[Downloaded free from http://www.asja.eg.net on Wednesday, December 30, 2015, IP: 117.248.131.

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
The well-known toxic effects of bupivacaine on central nervous system and cardiovascular
Girls, Al-Azhar University, Cairo, Egypt
system were a base for the development of new long-acting local anesthetics. Levobupivacaine
Correspondence to Sawsan Gaber Mohamed, is the pure S(-)-enantiomer of racemic bupivacaine. This study compares the efficacy of
MD, Department of Anesthesiology and
levobupivacaine as against bupivacaine by epidural clinical study and by different routes in
Intensive Care, Faculty of Medicine for Girls,
Al-Azhar University, Cairo 11835, Egypt animal study.
Tel: +20 111 540 8170; Fax: +20226853698 Materials and methods
e-mail: sawsan.saadawy@yahoo.com Evaluation of the analgesic activities by the hot plate method was carried out in nine groups
Received 15 January 2014 of mice. Each four groups were injected intraperitoneally with either levobupivacaine or
Accepted 15 March 2014 bupivacaine. The control group received saline. The hemodynamic effects of levobupivacaine
and bupivacaine were carried out on the isolated rabbit’s heart and anesthetized cats for
Ain-Shams Journal of Anesthesiology
2015, 08:585–593 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 08:585–593
© 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
central nervous system and on the cardiovascular
Regional anesthesia, particularly peripheral nerve system were a base for the development of new long-
blockade, is useful for orthopedic patients. These acting LAs, such as ropivacaine and levobupivacaine,
techniques are often used to provide not only anesthesia, to present a safer alternative to bupivacaine [3].
but also postoperative analgesia after limb surgery [1].
Bupivacaine is used as a racemic mixture of equimolar
Bupivacaine is a long-acting amide and is widely amounts of R(+)-bupivacaine and S(-)-bupivacaine.
used as local anesthetic (LA) for epidural anesthesia. R(+)-bupivacaine is found more toxic to both the
It has a beneficial ratio of sensory to motor block in central nervous system and the cardiovascular system.
Levobupivacaine (S-1-butyl-2-piperidylformo-2´,
epidural anesthesia. This agent provides also high
6´-xylididehydrochloride) is the pure S(-)-enantiomer
quality analgesia during the postoperative period. of racemic bupivacaine. Preclinical animal and
However, bupivacaine-induced cardiotoxicity in volunteer studies showed less cardiac toxicity than
patients following accidental intravascular injection bupivacaine. It seems to be an alternative LA agent in
limits its use [2]. epidural anesthesia [2].
1687-7934 © 2015 Department of Anesthesiology, Intensive Care and Pain Management,
Faculty of Medicine, Ain-Shams University, Cairo, Egypt DOI: 10.4103/1687-7934.172746

The last heart rate (HR). Experiments on the carotid arterial blood pressure and ECG Therefore. loss of resistance technique. University Hospital between the period of April 2012 blinded study was to compare the efficacy and safety of and November 2012. advantage. and skin infiltration with amplitude of myocardial contractions by injecting the 2 ml lignocaine 2% was performed. myocardial and bupivacaine (0.5% levobupivacaine and group B (The Staff of the Department of Pharmacology University (n = 15) received 15 ml of 0. or psychiatric disease. randomized. Exclusion criteria included 0.net on Wednesday. ECG (five leads). and Doses used in this work.asja.75–14 mg/kg bupivacaine. The patients were randomized into two groups Evaluation of the hemodynamic effects according to the LA solution used. allergy routes in animal study. each mouse of all groups was oxygen saturation (SpaO2) were recorded. 2015. operation to explain the procedure. Systemic Department of Pharmacology University of Edinburgh toxicity occurs as a result of excessive blood levels of [7]): Six cats of both sexes with an average weight of LAs in the central nervous and cardiovascular systems 2–3 kg were used. Consequently. An 18 G Tuohy drug into the perfusion fluid through the rubber tube needle was inserted using the midline approach and a proximal to the heart. an average weight of 1–2 kg were used. and fatal ventricular arrhythmias such 30 patients. Four groups were injected intraperitoneally with 1. a peripheral intravenous Evaluation of the analgesic activities cannula was inserted and all patients received 500 ml Hot plate method by Ghosh [5]: Nine groups of 10 mice in of Ringers lactate solution for volume expansion before each group (of both sexes and weighing 20–25 g) were the epidural block. The effect 34209 Melsungen. December 30. Group L (n = 15) Experiments on the isolated mammalian heart of rabbit received 15 ml of 0. QRS complex Clinical study widens. and pregnant women were excluded Experimental study from the study. The effect of intravenous injection when they are injected intravenously by mistake.5% racemic mixture of patients who had any contraindications to epidural bupivacaine by epidural clinical study and by different anesthesia. aged from 20 to as ventricular tachycardia or ventricular fibrillation 55 years old. clotting abnormalities.