Lipid therapy with two agents in ropivacaine-induced toxicity: experimental study in swine

Abstracts

OBJETIVO: Comparar alterações hemodinâmicas após intoxicação com ropivacaína seguida de terapia com duas emulsões lipídicas em suínos. MÉTODO: Suínos da raça Large White foram anestesiados com tiopental, intubados e mantidos em ventilação mecânica. Variáveis hemodinâmicas de repouso foram registradas através de pressão invasiva e cateterização da artéria pulmonar. Após 30 minutos, 7 mg.kg-1 de ropivacaína foram injetados por via venosa e novas medidas hemodinâmicas foram feitas em um minuto; os animais foram então aleatoriamente alocados em três grupos e receberam: 4 mL.kg-1 de solução salina, 4 mL.kg-1 de solução lipídica com triglicérides de cadeia longa e 4 mL.kg-1 de solução lipídica com triglicérides de cadeia média e longa. As alterações hemodinâmicas foram reavaliadas aos cinco, 10, 15, 20 e 30 minutos. RESULTADOS: A intoxicação pela ropivacaína causou queda da pressão arterial e do índice cardíaco, principalmente, sem importantes alterações das resistências vasculares. A terapia com as emulsões lipídicas restaurou a pressão arterial através, principalmente, do aumento das resistências vasculares, uma vez que o índice cardíaco não apresentou melhoria expressiva. A emulsão lipídica com triglicérides de cadeia média causou aumento superior das resistências vasculares, sobretudo pulmonares. CONCLUSÃO: Nos grupos que receberam emulsões lipídicas os resultados hemodinâmicos foram melhores do que no grupo controle; não foram observadas diferenças da pressão arterial sistêmica e do índice cardíaco entre os animais que receberam a solução com triglicérides de cadeia longa e a mistura de triglicérides de cadeia média e longa.

ANESTÉSICOS, Local, ropivacaína; ANIMAL, Porco; COMPLICAÇÕES, Injeção acidental; Emulsões Gordurosas Intravenosas

JUSTIFICATIVAS Y OBJETIVO: Comparar las alteraciones hemodinámicas después de la intoxicación con ropivacaína seguida de terapia con dos emulsiones lipídicas en cerdos. MÉTODO: Cerdos de la raza Large White que fueron anestesiados con tiopental, intubados y mantenidos bajo ventilación mecánica. Las variables hemodinámicas de reposo se registraron por medio de la presión invasiva y la cateterización de la arteria pulmonar. Después de 30 minutos, se inyectaron 7 mg.kg-1 de ropivacaína por vía venosa y nuevas medidas hemodinámicas se tomaron en un minuto. Los animales se dividieron entonces aleatoriamente en tres grupos y recibieron: 4 mL.kg-1 de solución salina, 4 mL.kg-1 de solución lipídica con triglicéridos de cadena larga y 4 mL.kg-1 de solución lipídica con triglicéridos de cadena media y larga. Las alteraciones hemodinámicas fueron nuevamente calculadas a los 5, 10, 15, 20 y 30 minutos. RESULTADOS: La intoxicación por ropivacaína ha causado la caída de la presión arterial y del índice cardíaco, principalmente, sin alteraciones importantes de las resistencias vasculares. La terapia con las emulsiones lipídicas ha restaurado la presión arterial principalmente por medio del aumento de las resistencias vasculares, una vez que el índice cardíaco no tuvo una mejoría expresiva. La emulsión lipídica con triglicéridos de cadena media causó un aumento superior de las resistencias vasculares, sobre todo en las pulmonares. CONCLUSIONES: En los grupos que recibieron emulsiones lipídicas, los resultados hemodinámicos fueron mejores que en el grupo control. No se observaron diferencias de la presión arterial sistémica y del índice cardíaco entre los animales que recibieron la solución con triglicéridos de cadena larga y la mezcla de triglicéridos de cadena media y larga.

ANESTÉSICOS, Local, ropivacaína; ANIMAL, Cerdo; COMPLICACIONES, Inyección accidental; Emulsiones Grasas Intravenosas

SCIENTIFIC ARTICLE

^IMSc; Fellow PhD degree in Surgical Sciences, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (Unicamp)

^IIFellow PhD degree in Surgical Sciences, Faculdade de Ciências Médicas, Unicamp

^IIIMSc; Nurse Multiprofessional Team of Nutrition Therapy, Hospital of the Unicamp

^IVAnesthesiologist, Hospital of the Unicamp

^V2nd year resident, Department of Anesthesiology, Faculdade de Ciências Médicas, Unicamp

^VIAssociate Professor, Department of Anesthesiology, Faculdade de Ciências Médicas, Unicamp

Correspondence to

SUMMARY

BACKGROUND AND OBJECTIVE: Compare hemodynamic changes after ropivacaine-induced toxicity followed by treatment with two lipid emulsions in swine.

