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Local Anaesthetics and Regional Anaesthesia: A Comprehensive Discussion

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1. CHEMISTRY AND CLASSIFICATION

The Local Anaesthetic Molecule

"The aromatic ring system gives a lipophilic (membrane-liking) character to its portion of the molecule, whereas the tertiary amine end is relatively hydrophilic, particularly since it is partially protonated and thus bears some positive charge in the physiologic pH range." — Miller's Anesthesia, 10e, p. 3545

"Most clinically relevant local anesthetics consist of a lipid-soluble, aromatic benzene ring connected to an amide group via either an amide or an ester moiety… Aminoesters are hydrolyzed by plasma cholinesterases and aminoamides are degraded by hepatic carboxylesterases." — Barash Clinical Anesthesia, 9e, p. 1688

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2. STRUCTURE–ACTIVITY RELATIONSHIPS

Lipophilicity

pKa and Onset

• Lidocaine pKa ≈ 7.9 → faster onset
• Bupivacaine pKa ≈ 8.1 → slower onset
• Chloroprocaine pKa ≈ 8.7 → slowest onset but rapid hydrolysis compensates

"The fraction of local anesthetic in the protonated, cationic form of an aqueous solution at physiologic pH (7.4) as a function of the pKa of the drug. Lidocaine, the drug with the lowest pKa, has the smallest fraction of its molecules protonated, the largest in the neutral form..." — Miller's Anesthesia, 10e, p. 3546

Protein Binding

Stereoisomerism

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3. NERVE FIBRE ANATOMY AND PHARMACOLOGY

Nerve Sheath Barriers

"Even with close proximity of deposition, only about 1% to 2% of injected local anesthetics ultimately penetrate into the nerve." — Barash Clinical Anesthesia, 9e, p. 1685

Nerve Fibre Classification

"Na+ channels that serve generation and propagation of impulses are highly concentrated at the nodes of Ranvier of myelinated fibres but are distributed all along the axon of nonmyelinated fibres." — Miller's Anesthesia, 10e, p. 3550

Myelinated vs Unmyelinated Conduction

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4. MECHANISM OF ACTION

Sodium Channel Blockade — The Core Mechanism

1. Resting (closed) — at normal resting potential (–85 mV)
2. Activated (open) — during depolarisation
3. Inactivated — rapid automatic closure after activation

"Binding of local anesthetic to sites on voltage-gated Na+ channels prevents opening of the channels by inhibiting the conformational changes that underlie channel activation… During onset of and recovery from local anesthesia, impulse blockade is incomplete and partially blocked fibres are further inhibited by repetitive stimulation, which produces an additional, use-dependent binding to Na+ channels." — Miller's Anesthesia, 10e, p. 3576

Decremental Conduction

"If the exposure distance is inadequate, action potentials can 'skip' over blocked segments and resume nerve conduction. In contrast, exposure over a long segment of nerve to even a relatively low drug concentration can still result in gradual extinction of impulse by decremental decay." — Barash Clinical Anesthesia, 9e, p. 1686

Chronological Summary of Impulse Blockade (Miller's)

1. Local anaesthetic is deposited near the nerve; penetration of nerve sheath by free drug
2. Drug permeates axonal membranes — speed depends on pKa and lipophilicity
3. Binding to voltage-gated Na⁺ channels prevents channel activation
4. During onset/recovery, use-dependent (phasic) blockade from repetitive stimulation
5. One binding site may account for both tonic and phasic actions
6. Clinically effective block lasting hours is governed by slow diffusion of drug into/out of the whole nerve — not by the faster (seconds) binding/dissociation from ion channels

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5. DIFFERENTIAL NERVE BLOCK

"Sodium channel isoforms NaV 1.7 and NaV 1.8 are highly expressed on the dorsal root ganglia, and have been shown to have distinct sensitivities to lidocaine... Because these transient receptor potential channels are found predominantly on sensory neurons mediating specific stimulus modalities, their activation may selectively facilitate entry of local anesthetics, thereby resulting in the observed progression of sensory, autonomic, and motor blockade." — Barash Clinical Anesthesia, 9e, p. 1687

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6. PHARMACOKINETICS

Absorption

Distribution, Metabolism, Elimination

Effect of Site on Duration

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7. ADJUVANTS AND ADDITIVES

Epinephrine

• Clinically used at 1:200,000 (5 µg/mL)
• Markedly prolongs shorter-acting agents (lidocaine, mepivacaine): increases duration by up to 50%
• Minimal effect on long-acting agents (bupivacaine, ropivacaine)
• Also used as a marker for inadvertent intravascular injection (HR ↑ ≥20 bpm after 15 µg IV, though false positives/negatives occur in beta-blocked or pregnant patients)
• Contraindicated near terminal vessels (digits, penis, ear, nose) and in IV regional anaesthesia

