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38]

Original article 585

Does levobupivacaine have a benefit over bupivacaine

in our practice?
Sahar Badr EL-Dina, Sawsan G. Mohamedb, Sameh H. Ghoneimb

Departments of aPharmacology, bAnaesthesia Background

and Intensive Care, Faculty of Medicine for
Girls, Al-Azhar University, Cairo, Egypt
Correspondence to Sawsan Gaber Mohamed,
MD, Department of Anesthesiology and
Intensive Care, Faculty of Medicine for Girls,
Al-Azhar University, Cairo 11835, Egypt
Tel: +20 111 540 8170; Fax: +20226853698
e-mail: sawsan.saadawy@yahoo.com
Received 15 January 2014
Accepted 15 March 2014
Ain-Shams Journal of Anesthesiology
2015, 08:585593
The well-known toxic effects of bupivacaine on central nervous system and cardiovascular
system were a base for the development of new long-acting local anesthetics. Levobupivacaine
is the pure S(-)-enantiomer of racemic bupivacaine. This study compares the efficacy of
levobupivacaine as against bupivacaine by epidural clinical study and by different routes in
animal study.
Materials and methods
Evaluation of the analgesic activities by the hot plate method was carried out in nine groups
of mice. Each four groups were injected intraperitoneally with either levobupivacaine or
bupivacaine. The control group received saline. The hemodynamic effects of levobupivacaine
and bupivacaine were carried out on the isolated rabbits heart and anesthetized cats for
carotid blood pressure and ECG. Thirty patients undergoing limb surgery were randomized to
receive 15 ml of 0.5% levobupivacaine or bupivacaine through epidural needle. Intraoperative
blood pressure and heart rate were recorded. Onset time of sensory and motor block, time
to T10 sensory block, complete motor block, quality of analgesia, and times for two segment
regressions were detected.
Results
Experimentally, the intensity and duration of analgesia produced by levobupivacaine was
more than that of bupivacaine. Both drugs induced significant dose-dependent negative
inotropic effect, but it was lesser in levobupivacaine than in bupivacaine. An amount of 2 mg/kg
levobupivacaine produced a significant rise in blood pressure and 4 mg/kg significantly
decreased it, whereas 1 and 2 mg/kg bupivacaine produced a significant decrease in blood
pressure. The ECG pattern of levobupivacaine showed no abnormalities, but bupivacaine at
a dose of 2 mg/kg produced significant bradycardia and ECG changes. Cardiac arrest and
death of cats occurred when 4 mg/kg of bupivacaine was injected. Clinically, the onset time
of sensory block, time to T10 sensory block and time to complete motor block are lower with
bupivacaine than with levobupivacaine.
Conclusion
We found, based on the current pharmacodynamics evidence from this experimental and
clinical study, that levobupivacaine has good analgesic activity and less cardiodepressant
effect, and it offers advantages over bupivacaine.

Keywords:
bupivacaine, epidural anesthesia, levobupivacaine, new local anesthetics

Ain-Shams J Anesthesiol 08:585593

2015 Department of Anesthesiology, Intensive Care and Pain Managment,
Faculty of Medicine, Ain-Shams University, Cairo, Egypt
1687-7934

