Comparison of the hemodynamic effects in acute intoxication with racemic bupivacaine and with 50% enantiomeric excess mixture (S75-R25): an experimental study in dogs

Abstracts

JUSTIFICATIVA E OBJETIVOS: A bupivacaína racêmica tem sido largamente utilizada em bloqueios locorregionais pela qualidade e duração da anestesia proporcionada. Sua toxicidade cardiovascular, no entanto, já há muito preocupa os anestesiologistas e novas opções têm sido procuradas. Uma delas é a utilização do seu isômero levógiro que por uma menor afinidade com os receptores dos canais de sódio da célula cardíaca seria menos cardiotóxico. Em nosso meio há a apresentação contendo 75% do isômero levógiro e 25% do isômero dextrógiro, denominada mistura com excesso enantiomérico de 50% (S75-R25). O objetivo deste estudo foi comparar em animais os efeitos hemodinâmicos da intoxicação aguda com bupivacaína racêmica e com a mistura S75-R25. MÉTODO: Quarenta e quatro cães foram anestesiados com pentobarbital, intubados e ventilados mecanicamente, sendo em seguida instalada monitorização hemodinâmica com cateter de Swan-Ganz e pressão invasiva. Após repouso foram divididos de forma aleatória em dois grupos de estudo encoberto, segundo a intoxicação com um ou outro agente na dose de 5 mg.kg-1. Os resultados hemodinâmicos foram coletados durante 30 minutos, tratados estatisticamente permitindo a comparação da ação dos dois agentes. RESULTADOS: A mistura S75-R25 causou maiores repercussões hemodinâmicas, particularmente, com importante diminuição da pressão arterial média, do índice cardíaco e do índice de trabalho do ventrículo esquerdo. CONCLUSÕES: Esses resultados se opõem aos encontrados em humanos, quando da utilização do isômero levógiro puro, mas estão de acordo com estudos recentes em animais. Extrapolar dados obtidos em animais para seres humanos exige muita cautela. Novos estudos são necessários em amostras maiores e em grupos mais homogêneos.

ANESTÉSICOS, Local; ANIMAIS; COMPLICAÇÕES; SISTEMA CARDIOVASCULAR

SCIENTIFIC ARTICLE

Comparison of the hemodynamic effects in acute intoxication with racemic bupivacaine and with 50% enantiomeric excess mixture (S75-R25). An experimental study in dogs^*

Comparación entre los Efectos Hemodinámicos de la Intoxicación Aguda con Bupivacaína Racémica y la Mezcla con Exceso Enatiomérico de 50% (S75-R25). Estudio Experimental en Perros

Artur Udelsmann, TSA^I; Derli Conceição Munhoz, TSA^II; William Adalberto Silva^III; Ana Cristina de Moraes^III; Giancarlo Marcondes^IV

^IProfessor Doutor do Departamento de Anestesiologia FCM/UNICAMP

^IIProfessora Doutora do Serviço de Anestesiologia do HC-UNICAMP

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

^IVPós-graduando do Departamento de Cirurgia da FCM/UNICAMP

^{Correspondence to}

SUMMARY

BACKGROUND AND OBJECTIVES: Racemic bupivacaine has been widely used in locoregional anesthesia due to the quality and duration of its anesthetic action. However, its cardiovascular toxicity has worried anesthesiologists for a long time, and new options have been sought. One of them is the use of its levorotatory isomer that, due to a lesser affinity for the sodium channel receptors in the cardiac cell, would be less toxic. The presentation containing 75% of the levorotatory isomer and 25% of the dextrorotatory isomer, named 50% enantiomeric excess mixture (S75-R25), is available in our country. The objective of this study was to compare the hemodynamic effects of the acute intoxication with racemic bupivacaine and with the S75-R25 mixture in animals.

METHODS: Forty-four dogs were anesthetized with pentobarbital, intubated and placed on mechanical ventilation. Hemodynamic monitorization was accomplished with a Swan-Ganz catheter and intra-arterial blood pressure measurements. After a period of rest, they were randomly and blindly divided in two groups, according to the intoxication with either agent at a dose of 5 mg.Kg^-1. Hemodynamic data were collected during 30 minutes and analyzed statically to allow for the comparison of both agents.