"Vasoconstrictors, usually epinephrine, are frequently included in local anesthetic solutions to decrease the rate of vascular absorption, thereby allowing more anesthetic molecules to reach the nerve membrane and thus improve the depth and duration of anesthesia." — Miller's Anesthesia, 10e, p. 3583

Alkalinisation

"Clinical studies on the association between alkalinization of local anesthetics and hastening of block onset have shown an improvement of less than [3 minutes]." — Barash Clinical Anesthesia, 9e, p. 1691

Other Adjuvants (Miller's, p. 3583–3586)

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8. INDIVIDUAL LOCAL ANAESTHETIC AGENTS

Short-Acting

• Procaine (ester): low potency, slow onset; mainly historical for spinal use
• Chloroprocaine 2–3%: fastest onset (rapid hydrolysis), shortest duration; ideal for surgical epidural; risk of transient neurological symptoms (TNS) and adhesive arachnoiditis with preservative-containing formulations

Intermediate-Acting

• Lidocaine 0.5–2%: the most versatile agent; gold-standard for topical, infiltration, spinal, epidural, nerve blocks; risk of TNS with spinal use (especially lithotomy position, dose-dependent)
• Mepivacaine 0.5–2%: similar to lidocaine, slightly longer duration; safe in neonates (unlike bupivacaine), less vasodilatory

Long-Acting

• Bupivacaine 0.125–0.75%: workhorse of obstetric and postoperative epidural analgesia; profound differential sensory/motor block at low concentrations; 0.5% hyperbaric widely used for spinal; high cardiac toxicity (particularly R(+)-enantiomer)
• Levobupivacaine: pure S(–)-enantiomer of bupivacaine; similar clinical profile, lower cardiac toxicity
• Ropivacaine 0.2–1%: pure S(–)-enantiomer; similar to bupivacaine but less potent and significantly less cardiotoxic; intrinsic vasoconstrictive properties (unlike bupivacaine which vasodilates)
• Tetracaine 0.5% hyperbaric: long-acting spinal agent; rarely used epidurally due to slow onset

Unique Agents

• Cocaine: only agent with intrinsic vasoconstrictive properties; used solely for topical nasal/airway anaesthesia
• Prilocaine: lowest CNS toxicity; however, its metabolite o-toluidine causes methaemoglobinaemia — contraindicated in neonates and compromised patients

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9. DOSAGE AND VOLUME PRINCIPLES

Concentration vs Volume

• 30 mL of 1% lidocaine epidurally spreads >4 dermatomes higher than 10 mL of 3% lidocaine
• Increasing epidural bupivacaine from 0.125% to 0.5% (same 10 mL) → shorter latency, longer sensory analgesia

Ultrasound Era and Minimum Volumes

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10. LOCAL ANAESTHETIC SYSTEMIC TOXICITY (LAST)

Mechanism

• Early: circumoral tingling, tinnitus, dizziness, metallic taste, restlessness, slurred speech
• Progressive: visual/auditory disturbance, muscle twitching
• Severe: generalised seizures → CNS depression → respiratory arrest

• Conduction disturbances, bradycardia, PR prolongation, QRS widening
• Re-entrant arrhythmias, ventricular tachycardia/fibrillation
• Cardiac depression and cardiovascular collapse

"LAST is a potential complication of local anesthetic administration by any route and most commonly manifests clinically as neurologic or cardiovascular sequelae… Despite these precautions, life-threatening convulsions and, rarely, cardiovascular collapse may occur." — Barash Clinical Anesthesia, 9e, p. 3503–3504

Incidence

Risk Factors

• Extremes of age (infants <6 months: 6× higher risk)
• Low α1-acid glycoprotein (pregnant women, neonates, liver failure)
• Cardiac disease
• Metabolic acidosis (reduces protein binding and slows elimination)
• High-vascularity injection sites

Prevention

• Aspiration before each injection (does not reliably exclude intravascular placement)
• Fractional/incremental injection (3–5 mL aliquots)
• Epinephrine test dose (detects intravascular injection — HR rise ≥20 bpm)
• Ultrasound guidance to visualise needle tip and drug spread
• Respect maximum safe doses (adjusted for patient weight, site, and comorbidity)

