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Rev. Bras. Anestesiol. vol.58 no.1 Campinas Jan./Feb. 2008
A comparative study of 0.125% racemic bupivacaine (S50-R50) and 0.125% and 0.25% 50% enantiomeric excess bupivacaine (S75-R25) in epidural anesthesia for labor analgesia*
Estudio comparativo entre bupivacaina racémica (S50-R50) a 0,125% y bupivacaina en exceso enantiomérico de 50% (S75-R25) a 0,125% y 0,25% en anestesia peridural para analgesia de parto
Nádia Maria da Conceição Duarte, TSAI; Ana Maria Menezes Caetano, TSAII; Luciana Cavalcanti LimaIII; Aumério Silva das ChagasIV
pelo CET/SBA do IMIP
IIResponsável pelo CET/SBA do IMIP; Mestre em Saúde Materno-Infantil pelo IMIP
IIIMestre em Saúde Materno-Infantil pelo IMIP
IVAnestesiologista do CET/SBA do IMIP
OBJECTIVES: Continuous epidural block is used for relief of labor pain and
it is associated with a low incidence of complications. Studies with the levorotatory
isomer of local anesthetics demonstrated that they are safer regarding the cardiotoxicity.
The objective of this study was to compare analgesia and motor blockade of 0.125%
bupivacaine (S50-R50) and 0.125% and 0.25% 50% enantiomeric excess bupivacaine
(S75-R25) in continuous epidural block for labor analgesia.
METHODS: Seventy-five patients in labor participated in this randomized, double-blind study after signing an informed consent. Patients were divided in three groups: GI 0.125% bupivacaine (S50-R50); GII 0.125% bupivacaine (S75-R25) and GIII 0.25% bupivacaine (S75-R25).
RESULTS: The latency of analgesia, levels of sensorial blockade, volume of local anesthetic, duration of labor and analgesia, frequency of instrumental delivery, Apgar scores, or pH of umbilical cord blood showed no statistically significant differences. The length of time until the first rescue dose was greater and pain scores at 45 minutes were also greater in the 0.25% bupivacaine (S75-R25) group. The intensity of the motor blockade was greater in the 0.125% bupivacaine (S50-R50) group.
CONCLUSIONS: The motor blockade was less intense with bupivacaine (S75-R25) regardless the concentration, resulting in analgesia of better quality without interfering with the evolution of labor or the vitality of newborns.
Key Words: ANALGESIA: labor; ANESTHETICS, Local: racemic bupivacaine, enantiomeric excess bupivacaine, levobupivacaine; ANESTHETIC TECHNIQUE, Regional: continuous epidural block.
Y OBJETIVOS: La peridural continua se utiliza para el alivio del dolor del
trabajo de parto y asociada a bajos índices de complicaciones. Estudios
con enantiómeros levógiros de los anestésicos locales demostraron
una mayor seguridad en función de una menor cardiotoxicidad. El objetivo
de este estudio fue comparar la analgesia y el bloqueo motor entre la Bupivacaina
(S50-R50) a 0,125% y la Bupivacaina en exceso enantiomérico de 50% (S75-R25)
a 0,125% e 0,25% en peridural continua para analgesia de parto.
MÉTODO: Se realizó un ensayo clínico doblemente encubierto, con distribución aleatoria de 75 participantes en trabajo de parto, distribuidas en tres grupos: GI Bupivacaina (S50-R50) a 0,125%, GII Bupivacaina (S75-R25) a 0,125% y GIII Bupivacaina (S75-R25) a 0,25%. La inclusión en el estudio fue hecha después de la firma del Consentimiento Libre y Aclarado.
RESULTADOS: No se encontraron diferencias estadísticas significativas en cuanto a la latencia de la analgesia, nivel sensorial del bloqueo, volumen de anestésico local, duración del trabajo de parto y de la analgesia, frecuencia de parto instrumental, puntuaciones de Apgar o pH del cordón umbilical. El intervalo para la primera dosis rescate fue mayor y los puntajes de dolor en 45 minutos fueron menores en el grupo Bupivacaina (S75-R25) a 0,25%. La intensidad del bloqueo motor fue mayor en el grupo Bupivacaina (S50-R50) a 0,125%.
