Neostigmine and Anticholinesterase Pharmacology

Quick Answer: Neostigmine is a quaternary ammonium anticholinesterase agent that reversibly inhibits acetylcholinesterase through carbamylation, increasing acetylcholine concentration at the neuromuscular junction to reverse non-depolarising neuromuscular blockade. Standard dose is 50-70 mcg/kg (maximum 5 mg) co-administered with glycopyrrolate (10 mcg/kg) or atropine (20 mcg/kg) to prevent muscarinic side effects. Onset occurs in 7-11 minutes with duration of 40-60 minutes. Must only be administered when TOF count is ≥2 (ideally ≥4) due to ceiling effect limiting maximum reversal capacity.

Learning Objectives

After studying this topic, candidates should be able to:

1. Describe the mechanism of action of anticholinesterase agents at the molecular level
2. Compare and contrast the pharmacology of neostigmine, edrophonium, pyridostigmine, and physostigmine
3. Explain the rationale for anticholinergic co-administration during NMBA reversal
4. Discuss the ceiling effect and its clinical implications for timing of reversal
5. Compare neostigmine-based reversal with sugammadex for aminosteroid NMBAs
6. Outline the pharmacokinetic parameters relevant to dose adjustment in special populations

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Pharmacology Overview

Drug Classification

Neostigmine belongs to the carbamate class of reversible acetylcholinesterase inhibitors. The anticholinesterases used in anaesthetic practice are classified by their mechanism and duration of action.

ANZCA Primary Focus: The distinction between quaternary (neostigmine, edrophonium, pyridostigmine) and tertiary (physostigmine) ammonium compounds is frequently examined. Quaternary compounds cannot cross the blood-brain barrier and lack CNS effects, while tertiary compounds have significant central activity.

Historical Context

Physostigmine was isolated from the Calabar bean (Physostigma venenosum) in 1864 by Jobst and Hesse. Neostigmine was synthesised in 1931 by Aeschlimann and Reinert as a synthetic alternative with improved safety profile for myasthenia gravis treatment [PMID: 16693897]. Its use for reversal of neuromuscular blockade was established in the 1950s following the introduction of d-tubocurarine into clinical practice [PMID: 13138532].

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Chemical Structure and Physicochemical Properties

Structural Features

Neostigmine (3-dimethylcarbamoyloxy-N,N,N-trimethylanilinium) is a synthetic quaternary ammonium compound with molecular weight of 223.3 Da (methylsulfate salt: 334.4 Da).

Key Structural Components:

Comparison of Anticholinesterase Structures

Clinical Pearl: Physostigmine is the only anticholinesterase that crosses the blood-brain barrier, making it useful for central anticholinergic syndrome but unsuitable for routine NMBA reversal due to CNS side effects including seizures [PMID: 6121881].

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Mechanism of Action

Acetylcholinesterase Enzyme Structure

Acetylcholinesterase (AChE) is a serine hydrolase located in the synaptic cleft at cholinergic synapses. The enzyme active site contains two subsites [PMID: 8290579]:

1. Anionic site: Binds the quaternary nitrogen of acetylcholine through electrostatic interaction
2. Esteratic site: Contains the catalytic triad (Ser200-His440-Glu327) that hydrolyses the ester bond

Normal Acetylcholine Hydrolysis

The catalytic cycle for acetylcholine hydrolysis occurs in approximately 150 microseconds:

1. ACh binds to anionic and esteratic sites
2. Serine hydroxyl attacks carbonyl carbon
3. Choline released; acetyl-enzyme intermediate formed
4. Water hydrolyses acetyl group
5. Acetic acid released; enzyme regenerated

Mechanism of Neostigmine Inhibition

Neostigmine inhibits AChE through a three-step carbamylation process [PMID: 9395489]:

Step 1 - Binding: The quaternary ammonium group binds to the anionic site while the carbamate ester positions near the esteratic site.

Step 2 - Carbamylation: The serine hydroxyl attacks the carbamate carbonyl, releasing the alcohol moiety and forming a carbamyl-enzyme intermediate.

Step 3 - Decarbamylation: Unlike acetylation (microseconds), decarbamylation requires 15-30 minutes for hydrolysis, during which the enzyme is inactive.

Exam Tip: The key difference between edrophonium and neostigmine is the mechanism of inhibition. Edrophonium binds reversibly through electrostatic and hydrogen bonding (no covalent modification), while neostigmine forms a covalent carbamyl-enzyme intermediate that requires hydrolysis for enzyme regeneration.

