Ep.36: Local Anaesthetic Systemic Toxicity (LAST) For the FRCA Primary

GasGasGas – The FRCA Primary Anaesthetics Exam Podcast

Duration: 34:00 | FRCA Primary Exam Preparation

---

Quick Reference Tables

Emergency Management Algorithm

Step	Action	Details
1	STOP the surgeon	Unless actively controlling bleeding etc
2	DECLARE emergency	Alert entire team
3	100% OXYGEN	Increase flow (Reduce volatile fraction)
4	CALL FOR HELP	Emergency bell/assistance
5	REQUEST EQUIPMENT	IReduce volatile if applicable
6	GET QRH	AAGBI quick reference handbook
7	DELEGATE	Have team member read handbook

Intralipid Dosing Protocol

Parameter	Dose	Timing
Initial bolus	1.5ml/kg over 1 minute	Immediately
Example (75kg)	~100ml	Use 2x50ml syringe
Infusion	15ml/kg/hour	Start after bolus
Additional boluses	1.5ml/kg	At 5 and 10 minutes
Infusion adjustment	Double rate	After 5 minutes if needed
Maximum dose	12ml/kg cumulative	Check guidelines

Risk Hierarchy by Injection Site

Site	Risk Level	Notes
Subcutaneous infiltration	Lowest	Minimal vascular uptake
Brachial plexus	Low-moderate	Good visualisation with USS
Epidural space	Moderate	Fractionate dosing if able
Caudal injections	Moderate-high	Vascular region
Intercostal injections	High	Highly vascular area
Intravenous	Highest	Direct systemic access

---

Classification & Basic Properties

Amide Local Anaesthetics (Primary LAST Risk)

Drug	Maximum Dose	Elimination	Relative Cardiotoxicity
Bupivacaine	2mg/kg (150mg total)	Hepatic	Highest
Levobupivacaine	2mg/kg	Hepatic	<Bupiva … > Ropiva
Ropivacaine	3mg/kg	Hepatic	Lowest
Lidocaine	3mg/kg (7mg/kg with adrenaline)	Hepatic	Moderate
Prilocaine	6mg/kg	Hepatic	Moderate

Key Points:

• Molecular mechanism: Primarily sodium channel blockade
• Distribution: Affects CNS, cardiovascular system, and other sodium channel-containing tissues
• Protein binding: Primarily to α-1 acid glycoprotein (this is also an acute phase reactant)
• Clearance: Hepatic metabolism for amides; plasma esterases for esters

Ester Local Anaesthetics (Lower LAST Risk)

• Cocaine, procaine, chloroprocaine
• Metabolism: Plasma esterases (extensive system)
• LAST risk: Significantly lower due to rapid clearance
• Clinical implication: Would likely require IV injection of large volumes to overwhelm esterase system

---

Pharmacodynamics

Mechanism of Action

Primary target: Voltage-gated sodium channels

• Normal function: Essential for action potential propagation
• Blockade effect: Prevents nerve conduction
• Problem: Sodium channels also present in CNS, myocardium and elsewhere

Multi-System Effects

System	Mechanism	Clinical Manifestation
CNS	Na+ channel blockade	Seizures, altered consciousness
Cardiovascular	Na+, K+, Ca2+ channel effects	Arrhythmias, conduction blocks
Mitochondrial	Complex I inhibition	Reduced ATP production
Cellular	Carnitine transport blockade	Impaired fatty acid metabolism

Pathophysiological Cascade

1. Initial exposure: High plasma concentration of local anaesthetic
2. Sodium channel blockade: CNS and then cardiac conduction abnormalities
3. Potassium channel interference: Impaired repolarisation
4. Calcium channel disruption: Sarcoplasmic reticulum dysfunction, less Ca available for contractility mechanisms
5. Mitochondrial impairment: ATP depletion (like primary mechanism of toxicity)
6. Vicious cycle: Acidosis displaces drug from proteins → increased free fraction → more badness

---

Pharmacokinetics

Absorption and Distribution

Factor	Effect on LAST Risk	Clinical Consideration
Injection site vascularity	Higher = increased risk	Use lowest dose that achieves goal
Cardiac output	Higher = increased uptake	Pregnancy, hyperdynamic states
Total dose	Linear relationship	Calculate on ideal body weight
Concentration	Higher = faster onset	Use minimum effective concentration