CONCLUSIONES: La Bupivacaina (S75-R25) determinó un bloqueo motor menos intenso, incluso cuando se utilizó en mayor concentración (0,25%), resultando en una mejor calidad de analgesia, sin interferir en la evolución del trabajo de parto o en la vitalidad de los recién nacidos.
Bupivacaine, a local anesthetic used commercially, is available as a racemic mixture (S50-R50), although the levorotatory S(-) isomer, levobupivacaine, is less toxic to the central nervous system and cardiovascular system than the dextrorotatory isomer R(+) 1.
Clinical studies with levorotatory isomers of local anesthetics demonstrated that, due to the reduced cardiotoxicity, they are clinically safer, which motivated studies on stereoselectivity 2. Bupivacaine and racemic bupivacaine refer to the local anesthetic formed by 50% of the R isomer and 50% of the S isomer (S50-R50). Levobupivacaine contains 100% of the S isomer, while 50% enantiomeric excess bupivacaine (S75-R25) refers to the solution formed by 75% of the S isomer and 25% of the R isomer.
The epidural administration of levobupivacaine is associated with reduced motor blockade, which is apparently dose-dependent, using concentrations ranging from 0.0625% to 0.5% 3.
Bupivacaine is used in obstetric anesthesia due to its greater potency and prolonged duration of action besides the differential sensory-motor blockade 4. However, with the reports of cardiotoxicity, its supremacy was questioned in 1979 by Albright 5.
As for the use of the isomers in labor analgesia, Nakamura et al. 6, studying the maternal-fetal repercussions of racemic ropivacaine and levobupivacaine in labor analgesia and anesthesia, observed that ropivacaine abolished pain in pregnant women with reduced motor blockade and their newborns presented better Apgar scores as well as better scores of adaptive and neurological capacity.
The objective of this study was to compare the enantiomeric excess mixture (S75-R25) bupivacaine and racemic bupivacaine in labor analgesia regarding quality of analgesia and intensity of the motor blockade.
After approval by the Ethics Commission on Research in Humans of the Instituto Materno Infantil Professor Fernando Figueira (IMIP), a randomized, double-blind study was undertaken to compare analgesia and motor blockade of racemic bupivacaine (S50-R50) and 50% enantiomeric excess bupivacaine (S75-R25) in continuous epidural block for labor analgesia.
Seventy-five pregnant women in labor, ASA I and II, were enrolled in this study and divided randomly into three groups: GI 0.125% racemic bupivacaine (S-50-R50), GII 0.125% enantiomeric excess bupivacaine (S75-R25), and GIII 0.25% enantiomeric excess bupivacaine (S75-R25). Women with relative or absolute contraindications for continuous epidural block, history of allergy or hypersensitivity to local anesthetics, who received opioids during labor or whose fetuses presented evidence of fetal distress were excluded. The following parameters were evaluated: latency of analgesia (length of time between the initial administration of the local anesthetic and establishment of the upper level of sensory blockade); level of sensory blockade, determined by the lack of thermal and painful sensitivity on sacral, lumbar, and thoracic dermatomes; length of time until the first request of rescue dose (length of time between the initial administration of local anesthetic and the first request of rescue dose by the patient or by the Visual Analog Scale (VAS) > 3); pain scores evaluated by the Visual Analog Scale 7; degree of motor blockade, evaluated by the RAM Scale 6 and ambulation; duration of the first and second stages of labor; duration of analgesia (length of time between the administration of the local anesthetic and the end of the second stage of labor); frequency of instrumental delivery; and total volume of local anesthetic administered. The degree of vitality of the newborns was evaluated by the Apgar scores on the 5th minute and neonatal acidosis defined as an umbilical cord blood pH below 7.20 8. Pregnant women in labor diagnosed by the obstetrics team who requested pain relief and fulfilled the inclusion criteria were enrolled in the study after signing an informed consent.
Venous access was established before patients underwent anesthetic block with an 18 G TeflonÒ catheter and monitoring consisted of cardioscope, pulse oximetry and non-invasive blood pressure. The initial pain score and the time the procedure was initiated were recorded. Epidural puncture was done with an 18G Tuohy needle, using the median access at the L2-L3 or L3-L4 level, and a 20G catheter was inserted and secured in place. According to the random distribution table, patients in groups GI, GII, and GIII received 10 mL of 0.125% bupivacaine (S50-R50), 10 mL of 0.125% enantiomeric excess bupivacaine (S75-R25) or 10 mL of 0.25% enantiomeric excess bupivacaine (S75-R25), respectively.
