Determination of the Minimum Local Analgesic

Concentrations of Epidural Bupivacaine and Lidocaine

in Labor
Malachy 0. Columb, FRCA, and Gordon Lyons, FRCA
St. Jamess University Hospital, Leeds, United Kingdom
The aim of this study was to devise a clinical model to
determine the effective concentrations in 50% of pa-
tients (EC,,) for bupivacaine and lidocaine in the first
stage of labor and define EC,, as the minimum local
analgesic concentration (MLAC). This should allow the
determination of relative analgesic potency and, subse-
quently, the local anesthetic sparing efficacy of other
epidural analgesics. Parturients not exceeding 5 cm cer-
vical dilation who requested epidural analgesia were
enrolled. The two studies involved 81 women (bupiva-
Caine y1 = 41, lidocaine n = 40). After a lumbar epidural
catheter was placed, 20 mL of the concentration of local
anesthetic being tested was given. The concentration
was determined by the response of the previous patient
to a higher or lower concentration using double-
blinded, up-down sequential allocation. Efficacy was
assessed using loo-mm visual analog pain scores with
less than 10 mm within 1 h defined as effective. MLAC
was determined using the formula of Dixon and Mas-
sey. Results show MLAC bupivacaine 0.065% (95% con-
fidence interval [CI] 0.045-0.085), MLAC lidocaine
0.37% (95% CI 0.32-0.42), equivalent to 2 and 14 mmol
solutions, respectively. Thus bupivacaine was 5.7 times
more potent than lidocaine in weighted and 7 times
more potent in molar ratios at analgesic EC,,, in the
volume of local anesthetic studied.
(Anesth Analg 1995;81:833-7)
T
here has been a tendency to reduce the concen-
trations of local anesthetics used for epidural
analgesia in labor. This has been further accom-
plished by the addition of other epidural analgesics
such as opioids and clonidine (1,2). There are many
studies describing and comparing various recipes
for providing epidural analgesia (3-5). It is difficult,
however, to determine the contribution of each drug
to the overall efficacy of the analgesia. The reason for
this is the lack of pharmacodynamic data detailing the
analgesic dose-response relationships of epidural local
anesthetics. The aim of this research was therefore to
devise a clinical model that would allow the estima-
tion of the epidural analgesic EC,, of local anesthetics
in the first stage of labor. This was defined as the
minimum local analgesic concentration (MLAC). The
model was then used to determine the relative anal-
gesic potencies of bupivacaine and lidocaine.
This work has been presented in part at the Obstetric Anaesthe-
tists Association, Derby, United Kingdom, April 1994, and the
European Society of Regional Anaesthesia, Barcelona, Spain, May
1994.
Accepted for publication May 22, 1995.
Address correspondence to Malachy 0. Columb, FRCA, St.
Jamess University Hospital, Beckett St., Leeds, United Kingdom
LS9 7TF.
01995 by the International Anesthesia Research Society
0003-2999/95/$5.00
Using this model, it should be possible to assess the
local anesthetic sparing efficacy of the various opioids
and other analgesics by their effect on MLAC as the
dependent variable. This should facilitate the estima-
tion of epidural potency ratios for the different opioids
and describe any interactions in terms of synergy,
addition, or antagonism.
Methods
After institutional ethical approval, 81 parturients,
ASA physical status I and II, at more than 36 wk
gestation requesting epidural analgesia for labor pain
at 3- to 5-cm cervical dilation were enrolled. Women
who had received opioid or sedative medication were
excluded from the studies.
After starting an intravenous 0.9% saline infusion, a
lumbar epidural catheter was inserted. A midline ap-
proach with the patient in the flexed sitting position
was used. After skin infiltration with 1 mL of 1%
lidocaine the epidural space was located using loss of
resistance to saline at the L2-3 or L3-4 level. Loss of
resistance to saline was preferred to air for identifying
entry to the epidural space to reduce the occurrence of
epidural air pockets affecting spread. The volume of
saline used was restricted to less than 2 mL to reduce
Anesth Analg 1995;81:833-7 833
834 OBSTETRIC ANESTHESIA COLUMB AND LYONS ANESTH ANALG
ANALGESIC EC,, OF EPIDURAL BUPIVACAINE AND LIDOCAINE IN LABOR 1995;81:833-7
the possibility of dilution. The catheter was advanced
3 cm into the epidural space and aspirated. A test dose
was omitted for the purposes of the study. The patient
was then given a 20-mL bolus over 5 min of the
particular concentration of local anesthetic being eval-
uated. The concentration received by a particular pa-
tient was determined by the response of the previous
patient to a higher or lower concentration using the
technique of double-blinded, up-down sequential al-
location. Patients were monitored using routine non-
invasive hemodynamics and tococardiography.
