**3. Early history of dextran as local anesthetic adjuvant and possible action mechanism**

Apart from the effects of dextran on lidocaine-adrenaline mixtures, the first description of the adjuvant effects of dextran with local anesthetics can be traced back to the 1960s [19]. Thereafter, prolongation and enhancement of analgesia by dextran were studied, and some favorable results reported [20–22], with possible mechanisms for those actions also investigated. Dextran may form a water-soluble complex with local anesthetics that is slowly absorbed and remains at the injection site for a longer period with increased viscosity [23, 24]. Moreover, addition of dextran was shown to change the pH of a local anesthetic solution and that may further contribute to prolongation of action [25]. Despite these positive results, several studies that failed to find potential effects for analgesia with dextran have also been reported [26, 27]. As a result, along with the expanding applicability of general anesthesia for surgery, dextran has gone largely unnoticed and its adjuvant effects remain inclusive.

## **4. Adjuvant effects of low-molecular weight dextran with current nerve block techniques**

Assuming an interaction of dextran with local anesthetics, its effectiveness as a local anesthetic adjuvant may be dependent on the type of nerve block employed and procedure used. Such nerve block dependency may induce inconsistent adjuvant effects, as shown in several previous studies. Because an interfascial compartment nerve block, such as a transversus abdominis plane block, is required to perform accurate injection of a large amount of local anesthetic solution into the targeted interfascial compartment, that is difficult to perform with a conventional landmark method. Fortunately, advancements in ultrasound guidance techniques have made this possible at a clinically acceptable quality. Consequently, an interfascial compartment nerve block has become popular. Maintaining the amount of injected local anesthetics in the compartment for a longer period is essential to induce sufficient analgesia in cases with such a compartment block, thus it is quite reasonable to assume that the possible fluid retention properties of dextran have a favorable impact. Based on findings obtained in previous studies reported by the

Ueda research team concerning use of a lidocaine-adrenaline mixture, we consider that low-molecular weight dextran is the most suitable local anesthetic adjuvant among the various dextran compounds available for interfascial compartment nerve block procedures currently used.

## **4.1 Pharmacokinetics and analgesia: transversus abdominis plane block and rectus sheath block cases**

First, we investigated the adjuvant effects of low-molecular weight dextran when used for a transversus abdominis plane block and rectus sheath block [12]. Patients scheduled for a laparoscopic colectomy [age 66 ± 9.8 years, body weight 59 ± 11.7 kg, anesthesia time 322 ± 69 minutes (values shown as mean ± standard deviation)] received a combination of two bilateral interfascial compartment blocks, a transversus abdominis plane block and rectus sheath block. Following anesthesia induction, they received this two-block combination with either 0.2% levobupivacaine in a saline solution (control group: 20 ml × 4 injections = total 160 mg of levobupivacaine in saline; n = 27), or 0.2% levobupivacaine and 8% lowmolecular weight dextran (LMWD) in a saline solution (LMWD group: 20 ml × 4 injections = total 160 mg of levobupivacaine in LMWD; n = 27). General anesthesia was maintained with sevoflurane and remifentanil, with 200 μg of fentanyl given at the end of surgery. Continuous intravenous infusions of fentanyl at 25 μg∙hr.−1 and droperidol at 63 μg∙hr−1 were postoperatively given for 24 hours as analgesia and antiemetic treatments.

There were no significant differences in regard to patient age, body weight, amount of intraoperative blood loss, or anesthesia time between the groups. Furthermore, no typical adverse effects, such as wound infection, delayed wound healing, tissue necrosis, or prolonged abnormal sensory disorder over the area of injection, or other systemic abnormalities were observed in either group. In the control group, the plasma concentration of levobupivacaine rose quickly just after performing the nerve block and reached a maximum at 51 ± 30 minutes (Tmax), while in the LMWD group, that rose in a more gradual manner with a significantly longer Tmax value (73 ± 25 minutes, P < 0.05 vs. control group) (**Figure 7**). The maximum concentration of levobupivacaine (Cmax) in the control group was 1410 ± 322 ng∙ml−1, whereas that in the LMWD group was significantly lower at 1141 ± 287 ng∙ml−1(P < 0.05). Also, the area under the plasma concentration-time curve (AUC) from 0 to 240 minutes was significantly lower in the LMWD as compared to the control group (172,484 ± 50,502 vs. 229,124 ± 87,254 ng∙min∙ml−1, P < 0.05). In contrast, the plasma levobupivacaine concentration in the LMWD group was higher than that seen in the control group after 1200 minutes. These results demonstrated that use of a low-molecular weight dextran mixture results in reduced systemic absorption of the local anesthetic from the injection compartment along with its longer retention in that compartment for more than 20 hours. Such a reduction in systemic absorption lowers the risk of local anesthetic systemic toxicity. In addition, the postoperative 24-hour numerical rating scale (NRS) for pain (0-no pain, 10-worst pain) demonstrated significantly better analgesia in patients with the local anesthetic mixture with low-molecular weight dextran as compared to those in the control group who received a standard local anesthetic solution (**Figure 7**). That result was considered to be due to extended presence of the injected local anesthetic in the injection compartment.

