Update on Neuromuscular Relaxants Charles E. Smith, MD Professor of Anesthesia Case Western Reserve University Director, Cardiothoracic Anesthesia MetroHealth Medical Center Cleveland, Ohio

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Hoffman elimination, histamine 1990 to present: newer agents to fill specific niche –roc, cis, miv, pip, dox; rap: withdrawn from market

Drachman, NEJM Classical Mechanism of Action Non-depolarizers: –competitive block –prevent binding of Ach to receptor Depolarizers- –mimic action of Ach –excitation followed by block

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

Standaert FG: 1984

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

Viby-Mogensen, 1984 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”

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

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

Concept of “Effective Dose” ED 90 : 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 ED 90 Repeat doses: < ED 90

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

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

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

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

Stanski Drug Disposition in Anesthesia Two Compartment Model

Stanski, Drug Disposition in Anesthesia

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

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

Vecuronium ED 90 : 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

Concerning rocuronium, which are true? 1.Onset delayed compared with vec (equipotent doses) 2.Onset faster at the diaphragm compared with muscles of the thumb 3.Duration is longer than that of equipotent doses of vecuronium 4.Duration is shorter in elderly patients compared with young adults

Rocuronium ED 90 : 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

Prielipp et al: Anesth Analg 1995;81:3-12 Cisatracurium ED 90 : 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

Succinylcholine ED 90 : 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  dose requirement for non-depolarizers after sux

Concerning sux, which are true? 1.Bradycardia + nodal rhythms unlikely after “2nd dose” sux 2.Hyperkalemia + cardiac arrest unlikely 1 week after major burns, or in children with Duchenne’s muscular dystrophy 3.Contraindicated in patients with head injury 4.May cause malignant hyperthermia or masseter spasm 5.Duration unaffected by prior administration of neostigmine

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

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

Bevan DR: Semin Anesth 1995;14:63-70 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, 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 Dystrophies: Others: –severe infections, closed head injury, crush, rhabdo, wound botulism, necrotizing pancreatitis Tx of Hyperkalemia:

Berg: Acta Anaesthesiol Scand 1997;41:1096. Eriksson: Anesthesiology 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 :  pharyngeal muscle coordination with TOF : 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]

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

Viby-Mogensen, 2000 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,

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!

Org 25969: A safer way to reverse NMB? Gijsenbergh et al, Anesthesiology 2005;103; Belgium Modified cyclodextrin Encapsulates roc Promotes dissociation of roc from AchR Phase 1 study, n=29 No recurarization

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

Adductor pollicis acceleromyography- TOF watch

Bevan DR: Can J Anaesth 1995;42:93. Quote from the internet 10/94 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