Treatment — ASRA Practice Advisory

1. Get help immediately, stop injection
2. Airway management — 100% O₂, prevent hypoxia and acidosis (worsen toxicity)
3. Seizure suppression — IV midazolam (1–5 mg) or propofol (small doses, avoid in haemodynamic compromise)
4. Lipid emulsion therapy (20% Intralipid) — 1.5 mL/kg bolus over 1 minute, then 0.25 mL/kg/min infusion for ≥10 minutes after haemodynamic stability
5. ACLS if cardiac arrest — prolonged resuscitation (local anaesthetic may clear over time)
6. Epinephrine: limit to <1 µg/kg boluses (higher doses may trigger malignant arrhythmias)
7. Avoid: vasopressin, calcium channel blockers, beta-blockers
8. Amiodarone for ventricular dysrhythmias (avoid other Na⁺/Ca²⁺ channel–blocking antiarrhythmics)
9. Cardiopulmonary bypass if refractory cardiovascular collapse

"Current society practice advisories unequivocally recommend initiation of lipid resuscitation therapy at the first sign of dysrhythmia from suspected LAST." — Barash Clinical Anesthesia, 9e, p. 1720

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11. NEURAXIAL ANAESTHESIA — KEY CONCEPTS

Spinal Anaesthesia

• Drug injected into the subarachnoid space (CSF)
• Key determinants of spread: baricity, patient position, dose (mg), volume, speed of injection, age, height, spinal anatomy
• Hyperbaric bupivacaine 0.75% (in 8.25% dextrose) is the most widely used spinal agent worldwide
• Tetracaine (hyperbaric) offers long surgical anaesthesia
• Lidocaine spinal: rapid onset/offset but TNS risk (buttock and posterior leg pain) especially in lithotomy; dosing strategies now favour chloroprocaine for short procedures

Epidural Anaesthesia

• Denser drug concentration needed vs. spinal (no CSF dilution; large volume, high vascularity of epidural space)
• Onset: 5–15 min for chloroprocaine, lidocaine, mepivacaine; slower for bupivacaine
• Epinephrine significantly prolongs lidocaine/mepivacaine epidural duration; minimal effect on bupivacaine
• Dilute bupivacaine (0.0625–0.1%) ± opioid for labour epidural analgesia — exploits differential block
• Bolus injections spread more cephalocaudally than continuous infusions

Hypotension with Spinal Anaesthesia

• Prophylactic phenylephrine infusion reduces incidence and physician interventions vs. reactive bolus treatment
• Norepinephrine (potency ratio ≈11:1 to phenylephrine) — emerging agent; dose ~6 µg IV bolus; maintains cardiac output better due to β₁ agonism

Postdural Puncture Headache (PDPH)

• Caused by CSF leakage through dural puncture → intracranial hypotension
• Incidence: >70% with 16G cutting needle → <1% with 25G pencil-point needle
• Pencil-point needles (Whitacre, Sprotte) substantially reduce PDPH vs. cutting (Quincke) needles
• Treatment: conservative (rest, hydration, caffeine, analgesics) → epidural blood patch (15–20 mL autologous blood) for severe/refractory cases
• Pregnant women at higher risk due to age, sex, and post-delivery factors

Total Spinal Anaesthesia

• Excessive cephalad spread of LA in subarachnoid/epidural space
• Rapid ascending sensory-motor blockade, dyspnoea, inability to phonate, cardiovascular collapse, loss of consciousness
• Immediate management: vasopressors, fluid, left uterine displacement (obstetric), rapid airway control

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12. PERIPHERAL NERVE BLOCKS (PNB) — KEY CONCEPTS

Nerve Localization Techniques

• Paraesthesia technique: historical; higher risk of nerve injury
• Nerve stimulation: motor twitch response at 0.2–0.5 mA confirms proximity; still useful as adjunct
• Ultrasound guidance: real-time visualisation of nerve, needle, and LA spread; reduces minimum effective volume; improves safety; now considered standard of care

Concentration Selection

• Lidocaine 1–1.5%, bupivacaine 0.125–0.5%
• Neural toxicity is concentration-dependent; reducing concentration when using large volumes is important to limit total dose

"Lower concentrations of local anesthetic (e.g., 1% to 1.5% lidocaine, 0.125% to 0.5% bupivacaine) compared to those used for epidural anesthesia are appropriate for peripheral nerves. The neural toxicity of these anesthetics appears to be concentration dependent." — Barash Clinical Anesthesia, 9e, p. 2901

Intraneural Injection and Nerve Injury

• Intrafascicular injection carries the highest risk of neural injury (endoneurial ischemia, Wallerian degeneration, demyelination)
• High injection pressure is the key correlate of nerve injury: injection pressure monitoring and resistance monitoring are recommended safety adjuncts
• Extrafascicular placement carries the mildest injury risk
• Most peripheral nerve injuries resolve spontaneously but may take months

Systemic Absorption Rates by Block Site

Intravenous Regional Anaesthesia (Bier Block)

