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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionAppendix 1References |
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We determined the minimum effective anesthetic concentration (MEAC) of bupivacaine for spinal anesthesia, defined as the median effective concentration at which a spinal anesthetic produces surgically equivalent anesthesia within 20 min of administration in 50% of human subjects. Two doses of spinal bupivacaine (7.5 mg and 10 mg) were administered to 45 volunteers (19–39 yr) in a randomized, double-blinded fashion. Hyperbaric bupivacaine solutions of 0.1% to 0.75% containing 8.25% dextrose were administered intrathecally and MEAC established by using the Dixon’s up-and-down method. Complete anesthesia was defined as: 1) pinprick anesthesia at or higher than T12; 2) anesthesia to transcutaneous tetanic electric stimulation (50 Hz at 60 mA for 5 s) in the knees; and 3) complete leg paralysis, all occurring in both lower extremities within 20 min of intrathecal injection. We found that the MEAC of spinal bupivacaine was 0.43% (95% confidence interval 0.24–0.62) when 10 mg was administered. At this dose, a concentration as low as 0.1% could provide complete anesthesia, but consistent blockade was obtained only with the 0.7% solution. The 7.5-mg dose failed to provide complete anesthesia consistently, even in the presence of 0.75% (maximum). The current commercially available 0.75% concentration of hyperbaric bupivacaine seems to be clinically optimal when 10 mg is used if complete bilateral lower extremity blockade is desired.
Implications: The value of the minimum effective anesthetic concentration for hyperbaric spinal bupivacaine is dose-dependent. Complete anesthesia can be achieved with smaller concentrations when the dose of spinal anesthetic is increased. The current commercially available 0.75% concentration of hyperbaric bupivacaine seems to be clinically optimal when 10 mg is used if complete bilateral lower extremity blockade is desired.
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Spinal bupivacaine is commercially available as a hyperbaric 0.75% solution in North America, and in concentrations as large as 1% in Europe. Previous studies have shown that 0.125% isobaric bupivacaine is effective for spinal anesthesia, and as effective as a 0.5% solution when bupivacaine 15 mg is administered for cesarean delivery (1). The observed difference in sensory block level, higher after the administration of 12 mL of 0.125% bupivacaine than 3 mL of 0.5%, dissipates rapidly when the parturients are turned supine from the lateral decubitus position. Other investigators also found little difference in the onset or duration of motor or sensory block produced by 15 mg of bupivacaine in a 0.5% or 0.25% solution (2). However, it is unclear whether dilute bupivacaine is as effective as the standard hyperbaric 0.75% solution when a smaller dose (<15 mg), as is commonly used for spinal anesthesia for short outpatient procedures (3), is administered.
Recently, we examined the concept of minimum effective anesthetic concentration (MEAC) for spinal lidocaine (4). Similar to the minimum alveolar anesthetic concentration (MAC) for inhaled anesthesia, MEAC is defined as the median effective concentration of a local anesthetic at which 50% of individuals (EC50) will satisfy the following anesthetic criteria within 20 min of spinal administration: 1) complete loss of response to pinprick at 
T12 level bilaterally; 2) anesthesia to tetanic electrical stimulation at the knee (L2-3 dermatome) bilaterally; and 3) complete motor block in both lower extremities. Using these strict criteria, we found that the MEAC of hyperbaric spinal lidocaine was dose-dependent (i.e., 0.54% when 48 mg was injected and <0.3% when 72 mg was injected) (4). These data confirm that the commercially available 5% solution is well above what is needed for spinal lidocaine anesthesia clinically. However, whether this is also true for commercially prepared spinal bupivacaine is unknown, and this determination was the goal of the present study.
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Methods |
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We conducted a prospective, randomized, double-blinded study to determine the MEAC of hyperbaric bupivacaine for spinal anesthesia in volunteers given either 7.5 mg or 10 mg. After obtaining institutional review board approval and informed consent, we studied 45 healthy ASA physical status I volunteers. The study of the 7.5-mg dose preceded that of the 10-mg dose.
Within each treatment group, the dose (7.5 mg or 10 mg) was kept constant, but the concentration of bupivacaine administered was preselected based on the modified Dixon’s up-and-down method (5). Specifically, depending on the motor and sensory responses to the previous concentration, the test concentration for the next volunteer would be adjusted up or down in increments of 0.1%. For example, if a volunteer developed complete anesthesia after a given concentration, the next volunteer in the same treatment group would receive a more dilute bupivacaine solution reduced by 0.1%. If anesthesia was incomplete, the next volunteer would receive a solution increased by 0.1%. The administered bupivacaine concentration ranged from 0.4% to 0.75% in the 7.5-mg group and from 0.1% to 0.7% in the 10-mg group. The anesthesiologist performing spinal anesthesia was aware of the composition of the test solution, but both the volunteer and the investigator performing neurologic assessment were blinded.
