Neuromuscular blockade

V. De Sloovere

Co-assistenten

2014-2015

Outline

• Why

• Neuromusculaire junction: physiology andpharmacology

• Depolarising NMB

• Nondepolarising NMB

• Monitoring

• Reversal NMB

• Book: Basic’s of Anesthesia 6th edition R. Miller

Why?

• 1942 neuromuscular blockade: milestone in anesthesia

• 1954 increased mortality: suboptimale use ventilators,

no reversal drugs

• Goal: improve intubation and ventilation, immobility

during surgery

• Side effects: increased awareness?? Not too muchneuromuscular blocking but too little anesthesia

• NMB must be worn off before pt regains consciousness

• Residual paralysis is still a problem

• Treshold complete NMB reversal is TOF ratio > 0,9%

Physiology and pharmacology

Physiology and pharmacology

• Neuromuscular junction: prejunctional motor nerveending, synaptic cleft and postjunctional membrane

• Nicotine acetylcholine receptors on pre- andpostjunctional sites

• Neuromuscular transmission: impulse at motor nerveterminal with associated Ca+ influx: release ligand ACh

• ACh binds to ACHRs postjunctional: ∆ membranepermeability to ions (Na+ and K+)

• ↓ transmembrane potential: AP spreads over musclefibers: muscle contraction

• Ach hydrolyzed by Acetylcholinesterase.

Acetylcholine receptors

• Nicotine acetylcholine receptors:

Nm-junction: pre- and postjunctional

Sympatic ganglia

Central nervous system

• Muscarinic acetylcholine receptors

Parasympatic system

Prejunctional receptors

Postjunctional receptors

Extrajunctional receptors

• Present throughout skeletal muscles

• Normally suppressed by neuronal activity

• Prolonged inactivity, sepsis, denervation or

trauma to skeletal muscles: proliferation

extrajunctional receptors

• Nicotine receptors and muscarine receptors

Neuromuscular blocking agents

Depolarizing neuromuscular blocking

drugs

Succinylcholine• Ultra Short acting: 5-10 minutes

• 0,5-1,5 mg/kg IV

• Non-competitive binding

• Sustained depolarization postjunctional membrane: binding 2 alpha subunits.

• Phase I block, high dose or continuous infusion: phase II block

• Fasciculations → flaccid paralysis

• Breakdown: hydrolisis by plasmacholinestrase (produced in liver) to inactive metabolites (succinic acid and choline)

• Use?

Succinylcholine

Side effects:

• Cardiac dysrythmias: Sinus bradycardia, junctional rythm, sinus arrest

• Hyperkalemia (?patients at risk? And why?)

• Myalgia, myoglobinuria

• Increased intra-ocular pressure and intra-gastric pressure

• Neuromuscular diseases

• Extended burns, muscle trauma

• Liver failure

• Anti-cholinesterasedeficienty, gen mutations

• Trismus

• Malignant hyperthermia

Nondepolarising neuromuscular

blocking Drugs

• Longterm, intermediate and short acting

• Competitive to acetylcholine for nicotine cholinergicreceptors

• Which NDMB? : onset, metabolism, clearcance, duration of action

→ Tabel 12,6

Basics of anesthesia, sixth edition, Miller R.D., Pardo M.C.

• Fade

• Antagonisation: anticholinesterase agents

• Onset variable

Nondepolarising neuromuscular

blocking Drugs

Pharmacokinetics

• No central nervous systemic effects

• Influenced hypovolemia, hypothermia and hepatic or renal disease.

• Competitive binding to α- subunit

• Elimination: liver, plasma cholinesterase, Hofmann, or combination

• Highly ionic, H2O soluble, limited lipid solubility

Pharmacodynamics

• Effect NMB can be enhanced or diminished by certain conditions, drugs

• Dose, duration, breakdown → Tabel 12,6 Miller p151 Basics of anesthesia,

sixth edition, Miller R.D., Pardo M.C.

