Local Anesthetic Systemic Toxicity

Environmental MONDO:0100335 Pathograph 23 Show in embeddings browser

Local anesthetic systemic toxicity is an acute drug toxicity that follows an excessive plasma concentration of a local anesthetic, usually after inadvertent intravascular injection, rapid absorption from a vascular tissue bed, or cumulative overdose during regional anesthesia. It affects the two tissues whose function depends most on fast sodium currents: the central nervous system and the heart. The shared molecular action is blockade of voltage-gated sodium channels. In the cortex, inhibitory interneurons are silenced before excitatory pathways, so the first clinical picture is excitation - perioral numbness, tinnitus, agitation, then seizure - and only at higher concentrations does global conduction failure produce coma and apnoea. In the heart, blockade of Nav1.5 slows conduction and sets up reentrant ventricular arrhythmia, while a separate mitochondrial action impairs the myocardium's fatty acid fuel supply. The two arms converge on cardiovascular collapse. Bupivacaine is the prototypical offender, and the reason is pharmacological rather than incidental: it accelerates the cardiac sodium channel's entry into slow inactivation, so blockade deepens with successive beats. Note that use-dependent block is a class property rather than something unique to bupivacaine - the electrophysiology paper cited below is explicit that this is "consistent with other local anesthetics" - and that the recent mortality literature reports lidocaine, not bupivacaine, as the leading reported cause of death attributed to this syndrome. Neither observation is curated as a claim here; both are reasons the prototypical-offender framing is a simplification. Treatment is unusual among toxidromes in having a specific antidote, intravenous lipid emulsion, whose mechanism remains unsettled. Incidence has fallen with ultrasound guidance, and the presentation has shifted: the classic progressive sequence described in textbooks fits only about three-fifths of published cases.

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11
Pathophys.
15
Phenotypes
2
Hypotheses
2
Gaps
23
Pathograph
1
Genes
3
Medical Actions
2
Models
3
References
1
Deep Research
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Mechanistic Hypotheses

2
Sodium channel blockade as the primary cardiotoxic mechanism
sodium_channel_cardiotoxicity CANONICAL
Evidence balance 1 support
Cardiac toxicity arises principally from blockade of the cardiac voltage-gated sodium channel Nav1.5, with the potency differences between agents explained by how fast each one leaves the channel. Reviews of the field describe the experimental data as mixed while still placing sodium channels first.
Pathograph links
Systemic Local Anesthetic Exposure -> Cardiac Sodium Channel Blockade DIRECT
Cardiac Sodium Channel Blockade -> Impaired Cardiac Impulse Conduction DIRECT
Show evidence (1 reference)
PMID:21841477 SUPPORT REVIEW SYNTHESIS Other
"Regarding mechanism(s) of LAST, the evidence remains mixed, but it is likely that local anesthetic cardiotoxicity primarily arises from a blockade of sodium channels."
States the hypothesis and its standing in one sentence, including the hedge. "The evidence remains mixed" is why this is curated as a hypothesis group rather than as settled fact. Graded OTHER because the quoted sentence is a review's summary judgement across a literature rather than any one study's result.
Mitochondrial carnitine-acylcarnitine translocase inhibition
mitochondrial_bioenergetic_contribution ALTERNATIVE
Evidence balance 2 support
A second, parallel mechanism: local anesthetics with a cardiotoxic profile inhibit the carnitine-acylcarnitine translocase, cutting off long-chain fatty acid entry into the mitochondrial matrix and starving the myocardium of its main fuel. The potency ranking across agents tracks their clinical cardiotoxicity, which is the observation the hypothesis rests on. It is not a rival to sodium channel blockade so much as a proposed amplifier of it, and its quantitative contribution in a whole organism is unresolved.
Pathograph links
Systemic Local Anesthetic Exposure -> Mitochondrial Carnitine-Acylcarnitine Translocase Inhibition DIRECT
Mitochondrial Carnitine-Acylcarnitine Translocase Inhibition -> Myocardial Bioenergetic Failure DIRECT
Show evidence (2 references)
PMID:10691241 SUPPORT PRIMARY RESULT In Vitro
"The authors hypothesize that differential inhibition of carnitine-stimulated pyruvate oxidation by various local anesthetics supports the clinical relevance of inhibition of carnitine-acylcarnitine translocase by local anesthetics with a cardiotoxic profile."
The hypothesis in the originating authors' own words, and quoted with "The authors hypothesize" intact: this is proposed, not demonstrated, in the paper that proposes it.
PMID:10691241 SUPPORT PRIMARY RESULT In Vitro
"Bupivacaine (IC50 = 0.26+/-0.06 mM) and etidocaine (IC50 = 0.30+/-0.12 mM) inhibit carnitine-stimulated pyruvate oxidation similarly, whereas the lidocaine IC50 is greater by a factor of roughly 5, (IC50 = 1.4+/-0.26 mM), and ropivacaine is intermediate, IC50 = 0.5+/-0.28 mM."
The potency ranking that makes the hypothesis interesting: bupivacaine and etidocaine most potent, lidocaine roughly fivefold weaker, ropivacaine between them - the same order as their clinical cardiotoxicity.
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Discussions and Knowledge Gaps

2
By what mechanism does intravenous lipid emulsion reverse local anesthetic cardiotoxicity - sequestration of the drug, a direct cardiotonic effect, post-conditioning, or some combination?
KNOWLEDGE GAP lipid_rescue_mechanism
Attached to
treatments#Intravenous Lipid Emulsion pathophysiology#Myocardial Contractile Depression
This is the unusual case of an antidote in routine guideline-endorsed use whose mechanism is still argued over. The "lipid sink" account - intravascular lipid sequestering drug away from target tissue - is the oldest and is supported by the cardiomyoblast work. Against it, a dose-response study in rats found recovery driven by a cardiotonic effect that the authors say complements rather than replaces sequestration, and the ASRA advisory names three mechanisms at once. Others have proposed that recovery is simply hemodilution. The question is not academic: if the sink dominates, the antidote should be reserved for the most lipophilic agents, and if inotropy dominates, it should not.
Show evidence (3 references)
PMID:29356773 SUPPORT REVIEW SYNTHESIS Other
"This interim update summarizes recent scientific findings that have enhanced our understanding of the mechanisms that lead to lipid emulsion reversal of LAST, including rapid partitioning, direct inotropy, and post-conditioning."
The guideline naming three distinct mechanisms, which is the state of the question rather than a resolution of it.
PMID:37242638 SUPPORT REVIEW SYNTHESIS Other
"Additional mechanisms based on ILE-attributed vasoactive and cytoprotective properties are still under investigation."
Confirms the list is still open, not merely contested between two settled options.
PMID:24496123 SUPPORT PRIMARY RESULT Model Organism
"An increase in arterial blood pressure underlay the recovery in both lipid emulsion-treated groups."
The observation behind the cardiotonic account: recovery tracked blood pressure, not heart rate, in a controlled dose-response design.
Why does the classic progressive neurological-then-cardiovascular sequence describe only about three-fifths of published cases, and what determines which patients present with cardiovascular signs alone or after a delay?
KNOWLEDGE GAP classic_presentation_is_the_minority_picture
Attached to
pathophysiology#Cortical Disinhibition phenotypes#Hypotension
The textbook model this entry's pathograph follows - rising concentration producing an ordered neurological sequence, with cardiovascular signs late - is the minority presentation in a 30-year review of published cases. The remainder were substantially delayed or purely cardiovascular with no central nervous system signs at all. The ASRA advisory reports the same drift and offers candidate explanations, all of them changes in practice rather than in biology: ultrasound guidance means fewer intravascular injections, infiltration techniques absorb more slowly, and continuous infusions accumulate. Whether the shift is entirely explained by technique or partly reflects who is now being affected is not settled; the advisory notes an increasing share of events outside hospitals and involving non-anesthesiologists.
Show evidence (3 references)
PMID:20301824 REFUTE PRIMARY RESULT Human Clinical
"Sixty percent of cases followed the classic pattern of presentation. However, in the remainder of cases, symptoms were substantially delayed after the injection of local anesthetic, or involved only signs of cardiovascular compromise, with no evidence of central nervous system toxicity."
REFUTE, and the object is the pathograph, not this discussion. The discussion's own rationale asserts what this sentence says, so read against the discussion it would be SUPPORT. It is graded REFUTE because the claim it cuts against is the ordered neurological-then-cardiovascular model that this entry's `Cortical Disinhibition` chain encodes, and which the same paper supplies as BACKGROUND two nodes away. Stating the object explicitly because `supports` is claim-relative and the two gradings of this reference would otherwise look inconsistent.
PMID:29356773 SUPPORT REVIEW SYNTHESIS Other
"Contemporary case reports suggest a trend toward delayed presentation, which may mirror the increased use of ultrasound guidance (fewer intravascular injections), local infiltration techniques (slower systemic uptake), and continuous local anesthetic infusions."
The candidate explanations, all of them practice changes, and offered by the guideline as a possibility ("may mirror") rather than as established.
PMID:39398741 SUPPORT PRIMARY RESULT Human Clinical
"Pregnant cohorts had a significantly higher risk of cardiac depression (risk ratio (RR)=1.96 (95% confidence interval (CI): 1.44-2.66), p<0.01) and significantly lower risk of cardiac excitation (RR=0.38 (95% CI: 0.22-0.63), p<0.01), prodromal symptoms (RR=0.17 (95% CI: 0.09-0.33), p<0.01),..."
The discussion asks what determines which patients skip the prodrome. This is the one cited source that measures a population where they do: matched pregnant and nonpregnant cohorts, with the prodrome roughly six times less likely in pregnancy and cardiac depression twice as likely. It narrows the question rather than settling it - the authors offer gestational physiology and earlier detection as competing explanations for the same numbers, and a matched retrospective database cohort cannot separate them.
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Pathophysiology

11
Systemic Local Anesthetic Exposure
An excessive free plasma concentration of local anesthetic, from inadvertent intravascular injection, rapid absorption from a vascular tissue bed, or cumulative overdose. Everything downstream is concentration-dependent, which is why the clinical picture is a sequence rather than a switch.
Mitochondrial carnitine-acylcarnitine translocase inhibition Sodium channel blockade as the primary cardiotoxic mechanism
Downstream
Cardiac Sodium Channel Blockade Sodium channel blockade as the primary cardiotoxic mechanism
Cortical GABAergic Interneuron Blockade
Mitochondrial Carnitine-Acylcarnitine Translocase Inhibition Mitochondrial carnitine-acylcarnitine translocase inhibition
Show evidence (1 reference)
PMID:42589553 SUPPORT REVIEW SYNTHESIS Other
"Their therapeutic effect is based mainly on reversible voltage-gated sodium channel inhibition, but toxicity is not limited to this mechanism."
Frames the entry's two-arm structure: the therapeutic action and the toxic action share a target, and the toxicity reaches past it.
Cortical GABAergic Interneuron Blockade
Inhibitory tone is lost before excitatory transmission, which is why the first manifestation of a central nervous system overdose is excitation rather than sedation. The route is not purely sodium channel blockade of interneurons: cited experimental work attributes it to suppressed presynaptic GABA release and reduced GABA-A receptor currents as well. The sodium channel binding on this node is the shared class action, not the whole account.
cortical GABAergic interneuron CL:0000617 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cortical GABAergic interneuron, annotated with GABAergic neuron (CL:0000617). CL:0000617 is a cell type from the Cell Ontology.
voltage-gated sodium channel activity GO:0005248 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased voltage-gated sodium channel activity (GO:0005248). GO:0005248 is a molecular function from the Gene Ontology. ↓ DECREASED
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Cortical Disinhibition
Show evidence (2 references)
PMID:42589553 SUPPORT REVIEW SYNTHESIS Other
"Experimental studies show that local anesthetics can suppress presynaptic γ-aminobutyric acid (GABA) release, reduce γ-aminobutyric acid type A (GABA-A) receptor-mediated currents in a subunit-dependent manner, and, particularly with lidocaine, shift the GABA-induced reversal potential in a..."
The mechanisms behind the loss of inhibitory tone this node names, and the reason its description does not attribute the effect to sodium channel blockade alone.
PMID:42589553 REFUTE REVIEW SYNTHESIS Other
"At the molecular level, CNS toxicity involves more than sodium channel block."
REFUTE against reading this node's sodium channel binding as the complete mechanism. Carried explicitly because an earlier draft of the node description asserted selective sodium channel blockade of interneurons with no evidence at all, and this is the sentence that corrects it.
Cortical Disinhibition
Net excitation of cortical circuits once inhibitory tone is removed, producing the excitatory prodrome and then seizure.
Downstream
Seizure
Agitation
Global Neuronal Conduction Failure Not a consequence of disinhibition itself but of the rising concentration that produced it: as blockade extends to excitatory pathways the excitatory phase gives way to depression. The intermediate is the continued rise in free drug concentration.
Show evidence (1 reference)
PMID:20301824 SUPPORT BACKGROUND Human Clinical
"The classic description of local anesthetic systemic toxicity (LAST) generally described in textbooks includes a series of progressively worsening neurologic symptoms and signs occurring shortly after the injection of local anesthetic and paralleling progressive increases in blood local..."
The concentration-dependent neurological sequence this node and the next one model. BACKGROUND because it is the paper's statement of the textbook picture, which the paper then goes on to test - see the REFUTE item on the same reference under `discussions`.
Global Neuronal Conduction Failure
At higher concentrations sodium channel blockade is no longer selective for inhibitory pathways, and widespread neuronal conduction failure produces depression of consciousness and respiratory drive.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Downstream
Coma
Cardiac Sodium Channel Blockade
Voltage- and use-dependent blockade of Nav1.5, the dominant sodium channel isoform in working myocardium. Bupivacaine blocks it within the clinical concentration range and accelerates the channel's entry into slow inactivation, so the block deepens with each beat rather than recovering between them.
Sodium channel blockade as the primary cardiotoxic mechanism
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Nav1.5 voltage-gated sodium channel activity GO:0086006 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased Nav1.5 voltage-gated sodium channel activity, annotated with voltage-gated sodium channel activity involved in cardiac muscle cell action potential (GO:0086006). GO:0086006 is a molecular function from the Gene Ontology. ↓ DECREASED
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Experimental models
Nav1.5 expressed in Xenopus oocytes OTHER Measures the block directly at the channel, giving the potency and the use-dependence the node claims.
Downstream
Impaired Cardiac Impulse Conduction Sodium channel blockade as the primary cardiotoxic mechanism
Show evidence (2 references)
PMID:25008571 SUPPORT PRIMARY RESULT In Vitro
"The electrophysiological measurements on Nav1.5 expressed in Xenopus oocytes showed that bupivacaine induced a voltage- and concentration-dependent blockade on the peak of I Na and the half-maximal inhibitory dose was 4.51 μmol/L."
The direct measurement of blockade on the channel this node names, with the potency figure. IN_VITRO because it is a heterologous expression system, not a heart.
PMID:25008571 SUPPORT PRIMARY RESULT In Vitro
"The underlying mechanisms of this blockade may contribute to the fact that bupivacaine not only dose-dependently affected the gating kinetics of Nav1.5 but also accelerated the development of its open-state slow inactivation."
The use-dependence this node's description rests on - accelerated open-state slow inactivation is why blockade accumulates rather than recovering between beats.
Impaired Cardiac Impulse Conduction
Slowed phase-0 depolarisation and conduction through working myocardium and the conduction system, widening the QRS and setting up the substrate for reentry.
cardiac conduction GO:0061337 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cardiac conduction (GO:0061337). GO:0061337 is a biological process from the Gene Ontology. ↓ DECREASED cardiac muscle cell action potential GO:0086001 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cardiac muscle cell action potential (GO:0086001). GO:0086001 is a biological process from the Gene Ontology. ↓ DECREASED
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Cardiac conduction abnormality
Reentrant Ventricular Arrhythmia
Bradycardia
Reentrant Ventricular Arrhythmia
Conduction slowing without uniform refractoriness creates reentry circuits, producing ventricular tachycardia and fibrillation.
Downstream
Ventricular arrhythmia
Cardiovascular Collapse
Mitochondrial Carnitine-Acylcarnitine Translocase Inhibition
Local anesthetics with a cardiotoxic profile inhibit the carnitine-acylcarnitine translocase specifically, sparing the carnitine palmitoyltransferases either side of it. The substrate specificity is what localises the lesion to the translocase rather than to fatty acid oxidation generally.
Mitochondrial carnitine-acylcarnitine translocase inhibition
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
carnitine shuttle GO:0006853 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased carnitine shuttle (GO:0006853). GO:0006853 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Myocardial Bioenergetic Failure Mitochondrial carnitine-acylcarnitine translocase inhibition
Show evidence (2 references)
PMID:10691241 SUPPORT PRIMARY RESULT In Vitro
"The substrate specificity of this effect rules out bupivacaine inhibition of carnitine palmitoyl transferases I and II, carnitine acetyltransferase, and fatty acid beta-oxidation."
Establishes the specificity this node claims, and does it by exclusion - which is what makes the translocase the named target rather than the pathway as a whole.
PMID:35135371 SUPPORT PRIMARY RESULT In Vitro
"CACT, without significantly altering CPT-I and CPT-II, was inhibited by toxic concentration of local anesthetics."
An independent replication of the same specificity in a different system - rat cardiomyoblasts rather than isolated cardiac mitochondria.
Myocardial Bioenergetic Failure
Loss of the fatty-acid route to ATP in a tissue that depends on it, together with the reactive oxygen species and loss of mitochondrial membrane potential that accompany it.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Downstream
Myocardial Contractile Depression
Show evidence (2 references)
PMID:35135371 SUPPORT PRIMARY RESULT In Vitro
"The bupivacaine-induced increase of ROS and calcium and the bupivacaine-induced decrease of MMP were attenuated by ROS scavengers NAC and mitotempo, and the lipid emulsion."
The downstream cellular consequences this node names - reactive oxygen species, calcium rise and loss of mitochondrial membrane potential - and shows them to be reversible, which is why the node sits upstream of a contractile rather than a structural lesion.
PMID:17643405 SUPPORT INDIRECT PRIMARY RESULT In Vitro
"Collectively, these data indicate that bupivacaine, but not lidocaine, interacts avidly and selectively with biomimetic small unilamellar liposomes containing cardiolipin and disrupts their integrity."
A second route to the same node, independent of the translocase arm upstream: direct disruption of the cardiolipin-rich inner mitochondrial membrane. INDIRECT because the preparation is a synthetic liposome rather than a mitochondrion in a myocyte, so it establishes the interaction and its agent selectivity but not that this is what happens in a poisoned heart. The selectivity is the reason it is carried at all: bupivacaine does it and lidocaine does not, which tracks their clinical cardiotoxicity in the same direction as the translocase potency series.
Myocardial Contractile Depression
Negative inotropy, arising from both the bioenergetic lesion and the direct channel effects on excitation-contraction coupling.
cardiac muscle contraction GO:0060048 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cardiac muscle contraction (GO:0060048). GO:0060048 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Bupivacaine cardiovascular toxicity in the anesthetized rat Rat recapitulates Reproduces the haemodynamic arm of the toxidrome and its reversal, with arterial pressure as the recovering variable.
Downstream
Hypotension
Cardiovascular Collapse
Cardiovascular Collapse
The convergence of the arrhythmic and contractile arms, and the terminal common pathway of severe systemic toxicity.
Downstream
Cardiac arrest
Show evidence (1 reference)
PMID:20301824 SUPPORT BACKGROUND Human Clinical
"In extreme cases, signs of hemodynamic instability follow and can lead to cardiovascular collapse."
Names collapse as the endpoint of the severe presentation. BACKGROUND for the same reason as the companion quote on the disinhibition node: it is this paper's statement of the accepted picture.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Local Anesthetic Systemic Toxicity Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

