Comparison of the plasma levels of 50% enantiomeric excess (S75/R25) 0.5% bupivacaine combined with 1: 200,000 epinephrine between the parasacral and infragluteal sciatic nerve blocks

Abstracts

JUSTIFICATIVA E OBJETIVOS: Anestésicos locais (AL) são fármacos seguros se administrados em dose e localização corretas. A velocidade de absorção do anestésico local depende de sua massa e vascularização do local de injeção. O objetivo deste estudo foi analisar a concentração sérica da mistura com excesso enantiomérico de 50% (S75/R25) de bupivacaína 0,5% com epinefrina 1:200.000, utilizada para bloqueio do nervo isquiático (BNI) nas vias parassacral (PS) e infraglútea (IG). MÉTODO: Vinte e oito pacientes agendados para operações no tornozelo e pé foram, aleatoriamente, distribuídos em dois grupos de maneira prospectiva. No Grupo 1, foi realizado BNI com neuroestimulação por via IG, enquanto no Grupo 2 foi utilizada a via PS. Nos dois grupos foram injetados 30 mL de bupivacaína (S75/R25) a 0,5% com adrenalina 1:200.000. Foram coletadas amostras de 5 mL de sangue arterial com 0, 15, 30, 60 e 90 minutos após injeção do AL. A análise da concentração sérica foi realizada pela cromatografia líquida de alto desempenho. Dados demográficos foram comparados, entre grupos, pelo teste t de Student para amostras independentes e pelo teste Exato de Fisher. Dados referentes às concentrações plasmáticas foram submetidos à Análise de Variância bifatorial para amostras repetidas. RESULTADOS: Os Grupos 1 e 2 não apresentaram diferenças demográficas significativas. A concentração máxima (Cmáx.) do Grupo 1 (308 ± 91 ng.mL-1) foi obtida nas amostras 5 (90 minutos), enquanto no Grupo 2 (425 ± 280 ng.mL-1) esta ocorreu nas amostras 2 (15 minutos). Nenhum paciente apresentou toxicidade sistêmica. CONCLUSÕES: A Cmáx. da bupivacaína (S75/R25) a 0,5% com adrenalina 1:200.000 no acesso parassacral foi superior, quando comparado com o acesso infraglúteo do BNI.

ANESTESIA, Regional; ANESTÉSICOS, local; TÉCNICAS ANESTÉSICAS, Regional

SCIENTIFIC ARTICLE

Comparison of the plasma levels of 50% enantiomeric excess (S75/R25) 0.5% bupivacaine combined with 1:200,000 epinephrine between the parasacral and infragluteal sciatic nerve blocks^*

Comparación de la Concentración máxima plasmática de la mezcla con exceso enantiomérico de 50% (S75/R25) de bupivacaína a 0,5% con epinefrina 1:200.000 entre los accesos parasacral e infraglúteo del bloqueo del nervio isquiático

Pablo Escovedo Helayel, TSA^I; André Roberto Bussman^II; Diogo Brüggemann da Conceição^III; Getúlio Rodrigues de Oliveira Filho, TSA^IV

^IAnestesiologista; Coordenador e Pesquisador do NEPAR; Instrutor Co-Responsável do CET/SBA Integrado de Anestesiologia da SES-SC

^IIMédico em Especialização em Anestesiologia

^IIIAnestesiologista; Pesquisador do NEPAR do CET/SBA Integrado de Anestesiologia da SES-SC

^IVAnestesiologista; Doutor em Anestesiologia; Pesquisador do NEPAR; Responsável do CET/SBA Integrado de Anestesiologia da SES-SC

Correspondence to

SUMMARY

BACKGROUND AND OBJECTIVES: Local anesthetics (LA) are safe drugs when the proper dose and localization are used. The rate of absorption of the local anesthetic depends on its mass and blood flow at the site of the injection. The objective of this study was to analyze the plasma concentration of 50% enantiomeric excess (S75R25) 0.5% bupivacaine combined with 1:200,000 epinephrine in the parasacral (PS) and infragluteal (IG) sciatic nerve block (SNB).

METHODS: Twenty-eight patients scheduled for ankle and foot surgeries were randomly divided into two groups in this prospective study. In Group 1, SNB was performed with IG neurostimulation, while in Group 2 the PS method was used. Both groups received 30 mL of 0.5% bupivacaine (S75/R25) with 1:200,000 epinephrine. Arterial blood samples, 5 mL, were drawn at 0, 15, 30, 60, and 90 minutes after the administration of the LA. High-performance liquid chromatography was used to analyze the serum concentrations. Demographic data of both groups were compared using the Student t test for independent samples and Fisher's Exact test. Bifactorial Analysis of Variance for repeated samples was used for the data concerning the plasma concentrations.