[Downloaded free from http://www. sodium. block occurs. used. with this mechanism.131.38] 586 Ain-Shams Journal of Anesthesiology LAs inhibit the sodium channels on neural membranes. cardiopulmonary. patients refusing regional anesthesia.5–4 mg/kg) on the arterial blood conduction abnormalities. to repolarization of potassium.5% bupivacaine through of Edinburgh [6]): Six rabbits of both sexes with epidural Tuohy needle (B. and arrhythmias. and peripheral 2 h from drug injection. Braun Melsungen AG. noninvasive mean arterial blood group received saline and was used as a control. In the operation theater.eg. pressure and ECG (lead II) of pentobarbitone- Arrhythmogenic effects of these drugs are related anesthetized intact cats was recorded. corresponding to the human possible side effects before informed written patient therapeutic doses. undergoing elective limb surgery were occurs [2]. Germany). and history of drug abuse. This study was conducted in Al-Zahraa The aim of this prospective randomized double. A nasal placed separately on a hot plate (55°C) and the time cannula was applied and supplemental oxygen was needed for leaking the mouse hind limbs was recorded. they cause a loss of conduction on neural of pentobarbitone-anesthetized intact cats (The Staff of the structure and a loss of sensorial innervation. The L2–3 or L3–4 of different doses of levobupivacaine (2–16 μg/ml) epidural space was identified with patients in the sitting and bupivacaine (2–16 μg/ml) was studied on the or lateral decubitus position. were calculated according to the consent was obtained and to instruct the patients about method given by Paget and Barnes [4]. After negative aspiration . double-blind study. They of different doses of levobupivacaine (0. whereas another four Standard monitoring was conducted and the basal groups were given 1.248. Al-Azhar University All patients were approached on the morning of their between the periods of October 2012 and April 2013. In addition. atrioventricular After obtaining local ethical committee approval. to LA solutions.5% levobupivacaine with a 0. cardiac impulse conduction slows down.75–14 mg/kg levobupivacaine. and calcium channels. IP: 117. patients with diabetes. ASA physical status I–II. any neurologic. PR distance gets longer.5–4 mg/kg) cause direct negative inotropic effect. usage of the visual analog scales (VAS) for assessing pain. All animals were housed at the animal house in the Faculty of Medicine for Girls. After pressure (MABP). given throughout the procedure at 4 l/min. those receiving antiarrhythmic/beta blockers/ Materials and methods anticoagulants. included in this prospective.

blood pressure compared with the baseline value.248.886% (P < 0. vital signs were and ECG of pentobarbitone-anesthetized intact recorded every 15 min for 2 h (unless there are cats: Levobupivacaine at doses of 0. confidence interval to 95%. whereas Any complications such as nausea. inability data. The P-value was considered significant every 5 min until complete loss of sensation at T10 at the level of less than 0. hypertension. with atropine 0. headache. arrhythmias) (Table 2 and Figs. revised.821 and up to 44. 587 for blood or cerebrospinal fluid. whereas the qualitative data were presented Sensory and motor blocks were assessed by the pinprick as number and percentages. was recorded as a 0–10 verbal numeric Evaluation of the hemodynamic effects pain score where 0 is no pain and 10 is the worst Experiments on the isolated mammalian heart of imaginable pain.net on Wednesday. were blinded to the solutions used. Recovery from motor block was rabbit: Levobupivacaine (2–16 μg/ml) reduced the assessed at the end of surgery. 2 = ability to move feet only. Sample size was calculated using Epi info statistical and respiratory rate were recorded every 15 min. Experimental study Evaluation of the analgesic activities Motor blockade was assessed according to the Hot plate method: In this test. data and the Fisher exact was used instead of the χ2- test when the expected count in any cell was found Level of analgesia to pinprick was assessed bilaterally less than 5. as defined by pain at the time of skin incision. and 4 = anesthesia) and modified Bromage two independent groups with parametric data. knees. HR. IP: 117. The anesthetists who performed paracetamol (500–1000 mg) in case of VAS greater the epidural catheterization and collected the data than 4. inability to raise difference between two paired groups with parametric extended legs. and a decrease in version 17 (International Business Machines Corp.eg. vomiting. whereas the χ2-test was used to assess the to flex knees. The quantitative data were presented as mean. SpaO2 to less than 93% was defined as hypoxia and (IBM). SDs. 3 = analgesia plus was used to assess the significant difference between hypoalgesia. myocardial contractility significantly by 8.447 ± 0.