Clinic:

• flaccid paralysis

• Histamine release

Nondepolarising neuromuscular

blocking Drugs

Long-acting NDNMD 1-2h

• Pancuronium: biquaternair aminosteroïd,

cave renal failure, vagolytic effect,

symphatomimetic effect, no histamine release

Long duration

Intermediate-acting NDNMB

• Rocuronium: aminosteroid compound,

different dosage different onset time (0,3-1

mg/kg), RSI, anaphylaxisis reported, renal

clearance, antidote

• Atracurium: bisquaternary ammonium

benzylisoquinoline, elimination by Hofmann

reaction and nonspecific, renal excretion

• Cisatracurium: benzylisoquinolinium, onset 3-

5 min, dose 0,15-0,2 mg/kg, Hofmann

elimination, organ independent clearance

• Vecuronuim: Monoquaternary aminosteroïd

Hepatic and renal excretion, No vagolytic

effect, no histamine release, antidote

Shortacting NDNMB

• Mivacurium: Benzyllisoquinoline, 0,2 mg/kg,

short acting, histamine release, elimination:

plasmacholinesterases

Drug interactions

• Diminished: calcium, corticisteroids,

anticonvulsants (Phenytoine), burns,

prolonged illness, NM diseases

• Enhanced: aminoglycosides, locale

anesthetica, inhalational anesthetics, anti-

arrythmica, dantrolene, magnesium, lithiums

tamoxifen

Monitoring Neuromuscular block

• Peripheral nerve stimulation: measuring force, electromyography, acceleration proportional to force.

→ visual, tactile, quantitative measurement

• Ulnar nerve, facial nerve (innervates?)

• Monitoring is a tool not a cure

• Standard of care monitoring

• Electric stimulation: current applied, duration current andposition electrodes:

• Different monitoring modalities:

Single twitch

Tetanus

Train of four

Double burst stimulation

Single Twitch:

• Supra maximal stimulus

interval 10 s (f <0,1Hz)

• Dose-respons curves

• Amplitude respons compared

to pre-blockade

• Little clinical use

(controle value required),

onset NMB

• >70 % twitch: recovery

Tetanus

• Continuous stimulation for 5 sec at 50 Hz

• Elicit minor degree NMB

• Painful!

• NDPNMB: fade

• DPNMB: no fade

Post tetanic count

• Deep neuromuscular block: No respons to

Single twitch, double burst, TOF

• Tetanic stimulation, 3 sec pause, single twitch

• Response in early stages of recovery (before

TOF)

• 6 min interval

• Post tetanic facilitation

Train of four

• 2Hz stimuli 4 times, TOF ratio: height of 4th to 1st twitch

• TOF ratio > 0,7: no fade, Extubation TOF ratio >0,9

• Twitch count

Double burst stimulation

• 2 burst of 3 electrical stimulations

interval 750 msec

• Detection small degrees NMB

(TOF ratio < 0,3)

• Easier to detect fade

• Close correlation to TOF

McGrath C D , and Hunter J M Contin Educ Anaesth CritCare Pain 2006;6:7-12

Clinic

Reversal

Avoid residual neuromuscular block:

• Residual block PAZA incidence 0,8-6,9%

• Nondepolarising NMB and Phase II block

• Wheiging adverse effects antagonisation

What?

• Anticholinesterase agents

• Anticholinergic agents

• Selective relaxant binding agents

Clinical signs of complete muscle

relaxant reversal

• Require awake, cooperative patient

• Ideal: test before extubation, beforeemergence

• Most clinical tests not specific for respiratoryfunction

• 5-second head lift, sustained handgrip, leg lift, eye opening

• Masseter strenght more sensitive notunfallible

When and what

When?

• TOF ratio: <0,9

• Clinical signs

• TOF 2/4

• What: anticholinesterases: inhibition activity

acetylcholinesterase : accumulation acetylcholine

at nicotine and muscarine receptors

• Neostigmine, pyridostigmine

• Side effect muscarine effects

• ALWAYS add Atropine/Glycopyrrolate

Deep neuromuscular block

• Indications: no absolute indications: option in robot assisted procedures,

eye surgery, laparascopic procedures: bariatric surgery, …

• Monitoring: 1-2 twitches post tetanic count

• Risks: residual NMB: hypoxia, pulmonary complications.

• Acetycholinesterase inhibitors: relatively slow in onset of reversal.

Side effects acetylcholine-induced muscarine receptor

stimulation bradycardia, hypersalivation, nausea and vomiting

• Co-administration of a muscarine agonist, such as atropine or

glycopyrrolate, to counteract some of these side effects.

