Neostigmine for Neuromuscular Reversal

Neostigmine is a quaternary ammonium cholinesterase inhibitor used to reverse non-depolarising neuromuscular block at the end of surgery. It raises acetylcholine at the nicotinic and muscarinic receptors, so it is always combined with an antimuscarinic drug to prevent bradycardia and secretions. It has a ceiling effect, works only once some spontaneous recovery has occurred, and is ineffective in deep block.

Class. Reversible cholinesterase inhibitor.

Mechanism. Inhibits acetylcholinesterase, increasing acetylcholine at the neuromuscular junction so that it outcompetes the residual non-depolarising drug. It also stimulates muscarinic receptors, causing bradycardia, bronchoconstriction, salivation and gut motility.

Pharmacokinetics. Intravenous onset 1 to 3 minutes, peak effect 7 to 10 minutes, duration 40 to 60 minutes. Elimination half-life about 80 minutes. About 50% is eliminated unchanged by the kidney, with the remainder hydrolysed by plasma esterases and the liver. Clearance is reduced in kidney failure and in older adults. Does not cross the blood-brain barrier.

Indications in this setting are reversal of non-depolarising neuromuscular block when the train-of-four count is at least 2 (ideally 4 with fade) or when return of spontaneous activity is established. It is not effective for deep block and is not used to reverse suxamethonium.

Adults

• 50 micrograms/kg intravenously over about 1 minute (maximum 5 mg; usual dose 2.5 mg), with glycopyrronium 10 micrograms/kg (maximum 1 mg) or atropine 20 micrograms/kg (maximum 1.2 mg) in the same syringe.
• Further dosing above 70 micrograms/kg gives no extra benefit (ceiling effect).
• Timing: give at least 5 to 10 minutes before the planned extubation, and wait for the train-of-four ratio to reach 0.9.
• Older adults and kidney impairment: use the lower end of the dose range and allow more time.
• Obesity: dose by ideal body weight, with the maximum of 5 mg.

Children

• 50 micrograms/kg intravenously (maximum 2.5 mg), with glycopyrronium 10 micrograms/kg or atropine 20 micrograms/kg.
• Neonates and infants: 50 micrograms/kg with the antimuscarinic drug, and monitor the heart rate.

Contraindications. Mechanical obstruction of the gut or urinary tract; peritonitis; hypersensitivity; use when the train-of-four count is under 2 (ineffective and may worsen block); reversal of suxamethonium (it prolongs phase I block); untreated bradycardia or heart block (relative); active asthma (relative).

Boxed-warning-level risks. Bradycardia or asystole if given without an antimuscarinic drug; cholinergic crisis with overdose (muscle weakness, bronchospasm, secretions); residual paralysis if given too early.

Adverse effects. Common: bradycardia, salivation, nausea and vomiting, abdominal cramps, miosis. Serious: asystole, bronchospasm, bronchial secretions, cholinergic crisis, aspiration, postoperative ileus, paradoxical weakness with a high dose given after full recovery.

Interactions. Beta blockers, digoxin and calcium channel blockers add bradycardia. Aminoglycosides, magnesium, lithium, clindamycin and volatile agents oppose reversal. It prolongs suxamethonium and ester local anaesthetics.

Common prescribing errors. Giving without glycopyrronium or atropine; giving at a deep block (train-of-four count under 2); doses over 5 mg; repeated doses after the ceiling is reached; using it for suxamethonium; extubating without confirming a train-of-four ratio of 0.9.

Special groups

• Pregnancy: crosses the placenta to a small extent; use glycopyrronium rather than atropine because it does not cross the placenta and avoids foetal tachycardia.
• Breastfeeding: compatible after a single dose.
• Older adults: slower onset and longer duration; allow more time.
• Kidney impairment: prolonged half-life; use the usual maximum of 5 mg and do not repeat.
• Liver impairment: usual doses.
• Regional: where sugammadex is not available, neostigmine with glycopyrronium remains the main reversal drug; if train-of-four monitoring is not available, delay reversal until clinical recovery (sustained head lift for 5 seconds, reliable tidal volume) and keep ventilating until adequate.

Formulations. Injection 2.5 mg/mL (2.5 mg in 1 mL and 5 mg in 2 mL ampoules); combined neostigmine and glycopyrronium (2.5 mg and 0.5 mg in 1 mL) in some markets.

Administration. Give slowly intravenously over about 1 minute with the antimuscarinic drug in the same syringe. Give after confirming the train-of-four count of at least 2.

Baseline. Time and dose of the muscle relaxant, train-of-four count, heart rate, history of asthma or heart block, kidney function.

Monitoring. Continuous electrocardiogram and heart rate, oxygen saturation and capnography. Train-of-four ratio until at least 0.9; observe for recurrence of block for at least 30 minutes.

Therapeutic drug monitoring. Not used.

Dose reduction and stopping thresholds. Do not exceed 5 mg or 70 micrograms/kg. Stop and treat for heart rate under 50 beats/minute, bronchospasm or severe salivation.

Referral and escalation. Bradycardia needs atropine 0.5 to 1 mg intravenously (10 to 20 micrograms/kg in children). Bronchospasm and cholinergic crisis need atropine, oxygen, airway support and, if needed, ventilation. Persistent block needs ventilation, sedation, and sugammadex if the relaxant was rocuronium or vecuronium.