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

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Hoffman elimination, histamine 1990 to present: newer agents to fill specific niche roc, cis, miv, pip, dox; rap: withdrawn from market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

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

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

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

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

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

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

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

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

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

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

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

Succinylcholine Maintenance dose: no longer used 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

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

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

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

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

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

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

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

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

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

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

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!

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

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

Adductor pollicis acceleromyography- TOF watch

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