**2. Local anaesthetic toxicity: what factors affect the presentation of toxicity and management of toxicity**

Local anaesthetic toxicity can be observed at local tissue level and systemically. The systemic toxicity of local anaesthetic depends on plasma concentration which in itself is closely related to the dose and the site of injection. We, the authors, will first discuss local tissue toxicity and thereafter expand on the clinical manifestation of the systemic toxicity.

#### **2.1. Local tissue toxicity**

#### *2.1.1. Local anaesthetic-induced neurotoxicity*

Local anaesthetics exert a direct time and dose‐dependant toxicity on neurons and myocytes. The mere injection of local anaesthetics perineurally or intrathecally is a risk factor for perioperative nerve injury. Local anaesthetic‐induced nerve injury may occur at clinical concentration levels when accidentally injected intrafascicularly. In an experimental model, axonal degeneration has been noticed in such instances [5].

Some local anaesthetics are packaged in concentration much higher than used in clinical practice. Care should be taken to prepare a safe dilution to reduce the risk of nerve toxic‐ ity. The outer layer of connective tissue surrounding the nerve fibre, the perineurium, forms the 'blood‐nerve barrier' and protects the nerve from chemical injury. The correct dilution of local anaesthetics will ensure that the concentration in the perineural and intraneural milieu is within the therapeutic range, thereby avoiding neural damage. The use of adjuncts to increase the viscosity of the solution also has been associated with increased incidence of nerve injury. The use of hyperbaric solution in continuous spinal anaesthesia cases leads to the pooling of the solution in the caudal dural sac and prolongs the toxic effect on the nerve fibres (i.e. cauda equina syndrome) [6]. Transient neurologic syndrome after a single bolus of lignocaine for spinal anaesthesia has been reported as well, though with a good outcome in the short term [7]. Lignocaine seems more prone to cause local anaesthetic neurotoxicity than bupivacaine with risk of 6.5 as high as bupivacaine probably due to the former's lower pKa, and hence, more unionised drug crosses into the axoplasm [8].

#### *2.1.2. Incidence and risk factors*

only. It is a pure enantiomer and less cardiotoxic compared with racemic mixtures of other local anaesthetics. With respect to its better safety profile, ropivacaine has become a preferred long‐acting local anaesthetic for peripheral nerve block anaesthesia for many providers. The motor block sparing properties associated with ropivacaine spinal and epidural analgesia may provide an advantage over bupivacaine. Despite its safety profile, all standard precau‐ tions pertaining to use of local anaesthetics are encouraged as they have been incidences of

*Bupivacaine* exists as levo and dextro enantiomer. Its racemic form was introduced in 1963,

96%. The higher degree of protein binding makes bupivacaine the longest acting and most cardiotoxic local anaesthetic if inadvertently administered intravenously. It has been used successfully over the years since its introduction and has become the yardstick for all other long‐acting local anaesthetics. Interestingly, at low concentration, bupivacaine has the pro‐ pensity for sensory blocks while mildly sparing the motor blocks (differential sensitivity). This property allows for 'walking epidural' in labour analgesia. The maximum recommended dose is 2 mg/kg with or without adrenaline as there is only a modest increase in the duration of action when combined with a vasoconstrictor. It is three to four times more potent than

**2. Local anaesthetic toxicity: what factors affect the presentation of** 

thereafter expand on the clinical manifestation of the systemic toxicity.

Local anaesthetic toxicity can be observed at local tissue level and systemically. The systemic toxicity of local anaesthetic depends on plasma concentration which in itself is closely related to the dose and the site of injection. We, the authors, will first discuss local tissue toxicity and

Local anaesthetics exert a direct time and dose‐dependant toxicity on neurons and myocytes. The mere injection of local anaesthetics perineurally or intrathecally is a risk factor for perioperative nerve injury. Local anaesthetic‐induced nerve injury may occur at clinical concentration levels when accidentally injected intrafascicularly. In an experimental model, axonal degeneration has

Some local anaesthetics are packaged in concentration much higher than used in clinical practice. Care should be taken to prepare a safe dilution to reduce the risk of nerve toxic‐ ity. The outer layer of connective tissue surrounding the nerve fibre, the perineurium, forms the 'blood‐nerve barrier' and protects the nerve from chemical injury. The correct dilution of local anaesthetics will ensure that the concentration in the perineural and intraneural milieu is within the therapeutic range, thereby avoiding neural damage. The use of adjuncts to increase the viscosity of the solution also has been associated with increased incidence of nerve injury.

of 8.1 and a protein binding of

cardiovascular collapse reported with its use [4].

