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Update on Neuromuscular Relaxants

Update on Neuromuscular Relaxants. Objectives. Mechanism of action Monitoring Pharmacology non-depolarizers depolarizers Reversal. Historical. 1942: dTC, long-acting, histamine 1952: sux 1954: 6 fold  in mortality with dTC 1967: panc, long acting, CV stimulation

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Update on Neuromuscular Relaxants

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  1. Update on Neuromuscular Relaxants

  2. Objectives • Mechanism of action • Monitoring • Pharmacology • 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Hoffman elimination, histamine • 1990 to present: newer agents to fill specific niche • roc, cis, miv, pip, dox; rap: withdrawn from market

  4. 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

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

  6. Standaert FG: 1984

  7. Margin of Safety • Wide margin of safety of neuromuscular transmission • 70% receptor occupancy before twitch depression • Receptor alterations • burns, MG, quadra- +hemiplegia

  8. 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

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

  10. 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

  11. 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

  12. DRC- show differences in potency, slope, efficacy + individual responses. Stoelting + Miller, 2000

  13. 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: • pharyngeal muscles, upper airway • muscles of the thumb Donati F: Semin Anesth 2002;21:120; Donati F: Anesthesiology 1986;65:1

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

  15. 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

  16. Two Compartment Model Stanski 1982. Drug Disposition in Anesthesia

  17. Stanski, 1982. Drug Disposition in Anesthesia

  18. Volume of Distribution • 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

  19. Altered Vd •  Vd:  [conc] for any given dose • neonates • burns • hepatic failure • cardiopulmonary bypass •  Vd:  [conc] for any given dose • elderly • shock • CHF

  20. 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

  21. Concerning rocuronium, which are true? • Onset delayed compared with vec (equipotent doses) • Onset faster at the diaphragm compared with muscles of the thumb • Duration is longer than that of equipotent doses of vecuronium • Duration is shorter in elderly patients compared with young adults

  22. 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

  23. 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

  24. 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 •  dose requirement for non-depolarizers after sux

  25. Concerning sux, which are true? • Bradycardia + nodal rhythms unlikely after “2nd dose” sux • Hyperkalemia + cardiac arrest unlikely 1 week after major burns, or in children with Duchenne’s muscular dystrophy • Contraindicated in patients with head injury • May cause malignant hyperthermia or masseter spasm • Duration unaffected by prior administration of neostigmine

  26. Succinylcholine + Arrhythmias • Bradycardia, nodal rhythms, asystole • Especially after 2nd dose: give atropine, 0.6 mg, IV prior Stoelting R, Miller RD: 2000

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

  28. Succinylcholine Adverse Effects • 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

  29. 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

  30. 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

  31. Elimination Half-Life, t 1/2  Time for conc to decrease by 1/2

  32. 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

  33. 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!

  34. 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

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

  36. Adductor pollicis acceleromyography- TOF watch

  37. How Much Relaxation? • 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

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