15
Cardiovascular 5
Cardiac arrest HP:0001695 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiac arrest (HP:0001695). HP:0001695 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23788067 SUPPORT PRIMARY RESULT Human Clinical
"The primary outcome was LAST comprising minor, major, and cardiac arrest (due to toxicity) events determined using standardized definitions."
Cardiac arrest is one of the three graded outcome categories this registry counted, which establishes it as a recognised LAST presentation rather than an incidental co-occurrence.
Cardiac conduction abnormality HP:0031546 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is PR and QRS prolongation, annotated with Cardiac conduction abnormality (HP:0031546), qualified as temporality acute. HP:0031546 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Bound at conduction-abnormality granularity rather than to `HP:0006677` Prolonged QRS complex because the two cited sentences say different things: the clinical review says "conduction abnormalities" without naming an interval, and the mechanistic review says PR and QRS together. Binding the QRS term alone would drop the PR half of what is quoted, and splitting one electrocardiographic observation across two phenotypes would assert two findings where the sources report one.
Show evidence (2 references)
PMID:29763139 SUPPORT REVIEW SYNTHESIS Other
"Progressive toxicity may cause seizures, loss of consciousness, respiratory depression, conduction abnormalities, hypotension, ventricular dysrhythmias, and cardiovascular collapse."
Names conduction abnormalities among the manifestations of progressive toxicity, which is the clinical statement that this phenotype occurs.
PMID:42589553 SUPPORT REVIEW SYNTHESIS Other
"In cardiomyocytes, sodium channel blockade slows phase 0 depolarization, reduces conduction velocity, and prolongs PR/QRS intervals."
Names the two intervals and ties them to the upstream node this phenotype hangs off, which is why the edge is drawn from `Impaired Cardiac Impulse Conduction` rather than from the exposure.
Ventricular arrhythmia HP:0004308 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular arrhythmia (HP:0004308). HP:0004308 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29763139 SUPPORT REVIEW SYNTHESIS Other
"Progressive toxicity may cause seizures, loss of consciousness, respiratory depression, conduction abnormalities, hypotension, ventricular dysrhythmias, and cardiovascular collapse."
Names ventricular dysrhythmias among the manifestations of progressive toxicity. This is the direct clinical statement; the electrophysiology item below is kept for the mechanism it points at.
PMID:25008571 SUPPORT INDIRECT BACKGROUND In Vitro
"Nav1.5 is the dominant isoform of VGSCs expressed in cardiac myocytes, and its dysfunction may be the cause of bupivacaine-triggered arrhythmia."
INDIRECT and BACKGROUND: an electrophysiology paper's framing sentence, naming bupivacaine-triggered arrhythmia as the clinical problem it studies rather than observing it. Kept because it ties the phenotype to the specific channel this entry's canonical arm blames.
Bradycardia HP:0001662 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bradycardia (HP:0001662). HP:0001662 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24496123 SUPPORT INDIRECT PRIMARY RESULT Model Organism
"Heart rates remained depressed in all four groups throughout the observation period."
INDIRECT and from a rat model: heart rate was depressed by bupivacaine in every arm and did not recover with any treatment. It supports bradycardia as part of the toxidrome, not as a human clinical observation, and the grading says so.
Hypotension HP:0002615 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotension (HP:0002615). HP:0002615 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29763139 SUPPORT REVIEW SYNTHESIS Other
"Progressive toxicity may cause seizures, loss of consciousness, respiratory depression, conduction abnormalities, hypotension, ventricular dysrhythmias, and cardiovascular collapse."
Names hypotension directly among the manifestations of progressive toxicity.
PMID:20301824 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"or involved only signs of cardiovascular compromise, with no evidence of central nervous system toxicity"
INDIRECT, and kept for a different point than the item above: it does not name hypotension, but it establishes cardiovascular compromise as a presentation in its own right, which is what makes this phenotype more than a late complication of the neurological sequence.
Ear 2
Tinnitus HP:0000360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tinnitus (HP:0000360), qualified as temporality acute. HP:0000360 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:29763139 SUPPORT REVIEW SYNTHESIS Other
"The central nervous system (CNS) is often affected first, producing circumoral paresthesia, metallic taste, tinnitus, dizziness, agitation, visual disturbances, dysarthria, or muscle twitching."
Names tinnitus among the early central nervous system features.
Dizziness Vertigo HP:0002321 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is dizziness, annotated with Vertigo (HP:0002321), qualified as temporality acute. HP:0002321 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
HPO files "Dizziness" only as a synonym of `HP:0002321` Vertigo, whose definition is narrower than the source's word: "an abnormal sensation of spinning while the body is actually stationary". The prodromal dizziness of this syndrome is not described as rotatory. The term is bound because HPO offers no separate concept and the synonym is the ontology's own decision, but the gap between the label and the quoted word is recorded here rather than hidden.
Show evidence (1 reference)
PMID:29763139 SUPPORT REVIEW SYNTHESIS Other
"The central nervous system (CNS) is often affected first, producing circumoral paresthesia, metallic taste, tinnitus, dizziness, agitation, visual disturbances, dysarthria, or muscle twitching."
Names dizziness among the early central nervous system features.
Eye 1
Visual disturbance Abnormality of vision HP:0000504 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is visual disturbances, annotated with Abnormality of vision (HP:0000504), qualified as temporality acute. HP:0000504 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:29763139 SUPPORT REVIEW SYNTHESIS Other
"The central nervous system (CNS) is often affected first, producing circumoral paresthesia, metallic taste, tinnitus, dizziness, agitation, visual disturbances, dysarthria, or muscle twitching."
Names visual disturbances among the early central nervous system features. `HP:0000504` is the binding rather than `HP:0000505` Visual impairment, which HPO defines as vision loss severe enough to qualify as an additional support need - a permanent disability, not a transient prodromal symptom.
Head and Neck 1
Metallic taste Parageusia HP:0031249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is metallic taste, annotated with Parageusia (HP:0031249), qualified as temporality acute. HP:0031249 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:29763139 SUPPORT REVIEW SYNTHESIS Other
"The central nervous system (CNS) is often affected first, producing circumoral paresthesia, metallic taste, tinnitus, dizziness, agitation, visual disturbances, dysarthria, or muscle twitching."
Names metallic taste among the early central nervous system features. `HP:0031249` is the binding because its own definition reads "often characterized by the sensation of a metallic taste" and it carries "Metallic taste" as an exact synonym.
Nervous System 6
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29303925 SUPPORT PRIMARY RESULT Human Clinical
"Seizure (53% and 61% from case reports and registries, respectively) was the most common presenting feature."
Gives both the rank and the two frequencies, from two different case sources, which is why the description says "most common" rather than naming one figure.
Agitation HP:0000713 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Agitation (HP:0000713), qualified as temporality acute. HP:0000713 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:29763139 SUPPORT REVIEW SYNTHESIS Other
"The central nervous system (CNS) is often affected first, producing circumoral paresthesia, metallic taste, tinnitus, dizziness, agitation, visual disturbances, dysarthria, or muscle twitching."
Names agitation among the early central nervous system features. Graded OTHER and REVIEW_SYNTHESIS because StatPearls is a point-of-care reference summarising the field rather than a study; it is cited here for the symptom list, which no primary source in this entry's cache itemises, and never as a baseline.
Dysarthria HP:0001260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysarthria (HP:0001260), qualified as temporality acute. HP:0001260 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:29763139 SUPPORT REVIEW SYNTHESIS Other
"The central nervous system (CNS) is often affected first, producing circumoral paresthesia, metallic taste, tinnitus, dizziness, agitation, visual disturbances, dysarthria, or muscle twitching."
Names dysarthria among the early central nervous system features.
Circumoral paresthesia HP:0003401 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is circumoral paresthesia, annotated with Paresthesia (HP:0003401), qualified as temporality acute. HP:0003401 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:29763139 SUPPORT REVIEW SYNTHESIS Other
"The central nervous system (CNS) is often affected first, producing circumoral paresthesia, metallic taste, tinnitus, dizziness, agitation, visual disturbances, dysarthria, or muscle twitching."
Names circumoral paresthesia first among the early central nervous system features. HPO has no perioral-specific paresthesia term, so the binding is the general one and `preferred_term` carries the distribution.
Muscle twitching Fasciculations HP:0002380 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is muscle twitching, annotated with Fasciculations (HP:0002380), qualified as temporality acute. HP:0002380 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
The HPO definition attributes fasciculation to irritability of a motor axon, which is a different origin from the cortical disinhibition this entry models. The term is bound on the exact synonym rather than on the mechanism, and no claim about the origin of the twitching is made by binding it.
Show evidence (1 reference)
PMID:29763139 SUPPORT REVIEW SYNTHESIS Other
"The central nervous system (CNS) is often affected first, producing circumoral paresthesia, metallic taste, tinnitus, dizziness, agitation, visual disturbances, dysarthria, or muscle twitching."
Names muscle twitching among the early central nervous system features. `HP:0002380` carries "Muscle twitch" as an exact synonym.
Coma HP:0001259 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coma (HP:0001259). HP:0001259 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301824 SUPPORT BACKGROUND Human Clinical
"culminating in seizures and coma"
Names coma as the endpoint of the neurological sequence.
🧬

Genetic Associations

1
SCN5A
Gene: SCN5A hgnc:10593 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SCN5A (hgnc:10593). hgnc:10593 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: RISK_FACTOR
Show evidence (2 references)
PMID:24445991 SUPPORT PRIMARY RESULT Human Clinical
"We report identification and functional characterization of a rare non-synonymous (p.A1427S) variant in the SCN5A gene that was associated with incessant and lethal ventricular tachycardia and fibrillation after administration of lidocaine to a patient with acute myocardial infarction."
The case and the variant. Note the confounder the authors state plainly - the lidocaine was given for acute myocardial infarction, so an infarcting myocardium is part of the picture.
PMID:24445991 SUPPORT PRIMARY RESULT In Vitro
"The variant, located in a highly conserved domain distinct from the predicted lidocaine-binding site, decreased peak current density of the sodium channel."
The functional characterisation, and the reason this is a susceptibility claim rather than an altered-drug-binding one: the variant sits away from the lidocaine site and lowers baseline current, so it reduces the reserve the drug then eats into. Graded IN_VITRO because this is the electrophysiology, separate from the clinical case above.
💊

Medical Actions

3
Intravenous Lipid Emulsion
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: intravenous lipid emulsion (soybean-oil based) CHEBI:166975 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses intravenous lipid emulsion (soybean-oil based), annotated with soybean oil (CHEBI:166975). CHEBI:166975 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Other
The specific antidote, and first-line for the cardiovascular manifestations. It works - the dose-response is established in animals and the case series are favourable - but by which of several mechanisms is unsettled, which the `lipid_rescue_mechanism` discussion records. Note that the evidence base behind the international recommendations is graded low to very low.
Mechanism Target:
INHIBITS Myocardial Contractile Depression — The cardiotonic arm of the antidote's action: lipid emulsion raises arterial pressure and accelerates haemodynamic recovery in a dose-dependent way.
Show evidence (1 reference)
PMID:24496123 SUPPORT PRIMARY RESULT Model Organism
"Intravenous lipid emulsion accelerates cardiovascular recovery from bupivacaine toxicity in a dose-dependent manner, which is driven by a cardiotonic response that complements the previously reported sequestration effect."
Supports this specific edge - an effect on contractile performance - and is careful that the cardiotonic response complements rather than replaces sequestration.
INHIBITS Global Neuronal Conduction Failure — Lipid emulsion also acts against the central nervous system arm, not only the cardiac one. In rats given local anesthetic directly into the lateral ventricle, emulsion given before the dose prevented respiratory arrest and emulsion given after it achieved resuscitation.
Show evidence (1 reference)
PMID:26622452 SUPPORT PRIMARY RESULT Model Organism
"The results of the present study therefore indicate that pre- and post-conditioning with lipid emulsion effectively mitigates LA-induced CNS toxicity in rats."
Supports this specific edge, which no other evidence in this entry covers: every other lipid emulsion item here is cardiac. Worth noting for the `lipid_rescue_mechanism` discussion that the anesthetic was injected intracerebroventricularly, so a purely intravascular sink is not an obvious explanation of the rescue - but the study was not designed to test that and the entry does not claim it did.
INHIBITS Mitochondrial Carnitine-Acylcarnitine Translocase Inhibition — Lipid emulsion reverses the translocase inhibition in cardiomyoblasts. The authors attribute this to sequestration of the drug rather than to any direct metabolic effect, which matters for the mechanism question.
Show evidence (1 reference)
PMID:35135371 SUPPORT PRIMARY RESULT In Vitro
"Collectively, these results suggested that the lipid emulsion attenuated the levobupivacaine-induced inhibition of CACT, probably through the lipid emulsion-mediated sequestration of levobupivacaine."
Supports the edge and names the proposed route, with the authors' own "probably" left in - this is the sequestration account, and the paper offers it as the likely explanation rather than a demonstrated one.
Show evidence (4 references)
PMID:28346007 SUPPORT PRIMARY RESULT Model Organism
"Lipid emulsion reduced the odds of death in resuscitative models (OR =0.24; 95%CI: 0.1-0.56, p = .0012)."
The strongest efficacy estimate available for this treatment, pooled across 16 resuscitative animal studies. MODEL_ORGANISM because every included study is an animal model - there is no randomised human trial in this indication and there is unlikely ever to be one.
PMID:28346007 SUPPORT INDIRECT PRIMARY RESULT Model Organism
"Analysis of outliers reinforced the need for good life support measures (securement of airway and chest compressions) along with prompt treatment with lipid."
INDIRECT, and the reason this entry lists airway management before the antidote: the same meta-analysis found the lipid benefit depends on basic life support being done alongside it.
PMID:37242638 SUPPORT REVIEW SYNTHESIS Other
"Present evidence supports the use of ILE as first-line therapy to reverse local anesthetic-related systemic toxicity and as adjunct therapy in lipophilic non-local anesthetic drug overdoses refractory to well-established antidotes and supportive care."
Establishes first-line status for this indication specifically.
+ 1 more reference
Airway Management and Ventilation
Action: airway management, oxygenation and ventilationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is airway management, oxygenation and ventilation, annotated with Oxygen Therapy (NCIT:C94624). NCIT:C94624 is a clinical intervention from the NCI Thesaurus. Ontology label: Oxygen Therapy NCIT:C94624
Oxygenation and ventilation come first, because hypoxia and acidosis worsen the toxicity that caused them. The binding covers one half of the treatment. `runoak`-equivalent OLS searches of NCIT return nothing for "Airway Management", `NCIT:C94624` Oxygen Therapy for "Oxygen Therapy", and `NCIT:C70909` Mechanical Ventilation for "Mechanical Ventilation". Oxygen Therapy is bound because first-line care here is bag-mask ventilation with 100% oxygen and Mechanical Ventilation names only the escalated form; an earlier draft bound the escalated term and then asserted no whole-airway term existed, which was a search of one phrase reported as a fact about the ontology. The airway-management half is carried in `preferred_term`.
Show evidence (1 reference)
PMID:21841477 SUPPORT REVIEW SYNTHESIS Other
"As for treatment, in addition to ventilation, oxygenation, and chest compressions, lipid emulsion therapy should be a primary element in the treatment of cardiovascular LAST."
Places ventilation and oxygenation alongside lipid emulsion in the treatment set.
Supportive Care and Modified Resuscitation
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Standard resuscitation modified for this toxidrome, notably by keeping vasopressor doses low.
Show evidence (1 reference)
PMID:21841477 SUPPORT REVIEW SYNTHESIS Other
"The use of epinephrine and vasopressin should be tailored to specifics of an episode of LAST, and doses should be kept as low as possible while still achieving the desired effects."
The specific modification that distinguishes LAST resuscitation from standard practice.
🌍

Environmental Factors

1
Injection of local anesthetic for regional or local anesthesia
exposure to a local anesthetic agent ECTO:9001759 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to a local anesthetic agent, annotated with exposure to local anaesthetic (ECTO:9001759). ECTO:9001759 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
ECTO spells this term the British way. `runoak -i ols:ecto search "exposure to local anesthetic"` returns nothing and `"exposure to anesthetic"` returns only the broad `ECTO:2000059`, which is what an earlier draft of this entry bound while asserting no specific term existed. `runoak -i ols:ecto search "anaesthetic"` returns `ECTO:9001759` exposure to local anaesthetic, which is exact, non-obsolete, and reachable from the `ExposureTerm` root via exposure to drug, so it validates. Searching one spelling and recording the absence as a fact is the failure this note now exists to document.
The exposure is a therapeutic procedure. Risk concentrates where injection is into a vascular bed, where the dose per weight is high, and where the agent is one of the more cardiotoxic amides.
Show evidence (2 references)
PMID:29303925 SUPPORT PRIMARY RESULT Human Clinical
"Local anesthetic systemic toxicity events occurred as a result of penile blocks (23%), local infiltration (17%), and upper/lower extremity, torso, and neuraxial blockade."
The distribution of procedures that produced events, which is the exposure this entry models.
PMID:35777259 SUPPORT REVIEW SYNTHESIS Other
"Patients at extremes of age or with organ dysfunction are at higher risk."
The patient-side half of the risk picture, which the procedure-side evidence above does not cover. Carried because this entry otherwise attributes risk entirely to dose and site, and the same review names host factors that modify it at a given dose.
Mechanism Target:
TRIGGERS Systemic Local Anesthetic Exposure — The administered dose is the sole source of the systemic concentration; there is no endogenous contribution.
Show evidence (1 reference)
PMID:23788067 SUPPORT PRIMARY RESULT Human Clinical
"Site of injection, local anesthetic type, dose per weight, dose, and patient weight were all predictors of LAST."
Identifies the features of the exposure that determine whether toxicity follows, which is what this edge asserts - dose and site, not patient idiosyncrasy.
📊

Prevalence

2
Peripheral nerve blocks, Australia and New Zealand registry, 2007-2012
Unknown 87.0 per 100,000 1–9 per 10,000
0.87 events per 1000 peripheral nerve blocks, converted to 87 per 100,000 blocks, which is `BAND_1_5_PER_10000` (10-99 per 100,000). Two slots here are compromises. The denominator is blocks performed, not people or person-years, and no `RateDenominatorEnum` value names that; POPULATION is the closest. And `measure_type` is UNKNOWN rather than ANNUAL_INCIDENCE because this is a per-procedure attack rate over 2007-2012, not a rate per year - an earlier draft said ANNUAL_INCIDENCE, which would have made the band read as cases per 100,000 per year. See the entry `notes:` for why this figure is not reconciled with the others.
Show evidence (1 reference)
PMID:23788067 SUPPORT PRIMARY RESULT Human Clinical
"There were 22 episodes of LAST, resulting in an incidence of LAST of 0.87 per 1000 PNBs (95% confidence interval, 0.54-1.3 per 1000)."
The event count, the rate and its confidence interval.
Peripheral nerve blocks, pooled registries reported 2018
Unknown 27.0 per 100,000 1–9 per 10,000
0.27 events per 1000 blocks over a denominator of 251,325, converted to 27 per 100,000 blocks, which is `BAND_1_5_PER_10000`. Lower than the earlier registry figure above; the entry does not reconcile the two. `measure_type` is UNKNOWN for the same reason as the record above - a per-procedure attack rate is not an annual incidence.
Show evidence (1 reference)
PMID:29303925 SUPPORT PRIMARY RESULT Human Clinical
"The incidence of LAST reported in registries is 0.03% or 0.27 (95% confidence interval, 0.21-0.35) per 1000 peripheral nerve blocks (denominator of 251,325)."
The pooled registry rate with its denominator.
⚖️

Clinical Burden

Moderate
Individually severe and occasionally fatal, but rare and getting rarer. Registry incidence is under one event per thousand peripheral nerve blocks and falling with ultrasound guidance; a single-centre series of 12,668 ultrasound-guided blocks recorded no cardiac arrests at all. Against that, events increasingly occur outside the operating theatre and in the hands of non-anesthesiologists, where the antidote and the expertise may not be at hand.
Show evidence (2 references)
PMID:22705953 SUPPORT PRIMARY RESULT Human Clinical
"Local anesthetic systemic toxicity, however, is extremely uncommon."
The authors' conclusion from a 12,668-block prospective registry, which is the basis for MODERATE rather than HIGH.
PMID:29356773 SUPPORT REVIEW SYNTHESIS Other
"An increasing number of reported events occur outside of the traditional hospital setting and involve non-anesthesiologists."
The countervailing consideration, and the reason the burden is not graded LOW despite the falling incidence.
🧫

Experimental Models

1
Nav1.5 expressed in Xenopus oocytes OTHER
Heterologous expression of the cardiac sodium channel for voltage-clamp measurement of bupivacaine block. Not a disease model - a target model, which is what the canonical arm of this entry needs.
Publication
PMID:25008571
Pathograph links
Cardiac Sodium Channel Blockade measures fidelity: moderate observes: molecular Measures the block directly at the channel, giving the potency and the use-dependence the node claims.
Limitations: An amphibian oocyte expressing one human channel is not a cardiomyocyte: there is no sarcomere, no mitochondrial arm, and none of the accessory subunits or lipid environment that modulate Nav1.5 in working myocardium. It can say what the drug does to the channel and nothing about what that does to a heart.
Show evidence (1 reference)
PMID:25008571 SUPPORT PRIMARY RESULT In Vitro
"Consistent with other local anesthetics, bupivacaine also induced a use-dependent blockade on Nav1.5 currents."
The use-dependence half of what this link claims to measure, observed in the oocyte preparation itself. The previous snippet here was the paper's aim sentence, which states what the study set out to do rather than what it found, and so could carry no `quote_role` at all.
🐁

Animal Models

1
Bupivacaine cardiovascular toxicity in the anesthetized rat
Instrumented rats given a non-lethal intravenous bupivacaine dose, then randomised to lipid emulsion at two concentrations, saline, or nothing. The model that supplies this entry's evidence on how the antidote works.
Species
Rat
Genotype
wild type Sprague-Dawley
Publication
PMID:24496123
Pathograph links
Myocardial Contractile Depression recapitulates fidelity: moderate observes: organism Reproduces the haemodynamic arm of the toxidrome and its reversal, with arterial pressure as the recovering variable.
Limitations: The dose is deliberately sub-lethal so that recovery happens without chest compressions, which is not the clinical scenario the antidote is used in. Heart rate did not recover in any arm, so the model reproduces the pressure half of the collapse and not the rate half.
Show evidence (1 reference)
PMID:24496123 SUPPORT PRIMARY RESULT Model Organism
"Rats treated with lipid emulsions recovered faster than did rats treated with saline or no treatment."
The controlled comparison that makes this a usable model of the treatment effect rather than of the toxicity alone.
{ }

Source YAML

click to show 
name: Local Anesthetic Systemic Toxicity
creation_date: "2026-09-19T04:30:00Z"
category: Environmental
categories:
- Toxic Exposure Disorder
- Iatrogenic Drug Toxicity
- Anesthetic Complication
synonyms:
- LAST
- local anesthetic poisoning
- local anaesthetic systemic toxicity
- local anesthetic toxicity
description: >-
  Local anesthetic systemic toxicity is an acute drug toxicity that follows an
  excessive plasma concentration of a local anesthetic, usually after
  inadvertent intravascular injection, rapid absorption from a vascular tissue
  bed, or cumulative overdose during regional anesthesia. It affects the two
  tissues whose function depends most on fast sodium currents: the central
  nervous system and the heart.