Hyperbaric spinal bupivacaine solutions we tested were prepared by mixing hyperbaric bupivacaine 0.75% with plain dextrose 8.25% solution to maintain the same dextrose content as the commercially available 0.75% solution. The dextrose 8.25% solution was prepared by mixing 3 mL of dextrose 10% solution with 0.6 mL of sterile water. In the 7.5-mg group, the total drug volume ranged from 1.9 mL to 1 mL for bupivacaine concentrations ranging from 0.4% to 0.75%, respectively; in the 10-mg group, the total injected volume ranged from 10 mL to 1.4 mL, for a concentration ranging from 0.1% to 0.7%, respectively. For example, a 0.5% solution was prepared by mixing 2 mL of 0.75% bupivacaine with 1 mL of dextrose 8.25% solution. To test the 0.5% solution, volumes of 1.5 mL and 2 mL, respectively, were used for the 7.5- and 10-mg doses.
After an overnight fast of at least 8 h and voiding immediately before study, each volunteer received an IV cannula through which normal saline was infused, initially at 6 mL/kg over 15 min, then at 4 mL · kg-1 · h-1 for 1 h and 2 mL · kg-1 · h-1 thereafter. With the volunteer in the lateral decubitus position, spinal anesthesia was induced in an aseptic fashion by advancing a 25-gauge Whitacre needle at the midline of the L2-3 or L3-4 interspace until reaching the subarachnoid space, as indicated by outflow of cerebrospinal fluid (CSF). The needle orifice was oriented toward the nondependent side of the volunteer before spinal anesthetic injection of bupivacaine at a rate of approximately 1 mL per 5 s. Immediately after needle withdrawal, the volunteer was positioned supine for the remaining study period. Volunteers were monitored by using electrocardiography, noninvasive automatic blood pressure measurement, and pulse oximetry. No sedative was given.
For each volunteer, we determined the following: 1) sensation to pinprick by using a 23-gauge needle to determine the peak sensory dermatomal level bilaterally; 2) sensation to transcutaneous electrical stimulation (TES) by applying a nerve stimulator bilaterally at the L2-3 dermatome (medial aspect above the knee); and 3) degree of motor block measured by using modified Bromage scale (0 = no block; 1 = hip movement block; 2 = hip and knee block; and 3 = complete block in hip, knee, and ankle). TES was determined by a 5-s stimulus of 50 Hz tetanus that was delivered in 10 mA increments until the volunteer reported the stimulus as a "tingling painful" sensation or we delivered a total of 60 mA, equivalent to a noxious surgical stimulus (6). Complete anesthesia was defined as a loss of sensation to pinprick T12 level bilaterally, anesthesia to TES at the knee bilaterally, and complete motor block in both lower extremities within 20 min after the injection of bupivacaine solution.
Anesthesia was assessed in all volunteers at 5-min intervals for 30 min after bupivacaine injection, then every 10 min for 30 min, followed by every 15 min until complete recovery from block. The times to peak sensory and motor block and the times to two segment regression and complete sensory block resolution were recorded, as was the duration of motor block, and anesthesia to TES. Hemodynamic data were collected at baseline before the induction of anesthesia and then during the same time intervals as the neurologic assessment.
For 3 days after the day of study, volunteers were monitored daily by telephone interview for symptoms of postdural puncture headache, back pain, and transient neurologic symptoms defined as pain and/or dysesthesia in the legs or buttocks that happens after recovery from spinal anesthesia and resolves within 3 days.
Demographic, hemodynamic, and anesthetic data from the two treatment groups were compared by using Student’s t-test for continuous variables and Fisher’s exact test for nominal variables. Values are reported as the median (range) for discrete variables and mean ± SD for continuous variables. Multiple linear regression analysis was used to determine any correlation between the administered concentration/volume of spinal bupivacaine and the level and duration of sensory block, motor block, and TES. Statistical significance was accepted at P < 0.05.