The solutions used in this study were conditioned in multiple-dose vials of 20 mL, according to an agreement with the scientific and product development department of the CristáliaÒ laboratory. A total of 243 multiple-dose vials were produced, including 81 vials of 0.125% enantiomeric excess bupivacaine (S75-R25), 81 with 0.25% enantiomeric excess bupivacaine (S75-R25), and 81 vials with 0.125% bupivacaine. Vials were identified with the number of the patient and its volume. The random distribution of the study was done by the researchers, using the statistical software EpiInfo 6.04b, which was under public domain and an integral part of the study protocol.
Motor blockade, pain scores and the need of rescue doses of local anesthetic were evaluated every 15 minutes (Mi = before beginning analgesia, M15 = 15 minutes after beginning analgesia, M30 = 30 minutes, and thereafter until the end of labor). Rescue doses of 5 mL of the same local anesthetic in the same concentration used at the beginning of analgesia were administered whenever the patient presented a pain score equal or greater than 3 by the Visual Analog Scale including during delivery. In the presence of any motor blockade that could interfere with labor the concentration of the rescue dose of the local anesthetic was reduced by 50%.
Continuous parameters were summarized as median, mean and standard deviation (SD). ANOVA was used to compare those parameters. Parameters whose suppositions were not satisfied by the ANOVA were evaluated by the Kruskal-Wallis test. Categorical parameters were summarized as the absolute and relative frequencies in the form of a table, and the Kruskal-Wallis test was also used to compare the three groups. Statistical differences for all hypothesis tested were considered significant when p < 0.05. The sample size was calculated considering a type I (alpha) error of 5% and type II (beta) error of 10%, with an estimated test power of at least 80%. The statistical software EpiInfo 6.04b indicated that a study group of 72 patients (24 patients in each group) was necessary and it was considered an estimated loss of 10%. To compensate for those probable losses, we increased n to 81, with 27 patients in each group.
Seventy-five pregnant women were analyzed. Twenty-six (GI) received 0.125% bupivacaine (S50-R50), 24 (GII) received 0.125% enantiomeric excess bupivacaine (S75-R25), and 25 (GII) received 0.25% enantiomeric excess bupivacaine (S75-R25). Six patients were excluded after they were included in the groups due to the impossibility to perform the anesthetic technique and incomplete data: one patient in GI, 3 in GII, and 2 in GII. All three groups were similar (ANOVA) regarding the anthropometric data age (p = 0.48), weight (p = 0.28), and height (p = 0.65) (Table I).
Only patients ASA I and II were included in the study; 76.9% of patients in GI were ASA I and 23.1% were ASA II; in GII, 83.3% were ASA I and 16.7% ASA II; and in GIII, 80% were ASA I and 20% ASA II. There were no statistical differences among them (c2 = 0.85).
As for the number of prior deliveries, we observed that in GI 76% were nullipara, 16% were primipara, and 8% gravida II. In GII, 78.3% were nullipara, 8.7% primipara, 8.7% gravida II, and 4.3% gravida III. In GIII, 78.3% were nullipara, 13% were primipara, and 8.7% gravida II. No statistically significant differences were observed among the groups (c2 = 0.85).
At the beginning of analgesia, the median dilation of the uterine cervix in all three groups (ANOVA) was 7 (p = 0.3) and median pain score (VAS) was 9 (p = 0.53) (Table II).
Regarding labor evolution, the latency of analgesia was similar in all three groups (ANOVA) with a mean of 11 minutes in GI, 13 minutes in GII and 9.6 minutes in GIII (p = 0.51). However, when the mean length of time for requesting a rescue dose was analyzed a significant difference (ANOVA) was observed among the three groups (p = 0.01) in which GIII > GI = GII, 67, 36, and 37 minutes, respectively (Table II).
The duration of the first stage of labor was similar in all three groups (p = 0.34), with a mean of 541.11 minutes (GI), 639.95 minutes (GII) and 510.93 (GIII). The duration of the second stage of labor also did not show any differences (p = 0.07) with a mean of 14.25 minutes, 17.73 minutes and 21.13 minutes in GI, GII and GIII, respectively (Table II).
