Atracurium Pharmacology

Quick Answer

Atracurium besylate is an intermediate-acting, non-depolarizing benzylisoquinolinium neuromuscular blocking agent (NMBA) characterised by organ-independent elimination through Hofmann elimination (spontaneous chemical degradation at physiological pH and temperature) and ester hydrolysis by non-specific plasma esterases. The ED95 is 0.2-0.25 mg/kg, with standard intubating doses of 0.4-0.5 mg/kg providing adequate conditions in 2-3 minutes and clinical duration of 30-45 minutes. Atracurium is a racemic mixture of 10 stereoisomers, of which the 1R-cis-1'R-cis isomer (cisatracurium) has been isolated as a separate drug with improved properties. The key clinical advantage of atracurium is its predictable pharmacokinetics in patients with renal and hepatic failure, as elimination does not depend on organ function. However, atracurium causes dose-dependent histamine release (particularly at doses ≥0.5 mg/kg or with rapid injection), potentially causing hypotension, tachycardia, bronchospasm, and cutaneous flushing. The principal metabolite, laudanosine, is a tertiary amine that crosses the blood-brain barrier and may cause CNS excitation at high concentrations during prolonged ICU infusions, though clinically significant neurotoxicity is rare. Hofmann elimination is temperature and pH-dependent: hypothermia and acidosis slow degradation and prolong block, while hyperthermia and alkalosis accelerate it. Reversal is achieved with neostigmine (with glycopyrrolate); atracurium is NOT reversed by sugammadex. In Australia, atracurium remains widely available and cost-effective compared to cisatracurium. [1-10]

Pharmacology Overview

Chemical Classification and Structure

Atracurium besylate is classified as a bis-quaternary benzylisoquinolinium diester neuromuscular blocking agent. The benzylisoquinolinium class is structurally distinct from aminosteroid NMBAs (rocuronium, vecuronium, pancuronium) and includes atracurium, cisatracurium, mivacurium, and the older agents d-tubocurarine and alcuronium. The molecular structure consists of two quaternary nitrogen-containing tetrahydroisoquinolinium units connected by a diester-containing chain. This diester linkage is crucial for ester hydrolysis, while the tertiary amine structure within the tetrahydroisoquinolinium units allows for Hofmann elimination. The molecular weight is 929.1 Da (as besylate salt), and the molecular formula is C53H72N2O12·2C6H5SO3H. [11-14]

The quaternary ammonium groups confer water solubility and positive charge at physiological pH, enabling interaction with the anionic binding site on nicotinic acetylcholine receptors. The bulky benzylisoquinolinium structure provides the competitive antagonism at the neuromuscular junction but also contributes to the histamine-releasing properties through direct mast cell degranulation (non-IgE mediated). [15-17]

Stereochemistry and Isomers

Atracurium contains four chiral centres, giving rise to 16 possible stereoisomers. However, because of molecular symmetry constraints, only 10 distinct isomers exist in the commercial preparation. These isomers vary in their potency, duration of action, and propensity for histamine release. The three main isomeric groups are:

The 1R-cis-1'R-cis isomer (cisatracurium) represents approximately 15% of the racemic mixture and is 3-4 times more potent than the racemic mixture. This isomer has been isolated and marketed separately (as cisatracurium besylate, Nimbex®) because it offers the advantages of organ-independent metabolism without the histamine-releasing properties of the other isomers. [18-22]

Mechanism of Action: Competitive Nicotinic Receptor Antagonism

Atracurium acts as a competitive (non-depolarizing) antagonist at the nicotinic acetylcholine receptor (nAChR) located on the motor end-plate of skeletal muscle. The adult muscle nicotinic receptor is a pentameric ligand-gated ion channel composed of five subunits (2α1, 1β1, 1δ, 1ε) arranged around a central cation-permeable pore. Acetylcholine must bind to both α-subunit recognition sites (located at the α-ε and α-δ interfaces) to trigger the conformational change that opens the ion channel. [23-25]

Atracurium competes with acetylcholine for binding at the α-subunit recognition sites. Binding of atracurium to even one α-subunit prevents channel opening, thus blocking neuromuscular transmission. Because this is a competitive antagonism, the block can be overcome by increasing the concentration of acetylcholine at the neuromuscular junction (the basis for reversal with acetylcholinesterase inhibitors). [26-28]

Key Characteristics of Non-Depolarizing Block:

