Hemodynamic effects of the acute intoxication with bupivacaine, levobupivacaine and 50% enantiomeric excess mixture: an experimental study in pigs

Abstracts

JUSTIFICATIVA E OBJETIVOS: Até recentemente, a bupivacaína tem sido o anestésico de escolha nos bloqueios locorregionais em razão da qualidade da anestesia proporcionada e pela sua duração. Apesar disso, sua toxicidade cardiovascular preocupa os anestesiologistas que procuram novas opções farmacológicas com menor grau desse inconveniente. Uma destas é o seu isômero levógiro, a levobupivacaína, que por uma menor afinidade aos receptores dos canais de sódio da célula cardíaca, seria menos cardiotóxica. Em nosso meio está disponível a apresentação contendo 75% do isômero levógiro e 25% do isômero dextrógiro, denominada mistura com excesso enantiomérico de 50%. O objetivo deste estudo foi avaliar as repercussões hemodinâmicas da injeção intravascular de dose tóxica desses três agentes, buscando encontrar qual deles tem menor impacto em caso de acidente. MÉTODO: Suínos da raça Large White foram anestesiados com tiopental, intubados e ventilados mecanicamente, sendo em seguida instalada monitorização hemodinâmica com cateter de Swan-Ganz e pressão invasiva para estudo das variáveis hemodinâmicas. Após repouso, foram divididos de forma aleatória em três grupos e realizada intoxicação duplamente encoberta com um dos agentes na dose de 4 mg.kg-1. Os resultados hemodinâmicos foram avaliados durante 30 minutos. Aos resultados foram aplicados testes estatísticos para comparação entre os grupos. RESULTADOS: A mistura com excesso enantiomérico de 50% e a levobupivacaína causaram maiores repercussões hemodinâmicas do que a mistura racêmica, sendo estas mais pronunciadas com o primeiro agente. Esses resultados se opõem aos encontrados em humanos, sobretudo quando da utilização do isômero levógiro puro, mas estão de acordo com resultados recentes também em animais. Extrapolar dados obtidos em suínos para seres humanos exige muita cautela e novos estudos são necessários. CONCLUSÔES: Em suínos, a mistura com excesso enantiomérico de 50% particularmente, e a levobupivacaína mostraram-se mais tóxicas quando administradas por via venosa do que a bupivacaína racêmica.

ANESTÉSICOS, Local; ANIMAL; COMPLICAÇÕES

SCIENTIFIC ARTICLE

Hemodynamic effects of the acute intoxication with bupivacaine, levobupivacaine and 50% enantiomeric excess mixture. An experimental study in pigs^*

Efectos hemodinámicos de la intoxicación aguda con bupivacaína, levobupivacaína y mezcla con exceso enantiomérico de 50%. Estudio experimental en cerdos

Artur Udelsmann, TSA^I; Sílvia Elaine Rodolfo de Sá Lorena^II; Samira Ubaid Girioli^III; William Adalberto Silva^IV; Ana Cristina de Moraes^IV

^IProfessor-Doutor do Departamento de Anestesiologia FCM/UNICAMP; Laboratório de Anestesia Experimental do Núcleo de Medicina e Cirurgia Experimental da FCM/UNICAMP

^IIPós-Graduanda do Departamento de Cirurgia da FCM/UNICAMP

^IIIMédica Cardiologista, Pós-Graduanda do Departamento de Farmacologia da FCM/UNICAMP

^IVBiólogo do Núcleo de Medicina e Cirurgia Experimental da FCM/UNICAMP

^{Correspondence to}

SUMMARY

BACKGROUND AND METHODS: Until recently, bupivacaine had been the anesthetic of choice for loco-regional blocks due to the quality and duration of the anesthesia. But its cardiovascular toxicity is a source of concern for anesthesiologists who seek new pharmacological options with a smaller degree of this problem. Its levorotatory isomer, levobupivacaine, that would be less cardiotoxic due a smaller affinity for the receptors of the sodium channels of the cardiac cell, is one of these options. In Brazil, a presentation containing 75% of the levorotatory isomer and 25% of the dextrorotatory isomer, called 50% enantiomeric excess mixture is available. The aim of this study was to evaluate the hemodynamic repercussions of the intravascular injection of a toxic dose of those three agents to determine which one has the least impact in the case of an accident.

METHODS: Large White pigs were anesthetized with thiopental, intubated, and placed on mechanical ventilation. Hemodynamic monitoring was achieved with a Swan-Ganz catheter and invasive blood pressure. After a period of rest, the animals were randomly divided in three groups. The intoxication was performed, on a double-blind fashion, with 4 mg.kg^-1 of one of the drugs. Hemodynamic parameters were evaluated during 30 minutes. Analytical tests were used to compare the results among the groups.

