Management and treatment of local anaesthetic toxicity.
Abstract: Local anaesthetics have been used within surgical practice since the late 1800s, when the ophthalmologist Carl Koller discovered the tissue numbing properties of cocaine (Odedra & Lyons 2010). Since that time, the ongoing development of anaesthetic drugs has provided many different local anaesthetics (LA) to clinical practice. The techniques for using these drugs in surgical practice have also developed, shaping the modern practices we know today. Increasing numbers of surgical procedures are now carried out under LA that once necessitated general anaesthetic, for example carotid endarterectomy as first described by Eastcott et al (1954). This type of procedure can now be safely carried out under LA but does require a large volume of the drug (up to 25 mls, see Table 1 for variations) to infiltrate a very vascular surgical field, and the LA may need supplementing during surgery (Allman & Wilson 2006). The practice of routinely injecting large volumes of LA agents into surgical wounds to aid post-operative pain control also increases the risk of inadvertent intravascular injection that could lead to LA toxicity (Parker et al 2009).

KEYWORDS Local anaesthetic toxicity / Maximum dose / Lipid emulsion / Lipid rescue Provenance and Peer review: Unsolicited contribution; Peer Reviewed; Accepted for publication September 2011.
Article Type: Report
Subject: Anesthetics (Health aspects)
Anesthetics (Research)
Drugs (Health aspects)
Drugs (Research)
Author: Parry, Andrew
Pub Date: 12/01/2011
Publication: Name: Journal of Perioperative Practice Publisher: Association for Perioperative Practice Audience: Academic Format: Magazine/Journal Subject: Health; Health care industry Copyright: COPYRIGHT 2011 Association for Perioperative Practice ISSN: 1750-4589
Issue: Date: Dec, 2011 Source Volume: 21 Source Issue: 12
Topic: Event Code: 310 Science & research
Product: Product Code: 2834280 Anesthetic Preparations NAICS Code: 325412 Pharmaceutical Preparation Manufacturing SIC Code: 2834 Pharmaceutical preparations
Geographic: Geographic Scope: United Kingdom Geographic Code: 4EUUK United Kingdom
Accession Number: 274700154
Full Text: Local anaesthetic toxicity has a high mortality rate as the limited treatment options make resuscitation particularly difficult. A high dose of LA into the vasculature has a significant depressive effect on the central nervous (CNS) and cardiovascular system (CVS) (Williamson & Haines 2008). Despite LA toxicity being a rare event, it is essential that the theatre team possesses knowledge of the risks involved in LA administration, as all too often LA procedures are perceived to be low risk cases. The team should be able to identify the signs and symptoms of LA toxicity in order to act promptly, and should also be aware of current recommendations for managing this condition.

This article will discuss the pharmacodynamics and pharmacokinetics of LA in relation to nerve impulses. The effect that LA toxicity has on both the central nervous system and the cardiovascular system will be discussed, and will be linked to the universal approach of airway, breathing, circulation, disability and exposure (ABCDE) in managing the immediate needs of a patient experiencing LA toxicity. Finally, suggested treatment methods for LA toxicity based on published research, along with national recommendations will be examined.

In order to fully understand how LA agents work and the sequence of events leading to LA toxicity, it is essential that the normal physiology of an action potential is understood.

Physiology of an action potential

An action potential is simply a nerve impulse that travels down a nerve fibre in either the central or the peripheral nervous system (Figure 1).

This peripheral nervous system is divided into the autonomic and vasomotor branches. The autonomic system is responsible for control of involuntary body systems such as breathing and cardiac function, whereas the vasomotor system controls voluntary aspects such as speech and limb movements. Both these systems achieve this through propagation of action potentials down an axon (Figure 2).

