Comparative study between 0.5% isobaric bupivacaine and a 0.5% isobaric mixture of 75% S(-) bupivacaine and 25% R(+) bupivacaine in spinal anesthesia for orthopedic surgery

Abstracts

JUSTIFICATIVA E OBJETIVOS: A bupivacaína comercialmente utilizada se apresenta como mistura racêmica RS(±)bupivacaína. Embora o enantiômero levógiro S(-), levobupivacaína, seja menos tóxico para o sistema nervoso central e cardiovascular do que a R(+) bupivacaína, sua relativa eficácia ainda não foi determinada na raquianestesia. O objetivo deste estudo foi comparar a mistura enantiomérica de bupivacaína (com 75% de S(-)bupivacaína e 25% de R(+)bupivacaína) - bupi S75-R25 - com a bupivacaína racêmica, na mesma dose e concentração, para raquianestesia em cirurgias ortopédicas de membros inferiores. MÉTODO: Participaram do estudo 120 pacientes com idades entre 16 e 94 anos, estado físico ASA I e II, programados para cirurgias ortopédicas de membros inferiores, sob raquianestesia. Os pacientes foram aleatoriamente separados em dois grupos de 60 pacientes: Grupo S75-R25, que recebeu 3 ml (15 mg) de solução a 0,5% isobárica, que continha mistura de 75% de S(-) bupivacaína e 25% de R(+)bupivacaína e Grupo S50-R50, que recebeu também 3 ml (15 mg) de bupivacaína racêmica 0,5% isobárica. Foram avaliados e comparados os seguintes parâmetros: latência da analgesia, bloqueio motor, duração dos efeitos, dispersão cefálica da analgesia, alterações cardiovasculares e sintomas neurológicos transitórios. RESULTADOS: Ambas as soluções de bupivacaína produziram efeitos comparáveis quando administrados na raquianestesia. Não foi observada diferença no nível superior da analgesia. O bloqueio motor apresentou tempo menor de instalação com a bupivacaína racêmica (S50-R50). Não foi observado bloqueio motor completo em todos os pacientes. A incidência de hipotensão arterial foi a mesma com ambas as soluções. Não ocorreram sintomas neurológicos transitórios. CONCLUSÕES: A mistura enantiomérica de 75% de levobupivacaína com 25% de dextrobupivacaína, a 0,5% isobárica, injetada no espaço subaracnóideo, produz bloqueio sensitivo e motor similar que a mesma dose de bupivacaína racêmica a 0,5% isobárica para cirurgias ortopédicas. A possibilidade de um bloqueio diferencial significativo com a mistura S75-R25 bupivacaína quando comparada com bupivacaína racêmica merece posteriores estudos.

ANESTÉSICOS, Local; ANESTÉSICOS, Local; TÉCNICAS ANESTÉSICAS, Regional

SCIENTIFIC ARTICLE

Comparative study between 0.5% isobaric bupivacaine and a 0.5% isobaric mixture of 75% S(-) bupivacaine and 25% R(+) bupivacaine in spinal anesthesia for orthopedic surgery^*

Comparación entre bupivacaína racémica (S50-R50) y mezcla enantiomérica de bupivacaína (S75-R25), ambas isobáricas, a 0,5% en raquianestesia. Estudio en cirugías ortopédicas

Luiz Eduardo Imbelloni, TSA, M.D.; Lúcia Beato, M.D.

Anestesiologista da Clínica São Bernardo e Casa de Saúde Santa Maria. Rio de Janeiro, RJ

Correspondence

SUMMARY

BACKGROUND AND OBJECTIVES: Commercially available bupivacaine is a racemic mixture of S(-) and R(+)-enantiomers. Although S(-) bupivacaine is less toxic to the cardiovascular and central nervous systems than R(+) bupivacaine, its relative efficacy has not been determined in spinal anesthesia. This study compared the same levobupivacaine and bupivacaine doses in spinal anesthesia for lower limb orthopedic surgeries.

METHODS: Participated in this study 120 patients aged 16 to 94 years, physical status ASA I and II, scheduled for lower limb orthopedic surgery under spinal anesthesia. Patients were randomly assigned to two groups (n=60): Group S75-R25 (levobupivacaine) received 3 ml (15 mg) of a 0.5% mixture containing 75% S(-)bupivacaine and 25% R(+)bupivacine, and Group S50-R50 received 3 ml (15 mg) of 0.5% plain bupivacaine. The following parameters were evaluated and compared: analgesia onset time, motor block, duration of effects, cephalad spread of analgesia, cardiovascular changes and transient neurological symptoms.