• Lidocaine 0.5% (3 mg/kg, max 250 mg) into isolated limb vein
• Requires reliable double-cuff tourniquet to prevent systemic toxicity
• Epinephrine absolutely contraindicated — would cause distal ischaemia without blood flow
• Block dissipates immediately upon tourniquet release (cuff must remain inflated ≥20–25 min)

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13. NEURAL TOXICITY OF LOCAL ANAESTHETICS

• Demyelination and Wallerian degeneration
• Dysregulation of axonal transport
• Disruption of the blood-nerve barrier
• Decreased blood flow to the vasa nervorum
• Loss of cell membrane integrity

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14. REGIONAL vs GENERAL ANAESTHESIA — CONSIDERATIONS

• Opioid consumption and related side-effects
• Pulmonary complications (especially neuraxial blocks for thoracoabdominal surgery)
• Postoperative nausea and vomiting
• Stress response and immunosuppression

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KEY TAKEAWAYS

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• Miller's Anesthesia, 2-Volume Set, 10th Edition (Elsevier) — Chapter 25 (Local Anesthetics); Chapter 41 (Neuraxial Anesthesia); Chapter 58 (Obstetric Anesthesia)
• Barash, Cullen & Stoelting's Clinical Anesthesia, 9th Edition (Wolters Kluwer) — Chapter 22 (Local Anesthetics); Chapter 12 (Peripheral Nerve Blocks); Chapter 14 (Neuraxial Anesthesia)This comprehensive discussion draws directly from both textbooks across 14 major topic areas. Here's a quick orientation to what was covered:

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Summary of What's Covered

1. Chemistry & Classification — ester vs. amide structure, metabolic pathways, allergy risk
2. Structure-Activity Relationships — lipophilicity, pKa, protein binding, stereoisomerism (levobupivacaine, ropivacaine)
3. Nerve Anatomy — barriers to diffusion (perineurium as the main barrier), nerve fibre classification table, myelinated vs unmyelinated conduction
4. Mechanism of Action — Na⁺ channel state theory (resting/open/inactivated), use-dependent blockade, decremental conduction, Miller's 6-step chronology
5. Differential Nerve Block — sequence of blockade, role of Nav1.7/Nav1.8 isoforms and TRPV1/TRPA1 channels (Barash)
6. Pharmacokinetics — absorption by site, elimination half-lives table, hepatic vs plasma hydrolysis
7. Adjuvants — epinephrine (mechanism, doses, effects per agent), alkalinisation, dexamethasone, dexmedetomidine, clonidine
8. Individual Agents — short/intermediate/long-acting, TNS risk, cardiac safety hierarchy
9. Dosage Principles — concentration vs volume, ultrasound-era MLAV, ED95 rationale
10. LAST — mechanism, incidence, risk factors, prevention, full ASRA treatment protocol with lipid emulsion
11. Neuraxial Anaesthesia — spinal factors, epidural principles, hypotension management (phenylephrine vs norepinephrine), PDPH, total spinal
12. Peripheral Nerve Blocks — localisation techniques, concentration selection, intraneural injection, absorption rates by site, Bier block
13. Neural Toxicity — direct neurotoxicity, cauda equina syndrome
14. Regional vs General — evidence-based benefits

Local Anaesthetics and Regional Anaesthesia

A Detailed Discussion from Miller's Anesthesia (10e) and Barash's Clinical Anesthesia (9e)

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SECTION 1 — CHEMISTRY AND CLASSIFICATION

1.1 The Local Anaesthetic Molecule (Miller's, Ch. 25)

1. A hydrophobic aromatic ring (benzene derivative) — confers lipophilicity
2. A hydrophilic tertiary amine — partially protonated at physiological pH, bears positive charge
3. An intermediate chain — either an ester (–C–O–) or an amide (–NHC–) linkage, classifying all local anaesthetics into two families

"The typical local anesthetic molecule… contains a tertiary amine attached to a substituted aromatic ring by an intermediate chain that almost always contains either an ester or an amide linkage; local anesthetics may therefore be classified as aminoester or aminoamide compounds. The aromatic ring system gives a lipophilic (membrane-liking) character to its portion of the molecule, whereas the tertiary amine end is relatively hydrophilic." — Miller's Anesthesia, 10e, p. 3545

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1.2 Aminoesters vs Aminoamides

"Aminoesters are hydrolyzed by plasma cholinesterases and aminoamides are degraded by hepatic carboxylesterases. Some metabolites of aminoesters, such as para-aminobenzoic acid, can induce immunologic reactions and are responsible for the slightly greater incidence of severe allergic reactions associated with aminoesters." — Barash Clinical Anesthesia, 9e, p. 1688

