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Anesthesia & Analgesia:
doi: 10.1213/ANE.0000000000000147
Regional Anesthesia: Research Report

The Effect of Age on the Median Effective Dose (ED50) of Intrathecally Administered Plain Bupivacaine for Motor Block

Chen, Mingquan MD; Chen, Chun; Ke, Qibin

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From the Department of Anesthesiology, The First College of Clinical Medical Science, China Three Gorges University, Yichang, China.

Accepted for publication xxx.

Funding: This study received no funding, but was supported at institutional and departmental levels by the Department of Anesthesiology, First College of Clinical Medical Science, China Three Gorges University, China.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Mingquan Chen, MD, Department of Anesthesiology, The First College of Clinical Medical Science, China Three Gorges University, Yichang 443003, China. Address e-mail to cmq2003@hotmail.com.

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Abstract

BACKGROUND: In this study, we sought to determine the median effective dose (ED50) for motor block of intrathecally administered plain bupivacaine in adults (20–80 years) and to assess the effect of age on ED50 required for motor block.

METHODS: This study was performed in 129 adult patients undergoing transurethral, urological, or lower limb surgery under combined spinal and epidural anesthesia. Patients were stratified according to age as follows: 20 to 30, 31 to 40, 41 to 50, 51 to 60, 61 to 70, and 71 to 80 years. The spinal component of the anesthetic was established by bolus administration of up-and-down doses of 0.75% plain bupivacaine, determined by Dixon’s method. The degree of motor block after intrathecal administration of each dose was evaluated by the modified Bromage and hip motor function score. The ED50 values were estimated from the up-and-down sequences using the method of Dixon and Massey and logistic regression. Other end points were included on the basis of sensory block level, duration of motor blockade, hypotension, and vasopressor requirements.

RESULTS: ED50 for motor block using intrathecal bupivacaine was 10.22 mg (95% confidence interval [CI], 9.96–10.49 mg) in 20- to 30-, 9.52 mg (95% CI, 9.02–10.07 mg) in 31- to 40-, 8.37 mg (95% CI, 7.56–9.26 mg) in 41- to 50-, 7.30 mg (95% CI, 6.84–7.79 mg) in 51 to 60, 6.55 mg (95% CI, 6.01–7.13 mg) in 61- to 70-, and 5.78 mg (95% CI, 5.01–6.67 mg) in 71- to 80-year-old patients. The maximum cephalic analgesic level was L1-L2 level at 5 minutes and T10-L1 at 10 minutes after administration of intrathecal plain bupivacaine in the 6 age groups. There was a significant difference in the duration of motor blockade among groups.

CONCLUSION: The ED50 for motor block of intrathecally administered plain bupivacaine decreased steeply with advancing age.

Previous studies have revealed that the baricity, dosage, volume, and concentration of local anesthetic are important factors determining the maximal spread as well as the sensory and motor blockade of spinal anesthesia.1–4 The effects of age on spinal anesthesia with intrathecal plain bupivacaine remain controversial, because some studies showed a faster onset and a higher level of analgesia with advancing age,5,6 while others found no correlation with age.7–9 However, using a hyperbaric solution, faster onset and a higher level of analgesia were demonstrated with minimal influence of advancing age.10,11 Because these studies used full doses of local anesthetics, they evaluated the level of sensory block and the time to maximum motor blockade and seldom focused on the potency of motor blockade of local anesthetics with age. Moreover, there were large variations in age in their study groups.

Previous studies have proposed a clinical model using the up-and-down sequential allocation technique to evaluate the relative potencies of local anesthetics among parturients.12–14 Using this methodology, the median effective dose (ED50) of the minimum local anesthetic dose for motor blockade (MMLAD) was determined, which can also be used to determine the motor-blocking potency ratios for local anesthetics.15,16 It is also possible to use this methodology to determine the motor block potency of bupivacaine according to patient age. However, the appropriate age-dependent doses of plain bupivacaine for motor blockade have not been determined, nor has the ED50 until now. In addition, the effect of age on spinal anesthesia with smaller doses of 0.75% plain bupivacaine has not yet been determined.

The aim of this study was to determine the ED50 for motor block of intrathecally administered 0.75% plain bupivacaine in adult patients and to determine the effect of age on the dose required for motor block.