  The shared molecular action is blockade of voltage-gated sodium channels. In
  the cortex, inhibitory interneurons are silenced before excitatory pathways,
  so the first clinical picture is excitation - perioral numbness, tinnitus,
  agitation, then seizure - and only at higher concentrations does global
  conduction failure produce coma and apnoea. In the heart, blockade of Nav1.5
  slows conduction and sets up reentrant ventricular arrhythmia, while a
  separate mitochondrial action impairs the myocardium's fatty acid fuel
  supply. The two arms converge on cardiovascular collapse.

  Bupivacaine is the prototypical offender, and the reason is pharmacological
  rather than incidental: it accelerates the cardiac sodium channel's entry
  into slow inactivation, so blockade deepens with successive beats. Note that
  use-dependent block is a class property rather than something unique to
  bupivacaine - the electrophysiology paper cited below is explicit that this
  is "consistent with other local anesthetics" - and that the recent mortality
  literature reports lidocaine, not bupivacaine, as the leading reported cause
  of death attributed to this syndrome. Neither observation is curated as a
  claim here; both are reasons the prototypical-offender framing is a
  simplification.

  Treatment is unusual among toxidromes in having a specific antidote,
  intravenous lipid emulsion, whose mechanism remains unsettled. Incidence has
  fallen with ultrasound guidance, and the presentation has shifted: the
  classic progressive sequence described in textbooks fits only about
  three-fifths of published cases.
disease_term:
  preferred_term: local anesthetic poisoning
  term:
    id: MONDO:0100335
    label: local anesthetic poisoning
notes: >-
  **Two incidence figures are carried here and are not reconciled.** A
  multicentre registry of 25,336 peripheral nerve blocks reports 0.87 per 1000
  (`PMID:23788067`); a later review of registries reports 0.27 per 1000 over a
  denominator of 251,325 (`PMID:29303925`); and a single-centre series of
  12,668 ultrasound-guided blocks reports a seizure rate of 0.08 per 1000 and
  no cardiac arrests (`PMID:22705953`). These differ in period, case
  definition, technique mix and denominator. The entry reports each with its
  source rather than averaging them, and the direction they agree on - that
  LAST is rare and getting rarer - is the claim worth making.

  **This entry is about systemic toxicity, not local tissue toxicity.** The two
  share molecular injury pathways and are routinely reviewed together
  (`PMID:42589553` does exactly that), but direct neurotoxicity or myotoxicity
  at the injection site is a different clinical problem with a different
  exposure profile, and is out of scope here. True local anesthetic
  hypersensitivity is also excluded: it is immune-mediated and rarer, and
  nothing in this entry's pathograph applies to it.

  **No GeneReviews chapter exists and none is expected** - this is an acquired
  iatrogenic drug toxicity with no Mendelian basis. `just check-genereviews`
  returns `GeneReviews NO_CHAPTER`. It returns `StatPearls TAGGED`: a
  StatPearls chapter does exist and is cited and tagged below, for the symptom
  list only. StatPearls is never a baseline.

  **Host susceptibility: one half curated, one half not, and the difference is
  the evidence.** The deep research report proposes that SCN5A channelopathy
  and carnitine palmitoyltransferase II deficiency would each lower the
  threshold for this cascade, which is mechanistically coherent given the two
  arms curated below. The SCN5A half is now a `genetic:` record: a single
  functionally characterised case of lidocaine-induced lethal ventricular
  fibrillation in a rare SCN5A variant carrier. The fatty-acid-oxidation half
  is not, and the reason is specific rather than general - the cached review on
  anesthetic management in those patients (`PMID:35363184`) is about general
  anesthesia, recommends avoiding propofol, and never mentions local
  anesthetics or this syndrome. It is the wrong paper for the claim, not merely
  a weak one. An earlier draft of this note asserted that no case report had
  been cached at all, which was false: `PMID:24445991` was sitting in this PR's
  own cache when it was written.