[Downloaded free from http://www. 30. or hemodynamic 17. Then after a 5-min period. 1 = ability to move knees only.5 mg intravenously.01. inability to flex significant difference between groups with qualitative ankle joints). Georgia. The independent t-test test (1 = hypoalgesia.988% (P < 0. The data were collected. different doses of levobupivacaine showed a highly 1 = inability to raise extended legs. 2 = inability to significant analgesic effect in comparison with flex knees.001). and thereafter every 15 min to determine the time for two segment regression and regression of sensory block Results at T12 (taken as duration of sensory block).131. USA). and SEM. 2 = analgesia.5 and 1 mg/ complications. program version 7 (Centers for Disease Control Hypotension was defined as a 30% decrease of systolic and Prevention (CDC). and 60 min after the injection. Measurements of MABP.515 ± 0. and 3 = full motor block. 2015. 1). 2 and 3). An HR less than accepted to 5%. determine the time taken for maximum height of block.38] Levobupivacaine benefits over bupivacaine EL-Din et al.05 and considered highly (taken as onset of sensory block) and then every 5 min to significant at the level of less than 0. and 3 = inability to flex ankle joints) at bupivacaine (Table 1 and Fig. respectively. 1600 Clifton Road Atlanta. The drug . the analgesic activity of modified Bromage scale (0 = no motor block. 5. 15. and the paired t-test was used to assess the significant ankles.036 ± 0. Eventual needle. bupivacaine (2–16 μg/ml) decreased it significantly by tinnitus. confusion. and scale (0 = no motor block. The quality of analgesia.915 and up to 82.001) variables (hypotension. Experiments on the carotid arterial blood pressure In the postanesthesia care unit. December 30. were recorded and tabulated. treated with supplemental oxygen by face mask. and margin of error or if it was lower than 90 mmHg.asja. Standard monitoring was continued throughout Statistical analysis the operation. full flexion of hips. convulsion. All patients kg produced insignificant rise in MABP. Chicago.105 ± 0. USA) by adjusting power of the test to ephedrine bolus 5 mg was given intravenously as needed 80%. the study drug was rescue analgesia was obtained by additional doses of injected over 2 min. a 3 ml of lignocaine were asked to define hourly their degree of pain during with 1 : 200 000 adrenaline test dose was administered 24 h postoperatively by means of VAS ranging from to exclude intravascular or intrathecal placement of the 0 to 10 (0 = no pain and 10 = worst pain). and 50  beats/min was defined as bradycardia and treated entered to the statistical package for social science. irrespective of the causes). 233 South Wacker Drive.

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. Figure 2 Figure 1 Figure 3 Fig.000* 0.481 ± 0.441 Data were presented as mean ± SEM.000* 0.800 ± 0.788 10.987 82.898 61.5 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 .131.847 419.800 ± 0.034 153.974 ± 0. Fig. whereas the last dose of the drug (4 mg/kg) at a dose of 2 mg/kg produced significant rise in However.864 186.509 ± 0.800 ± 0.374 54. 5).694 36. test of significance between the control group and the group that received levobupivacaine and bupivacaine.915 35.886 17.821 9.492 33.389 250.300 ± 0.315 41.5 7 14 Mean ± SEM (s) 11.300 ± 0.900 ± 0.947 ± 0.000* 0.400 ± 0.net on Wednesday.248. [Downloaded free from http://www. bupivacaine at a dose of 0.105 ± 0.941 13.243 18.000* 0.327 20. *P < 0. 4).036 ± 0.448 P-value 0.974 44.000* Activity (%) 0 72.000* 0. whereas at doses of significantly decreased blood pressure (Table 3 and MABP. December 30. 2015.988 t-test 9. Table 2 Percentage reduction in the amplitude of contractions (cm) of isolated rabbit’s heart in response to different doses of levobupivacaine and bupivacaine (μg/ml) Ain-Shams Journal of Anesthesiology Levobupivacaine (μg/ml) Bupivacaine (μg/ml) 2 4 8 16 2 4 8 16 Mean ± SEM 8.396 15.000* 0.000* 0.333 33.5 7 14 1. no abnormality in the MABP.515 ± 0.001 highly statistically significant.870 50.075 13.300 29. The animals died after being injected with 1 and 2 mg/kg it produced significant decrease in insignificant rise in the MABP.291 19. levobupivacaine and bupivacaine.000* 0.000* 0.100 ± 0.658 83. Percentage activity of the reaction time in the hot plate test by ECG pattern was observed with levobupivacaine With respect to the ECG.864 111. IP: 117.233 25.000* 0.001 highly statistically significant.000* Data were presented as mean percentage ± SEM.000* 0.000* 0.221 61. *P < 0.75 3.75 3.000 ± 0.38] of isolated rabbit’s heart.989 53. P.000* 0. isolated rabbit’s heart.249 P 0.asja.eg.000* 0.447 ± 0.

