CONTENTS

• Epidemiology
• Presentation
• Differential diagnosis
• Treatment
  • Lipid Emulsion therapy

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epidemiology

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suggested maximal safe doses of local anesthetics (based on ideal body weight)

• Bupivacaine/Levobupivacaine: 2 mg/kg alone; 3 mg/kg with epinephrine.
• Lidocaine: 5 mg/kg alone; 7 mg/kg with epinephrine.
• Mepivacaine: 5 mg/kg alone; 7 mg/kg with epinephrine.
• Ropivacaine: 3 mg/kg.
• Prilocaine: 6 mg/kg alone; 8 mg/kg with epinephrine. (35777259, 30122981)

exposure-related risk factors

• Nerve blocks (LAST occurs in ~1/5000 blocks): (35777259)
  • High-volume blocks, with doses approaching the maximal safe dose range (listed above).
  • Placement of a catheter for prolonged anesthetic infusion.
  • Failure to use ultrasound guidance. (29356773)
  • Bupivacaine has greater risks than ropivacaine or lidocaine. (29356773)
• Intravenous lidocaine infusions:
  • Prolonged, high-dose infusions.
• Less common causes of LAST:
  • Mucosal administration (e.g., bronchoscopy or awake intubation).
  • Large-volume, subcutaneous administration (e.g., to facilitate liposuction).

patient-dependent risk factors

• Hepatic dysfunction: Most anesthetics are hepatically cleared. Clearance rate is most relevant if the agent is slowly absorbed, administered in multiple doses, or provided as a continuous infusion.
• Cardiac dysfunction: Reduced cardiac reserve function may render LAST more dangerous (e.g., patients with severe chronic systolic heart failure or underlying conduction disease).
• Renal dysfunction: Uremia and acidosis may increase free drug levels, exacerbating toxicity. (33426662)
• Low muscle mass (e.g., older age, cachexia).
• Pregnancy (hyperdynamic circulation may accelerate systemic absorption following nerve blocks; reduced concentration of alpha-1 acid glycoprotein leads to higher free drug levels).
• Mitochondrial dysfunction (e.g., carnitine deficiency).

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presentation

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timing

• LAST can occur within minutes of local anesthetic administration (due to inadvertent intravenous administration).
• LAST can occur in a delayed fashion under some circumstances:
  • Gradual systemic absorption following a single administration of local anesthetic. This may occur several hours after administration.
  • Continuous infusion of local or systemic medication with eventual accumulation(e.g., intravenous lidocaine infusion).
• Delayed-onset LAST may be harder to diagnose because it's not obviously temporally linked to anesthetic administration, and clinically, it may evolve in a more gradual fashion. (31461049)

LAST typically begins with CNS symptoms

• Early symptoms may include:
  • Sensory abnormalities:
    • Auditory changes, tinnitus.
    • Metallic taste.
    • Circumoral numbness or paresthesias.
    • Visual disturbance (e.g., blurred vision).
    • Dizziness.
  • Dysarthria.
  • Tremor or muscular twitching.
  • Anxiety.
  • Delirium.
• Later symptoms:
  • Somnolence, coma, and respiratory suppression may eventually occur.
  • Seizure was the most common presentation in one literature review. (31461049)
• ⚠️ Intubated patients may fail to manifest CNS symptoms. This creates a dangerous situation wherein LAST may be diagnosed late (when it causes hemodynamic abnormalities).

cardiovascular symptoms usually occur second

• 🔑 Neurologic symptoms usually occur first, but a fifth of patients may initially present with cardiovascular abnormalities. (30122981)
• Initial features may include sympathetic activation:
  • Tachycardia.
  • Hypertension.
  • Diaphoresis.
• Later features may vary, including:
  • Bradycardia and AV block, widened QRS complexes.
  • Reduced contractility, which may manifest predominantly as hypotension.
• Ultimately, any form of cardiac arrest can occur (ventricular tachycardia, ventricular fibrillation, PEA, or asystole).
• Different effects from various agents:
  • Lidocaine and mepivacaine tend to reduce contractility more.
  • Bupivacaine and ropivacaine tend to cause more arrhythmias. (35777259)