  **Two cached references are deliberately uncited by this entry and are not
  orphans.** `references_cache/` here backs two things: this entry's snippets
  and the deep research report committed beside it, whose citation list is
  checked against the same cache. `PMID:33148630` (the ASRA 2020 checklist)
  and `PMID:27243970` (whole-exome sequencing of a family with local
  anesthetic resistance) are both cited by the report and neither is quotable
  here. The checklist's abstract records only that the 2020 version exists and
  why it was revised, which is bibliographic rather than a finding. The exome
  study is about resistance to the intended block - an SCN5A A572D variant
  causing anesthesia to fail - which is the opposite clinical problem from
  systemic toxicity and does not belong in this entry's `genetic:` section
  merely because it names the same gene.
mechanistic_hypotheses:
- hypothesis_group_id: sodium_channel_cardiotoxicity
  hypothesis_label: Sodium channel blockade as the primary cardiotoxic mechanism
  status: CANONICAL
  description: >-
    Cardiac toxicity arises principally from blockade of the cardiac
    voltage-gated sodium channel Nav1.5, with the potency differences between
    agents explained by how fast each one leaves the channel. Reviews of the
    field describe the experimental data as mixed while still placing sodium
    channels first.
  evidence:
  - reference: PMID:21841477
    reference_title: "Local anesthetic systemic toxicity: update on mechanisms and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Regarding mechanism(s) of LAST, the evidence remains mixed, but it is likely that local anesthetic cardiotoxicity primarily arises from a blockade of sodium channels."
    explanation: >-
      States the hypothesis and its standing in one sentence, including the
      hedge. "The evidence remains mixed" is why this is curated as a
      hypothesis group rather than as settled fact. Graded OTHER because the
      quoted sentence is a review's summary judgement across a literature
      rather than any one study's result.
- hypothesis_group_id: mitochondrial_bioenergetic_contribution
  hypothesis_label: Mitochondrial carnitine-acylcarnitine translocase inhibition
  status: ALTERNATIVE
  description: >-
    A second, parallel mechanism: local anesthetics with a cardiotoxic profile
    inhibit the carnitine-acylcarnitine translocase, cutting off long-chain
    fatty acid entry into the mitochondrial matrix and starving the myocardium
    of its main fuel. The potency ranking across agents tracks their clinical
    cardiotoxicity, which is the observation the hypothesis rests on. It is not
    a rival to sodium channel blockade so much as a proposed amplifier of it,
    and its quantitative contribution in a whole organism is unresolved.
  evidence:
  - reference: PMID:10691241
    reference_title: Bupivacaine inhibits acylcarnitine exchange in cardiac mitochondria.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "The authors hypothesize that differential inhibition of carnitine-stimulated pyruvate oxidation by various local anesthetics supports the clinical relevance of inhibition of carnitine-acylcarnitine translocase by local anesthetics with a cardiotoxic profile."
    explanation: >-
      The hypothesis in the originating authors' own words, and quoted with
      "The authors hypothesize" intact: this is proposed, not demonstrated, in
      the paper that proposes it.
  - reference: PMID:10691241
    reference_title: Bupivacaine inhibits acylcarnitine exchange in cardiac mitochondria.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Bupivacaine (IC50 = 0.26+/-0.06 mM) and etidocaine (IC50 = 0.30+/-0.12 mM) inhibit carnitine-stimulated pyruvate oxidation similarly, whereas the lidocaine IC50 is greater by a factor of roughly 5, (IC50 = 1.4+/-0.26 mM), and ropivacaine is intermediate, IC50 = 0.5+/-0.28 mM."
    explanation: >-
      The potency ranking that makes the hypothesis interesting: bupivacaine
      and etidocaine most potent, lidocaine roughly fivefold weaker, ropivacaine
      between them - the same order as their clinical cardiotoxicity.
pathophysiology:
- name: Systemic Local Anesthetic Exposure
  biological_scale: ORGANISM
  description: >-
    An excessive free plasma concentration of local anesthetic, from
    inadvertent intravascular injection, rapid absorption from a vascular
    tissue bed, or cumulative overdose. Everything downstream is
    concentration-dependent, which is why the clinical picture is a sequence
    rather than a switch.
  chemical_entities:
  - preferred_term: bupivacaine
    term:
      id: CHEBI:3215
      label: bupivacaine
  downstream:
  - target: Cardiac Sodium Channel Blockade
    causal_link_type: DIRECT
    hypothesis_groups:
    - sodium_channel_cardiotoxicity
  - target: Cortical GABAergic Interneuron Blockade
    causal_link_type: DIRECT
  - target: Mitochondrial Carnitine-Acylcarnitine Translocase Inhibition
    causal_link_type: DIRECT
    hypothesis_groups:
    - mitochondrial_bioenergetic_contribution
  evidence:
  - reference: PMID:42589553
    reference_title: "Molecular Mechanisms of Local Anesthetic Toxicity: From Ion Channel Dysregulation to Mitochondrial Dysfunction and Tissue-Specific Injury."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Their therapeutic effect is based mainly on reversible voltage-gated sodium channel inhibition, but toxicity is not limited to this mechanism."
    explanation: >-
      Frames the entry's two-arm structure: the therapeutic action and the
      toxic action share a target, and the toxicity reaches past it.
- name: Cortical GABAergic Interneuron Blockade
  biological_scale: CELLULAR
  description: >-
    Inhibitory tone is lost before excitatory transmission, which is why the
    first manifestation of a central nervous system overdose is excitation
    rather than sedation. The route is not purely sodium channel blockade of
    interneurons: cited experimental work attributes it to suppressed
    presynaptic GABA release and reduced GABA-A receptor currents as well. The
    sodium channel binding on this node is the shared class action, not the
    whole account.
  cell_types:
  - preferred_term: cortical GABAergic interneuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  molecular_functions:
  - preferred_term: voltage-gated sodium channel activity
    term:
      id: GO:0005248
      label: voltage-gated sodium channel activity
    modifier: DECREASED
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  downstream:
  - target: Cortical Disinhibition
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:42589553
    reference_title: "Molecular Mechanisms of Local Anesthetic Toxicity: From Ion Channel Dysregulation to Mitochondrial Dysfunction and Tissue-Specific Injury."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Experimental studies show that local anesthetics can suppress presynaptic γ-aminobutyric acid (GABA) release, reduce γ-aminobutyric acid type A (GABA-A) receptor-mediated currents in a subunit-dependent manner, and, particularly with lidocaine, shift the GABA-induced reversal potential in a depolarizing direction."
    explanation: >-
      The mechanisms behind the loss of inhibitory tone this node names, and the
      reason its description does not attribute the effect to sodium channel
      blockade alone.
  - reference: PMID:42589553
    reference_title: "Molecular Mechanisms of Local Anesthetic Toxicity: From Ion Channel Dysregulation to Mitochondrial Dysfunction and Tissue-Specific Injury."
    supports: REFUTE
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "At the molecular level, CNS toxicity involves more than sodium channel block."
    explanation: >-
      REFUTE against reading this node's sodium channel binding as the complete
      mechanism. Carried explicitly because an earlier draft of the node
      description asserted selective sodium channel blockade of interneurons
      with no evidence at all, and this is the sentence that corrects it.
- name: Cortical Disinhibition
  biological_scale: CELLULAR
  description: >-
    Net excitation of cortical circuits once inhibitory tone is removed,
    producing the excitatory prodrome and then seizure.
  downstream:
  - target: Seizure
    causal_link_type: DIRECT
  - target: Agitation
    causal_link_type: DIRECT
  - target: Global Neuronal Conduction Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Not a consequence of disinhibition itself but of the rising
      concentration that produced it: as blockade extends to excitatory
      pathways the excitatory phase gives way to depression. The intermediate
      is the continued rise in free drug concentration.
  evidence:
  - reference: PMID:20301824
    reference_title: "Clinical presentation of local anesthetic systemic toxicity: a review of published cases, 1979 to 2009."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The classic description of local anesthetic systemic toxicity (LAST) generally described in textbooks includes a series of progressively worsening neurologic symptoms and signs occurring shortly after the injection of local anesthetic and paralleling progressive increases in blood local anesthetic concentration, culminating in seizures and coma."
    explanation: >-
      The concentration-dependent neurological sequence this node and the next
      one model. BACKGROUND because it is the paper's statement of the textbook
      picture, which the paper then goes on to test - see the REFUTE item on
      the same reference under `discussions`.
- name: Global Neuronal Conduction Failure
  biological_scale: ORGANISM
  description: >-
    At higher concentrations sodium channel blockade is no longer selective for
    inhibitory pathways, and widespread neuronal conduction failure produces
    depression of consciousness and respiratory drive.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  downstream:
  - target: Coma
    causal_link_type: DIRECT
- name: Cardiac Sodium Channel Blockade
  biological_scale: MOLECULAR
  description: >-
    Voltage- and use-dependent blockade of Nav1.5, the dominant sodium channel
    isoform in working myocardium. Bupivacaine blocks it within the clinical
    concentration range and accelerates the channel's entry into slow
    inactivation, so the block deepens with each beat rather than recovering
    between them.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  molecular_functions:
  - preferred_term: Nav1.5 voltage-gated sodium channel activity
    term:
      id: GO:0086006
      label: voltage-gated sodium channel activity involved in cardiac muscle cell action potential
    modifier: DECREASED
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  downstream:
  - target: Impaired Cardiac Impulse Conduction
    causal_link_type: DIRECT
    hypothesis_groups:
    - sodium_channel_cardiotoxicity
  evidence:
  - reference: PMID:25008571
    reference_title: Voltage-dependent blockade by bupivacaine of cardiac sodium channels expressed in Xenopus oocytes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "The electrophysiological measurements on Nav1.5 expressed in Xenopus oocytes showed that bupivacaine induced a voltage- and concentration-dependent blockade on the peak of I Na and the half-maximal inhibitory dose was 4.51 μmol/L."
    explanation: >-
      The direct measurement of blockade on the channel this node names, with
      the potency figure. IN_VITRO because it is a heterologous expression
      system, not a heart.
  - reference: PMID:25008571
    reference_title: Voltage-dependent blockade by bupivacaine of cardiac sodium channels expressed in Xenopus oocytes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "The underlying mechanisms of this blockade may contribute to the fact that bupivacaine not only dose-dependently affected the gating kinetics of Nav1.5 but also accelerated the development of its open-state slow inactivation."
    explanation: >-
      The use-dependence this node's description rests on - accelerated
      open-state slow inactivation is why blockade accumulates rather than
      recovering between beats.
- name: Impaired Cardiac Impulse Conduction
  biological_scale: TISSUE
  description: >-
    Slowed phase-0 depolarisation and conduction through working myocardium
    and the conduction system, widening the QRS and setting up the substrate
    for reentry.
  biological_processes:
  - preferred_term: cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: DECREASED
  - preferred_term: cardiac muscle cell action potential
    term:
      id: GO:0086001
      label: cardiac muscle cell action potential
    modifier: DECREASED
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  downstream:
  - target: Cardiac conduction abnormality
    causal_link_type: DIRECT
  - target: Reentrant Ventricular Arrhythmia
    causal_link_type: DIRECT
  - target: Bradycardia
    causal_link_type: DIRECT
- name: Reentrant Ventricular Arrhythmia
  biological_scale: TISSUE
  description: >-
    Conduction slowing without uniform refractoriness creates reentry circuits,
    producing ventricular tachycardia and fibrillation.
  downstream:
  - target: Ventricular arrhythmia
    causal_link_type: DIRECT
  - target: Cardiovascular Collapse
    causal_link_type: DIRECT
- name: Mitochondrial Carnitine-Acylcarnitine Translocase Inhibition
  biological_scale: MOLECULAR
  description: >-
    Local anesthetics with a cardiotoxic profile inhibit the
    carnitine-acylcarnitine translocase specifically, sparing the carnitine
    palmitoyltransferases either side of it. The substrate specificity is what
    localises the lesion to the translocase rather than to fatty acid oxidation
    generally.
  biological_processes:
  - preferred_term: carnitine shuttle
    term:
      id: GO:0006853
      label: carnitine shuttle
    modifier: DECREASED
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  downstream:
  - target: Myocardial Bioenergetic Failure
    causal_link_type: DIRECT
    hypothesis_groups:
    - mitochondrial_bioenergetic_contribution
  evidence:
  - reference: PMID:10691241
    reference_title: Bupivacaine inhibits acylcarnitine exchange in cardiac mitochondria.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "The substrate specificity of this effect rules out bupivacaine inhibition of carnitine palmitoyl transferases I and II, carnitine acetyltransferase, and fatty acid beta-oxidation."
    explanation: >-
      Establishes the specificity this node claims, and does it by exclusion -
      which is what makes the translocase the named target rather than the
      pathway as a whole.
  - reference: PMID:35135371
    reference_title: Lipid emulsions attenuate the inhibition of carnitine acylcarnitine translocase induced by toxic doses of local anesthetics in rat cardiomyoblasts.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "CACT, without significantly altering CPT-I and CPT-II, was inhibited by toxic concentration of local anesthetics."
    explanation: >-
      An independent replication of the same specificity in a different system
      - rat cardiomyoblasts rather than isolated cardiac mitochondria.
- name: Myocardial Bioenergetic Failure
  biological_scale: CELLULAR
  description: >-
    Loss of the fatty-acid route to ATP in a tissue that depends on it,
    together with the reactive oxygen species and loss of mitochondrial
    membrane potential that accompany it.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  downstream:
  - target: Myocardial Contractile Depression
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:35135371
    reference_title: Lipid emulsions attenuate the inhibition of carnitine acylcarnitine translocase induced by toxic doses of local anesthetics in rat cardiomyoblasts.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "The bupivacaine-induced increase of ROS and calcium and the bupivacaine-induced decrease of MMP were attenuated by ROS scavengers NAC and mitotempo, and the lipid emulsion."
    explanation: >-
      The downstream cellular consequences this node names - reactive oxygen
      species, calcium rise and loss of mitochondrial membrane potential - and
      shows them to be reversible, which is why the node sits upstream of a
      contractile rather than a structural lesion.
  - reference: PMID:17643405
    reference_title: "Bupivacaine, but not lidocaine, disrupts cardiolipin-containing small biomimetic unilamellar liposomes."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Collectively, these data indicate that bupivacaine, but not lidocaine, interacts avidly and selectively with biomimetic small unilamellar liposomes containing cardiolipin and disrupts their integrity."
    explanation: >-
      A second route to the same node, independent of the translocase arm
      upstream: direct disruption of the cardiolipin-rich inner mitochondrial
      membrane. INDIRECT because the preparation is a synthetic liposome
      rather than a mitochondrion in a myocyte, so it establishes the
      interaction and its agent selectivity but not that this is what happens
      in a poisoned heart. The selectivity is the reason it is carried at all:
      bupivacaine does it and lidocaine does not, which tracks their clinical
      cardiotoxicity in the same direction as the translocase potency series.
- name: Myocardial Contractile Depression
  biological_scale: TISSUE
  description: >-
    Negative inotropy, arising from both the bioenergetic lesion and the direct
    channel effects on excitation-contraction coupling.
  biological_processes:
  - preferred_term: cardiac muscle contraction
    term:
      id: GO:0060048
      label: cardiac muscle contraction
    modifier: DECREASED
  downstream:
  - target: Hypotension
    causal_link_type: DIRECT
  - target: Cardiovascular Collapse
    causal_link_type: DIRECT
- name: Cardiovascular Collapse
  biological_scale: ORGANISM
  description: >-
    The convergence of the arrhythmic and contractile arms, and the terminal
    common pathway of severe systemic toxicity.
  downstream:
  - target: Cardiac arrest
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:20301824
    reference_title: "Clinical presentation of local anesthetic systemic toxicity: a review of published cases, 1979 to 2009."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "In extreme cases, signs of hemodynamic instability follow and can lead to cardiovascular collapse."
    explanation: >-
      Names collapse as the endpoint of the severe presentation. BACKGROUND for
      the same reason as the companion quote on the disinhibition node: it is
      this paper's statement of the accepted picture.
phenotypes:
- category: Neurologic
  name: Seizure
  description: >-
    The most common presenting feature of LAST in both published cases and
    registries.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:29303925
    reference_title: "Local Anesthetic Systemic Toxicity: A Review of Recent Case Reports and Registries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Seizure (53% and 61% from case reports and registries, respectively) was the most common presenting feature."
    explanation: >-
      Gives both the rank and the two frequencies, from two different case
      sources, which is why the description says "most common" rather than
      naming one figure.
- category: Neurologic
  name: Agitation
  phenotype_term:
    preferred_term: Agitation
    term:
      id: HP:0000713
      label: Agitation
    temporality: ACUTE
  evidence:
  - reference: PMID:29763139
    reference_title: Local Anesthetic Toxicity.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The central nervous system (CNS) is often affected first, producing circumoral paresthesia, metallic taste, tinnitus, dizziness, agitation, visual disturbances, dysarthria, or muscle twitching."
    explanation: >-
      Names agitation among the early central nervous system features. Graded
      OTHER and REVIEW_SYNTHESIS because StatPearls is a point-of-care
      reference summarising the field rather than a study; it is cited here for
      the symptom list, which no primary source in this entry's cache itemises,
      and never as a baseline.
- category: Neurologic
  name: Tinnitus
  description: >-
    One of the early auditory features of the excitatory prodrome, and part of
    the symptom cluster that should stop an injection.
  phenotype_term:
    preferred_term: Tinnitus
    term:
      id: HP:0000360
      label: Tinnitus
    temporality: ACUTE
  evidence:
  - reference: PMID:29763139
    reference_title: Local Anesthetic Toxicity.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The central nervous system (CNS) is often affected first, producing circumoral paresthesia, metallic taste, tinnitus, dizziness, agitation, visual disturbances, dysarthria, or muscle twitching."
    explanation: Names tinnitus among the early central nervous system features.
- category: Neurologic
  name: Dysarthria
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
    temporality: ACUTE
  evidence:
  - reference: PMID:29763139
    reference_title: Local Anesthetic Toxicity.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The central nervous system (CNS) is often affected first, producing circumoral paresthesia, metallic taste, tinnitus, dizziness, agitation, visual disturbances, dysarthria, or muscle twitching."
    explanation: Names dysarthria among the early central nervous system features.
- category: Neurologic
  name: Circumoral paresthesia
  description: >-
    Numbness or tingling around the mouth, conventionally the earliest
    sign and the one that should stop an injection. The distribution is
    attributed to the high regional blood flow of the perioral tissues
    rather than to any selective action there.
  phenotype_term:
    preferred_term: circumoral paresthesia
    term:
      id: HP:0003401
      label: Paresthesia
    temporality: ACUTE
  evidence:
  - reference: PMID:29763139
    reference_title: Local Anesthetic Toxicity.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The central nervous system (CNS) is often affected first, producing circumoral paresthesia, metallic taste, tinnitus, dizziness, agitation, visual disturbances, dysarthria, or muscle twitching."
    explanation: >-
      Names circumoral paresthesia first among the early central nervous
      system features. HPO has no perioral-specific paresthesia term, so the
      binding is the general one and `preferred_term` carries the
      distribution.
- category: Neurologic
  name: Metallic taste
  phenotype_term:
    preferred_term: metallic taste
    term:
      id: HP:0031249
      label: Parageusia
    temporality: ACUTE
  evidence:
  - reference: PMID:29763139
    reference_title: Local Anesthetic Toxicity.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The central nervous system (CNS) is often affected first, producing circumoral paresthesia, metallic taste, tinnitus, dizziness, agitation, visual disturbances, dysarthria, or muscle twitching."
    explanation: >-
      Names metallic taste among the early central nervous system features.
      `HP:0031249` is the binding because its own definition reads "often
      characterized by the sensation of a metallic taste" and it carries
      "Metallic taste" as an exact synonym.
- category: Neurologic
  name: Dizziness
  phenotype_term:
    preferred_term: dizziness
    term:
      id: HP:0002321
      label: Vertigo
    temporality: ACUTE
  notes: >-
    HPO files "Dizziness" only as a synonym of `HP:0002321` Vertigo,
    whose definition is narrower than the source's word: "an abnormal
    sensation of spinning while the body is actually stationary". The
    prodromal dizziness of this syndrome is not described as rotatory.
    The term is bound because HPO offers no separate concept and the
    synonym is the ontology's own decision, but the gap between the
    label and the quoted word is recorded here rather than hidden.
  evidence:
  - reference: PMID:29763139
    reference_title: Local Anesthetic Toxicity.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The central nervous system (CNS) is often affected first, producing circumoral paresthesia, metallic taste, tinnitus, dizziness, agitation, visual disturbances, dysarthria, or muscle twitching."
    explanation: >-
      Names dizziness among the early central nervous system features.
- category: Neurologic
  name: Visual disturbance
  phenotype_term:
    preferred_term: visual disturbances
    term:
      id: HP:0000504
      label: Abnormality of vision
    temporality: ACUTE
  evidence:
  - reference: PMID:29763139
    reference_title: Local Anesthetic Toxicity.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The central nervous system (CNS) is often affected first, producing circumoral paresthesia, metallic taste, tinnitus, dizziness, agitation, visual disturbances, dysarthria, or muscle twitching."
    explanation: >-
      Names visual disturbances among the early central nervous system
      features. `HP:0000504` is the binding rather than `HP:0000505` Visual
      impairment, which HPO defines as vision loss severe enough to qualify
      as an additional support need - a permanent disability, not a
      transient prodromal symptom.
- category: Neurologic
  name: Muscle twitching
  phenotype_term:
    preferred_term: muscle twitching
    term:
      id: HP:0002380
      label: Fasciculations
    temporality: ACUTE
  notes: >-
    The HPO definition attributes fasciculation to irritability of a
    motor axon, which is a different origin from the cortical
    disinhibition this entry models. The term is bound on the exact
    synonym rather than on the mechanism, and no claim about the
    origin of the twitching is made by binding it.
  evidence:
  - reference: PMID:29763139
    reference_title: Local Anesthetic Toxicity.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The central nervous system (CNS) is often affected first, producing circumoral paresthesia, metallic taste, tinnitus, dizziness, agitation, visual disturbances, dysarthria, or muscle twitching."
    explanation: >-
      Names muscle twitching among the early central nervous system
      features. `HP:0002380` carries "Muscle twitch" as an exact synonym.
- category: Neurologic
  name: Coma
  phenotype_term:
    preferred_term: Coma
    term:
      id: HP:0001259
      label: Coma
  evidence:
  - reference: PMID:20301824
    reference_title: "Clinical presentation of local anesthetic systemic toxicity: a review of published cases, 1979 to 2009."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "culminating in seizures and coma"
    explanation: Names coma as the endpoint of the neurological sequence.
- category: Cardiovascular
  name: Cardiac arrest
  description: >-
    The terminal presentation, and the reason LAST is treated as an emergency
    even when it presents with neurological signs alone.
  phenotype_term:
    preferred_term: Cardiac arrest
    term:
      id: HP:0001695
      label: Cardiac arrest
  evidence:
  - reference: PMID:23788067
    reference_title: Ultrasound guidance reduces the risk of local anesthetic systemic toxicity following peripheral nerve blockade.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The primary outcome was LAST comprising minor, major, and cardiac arrest (due to toxicity) events determined using standardized definitions."
    explanation: >-
      Cardiac arrest is one of the three graded outcome categories this
      registry counted, which establishes it as a recognised LAST presentation
      rather than an incidental co-occurrence.
- category: Cardiovascular
  name: Cardiac conduction abnormality
  description: >-
    The electrocardiographic readout of sodium channel blockade in working
    myocardium: slowed phase-0 depolarisation lengthens the PR interval and
    widens the QRS before any arrhythmia appears. This is what monitoring
    during a high-risk block is watching for.
  phenotype_term:
    preferred_term: PR and QRS prolongation
    term:
      id: HP:0031546
      label: Cardiac conduction abnormality
    temporality: ACUTE
  notes: >-
    Bound at conduction-abnormality granularity rather than to `HP:0006677`
    Prolonged QRS complex because the two cited sentences say different
    things: the clinical review says "conduction abnormalities" without
    naming an interval, and the mechanistic review says PR and QRS together.
    Binding the QRS term alone would drop the PR half of what is quoted, and
    splitting one electrocardiographic observation across two phenotypes
    would assert two findings where the sources report one.
  evidence:
  - reference: PMID:29763139
    reference_title: Local Anesthetic Toxicity.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Progressive toxicity may cause seizures, loss of consciousness, respiratory depression, conduction abnormalities, hypotension, ventricular dysrhythmias, and cardiovascular collapse."
    explanation: >-
      Names conduction abnormalities among the manifestations of progressive
      toxicity, which is the clinical statement that this phenotype occurs.
  - reference: PMID:42589553
    reference_title: "Molecular Mechanisms of Local Anesthetic Toxicity: From Ion Channel Dysregulation to Mitochondrial Dysfunction and Tissue-Specific Injury."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "In cardiomyocytes, sodium channel blockade slows phase 0 depolarization, reduces conduction velocity, and prolongs PR/QRS intervals."
    explanation: >-
      Names the two intervals and ties them to the upstream node this
      phenotype hangs off, which is why the edge is drawn from
      `Impaired Cardiac Impulse Conduction` rather than from the exposure.
- category: Cardiovascular
  name: Ventricular arrhythmia
  phenotype_term:
    preferred_term: Ventricular arrhythmia
    term:
      id: HP:0004308
      label: Ventricular arrhythmia
  evidence:
  - reference: PMID:29763139
    reference_title: Local Anesthetic Toxicity.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Progressive toxicity may cause seizures, loss of consciousness, respiratory depression, conduction abnormalities, hypotension, ventricular dysrhythmias, and cardiovascular collapse."
    explanation: >-
      Names ventricular dysrhythmias among the manifestations of progressive
      toxicity. This is the direct clinical statement; the electrophysiology
      item below is kept for the mechanism it points at.
  - reference: PMID:25008571
    reference_title: Voltage-dependent blockade by bupivacaine of cardiac sodium channels expressed in Xenopus oocytes.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "Nav1.5 is the dominant isoform of VGSCs expressed in cardiac myocytes, and its dysfunction may be the cause of bupivacaine-triggered arrhythmia."
    explanation: >-
      INDIRECT and BACKGROUND: an electrophysiology paper's framing sentence,
      naming bupivacaine-triggered arrhythmia as the clinical problem it
      studies rather than observing it. Kept because it ties the phenotype to
      the specific channel this entry's canonical arm blames.
- category: Cardiovascular
  name: Bradycardia
  phenotype_term:
    preferred_term: Bradycardia
    term:
      id: HP:0001662
      label: Bradycardia
  evidence:
  - reference: PMID:24496123
    reference_title: "Resuscitation with lipid emulsion: dose-dependent recovery from cardiac pharmacotoxicity requires a cardiotonic effect."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Heart rates remained depressed in all four groups throughout the observation period."
    explanation: >-
      INDIRECT and from a rat model: heart rate was depressed by bupivacaine in
      every arm and did not recover with any treatment. It supports bradycardia
      as part of the toxidrome, not as a human clinical observation, and the
      grading says so.
- category: Cardiovascular
  name: Hypotension
  phenotype_term:
    preferred_term: Hypotension
    term:
      id: HP:0002615
      label: Hypotension
  evidence:
  - reference: PMID:29763139
    reference_title: Local Anesthetic Toxicity.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Progressive toxicity may cause seizures, loss of consciousness, respiratory depression, conduction abnormalities, hypotension, ventricular dysrhythmias, and cardiovascular collapse."
    explanation: Names hypotension directly among the manifestations of progressive toxicity.
  - reference: PMID:20301824
    reference_title: "Clinical presentation of local anesthetic systemic toxicity: a review of published cases, 1979 to 2009."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "or involved only signs of cardiovascular compromise, with no evidence of central nervous system toxicity"
    explanation: >-
      INDIRECT, and kept for a different point than the item above: it does not
      name hypotension, but it establishes cardiovascular compromise as a
      presentation in its own right, which is what makes this phenotype more
      than a late complication of the neurological sequence.
genetic:
- name: SCN5A
  relationship_type: RISK_FACTOR
  notes: >-
    A single functionally characterised case, not a population association.
    It is curated because the mechanism is exactly the one this entry's
    canonical arm describes - a variant that reduces peak sodium current,
    in a patient who then fibrillated on lidocaine - and because a
    loss-of-function channel variant lowering the threshold for channel-blocker
    toxicity is a coherent claim rather than a coincidence. It is not evidence
    that SCN5A genotype predicts risk in the general population.
  gene_term:
    preferred_term: SCN5A
    term:
      id: hgnc:10593
      label: SCN5A
  evidence:
  - reference: PMID:24445991
    reference_title: A rare loss-of-function SCN5A variant is associated with lidocaine-induced ventricular fibrillation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "We report identification and functional characterization of a rare non-synonymous (p.A1427S) variant in the SCN5A gene that was associated with incessant and lethal ventricular tachycardia and fibrillation after administration of lidocaine to a patient with acute myocardial infarction."
    explanation: >-
      The case and the variant. Note the confounder the authors state plainly -
      the lidocaine was given for acute myocardial infarction, so an infarcting
      myocardium is part of the picture.
  - reference: PMID:24445991
    reference_title: A rare loss-of-function SCN5A variant is associated with lidocaine-induced ventricular fibrillation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "The variant, located in a highly conserved domain distinct from the predicted lidocaine-binding site, decreased peak current density of the sodium channel."
    explanation: >-
      The functional characterisation, and the reason this is a susceptibility
      claim rather than an altered-drug-binding one: the variant sits away from
      the lidocaine site and lowers baseline current, so it reduces the reserve
      the drug then eats into. Graded IN_VITRO because this is the
      electrophysiology, separate from the clinical case above.
environmental:
- name: Injection of local anesthetic for regional or local anesthesia
  description: >-
    The exposure is a therapeutic procedure. Risk concentrates where injection
    is into a vascular bed, where the dose per weight is high, and where the
    agent is one of the more cardiotoxic amides.
  exposure_term:
    preferred_term: exposure to a local anesthetic agent
    term:
      id: ECTO:9001759
      label: exposure to local anaesthetic
  influences_mechanisms:
  - target: Systemic Local Anesthetic Exposure
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      The administered dose is the sole source of the systemic concentration;
      there is no endogenous contribution.
    evidence:
    - reference: PMID:23788067
      reference_title: Ultrasound guidance reduces the risk of local anesthetic systemic toxicity following peripheral nerve blockade.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "Site of injection, local anesthetic type, dose per weight, dose, and patient weight were all predictors of LAST."
      explanation: >-
        Identifies the features of the exposure that determine whether toxicity
        follows, which is what this edge asserts - dose and site, not patient
        idiosyncrasy.
  evidence:
  - reference: PMID:29303925
    reference_title: "Local Anesthetic Systemic Toxicity: A Review of Recent Case Reports and Registries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Local anesthetic systemic toxicity events occurred as a result of penile blocks (23%), local infiltration (17%), and upper/lower extremity, torso, and neuraxial blockade."
    explanation: >-
      The distribution of procedures that produced events, which is the
      exposure this entry models.
  - reference: PMID:35777259
    reference_title: "Local anesthetic systemic toxicity: A narrative review for emergency clinicians."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Patients at extremes of age or with organ dysfunction are at higher risk."
    explanation: >-
      The patient-side half of the risk picture, which the procedure-side
      evidence above does not cover. Carried because this entry otherwise
      attributes risk entirely to dose and site, and the same review names
      host factors that modify it at a given dose.
  notes: >-
    ECTO spells this term the British way. `runoak -i ols:ecto search "exposure
    to local anesthetic"` returns nothing and `"exposure to anesthetic"` returns
    only the broad `ECTO:2000059`, which is what an earlier draft of this entry
    bound while asserting no specific term existed. `runoak -i ols:ecto search
    "anaesthetic"` returns `ECTO:9001759` exposure to local anaesthetic, which
    is exact, non-obsolete, and reachable from the `ExposureTerm` root via
    exposure to drug, so it validates. Searching one spelling and recording the
    absence as a fact is the failure this note now exists to document.
treatments:
- name: Intravenous Lipid Emulsion
  description: >-
    The specific antidote, and first-line for the cardiovascular manifestations.
    It works - the dose-response is established in animals and the case series
    are favourable - but by which of several mechanisms is unsettled, which the
    `lipid_rescue_mechanism` discussion records. Note that the evidence base
    behind the international recommendations is graded low to very low.
  therapeutic_modality: OTHER
  notes: >-
    The agent binding is a compromise and the reason is worth recording.
    `NCIT:C2575` Fat Emulsion names the formulation exactly, but it is not
    reachable from the `ChemicalEntityTerm` enum root, so `just validate-terms`
    rejects it in `therapeutic_agent` - the same class of failure as binding a
    device term in a clinical-action slot. `CHEBI:166975` soybean oil is bound
    instead: it is the lipid phase of the standard 20% emulsion, not the
    emulsion itself. What is lost is the formulation, which matters here
    because medium-chain and long-chain preparations are not interchangeable
    in this indication; `preferred_term` carries it.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: intravenous lipid emulsion (soybean-oil based)
      term:
        id: CHEBI:166975
        label: soybean oil
  target_mechanisms:
  - target: Myocardial Contractile Depression
    treatment_effect: INHIBITS
    description: >-
      The cardiotonic arm of the antidote's action: lipid emulsion raises
      arterial pressure and accelerates haemodynamic recovery in a
      dose-dependent way.
    evidence:
    - reference: PMID:24496123
      reference_title: "Resuscitation with lipid emulsion: dose-dependent recovery from cardiac pharmacotoxicity requires a cardiotonic effect."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "Intravenous lipid emulsion accelerates cardiovascular recovery from bupivacaine toxicity in a dose-dependent manner, which is driven by a cardiotonic response that complements the previously reported sequestration effect."
      explanation: >-
        Supports this specific edge - an effect on contractile performance -
        and is careful that the cardiotonic response complements rather than
        replaces sequestration.
  - target: Global Neuronal Conduction Failure
    treatment_effect: INHIBITS
    description: >-
      Lipid emulsion also acts against the central nervous system arm, not
      only the cardiac one. In rats given local anesthetic directly into the
      lateral ventricle, emulsion given before the dose prevented respiratory
      arrest and emulsion given after it achieved resuscitation.
    evidence:
    - reference: PMID:26622452
      reference_title: Lipid emulsion mitigates local anesthesia-induced central nervous system toxicity in rats.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "The results of the present study therefore indicate that pre- and post-conditioning with lipid emulsion effectively mitigates LA-induced CNS toxicity in rats."
      explanation: >-
        Supports this specific edge, which no other evidence in this entry
        covers: every other lipid emulsion item here is cardiac. Worth noting
        for the `lipid_rescue_mechanism` discussion that the anesthetic was
        injected intracerebroventricularly, so a purely intravascular sink
        is not an obvious explanation of the rescue - but the study was not
        designed to test that and the entry does not claim it did.
  - target: Mitochondrial Carnitine-Acylcarnitine Translocase Inhibition
    treatment_effect: INHIBITS
    description: >-
      Lipid emulsion reverses the translocase inhibition in cardiomyoblasts.
      The authors attribute this to sequestration of the drug rather than to
      any direct metabolic effect, which matters for the mechanism question.
    evidence:
    - reference: PMID:35135371
      reference_title: Lipid emulsions attenuate the inhibition of carnitine acylcarnitine translocase induced by toxic doses of local anesthetics in rat cardiomyoblasts.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "Collectively, these results suggested that the lipid emulsion attenuated the levobupivacaine-induced inhibition of CACT, probably through the lipid emulsion-mediated sequestration of levobupivacaine."
      explanation: >-
        Supports the edge and names the proposed route, with the authors' own
        "probably" left in - this is the sequestration account, and the paper
        offers it as the likely explanation rather than a demonstrated one.
  evidence:
  - reference: PMID:28346007
    reference_title: "Lipid emulsion improves survival in animal models of local anesthetic toxicity: a meta-analysis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Lipid emulsion reduced the odds of death in resuscitative models (OR =0.24; 95%CI: 0.1-0.56, p = .0012)."
    explanation: >-
      The strongest efficacy estimate available for this treatment, pooled
      across 16 resuscitative animal studies. MODEL_ORGANISM because every
      included study is an animal model - there is no randomised human trial in
      this indication and there is unlikely ever to be one.
  - reference: PMID:28346007
    reference_title: "Lipid emulsion improves survival in animal models of local anesthetic toxicity: a meta-analysis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Analysis of outliers reinforced the need for good life support measures (securement of airway and chest compressions) along with prompt treatment with lipid."
    explanation: >-
      INDIRECT, and the reason this entry lists airway management before the
      antidote: the same meta-analysis found the lipid benefit depends on basic
      life support being done alongside it.
  - reference: PMID:37242638
    reference_title: "Lipid Emulsion to Treat Acute Poisonings: Mechanisms of Action, Indications, and Controversies."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Present evidence supports the use of ILE as first-line therapy to reverse local anesthetic-related systemic toxicity and as adjunct therapy in lipophilic non-local anesthetic drug overdoses refractory to well-established antidotes and supportive care."
    explanation: Establishes first-line status for this indication specifically.
  - reference: PMID:37242638
    reference_title: "Lipid Emulsion to Treat Acute Poisonings: Mechanisms of Action, Indications, and Controversies."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "However, the level of evidence is low to very low, as for most other commonly used antidotes."
    explanation: >-
      The same review's grading of that recommendation, carried so the
      first-line status is not read as a strong evidence base. INDIRECT because
      it qualifies the recommendation rather than bearing on efficacy directly.
- name: Airway Management and Ventilation
  description: >-
    Oxygenation and ventilation come first, because hypoxia and acidosis
    worsen the toxicity that caused them. The binding covers one half of the
    treatment. `runoak`-equivalent OLS searches of NCIT return nothing for
    "Airway Management", `NCIT:C94624` Oxygen Therapy for "Oxygen Therapy", and
    `NCIT:C70909` Mechanical Ventilation for "Mechanical Ventilation". Oxygen
    Therapy is bound because first-line care here is bag-mask ventilation with
    100% oxygen and Mechanical Ventilation names only the escalated form; an
    earlier draft bound the escalated term and then asserted no whole-airway
    term existed, which was a search of one phrase reported as a fact about the
    ontology. The airway-management half is carried in `preferred_term`.
  treatment_term:
    preferred_term: airway management, oxygenation and ventilation
    term:
      id: NCIT:C94624
      label: Oxygen Therapy
  evidence:
  - reference: PMID:21841477
    reference_title: "Local anesthetic systemic toxicity: update on mechanisms and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "As for treatment, in addition to ventilation, oxygenation, and chest compressions, lipid emulsion therapy should be a primary element in the treatment of cardiovascular LAST."
    explanation: >-
      Places ventilation and oxygenation alongside lipid emulsion in the
      treatment set.
- name: Supportive Care and Modified Resuscitation
  description: >-
    Standard resuscitation modified for this toxidrome, notably by keeping
    vasopressor doses low.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:21841477
    reference_title: "Local anesthetic systemic toxicity: update on mechanisms and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The use of epinephrine and vasopressin should be tailored to specifics of an episode of LAST, and doses should be kept as low as possible while still achieving the desired effects."
    explanation: >-
      The specific modification that distinguishes LAST resuscitation from
      standard practice.
prevalence:
- population: Peripheral nerve blocks, Australia and New Zealand registry, 2007-2012
  measure_type: UNKNOWN
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 87.0
  rate_denominator: POPULATION
  notes: >-
    0.87 events per 1000 peripheral nerve blocks, converted to 87 per 100,000
    blocks, which is `BAND_1_5_PER_10000` (10-99 per 100,000). Two slots here
    are compromises. The denominator is blocks performed, not people or
    person-years, and no `RateDenominatorEnum` value names that; POPULATION is
    the closest. And `measure_type` is UNKNOWN rather than ANNUAL_INCIDENCE
    because this is a per-procedure attack rate over 2007-2012, not a rate per
    year - an earlier draft said ANNUAL_INCIDENCE, which would have made the
    band read as cases per 100,000 per year. See the entry `notes:` for why
    this figure is not reconciled with the others.
  evidence:
  - reference: PMID:23788067
    reference_title: Ultrasound guidance reduces the risk of local anesthetic systemic toxicity following peripheral nerve blockade.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "There were 22 episodes of LAST, resulting in an incidence of LAST of 0.87 per 1000 PNBs (95% confidence interval, 0.54-1.3 per 1000)."
    explanation: The event count, the rate and its confidence interval.
- population: Peripheral nerve blocks, pooled registries reported 2018
  measure_type: UNKNOWN
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 27.0
  rate_denominator: POPULATION
  notes: >-
    0.27 events per 1000 blocks over a denominator of 251,325, converted to 27
    per 100,000 blocks, which is `BAND_1_5_PER_10000`. Lower than the earlier
    registry figure above; the entry does not reconcile the two. `measure_type`
    is UNKNOWN for the same reason as the record above - a per-procedure attack
    rate is not an annual incidence.
  evidence:
  - reference: PMID:29303925
    reference_title: "Local Anesthetic Systemic Toxicity: A Review of Recent Case Reports and Registries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The incidence of LAST reported in registries is 0.03% or 0.27 (95% confidence interval, 0.21-0.35) per 1000 peripheral nerve blocks (denominator of 251,325)."
    explanation: The pooled registry rate with its denominator.
animal_models:
- name: Bupivacaine cardiovascular toxicity in the anesthetized rat
  species: Rat
  genotype: wild type Sprague-Dawley
  publication: PMID:24496123
  description: >-
    Instrumented rats given a non-lethal intravenous bupivacaine dose, then
    randomised to lipid emulsion at two concentrations, saline, or nothing. The
    model that supplies this entry's evidence on how the antidote works.
  modeled_mechanisms:
  - target: Myocardial Contractile Depression
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Reproduces the haemodynamic arm of the toxidrome and its reversal, with
      arterial pressure as the recovering variable.
    limitations: >-
      The dose is deliberately sub-lethal so that recovery happens without
      chest compressions, which is not the clinical scenario the antidote is
      used in. Heart rate did not recover in any arm, so the model reproduces
      the pressure half of the collapse and not the rate half.
    evidence:
    - reference: PMID:24496123
      reference_title: "Resuscitation with lipid emulsion: dose-dependent recovery from cardiac pharmacotoxicity requires a cardiotonic effect."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "Rats treated with lipid emulsions recovered faster than did rats treated with saline or no treatment."
      explanation: >-
        The controlled comparison that makes this a usable model of the
        treatment effect rather than of the toxicity alone.
experimental_models:
- name: Nav1.5 expressed in Xenopus oocytes
  experimental_model_type: OTHER
  publication: PMID:25008571
  description: >-
    Heterologous expression of the cardiac sodium channel for voltage-clamp
    measurement of bupivacaine block. Not a disease model - a target model,
    which is what the canonical arm of this entry needs.
  modeled_mechanisms:
  - target: Cardiac Sodium Channel Blockade
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Measures the block directly at the channel, giving the potency and the
      use-dependence the node claims.
    limitations: >-
      An amphibian oocyte expressing one human channel is not a cardiomyocyte:
      there is no sarcomere, no mitochondrial arm, and none of the accessory
      subunits or lipid environment that modulate Nav1.5 in working myocardium.
      It can say what the drug does to the channel and nothing about what that
      does to a heart.
    evidence:
    - reference: PMID:25008571
      reference_title: Voltage-dependent blockade by bupivacaine of cardiac sodium channels expressed in Xenopus oocytes.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "Consistent with other local anesthetics, bupivacaine also induced a use-dependent blockade on Nav1.5 currents."
      explanation: >-
        The use-dependence half of what this link claims to measure, observed
        in the oocyte preparation itself. The previous snippet here was the
        paper's aim sentence, which states what the study set out to do rather
        than what it found, and so could carry no `quote_role` at all.
discussions:
- kind: KNOWLEDGE_GAP
  discussion_id: lipid_rescue_mechanism
  prompt: >-
    By what mechanism does intravenous lipid emulsion reverse local anesthetic
    cardiotoxicity - sequestration of the drug, a direct cardiotonic effect,
    post-conditioning, or some combination?
  attaches_to:
  - treatments#Intravenous Lipid Emulsion
  - pathophysiology#Myocardial Contractile Depression
  rationale: >-
    This is the unusual case of an antidote in routine guideline-endorsed use
    whose mechanism is still argued over. The "lipid sink" account -
    intravascular lipid sequestering drug away from target tissue - is the
    oldest and is supported by the cardiomyoblast work. Against it, a
    dose-response study in rats found recovery driven by a cardiotonic effect
    that the authors say complements rather than replaces sequestration, and
    the ASRA advisory names three mechanisms at once. Others have proposed
    that recovery is simply hemodilution. The question is not academic: if the
    sink dominates, the antidote should be reserved for the most lipophilic
    agents, and if inotropy dominates, it should not.
  evidence:
  - reference: PMID:29356773
    reference_title: "The Third American Society of Regional Anesthesia and Pain Medicine Practice Advisory on Local Anesthetic Systemic Toxicity: Executive Summary 2017."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "This interim update summarizes recent scientific findings that have enhanced our understanding of the mechanisms that lead to lipid emulsion reversal of LAST, including rapid partitioning, direct inotropy, and post-conditioning."
    explanation: >-
      The guideline naming three distinct mechanisms, which is the state of the
      question rather than a resolution of it.
  - reference: PMID:37242638
    reference_title: "Lipid Emulsion to Treat Acute Poisonings: Mechanisms of Action, Indications, and Controversies."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Additional mechanisms based on ILE-attributed vasoactive and cytoprotective properties are still under investigation."
    explanation: >-
      Confirms the list is still open, not merely contested between two
      settled options.
  - reference: PMID:24496123
    reference_title: "Resuscitation with lipid emulsion: dose-dependent recovery from cardiac pharmacotoxicity requires a cardiotonic effect."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "An increase in arterial blood pressure underlay the recovery in both lipid emulsion-treated groups."
    explanation: >-
      The observation behind the cardiotonic account: recovery tracked blood
      pressure, not heart rate, in a controlled dose-response design.
- kind: KNOWLEDGE_GAP
  discussion_id: classic_presentation_is_the_minority_picture
  prompt: >-
    Why does the classic progressive neurological-then-cardiovascular sequence
    describe only about three-fifths of published cases, and what determines
    which patients present with cardiovascular signs alone or after a delay?
  attaches_to:
  - pathophysiology#Cortical Disinhibition
  - phenotypes#Hypotension
  rationale: >-
    The textbook model this entry's pathograph follows - rising concentration
    producing an ordered neurological sequence, with cardiovascular signs late
    - is the minority presentation in a 30-year review of published cases. The
    remainder were substantially delayed or purely cardiovascular with no
    central nervous system signs at all. The ASRA advisory reports the same
    drift and offers candidate explanations, all of them changes in practice
    rather than in biology: ultrasound guidance means fewer intravascular
    injections, infiltration techniques absorb more slowly, and continuous
    infusions accumulate. Whether the shift is entirely explained by technique
    or partly reflects who is now being affected is not settled; the advisory
    notes an increasing share of events outside hospitals and involving
    non-anesthesiologists.
  evidence:
  - reference: PMID:20301824
    reference_title: "Clinical presentation of local anesthetic systemic toxicity: a review of published cases, 1979 to 2009."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Sixty percent of cases followed the classic pattern of presentation. However, in the remainder of cases, symptoms were substantially delayed after the injection of local anesthetic, or involved only signs of cardiovascular compromise, with no evidence of central nervous system toxicity."
    explanation: >-
      REFUTE, and the object is the pathograph, not this discussion. The
      discussion's own rationale asserts what this sentence says, so read
      against the discussion it would be SUPPORT. It is graded REFUTE because
      the claim it cuts against is the ordered neurological-then-cardiovascular
      model that this entry's `Cortical Disinhibition` chain encodes, and which
      the same paper supplies as BACKGROUND two nodes away. Stating the object
      explicitly because `supports` is claim-relative and the two gradings of
      this reference would otherwise look inconsistent.
  - reference: PMID:29356773
    reference_title: "The Third American Society of Regional Anesthesia and Pain Medicine Practice Advisory on Local Anesthetic Systemic Toxicity: Executive Summary 2017."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Contemporary case reports suggest a trend toward delayed presentation, which may mirror the increased use of ultrasound guidance (fewer intravascular injections), local infiltration techniques (slower systemic uptake), and continuous local anesthetic infusions."
    explanation: >-
      The candidate explanations, all of them practice changes, and offered by
      the guideline as a possibility ("may mirror") rather than as established.
  - reference: PMID:39398741
    reference_title: "Local Anesthetic Systemic Toxicity in Pregnancy: A Retrospective Cohort Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Pregnant cohorts had a significantly higher risk of cardiac depression (risk ratio (RR)=1.96 (95% confidence interval (CI): 1.44-2.66), p<0.01) and significantly lower risk of cardiac excitation (RR=0.38 (95% CI: 0.22-0.63), p<0.01), prodromal symptoms (RR=0.17 (95% CI: 0.09-0.33), p<0.01), central nervous system excitation (RR=0.44 (95% CI: 0.21-0.90), p=0.02), and central nervous system depression (RR=0.24 (95% CI: 0.13-0.48), p<0.01) than nonpregnant cohorts."
    explanation: >-
      The discussion asks what determines which patients skip the prodrome.
      This is the one cited source that measures a population where they do:
      matched pregnant and nonpregnant cohorts, with the prodrome roughly six
      times less likely in pregnancy and cardiac depression twice as likely.
      It narrows the question rather than settling it - the authors offer
      gestational physiology and earlier detection as competing explanations
      for the same numbers, and a matched retrospective database cohort
      cannot separate them.
clinical_burden:
  burden_level: MODERATE
  rationale: >-
    Individually severe and occasionally fatal, but rare and getting rarer.
    Registry incidence is under one event per thousand peripheral nerve blocks
    and falling with ultrasound guidance; a single-centre series of 12,668
    ultrasound-guided blocks recorded no cardiac arrests at all. Against that,
    events increasingly occur outside the operating theatre and in the hands of
    non-anesthesiologists, where the antidote and the expertise may not be at
    hand.
  evidence:
  - reference: PMID:22705953
    reference_title: "Incidence of local anesthetic systemic toxicity and postoperative neurologic symptoms associated with 12,668 ultrasound-guided nerve blocks: an analysis from a prospective clinical registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Local anesthetic systemic toxicity, however, is extremely uncommon."
    explanation: >-
      The authors' conclusion from a 12,668-block prospective registry, which
      is the basis for MODERATE rather than HIGH.
  - reference: PMID:29356773
    reference_title: "The Third American Society of Regional Anesthesia and Pain Medicine Practice Advisory on Local Anesthetic Systemic Toxicity: Executive Summary 2017."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "An increasing number of reported events occur outside of the traditional hospital setting and involve non-anesthesiologists."
    explanation: >-
      The countervailing consideration, and the reason the burden is not graded
      LOW despite the falling incidence.
references:
- reference: PMID:29356773
  title: "The Third American Society of Regional Anesthesia and Pain Medicine Practice Advisory on Local Anesthetic Systemic Toxicity: Executive Summary 2017."
- reference: PMID:20301824
  title: "Clinical presentation of local anesthetic systemic toxicity: a review of published cases, 1979 to 2009."
- reference: PMID:29763139
  title: Local Anesthetic Toxicity.
  tags:
  - StatPearls
📚