Together, our findings indicated that low-molecular weight dextran as a local anesthetic adjuvant provides great clinical advantages for enhancement of analgesia effect as well as reduction in systemic toxicity of a local anesthetic.

#### **Figure 7.**

*Left panel: Changes in levobupivacaine plasma concentration in patients receiving bilateral transversus abdominis plane blocks plus rectus sheath blocks with 160 mg of levobupivacaine [12]. For nerve blocks, the control group (n = 27) received nerve blocks using 80 ml of 0.2% levobupivacaine in a saline solution, while the +LMWD group (n = 27) received 80 ml of 0.2% levobupivacaine and 8% low-molecular weight dextran in a saline solution just before starting a laparoscopic colectomy. Values are expressed as the mean ± standard deviation. Addition of low-molecular weight dextran to the levobupivacaine solution was shown to lower the peak level of levobupivacaine plasma concentration, indicating that dextran suppresses systemic absorption of levobupivacaine from the injection site, which may prolong analgesic effects and decrease the systemic toxicity of levobupivacaine. After 1200 minutes, plasma levobupivacaine concentration in the +LMWD group was significantly higher than that in the control group, indicating longer retention of levobupivacaine at the injection site following its slow release. Right panel: Numerical rating scale (NRS) scores for postoperative pain in the same patients. Values are expressed as the mean ± standard deviation. NRS: 0, no pain, to 10, worst pain. NRS scores in the +LMWD group were significantly lower at each time point after surgery as compared to the control group (P < 0.01 at 2, 8, 16 hours; P = 0.035 at 24 hours).*

#### **4.2 Extended retention time in injected area: quadratus lumborum block cases**

To confirm the longer retention time of the local anesthetic and low-molecular weight dextran mixture at the injection site, a different group of cases that underwent a quadratus lumborum block, another type of interfascial compartment nerve block, were investigated [10]. A quadratus lumborum block using a low-molecular weight dextran mixture with ropivacaine was applied in 18 patients undergoing open abdominal surgery (age 67 ± 8.4 years, body weight 72.6 ± 4.6 kg, anesthesia time 429 ± 123 minutes) following anesthesia induction (**Figure 8**). One hundred ml of 0.1% ropivacaine and 8% low-molecular weight dextran in saline solution with 2 mg of morphine was injected into interfascial space posterior of the quadratus lumborum muscle (so-called QLB2 nerve block) on each side (total 200 ml in both sides). Anesthesia was maintained with desflurane and remifentanil. Postoperatively, intravenous flurbiprofen (50 mg) was given every 8 hours, with acetaminophen (15 mg•kg−1) used as rescue treatment for pain.

No rescue drug was given to any of the patients on the first night after surgery and the NRS for pain (0-no pain, 10-worst pain) during that period was 2.2 ± 1.7.

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

#### **Figure 8.**

*Upper panel: Transverse ultrasound image obtained just when nerve block needle reached target site in posterior quadratus lumborum block (so-called QLB2 nerve block) and related anatomical schema [10]. Middle panel: Transverse and sagittal ultrasound images obtained just after completion of posterior quadratus lumborum block with 100 ml of 0.1% ropivacaine with 8% low-molecular weight dextran in a saline solution in the same patient shown in the upper panel. The injected local anesthetic mixture (LA-LMWD) was correctly and widely spread over the interfascial space posterior to the quadratus lumborum muscle. Lower panel: Sagittal ultrasound image obtained from the same injection site at 24 hours after completion of quadratus lumborum block in the same patient shown in the upper panel. Some of the local anesthetic mixture (LA-LMWD) remained. PM: psoas major muscle; QL: quadratus lumborum muscle; TP: transverse process.*

Each successfully walked more than 20 meters with less pain the next day. No local or systemic adverse effects from use of low-molecular weight dextran including tissue necrosis over the area of injection were observed. Ultrasound examinations performed after 24 hours indicated that some amount of local anesthetic mixture remained at the injected site (**Figure 8**). These findings well support the proposed mechanism of low-molecular weight dextran as an adjuvant that maintains the analgesic mixture at the injection site for an extended time, thus enabling longer lasting effects. The analgesia effect obtained with this method seems to be comparable with that with epidural anesthesia during the initial 24 hours follow surgery, thus is adequate for early postoperative pain control.
