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Print version ISSN 0034-7094
On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.55 no.2 Campinas Mar./Apr. 2005
Comparative study of 0.5% racemic bupivacaine versus enantiomeric mixture (S75-R25) of 0.5% bupivacaine in brachial plexus block for orthopedic surgery*
Bupivacaína racémica a 0,5% y mezcla con exceso enantiomérico del 50% (S75-R25) a 0,5% en el bloqueo del plexo braquial para cirugía ortopédica. Estudio comparativo
Roberto Tsuneo Cervato Sato, M.D.I; Douglas Flávio Porsani, TSA, M.D.II; Antônio Garibaldino Vieira do Amaral, TSA, M.D.III; Oscar Vilmar Schulz Júnior, M.D.IV; Ângelo Manoel Grande Carstens, M.D.V
IPreceptor do CET do Hospital Universitário
Cajuru PUCPR, MEC/SBA
IIResponsável pelo CET do Hospital Universitário Cajuru PUCPR, MEC/SBA
IIICo-responsável pelo CET do Hospital Universitário Cajuru PUCPR, MEC/SBA
IVME2 do CET do Hospital Universitário Cajuru PUCPR, MEC/SBA
VME1 do CET do Hospital Universitário Cajuru PUCPR, MEC/SBA
BACKGROUND AND OBJECTIVES: Several studies
were performed with bupivacaine isomers in the attempt to find a safer drug
than racemic bupivacaine. This study aimed at evaluating the efficacy of 0.5%
bupivacaine enantiomeric mixture (MEE50%) as compared to 0.5% racemic bupivacaine
in brachial plexus block for upper limb orthopedic surgery.
METHODS: Participated of this randomized double-blind study 40 patients aged 18 to 90 years, physical status ASA I and II, submitted to upper limb orthopedic surgeries, who were divided in two groups: Group R received 0.5% racemic bupivacaine; and Group L received 0.5% enantiomeric mixture (S75-R25) of bupivacaine both with 1:200,000 epinephrine, in a volume of 0.6 mL.kg-1 (3 mg.kg-1), limited to 40 mL. Motor and/or sensory characteristics of each nerve involved (musculocutaneous, radial, median, ulnar and medial cutaneous nerve of forearm), as well as the incidence of side effects were evaluated.
RESULTS: There were no statistical differences in demographics. Hemodynamic parameters were similar between groups but systolic pressure was higher for Group R. There were no statistically significant differences in time to reach the greatest intensity of sensory and motor blocks. With one exception, the onset of motor block within the muscles innervated by the ulnar nerve was longer for Group L (10.75 versus 14.25 minutes).
CONCLUSIONS: There were adequate sensory and motor blocks in both groups, with few side effects, suggesting that the 0.5% enantiomeric mixture (S75-R25) of bupivacaine with epinephrine is safe and effective for brachial plexus block of upper limb orthopedic surgeries.
Key words: ANESTHETICS, Local: bupivacaine, 50% enantiomeric mixture; ANESTHETIC TECHNIQUES, Regional: brachial plexus block
JUSTIFICATIVA Y OBJETIVOS: Con la finalidad
de encontrar una droga más segura que la bupivacaína racémica, varios estudios
fueron realizados con sus isómeros. Este estudio tiene como objetivo evaluar
la eficacia de la mezcla con exceso enantiomérico del 50% (MEE50%) de bupivacaína
(S75-R25) a 0,5% comparada la de la bupivacaína racémica a 0,5% en el bloqueo
del plexo braquial en pacientes sometidos a cirugía ortopédica de miembros superiores.
MÉTODO: Participaron de este estudio, aleatorio y doblemente encubierto, 40 pacientes, con edade entre 18 y 90 años, estado físico ASA I y II, sometidos a cirugía ortopédica de miembros superiores, distribuidos en dos grupos: Grupo R, que recibió la solución de bupivacaína racémica a 0,5%, y Grupo L, que recibió la solución de la mezcla con exceso enantiomérico del 50% de bupivacaína (S75-R25) a 0,5%, ambas con epinefrina 1:200.000 y en un volumen de 0,6 mL.kg-1 (3 mg.kg-1), limitados a 40 mL. Fueron investigadas las características motoras y sensoriales de cada nervio envolvido (nervios musculocutáneo, radial, mediano, ulnar y cutáneo medial del antebrazo), bien como la incidencia de efectos colaterales.
RESULTADOS: No hubo diferencia estadística significativa con relación a los aspectos demográficos. Los parámetros hemodinámicos fueron semejantes entre los grupos, solo que la presión arterial sistólica fue mayor en el Grupo R. No hubo diferencia significativa con relación al tiempo necesario para alcanzar la mayor intensidad de los bloqueos motor y sensitivo. Con una excepción, la latencia del bloqueo motor del grupo muscular inervado por el n. ulnar fue mayor en el Grupo L (10,75 versus 14,25 minutos).