References & Deep Research

References

3
PMID:29356773
The Third American Society of Regional Anesthesia and Pain Medicine Practice Advisory on Local Anesthetic Systemic Toxicity: Executive Summary 2017.
No top-level findings curated for this source.
PMID:20301824
Clinical presentation of local anesthetic systemic toxicity: a review of published cases, 1979 to 2009.
No top-level findings curated for this source.
PMID:29763139
Local Anesthetic Toxicity.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record notes

**Two incidence figures are carried here and are not reconciled.** A multicentre registry of 25,336 peripheral nerve blocks reports 0.87 per 1000 (`PMID:23788067`); a later review of registries reports 0.27 per 1000 over a denominator of 251,325 (`PMID:29303925`); and a single-centre series of 12,668 ultrasound-guided blocks reports a seizure rate of 0.08 per 1000 and no cardiac arrests (`PMID:22705953`). These differ in period, case definition, technique mix and denominator. The entry reports each with its source rather than averaging them, and the direction they agree on - that LAST is rare and getting rarer - is the claim worth making. **This entry is about systemic toxicity, not local tissue toxicity.** The two share molecular injury pathways and are routinely reviewed together (`PMID:42589553` does exactly that), but direct neurotoxicity or myotoxicity at the injection site is a different clinical problem with a different exposure profile, and is out of scope here. True local anesthetic hypersensitivity is also excluded: it is immune-mediated and rarer, and nothing in this entry's pathograph applies to it. **No GeneReviews chapter exists and none is expected** - this is an acquired iatrogenic drug toxicity with no Mendelian basis. `just check-genereviews` returns `GeneReviews NO_CHAPTER`. It returns `StatPearls TAGGED`: a StatPearls chapter does exist and is cited and tagged below, for the symptom list only. StatPearls is never a baseline. **Host susceptibility: one half curated, one half not, and the difference is the evidence.** The deep research report proposes that SCN5A channelopathy and carnitine palmitoyltransferase II deficiency would each lower the threshold for this cascade, which is mechanistically coherent given the two arms curated below. The SCN5A half is now a `genetic:` record: a single functionally characterised case of lidocaine-induced lethal ventricular fibrillation in a rare SCN5A variant carrier. The fatty-acid-oxidation half is not, and the reason is specific rather than general - the cached review on anesthetic management in those patients (`PMID:35363184`) is about general anesthesia, recommends avoiding propofol, and never mentions local anesthetics or this syndrome. It is the wrong paper for the claim, not merely a weak one. An earlier draft of this note asserted that no case report had been cached at all, which was false: `PMID:24445991` was sitting in this PR's own cache when it was written. **Two cached references are deliberately uncited by this entry and are not orphans.** `references_cache/` here backs two things: this entry's snippets and the deep research report committed beside it, whose citation list is checked against the same cache. `PMID:33148630` (the ASRA 2020 checklist) and `PMID:27243970` (whole-exome sequencing of a family with local anesthetic resistance) are both cited by the report and neither is quotable here. The checklist's abstract records only that the 2020 version exists and why it was revised, which is bibliographic rather than a finding. The exome study is about resistance to the intended block - an SCN5A A572D variant causing anesthesia to fail - which is the opposite clinical problem from systemic toxicity and does not belong in this entry's `genetic:` section merely because it names the same gene.