Effects at the Neuromuscular Junction

Inhibition of AChE at the neuromuscular junction results in:

1. Increased ACh concentration in the synaptic cleft
2. Prolonged ACh half-life from ~1 ms to several milliseconds
3. Enhanced ACh binding to nicotinic receptors
4. Competitive displacement of NMBA from receptors
5. Restoration of neuromuscular transmission

The reversal of non-depolarising blockade depends on the relative concentrations of ACh and NMBA at the receptor. Neostigmine increases ACh concentration approximately 10-fold, shifting the competitive equilibrium toward ACh binding [PMID: 7943798].

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Pharmacokinetics

Absorption

Clinical Pearl: The poor oral bioavailability (1-2%) of neostigmine necessitates significantly higher oral doses for myasthenia gravis treatment (15-30 mg orally equivalent to 0.5-1 mg parenterally). Pyridostigmine has better oral bioavailability (10-20%) and is preferred for chronic therapy [PMID: 2897627].

Distribution

The quaternary ammonium structure prevents significant CNS penetration. Studies using radiolabelled neostigmine demonstrate less than 1% of administered dose reaches cerebrospinal fluid [PMID: 3377583].

Metabolism and Elimination

Metabolic Pathways:

1. Plasma cholinesterase hydrolysis (30-50%): Cleaves carbamate ester to form 3-hydroxyphenyltrimethylammonium
2. Hepatic metabolism (10-20%): Conjugation reactions
3. Renal excretion unchanged (50-75%): Primary elimination route

ANZCA Primary Focus: The elimination half-life of neostigmine (77 min) exceeds that of intermediate-acting NMBAs such as rocuronium (66-80 min) and vecuronium (51-80 min), but may be shorter than the NMBA in patients with hepatic dysfunction, potentially leading to recurarisation [PMID: 8092513].

Pharmacokinetic Comparison of Anticholinesterases

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Pharmacodynamics

Dose-Response Relationships

ED50 and ED95 for NMBA Reversal:

The dose of neostigmine required for reversal depends on the depth of blockade:

Clinical Pearl: The standard neostigmine dose of 50-70 mcg/kg represents approximately ED95 for reversal at moderate blockade (TOF count 2-3). Higher doses do not improve reversal due to the ceiling effect but increase muscarinic side effects [PMID: 17122570].

The Ceiling Effect

The ceiling effect is a critical concept describing the maximum efficacy of anticholinesterase reversal [PMID: 20418538]:

Mechanism:

• Maximum AChE inhibition is achieved at 70 mcg/kg neostigmine
• Further doses cannot increase ACh concentration above this maximum
• If NMBA concentration exceeds the competitive capacity of accumulated ACh, complete reversal is impossible
• Excess neostigmine causes paradoxical weakness through:
  • Desensitisation block from excessive ACh
  • Direct nicotinic receptor effects (open channel block)

Clinical Implications:

• Maximum dose: 5 mg (approximately 70 mcg/kg in 70 kg adult)
• Do not re-dose if initial reversal inadequate
• Ensure adequate spontaneous recovery before administration (TOF ≥2)

Muscarinic Effects

Increased ACh at muscarinic receptors produces widespread parasympathomimetic effects:

Red Flag - Bradycardia: Neostigmine without anticholinergic co-administration can cause profound bradycardia, junctional rhythm, or asystole. The muscarinic effects of neostigmine have faster onset than the nicotinic effects at the NMJ, making anticholinergic pre-treatment or co-administration mandatory [PMID: 8533919].

Nicotinic Effects

At the Neuromuscular Junction:

• Reversal of non-depolarising blockade
• Restoration of TOF ratio and sustained tetanus
• No effect on depolarising blockade (may worsen phase II block)

At Autonomic Ganglia:

• Generally minimal at clinical doses
• High doses may stimulate then block ganglionic transmission

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Clinical Pharmacology

Indications

NMBA Reversal Protocol

Standard Reversal (TOF Count ≥2):

1. Confirm adequate spontaneous recovery: TOF count ≥2 (ideally ≥4)
2. Calculate doses:
   • Neostigmine: 50-70 mcg/kg (maximum 5 mg)
   • Glycopyrrolate: 10 mcg/kg OR Atropine: 20 mcg/kg
3. Administration: Give anticholinergic with or immediately before neostigmine
4. Monitor: Continuous TOF monitoring; target TOF ratio ≥0.9
5. Time: Allow 10-15 minutes for peak effect before extubation

Clinical Pearl: Glycopyrrolate is preferred over atropine for co-administration with neostigmine because their onset times are better matched. Atropine has faster onset, potentially causing initial tachycardia before neostigmine's bradycardic effect manifests. Glycopyrrolate also produces less tachycardia and has no CNS effects [PMID: 6742435].