• Recent studies: high-dose neostigmine is associated with postoperative

complications: muscle weakness and reintubation

• Introduction Sugammadex: improve surgical conditions without adverse

events

• Rocuronium bolus and continuous infusion aiming PTC 1-2.

Selective NMB reversal agentsSugammadex

• Antagonisation steriodal NDNMB: encapsulating, modified

gamma cyclodextrine

• Fast (2-3min)

• No CV side effects

• Cannot intubate-cannot ventilate

• Expensive! Only use on indication

1. General Principles for Avoidance of Residual Paralysis

* NMBDs should only be administered to patients who require

this therapy. Dosing should be individualized based on surgical

necessity, patient factors, and presence of coexisting disease.

* Long-acting NMBDs (e.g., pancuronium) should be avoided.

Intermediate-acting NMBDs should be used whenever feasible.

* Clinical tests of muscle function (head lift, jaw clenching, grip

strength, tidal volume, etc.) are unreliable predictors of recovery

of neuromuscular function.

* To exclude with certainty the possibility of residual paralysis in

patients at risk, clinicians should use objective (quantitative)

neuromuscular monitoring tests.

* Ideally, neuromuscular function should be monitored

objectively (quantitatively) in all patients receiving NMBDs.

2. Principles of Monitoring in Clinical Practice

* Objective (quantitative) monitoring of neuromuscular function should be used.

* Peripheral nerve stimulator units should display the delivered current output, which should be at least 30 mA.

* Assessment of neuromuscular responses should take into consideration the musculature group that is monitored. The time course (onset, recovery) of muscle relaxants is different at peripheral muscles (adductor pollicis) than at central muscles (orbicularis oculi, corrugator supercilii).

* Adequate spontaneous recovery should be established before pharmacologic antagonism of NMBD block with anticholinesterases. This requirement does not apply to reversal with sugammadex.

* The timing of tracheal extubation should be guided by quantitative monitoring tests such as TOF >0.9 or DBS3,3 >0.9.

3. Principles for Pharmacologic Reversal with Anticholinesterases

* During anesthetic techniques that do not enhance the effects of muscle relaxants (such as total IV anesthesia), a minimal TOF count of 2 should be present before administration of anticholinesterases.90

* During anesthetic techniques that enhance the effects of muscle relaxants (such as inhaled volatile anesthesia), a TOF count of 4 should be present before administration of anticholinesterases.19,90

* If recovery to TOF >0.90 is documented by MMG (quantitatively), neostigmine administration should be withheld. Administration of neostigmine to fully recovered patients may decrease upper airway muscle activity and tidal volume.64

4. Reversal Considerations in Clinical Practice * No neuromuscular monitor or peripheral nerve stimulator used.

I. Clinical tests of adequacy of reversal are unreliable—pharmacologic reversal should be administered routinely and only when spontaneous muscle activity is present.

* Peripheral nerve stimulator—subjective (visual, tactile) assessment

I. TOF count 1 or no TOF response—delay reversal.

II. TOF count 2 or 3—administer pharmacologic reversal.

III. TOF with fade (TOF <0.40)—administer pharmacologic reversal.

IV. TOF with no perceived fade (TOF ≥0.40)—administer

pharmacologic reversal, consider low dose (20 μg/kg) of neostigmine.91

* Quantitative evoked response monitor (e.g., AMG, KMG, and EMG)

I. No TOF response or TOF count of 1—delay reversal.

II. TOF count 2 or 3—administer pharmacologic reversal.

III. TOF <0.40—administer pharmacologic reversal.

IV. TOF = 0.40 to 0.90—administer pharmacologic reversal, consider low

dose (20 μg/kg) of neostigmine.

V. TOF >0.90—no reversal recommended

References

• S.J. Brul, S. Murphy Residual neuromuscular block: lessons unlearned. Part II:

methods to reduce the risk of residual weakness Anesth Analg 2010 Jul;

111(1):129-40

• Basics of anesthesia, sixth edition, Miller R.D., Pardo M.C.

Basishandboek voor het studeren!

• Clinical anesthesia, sixth edition, Barash P.G.,Cullen B.F., Stoelting R.K.

Cahalan M., Stock M.C.