Review round 1: prodromal CNS phenotypes, aim-statement snippet, cardiac GO terms · 2026-09-19T07:06:10Z · View source

Review round 1 on PR #12286, answered in one push. Two blocking findings from the automated reviewer: 1. Five prodromal CNS features named in a snippet already verified in this entry were not modeled. Added circumoral paresthesia, metallic taste, dizziness, visual disturbances and muscle twitching as Neurologic phenotypes with temporality ACUTE, citing the same PMID:29763139 sentence that already backed tinnitus, agitation and dysarthria. Every HPO CURIE was taken from a live OLS lookup at the point of writing. Three bindings are looser than the source's word and each records why in notes: HP:0003401 Paresthesia has no perioral-specific child; HP:0002321 Vertigo carries "Dizziness" only as a synonym while its definition specifies a rotatory sensation the source does not claim; HP:0002380 Fasciculations carries "Muscle twitch" as an exact synonym but defines the finding by a motor-axon origin that is not the mechanism this entry models. HP:0000504 Abnormality of vision was chosen over HP:0000505 Visual impairment, whose HPO definition is permanent disabling vision loss. 2. The Xenopus oocyte model's evidence quoted the paper's aim sentence and graded it PRIMARY_RESULT. CLAUDE.md says an aim statement has no value in quote_role. Replaced the snippet with the paper's own use-dependence result, which is what the link's description claims to measure, leaving PRIMARY_RESULT correct rather than merely removing the field. Non-blocking findings also taken: - Bound the conduction node to GO:0061337 cardiac conduction and GO:0086001 cardiac muscle cell action potential in place of the generic GO:0001508. - Added a Cardiac conduction abnormality phenotype (HP:0031546) wired from Impaired Cardiac Impulse Conduction. Bound at conduction-abnormality granularity rather than HP:0006677 Prolonged QRS complex because the two cited sentences say "conduction abnormalities" and "PR/QRS" respectively, and the QRS term alone would drop the PR half. - Consumed four of the six cached-but-uncited references: PMID:17643405 (cardiolipin liposome disruption, a second mitochondrial route distinct from the translocase arm, INDIRECT because the preparation is synthetic), PMID:26622452 (lipid emulsion against the CNS arm, the first non-cardiac target_mechanism on that treatment), PMID:35777259 (patient-side risk factors on the exposure entry), PMID:39398741 (matched pregnant/nonpregnant cohort, which measures a population that skips the prodrome and so bears directly on the classic_presentation_is_the_minority_picture discussion). Declined: pruning the remaining two caches. The reviewer suggested pruning what the entry does not cite, but PMID:33148630 and PMID:27243970 are both cited by the deep research report committed in the same PR, whose citation list validates against the same cache. Recorded in entry notes, with the reason each is unquotable here: the ASRA checklist abstract states only that the 2020 revision exists, and the exome study is about resistance to the intended block rather than systemic toxicity. Also declined: a diagnosis: section. The ASRA checklist is the obvious source and its cached abstract carries no clinical content to quote, so the section cannot be written from what is in the branch. A reference_title written from memory during this round was caught and corrected by rewriting every title in the file from its cache frontmatter. The invented string bore no resemblance to the real title. Validation after the round: just validate clean with 58/58 snippets verified (was 47/47); just validate-terms passed; check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values and check-qualifier-terms all clean.

Create: Local Anesthetic Systemic Toxicity (MONDO:0100335) · 2026-09-19T05:04:53Z · View source

New entry for local anesthetic systemic toxicity. Deep research via the claude_code provider (the only one with credentials in this environment). Report validated retrospectively: 25/25 references resolved, 0 unresolved, 0 off topic; 33/33 terms resolved with matching labels. just preflight-dr returned SKIP because MONDO records no causal gene for a non-genetic disease; identity was checked manually instead, and the report's top gene mentions - SCN5A, CPT2, BCHE - are all on-topic for this syndrome, which is a useful corroborating signal. Every ontology CURIE was re-derived from a live OLS lookup at the point of writing. Pathograph is one connected component: exposure, then three parallel arms - cortical inhibitory-tone loss, Nav1.5 blockade, and mitochondrial carnitine-acylcarnitine translocase inhibition - converging on cardiovascular collapse. Two mechanistic_hypotheses: sodium channel blockade as CANONICAL, quoted with the source's own hedge that the evidence remains mixed, and the mitochondrial arm as ALTERNATIVE, quoted with its originating authors' 'The authors hypothesize' intact. A KNOWLEDGE_GAP records that the antidote's mechanism is unsettled between sequestration, direct inotropy and post-conditioning; a second records that the textbook progressive presentation fits only 60 percent of published cases. A fresh-context red-team subagent reviewed the entry against dismech-pr-review and returned 17 findings including 3 blocking; all were acted on. The blocking ones are the record worth keeping, because two are the same defect in the same session. First, an entry note asserted that no case report of host susceptibility had been retrieved or cached, when PMID:24445991 - a functionally characterised SCN5A variant with lidocaine-induced ventricular fibrillation - was already in this PR's own cache; it is now curated as a RISK_FACTOR genetic record. The reviewer also offered PMID:35363184 as the CPT-II half of that lead, and that part does not hold: the paper is about general anesthesia in fatty-acid-oxidation disorders, recommends avoiding propofol, and never mentions local anesthetics, so it is the wrong paper for the claim and the note now says so. Second, the environmental exposure note asserted that ECTO has no local-anesthetic-specific class, on the strength of two searches in American spelling; ECTO:9001759 exposure to local anaesthetic exists under the British spelling, is non-obsolete and validates, and is now bound in place of the broader ECTO:2000059. Third, both prevalence records carried prevalence_class BAND_1_9_PER_100000 against rates of 87.0 and 27.0 per 100,000, which the repo's own bucketer maps to BAND_1_5_PER_10000; both were corrected, and measure_type moved from ANNUAL_INCIDENCE to UNKNOWN because these are per-procedure attack rates rather than annual rates. While fixing the airway treatment binding I wrote a fourth negative-existence claim, that NCIT has no whole-airway clinical-action term; searching found NCIT:C94624 Oxygen Therapy, which is now bound in place of NCIT:C70909 Mechanical Ventilation, and the note records all three searches and what each returned. Other findings acted on: the cortical inhibition node had no evidence at all and attributed the effect solely to sodium channel blockade of interneurons, which the entry's own cited review contradicts - it now carries two items from PMID:42589553 including a REFUTE against reading the sodium binding as the complete mechanism; two evidence items were exact but off-claim and were supplemented with a sentence that names the phenotype directly; a false claim that a chosen quote was the best available in the cache was removed; PMID:28346007, an animal survival meta-analysis giving OR 0.24 for lipid emulsion, was added as the strongest efficacy evidence for the flagship treatment; an unsourced claim about refractory arrests and an unsourced lidocaine comparison were removed from prose; the two model systems already doing evidentiary work were recorded as animal_models and experimental_models with modeled_mechanisms links; and two phenotype edges that were unsourced mechanistic attributions were deleted, which lowered causal connectivity from 9/9 to 7/9 and is the honest figure. Validation: just validate-disorders passes with 47/47 snippets verified; entity-refs, causal-targets, duplicate-keys, enum-values, qualifier-terms, snippet-grading, title-snippets, snippet-length, folded-hyphens, environmental-evidence, case-collisions and reference-titles all clean. just check-genereviews returns GeneReviews NO_CHAPTER and StatPearls TAGGED. Note for the environment: three whole-KB gates failed mid-run with OSError errno 28 no space left on device, not with content findings - they extract an origin/main tarball to build their baseline and the disk was 100 percent full with five worktrees of a 96,000-file repo. Removing the two worktrees for already-merged PRs freed 8.2 GB and all three passed on re-run.

Claude Code ▸
Local Anesthetic Systemic Toxicity (LAST): Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 35 citations 2026-09-19T04:24:43.461336

Local Anesthetic Systemic Toxicity (LAST): Comprehensive Research Report

Note on ontology term suggestions

Per standard curation practice, every ontology identifier (HP, GO, CL, UBERON, CHEBI, NCIT, MONDO) suggested below is a lead only and has not been verified against a live ontology lookup (e.g., OAK/OLS) in this session. Anyone using these terms to populate a structured knowledge base entry should independently confirm the CURIE and canonical label before binding it — do not treat any ID below as verified.

1. Disease Information

Overview. Local anesthetic systemic toxicity (LAST) is a potentially life-threatening, iatrogenic/procedural drug-toxicity syndrome that occurs when the circulating unbound (free) plasma concentration of a local anesthetic (LA) — most often an amide agent such as bupivacaine, ropivacaine, or lidocaine — rises high enough to impair central nervous system (CNS) and cardiovascular function. It is a complication of regional anesthesia (peripheral nerve blocks, neuraxial/epidural blocks, paravertebral blocks), local infiltration, tumescent anesthesia, topical/mucosal application, and intravenous lidocaine infusion, rather than a disease with an independent genetic etiology in the classic Mendelian sense — dismech's "Environmental" category designation reflects that the primary driver is drug exposure/dose, modulated by patient physiology and (in rare cases) genetic susceptibility (StatPearls NBK499964; PMID:35777259).

Key identifiers: - MONDO: MONDO:0100335 (as supplied; not independently re-verified here — confirm before use) - ICD-10-CM: T41.3X1A (Poisoning by local anesthetics, accidental/unintentional, initial encounter); T41.3X5A (Adverse effect of local anesthetics, initial encounter) (icd10data.com) - MeSH: Consider "Anesthetics, Local/adverse effects" (D000777) or a poisoning/toxicity qualifier; there is no single dedicated MeSH descriptor for "LAST" as a named syndrome. - OMIM/Orphanet: No dedicated OMIM or Orphanet entry was found for LAST as a discrete disease; it is catalogued in clinical toxicology and anesthesiology references (StatPearls, UpToDate, NYSORA) rather than as a rare/genetic disease registry entry.

Synonyms/alternative names: Local anesthetic toxicity; systemic local anesthetic toxicity; LA-induced cardiotoxicity/neurotoxicity; bupivacaine cardiotoxicity (agent-specific); "cardiac arrest following regional anesthesia."

Data derivation: Most epidemiological knowledge comes from aggregated, disease/event-level resources rather than individual EHR-linked cohorts: national/international case registries and pharmacovigilance databases (e.g., the FDA Adverse Event Reporting System, FAERS), multicenter simulation collaboratives, systematic reviews of published case reports, and a small number of retrospective EHR cohort studies using federated networks such as TriNetX (e.g., the 2024 pregnancy cohort study) (PMID:39398741; BJA 2025 editorial, Schwenk/Sneyd/Wu).

2. Etiology

Disease causal factors. LAST is fundamentally a pharmacologic/toxicologic disorder: excessive systemic (blood/plasma) exposure to a local anesthetic molecule, arising from (a) inadvertent intravascular injection during a nerve block or epidural, (b) rapid systemic absorption from a highly vascular injection site (e.g., intercostal or paracervical blocks), (c) cumulative overdose exceeding weight-based maximum recommended doses, especially with repeated dosing or continuous infusions, or (d) impaired clearance/altered protein binding that raises the free (unbound, pharmacologically active) fraction of drug for a given total dose (StatPearls NBK499964; NYSORA LAST topic page).

Genetic risk factors: - Inherited fatty-acid β-oxidation defects, especially carnitine palmitoyltransferase II (CPT II) deficiency and other carnitine-cycle disorders. Because bupivacaine impairs the mitochondrial carnitine-acylcarnitine translocase and fatty-acid-supported oxidative phosphorylation, patients whose myocardium already relies precariously on fatty-acid oxidation are more susceptible to LA-induced cardiotoxicity at sub-toxic doses. CPT II deficiency is autosomal recessive; case literature reports that "carnitine deficiency reportedly produces ventricular arrhythmia and hypotension induced by subtoxic doses of bupivacaine," implicating this pathway directly (PMID: review — Anesthetic management of patients with carnitine deficiency, PMC9282055). - Cardiac sodium-channelopathy variants (SCN5A). Pathogenic SCN5A variants (the gene encoding cardiac Nav1.5, the principal off-target cardiac channel for LAs), including those underlying Brugada syndrome and other conduction-system disease, have been associated in case reports with exaggerated cardiotoxic responses to LA exposure — e.g., a loss-of-function SCN5A variant associated with lidocaine-induced ventricular fibrillation after a therapeutic antiarrhythmic dose in a myocardial-infarction patient (PMID:24445991), and case reports of epidural/neuraxial LA use in parturients with known SCN5A mutations requiring modified management (van der Knijff-van Dortmont et al., Case Reports in Anesthesiology 2016). - Local anesthetic resistance variants have also been reported at the opposite end of the spectrum: a whole-exome sequencing study of a family with clinical local-anesthetic resistance (requiring unusually high doses for adequate block) identified a shared voltage-gated sodium channel gene variant, illustrating that SCN family variation modulates LA pharmacodynamics bidirectionally (PMID:27243970 — note: exact channel isoform and variant should be re-verified from the primary source before citation as fact). - Pseudocholinesterase (BCHE) variants are relevant to ester-type LA metabolism (e.g., chloroprocaine, tetracaine, cocaine); atypical or deficient plasma cholinesterase activity slows hydrolysis and can prolong systemic exposure, though this is a much smaller contributor to LAST than amide-LA pharmacokinetics in modern practice.

Environmental/procedural risk factors: - Injection site vascularity (intercostal > caudal/epidural > brachial plexus > femoral/sciatic, in classic teaching on absorption rank order), with paravertebral blocks now reported as carrying among the highest LAST incidence of common block types. - Dose and concentration exceeding recommended maxima; use of long-acting, highly lipophilic and cardiotoxic agents (bupivacaine >> ropivacaine > lidocaine in intrinsic cardiotoxic potency). - Non-anesthesiologist administration (dentists, emergency physicians, paramedics, cosmetic/dermatologic proceduralists) with less formal LAST training — a 2025 editorial analysis found up to 10% of surveyed cosmetic surgeons exceeded maximum recommended tumescent lidocaine doses, and only ~25% of non-anesthesia postgraduate trainees correctly identified toxic lidocaine dose thresholds (BJA 2025 editorial, Schwenk/Sneyd/Wu, PMC12674017). - Extremes of age (neonates/infants have immature hepatic clearance and lower plasma protein [α1-acid glycoprotein] levels; the elderly have reduced clearance and cardiac reserve). - Pregnancy — reduced plasma protein binding, increased cardiac output/absorption, and aortocaval compression alter presentation and risk (see Section 9). - Reduced muscle mass, low plasma protein (albumin, α1-acid glycoprotein) concentration, hepatic dysfunction, cardiac disease (conduction defects, ischemic heart disease), renal impairment, and metabolic or respiratory acidosis — acidosis in particular increases the free fraction of LA and enhances ion trapping in tissue, compounding toxicity (NYSORA; StatPearls NBK499964). - Liposomal bupivacaine (Exparel) co-administration with additional amide LAs within a 96-hour window — labeled as an additive-toxicity risk requiring dose adjustment (EMA Exparel SmPC).

Protective factors: - Ultrasound-guided regional anesthesia — associated with a reduced risk of LAST versus landmark/nerve-stimulator techniques, attributed to more accurate needle placement, reduced total dose, and earlier recognition of intravascular puncture (PMID:23788067). - Incremental (aliquoted) injection with intermittent aspiration and epinephrine-containing test dosing (10–15 μg), which allows early detection of intravascular placement via a heart-rate rise ≥10 bpm or systolic BP rise ≥15 mmHg before a full dose is delivered. - Benzodiazepine premedication may raise the seizure threshold, delaying/attenuating the CNS-excitatory phase. - No specific genetic protective variant for LAST has been characterized in the literature reviewed (in contrast to the resistance-variant case above, which is pharmacodynamic rather than protective in a health sense).

Gene–environment interactions. The clearest documented interaction is between an underlying mitochondrial fatty-acid oxidation defect (CPT II deficiency or related carnitine-cycle disorders) and standard/subtoxic doses of bupivacaine, where the genetic lesion converts an otherwise safe dose into a cardiotoxic one by removing the myocardium's metabolic reserve for handling LA-induced mitochondrial stress. Similarly, SCN5A conduction-disease variants interact with amide LAs (which are themselves sodium-channel blockers) to produce exaggerated or atypical (bradyarrhythmic rather than tachyarrhythmic) cardiac presentations even at doses tolerated by patients with normal cardiac conduction.

3. Phenotypes

LAST classically presents along a CNS-then-cardiovascular continuum, though atypical presentations occur in nearly 50% of reported cases — i.e., cardiovascular signs may appear without preceding neurologic prodrome, or the two systems may be involved simultaneously (PMID:35777259; Formosan J Surg 2025 review).

CNS phenotypes (excitatory phase, low-to-moderate plasma concentration)

  • Perioral/circumoral numbness and tingling (paresthesia) — HP term: consider HP:0040194 (Paresthesia)
  • Metallic taste — no precise HPO term identified; record as free text/notes
  • Tinnitus — HP:0000360 (Tinnitus)
  • Visual disturbance (blurred/tunnel vision) — HP:0000505 (Visual impairment, generic)
  • Lightheadedness / dizziness — HP:0002321 (Vertigo) or a dizziness-specific term
  • Agitation, confusion, dysarthria (slurred speech) — HP:0031466 (Confusion, if it exists in current HPO release); HP:0001260 (Dysarthria)
  • Muscle twitching / myoclonus, progressing to generalized tonic-clonic seizures — HP:0001336 (Myoclonus); HP:0001250 (Seizure)

CNS phenotypes (depressive phase, higher concentration)

  • Drowsiness progressing to unresponsiveness/coma, respiratory depression/apnea — HP:0001259 (Coma, generic term to be confirmed); HP:0002105 (Respiratory failure)

Cardiovascular phenotypes

  • Excitatory phase: hypertension, tachycardia, ventricular ectopy/ventricular tachycardia
  • Depressive/collapse phase: progressive conduction delay (PR/QRS widening), bradycardia, hypotension, ventricular arrhythmias (including polymorphic VT/torsades in some case reports), and cardiovascular collapse/cardiac arrest, sometimes with pulseless electrical activity refractory to standard ACLS (PMC6068002; PMC9566458).
  • Candidate HP terms: HP:0011675 (Arrhythmia), HP:0001662 (Sinus bradycardia), HP:0004756 (Ventricular tachycardia — verify exact code), HP:0001695 (Cardiac arrest), HP:0002615 (Hypotension), HP:0001657 (Prolonged QT interval — if QT prolongation specifically implicated with certain agents/metabolites).
  • Delayed presentation: cardiac events (including arrest) have been reported hours after the causative block (e.g., 5 hours post continuous femoral nerve block in one case, PMC9566458), underscoring the need for extended monitoring.

Laboratory abnormalities

  • Metabolic/respiratory acidosis (both a risk factor and a consequence, since acidosis potentiates further LA toxicity in a feed-forward loop).
  • Elevated free (unbound) LA plasma concentration on assay, where available — toxic effects of bupivacaine have been documented at plasma concentrations as low as 800 ng/mL, while early subjective CNS symptoms are typically reported at higher concentrations of 2500–4000 ng/mL (Exparel/EMA labeling data).
  • Methemoglobinemia can occur with certain LA classes/metabolites (notably prilocaine and, less commonly, benzocaine and its metabolite o-toluidine), presenting as cyanosis unresponsive to supplemental oxygen with a characteristic "chocolate brown" arterial blood sample — treated with methylene blue.