RESULTS: Groups 1 and 2 showed no significant demographic differences. The maximal concentration (Cmax) in Group 1 (308 ± 91 ng.mL^-1) was obtained in samples number 5 (90 minutes), while in Group 2 (425 ± 280 ng.mL^-1) it was obtained in samples number 2 (15 minutes). Cases of systemic toxicity were not observed.

CONCLUSIONS: Cmax of 0.5 % bupivacaine (S75/R25) with 1:200,000 in the parasacral approach was higher when compared with the infragluteal SNB.

Key Words: ANESTHESIA, Regional; ANESTHETICS, local: bupivacaine (S75/R25); ANESTHETIC TECHNIQUES, Regional: sciatic nerve block.

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: Los anestésicos locales (AL) son fármacos seguros si se administran en las dosis y en las ubicaciones correctas. La velocidad de absorción del anestésico local depende de su masa y de la vascularización del local de inyección. El objetivo de este estudio fue el de analizar la concentración sérica de la mezcla con exceso enantiomérico de 50% (S75/R25) de bupivacaína 0,5% con epinefrina 1:200.000, utilizada para bloqueo del nervio isquiático (BNI) en las vías parasacral (PS) e infraglútea (IG).

MÉTODO: Veinte pacientes que tenían su consulta marcada para operaciones en el tobillo y en el pie fueron distribuidos aleatoriamente en dos grupos de manera prospectiva. En el Grupo 1, se realizó BNI con neuro-estimulación por vía IG, mientras que en el Grupo 2 se usó la vía PS. En los dos grupos se inyectaron 30 mL de bupivacaína (S75/R25) a 0,5% con adrenalina 1:200.000. Fueron recolectadas muestras de 5 mL de sangre arterial con 0, 15, 30, 60 y 90 minutos después de la inyección del AL. El análisis de la concentración sérica fue realizada por la cromatografía líquida de alto desempeño. Datos demográficos fueron comparados entre grupos, por el test t de Student para muestras independientes y por el test Exacto de Fisher. Datos referentes a las concentraciones plasmáticas se sometieron al Análisis de Variancia bifactorial para muestras repetidas.

RESULTADOS: Los Grupos 1 y 2 no presentaron diferencias demográficas significativas. La concentración máxima (Cmax) del Grupo 1 (308 ± 91 ng.mL^-1) fue obtenida en las muestras 5 (90 minutos), mientras que en el Grupo 2 (425 ± 280 ng.mL^-1) esta se dio en las muestras 2 (15 minutos). Ningún paciente presentó toxicidad sistémica.

CONCLUSIONES: La Cmax de la bupivacaína (S75/R25) a 0,5% con adrenalina 1:200.000 en el acceso parasacral fue superior, cuando se le comparó al acceso infraglúteo del BNI.

INTRODUCTION

Local anesthetics are safe drugs when administered in the proper dose and at the right anatomical location. The injection of local anesthetics in any area of the body is not devoid of risks because they are absorbed into the blood stream and can reach toxic levels ¹. Among the undesirable side effects, one can mention cardiotoxicity and neurotoxicity associated with the local anesthetics, which can cause cardiovascular depression, arrhythmias, seizures, and coma ². The intensity of those manifestations is directly related with the plasma levels achieved by those agents ³. The rate of absorption depends, mainly, of the mass of local anesthetic administered and the blood flow at the site of injection ^1,4. Thus, keeping the mass of the local anesthetic, its absorption into the blood stream will be directly proportional to the blood flow in the area, and it might reach higher serum levels ¹.

In orthopedic surgeries of the lower limb, sciatic nerve blockade that promote long-standing postoperative analgesia with a reduced incidence of side effects when compared to opioids administered in the neuroaxis is routinely used⁵. Sciatic nerve blockade can be achieved through several approaches, and the infragluteal (IG) and parasacral (PS) are among them. However, there is a lack of evidence in the medical literature regarding the different absorption rates of local anesthetics in relation with the technique used for the sciatic nerve block. The objective of this study was to analyze the serum concentration of 50% enantiomeric excess (S75/R25) 0.5% bupivacaine associated with 1:200,000 epinephrine (Novabupi®, Cristália) during parasacral and infragluteal sciatic nerve block.

The hypothesis of this study was that there should be a difference in plasma levels of local anesthetics injected in different approaches of the sciatic nerve block.