RESULTS: Levobupivacaine and bupivacaine produced comparable effects following intrathecal administration. There were no significant differences in the upper blockade level between groups. Motor block onset time was shorter for bupivacaine. Motor block was not complete in all patients. The incidence of hypotension was similar for both solutions. Transient neurological toxicity was not observed.

CONCLUSIONS: Plain intrathecal 0.5% levobupivacaine produced a similar sensory and motor block effect to that of 0.5% bupivacaine for orthopedic surgeries. The possibility of a significant differential blockade with levobupivacaine as compared to bupivacaine warrants further studies.

Key words: ANESTHETICS, Local: bupivacaine, levobupivacaine; ANESTHETIC TECHNIQUES, Regional: spinal block

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: La bupivacaína comercialmente utilizada se presenta como mezcla racémica RS(±)bupivacaína. Aun cuando el enantiómero levógiro S(-), levobupivacaína, sea menos tóxico para el sistema nervioso central y cardiovascular de que la R(+) bupivacaína, su relativa eficacia aun no fue determinada en la raquianestesia. El objetivo de este estudio fue comparar la mezcla enantiomérica de bupivacaína(con 75% de S(-)bupivacaína y 25% de R(+)bupivacaína) - bupi S75-R25 - con la bupivacaína racémica, en la misma dosis y concentración, para raquianestesia en cirugías ortopédicas de miembros inferiores.

MÉTODO: Participaron del estudio 120 pacientes con edades entre 16 y 94 años, estado físico ASA I y II, programados para cirugías ortopédicas de miembros inferiores, bajo raquianestesia. Los pacientes fueron aleatoriamente separados en dos grupos de 60 pacientes: Grupo S75-R25, que recibió 3 ml (15 mg) de solución a 0,5% isobárica que contenía mezcla de 75% de S(-) bupivacaína y 25% de R(+)bupivacaína y Grupo S50-R50, que recibió también 3 ml (15 mg) de bupivacaína racémica 0,5% isobárica. Fueron evaluados y comparados los siguientes parámetros: latencia de la analgesia, bloqueo motor, duración de los efectos, dispersión cefálica de la analgesia, alteraciones cardiovasculares y síntomas neurológicos transitorios.

RESULTADOS: Ambas soluciones de bupivacaína produjeron efectos comparables cuando administrados en la raquianestesia. No fue observada diferencia en el nivel superior de la analgesia. El bloqueo motor presentó tiempo menor de instalación con la bupivacaína racémica (S50-R50). No fue observado bloqueo motor completo en todos los pacientes. La incidencia de hipotensión arterial fue la misma con ambas soluciones. No ocurrieron síntomas neurológicos transitorios.

CONCLUSIONES: La mezcla enantiomérica de 75% de levobupivacaína con 25% de dextrobupivacaína, a 0,5% isobárica, inyectada en el espacio subaracnóideo, produce bloqueo sensitivo y motor similar que la misma dosis de bupivacaína racémica a 0,5% isobárica para cirugías ortopédicas. La posibilidad de un bloqueo diferencial significativo con la mezcla S75-R25 bupivacaína cuando comparada con bupivacaína racémica merece estudios posteriores.

INTRODUCTION

Biological differences among cocaine enantiomers have been described in the early 20^th Century ¹. Commercially available bupivacaine is a racemic mixture of S(-) and R(+) enantiomers and was firstly used for spinal anesthesia in 1966 in concentrations of 0.5%, 0.75% and 1%, with or without epinephrine ². There are evidences that bupivacaine isomers have different Na⁺ channel blockade properties, being R(+) bupivacaine three times more potent than S(-) bupivacaine ³. Levobupivacaine (the S(-) enantiomer) is now being clinically studied and was obtained by resolution of its respective racemic form and seems to have a pharmacologically similar profile.