The well-known toxic effects of bupivacaine on the

Introduction
Regional anesthesia, particularly peripheral nerve
blockade, is useful for orthopedic patients. These
techniques are often used to provide not only anesthesia,
but also postoperative analgesia after limb surgery [1].
Bupivacaine is a long-acting amide and is widely
used as local anesthetic (LA) for epidural anesthesia.
It has a beneficial ratio of sensory to motor block in
epidural anesthesia. This agent provides also high
quality analgesia during the postoperative period.
However, bupivacaine-induced cardiotoxicity in
patients following accidental intravascular injection
limits its use [2].
1687-7934 2015 Department of Anesthesiology, Intensive Care and Pain Management,
Faculty of Medicine, Ain-Shams University, Cairo, Egypt
central nervous system and on the cardiovascular
system were a base for the development of new long-
acting LAs, such as ropivacaine and levobupivacaine,
to present a safer alternative to bupivacaine [3].
Bupivacaine is used as a racemic mixture of equimolar
amounts of R(+)-bupivacaine and S(-)-bupivacaine.
R(+)-bupivacaine is found more toxic to both the
central nervous system and the cardiovascular system.
Levobupivacaine (S-1-butyl-2-piperidylformo-2,
6-xylididehydrochloride) is the pure S(-)-enantiomer
of racemic bupivacaine. Preclinical animal and
volunteer studies showed less cardiac toxicity than
bupivacaine. It seems to be an alternative LA agent in
epidural anesthesia [2].
DOI: 10.4103/1687-7934.172746
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586 Ain-Shams Journal of Anesthesiology
LAs inhibit the sodium channels on neural membranes.
Therefore, they cause a loss of conduction on neural
structure and a loss of sensorial innervation. Systemic
toxicity occurs as a result of excessive blood levels of
LAs in the central nervous and cardiovascular systems
when they are injected intravenously by mistake. They
cause direct negative inotropic effect, myocardial
conduction abnormalities, and arrhythmias.
Arrhythmogenic effects of these drugs are related
to repolarization of potassium, sodium, and calcium
channels. Consequently, with this mechanism, cardiac
impulse conduction slows down, QRS complex
widens, PR distance gets longer, atrioventricular
block occurs, and fatal ventricular arrhythmias such
as ventricular tachycardia or ventricular fibrillation
occurs [2].
The aim of this prospective randomized double-
blinded study was to compare the efficacy and safety of
0.5% levobupivacaine with a 0.5% racemic mixture of
bupivacaine by epidural clinical study and by different
routes in animal study.
Materials and methods
Experimental study
All animals were housed at the animal house in the
Faculty of Medicine for Girls, Al-Azhar University
between the periods of October 2012 and April 2013.
Doses used in this work, corresponding to the human
therapeutic doses, were calculated according to the
method given by Paget and Barnes [4].
Evaluation of the analgesic activities
Hot plate method by Ghosh [5]: Nine groups of 10 mice in
each group (of both sexes and weighing 2025 g) were
used. Four groups were injected intraperitoneally with
1.7514 mg/kg levobupivacaine, whereas another four
groups were given 1.7514 mg/kg bupivacaine. The last
group received saline and was used as a control. After
2 h from drug injection, each mouse of all groups was
placed separately on a hot plate (55C) and the time
needed for leaking the mouse hind limbs was recorded.
Evaluation of the hemodynamic effects
Experiments on the isolated mammalian heart of rabbit
(The Staff of the Department of Pharmacology University
of Edinburgh [6]): Six rabbits of both sexes with
an average weight of 12 kg were used. The effect
of different doses of levobupivacaine (216 g/ml)
and bupivacaine (216 g/ml) was studied on the
amplitude of myocardial contractions by injecting the
drug into the perfusion fluid through the rubber tube
proximal to the heart.
Experiments on the carotid arterial blood pressure and ECG
of pentobarbitone-anesthetized intact cats (The Staff of the
Department of Pharmacology University of Edinburgh
[7]): Six cats of both sexes with an average weight of
23 kg were used. The effect of intravenous injection
of different doses of levobupivacaine (0.54 mg/kg)
and bupivacaine (0.54 mg/kg) on the arterial blood
pressure and ECG (lead II) of pentobarbitone-
anesthetized intact cats was recorded.
Clinical study
After obtaining local ethical committee approval,
30patients, ASA physical status III, aged from 20to
55 years old, undergoing elective limb surgery were
included in this prospective, randomized, double-blind
study. This study was conducted in Al-Zahraa
University Hospital between the period of April 2012
and November 2012. Exclusion criteria included
patients who had any contraindications to epidural
anesthesia, patients refusing regional anesthesia, allergy
to LA solutions, clotting abnormalities, and history
of drug abuse. In addition, patients with diabetes,
any neurologic, cardiopulmonary, or psychiatric
disease, those receiving antiarrhythmic/beta blockers/
anticoagulants, and pregnant women were excluded
from the study.
All patients were approached on the morning of their
operation to explain the procedure, advantage, and
possible side effects before informed written patient
consent was obtained and to instruct the patients about
usage of the visual analog scales (VAS) for assessing
pain. In the operation theater, a peripheral intravenous
cannula was inserted and all patients received 500 ml
of Ringers lactate solution for volume expansion before
the epidural block.
Standard monitoring was conducted and the basal
heart rate (HR), noninvasive mean arterial blood
pressure (MABP), ECG (five leads), and peripheral