METHODS

After approval by the Ethics Committee on Research of the Hospital Governador Celso Ramos, 28 patients signed an informed consent. Patients were classified as ASA I and II, with ages varying from 18 to 65 years, and were scheduled for unilateral, elective surgery of the ankle or foot. This is a prospective study with random allocation of patients into two groups through numbers generated electronically. Patients with respiratory, liver, or cardiac disorders; diabetes mellitus or peripheral neuropathies; patients under analgesia for chronic pain; and patients with known allergies to the study drugs or limited lower limb mobility were excluded from the study. Venipuncture was performed in the forearm of every patient with a 20G catheter; they received intravenous midazolam (0.05 mg.kg^-1) 10 minutes before the sciatic nerve block (SNB). A 20G catheter was introduced in the radial artery of the contralateral arm for sequential blood drawings. The skin was infiltrated with 1 mL of 1% lidocaine with a 38-mm, 25G needle before insertion of this catheter. Monitoring consisted of pulse oximetry, continuous electrocardiography, and automatic non-invasive blood pressure.

Group 1 (IG) underwent infragluteal parabicipital SNB, while in Group 2 (PS) the parasacral approach was used. In both groups, the local anesthetic used was the 50% enantiomeric excess (S75/R25) 0.5% bupivacaine with 1:200,000 epinephrine, for a total volume of 30 mL. In both approaches, patients were in ventral decubitus with their legs supported by a cushion, allowing free movement of the foot in response to nerve stimulation.

For the sciatic nerve block via the infragluteal parabicipital approach, the place of needle insertion was located 1 cm distal from the gluteal fold, along the medial border of the femoris biceps muscle. The skin in the area of needle placement was infiltrated with 2 mL of 1% lidocaine with a 25G, 38-mm needle. An isolated, 55-mm, 22G short-beveled Teflon^® needle (Stimuplex^® A50, B Braun, Melsungen Germany) connected to a neurostimulator (Stimuplex Dig RC^®; B Braun, Melsungen, Germany) was inserted in the anterior-cephalad orientation in the parasagittal plane at a 70° to 80° angle with the skin. The expected response was the flexion of the toes or ankle (tibial branch of the sciatic nerve), as well as dorsal-flexion / eversion of toes or ankle (common fibular branch of the sciatic nerve). For the injection of the anesthetic, a stimulus of 0.2 to 0.5 mA with pulse amplitude of 100 µsec was accepted. After adequate nerve identification, 30 mL of the local anesthetic solution were injected.

For the parasacral sciatic nerve block, a line running from the posterior-superior iliac spine (PSIS) to the ischial tuberosity was drawn and the area of needle insertion was determined to be 6 cm from the PSIS. The skin of the area was, then, infiltrated with 2 mL of 1% lidocaine with a 25G, 38-mm needle. An isolated, Teflon^®, short-beveled 21G, 100-mm needle (Stimuplex^® A100, B Braun, Melsungen, Germany) was introduced through the skin and advanced in the sagittal plane with a slight caudal angulation (10°). The needle was directed to avoid the margin of the greater sciatic notch until stimulation of the sciatic nerve was identified. Plantar flexion of the ankle or toes (tibial branch of the sciatic nerve), and the dorsal flexion / eversion of toes or ankle (common fibular branch of the sciatic nerve) were accepted in the presence of a stimulus between 0.2 and 0.5 mA and pulse amplitude of 100 µsec. Thirty milliliters of the local anesthetic solution were administered. The end of the administration of the local anesthetic was considered moment zero for sequential blood drawings in both groups.

After the end of the sciatic nerve blockade a femoral nerve block with 15 mL of 1.5% lidocaine with 1:200,000 epinephrine was performed with the patient in the supine position.

All patients were transferred to the operating room 30 minutes after the end of the injection of the local anesthetic solution and were sedated with intravenous midazolam (0.05 mg.kg^-1). The quality of the surgical anesthesia of the sciatic nerve blocks was evaluated and it was considered complete when the patient did not need supplementary analgesia during incision of the skin. Patients who also needed the intravenous administration of fentanyl (50 µg) were considered partial failures, while those who needed general anesthesia were considered complete failures.

Arterial blood samples, 5 mL, were drawn at 0, 15, 30, 60, and 90 minutes after the administration of the local anesthetic. Blood samples were transferred immediately into tubes containing heparin, centrifuged up to 60 minutes after being drawn, and the plasma was frozen at -20° Celsius to be analyzed later.

High-performance liquid chromatography (HPLC)⁶ was used to analyze the concentrated serum samples. Standard solutions used included bupivacaine chloride (Sigma-Aldrich, 99% pure) and lidocaine chloride (internal standard) (Sigma-Aldrich, 99% pure). To determine the calibration curve, separate dilutions of methanol were prepared from the standard solution of 1.0 mg.mL^-1, at concentrations of 20.0, 10.0, 4.0, 2.0, and 1.0 µg.mL^-1, corresponding to the concentrations of 1,000, 500, 200, 100, and 50 ng.mL^-1 of plasma. Lidocaine was diluted in methanol at a concentration of 20 µg.mL^{-1 7}.

