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Update on Neuromuscular Relaxants
Objectives
• Mechanism of action
• Monitoring
• Pharmacology
– non-depolarizers
– depolarizers
• Reversal
Historical
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1942: dTC, long-acting, histamine
1952: sux
1954: 6 fold  in mortality with dTC
1967: panc, long acting, CV stimulation
1986: interm acting relaxants:
– vec: no CV effects
– atrac: Hoffman elimination, histamine
• 1990 to present: newer agents to fill specific niche
– roc, cis, miv, pip, dox; rap: withdrawn from market
Classical Mechanism of Action
• Non-depolarizers:
– competitive block
– prevent binding of Ach
to receptor
• Depolarizers– mimic action of Ach
– excitation followed by
block
Drachman, NEJM
Postjunctional Nicotinic AchR
Taylor: Anesthesiology 1985;63:1-3
Standaert FG: 1984
Margin of Safety
• Wide margin of safety
of neuromuscular
transmission
– 70% receptor
occupancy before
twitch depression
• Receptor alterations
– burns, MG, quadra+hemiplegia
TOF Monitoring
• TOF:
– 4 supramaximal stimuli at 2
Hz, every 0.5 sec
– observe ratio of 4rth twitch
to first
• Loss of all 4 twitches:
– profound block
• Return of 1-2 twitches:
– sufficient for most surgeries
• Return of all 4 twitches:
– easily “reversible”
Viby-Mogensen, 1984
Onset + Recovery of NM Block
A-Nondepolarizing. B- Sux. Viby-Mogensen: BJA 1982;54:209
Terminology
• Efficacy: ability of drug to produce a desired
effect
• Potency: quantity of drug to produce
maximum effect
• Biologic variability: individual variation in
response to identical dose of drug
• DRC:
– measure efficacy and potency
– compare drugs, disease states
Concept of “Effective Dose”
• ED90: dose that produces 90% block (+ SD) in
average patient at standard muscle group
• Usually adductor pollicis- ulnar nerve
• Derived from dose-response studies
• Intubating dose: 2- 3 x ED90
• Repeat doses: < ED90
DRC- show differences in potency, slope, efficacy + individual responses. Stoelting + Miller, 2000
Altered Dose-Response
• Some muscle groups more resistantDRC shifted to right:
– diaphragm, larynx, eye, abdominal
• Some muscle groups more sensitiveDRC shifted to left:
– pharyngeal muscles, upper airway
– muscles of the thumb
Donati F: Semin Anesth 2002;21:120; Donati F: Anesthesiology 1986;65:1
Rocuronium: Larynx v. Thumb
Muscles of the larynx, diaph, + eye are more resistant to nondepolarizers v. thumb
Meistelman: CJA 1992;39:665-9
Elimination
• Most NMBA: 2 compartment models:
redistribution, then elimination
– a) NM junction  non-effector site tissue
– b) elimination from plasma
• Exceptions: sux, miv, atrac, cistrac
Two Compartment Model
Stanski 1982. Drug Disposition in Anesthesia
Stanski, 1982. Drug Disposition in Anesthesia
Volume of Distribution
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Calculated number, [conc] = dose / Vd
Inject known amount of drug
Measure plasma concentration
Does not refer to anatomic volumes
– reflects volume of compartments that drug is
distributed in
– influenced by: protein binding, degree of
ionization + water solubility
Altered Vd
•  Vd:  [conc] for any given dose
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neonates
burns
hepatic failure
cardiopulmonary bypass
•  Vd:  [conc] for any given dose
– elderly
– shock
– CHF
Vecuronium
• ED90: 0.04 mg/kg
– intubating dose: 0.1-0.2 mg/kg
– onset: 2-4 min, clinical duration: 30-60 min
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Maintenance dose: 0.01-0.02 mg/kg, duration: 15-30 min
Metabolized by liver, 75-80%
Excreted by kidney, 20-25%
½ life : 60 minutes
Prolonged duration in elderly + liver disease
No CV effects, no histamine release, no vagolysis
May precipitate after thiopental
Concerning rocuronium, which are true?