oxygen saturation (SpaO2) were recorded. A nasal
cannula was applied and supplemental oxygen was
given throughout the procedure at 4 l/min.
The patients were randomized into two groups
according to the LA solution used. Group L (n = 15)
received 15 ml of 0.5% levobupivacaine and group B
(n = 15) received 15 ml of 0.5% bupivacaine through
epidural Tuohy needle (B. Braun Melsungen AG,
34209 Melsungen, Germany). The L23 or L34
epidural space was identified with patients in the sitting
or lateral decubitus position, and skin infiltration with
2 ml lignocaine 2% was performed. An 18 G Tuohy
needle was inserted using the midline approach and a
loss of resistance technique. After negative aspiration
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for blood or cerebrospinal fluid, a 3 ml of lignocaine
with 1 : 200 000 adrenaline test dose was administered
to exclude intravascular or intrathecal placement of the
needle. Then after a 5-min period, the study drug was
injected over 2 min. The anesthetists who performed
the epidural catheterization and collected the data
were blinded to the solutions used.
Standard monitoring was continued throughout
the operation. Measurements of MABP, HR,
and respiratory rate were recorded every 15 min.
Hypotension was defined as a 30% decrease of systolic
blood pressure compared with the baseline value;
ephedrine bolus 5 mg was given intravenously as needed
or if it was lower than 90 mmHg. An HR less than
50 beats/min was defined as bradycardia and treated
with atropine 0.5 mg intravenously, and a decrease in
SpaO2 to less than 93% was defined as hypoxia and
treated with supplemental oxygen by face mask.
Sensory and motor blocks were assessed by the pinprick
test (1 = hypoalgesia, 2 = analgesia, 3 = analgesia plus
hypoalgesia, and 4 = anesthesia) and modified Bromage
scale (0 = no motor block, full flexion of hips, knees, and
ankles, 1 = ability to move knees only, inability to raise
extended legs, 2 = ability to move feet only, inability
to flex knees, and 3 = full motor block, inability to flex
ankle joints), respectively.
Level of analgesia to pinprick was assessed bilaterally
every 5 min until complete loss of sensation at T10
(taken as onset of sensory block) and then every 5min to
determine the time taken for maximum height of block,
and thereafter every 15 min to determine the time for
two segment regression and regression of sensory block
at T12 (taken as duration of sensory block).
Motor blockade was assessed according to the
modified Bromage scale (0 = no motor block,
1 = inability to raise extended legs, 2 = inability to
flex knees, and 3 = inability to flex ankle joints) at
5, 15, 30, and 60 min after the injection. The quality
of analgesia, as defined by pain at the time of skin
incision, was recorded as a 010 verbal numeric
pain score where 0 is no pain and 10 is the worst
imaginable pain. Recovery from motor block was
assessed at the end of surgery.
Any complications such as nausea, vomiting, headache,
tinnitus, confusion, convulsion, or hemodynamic
variables (hypotension, hypertension, arrhythmias)
were recorded and tabulated.
In the postanesthesia care unit, vital signs were
recorded every 15 min for 2 h (unless there are
complications, irrespective of the causes). All patients
Levobupivacaine benefits over bupivacaine EL-Din et al. 587
were asked to define hourly their degree of pain during
24 h postoperatively by means of VAS ranging from
0 to 10 (0 = no pain and 10 = worst pain). Eventual
rescue analgesia was obtained by additional doses of
paracetamol (5001000 mg) in case of VAS greater
than 4.
Statistical analysis
Sample size was calculated using Epi info statistical
program version 7 (Centers for Disease Control
and Prevention (CDC), 1600 Clifton Road Atlanta,
Georgia, USA) by adjusting power of the test to
80%, confidence interval to 95%, and margin of error
accepted to 5%. The data were collected, revised, and
entered to the statistical package for social science,
version 17 (International Business Machines Corp.
(IBM), 233 South Wacker Drive, Chicago, USA).
The quantitative data were presented as mean, SDs,
and SEM, whereas the qualitative data were presented
as number and percentages. The independent t-test
was used to assess the significant difference between
two independent groups with parametric data, and
the paired t-test was used to assess the significant
difference between two paired groups with parametric
data, whereas the 2-test was used to assess the
significant difference between groups with qualitative
data and the Fisher exact was used instead of the 2-
test when the expected count in any cell was found
less than 5. The P-value was considered significant
at the level of less than 0.05 and considered highly
significant at the level of less than 0.01.
Results
Experimental study
Evaluation of the analgesic activities
Hot plate method: In this test, the analgesic activity of
different doses of levobupivacaine showed a highly
significant analgesic effect in comparison with
bupivacaine (Table 1 and Fig. 1).
Evaluation of the hemodynamic effects
Experiments on the isolated mammalian heart of
rabbit: Levobupivacaine (216 g/ml) reduced the
myocardial contractility significantly by 8.036 0.821
and up to 44.515 0.886% (P < 0.001), whereas
bupivacaine (216 g/ml) decreased it significantly by
17.105 0.915 and up to 82.447 0.988% (P < 0.001)
(Table 2 and Figs. 2 and 3).
Experiments on the carotid arterial blood pressure
and ECG of pentobarbitone-anesthetized intact
cats: Levobupivacaine at doses of 0.5 and 1 mg/
kg produced insignificant rise in MABP. The drug
Table 1 Mean reaction time (s) to the stimulus of hot plate test of mice treated (intraperitoneally) by different doses of levobupivacaine or bupivacaine and of control untreated mice
588

