Hemodynamic changes with two lipid emulsions for treatment of bupivacaine toxicity in swines 1

PURPOSE: To compare the hemodynamic changes following two different lipid emulsion therapies after bupivacaine intoxication in swines. METHODS: Large White pigs were anesthetized with thiopental, tracheal intubation performed and mechanical ventilation instituted. Hemodynamic variables were recorded with invasive pressure monitoring and pulmonary artery catheterization (Swan-Ganz catheter). After a 30-minute resting period, 5 mg.kg-1 of bupivacaine by intravenous injection was administered and new hemodynamic measures were performed 1 minute later; the animals were than randomly divided into three groups and received 4 ml.kg-1 of one of the two different lipid emulsion with standard long-chaim triglyceride, or mixture of long and medium-chain triglyceride, or saline solution. Hemodynamic changes were then re-evaluated at 5, 10, 15, 20 and 30 minutes. RESULTS: Bupivacaine intoxication caused fall in arterial blood pressure, cardiac index, ventricular systolic work index mainly and no important changes in vascular resistances. Both emulsion improved arterial blood pressure mainly increasing vascular resistance since the cardiac index had no significant improvement. On the systemic circulation the hemodynamic results were similar with both lipid emulsions. CONCLUSION: Both lipid emulsions were efficient and similar options to reverse hypotension in cases of bupivacaine toxicity.


Introduction
Local anesthetics (LA) are drugs commonly used in medical practice. Despite major advances in pharmaceutical products and regional anesthesia techniques, adverse effects such as overdose from intravascular injection still occur.
Although local anesthetic overdose is uncommon, severe toxicity is estimated at 0.075 to 0.2% in peripheral nerve blocks and approximately 0.04% in epidural anesthesia 1  Manifestations of neurologic toxicity include tinnitus, metallic taste, visual disturbances, perioral numbness, unconsciousness, seizures and coma. Cardiac toxicity is characterized by decreased ventricular contractility, loss of vasomotor tonus, cardiovascular collapse, dysrhythmia and asystole 5 . In an attempt to decrease these complications, safety measures such as aspiration before local anesthetic injection, use of a test dose and epinephrine have been adopted 6 . In a review article from 1995, Brown et al. 7 reported that the incidence of complications was 1.2 per 10,000 epidural anesthesias, obtaining a result similar to that found by Auroy et al. 8 in France. Other longacting local anesthetics expected to be safer alternatives, e.g. ropivacaine and levobupivacaine were synthesized and launched on the market 9 . Weinberg et al. 10 demonstrated that lipid emulsions (LE) used in parenteral nutrition were efficient to decrease local anesthetic cardiotoxicity, increasing the mean lethal bupivacaine dose by 50% in rats. Rosenblatt et al. 11 and subsequently Litz et al. 12 were the first authors to publish the successful use of LE for treatment of cardiac arrest due to local anesthetic toxicity in human. Since that time, the successful use of LE in the management of local anesthetic toxicity has been reported 13,14 . Several lipid preparations are available in the market and have been used in-vivo and in-vitro experiments. The source of lipids is the most significant difference between these preparations. Solutions derived from soybean oil, containing long-chain triglycerides (LCT), emulsions based on coconut oil and soybean oil (MCT) containing 50% medium-chain and 50% long-chain triglycerides, and more recently solutions that also incorporate olive oil and fish oil 15 are currently the most widely used preparations. Each solution is of particular interest to parenteral nutrition, although results are controversial in the management of local anesthetic toxicity. According to some authors, LCT lipid emulsions is more effective 16,17 . Others believe that LCT is as efficient as MCT 18 . Still other authors have found better results with MCT emulsions 19 . Lipid emulsions have also been recently used in the treatment of toxicity due to several other lipophilic drugs such as cyclic antidepressants, verapamil, β-blockers and barbiturates among others 20 . The aim of this study was to evaluate the hemodynamic results produced by management of bupivacaine toxicity in swines, using two different lipid emulsions in our setting that contain different types of triglycerides, in comparison to saline use.

The protocol was approved by the Institutional Animal
Research Ethics Committee, State University of Campinas under number 2157-1.
Thirty pigs, weighing from 19.5 to 25 kg were fasted on the night before the experiment, with free access to water.
On the morning of the study, animal weight was recorded, with estimation of body surface area 21  and respiratory rate adequate to achieve P ET CO 2 between 32 and 34 mmHg. Hemoglobin saturation was maintained >97% and measured by a probe placed on the animal tongue. A cardioscope was also used in a lead similar to DII. Maintenance of anesthesia was performed with isoflurane in O 2 at an expired fraction of 1%. Local anesthesia was applied to the inner thigh of the animal unilaterally, using 5 ml of 1% lidocaine without vasopressor for dissection of the femoral artery and vein.
Dissection was required for continuous monitoring of arterial blood pressure and insertion of a Swan-Ganz 7F catheter, which was located in a pulmonary artery branch identified by the morphology of the pressure curve obtained. Thirty minutes after a stabilization and resting period, the first baseline

Results
There were no significant differences between groups regarding weight, body surface area, or baseline hemodynamic parameters, as shown in Table 1.
Heart rate (HR) Figure 2 shows that after bupivacaine injection in   In the LCT group, values were higher than T 0 until T 20 (p<0.001).
There were no differences between LCT and MCT. However, CTRL<LCT in T 5 and CTRL<MCT from T 5 to T 15 (p=0.023).

Mean pulmonary artery blood pressure (MPAP)
As shown in Figure      between LCT and MCT. However, CTRL<LCT from T 5 to T 15 and CTRL<MCT in T 5 and T 10 (p=0.017).    The third mechanism is based on the known fact that fatty acids can increase calcium levels in cardiac myocytes and may thus activate a direct inotropic route 22,24 27 investigating bupivacaine and mepivacaine toxicity in pigs. However, these findings differed from results described by Stehr et al. 28 who reported a positive inotropic effect on the isolated rat heart. In this study, arterial blood pressure improved with lipid emulsions after toxicity, but solutions with long-chain triglycerides and those with a mixture of medium-chain and longchain triglycerides did not achieve different results of interest.
The use of lipid emulsions needs to be further investigated.
However, the lack of adverse effects until recently 29 has been encouraging and these solutions are even recommended in case of accidents during obstetric anesthesia 30 .

Conclusions
Lipid emulsions with long-chain or a combination of long-chain and medium-chain triglycerides have proven to be efficient at reversing hypotension due to bupivacaine toxicity in pigs. It has been suggested that the early use of lipid emulsions may help to attenuate local anesthetic cardiotoxicity. Nevertheless, no significant differences were observed when either solution was used.