update on neuromuscular relaxants. objectives mechanism of action monitoring pharmacology...

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

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– roc, cis, miv, pip, dox; rap: withdrawn from market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

• 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

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 1982. Drug Disposition in Anesthesia

Two Compartment Model

Stanski, 1982. 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

• 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

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

• 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 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 injury4. May cause malignant hyperthermia or masseter

spasm5. 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;78:469-73

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 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]

Time for conc to decrease by 1/2

Elimination Half-Life, t 1/2

# of half-lives % remaining % eliminated

0 100 0

1 50 50

2 25 75

3 12.5 87.5

4 6.25 93.75

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

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;695-703. 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