Levobupivacaine (mg/kg) Bupivacaine (mg/kg)

Control 1.75 3.5 7 14 1.75 3.5 7 14
Mean SEM (s) 11.800 0.327 20.300 0.300 29.900 0.315 41.400 0.221 61.300 0.396 15.800 0.291 19.100 0.233 25.000 0.333 33.800 0.249
P 0.000* 0.000* 0.000* 0.000* 0.000* 0.000* 0.000* 0.000*
Activity (%) 0 72.034 153.389 250.847 419.492 33.898 61.864 111.864 186.441
Data were presented as mean SEM; P, test of significance between the control group and the group that received levobupivacaine and bupivacaine; *P < 0.001 highly statistically significant.

Table 2 Percentage reduction in the amplitude of contractions (cm) of isolated rabbits heart in response to different doses of levobupivacaine and bupivacaine (g/ml)
Ain-Shams Journal of Anesthesiology

Levobupivacaine (g/ml) Bupivacaine (g/ml)

2 4 8 16 2 4 8 16
Mean SEM 8.036 0.821 9.481 0.941 13.509 0.974 44.515 0.886 17.105 0.915 35.974 0.989 53.947 0.987 82.447 0.988
t-test 9.788 10.075 13.870 50.243 18.694 36.374 54.658 83.448
P-value 0.000* 0.000* 0.000* 0.000* 0.000* 0.000* 0.000* 0.000*
Data were presented as mean percentage SEM; *P < 0.001 highly statistically significant.

Figure 2
Figure 1

Figure 3
Fig. 5).
Fig. 4).

isolated rabbits heart.

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of isolated rabbits heart.

levobupivacaine and bupivacaine.
Percentage activity of the reaction time in the hot plate test by
ECG pattern was observed with levobupivacaine
With respect to the ECG, no abnormality in the
MABP. The animals died after being injected with
1 and 2 mg/kg it produced significant decrease in
insignificant rise in the MABP, whereas at doses of
significantly decreased blood pressure (Table 3 and
MABP, whereas the last dose of the drug (4 mg/kg)
at a dose of 2 mg/kg produced significant rise in

However, bupivacaine at a dose of 0.5 mg/kg produced

the last dose of bupivacaine (4 mg/kg) (Table 3 and

Effect of bupivacaine on the amplitude of myocardial contractions of

Effect of levobupivacaine on the amplitude of myocardial contractions
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Levobupivacaine benefits over bupivacaine EL-Din et al. 589

and the first two doses of bupivacaine. Concerning
the effect of 2 mg/kg bupivacaine, there was a
significant decrease in the HR and ECG changes in
form of depression of ST segment, widening of QRS
complex, decreased QRS voltage, and prolongation
of PR interval, finally ending with cardiac arrest and
death of cats when the last dose of bupivacaine was
injected (Table 4).
levobupivacaine and group B received 15 ml of 0.5%
bupivacaine through epidural Tuohy needle into the
epidural space.
Patients age, sex, and weight and duration of surgery
were comparable, and there were no statistically
significant differences between the two groups
(Table 5).