Anticholinergic Selection: Glycopyrrolate vs Atropine

Timing of Administration

The success of neostigmine reversal is critically dependent on timing:

ANZCA Primary Focus: Candidates must understand that neostigmine cannot reliably reverse deep blockade (TOF count 0-1) due to the ceiling effect. Administration at deep block wastes time and may cause recurarisation when the neostigmine effect wanes before the NMBA [PMID: 27199451].

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Neostigmine vs Sugammadex Comparison

Mechanism Comparison

Clinical Comparison

Clinical Pearl: Sugammadex provides faster and more reliable reversal than neostigmine, particularly at deeper levels of blockade. However, it only reverses aminosteroid NMBAs (rocuronium, vecuronium, pancuronium). Neostigmine remains necessary for benzylisoquinolinium agents (atracurium, cisatracurium, mivacurium) [PMID: 27755321].

When to Use Each Agent

Prefer Neostigmine When:

• Benzylisoquinolinium NMBA used (atracurium, cisatracurium)
• Shallow block with TOF count ≥4
• Cost considerations paramount
• Sugammadex unavailable or contraindicated

Prefer Sugammadex When:

• Deep or profound block requiring rapid reversal
• Aminosteroid NMBA used (rocuronium, vecuronium)
• Cannot-intubate-cannot-oxygenate emergency (rocuronium reversal)
• Contraindications to anticholinergics
• Cardiovascular instability where muscarinic effects undesirable

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Drug Interactions

Pharmacodynamic Interactions

Pharmacokinetic Interactions

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Adverse Effects

Cardiovascular

Red Flag - Cardiac Risk: Patients taking beta-blockers, calcium channel blockers, or digoxin are at increased risk of severe bradycardia with neostigmine. Consider higher anticholinergic doses and have atropine immediately available [PMID: 8533919].

Respiratory

Gastrointestinal

Neuromuscular

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Special Populations

Renal Impairment

Neostigmine elimination is significantly affected by renal function:

Clinical Pearl: In severe renal impairment, the duration of neostigmine effect may exceed that of NMBAs, but initial reversal may still be incomplete. The combination of reduced neostigmine clearance and altered NMBA kinetics makes monitoring essential [PMID: 8092513].

Hepatic Impairment

Elderly Patients

Paediatric Patients

Clinical Pearl: Neonates and infants have immature neuromuscular junctions with reduced safety margin and may show prolonged responses to both NMBAs and neostigmine. Quantitative neuromuscular monitoring is particularly valuable in this population [PMID: 16990970].

Pregnancy and Lactation

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Contraindications and Precautions

Absolute Contraindications

Relative Contraindications/Precautions

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Australian/New Zealand Considerations

Regulatory Status

• TGA Status: Registered medicine; Prescription Only (S4)
• Medsafe Status: Registered medicine; Prescription Medicine
• PBS Listing: Available; various restrictions apply to different indications
• Hospital formulary: Standard item in all Australian and New Zealand hospitals

Available Formulations in Australia/NZ

Cost Comparison (Approximate AUD)

Clinical Pearl: Cost-effectiveness analyses from Australian institutions suggest reserving sugammadex for situations where neostigmine is contraindicated, reversal is urgent, or deep block requires immediate reversal. Routine sugammadex use for shallow block is not cost-effective in most settings [PMID: 28817387].

ANZCA Professional Documents

Relevant ANZCA guidelines and statements:

• PS18: Guidelines on Monitoring During Anaesthesia - recommends neuromuscular monitoring when NMBAs used
• PS26: Guidelines on Consent for Anaesthesia or Sedation - informed consent for NMBA use
• PS54: Statement on the Minimum Safety Requirements for Anaesthetic Machines - drug availability

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Indigenous Health Considerations

Aboriginal and Torres Strait Islander Populations

Healthcare disparities affecting Aboriginal and Torres Strait Islander Australians have implications for perioperative neuromuscular management:

Renal Disease Prevalence: End-stage renal disease affects Aboriginal and Torres Strait Islander peoples at 6-10 times the rate of non-Indigenous Australians, with highest rates in remote communities [PMID: 31283889]. Given neostigmine's predominantly renal elimination, dose adjustment and prolonged monitoring are frequently required. Point-of-care creatinine testing may be valuable in remote settings.