In simple terms, an action potential originates in the axon hillock, and then travels along the axon eventually arriving at the axon terminals where it stimulates an action such as movement of a limb or the sensation of pain (Parsons & Preece 2010). In order for the action potential to travel along the axon there must be a negative charge in the axon cytoplasm and a positive charge in the extracellular space; this is called a resting membrane potential. The high concentration of positive sodium (Na) ions in the extracellular space provides a positive charge outside the axon, with potassium (K) ions contributing to this positive charge as they leave the axon via 'leak channels'. Meanwhile, large negatively charged proteins and phosphate ions inside the axon provide a negative intracellular charge, thus generating a resting membrane potential (Figure 3).



Action potentials travel along the axon through depolarisation of the resting membrane potential. This occurs via opening of membrane Na channels allowing a large number of Na ions to rapidly move into the axon and some potassium (K) ions to exit via K channels. This occurs along the axon at points called nodes of ranvier, located at gaps in the myelin sheath of peripheral nerves (Hall 2011). At these locations there are a large number of Na and K channels, allowing the action potential to travel down the axon by leaping from on node to the next. The myelin sheath is a lipid coating that coils around the axon, providing a form of insulation for the action potential allowing for rapid conduction of action potentials (Tortora & Derrickson 2011) (Figure 1).

Pharmacodynamics of local anaesthetics

LA agents generally work by diffusing into the axon through the axon membrane and block Na channels, keeping them in the closed state (Smith 2004). It is suggested that 75% of Na channels need to be inhibited for an effective block to be established in unmyelinated axons, while the blocking of three or more nodes of ranvier in myelinated axons will produce the desired block (Cox et al 2003). By preventing the movement of Na ions across the membrane, action potentials are unable to travel along the axon, thereby causing the numbing effect seen in clinical practice.

The duration of this block will depend on the properties of the agent used. Some will act quickly and have a short duration of action (e.g. lignocaine), while others will take effect rapidly and have a long duration of action (e.g. bupivacaine) (Columb & MacLennan 2007). Therefore, the type of LA drug selected for the case will depend on the length of action required to safely complete the surgical intervention.

It is important to note that the effectiveness of a LA agent is dependant on there being a physiological pH (normally ~7.4mmHg). States of acidosis will inhibit the action of LA, while alkalotic states enhance their actions (Rang et al 2007). This is of clinical importance as inflamed tissue usually has an acidotic chemistry which lowers the effectiveness of LA, and can be problematic if you are attempting to suture a wound or drain an abscess (Rang et al 2007).


Pharmacokinetics of local anaesthetics

As with any medicine, once the LA is injected the process of metabolising the drug will be instigated. Local anaesthetics are divided into two broad categories: the ester group which includes benzocaine and cocaine, and the amide group such as lignocaine and bupivacaine (Clark 2008). Following absorption into the vasculature, LAs in the ester group are metabolised via hydrolisation in the bloodstream by plasma esterases (Cox et al 2003). LA drugs in the amide group on the other hand are metabolised slowly in the liver, making them more likely to cause toxicity as the plasma levels may remain high for a longer period of time (Table 1) (Karch 2008). As you would expect, metabolism of the esterase and amide groups can be affected by perfusion and liver disease respectively, therefore a detailed pre-operative assessment is essential to ensure patient safety.

Patient factors such as pre-existing disease should be taken into account when assessing the dose of LA required, as maximum dose guidelines exist in order to minimise the risk of LA toxicity. The addition of a vasoconstrictor, such as adrenaline, can limit perfusion to the infiltration area. This reduces the rate of absorption into the vasculature, thus increasing the duration of action of LA agents by 30 to 50%, with the added benefit of reducing bleeding at the surgical site (Cox et al 2003). Pharmacokinetic factors associated with LA agents are summarised in Table 1.

Despite these recommendations, some patients will experience toxicity even if maximum doses are not exceeded. This can be due to the site of injection or the injection technique. Some areas of the body are highly vascular and may absorb the LA agent quicker than it can be metabolised, thus causing high plasma levels of LA. Increased risk of toxicity is associated with, in descending order, the intercostal space, epidural space, brachial plexus and subcutaneous layers (Odedra & Lyons 2010). Therefore LA infiltration into the intercostal space should be undertaken with caution, with continuous monitoring postinjection.

