8.4 Local Anaesthetic Toxicity Flashcards
Local anaesthetic toxicity includes the following
1
Allergic response –
immediate (anaphylaxis)
or delayed (urticaria)
2
Myotoxicity –
muscle damage consequent
to intramuscular injection
3
Neurotrauma –
direct nerve injury or
transient neurological syndromes
4
Systemic toxicity –
most severe (life-threatening); manifests as
central nervous system symptoms and cardiovascular system collapse.
Response to vasoconstrictor
Response to vasoconstrictors
(manifested as headache, apprehension,
tachycardia and hypertension)
constitutes another differential diagnosis of local anaesthetic (LA) toxicity
Adhesive arachnoiditis
Adhesive arachnoiditis is due to
contamination of LA solution
with skin-prep solutions (betadine or
chlorhexidine) and is not due to LA toxicity.
Systemic toxicity onset
Systemic toxicity can manifest
either immediately
(within minutes),
because of too rapid
an intravascular injection,
or be delayed (after 5–15 minutes),
because of toxic plasma concentrations
of LA achieved over a period of time.
Is toxicity additive
toxicity is additive; mixtures may be more toxic than individual drugs.
Determinants of systemic toxicity
Specific agents: physicochemical properties
amide v ester
Amides > esters
rapidly metabolised by esterases: lower toxicity
Determinants of systemic toxicity
Specific agents: physicochemical properties
lipophilicty
Hydrophobic (lipohilic) >
hydrophilic (less lipophilic) agents
Determinants of systemic toxicity
Specific agents: physicochemical properties
side chain
More potent (bigger side chains) > less potent (smaller side chains
Determinants of systemic toxicity
Specific agents: physicochemical properties
vdil v constrictor
Vasodilators > vasoconstrictors
ropivacaine
Determinants of systemic toxicity
Specific agents: physicochemical properties
binding
Protein binding:
only free fraction causes toxicity
Determinants of systemic toxicity
Specific agents: physicochemical properties
S v R
Stereospecificity:
levorotatory or S/(–) stereoisomers
less toxic than dextrorotatory or R/(+)
Determinants of systemic toxicity
Specific agents: physicochemical properties
drugs order
Bupivacaine > l-bupicavaine > ropivacaine > lignocaine
Determinants of systemic toxicity
Specific agents: physicochemical properties
least and most toxic esters and amides
Least toxic
Ester
2-Chlorprocaine
Amide
Prilocaine
Most toxic
Ester
Tetracaine
Amide
Dibucaine
> bupivacaine
Specific agents: Dose
[peak plasma]
Dose
Higher dose > lower dose
High peak plasma concentration
(greater than toxic levels)
Peak plasma conc and weight
Peak plasma concentration is not a function of body weight in adults, and
basing LA doses on body weight in adults has no scientific foundation
(except in paediatrics)
Factors increasing systemic toxicity
Site of injection
Factors increasing systemic toxicity
Site of injection
(influences rate of absorption):
intravascular > intrapleural > intercostal > caudal > epidural > brachial plexus > femorosciatic > sub-cutaneous > intra-articular > spinal
Factors increasing systemic toxicity
Physiological parameters
Physiological parameters:
acidosis (decreases plasma protein binding),
hypercarbia,
hypoxia and
hyperkalaemia (increased proportion of Na+ channels in inactivated state)
Factors increasing systemic toxicity
obs
geris
paeds
Specific populations:
obstetrics (progesterone-induced sensitivity to LA)
geriatric: low dose requirements
paediatrics: lower weight and performance of blocks under sedation
Protective factors
additives
breathing
meds
Protective factors
Vasoconstrictors:
may decrease rate of
systemic absorption and may help
reducing total dose
Hyperventilation
(reduces respiratory acidosis and
raises seizure threshold)
Benzodiazepine premedication (raises seizure threshold)
LAs cause toxicity by blocking the following
Which channels
Cardiac
Voltage-gated Na+ channels:
most important.
LA blocks these
channels in open
or inactivated state,
rather than in closed state.
This is a phasic or use-dependent block.
In cardiac muscle fibres,
Ca+ influx during ‘plateau’
phase favours LA binding as the Na+
channels are in the inactivated state.