10 Current Topics in Anesthesiology

lidocaine, but the onset of action is much slower.

**toxicity and management of toxicity**

*2.1.1. Local anaesthetic-induced neurotoxicity*

been noticed in such instances [5].

**2.1. Local tissue toxicity**

while levobupivacaine was introduced in 1995. It has a p*K*<sup>a</sup>

The true incidence of local anaesthetic‐induced neurotoxicity is difficult to account for as there are many confounding risk factors in the perioperative period that can lead to nerve injury. Large prospective studies have shown that the overall incidence of neurologic compli‐ cation with peripheral nerve block technique is <3%. Most of these complications are transient sensory deficits [9, 10]. The risk factors pertaining to neurotoxicity will further be grouped as anaesthetic factors, surgical factors and patient factors.

#### **1. Anaesthetic factors**


#### **2. Surgical risk factors**

The use of tourniquet to reduce blood loss and provide favourable operative field causes compression of nerve fibre and tissue ischaemia which has synergetic effect as far as local anaesthetic neurotoxicity is concerned. Furthermore, the vasa nervo‐ rum is compressed by tourniquet use, and the washout of local anaesthetic is reduced, thereby prolonging the exposure of nerve fibre to local anaesthesia.

#### **3. Patient risk factors**


#### *2.1.3. Pathophysiology*

The mechanism of this neurotoxicity at a cellular level is not well elucidated. The postulated mechanisms involve the intrinsic caspase pathway, the phosphoinositide 3‐kinase (PI3K) pathway and the mitogen‐activated protein kinase (MAPK) pathway, but there is no consen‐

sus on what the predominant pathway may be [14, 15]. The interaction of the local anaesthetic and the voltage‐gated sodium channel (VGSC) and G‐coupled protein receptors is unlikely to be the pathophysiological pathway through which local anaesthetics exert their neuro‐ toxicity. A study using tetrodotoxin, another sodium channel blocker, does not support that hypothesis [16].

#### *2.1.4. Local anaesthetic-induced muscle toxicity*

Local anaesthetics cause muscle damage after intramuscular injection. The effect is more pro‐ nounced with potent and long‐acting local anaesthetic like bupivacaine. These effects on skeletal muscle are transient and with full recovery within 2 weeks.

The tissue toxicity may also be the result of preservative used to maintain stability of drug molecules in solution. Sodium bisulphite and ethylene glycol tetra acetic acid are thought to be the culprits for the neurotoxicity of chloroprocaine.

### **2.2. Systemic toxicity**

Systemic toxicity from local anaesthetics is closely related to the systemic concentration achieved either through excessive dose or inadvertent intravascular injection of local anaes‐ thetics. The cardiovascular system and central nervous system are the most affected systems, the latter being more sensitive than the former. This entails that the local anaesthetic blood concentration required to produce the toxic sign and symptoms is lower for the CNS than for the cardiovascular system (CVS). This translates in clinical practice as the appearance of signs and symptoms of CNS toxicity first, followed by those of the CVS. However, caution needs to be exercised here as when a patient is having a conscious sedation or a full general anaes‐ thetic, the CNS toxicity may be masked and the cardiotoxicity in the form of cardiovascular collapse may be the only manifestation of the local anaesthetic toxicity. The main risk factors for developing systemic toxicity are:


#### *2.2.1. Central nervous system toxicity*

The signs and symptoms of central nervous system toxicity are generally classified into two distinct phases, the excitatory phase and the depression phase, respectively.

#### *2.2.1.1. The excitatory phase*

sus on what the predominant pathway may be [14, 15]. The interaction of the local anaesthetic and the voltage‐gated sodium channel (VGSC) and G‐coupled protein receptors is unlikely to be the pathophysiological pathway through which local anaesthetics exert their neuro‐ toxicity. A study using tetrodotoxin, another sodium channel blocker, does not support that

Local anaesthetics cause muscle damage after intramuscular injection. The effect is more pro‐ nounced with potent and long‐acting local anaesthetic like bupivacaine. These effects on skeletal

The tissue toxicity may also be the result of preservative used to maintain stability of drug molecules in solution. Sodium bisulphite and ethylene glycol tetra acetic acid are thought to

Systemic toxicity from local anaesthetics is closely related to the systemic concentration achieved either through excessive dose or inadvertent intravascular injection of local anaes‐ thetics. The cardiovascular system and central nervous system are the most affected systems, the latter being more sensitive than the former. This entails that the local anaesthetic blood concentration required to produce the toxic sign and symptoms is lower for the CNS than for the cardiovascular system (CVS). This translates in clinical practice as the appearance of signs and symptoms of CNS toxicity first, followed by those of the CVS. However, caution needs to be exercised here as when a patient is having a conscious sedation or a full general anaes‐ thetic, the CNS toxicity may be masked and the cardiotoxicity in the form of cardiovascular collapse may be the only manifestation of the local anaesthetic toxicity. The main risk factors

The signs and symptoms of central nervous system toxicity are generally classified into two

distinct phases, the excitatory phase and the depression phase, respectively.

hypothesis [16].