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METHODS

This study was approved by the Ethics Committee of the First College of Clinical Medical Science, China Three Gorges University (Yichang, China). Written informed consent was obtained from all enrolled patients. This study was conducted at the Department of Anesthesiology, First College of Clinical Medical Science, China Three Gorges University between July 15, 2010, and July 15, 2012. There were 129 ASA physical status I and II adult patients undergoing transurethral, urological, or lower limb surgery, primarily under the spinal component of established combined epidural and spinal anesthesia, with the epidural component to be used if there was a need for intraoperative analgesic supplementation or for postoperative analgesia. Patients with diabetes, obesity, neuromuscular diseases, bleeding diathesis, hypersensitivity to amide local anesthetics, lumbar vertebrae abnormality, chronic back pain, or who were pregnant were excluded from this study. The ED50 was determined in subjects stratified according to age as follows: 20 to 30 (group 1), 31 to 40 (group 2), 41 to 50 (group 3), 51 to 60 (group 4), 61 to 70 (group 5), and 71 to 80 years (group 6).

Spinal block was established by bolus administration of up-and-down doses of 0.75% plain bupivacaine. The first anesthesiologist who performed the anesthesia procedure had >18 years of clinical experience and was blinded to the results. The second anesthesiologist who assessed the patients and collected the data was blinded to the intrathecally administered local anesthetic dose. The third anesthesiologist prepared the study drug, including concentration, volume, and dose, according to the second anesthesiologist’s results.

All patients were premedicated with midazolam (0.15–0.2 mg/kg IM) and atropine (0.5 mg IM) 30 minutes before establishing the spinal component of the combined spinal and epidural anesthesia. Noninvasive arterial blood pressure (NBP), electrocardiogram, and oxygen saturation were monitored (Datex-Ohmeda, Helsinki, Finland). Fluid administration was performed before the spinal block with IV infusion of 500 mL lactated Ringer’s solution. Combined epidural and spinal anesthesia was performed with the patient in left lateral decubitus position, using palpation of the iliac crests to identify the L3/4 interspace. A 16-gauge Tuohy needle (connected to an air-filled 2-mL syringe) was inserted in this interspace via a midline approach and advanced until its tip entered the epidural space, which was identified by the sudden loss of resistance to air technique. The air injected during identification of the epidural space was <2 mL. After identification of the epidural space, a 25-gauge Whitacre spinal needle was introduced through the Tuohy needle and advanced until clear drops of cerebrospinal fluid (CSF) fell from the spinal needle. At this point, the initial dose of bupivacaine was injected into the subarachnoid space at a rate of 0.1 mL/s. The spinal needle was withdrawn, and a 20-gauge epidural catheter was inserted through the Tuohy needle, with the aim of introducing 3 cm of catheter into the epidural space in the cephalad direction. Immediately after insertion of the epidural catheter, removal of the Tuohy needle, and catheter fixation, the patient was placed in supine position and then repositioned according to surgical requirements at the end of the preoperative assessment.

The commercially available plain solution of 0.75% bupivacaine was used in this study. The concentration of anesthetic solution was kept constant (0.75% plain bupivacaine) in spinal anesthesia for all patients, and only the volume was adjusted according to the preceding result. According to previous studies,16,17 considering the differences between parturients and nonparturient patients and clinical measurements, the initial dose was 7.50 mg bupivacaine (1.0 mL plain solution of 0.75% bupivacaine), and the testing interval was 0.75 mg (0.1 mL), which was prepared in a syringe immediately before injection.

The doses varied according to the up-and-down method for the evaluation of the spinal ED50 for local anesthetics.18 Up-and-down sequential allocation of bupivacaine doses was performed according to the motor effect of the previous patient in each group. The efficacy of the administered bupivacaine dose was assessed using the Bromage scale19 and the hip motor function scale20 (Table 1) every minute for the first 5 minutes and at 10 minutes after the end of intrathecal injection of bupivacaine.

Table 1
Table 1
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The end point was determined according to the degree of motor power in any lower limb (according to the modified Bromage scale and the hip motor function scale) within 5 minutes after intrathecal administration of the tested bupivacaine dose. If the detected motor power score was equal to 0 in either leg within 5 minutes after intrathecal administration of any tested bupivacaine dose, motor blockade was considered a failure, and the bupivacaine dose was increased by 0.75 mg in the next patient of the same group. In contrast, if the detected motor power score was >0 in either leg within 5 minutes after intrathecal administration of any tested bupivacaine dose, motor block was considered successful, and the bupivacaine dose was decreased by 0.75 mg in the next patient of the same group. The mean dose of bupivacaine required for motor block was obtained from the midpoints of the crossover from failure to success. According to the study by Paul and Fisher,21 individual experiments might produce inaccurate estimates, and the inaccuracy can be minimized as the number of crossovers increases; however, improvement diminished as the number of crossovers exceeds 6. Therefore, the patients in our studies were enrolled until 6 crossovers were obtained.

