Lipids in local anesthetic toxicity

Abstracts

INTRODUÇÃO: Com o advento dos anestésicos locais de longa duração, a anestesia locorregional ganhou grande impulso sendo cada vez mais utilizada. Novas técnicas de bloqueios foram descritas e a técnica é frequentemente associada à anestesia geral com o objetivo de proporcionar analgesia pós-operatória. A contra-partida é a necessidade da utilização de grandes doses com risco de acidentes por injeção intravascular inadvertida; trata-se de complicação grave sem tratamento específico até há alguns anos. Em 1998 foi proposta a utilização de emulsões lipídicas em animais e a partir de 2006 vários trabalhos demonstraram o interesse dessas soluções nos casos de intoxicações por anestésicos locais com diminuição da morbi-mortalidade. O objetivo desta revisão foi fazer um levantamento da metodologia, revisando os mecanismos, interesses, limites e as condutas preconizadas atualmente. MÉTODO: Foram revistas algumas referências históricas sobre anestésicos locais, artigos publicados nos últimos 30 anos em revistas indexadas no Medline e em dois livros-texto. Foram selecionados os artigos que tratavam da intoxicação por anestésicos locais, da terapia com emulsões lipídicas, os de revisão sobre o assunto e as condutas adotadas em diversos serviços e países, sendo realizada uma síntese. CONCLUSÕES: A eficiência e interesse da terapia com emulsões lipídicas nas intoxicações por anestésicos locais não é mais a demonstrar; várias sociedades da especialidade já publicaram suas diretrizes e aconselham que se disponha desses produtos nos locais onde se pratica a anestesia locorregional.

Anestesia local; Toxicidade; Lipídeos

REVIEW ARTICLE

Lipids in local anesthetic toxicity

Artur Udelsmann; Elisabeth Dreyer; Marcos De Simone Melo; Matheus Rodrigues Bonfim; Luís Fernando Affini Borsoi; Thales Gê de Oliveira

Departament of Anesthesiology and Experimental Anesthesia Laboratory of Medical Sciences Faculty of Campinas State University - UNICAMP, Campinas, SP, Brazil

Correspondence

ABSTRACT

INTRODUCTION: With the advent of long-lasting local anesthetics, local and regional anesthesia gained considerable impetus and the use of these techniques has become increasingly widespread. New block techniques have been described and regional anesthesia is frequently associated with general anesthesia to provide postoperative analgesia. In contrast, large doses of local anesthetics are required with the risk of accidents due to inadvertent intravascular injection, which is a severe complication without a specific treatment until a few years ago. In 1998, the use of lipid emulsions was proposed in animals. Since 2006, many studies have demonstrated an interest in these solutions in cases of local anesthetic-induced toxicity with a decrease in morbidity and mortality. The aim of this review article was to research the methodology, reviewing mechanisms, interests, limitations and currently recommended treatment.

METHOD: Some historical references on local anesthetics, articles published during the last 30 years in journals indexed in Medline and in two textbooks were reviewed. Articles on local anesthetic toxicity, lipid emulsion therapy, review articles on the topic and treatment adopted in diverse services and countries were selected, producing a summary.

CONCLUSIONS: It is no longer necessary to show the effectiveness and interest in lipid emulsion therapy for local anesthetic toxicity. Various specialty societies have already published their guidelines and advice about stocking these products in any setting in which local and regional anesthetic techniques are practiced.

Headings: Anesthesia , local. Toxicity. Lipids.