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SECTION 2 — STRUCTURE–ACTIVITY RELATIONSHIPS

2.1 Lipophilicity — The Most Important Property

1. At the cell membrane level — facilitates penetration through the lipid bilayer
2. At the sodium channel binding pocket — crystallographic studies show local anaesthetics bind to a hydrophobic pocket within Na⁺ channels via hydrophobic and van der Waals interactions

"By far the most important physicochemical property of local anesthetics is their lipophilicity… Highly lipid-soluble agents are more potent and tend to have a longer duration of action than ones that are less lipid soluble." — Barash Clinical Anesthesia, 9e, p. 1689

2.2 pKa and Onset of Action

• Cationic protonated form (BH⁺) — hydrophilic; responsible for Na⁺ channel binding once inside the cell
• Neutral lipid-soluble base form (B) — crosses the lipid membrane

"Clinically, the proportion of the lipid-soluble form can be increased by alkalization of local anesthetic solution and thus accelerate the onset of action. Once inside the cell, equilibrium is reestablished between the cationic and the neutral forms, and experimental findings have shown that the cationic form is principally responsible for blockade of sodium channels." — Barash Clinical Anesthesia, 9e, p. 1688

2.3 Protein Binding and Duration

2.4 Stereoisomerism

• Levobupivacaine = pure S(–)-enantiomer of bupivacaine
• Ropivacaine = pure S(–)-enantiomer

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SECTION 3 — ANATOMY OF THE PERIPHERAL NERVE

3.1 Nerve Sheath Barriers (Miller's, Ch. 25)

• Desheathed nerves in vitro require ~100-fold lower concentrations (0.7–0.9 mM lidocaine)
• Clinically used 2% lidocaine = 75 mM concentration
• Only 1–2% of injected drug ultimately penetrates into the nerve (Barash, p. 1685)

3.2 Myelinated vs. Unmyelinated Axons

• Myelinated fibres: Schwann cells wrap the axon in multiple myelin layers. Na⁺ channels are concentrated at nodes of Ranvier. Impulse propagates by saltatory conduction (jumping from node to node), requiring block of at least 2–3 successive nodes to extinguish the impulse
• Unmyelinated C fibres: Na⁺ channels are distributed along the entire axon; impulse travels continuously; adequate length of fibre must be blocked

3.3 Nerve Fibre Classification

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SECTION 4 — PHYSIOLOGY OF NERVE CONDUCTION

4.1 The Resting Membrane Potential

• Selective K⁺ permeability at rest (K⁺ inside:outside = 150:5 mM = 30:1; Nernst potential ≈ –86 mV)
• Na⁺/K⁺-ATPase pump constantly extrudes Na⁺, takes in K⁺
• Na⁺ is higher extracellularly (Nernst potential for Na⁺ ≈ +60 mV)

4.2 The Action Potential

• Membrane depolarisation opens both Na⁺ and K⁺ channels
• Na⁺ channels open faster → inward Na⁺ current → further depolarisation (positive feedback)
• Na⁺ channels then inactivate automatically
• K⁺ channels restore repolarisation
• Na⁺/K⁺ pump restores ionic gradients

1. Resting (closed) — at –85 mV, available for activation
2. Activated (open) — during depolarisation, Na⁺ flows in
3. Inactivated — automatic closure after opening; refractory period

4.3 The Voltage-Gated Na⁺ Channel — LA Binding Site

• Nav1.7: expressed on peripheral sensory neurons; mutations cause erythromelalgia (gain of function) or congenital insensitivity to pain (loss of function) — making it a major target for selective analgesics
• Nav1.8: DRG sensory neurons; distinct sensitivity to lidocaine
• Nav1.9: visceral pain; Nav1.9 block effective where Nav1.7 block is not
• Nav1.4: skeletal muscle; mutations → myotonia, periodic paralysis

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SECTION 5 — MECHANISM OF ACTION

5.1 Na⁺ Channel Blockade

• LA binds with greater affinity to open and inactivated states than to the resting state
• This produces use-dependent (phasic) blockade — rapidly firing nerves (e.g., nociceptors during injury) accumulate more block because more channels cycle through open/inactivated states
• Tonic (resting) blockade occurs at resting channels but at lower affinity

5.2 Decremental Conduction (Barash, Ch. 22)

"If the exposure distance is inadequate, action potentials can 'skip' over blocked segments and resume nerve conduction. In contrast, exposure over a long segment of nerve to even a relatively low drug concentration can still result in gradual extinction of impulse by decremental decay." — Barash Clinical Anesthesia, 9e, p. 1686

