Effect of Concentration on Median Effective Dose (ED₅₀) for Motor Block of Intrathecal Plain Bupivacaine in Elderly Patients

Background

Both motor blockade and sensory level can be used as a primary endpoint to evaluate the relative potency of local anesthetics. The potency can be determined by investigating the median effective doses (ED50) of motor block using the up-down sequential allocation technique [1,2]. The ED50 for motor block of several anesthetics (bupivacaine, levobupivacaine, and ropivacaine) have been determined [3,4]. Using these approaches, we previously determined the ED50 for motor block of spinal 0.75% plain bupivacaine in adult patients undergoing urological or lower limb surgery, and found this to be 10.22 mg in patients aged 20–30 years, and 5.78 mg in those aged 70–80 years [5].

Some researchers have reported that the concentration of local anesthetic is an important factor determining the maximum sensory level and motor block of spinal anesthesia [6,7]. Camorcia et al. [8] reported that the concentration of local anesthetic affected the ED50 for motor block in adults. In our previous study, we also found that the concentration of plain bupivacaine influenced the ED50 in young patients, demonstrating that the ED50 for motor block of intrathecally administered bupivacaine with 0.75% bupivacaine was higher than that of the lower concentration (0.375% bupivacaine) [9].

Researchers have found that the spinal cord and nerves changed significantly with age in the biochemical, morphological, and histochemical patterns, and in the anatomical structure [10–12]. It has been reported that age not only affects the compound action potential amplitude of the muscle and its duration on motor and sensory nerves [13,14], but also affects the conduction velocity of the motor nerve [15–17].

There are no reports in the literature about the ED50 for motor block in elderly patients using different concentrations of bupivacaine solutions. The aim of the study was to determine the median effective dose (ED50) for motor block using 3 different concentrations of intrathecally administered plain bupivacaine in elderly patients.

Material and Methods

STATISTICAL ANALYSIS:

SPSS 17.0 package for Windows (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Data are expressed as the mean (SD), median (range), or count/number. The means were compared using one-way analysis of variance (ANOVA), while medians (ranges) were analyzed by Kruskal-Wallis one-way analysis, and counts or proportions were analyzed by using the Fisher’s exact test. The ED50 for motor block was determined according to the up-and-down sequences method of Dixon and Massey [22], while the probit regression analysis was used as a backup or sensitivity test. One-way analysis of variance (ANOVA) was used for comparisons of the ED50, and the Tukey multiple comparison test was used for multiple comparisons between groups. Based on the study by Paul and Fisher, patients were enrolled until 6 crossovers were obtained [21]; therefore, we could complete the study enrollment when we had enrolled 64 patients. A P value <0.01 was considered statistically significant.

Results

The patient characteristics and demographic data were not signifigantly different among the 3 groups (Table 3). One patient in Group 1 and 1 patient in Group 2 required general anesthesia due to technical difficulty during epidural space detection; these patients were excluded from the analysis. Sixty-two patients were punctured successfully and felt sensations of heat or numbness in the leg and sacral dermatomes within 2 min, indicating that the study drug had been correctly injected into the subarachnoid space. In Group 3, there were 3 patients whose motor nerves were not blocked completely during the entire period of surgery (Bromage scale <2). There was 1 patient each in Group 2 and 3 whose level of analgesia did not allow surgery; therefore, they were administered epidural supplement drugs. One patient in Group 3 needed epidural supplementation because of longer surgery. One patient in group 1 needed general anesthesia because the sensory block level was insufficient to start surgery. These patients were excluded from the data collected for duration of motor block. The number of patients who needed supplemental epidural anesthesia did not differ significantly among the 3 groups. Surgery was completed successfully in all enrolled patients.

There were no significant differences among the groups in maximum sensory block level at 5 min and 10 min after completion of spinal injection (Table 2). The sequences of effective and ineffective outcomes are shown in Figure 1. The ED50 for motor blockade of bupivacaine was 6.10 (95% CI 5.58–6.66) mg in Group 1, 6.04 (95% CI 5.82–6.28) mg in Group 2, and 5.43 (95% CI 5.19–5.67) mg in Group 3. The ED50 for motor block of bupivacaine was significantly different among groups (one-way analysis of variance: p=0.008), and the ED50 for motor block of Group 1 was significantly higher than Group 3 (Tukey multiple comparison test: p=0.005). Using probit regression analysis, the ED50 for motor block was 6.04 (95% CI 5.10–6.89) mg in Group 1, 5.90 (95% CI 5.35–6.42) mg in Group 2, and 5.30 (95% CI 5.05–5.57) mg in Group 3 (Table 4).