2a 4. and weight and duration of surgery of PR interval. form of depression of ST segment.39 4.569 1.314 0.098 1.000** Data were presented as mean percentage ± SEM.992 Weight (mean ± SD) (kg) 82 ± 5 84 ± 8 0.803 ± 0.736 3.569 10.000** 0.821 0. there was a bupivacaine through epidural Tuohy needle into the significant decrease in the HR and ECG changes in epidural space.127 0.67 ± 7. P > 0.986 1.51 ± 0. P > 0.024 1.000** 0.46 42.3) 0. Concerning levobupivacaine and group B received 15 ml of 0. widening of QRS complex.[Downloaded free from http://www.009 0.89 ± 0. Values represent mean percentage decrease ± SEM. Cats developed cardiac arrest b c and died.281 0.377 ± 0. 589 and the first two doses of bupivacaine.52 18.99a 7. .131.454 Sex (female/male) [N (%)] 3 (25)/12 (75.001 highly statistically significant.12 ± 2.000** 0.07 3.04 4.5 1 2 4 Mean ± SEM 1.0) 4 (26.892b c t 1.11 ± 3. **P < 0. 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) 0.953 4.05 were considered statistically insignificant.923a 4.724 1. 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) 0.978b 20. solution used.311 ± 1.755 P-value 0.22 2.5 1 2 4 0.05 statistically significant. IP: 117. and prolongation Patient’s age.5% the effect of 2 mg/kg bupivacaine.433 P-value 0.524 ± 0.asja.47 0.7)/11 (73.82 a t 1.418 Duration of surgery (min) 122 ± 30 114 ± 45 0.012 ± 2.60 ± 7.02 6.1 ± 4.064 0.926 4. sex.000** a Values represent mean percentage increase ± SEM.475 22.909 1. 2015. aCats developed cardiac arrest and died. *P < 0.095 0. P > 0. decreased QRS voltage.05) randomized into two groups according to the LA (Tables 6 and 7).248.34 ± 1. finally ending with cardiac arrest and were comparable.12 ± 2.01 ± 0.691b 1.5% There were high statistically significant differences Figure 4 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.573 0. ASA physical status I–II were hour and all over the duration of surgery (P > 0.093 0.001 highly statistically significant.38] Levobupivacaine benefits over bupivacaine EL-Din et al. **P < 0.05 were considered statistically insignificant. There were no statistically significant differences Clinical study between two groups for the HR and MABP in the first A total of 30 patients. and there were no statistically death of cats when the last dose of bupivacaine was significant differences between the two groups injected (Table 4).066 0.eg.759 0.571 Values are expressed as mean ± SD. anesthetized intact cat.99a 2. (Table 5). 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) 40.5 1 2 4 Mean ± SEM 1. December 30.05 were considered statistically insignificant.060 0.net on Wednesday.056* 0.2 ± 2. Group L (n = 15) received 15 ml of 0.5 1 2 4 0.868 1.

2 ± 10. In the postanesthesia care unit. 6).38] 590 Ain-Shams Journal of Anesthesiology time of sensory block (19.732 0. 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) 89.701 0.7 Bupivacaine (B)group (n = 15) 90.4 ± 6. and none of the patients in both groups required supplement Onset time and time to T10 of sensory block in both groups. which is statistically significant (Table 8 and Fig.0 0. 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) 19.79 16.0 1.8 ± 10.0 28.5 ± 0.673 0.05 were considered statistically insignificant. min).345 0.5 ± 0.387 0.7 ± 9.05 statistically significant.631 0.8 88. 2015.253 0.05.4 ± 11.05 were considered statistically insignificant.013 0.000** Time to T10 sensory block (min) 29 ± 2.000** Onset time of motor block (modified 20.7 ± 7.85 min) analgesics for 2 h postoperatively.923 0. 16.[Downloaded free from http://www.1 89. In addition.85 10. **P < 0.0 vs. .9 Bupivacaine (B) group (n = 15) 93.5 ± 8.0 17.207 P-value 0.166 0. P > 0.6 ± 5. IP: 117.0 90.0 91.7 ± 10.260 0. mean arterial blood pressure. *P < 0.610 0.3 ± 11.348 0.0 25 ± 0.188 Bromage scale 1) (min) Time to complete motor block (modified 30.05 were considered statistically insignificant.105 Values are expressed as mean ± SD/quality of analgesia is expressed as median (range).0 85.131.6 t-test t 0.515 1.192 0.8 7.6 92.79 t-test t 0. There were no statistically significant differences between the two groups in onset time of motor block and the quality of analgesia.837 Values are expressed as mean ± SD.097 0.2 ± 6. Although the mean times for two segment regression and recovery from motor block were shorter in the L group.6 ± 4.248. there were no statistically significant differences between the two groups in the HR and MABP.934 0.eg.7 86.0 vs.001 highly statistically significant.08 84.0 ± 3.0 224 ± 57.6 ± 2.000 incision) [Median (range)] Time for two segment regression (min) 117 ± 48.050* Bromage scale 3) (min) Quality of analgesia (at the time of skin 4 (3–4) 4 (3–4) z = 0.6 ± 2.9 ± 5. MABP. where VAS was and time to T10 sensory block (29 ± 2. December 30.4 ± 3. the time to complete motor block in the L group was more than the time in the B group Figure 6 (30.2 ± 4.796 Recovery from motor block (min) 186 ± 67. 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) 93.0 122 ± 57. P > 0. there was no statistically significant difference (Table 8).7 93.8 ± 7.4 ± 3.000 1.5 88.9 86.asja.4 1.5 ± 0.2 ± 3.79 vs.816 P-value 0.net on Wednesday.421 Values are expressed as mean ± SD. 28.533 0.0 min) with P equal to 0.5 ± 0.8 greater than 4.0 1. 25 ± 0.25 85.4 ± 6. P > 0.