How does the binding of LA To cardiac fibres affect rhythm
Consequently, Vmax
(max upstroke velocity of the action potential)
is reduced,
causing QRS widening,
and action potential duration
(APD) is prolonged,
causing QT prolongation
(leading to ventricular arrhythmias).
How does physiologica state affect cardiac arrhytmia
Hypoxia, acidosis and hyperkalaemia increase the proportion of Na+ channels in the inactivated state,
favouring LA binding and hence toxicity
Type of sodium channel blockade by local anaesthetic
Blockade Local anaesthetic Toxicity
Fast in, fast out
Lignocaine Less toxic
Slow in, slow out
Bupivacaine – lower doses Intermediate
Fast in, slow out
Bupivacaine – high doses More toxic
Voltage-sensitive K+ channels:
Voltage-sensitive K+ channels:
APD increased; QT prolongation
leading to ventricular arrhythmias
Voltage-sensitive Ca+ channels:
Voltage-sensitive Ca+ channels: inhibition of myocyte Ca+ release
and utilisation
Other sites of LA toxicity
Other channels: HERG, NMDA, nicotinic acetlycholie receptors, β-
adrenergic, KATP channels and so forth.
Mitochondrial dysfunction: uncouple oxidative phosphorylation.
How does LAST present generally
In general, central nervous system (CNS) signs are first to manifest,
followed by cardiovascular system (CVS) signs.
CNS toxicity
early
CNS toxicity Early excitement phase: perioral numbness, tinnitus tremors myoclonic jerks convulsions
CNS toxicity
late
Late depression phase:
hypoventilation
respiratory acidosis and hypoxia
coma
CVS toxicity
CVS toxicity
Early excitement from CNS stimulation:
tachycardia
hypertension
Late CVS depression (from direct LA toxicity): arrhythmias pump failure arrest
ECG changes
ECG:
QRS widening and QT prolongation;
ventricular arrhythmias
CNS Ratio
CVS :
CNS ratio describes ratio of dose
required to cause CV toxicity to that
required to cause CNS toxicity.
It is 2:1 for bupivacaine and
7 : 1 for lignocaine.
This implies that bupivacaine is more cardiotoxic than lignocaine
The order of toxicity (and cardiotoxicity) is:
The order of toxicity (and cardiotoxicity) is:
Bupivacaine >
l-bupicavaine >
ropivacaine >
lignocaine.
There are clinical reports
of simultaneous CNS and CVS toxicity with
bupivacaine
TABLE 8.12 Recommended doses of common local anaesthetics (LAs)
Procaine
7
8.5 (w epi)
Metabolised rapidly by esterases
2-Chlorprocaine
11
14
w epi
Lignocaine
Without epinephrine With epinephrine Toxic plasma levels
4
7 w epi
5
Mepivacaine
Without epinephrine With epinephrine Toxic plasma levels
4
7 w epi / not reco
5
Bupivacaine
2
2 w epi not reco
3
Levo-bupivacaine
2
2 not reco
4
Ropivacaine
3
3 not reco
5
Max dose influenced by
shows the generally accepted guideline. However, maximum
recommended doses by the manufacturer should be abided by. Dosages are
said to be site- and block-specific rather than dependent upon weight of the
patient.
Dose-dependent systemic effects of lignocaine
Analgesia 1–5
Tinnitus, perioral numbness 5-10
Seizures 10-15
Coma and respiratory arrest 15-25
Cardiovascular depression >25
Measures to reduce LA likelihood of toxicity are:
1
using smallest possible doses for the given block
2
using less cardiotoxic agents
3
use of vasoconstrictors to reduce systemic absorption
4
fractionation of total dose
5
aspiration before injection and using test doses
Monitoring
Adequate patient monitoring may help to recognise LA toxicity at an
earlier stage, but it may not reduce its likelihood.
Rx of LA toxicity
abc
Treatment of LA toxicity: always start with ABC (resuscitation).
Airway:
Clear the airway and suction (if needed).
Breathing:
Oxygenation and adequate ventilation to avoid hypoxia and respiratory
acidosis (both potentiate LA toxicity).
Intubation and controlled ventilation if needed.