The first study was conducted using bupivacaine
and involved 41 women. Lidocaine was used in the
second study and involved a further 40 women. The
injectate was freshly prepared using saline 0.9% to
dilute the local anesthetic to achieve 20 mL of the
desired concentration at room temperature (20C).
The assessment was performed by an observer who
was blinded to the concentration being tested. Efficacy
was assessed using loo-mm visual analog pain scores
(VAPS), where 0 represented no pain and 100 as
worst possible pain at 0, 30, and 60 min after the
bolus
1.
was injected. Three outcomes were considered:
Effective: VAPS less than 10 mm during con-
tractions within 60 min of the injection. A result
defined as effective directed a decrement for the
next patient.
Ineffective: VAPS greater than 10 mm due to
nonlocalizing pain, which responded to rescue
with a 12-mL bolus of 0.25% bupivacaine or 1%
lidocaine as appropriate. A result defined as
ineffective directed an increment for the next
patient.
Reject: VAPS greater than 10 mm due to local-
izing pain (segmental, unilateral, perineal) or
pain not responding to rescue. A result defined
as reject directed that the same concentration be
repeated for the next patient.
At 30 min subjects not defined as effective were
examined (using pinprick) for evidence of localizing
features such as unilateral, segmental, or perineal
sparing. Those patients demonstrating localizing fea-
tures were defined as rejects. The remainder were
given the rescue bolus if VAPS was larger than 30 mm
or at patient request. At 60 min any remaining patients
who had not requested the rescue bolus and had not
yet been defined as effective for the purposes of the
study were also given the rescue. Subjects not re-
sponding to the rescue bolus were also defined as
rejects.
Demographic and obstetric data were collected and
are presented as mean (SD) and median (range) as
appropriate. The up-down sequences were analyzed
using the formula of Dixon and Massey (6) which
enabled MLAC with 95% confidence interval (CI) of
Table 1. Demographic and Obstetric Data
Bupivacaine Lidocaine
Age (yr) 25.9 (5.5) 27.5 (4.7)
Height (cm) 162 (6.6) 163 (6.0)
Weight (kg) 74.1 (11.6) 75 (12.5)
Gestation (wk) 39.8 (1.1) 39.6 (1.73)
Cervical dilation (cm) 4.5 [3-51 4.5 [3-51
Nulliparous/multiparous 26/4 24/6
Oxytocin 4 3
Initial VAPS (mm) 79 [48-1001 77 [47-1001
Results are expressed as mean (SD), median [range], and count as
appropriate.
VAPS = visual analog pain score.
the mean to be derived. The data were also subjected
to logit maximum likelihood analysis as a back-up
sensitivity test.
Results
There were no significant demographic or obstetric
differences in the two studies (Table 1).
Of the 41 women entered into the bupivacaine
study, 11 were rejected (Table 21, leaving 30 for anal-
ysis. The sequences of effective and ineffective anal-
gesia are shown in Figure 1.
MLAC of bupivacaine was 0.065% (95% CI 0.045-
0.085) using the formula of Dixon and Massey (6) and
was 0.062% (95% CI 0.052-0.072) by logit analysis, in
the volume studied. MLAC 0.065% is equivalent to a
2-mm01 solution.
Of the 40 women entered into the lidocaine study,
10 were rejected (Table 2), leaving 30 for analysis. The
sequences of effective and ineffective analgesia are
shown in Figure 2.
MLAC of lidocaine was 0.37% (95% CI 0.32-0.42)
using the formula of Dixon and Massey (6) and was
0.36% (95% CI 0.31-0.41) by logit analysis, in the vol-
ume studied. MLAC 0.37% is equivalent to a 14-mmol
solution.