There were no statistically significant differences

Clinical study
A total of 30 patients, ASA physical status III were
randomized into two groups according to the LA
solution used. Group L (n = 15) received 15 ml of 0.5%
Figure 4
between two groups for the HR and MABP in the first
hour and all over the duration of surgery (P > 0.05)
(Tables 6 and 7).
There were high statistically significant differences
between the L and B groups with respect to the onset

Figure 5

Effect of levobupivacaine on the mean blood pressure of normal Effect of bupivacaine on the mean blood pressure of normal
anesthetized intact cat. anesthetized intact cat.

Table 3 Percentage change in the mean arterial blood pressure (mmHg) of pentobarbitone-anesthetized intact cats in response
to different doses of levobupivacaine and bupivacaine (mg/kg)
Levobupivacaine (mg/kg) Bupivacaine (mg/kg)
0.5 1 2 4 0.5 1 2 4
Mean SEM 1.89 0.99a 2.311 1.2a 4.524 0.99a 7.51 0.691b 1.803 0.923a 4.377 0.978b 20.01 0.892b c

t 1.909 1.926 4.569 10.868 1.953 4.475 22.433

P-value 0.066 0.064 0.000** 0.000** 0.060 0.000** 0.000**
a
Values represent mean percentage increase SEM; Values represent mean percentage decrease SEM; Cats developed cardiac arrest
b c

and died; P > 0.05 were considered statistically insignificant; **P < 0.001 highly statistically significant.

Table 4 Percentage reduction in the heart rate (beats/min) of pentobarbitone-anesthetized intact cats in response to different
doses of levobupivacaine and bupivacaine (mg/kg)
Levobupivacaine (mg/kg) Bupivacaine (mg/kg)
0.5 1 2 4 0.5 1 2 4
Mean SEM 1.34 1.22 2.12 2.07 3.2 2.04 4.12 2.39 4.012 2.02 6.11 3.52 18.1 4.82 a

t 1.098 1.024 1.569 1.724 1.986 1.736 3.755

P-value 0.281 0.314 0.127 0.095 0.056* 0.093 0.000**
Data were presented as mean percentage SEM; aCats developed cardiac arrest and died; P > 0.05 were considered statistically
insignificant; *P < 0.05 statistically significant; **P < 0.001 highly statistically significant.

Table 5 Demographic variables and duration of surgery (min)

Variables Levobupivacaine (L) group (n = 15) Bupivacaine (B) group (n = 15) t-test
t P-value
Age (years) 40.60 7.46 42.67 7.47 0.759 0.454
Sex (female/male) [N (%)] 3 (25)/12 (75.0) 4 (26.7)/11 (73.3) 0.009 0.992
Weight (mean SD) (kg) 82 5 84 8 0.821 0.418
Duration of surgery (min) 122 30 114 45 0.573 0.571
Values are expressed as mean SD; P > 0.05 were considered statistically insignificant.
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590 Ain-Shams Journal of Anesthesiology

time of sensory block (19.5 0.79 vs. 16.5 0.85 min) analgesics for 2 h postoperatively, where VAS was
and time to T10 sensory block (29 2.0 vs. 25 0.8 greater than 4.
min). In addition, the time to complete motor block
in the L group was more than the time in the B group Figure 6
(30.4 3.0 vs. 28.6 2.0 min) with P equal to 0.05,
which is statistically significant (Table 8 and Fig. 6).

There were no statistically significant differences

between the two groups in onset time of motor block
and the quality of analgesia. Although the mean
times for two segment regression and recovery from
motor block were shorter in the L group, there was no
statistically significant difference (Table 8).

In the postanesthesia care unit, there were no

statistically significant differences between the
two groups in the HR and MABP, and none of
the patients in both groups required supplement
Onset time and time to T10 of sensory block in both groups.

