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Neuromuscular Relaxants + Reversal Agents

Neuromuscular Relaxants + Reversal Agents. 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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Neuromuscular Relaxants + Reversal Agents

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  1. Neuromuscular Relaxants + Reversal Agents

  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Hoffman elimination, histamine • 1990 to present: newer agents to fill specific niche • roc, cis, miv, pip, dox; rap: withdrawn from market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: • 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

  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

  8. 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

  9. 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

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

  11. 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

  12. 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

  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: • muscles that maintain patency of 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 effects of non-depolarizers v. thumb Meistelman: CJA 1992;39:665-9

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

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

  21. 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

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

  23. 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

  24. 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

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

  26. 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

  27. 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

  28. 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

  29. 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!

  30. Suggamadex (Org 25969): Safer way to reverse NMB • Gijsenbergh et al, Anesthesiology 2005;103;695-703. Belgium. Phase 1 study • Modified cyclodextrin • Encapsulates roc • Promotes dissociation of roc from AchR • No recurarization

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

  32. Adductor pollicis acceleromyography- TOF watch

  33. 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

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