarbonate, in concentrations of 10:1 and 9:1, respectively, resulted in an alkalization of >7.5.
• Mixtures 3 and 4: Consisting of 2% lidocaine with epinephrine plus 1 mL of bicarbonate, in concentrations of 10:1 or 9:1, respectively, had a pH close to physiological levels, ranging from 7.33 to 7.40.
• Mixtures 5 and 6: Consisting of 0.5% bupivacaine plus 1 mL of bicarbonate, in concentrations of 10:1 and 9:1, respectively, had a pH ranging from 7.43 to 7.49; the 9:1 formulation (mixture 6) precipitated in 0.02 seconds.
• Mixtures 7 and 8: Consisting of 1% and 2% lidocaine, respectively, plus 50% epinephrine, had alkaline pH values ranging from 8.12 to 8.30; the 2% mixture precipitated in 0.01 seconds, while the other solution did not precipitate during 20 minutes of observation.
• -Mixtures 9 and 10: Composed of 5 mL of bupivacaine plus 5 mL of lidocaine with 1% or 2% epinephrine, respectively, plus 1 mL of bicarbonate, in concentrations of 10:1 or 9:1, had acidic pH values ranging from 7.09 to 7.34, with no precipitation.
• Mixtures 11 and 12: Composed of 4.5 mL of bupivacaine plus 4.5 mL of lidocaine with 1% or 2% epinephrine, respectively, plus 1 mL of bicarbonate, in concentrations of 10:1 or 9:1, exhibited acidic pH values ranging from 7.13 to 7.24, without precipitation.
• Mixture 13: Composed of 5 mL of 1% lidocaine plus 5 mL of 0.5% bupivacaine and 1 mL of bicarbonate had alkaline pH values ranging from 7.63 to 7.67, with precipitation occurring 11 minutes and 18 seconds after observation and agitation.
• Mixture 14: Composed of 4.5 mL of 2% lidocaine without epinephrine plus 5 mL of 0.5% bupivacaine and 1 mL of bicarbonate had alkaline pH values ranging from 7.55 to 7.57, with precipitation occurring 11 minutes and 43 seconds after observation and agitation.

Table 1. Mixtures analyzed and measurements obtained.

Mixture number	Mixtures	pH 1	pH2	pH3	Temperature 1	Temperature 2	Temperature 3	Precipitation
	Lidocaine 1%	6.10	6.09	5.92	20.4°C	19.7°C	19.8°C
	Lidocaine 2%	6.32	6.47	6.36	20.9°C	19.8°C	19.8°C
	Bupivacaine 0.5%	5.73	5.93	6.01	21°C	19.6°C	19.9°C
	Lidocaine 1% + epinephrine 1:200,000	3.69	3.77	3.67	21.3°C	20.0°C	20.0°C
	Lidocaine 2% + epinephrine 1:200,000	3.70	3.66	3.64	21.6°C	20.0°C	20.1°C
1	Lidocaine 1% + epinephrine + 1 mL of bicarbonate at 10:1 concentration.	7.54	7.58	7.56	20.1°C	20°C	20°C
2	Lidocaine 1% + epinephrine + 1 mL of bicarbonate at 9:1 concentration.	7.6	7.61	7.59	20.4°C	20.3°C	20.1°C
3	Lidocaine 2% with epinephrine + 1 mL of bicarbonate at 10:1 concentration.	7.33	7.33	7.31	20.1°C	20°C	20°C
4	Lidocaine 2% with epinephrine + 1 mL of bicarbonate at 9:1 concentration.	7.38	7.40	7.34	20.5°C	20.2°C	20.2°C
5	Bupivacaine 0.5% + 1 mL of bicarbonate at 10:1 concentration.	7.49	7.49	7.49	20.1°C	20°C	19.9°C
6	Bupivacaine 0.5% + 1 mL of bicarbonate at 9:1 concentration.	7.44	7.43	7.47	20.2°C	19.9°C	19.9°C	Precipitated in 0.02 seconds.
7	Lidocaine 1% with epinephrine 50%ª.	8.28	8.30	8.30	21.4°C	21.3°C	21.3°C	Did not precipitate during 20 minutes of observation.
8	Lidocaine 2% with epinephrine 50%.	8.14	8.13	8.12	21.7°C	21.6°C	21.6°C	Precipitated in 0.01 seconds.
9	5 mL of bupivacaine + 5 mL of lidocaine with epinephrine 1% + 1 mL of bicarbonate.	7.30	7.34	7.31	20.2°C	20.1°C	20.1°C
10	5 mL of bupivacaine + 5 mL of lidocaine with epinephrine 2% + 1 mL of bicarbonate.	7.10	7.15	7.09	20.6°C	20.4°C	20.7°C
11	4,5mL de bupivacaina + 4,5mL de lidocaína con epinefrina 1% + 1mL bicarbonato.	7.24	7.23	7.25	20.8°C	20.7°C	20.5°C
12	4.5 mL of bupivacaine + 4.5 mL of lidocaine with epinephrine 2% + 1 mL of bicarbonate.	7.15	7.15	7.13	21.0°C	20.8°C	20.9°C
13	5 mL of lidocaine 1% + 5 mL of bupivacaine 0.5% + 1 mL of bicarbonate.	7.63	7.67	7.64	20.9°C	20.8°C	20.7°C	Precipitated at 11 minutes and 18 seconds of observation plus agitation.
14	4.5 mL of lidocaine 1% + 4.5 mL of bupivacaine 0.5% + 1 mL of bicarbonate.	7.56	7.57	7.55	21.2°C	21.1°C	21.3°C	Did not precipitate during 2 minutes of observation plus agitation. Precipitated at 11 minutes and 43 seconds of observation plus agitation.