METHODS: Large White pigs were anesthetized with thiopental, followed by intubation, and kept on mechanical ventilation. Hemodynamic variables at rest were recorded with invasive pressure monitoring and pulmonary artery catheterization. After 30 minutes, 7 mg.kg^-1 ropivacaine were injected intravenously and new hemodynamic measurements were performed within one minute. The animals were then randomly allocated into three groups and received: 4 mL.kg^-1 saline solution, or 4 mL.kg^-1 lipid emulsion with long-chain triglycerides, or 4 mL.kg^-1 lipid emulsion with long-and medium-chain triglycerides. Hemodynamic changes were reevaluated at 5, 10, 15, 20 and 30 minutes.

RESULTS: Ropivacaine-induced toxicity mainly caused a drop in blood pressure and cardiac index without significant changes in vascular resistance. Therapy with lipid emulsions restored blood pressure primarily through increased vascular resistance, as cardiac index showed no significant improvement. Lipid emulsion with medium-chain triglycerides caused a greater increase in vascular resistance, particularly pulmonary.

CONCLUSION: In groups receiving lipid emulsions, hemodynamic results were better than in control group. There were no differences in systemic arterial pressure and cardiac index between animals receiving lipid emulsion with long-chain triglycerides and mixed long- and medium-chain triglycerides.

Keywords: Anesthetics, Local/ropivacaine; Accidents; Fat Emulsions, Intravenous; Swine.

INTRODUCTION

Local anesthetics (LA) are agents widely used in medical practice. Although there have been many advances in recent years on drugs and methods of administration, adverse effects and complications still occur and, although rare, it may compromise the patient's prognosis. In a 2006 estimate, the incidence of these events was 7.5 - 20:10.000 peripheral nerve blocks and 4:10.000 epidural anesthesia¹. In case of accidental intravenous injection of high doses, the most feared effects are on central nervous system and cardiovascular system. The first precede the cardiovascular condition, ranging from a metallic taste to tingling that may progress to convulsions and coma, and the latter are characterized by decreased cardiac contractility, loss of vasomotor tone, cardiovascular collapse, arrhythmias difficult to reverse, and even asystole ². Several factors may influence the severity of LA systemic toxicity, including the patient's individual risk factors, concurrent medication, location and block technique, as well as the agent used, its dosage and volume ³. Bupivacaine is still the most widely used LA in locoregional blocks. In 1979, Albright called attention to this agent toxicity in an Anesthesiology editorial ⁴. Since then, efforts were made initially to find less toxic drugs. In 1996, ropivacaine was released, an agent with less lipid solubility and marketed only with its levorotatory isomer, which gives it a significantly better safety profile ⁵. Although the results have been encouraging, accidents are still happening and may even manifest late after the blockade ⁶. The next step was to find a specific agent to treat injuries caused by inadvertent intravascular injection of large doses of LA. In 1998, Weinberg et al. demonstrated in a preliminary study that lipid emulsions (LE), used since 1961 in parenteral nutrition, were able to mitigate the cardiotoxicity of bupivacaine in rats ⁷ and in 2003 they confirmed this finding in dogs ⁸. Since then, the use of LE has gained international approval as an antidote in the clinical setting, reaching a recommendation from Anesthesiology societies of various countries ^3,9,10. Indeed, lipid therapy has shown to be more effective than conventional therapies in cases of resuscitation post-intoxication 11, but some limits have been identified and, in case of intoxication accompanied by significant hypoxia, these emulsions seem to compromise the normal cardiac function recovery 10. The available LE for parenteral nutrition may have long-chain triglycerides or a mixture of long- and medium-chain triglycerides in its composition, and others may contain olive oil and fish oil. Mazoit et al. observed in vitro that LE with long-chain triglycerides have greater binding ability to local anesthetics 12 and, therefore, could be more effective as an antidote in cases of toxicity.

OBJECTIVE

The aim of this study was to evaluate the hemodynamic changes in pigs subjected to ropicavacaine-induced toxicity and treated with two types of LE: one with long-chain triglycerides and another with 50% medium- and 50% long-chain triglycerides.