The mean duration of labor analgesia was 43.65 min in GI, 67.5 min in GII and 81.45 min in GIII and no statistically significant differences were observed (p = 0.20) (Table II).
The sensorial level of the blockade stabilized between T10 and T12 in patients, with no statistically significant differences (c2 = 0.63). Only two patients in GII and one in GIII had a level below T12, while in all other patients it was above T10. In all three groups, 48.6% of the patients ambulated voluntarily during labor with no statistically significant differences (c2 = 0.48) (Table III).
The motor blockade differed among the three groups as follows: in GI it was more intense than GIII at M75 (ANOVA p = 0.01) and M90 (Kruskal-Wallis p = 0.02); at M105 the motor blockade was more intense in GI than in GII (ANOVA p = 0.02) and GIII (ANOVA p = 0.0004); at M120 it was stronger in GI than in GIII (ANOVA p = 0.008). Despite the differences in motor blockade, patients did not have difficulties to ambulate and it also did not show any relationship with the number of supplementary doses of local anesthetics among the groups.
There was a statistically significant difference in analgesia among the three groups (ANOVA) 45 minutes after the epidural block, but pain scores were greater in GI than GII (p = 0.03) and GIII (p = 0.01).
The groups did not differ on the administration of rescue doses (c2 = 0.68), and 86.7% of all patients requested supplementary doses of local anesthetic at some time during the analgesia, with a mean of 3 (three) doses for each patients. Analyzing labor analgesia every 15 minutes, it also did not show any differences on requests for rescue doses.
The frequency of spontaneous or instrumental delivery did not differ among the three groups (c2 = 0.31). The frequency of cesarean sections was 11.5%, 8.3%, and 28%, and forceps were used in 26.9%, 20.4%, and 28% of deliveries in GI, GII, and GIII, respectively (Table IV). When stratified in groups, the frequency of the use of forceps or cesarean sections also did not show significant differences.
The total volume of local anesthetic used was similar among all three groups (ANOVA p = 0.87), with a mean of 20.38 mL (GI), 19.33 mL (GII), and 20 mL (GIII).
Apgar scores of the newborns also did not differ among the three groups, with a median of 9 (Kruskal-Wallis p = 0.75) and only two newborns had Apgar scores below 7, one in GI and one in GIII. The frequency of neonatal acidosis (pH < 7.20) was 23.5%, 42.1% and 7.1% in GI, GII and GIII, respectively, which was not statistically significant (c2 = 0.07) (Table V). However, when the groups were stratified a significant difference (p = 0.02) was observed and the frequency of acidosis was greater in GII than GIII.
Clinical studies with levorotatory isomers of local anesthetics demonstrated their greater clinical safety due to decreased neuro and cardiotoxicity 2. Studies published have demonstrated that the administration of epidural levobupivacaine is associated with reduced intensity of the motor blockade, which represents an advantage for its clinical application in labor analgesia 3. The patients enrolled in this study received 0.125% racemic bupivacaine (S50-R50) and two different concentrations (0.125% and 0.25%) of 50% enantiomeric excess bupivacaine (S75-R25). The length of time until the first request of rescue analgesia was greater in patients who received 0.25% enantiomeric excess bupivacaine (S75-R25) who initially had lower pain scores than the other two groups. Although the frequency of spontaneous ambulation did not differ among the different groups, the degree of the motor blockade evaluated by the RAM scale was greater in patients who received racemic bupivacaine (S50-R50) than in those receiving 50% enantiomeric excess bupivacaine (S75-R25).
Evaluating labor analgesia in a clinical study with random distribution of patients, Nakamura et al. 6 analyzed 33 patients who received epidural bupivacaine, ropivacaine or levobupivacaine all at a concentration of 0.125% and concluded that motor blockade was stronger with levobupivacaine than bupivacaine and ropivacaine. Those results conflict with the results of the present study that showed a stronger motor blockade in patients who received racemic bupivacaine (S50-R50) than in patients receiving two different concentrations of 50% enantiomeric excess bupivacaine (S75-R25). Although the in vitro studies suggest that the motor blockade of both isomers of bupivacaine is similar 9, a recent study observed that sodium channels blockade is more potent with the dextrorotatory isomer than the levorotatory isomer 10 justifying the weaker motor blockade of enantiomeric excess bupivacaine observed in the present study.
