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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.56 no.4 Campinas Set./Aug. 2006
Toxicity of local anesthetics: The debate continues!
In the last 40 years we have won over some of the complications caused by local anesthetics. However, it seems that we are still far from solving them.
Recent reports on cardiac arrests secondary to the use of ropivacaine in peripheral blockade1,2, considered by many to be free of clinical cardiotoxicity, demonstrated that our concerns about the toxic effects of local anesthetics are still alive.
This Issue of the Rev Bras Anestesiol presents an experimental study3 in dogs that evaluates the cardiotoxicity of excess enantomeric bupivacaine (S75-R25) compared to racemic bupivacaine, showing that the former compound presents worse cardiac effects than the latter.
Ropivacaine was introduced in clinical practice in the beginning of the 1990s as a possible safe alternative to bupivacaine. In 19794 Albright published an editorial reporting informally 6 cases in which there were seizures and cardiovascular collapse almost simultaneously after the inadverted intravascular administration of bupivacaine. In most cases, the efforts to reverse the situation were unsuccessful, making it clear that, unlike lidocaine, this new local anesthetic presented plasma concentrations capable to induce seizures that were very close to the plasma concentrations necessary to induce cardiac arrest. Therefore, it presents a narrower safety margin. The cardiovascular collapse is secondary to severe ventricular arrhythmias that are not proportional to the potency of the drug when compared to other local anesthetics.
Since ropivacaine is composed basically of the levorotatory isomer, it was concluded that the cardiotoxicity was associated to the dextrorotatory isomer. That is when the development of levobupivacaine, a local anesthetic composed only of the levorotatory isomer of bupivacaine started. Comparing bupivacaine, ropivacaine and levobupivacaine, one can observe5 that bupivacaine has the greatest toxicity followed by levobupivacaine, and ropivacaine being the least toxic (Figure 1).
However, it was observed that the local anesthetics mentioned presented different potencies. Ropivacaine is less potent than bupivacaine6, while the potency of levobupivacaine is intermediary. In other words, what is the point of being less toxic and causing less clinical anesthesia if this means that a higher concentration of the drug must be used? Notwithstanding the features mentioned being true, racemic bupivacaine presents the greatest potential to develop severe ventricular arrhythmias with slow dissociation of the sodium channels during ventricular diastole7.
In the article published in this issue of the journal3, in theory the anesthetic with the greatest levorotatory component should present the least cardiotoxicity; however, it was observed that racemic bupivacaine presented less myocardial depression. It is also intriguing the behavior of the central venous pressure and pulmonary capillary pressure, which increased significantly with racemic bupivacaine when compared to excess enatomeric bupivacaine, despite of the fact that racemic bupivacaine causes less myocardial depression. Another fact that was not studied was the assessment of the cardiac rhythm. The intravascular administration of bupivacaine causes severe ventricular arrhythmias in doses greater than those necessary to cause seizures, which is usually the mechanism of the cardiovascular collapse.
Currently, it seems that the greatest risk of systemic toxicity with local anesthetics is not due to peridural anesthesia in general surgeries or in obstetrics. The peripheral blockades represent the majority of the cases of cardiac and neurological toxicity described2,3. The rational use of peridural anesthesia, taking into consideration the toxic doses, use of a test dose, use of a catheter to break down the doses, monitoring the cardiac rhythm during the blockade, attention to clinical signs of intoxication, and the standardization of maneuvers and training personnel on how to conduct resuscitation maneuvers, are responsible for a marked reduction in the toxicity reported.
In the field of obstetric anesthesia, besides the precautions mentioned above, we could add the fact that very small doses of local anesthetics at very slow infusion rates are used for labor analgesia. Concurrently, in the last 10 years, especially in Brazil, but also in other countries, anesthesia for cesareans has also changed. Nowadays, in most centers spinal anesthesia has become the technique of choice. The dose used varies from 10 to 15 mg of 0.5% hyperbaric bupivacaine, making it possible the use of intravenous administration with a very low probability of cardiac intoxication or seizures. In the hospital complex of Pró-Matre Paulista Santa Joana and in the Hospital das Clínicas da Universidade de São Paulo, almost 100% of the cesareans are done under spinal anesthesia.
In the peripheral blockades there seems to be a tendency to substitute the traditional bupivacaine by the local levorotatory local anesthetics. Ropivacaine, levobupivacaine, and currently enantomeric excess bupivacaine seem to be preferred over racemic bupivacaine. Nonetheless, cases of cardiovascular collapse and seizures after peripheral blockades with these drugs are still reported. It is obviously that we should look for the ideal drugs but we should not forget that the mechanism of blocking nervous conduction (reversible blockade of sodium channels), which is so useful in regional anesthesia, is also the mechanism that triggers the cardiotoxicity and seizures. In the peripheral blockades the use of new techniques to localize precisely the plexus and nerves, such as the peripheral nerve stimulator, which is a reality, and the ultrasound, currently being introduced for clinical use, should be used more frequently. The use of catheters that make it possible the fractioned administration of local anesthetics, despite the technical difficulties for its introduction, may also represent advancement. We should not forget that on peripheral blockades the nerves usually are located very close to veins and arteries and, even if the drug is not inadvertently administered intravenously, the systemic absorption may be fast, causing high plasma concentrations of the local anesthetics. The difference has always depended, and probably will always depend, on the person introducing the needle. We, anesthesiologists, cannot agree to be just excellent "blockade technicians", we should also possess current scientific knowledge and incorporate new technical resources to the daily clinical practice.
We should also consider the importance of critical analysis when reading scientific reports. A scientific work always presents some information. But it should be considered part of a whole in the search of global knowledge. The information presented in this issue of the journal is intriguing3. A local anesthetic whose formula presents a greater amount of the levorotatory isomer than the dextrorotatory one presented greater cardiac depression than the racemic mixture. However, such result cannot be analyzed mathematically. There are several interpretations to explain this fact and it should be reproduced in other species and with other methods to reach definitive conclusions.
Key Words: ANESTHETICS, Local: bupivacaine; enantiomeric excess mixture, levobupivacaine, ropivacaine; COMPLICATIONS: systemic toxicity.
Marcelo Luís Abramides Torres, TSA
Professor Doutor da Disciplina de Anestesiologia da FMUSP
Coordenador da equipe de Anestesiologia da Maternidade Pró-Matre Paulista
Presidente da LASRA
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