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Local Anaesthetics

Calgary- Local anaesthetics complications

Calgary- Local anaesthetics

Classification & Structure

Class	Examples (UK formulations)	Key metabolic pathway	†Max dose mg kg⁻¹ (plain / with adrenaline)	Relative cardiotoxicity*	Duration
Esters	Chloroprocaine, Tetracaine, Cocaine	Plasma pseudo-cholinesterase → PABA	12 /—	Low	Short-acting
Amides	Lidocaine, Prilocaine, Mepivacaine	Hepatic CYP-mediation	4.5 / 7 (lido)	Low	Short–intermediate
Amides	Ropivacaine (S-isomer), Levobupivacaine (S-isomer)	Hepatic CYP-mediated	3 / 3 (ropi)	Medium	Long-acting
Amides	Bupivacaine (racemic)	Hepatic CYP-mediated	2 / 2	High	Long-acting

• †Adults with normal physiology; reduce by ≥20 % in neonates, pregnancy, low albumin, severe heart, liver or renal disease.
• *Cardiotoxicity: Bupivacaine > Levobupivacaine ≥ Ropivacaine > Lidocaine.

Molecular Structure

• Aromatic ring (lipophilic), intermediate ester/amide linkage, tertiary amine (hydrophilic).
• Drug pKₐ 7.6–8.9 ⇒ in vivo (pH 7.4) ≈ 25 % un-ionised for lidocaine (pKₐ 7.8) but < 5 % for bupivacaine (pKₐ 8.1).
• Un-ionised base crosses axolemma; ionised form blocks the intracellular voltage-gated Na⁺ channel (state and use-dependent).

Addition of a Vasoconstrictor (e.g., Epinephrine)

• Local vasoconstriction at the site of anesthetic infiltration.
  • Decreases systemic absorption of the anesthetic.
  • Increases anesthesia duration.
  • Decreases bleeding at the site of infiltration.
  • Larger amounts of local anesthetic can be safely administered.

pH Adjustment

• Increasing pH of injected solution (e.g., adding sodium bicarbonate).
  • Decreases pKa of local anesthetic.
  • Increases unprotonated form of local anesthetic.
  • Increases uptake of anesthetic into neurons.
  • Shortens onset time.

Local Infiltration

• Diffusion of the drug into tissue.
  • When the tertiary amine of the anesthetic is unprotonated, it is lipophilic and can diffuse across nerve cell lipid membranes.
  • Anesthetic molecule becomes protonated within the neuron.
  • Protonated anesthetic binds to the transmembrane sodium channel.
  • Sodium channels become impermeable to sodium ions, preventing movement across the membrane.
  • Decreases nociceptive neuronal depolarization.
  • Decreases pain sensation.

Structural Traits

• Aliphatic side chains and lipophilic linkages.
  • High molecular weight.
  • High lipophilicity.
  • Increases anesthetic diffusion through nerve sheaths.
  • Increases anesthetic potency.

Differential Nerve Blockade

• Anesthetics’ effect differs based on neuronal features.
  • Small diameter neurons (e.g., unmyelinated nociceptive neurons) have fewer sodium channels for anesthetic to inhibit, thus blocking pain sensation more quickly than motor function.
  • Unmyelinated neurons allow anesthetic to diffuse freely anywhere along the neuron.

Pharmacodynamics & Differential Blockade

Order of block	Fibre type	Function	Clinical correlate
1	B, A-δ	Preganglionic, pain/temperature	Sympathectomy → warm skin, analgesia
2	A-γ	Muscle spindle	↓ Reflexes
3	A-β	Touch/pressure	Loss of light touch
4	A-α	Motor	Motor weakness/paralysis

• Factors delaying onset / reducing potency: acidic/infected tissue (↓ pH → more ionised drug), high pKa, low lipid solubility, large nerve diameter, myelin thickness.