Similarly, a clinical study comparing 0.5% bupivacaine with 0.5% enantiomeric excess bupivacaine (S75-R25) in 44 patients undergoing epidural block for vascular or orthopedic surgeries of the lower limbs concluded that the degree of the motor blockade was greater in the group that received 0.5% of bupivacaine 11.
Skeletal muscle blockade is one of the most undesirable effects during labor analgesia due to the increased risk of instrumental delivery, longer duration of labor and maternal dissatisfaction 6,12. Labor analgesia, when properly done, does not interfere with uterine dynamics and does not prolong the first stage of labor. During the second stage of labor, one should be careful with the volume and concentration of the local anesthetic to preserve muscle strength 13. The use of local anesthetics in low concentrations in epidural block does not seem to interfere with the evolution of labor 14. Even though the present study included a group of patients who received an elevated concentration (0.25%) of enantiomeric excess bupivacaine (S75-R25), differences in the frequency of instrumental delivery among the groups were not observed and this frequency was similar to that reported in the literature 6,15. The duration of labor analgesia also did not differ despite the use of a greater concentration (0.25%) of the local anesthetic.
In the study of Nakamura et al. 6, the authors also observed a tendency for greater pain severity in the bupivacaine group than in the levobupivacaine group. Those results are similar to ours, since we observed that pain severity during labor was similar among the groups except at the 45-minute evaluation mark when patients who received 0.25% of enantiomeric excess bupivacaine (S75-R25) had lower pain scores. It should be mentioned that the first request of a rescue dose in this group was made later (67.08 min) than in the other two.
In order to evaluate the quality of the block and maternal-fetal repercussions of the epidural administration of 0.5% bupivacaine, 0.5% enantiomeric excess mixture (S75-R25) or 0.75% ropivacaine associated with fentanyl in pregnant women undergoing cesarean sections, Cortes et al. 16 did not observe any differences among the study groups except for the quality of the block, which was clinically inferior in the groups with a predominance of the levorotatory form, with a need to complement the analgesia in three cases. In the present study, the quality of analgesia was superior in the group who received a greater concentration of the enantiomeric excess solution. Although most studies on labor analgesia use local anesthetics with concentrations lower than 0.25% 17-18, the pharmacological profile of anesthetics with greater proportion of the levorotatory isomer allows them to be used in higher concentrations without the consequent increase in the degree of motor blockade 3.
In this study, we did not observe any difference in the Apgar scores of newborns. Newborns whose mothers received 0.125% enantiomeric excess bupivacaine (S75-R25) had a higher incidence of acidosis (pH < 7.2) than those whose mothers received the same anesthetic, but at a higher concentration (0.25%). This could be explained by the longer time in the delivery channel. Although there were no statistically significance differences, the second stage of labor was longer in the group that received 0.25% enantiomeric excess bupivacaine (S75-R25), which had the lower incidence of acidosis.
When studying the efficacy of levobupivacaine (100% levorotatory bupivacaine) and enantiomeric excess bupivacaine (S75-R25) in epidural blocks, some authors observed a reduction in the incidence of side effects, good receptivity of the method by the patients, absence of postoperative transitory neurological symptoms and adequate motor and sensitive blockades, which indicate that the use of those solutions is safe in lumbar epidural blocks 19,20.
When comparing both local anesthetics, racemic bupivacaine (S50-R50) and enantiomeric excess bupivacaine (S75-R25), although the latter is associated with lower neuro- and cardiotoxicity, one can conclude that in low concentrations both drugs can be used in labor analgesia. However, since the degree of the motor blockade induced by enantiomeric excess bupivacaine (S75-R25) is weaker, it could be used at a higher concentration (0.25%), resulting in better quality analgesia and greater interval before the request of the first rescue dose without interfering with the evolution of labor or the degree of vitality of the newborns.
ACKNOWLEDGEMENTS: The authors would like to express their gratitude to Laboratório Cristália Produtos Químicos Farmacêuticos Ltda for providing the different concentrations of the local anesthetics.
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Dra. Nádia Maria da Conceição Duarte
Rua Feliciano José de Farias, 160/1.101 Boa Viagem
51030-450 Recife, PE
Submitted em 4
de janeiro de 2007
Accepted para publicação em 23 de outubro de 2007
* Received from Instituto Materno Infantil Professor Fernando Figueira (IMIP), Recife, PE