Ropivacaine and bupivacaine plasma concentration during lumbar epidural anesthesia in children

Abstracts

JUSTIFICATIVA E OBJETIVOS: A ropivacaína é o mais novo anestésico local de uso na prática clínica. Sua estrutura é semelhante a forma levógira da bupivacaína, tendo portanto baixa toxicidade. Os valores das concentrações plasmáticas que podem ser atingidos em crianças, com o uso desta droga e também da bupivacaína (mesmo a forma racêmica) administradas por via peridural lombar, são ainda pouco conhecidos. O objetivo desse estudo foi avaliar as concentrações sangüíneas de ropivacaína e bupivacaína por via peridural lombar em crianças, em bloqueios eficientes, relacionando-as aos valores descritos como níveis plasmáticos seguros. MÉTODO: Oitenta e um pacientes de ambos os sexos, submetidos à cirurgia de membros inferiores, receberam aleatoriamente ropivacaína (n = 41) ou bupivacaína (n = 40) por via peridural lombar associado à anestesia geral. Foram coletadas oito amostras de sangue venoso nos intervalos de tempo: zero (controle), 5, 25, 40, 60, 120, 180 e 240 minutos, e através de cromatografia de gás foram dosadas as concentrações plasmáticas da ropivacaína e da bupivacaína. RESULTADOS: Não houve diferença estatisticamente significante com relação aos dados antropométricos e variáveis fisiológicas estudadas entre os pacientes que receberam ropivacaína e bupivacaína. As doses médias administradas de ropivacaína e bupivacaína foram 2,35 mg.kg-1 e 2,13 mg.kg-1, respectivamente, que geraram as concentrações plasmáticas de 2,334 µg.ml-1 e 1,111 µg.ml-1, aos 25 e 40 minutos. Ambas abaixo do nível considerado seguro (3 µg.kg-1). CONCLUSÕES: A administração peridural lombar de ropivacaína e bupivacaína em crianças, nas doses abaixo de 3 mg.kg-1, produz bloqueio anestésico eficaz e determina concentrações plasmáticas que podem ser consideradas seguras.

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

SCIENTIFIC ARTICLE

Ropivacaine and bupivacaine plasma concentration during lumbar epidural anesthesia in children

Verônica Vieira da Costa, M.D.^I; Denise Pereira de Oliveira Souza, M.D.^I; Marcelo Buzzi, M.D.^II; Márcio Corrêa de Mello, M.D.^III; Renato Ângelo Saraiva, TSA, M.D.^IV

^IAnestesiologista do Hospital Sarah Brasília

^IIBioquímico do Hospital Sarah Brasília

^IIIMestre em Estatística do Hospital Sarah Brasília

^IVCoordenador de Anestesiologia da Rede Sarah de Hospitais do Aparelho Locomotor

SUMMARY

BACKGROUND AND OBJECTIVES: Ropivacaine is the newest local anesthetic drug for clinical practice. Its structure is similar to levogyrous bupivacaine, therefore exibiting low toxicity. Little is known about plasma concentrations that can be reached in children after lumbar epidural administration of these drugs (including racemic bupivacaine). The aim of this study was to evaluate ropivacaine and bupivacaine plasma concentrations following successful lumbar epidural blocks in children, correlating them to known safe plasma levels.

METHODS: Eight-one children of both genders, aged between 2 and 16 year, scheduled to undergo lower limbs surgeries, were randomly divided in two groups to receive lumbar epidural ropivacaine ( n = 41) or bupivacaine (n = 40), associated to general anesthesia. Venous blood samples were collected at times 0 (control), 5, 25, 40, 60, 120, 180 and 240 minutes. Ropivacaine and bupivacaine plasma concentrations were measured by gas chromatography.

RESULTS: There was no statistically significant difference in anthropometric and physiological variables between groups. Mean ropivacaine and bupivacaine doses were 2.35 mg.kg^-1 and 2.13 mg.kg^-1 respectively, leading to peak plasma concentrations of 2.334 µg.ml^-1 and 1.111 µg.ml^-1 at 25 and 40 minutes respectively, both below the safety level of 3 µg.ml^-1.