Adjuvants

• Adrenaline 1:200 000–vasoconstriction ↓ systemic uptake (2–3× LA duration), marker of intravascular injection (HR ↑ >20 bpm).
• Bicarbonate 1 mL 8.4 % per 10 mL lidocaine–↑ un-ionised fraction, onset ↓ ≈ 30 %.
• Dexamethasone 4 mg (peripheral blocks)–prolongs analgesia 6–10 h via anti-inflammatory/neuronal K-channel modulation.

Comparative Profile – Bupivacaine Vs Ropivacaine Vs Levobupivacaine

Property	Bupivacaine	Levobupivacaine	Ropivacaine
Enantiomer	Racemate	S-(-)	S-(-)
Lipid solubility	Highest	Intermediate	Lower
Potency	1.0	0.9	0.8
Motor block	Dense	Moderate	Mild
Vasomotor effect	Vasodilatory	Neutral	Mild vasoconstriction (≤0.2 %, spinal cord BF ↓)
Cardiac Na⁺ channel affinity	High, slow unbinding → increased re-entry risk	20 % lower	40 % lower
Clinical use	Dense neuraxial, PNB	PNB, epidural labour	Labour analgesia, ambulatory PNB
Evidence highlights	Higher arrest-to-seizure ratio	Similar block duration but ↓ motor (meta-analysis 2025)	Equi-analgesic but safer haemodynamic profile (BMC Anaesth 2024)

Local Anaesthetic Systemic Toxicity (LAST)

• Incidence ≈ 1:10 000 peripheral nerve blocks; ↓ 65 % with real-time ultrasound guidance

Pathophysiology

• Central nervous system Rapid Na⁺-channel blockade in inhibitory cortical pathways → unopposed excitation (tinnitus, circumoral numbness, agitation) followed by global depression and seizures.
• Cardiovascular system
  • Direct: myocardial Na⁺, Ca²⁺ and K⁺-channel blockade → slowed conduction (PR/QRS prolongation), negative inotropy, arrhythmias.
  • Mitochondrial dysfunction: inhibition of oxidative phosphorylation and fatty-acid transport (especially with bupivacaine) ↓ ATP reserve.
  • Peripheral: biphasic vascular tone–initial vasoconstriction (low dose) then vasodilatation (high dose) contributing to hypotension.

Risk Factors

• Extremes of age, pregnancy, sepsis, low albumin, β-blockade, cardiac disease, renal/hepatic failure.
• Large volume, high concentration, multiple agents, intravascular injection, rapid absorption sites (intercostal, caudal, epidural).

Recognition (prodrome → Major toxicity)

• Tinnitus → perioral paraesthesia → metallic taste → agitation → seizure → coma; then CVS collapse (PR/QRS prolongation, VT/VF, asystole, profound vasodilatation).

Immediate Management (ASRA 2020 / AAGBI QRH 2023)

1. Stop LA; call for help.
2. Airway & Breathing: 100 % O₂, intubate early, hyperventilate (alkalinisation).
3. Circulation:
   • Seizures: midazolam 0.05 mg kg⁻¹ IV; avoid large propofol bolus.
   • Epinephrine ≤ 1 µg kg⁻¹ boluses
   • Avoid vasopressin, Ca-channel & β-blockers.
4. 20 % Lipid Emulsion
   • Bolus 1.5 mL kg⁻¹ over 1 min → infusion 0.25 mL kg⁻¹ min⁻¹.
     • 15ml/kg/hour (1000ml/hour)
   • Re-bolus ×2 if instability persists; increase infusion to 0.5 mL kg⁻¹ min⁻¹.
     • Double to 30ml/kg/hour
   • Upper limit 12 mL kg⁻¹ in 30 min
     • 70kg (840ml)
5. Refractory arrest: consider ECMO / cardiopulmonary bypass (notify early).
6. Post-event: minimum 12 h monitored care; assay LA level if available.

Vasopressin is avoided because it markedly increases pulmonary vascular resistance and myocardial oxygen demand without improving coronary perfusion, which can worsen the refractory cardiac arrest typical of LAST. Calcium-channel antagonists and β-blockers are also contraindicated as they compound the local anaesthetic–induced depression of myocardial contractility and conduction, risking intractable hypotension, bradyarrhythmias and cardiac arrest.