Phenotype characteristics

  • Onset: Typically rapid — seconds to a few minutes after intravascular injection; delayed onset (minutes to several hours) is well described with slower systemic absorption from tissue depots (e.g., continuous peripheral nerve block catheters, tumescent infiltration, topical/mucosal application).
  • Severity: Highly variable, from isolated perioral numbness to fatal cardiac arrest; severity correlates with peak free plasma concentration, agent lipophilicity/potency, and patient risk factors.
  • Progression: Classically progressive along the excitatory→depressive continuum, but course can be non-linear; nearly half of reported cases skip or truncate the classical sequence.
  • Frequency: Systemic toxicity from local anesthetics has been estimated in ~0.03% of peripheral nerve blocks (0.27 episodes/1000 blocks); more recent pooled estimates place major LAST events at 0.04–1.8 per 1000 peripheral nerve blocks, and overall incidence across high-risk procedures at 1–3 per 1000 (NYSORA; UpToDate; PMID:35777259).

Quality of life impact

Acute LAST events, when survived, are generally not associated with chronic disability if promptly treated; however, cardiac arrest with prolonged resuscitation carries the same post-cardiac-arrest morbidity risk (hypoxic-ischemic brain injury, reduced functional status) as arrest from any other cause. Data specifically quantifying QoL instruments (EQ-5D, SF-36) post-LAST were not identified in the literature searched — this is likely a genuine data gap given the acute, procedural nature of the condition and the rarity of long-term follow-up cohorts.

4. Genetic/Molecular Information

LAST is not a monogenic disease, so this section addresses (a) genes implicated in modifying susceptibility and (b) the molecular drug targets whose engagement constitutes the toxic mechanism.

Modifier/susceptibility genes: - CPT2 (Carnitine Palmitoyltransferase 2; HGNC gene) — biallelic pathogenic variants cause CPT II deficiency; implicated in increased bupivacaine cardiotoxicity susceptibility at otherwise sub-toxic doses. - SLC22A5 (OCTN2) and other carnitine-cycle genes (CPT1A, CACT/SLC25A20) — broader fatty-acid oxidation pathway; theoretically relevant by the same mitochondrial mechanism, though direct LAST case evidence is sparser than for CPT2. - SCN5A (cardiac Nav1.5 gene) — pathogenic/likely pathogenic variants (Brugada syndrome, progressive cardiac conduction disease, dilated cardiomyopathy with conduction defect) confer heightened cardiac sensitivity to sodium-channel-blocking LAs. Suggested reference: ClinVar/ClinGen SCN5A-Brugada syndrome gene-disease validity assertions (dismech CGGV: structured-source citation pattern would apply if curating). - BCHE (butyrylcholinesterase/pseudocholinesterase) — variants affecting ester-LA hydrolysis rate; more classically linked to succinylcholine sensitivity but mechanistically analogous for ester-type LAs.

Molecular drug targets (the toxicity mechanism itself, not inherited variants): - Voltage-gated sodium channels (Nav) — the primary target. LAs bind the intracellular pore-lining domain, producing tonic and use-dependent block; cardiac Nav1.5 is the dominant cardiac isoform, and bupivacaine's high lipophilicity and slow "fast-in/slow-out" channel kinetics ("fast in, slow out" dissociation from the inactivated state) account for its disproportionate cardiotoxic potency relative to lidocaine (PMID:25008571). Bupivacaine also accelerates development of Nav1.5 open-state slow inactivation. - Voltage-gated potassium channels — TREK-1 (two-pore-domain K+ channel), KATP, and SK2 channels are all inhibited by bupivacaine, contributing to membrane excitability changes and impaired ischemic myocardial protection (PMID:42589553; Int J Mol Sci 2025 molecular mechanisms review). - Voltage-gated calcium channels (CaV1.3 and related L-type channels) — suppressed by bupivacaine, impairing excitation-contraction coupling. - Mitochondrial carnitine-acylcarnitine translocase — directly inhibited by bupivacaine, blocking long-chain fatty-acid entry into the mitochondrial matrix and impairing fatty-acid-supported oxidative phosphorylation, the myocardium's dominant energy source. - Cardiolipin (inner mitochondrial membrane phospholipid) — bupivacaine, but not lidocaine, disrupts cardiolipin-containing membranes/liposomes, degrading respiratory-chain organization (PMID:17643405). - GABA-A receptors and NMDA/non-NMDA glutamate receptors — LA-mediated disinhibition of GABAergic tone plus glutamatergic receptor involvement underlies the CNS excitatory (seizure) phase.

Variant classification / allele frequency: Because LAST susceptibility variants are drawn from rare-disease genes (CPT2, SCN5A) rather than a LAST-specific gene, standard ClinVar/gnomAD resources apply to the underlying conditions (CPT II deficiency, Brugada syndrome/SCN5A-related disease) rather than to a LAST-specific allele. No LAST-specific pathogenic allele frequency data were identified.

Epigenetics / chromosomal abnormalities: No literature was identified describing epigenetic regulation or chromosomal-abnormality contributions specific to LAST susceptibility; this reflects the condition's fundamentally pharmacologic/toxicologic rather than developmental-genetic nature.

5. Environmental Information

  • Primary environmental factor: the local anesthetic drug itself, administered via injection, infiltration, or topical/mucosal/transdermal application, functions as the causal exposure. Relevant CHEBI entities include bupivacaine, levobupivacaine, ropivacaine, lidocaine, mepivacaine, prilocaine, chloroprocaine, and tetracaine (amide and ester classes).
  • Route and setting of exposure matter greatly: peripheral nerve block, epidural/neuraxial, paravertebral block, tumescent liposuction infiltration, dental nerve block, topical anesthesia prior to endoscopy/transesophageal echocardiography (documented case: ~3000 mg topical lidocaine causing cardiac arrest requiring ECMO, PMC6068002), and perioperative/ERAS intravenous lidocaine infusions.
  • Out-of-hospital/non-monitored settings: an estimated 23% of LAST cases occur outside the hospital (e.g., dental offices, outpatient cosmetic clinics), where rescue resources (lipid emulsion, advanced airway, ACLS) may be less immediately available (BJA 2025 editorial).
  • Lifestyle/behavioral factors: none specific to LAST causation itself have been identified (unlike chronic diseases influenced by smoking/diet); the principal modifiable "behavioral" factor is clinician practice — dose calculation errors, failure to aspirate before injection, and lack of ultrasound guidance.
  • Infectious agents: not applicable — LAST is not an infectious disease.

6. Mechanism / Pathophysiology

Ordered causal chain

  1. A local anesthetic (e.g., bupivacaine) is administered for regional/local anesthesia and enters the systemic circulation in excess — via inadvertent intravascular injection, rapid absorption from a vascular tissue bed, or cumulative/absolute overdose. (Demonstrated — the defining initiating event.)
  2. The rising free (unbound) plasma concentration of the drug leads to engagement of voltage-gated sodium channels throughout excitable tissue, with the CNS and heart affected earliest owing to their high perfusion and channel density. (Demonstrated.)
  3. In the CNS, LA blockade preferentially inhibits inhibitory GABAergic interneurons before excitatory glutamatergic pathways (differential susceptibility of inhibitory pathways), which results in a net disinhibition of cortical excitatory circuits — leading to the excitatory phenotype (perioral numbness, tinnitus, agitation, myoclonus, seizures). (Demonstrated in animal/ex vivo pharmacology; the differential-sensitivity account is a long-standing accepted model.)
  4. With continued rising concentration, global sodium (and other ion) channel blockade in the CNS causes widespread neuronal conduction failure, resulting in the depressive phase (coma, respiratory depression/apnea). (Demonstrated.)
  5. In parallel, in the heart, LA binding to cardiac Nav1.5 produces tonic and use-dependent sodium-channel blockade, which slows phase-0 depolarization and impairs conduction — leading to PR/QRS prolongation, bradyarrhythmia, and re-entrant ventricular arrhythmias (including ventricular tachycardia/fibrillation). Bupivacaine's high lipophilicity causes disproportionately slow dissociation ("fast-in, slow-out") from the inactivated channel state relative to lidocaine, explaining its greater arrhythmogenic potency at equi-analgesic doses. (Demonstrated via electrophysiology studies, PMID:25008571.)
  6. Concurrently, LA molecules inhibit cardiac potassium channels (TREK-1, KATP, SK2) and L-type calcium channels, which further destabilizes membrane excitability and impairs excitation-contraction coupling, contributing to contractile dysfunction independent of the sodium-channel effect. (Demonstrated in cellular electrophysiology models; translational magnitude in vivo is less certain — flagged as partially inferred.)
  7. At the mitochondrial level, bupivacaine inhibits the carnitine-acylcarnitine translocase, which blocks long-chain fatty acid entry into the mitochondrial matrix, impairing the myocardium's primary (fatty-acid-based) route of ATP generation. Bupivacaine additionally disrupts cardiolipin-containing inner mitochondrial membranes, which degrades respiratory-chain (electron transport chain) organization, compounding the energy-production failure. Together these result in progressive myocardial bioenergetic failure, which potentiates the electrophysiological effects above and drives the transition from arrhythmia to pump failure and cardiovascular collapse. (Demonstrated in isolated mitochondria/cardiomyocyte models; the quantitative contribution relative to direct channel block in whole-organism toxicity is inferred rather than fully resolved — an open mechanistic question.)
  8. Systemic physiological derangements — hypoxia, acidosis, and reduced tissue perfusion arising from the seizure and/or the evolving cardiovascular collapse — create a feed-forward loop: acidosis increases the ionized (protonated) fraction of LA trapped intracellularly ("ion trapping") and increases the free fraction available to bind channels, amplifying both CNS and cardiac toxicity and worsening resuscitation difficulty. (Demonstrated clinically and pharmacologically — this is the physiological basis for aggressive airway/ventilation management as first-line LAST treatment.)
  9. In patients with a pre-existing mitochondrial fatty-acid oxidation defect (e.g., CPT II deficiency) or a cardiac sodium-channelopathy (SCN5A variant), the above cascade is triggered at markedly lower LA doses/concentrations than in the general population, because the myocardium's metabolic reserve (step 7) or baseline channel function (step 5) is already compromised. (Demonstrated via case reports; not systematically quantified.)
  10. Without intervention, the terminal common pathway is refractory ventricular arrhythmia, pulseless electrical activity, or asystole — cardiac arrest, which in a minority of cases is resistant to standard resuscitation and lipid emulsion, necessitating extracorporeal cardiopulmonary resuscitation (ECPR/ECMO) as rescue. (Demonstrated in multiple case reports, e.g., PMC6068002.)

Molecular pathways

No single canonical signaling pathway (Wnt/MAPK/mTOR/PI3K-AKT) drives LAST; the dominant "pathways" are ion-channel electrophysiology (Nav1.5/Nav1.1 family, Kv/TREK-1/KATP/SK2, CaV1.3) and mitochondrial bioenergetics (fatty-acid β-oxidation entry via carnitine shuttle, oxidative phosphorylation/electron transport chain). Suggested GO Biological Process terms: GO:0086006 (voltage-gated sodium channel activity involved in cardiac muscle cell action potential), GO:0034642/oxidative-phosphorylation-related terms, GO:0006635 (fatty acid beta-oxidation).

Cellular processes

  • Excitotoxicity/seizure generation in cortical neurons (GABAergic disinhibition + NMDA receptor involvement).
  • Apoptosis in neuronal cell models: in SH-SY5Y neuroblastoma cells, bupivacaine induces apoptosis via reactive oxygen species (ROS) production, mitochondrial complex I/III impairment, and loss of mitochondrial membrane potential (PMID:42589553).
  • Endoplasmic reticulum (ER) stress — activation of ATF6, IRE1, and PERK arms of the unfolded protein response, with downstream Bcl-2 family dysregulation and caspase activation, has been demonstrated across multiple LA-exposed cell models.
  • Suggested GO terms: GO:0006915 (apoptotic process), GO:0034976 (response to endoplasmic reticulum stress), GO:0006979 (response to oxidative stress).

Protein dysfunction

LA binding does not cause classical misfolding/aggregation; rather it produces acute, reversible functional inhibition (channel block) of Nav/Kv/CaV channels and the carnitine-acylcarnitine translocase, and disruption of the cardiolipin lipid microenvironment that organizes electron-transport-chain complexes.

Metabolic changes

Impaired fatty-acid oxidation and reduced ATP availability in cardiac and neural tissue are central; amide LAs "acutely inhibit myocardial oxygen consumption," with bupivacaine producing stronger respiratory-chain inhibition than lidocaine (PMID:42589553).

Immune system involvement

Not a primary feature; LAST is not classically an immune-mediated or inflammatory condition (in contrast to true LA hypersensitivity/allergic reactions, which are a distinct, much rarer entity, typically to ester LAs or amide-LA preservatives).

Tissue damage mechanisms

Oxidative stress (ROS generation, complex I/III impairment) and bioenergetic failure rather than classical ischemia/fibrosis/necrosis dominate the acute injury; myocardial and neuronal injury is primarily functional/electrophysiological rather than structural in the acute phase, though prolonged arrest can secondarily cause hypoxic-ischemic injury to brain and other organs.

Biochemical abnormalities

Direct ion channel dysfunction (Nav, Kv, CaV) and enzyme inhibition (carnitine-acylcarnitine translocase) constitute the core biochemical lesions, rather than an inherited enzyme deficiency (except in the CPT II-deficient subgroup, where the LA effect is superimposed on a baseline enzymatic deficiency).

Molecular profiling / advanced technologies

No transcriptomic, proteomic, metabolomic, lipidomic, single-cell, or spatial-transcriptomic dataset specific to human LAST was identified in this search — this is an area of the mechanism space that remains largely uncharacterized at the -omics level in humans, with mechanistic insight instead derived from targeted electrophysiology and isolated-mitochondria/cell-line studies (SH-SY5Y neuroblastoma cells, isolated cardiomyocytes, Xenopus oocyte channel expression systems).

Cell types implicated (suggested CL terms): cardiac muscle cell/cardiomyocyte (CL:0000746), Purkinje myocyte, GABAergic interneuron (CL:0000617 or more specific), glutamatergic neuron, neuroblastoma-derived neuron-like cell (SH-SY5Y, a model system rather than a native cell type).

7. Anatomical Structures Affected

Organ level: - Primary: Central nervous system (brain/cortex) and heart (myocardium and cardiac conduction system) — the two most richly perfused, ion-channel-dense organ systems. - Secondary: Respiratory system (apnea/respiratory failure secondary to CNS depression or seizure), vasculature (hypotension from combined direct vasodilation and myocardial depression). - Body systems: Nervous system, cardiovascular system, and secondarily the respiratory system. - Suggested UBERON terms: UBERON:0000955 (brain), UBERON:0000948 (heart), UBERON:0001987 (placenta, relevant in the pregnancy-specific pharmacokinetic discussion).

Tissue and cell level: - Cardiac conduction tissue (SA/AV node, His-Purkinje system) and ventricular myocardium (cell type: cardiomyocyte). - Cortical and subcortical neurons, with particular vulnerability of inhibitory GABAergic interneurons in the early excitatory phase. - Suggested CL terms: cardiac muscle cell (CL:0000746), Purkinje myocyte of heart conducting system, cortical GABAergic interneuron, cortical glutamatergic neuron.

Subcellular level: - Plasma membrane (site of Nav/Kv/CaV channel blockade) — GO Cellular Component GO:0005886 (plasma membrane). - Mitochondria, specifically the inner mitochondrial membrane (cardiolipin disruption, electron transport chain) and mitochondrial matrix (carnitine-acylcarnitine translocase site) — GO terms GO:0005743 (mitochondrial inner membrane), GO:0005759 (mitochondrial matrix). - Endoplasmic reticulum (ER-stress pathway activation) — GO:0005783.

Localization: LAST is a systemic/generalized process rather than a laterality-defined disease; it is not unilateral or asymmetric, given hematogenous distribution of the causative drug throughout the CNS and myocardium.

8. Temporal Development

Onset: LAST has no age-of-onset in the developmental sense (it is not a genetic/developmental disease); rather, it can occur at any age, from neonates (e.g., inadvertent intravenous levobupivacaine infusion in infants, PMC10221613; LAST after caudal block in an infant, PMC11830499) through late adulthood, whenever a local anesthetic is administered. Onset pattern is typically acute, occurring within seconds to minutes of intravascular injection, though delayed presentations of minutes to several hours are well documented with slower absorption routes (continuous infusion catheters, tumescent infiltration, topical/mucosal application).

Progression: No formal disease-staging system exists (unlike cancer staging); clinically, LAST is often described along a severity continuum from mild prodromal symptoms → CNS excitation → CNS depression, and, on the cardiovascular axis, from excitation (hypertension/tachyarrhythmia) → depression (bradycardia/hypotension/conduction block) → collapse/cardiac arrest. Progression rate is variable — some cases progress from first symptom to cardiac arrest within minutes; others plateau at mild prodromal symptoms if the anesthetic is stopped and supportive care instituted promptly. The disease course is acute and self-limited once the causative exposure is terminated and the drug is redistributed/metabolized/cleared (aided by lipid emulsion sequestration) — LAST does not have a chronic or relapsing-remitting natural history.

Patterns: - Remission is generally treatment-induced (cessation of LA administration, airway/ventilatory support, benzodiazepines for seizures, lipid emulsion, and ACLS as needed) rather than spontaneous, though very mild cases (isolated perioral numbness) may resolve without specific intervention as the drug redistributes. - Critical/vulnerable periods: the immediate post-injection window (first several minutes) is the period of highest vulnerability for rapid-onset cardiovascular collapse from intravascular injection; a second, distinct vulnerable window exists hours after block placement or catheter initiation, when slow absorption from a tissue depot or continuous infusion can produce delayed-onset toxicity — this underlies ASRA's post-stabilization monitoring recommendations (see Section 12).

9. Inheritance and Population

Epidemiology: - Estimated incidence: 1–3 per 1000 high-risk procedures overall; 0.04–1.8 per 1000 peripheral nerve blocks for major LAST events; an older but frequently cited estimate places systemic toxicity at 0.03% of peripheral nerve blocks (0.27/1000 blocks). - Paravertebral nerve blocks carry the highest reported incidence among common block types, followed by upper-extremity and trunk/lower-extremity blocks (NYSORA; PMID:35777259). - Ultrasound guidance has reduced incidence from peripheral nerve blocks compared with a decade ago, but incidence from infiltrative anesthesia in non-operating-room settings has remained static — an important recent (2025) epidemiological finding highlighting a shift in the risk landscape toward office-based and non-anesthesiologist-administered LA use (PMC12674017, BJA 2025 editorial). - Mortality data (FAERS, 1968–2023): 1,473 total reported LAST deaths across all local anesthetics; 813 (55%) attributed to lidocaine, averaging 49 lidocaine-related deaths/year versus 13/year for all other agents combined over the past three years — a marked and unexpected shift, since bupivacaine-associated deaths fell substantially after the 2010-era practice advisories while lidocaine deaths remained essentially unchanged (BJA 2025 editorial, PMC12674017). In a parallel literature review of case reports from 2011 onward, 69 deaths were identified, with lidocaine responsible for 74%. - Lipid emulsion was administered in only ~12% of documented LAST cases, indicating a substantial treatment/education gap.

For genetic etiology (in the susceptibility-modifier sense): - CPT II deficiency: autosomal recessive inheritance; the most common inherited long-chain fatty-acid oxidation defect, though still individually rare. - SCN5A-related cardiac disease (e.g., Brugada syndrome): typically autosomal dominant with incomplete penetrance and variable expressivity — well documented for the underlying channelopathy, though penetrance/expressivity data specific to "LAST susceptibility" (as opposed to the channelopathy's primary arrhythmic phenotype) have not been separately quantified. - Founder effects / carrier frequency: Not established for a LAST-specific allele; carrier frequency data would need to be drawn from the underlying CPT2 or SCN5A disease-gene literature (gnomAD) rather than from a LAST-specific registry. - Consanguinity: relevant only insofar as it increases the prior probability of biallelic CPT2 (or other autosomal recessive metabolic) variants in a given patient/population.