MEAC was determined according to the formula of Dixon and Massey (5), and a minimum of four independent crossovers was obtained (i.e., a sequence of complete block–incomplete block–complete block–incomplete block represents two independent crossovers). The estimated median of MEAC is 
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Forty-five volunteers entered the study: 12 received 7.5 mg bupivacaine and 33 received 10 mg. Demographic data were similar for the two treatment groups (7.5-mg group 10-mg group: 28 ± 5 vs 29 ± 7 yr, 174 ± 7 vs 173 ± 8 cm, 66 ± 7 vs 70 ± 12 kg). Spinal anesthesia was successfully performed in all volunteers (6 men/6 women in the 7.5-mg group and 18 men/15 women in the 10-mg group) without technical failure.
Of the 12 volunteers who received 7.5 mg bupivacaine, only two developed complete anesthesia: one after 0.5% and the other after 0.7% (Fig. 1). When anesthesia was incomplete after the injection of 0.7% solution, we increased the maximum concentration to 0.75% (the maximum concentration available). When incomplete anesthesia occurred in five consecutive volunteers with the 0.75% solution, we terminated administration of the 7.5-mg dose, bringing the total to 10 volunteers with incomplete block in this group. The reasons for anesthetic failure were incomplete motor block in eight volunteers, incomplete pinprick anesthesia in five volunteers, and incomplete anesthesia to TES in nine volunteers (the reasons for incomplete anesthesia overlap in some volunteers). Accordingly, we could not determine the value of MEAC in the 7.5-mg group.
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Based on results from 33 volunteers, the MEAC of 10 mg hyperbaric bupivacaine was 0.43% (95% confidence interval 0.24–0.62). Complete anesthesia occurred in 17 volunteers within 20 min after receiving bupivacaine solutions ranging from 0.1% to 0.7% (Fig. 2). In these 17 volunteers, peak sensory anesthesia level was T7 (median, range T2–12), occurring at 15 min (median, range 10–20 min). The respective times to two-segment regression and complete sensory block resolution were 60 min (median, range 20–125 min) and 255 min (median, range 135–455 min), respectively. Motor block was complete within 10 min (median, range 5–20 min) of bupivacaine injection and lasted for 150 min (median, range 75–385 min). Anesthesia to TES was observed within 10 min (median, range 5–20 min) and lasted for 95 min (median, range 15–185 min). The pattern of incomplete anesthesia found in the remaining 16 volunteers was: incomplete motor block in 13, incomplete sensory block in 6, and incomplete anesthesia to TES in 10 (the reasons for incomplete anesthesia again overlap in some volunteers).
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In the 17 volunteers who had complete anesthesia after 10 mg, the anesthetic effect of 1.4 mL of 0.7% bupivacaine did not differ statistically from the effect of 10 mL of 0.1%. Multiple linear regression analysis did not show correlation between the volume or concentration administered and the following variables: peak level of sensory block (Fig. 3), onset of sensory anesthesia, duration of sensory anesthesia, onset of motor block, duration of motor block, onset of anesthesia to TES, and duration of anesthesia to TES.
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The mean maximal decline in systolic, diastolic, and mean blood pressure and heart rate was 9%, 12%, 13%, and 13%, respectively, in the 10-mg group and that for the 7.5-mg group was 8%, 14%, 10%, and 14%, respectively. Symptomatic urinary retention developed in three male volunteers, necessitating urinary catheterization. Postblock followup did not reveal symptoms of postdural puncture headache or transient neurologic symptoms in any of the volunteers. Transient back soreness of a mild nature in eight volunteers was treated successfully with an oral nonopioid analgesic.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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We have recently introduced the concept of MEAC for spinal anesthetics similar to MAC for inhaled anesthetics (6). This pharmacological concept may help to define the relative potency of spinal anesthetics in humans in the clinical setting. Previous investigators have compared local anesthetic potencies in in vitro nerve preparation by determining the minimum blocking concentration (MBC), defined as the threshold concentration of a local anesthetic required to completely abolish, within 10–15 min, the action potential of an isolated nerve immersed in a bathing solution (7). However, the applicability of MBC to the clinical setting is limited by several major differences between the experimental and clinical conditions in which local anesthetic potencies are determined. Unlike in vitro experimental conditions, the dose of spinal anesthetic administered clinically does not produce a uniform anesthetic concentration within the CSF. Unlike MBC, the value of MEAC described herein indicates the administered local anesthetic concentration and does not reflect the actual CSF local anesthetic concentration that is not practical to measure clinically. Finally, the value of MEAC is the median effective concentration of a local anesthetic (EC50), not the 95% effective concentration as with MBC.