INTRODUCTION

Local anesthetic toxicity has been recognized long before the introduction of cocaine in clinical practice. In 1868, a Peruvian physician named Moreno y Maiz in pursuit a doctorate degree in Paris described the first signs and symptoms of cocaine toxicity in an animal study²². This occurred 16 years before cocaine was used for the first time by Karl Köller in ophthalmic anesthesia in 1884¹⁴. Afterwards, the use of the local anesthetic was rapidly disseminated. In the following years, it began to be administered in nerve trunk injections, as well as in spinal and epidural blocks¹⁰. Reports describing cocaine toxicity rapidly appeared⁵ and included various deaths¹⁹. It soon became clear that it was necessary to synthesize less toxic drugs. A number of agents slowly emerged, e.g. synthetic procaine in 1905, tetracaine in 1930, lidocaine in 1944, chloroprocaine in 1955, mepivacaine in 1957, prilocaine in 1960 and bupivacaine in 1963. The discovery of the latter, which is the most frequently used local anesthetic to date, was a major step forward in local and regional anesthesia because of the quality of anesthesia provided and also its duration of action. As expected, descriptions of its adverse effects soon began to be reported. In 1979, Albright highlighted the severe toxic complications of bupivacaine and etidocaine in a seminal editorial of the journal Anesthesiology³. Since then, a number of cases of refractory cardiac arrest with seizures have been notified⁸. Initially, there were attempts to find agents with similar but less toxic characteristics. In 1996, ropivacaine emerged, followed by levobupivacaine²⁹ in 1999. Other authors were dedicated to find an antidote for local anesthetic toxicity. In 1998, Weinberg et al. demonstrated that lipid emulsions used in parenteral nutrition since 1961 were efficient in the combat of local anesthetic cardiotoxicity, increasing by 50% the mean lethal dose³¹. Rosenblatt et al. and later Litz et al. were the first authors to publish the successful use of lipid emulsions in the treatment of cardiac arrest due to local anesthetics, when conventional resuscitation had failed^16,25. Since then, successful cases of lipid emulsion use have been reported for management of these toxicity reactions^9,30. However, before acceptance by the medical community, new therapies must always meet certain requirements and overcome an initial reluctance until scientific and clinical evidence appears to confirm therapy efficiency. Lipid therapy in the reversal of local anesthetic toxicity, however, seems to be in accordance with the recommendations of the medical societies of Anesthesiology^1,18,23. It is worth mentioning that lipid emulsions have also been applied in Anesthesiology for a long time. As an example, propofol is a hypnotic used in routine practice for more than 25 years and its vehicle for solution is a lipid agent²¹!

Local Anesthetic toxicity

In case of local anesthetic toxicity, the attention of the physician should be focused mainly on the central nervous system and the cardiovascular system. In the brain, inhibiting pathways are the first to be suppressed and initially produce patient complaints such as a metallic taste in the mouth that may progress to seizures as concentrations of the anesthetic rise. When the excitatory pathways are also affected, apnea and coma occur. With the exception of bupivacaine, cardiovascular toxicity becomes evident after plasma levels have compromised the central nervous system. Cardiovascular toxicity is manifested by arrhythmias and refractory myocardial depression, especially when the agent used is bupivacaine²⁸. Toxic doses are capable of inhibiting sinoatrial and atrioventricular node conduction, prolonging the PR space, widening the QRS complex, generating atrioventricular blocks of varying degrees and arrhythmias, both bradycardias and reentrant tachyarrhythmias with ventricular tachycardia or fibrillation¹¹. Therapeutic activity and local anesthetic toxicity is attributed to Na+ channel block, although the flow of K+ and Ca++ is also altered. Bupivacaine is bound predominantly to open and inactive Na+ channels, which may justify the severity of toxicity. Myocardial depression occurs because of several factors: inhibition of Ca++ release in the sarcoplasmic reticulum by blockade of β-adrenergic receptors, decreasing adenylate cyclase activity by reducing the synthesis of cyclic adenosine monophosphate and the conversion of ADP into ATP²⁸.

Lipid therapy

Until recently, cardiopulmonary bypass was the only method known to be effective in the treatment of refractory cardiac arrest from local anesthetic overdose¹⁷. It is easy to imagine the difficulty encountered with this methodology in daily practice. Fortunately, nowadays the efficiency of lipid therapy in local anesthetic toxicity is no longer a questionable debate. The use and interest in these solutions, even in toxicity due to a number of other drugs have been demonstrated both in animals and in humans. Lipid emulsions have already been used in the treatment of toxicity due to cyclic antidepressants, verapamil, β-blockers, barbiturates among others⁷. Local anesthetics are hydrophobic molecules and their lipid solubility is related to potency and toxicity. The higher the lipid solubility of the agent, the easier it is transported through the cell membrane to reach its site of action. Three non-excluding hypothetical mechanisms of action of lipid emulsions have been proposed.

The first and most widely accepted mechanism is the creation of an expanded plasma lipid phase, into which local anesthetic molecules are sequestered. Lipophilic local anesthetic molecules are chelated, reducing the concentration of the free-base form of the local anesthetic, thus making local anesthetics unavailable to tissues and resulting in decreased toxicity. In the Anglo-Saxon literature this theory is termed 'lipid sink'. This schematic representation is based on three facts: the speed of functional recovery of the cardiac tissue after the use of lipid emulsion is important and consistent with a physical phenomenon. Local anesthetics are sequestered in vitro by lipids. Sequestration is greater with increasing lipid solubility. Finally, in an isolated heart preparation submitted to toxic concentrations of local anesthetics, lipids accelerate the elimination of these agents⁴.