Cardiovascular Comorbidities: Higher rates of ischaemic heart disease and cardiomyopathy in Indigenous populations increase the risk of bradycardia-related complications with neostigmine. Thorough preoperative cardiac assessment and adequate anticholinergic co-administration are essential.

Access to Care: Remote and very remote communities may have limited access to sugammadex due to cost and cold-chain requirements, making neostigmine the primary reversal agent. Aeromedical retrieval services should stock both agents. Quantitative neuromuscular monitoring may not be available in all remote facilities, emphasising the importance of clinical assessment skills and conservative timing of reversal.

Maori and Pacific Islander Populations

Similar considerations apply to Maori and Pacific Islander populations in New Zealand:

Metabolic Syndrome: Higher prevalence of type 2 diabetes and chronic kidney disease affects drug elimination. Routine renal function assessment is recommended.

Cultural Considerations: Whanau (family) involvement in perioperative care planning is important. Explaining the rationale for neuromuscular monitoring and reversal in culturally appropriate terms enhances patient and family understanding.

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ANZCA Primary Examination Focus

Commonly Examined Topics

Key Examinable Concepts

Must Know for ANZCA Primary:

1. Carbamylation mechanism and why it produces intermediate duration
2. Quaternary structure prevents BBB penetration - no CNS effects
3. Ceiling effect: maximum dose 70 mcg/kg; cannot reverse deep block
4. TOF count ≥2 required before administration
5. Glycopyrrolate preferred over atropine (matched onset times)
6. Renal elimination predominates - dose adjust in renal impairment
7. Sugammadex for aminosteroids only; neostigmine for all non-depolarisers
8. Muscarinic effects: bradycardia, bronchospasm, secretions, GI motility

Previous Examination Questions (Themes)

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Assessment Content

SAQ Practice Question

ANZCA Primary SAQ Format Topic: Neostigmine Pharmacology Time: 15 minutes Marks: 20

Question:

A 65-year-old patient with chronic kidney disease (eGFR 25 mL/min/1.73m²) has received rocuronium for an abdominal laparotomy. At the end of surgery, the TOF count is 2.

a) Describe the mechanism of action of neostigmine for reversal of neuromuscular blockade. (6 marks)

b) Outline the pharmacokinetic considerations for neostigmine in this patient. (6 marks)

c) Compare neostigmine with sugammadex for reversal in this clinical scenario. (8 marks)

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Model Answer:

a) Mechanism of Action (6 marks)

Neostigmine is a quaternary ammonium carbamate anticholinesterase that reversibly inhibits acetylcholinesterase (AChE) at the neuromuscular junction (1 mark).

Molecular mechanism:

• Binds to anionic site via quaternary nitrogen (electrostatic interaction) (1 mark)
• Carbamate group carbamylates the serine hydroxyl at the esteratic site (1 mark)
• Forms carbamyl-enzyme intermediate that requires 15-30 minutes for hydrolysis (1 mark)
• During this time, AChE is inactive

Effect at NMJ:

• Prevents hydrolysis of acetylcholine (ACh)
• ACh concentration in synaptic cleft increases approximately 10-fold (1 mark)
• Increased ACh competitively displaces rocuronium from nicotinic receptors
• Restores neuromuscular transmission (1 mark)

b) Pharmacokinetic Considerations (6 marks)

(2 marks for table with appropriate values)

Clinical implications:

• Dose reduction recommended (reduce by 50% to 25-35 mcg/kg) (1 mark)
• Prolonged duration of action - may exceed NMBA duration (1 mark)
• Risk of recurarisation is reduced but initial reversal may be slow (1 mark)
• Extended PACU monitoring required (1 mark)

c) Comparison: Neostigmine vs Sugammadex (8 marks)

(4 marks for comprehensive comparison table)

In this specific patient (CKD, eGFR 25):

Arguments for sugammadex:

• Faster, more predictable reversal (1 mark)
• No muscarinic effects (important if cardiovascular comorbidity) (0.5 marks)
• No ceiling effect concern (0.5 marks)

Arguments for neostigmine:

• Lower cost (1 mark)
• TOF count 2 is adequate for neostigmine reversal (0.5 marks)
• Rocuronium also renally excreted; both agents prolonged proportionally (0.5 marks)

Recommendation: Either agent acceptable at TOF count 2. Sugammadex preferred if rapid reversal required or cardiovascular instability. Neostigmine acceptable with dose reduction and extended monitoring.