however.248. intravenous LAs [18]. we found that the onset time of sensory block. It seems to be an alternative LA agent in epidural In addition.38] Levobupivacaine benefits over bupivacaine EL-Din et al. [12] reported levobupivacaine was less potent in depressing cardiac that levobupivacaine and bupivacaine have similar electrophysiological parameters than bupivacaine in an efficiency. but also Ca2+ and K+ motor block are lower with bupivacaine than channels [16]. particularly on the discrepancies between experimental and clinical neutrophil priming reactions [19]. blocked at the sodium ionophore during depolarization. December 30. faster unblocking of sodium channels. levobupivacaine and bupivacaine at all Levobupivacaine is currently the closest to the ideal concentrations exerted a significant negative inotropic agent for neural blockade. Concerning the analgesic activity of levobupivacaine which might be attributable to a greater intrinsic and bupivacaine. 45. Both the cardiovascular and central nervous assessed by the investigator was ‘excellent’ or ‘good’ systems are the primary target organs of LA toxicity in 96% of patients in the levobupivacaine group and with accidental intravascular injection. and time to complete LAs not only block Na+ channels. the mean occurred 45 min sooner with bupivacaine and slower fatal dose for levobupivacaine was found to be 277 mg onset of lower extremity motor block occurred with compared with 156 mg for bupivacaine [23]. and their efficacy results from more than bupivacaine. where complete regression to explore the effects of larger doses in sheep. with levobupivacaine compared 0. than bupivacaine when it is given for epidural pain relief during labor.asja. but levobupivacaine has a greater degree isolated heart model. With respect to the cardiovascular experiments in this study. Arslantas et al. of bupivacaine (16 ug/ml) caused 82. Through this action. and Bergamaschi et al. that the sensory blockade lasted significantly longer with levobupivacaine than with racemic bupivacaine. and other ligand-gated receptors. a significant levobupivacaine is less cardiotoxic. and and observed similar onset times but a significantly a marked decrease in potassium blockade compared longer duration of sensory blockade when with racemic bupivacaine [22] and that. these potent anti-inflammatory effects.net on Wednesday. Kopacz et al.eg. 2015.447% reduction. LAs exert there is no statistically significant difference. Although and their associated receptors. Bupivacaine was 82% of patients in the bupivacaine group. as a result. the experimental result in the vasoconstrictor potency of levobupivacaine. [9].10]. The onset of sensory and effect on the isolated perfused rabbit heart. in addition to a variety the mean times for two segment regression and of other antithrombotic and neuroprotective actions of recovery from motor block are shorter in the L group. and there is always the potential risk for toxic The overall quality of sensory and motor blocks as reactions. IP: 117.75% levobupivacaine and bupivacaine [S(–) bupivacaine]. However. LAs difference in the onset time of motor block and the also disrupt the coupling between certain G proteins quality of analgesia between both drugs. [2]. Glaser et al. Uzuner Nau et al. present study showed that the analgesia produced by levobupivacaine was rapid onset and long duration The analgesic activities result from direct block of than that of bupivacaine. agreement with clinical results. and 90 min. the duration of lower Discussion extremity motor block was similar for patients Regional anesthesia might require high doses of LA agents administered levobupivacaine and bupivacaine. . levobupivacaine prolonged transmission of pain from nociceptive afferents. there is less sodium channel for epidural anesthesia in lower abdominal surgery blockade. in the clinical action on the nerve where the inward Na+ current is study. No serious one of the most widely used LAs because of its quality of adverse events were related to study medication.131. Foster and Markham [15] have shown anesthesia [9. The motor block is related to the physicochemical properties myocardial depressant action of bupivacaine was found of the individual drugs. monitored less in group L at 15. and pH of the tissues [11]. [13] In-vitro studies indicate that. with levobupivacaine being the of separation between motor and sensory blockade least toxic than that of bupivacaine. Such finding was in agreement with the studies by In contrast to our results. time to T10 sensory block. results may be due to animal to human variation and the route of administration. and there was no statistical receptors [17]. [20] and Heavner [21] who stated that et al. In addition. In a further study difference was observed. 591 levobupivacaine. for surgery. 30. levobupivacaine was used. [14] Levobupivacaine is the pure S(-)-enantiomer of found no difference as to motor block development racemic bupivacaine. LA the reaction time to the stimulus of hot plate test agents are applied directly. preclinical animal and volunteer between the groups.[Downloaded free from http://www. In anesthesia and prolonged duration of action [8]. transient receptor potential vanniloid-1 with levobupivacaine. namely the mass of the injected greater than that of levobupivacaine and the last dose LA. but the sensory block was studies showed less cardiac toxicity than bupivacaine. the pKa of the drug. Overall.