Protein Binding

• Primary protein: α-1 acid glycoprotein (AAG)
• Acute phase reactant: Increases in inflammation/infection/post op
• Clinical relevance: Low AAG = higher free fraction = increased toxicity
• Displacement: Acidosis reduces protein binding

Metabolism and Elimination

• Amides: Hepatic metabolism (CYP enzymes)
• Half-life: Significantly prolonged in neonates (3-8x adult values)
• Clearance: Reduced in liver disease, elderly patients, those with renal dysfunction
• Accumulation risk: Continuous infusions, repeat dosing

---

Clinical Presentation

Classical Biphasic Description vs Reality

Textbook presentation:

• CNS
  • Phase 1: Excitation, agitation, sensory disturbance
  • Phase 2: Depression, coma, respiratory arrest
• CVS
  • Phase 1: Hypertension, tachycardia, arrhythmias
  • Phase 2: Bradycardia, conduction blocks, asystole

Clinical reality: Only 60% follow this pattern!

Actual Presentation Statistics

Feature	Frequency	Notes
Seizures	68%	Most common presenting feature
Cardiovascular signs	50%	Including arrhythmias
Bradycardia/asystole	27% of arrhythmias	Can be presenting feature
Isolated CVS disturbance	20%	No preceding CNS signs

Prodromal Symptoms

• Sensory: Circumoral tingling, metallic taste
• Auditory: Tinnitus, pressure sensation in ears
• Visual: Blurred vision, difficulty focusing
• Neurological: Dizziness, lightheadedness, agitation
• Note: May not occur in 40% of cases

Timing Considerations

• Pre-ultrasound era: Average onset ~50 seconds
• Current practice: More delayed presentations as odds of intravascular injection less again
• Infusion-related: May take hours to days to accumulate a toxic fraction in plasma
• Location shift: Now occurring outside theatre complexes as LA catheters are used for pain

---

Special Clinical Applications

Historical Dosing Research

Mather, Long, and Thomas (1971) Study:

• Volunteers: 3 subjects receiving bupivacaine infusions
• Dosing: 0.6mg/kg for 5 minutes, then 0.75mg/kg for 4 minutes
• Total doses: 130mg, 102mg, 104mg IV
• Findings: Mild toxicity symptoms at ~1.35mg/kg (below current 2mg/kg threshold) but this was IV
• Limitation: Infusion over 13 minutes vs fare more instantaneous injection in clinical mishaps

Tumescent Anaesthesia

Unique dosing paradigm:

• Lidocaine concentration: 0.1% or less
• Maximum dose: 35-55mg/kg (controversy exists)
• Mechanism: Epinephrine-induced vasoconstriction slows absorption
• Pharmacokinetics: Plateau concentration ~2μg/mL for up to 12 hours
• Safety concern: Reports of toxicity even with “safe” doses

CNS to CVS Ratio Concept

Definition: Ratio of dose causing cardiovascular collapse to dose causing seizures

• Clinical preference: Higher ratio preferred (seizures before cardiac arrest)
• Drug comparison:
  • Bupivacaine: Better ratio than lidocaine
  • Ropivacaine: Best safety profile
  • Clinical implication: Seizures provide warning before cardiovascular collapse

---

Safety Considerations

Contraindications and Cautions

Factor	Consideration	Dose Adjustment
Hepatic dysfunction	Single shot: normal dose	Infusions: 10-50% reduction
Renal dysfunction	Reduced clearance	10-20% reduction
Cardiac disease	Increased fragility	Consider dose reduction
Extremes of age	Altered pharmacokinetics	Weight-based dosing
Pregnancy	Reduced protein binding, increased CO	Standard dosing with vigilance

Risk Mitigation Strategies

Pre-procedure:

• Calculate maximum dose for patient weight
• Consider individual pharmacokinetics
• Ensure appropriate monitoring
• Be prepared with emergency equipment (does your suction work etc)

During procedure:

• Incremental injection with aspiration
• Ultrasound guidance (reduces risk 4-fold)
• [Test doses with epinephrine (2.5-5μg/ml)] not uk practice
• Communication with surgical team about LA use
• NRFit syringes to prevent IV injection

Post-procedure:

• Monitor for delayed presentations
• Clear documentation of doses used
• Patient education about symptoms to report

Drug Interactions

Medication	Effect	Clinical Consideration
Propofol	Contains negative inotrope	NOT substitute for intralipid
Adrenaline	Reduced doses recommended	≤1μg/kg in LAST
Vasopressin	Associated with worse outcomes	Avoid in LAST
Benzodiazepines	Treat seizures	First-line for seizure control

---

Educational Elements

Three Viva-Style Questions

Question 1: Emergency Management

“A 45-year-old patient receiving an interscalene block suddenly becomes agitated and complains of tinnitus 30 seconds after injection. Describe your immediate management.”