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Viva Scenario

ANZCA Primary Viva Format Topic: Neuromuscular Blockade Reversal Time: 7 minutes Marks: 15

Clinical Scenario:

You are called to the operating theatre to assist with a difficult emergence. A 72-year-old man with a history of COPD and atrial fibrillation on bisoprolol has undergone a hemicolectomy under general anaesthesia with rocuronium for muscle relaxation. The anaesthetic trainee has administered neostigmine 2.5 mg with glycopyrrolate 0.5 mg "about 5 minutes ago" but the patient remains paralysed with a TOF count of 1.

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Examiner Questions and Model Answers:

Q1: What are the possible reasons for inadequate reversal in this patient?

Model Answer:

• Timing of neostigmine administration: TOF count was likely 0-1 when given; neostigmine has a ceiling effect and cannot reverse deep blockade (most likely cause)
• Insufficient time: Peak effect of neostigmine is 7-11 minutes; only 5 minutes elapsed
• Increased rocuronium effect: Elderly patients have prolonged NMBA duration; renal/hepatic impairment possible
• Drug interactions: Bisoprolol may impair reversal; aminoglycosides if administered
• Hypothermia: Prolongs NMBA effect and impairs neostigmine efficacy
• Residual volatile anaesthetic: Potentiates neuromuscular blockade

Q2: How would you assess the depth of residual blockade?

Model Answer:

• Quantitative monitoring: Acceleromyography (TOF-Watch) or electromyography for objective TOF ratio
• Qualitative monitoring: Currently showing TOF count 1
• Post-tetanic count (PTC): If TOF count 0, PTC indicates depth of profound block
• Clinical signs: Unable to assess adequately under anaesthesia; head lift, grip strength, tidal volume require patient cooperation
• Target: TOF ratio ≥0.9 (0.7 was previously used but shown to be inadequate)

Q3: The TOF count remains at 1 after 15 minutes. What are your options?

Model Answer:

• Option 1 - Wait: Spontaneous recovery will continue; recheck in 10-15 minute intervals
• Option 2 - Sugammadex: 4 mg/kg for deep block (PTC 1-2) or consider 2 mg/kg if expecting shallow block soon
• Do NOT repeat neostigmine: Ceiling effect already reached; additional doses increase muscarinic effects without improving reversal
• Supportive care: Maintain anaesthesia, ventilation, normothermia
• Communication: Inform surgical team of delay; discuss with patient family if prolonged

Q4: What specific concerns does this patient's COPD and atrial fibrillation raise regarding neostigmine use?

Model Answer: COPD concerns:

• Bronchospasm risk from muscarinic M3 receptor activation in airways
• Increased secretions may worsen airway obstruction
• Glycopyrrolate helps but may not completely prevent bronchospasm
• Should have salbutamol available

Atrial fibrillation on bisoprolol concerns:

• Beta-blocker reduces heart rate reserve
• Neostigmine causes bradycardia via M2 receptor activation
• Combined effect risks severe bradycardia or AV block
• Glycopyrrolate dose may need to be increased (0.6-0.8 mg)
• Have atropine immediately available
• Monitor ECG continuously during reversal

Q5: If you decided to use sugammadex instead, what dose would you give and what monitoring would you perform?

Model Answer: Dose selection:

• TOF count 1 = moderate block: 2-4 mg/kg appropriate
• Would use 4 mg/kg (approximately 300-400 mg for 70-80 kg patient) for more reliable reversal
• If PTC available and shows deep block: definitely 4 mg/kg

Monitoring:

• Continuous ECG (bradycardia can occur, though less than neostigmine)
• Quantitative neuromuscular monitoring to confirm TOF ratio ≥0.9
• Observe for hypersensitivity (0.3-0.5% incidence)
• Monitor for recurrence of blockade (rare, may occur if additional rocuronium given)

Special consideration:

• Patient already received neostigmine; sugammadex still effective as mechanisms are independent
• Rocuronium-sugammadex complex is renally excreted; assess renal function for prolonged monitoring needs

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Summary Points

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References

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