12 Current Topics in Anesthesiology

**2.2. Systemic toxicity**

for developing systemic toxicity are:

*2.2.1. Central nervous system toxicity*

• ischaemic heart disease

• renal dysfunction

• pregnant women

• hepatic dysfunction

• pre‐existing heart conduction abnormality

*2.1.4. Local anaesthetic-induced muscle toxicity*

muscle are transient and with full recovery within 2 weeks.

be the culprits for the neurotoxicity of chloroprocaine.

• extremes of age (younger than 4 months or older than 79 years)

• injection at a highly vascular site (e.g. intercostal block).

The earliest symptom is usually the metallic taste, followed by circumoral numbness, light‐ headedness, dizziness, visual disturbances, disorientation, tinnitus and agitation. During this period, signs of toxicity include shivering, muscular twitching, tremor and generalised tonic‐ clonic convulsion. The generally accepted explanation for this sequence of events is that the inhibitory neurons are the first to be blocked by local anaesthetics leaving the activity of the excitatory neurons unopposed [17].

#### *2.2.1.2. The depression phase*

The muscle twitches and convulsion subsides, followed by respiratory depression and respira‐ tory arrest. The respiratory depression will lead to hypoventilation and raised plasma pCO2 and a state of respiratory acidosis which will potentiate the CNS toxicity of local anaesthetics [18]. The explanation for this increased CNS toxicity relies on the fact that raised plasma CO2 level increases its diffusion into the cell, therefore decreasing the intracellular pH. The acidic intra‐ cellular environment will favour the conversion of the unionised local anaesthetics to the ionised form, which will be unable to diffuse out of the cell leading to a phenomenon known as ion trapping. Decreased plasma binding of local anaesthetics [19] and increased cerebral blood flow contribute to the increased delivery of local anaesthetics to the brain, and this too increases the likelihood of CNS toxicity.

The clinician needs to be aware of these facts as they will influence the approach to manage‐ ment of the CNS toxicity of local anaesthetics.

#### *2.2.2. Cardiovascular system toxicity*

The effect of local anaesthetics on the cardiovascular system is direct and indirect. They affect the heart directly through the decrease in the rate of depolarisation of conducting cell and cardiomyocytes secondary to the block of voltage‐gated sodium channel. There is a decrease in the duration of action potential and refractory period [20, 21]. Various local anaesthetics have a different degree of disruption of the conduction of action potential through the heart. Bupivacaine depresses the conduction to a greater degree than ligno‐ caine. It produces cardiovascular toxicity at a lower concentration than that of lignocaine and has a worse outcome after cardiac resuscitation. However, ropivacaine and levobupi‐ vacaine, a pure S‐enantiomer of bupivacaine, do not share this tendency for greater cardiac toxicity [22].

A raised plasma level of local anaesthetics first prolongs the duration of conduction in the atrium and ventricle noticed on an electrocardiogram as PR interval prolongation and QRS complex widening. The spontaneous pacemaker activity is depressed at a higher plasma level resulting in bradycardia and sinus arrest successively. Ventricular arrhythmia occurs more often with bupivacaine than lignocaine, with an increased risk in pregnant patients. Apart from conduction disturbance, local anaesthetics also have a negative inotropic activity [23] on the heart through interference with sarcolemmal sodium and calcium channel activities [24].

Low concentration of local anaesthetics causes vasoconstriction, and higher concentration causes vasodilation with the exception of cocaine, which consistently produces vasoconstric‐ tion regardless of the concentration [21].

#### *2.2.3. Management of local anaesthetic toxicity*

The management of cardiovascular toxicity is based on sound understanding and imple‐ mentation of the basic principle of cardiopulmonary resuscitation [25]. The steps for effective management of CNS toxicity of local anaesthetics include:


#### **2.3. Methaemoglobinemia**

This is a complication associated with a specific local anaesthetic, namely prilocaine. Prilocaine is metabolised in the liver, and o‐toluidine is produced as a by‐product of this metabolism.

O‐toluidine is a strong oxidant that oxidises haemoglobin to methaemoglobin. Severe meth‐ aemoglobinemia can be treated effectively with an infusion of methylene blue [21].