Model Answer:

• Recognition: High index of suspicion for LAST given timing and symptoms
• Immediate actions: Stop injection, declare emergency, 100% oxygen
• Call for help: Emergency bell, request LAST kit and arrest trolley
• Obtain QRH: Delegate reading to competent team member
• Prepare intralipid: Calculate dose (1.5ml/kg) – approximately 100ml for 75kg patient
• Monitor: Continuous ECG, blood pressure, oxygen saturation
• Be prepared: For seizure activity (benzodiazepines ready) and cardiovascular collapse
• Communicate: Clear handover to arriving help including agent used, dose, and timeline

Key teaching points:

• Early recognition crucial for optimal outcomes
• Systematic approach prevents missing critical steps
• Delegation allows focus on patient care
• Intralipid should be started early, not as last resort

Question 2: Pathophysiology

“Explain the pathophysiological mechanisms underlying local anaesthetic systemic toxicity and why intralipid therapy is effective.”

Model Answer:

• Primary mechanism: Sodium channel blockade in CNS and myocardium
• Additional effects: Potassium and calcium channel interference
• Mitochondrial toxicity: Complex I inhibition, reduced ATP production
• Vicious cycle: Acidosis displaces LA from plasma proteins → increased free fraction
• Intralipid mechanism:
  • Lipid sink theory: Creates an ‘intraplasma lipophilic compartment’ for drug sequestration
  • Shuttling effect: Redistributes drug from high to low concentration tissues
  • (possible) Additional benefits: Direct cardiac energy source, improved calcium handling
• Clinical correlation: Explains why early administration more effective than late rescue

Key teaching points:

• Multiple mechanisms beyond simple sodium channel blockade
• Mitochondrial impairment likely primary mechanism for cardiac toxicity
• Acidosis worsens toxicity through pharmacokinetic mechanisms
• Intralipid works by redistribution, not elimination

Question 3: Risk Factors and Prevention

“A 75-year-old diabetic patient with mild heart failure requires a femoral nerve block for hip fracture repair. What factors increase their LAST risk and how would you modify your technique?”

Model Answer:

• Risk factors identified:
  • Age: Reduced clearance, altered distribution
  • Cardiac disease: Increased susceptibility to arrhythmias
  • Diabetes: Multi-system effects on drug handling
  • Potential frailty: Reduced muscle mass affects distribution
• Technique modifications:
  • Dose calculation: Use ideal body weight, consider 10-20% reduction
  • Ultrasound guidance: Mandatory to reduce 4-fold risk increase
  • Incremental injection: 5ml aliquots with aspiration
  • Lower concentration: Use minimum effective dose
  • Monitoring: BP/Spo2/ECG throughout procedure
  • Emergency preparation: Have in your mind the intralipid dose, ensure kit available

Key teaching points:

• Multiple patient factors can compound LAST risk
• Risk mitigation requires systematic approach
• Individual patient assessment crucial for dosing decisions
• Ultrasound guidance very effective risk reduction strategy

Key Clinical Pearls

Recognition Pearls

• “Not all LAST looks like the textbook” – 40% don’t follow classical progression
• “Think LAST with any weird behaviour” after LA injection
• “Timing varies” – immediate or delayed (hours to days with infusions)
• “Location matters” – now occurring outside traditional theatre settings

Management Pearls

• “100ml intralipid for 75kg patient” – easy emergency calculation
• “QRH and delegate” – don’t try to remember everything under pressure
• “Less adrenaline” – ≤1μg/kg doses if needed for resuscitation
• “No propofol” – contains negative inotrope, not substitute for intralipid