Table 6 Heart rate changes before and after epidural injection of studied drugs
Variables Heart rate (mean SD)
Baseline 15 min 30 min 60 min
Groups
Levobupivacaine(L) group (n = 15) 89.9 5.0 85.4 11.7 86.3 11.25 85.0 3.7
Bupivacaine (B)group (n = 15) 90.6 4.9 86.8 10.5 88.2 3.08 84.5 8.6
t-test
t 0.387 0.345 0.631 0.207
P-value 0.701 0.732 0.533 0.837
Values are expressed as mean SD; P > 0.05 were considered statistically insignificant.

Table 7 MABP changes before and after epidural injection of studied drugs
Variables Mean arterial blood pressure (mean SD)
Baseline 15 min 30 min 60 min
Groups
Levobupivacaine (L) group (n = 15) 93.7 10.0 91.7 9.0 90.8 7.6 92.2 10.9
Bupivacaine (B) group (n = 15) 93.4 6.7 93.2 6.8 88.2 4.1 89.6 5.79
t-test
t 0.097 0.515 1.166 0.816
P-value 0.923 0.610 0.253 0.421
Values are expressed as mean SD; MABP, mean arterial blood pressure; P > 0.05 were considered statistically insignificant.

Table 8 Parameters of epidural anesthesia in both groups

Variables Mean SD t-test
L group (n =1 5) B group (n = 15) t P-value
Onset time of sensory block (min) 19.5 0.79 16.5 0.85 10.013 0.000**
Time to T10 sensory block (min) 29 2.0 25 0.8 7.192 0.000**
Onset time of motor block (modified 20.7 7.0 17.4 6.4 1.348 0.188
Bromage scale 1) (min)
Time to complete motor block (modified 30.4 3.0 28.6 2.0 1.934 0.050*
Bromage scale 3) (min)
Quality of analgesia (at the time of skin 4 (34) 4 (34) z = 0.000 1.000
incision) [Median (range)]
Time for two segment regression (min) 117 48.0 122 57.0 0.260 0.796
Recovery from motor block (min) 186 67.0 224 57.0 1.673 0.105
Values are expressed as mean SD/quality of analgesia is expressed as median (range); P > 0.05 were considered statistically insignificant;
*P < 0.05 statistically significant; **P < 0.001 highly statistically significant.
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Discussion
Regional anesthesia might require high doses of LA agents
for surgery, and there is always the potential risk for toxic
reactions. Both the cardiovascular and central nervous
systems are the primary target organs of LA toxicity
with accidental intravascular injection. Bupivacaine was
one of the most widely used LAs because of its quality of
anesthesia and prolonged duration of action [8].
Levobupivacaine is the pure S(-)-enantiomer of
racemic bupivacaine; preclinical animal and volunteer
studies showed less cardiac toxicity than bupivacaine.
It seems to be an alternative LA agent in epidural
anesthesia [9,10].
Concerning the analgesic activity of levobupivacaine
and bupivacaine, the experimental result in the
present study showed that the analgesia produced by
levobupivacaine was rapid onset and long duration
than that of bupivacaine; levobupivacaine prolonged
the reaction time to the stimulus of hot plate test
more than bupivacaine; however, in the clinical
study, we found that the onset time of sensory block,
time to T10 sensory block, and time to complete
motor block are lower with bupivacaine than
with levobupivacaine, and there was no statistical
difference in the onset time of motor block and the
quality of analgesia between both drugs. Although
the mean times for two segment regression and
recovery from motor block are shorter in the L group,
there is no statistically significant difference; these
discrepancies between experimental and clinical
results may be due to animal to human variation and
the route of administration.
Levobupivacaine is currently the closest to the ideal
agent for neural blockade. The onset of sensory and
motor block is related to the physicochemical properties
of the individual drugs, namely the mass of the injected
LA, the pKa of the drug, and pH of the tissues [11].
In contrast to our results, Glaser et al. [9], Uzuner
et al. [2], and Bergamaschi et al. [12] reported
that levobupivacaine and bupivacaine have similar
efficiency, but levobupivacaine has a greater degree
of separation between motor and sensory blockade
than bupivacaine when it is given for epidural pain
relief during labor. In addition, Kopacz et al. [13]
compared 0.75% levobupivacaine and bupivacaine
for epidural anesthesia in lower abdominal surgery
and observed similar onset times but a significantly
longer duration of sensory blockade when
levobupivacaine was used. However, a significant
difference was observed, where complete regression
occurred 45 min sooner with bupivacaine and slower
onset of lower extremity motor block occurred with
