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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.55 no.6 Campinas Nov./Dec. 2005
Levobupivacaine versus bupivacaine in epidural anesthesia for cesarean section. Comparative study*
Levobupivacaína versus bupivacaína en anestesia peridural para cesáreas. Estudio comparativo
Felipe Bergamaschi, M.D.I; Vanessa Rezende Balle, M.D.II; Marcos Emanuel Wortmann Gomes, M.D.III; Sheila Braga Machado, M.D.III; Florentino Fernandes Mendes, TSA, M.D.IV
do CET da Faculdade de Ciências Médicas de Porto Alegre (FCMPA)
IIAnestesiologista do Núcleo de Analgesia e Anestesia Obstétrica da Santa Casa de Porto Alegre, Mestranda em Farmacologia (FCMPA)
IIIAnestesiologista do Núcleo de Analgesia e Anestesia Obstétrica da Santa Casa de Porto Alegre
IVChefe do Serviço de Anestesiologia da Santa Casa de Porto Alegre, Mestre em Farmacologia pela FCMPA, Doutor em Medicina pela FMSCSP
OBJECTIVES: Local anesthetic bupivacaine is found in two different enantiomers:
levobupivacaine - S (-) and dextrobupivacaine - R (+). Based on studies showing
that S(-) enantiomers are less cardiotoxic, their use has been increasing in
clinical practice. This study aimed at comparing racemic bupivacaine and levobupivacaine
in epidural anesthesia for elective cesarean section.
METHODS: Randomized, double blind clinical trial enrolling physical status ASA I and II parturients. Patients were assigned to receive either 20 mL of 0.5% racemic bupivacaine or 20 mL of 0.5% levobupivacaine, both with 10 µg sufentanil and epinephrine 1:200,000.
RESULTS: Participated in this study 47 patients being 24 in the levobupivacaine group and 23 in the bupivacaine group. Both groups were comparable regarding maternal-fetal characteristics. Fifteen minutes after epidural anesthesia, 62.5% of levobupivacaine group patients experienced Bromage 2 or 3 motor block, whereas the same event was documented in 72.7% of bupivacaine group patients (p = 0.83). After 20 minutes, 66.7% of levobupivacaine group patients experienced Bromage 2 or 3 motor block versus 86.3% of bupivacaine group patients (p = 0.21). Most common complication was hypotension, detected in 16 (66.7%) levobupivacaine group patients and in 10 (43.5%) bupivacaine group patients (p = 0.11).
CONCLUSIONS: Levobupivacaine and bupivacaine were equally effective for epidural block in patients undergoing cesarean section.
Key words: ANESTHETICS: bupivacaine, levobupivacaine; SURGERY, Obstetric: cesarean section
Y OBJETIVOS: El anestésico local bupivacaína es encontrado en
la forma de dos enantiómeros: levobupivacaína - S (-) y dextrobupivacaína
- R (+). Basado en estudios que demuestran que la cardiotoxicidad es menor con
el enantiómero S(-), fue difundido el uso de este agente en la práctica
clínica. El objetivo de este estudio es comparar la eficacia y la efectividad
del uso de bupivacaína racémica con levobupivacaína en anestesia
peridural de pacientes sometidas a cesárea electiva.
MÉTODO: Ensayo clínico eventual, doblemente encubierto, con gestantes estado físico ASA I y II. Las pacientes fueron distribuidas para recibir 20 mL de bupivacaína a 0,5% racémica ó 20 mL de levobupivacaína a 0,5%, ambas con 10 µg de sufentanil y vasoconstrictor.
RESULTADOS: Participaron del estudio 47 pacientes, 24 en el grupo de la levobupivacaína y 23 en el grupo de la bupivacaína. Los grupos eran comparables entre sí en lo que se refiere a las características materno-fetales. Transcurridos 15 minutos después del término de la punción peridural, 62,5% de las pacientes del grupo de la levobupivacaína tenían Bromage 2 ó 3 contra 72,7% en el grupo de la bupivacaína (p = 0,83). Transcurridos veinte minutos, 66,7% de las pacientes del grupo de la levobupivacaína tenían Bromage 2 ó 3 contra 86,3% del grupo de la bupivacaína (p = 0,21). La complicación más frecuente fue la hipotensión arterial, encontrada en 16 (66,7%) pacientes del grupo de la levobupivacaína y en 10 (43,5%) pacientes del grupo de la bupivacaína (p = 0,11).
CONCLUSIONES: La levobupivacaína y la bupivacaína fueron igualmente efectivas en el bloqueo peridural de pacientes sometidas a cesárea.
Epidural local anesthetics associated to opioids are often used for cesarean section anesthesia. Their use has increased with the development of epidural catheters for obstetric analgesia, which help the conversion to anesthesia when needed 1. A feared, although uncommon complication is massive local anesthetics absorption. Its toxic effects may be severe and of difficult reversal.
Currently, most common drug for obstetric epidural anesthesia is bupivacaine. An inadvertent intravascular injection reaching toxic plasma concentrations may have effects on central nervous system (CNS), especially seizures, and on cardiovascular system, and may result in cardiac arrest and death1. All local anesthetics induce toxicity by direct and indirect mechanisms, always related to voltage-dependent ion channels inhibition 2.