Prevention Pearls

• “2mg/kg bupivacaine on ideal body weight” – standard UK dosing
• “Ultrasound reduces risk 4-fold” – use whenever possible
• “Incremental injection with aspiration” – basic safety measure
• “Calculate before you inject” – know your maximum dose

Clinical Tips and Tricks

Practical Dosing

• Consider Pre-calculating emergency intralipid dose for each patient, at least till you have it in your brain
• Use weight-based dosing cards for quick reference
• Consider dose reduction in high-risk patients rather than arbitrary standard doses
• Document total daily LA dose for patients with multiple procedures/infusions

Communication Strategies

• Patient education: Explain possibility and potential mitigation strategies for it, ‘alert me to any unusual sensations’ ‘I’d rather know and reassure than have you wondering what’s happening’
• Team communication: Clear handover of LA doses between teams
• Surgical coordination: Ensure surgeons don’t add LA without discussion
• Emergency communication: Clear, structured SBAR approach, get to the point, state diagnosis and enquire if there is anything else that could be happening

Equipment and Preparation

• NRFit syringes prevent accidental IV injection
• Emergency kit location known to all team members
• QRH readily accessible 
• Regular equipment checks ensure intralipid not expired

---

Supporting Materials

References and Further Reading

Key Studies and Guidelines

• Mather, L.E., Long, G.J. and Thomas, J., 1971. The intravenous toxicity and clearance of bupivacaine in man. Clinical Pharmacology & Therapeutics, 12(6), pp.935-943.
• G. L. Weinberg, J. W. Palmer, T. R. VadeBoncouer, M. B. Zuechner, G. Edelman, and C. L. Hoppel, “Bupivacaine inhibits acylcarnitine exchange in cardiac mitochondria,” Anesthesiology, vol. 92, no. 2, pp. 523–528, 2000.
• Rosenblatt MA, et al. Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest. Anesthesiology 2006;105:217-218.
• Heavner JE, Dryden CF Jr, Sanghani V, Huemer G, Bessire A, Badgwell JM. Severe hypoxia enhances central nervous system and cardiovascular toxicity of bupivacaine in lightly anesthetized pigs. Anesthesiology 1992; 77: 142–7.
• G. L. Weinberg, T. VadeBoncouer, G. A. Ramaraju, M. F.Garcia-Amaro, and M. J. Cwik, “Pretreatment or resuscitation with a lipid infusion shifts the dose-response tobupivacaine-induced asystole in rats,” Anesthesiology, vol. 88,no. 4, pp. 1071–1075, 1998.
• G. Weinberg, R. Ripper, D. L. Feinstein, and W. Hoffman,”Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity,” Regional Anesthesia and PainMedicine, vol. 28, no. 3, pp. 198–202, 2003.
• Di Gregorio G, et al. Clinical presentation of local anesthetic systemic toxicity: a review of published cases, 1979 to 2009. Regional Anesthesia and Pain Medicine 2010;35:181-187.
• Lamhaut, L., Hutin, A., Deutsch, J., Raphalen, J. H., Jouffroy, R., Orsini, J. P., … Carli, P. (2017). Extracorporeal Cardiopulmonary Resuscitation (ECPR) in the Prehospital Setting: An Illustrative Case of ECPR Performed in the Louvre Museum. Prehospital Emergency Care, 21(3), 386–389. https://doi.org/10.1080/10903127.2016.1263372
• Brenner, D.J., Larsen, R.S., Dickinson, P.J., Wack, R.F., Williams, D.C. and Pascoe, P.J., 2010. Development of an avian brachial plexusnerve block technique for perioperative analgesia in mallard ducks (Anas platyrhynchos). Journal of Avian Medicine and Surgery, 24(1), pp.24-34.

