4. Local Anaesthetics: Toxicity

Site of injection Drug dosage and concentration Vasoconstrictors Binding: Mechanisms of toxicity

ascularity of the anatomical site of injection and the presence locally of tissue such as fat, which may bind local anaesthetics. after intercostal and paracervical block, sacral extradural (caudal) block, lumbar and thoracic extradural block, brachial plexus block, sciatic and femoral nerve block and subcutaneous infiltration

not only the peak level but also the rate of rise that may contribute to local anaesthetic toxicity. total mass less important than its concentration lidocaine 3.0 mg kg−1, 7.0 mg kg−1 with adrenaline; bupivacaine 2.0 mg k convulsive activity supervenes when bupivacaine concentrations reach around 4 μg ml lidocaine levels reach 10–12 μgm

use of vasoconstrictors lowers the maximum blood concentrations but does not prolong the time to peak. There is also a complex interrelation with the inherent vasoactivity of local anaesthetics At very low concentrations all enhance vascular smooth muscle activity and cause vasoconstriction clinical doses they demonstrate vasodilator activity that is dose-dependent and which varies for each drug.

local anaesthetics bind mainly to α1-acid glycoprotein, which is a high affinity, low-capacity site and, to a lesser extent, to low-affinity, high-capacity sites on albumin. The binding decreases as pH decreases, and so toxicity is increased by hypoxia and acidosis. A decrease in intracellular pH will lead to increased ionization within the axoplasm and ion trapping. The convulsive threshold is inversely related to arterial PCO2

cardiovascular and CNS toxicities that may be seen are common to all local anaesthetic agents are predictable in light of the known mechanism of action of these drug Local anaesthetics work by stabilizing the axonal membrane, and will stabilize all excitable membranes, including those of skeletal, smooth and cardiac muscle Myocardial the block of Ca2+ channels in the myocardium Mg-adenosine triphosphate (Mg ATP) concentrations Inhibition of the carrier, carnitine acylcarnitine transferase which transports AcylCoA moieties utilization by myocyte mitochondria

complain of circumoral tingling and paraesthesia, light-headedness and dizziness. They may have visual and auditory disturbance manifested by difficulty in focusing and tinnitus. They may be disorientated. The objective signs are usually excitatory, with shivering, twitching, and tremors in the face and extremities preceding full grand mal convulsions Cardiac arrhythmias may be obvious on ECG monitoring, but these do not usually supervene until blood concentrations exceed by several times the convulsant levels.

the generic supportive ABC approach includes ventilation and inotropes as indicated

: if bupivacaine has been used, then resuscitation may be prolonged. Amiodarone (5 mg kg−1 in glucose 5% as the drug is incompatible with saline solutions) is the drug of choice for most induced arrhythmias, apart from ventricular fibrillation infusion of lipid emulsion. The effects of the intramyocardial inhibition of carnitine acylcarnitine transferase may be attenuated enhanced energy substrate for myocardial mitochondria lipid sink’ hypothesis which suggests that the lipophilic drugs are bound preferentially by the locally high concentration of intravascular lipid rather than to tissues

20%, 1.5 ml kg−1 stat over 1 minute, followed by an infusion at a rate of 15 ml kg–

BZD phenytoin (usually given in a starting dose of 15 mg kg−1) has a membrane-stabilizing local anaesthetic action. A better choice might be thiopental It is a very effective anticonvulsant which, in small bolus doses of 50 mg, should suppress a fit that has been induced by local anaesthetic toxicity, but if necessary can be given as an infusion of 1–3 mg

high blood levels may be attenuated by temporary sequestration of local anaesthetic within the lung. A high lung:blood partition coefficient encourages some uptake by the lung, and because the extravascular pH of lung is lower than that of plasma, this encourages ion trapping. Prilocaine is sequestered more effectively than bupivacaine, whose uptake in turn is greater than that of lidocaine.

genuine allergy to amides is extremely rare, but is commoner with esters. Allergic reactions are due mainly to para-aminobenzoic acid (PABA), which is a product of the metabolism of ester local anaesthetics such as procaine, benzocaine, chloroprocaine and amethocaine.

Lidocaine can be used as a primary treatment for ventricular arrhythmias. It decreases the maximum rate of depolarization but does not alter the resting membrane potential

Depolarization is related to sodium influx through fast channels calcium influx through slow channels slow channels are responsible for the spontaneous depolarization of the sinoatrial node (SAN).

Cardiac conduction slows with increasing blood levels, and this is manifest by an increased PR interval and duration of the QRS complex (ventricular depolarization). High doses depress SAN pacemaker activity, perhaps by inhibiting the slow calcium channels, and they also depress atrioventricular nodal conduction.

local anaesthetics exert a dose-dependent negatively inotropic action on the myocardium Bupivacaine is more dangerous than lidocaine in overdose by predisposing patients to arrhythmias and VF underlying mechanism for this effect is not known, but it appears to cause a unidirectional block with re-entrant tachyarrhythmias. The drug binds avidly to myocardial cells, and there is a decrease in the rate of depolarization and action potential duration, with subsequent conduction block and electrical inexcitability

: local anaesthetics will damage muscle into which they are injected directly. Skeletal muscle is a regenerating tissue, and so this is not usually a clinical problem, although persistent diplopia has been reported following the use of bupivacaine 0.75% concentrations for retrobulbar ophthalmic block.

toxicity: prilocaine is considered to be one of the safest local anaesthetics. Its use in high doses may lead to methaemoglobinaemia.