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differential diagnosis

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procedural complication (if nerve block is done to facilitate a procedure)

• Pneumothorax.
• Hemorrhage.
• Side effects from other medications that were co-administered to facilitate procedural sedation.

methemoglobinemia

• This may occur with benzocaine, lidocaine, or prilocaine.
• Typically, methemoglobinemia presents initially with desaturation and cyanosis.
• (More on methemoglobinemia here.)

anaphylaxis

• Anaphylaxis due to local anesthetics is very rare.
• Anaphylaxis is more likely if other medications are co-administered (e.g., antibiotic).
• (More on anaphylaxis here.)

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treatment

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stop further administration

• If anesthetic is being infused, stop it.

lipid emulsion

• Lipid Emulsion therapy

airway management

• Hypoxemia and hypercapnia may both exacerbate LAST.
  • ⚠️ Hypoventilation may lead to a vicious spiral that exacerbates LAST.
• There should be a relatively low threshold for intubation to secure the airway.

hemodynamic management

• If arrhythmias occur:
  • Don't give lidocaine or procainamide!
  • Avoid pure beta-blockers or calcium channel blockers, which may exacerbate hypotension.
  • Amiodarone is the front-line antiarrhythmic for ventricular arrhythmias. (29356773)
• If epinephrine is required (e.g., for PEA arrest), it should be dose-reduced by a factor of about ten to avoid arrhythmia:
  • Instead of 1 mg doses, 1 microgram/kilogram doses are recommended. (29356773)
• Vasopressin is generally avoided (the primary problem is cardiogenic failure, so increasing the afterload may merely exacerbate that). (33426662)

seizures

• First-line therapy is with benzodiazepines; for example, beginning with an initial dose of:
  • Lorazepam 0.1 mg/kg IV.
  • Midazolam 10 mg IV or IM.
• Use propofol cautiously, as this may promote cardiac collapse.
• ⚠️ Avoid phenytoin, because phenytoin exerts anti-sodium channel activity.
• Ketamine and/or levetiracetam could be reasonable antiepileptic agents in this context, but no high-level evidence exists.
• Convulsions may worsen acidosis and thereby exacerbate the overall LAST toxicity. If seizures are resistant to benzodiazepine and intubation (with ketamine and/or propofol), neuromuscular paralysis might be an acceptable therapy to avoid muscular exertion that causes acidosis. (29356773) However, paralysis will not protect the brain from ongoing seizure activity, so simultaneous and aggressive efforts must be made to stop the seizures (e.g., including placement of video EEG monitoring and administration of additional antiepileptic medications).
• (More on the management of status epilepticus here.)

cardiopulmonary bypass or ECMO

• Toxicity can last 1-2 hours.
• Prolonged CPR may be indicated.
• If cardiopulmonary bypass or ECMO are available, these are indicated for refractory LAST.

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lipid emulsion therapy for poisoning

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contraindications, drug interactions, side effects 👎

contraindications

• Pre-existing hypertriglyceridemia.
  • Inherited disorders of fat metabolism (e.g., familial hyperlipoproteinemia).
• Acute pancreatitis.
• Pre-existing ARDS.
• Severe hepatic dysfunction (impaired clearance of fat may increase the risk of fat-overload syndrome).
• ECMO/CRRT circuits (lipid may accumulate and obstruct filters).

drug-drug interactions

• Propofol or clevidipine (may promote fat overload; patients are too unstable for these medications any so discontinue propofol).
• Warfarin (intralipid contains vitamin K).
• Reduced levels of co-administered lipophilic drugs (due to sequestration).

