reversal of nmb

7/30/2019 Reversal of Nmb

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REVERSAL OF

NEUROMUSCULAR

BLOCKADE

Speaker: Dr Srikanth alladi


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Reversal agents are drugs that aregiven to counteract, or reverse, the

effects of drugs used for NDMB.

Facilitates the speed of recovery from the

skeletal muscle effects associated with

NDMRs.


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THE QUALITIES OF AN IDEAL REVERSAL

AGENT

have a fast onset.

efficient at any time, even soon after

curarization of the patient.

able to provide complete reversal

either for light or profound block.


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free of any side effects.

able to restore sustained

neuromuscular function rapidly even

when NM blockade is profound at the

time of administration.

longer half life than the NM blocking

agent.


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THE DIFFERENT PHARMACOLOGICAL REVERSALDRUGS ARE CLASSIFIED AS:

A) Older drugs

Traditional & currently in clinical use-anticholinesterases.

Neostigmine ,Physostigmine,

Edrophonium,

Pyridostigmine .

B) Newer agents

1) Sugammadex(Org 25969) ,

2) Cysteine.


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Currently not much in clinical use :

Ambenonium, 4-aminopyridine,

Suramine, Gallantamine,Germine diacetate ,Tetraethylammonium,Congo red, Chlorasol fast

pink, Evans blue,

Purified human plasma cholinesterase formivacurium block.


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Anticholinesterase Agents

Blocks the activity of both types ofcholinesterase enzymes.

Most noticeable effects are muscarinicones.

Cholinesterase enzyme has an active

site, having an anionic site and anesteritic site.

Esteritic site is more responsible for theh drol sis of acet lcholine.


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Mechanism of action

Depression of both true andpseudocholinesterase by reversible binding.

mainly by inhibition of acetylcholinesterasewhich results in increased concentration of

Ach at the NMJ .

local conc. of Ach competes with NDMR.


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Edrophonium electrostatic attraction

Neostigmine and pyridostigmine

covalent bonding.

Organophosphates irreversible

binding.


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Other actions:

Ach mobilisation and release may be

enhanced (Presynaptic effects) mainlyseen with edrophonium.

Neostigmine has direct but weak agonistic

effect on nicotinic receptors.


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Actions..

Muscarinic effects Nicotinic effects

Myocardium = Bradycardia

Gut = ContractionBronchioles = Constriction

Pupil = Contraction

Salivary gland = stimulated

Bladder = contracted

Autonomic ganglia =

stimulated

Skeletal muscle =

stimulated


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Atropine is used to oppose the muscarinic

effects.

Excessive doses of anticholinesterase can

paradoxically potentiate NDM blockade and

also prolong Sch block.

Vd = 0.7 1.4 ltrs, t = 60 to 120 mins

and clearance 8 to 16 ml/kg/min.

Clearance is due to both hepatic (25 50%)

and renal excretion (50-75%).


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Pharmacodynamics

Onset of action Edrophonium = 1 2 mins ( due to its

presynaptic effect).

Neostigmine = 7 11 mins. Pyridostigmine = 15 20 mins.

Elimination half lives of all agents arerelatively long (80 120 mins)

comparable in length to the half life of the

long acting NDMR.


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CVS effects

Bradycardia is the initial response.

Its exaggerated in pts on blockers, elderly

or in pts with abnormal sinus node function.

So larger doses of anticholinergic may be

required in these pts.


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Atropine is usually combined withedrophonium.

Glycopyrrolate is combined withneostigmine or pyridostigmine.

Glycopyrrolate does not cross BBB henceincidence of memory deficits after

anesthesia is less than that for atropine.


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Total dose administered should be carefullytitrated, monitoring the effect with nervestimulator.

Arrhythmias can occur use with caution in ptswith autonomic neuropathy.

Glyco preferable to atropine in such cases.

Drugs may be administered over a longertime(2-5 mins) in order to reduce the incidenceand severity of disorders of rhythm.


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Transient arrhythmias can occur, variesfrom innocuous changes in atrial pacemaker

to junctional rhythm, ectopic ventricular foci,

high grade heart block, including completeheart block and cardiac arrest.

ECG must be monitored during reversalprocess to detect these and treat

appropriately.


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Neostigmine

Synthesized by Aeschliman andReinert in 1931.

Quaternary ammonium compound(

low lipid solubility). Poorly absorbed by mouth and largely

confined to the ECF phase.

Partly broken down by serumcholinesterase and partly excreted

unchanged by the kidneys.


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It binds to esteratic site with itscarbamate group- carbamylates the

enzyme.

It is also a depolariser and can cause

on its own a depolarising type of

block.High doses >5 mg can causeparesis.


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Systemic effects:

CVS peripheral vagal stimulation willcause bradycardia, vasodilation andfall in BP.