We determined a MEAC of 0.43% for the 10 mg dose of spinal bupivacaine. Interestingly, complete surgically equivalent anesthesia (as defined by the criteria provided in Methods) was achieved over a wide range of concentrations (i.e., from 0.1% to 0.7%). However, although dilute spinal bupivacaine solutions can be effective, the resultant anesthetic effect is highly variable. For example, incomplete anesthesia was observed in two of four volunteers (50%) who received the 0.1% solution and in two of six (33%) given 0.6%, whereas all volunteers given the 0.7% solution developed complete anesthesia (Fig. 2). This finding suggests that the commercially available 0.75% solution of hyperbaric spinal bupivacaine is appropriate for clinical use. In contrast, the commercially available 5% solution of spinal lidocaine is many times above the concentration required clinically and the determined MEAC value (4).
Our data show that block completeness is influenced by both spinal anesthetic concentration and dose. Our findings seem to contradict those of earlier studies reporting that anesthetic effect was influenced by the administered dose and not the anesthetic concentration. For example, van Zundert et al. (8) found that the anesthetic effect of 70 mg of spinal lidocaine was similar with solutions ranging from 0.5% to 10%. Nielsen et al. (2) found no difference in the onset, duration, or extent of anesthetic block in response to the administration of 15 mg of isobaric bupivacaine given as 0.25% or 0.5%. Similarly, Vucevic and Russell (1) found no major difference in block height among parturients when 15 mg of isobaric spinal bupivacaine was given in 0.125% or 0.5% solution, once parturients were positioned supine. These studies demonstrating a lack of effect of concentration on spinal anesthesia are based on the administration of relatively large doses of spinal lidocaine (70 mg) and bupivacaine (15 mg). The administered concentrations in these previous studies likely have exceeded MEAC of spinal lidocaine and bupivacaine. As we have shown previously, the MEAC of spinal lidocaine is less than 0.3% when 72 mg is given. It is therefore not surprising to find that 70 mg lidocaine given in 0.5% provides consistent surgical anesthesia in Van Zundert et al.’s (8) study. Likewise, it is not surprising to find that 0.125% bupivacaine is effective when 15 mg is administered, suggesting that the MEAC of spinal bupivacaine is less than 0.125% at this dose.
In the 10-mg group, the volume and concentration of bupivacaine administered varied seven-fold in the 17 patients who developed complete block. One may anticipate seeing a higher peak level of sensory anesthesia or a greater decline of arterial blood pressure after the administration of 10 mL of 0.1% solution than that after 1.4 mL of 0.7%. Interestingly, we did not observe such a correlation. This is consistent with the findings in van Zundert et al.’s (8) study when 70 mg of lidocaine was administered as a 0.5% or 10% solution. Neither the administered volume nor concentration affected the onset or duration of anesthesia measured by sensory, motor, or tetanic electrical testing.
In agreement with our earlier study on spinal lidocaine, the value of MEAC for spinal bupivacaine anesthesia is again found to be dose-dependent. Previously, we demonstrated a MEAC of spinal lidocaine of 0.54% at a dose of 48 mg and a MEAC of <0.3% at a dose of 72 mg (4). We have now determined a MEAC of 0.43% for spinal bupivacaine at a dose of 10 mg. Our failure to establish a value for MEAC for the 7.5-mg dose suggests that, when a smaller spinal anesthetic dose is administered, a larger concentration is required to achieve the same degree of motor and sensory block.
We were unable to determine the value of MEAC for 7.5 mg of hyperbaric spinal bupivacaine. Block was incomplete in 10 of 12 volunteers, manifested by unilateral (complete unilateral block in 3 of 12) or incomplete motor block and anesthesia to TES, even in the presence of a maximum 0.75% solution. These findings are consistent with those obtained in a spinal bupivacaine dose-response study (9), in which motor block, especially at the gastrocnemius, often was incomplete and of brief duration after the administration of 0.75% hyperbaric bupivacaine at a dose of 7.5 mg. Alternatively, in another study, the same dose of hyperbaric bupivacaine failed to provide complete motor block in 15 of 15 patients undergoing knee arthroscopy (3). The poor motor blocking characteristics of spinal bupivacaine may be caused by preferential blockade of sensory fibers. Thus, although small-dose spinal bupivacaine (5–7.5 mg) has been advocated as a substitute for spinal lidocaine for outpatient procedures, the degree of motor block achieved in the lower extremities would not be as complete as spinal lidocaine.
It is not clear whether the concept of MEAC is useful for defining the relative potency of spinal anesthetics in humans. Our data on spinal lidocaine and bupivacaine indicate that MEAC is dose-dependent and not a constant value. This is distinctly different from the MAC value determined for an individual inhaled anesthetic that is independent of the administered dose. Furthermore, MAC is determined at a state of equilibrium, whereas MEAC for spinal anesthetic is not. The clinical determination of MEAC is also different from the determination of MBC in vitro. The MBC represents the actual local anesthetic concentration to which the study nerve is exposed. MEAC, however, represents the administered local anesthetic concentration and not the actual CSF local anesthetic concentration in which the spinal nerves are immersed.
