Neuromuscular Relaxants Reversal Agents

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Neuromuscular Relaxants Reversal Agents

• Charles E. Smith, MD
• Professor, Case Western Reserve University
• Director, Cardiothoracic Anesthesia
• MetroHealth Medical Center
• Cleveland, Ohio

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Objectives

• Mechanism of action
• Monitoring
• Pharmacology
• non-depolarizers
• depolarizers
• Reversal

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Historical

• 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• roc, cis, miv, pip, dox rap withdrawn from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

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Classical Mechanism of Action

• Non-depolarizers
• bind to AchR, post junctional nicotinic receptor
• competitively prevent binding of Ach to receptor
• ion channel closed, no current can flow
• Depolarizers- succinylcholine
• mimic action of Ach
• excitation of muscle contraction followed by
  blockade of neuromuscular transmission

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Postjunctional Nicotinic AchR
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Margin of Safety

• Wide margin of safety of neuromuscular
  transmission
• 70 receptor occupancy before twitch depression

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Clinical Use

• Anesthesia
• facilitate tracheal intubation
• paralysis for surgery mechanical ventilation
• ICU
• ? VO2
• tetanus
• status epilepticus
• ? ICP
• ? shivering

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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

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Onset Recovery of NM Block
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Concept of Effective Dose

• ED90 dose that produces 90 block ( SD) in
  average patient, derived from dose-response
  studies
• Clinical practice
• 3 x ED90 at start of case
• smaller repeat doses during case
• lighten up NM block at end of case
• titrate opioids to respiratory rate
• reverse after dressing applied

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Effective Dose

• Method to describe potency of NMBA
• Derived from DRC in many patients
• ED 90- dose that produces 90 block
• ED 90 suc- 0.3 mg/kg
• ED 90 roc- 0.3 mg/kg
• ED 90 vec- 0.04 mg/kg

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Altered Dose-Response

• Some muscle groups more resistant- DRC
  shifted to right
• diaphragm, larynx, eye, abdominal
• Some muscle groups more sensitive- DRC
  shifted to left
• muscles that maintain patency of upper airway
• muscles of the thumb

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Rocuronium Larynx v. Thumb

• Muscles of the larynx, diaph, eye are more
  resistant to effects of non-depolarizers v. thumb

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Vecuronium

• ED90 0.04 mg/kg
• intubating dose 0.1-0.2 mg/kg
• onset 2-4 min, clinical duration 30-60 min
• 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

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Rocuronium

• ED90 0.3 mg/kg
• intubating dose 0.6-1.0 mg/kg
• onset 1-1.5 minutes, clinical duration 30-60
  min
• 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

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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

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Succinylcholine

• ED90 0.3 mg/kg
• 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

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Succinylcholine Key Concepts

• Bradycardia nodal rhythms after 2nd dose in
  adults after initial dose in children
• Hyperkalemia cardiac arrest likely 1 week after
  major burns, or in children with Duchennes
  muscular dystrophy
• Not contraindicated in patients with head injury
• May cause malignant hyperthermia or masseter
  spasm
• Duration increased by prior administration of
  neostigmine

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Succinylcholine Adverse Effects

• Bradycardia, nodal rhythms, asystole
• Especially after 2nd dose give atropine, 0.6 mg,
  IV prior

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Succinylcholine Adverse Effects

• Hyperkalemia cardiac arrest in at risk
  patients
• denervation, burns, myopathy
• Malignant hyperthermia, masseter spasm
• ? IOP- blood flow mechanism
• Myalgias, ? intragastric pressure
• ? dose requirement for non-depolarizers after sux
• ? ICP- blood flow mechanism clinically irrelevant

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Head Injury Sux
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Sux Hyperkalemia

• Burns, Hemiplegia, Paraplegia, Quadraplegia
• ? extrajunctional receptors after burn or
  denervation
• Danger of hyperkalemia with sux 48 hrs post
  injury until ?
• Muscular Dystrophy
• Miscellaneous
• severe infections, closed head injury, crush,
  rhabdo, wound botulism, necrotizing pancreatitis
• Renal failure pre-existing hyperkalemia
• Acidosis ? extracellular K

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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

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Cholinesterase Inhibitors

• ? Ach at nicotinic muscarinic receptors to
  antagonize NMB
• Full reversal depends on diffusion,
  redistribution, metabolism excretion

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Key Concepts of NMBA Reversal

• Cholinesterase inhibitors indirectly reverse NMB
• Head lift x 5 sec- reliable sign of reversal
• Teeth clenching x 5 sec- reliable sign of
  reversal
• Usually not difficult to reverse block if 2
  twitches are visible in response to TOF
• Neostigmine is a minor risk factor for PONV
• Anticholinergic agents should never be omitted
  with reversal

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Double Burst

• TOF fade difficult to detect clinically until lt
  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

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Clinical Evaluation

• Reliable signs of adequate NM transmission
• Head lift x 5 s
• Leg lift x 5 s
• Hand grip as strong as preop x 5 s
• Sustained bite
• Helpful, but unreliable
• Normal Vt , Vc, cough

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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!

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Suggamadex (Org 25969) Safer way to reverse NMB

• Gijsenbergh et al, Anesthesiology
  2005103695-703. Belgium. Phase 1 study
• Modified cyclodextrin
• Encapsulates roc
• Promotes dissociation of roc from AchR
• No recurarization

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Roc
Org 25969

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Summary

• Indications tracheal intubation, surgery, mech
  ventilation
• Choice of drug pharmacology other factors
  (histamine)
• Onset of action
• sux is fastest
• roc is suitable alternative
• Duration
• non-depolarizing block easily reversible if 2
  twitches
• residual block ? incidence with intermediate rx
• Monitoring Reversal TOF, double burst,
  clinical signs
• Suggmadex will likely replace neostigmine for
  reversal