Levobupivacaine benefits over bupivacaine EL-Din et al. 591
levobupivacaine. Overall, the duration of lower
extremity motor block was similar for patients
administered levobupivacaine and bupivacaine.
The overall quality of sensory and motor blocks as
assessed by the investigator was excellent or good
in 96% of patients in the levobupivacaine group and
82% of patients in the bupivacaine group. No serious
adverse events were related to study medication. In
agreement with clinical results, Arslantas et al. [14]
found no difference as to motor block development
between the groups, but the sensory block was
monitored less in group L at 15, 30, 45, and 90 min.
In addition, Foster and Markham [15] have shown
that the sensory blockade lasted significantly longer
with levobupivacaine than with racemic bupivacaine,
which might be attributable to a greater intrinsic
vasoconstrictor potency of levobupivacaine.
The analgesic activities result from direct block of
transmission of pain from nociceptive afferents. LA
agents are applied directly, and their efficacy results from
action on the nerve where the inward Na+ current is
blocked at the sodium ionophore during depolarization.
LAs not only block Na+ channels, but also Ca2+ and K+
channels [16], transient receptor potential vanniloid-1
receptors [17], and other ligand-gated receptors. LAs
also disrupt the coupling between certain G proteins
and their associated receptors, in addition to a variety
of other antithrombotic and neuroprotective actions of
intravenous LAs [18]. Through this action, LAs exert
potent anti-inflammatory effects, particularly on the
neutrophil priming reactions [19].
With respect to the cardiovascular experiments in
this study, levobupivacaine and bupivacaine at all
concentrations exerted a significant negative inotropic
effect on the isolated perfused rabbit heart. The
myocardial depressant action of bupivacaine was found
greater than that of levobupivacaine and the last dose
of bupivacaine (16 ug/ml) caused 82.447% reduction.
Such finding was in agreement with the studies by
Nau et al. [20] and Heavner [21] who stated that
levobupivacaine was less potent in depressing cardiac
electrophysiological parameters than bupivacaine in an
isolated heart model, with levobupivacaine being the
least toxic than that of bupivacaine.
In-vitro studies indicate that, with levobupivacaine
[S() bupivacaine], there is less sodium channel
blockade, faster unblocking of sodium channels, and
a marked decrease in potassium blockade compared
with racemic bupivacaine [22] and that, as a result,
levobupivacaine is less cardiotoxic. In a further study
to explore the effects of larger doses in sheep, the mean
fatal dose for levobupivacaine was found to be 277 mg
compared with 156 mg for bupivacaine [23].
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592 Ain-Shams Journal of Anesthesiology
Butterworth [24] and Mio et al. [25] attributed
the potent cardiodepressant activity of bupivacaine
compared with that of levobupivacaine for its slow
release from Na+ channel-binding sites as well as
Ca+ channel-binding sites. Similarly, Punke and
Friederich [26] suggested that binding of bupivacaine
more than levobupivacaine with the dihydropyridine-
binding sites on neuronal L-type of Ca+ channels may
be involved in the cardiotoxicity. Bupivacaine has also
been shown to inhibit carnitine-acylcarnitine transferase
in rat cardiac interfibrillar mitochondria. Carnitine-
acylcarnitine transferase is the only enzyme responsible
for transporting acylcarnitines across the mitochondrial
membranes in the fatty acid transport chain during
phase I mitochondrial respiration important for aerobic
metabolism [27]; this may be a key factor in the nature
of LA-induced toxicity being unresponsive to advanced
cardiac resuscitation techniques.
Apart from the channel blockade, the membrane
interaction (especially with cardiac mitochondria)
that modifies membrane biophysical properties such
as fluidity, ordering, and permeability is altered by
cardiotoxic drugs. Bupivacaine affects and rapidly reach
mitochondrial membranes of cardiomyocytes even
when applied extracellularly by its action on membrane
cardiolipin [2830]. Ngamprasertwong et al. [31] and
Tsuchiya et al. [32] reported that the high lipophilicity
and protein binding of bupivacaine may favor
enhanced uptake and binding in the myocardial tissue,
making cardiac resuscitation more difficult following
bupivacaine-induced cardiovascular collapse.