Cardiac arrhythmias and arrest mayoccur following large doses especiallyin the presence of hypercapnia.

RS little effect, bronchoconstrictionand increases secretion.


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Skeletal muscle prolongs andintensifies local depolarisation producedat the endplate by Ach.

Small dose will increase the musclecontraction, larger doses may causedepression.

In myasthenia gravis, the strength ofmuscle contraction is increased.


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Smooth muscle peristalsis of stomach,

intestine, ureter and bile duct is increased andmay give rise to colic.

Bladder and bowel may be emptied.

Others sweating, salivation and increase inmucus and other exocrine secretions, pupilconstricted.

Neostigmine may increase the intensity andduration of action of analgesics.


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Clinical comment

Neostigmine and atropine can be combinedsafely.

Giving atropine prior may precipitatetachycardia and more serious arrhythmiasin certain conditions.

Serious arrhythmias can occur in presenceof resp acidosis and hypoventilation shouldbe avoided during its administration.


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Reversal agents should be administeredslowly over about 60 secs.

Initial tachycardia followed by bradycardia

occurs because duration of action ofneostigmine exceeds that of atropine.

Glycopyrrolate has a longer duration ofaction and is therefore preferred by many.


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Optimum time to administer reversal is whenthe pt is still being hyperventilated and CO2level in the blood is low.

Atleast 5 mins should be allowed for its effectand improvement in neuromuscularconduction may occur upto 10 mins.

Never administered in the presence ofhalothane or cyclopropane .


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Recovery of respiratory muscles alwaysprecedes that of peripheral hand muscles.

Should be used in particular care in thepresence of asthma and heart disease.

In small children, cardiac case and inseverely ill titrate the exact dose ofneostigmine and atropine.

Never exceed total dose of 5mg ofneostigmine and 2mg of atropine.


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Other uses:

In treatment of intestinal and bladder atony

15-30mg can be given by mouth of 0.5-1mgparenterally.

MG 15mg orally tid, increasing upto twohourly according to tolerance.

Glaucoma 1 drop of 3% solution, repeatevery 10 mins upto 12 doses.

As an adjunct to intrathecal anesthesia causinga prolongation of sensory and motor blockade.


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Over dosage:

Overdose of neostigmine may cause sudden

death due to cardiac arrest.

Restlessness, weakness, musculartwitchings, dysarthria, pinpoint pupils,nystagmus, sweating, salivation, nausea andvomiting, colic, defecation and a desire tourinate are other signs.

Respiration embarassed due tobronchospasm and excessive secretion.


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Tx:

Death due to respiratory paralysis andpulmonary edema may follow .

Atropine will antagonise these effects.

Muscular twitchings may be relieved by

small doses of competitive NDMR.

Respiration must be assisted or

controlled.


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PhysostigmineAlkaloid obtained from calabar bean, the seed of

physostigma venenosum.

Tertiary amine structure, lipid soluble, crossesBBB, placenta and penetrates eye.

Used to treat anticholinergic syndrome producedby atropine, hyoscine and other alkaloids.

More potent than neostigmine, greater effect onCNS and CVS.

Destroyed in body by hydrolysis.


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Indications

It can antagonise psychomimetic side effects

of ketamine without reversing analgesia.

It abolishes the somnolent effect of morphine.

Used to reverse sedative effects of CNSdepressants like atropine, hyoscine,promethazine, BZD and TCAs.

NMB can be antagonised .


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Pyridostigmine

Pyridine analogue of neostigmine, lesspotent.

10mg of pyrido = 2.5 mg of neo.

Less nicotinic action, onset and duration ofaction are longer.

Muscarinic effects are weaker.

Duration of action 6 hrs, useful in renal

failure.


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It has minimal BBB penetration.

Uses - Used for similar purposes to

neostigmine, more useful when aprolonged action is required as in MG.

60mg by mouth, 1mg iv is the dose.


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Edrophonium

Functions mainly by direct action butalso as prosthetic cholinesterase

inhibitor.

Action on skeletal muscle is more

marked than on ganglia and visceral

effector organ.

Less potent, 35 mg edro = 3mg of neo


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It has rapid onset of action and plasma

level is sustained at an effective level for 20mins.

It has anticholinesterase, depolarising anddirect stimulating action on motor end plate.

Recurarisation can occur coz magnitudeand duration of inhibition is less.


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Main advantage is rapid onset ofaction (5 mins compared to 7-10 minsfor neo, 12-15 mins for pyrido).

It possess less potent muscarinic sideeffects than neostigmine andpyridostigmine.

Dose is 10 70 mg.


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Indications

Antagonise the effects of NDMR.

For diagnosis and assessment of

therapy in MG.

Differentiate b/w Myasthenic and

cholinergic crisis.


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SUGAMMADEX (ORG

25969) It was discovered at the Newhouse Research

site in Scotland.