Useful Resources

• AAGBI Quick Reference Handbook – essential for emergency management
• Lipidrescue.org – case reports and dosing calculators
• ASRA website – regional anaesthesia safety guidelines
• BNF online – current dosing recommendations

Equipment and Supplies

Essential Emergency Kit Contents

• 20% Intralipid (250ml minimum)
• Large syringes (50ml or 250ml for rapid administration)
• AAGBI Quick Reference Handbook
• Benzodiazepines for seizure management
• Standard resuscitation equipment

Monitoring Requirements

• Continuous ECG monitoring during regional blocks
• Blood pressure monitoring throughout procedure
• Pulse oximetry for all patients
• End-tidal CO₂  for early detection of respiratory issues

---

Additional Considerations for Clinical Practice

Medicolegal Aspects

• Documentation: Clear recording of doses, injection sites, and patient monitoring
• Consent process: Discussion of LAST risk as part of informed consent
• Incident reporting: All suspected LAST cases should be reported for registry data
• Follow-up: Appropriate post-incident care and investigation

Quality Improvement

• Regular audit of local anaesthetic dosing practices
• Team training in LAST recognition and management
• Equipment checks ensuring emergency kit availability
• Case review of any suspected LAST incidents

---

Contact and Subscription Information

Acknowledgments: Special thanks to Dr. Weinberg for pioneering research in lipid rescue therapy and to the contributors of case reports that have advanced our understanding of LAST management.

---

---

“Thanks for listening guys… Every day you are getting better at this. Take it day by day, don’t overcook yourself, don’t freak out, and keep studying!”

Podcast Information & Support

Support the Show

• Donations: Help us keep the lights on and click the Support link here!

Contact & Feedback

• Comments: Share your clinical experiences and ask questions!
• Corrections: Help us improve accuracy and clarity

Follow GasGasGas On

• BlueSky:Gas Gas Gas (@gasgasgaspodcast.bsky.social)
• X / Twitter: GasGasGasFRCA (@GasGasGasFRCA) / X
• FaceBook: Facebook – Gas Gas Gas
• InstaGram: GasGasGas

Transcript

Gas Gas Gas Episode 36: Local Anaesthetic Systemic Toxicity (LAST)

Duration: 34:00 | Host Discussion on FRCA Primary Exam Preparation

---

Introduction and Welcome

00:00-00:32

Hello, and welcome to Gas, Gas, Gas – the best podcast for the FRCA primary exam. Our goal is to fill your brain with highly useful information. You might be in the gym right now, commuting, or ironing your scrubs. Regardless, revision is eventually going to end, but for now expect facts, concepts, model answers and the odd tangent. Make sure to check out gasgasgas.uk for show notes and loads more detail. Anyway, buckle up, get ready for your mind to be bent into a new shape, and let’s get on with the show.

---

Episode Overview and Guest Announcement

00:33-02:08

Today we are exploring local anaesthetic systemic toxicity with interminable joy (which I’m sure you’re all experiencing as you study for this exam). This is certainly something that I’ve quite enjoyed looking up and understanding to convey to you because it really does make us remember that every drug has complications – that’s true from paracetamol to propofol. There is such a thing as too much of a good thing.

What we’re covering today:

• Emergency immediate actions that you can apply to any unfolding disaster in theatre or elsewhere in the hospital
• Treatment of local anaesthetic systemic toxicity
• Incidence and clinical presentation
• Strategies to mitigate risk
• Pathophysiological basis of LAST
• Lipid emulsion therapy – where it came from and how we use it
• Risk factors for LAST

We are professionals and we should understand how to tailor our approach. We could just arbitrarily stick to one dose of drug for everyone, but this will ultimately lead us to having a marginally greater chance of becoming unstuck. Someone who might take that one little further cognitive step and reduce that risk really is narrowing off that bell curve, pushing those problems to the very peripheries because one size does not fit all.

Special announcement: Our dear friend Tom has returned to the show victorious – he’s now primary FRCA positive! We’re going to do reciprocal viva sessions, probably once a month, where I put him through his paces and he puts me through mine.

---

Introduction to Local Anaesthetic Systemic Toxicity

02:09-04:04

My first port of call is to introduce local anaesthetic systemic toxicity. Systemic is the key point here because we’re seeing symptoms across multiple body systems. From now on, I’m going to call it LAST (L-A-S-T), because it’s a mouthful and I’m going to say it about a hundred times.

We know local anaesthetics are chiefly sodium channel blockers. However, inconveniently for us, sodium channels are not just located on nerves (our target), but elsewhere – and herein lies the problem. Sodium channels are critical to the functioning of your central nervous system (spinal cord and brain) as well as your myocardium, that very important diffusing apparatus that keeps the blood going round and round.