[37] who speculated that the primary cause been shown to inhibit carnitine-acylcarnitine transferase of cardiovascular collapse induced by bupivacaine may in rat cardiac interfibrillar mitochondria. [32] reported that the high lipophilicity differences between the two groups for HR and MABP and protein binding of bupivacaine may favor all over the duration of surgery. compared with that of levobupivacaine for its slow elicited insignificant effect on blood pressure. compared the epidural ECG of pentobarbitone-anesthetized intact cats.7% in the blood level. enhanced uptake and binding in the myocardial tissue. complications such as nausea. Similarly. as well as the way of injection may influence the was attributed to both study drugs. 38. [31] and limb surgeries provides no statistically significant Tsuchiya et al. causing significant decreases in blood pressure and However. Bupivacaine has also Groban et al. IP: 117. ordering. and inhibition of the study drug. [36] and be involved in the cardiotoxicity. Punke and produced hypotension. vomiting.net on Wednesday. 4 mg/kg of levobupivacaine in the present study might Bergamaschi et al. [12] demonstrated that the most be explained by achievement of high blood level of frequent complication was hypotension.248. Animal variability. severe more than levobupivacaine with the dihydropyridine. which is related to its depressant effect in our clinical study. [33] surgeries and labor analgesia. this may be a key factor in the nature has been a popular LA agent [38]. When the blood level of Friederich [26] suggested that binding of bupivacaine bupivacaine became highly elevated in some cats. and there and Lefrant et al. dilatation of blood vessels. which increased drug blood level. in general.5% of the bupivacaine group patients. Ngamprasertwong et al. [34] have revealed bupivacaine as a were no significant differences in systolic and diastolic negative inotropic agent. and there were no differences between the firing rate of the sinoatrial node.40].7% of the levobupivacaine group patients and in depression.131. 2015. of absorption.75% levobupivacaine is a suitable anesthetic Hypotension that occurred in the cats injected with for use in lower abdominal surgery. [25] attributed In contrast to the vasopressor effect of levobupivacaine the potent cardiodepressant activity of bupivacaine in this study. [14]. cardiovascular bupivacaine group. and Arslantas et al. related to either study drug. and permeability is altered by cardiotoxic drugs. This study demonstrates that 0. De La Coussaye et al. Kopacz et al. the ECG include widening of the QRS complex and and there were no clinically significant ECG changes lengthening of the PR interval.38] 592 Ain-Shams Journal of Anesthesiology Butterworth [24] and Mio et al. small doses of bupivacaine.5% levobupivacaine or when applied extracellularly by its action on membrane racemic bupivacaine in patients undergoing elective cardiolipin [28–30]. and contradicted with the results of Kopacz et al. Although there are no adverse depression occurs. Bupivacaine affects and rapidly reach The present clinical study demonstrates that the epidural mitochondrial membranes of cardiomyocytes even administration of 15 ml of 0. Carnitine. Typical effects on groups with respect to change from baseline in HR. for transporting acylcarnitines across the mitochondrial membranes in the fatty acid transport chain during As levobupivacaine has less potential for sodium phase I mitochondrial respiration important for aerobic channel blockade and produces less arrhythmias. agitation. [13] found that hypotension HR through alterations in electrical excitability of the was the most common side effect attributed to the heart. the other studies observed effect on myocardial contractility and HR [35].7% in the blood level of LA is excessively elevated. in levobupivacaine and bupivacaine in major abdominal accordance to our results. December 30. as fluidity. respectively. whereas release from Na+ channel-binding sites as well as larger doses. It was thought of LA-induced toxicity being unresponsive to advanced that it can be used instead of bupivacaine because cardiac resuscitation techniques. . [31] found that hypotension drug. [2] and Arslantas et al. This result binding sites on neuronal L-type of Ca+ channels may is in accordance with the studies by Jung et al. and excretion of the injected Ngamprasertwong et al. it metabolism [27]. found in the drug in these animals leading to myocardial 66. with intravenous infusions pressures or in HR values between the groups. and accordingly toxicity of the drug.asja. If the levobupivacaine group compared with 66. metabolism. of its less toxic side effects to the cardiovascular and central nervous system [39. results of Uzuner et al. making cardiac resuscitation more difficult following Our hemodynamic results are comparable with the bupivacaine-induced cardiovascular collapse.[Downloaded free from http://www. hypotension and death of the cats occurred. with respect to the rate 43. In experiments on the arterial blood pressure and Uzuner et al. Corrected QT is used Apart from the channel blockade. be due to hypotension from diminished contractility acylcarnitine transferase is the only enzyme responsible rather than arrhythmias in anesthetized dogs. [13]. the membrane to evaluate the arrhythmogenic potential of drugs. In addition.eg. Ca+ channel-binding sites. However. interaction (especially with cardiac mitochondria) Levobupivacaine has also a poor influence on QRS or that modifies membrane biophysical properties such corrected QT [41].