aMix 10 mL of lidocaine + 0.01 mL of epinephrine: take 5 mL of the mixture and add 5 mL of bicarbonate.

Note: Rinse the electrode with distilled water before each measurement.

Source: Own elaboration.

Discussion

Most local anesthetics have a low pH (3-4), which improves solubility, stability, and water solubility and provides a longer shelf life, but is associated with adverse effects such as pain at the time of injection, a longer onset time, and reduced efficacy.13 These disadvantages can be offset using sodium bicarbonate, which helps reduce pain at the time of application and shortens the onset time, while increasing the spread of the effect.4

The normal tissue pH is 7.4. When an anesthetic with a lower pH (3-5) is injected into tissues, it is buffered by the body, and the pH of the injected solution slowly rises to 7.4.13 However, in cases of inflammation or infection, tissue acidity reduces the amount of local anesthetic available to penetrate the nerve membrane, as it decreases its fat-soluble fraction.10,12

Based on the above and the findings of our study, mixtures 3 and 4 (2% lidocaine with epinephrine plus 1 mL of bicarbonate, in ratios of 10:1 or 9:1) could be recommended as first-line options, since they yielded pH levels close to physiological levels (7.33–7.40), and mixture 9 (5 mL of bupivacaine plus 5 mL of lidocaine with 1% epinephrine plus 1 mL of bicarbonate) as a second option, noting that the pH of bupivacaine is typically more acidic than that of lidocaine and that mixing these two anesthetics can cause a slight alkalization of the bupivacaine, as well as a slight acidification of lidocaine; theoretically, this could result in greater bioavailability of bupivacaine and lower bioavailability of lidocaine due to a difference in the levels of the unionized form, which could alter the action of the two substances.15

Most surgical procedures on the hand can be performed within the duration of anesthesia provided by lidocaine with epinephrine (5 hours in the wrist and 10 hours in the fingers). However, it has been established that bupivacaine may be a better option for operations lasting between 2.5 and 3 hours, following which pain may be severe.4,6

The maximum effect of epinephrine on arterial vasoconstriction occurs within 7-10 minutes, but it takes much longer to achieve a new microvascular equilibrium, with the peak effect potentially occurring 25 minutes after administration.7

The onset of analgesia with lidocaine in digital nerve blocks varies between 1-10 minutes, while with bupivacaine the range is 8-20 minutes.9,10 Regarding duration of action, it has been reported that for lidocaine it ranges from 60 minutes to 4.9 hours and that for bupivacaine it is 7.9 hours.15-17

Thomson & Lalonde11 compared the duration of the anesthetic effect of 2% lidocaine alone, 2% lidocaine with epinephrine 1:100,000, and 0.5% bupivacaine, finding that 0.5% bupivacaine had the longest duration of action (mean: 24.9 hours), followed by 2% lidocaine with epinephrine 1:100,000 (mean: 10.4 hours) and 2% lidocaine alone (mean: 4.9 hours). In the present study, these variables were not determined because this was a purely in vitro first phase; therefore, further in vivo research is required, which is planned as the second phase of the study.