Discussion
The reason for establishing this clinical model was
derived from the need to determine the local anes-
thetic sparing potential of the various opioids used for
epidural analgesia in labor. Although EC,, is usually
more relevant clinically, we concluded that estimation
of EC,, would provide a more sensitive research tool
due to the respective positions of each on the cumu-
lative concentration-response curve. The EC,, corre-
sponds to the inflection point where the slope is larg-
est. Bupivacaine was studied first because it is the
most prevalent in use in the United Kingdom and is
the most commonly reported in opioid recipe regi-
mens. Lidocaine was then studied as the prototypical
ANESTH ANALG OBSTETRIC ANESTHESIA COLUMB AND LYONS 835
1995;81:833-7 ANALGESIC EC,, OF EPIDURAL BUPIVACAINE AND LIDOCAINE IN LABOR
Table 2. Distribution of Rejects
Bupivacaine No. of
% wt/vol rejects
Lidocaine
% wt/vol
No. of
rejects
0.11 1 0.6 1
0.08 1 0.45 1
0.07 2 0.4 2
0.06 3 0.35 3
0.05 3 0.3 2
0.04 1 0.25 1
0.167
MLAC Bupivacaine in Labor
n Effective
0 Ineffective
* 0021
0 10 20 30 40
Patient Number
Figure 1. EC,, bupivacaine as determined by the technique of up-
down sequential allocation. Minimum local analgesic concentration
(MLAC) is 0.065% which is equivalent to a 2-mmol solution. Error
bars represent 95% confidence interval of mean. Testing interval
was 0.01%.
1.2 -
MLAC Lidocaine in Labor
5 W Effective
8
1.0-w
0 Ineffective
Fi n
.-
2
L
;
0.8- n
z n
E
0 0.6- n
0
0.2 I I
0 10 20 3b 40
Patient Number
Figure 2. EC,, of lidocaine as determined by the technique of up-
down sequential allocation. Minimum local analgesic concentration
(MLAC) is 0.37% which is equivalent to a 14.mmol solution. Error
bars represent 95% confidence interval of mean. Testing interval
was O.l%, reduced to 0.05%.
amino-amide. In addition, the analgesic potency ratio
could be determined and will be discussed later. Sev-
eral aspects of the methodology require further
discussion.
Table 3. Concentration-Response Point Estimates
Effective
concentration Bupivacaine Lidocaine Potency
(%) % wt/vol % wt/vol ratio
95 0.129 0.52 4.0
90 0.115 0.49 4.3
75 0.091 0.43 4.7
50 MLAC 0.065 (2 mmol) 0.37 (14 mmol) 5.7
25 0.039 0.31 7.9
10 0.015 0.25 16.7
Pomt estnnates are derived from the EC,, expemnental result usrng the
table of normal dewates Potency ratlo descrrbes the werght for werght
potency of buprvacarne relative to hdocalne.
MLAC = nummum local analgesr concentratmn
The up-down sequential allocation technique,
rather than random allocation, was chosen due to the
ease with which it estimates the mean of a sample. By
starting from effective concentrations and approach-
ing the EC,, from above, the number of women sub-
jected to potentially inadequate analgesia is mini-
mized. This technique has been used to determine
dose-response pharmacodynamics for both inhala-
tional and intravenous anesthetics (7-9).
Parturients who had exceeded 5 cm cervical dila-
tion were excluded in order to minimize the loss of
women from the study due to the approach of the
second stage of labor with the onset of perineal pain
outside the TlO to Ll distribution. Omission of a
lidocaine test dose was essential to eliminate any
potential analgesic effect due to this. A 20-mL bolus
was used to give each concentration being tested
every possible chance to achieve adequate spread.
The use of a 12-mL bolus in the sitting position has
been shown to result in an upper sensory level only
to TlO in some patients (10).
The estimation of analgesic EC,, in a clinical setting
required that we be exacting and only accept VAPS
less than 10 mm as being effective. This was to ensure
that MLAC would imply very effective analgesia.