33 De La Coussaye JE. ropivacaine for peribulbar anesthesia in vitreoretinal surgery. .net on Wednesday. based on these results. Edinburgh and hexamethonium in anesthetized dogs given a large dose of bupivacaine.248. Hemodynamic effects of 34 Lefrant JY. 4:381–392. Balle V. J 11 Piangatelli C. The effects of local and intravenous Anesthesiology 2004. Khan F. Rev Bras Anestesiol 2010. 90:642–648. triphosphate-sensitive potassium channels in the cardiovascular system. Anesthesiology 2000. Bupivacaine inhibits acylcarnitine exchange in cardiac levobupivacaine for infraclavicular brachial plexus block.5% Hoppel CL. Udomtecha D. Wang F. and large dose intravenous levobupivacaine in sheep. Kitahata H. et al. Choy Y. Blanck T. Mather LE. IP: 117. Recio-Pinto E. Tolerability of analgesic activity and less cardiodepressant effect. Cochrane Database Syst Rev 2012. Lalourcey L. VadeBoncouer TR. Muller L. arrhythmia with bupivacaine during the postoperative 95:113–122. Wang G. 201:1–8. Thompson GE. [12. eds Toxicity test. 12 Bergamaschi F. 15 Foster RH. pruritus. 101:888–894. Fukuda N. Finally. Marhofer P. Galbes O. Edinburgh and modify the fluidity. J Med Assoc Thai 2005. 8 Udelsmann A. Lambert D. Silva W. Acknowledgements 25 Mio Y. 1970a. Durieux M. large dose of ropivacaine and bupivacaine in anesthetized and ventilated 9 Glaser C. and their interactions.asja. Agri 2012. ropivacaine and levobupivacaine intravenous injection in swines. The efficacy of 0. The comparative electrophysiologic and hemodynamic effects of a Bras 2009. The hemodynamic effects of insulin following repair. Allen HW. peripheral human skin. 90:1308–1314. Minerva Anestestiol 2006. London: E & S Livingstone. et al. 60:445–454. Levobupivacaine. 96–99. resuscitation after incremental overdosage with lidocaine. Takahashi A. Anesthesiology 1994. A comparison of 14 Arslantas R. Peray PA. 38 Chang DH. 22:342–346. and ropivacaine in anesthetized swine. Br J Anaesth 2005. Saracoglu A. Acta Cir et al. Rev Bras Anestesiol 2005. Saracoglu K. 4:1–49. overdosage with levobupivacaine or racemic bupivacaine in dogs. bupivacaine and levobupivacaine with and without adjuvant epinephrine in 10 Amato B. it offers advantages over the racemic bupivacaine. Baogham S. Levobupivacaine versus racemic bupivacaine 5 Ghosh MN. Comparative Conflicts of interest effects of bupivacaine and ropivacaine on intracellular calcium transients and None declared. Eur J Pharmacol 2002. Anesth Analg Levobupivacaine versus bupivacaine in epidural anesthesia for cesarean 2001. J Membr Biol 2004. Vasoactive characteristics of anesthesia. London and New York: 31 Ngamprasertwong P. Dadure C. Interactions of local anesthetics with voltage-gated Na+ levobupivacaine. Gelgor L. Bruelle P. Cerchiara P. actions and misconceptions. Calcutta: Scientific Book Agency. Takakura K. 93:1022–1033. 109:895–904.38] Levobupivacaine benefits over bupivacaine EL-Din et al. 19 Hollmann M. et al. Herroeder S. Anesthesiology 2001. Anesth Analg 2000. Wang S. 593 ventricular premature complexes (bigeminy). Lefrant JY. Ther Clin Risk Manag 2008. 17 Hirota K. Lee KH. Las Vegas. Ueno T. Local anesthetic effects [2] detected a higher incidence for supraventricular on priming and activation of human neutrophils. 32 Tsuchiya H. 56:331–341. Amaki Y. Comparison of 0. References 27 Weinberg GL. Wilson KA. Peray PA. experimental pharmacology. Anesthesiology 2008.75% of local anesthetic cardiotoxicity?. levobupivacaine with epidural technique for labor analgesia. Arslantas M. Liu Y. Kurihara S. Durieux M. et al. de La Coussaye JE. Rocco N. 94:194–198. Res Med Sci 2011. Eledjam JJ. James RL. Persico G. anesthetics on recombinant rat VR1 vanilloid receptors. Cardiac brachial plexus block. Zuechner MB. Oshita S. A comparison of epidural large-dose intravenous levobupivacaine in sheep. Moschetti I. 94:662–667. 