CONCLUSIONS: Lumbar epidural administration of ropivacaine and bupivacaine in children, in doses below 3 mg.kg^-1, result in efficient anesthetic blocks and safe plasma concentrations.

Key Words: ANESTHETICS, Local: bupivacaine, ropivacaine; ANESTHETIC TECHNIQUES, Regional, epidural

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: La ropivacaína es el más nuevo anestésico local de uso en la práctica clínica. Su estructura es semejante a la forma levógira de la bupivacaína, teniendo por tanto baja toxicidad. Los valores de las concentraciones plasmáticas que pueden ser alcanzados en niños, con el uso de esta droga y también de la bupivacaína (mismo la forma racemica) administradas por vía peridural lumbar, son aun poco conocidos. O objetivo de ese estudio fue evaluar las concentraciones sanguíneas de ropivacaína y bupivacaína por vía peridural lumbar en niños, en bloqueos eficientes, relacionándolas a los valores descritos como niveles plasmáticos seguros.

MÉTODO: Ochenta y un pacientes de ambos sexos, sometidos a cirugía de miembros inferiores, recibieron aleatoriamente ropivacaína (n = 41) o bupivacaína (n = 40) por vía peridural lumbar asociado a anestesia general. Fueron colectadas ocho muestras de sangre venoso en los intervalos de tiempo: cero (control), 5, 25, 40, 60, 120, 180 y 240 minutos, y a través de cromatografia de gas fueron dosificadas las concentraciones plasmáticas de la ropivacaína y de la bupivacaína.

RESULTADOS: No hubo diferencia estadísticamente significante con relación a los datos antropométricos y variables fisiológicas estudiadas entre los pacientes que recibieron ropivacaína y bupivacaína. Las dosis medias administradas de ropivacaína y bupivacaína fueron 2,35 mg.kg^-1 e 2,13 mg.kg^-1, respectivamente, que generaron las concentraciones plasmáticas de 2,334 µg.ml^-1 y 1,111 µg.ml^-1, a los 25 y 40 minutos. Ambas abajo del nivel considerado seguro.

CONCLUSIONES: La administración peridural lumbar de ropivacaína y bupivacaína en niños, en las dosis abajo de 3 mg.kg^-1, produce bloqueo anestésico eficaz y determina concentraciones plasmáticas que pueden ser consideradas seguras.

INTRODUCTION

Ropivacaine is an amide-type local anesthetic which has been extensively studied in adults and teen agers ¹. It is considered very suitable for children, for inducing a differential nervous block, with less motor block and lower cardiovascular and neurological toxicity, thus allowing safer outpatient procedures ¹. There are recent reports about the efficacy and safety of caudal ^2-5 and lumbar epidural ropivacaine administration in children ^6,7. For some time, bupivacaine was the only local anesthetic available for medium and long duration orthopedic surgeries. In its racemic form, this agent has low neurological and high cardiovascular toxicity potential ^1,8,9.

Ropivacaine was introduced for preliminary studies in 1985. In 1989 Scott reported his study’s results showing less central nervous system toxicity with this agent compared to bupivacaine ⁸. Ropivacaine and bupivacaine had their pharmacokinetics in dogs studied in parallel, when the authors observed that, after intravenous administration, ropivacaine´s concentration decreased more rapidly during the elimination phase, suggesting a better safety margin. However, after epidural administration both drugs showed similar pharmacokinetics ¹⁰. Due to its minor vasoconstrictor effect, ropivacaine can be administered without epinephrine ¹.

Epidural ropivacaine in adult humans presents a two-phase absorption, with a fast initial phase (T_1/2 = 14 min) followed by a slower phase, with terminal half-life of approximately 4.2 hours ^11,12. In children, pharmacokinetic parameters have been calculated for different age groups after epidural continuous infusion ⁷.

The purpose of this study was to evaluate plasma concentrations reached with bolus lumbar epidural ropivacaine or bupivacaine in children after successful blocks, correlating them to values described as safe in the literature ^13,14.