RESULTS: The mixture S75-R25 had more hemodynamic repercussions causing, especially, a significant reduction of the mean arterial pressure, cardiac index, and the left ventricle work index.

CONCLUSIONS: These results contradict those found in human beings regarding the pure levorotatory isomer, but confirm recent animal studies. One must be very careful when extrapolating animal data to human beings. Further studies involving larger samples and more homogeneous groups are necessary.

Key Words: ANESTHETICS, local: racemic, bupivacaine, enantiomeric excess mixture; ANIMALS: dogs; CARDIOVASCULAR SYSTEM: hemodynamics alterations; COMPLICATIONS: sistemic toxicity; HEMODYNAMIC: intoxication effects.

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: La bupivacaína racémica ha sido ampliamente utilizada en bloqueos locorregionales por la calidad y duración de la anestesia proporcionada. Su toxicidad cardiovascular, sin embargo ya hace mucho tiempo preocupa a los anestesiólogos y nuevas opciones han sido buscadas. Una de ellas es la utilización de su isómero levógiro que por una menor afinidad con los receptores de los canales de sodio de la célula cardiaca que sería menos cardiotóxico. En nuestro medio existe la presentación que contiene un 75% del isómero levógiro y 25% del isómero dextrógiro, denominada mezcla con exceso enantiomérico de 50% (S75-R25). El objetivo de este estudio fue comparar en animales los efectos hemodinámicos de la intoxicación aguda con bupivacaína racémica y con la mezcla S75-R25.

MÉTODO: Cuarenta y cuatro perros fueron anestesiados con pentobarbital, entubados y ventilados mecánicamente, siendo en seguida instalada la monitorización hemodinámica con catéter de Swan-Ganz y presión invasiva. Después del período de reposo fueron divididos aleatoriamente en dos grupos de estudio encubierto, según la intoxicación con uno u otro agente en la dosis de 5 mg.kg^-1. Los resultados hemodinámicos se recolectaron durante 30 minutos, tratados estadísticamente permitiendo la comparación de la acción de los dos agentes.

RESULTADOS: La mezcla S75-R25 causó mayores repercusiones hemodinámicas, particularmente, con importante disminución de la presión arterial promedio, del índice cardiaco y del índice de trabajo del ventrículo izquierdo.

CONCLUSIONES: Esos resultados se contraponen con los encontrados en humanos, cuando se utiliza el isómero levógiro puro, pero están de acuerdo con estudios recientes en animales. Rebasar datos obtenidos en animales para seres humanos exige mucha cautela. Nuevos estudios se hacen necesarios en muestras más abarcadoras y en grupos más homogéneos.

INTRODUCTION

Epidural anesthesia is widely used in a number of surgical and obstetric procedures. High doses of local anesthetics are normally used with this technique, carrying the risk of toxic reactions, especially regarding the central nervous system, with the accidental intravenous injection. Due to its long action, bupivacaine is one of the local anesthetics used more frequently in this technique^1,2. However, since Albright³ published a report on the severe cardiovascular effects of the intoxication with this drug, laboratory researches have been aimed at synthesizing new long lasting and less toxic local anesthetics. Even though bupivacaine is synthesized in the form of its two isomers, dextro- and levorotatory⁴, until recently only its racemic formulation, containing equal amounts of both isomers, was commercially available. However, it is common knowledge, since 1972, that its levorotatory isomer is less toxic^5,6. Recently, studies with the levorotatory isomer, called levobupivacaine, in animal models showed that its lethal dose is 1.3 to 1.6 times greater than that of the racemic presentation⁷. In human beings, levobupivacaine would have a less pronounced negative inotropic effect and would cause a smaller lengthening of the PR and QT intervals in the EKG, which characterizes the intoxication of the racemic formulation. The pharmaceutical industry in Brazil manufactures a product containing 75% of the levorotatory isomer and 25% of the dextrorotatory isomer, known as 50% enantiomeric excess (S75-R25). Since this form is available only in our country, it was interesting to investigate the hemodynamic impact in the case of an accidental intoxication.

The objective of this study was to compare, in animals, the hemodynamic effects of the acute intoxication with racemic bupivacaine and with 50% enantiomeric excess (S75-R25).