CONCLUSIONES: En ambos grupos fueron observados bloqueos motor y sensitivo adecuados para la realización de la cirugía, con pocos efectos colaterales, sugiriendo que la mezcla con exceso enantiomérico del 50% de bupivacaína (S75-R25) a 0,5% con epinefrina es segura y efectiva para el bloqueo del plexo braquial para cirugía ortopédica de miembro superior.
For many decades, bupivacaine has been successfully used for regional anesthesia in long procedures. However, some unexpected accidents have encouraged the search for safer alternatives in terms of cardiovascular complications and central nervous system (CNS) toxicity 1. Bupivacaine is an equimolar mixture of two enantiomers: R(+) and S(-) bupivacaine 2. From purified local anesthetic molecule isomers, it is possible to manipulate the enantiomeric ratio of a racemic compound. This contributes to its efficacy and decreases potential toxicity, so increasing the therapeutic index 3,4. This study aimed at comparing 0.5% enantiomeric mixture (S75-R25) of bupivacaine and 0.5% racemic bupivacaine in brachial plexus block for orthopedic procedures on the upper limb.
After the Research Ethics Committee, Hospital Universitário Cajuru - PCUPR approval, participated of this randomized double-blind study 40 patients aged 18 to 90 years, physical status ASA I and II, submitted to orthopedic surgeries on the upper limb. Exclusion criteria were peripheral neuropathy, hypersensitivity to bupivacaine, septicemia, cervical deformities, morbid obesity and pulmonary disease with above 25% decrease in forced expiratory volume in the 1st second (FEV1).
Patients were distributed in two equal groups, according to the local anesthetic used: Group L - 0.5% enantiomeric mixture (S75-R25) of bupivacaine; and Group R - 0.5% racemic bupivacaine, both added of 1:200,000 epinephrine. Patients' physical conditions were evaluated the evening before surgery, when authorization to participate in the study was also given. Next morning in the operating room and after local anesthesia with 2 mL of 1% lidocaine, patients were submitted to venous cannulation with a 20G or 18G catheter. Monitoring consisted of cardioscopy on DII lead, noninvasive blood pressure and pulse oximetry. All patients received oxygen under mask at 8 L.min-1 plus intravenous midazolam (2 mg) and fentanyl (50 µg).
The double puncture 5, interscalene 6 and axillary 5 technique was used. After skin preparation and placement of surgical drapes for skin and subcutaneous infiltration with 1 mL of the solution of choice, interscalene puncture (at crycoid cartilage level) was performed with patients in the supine position with the head turned away from the puncture site and having the arms parallel to the body. Injection site was identified with the aid of peripheral nerve stimulator (Stimuplex®) with A50 needle, initially adjusted to 1 mA at the frequency of 2 Hz and decreased to 0.4 mA with maintenance of muscle contractions on the respective nerve territor. Half the proposed volume was injected after identification.
Axillary puncture was performed next, with patients in the same position, except for the arm which was abduced to expose the axillary cavum. The puncture site was chosen by palpating the axillary artery as proximally as possible. The same nerve location procedures were followed, and the second half of the proposed volume was injected, following negative aspiration of blood or CSF, the latter during interscalene puncture.
Peripheral nerve stimulation should obtain 4 different muscle responses, corresponding to radial nerve, elbow extension; musculocutaneous nerve, elbow flexion; median nerve, wrist flexion; and ulnar nerve, thumb adduction, either during interscalene or axillary puncture. Smal boluses of intravenous midazolam were allowed during the procedure for sedation. Total anesthetic volume was 0.6 mL.kg-1 (3 mg.kg-1), limited to 40 mL.
Moment zero (0) was that immediately before punctures. Moments 5, 10, 15, 20, 25 and 30 corresponded to time in minutes after axillary puncture. Heart rate, blood pressure and sensory and motor blocks were evaluated at the mentioned moments.
Motor block was evaluated by muscle contraction 7,8, similar to neurostimulation. Patients were asked to extend the elbow for radial nerve block evaluation; to flex the elbow for musculocutaneous nerve block evaluation; to flex the wrist, for median nerve evaluation and to adduct thumb, for ulnar nerve evaluation. The degree of motor block was defined as 0 in the absence of motor block, 1 when there was partial block and 2 in the presence of total block.
Sensory block was evaluated by painful stimulation with 14 x 8 needle in the areas of corresponding cutaneous innervation 7,8. Questioning the patient and observing his/her facies during paintful stimuli were used to assess block effectiveness. Radial nerve block was assessed on the dorsum of the hand at the first metacarpal space: musculocutaneous nerve was assessed on the lateral aspect of the forearm; median nerve was assessed on the skin of the palmar aspect of the hand at the level of the 2nd metacarpus; medial cutaneous nerve of forearm was assessed on the medial aspect of the forearm, and the ulnar nerve was assessed on the hypotenar regional of the hand. The degree of sensory block was defined as 0, when sensitivity was normal, 1, when there was partial lack of sensivity and 2, when there was surgical anesthesia.