There are several limitations to this study. We have applied very strict criteria to define complete block-bilateral anesthesia, complete motor and sensory block in the lower extremities, and anesthesia to TES within 20 min after spinal injection. We chose the 20-min cut-off point because it is clinically relevant to expect block completion within 20 min of intrathecal anesthetic administration. Under these criteria, spinal bupivacaine 7.5 mg failed to provide complete anesthesia at a concentration as large as 0.75% solution (maximum), even though this dose of spinal bupivacaine is clinically useful for spinal anesthesia. Complete unilateral anesthesia was found in 3 of 12 volunteers. Although complete bilateral sensory and motor block are not necessary for surgery, we elected to apply strict criteria to ensure application of the same endpoints (i.e., an equal degree of sensory and motor block), when the anesthetic effect of one bupivacaine concentration was compared with another. By applying such strict criteria, we may have overestimated the concentration of spinal bupivicaine required for clinical spinal anesthesia. We recognize that 7.5 mg of bupivacaine 0.75% or 10 mg of bupivacaine 0.5% is adequate clinically, because bilateral complete block is often not necessary. Second, the MEAC of spinal bupivacaine reported herein applies to human subjects aged 19–39 years. The value of MEAC in an older population remains to be determined.
In summary, we found that the MEAC of hyperbaric spinal bupivacaine is dose-dependent. Under the present study conditions, the value of MEAC for 10 mg is 0.43%, but that for 7.5 mg cannot be determined (i.e., >0.75%, the maximum concentration used clinically). At 10 mg, bupivacaine concentrations ranging from 0.1% to 0.7% can provide complete bilateral sensory and motor block, but complete anesthesia was more consistently seen with the higher concentrations.
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Calculation of the 95% confidence interval for MEAC according to the Dixon’s up-and-down method.The standard deviation s = 1.62 d (S2/d2 + 0.029) and the variance
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where d = concentration increment of 0.1%, n = number of failed blocks.
And is true as long as S2/d2 is greater than 0.3 (S2/d2 is 2.7 in this study).
The 95% confidence interval for MEAC is
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where X = mean value of MEAC, G = constant depending on the ratio of d/s.
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Acknowledgments |
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The authors thank Winifred von Ehrenberg, PhD, for her excellent editorial assistance.
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Footnotes |
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Presented in part at the 1998 American Society of Regional Anesthesia annual meeting, Seattle, WA.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Vucevic M, Russel IF. Spinal anaesthesia for caesarean section: 0.125% plain bupivacaine 12 mL compared with 0.5% plain bupivacaine 3 mL. Br J Anaesth 1992;68:590–5.
[Abstract/Free Full Text] -
Nielsen TH, Kristoffersen E, Olsen KH, et al. Plain bupivacaine: 0.5% or 0.25% for spinal analgesia? Br J Anaesth 1989;62:164–7.
[Abstract/Free Full Text] - Ben-David B, Levin H, Solomon E, et al. Spinal bupivacaine in ambulatory surgery: the effect of saline dilution. Anesth Analg 1996;83:716–20.[Abstract]
- Peng PWH, Chan VWS, Perlas A. Minimum effective anaesthetic concentration of hyperbaric lidocaine for spinal anaesthesia. Can J Anaesth 1998;45:122–9.[Web of Science][Medline]
- Dixon WJ, Massey FJ Jr. Introduction to statistical analysis, 4th ed. New York:McGraw Hill, 1983:428–49.
- Petersen-Felix S, Zbinden AM, Fischer M, Thomson DA. Isoflurane minimum alveolar concentration decreases during anesthesia and surgery. Anesthesiology 1993;79:959–65.[Web of Science][Medline]
- de Jong RH. Local anesthetics, 1st ed. St. Louis, MO:Mosby, 1994:64–77.
- Van Zundert AA, Grouls RJ, Korsten HH, Lambert DH. Spinal anesthesia. Volume or concentration—what matters? Reg Anesth 1996;21:112–8.[Web of Science][Medline]
- Liu SS, Ware PD, Allen HW, et al. Dose-response characteristics of spinal bupivacaine in volunteers. Clinical implications for ambulatory anesthesia. Anesthesiology 1996;85:729–36.[Web of Science][Medline]
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