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

• 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– roc, cis, miv, pip, dox; rap: withdrawn from market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

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

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

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

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

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: – muscles that maintain patency of 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 effects of non-depolarizers v. thumb

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

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

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

Stoelting R, Miller RD: 2000

Succinylcholine Adverse Effects

• Bradycardia, nodal rhythms, asystole

• Especially after 2nd dose: give atropine, 0.6 mg, IV prior

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

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

Kovarik, Mayberg, Lam: Anesth Analg 1994;78:469-73

Head Injury + Sux

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

Berg: Acta Anaesthesiol Scand 1997;41:1096. Eriksson: Anesthesiology 1993+1997

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]

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

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, 0.2-0.7

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

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!

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

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