The injection technique should also be undertaken with consideration for the anatomical structures in the infiltration area (Maher et al 2008), as injecting into a highly vascular area may increase the risk of inadvertent intravascular injection that could result in toxicity. It is considered good practice to aspirate before commencing injecting the LA agent, only administering 5mls at a time before aspirating again to ensure that a vessel has not been inadvertently cannulated (Smith 2007).

If an LA agent is inadvertently injected into the vasculature or the absorbed dose exceeds the patient's ability to metabolise the drug, there is significant risk of LA toxicity. This situation requires rapid identification of signs and symptoms and emergency intervention.

Signs and symptoms of LA toxicity

Local anaesthetic toxicity has an adverse effect on both the central nervous system (CNS) and the cardiovascular system (CVS). The first effects will usually be seen on the CNS.

Effects of LA toxicity on the central nervous system

Commonly the effects of toxicity are first observed on the CNS, as the CNS is affected by lower levels of the drug (Cox et al 2003). The effects can manifest as a metallic taste in the patient's mouth, slurred speech, tingling lips, ringing in the ears, dizziness or light headedness, visual disturbances, limb tingling and muscle twitching (Clark 2008, Odedra & Lyons 2010, Cox et al 2003). These initial symptoms represent the excitatory stage of CNS toxicity as the LA blocks the Na channels in the inhibitory pathways of the CNS (Lullmann et al 2000).

As toxicity progresses, tonic-clonic convulsions will develop, leading to unconsciousness and apnoea (Allman et al 2009). This apnoea will result in hypoxia and myocardial ischemia, compromising cardiac function. In addition the hypercapnia (pCO2) that develops with periods of apnoea will result in acidosis, which in turn compromises myocardial contractility as hydrogen ions bind to calcium receptors on the actin-myosin mechanism within cardiac muscle fibres (Devlin 2011). However, the CVS compromise is not isolated to deficiencies in gas exchange during LA toxicity, as the myocardium is also directly affected by toxic levels of LA in the plasma.

Effects of LA toxicity on the cardiovascular system

High levels of LA in the blood will effect the CVS. The symptoms are profound hypotension due to systemic vasodilation and reduced cardiac output (CO), which result from the acidotic state caused by apnoea and compromised myocardial contractility by the LA (Cox et al 2003). Compensatory mechanisms are disabled as vasodilation would usually be compensated for by an increase in contractility, while a decrease in CO would result in vasoconstriction. However, the effects of the LA blocking the Na channels that would usually facilitate compensatory mechanisms to travel along the sympathetic nervous system, inhibits this compensation occurring. Furthermore, the blocking of Na channels within the cardiac conduction system results in delayed conductivity, evident as prolonged ECG intervals and bradychardia (Maher et al 2008). As the heart loses automaticity, supraventricular tachycardias, ventricular tachycardia and ventricular fibrillation will be observed, leading eventually to cardiac arrest (Cox et al 2003, Maher et al 2008, Allman et al 2009).

Treatment and recovery from this situation can be very difficult as more of the LA agent becomes positively charged by the high concentration of hydrogen ions (acidosis) in the myocardium, thus increasing the amount of active LA blocking Na channels and resulting in a vicious circle (Smith 2007). This means that prolonged resuscitation attempts must be undertaken, giving recommended antidotes such as lipid emulsion, while cardiac massage continues in order to circulate the drug in the hope that the toxic levels of LA can be reduced to allow cardiac conduction (Clark 2008, Odedra & Lyons 2010). The duration of resuscitation will vary according to the duration of action of the LA agent used (Table 1); lignocaine will dissociate more quickly from cardiac Na channels that bupivacaine would (Cox et al 2003).

