Local Anaesthetic Systemic Toxicity

• Lipophilic LA crosses cell membranes and causes adverse effects on a wide range of pathways, including ionotropic and metabotropic cell signalling and cell energy transduction
• The classical clinical features suggest mitochondrial metabolism as the most important pathophysiological target
• As both heart and brain are highly intolerant of anaerobic metabolism, depletion of tissue ATP by inhibition of oxidative phosphorylation is felt to be the underlying mechanism
• Also explains why traditional haemodynamic management steps are only partially effective


• Within the brain, there may be altered balance of inhibitory and excitatory neuronal pathways i.e. excessively suppressed inhibitory pathways, leading to seizures
• Within the myocardium there is:
• Conduction block effects on sodium, but also potassium and calcium channels
• Reduced contractility via effect on metabotropic receptors and consequent reduced cAMP concentration
• Inhibition of translocase system on the mitochondrial membrane, preventing oxidation of fatty acids

• Toxicity relates to the peak free plasma concentration

• Paediatric patients
• Neonates and infants have reduced alpha1 acid glycoprotein levels (at birth 50% of adult levels)
• Increased elimination half-life (2-3x vs. adults)
• Elderly patients due to lower clearance, age-related alterations to LA pharmacokinetics/dynamics and accumulated comorbidities
• Pregnant patients
• Lower ɑ₁-acid glycoprotein levels
• Accelerated perfusion of sites due to raised CO leads to higher peak free LA concentration
• Increased vascularity of epidural space leads to more rapid absorption of LA


• Renal failure
• Have lower LA clearance yet increased ɑ₁-acid glycoprotein levels
• Dose reductions of 10 - 20% are recommended
• Liver failure
• Have reduced LA clearance
• Fortunately ɑ₁-acid glycoprotein levels is still synthesised even in end-stage liver disease
• Cardiac failure
• Increased susceptibility to myocardial depression and arrhythmias
• Conversely, poor perfusion at the injection site may reduce peak plasma LA concentrations and therefore risk of toxicity


• Any patient with:
• Acidosis
• Reduced ɑ₁-acid glycoprotein levels
• Reduced clearance

• Excessive dose
Drug	'Safe' dose
Lidocaine	3mg/kg 7mg/kg with adrenaline 9mg/kg for airway topicalisation
(Levo-)bupivacaine	2mg/kg regardless of adrenaline
Ropivacaine	3mg/kg regardless of adrenaline
Prilocaine	6mg/kg 8mg/kg with adrenaline



• Some suggest that the quoted safe doses are irrational as they do not correlate to the resulting plasma level of LA, do not account for individual patient factors and are not robustly evidence-based


• Choice of agent
• Bupivacaine more cardiotoxic than levo-bupivacaine and possibly ropivacaine
• The ratio of the dose required to produce cardiovascular collapse (CC) to the dose required to induces seizures (CNS) leads to the CC:CNS ratio
• Drugs with a lower ratio progress more readily from cardiovascular collapse to CNS features
• Bupivacaine has a CC/CNS ratio of 2
• Lidocaine has a CC/CNS ratio of 7.1


• Administration-related
• Site at increased risk of direct vascular injection - interscalene, stellate ganglion
• Site at increased risk of rapid vascular absorption - scalp, pleural, intercostal
• Continuous administration i.e. catheter-based techniques
• Wrong-site administration e.g. IV rather than epidural or other accidental intravascular injection; somewhat mitigated by advent of NR Fit systems

• Clinical features depend on the plasma concentration of LA
• Approximately half of the cases occur within 10mins of completion of LA administration
• Although a CNS prodrome is classically described, it mayn't occur and up to a quarter of patients have isolated cardiovascular effects

• Local anaesthetics penetrate the brain rapidly and have a biphasic effect:

1. Excitatory phenomenon due to blocking of inhibitory neurones
• 2 - 4μg/ml: peri-oral tingling, tinnitus, tongue numbness, light-headedness, slurred speech
• 5 - 10μg/ml: visual disturbance, agitation, tremors, generalised seizures


2. Depressant phenomenon (i.e. apnoea and coma) due to blocking of all central neurones typically occurs above 10μg/ml

• Plasma concentrations of >15μg/ml can lead to:
• Initial hypertension and tachycardia
• Followed by myocardioal depression and hypotension
• Terminal phase includes cardiovascular collapse due to profound vasodilation and malignant arrhythmias e.g. heart block, VT/VF, asystole

Local anaesthetic systemic toxicity is an anaesthetic emergency and I would seek senior anaesthetic support as well as making a rapid but thorough assessment of the patient

• The initial step, if relevant, should be to stop injecting or infusing the local anaesthetic, followed by an ABCDE approach

1. Maintain and, if necessary, secure the airway with endotracheal intubation


2. Apply 100% oxygen and ensure adequate ventilation
• Consider hyperventilating to low-normal PCO₂ as the alkalosis can increase protein binding of the LA


3. Establish IV access
• Manage hypotension with fluids and vasopressors
• Consider arterial line insertion
• Manage dysrhythmia as per standard ALS algorithms, although should avoid lidocaine (obviously) and negatively inotropic agents e.g. beta blockers, calcium channel blockers
• Manage cardiac arrest as per the ALS algorithm
• Acknowledge arrhythmias may be refractory and require prolonged resuscitation for >1hr
• Consider lower-than-normal doses of adrenaline (≤1μg/kg) as the full 1mg dose may exacerbate arrhythmia and impair lipid-based resuscitation
• Avoid vasopressin as associated with worse outcomes in animal studies of LAST


4. Control seizures using preferably benzodiazepines, or if necessary small, incremental doses of propofol
• Propofol benefits from being readily available and familiar, although may exacerbate hypotension
• The fact it is a lipid is irrelevant, as to achieve sufficient lipid doses with propofol would cause overdose


5. Administer intralipid (see below) - should be administered early as it can attenuate progression of toxicity

• A 20% lipid emulsion of soya oil, glycerol and egg phospholipid emulsion for intravenous use


• Dosing
• Administer a bolus of 1.5ml/kg of 20% intralipid over 2-3 minutes (e.g. for 70kg patient administer 105ml)
• Start an infusion of 15ml/kg/hr of 20% intralipid over 20mins (e.g. for 70kg patient administer 1050ml/hr infusion)
• Repeat bolus doses up to two more times (at the 5 minute and 10 minute marks) if inadequate circulation not restored
• At the 15 minute mark, if circulation not restored, increase the rate of infusion to 30ml/kg/hr
• Maximum cumulative dose 12ml/kg i.e. for 70kg patient maximum dose is 840ml


• Mechanisms of action
• 'Lipid sink' i.e. expands the intravascular lipid compartment, partitioning positively charged LA off receptor sites and onto the negatively charged lipid particles
• Reduced context-sensitive half-life of plasma LA
• Enhanced fatty acid metabolism i.e. provides a source of myocardial fatty acids for metabolism to ATP
• Competes with LA i.e. fatty acids within the lipid emulsion inhibit LA binding to cardiac sodium channels
• Cytoprotection - activates protein kinase B, which is important in cell survival and proliferation
• Positive inotropic (perhaps via increased intracellular calcium) and lusitropic effects
• Reduced ischaemia-perfusion injury
• Reduced nitric oxide-mediated vasodilation

• Fulfil duty of candour - inform the patient of the events
• Exclude pancreatitis by regular clinical review including daily amylase/lipase for two days
• Ensure medical documentation is complete
• Fill out hospital critical incident form
• Report the case to the National Patient Safety Agency (NPSA)
• Ensure store of intralipid is restored