METHOD

The study protocol was approved by the Animal Ethics Research Committee of the Instituto de Biologia da Universidade Estadual de Campinas. Thirty Large White pigs, weighing between 20 and 25 kg, were fasted from solid food overnight but free access to water. On the study morning, the animals received 10 mg.kg^-1 intramuscular ketamine, followed by weighing, and an estimate of the body surface using the formula 13 SC (m²) = (9 x weight in grams^2/3) x 10^-4. The result was entered into the monitor system AS/3 Engstrom^® for subsequent calculation of hemodynamic indices. Subsequently, venipuncture was made in the ear and anesthesia induced with sodium thiopental 2.5% at a dose of 25 mg.kg^-1. The animals were intubated and maintained under controlled mechanical ventilation with partial rebreathing circuit, tidal volume of 15 mL. kg^-1, and respiratory rate adjusted to obtain an ETCO₂ of 32- 34 mm Hg. A mixture of air and 100% O₂ was used to keep hemoglobin O₂ saturation above 97%, measured by pulse oximetry positioned on the tongue. An electrocardioscope in lead II was installed for heart rhythm monitoring. Anesthesia was maintained with 1% end-tidal isoflurane concentration. Local anesthesia was performed with 5 mL of lidocaine 1% without vasoconstrictor in the inner portion of posterior left leg for dissection of artery and femoral veins for catheterization and continuous measurement of blood pressure, introduction of Swan-Ganz catheter 7F placed in the pulmonary artery branch by checking the morphological aspect of the curve obtained. The following variables were measured: mean blood pressure (mBP), heart rate (HR), central venous pressure (CVP), cardiac index (CI), mean pulmonary artery pressure (mPAP), pulmonary capillary wedge pressure (PCWP), systemic vascular resistance index (SVRI) and pulmonary vascular resistance index (PVRI). After 30 minutes of stabilization, hemodynamic measurements were performed at rest (M₀), followed by intravenous administration of ropivacaine 1% (7 mg.kg^-1) in 30 seconds. One minute later, new hemodynamic measurements (M1) were performed. The animals were then randomly allocated into three groups. After M1 and at 1 minute, CTRL group (control) received 4 mL.kg^-1 of 0.9% saline solution; group LCT received 4 mL.kg^-1 of lipid emulsion with long-chain triglycerides; and group MCT received 4 mL.kg^-1 of lipid emulsion with 50% medium- and 50% longchain triglycerides. Hemodynamic measurements were performed again at 5, 10, 15, 20 and 30 minutes after intoxication (M₅ to M₃₀ respectively). To compare numerical variables between groups at baseline, the Kruskal-Wallis test was used. To compare longitudinal measurements between groups and times, we used analysis of variance (ANOVA) for repeated measures followed by multiple comparison using Tukey's test for groups at all times, and the contrast profile test to analyze the evolution between assessments in each group. The level of significance for statistical tests was 5%.

RESULTS

Table I shows the mean and standard deviations (SD), weight, and body surface (BS) in both groups. There were no significant differences between groups.

Figure 1 shows that after intoxication there was a significant decrease in mean arterial pressure in the three groups: in CTRL blood pressure returned to values similar to M₀ from M₁₀; in LCT and MCT these values became greater than M₀ at M₁₀ and M₅, respectively, and remained that way (p < 0.001). The values were lower in CTRL than in LCT and MCT up to M₃₀ and there was no difference between LCT and MCT (p < 0.001).

As shown in Figure 2, there was a decrease in heart rate after intoxication in the three groups: in CTRL heart rate remained below resting values up to M₃₀; in LCT and MCT it returned to values similar to M₀ from M₅ (p = 0.02 .) There were no differences between LCT and MCT, and CTRL values were lower than LCT at M₁₀ and MCT at M₅ and M₁₀ (p < 0.001).

Figure 3 shows increased central venous pressure after intoxication in the three groups, not returning to values similar to those at rest in none of the groups. In CTRL, M₂₀ was higher than M₃₀; in LTC, it was also higher at M1<M₅>M₁₀>M₁₅; and in MCT it was M1<M₅>M₁₀>M₁₅>M₂₀ (p < 0.001). In CTRL, it was lower than in MCT at M₅ a M₁₅ and in LCT lower than in MCT at M₁₅ e M₃₀ (p < 0.001).

As shown in Figure 4, there was a decrease in cardiac index after intoxication in the three groups, and they have not returned to levels similar to M₀. In CTRL, the values increased at M₅, M₁₀, M₂₀ and M₃₀; in LTC, only at M₅; and in MCT, at M₃₀ (p < 0.001). There was no difference between groups (p = 0.38).

Figure 5 shows that there was an increase in mean pulmonary artery pressure in all three groups immediately after intoxication and values did not return to similar ones at rest. In CTRL, the values from M₁ did not differ; in LCT, M₅>M₁ and M₁₅<M₂₀<M₃₀; in MCT, M₅>M₁ e M₁₅<M₂₀ (p < 0,001). CTRL values were lower than in LCT from M₅ to M₂₀ and lower than in MCT from M₅ to M₃₀, and LCT values were lower than in MCT at M₂₀ and M₃₀ (p < 0.001).