Several animal and human studies have shown that levogyrous local anesthetics are less toxic than racemic or dextrogyrous bupivacaine for cardiovascular and central nervous systems and have an intrinsic ability of producing vasoconstriction and lower motor block ^1,4,5. However, the preservation of compound's clinical advantages is fundamental for the manipulation of its enantiomeric relations ⁶.

The experience with S(-) bupivacaine in epidural anesthesia has shown an unsatisfactory blockade ⁷, so there is a trend to use it in higher concentrations (0.75%) ^7,8. Recently, 0.5% bupivacaine has become the most popular local anesthetic for spinal anesthesia. It is available in the racemic form with both enantiomers in the equimolar ratio of 50:50 RS (±) bupivacaine. When intrathecally administered, 0.5% bupivacaine induces effective surgical anesthesia. Conversely, 0.5% levobupivacaine is being seldom used for spinal anesthesia ⁹.

This study aimed at comparing the spinal blockade produced by 0.5% racemic bupivacaine to that induced by a 0.5% isobaric enantiomeric mixture containing 75% S(-)bupivacaine and 25% R(+)bupivacaine (S75-R25) in major and medium size orthopedic surgeries.

METHODS

After approval by the Hospital Publications Board and their formal consent, participated in this prospective study 120 patients aged 16 years or above, physical status ASA I or II scheduled for major and medium size orthopedic surgeries. Exclusion criteria were hypovolemia, coagulation disorders, infection and refusal to participate. Patients were randomly allocated in two groups of 60, according to the drug used: Group S75-R25, received a 0.5% enantiomeric mixture of 75% S(-)bupivacaine plus 25% R(+)bupivacaine and Group S50-R50, 0.5% racemic bupivacaine (Table I).

Brazilian Journal of Anesthesiology, 2001; 51: 5: 369-376

Comparative study between 0.5% isobaric bupivacaine and a 0.5% isobaric mixture of 75%

S(-) bupivacaine and 25% R(+) bupivacaine in spinal anesthesia for orthopedic surgery

Luiz Eduardo Imbelloni; Lúcia Beato

Patients were not premedicated. Lactated Ringer's solution was infused after venoclysis through a 18G catheter for hydration, expansion and maintenance of vein's patency. After sedation with 1.5 to 4.5 mg midazolam and 20 to 30 mg meperidine, spinal anesthesia was induced in the left lateral position with 3 ml (15 mg) of one of the studied solutions by the paramedian approach in the L₂-L₃ or L₃-L₄ interspace with a 27G Quincke needle. After CSF confirmation, anesthetic solutions were injected without barbotage, at a rate of 0.2 ml.s^-1. Patients with hip fracture received ketamine (0.05 mg.kg^-1) before blockade.

Depth of anesthesia (loss of pinprick sensation) was bilaterally determined at 1-minute intervals in the beginning and at every 5 minutes up to 30 minutes. Lower extremities motor block was determined in the same times, using Bromage's scale. Blockade onset was defined as time elapsed for the first loss of sensitivity in the region corresponding to the puncture metamer. Analgesia duration was the time for total sensitivity recovery and blockade duration was defined as the time elapsed until complete lower limbs muscular activity recovery. In case of blockade failure, the procedure was repeated before surgery and another anesthetic injection was done. In the presence of any perioperative failure (insufficient level or time), the technique was changed to general anesthesia. Headache was evaluated for all patients up to the 5^th postoperative day, as well as transient neurological symptoms or other neurological complications. Patients were followed-up until the 30^th postoperative day.

Blood pressure, heart rate and SpO₂ were recorded at every 5 minutes and ECG was continuously monitored at CM5. Hypotension, defined as a systolic blood pressure (SBP) below 30% of baseline pressure, was firstly treated by increasing hydration and, in the case of no response, with vasopressors. Heart rate below 50 bpm was treated with atropine. All patients received a nasal catheter with oxygen (1-2 L.min^-1) and no patient received vesical catheter.

Results were analyzed by Student's t, Brieger's F, chi-square, Mann-Whitney and Kruskal-Wallis tests being considered significant wnen p < 0.05.

RESULTS

Participated in this study 120 patients, being 64 males and 56 females. There were no differences in mean age, weight and height in both groups (Table II). Three patients had no blockade after 15 minutes (2 in Group S75-R25 and 1 in Group S50R50) and received a new puncture (Table III). There was no need for complementation with general anesthesia.

