**2. Toxicity of adjuvant adrenaline and prevention by low-molecular weight dextran**

Adrenaline (epinephrine) is the oldest adjuvant given with local anesthetics and continues to be used. When used as an adjuvant it is typically applied with lidocaine, and known to induce vasoconstriction for reducing systemic absorption of the administered local anesthetic and enhancing the analgesia effects, and seems to be an optimal application. However, the combination of adrenaline and lidocaine does not always lead to good results.

Lidocaine has potent vasodilation effects, thus it can enhance the absorption of adrenaline into systemic circulation when a lidocaine-adrenaline mixture is administered. Wasa Ueda, presently professor emeritus and executive advisor of our research team, validated this issue in a clinical study, in which application of a lidocaine-adrenaline mixture for infiltration anesthesia was shown to significantly increase the plasma concentration of adrenaline in comparison with an infiltration injection of the same amount of a pure adrenaline solution [16] (**Figure 4**). An increase in adrenaline concentration in the circulation can increase blood pressure and heart rate, sometimes leading to severe lethal cardiac dysrhythmia. Such toxic effects of a lidocaine-adrenaline mixture are a significant problem for patients under general anesthesia using halothane, which has a characteristic property to increase sensitivity to adrenaline, whereas aggravating effects on circulation, such as increase in blood pressure, can still develop when the more recently introduced anesthetics desflurane and sevoflurane are used as an inhalant (**Figure 5**).

#### **Figure 4.**

*Peak plasma concentration of adrenaline (epinephrine) following subcutaneous infiltrative injection of various adrenaline solutions in humans [16]. Each column indicates the following. (1) epinephrine: 1:200,000 adrenaline in normal saline solution. (2) lidocaine epinephrine: 1:200,000 adrenaline with 0.5% lidocaine in normal saline solution. (3) epinephrine dextran: 1:200,000 adrenaline with 10% low-molecular weight dextran in saline solution. (4) lidocaine epinephrine dextran: 1:200,000 adrenaline with 0.5% lidocaine and 10% low-molecular weight dextran in saline solution. The adrenaline concentration in the solutions was the same in all four groups. Values are expressed as the mean ± standard deviation. When adrenaline was subcutaneously injected with lidocaine (lidocaine epinephrine), the peak plasma adrenaline concentration showed an approximately 7-fold increase as compared with injection of the pure adrenaline solution (epinephrine). However, the presence of low-molecular weight dextran in the lidocaine adrenaline solution (lidocaine epinephrine dextran) suppressed the toxic increase in plasma adrenaline concentration.*

*New Application of Low-Molecular Weight Dextran as Local Anesthetic Adjuvant… DOI: http://dx.doi.org/10.5772/intechopen.98797*

#### **Figure 5.**

*Typical increases in blood pressure and heart rate with subcutaneous infiltration anesthesia using 20 ml of 0.5% lidocaine and 1:200,000 adrenaline in normal saline solution in patients receiving sevoflurane general anesthesia. Soon after injection of the lidocaine-adrenaline mixture, blood pressure was slightly decreased due to the* β*2-adrenergic effect of a small amount of absorbed adrenaline. Thereafter, blood pressure and heart rate were greatly increased due to the* α*- and* β*1-adrenergic effects of adrenaline.*

#### **Figure 6.**

*Convulsion dose of plasma concentration of lidocaine in rat [17]. Male Wistar rats were divided into three groups and received continuous intravenous injections of 1.5% lidocaine, 1.5% lidocaine with 1:200,000 adrenaline (epinephrine), or 1.5% lidocaine with 1:100,000 adrenaline (epinephrine). Values are expressed as the mean ± standard deviation. The total lidocaine dose from the beginning of infusion of the lidocaine mixture to onset of generalized convulsions was analyzed. Addition of adrenaline to the lidocaine solutions significantly decreased the threshold of lidocaine-induced convulsions in a dose-dependent manner, indicating that adrenaline increased lidocaine systemic toxicity.*

Furthermore, the presence of adrenaline decreases the threshold concentration of lidocaine to induce convulsions, leading to enhancement of the central nervous system toxicity of lidocaine [17] (**Figure 6**). Another study showed that concomitant administration of adrenaline with lidocaine increased the concentration of extracellular lidocaine in the brain [18], which may be another supporting mechanism by which adrenaline increases the toxicity of lidocaine for the central nervous system. Therefore, though this combination can be useful for regional anesthesia, a lidocaine-adrenaline mixture is not completely safe.

The Ueda research team found a solution to the hazardous risk of a lidocaineadrenaline mixture, as addition of low-molecular dextran into the mixture was shown to suppress absorption of adrenalin into circulation [16]. The peak plasma adrenaline concentration with a lidocaine-adrenaline mixture with low-molecular weight dextran was 0.15 ± 0.07 ng∙ml−1, while that was 1.04 ± 0.22 ng∙ml−1 with the standard lidocaine-adrenaline mixture (**Figure 4**). Thus, it was concluded that a lidocaine-adrenaline-dextran mixture is safe for application as regional anesthesia, which is now considered to be a landmark finding indicating an adjuvant function of low-molecular weight dextran to improve the safety of local anesthetic usage.