20 Nau C. Anesthesiology 2000. Tanifuji Y. Wang G. Academic Press. Moja L. Reiz S. 7 The Staff of the Department of Pharmacology University of Edinburgh. In: Laurence DR. levobupivacaine. Cardiac toxicity of local anesthetics in the intact isolated heart pharmacodynamic evidence from animal and human model: a review. 22 Mc Leod G. Receptors. 92:523–528. Xu S. 101:390–398. Local anesthetics 6 The Staff of the Department of Pharmacology University of Edinburgh. Local anaesthetics: agents. Butterworth J. 26 Punke M. levobupivacaine 0. channels by the enantiomers of bupivacaine. Levobupivacaine versus racemic bupivacaine for spinal 35 Newton DJ. 1970b. Bassoul B. dyspnea. 103:1066–1078. Nevada: Lippincott Williams & Wilkins. section. 2010. Is cardiolipin the target 3 Ghali AM. 1984. Pertuiset C. 455:81–90. Anesth Analg 2001. Uzuner et al. Charuluxananan S. 6:22–26. Fundamentals of for extradural anesthesia for cesarean delivery.75% with racemic bupivacaine for lower abdominal 91:671–679. bupivacaine. Ladd AL. 1964. Mechanisms of the putative cardioprotective effect of Pharmacological experiments on isolated preparations. Barnes JM. Morau D. 144–152. Tomiyama Y. Anesth Analg 41 Burlacu CL. Vernon JC. 311: 1–12. piglets.75% levobupivacaine versus 0. 111:1120–1127. Burke D. 28 Pardo L. Dominguez JJ. 16:1159–1167. Anesth Analg 24:23–31. Chem Biol Interact 2010. Reg Anesth Pain Med 2002. Recanatini F.31] and bradycardia [12]. Zimpfer G. 135. 27:545–555. 65:302–305. Anesth Analg 2000. Markham A.1 channels. McLeod GA. Anesthesiology 2009. Gelgo L. 24:296–302. G proteins. 72:217–221. Heinz MT. Sitzwohl C.[Downloaded free from http://www. Deal DD. Comparison of bupivacaine and the electrocardiographic cardiotoxic effects of racemic bupivacaine. Yuan H. Korean Med Sci 2007. December 30. Ripart J. Anesth Analg 2002. Hayot M. 91:671–679. Tsutsumi Y. Machado S. the current 21 Heavner JE. levobupivacaine. Dreyer E. Drugs 2000. Qian Y. 2000. Tolerability of 13 Kopacz DJ. 2nd ed. 39 Morrison SG. structure-dependently interact with anionic phospholipid membranes to Pharmacological experiments on isolated preparations. 80:595–605. 183:19–24. 2015. Palmer JW. Lipophilic and stereospecific interactions of amino- amide local anesthetics with human Kv1. Levobupivacaine and ropivacaine in the infraclavicular 37 Groban L. Wilson KA. 59:551–579. 24 Butterworth JF. Ladd LA. Mather LE. Srihatajati C. 16 Nau C. Kapral S. de Moraes A. studies suggests that levobupivacaine has good 23 Chang DH. Age-dependent bupivacaine-induced muscle toxicity during continuous 4 Paget GE. Levobupivacaine: a review of its pharmacology 40 Kawano T. Pecora L. and ropivacaine on sarcolemmal adenosine channels. Anaesth 2012. Anesthesiology 2005. 55:606–613. tension in ferret ventricular muscle. Ozyuvaci E. Anesth Analg 2000. 116–118. levobupivacaine. Bacharach AL. Update on local anesthetics: focus on 2003. Block of human heart hH1 sodium period. Strumper D. Panico S. Anaesthesia 2001. Mendes F. 93:1598–1605. 18 Hollmann M.eg. Kusakari Y. The neuronal lipid membrane 2 Uzuner A. 1 Mageswaran R. Belch JJ.131. Testasecca D. Shouldice technique versus other open techniques for inguinal hernia 36 Jung CW. Saudi J 30 Nouette-Gaulain K. 96:1656–1660. Med J Malaysia mitochondria. Jelacin N. Kim JT. Some common evaluation techniques. American Society of Anaesthesiologists’ Annual Meeting refresher course lectures. 88:1563–1568. Schindler I. Erdemli O. surgery. Molecular mechanisms of the inhibitory effects of bupivacaine. Rodanant O. Buggy DJ. Anesthesiology 2004. Evaluation of drug activities: pharmcometrics. 2004. and use as a local anaesthetic. London: E & S Livingstone. J by lidocaine and ropivacaine. 92:37–43. Strichartz G. The comparative study of permeability was markedly increased by bupivacaine and mildly affected epidural levobupivacaine and bupivacaine in major abdominal surgeries. peripheral nerve block in rats. Smart D. Rispoli C. Comparative study. Edelman G. and ropivacaine in anesthetized dogs. 29 Shen X. Mizogami M.5% ropivacaine and 0. Gross A. Friederich P. Angelis C. Frascarolo P. Gomes M.