It is worthy to make special note that pregnant women are at greater risk of toxicity due to hormonal changes which make tissue membranes more permeable (Cox et al 2003). The foetus adds a further dimension to the complexity of resuscitation, as the mother of greater than 20 weeks gestation must be positioned on a left lateral tilt to optimise circulation from the chest compressions which are required to circulate any lipid emulsion infusion (Resuscitation Council 2011). The need to consider the foetus also complicates the effort, as a decision has to be made whether or not to carry out a caesarean section to either facilitate resuscitation of the mother, or to save the foetus. The number of weeks gestation at the time of cardiac arrest will influence the options (Resuscitation Council 2011).

The ABCDE assessment and treatment method for LA toxicity

Whatever the stage of toxicity, a practical approach to care for patients experiencing LA toxicity is the ABCDE assessment and treatment method.


Airway compromise will occur as CNS effects ensue. It is recommended that airway equipment is readily available in areas administering LA agents, along with personnel skilled in its use (AAGBI 2010). As soon as a patient displays signs of airway compromise such as tingling lips, slurred speech or rapid loss of consciousness, endotracheal intubation should be considered. This requires the rapid and safe preparation of airway equipment and anaesthetic drugs. Furthermore the patient may require a rapid sequence induction depending on their fasting state, a procedure that requires specialist training and experience to be executed safely. Following intubation, the patient should be well oxygenated and ventilated to minimise hypoxia and hypercapnia, factors that will exacerbate the degree of toxicity (Smith 2007). Maintaining oxygenation will also reduce the likelihood of myocardial ischemia that would further compromise cardiac function (Katz 2011).


The initial CNS effects of toxicity will result in apnoea, therefore artificial ventilation is required to maintain oxygenation and normocapnia as hypercapnia will induce acidosis, compounding the effects of the LA (Maher et al 2008). If the event is a result of a low level toxicity it is feasible that cardiac arrest may not occur, as CVS effects require higher levels of toxicity. But even at low levels it is likely that CNS induced respiratory arrest will occur, until the levels of LA are reduced below toxic parameters. Therefore arrangements should be made to transfer the patient to a critical care unit for artificial ventilation and continuous monitoring (AAGBI 2010).


Due to the risk of toxicity to any patient receiving an LA agent, it is good practice to insert an intravenous cannula before a patient undergoes the procedure. This allows for rapid intravenous (IV) access should it be required (Maher et al 2008). Even a low level of toxicity that affects the CNS will result in myocardial depression if the patient's breathing is not supported. Respiratory acidosis and hypoxia will cause myocardial depression and ischemia respectively, compromising circulation. The profound effects on the CVS due to toxicity that require immediate treatment are vasodilatation and reduced myocardial contractility. Continuous monitoring should be instigated including: ECG, saturations, stat non-invasive blood pressure and capnography in the intubated patient. These measures will serve to guide treatment and indicate the patient's response to those treatments.

Rapid fluid bolus is required to support blood pressure (BP). Hartman's solution or normal saline could be given, but caution should be exercised in patients with known heart failure due to the risk of fluid overload causing pulmonary oedema (Resuscitation Council 2011). The state of vasodilation could be treated with the addition of a vasoconstrictor such as noradrenaline (Smith 2007). Research into antidotes for LA toxicity has been unable to conclusively recommend lipid emulsion as a rescue method (Cave et al 2011). However, in the face of limited alternative methods for treating this difficult situation, the AAGBI have issued guidelines on using lipid emulsion as a rescue method. These have been further endorsed by the Resuscitation Council (UK) (AAGBI 2010, Resuscitation Council 2011). The difficulty in conclusively demonstrating the benefits of lipid emulsion lies in the fact that researchers can only theorise about how it works (Toledo 2011), as human research would be implausible on ethical grounds. The main theory is that LA binds to lipid emulsion, reducing the amount of LA free in the plasma and available to inhibit Na channels, thereby reducing the toxic effect (Greensmith & Murray 2006).