Population demographics: - No specific ethnic or geographic predisposition to LAST itself has been described (as expected for a predominantly iatrogenic/pharmacologic condition), though the prevalence of underlying susceptibility genotypes (e.g., specific SCN5A variants more common in certain Southeast Asian populations in the context of Brugada syndrome) could theoretically skew regional risk — this has not been formally studied for LAST outcomes specifically. - Sex ratio: Not clearly reported as skewed in the general LAST literature; the 2024 pregnancy-focused cohort study specifically examined a female (pregnant vs. non-pregnant) comparison rather than an overall male:female LAST ratio (PMID:39398741). - Pregnancy-specific findings (TriNetX retrospective cohort, 2013–2023, n=276 matched pregnant vs. 276 non-pregnant LAST patients): pregnant patients had significantly higher risk of cardiac depression (RR 1.96, 95% CI 1.44–2.66, p<0.01) and significantly lower risk of cardiac excitation (RR 0.38), prodromal symptoms (RR 0.17), CNS excitation (RR 0.44), and CNS depression (RR 0.24) compared with non-pregnant patients — i.e., pregnant patients with LAST are more likely to present with direct cardiac depression, skipping the classical prodrome and excitatory phases (PMID:39398741). This atypical presentation pattern has direct clinical-recognition implications and reflects pregnancy-associated physiologic changes (increased cardiac output, aortocaval compression, reduced plasma protein binding capacity, and possibly altered receptor sensitivity). - Age distribution: LAST is reported across the full age spectrum, from neonates/infants (caudal block, IV infiltration errors) to elderly patients undergoing regional anesthesia for orthopedic and other procedures; extremes of age are independently identified risk factors rather than age itself defining a typical "affected population."

10. Diagnostics

LAST is fundamentally a clinical diagnosis made on the basis of a temporally plausible LA exposure plus compatible CNS and/or cardiovascular signs; there is no single confirmatory laboratory test used in real time.

Clinical tests: - Continuous ECG monitoring is the standard of care during and after any regional anesthesia procedure, allowing detection of PR/QRS widening, arrhythmia, and ST/T-wave changes. - Continuous pulse oximetry and blood pressure monitoring to detect hypoxia and hemodynamic compromise. - Plasma/serum local anesthetic level assay (where available, typically in specialized/research settings rather than routine point-of-care practice) can retrospectively confirm elevated total or free LA concentration; not useful for real-time diagnosis given turnaround time. - Arterial blood gas to assess for acidosis, which both signals severity and worsens further toxicity if uncorrected. - Co-oximetry if methemoglobinemia is suspected (cyanosis unresponsive to oxygen, "chocolate brown" blood) — relevant particularly for prilocaine and benzocaine exposures.

Genetic testing: Not part of acute LAST diagnosis. It becomes relevant retrospectively or prospectively in two scenarios: (1) after an unexplained severe/refractory LAST event at a sub-toxic dose, prompting consideration of an underlying fatty-acid oxidation disorder (CPT2 gene sequencing) or cardiac channelopathy (SCN5A and related arrhythmia gene panel); (2) before regional anesthesia in a patient with a known family history of a fatty-acid oxidation disorder or inherited arrhythmia syndrome, to inform anesthetic risk stratification and dose conservatism.

Clinical criteria / differential diagnosis: No DSM/ICD-based formal diagnostic criteria exist; clinicians rely on temporal association with LA administration plus exclusion of alternative causes of seizure (epilepsy, hypoglycemia, eclampsia in obstetric patients, high/total spinal anesthesia) and of cardiac arrest/arrhythmia (myocardial infarction, pulmonary embolism, anaphylaxis, vasovagal collapse, primary arrhythmic disease). High/total spinal anesthesia is an important mimic/co-occurring differential in the neuraxial setting, since it also produces hypotension, bradycardia, and loss of consciousness without necessarily reflecting systemic LA toxicity per se (distinguished by the mechanism — neuraxial sympathetic blockade vs. systemic drug toxicity — though clinically the two can be difficult to distinguish acutely and management overlaps).

Screening: No population-level screening program exists for LAST susceptibility; the closest analog is pre-procedural risk-factor assessment (age, pregnancy, hepatic/renal/cardiac disease, personal/family history of unexplained anesthesia complications or metabolic myopathy) rather than a formal genetic or biomarker screening test.

Diagnostic guideline references: The current reference frameworks are professional society guidelines rather than diagnostic-code-based criteria — principally the ASRA (American Society of Regional Anesthesia and Pain Medicine) Practice Advisories (2010 original; Third Practice Advisory Executive Summary, 2018, PMID:29356773) and the ASRA LAST Checklist, 2020 version (PMID:33148630), plus emergency-medicine-oriented narrative reviews (PMID:35777259) and specialty protocols such as the International Pain and Spine Intervention Society's LAST emergency protocol.

11. Outcome/Prognosis

Survival and mortality: With prompt recognition and treatment (cessation of LA, airway management, benzodiazepines, lipid emulsion, ACLS as needed), the majority of LAST events resolve without permanent sequelae. However, LAST remains a recognized cause of anesthesia-related death: FAERS data (1968–2023) recorded 1,473 LAST-attributed deaths, with lidocaine now responsible for the majority (55% of FAERS deaths; 74% of recent case-report deaths) despite its reputation as a "safer" agent — reflecting both its widespread, often less-supervised use and possibly under-recognition of its cardiotoxic potential at high cumulative/infusion doses (BJA 2025 editorial).

Morbidity and function: Acute morbidity is dominated by the direct consequences of seizure (aspiration risk, injury) and of cardiac arrest/hypotension (organ hypoperfusion, and — in prolonged arrest — hypoxic-ischemic brain injury). There is no described chronic LAST-specific disability syndrome in survivors who receive timely treatment; outcomes in refractory cases requiring ECMO-supported resuscitation mirror those of cardiac arrest from other causes and depend heavily on time-to-ECMO cannulation and total downtime.

Disease course / complications: Documented complications include refractory ventricular arrhythmia, pulseless electrical activity/asystole, aspiration pneumonitis (from seizure-associated loss of airway protection), and, in the methemoglobinemia subgroup, tissue hypoxia from impaired oxygen-carrying capacity if unrecognized/untreated. Extracorporeal cardiopulmonary resuscitation (ECPR) has emerged in case reports as a rescue therapy for LAST-associated cardiac arrest refractory to lipid emulsion and standard ACLS (PMC6068002).

Recovery potential: Generally favorable when treatment is initiated promptly (within the first few minutes of symptom onset), given the pharmacokinetically reversible nature of LA channel blockade once tissue/plasma drug concentration falls (aided by lipid-emulsion-facilitated redistribution/clearance — see Section 12). Recovery potential is markedly worse in delayed-recognition or refractory-arrest scenarios.

Prognostic factors: Time to cessation of LA administration and time to initiation of lipid emulsion/ACLS are the most clinically actionable prognostic determinants; presence of underlying cardiac disease, pregnancy (via atypical presentation delaying recognition), and extremes of age are additional adverse prognostic modifiers. A 2023 multicenter simulation initiative (the LAST Collaborative, 10 hospitals) found that simulation-based training reduced time to lipid emulsion administration by ~30% on average after a single drill, directly linking systems-level preparedness to a key prognostic time-interval.

12. Treatment

Pharmacotherapy

  • 20% intravenous lipid emulsion (ILE) is the specific antidote and first-line pharmacologic treatment. ASRA 2020 dosing: for patients <70 kg, a bolus of 1.5 mL/kg over 2–3 minutes, followed by an infusion of 0.25 mL/kg/min; for patients >70 kg, a bolus of 100 mL over 2–3 minutes, followed by an infusion of 250 mL over 15–20 minutes. Continue the infusion for at least 15 minutes after achieving hemodynamic stability; if inadequate, repeat the bolus or double the infusion rate. Upper dosing limit: ~12 mL/kg. The order of bolus vs. infusion administration and the specific infusion method are not considered critical (ASRA 2020 Checklist, PMID:33148630; NYSORA).
  • Suggested NCIT term for lipid emulsion therapy: consider NCIT:C15986 (Pharmacotherapy) as the generic treatment_term with a therapeutic_agent binding for the lipid emulsion product (verify a specific NCIT CHEBI/agent code before curation use).
  • Benzodiazepines are the drugs of choice for seizure termination (e.g., midazolam, lorazepam); propofol is discouraged as an anticonvulsant in this setting due to its own cardiodepressant potential compounding LAST-induced cardiac depression.
  • Epinephrine, when needed for severe arrhythmia or hypotension, should be given in small bolus doses (≤1 mcg/kg) rather than standard ACLS doses, per ASRA guidance, given evidence that larger doses may worsen outcomes in the lipid-emulsion-treated LAST arrest model.
  • Avoid: vasopressin, calcium-channel blockers, beta-blockers, and additional local anesthetics (including as antiarrhythmics) during LAST management, per ASRA 2020.
  • Methylene blue (1–2 mg/kg IV over 5 minutes) is used specifically for LA-associated methemoglobinemia (notably prilocaine, benzocaine).

Advanced therapeutics

  • Extracorporeal membrane oxygenation (ECMO)/ECPR is reserved for refractory cardiac arrest unresponsive to lipid emulsion and standard ACLS — documented as successful rescue in case reports of severe LAST (e.g., topical lidocaine-induced arrest before transesophageal echocardiography, PMC6068002).
  • No gene therapy, cell therapy, RNA-based therapy, targeted therapy, or immunotherapy is applicable to LAST, consistent with its acute pharmacotoxicologic (rather than molecular-genetic) disease mechanism.

Surgical/interventional

Not applicable as primary treatment; the causative regional-anesthesia procedure itself is, of course, surgical/interventional in origin but is not a "treatment" for LAST.

Supportive and rehabilitative

  • Airway management and 100% oxygen/ventilatory support to prevent hypoxia and acidosis, both of which potentiate further LA toxicity — this is emphasized as a first-line, arguably highest-priority intervention in all major guidelines, preceding even lipid emulsion in sequence (though both should be pursued in parallel when possible).
  • Correction of acidosis (via adequate ventilation ± sodium bicarbonate) to reduce ion trapping and free LA fraction.
  • Standard ACLS/CPR for cardiac arrest, modified per the epinephrine-dosing and drug-avoidance guidance above.
  • Rehabilitation (physical/occupational therapy) is relevant only in the rare setting of post-arrest hypoxic-ischemic injury, and is not disease-specific to LAST.

Experimental

No LAST-specific investigational drug trials were identified in the search (ClinicalTrials.gov results returned were primarily about causes of neurologic events after regional anesthesia rather than LAST-treatment trials, e.g., NCT07238933). Current "experimental" activity in this space is concentrated on refining lipid-emulsion mechanistic understanding and dosing (the emerging "lipid shuttle/lipid subway" model, described below) rather than novel pharmacologic agents.

Treatment outcomes and gaps

  • Lipid emulsion was used in only ~12% of documented LAST cases, and only ~25% of non-anesthesia postgraduate trainees correctly identified toxic lidocaine dose thresholds in surveys — indicating substantial gaps in both treatment application and provider knowledge, particularly outside anesthesiology (BJA 2025 editorial).
  • A 2023 multicenter simulation collaborative (LAST Collaborative, 10 hospitals) demonstrated that a single simulation drill per site reduced time-to-lipid-emulsion-administration by ~30% on average, supporting simulation-based training as an effective systems intervention.

Mechanism of lipid emulsion (relevant to understanding treatment rationale)

The classical "lipid sink" model holds that IV lipid emulsion creates an expanded intravascular lipid phase that sequesters lipophilic LA molecules away from cardiac and neural tissue. More recent mechanistic work refines this into a "lipid shuttle"/"lipid subway" model, in which the lipid compartment scavenges LA from high-blood-flow, sensitive organs (heart, brain) and redistributes it to muscle for storage and to the liver for detoxification, rather than simply acting as a static reservoir. Lipid emulsion also exerts direct cardiotonic effects — increasing myocardial contractility and cardiac output, partly via enhanced fatty-acid substrate delivery for mitochondrial ATP production (counteracting the carnitine-shuttle blockade described in Section 6) and partly via volume-expansion-mediated preload augmentation, along with modulatory effects on cardiac ion channels. A meta-analysis of animal LAST models found lipid emulsion reduced the odds of death in resuscitative models (OR 0.24, 95% CI 0.1–0.56, p=0.0012) (PMID:28346007).

Therapeutic modality mapping (for structured curation)

  • Lipid emulsion therapy: therapeutic_modality: OTHER (or a lipid-based pharmacotherapy category if a more specific value exists in the target schema) — not a standard small-molecule/biologic category.
  • Benzodiazepines, epinephrine, methylene blue: SMALL_MOLECULE.
  • ECMO: DEVICE.

13. Prevention

Primary prevention is the dominant prevention strategy for LAST, since there is no vaccine or population-level primary-prevention program analogous to infectious or chronic disease prevention:

  • Dose vigilance: calculating the cumulative dose of all local anesthetics to be administered (accounting for any prior or concurrent LA exposure, including liposomal bupivacaine's 96-hour additive-toxicity window) and selecting the lowest effective dose.
  • Ultrasound guidance for peripheral nerve blocks, associated with reduced LAST incidence (PMID:23788067).
  • Incremental injection in small aliquots (3–5 mL) with 15–30 second pauses between injections, combined with frequent aspiration to detect inadvertent intravascular needle/catheter placement.
  • Epinephrine-containing test dosing (10–15 μg) in selected higher-risk techniques (e.g., epidural), using a heart-rate increase ≥10 bpm or systolic BP increase ≥15 mmHg as a positive intravascular marker.
  • Patient-specific risk-factor evaluation before block placement (extremes of age, pregnancy, hepatic/renal/cardiac disease, low plasma protein states, personal/family history suggestive of a fatty-acid oxidation disorder or inherited arrhythmia syndrome).

Secondary prevention (early detection): - Continuous vital-sign and ECG monitoring throughout LA administration and for an appropriate post-procedure window (ASRA recommends observation for at least 2 hours after a seizure and 4–6 hours after cardiovascular instability, with longer critical-care-level monitoring after cardiac arrest or persistent symptoms). - Institutional immediate availability of 20% lipid emulsion and a LAST rescue kit/checklist at any site where LA is administered, including non-operating-room and outpatient settings.

Tertiary prevention: Prompt, guideline-concordant treatment (Section 12) to prevent progression to refractory arrest and to minimize post-arrest morbidity in patients who do experience a severe event.

Genetic counseling: Relevant in the narrow context of a patient or family member with known CPT II deficiency or an inherited cardiac channelopathy (SCN5A-related disease) — pre-procedural genetic counseling and anesthesia-risk discussion, along with conservative LA dosing/monitoring plans, would be the applicable preventive genetic intervention, though this is not a formal, guideline-codified "genetic screening" program specific to LAST.

Public health/systems interventions: - Simulation-based training programs (e.g., the 2023 LAST Collaborative) as an institutional-level intervention proven to shorten time-to-treatment. - Educational initiatives targeting non-anesthesiologist prescribers/proceduralists (dentistry, emergency medicine, dermatology/cosmetic surgery, paramedicine) given the documented knowledge gaps and the rising share of LAST events and deaths attributable to lidocaine used by these groups. - Standardized maximum-dose labeling/decision-support tools (e.g., electronic health record dose-calculators/alerts) to reduce the cosmetic-surgery-reported ~10% rate of exceeding maximum recommended tumescent lidocaine doses.

Prophylaxis: No pre-procedural prophylactic medication is used to prevent LAST in standard practice; prevention is procedural/behavioral rather than pharmacologic.

14. Other Species / Natural Disease

LAST is not a naturally occurring disease entity documented in veterinary case series or wildlife populations in the way inherited or infectious diseases are catalogued in OMIA; rather, it is an iatrogenic complication that can occur in any species receiving local anesthetics, including in veterinary clinical practice (e.g., inadvertent overdose or intravascular injection of lidocaine/bupivacaine in dogs, cats, and horses during regional anesthesia or dental procedures). No taxonomy-specific "natural disease" registry entry (OMIA) was identified for LAST, consistent with its classification as a drug-toxicity syndrome rather than a heritable veterinary disease. Veterinary relevance is chiefly as a procedural safety consideration analogous to human practice (weight-based dosing limits, aspiration before injection), rather than as a model of spontaneous animal disease.

Comparative biology: The core molecular targets (voltage-gated sodium channels, cardiac Nav1.5, mitochondrial fatty-acid oxidation machinery) are highly evolutionarily conserved across mammals, which is precisely why rodent and other mammalian models (see Section 15) are considered informative for human LAST mechanism and lipid-emulsion treatment efficacy.

15. Model Organisms

Model types and specific systems: - Rodent (rat, primarily Sprague-Dawley and Wistar) models are the dominant in vivo model system. Examples: a study of 100 male Sprague-Dawley rats randomized to lidocaine, levobupivacaine, or ropivacaine examined lipid emulsion's mitigating effect on LA-induced CNS toxicity (PMID:26622452); a Wistar rat model examined intrathecal lipid emulsion for total-spinal-block-induced hemodynamic instability. - Isolated/perfused rat heart models have been used to demonstrate the lipid-sink mechanism directly — bupivacaine combines with infused lipid molecules and is cleared more rapidly from isolated hearts under lipid treatment. - Xenopus oocyte heterologous expression systems for cardiac sodium channels (Nav1.5) have been used to characterize the voltage- and use-dependent block by bupivacaine at the single-channel/whole-cell electrophysiology level (PMID:25008571). - Cell-line models: SH-SY5Y human neuroblastoma cells for studying LA-induced apoptosis, ROS generation, and mitochondrial dysfunction in a neuronal context (PMID:42589553). - Isolated mitochondria preparations (cardiac) for direct study of carnitine-acylcarnitine translocase inhibition and cardiolipin membrane disruption (PMID:17643405).

Induced models: All LAST animal models are induced/pharmacological (drug-treatment models) rather than genetic knockout/transgenic models, since LAST is fundamentally a toxic drug-exposure phenomenon rather than a gene-driven disease. This is a key distinction from most dismech-style Mendelian disease entries.

Genetic models: Not a primary modeling approach for LAST itself, though Scn5a knockout/knock-in mouse models (developed originally for Brugada syndrome/cardiac conduction disease research) could in principle be used to study genotype-dependent LA cardiotoxicity susceptibility — no specific published study combining an Scn5a genetic model with LA-challenge toxicity testing was identified in this search, representing a plausible translational research gap.

Model characteristics: - Phenotype recapitulation: Rodent and isolated-heart models reproduce the key electrophysiological (conduction block, arrhythmia) and CNS-excitatory (seizure) phenotypes of human LAST reasonably well, and have been the primary evidence base for lipid-emulsion efficacy — a meta-analysis of animal LAST models found lipid emulsion reduced mortality odds (OR 0.24, 95% CI 0.1–0.56) in resuscitative protocols (PMID:28346007). - Model limitations: Rodent cardiac electrophysiology (heart rate, ion channel kinetics, and relative Nav/Kv channel density) differs quantitatively from human cardiac physiology, so absolute dose/concentration thresholds for toxicity and lipid-emulsion dosing extrapolated from rodent data require clinical calibration — this is an important, generically acknowledged translational caveat rather than one specifically quantified in the literature reviewed here. Isolated-organ and cell-line models cannot capture the systemic feed-forward effects of acidosis/hypoxia described in Section 6, step 8.

Applications: These models have been used to (a) establish and refine the "lipid sink"/"lipid shuttle" mechanistic model of lipid-emulsion rescue, (b) characterize agent-specific cardiotoxic potency differences (bupivacaine > ropivacaine > lidocaine) at the channel and mitochondrial level, and (c) test alternative rescue strategies (e.g., intrathecal lipid emulsion for spinal-anesthesia-associated hemodynamic collapse).

Resources: No LAST-specific model-organism database exists; relevant data are distributed across general pharmacology/toxicology literature (PubMed/PMC) rather than a dedicated registry such as MGI, RGD, or ZFIN, reflecting the acute-pharmacologic (rather than developmental-genetic) nature of the condition.

Summary of Key Evidence Gaps (for curation notes)

  1. No dedicated OMIM/Orphanet entry exists for LAST; MONDO:0100335 should be independently verified.
  2. No population-level denominator data exist for total LA administrations, limiting precise incidence/mortality-rate calculation (explicitly flagged as a limitation in the 2025 BJA editorial).
  3. No -omics (transcriptomic/proteomic/metabolomic) profiling of human LAST tissue was identified — mechanistic evidence is drawn from targeted electrophysiology and cell/mitochondria models.
  4. No genetic (Scn5a) mouse model study specifically combining channelopathy genotype with LA-challenge toxicity was identified — a plausible research gap.
  5. Quality-of-life instrument data specific to LAST survivors were not identified.
  6. The exact HPO term IDs suggested in Section 3 are provisional and require confirmation against a current HPO release before use in formal curation.

Sources

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