**8. Addition of low‐molecular weight dextran to local anesthetics: enhancement of analgesic effect and reduction of toxicity**

Regional anesthesia, though useful, has some limitations. It is often performed as a single‐shot procedure with a large dose of a local anesthetic drug, except for cases of epidural anesthesia, which is usually performed with insertion of a catheter for continuous administration. Therefore, prolonging analgesia without toxicity is clinically important for most regional anesthesia proce‐ dures. Furthermore, when performed in combination with general anesthesia, a prolonged anal‐ gesia duration is required, because the period of postoperative analgesia is shortened depending on operation time. In light of these limitations and demands, studies aimed at improving the effects of local anesthetics have been performed, some of which have provided evidence show‐ ing that addition of low‐molecular weight dextran (LMWD) to a local anesthetic and epinephrine mixture when given as infiltration anesthesia [24], or to a local anesthetic alone when performing a regional block [25] safely prolonged the effective action by reducing systemic absorption.

We demonstrated this favorable effect of LMWD as an adjuvant in patients being prepared for laparoscopic colon surgery, who received anesthesia with a combination of TAPB and rectus sheath block (RSB) using either 80 ml of 0.2% levobupivacaine in saline (control group, *n* = 27) or 80 ml of 0.2% levobupivacaine in 8% LMWD (LMWD group, *n* = 27). Following anesthesia induction, the combined block was performed under a double‐blind condition. Levobupivacaine plasma concentration and postoperative analgesia were assessed using a numerical rating scale (NRS).

In the LMWD group, the time to reach the maximum plasma concentration of levobupiva‐ caine (Tmax) was longer (73 ± 25 vs. 51 ± 30 min, *P* = 0.006) and the maximum plasma concentra‐ tion (Cmax) was lower (1141 ± 287 vs. 1410 ± 322 ng•ml‐1 , *P* = 0.004), as compared to the control group (**Figure 14**). The area under the plasma concentration‐time curve (AUC) from 0 to

**Figure 14.** Changes in plasma concentration of levobupivacaine in patients receiving levobupivacaine at 160 mg (0.2%) in saline (control group, *n* = 27) or an 8% low‐molecular weight dextran solution (LMWD group, *n* = 27) following a bilateral transversus abdominis block (TAPB) or rectus sheath block (RSB). Error bars show the SD and time 0 indicates completion of the nerve block procedure. In the control group, the plasma concentration of levobupivacaine quickly rose just after performing the nerve block. In the LMWD group, that rose in a more gradual manner with a lower maximum concentration. Subsequently, the plasma concentration of levobupivacaine gradually decreased in both groups, though a faster decline was seen in the control group. At 1200 min after performing the block, the plasma concentration of levobupivacaine was significantly higher in the LMWD group as compared to the control group.

240 min was also lower (172,484 ± 50,502 vs. 229,124 ± 87,254 ng min•ml‐1 , *P* = 0.007) in the LMWD group, while their NRS scores up to 24 h after surgery were reduced (**Figure 15**). Also, rescue treatment with IV flurbiprofen (50 mg) was utilized significantly less often in the LMWD group. No typical adverse effects, such as wound infection, delayed wound healing, tissue necrosis, or prolonged abnormal sensory disorder over the area of injec‐ tion, were observed in either group. The lower Cmax value was associated with reduced risk of levobupivacaine toxicity, while lower AUC indicated that the addition of LMWD reduced systemic absorption of levobupivacaine. Thus, those results indicated that addi‐ tion of LMWD enhances analgesia for a longer duration along with decreased risk of local anesthetic toxicity.

prolonging analgesia without toxicity is clinically important for most regional anesthesia proce‐ dures. Furthermore, when performed in combination with general anesthesia, a prolonged anal‐ gesia duration is required, because the period of postoperative analgesia is shortened depending on operation time. In light of these limitations and demands, studies aimed at improving the effects of local anesthetics have been performed, some of which have provided evidence show‐ ing that addition of low‐molecular weight dextran (LMWD) to a local anesthetic and epinephrine mixture when given as infiltration anesthesia [24], or to a local anesthetic alone when performing a regional block [25] safely prolonged the effective action by reducing systemic absorption.

We demonstrated this favorable effect of LMWD as an adjuvant in patients being prepared for laparoscopic colon surgery, who received anesthesia with a combination of TAPB and rectus sheath block (RSB) using either 80 ml of 0.2% levobupivacaine in saline (control group, *n* = 27) or 80 ml of 0.2% levobupivacaine in 8% LMWD (LMWD group, *n* = 27). Following anesthesia induction, the combined block was performed under a double‐blind condition. Levobupivacaine plasma concentration and postoperative analgesia were assessed using a

In the LMWD group, the time to reach the maximum plasma concentration of levobupiva‐ caine (Tmax) was longer (73 ± 25 vs. 51 ± 30 min, *P* = 0.006) and the maximum plasma concentra‐

group (**Figure 14**). The area under the plasma concentration‐time curve (AUC) from 0 to

**Figure 14.** Changes in plasma concentration of levobupivacaine in patients receiving levobupivacaine at 160 mg (0.2%) in saline (control group, *n* = 27) or an 8% low‐molecular weight dextran solution (LMWD group, *n* = 27) following a bilateral transversus abdominis block (TAPB) or rectus sheath block (RSB). Error bars show the SD and time 0 indicates completion of the nerve block procedure. In the control group, the plasma concentration of levobupivacaine quickly rose just after performing the nerve block. In the LMWD group, that rose in a more gradual manner with a lower maximum concentration. Subsequently, the plasma concentration of levobupivacaine gradually decreased in both groups, though a faster decline was seen in the control group. At 1200 min after performing the block, the plasma concentration of

levobupivacaine was significantly higher in the LMWD group as compared to the control group.

, *P* = 0.004), as compared to the control

numerical rating scale (NRS).

38 Current Topics in Anesthesiology

tion (Cmax) was lower (1141 ± 287 vs. 1410 ± 322 ng•ml‐1

However, the efficacy of dextrans including LMWD remains controversial, as several sub‐ sequent studies have reported an absence of any substantial difference in analgesic dura‐ tion with their addition [26, 27]. These inconsistent findings related to the effects of dextrans may be due to differences in regional anesthesia techniques. Recent advances in ultrasound technology have greatly increased the accuracy of various types of nerve blocks, thus local anesthetics can be precisely injected into the target compartment or very near the target with‐ out complications in this modern era. Such improved accuracy may reveal the effects of dex‐ trans not seen with classical techniques.

**Figure 15.** Box‐plots for comparing postoperative pain between the control and LMWD groups at rest and during coughing using a numerical rating scale (NRS). Details of the nerve block procedures used in each group are described in the legend to **Figure 14**. NRS scores at both rest and during coughing at all time points up to 24 h after surgery were significantly lower in the LMWD group as compared to the control group.

Nevertheless, use of LMWD as a local anesthetic adjuvant has nearly been forgotten in recent years. We rediscovered its value with the aid of ultrasound technology and found that use of LMWD with a local anesthetic mixture is a good option to further improve the performance of TAPB or RSB, and likely other regional anesthesia procedures as well. Extension of the analgesia period to the next day after surgery by a simple single‐shot approach is fully adequate for most surgery patients, making unnecessary the compli‐ cated procedure of inserting a catheter for continuous administration and subsequent management during the postoperative period. Thus, use of LMWD makes regional anes‐ thesia more easily accessible to many anesthesiologists and may open a new horizon for them.