To ensure that the drug was correctly administered into the subarachnoid space, sensory block was evaluated by assessing changes to pinprick sensation using a 25-gauge needle every minute up to 5 minutes (i.e., the number of blocked lumbar and sacral dermatomes, bilaterally). If sensory block was achieved within 5 minutes, subarachnoid administration of the anesthetic was considered correct. Otherwise, it was considered a technical failure, and the same dose was repeated in the next patient of the same group. At the same time, the highest sensory block level detected by pinprick sensation in the midaxillary line was detected and recorded. The time until full recovery from sensory and motor blockade was also detected and recorded.

In the event that spinal sensory blockade was unsatisfactory, supplemental epidural administration (via the preplaced epidural catheter) of 3 mL of 2% lidocaine was given and was repeated after 5 minutes until adequate sensory block level was achieved. If the patient was still uncomfortable during the surgical procedure despite repeated supplemental epidural administrations of lidocaine, general anesthesia was performed. The number of patients who required supplemental epidural analgesia, general anesthesia, and the total volume of the administered local anesthetic were recorded. Postoperative side effects, such as urine retention, pain, and postspinal headache, were recorded.

NBP and heart rate were recorded at 5-minute intervals during the procedure. Hypotension was defined as a mean NBP decrease by >30% compared with the preanesthetic value, or to <90 mm Hg, and rapid correction was provided by administration of 5 mg ephedrine sulfate IV. Bradycardia was defined as a heart rate decrease <55 beats/min, and rapid correction was provided by administration of 0.25 mg atropine sulfate IV.

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Statistical Analysis

Statistical analysis was performed using SPSS 17.0 for windows (SPSS Inc., Chicago, IL). Data are expressed as mean (SD), median (range), and count as appropriate. Demographic data were collected and presented as mean (SD). Means (SD) were analyzed using 1-way analysis of variance, and the least significan difference method was used for multiple comparison tests among groups. Counts were analyzed using the Fisher exact test. The ED50 was estimated from the up-and-down sequences using the method of Dixon and Massey22 and logistic regression. The ED50 was analyzed using analysis of variance and followed by post hoc pairwise comparisons with Bonferroni correction. The mean dosage was determined from the midpoints of all independent pairs of patients involving a crossover from failure to success. According to the study by Paul and Fisher,21 patients were enrolled until 6 pairs were obtained. A P value <0.01 was considered statistically significant.

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RESULTS

Demographic data among the different age groups were similar except weight (Table 2). Sensory block was achieved within 5 minutes after intrathecal administration of bupivacaine in all patients. Analgesia was adequate for surgery in all patients, and all enrolled patients successfully completed their surgery. No patient had headache after the operation, and no patient required general anesthesia or heavy sedation.

Table 2
Table 2
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The sequences of effective and ineffective outcomes are presented in Figure 1. Using the formula of Dixon and Massey,22 the ED50 for motor block of intrathecal bupivacaine was 10.22 mg (95% confidence interval [CI], 9.96–10.49 mg) in group 1, 9.52 mg (95% CI, 9.02–10.07 mg) in group 2, 8.37 mg (95% CI, 7.56–9.26 mg) in group 3, 7.30 mg (95% CI, 6.84–7.79 mg) in group 4, 6.55 mg (95% CI, 6.01–7.13 mg) in group 5, and 5.78 mg (95% CI, 5.01–6.67 mg) in group 6 (Table 2 and Fig. 2).

Figure 1
Figure 1
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Figure 2
Figure 2
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The maximum cephalic analgesic level was L1-L2 level at 5 minutes and T10-L1 at 10 minutes after intrathecal bupivacaine administration (Table 3). The duration of motor block was significantly different among groups (Table 2). The number of patients who needed intraoperative supplemental epidural analgesia was not different among the 6 groups (Table 2).

Table 3
Table 3
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Hemodynamic variables were kept stable during anesthesia and surgery in all patients, and no hypotension or bradycardia events occurred during surgery.