As shown in Figure 6, there was increased pulmonary capillary wedge pressure in the three groups, and values at M₀ were lower to all other measures. In CTRL, M₅>M₁₀>M₁₅ e M₂₀>M₃₀; in LCT, M₂₀>M₃₀; and in MCT, M₁<M₅, M₁₀>M₁₅ and M₂₀>M₃₀ (p = 0.035). There were no differences between groups (p = 0.45).

As shown in Figure 7, CTRL values of systemic vascular resistance index at M₁₀, M₁₅ and M₂₀ were higher to the one the rest, in additional to M₁₅>M₂₀>M₃₀; in LCT, from M₅, all values were higher than the one at M₀ and M₁<M₅<M₁₀>M₁₅ and M₂₀>M₃₀; in MCT, also from M₅, all values were higher than the one at M₀ and M₁<M₅<M₁₀ (p < 0.001). In CTRL, results were lower than that in LCT and MCT from M₅ to M₃₀; and MCT had a lower value than LTC at M₅ (p < 0.001).

Figure 8 shows that, with intoxication, there was an increase in pulmonary vascular resistance at M₁ in the three groups. In CTRL, values at M₁ and M₅ were higher than at M₀; in LCT, all values were higher than the ones at M₀ and M₁<M₅, M₁₀>M₁₅, and M₂₀>M₃₀; in MCT, all values were also higher than the ones at M₀ and M₁<M₅ (p < 0.001). CTRL showed results lower than LCT from M₅ to M₂₀ and lower than MCT from M₅ to M₃₀; in addition, LCT had lower results than MCT at M₅, M₁₅, M₂₀ and M₃₀ (p < 0.001).

DISCUSSION

Locoregional anesthesia has gone through major advances in recent years. New drugs have been synthesized, and new ways to localize nerve trunks is placed in evidence and are already part of the clinical practice in order to improve procedure quality and decrease the necessary dosage in blockades. Such care does not completely prevent the occurrence of adverse effects and complications; thus, a more specific therapy for cases of large dose intravascular injections was investigated, such as lipid emulsions. Three mechanisms have been proposed to explain the effects of these agents. The first suggest the pharmacokinetic balance with the expansion stage of plasma lipid, reducing the plasma levels of lipophilic drug free fractions and therefore the toxicity. This effect is achieved by chelating LA molecules and is known as "lipid sink" in Anglo-Saxon literature ¹⁴. The second is based on the notion that local anesthetics are known to inhibit carnitine acetyltransferase, which is essential for transporting fatty acids into mitochondria ¹⁵, and LE could overcome this inhibition and the metabolic and toxic effect by "mass effect" alone or some other yet unknown mechanism. The third mechanism is based on the fact that fatty acids are known to increase the calcium levels of cardiac myocytes and thus may activate a direct inotropic route^14,16. The hypothesis that lipid emulsions with in vitro long-chain triglycerides would be more effective ¹⁵ motivated this study to evaluate the hemodynamic effects of ropivacaine-induced toxicity in swine. In our experiments, we observed no significant differences in blood pressure using LE with long-chain triglycerides and mixed with long- and medium-chain. Improvement in hemodynamic deterioration after intravenous injection was achieved mainly by increasing systemic and pulmonary vascular resistance in pigs treated with lipid emulsion, a result similar to that found by Stojiljkovic et al. ¹⁷, who studied the hemodynamic changes of lipid infusion in humans, but different from those found by Kearney et al. ¹⁸. In this study, increased resistance was seen mainly in the pulmonary circulation in which LE with medium-chain triglycerides was significantly superior to the emulsion with only long-chain triglycerides. There was no improvement in cardiac index, a result similar to that of Litonius et al. ¹⁹ in a study of pigs with bupivacaine- and mepivacaine-induced toxicity, but different from that found by Stehr et al., who reported a positive inotropic effect in a study of isolated rat hearts ²⁰.

In this study, lipid emulsions improved blood pressure after ropivacaine-induced toxicity, but emulsions with long-chain triglycerides and mixed with long- and medium-chain triglycerides had no significantly different outcomes. Still, much remains to be investigate about the use of lipid emulsions, but judging by the lack of adverse effects to date ²¹, expectations are encouraging and even recommended for accidents in case of obstetric anesthesia ²².

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Lipid therapy with two agents in ropivacaine-induced toxicity: Experimental study in swine

Matheus Rodrigues Bonfim^I; Marcos De Simone Melo^II; Elisabeth Dreyer^III; Luís Fernando Affini Borsoi^IV; Thales Gê de Oliveira^V; Artur Udelsmann, TSA^VI

Publication Dates

• Publication in this collection
  25 Sept 2012
• Date of issue
  Oct 2012

History

• Received
  09 Nov 2011
• Accepted
  09 Dec 2011