5.3 Miller's Six-Step Chronology of Impulse Blockade

1. LA deposited near nerve; drug removed by tissue binding, circulation, or local hydrolysis (esters); net: penetration of nerve sheath
2. LA permeates axonal membranes — speed depends on pKa and lipophilicity
3. Binding to Na⁺ channels prevents activation (channel opening)
4. Use-dependent binding during onset/recovery: incompletely blocked fibres are further inhibited by repetitive stimulation
5. One binding site accounts for both tonic (resting) and phasic (use-dependent) actions
6. Clinically observed onset and recovery (hours) are governed by slow diffusion of drug into/out of the whole nerve — not by fast drug-channel binding/dissociation (seconds)

"A clinically effective block that may last for hours can be accomplished with local anesthetic drugs that dissociate from Na+ channels in a few seconds." — Miller's Anesthesia, 10e, p. 3576

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SECTION 6 — DIFFERENTIAL NERVE BLOCK

6.1 Sequence of Block and Recovery

• Cold sensation (ethyl chloride spray) → Aδ and C fibres
• Pinprick → Aδ fibres
• Light touch → Aβ fibres
• Motor power → Aα fibres

6.2 Why Differential Block Occurs — Beyond Fibre Size

"Sodium channel isoforms NaV 1.7 and NaV 1.8 are highly expressed on the dorsal root ganglia, and have been shown to have distinct sensitivities to lidocaine. Similarly, experiments with large pore, nonspecific cation channels, the transient receptor potential channel subfamily V (TRPV1) and member A1 (TRPA1), suggest that they can be activated by lidocaine and other local anesthetics. Because these transient receptor potential channels are found predominantly on sensory neurons mediating specific stimulus modalities, their activation may selectively facilitate entry of local anesthetics, thereby resulting in the observed progression of sensory, autonomic, and motor blockade." — Barash Clinical Anesthesia, 9e, p. 1687

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SECTION 7 — PHARMACOKINETICS

7.1 Absorption: Site Vascularity is the Key Determinant

"The highest blood levels of local anesthetic occur after intercostal blocks, followed by caudal, epidural, brachial plexus, intravenous regional, and lower extremity blocks." — Barash Clinical Anesthesia, 9e, p. 2901

7.2 Distribution and Elimination

7.3 Effect of Injection Site on Duration of Anaesthesia

• Epidural: 3–4 hours
• Brachial plexus/arm: 12–14 hours
• Sciatic nerve: 24–36 hours

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SECTION 8 — INDIVIDUAL LOCAL ANAESTHETIC AGENTS

Short-Acting

Intermediate-Acting

• Topical (4–10%): airway anaesthesia
• Infiltration (0.5–1%): surgical anaesthesia
• IV regional (Bier block) (0.5%): 3 mg/kg, max 250 mg
• Epidural (1–2%): fast onset, reliable surgical block
• Spinal (0.5–5%): BUT significant TNS risk — particularly in lithotomy position; dose-dependent; now replaced in many centres by chloroprocaine for ambulatory spinal anaesthesia
• IV infusion: antiarrhythmic, systemic analgesia for neuropathic pain

Long-Acting

• Profound differential sensory/motor block at low concentrations (0.0625–0.1% for labour epidural)
• 0.5% hyperbaric widely used for spinal anaesthesia
• 0.75% spinal is the MAXIMUM concentration — never for epidural (cardiac arrest risk)
• High cardiotoxicity — R(+)-enantiomer binds Na⁺ channels with "fast-in, slow-out" kinetics → prolonged cardiac depression
• Bupivacaine is absolutely contraindicated for IV regional anaesthesia

• Slightly less potent than bupivacaine (motor block is less dense at equivalent sensory-block concentrations)
• Intrinsic vasoconstriction (unlike bupivacaine which vasodilates), so epinephrine adds less benefit
• 30–40% less cardiotoxic than bupivacaine
• Preferred for epidural labour analgesia in many centres

Unique Agent

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SECTION 9 — DOSAGE PRINCIPLES AND VOLUME vs. CONCENTRATION

9.1 Dose, Volume, and Concentration (Miller's, Ch. 25)

• Higher concentration (same volume) → deeper block, shorter onset (e.g., bupivacaine 0.5% vs. 0.125% at 10 mL → shorter latency, better quality, longer sensory duration)
• Larger volume (same concentration) → greater spread (e.g., 30 mL of 1% lidocaine epidurally spreads >4 dermatomes higher than 10 mL of 3% lidocaine)

9.2 Ultrasound and Minimum Local Anaesthetic Volume (MLAV)

• Ultrasound-guided femoral nerve block required only 54–57% of the volume needed with nerve stimulation (Miller's, p. 3582)
• MLAV normalised to nerve size ≈ 0.1–0.15 mL/mm² of nerve diameter
• However, reducing dose below clinical effective doses may shorten duration — important when block must outlast surgical pain

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SECTION 10 — ADJUVANTS AND ADDITIVES