RESULTS: The 50% enantiomeric excess mixture and levobupivacaine had greater hemodynamic repercussions than the racemic mixture, which were more pronounced with the first drug. These results go against those found in humans, especially regarding the pure levorotatory isomer, but are similar to recent results reported in animals. One should be careful when extrapolating the data obtained in pigs to humans and further studies are necessary.

CONCLUSIONS: In pigs, the 50% enantiomeric excess mixture, in particular, and levobupivacaine were more toxic when administered intravenously than racemic bupivacaine.

Key Words: ANESTHETICS, Local: bupivacaine, 50% enantiomeric excess mixture, levobupivacaine; ANIMAL: pig; COMPLICATIONS: hemodynamic.

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: La bupivacaína ha sido hasta hace poco tiempo el anestésico por elección en los bloqueos loco-regionales en razón de la calidad de la anestesia proporcionada y por su duración. A pesar de eso, su toxicidad cardiovascular preocupa a los anestesiólogos que buscan nuevas opciones farmacológicas con un menor grado de ese inconveniente. Una de ellas es su isómero levógiro, la levobupivacaína, que por una menor afinidad con los receptores de los canales de sodio de la célula cardiaca, sería menos cardiotóxica. En nuestro medio está disponible la presentación que contiene un 75% del isómero levógiro y un 25% del isómero dextrógiro, denominada mezcla con exceso enantiomérico de 50%. El objetivo de este estudio fue el de evaluar las repercusiones hemodinámicas de la inyección intravascular de dosis tóxica de esos tres agentes, buscando encontrar cuál de ellos registra un menor impacto en caso de accidente.

MÉTODO: Cerdos de la raza Large White fueron anestesiados con tiopental, intubados y ventilados mecánicamente, siendo a continuación instalada la monitorización hemodinámica con catéter de Swan-Ganz y presión invasiva para estudio de las variables hemodinámicas. Después del reposo, fueron divididos aleatoriamente en tres grupos y realizada intoxicación doble encubierta con uno de los agentes en dosis de 4 mg.kg^-1. Los resultados hemodinámicos fueron evaluados durante 30 minutos. A los resultados se les aplicó pruebas estadísticas para la comparación entre los grupos.

RESULTADOS: La mezcla con exceso enantiomérico de 50% y la levobupivacaína causaron mayores repercusiones hemodinámicas que la mezcla racémica, siendo esas más fuertes con el primer agente. Esos resultados se oponen a los ya encontrados en humanos, particularmente cuando se utiliza el isómero levógiro puro, pero están a tono con los resultados recientes también obtenidos en animales. Rebasar los datos obtenidos en cerdos con los obtenidos en seres humanos, exige mucha cautela y nuevos estudios se hacen necesarios.

CONCLUSIONES: En cerdos, la mezcla con exceso enantiomérico de 50% particularmente, y la levobupivacaína fueron más tóxicas cuando se administraron por vía venosa que la bupivacaína racémica.

INTRODUCTION

Some anesthetic procedures require large doses of local anesthetics and there is always the risk of toxic reactions, especially in the cardiovascular and central nervous systems, in case of an accidental intravascular injection. Due to the quality of the anesthesia and the prolonged action, bupivacaine is one of the local anesthetics used more often ^1,2. However, since the publication in 1979 of the Anesthesiology editorial on the severe cardiovascular effects of the intoxication with this drug ³, several studies have been conducted to find new long-acting local anesthetics with reduced toxic potential. Although bupivacaine is synthesized in the form of two isomers, dextrorotatory R(+) and levorotatory L(-) ⁴, until recently it was commercialized only in the racemic presentation, which contains 50% of each isomer. However, it is known, since 1972, that the levorotatory isomer is less toxic ^5,6. Recently, this levorotatory isomer, known as levobupivacaine, became the focus of several studies and, in animal models, it has been shown that its lethal dose would be up to 1.6 times greater than that of the racemic mixture ⁷! In humans, levobupivacaine would have a smaller negative inotropic effect and would cause a smaller increase in the PR and QT intervals in the electrocardiogram, characteristics of the racemic intoxication. However, although this new agent presents the same analgesic potency ⁸, it is not devoid of problems: decreased motor blockade ⁹. For this reason, besides levobupivacaine, the pharmaceutical industry also manufactures a product with 75% of the levorotatory isomer and 25% of the dextrorotatory isomer, known as "50% enantiomeric excess mixture". Since this is a genuinely national product, the aim of this study was to determine its hemodynamic impact in case of an accidental intoxication, and to compare it with the intoxication with levobupivacaine and the racemic mixture.