METHODS

After the Hospital’s Ethics Committee approval, participated in this study 81 ASA I and II patients of both genders, aged 2 to 16 years, scheduled to undergo lower limb orthopedic or corrective plastic surgeries under general/lumbar epidural anesthesia. All patients were premedicated with oral 0.8 mg.kg^-1 midazolam 40 minutes before surgery. Patients aged 2 to 8 years were induced with halothane or sevoflurane, while those above 8 years of age were induced with venous thiopental (5 mg.kg^-1) or propofol (3 mg.kg^-1). Perioperative hydration was made with lactated Ringer’s solution. After tracheal intubation, anesthesia was maintained with inhalational anesthetics. After general anesthesia, patients were placed in the lateral position for lumbar epidural puncture with a 50 x 0.9 mm Tuohy needle. Bupivacaine with epinephrine 1:200.000 (n = 40) or plain ropivacaine (n = 41) were randomly administered in volumes and concentrations according to patients age and weight, not exceeding 3 mg.kg^-1.

Exclusion criteria were coagulopathies, hepatopathies, cardiopathies and neurological diseases.

Venous blood samples were collected for local anesthetics measurement in the following moments: zero (before local anesthetic injection), 5, 25, 40, 50, 60, 120, 180 and 240 minutes after local anesthetics administration. Local anesthetics plasma concentrations were measured by gas chromatography and mass spectometry (GC-MS), performed in a Hewlett-Packard model 6890 chromatographer interfaced with a mass detector MSD 6890. Bupivacaine and ropivacaine were extracted from the serum through a modified Tahraoui method ¹⁵.

The following parameters were continuously monitored: inhalational anesthetics inspired and end tidal (alveolar) fractions, heart rate, non invasive blood pressure, oxygen peripheral saturation (SpO₂), expired CO₂ (P_ETCO₂) and temperature. Blockade onset was confirmed by anal sphincter relaxation, as well as temperature and vasodilatation differences between anesthetized and non anesthetized areas. Blockade success was indirectly confirmed by inhalational anesthetics alveolar concentration (when kept always below minimum alveolar concentration - MAC) and consumption. Clinical neurological evaluations were performed in the preanesthetic visit, after premedication and in the post-anesthetic recovery unit.

Statistical analysis were data exploratory analysis for administered doses and plasma concentrations of local anesthetics, as well as analysis of variance through Fisher’s F test to compare mean demographics and physiological variables.

RESULTS

There was no statistical difference between groups in weight, age, gender and physical status (Table I).

There was no blockade failure. Inhalational anesthetics consumption was low and all patients were maintained with end expired fractions equal to or lower than 0.5 MAC.

Physiological variables (blood pressure, heart rate, ECG, SpO₂, P_ETCO₂ and temperature) showed good cardiovascular and respiratory stability in both groups with no statistically significant difference (Figure 1, Figure 2 and Figure 3). There was no significant change in pharyngeal temperature in both groups.

Mean ropivacaine dose was 2.35 mg.kg^-1, which produced a maximum plasma concentration of 2.334 µg.ml^-1 at 40 minutes. Mean bupivacaine dose was 2.13 mg.kg^-1, which produced a maximum plasma concentration of 1.111 µg.ml^-1 at 25 minutes (Figure 4).

Ropivacaine plasma concentration curve shows that there has been a progressive concentration increase for 40 minutes. Then, plasma levels started to decrease and showed a low plasma concentration at the end of the third hour after local anesthetics administration. Bupivacaine levels has shown a progressive increase for 25 minutes followed by a decrease as well (Figure 5).

All patients were clinically evaluated in PACU, without signs of neurological changes that could indicate neurotoxic reaction, that is, maintaining the same normal pattern of the initial neurological evaluation.