Local anesthetics are weak bases whose relative proportions depend on the pH of the solution and the pKa of the drug. The pKa is defined as the pH at which the ionized and unionized fractions are in equilibrium. The relationship between pH and pKa is described by the Henderson-Hasselbalch equation: pKa - pH = log (LH+)/(L), where LH+ denotes the ionized fraction and L represents the unionized fraction.18 Therefore, raising the pH to values close to the pKa increases the fraction of the drug in the non-ionized form, thereby increasing the proportion of the administered dose that can enter neurons. This accelerates the onset of anesthesia, reduces pain transmission, and consequently decreases the sensation of pain at the time of local anesthetic infiltration into the tissues, which, although considered a positive point, is difficult to demonstrate in clinical practice.18

Based on the results of this study, of the 14 local anesthetic mixtures analyzed, the use of 2% lidocaine with epinephrine plus 1 mL of bicarbonate is recommended, either in a 10:1 or 9:1 ratio, since these options had pH levels closer to physiological levels (7.31-7.40), which may be reflected in reduced pain at the time of administration, in addition to the well-known advantages of using epinephrine, such as prolonging the duration of action, increasing the intensity of the block, reducing intraoperative bleeding to improve visibility during surgery, and slowing the absorption rate of the anesthetic and, consequently, its toxicity.17,19,20

The second mixture that approached physiological pH was that of 5 mL of bupivacaine plus 5 mL of lidocaine with 1% epinephrine plus 1 mL of bicarbonate, whose pH ranged between 7.30 and 7.31. It should be noted that none of the three mixtures (mixtures 3, 4, and 9) exhibited precipitation during the 1-hour observation period. This finding is relevant, as the literature has reported that there is no clinical advantage, in terms of the onset and duration of local block, when using a 50/50 mixture of plain lidocaine and plain bupivacaine instead of using them separately.14,17,21 The question regarding the time to onset of action remains unresolved.

Mixtures 10, 11, and 12 are not recommended for conscious patients due to the pain they may cause during administration because of their high acidity, as indicated by pH values ranging from 7.1 to 7.25. Similarly, mixtures 6 and 8 are not recommended because they precipitated in less than 3 seconds, making them impossible to administer. Finally, mixtures 7 and 8 are also not recommended for use in humans because they were the most alkaline.

It is important to note that the above mixtures do not exceed the maximum doses of lidocaine alone (6 mg/kg), lidocaine with epinephrine (10 mg/kg and 8 mg/kg in highly vascularized sites), and bupivacaine (3 mg/kg).22 The two most used anesthetics in Colombia are of the amide type: lidocaine (Xylocaine) and bupivacaine (Marcaine), with the former having a faster onset and the latter a longer duration of action. The anesthetic effect obtained with 2% lidocaine is like that produced by 0.5% bupivacaine.19,23

Bicarbonate accelerates the onset of action of the local anesthetic by raising the pH, bringing it closer to physiological levels. For this reason, and given the known benefits of epinephrine, the use of the two mixtures is recommended.

Conclusions

Based on the results of this study, for patients undergoing hand surgery, the use of 2% lidocaine with epinephrine is recommended, either in a 10:1 or 9:1 concentration, plus 1 mL of bicarbonate, since these mixtures yield a pH close to physiological levels, which, in theory, reduces pain at the time of administration, while also offering the benefits of epinephrine. A second phase of this study will investigate the clinical characteristics of these solutions and their application in patients.

Conflict of Interest

None declared by the authors.

Funding

None declared by the authors.

Acknowledgments

To pharmaceutical chemist María Angelica Velandia Paris and the staff of the Chemistry Laboratory at El Bosque University, for providing the laboratory equipment and technical support necessary to conduct this study.

Use of Artificial Intelligence

Artificial intelligence was not used in this study.

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