Bupivacaine is a racemic mixture consisting of equal amounts of the optic isomers levobupivacaine and dextrobupivacaine, also known as S(-) and R(+) enantiomers 3. Based on demonstrations that racemic bupivacaine cardiotoxicity is enantio-selective, that is, more pronounced with R(+) enantiomer, S(-) enantiomer was developed for clinical use as long-lasting local anesthetic agent 4.
Several experimental studies have shown that lower bupivacaine doses as compared to ropivacaine and levobupivacaine may induce toxic manifestations, such as seizures, hypotension, apnea and circulatory collapse 5-8. Seizures were observed with lower doses in pregnant ewes as compared to non-pregnant animals. This was not observed with regard to other manifestations 5.
In human volunteers, levobupivacaine has shown lower negative inotropic effect as compared to bupivacaine. There were also less changes indicating CNS depression at EEG 4. A different study has shown lower incidence of hypotension in pregnant patients anesthetized for cesarean section with levobupivacaine as compared to bupivacaine. Conversely, there were no differences in neonates' vitality and neurobehavioral evaluation. Local anesthetics plasma levels and placental crossing were similar 9.
In 1999, Bader et al. have compared in a randomized clinical trial 0.5% racemic bupivacaine and 0.5% levobupivacaine in epidural blocks of patients submitted to elective cesarean section. They have observed similar effectiveness between drugs, with just a trend to faster blockade and higher incidence of hypotension with bupivacaíne 9. In 2000, Kopacz et al., in a randomized clinical trial, have evaluated 0.75% levobupivacaine and 0.75% bupivacaine for lower abdominal procedures. Motor block onset (Bromage 2 or 3) was longer for the levobupivacaine group and mean sensory block recovery time was 45 minutes longer for the levobupivacaine group 10.
Based on these data, this study aimed at comparing characteristics and possible complications of epidural block with bupivacaine or levobupivacaine in anesthesia for elective cesarean sections.
After the Research Ethics Committee approval, this randomized double-blind clinical trial was carried out at Centro Obstétrico, Maternidade Mario Totta, Complexo Hospitalar Santa Casa, Porto Alegre, in the period January 2003 to April 2004. Participated in the study patients above 14 years of age, physical status ASA I or II, to be submitted to elective cesarean section. Exclusion criteria were patients with counterindication for epidural block or history of sensitivity to any studied drug. All patients gave their informed consent.
Patients were randomly allocated to the following groups immediately before the anesthetic procedure: levobupivacaine (100 mg) and sufentanil (10 µg); or bupivacaine (100 mg) and sufentanil (10 µg), both with epinephrine 1:200,000. Levobupivacaine was supplied by Laboratório Cristália, Itapira, Brazil. Neither the investigator in charge of data collection nor the patients knew the group they belonged to. Anesthetic procedure was standardized and performed by an investigator not involved in data collection.
After volume expansion with 500 mL lactated Ringer's solution, epidural puncture with 17G Tuohy needle was performed in L3-L4 or L2-L3 interspace with patients in the left lateral position. Epidural space was identified by the loss of resistance to air technique. After negative blood and CSF aspiration, 3 mL of the studied solution were injected in the epidural space as test-dose. Three minutes later, in the absence of tachycardia or motor block, additional 17 mL of the same solution were administered during 5 minutes. Uterus was displaced with standardized Crawford wedge in all patients.
Moment zero was defined as end of epidural injection. Sensory block level was determined by the lack of painful sensitivity at 25 x 7 needle prick on the medium axillary line at 5, 10, 15 and 20 minutes. Motor block was evaluated through modified Bromage scale (0 - no paralysis; 1 - inability to raise extended leg; 2 - inability to bend knees; 3 - inability to bend ankle) at 5, 10, 15, 20 minutes and at surgery completion.
Heart rate and noninvasive blood pressure were measured at 2.5-minute intervals. Hypotension was defined as baseline systolic blood pressure decrease equal to or above 30%, and was treated with hydration and ephedrine. Bradycardia was defined as HR below 60 bpm. Other complications, such as nausea and vomiting were also observed. Data on Apgar scores at 1 and 5 minutes and neonate body mass were collected.
Sample characteristics were presented by frequency, mean, mode and p value. Student's t or Fisher Exact tests were used to compare groups, when indicated, considering statistically significant p < 0.05.
Participated in this study 47 patients, being 24 in the levobupivacaine group and 23 in the bupivacaine group. There were no statistically significant differences between groups in major maternal characteristics (Table I).
There were no differences between groups in surgical indication and co-morbidities. Epidural puncture level and surgery length were comparable (Table II).
There was no statistically significant difference in neonates evaluation (Table III).
Fifteen minutes after epidural puncture, 62.5% of levobupivacaine group patients experienced Bromage 2 or 3, as compared to 72.7% in the bupivacaine group. In 20 minutes, 66.7% of levobupivacaine group patients expe- rienced Bromage 2 or 3 as compared to 86.4% of bupivacaine group (Figure 1).