In experiments on the arterial blood pressure and
ECG of pentobarbitone-anesthetized intact cats, in
accordance to our results, De La Coussaye et al. [33]
and Lefrant et al. [34] have revealed bupivacaine as a
negative inotropic agent, with intravenous infusions
causing significant decreases in blood pressure and
HR through alterations in electrical excitability of the
heart, dilatation of blood vessels, and inhibition of the
firing rate of the sinoatrial node. Typical effects on
the ECG include widening of the QRS complex and
lengthening of the PR interval.
Hypotension that occurred in the cats injected with
4 mg/kg of levobupivacaine in the present study might
be explained by achievement of high blood level of
the drug in these animals leading to myocardial
depression. Animal variability, with respect to the rate
of absorption, metabolism, and excretion of the injected
drug, as well as the way of injection may influence the
blood level, and accordingly toxicity of the drug. If the
blood level of LA is excessively elevated, cardiovascular
depression occurs, which is related to its depressant
effect on myocardial contractility and HR [35].
In contrast to the vasopressor effect of levobupivacaine
in this study, small doses of bupivacaine, in general,
elicited insignificant effect on blood pressure, whereas
larger doses, which increased drug blood level,
produced hypotension. When the blood level of
bupivacaine became highly elevated in some cats, severe
hypotension and death of the cats occurred. This result
is in accordance with the studies by Jung et al. [36] and
Groban et al. [37] who speculated that the primary cause
of cardiovascular collapse induced by bupivacaine may
be due to hypotension from diminished contractility
rather than arrhythmias in anesthetized dogs.
As levobupivacaine has less potential for sodium
channel blockade and produces less arrhythmias, it
has been a popular LA agent [38]. It was thought
that it can be used instead of bupivacaine because
of its less toxic side effects to the cardiovascular and
central nervous system [39,40]. Corrected QT is used
to evaluate the arrhythmogenic potential of drugs.
Levobupivacaine has also a poor influence on QRS or
corrected QT [41].
The present clinical study demonstrates that the epidural
administration of 15 ml of 0.5% levobupivacaine or
racemic bupivacaine in patients undergoing elective
limb surgeries provides no statistically significant
differences between the two groups for HR and MABP
all over the duration of surgery.
Our hemodynamic results are comparable with the
results of Uzuner et al. [2] and Arslantas et al. [14],
and contradicted with the results of Kopacz et al. [13].
Uzuner et al. and Arslantas et al. compared the epidural
levobupivacaine and bupivacaine in major abdominal
surgeries and labor analgesia, respectively, and there
were no significant differences in systolic and diastolic
pressures or in HR values between the groups.
However, Kopacz et al. [13] found that hypotension
was the most common side effect attributed to the
study drug, and there were no differences between the
groups with respect to change from baseline in HR,
and there were no clinically significant ECG changes
related to either study drug. This study demonstrates
that 0.75% levobupivacaine is a suitable anesthetic
for use in lower abdominal surgery. In addition,
Bergamaschi et al. [12] demonstrated that the most
frequent complication was hypotension, found in
66.7% of the levobupivacaine group patients and in
43.5% of the bupivacaine group patients. However,
Ngamprasertwong et al. [31] found that hypotension
was attributed to both study drugs, 38.7% in the
levobupivacaine group compared with 66.7% in the
bupivacaine group. Although there are no adverse
effect in our clinical study, the other studies observed
complications such as nausea, vomiting, agitation,
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ventricular premature complexes (bigeminy), dyspnea,
pruritus, [12,31] and bradycardia [12]. Uzuner et al.
[2] detected a higher incidence for supraventricular
arrhythmia with bupivacaine during the postoperative
period.
Finally, based on these results, the current
pharmacodynamic evidence from animal and human
studies suggests that levobupivacaine has good
analgesic activity and less cardiodepressant effect, and
it offers advantages over the racemic bupivacaine.
Acknowledgements
Conflicts of interest
None declared.
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