10.1 Epinephrine (Miller's, Ch. 25)

• Standard concentration: 1:200,000 (5 µg/mL)
• Also used as an intravascular injection marker: HR rise ≥20 bpm after 15 µg IV epinephrine (though false positives/negatives occur in beta-blocked patients, parturients, and deeply anaesthetised patients)

10.2 Alkalinisation (Barash, Ch. 22)

"Clinically used local anesthetics cannot be alkalized beyond a pH of 6.05 to 8 before precipitation occurs, and these pH values will only increase the neutral form to about 10%." — Barash Clinical Anesthesia, 9e, p. 1691

10.3 Other Adjuvants (Miller's, Ch. 25)

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SECTION 11 — LOCAL ANAESTHETIC SYSTEMIC TOXICITY (LAST)

11.1 Mechanisms and Target Organs

• Conduction disturbances (PR/QRS prolongation), bradycardia
• Hypotension from myocardial depression and vasodilation
• Re-entrant arrhythmias, ventricular tachycardia/fibrillation
• Cardiovascular collapse

11.2 Incidence and Risk Factors

• Infants <6 months — sixfold higher risk than older children
• Pregnant women — reduced protein binding, ↑ cardiac output → faster absorption
• Elderly — reduced plasma protein levels
• Patients with liver failure (amides), pseudocholinesterase deficiency (esters)
• Metabolic acidosis (reduces protein binding, impairs elimination)
• Pre-existing cardiac disease

11.3 Prevention

• Aspiration before each injection (though not fully reliable — aspiration of blood is only 50–75% sensitive)
• Incremental, fractional injection (3–5 mL aliquots with 30-second intervals)
• Epinephrine test dose (15 µg, detects intravascular injection as HR rise ≥20 bpm)
• Ultrasound guidance — real-time visualisation of needle and drug spread
• Respect maximum safe doses (adjusted for weight, site, patient risk factors)
• Use lower concentrations for peripheral nerve blocks vs. epidural

11.4 Treatment — ASRA Practice Advisory (Barash Table 22-13)

1. Airway management: 100% O₂, avoid hypoxia and acidosis (worsen toxicity)
2. Seizures: IV midazolam 1–5 mg or small-dose propofol (avoid in haemodynamic compromise); succinylcholine if needed for intubation (does NOT treat CNS seizures)
3. Lipid emulsion (20% Intralipid):
   • Bolus: 1.5 mL/kg over 1 minute IV
   • Infusion: 0.25 mL/kg/min for ≥10 minutes after haemodynamic stability
   • May repeat bolus x1–2 for refractory cardiovascular collapse
4. Cardiovascular support (ACLS principles):
   • Epinephrine: limit to <1 µg/kg (higher doses may trigger malignant arrhythmias in bupivacaine toxicity)
   • Amiodarone for ventricular arrhythmias
5. AVOID: vasopressin, calcium channel blockers, beta-blockers, lidocaine and other Na⁺/Ca²⁺ channel-blocking antiarrhythmics
6. Cardiopulmonary bypass if refractory cardiovascular collapse — lifesaving bridge to recovery

• "Lipid shuttle/sink" — lipid particles act as scavengers, removing tissue-bound local anaesthetic via partition principles, redistributing it away from the heart and brain
• Direct cardiotonic effect — lipid emulsion restores vascular tone and contractility, possibly via alternative mitochondrial energy substrate or modifying intracellular signalling downstream of Na⁺ channel inhibition

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SECTION 12 — NEURAXIAL ANAESTHESIA

12.1 Spinal Anaesthesia

Factors Determining Block Height — Miller's Ch. 41

• Hyperbaric (denser than CSF, e.g., bupivacaine 0.75% in 8.25% dextrose): spreads to dependent regions by gravity → most predictable, least interpatient variability
• Hypobaric (less dense, e.g., tetracaine in sterile water): spreads to non-dependent regions
• Isobaric: unaffected by gravity; more operator-dependent spread

"The spread of hyperbaric solutions is more predictable, with less interpatient variability… Anesthesiologists can capitalize on this phenomenon by altering the position of the patient." — Miller's Anesthesia, 10e, p. 6045

Intrathecal Drugs

Special Spinal Techniques (Miller's, p. 6076–6077)

Block Monitoring

12.2 Epidural Anaesthesia

• Larger volumes and doses required (drug not diluted in CSF; must diffuse through dura; larger vascular space)
• Slower onset (5–15 min for lidocaine/chloroprocaine; slower for bupivacaine)
• Titratable duration — catheter technique allows continuous or repeated dosing
• Test dose essential to detect intrathecal or intravascular catheter placement