Circulation:
Maintain BP: leg elevation, fluids, inotropes or vasoconstricto
Drugs:
Seizures
Drugs:
Seizures:
diazepam, midazolam, thiopentone or propofol
Muscle relaxant:
Muscle relaxant: succinylcholine
Arrhythmias
Arrhythmias:
amiodarone (best choice out of anti-arrhythmics),
epinephrine (higher doses may be needed)
Specific therapy:
Specific therapy: Intralipid.
anti-arrhythmics to be avoided in setting of LA-induced arrhythmias are
anti-arrhythmics to be avoided in
setting of LA-induced arrhythmias are
sodium valproate,
phenytoin,
Ca+ channel blockers,
lignocaine and
bretylium.
Regarding Intralipid rescue therapy
what % available
what’s recommended
Intralipid is available as a 10%, 20% and 30% lipid emulsion.
However, the recommended concentration to be used (lipid rescue) is 20%.
Propofol is not an appropriate substitute.`
cpr and intralipid
CPR should be continued while giving Intralipid in cardiac arrest
(lipids must circulate).
Proposed MOA intralipid
indirect
Indirect:
acts as a sink for the
lipid-soluble LA,
drawing it back into circulation
(from tissues)
Proposed MOA intralipid
Direct
Direct:
the inhibition of mitochondrial
carnitine-acylcarnitine translocase
by LA is overridden by
high plasma triglycerides
(this enzyme is essential for the
tricarboxylic acid cycle in mitochondria,
i.e. oxidative phosphorylation).
Intralipid
Dose
bolus
infusion
Dose used:
initially 1.5 mL/kg bolus
over 1 minute followed by
infusion of 0.25 mL/kg/minute.
Intralipid
can further doses be given?
If CVS stability is not restored or
adequate circulation deteriorates,
give an additional two boluses at an
interval of 5 minutes
and continue infusion at the
same or double rate (0.5 mL/kg/minute).
The maximum cumulative dose
should not exceed
12 mL/kg
840 mL in a 70-kg man
Which is metabolised to PABA
Ester LAs are metabolised to
PABA compounds,
which make them
more allergenic than amides
PABA compounds may be present in cosmetic
products, causing patients to react
True allergy to LA?
True allergy to preservative-free amide
LA is rare,
and patients may react to paraben derivatives used as preservative.
Cauda equina with 2 chlorprocaine
Reports of ‘cauda equina syndrome’ with unintentional
intrathecal administration of high doses of 2- chlorprocaine intended for epidural use were attributed to sodium metabisulphite added to the solution.
The present preparations for intrathecal use are free of such
preservatives.
Cauda equina syndrome (CES) with regional
Cauda equina syndrome (CES) has been reported after unintentional
intrathecal injection of high doses of LA (mainly lignocaine) intended for
the epidural space.
In other reports, the administration of LA through continuous spinal microcatheters (smaller than 27 G) produced a restricted
sacral block, and repeated doses were required to achieve adequate surgical
anaesthesia.
CES attributed to
adding what worsens
The neurotoxicity was attributed to the maldistribution of LA
within the CSF, and subsequently the use of microcatheters was withdrawn.
The addition of vasoconstrictors is another risk factor
CES presents
The syndrome presents as multiple-root involvement, varying degrees of bowel and bladder dysfunction, perineal sensory loss and lower-limb motor weakness.
CES ix and Rx
The differentials may include epidural haematoma or epidural abscess, with urgent MRI to ascertain the cause.
There is no effective treatment, and
the patient may need considerable supportive care
Transient neurologic symptoms are a group of neurologic symptoms
experienced by patients after spinal anaesthesia, characterised by:
1
mostly aching/pain in one or both buttocks
2
often with dysaethesia radiating into anterior or posterior thighs
3
with lower-back pain in some patients
4
symptoms beginning within 24 hours after the resolution of spinal
anaesthetic
5
symptoms resolving in 6 hours to 4 days
6
no neurological finding upon physical examination.
TNS name
The name ‘transient neurologic symptoms’ itself is controversial, as it
implies a neurologic aetiology that is not yet proven.
TNS RF
Proposed risk factors include
use of intrathecal lignocaine,
lithotomy position,
outpatient surgery
and obstetric patient population,
but not baricity and dose of LA used.
TNS RF
Treatment constitutes use of
NSAIDs,
muscle relaxants,
leg elevation,
heat pads,
trigger-point injections and reassurance.
Abnormal Neuro exam
An abnormal neurological exam should prompt an evaluation for
epidural haematoma, abscess or CES