Brownridge (11) has shown that parturients request
further intervention during epidural analgesia only
when the VAPS exceeds 30 mm. It was particularly
important to reject those epidural injections with any
evidence of inadequate spread as these would obvi-
ously bias the results. This was to ensure, as far as was
practicable, that those injections designated as ineffec-
tive were due to failure of the particular concentration
being tested as demonstrated by the response to res-
cue with higher concentrations. It is, of course, possi-
ble that true effective or ineffective boluses might have
been rejected, but as the assessment was blinded to
concentration, each concentration in turn had the
same criteria applied to it and any bias applied
equally. The incidence of reject epidural injections was
similar for both local anesthetics, in that 25% demon-
strated some evidence of inadequate spread, although
836 OBSTETRIC ANESTHESIA COLUMB AND LYONS
ANALGESIC EC,, OF EPIDURAL BUIIVACAINE AND LIDOCAINE IN LABOR
ANESTH ANALG
1995;81:833-7
Concentration-Response Plots
Figure 3. The experimental result, minimum local
analgesic concentration (EC,,) is shown with 95%
confidence interval of mean. Derived point esti-
mates are plotted to demonstrate the concentration-
response relationship. The differential slopes imply
that the potency of bupivacaine relative to lidocaine
increases as concentration decreases.
I I I I I I
0.0 0.1 0.2 0.3 0.4 0.5 0.6
Concentration %wlv
this did not necessarily imply unsatisfactory analgesia
as far as the patient was concerned.
The formula of Dixon and Massey (6) was used to
derive MLAC and 95% CI from the results of the
sequential allocation. This technique analyzed the
least common outcome, those tests defined as ineffec-
tive, which assumed a normal distribution and are
shown in Figures 1 and 2. Logit maximum likelihood
analysis has been used by other workers to analyze
similar up-down data so we applied this as a back-up
sensitivity test (8). We believe that the former test is
the more appropriate, even though the latter is gener-
ally less conservative with the data. Logit analysis
usually is applied to randomly, rather than sequen-
tially, allocated data which may result in bias, partic-
ularly at the extremes of the logit curve (12,13).
It is common in clinical practice to make potency
comparisons on a weight-for-weight basis rather than
a molar basis, although the latter is more in keeping
with proper pharmacodynamics. The results show
that bupivacaine is 5.7 times more potent than lido-
Caine on a weighted basis and 7 times more potent on
a molar basis at EC,,. Using the table of normal devi-
ates (Za), values for the lOth, 25th, 75th, 90th, and 95th
percentiles can be calculated from the formula (6):
mean + Z9su
The derived point estimates are shown in Table 3. The
cumulative concentration-response plots for both local
anesthetics are shown in Figure 3. The graph shows
that the plots are not parallel. This implies, therefore,
a concentration-dependent variation in relative po-
tency ratios. At EC,, the weighted potency ratio is 4:1,
in agreement with current understanding (14,15). It is
interesting, therefore, that bupivacaine becomes more
potent with respect to lidocaine as the concentrations
are reduced. This has obvious implications when com-
parisons are being made between different epidural
local anesthetics with respect to side effects such as
unwanted motor blockade. Comparisons should be
made at equianalgesic concentrations, rather than at
presumed equivalent somatic sensory denervation,
because it is analgesia that is the aim, not indiscrimi-
nate deafferentation. The concept of differential block-
ade applies to epidural analgesia for both postopera-
tive and labor pain (16). The need exists therefore for
continuing research to determine the pharmacody-
namic concentration-response relationships for the
various drugs and recipe combinations being used
to provide epidural analgesia. By using these types of
data it should be possible to optimize the combina-
tions to provide the greatest effect at the minimum
disadvantage.
In conclusion, we have devised a clinical model to
determine MLAC of local anesthetics in the first stage
of labor. This research shows that bupivacaine is 5.7
times more potent than lidocaine in weighted and 7
times more potent in molar ratios at EC,,, when used
for epidural analgesia in labor for the parturients in
these studies. We are now in the process of systemat-
ically evaluating the local anesthetic sparing efficacies
of the various epidural analgesics in current use.
The authors gratefully acknowledge Andrew Vail, Medical Re-
search Institute, University of Leeds, for valuable statistical advice.
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