METHODS

After approval by the Animal Experiment Ethics Committee of UNICAMP, 60 healthy Large White pigs of both genders, with weight ranging between 17 and 29 kg, were submitted to the following protocol:

1. Fasting since the day before with free access to water. 2. In the morning of the protocol, the animal was weighted and, after venous cannulation in one of its hears, anesthesia was induced with 25 mg.kg^-1 of 2.5% sodium thiopental. 3. The animal was then intubated and connected to a pneumatic respirator with a partial rebreather and absorber of CO₂, with a tidal volume of 15 mL.kg^-1 and a respiratory rate to maintain P_ETCO₂ between 32 and 34 mmHg. An additional flow of O₂ was added to the system, and the hemoglobin saturation was measured by a sensor placed on the tongue of the animal. The aim was to maintain it above 97%. 4. ECG was monitored. 5. Anesthesia was maintained with the intravenous infusion of 5 mg.kg^-1.h of thiopental. 6. Monitoring of the blood pressure was accomplished through the catheterization of the femoral artery, which was done after the administration of 5 mL of 1% lidocaine without vasoconstrictor to anesthetize the medial aspect of one of the thighs of the animal. The femoral vein was dissected through the same incision for the placement of a 7F Swan-Ganz catheter, which was introduced until the pulmonary arteries. The proper position of the catheter was determined by the morphology of the pressure curve in the multiparametric Engstrom AS/3 monitor. This catheter provided the following parameters: cardiac output (CO) by thermodilution, mean arterial pressure (MAP), mean pulmonary artery pressure (MPAP), central venous pressure (CVP), and pulmonary capillary wedge pressure (PCWP). Using the classical formulas in the literature, the monitor also calculated other hemodynamic parameters, such as: cardiac index (CI), systolic index (SI), systemic vascular resistance index (SVRI), pulmonary vascular resistance index (PVRI), left ventricle work index (LVWI), right ventricle work index (RVWI). At this time, blood samples were drawn to determine the hematocrit and hemoglobin. 7. The body surface area (BSA), in square meters, was determined using the classical formula ¹²: S = (9 x weight in grams^2/3) x 10^-4, and the parameters were programmed into the monitor to determine the values of the body indexes. 8. After a 30-minute period of stabilization and rest, the first series of hemodynamic parameters was measured, and these results were considered the standard measurements (M1). 9. The animals were randomly divided in three groups: bupivacaine group (BG), 50% enantiomeric excess group (EG), and levobupivacaine group (LG). They received a toxic dose of 4 mg.kg^-1 of the local anesthetic intravenously ¹³. 10. Hemodynamic parameters were measured 1, 5, 10, 15, 20, and 30 minutes after the intoxication (M2 to M7, respectively). 11. At the end of the experiment, the animal was sacrificed, while still under the effects of the anesthesia, with the administration of 10 mL of 10.1% potassium chloride IV.

The results of the categorical variables were analyzed by the Chi-square test and, whenever necessary, Fisher Exact test. One-way ANOVA was used to compare the distribution of the continuous variables in one moment, while the ANOVA was used to study the continuous variables measured in several moments. A level of 5%, i.e., p < 0.05 was considered significant; results between 5% and 10% were considered a tendency.

RESULTS

Table I shows the mean and standard deviation of the weight, body surface area, hematocrit, and hemoglobin of the three groups.

The groups were homogenous regarding gender (p = 0.803), weight (p = 0.88), hematocrit (p = 0.58), hemoglobin (p = 0.2), and body surface area (p = 0.91). There were no differences in hemodynamic parameters at rest among the groups.

After the intoxication, the cardiac index (Figure 1) was reduce in all three groups, but it was more pronounced in EG and LG (p = 0.0051). The values in BG were higher than EG until M6 and than LG until M4 (p = 0.0001).

Mean arterial pressure (Figure 2) demonstrated a marked reduction in the three groups at M2, but it was more pronounced in EG and LG. The bupivacaine group had higher values than the other two groups until M7 (p = 0.0001). Blood pressure returned to baseline values in BG at M4, in LG at M5, and in EG at M6 (p = 0.0001).

After the intoxication the heart rate (Figure 3) decreased in all three groups, and this difference was maintained until the end of the experiment (p = 0.0001). In EG this reduction had a sustained statistically significant difference when compared with BG until the end of the experiment, and until M3 when compared with LG (p = 0.0007).