Brazilian Journal of Anesthesiology, 2001; 51: 5: 369-376

Comparative study between 0.5% isobaric bupivacaine and a 0.5% isobaric mixture of 75%

S(-) bupivacaine and 25% R(+) bupivacaine in spinal anesthesia for orthopedic surgery

Luiz Eduardo Imbelloni; Lúcia Beato

Brazilian Journal of Anesthesiology, 2001; 51: 5: 369-376

Comparative study between 0.5% isobaric bupivacaine and a 0.5% isobaric mixture of 75%

S(-) bupivacaine and 25% R(+) bupivacaine in spinal anesthesia for orthopedic surgery

Luiz Eduardo Imbelloni; Lúcia Beato

Analgesia onset was fast and comparable between groups. There were no significant differences in sensory block onset or duration between groups (Table III).

The spread of analgesia was the same with both mixtures at 5, 10, 20, 25 and 30 minutes (Figure 1). A wide analgesia spread variation was observed among patients in both groups (Figure 2).

Brazilian Journal of Anesthesiology, 2001; 51: 5: 369-376

Comparative study between 0.5% isobaric bupivacaine and a 0.5% isobaric mixture of 75%

S(-) bupivacaine and 25% R(+) bupivacaine in spinal anesthesia for orthopedic surgery

Luiz Eduardo Imbelloni; Lúcia Beato

Brazilian Journal of Anesthesiology, 2001; 51: 5: 369-376

Comparative study between 0.5% isobaric bupivacaine and a 0.5% isobaric mixture of 75%

S(-) bupivacaine and 25% R(+) bupivacaine in spinal anesthesia for orthopedic surgery

Luiz Eduardo Imbelloni; Lúcia Beato

Motor block onset was fast and total motor block was present in 96.5% of Group S75-R25 patients and in 95% of Group S50-R50 patients. There were no significant differences in time to reach motor block levels 1 and 2. Time elapsed for total motor block was significantly longer in Group S75-R25 (Table IV). No significant difference in the motor block duration between both substances was observed (Table IV).

Brazilian Journal of Anesthesiology, 2001; 51: 5: 369-376

Comparative study between 0.5% isobaric bupivacaine and a 0.5% isobaric mixture of 75%

S(-) bupivacaine and 25% R(+) bupivacaine in spinal anesthesia for orthopedic surgery

Luiz Eduardo Imbelloni; Lúcia Beato

There were no significant differences in hypotension and bradycardia with both drugs. There were no headache or neurological complications in both groups (Table V).

Brazilian Journal of Anesthesiology, 2001; 51: 5: 369-376

Comparative study between 0.5% isobaric bupivacaine and a 0.5% isobaric mixture of 75%

S(-) bupivacaine and 25% R(+) bupivacaine in spinal anesthesia for orthopedic surgery

Luiz Eduardo Imbelloni; Lúcia Beato

Pneumatic tourniquet was used in 36 patients, being 21 in Group S75-R25 and 15 in Group S50-R50; no patient referred pain (Table VI).

Brazilian Journal of Anesthesiology, 2001; 51: 5: 369-376

Comparative study between 0.5% isobaric bupivacaine and a 0.5% isobaric mixture of 75%

S(-) bupivacaine and 25% R(+) bupivacaine in spinal anesthesia for orthopedic surgery

Luiz Eduardo Imbelloni; Lúcia Beato

DISCUSSION

This study has shown that the enantiomeric mixture of 75% S(-)bupivacaine and 25% R(+)bupivacaine, as the racemic bupivacaine, may be used for spinal anesthesia in major and medium size orthopedic surgeries, with low incidence of hypotension and no transient neurological symptoms. Some orthopedic surgeries may need a long time on the orthopedic table. So, both solutions are good indications for these surgeries since both provided long lasting anesthesia.

The separation of racemic bupivacaine permitted the production of levogyrous and dextrogyrous enantiomers. Levobupivacaine may be use as the pure enantiomer⁶ or in the ratios of 10% R(+) bupivacaine plus 90% S(-) bupivacaine or 25% R(+) bupivacaine plus 75% S(-) bupivacaine ^8,10, ratio used in this study. The racemic bupivacaine was compared to the levogyrous enantiomer in human ulnar nerves ¹¹by evaluating their sensory block property. Levobupivacaine has been compared also to the racemic form in epidural anesthesia and confirmed its similar potency and efficacy, with less potential cardiotoxicity ¹². Similarly to racemic bupivacaine, the S75-R25 mixture is mildly hypobaric with a density of 1.004 g/ml at 20 ºC determined by picnometry. Similar results were obtained with levobupivacaine, namely 1.0048 g/ml at 23 ºC and 1.005 g/ml at 37 ºC ⁹.