All complications and intercurrences 9 observed throughout the follow up period were recorded and defined as: Early events - muscle shakes, tinnitus, sleepiness, psychomotor agitation, arrhythmia, seizure, systolic blood pressure decrease bellow 30% of baseline, heart rate below 50 bpm; or late events (24 hours postoperativelly) - pain at the injection site, inflammation at the injection site, areas of anesthesia and motor deficit. Student's t test and Mann-Whitney U test were used for statistical comparisons between groups, as appropriate.
There were no statistically significant differences between groups regarding demographic data (Table I).
The distribution of surgical procedures between groups was similar (Table II).
There were no differences between groups in total anesthetic volume and duration of surgery (Table III).
Systolic blood pressure was significantly higher for Group R and maintained the same behavior throughout surgery. There has been no statistical difference in diastolic pressure. There were no bradycardia or hypotension (Figure 1, Figure 2 and Figure 3).
There were no complete anesthetic failures, defined as absence of motor block or total sensory block equal to 0 at moment 30, in the corresponding nerve distribution. All patients presented sensory or motor block of at least one (1) in moment 5, in the corresponding nerve distribution. The onset of sensory and motor blocks in each nerve distribution territory was not significantly different, except for the onset of motor of the ulnar nerve territory (Table IV and Figure 4 and Figure 5).
There was no statistically significant difference between groups in the temporal evolution of total motor block, except for the ulnar nerve block which was more intense in Group L (Figure 8 and Figure 9).
The hospital in which the study was performed is primarily dedicated to trauma, assuming the need to decrease blockade failures as much as possible. This decrease aims at decreasing the risk of aspiration of gastric contents which may be present when blockade has to be supplemented with deep sedation or general anesthesia. These were the reasons leading us to adopt the double injection technique as routine, since it is associated to lower incidence of failures as compared to single puncture 5.
Safety limit for 0.5% racemic bupivacaine or 0.25% enantiomeric mixture (S75-R25) of bupivacaine, both with 1:200,000 epinephrine was determined as 3 mg.kg-1 10 or 0.6 mL.kg-1. Epinephrine in this concentration (5 µg.mL-1) decreases approximately one third of systemic absorption 11 as a consequence of vasoconstriction at injection site, with slower drug absorption which makes the anesthetic to remain in contact with nervous roots for a longer time 12.
No studies were found in the literature about the enantiomeric mixture (S75-R25) of bupivacaine for brachial plexus block. No difference in success rates were found in a study comparing 0.5% racemic and levogyrous bupivacaine for brachial plexus block 13.
In our study, both groups had similar behaviors without statistical difference, both for total sensory and total motor block onset. Mean total motor onset for the ulnar nerve was significantly longer in Group L. However, the mean difference of 3.5 minutes is clinically irrelevant.
Onset of 12.5 minutes for sensory axillary block with 0.5% levobupivacaine found in the literature 14 confirms our results, although we have used double block and 0.5% enantiomeric mixture (S75-R25) of bupivacaine with 1:200,000 epinephrine with onset of 7.55 minutes.
In a different brachial plexus study 15 the time for the start of surgery was similar for both 0.5% racemic and levogyrous bupivacaine groups, confirming our results.
Recent studies suggest that intravascular injection and systemic toxicity are more common in peripheral regional anesthetic techniques 16. So, the search for long-acting local anesthetics with low potential for toxicity, effective sensory and motor block even if comparable to widely used anesthetics is needed since potentially lethal reactions with racemic bupivacaine are well known 17. Incidents with levobupivacaine are also described 18, however with lower toxicity 19-22.
There were no statistically significant differences in heart rate and diastolic blood pressure in different studied moments. However, systolic blood pressure was statistically different, being higher for Group R, leading us to assume that this difference was a consequence of intrinsic properties of the racemic drug, since groups were demographically homogeneous, but further studies are needed to confirm this assumption.
There have been adequate surgical sensory and motor blocks in both groups, with no side effects, suggesting that solutions are adequate for brachial plexus block for orthopedic procedures. However, due to lower toxicity of enantiomeric mixture (S75-R25) of bupivacaine, it is a safer alternative as compared to racemic bupivacaine.
To Laboratório Cristália for supplying anesthetic solutions for this study.