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DISCUSSION

This is the first study using MMLAD methodology to specifically assess the ED50 for motor block of intrathecally administered 0.75% plain bupivacaine stratified by age. MMLAD methodology is a very useful tool for estimation of ED50, producing strong results while requiring fewer patients to be enrolled.16,17

We found that the MMLAD with bupivacaine decreased steeply with advancing age. This effect was similar to the study by Li et al.,23 in which the median effective concentration (EC50) of ropivacaine for motor block with epidural anesthesia in different age groups (≥70 years, <70 years) was compared and found that the motor block EC50 of ropivacaine decreased significantly with advancing age. It is interesting that in both studies, consistency in the direction of motor block potency was obtained, although the local anesthetic was different. Therefore, it seems that local anesthetic potency was increased in older rather than younger patients, regardless of administration route, epidural or intrathecal.

In our study, the motor block ED50 of intrathecal bupivacaine was decreased almost by half in older patients, being 10.22 mg in younger patients and 5.78 mg in older patients. Several possible explanations may account for this phenomenon. First, CSF volume progressively decreases with age,24,25 leading to higher CSF concentrations of anesthetic in older patients, which may contribute to the faster onset of sensory and motor blockade after intrathecal administration of local anesthetic.8 Second, the biochemical characteristics and anatomical structure of the spinal cord change significantly with advancing age,26 and consequently, local anesthetic drugs may have a greater effect on motor nerves in older patients. Thus, the dose requirement for motor blockade was markedly reduced with advancing age. Furthermore, anatomical changes in lumbar and thoracic vertebrae,27 axonal degeneration, reduced number of nerve fibers, and increased mass of connective tissue within peripheral pathways can also reduce local anesthetic requirements.26,28

Camorcia et al.16 reported the ED50 for motor block in parturients to be 3.44 mg, while in our study, it was larger (10.22 mg) in the youngest group (group 1). The reason for this large variation might have been due to the difference in types of patients. Although patients in the study by Camorcia et al.16 were young, all of them were parturients, whereas none of the patients in our study were pregnant. Many physiological characteristics (including lumbar lordosis, volume, and density of CSF) are different between parturient and nonparturient patients.29–32 These factors might have played a role in the differences in the ED50 for motor block.

Previous studies reported that the effects of age on spinal anesthesia with intrathecal full doses were controversial and the effects of age on the maximal level of analgesia with full doses were not obvious regardless of the baricity of bupivacaine.6,7,10,11 The reason might be the large variation in age.6,8,10,11 Results in those studies could have been more precise if patients had been stratified according to many age groups, each covering a smaller age span, as in the present study. In our study, the highest anesthesia level was from L1 to T10 in the 6 groups, which was lower by 2 sensory dermatomes than these previous studies. This could have been due to the mean doses in our study, which were at least one-third less than the doses in these previous studies. When the doses were reduced, the effects of age on the bupivacaine requirement for motor blockade became more apparent.

The duration of motor blockade was longer as the patient’s age increased with full doses of plain bupivacaine, being 286 minutes in younger patients and 320 minutes in older patients as reported by Veering et al.8 However, in our study, the duration of motor block was 200 minutes in older patients and 256 minutes in younger patients. This could have been due to the fact that doses were lower in the older group than in the younger group. The duration of motor blockade was related to intrathecally administered doses. Therefore, it is reasonable that the duration of motor blockade was shorter in older patients.

In our study, the doses and volume of solution were adjusted according to the guidelines from previous studies.16,33 While we adjusted doses, we changed the solution volume (although potentially only 0.1 mL). This change in solution volume may, or may not, have affected the ED50 for motor block. Thus, this is a limitation of the present study. Likewise, the up-and-down method is often used in small samples to determine the ED50 of a drug. Many studies used logistic regression to determine the ED50 of a drug.34,35 However, the up-and-down method cannot provide reliable insight into the upper tail of distribution. Hence, the ED95 of bupivacaine could not be accurately assessed in the present study. This is a limitation of the present study, and the ED95 of bupivacaine requires further investigation.

In conclusion, the ED50 for motor block of intrathecally administered bupivacaine decreased steeply with advancing age, indicating that age had an influence on the potency of intrathecal bupivacaine.

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DISCLOSURES

Name: Mingquan Chen, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Mingquan Chen has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Name: Chun Chen.

Contribution: This author helped conduct the study.

Attestation: Chun Chen has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Name: Qibin Ke.

Contribution: This author helped conduct the study.

Attestation: Qibin Ke has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

This manuscript was handled by: Terese T. Horlocker, MD.

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