Case reports of lipid emulsion having a positive effect on resuscitation efforts during LA toxicity (Foxall et al 2007, Rosenblatt et al 2006), have provided the basis for continued use and recommendation. Animal research into LA toxicity treatment is on-going, with one study on canine subjects conducted by Kim et al (2004) suggesting that insulin infusion may aid recovery from an LA toxicity event, possibly by increasing calcium activity in the myocardium.


The neurologic status of the patient must be closely monitored. The advent of seizures could be treated with a benzodiazepine (e.g. midazolam); these drugs are widely recognised in treating seizures (Karch 2008). Although the effects of the LA may cause paralysis, it would be good practice to regularly asses the patient using the Glasgow coma scale. Blood glucose should also be closely monitored as hypoglycaemia can cause neurological disturbances. Furthermore, if noradrenaline is used in treatment it can cause hyperglycaemia, a factor that has been shown to adversely affect recovery from critical illness. Recent research has indicated that glycaemic treatment should aim to maintain BM <10 mmol/ltr (Finfer et al 2009).


Although the patient would be unlikely to have external injuries, they should be assessed in case they have sustained an injury as a result of tonic-clonic seizures. Any violent convulsions may have caused them to flail against the hard structures of the patient trolley resulting in soft tissue injury. Intravenous cannulas that were sited prior to the LA being injected should be assessed for security and patency as the violent movement of a seizure could cause lines to become dislodged. It is therefore imperative that measures are taken to ensure that the patient does not sustain an injury during seizures. Simple steps such as using padded cot sides could achieve this aim.


LA agents mainly exert their effects by inhibiting Na channels along nerve axons. Each LA agent has a specific rate of onset and duration. While LA toxicity is a rare event, the recovery rate from these incidents is poor. The best approach to LA toxicity is prevention. This can be achieved by exercising a safe injection technique by aspirating before injecting and only administering 5 mls at a time. Observing maximum recommended doses and having an acute awareness of the vascularity of the area being infiltrated will also increase the safety margin.

The first indications of toxicity are usually associated with CNS effects; patients complain of mouth tingling and a metallic taste that may eventually lead to tonic-clonic seizures. Higher doses will exert toxicity on the CVS, and this will result in profound cardiovascular collapse that requires a prolonged resuscitation attempt. The most practical approach to a patient experiencing toxicity is the ABCDE assessment method, giving a logical systematic treatment path. Lipid emulsion has been recommended as the rescue method in this situation, although its precise action is unknown. Case reports and animal research indicate that it does work and has no known adverse effects on patients,however on-going research in this area may provide a different opinion.


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Andrew Parry

Dip Nursing, Cert Critical Care, Dip Intensive Care Nursing, BSc (Hons) Community Health Studies, De113 (Anaesthetics), PCGE

Senior Lecturer in Critical Care, University of Glamorgan

No competing interests declared

Correspondence address: Faculty of Health, Sport and Science, Lower Glyntaf Campus, University of Glamorgan, Pontypridd, CF371DL. Email:
Table 1 Pharmacokinetic profiles of local anaesthetics
Local                                             Max       recommended
anaesthetic                                   recommended    dose with
agent             Group   Onset    Duration      dose       adrenaline

Lignocaine        Amide   Rapid     Medium      3 mg/kg       6 mg/kg
Bupivacaine       Amide   Medium     Long       2 mg/kg       2 mg/kg
Levobupivacaine   Amide   Medium     Long       2 mg/kg       2 mg/kg
Ropivacaine       Amide   Medium     Long       3 mg/kg       3 mg/kg
Prilocaine        Amide   Rapid     Medium      6 mg/kg       8 mg/kg
Cocaine           Ester    Slow     Short     1.5-3 mg/kg       N/A

Adapted from Allman and Wilson (2006), Columb and MacLennan (2007),
Smith (2004).
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