There was no statistically significant difference between groups in sensory block level in all studied moments (Table IV).
Most frequent complication was hypotension, found in 16 (66.7%) levobupivacaine group patients and in 10 (43.5%) bupivacaine group patients. There was no difference between groups (p = 0.11).
Other observed complications were nausea, vomiting, agitation, ventricular premature complexes (bigeminy), dyspnea, pruritus, bradycardia, and partial sensory block failure (Table V).
After reports on bupivacaine toxicity in obstetric anesthesia11, alternatives were searched through the research of local anesthetics which could offer similar blockade quality, however with higher safety in terms of central nervous (CNS) an cardiovascular systems toxicity.
New levogyrous anesthetics seem to be less toxic. It is known that voltage-dependent sodium channels affinity is higher with dextrogyrous enantiomers (R) as compared to levogyrous enantiomers (S), being the former more toxic to the cardiovascular system 11. As compared to S, R enantiomer is three times more firmly bound to sodium channels and takes 4.4 times longer to release such channels. So, R enantiomer is more arrhythmogenic and delays ventricular conduction 4.6 times more than S enantiomer 12.
Studies with levobupivacaine were started as from these observations. Levobupivacaine is the pure bupivacaine S-enantiomer. Its toxicity is intermediary to ropivacaine and bupivacaíne 2,4-8. Levobupivacaine seems to have the same cardiovascular and neurological effects as compared to ropivacaine, when administered to volunteers 13.
Our study has not shown statistically significant difference between groups in major observed characteristics. Motor and sensory block were similar between groups in all evaluated aspects. Observing motor block, Lacassie et al. have shown that levobupivacaine is less potent as compared to bupivacaine (levobupivacaine / bupivacaine ratio 0.87) 14. A different study confirms these results, since there has been less intense motor block after epidural levobupivacaine and ropivacaine as compared to bupivacaína 15. In lower concentrations and during labor analgesia, these anesthetic agents have similar potency, with no difference in motor effects 16.
In spinal anesthesia, sensory and motor blocks were equivalent with levobupivacaine and bupivacaine for orthopedic procedures 17. For spinal analgesia, bupivacaine had longer motor block duration and intensity as compared to levobupivacaine and ropivacaína 18. Bupivacaine has been more effective for Cesarean section anesthesia as compared to these two anesthetic agents 19. So, a joint reading of these results seems to point to higher potency of bupivacaine as compared to levobupivacaine.
Some studies have investigated blockade characteristics after S75-R25 bupivacaine. A study has shown similar characteristics of sensory and motor blocks with 0.5% concentrations for Cesarean section anesthesia, as compared to (R+) bupivacaine and S75-R25 bupivacaine 20. As opposed, another study with similar concentrations in non-pregnant patients has shown more intense motor block with R(+) bupivacaine as compared to S75-R25 bupivacaine 21. Still, and as opposed to what has been observed in these studies, a third evaluation of 0.5% R(+) bupivacaine and S75-R25 bupivacaine for Cesarean sections has shown lower analgesia quality of the latter 22.
Longer onset and less intense motor block have been shown with S75-R25 bupivacaine as compared to bupivacaíne 11,21-23.
Another challenged effect of pure levogyrous isomers of local anesthetics such as levobupivacaine and ropivacaine is vasoconstriction observed in some vascular beds, which could decrease placental blood flow and affect fetal conditions. In evaluating pregnant rabbits receiving intravenous infusion of similar doses of levobupivacaine, bupivacaine or ropivacaine, no significant changes were observed in fetal wellbeing parameters, such as heart rate, mean blood pressure, pH and gases tensions 24. Plasma levels were calculated to simulate absorption observed during epidural blocks. With regard to tested local anesthetics, there has been no change in uterine blood flow. Our study has not shown differences in Apgar scores at 1 and 5 minutes. So, levobupivacaine does not seem to affect fetal wellbeing as compared to bupivacaine.
Although Modified Bromage Scale (MBS) is an imprecise motor block evaluator, it is the most used method to measure such effect. It measures both spread and intensity of lower limbs motor block, since it evaluates different muscle groups with different innervations 25. For MBS to be able to detect motor block differences, effects have to be severe. A study from 1991 has shown that when MBS level 1 is reached, 60% of muscle strength have been lost 26. Qualitative motor block evaluation scales were considered 25, however service standardization 27 has favored MBS.
Major complication has been hypotension without statistically significant difference between groups.
Levobupivacaine and bupivacaine were equally effective in patients submitted to epidural block for Cesarean sections.
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Dra. Sheila Braga Machado
Address: Rua Cel. Orlando Pacheco, 96
ZIP: 91440-050 City: Porto Alegre, RS
Submitted for publication
December 7, 2004
Accepted for publication August 17, 2005
* Received from Núcleo de Analgesia e Anestesia Obstétrica e Núcleo de Pesquisa em Anestesia do Serviço de Anestesiologia do Complexo Hospitalar da Santa Casa de Porto Alegre, RS