Important distinction: It’s chiefly amide local anaesthetic agents that cause LAST. You have to remember that ester local anaesthetic agents are cleared by plasma esterases in an extensive system, which means their capacity to achieve a plasma concentration sufficient to get about and cause bother elsewhere is less (not completely zero, but less). Therefore, to achieve LAST with an ester agent, you’d probably have to be injecting it intravenously with a reasonable quantity.

We’re focusing on amide local anaesthetic agents:

• Bupivacaine
• Ropivacaine
• Lidocaine
• Prilocaine

These are the chief offenders because they are cleared hepatically, so you can imagine they have a higher risk of accumulating in people.

---

Dosing and Toxicity Thresholds

04:04-04:48

Toxicity is directly related to the plasma concentration. This is why we’re quite interested in how vascular a site is where we are injecting agent, because that’s directly going to relate to uptake of agent from site to systemic circulation.

LAST can come about through:

• Inadvertent intravascular injection
• Rapid uptake from a vascular space
• Uptake from a field block

Safety hierarchy of injection sites (safest to most dangerous):

1. Subcutaneous infiltration (safest)
2. Brachial plexus
3. Epidural space
4. Caudal injections
5. Intercostal injections
6. Intravenous (the big baddie)

---

Historical Dosing Studies

04:48-07:09

How much is too much intravenously? I can tell you that 2mg/kg of bupivacaine IV is certainly bad news. These doses are probably slightly conservative for safety reasons.

Historical study (Mother, Long, and Thomas, 1971): Three volunteer subjects received bupivacaine infusions:

• 0.6mg/kg for first 5 minutes
• 0.75mg/kg from minutes 9-13
• Total doses: 130mg, 102mg, and 104mg intravenously
• None had lethal side effects
• All experienced sensory symptoms: dizziness, limb numbness, pressure in ears, feeling vague
• One subject complained of inability to focus eyes on objects (no clinical nystagmus)

The trouble is that none of us are injecting bupivacaine into someone’s interscalene region over 13 minutes, so we would find a peak plasma concentration much higher if we were to inadvertently inject. But we could apply this principle when loading an epidural during a laparotomy – think about not putting the whole dose in at once.

Current BNF dosing for bupivacaine:

• 150mg maximum dose in one go (30ml of 0.5%)
• 400mg in 24 hours (80ml of 0.5%)

This should be dosed on ideal body weight: 2mg/kg is the quoted number in the UK. There are suggestions you could go higher, but few people do for very good reason – we don’t know how the person in front of us is going to behave with their clearance mechanisms, redistribution, and other pharmacokinetic factors.

---

Emergency Management – Core Actions

07:09-10:26

Let’s talk about what you should do when you see an emergency happening in front of your eyes in theatre. I’ll classify this as the “core badness happening opening lines”:

Immediate actions:

1. Stop the surgeon (unless they’re doing something they absolutely can’t stop, like stopping bleeding)
2. Declare an emergency to the team
3. Administer 100% oxygen (if on volatile, think about not overdosing on anaesthetic agent)
4. Call for help/pull emergency bell
5. Declare what you need – arrest trolley, malignant hyperthermia kit, LAST kit, anaphylaxis kit
6. Obtain quick reference handbook from AAGBI (otherwise you’re going to miss something)
7. Delegate – get the theatre leader to read the handbook whilst you focus on patient care

---

Specific LAST Treatment

10:26-13:07

Resuscitation priorities:

• Airway, breathing, circulation – 100% oxygen and appropriate ventilation to avoid CO₂ accumulation and acidosis
• Treat seizures with benzodiazepines (could also use thiopentone)
• Consider paralysing and intubating for florid seizure activity (reduces metabolic demand and lactic acid accumulation)
• Don’t reach for propofol – there’s no intralipid, and propofol contains negative inotrope and systemic vasodilator

Intralipid dosing:

• Initial bolus: 1.5ml/kg over 1 minute (approximately 100ml for 75kg person – use 250ml syringe)
• Infusion: 15ml/kg/hour
• Additional boluses: at 5 and 10 minutes
• Can double infusion rate after 5 minutes
• Maximum cumulative dose exists (check guidelines)

Other considerations:

• Use less adrenaline – 1mcg/kg doses
• Vasopressin associated with worse outcomes in animal models
• Consider prolonged resuscitation and ECMO if available

---

Incidence and Epidemiology

13:07-14:46

LAST has become less common over time, probably due to awareness and mitigation strategies.