side effects

• Lipemic interference with laboratory studies. Centrifugation of blood specimens may enable more accurate testing.
• Fat excess:
  • Fat overload syndrome (may include hyperlipidemia, fever, hepatomegaly, splenomegaly, thrombocytopenia, and multi-organ failure).
  • Hypertriglyceridemia and pancreatitis.
• Allergic-type reactions:
  • Anaphylactoid reactions (e.g., pruritus, urticaria, diffuse erythema, hypotension, nausea, vomiting, diarrhea).
  • Anaphylaxis.
• Organ failures:
  • ARDS.
  • Renal failure.
  • DIC.
  • Altered mental status, seizures.
• Clogging of ECMO or dialysis circuits. (31461049)

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indications, advantages 👍

• [1] The primary indication is LAST (local anesthetic systemic toxicity), with features such as:
  • Substantial neurologic toxicity (e.g., seizures).
  • Substantial cardiovascular effects:
    • Malignant arrhythmias.
    • Hypotension.
    • Cardiac arrest.
  • Rapid clinical deterioration.
• [2] Potential indication for other lipophilic cardiotoxic medications (especially bupropion and amitriptyline). Intralipid should only be utilized for patients failing to respond to other measures. (37242638)

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dosing of 20% lipid emulsion (INTRALIPID)

2017 AMCT protocol for Intralipid dosing 

• [1] First loading bolus:
  • 1.5 ml/kg (or 100 ml).
  • Give over 2-3 minutes.
• [2] Second bolus of 50-100 ml over three minutes:
  • No response to the first bolus: administer a full bolus (100 ml) again.
  • Some response to first bolus: give half of the initial bolus (0.75 ml/kg, or ~50 ml).
• [3] Infusion rate depends on the tempo of the toxicity:
  • [a] 1.5 ml/kg/hour (e.g., ~100 ml/hour).
    • This rate is recommended in the 2017 AMCT guidelines. (27121236)  
    • This rate seems appropriate for a subacute poisoning (e.g., bupropion), which may last for many hours or even days.
  • [b] Severe, peri-coding local anesthetic systemic toxicity:
    • Many sources recommend ten times this rate, or 15 ml/kg/hr (~1000 ml/hour).
    • This seems reasonable for a severely ill LAST patient.
    • You must shut off the infusion after achieving hemodynamic stability, ideally within 30 minutes.
    • Continuing a rate of 15 ml/kg/hr for >>30 minutes will probably cause more harm than benefit.
• [4] Subsequent management:
  • For deterioration, re-bolusing could be attempted.
  • For resolution, wean or stop the infusion.  Ideally, the infusion will be stopped or reduced within ~6 hours. (27608281)  
• Maximal cumulative safe dose?
  • This is not well known.
  • Many sources refer to a maximal cumulative volume of ~10-12 ml/kg over 24 hours. (27121236) 
  • For patients weighing >84 kg, the exposure should probably be capped at one liter of Intralipid.
  • For more acute poisoning with a shorter anticipated duration (e.g., local anesthetic systemic toxicity), higher doses may be reasonable for a shorter period (e.g., 500-1,000 ml infused over 30-60 minutes). Alternatively, for prolonged intoxications, a lower infusion may be desirable for a prolonged period of time.
  • 🔑 The key thing is to actually, truly, legitimately keep track of the cumulative intralipid administration. Ridiculously toxic doses occur when someone starts an infusion, gets distracted, and nobody is paying attention to the cumulative dose.

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monitoring

• Triglyceride levels. (Let's be honest, though: the labs will be lipemic and you probably won't have any idea what the triglyceride level is.)

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pharmacology

• Administration: IV
• Distribution:
  • Lipid emulsion is distributed to the intravascular compartment.
• Metabolism:
  • Lipoprotein lipase in capillary beds hydrolyzes lipid emulsion into free fatty acids and glycerol.
  • Free fatty acids may undergo oxidation for energy (via beta-oxidation), re-esterification and storage in adipose tissue, or incorporation into cell membranes.
  • Glycerol is either burned as fuel or used in glyconeogenesis and triglyceride synthesis.
• Elimination:
  • Critically ill patients have reduced metabolism of Intralipid.
• Half-life & duration of action:
  • Intralipid is usually cleared within 6 hours of infusion cessation.

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questions & discussion

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