1. Neuromuscular Relaxants + Reversal Agents*
Neuromuscular Relaxants + Reversal Agents
Thank you *

2. Objectives Mechanism of action Monitoring Pharmacology Reversal
non-depolarizers
depolarizers
Reversal

3. 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roc, cis, miv, pip, dox; rap: withdrawn from market

5. 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

7. Postjunctional Nicotinic AchR
Taylor: Anesthesiology 1985;63:1-3

8. Standaert FG: 1984

9. Margin of Safety Wide margin of safety of neuromuscular transmission
70% receptor occupancy before twitch depression

10. Smith CE, Peerless JR: ITACCS Monograph 1996
Clinical Use
Anesthesia:
facilitate tracheal intubation
paralysis for surgery + mechanical ventilation
ICU:
 VO2
tetanus
status epilepticus
 ICP
 shivering
Smith CE, Peerless JR: ITACCS Monograph 1996

11. TOF Monitoring TOF: Loss of all 4 twitches: Return of 1-2 twitches:
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

12. Onset + Recovery of NM Block
A-Nondepolarizing. B- Sux. Viby-Mogensen: BJA 1982;54:209

13. 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

14. 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 mg/kg
ED 90 vec mg/kg

15. 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
Donati F: Semin Anesth 2002;21:120; Donati F: Anesthesiology 1986;65:1

16. Rocuronium: Larynx v. Thumb
Muscles of the larynx, diaph, + eye are more resistant to effects of non-depolarizers v. thumb
Meistelman: CJA 1992;39:665-9

17. Vecuronium
ED90: 0.04 mg/kg
intubating dose: mg/kg
onset: 2-4 min, clinical duration: min
Maintenance dose: mg/kg, duration: 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

18. Rocuronium
ED90: 0.3 mg/kg
intubating dose: mg/kg
onset: minutes, clinical duration: min
Maintenance dose: mg/kg, duration: 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

19. Prielipp et al: Anesth Analg 1995;81:3-12
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

20. Succinylcholine Maintenance dose: no longer used
ED90: 0.3 mg/kg
intubating dose: mg/kg
onset: 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

21. 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 Duchenne’s muscular dystrophy
Not contraindicated in patients with head injury
May cause malignant hyperthermia or masseter spasm
Duration increased by prior administration of neostigmine

22. Succinylcholine Adverse Effects
Bradycardia, nodal rhythms, asystole
Especially after 2nd dose: give atropine, 0.6 mg, IV prior
Stoelting R, Miller RD: 2000

23. 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
Bevan DR: Semin Anesth 1995;14:63-70

24. Kovarik, Mayberg, Lam: Anesth Analg 1994;78:469-73
Head Injury + Sux
Kovarik, Mayberg, Lam: Anesth Analg 1994;78:469-73

25. Bevan DR, Bevan JC, Donati F: 1988
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
Bevan DR, Bevan JC, Donati F: 1988

27. 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
1997:  pharyngeal muscle coordination with TOF
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: Eriksson: Anesthesiology

28. Cholinesterase Inhibitors
↑ Ach at nicotinic + muscarinic receptors to antagonize NMB
Full reversal depends on diffusion, redistribution, metabolism + excretion

29. 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

31. 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,
Viby-Mogensen, 2000

32. Savarese JJ, Caldwell JE, Lien CA, Miller RD: 2000
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
Savarese JJ, Caldwell JE, Lien CA, Miller RD: 2000

33. Reversal of NM Block Clinical practice: Rule of thumb:
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!

34. Suggamadex (Org 25969): Safer way to reverse NMB
Gijsenbergh et al, Anesthesiology 2005;103; Belgium. Phase 1 study
Modified cyclodextrin
Encapsulates roc
Promotes dissociation of roc from AchR
No recurarization

35. Gijsenbergh et al. Anesthesiology 2005;103:695+
Roc
Org 25969 =
Gijsenbergh et al. Anesthesiology 2005;103:695

36. Adductor pollicis acceleromyography- TOF watch

37. 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