01. Simonetti MPB, Batista RA, Ferreira FMC - Estereoisomeria: a interface da tecnologia industrial de medicamentos e da racionalização terapêutica. Rev Bras Anestesiol, 1999;48: 390-399. [ Links ]
02. Vale N, Delfino J - Farmacologia dos Anestésicos Locais, em: Vale N, Delfino J - Anestesia Peridural: Atualização e Perspectiva, São Paulo, Editora Atheneu, 2000;41-64. [ Links ]
03. Simonetti MPB - Anestésicos Locais Espinhais Levógiros, em: Vale N, Delfino J - Anestesia Peridural: Atualização e Perspectiva, São Paulo, Editora Atheneu, 2000;81-92. [ Links ]
04. Foster RH, Markham A - Levobupivacaine: a review of its pharmacology and use as a local anaesthetic. Drugs. 2000;59:551-579. [ Links ]
05. Weksler N, Kessler D, Ovadia L - Extended axillary block (EAB), J Anesth, 1988;2:110-112. [ Links ]
06. Winnie AP - Interscalene brachial plexus block. Anesth Analg, 1970;49:455-466. [ Links ]
07. Janzen PR, Vipond AJ, Bush DJ et al - A comparison of 1% prilocaine with 0.5% ropivacaine for outpatient-based surgery under axillary brachial plexus block. Anesth Analg, 2001;93:187-191. [ Links ]
08. Borgeat A, Ekatodramis G, Dumont C - An evaluation of the infraclavicular block via a modified approach of the Raj technique. Anesth Analg, 2001;93:436-441. [ Links ]
09. Tanaka PP, Souza RO, Salvallagio MFO et al - Estudo comparativo entre a bupivacaína a 0,5% e a mistura enantiomérica de bupivacaína (S75-R25) a 0,5% em anestesia peridural em pacientes submetidos à cirurgia ortopédica de membros inferiores. Rev Bras Anestesiol, 2003;53:331-337. [ Links ]
10. Bardsley H, Gristwood R, Baker H et al - A comparison of the cardiovascular effects of levobupivacaine and racemic bupivacaine following intravenous administration to healthy volunteers. Br J Clin Pharmacol, 1998;46:245-249. [ Links ]
11. Stoelting RK - Prática Anestésica, 1ª Ed, Porto Alegre, Editora Artes Médicas Sul, 1997;109. [ Links ]
12. Gouveia MA, Labrunie G - Fatores que Influenciam o Bloqueio Peridural, em: Vale N, Delfino J - Anestesia Peridural: Atualização e Perspectiva, São Paulo, Editora Atheneu, 2000;117-126. [ Links ]
13. Cox CR, Checketts MR, Mackenzie N et al - Comparison of S(-) -bupivacaine with racemic (RS)-bupivacaine in supraclavicular brachial plexus block. Br J Anaesth, 1998;80:594-598. [ Links ]
14. Crews JC, Weller RS, Moss J et al - Levobupivacaine for axillary brachial plexus block: a pharmacokinetic and clinical comparison in patients with normal renal function or renal disease. Anesth Analg, 2002;95:219-223. [ Links ]
15. D'Ambrosio A, De Negri P, Damato A et al - S(-) bupivacaine (levobupivacaine) in peripheral blocks: preliminary results. Minerva Anestesiol, 2001;67:(Suppl1):37-43. [ Links ]
16. Horlocker TT, Wedel DJ - Local anesthetic toxicity-does product labeling reflect actual risk? Reg Anesth Pain Med, 2002;27:562-567. [ Links ]
17. Albright GA - Cardiac arrest following regional anesthesia with etidocaine or bupivacaine. Anesthesiology, 1979;51:285-287. [ Links ]
18. Crews JC, Rothman TE - Seizure after levobupivacaine for interscalene brachial plexus block. Anesth Analg, 2003;96: 1188-1190. [ Links ]
19. Chang DH, Ladd LA, Wilson KA et al - Tolerability of large-dose intravenous levobupivacaine in sheep. Anesth Analg, 2000;91: 671-679. [ Links ]
20. Kopacz DJ, Allen HW - Accidental intravenous levobupivacaine. Anesth Analg, 1999;89:1027-1029. [ Links ]
21. Pirotta D, Sprigge J - Convulsions following axillary brachial plexus blockade with levobupivacaine. Case report. Anaesthesia, 2002;57:1187-1189. [ Links ]
22. Huang YF, Pryor ME, Mather LE et al - Cardiovascular and central nervous system effects of intravenous bupivacaine and levobupivacaine in sheep. Anesth Analg, 1998;86:797-804. [ Links ]
Dr. Roberto Tsuneo Cervato Sato
Address: Rua Rubens Santos Costa, 32/1302 Cristo Rei
ZIP: 80050-500 City: Curitiba, Brazil
Submitted for publication July 7, 2004
Accepted for publication December 17, 2004
* Received from CET do Hospital Universitário Cajuru da Universidade Católica do Paraná (UCPR), Curitiba, PR