Historical data:

• 1995 (Brown et al.): 79 episodes of seizures in 10,000 interscalene blocks (pre-1981)
• Pre-1981: 100 episodes of LAST in 10,000 epidural anaesthetics

Recent data (March 2014-November 2016):

• 47 cases of LAST described
• 22 treated with lipid emulsion
• 2 patients died overall

Common causes:

• Historically: accidental intravascular injection
• Currently: continuous bupivacaine infusions, weight miscalculations in children

---

Clinical Presentation

14:46-18:02

Classical description (biphasic):

Phase 1 – CNS effects (occur first):

• Sensory disturbance, agitation
• Auditory changes (tinnitus, pressure in ears)
• Metallic taste
• Circumoral tingling or numbness
• Seizure activity
• Drowsiness, coma
• Respiratory arrest (brainstem affected)

Phase 2 – Cardiovascular effects:

• Initial: hypertensive, tachycardic
• Ventricular arrhythmias
• Later: bradycardia, conduction blocks, asystole

Reality check: Patients don’t read textbooks! About 40% of cases (case series 1979-2009) didn’t fit this classical pattern. It’s more like any and all of this can happen in rapid, intermingled succession.

Actual statistics:

• 68% had seizures
• 50% had cardiovascular signs including arrhythmias
• 27% of arrhythmias were bradycardia/asystole
• 20% presented with isolated cardiovascular disturbance

Timing:

• Pre-ultrasound era: onset ~50 seconds from injection
• Current era: onset stretching out (less inadvertent intravascular injection)
• Location shifting from theatre complexes to other hospital areas (A&E fascia iliaca blocks, ward patients with erector spinae plane catheters)

---

Risk Mitigation Strategies

18:02-19:46

Clinical strategies:

• Pre-calculated dosing – know maximum dose for each patient
• Consider individual pharmacokinetics – frailty, cardiovascular status, hepatic clearance
• Incremental injection with aspiration checks
• Fractionate epidural dosing over time
• Use lowest effective dose for adequate sensory blockade
• Clear team communication about local anaesthetic administration
• Use NRFit syringes to prevent accidental IV injection
• Ultrasound guidance wherever available ± nerve stimulators
• Consider adrenaline for intravascular detection (regional practice)
• Full monitoring – SpO₂, blood pressure, ECG

Risk reduction with ultrasound: Not using ultrasound increases risk 4-fold.

---

Pathophysiology

19:46-23:26

Primary mechanism: Whilst sodium channels are the obvious target, nothing is ever that simple.

Multiple mechanisms involved:

1. Sodium channel blockade (CNS and myocardium)
2. Potassium channel interference (impairs repolarisation)
3. Calcium channel disruption (sarcoplasmic reticulum)
4. Mitochondrial impairment (probably the main offender)

Drug specificity: Bupivacaine is more cardiotoxic than lidocaine. Ropivacaine is safer again. Studies show bupivacaine’s conduction-altering properties persist longer than lidocaine, disproportionate to relative potencies.

Mitochondrial mechanism (Weinberg et al.):

• Local anaesthetics block carnitine-like molecules entering mitochondria
• Inhibits electron transport chain (particularly complex I)
• Reduces ATP generation
• Critical problem for cardiac myocytes dependent on rapid ion shifts and contraction

The vicious cycle:

1. Patient in VF arrest → no circulation
2. CO₂ rises, cellular metabolism shifts anaerobic
3. Lactate production, acidosis develops
4. Acidosis displaces local anaesthetic from α-1 acid glycoprotein
5. More free drug available to cause further problems
6. Accelerating process of badness

This is why we need to get intralipid in promptly.

---

Lipid Emulsion Therapy

23:26-26:52

What is intralipid?

• Same stuff used in TPN (total parenteral nutrition)
• Derived from soybean oil
• Contains egg phospholipids and anhydrous glycerol

Discovery story: Dr Weinberg (University of Illinois) stumbled across intralipid whilst exploring carnitine deficiency in rats. He accidentally found it made rats ~50% more resistant to local anaesthetic cardiotoxicity. Published successful dog rescue study in 2003.

First human case: Rosenblatt (2006) – successful resuscitation following interscalene block toxicity.

UK guidance: Intralipid in LAST guidance since 2007.