METHODS

After approval by UNICAMP's Ethical Committee on Animal Experiments, we conducted a study with 44 mongrel dogs, weighing from 15 to 30 kg, of both genders, healthy, supplied by UNICAMP's vivarium, that were submitted to the following protocol:

1. Dogs were fasted the day before the study, with free access to water; 2. On the morning of the experiment, the animals were weighed and, after establishment of a venous access in one of its fore-foot, anesthesia was induced with 3% sodium pentobarbital (30 mg.kg^-1)⁹; 3. The animal was then intubated and submitted to controlled ventilation with a pneumatic ventilator with partial rebreathing and CO₂ absorber system, with a tidal volume of 15 mL.kg^-1 and a respiratory frequency capable of maintaining a P_ETCO₂ between 32 and 34 mmHg. An additional flow of O₂ (1 l.min^-1) was added and the hemoglobin O₂ saturation was measured by a sensor placed in the animal's tongue with the objective of maintaining a value above 97%; 4. The ECG was monitored; 5. A continuous infusion of pentobarbital (5 mg.kg^-1.h^-1) was administered to maintain the anesthesia; 6. Local anesthesia with 5 mL 1% lidocaine without vasoconstrictor was applied in the inner aspect of one of the thighs of the animal for the catheterization of the femoral artery and monitoring of the mean arterial pressure (MAP). Afterwards, using the same incision, the femoral vein was dissected and a 7-French Swan-Ganz catheter was introduced. The catheter was placed in a branch of one of the pulmonary arteries. The placement was confirmed by the morphological aspect of the pressure wave on the multi-parametric Engstrom AS/3 monitor. This catheter provided the hemodynamic parameters: cardiac index (CI), hear rate (HR), central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP), mean pulmonary artery pressure (MPAP), systemic vascular resistance index (SVRI), pulmonary vascular resistance index (PVRI), left ventricle work index (LVWI), left ventricle systolic work index (LVSWI), right ventricle systolic work index (RVSWI) and the systolic volume index (SVI). During this first step, a blood sample was drawn to determine the animals' hematocrit and hemoglobin values; 7. The animal's body surface area, expressed in m², was calculated using the classic formula found in literature¹⁰: S = (10.1 x 2/3 weight in grams)/10⁴, introducing it in the monitor to calculate the body's indexes; 8. After a 30-minute period of stabilization and rest, the first series of hemodynamic measurements was performed (M1); 9. The animals were randomly and blindly divided in 2 groups, called bupivacaine group (BG) and 50% enantiomeric excess bupivacaine group (EG). Bupivacaine or the S75-R25 mixture was administered by the intravenous route, at the maximal toxic non-lethal dose of 5 mg.kg^{-1 11}.

Hemodynamic measurements were taken at 1, 5, 10, 15, 20, and 30 minutes (M2 to M7, respectively) after intoxication. At the end of the experiment the animal was sacrificed, while still under anesthesia, with an intravenous injection of 10 mL of 19.1% potassium chloride.

The results of the different variables underwent statistical analysis using the Chi-square and, when necessary, Fisher's Exact test. The Mann-Whitney test was used to compare the distribution of continual variables measured in a single moment, and the analysis of variance (ANOVA) was used for the variables measured at different times. A level of 5%, i.e., p £ 0.05 was considered statistically significant; results between 5% and 10% were considered a tendency.

RESULTS

Table I presents the distribution of weight, body surface area, hematocrit, hemoglobin, gender, and number of animals that died in each group. The groups were homogenous, except for gender distribution, since there were more females in the BG. There were no differences between the groups at rest regarding the hemodynamic parameters measured.

After the intoxication, there was a reduction of the cardiac index in both groups (Figure 1), which was statistically significant in the EG (p = 0.0416). The values remained lower than M1 until the end of the experiment.

The MAP was significantly reduced in both groups in M2; however, this reduction was more pronounced in EG (p = 0.0389), and this difference remained until M5. In BG the pressure remained reduced form M2 to M4, recovering in M5. In EG this recovery occurred only in M7 (p = 0.0152) (Figure 2). The HR did not show differences between both groups, but the levels in M1 were different from the other levels measured until M7 (p = 0.0001) (Figure 3).

The CVP did not show differences between both groups, but from M2 the values were different from those obtained initially (p = 0.001) (Figure 4). The behavior of the PCWP was similar; there were no differences between both groups, but the levels after intoxication were different from those obtained initially (p = 0.0001) (Figure 5).