Prevention

• Calculate cumulative dose; use fractional, incremental injections with aspiration every 5 mL.
• Prefer ultrasound guidance for PNB; document negative test dose (e.g., 15 µg adrenaline epidural).
• Stock dedicated LAST kit with 20 % lipid–mandated in SASA procedural sedation standard (2019)

Mechanisms of Lipid Emulsion Rescue

• Lipid sink / shuttle–Intravenous lipid creates an expanded intravascular lipid phase attracting lipophilic LA molecules, reducing free drug concentration at cardiac and neural tissue.
• Metabolic substrate–Provides fatty acids that bypass LA-induced inhibition of carnitine-acylcarnitine translocase, restoring myocardial ATP production.
• Inotropic effect–Increases intracellular Ca²⁺ via activation of voltage-dependent Ca²⁺ channels and improves stroke volume.
• Membrane stabilisation–Counteracts LA-induced Na⁺-channel blockade by altering membrane fluidity and channel conformation.

Links

• Neuraxial and Epidural
• Upper limb blocks
• Lower limb blocks
• Ortho regionals
• Pharmacology summaries

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References:

1. Weinberg GL, et al. Checklist for treatment of local anaesthetic systemic toxicity. ASRA Pain Med 2020. Available from: https://www.asra.com asra.com
2. Association of Anaesthetists. Quick Reference Handbook–Local anaesthetic toxicity (page 3-10). London; 2023. Available from: https://anaesthetists.org anaesthetists.org
3. Iowa Protocols. Maximum recommended doses and duration of local anaesthetics. Univ Iowa Health 2024. Available from: https://medicine.uiowa.edu medicine.uiowa.edu
4. StatPearls. Local anaesthetic toxicity. Treasure Island (FL): StatPearls Publishing; 2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499964/ ncbi.nlm.nih.gov
5. Nouette-Gaulain K, Capdevila X, Robin F, Beloeil H. Intravenous lipid emulsion and local anaesthetic-induced systemic toxicity: mechanisms and limits. Ann Fr Anesth Reanim 2014;33:411-7. Available from: https://pubmed.ncbi.nlm.nih.gov/24951487/
6. Guler M, et al. Intravenous lipid emulsion in LAST–Review. Eurasian J Med 2024;56:205-12. Available from: https://pubmed.ncbi.nlm.nih.gov/37907541/ ncbi.nlm.nih.gov
7. Taha AA, et al. Levobupivacaine vs ropivacaine for brachial plexus block: systematic review & meta-analysis. Pain Pract 2025;25:xxx-xxx. Available from: https://pubmed.ncbi.nlm.nih.gov/ pmc.ncbi.nlm.nih.gov
8. Maharaj R, et al. Awareness of LAST among South African registrars. SAJAA 2023;29:15-22. Available from: https://www.sajaa.co.za sajaa.co.za
9. SASA. Guidelines for safe procedural sedation and analgesia for diagnostic and therapeutic procedures in adults. SAJAA 2019;25(Suppl):S1-S42. Available from: https://www.sajaa.co.za sajaa.co.za
10. Neal JM, et al. Ultrasound guidance and the risk of local anaesthetic systemic toxicity. Reg Anesth Pain Med 2022;47:428-35. Available from: https://pubmed.ncbi.nlm.nih.gov/
11. The Calgary Guide to Understanding Disease. (2024). Retrieved June 5, 2024, from https://calgaryguide.ucalgary.ca/
12. FRCA Mind Maps. (2024). Retrieved June 5, 2024, from https://www.frcamindmaps.org/
13. Anesthesia Considerations. (2024). Retrieved June 5, 2024, from https://www.anesthesiaconsiderations.com/
14. ICU One Pager. (2024). Retrieved June 5, 2024, from https://onepagericu.com/

Summaries:
LAST
Local anaesthetics

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