Central venous pressure (Figure 4) showed a marked increase in the three groups after intoxication (p = 0.0001); however, it was more pronounced in EG and LG. The difference between EG and BG persisted throughout the experiment, while the difference between LG and BG persisted until M5 and from then on both groups had similar parameters (p = 0.0311).

There were no differences in MPAP (Figure 5) between the groups but, from M4 on the results were different than those at rest for the three groups (p = 0.0001).

Pulmonary capillary pressure (Figure 6) in the three groups at M2 was different than at M1; this change persisted until the end of the experiment (p = 0.0001) but without differences among the groups.

There was a marked reduction in the work index (Figure 7) in the three groups from M2 to M5 (p = 0.0001). Statistical analysis demonstrated that LG values were smaller than BG values until M3 (p = 0.001).

The systemic vascular resistance index (Figure 8) showed important variations after the intoxication in all three groups (p = 0.0001). It was more pronounced in LG than in EG but in BG it showed a slight increment. There was a significant difference between BG and LG and EG at M2 and M3 (p = 0.0463).

The pulmonary vascular resistance index (Figure 9) was higher than at rest from M2 on (p = 0.0001) but there were no significant differences among the groups.

The left ventricle work index (Figure 10) showed a marked reduction in the three groups after intoxication (p = 0.0001), and this reduction persisted until M4 in BG and until M5 in LG and EG (p = 0.0001). Comparing the groups, BG was higher than EG until M6 and higher than LG until M4; LG was higher than EG at M5 (p = 0.0005).

The right ventricle work index (Figure 11) was also decreased after the intoxication and remained so in BG until M3, in LG until M4, and in EG until M5 (p = 0.0001). The values in LG and EG were significantly inferior to BG until M5 (p = 0.0006).

DISCUSSION

Levobupivacaine causes less motor blockade than the racemic mixture ^7,14-17 the reason why the interest in adding a small amount of the dextrorotatory isomer to reduce this effect ¹⁶. The national industry synthesized this product and since then it has been widely used, because it is also considered less toxic. Since this presentation is available only in Brazil, the aim of this study was to determine its cardiotoxicity in pigs, comparing it to racemic bupivacaine and levobupivacaine. The decreased toxicity of the S(-) isomer would be a consequence of its decreased affinity for the sodium channels of the cardiac cells, inferior to that of the R(+) isomer ¹⁸, which had been demonstrated in animals. Such data should be considered with caution before extrapolating to humans. Like to the animal data of other authors comparing levobupivacaine, racemic bupivacaine, and ropivacaine showing that levobupivacaine had similar ¹⁹, or even greater, toxicity^20,21, our results demonstrated that the hemodynamic consequences of the 50% enantiomeric excess mixture were more pronounced, followed by levobupivacaine and racemic bupivacaine in case of an acute intoxication in pigs, similar to the accidental administration of the drug during loco-regional anesthesia in humans. This is evident in the marked reduction of the cardiac index, mean blood pressure, heart rate, and left ventricle work load. These results confirm the data obtained previously comparing racemic bupivacaine and 50% enantiomeric excess mixture in dogs ²². Animal results should be analyzed carefully and their extrapolation to humans demand caution. However, these results allow for some reflections and should stimulate further studies, since this is the second series with similar results. The accidental intravenous administration of high doses, with toxic reactions, when applying loco-regional anesthesia have decreased drastically in the last 30 years, from 0.2% to 0.01%, and peripheral nerve blocks account for the majority of the cases (7.5 per 10.000) ²³. Such reflections should encourage renewed efforts at developing drugs and techniques that would allow the morbidity and mortality to be closer to zero. This purpose is aimed at protecting patients from undesirable and unforeseen effects resulting from loco-regional anesthetic techniques with high doses of local anesthetics and, therefore, protecting the anesthesiologist, avoiding the consequences of legal actions that are so common nowadays.

ACKNOWLEDGEMENTS

To the Cristália Laboratory.

REFERENCES

Submitted em 08 de maio de 2006

Accepted para publicação em 27 de novembro de 2006

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*

Received from Laboratório de Anestesia Experimental do Núcleo de Medicina e Cirurgia Experimental da Faculdade de Ciências Médicas da Universidade Estadual de Campinas (FCM/UNICAMP), Campinas, SP

Publication Dates

• Publication in this collection
  19 Jan 2007
• Date of issue
  Feb 2007

History

• Received
  08 May 2006
• Accepted
  27 Nov 2006