The data obtained at each chromatographic reading were integrated using a specific software (Masslynx, version 3.5) to elaborate analytical curves and calculate the concentrations of the samples.

Sample size was calculated to detect a difference of at least 1 standard-deviation among maximal concentrations (Cmax), indicating the need of 14 patients per group. The demographic data of the study groups were compared by the Student t test for independent samples (age, weight, height, BMI, and Cmax) and by the Fisher's Exact test (gender).

Bifactorial Analysis of Variance (moments x groups) for repeated samples was used to evaluate the data regarding the plasma concentrations, followed by the Student-Newman-Keuls post-hoc tests. For those calculations, the data were submitted to logarithmic transformation (0 base) in order to obtain a normal distribution. A p < 0.05 was considered statistically significant.

RESULTS

Groups 1 and 2 did not show any significant demographic differences (Table I).

All 28 patients completed the study and the 5 blood samples drawn and analyzed resulted on a total of 140 samples. A significant elevation in plasma concentrations from the first sample until the end of the observation period was seen. The range of plasma concentration peaks in the study patients was 173.13 to 1037.59 ng.mL^-1. The peak plasma concentration (Cmax) in Group 1 occurred in sample number 5 (90 minutes), while in Group 2 it occurred in the second sample (15 minutes) and, therefore, Cmax was significantly higher than in Group 1 (p < 0.01). Plasma levels in Group 2 were higher than in Group 1 (p < 0.01) in samples number 2 (15 minutes) and 3 (30 minutes), as can be seen in Figure 1. Both groups demonstrated sciatic nerve blockade of good surgical quality and similar between them, without the need of supplementary analgesia.

DISCUSSION

A search of the literature failed to find a similar study that investigated the rate of absorption of local anesthetics in different approaches o the sciatic nerve block. The main result of the present study was the greater absorption of the solution of 50% enantiomeric excess (S75/R25) 0.5% bupivacaine with 1:200,000 of epinephrine when administered in the parasacral region for the sciatic nerve block. Differences in the rate of absorption of the local anesthetic between two blockade areas can be explained by the blood flow (capillary density) and the rate of binding of the anesthetic to the surrounding tissues ⁸. Thus, the results of the present study can be justified, anatomically, by the greater vascularization in the parasacral area when compared with the infragluteal region ^9,10. Rettig et al. ¹¹ also demonstrated differences in the rate of absorption of local anesthetics between the supraclavicular (lateral and posterior interscalene) and infraclavicular (ventral and axillary infraclavicular) approaches used in the brachial plexus block. However, Kalaoul et al. ¹² did not demonstrate significant differences among the rates of absorption of the local anesthetic in the anterior and posterior approach to the lumbar plexus. In this case, for example, local (vasoconstriction or vasodilation) or systemic changes in vasomotor tonus could have influenced absorption in those areas, indicating a multifactorial influence in the systemic absorption of local anesthetics¹.

In the range of peak plasma concentrations in the study patients (173.13 to 1037.59 ng.mL^-1), neurological or cardiovascular toxicity was not observed. The toxicity threshold of the enantiomeric mixture (S75/R25) of bupivacaine in humans has not been experimentally determined. However, this mixture has an extremely distinct pharmacokinetic profile when compared with the racemic mixture of bupivacaine, and is considered to be less neurotoxic and cardiotoxic ^13,14. Besides, the use of sedation and the characteristics of the study population could also have contributed to the absence of systemic toxicity.

The maximal plasma concentration of the 50% enantiomeric excess mixture (S75/R25) 0.5% bupivacaine with 1:200,000 of epinephrine achieved in the parasacral approach was superior to that of the infragluteal sciatic nerve block. Patients with compromised organic function such as those with heart, liver, or lung diseases could benefit from the infragluteal approach, since lower plasma levels of the enantiomeric excess (S75/R25) mixture of bupivacaine are achieved.

Laboratorial analysis were done by Laboratório Cristália,

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*

Recebido do Núcleo de Ensino e Pesquisa em Anestesia Regional (NEPAR) do CET/SBA Integrado de Anestesiologia da Secretaria de Estado da Saúde de Santa Catarina (SES-SC) do Hospital Governador Celso Ramos, Florianópolis, SC

Publication Dates

• Publication in this collection
  14 Oct 2011
• Date of issue
  Aug 2008

History

• Received
  07 Nov 2007
• Accepted
  21 Apr 2008