Several studies have shown a wide variation of the blockade level with isobaric bupivacaine, especially when injected in the sitting position. In our study, a wide variation in blockade levels, both with S75-R25 and racemic bupivacaine, was also observed.

A study comparing the levogyrous form to the racemic form in sciatic nerves of rats has shown that levobupivacaine has the same blocking efficacy as the racemic mixture, with the same motor and sensory block intensity and duration, however with a markedly shorter onset ¹³. In our clinical trial no differences were observed in sensory block onset, but the motor block was faster with racemic bupivacaine. There were no differences in sensory and motor block duration between groups. There were no differences in failure incidence between groups, which is in line with other studies with bupivacaine ^14,15 and levobupivacaine ⁹.

After intrathecal injection in the lateral position, 3 ml hyperbaric bupivacaine produce cephalad analgesia spread significantly higher than the isobaric solution ¹⁶. In our study, both isobaric S75-R25 and racemic bupivacaine mixtures presented the same density and had the same behavior in the cephalad spread of analgesia up to 30 minutes after lateral position injection.

Hypotension during spinal anesthesia has been related to sensory block spread, previous hydration and patient's age. A study on the influence of age in spinal anesthesia with 0.5% isobaric bupivacaine has shown a higher hypotension incidence in elderly patients ¹⁷. In our study, both racemic and the S75-R25 mixture caused the same incidence of hypotension (8.3%) in major and medium size orthopedic surgeries without differences in the incidence of bradycardia for both drugs.

There were no differences in sensory block onset between both local anesthetic solutions with results similar to those obtained with levobupivacaine ⁹ and 0.75% ropivacaine and equivalent to half the time needed for spinal anesthesia with 0.5% ropivacaine ¹⁸. So, there were no differences in sensory block duration between both drugs but it was slightly longer than with 0.5% ropivacaine and shorter than with 0.75% ropivacaine ¹⁸. Sensory block duration with S75-R25 was longer than with pure levobupivacaine ⁹ and shorter than with 0.75% bupivacaine ¹⁹.

Lower limb motor block is dose-dependent ¹¹ and total motor block is more frequently obtained with pure solutions. Differently from spinal anesthesia with 0.5% and 0.75% ropivacaine ¹⁸, our study has not observed total motor block in 2 patients in Group S75-R25 and in 3 patients in Group S50-R50. The results of 96% total motor block with S75-R25 bupivacaine are similar to 95% found with pure levobupivacaine ⁹. A faster total motor block was observed with the racemic form.

Although the absence of difference in the motor block produced by both substances in humans ⁴ a shorter motor block duration was observed with levobupivacaine ²⁰. In our study, there have been no differences in motor and sensory block duration. Mean motor block duration with S75-R25 bupivacaine in this study was 265.8 minutes, similar to 266.5 minutes found with the racemic form ⁹. Differently from studies performed in rats ²⁰ and humans ⁹, motor block recovery time was longer than sensory block recovery time with both forms of bupivacaine without differences between them. Further studies are needed to understand the possible dose-response variability of motor block with levobupivacaine.

Our study has not observed differences in spinal anesthesia latency time, duration and quality and this is in line with studies in human ulnar nerves where there were no differences in sensory and motor block between levogyrous and racemic bupivacaine ¹⁰. Cardiocirculatory changes were minor in spite of high sensory block levels in some patients. The enantiomeric mixture of bupivacaine (75% levogyrous + 25% dextrogyrous) has a similar behavior as the racemic form and is a new option for spinal anesthesia in major and medium size orthopedic surgeries.

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Recebido da Clínica São Bernardo, Casa de Saúde Santa Maria, Rio de Janeiro, RJ

Publication Dates

• Publication in this collection
  14 Mar 2011
• Date of issue
  Oct 2001

History

• Received
  26 Jan 2001
• Accepted
  20 Mar 2001