• Lidocaine 45 mg or bupivacaine 5 mg → intrathecal placement produces identifiable sensory/motor block
• Epinephrine 15 µg → intravascular placement produces HR/BP rise
• A negative test dose does not eliminate the need for incremental dosing

• 2% lidocaine + epinephrine 1:200,000 ± NaHCO₃ ± fentanyl: rapid onset for urgent Caesarean
• 3% 2-chloroprocaine: fastest onset, lowest toxicity risk — preferred when speed is critical
• 0.5% ropivacaine: surgical anaesthesia; less cardiotoxic than bupivacaine
• 0.0625–0.1% bupivacaine ± opioid: labour epidural analgesia — exploits differential sensory/motor block
• Bupivacaine is no longer commonly used for epidural Caesarean in the US — intravascular injection has been associated with high maternal mortality

Lumbar Epidural Catheter Technique (Miller's, Ch. 30)

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SECTION 13 — SPINAL COMPLICATIONS

13.1 Hypotension

• Prophylactic phenylephrine infusion (preferred over reactive bolus) — fewer physician interventions, less patient nausea
• Norepinephrine (potency ratio ~11:1 vs. phenylephrine) — maintains cardiac output better due to β₁ agonism; bolus dose ~6 µg IV
• Ephedrine: mixed α/β agonist; historically preferred in obstetrics but now second-line (associated with fetal acidosis vs. phenylephrine)
• IV fluid preloading: crystalloid co-load (simultaneously with spinal injection) more effective than pre-load

13.2 Postdural Puncture Headache (PDPH) (Barash, Ch. 14)

• 16G Quincke (cutting): >70%
• 22G Quincke: ~30%
• 25G Quincke: ~3%
• 25G Whitacre/Sprotte (pencil-point): <1%

• Conservative: bed rest, hydration, caffeine (300–500 mg — transient effect), analgesics
• Definitive: Epidural blood patch (EBP) — 15–20 mL autologous blood; 90%+ success rate for severe/refractory PDPH

13.3 Total Spinal Anaesthesia (Barash, Ch. 14)

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SECTION 14 — PERIPHERAL NERVE BLOCKS (PNB)

14.1 Nerve Localisation Techniques

14.2 Concentration Selection for PNB (Barash, Ch. 12)

• Lidocaine 1–1.5% (vs. 2% epidural)
• Bupivacaine 0.125–0.5% (vs. 0.5–0.75% epidural)

"No clinical evidence suggests that prolonged nerve exposure (as with continuous PNB) to local anesthetic solutions of appropriate concentration predisposes to neurotoxic injury." — Barash Clinical Anesthesia, 9e, p. 2901

14.3 Intraneural Injection and Nerve Injury

• Endoneurial ischaemia
• Demyelination, Wallerian degeneration
• Dysregulation of axonal transport

• High injection pressure — injection pressure monitoring recommended
• Concentrated local anaesthetic solutions
• Intraneural (especially intrafascicular) placement

14.4 Intravenous Regional Anaesthesia (Bier Block) (Miller's, Ch. 25)

• Drug: Lidocaine 0.5%, 3 mg/kg, maximum 250 mg
• Injected into an isolated exsanguinated limb vein with double pneumatic tourniquet
• Block provides uniform distal anaesthesia
• Epinephrine absolutely contraindicated (distal ischaemia without circulation)
• Tourniquet must remain inflated ≥20–25 min (to prevent acute LA bolus release)
• Block dissipates immediately on tourniquet deflation

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SECTION 15 — NEURAL TOXICITY OF LOCAL ANAESTHETICS

15.1 Direct Neurotoxicity (Barash, Ch. 22)

• Demyelination and Wallerian degeneration
• Dysregulation of axonal transport
• Disruption of blood-nerve barrier
• Decreased blood flow to the vasa nervorum
• Loss of cell membrane integrity

15.2 Cauda Equina Syndrome

15.3 Transient Neurological Symptoms (TNS)

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SECTION 16 — KEY CONCEPTS SUMMARY TABLE

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• Miller's Anesthesia, 2-Volume Set, 10th Edition (Elsevier, 2023) — Chapter 25: Local Anesthetics; Chapter 41: Spinal, Epidural, and Caudal Anesthesia; Chapter 30: Neuraxial Anesthesia
• Barash, Cullen & Stoelting's Clinical Anesthesia, 9th Edition (Wolters Kluwer, 2022) — Chapter 22: Local Anesthetics and Regional Anesthesia; Chapter 12: Peripheral Nerve Blocks; Chapter 14: Obstetric Anesthesia; Chapter 35: Spinal Anesthesia TechniqueThis is a complete, deeply sourced discussion across 16 major sections drawn directly from both textbooks. Here is an orientation to the full content:

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What's Covered — Section Guide