2019A Question 12
Outline the factors that determine the rate of recovery from non-depolarising neuromuscular block.
Examiner Report
42% of candidates achieved a pass in this question.
Candidates who were able to grasp the significance of the factors that change the offset duration and explain why this occurred typically scored very well in this question. Broadly the topics for which marks were allocated were: Drug dosing; type of agent; metabolism; effect of acetylcholine receptor changes; effect of altered physiological states; significant drug-drug interactions and reversal agents.
Many candidates demonstrated an excellent understanding of one or two areas but were let down by omitting from their discussion other areas altogether (typically metabolism and reversal agents).
Model Answer
Structure:
- Introduction
- Initial drug concentration
- Biophasics
Rate of transfer from effect site to central compartment. - Kinetics
Rate of ↓ [drug]. - Dynamics
[Drug] for offset (could technically write about ↑ sensitivity and ↓ sensitivity).
Introduction
| Property | Detail |
|---|---|
| Determinants of Time to Recovery | - Final effect site concentration after bolus or at end of infusion - Rate of removal from effect site - Rate of elimination from the plasma - Effect site concentration required for recovery of neuromuscular function |
| Compartment Model |  |
| Standard | - Train-of-four ratio 0.9 (or return to 25% baseline twitch height?) |
| Usual Duration | - 30-45 mins for 2x ED95 - 45-60 mins for 4x ED95 |
Initial Drug Concentration
| Factor | Mechanism to ↑ Ce |
|---|---|
| Administration | - ↑ Bolus size (e.g. 4x ED95 rocuronium cf. 2x ED95) - ↑ Infusion rate - ↑ Infusion duration |
| Drug | ↓ Elimination rate (see below) |
| Patient | ↓ Volume of distribution (see below) |
Drug Removal from Effect Site
| Factor | Detail |
|---|---|
| Fick’s Law | |
| Chelation Reversal | - γ-cyclodextrin chelates rocuronium > vecuronium >> pancuronium - Interaction occurs in plasma, not receptor site - ↓ C2 → ↑ Concentration gradient → ↑ Rate of removal - i.e. Kinetic not dynamic interference - Dosing - 16mg.kg-1 immediately after intubating dose - 4mg.kg-1 moderate blockade - 2mg.kg-1 minimal residual blockade |
Elimination from V1
| Factor | Mechanism to ↓ Rate of Removal |
|---|---|
| Short infusion | Offset during distribution phase - ↓ Cardiac output (e.g. Shock) - ↓ Volume of distribution - ↓ Muscle mass (e.g. Elderly, cachectic) - ↑ Water mass (e.g. Hypovolaemia) |
| Long Infusion | Offset during terminal elimination phase - ↑ Cardiac output (e.g. Pregnant, neonate) - ↑ Volume of distribution - ↑ Muscle mass (e.g. Athletic) - ↑ Water mass (e.g. Heart failure, renal failure, liver failure) - ↓ Metabolism - ↓ Phase 1,2 reactions (e.g. Liver failure) → ↑ Duration aminosteroids - ↓ Hoffman degradation (↓ temp, ↓ pH) → ↑ Duration benzylisoquinoliniums - ↓ Ester hydrolysis (↓ temp, ↑ pH) → ↑ Duration benzylisoquinoliniums - ↓ Excretion of drug or active metabolite - ↓ Renal excretion (renal failure → Accumulate pancuronium, gallamine) - ↓ Biliary excretion (liver failure → Accumulate vecuronium, rocuronium) |
Effect Site Concentration Required for Drug Offset
| Factor | Mechanism to ↓ Required Ce |
|---|---|
| Muscle group | - Laryngeal adductors recover before adductor pollicis due to - ↑ Blood flow - ↑ ACh vesicles released - ↑ Number of receptors |
| Physiological Factors | ↓ ACh release → ↑ Drug:ACh ratio - Neonate: Immature NMJ - Elderly: ↓ ACh spare receptors - ↑ Mg2+: Antagonize Ca2+ at pre-synaptic L-Ca2+ channel - ↓ K+: Hyperpolarization - Hypothermia - Respiratory acidosis |
| Pathological Factors | - Myasthaenia gravis (↓↓ spare receptors) - Lambert-Eaton syndrome (antibody against VDCC, ↓ ACh released) (note: Denervation → Upregulation of extra-junctional receptors → ↑ Ce for offset) |
| Pre-synaptic Drugs | - ↓ α-motor neuron activity: Volatile anaesthetic - ↓ Axonal action potential: Peripheral nerve local anaesthetic (↓ Na+ flux) - ↓ Choline uptake: Hemicholinium - ↓ ACh transport into vesicles: Vesamicol - ↓ AMP/ATP synthesis (frusemide) - Block pre-synaptic nAChR (volatiles) - Block L-Ca2+ (CCB, Mg2+, aminoglycosides, volatiles) |
| Post-synaptic Drugs | - Block post-synaptic nAChR: Other non-depolarisers, volatiles, aminoglycoside, quinidine - Desensitisation blockade (volatiles, barbiturates) - Inhibit peri-junctional action potential: Local anaesthetic ↓ Na+ flux |
| Post-junctional Drugs | - Dantrolene: Inhibit skeletal muscle ryanodine receptor |
| Toxins | - Botox: Cleave SNARE protein, ↓ ACh release - Tetrodotoxin: VDNaC inhibition |
Factors Affecting Offset
| Factor | Ce offset ↑ with: |
|---|---|
| Physiology | - ↑ K+: Membrane potential less negative → ↑ ACh release → ↓ Drug:ACh ratio |
| Pathology | - Critical illness myopathy, burns → Proliferation of extrajunctional receptors → ↓ Drug:ACh ratio - Malignant hyperthermia→ Post-junctional activation |
| Competitive reversal | - Acetylcholinesterase inhibitor (e.g. Neostigmine → ↑ ACh:Drug ratio → Displacement - Obtain train-of-four ratio of >0.9 earlier - Should not be given until three TOF twitches |
| Toxins | - Tetanus toxin: ↓ Inhibition of a-motor neurons → ↑ NMJ activity → ↓ Drug:ACh ratio |