1. Onset delayed compared with vec
(equipotent doses)
2. Onset faster at the diaphragm compared
with muscles of the thumb
3. Duration is longer than that of equipotent
doses of vecuronium
4. Duration is shorter in elderly patients
compared with young adults
Rocuronium
• ED90: 0.3 mg/kg
– intubating dose: 0.6-1.0 mg/kg
– onset: 1-1.5 minutes, clinical duration: 30-60 min
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Maintenance dose: 0.1-0.15 mg/kg, duration: 15-30 min
Metabolized by liver, 75-80%
Excreted by kidney, 20-25%
½ life : ~ 60 minutes
Mild CV effects- vagolysis, no histamine release,
Prolonged duration in elderly + liver disease
Only non-depolarizer approved for RSI
Cisatracurium
• ED90: 0.05 mg/kg
– intubating dose: 0.2 mg/kg
– onset: 2-4 minutes, clinical duration: 60 min
• Hofmann elimination: not dependent on liver or kidney for
elimination
• Predictable spontaneous recovery regardless of dose
• ½ life : ~ 60 minutes
• No histamine release
• CV stability
• Agent of choice for infusion in ICU
Prielipp et al: Anesth Analg 1995;81:3-12
Succinylcholine
• ED90: 0.3 mg/kg
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intubating dose: 1.0-1.5 mg/kg
onset: 30-45 sec, clinical duration: 5-10 min
can be given IM or sublingual
dose to relieve laryngospasm: 0.3 mg/kg
• Maintenance dose: no longer used
• Metabolized by pseudocholinesterase
– prolonged duration if abnormal pc (dibucaine # 20)
• Prolonged effect if given after neostigmine
•  dose requirement for non-depolarizers after sux
Concerning sux, which are true?
1. Bradycardia + nodal rhythms unlikely after “2nd
dose” sux
2. Hyperkalemia + cardiac arrest unlikely 1 week
after major burns, or in children with Duchenne’s
muscular dystrophy
3. Contraindicated in patients with head injury
4. May cause malignant hyperthermia or masseter
spasm
5. Duration unaffected by prior administration of
neostigmine
Succinylcholine + Arrhythmias
• Bradycardia, nodal rhythms, asystole
• Especially after 2nd dose: give atropine, 0.6 mg, IV prior
Stoelting R, Miller RD: 2000
Head Injury + Sux
Kovarik, Mayberg, Lam: Anesth Analg 1994;78:469-73
Succinylcholine Adverse Effects
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Malignant hyperthermia, masseter spasm
 IOP, myalgias,  intragastric pressure
 ICP: doubtful significance
Hyperkalemia + cardiac arrest in “at risk patients”
– Receptor alterations: denervation, burns
– Myopathy rhabdomyoslysis
Bevan DR: Semin Anesth 1995;14:63-70
Sux + Hyperkalemia
• Burns, Hemiplegia, Paraplegia, Quadraplegia:
–  extrajunctional receptors after burn or
denervation
– Danger of hyperkalemia with sux: 48 hrs post
injury until …?
• Muscular Dystrophies:
• Others:
– severe infections, closed head injury, crush,
rhabdo, wound botulism, necrotizing pancreatitis
• Tx of Hyperkalemia:
Bevan DR, Bevan JC, Donati F: 1988
Residual NM Block
• 1979: 42% incidence with long acting drugs [Viby-Mogensen]
• 1988:  incidence with vec + atrac [Bevan, Smith, Donati- Mtl]
• 1992:  ventilatory response to hypoxia, TOF 0.6-0.7
• 1997:  pharyngeal muscle coordination with TOF 0.6-0.8
• 1997: panc is risk factor for postop pulmonary
complications [v. vec + atrac; RCT n= 693 patients]
• 2003: 45% incidence with interm acting drugs w/o
reversal, TOF 0.9 [Debaene, Plaud, Donati- France]
Berg: Acta Anaesthesiol Scand 1997;41:1096. Eriksson: Anesthesiology 1993+1997
Elimination Half-Life, t 1/2 
# of half-lives
% remaining
% eliminated
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100
0
1
50
50
2
25
75
3
12.5
87.5
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6.25
93.75
Time for conc to decrease by 1/2
Double Burst
• TOF fade: difficult to
detect clinically until <
0.2
• Use double burst:
– 2 short bursts of
tetanic stimulation
separated by 750 ms
– Easier to detect fade +
residual block, 0.2-0.7
Viby-Mogensen, 2000
Reversal of NM Block
• Clinical practice:
– if no evidence block + 4 half-lives: omit reversal
– if still evidence block: give reversal
– if unsure: give reversal
• Rule of thumb:
– if 2 twitches of TOF visible, block is usually reversible
– if no twitches visible, best to wait (check battery)
• Neostigmine 2.5 mg/Glycopyrolate 0.5 mg
– do not omit anti-cholinergic!
Org 25969: A safer way to reverse NMB?
• Gijsenbergh et al, Anesthesiology
2005;103;695-703. Belgium
• Modified cyclodextrin
• Encapsulates roc
• Promotes dissociation of roc from AchR
• Phase 1 study, n=29
• No recurarization
+
Roc
Org 25969
=
Gijsenbergh et al. Anesthesiology 2005;103:695
Adductor pollicis acceleromyography- TOF watch
How Much Relaxation?
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Muscle relaxants do not make the hole bigger.
They do not relax bone
They do not decompress bowel
They do not give a surgeon judgement
They do not relax fat
Bevan DR: Can J Anaesth 1995;42:93. Quote from the internet 10/94