The first phase/ study of sugammdex inhuman voluntaries was published in 2005.

It is the first compound in a new class ofneuromuscular reversal drugs called SelectiveReversal Binding Agents (SRBA).


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Chemistry- It is a synthetic modified -cyclodextrin.

Su refers to sugar & -dex refers to thestructural molecule -cyclodextrin.

Unmodified -cyclodextrin has a 3 dimensionalstructure which resembles the doughnut.

Hydrophobic interactions trap the drug molecule(rocuronium/ vecuronium) into the doughnut holeresulting in the formation of water-solubleguesthost complex.


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Pharmacokinetics & dynamics- It has a plasmaclearance at approaching the GFR (120ml/min).

with upto 80% of the dose eliminated unchangedin urine within 24hrs.

Its clearance is decreased in patients withdecreased creatinine clearance.

Hepatic impairment does not influence itsexcretion.


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Doses of 0.1-8.0mg/kg sugammadexhas a

clearance rate of 88ml/min.

elimination half-life of 1.8hrs.

volume of distribution of 11-14litres.


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Mechanism of action- It exerts itseffect by forming very tight water

soluble complexes at 1:1 ratio with

steroidal NMB drugs (rocuronium >vecuronium > pancuronium).

The iv administration of sugammadexresults in rapid removal of free

rocuronium molecules from plasma.


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This creates a concentration gradientfavouring the movement of remaining

rocuronium molecules from the NM

junction back into the plasma wherethey are encapsulated by free

sugammadex molecule thus resulting

in fast recovery of NM function.


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SUGAMMADEX

Gijsenbergh et al. Anesthesiology 2005;103:695

=

Roc Org 25969+


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The rocuronium-sugammadexcomplex has a very low dissociation

rate & hence chances of residual

muscle weakness are very low.

It has no effect onacetylcholinesterase or any receptor

system in the body.


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Adult dosage

A) Reversal of shallow neuromuscularblockade induced by rocuronium

Use at a dose of 2 mg/kg (reversal

likely within 1.2 and 1.5 minutes).

B)Reversal of profound

neuromuscular blockade induced byrocuronium

Use at a dose of 4 mg/kg (reversal

likely within 2.3 and 3.3 minutes).


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Adult dosage

c) Immediate reversal ofneuromuscular blockade induced by

rocuronium

Use sugammadex at a dose of 16mg/kg (reversal likely within 5.7 and

6.7 minutes.)


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Cysteine

Gantacurium undergoes rapiddegradation in plasma by chemical

hydrolysis and inactivation by cysteine

adduction.

Exogenous administration of cysteine

can accelerate the antagonism ofgantacurium-induced neuromuscular

blockade.


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THE CLINICAL CRITERIA FOR ADEQUATEREVERSAL INCLUDE :

TOF ratio of 0.9 or greater is predictive of recovery of pharyngealmuscles, masseter muscle and striated muscles of upperoesophagus.

At TOF


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It tells us only that they are adequate at presentbut indicate nothing about the reserve strengthavailable in the event of increased ventilatoryrequirements due to pain, shivering or airwayresistance.

VC

Better test of return of insp function.

It indicates a reserve that would be required in

the event of increased ventilatory requirement. To take a deep breath for prevention of

atelectasis and enhance the velocity to cough toremove secretions.

15ml/kg is the minimum acceptable value.


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Ability to sustain a 5 sec head lift. This indicates sufficient strength in normal patients to

protect the airway against obstruction & aspiration of

oral contents.

It corresponds to TOF ratio of 0.75.

Grip strength (presence of a firm & sustained

handgrip): More sensitive indicator of residual

weakness than head lift.

It requires the use of a dynamometer & pre-op control

values. So, it is less useful as a clinical tool.

At TOF of 0.9 the grip strength will be 70-100% of

control.


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Sustained leg liftfor 5 sec:

It is a valuable sign of adequate reversal in children as

old as 12 weeks of age & it indicates adequate airwaycontrol and ventilatory function.

It usually corresponds to TOF ratio of 0.75.

Absence of double vision over 2hrs.

Masseter strengthability to prevent a wooden tonguedepressor clenched between two incisors from being

pulled out by even a vigorous effort. Difficulty in speaking, swallowing if TOF


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FACTORS WHICH INFLUENCE THE

EFFECTIVENESSOF REVERSAL:

INTENSITY OF BLOCK the depth of NM blockade at

the time of administration of reversal agents has a

profound influence on the speed & efficacy of reversal.

Reversal of a profound blockade proceeds more slowly

than reversal of less intense block.


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CHOICE OF RELAXANT Intermediate actingdrugs are easier & faster to reverse than are long

acting relaxants.

CHOICE OF REVERSAL AGENT - Neostigmine

has been found to be a more reliable antagonist

than edrophonium for antagonism of deep blocks.