DISCUSSION

Our results confirm those obtained by other authors in which both drugs produced effective blockades without significant cardiovascular and neurological changes ¹⁶. This study, however, was performed in adult patients and drug plasma concentrations were not measured. In a different study with adult volunteers ⁸, intravenous bupivacaine or ropivacaine were continuously administered until 150 mg or the appearance of clinical intoxication signs or symptoms. The conclusion was that ropivacaine causes 25% less central nervous system toxicity and that both drugs increase heart rate and blood pressure, decreasing blood flow and ejection fraction. Although bupivacaine and ropivacaine cause cardiac conductivity and contractility depression, such signs appear in lower bupivacaine concentrations as compared to ropivacaine ⁸. A previous study in rats has shown that both drugs increase heart rate and blood pressure, decreasing blood volume and ejection fraction ¹⁷. It is possible that the good cardiopulmonary stability observed in our study has been due to plasma concentrations for below that found in the study with rats, which was 6 µg.ml^-1 for bupivacaine and 13 µg.ml^-1 for ropivacaine. Safe plasma level is 3 µg.ml^-1 for both agents ^13,14. There is a report on toxicity signs and symptoms in healthy volunteers after bupivacaine and ropivacaine intravenous infusion with plasma levels between 1 and 2 µg.ml^{-1 8}. The same study, however, argues whether such signs could be attributed to the anxiety shown by those volunteers ⁸.

An experiment with dogs ¹⁸ showed that ropivacaine dose and plasma concentration leading to seizure would be 4.9 mg.kg^-1 and 11.4 µg.kg^-1, respectively. For bupivacaine this dose would be 4.3 mg.kg^-1 and plasma concentration 18 µg.ml^-1. In our study, the doses used were lower, producing plasma concentrations for below those leading to seizure in dogs. Ropivacaine and bupivacaine showed good cardiovascular and respiratory stability. Absorption to circulation after epidural administration followed a two-phase pattern, with an initial rapid phase followed by a slower one accordance with previous studies ^10,13. This same kind of absorption had been previously described for bupivacaine and other local anesthetics, such as lidocaine and ethiocaine, in humans ^19-21 and monkeys ²².

Ropivacaine reached higher plasma concentrations than bupivacaine, in agreement with some previous studies ^1,10,12. In addition to a higher ropivacaine dose, other possible reason could be that, as opposed to bupivacaine, ropivacaine was administered without epinephrine. In vitro studies ¹⁶ confirmed that ropivacaine has a vasoconstrictor effect, but this effect might be negligible with the concentration used in clinical practice. In our study, ropivacaine was administered in low volumes and concentrations which could further decrease its vasoconstrictor effect. Other studies, however, state that the addiction of epinephrine will not decrease ropivacaine’s plasma peak concentration after epidural injection ^1,2. Mean bupivacaine plasma concentration peak found here is in line with a previous study also performed in children where the authors found a peak varying from 0.94 to 2.93 µg.ml^{-1 23}. Peak time (25 minutes) is also in agreement with the same study, where it ranged between 12 and 30 minutes. After that, there has been a gradual concentration decrease, similarly to what was observed in our study. We have found no study in the literature performed with ropivacaine in children measuring its venous blood concentration after bolus lumbar epidural administration. Some studies were performed in adults after intravenous infusion ^8,10,11,24, while others were performed in animals ^17,18. Most studies in children have evaluated sensory and motor block quality and level ^2,3,6 with caudal administration route ^2-6, and not lumbar epidural. In a more recent investigation of ropivacaine pharmacokinetics in children ⁷, the author studied clinical efficacy and safety of lumbar epidural administration, but in continuous infusion.

Difference in time elapsed for both drugs peak, that is, 25 minutes for bupivacaine and 40 minutes for ropivacaine, may be explained by a better ropivacaine lipidic solubility as compared to bupivacaine, which is beneficial for decreasing epidural space absorption ¹.

In conclusion, bolus ropivacaine or bupivacaine lumbar epidural administration in children, in doses below 3 mg.kg^-1, produces effective blockades and plasma concentrations below those considered potentially toxic, which progressively decrease after 40 minutes and remain in negligible levels after 4 hours of administration.

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Concentración plasmática de ropivacaína durante anestesia peridural lumbar en niños

Correspondence

Publication Dates

• Publication in this collection
  17 Jan 2011
• Date of issue
  Feb 2002

History

• Accepted
  18 July 2001
• Received
  09 Apr 2001