Mechanism of action:

• Primary: Formation of lipid sink for free local anaesthetic in plasma
• Process: “Shuttling” – liberates drug from high-concentration tissues, redistributes to low-concentration areas
• Effect: Homogenises concentration throughout body compartments
• Additional benefits: May provide direct energy source (fatty acids to mitochondria), alter myocardial calcium concentrations

Important notes:

• Intralipid doesn’t work every time
• More effective than nothing
• Contractility improvement only occurs after sufficient drug redistribution

---

Risk Factors for LAST

26:52-31:14

Patient factors:

• Pre-existing heart disease (cardiovascular fragility)
• General frailty, diminished muscle mass
• Age extremes (very young and very old)
• Diabetic patients (multi-system effects)
• Poor hepatic perfusion (though liver still produces proteins when compromised)
• Acidosis (displaces drug from plasma proteins)
• Reduced plasma proteins (particularly α-1 acid glycoprotein)

α-1 acid glycoprotein note: This is an acute phase reactant – increases in post-operative, inflamed, infected patients, potentially offering some protection.

Procedural factors:

• Not using ultrasound (4x increased risk)

---

Special Populations

27:02-31:00

Pregnant patients:

• Increased cardiac output (30-50% above baseline) → increased perfusion and drug uptake
• Decreased α-1 acid glycoprotein → less protein binding
• Engorged epidural venous systems → more space for drug distribution
• Still typically use 20ml of 0.5% for epidural top-ups despite ongoing infusions
• Technically higher risk, but doses remain standard

Paediatric patients:

• Immature hepatic metabolism
• Less α-1 acid glycoprotein
• Clearance doesn’t reach adult levels until 6-9 months
• Harder to identify CNS toxicity signs (can’t complain of tinnitus or lip tingling)

Elderly patients:

• Lower clearance rates → potential accumulation with infusions
• Reduced muscle mass and total body water (babies are watery, elderly are fatty)
• Larger volume of distribution → bigger “swimming pool” for drug distribution

Liver disease:

• Single shot blocks: normal dose acceptable
• Continuous infusions/repeat blocks: consider 10-50% dose reduction

Renal dysfunction:

• Consider 10-20% dose reduction relative to degree of dysfunction
• Reduced clearance capacity

---

CNS to CVS Ratio Concept

31:00-32:04

This concept examines the dose causing seizures versus cardiac compromise. We’re happier for patients to have seizures than asystolic arrest – seizures give us warning and opportunity for intervention.

Drug comparison:

• Bupivacaine: Better CNS:CVS ratio than lidocaine
• Ropivacaine: Probably safest of all

Important distinction: Direct nerve injection causes neurotoxicity (local effect), and injection into joint spaces causes cartilage toxicity – these are different from systemic toxicity.

---

Summary and Key Messages

32:04-34:01

Clinical pearls:

• High index of suspicion for weird happenings after local anaesthetic administration
• Patient education: Explain potential for toxic effects, ask them to report unusual sensations (don’t specify tinnitus/lip tingling – they might ignore other symptoms)
• Emergency management: 100ml intralipid for 75kg patient in arrest situation
• Always use quick reference handbook and delegate if possible
• Be wary of continuous high-concentration local anaesthetic infusions
• Clear communication with team about blocks performed
• Minimum effective dosing for required block goals

Pathophysiology summary:

• Sodium blockade PLUS potassium channels, calcium channels, and mitochondrial impairment
• Intralipid works by shuttling drug from high to low concentration compartments
• Speeds redistribution to get below toxic threshold

Special acknowledgment: Thanks to Dr Weinberg for his discovery work.

Further reading: Visit lipidrescue.org for case reports of lipid rescue in other lipophilic poisonings.

---

Closing Remarks

34:00-34:25

Thanks for listening! I quite enjoyed this episode – who doesn’t enjoy reading about interesting physiology and how the science came about? Check out the show notes for more detail, and remember: every day you are getting better at this. There’s a bucket of content to consume and it’s like drinking from a fire hose. Take it day by day, don’t overcook yourself, don’t freak out, and keep studying.

---

This transcript has been edited for clarity and structure whilst preserving all clinical content and the engaging conversational style of the original podcast.

This is the full Show Transcript – Courtesy of Whisper LLM