Discussion

The present study showed that the ED50 for motor block in older patients was significantly different when various concentration of intrathecal plain bupivacaine solutions were used, which was significantly higher when 0.75% bupivacaine was used compared to when 0.25% bupivacaine was used.

This study used the motor blocking minimum local anesthetic dose methodology to assess the motor block potencies of various concentrations of anesthetic solution, administered as spinal anesthesia, in older patients. This approach for estimating ED50 has been described in previous studies [3–5].

Camorcia et al. reported that the ED50 for motor block of intrathecal ropivacaine was 50% higher in a 0.1% solution [23], but this trend was not consistent with our present findings. This phenomenon can be explained as follows. First, plain ropivacaine has lower lipid solubility, which results in lower distribution of ropivacaine into the cord. Second, the plain ropivacaine solution is slightly hypobaric, and the spread is likely to be more dependent on other factors such as injection rate, and volume and doses of ropivacaine. This may result in unpredictable effects, as reported by others [24,25]. Finally, the great difference of anesthetic concentration (a 10-fold difference) results in a different trend. In the present study only a 3-fold difference in hyperbaric bupivacaine was used for spinal anesthesia. Peng et al. [26] observed that slightly increasing local anesthetic concentration (lidocaine), and comparing it with a small increase in the dose at a lower concentration, achieved the same degree of motor and sensory block. However, with the plain bupivacaine in the present study, we noted that the doses for motor block were higher in the higher concentration group. This is probably because the density of the local anesthetic solution determines the spread of the anesthetic drugs. According to previous research using highly precise equipment to accurately measure the density of commonly used intrathecal drugs in human CSF at 37°C, plain bupivacaine is indeed hypobaric [27–29].

In a previous study, we determined the ED50 for motor block with 0.75% plain bupivacaine for spinal anesthesia, and compared the values between adults of various age groups. The ED50 was found to be 5.78 mg in adults aged 70–80 years [5], which is similar to the result of the present study. Furthermore, we have measured the ED50 for motor block of 2 different concentrations of bupivacaine (0.375% and 0.75%) in young patients, and observed that the ED50 for motor block of intrathecally administered bupivacaine with higher concentration (0.75%) was higher (9.998 mg) than that of a lower concentration (0.375%, 8.890 mg) [9]. Age-related differences probably remained, and were justified before.

Many factors influence the level of spinal sensory anesthesia, including the dose and volume of the anesthetics and the lumbosacral CSF volume. Lee et al. [30] found that the ratio of the long axis and the transection area of the abdomen also affected maximal spinal level. In this study, although dosage variations existed between different individuals and also the volume of bupivacaine solution was different in different groups, the level of sensory analgesia was similar at 5 min and 10 min after spinal injection, differing by just 1 or 2 sensory dermatomes among the 3 groups. This is probably because the volumes of local anesthetic used in our current study (<3 mL) are substantially lower than the lumbosacral CSF volumes, which have been reported to range from 42.7 to 81.1 mL [31]. Previous studies have also shown that the volume of intrathecal bupivacaine is not an important determinant of local anesthetic spread [32].

Kim et al. [33] and Bachmann et al. [34] achieved a T10 sensory peak block level using low hyperbaric bupivacaine doses (6 and 7 mg, respectively) and used head-down tilt to reach it, thus explaining the differences with our work (lower sensory block level reached). For reducing the incidence of hypotension and fast recovery from anesthesia, Errando et al. [35,36] used very low hyperbaric bupivacaine doses (3.75 mg) at very low concentration (0.25%) for fracture repair in the elderly, but some of their patients needed intravenous anesthesia rescue in hip fracture repair surgery. In our study, we determined the ED50 was 5.43 mg in 0.25% plain bupivacaine, a slightly higher dose.

The average duration of motor block in the 3 groups assessed here was 150~220 min, with no significant difference among groups.

The limitations of our study are:

Moreover, as we have previously described [5,9], although the up-and-down method is often used in small samples to determine the ED50 of a drug, the ED95 cannot be accurately assessed using this approach. Therefore, further investigations are required to determine the ED95 of bupivacaine for different anesthetic concentrations and injection volumes. In addition, although our results showed statistically significant differences, in the clinical setting these could be less important.

Conclusions

The concentration of bupivacaine solutions affects the ED50 for motor block with intrathecally administered bupivacaine in elderly patients. The ED50 doses of these 3 concentrations were significantly different and the dose of 0.75% bupivacaine was significantly higher than that of 0.25% bupivacaine.