The second mechanism is based upon the concept of inhibition of fatty acid transport at the inner mitochondrial membrane, particularly by bupivacaine. The hypothesis formulated is that lipid emulsions would counteract the reduction in the main source of myocardial energy⁴.

Finally, the third mechanism originates from evidence that lipid emulsions have a positive inotropic effect on the isolated heart and may reverse myocardial depression due to bupivacaine at lipid levels lower than those needed to reduce the aqueous bupivacaine concentration²⁶, occurring with increased levels of intracellular Ca++. Thus, physiologic, metabolic or inotropic pathways may all contribute to antagonize local anesthetic toxicity³².

Various lipid preparations are available in the market. With respect to the nature of the lipid source, these solutions differ greatly. The most widely used preparations are derived from soybean oil with long-chain triglycerides, soybean oil and coconut oil with medium-chain and long-chain triglycerides and those incorporating olive oil and fish oil. Each of these solutions is of specific interest to parenteral nutrition. According to some authors, emulsions based on long-chained triglycerides were shown to be 2.5 times more efficient in the treatment of local anesthetic toxicity²⁰, while others consider that their efficiency is equivalent⁶. Preparations that incorporate olive oil and fish oil are still less frequently used.

Limitations of lipid therapy

Experimental and clinical studies have demonstrated an unquestionable interest in lipid emulsions for the treatment of local anesthetic-induced toxicity. However, interference with other eventual drug treatments in patients must be considered. Although lipid emulsions are predicted to be slowly infused for nutrition, tolerance to large-dose and bolus administration should still be confirmed. Furthermore, recent studies have demonstrated that in the event of hypoxia lipid emulsions could have deleterious effects¹² and acidosis could reduce lipid affinity for local anesthetics²⁰. This may imply an interest in the early administration of these emulsions in cases of toxic accidents, before acidosis or hypoxia can limit their therapeutic effect.

Guidelines

Lipid emulsions may be infused into peripheral veins because these solutions have a low osmolarity (between 270 and 345 mOsm/l-1 in 20% solutions). In parenteral nutrition, the recommended dose is 0.7 to 1.3 g of triglycerides/kg-1/day. Triglyceride levels should be monitored. The infusion must be reduced if levels reach 400 mg/dl-1 and discontinued if levels of 1000 mg/dl-1 are obtained². Despite the respect for these recommendations, however, doses have been adapted for acute cases of severe local anesthetic toxicity. Currently, it seems unreasonable to wait until asystole develops to start to administer a bolus of lipid emulsion³². In 2007, the Association of Anaesthetists of Great Britain and Ireland published the guidelines currently accepted for the treatment of local anesthetic toxicity. These guidelines were rapidly followed by other specialty societies such as the American Society of Regional Anesthesia and Pain Medicine²³. The recommended guidelines are:

1. Secure the airway and maintain oxygenation.

2. Treat seizures with benzodiazepines.

3. Inject a 1.5 ml/kg-1 bolus of 20% lipid emulsion over 1 minute.

4. Start an infusion at a rate of 0.25 ml/kg-1/min of 20% lipid emulsion.

5. Repeat the bolus twice with 5-minute intervals, if adequate circulation is not restored.

6. After five more minutes, increase the infusion to 0.50 ml/kg-1/min.

7. Respect the superior dose limit recommended for 20% lipid emulsion, which is 10 ml/kg-1 over 30 minutes.

CONCLUSION

Local and regional anesthetic techniques are currently comfortable and safe procedures. However, they are not totally devoid of risks, even in capable hands. In the past few years, substantial progress has been made. Nevertheless, recent estimates still report a rate of 7.5 to 20 cases of local anesthetic toxicity per 10,000 peripheral blockades performed. Data also indicate that four out of 10,000 epidural blocks result in systemic local anesthetic toxicity¹⁸. Lipid emulsion therapy is no longer a matter of controversy because its benefit and low risk are evident. Lipid emulsions should always be stocked in any setting where patients receive large doses of local anesthetics as occurs in operating rooms¹⁵. Since surgeons frequently perform procedures with large doses of local anesthetics^24,27, it is wise for them to know these recommendations too.

REFERENCES

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Publication Dates

• Publication in this collection
  06 Feb 2013
• Date of issue
  Sept 2012

History

• Received
  13 Sept 2011
• Accepted
  20 Mar 2012