Sugammadex can reverse very deep NM blockadeinduced by Rocuronium without muscle weakness.


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DOSE OF REVERSAL AGENTAnticholinesterases like neostigmine, edrophonium

& pyridostigmine have a ceiling effect.

The effect of these drugs is dose dependent until a

plateau is reached at which point an increase indose does not produce further reversal of NM

blockade. This is known as the ceiling effect.

This plateau corresponds to a TOF ratio of approx0.6.


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PLASMA CONCENTRATION OF RELAXANTAfter a prolonged continuous infusion or after

numerous boluses, the plasma concentration

associated with a given level of NM blockade might

be expected to be greater than after a single bolus.

Hence the recovery after a single bolus dose of

relaxant is more rapid compared with a prolonged

continuous infusion.


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ANAESTHETIC AGENT potent volatile agentsresult in slower recovery following pharmacologicmuscle relaxant reversal if their use is continuedduring reversal.

RENAL FAILURE - anticholinesterases likeneostigmine are actively secreted into the renaltubules & their plasma clearance is reduced inrenal failure.

The plasma clearance decreases for neostigmineby 2 folds & edrophonium by 3 folds.

The elimination of muscle relaxants eg:vecuronium is also delayed in renal failure. Hence,the rate of reversal may be unaffected or

decreased.


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DRUG INTERACTIONS any drug whichpotentiates NM blocking drugs will impede thereversal of NM blockade. Eg: aminoglycosidesantibiotics, hypotensive drugs,immunosuppressants & anti-cancer drugs, mag

sulphate, Ca channel blockers.

ELECTROLYTE & ACIDBASE DISORDERSrespiratory acidosis, metabolic alkalosis &hypokalemia impede/delay reversal of NM block.

The degradation of atracurium is partially pHdependant (hofmann elimination) but there is noevidence that acidosis impedes its antagonism byneostigmine in the clinical situation.


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AGE the plasma clearance of anticholinesterasesis reduced in the elderly in common with plasma

clearance of NDMR because of age related

decrease in hepatic metabolism & renal clearance.

The speed & extent of recovery is no differentbetween young & old if the reversal agent is given

at the same level of NM blockade.

Atracurium, because of metabolism by Hoffman

elimination & enzyme hydrolysis is not affected by

age.


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Spontaneous recovery from NM blocking drugs ismore rapid in children aged 1-10yrs than in adults.

Recovery in infants is slower than in children for

pancuronium, atracurium & vecuronium.

Reversal occurs more rapidly & the dose of

reversal agent required to produce equivalent

effects is less in infants & children than in adults.


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PRE EXISTING MEDICAL CONDITONS DM,underlying neurological diseases & obesity. Here,

reversal of NM block is less predictable.

HYPOTHERMIA it can prolong the spontaneous

recovery from NDPR & delay reversal.

RESIDUAL NEUROMUSCULAR


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RESIDUAL NEUROMUSCULAR

BLOCK (RNMB)

FACTORS CONTRIBUTING TO RESIDUAL NMBLOCK

Use of long acting muscle relaxants.

Many anaesthesiologists do not routinely use quantitative NM

function monitor to ensure adequate recovery to a TOF ratioof 0.9 or more.

Neostigmine has a ceiling effect & when administered at adeep level of NM blockade, it can result in an inadequaterecovery of NM function.

Failure to pharmacologically reverse the block.


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SIGNS OF RESIDUAL CURARIZATION:

Typical myasthenic facies = ptosis, lack of expression & loss of tone

in masseter. Inability to raise head from pillow & hold it up for atleast 5 sec.

Loss of firm sustained hand grip.

Tracheal tug, any paradoxical indrawing of intercostals musclesduring inspiration in the absence of any CNS, CVS or RS problems

RR > 20 breaths/min. TOF ratio < 0.7.

Presence of double burst fade.

Lack of sustained leg lift for 5 sec.

Poor massetter strength by tongue depressor test.

Presence of diplopia, blurred vision. Difficulty in speaking, swallowing.

Hypoxaemia (SpO2< 90% on room air).

PREVENTION OF RESIDUAL NEUROMUSCULAR


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BLOCK:

Avoid using long acting muscle relaxants.

Routine use of intra-op quantitative NM monitoring.

Do not give reversal agents at deep levels of block.

Use of newer agents like sugammadex which can reverse even deeperlevels of rocuronium/vecuronium block.

Return of TOF ratio of 0.9 should be one goal before shifting to PACU.

Titrate muscle relaxants & their reversal agents to effect.


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CONSEQUENCES OF RESIDUALNEUROMUSCULAR BLOCKADE:

Impairment of respiratory response to hypoxaemia.

Pharynx dysfunction & dysfunction of upper

oesophagus- risk of aspiration.

Upper airway obstruction.

Inadequate return of pulmonary function


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reversal of nmb

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