There were no differences between the groups regarding the mean pulmonary artery pressure, but the values found after the intoxication were different from those at rest (p = 0.0001) (Figure 6)

The systemic vascular resistance index did not differ between both groups and among the different times up to M4. From this moment the values were higher than the ones at rest in both groups (p = 0.0001) (Figure 7).

The pulmonary vascular resistance index also did not show any differences between both groups, but it increased in M2, just after the intoxication (p = 0.003 and p = 0.004) in both groups (Figure 8).

The left ventricle systolic work index decreased significantly in both groups after intoxication, but this reduction was more important in EG than in BG (p = 0.0451). This difference was maintained until M5. All the measurements obtained in each group after the intoxication were different from those obtained at rest (p = 0.0001) (Figure 9).

The right ventricle systolic work index showed a tendency to decrease in M2 (p = 0.0595 and p = 0.0505) without any differences between both groups, but the measurements obtained from M2 through M7 were different from the initial ones (p = 0.0001) (Figure 10).

The systolic volume index also decreased significantly in M2 (p = 0.0001), but there were no differences between both groups; those values remained below the initial levels until the end of the experiment (Figure 11).

DISCUSSION

The accidental intravenous injection of local anesthetics has been a constant source of concern for anesthesiologists. Racemic bupivacaine was widely used for several years until reports about its nervous and cardiovascular toxicity were published. From then on the research for new local anesthetics increased. One of the first discoveries in this area, which was introduced in the clinical practice in a relatively short period of time, was the levorotatory isomers, which are less toxic; soon, levobupivacaine and ropivacaine, agents containing only the levorotatory isomer, were commercially available, and since then several authors have demonstrated that they are less toxic. However, the motor blockade caused by levobupivacaine is weaker than that of its racemic form^7,12-15. For this reason, there would be a theoretical advantage of adding a small amount of its dextrotatory isomer to balance its action¹⁴ while still guaranteeing a product that is less toxic. The Brazilian pharmaceutical industry has synthesized such a drug, which has been widely used and known for being less toxic. Since this presentation is available only in our country, its cardiotoxicity was evaluated in dogs. The isomer S(-) is less cardiotoxic because of its reduced affinity, compared to the isomer R(+)¹⁶, for blocking the sodium channels of myocardial cells, which was demonstrated in laboratory animals. Such data, however, must be looked at with some reservation before being extrapolated to human beings. According to the data gathered by other authors comparing the effects of levobupivacaine, racemic bupivacaine, and ropivacaine in dogs, who have found a similar degree of toxicity¹⁷, or even a higher toxicity in the former drug^18,19, the results of this study showed a greater hemodynamic effect of the enantiomeric excess presentation than racemic bupivacaine in cases of acute intoxication similar to what happens with an accidental intravenous injection when applying a locoregional anesthesia. These results are very clear from the significant reduction in mean arterial pressure, cardiac index, and left ventricle systolic work index; the mean of these results in EG were considerably lower, and remained so almost until the end of the experiment, showing a greater impact of this preparation on the cardiovascular system. Four animals in the group intoxicated with the 50% enantiomeric excess presentation died, but this was not statistically significant, and it probably needs a larger sample for a definitive conclusion. The results are contrary to what is seen in human beings treated with levobupivacaine, which has a lesser impact on the cardiovascular system. However, these results in animals should be viewed cautiously; one should be careful when extrapolating these results to human beings, but it should stimulate more studies involving this drug. The accidents caused by locoregional anesthesia, with the intravascular injection of high doses and toxic reactions, have been decreasing drastically for the last 30 years, from 0.2% to 0.01%, but peripheral nerve blockades still account for the majority of cases (7.5 per 10,000)²⁰. Clinical and pharmacological efforts should continue to be made to decrease those accidents and their repercussions to a level compatible to the current scientific knowledge. Every effort should be made to reduce the morbidity and mortality related to anesthesia.

REFERENCES

Submitted for publication 7 de novembro de 2005

Accepted for publication 7 de abril 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 UNICAMP, Campinas, SP.

Publication Dates

• Publication in this collection
  24 July 2006
• Date of issue
  Aug 2006

History

• Accepted
  07 Apr 2006
• Received
  07 Nov 2005