• Fade on train-of-four (TOF): Decreasing amplitude of successive twitches (T4 < T3 < T2 < T1)
• Post-tetanic facilitation: Transient increase in twitch height after tetanic stimulation
• No fasciculations at onset
• Reversible with acetylcholinesterase inhibitors (neostigmine)
• Potentiated by volatile anaesthetics, aminoglycosides, magnesium

The safety margin of neuromuscular transmission is substantial (70-80% receptor reserve), meaning that >75% of receptors must be blocked before any reduction in twitch height occurs, and >90-95% receptor occupancy is required for complete clinical paralysis. [29-31]

Pharmacokinetic Principles

Organ-Independent Elimination: Hofmann Elimination and Ester Hydrolysis

The defining pharmacokinetic characteristic of atracurium is its elimination through two organ-independent pathways that do not require hepatic metabolism or renal excretion:

1. Hofmann Elimination (~30-45% of clearance):

Hofmann elimination is a spontaneous, non-enzymatic chemical degradation that occurs at physiological pH (7.4) and temperature (37°C). The reaction involves base-catalysed elimination of a quaternary ammonium group, resulting in cleavage of the molecule at the ester linkage. This process produces two main fragments:

• Laudanosine (a tertiary amine)
• Monoacrylate (subsequently converted to monoquaternary alcohol)

The rate of Hofmann elimination is critically dependent on temperature and pH:

• Temperature coefficient: ~4% increase in degradation rate per 1°C increase in temperature
• pH effect: Rate approximately doubles for each 0.5 unit increase in pH

Clinical implications:

• Hypothermia (cardiac surgery, therapeutic hypothermia): Significantly prolongs duration of action
• Acidosis: Prolongs duration of action
• Hyperthermia/alkalosis: May shorten duration (rarely clinically significant)

2. Ester Hydrolysis (~55-70% of clearance):

Ester hydrolysis is catalysed by non-specific plasma esterases (NOT pseudocholinesterase/plasma cholinesterase). These esterases are distinct from the enzyme that metabolises succinylcholine and mivacurium. Consequently, patients with pseudocholinesterase deficiency have normal atracurium metabolism. The ester hydrolysis pathway produces similar metabolites to Hofmann elimination. [32-38]

Volume of Distribution and Protein Binding

The relatively small volume of distribution (approximating extracellular fluid) reflects the quaternary ammonium structure that limits membrane permeability. Critical illness with fluid overload, capillary leak, and expanded extracellular fluid volume may increase Vd and necessitate higher loading doses. Conversely, protein binding is substantial, and hypoalbuminaemia increases the free fraction, potentially enhancing both effect and clearance. [39-43]

Laudanosine: Metabolite Pharmacology

Laudanosine is the primary metabolite of atracurium (and cisatracurium), accounting for approximately 10-40% of administered atracurium by weight. Unlike the parent compound, laudanosine is a tertiary amine that is lipophilic, crosses the blood-brain barrier, and is eliminated primarily by hepatic metabolism with renal excretion of metabolites. The elimination half-life of laudanosine is 150-350 minutes (significantly longer than atracurium). [44-47]

CNS Effects of Laudanosine:

In animal studies, laudanosine causes dose-dependent CNS excitation:

• Low doses: EEG arousal patterns
• Moderate doses: Increased seizure susceptibility
• High doses (≥17 mg/kg in dogs): Generalised seizures

The threshold for seizure activity in experimental animals corresponds to plasma laudanosine concentrations of approximately 5-10 μg/mL. In humans receiving standard surgical doses of atracurium, peak laudanosine levels are typically 0.3-1.0 μg/mL—well below the experimental seizure threshold. However, during prolonged ICU infusions, particularly in patients with hepatic failure (impaired laudanosine clearance), plasma levels may accumulate to 2-5 μg/mL, raising theoretical concerns about CNS excitation. [48-52]

Clinical Significance:

• Clinically apparent laudanosine toxicity is rare in humans
• Theoretical risk with prolonged (>24-48 hours) ICU infusions
• Greater concern with atracurium than cisatracurium (cisatracurium produces ~5-fold less laudanosine due to higher potency)
• Consider cisatracurium for prolonged ICU paralysis in hepatic failure

Comparison: Atracurium vs Cisatracurium

Cisatracurium (Nimbex®) is the isolated 1R-cis-1'R-cis isomer of atracurium, representing ~15% of the racemic mixture. The clinical differences reflect the distinct pharmacological profile of this single isomer:

The clinical advantages of cisatracurium include absence of histamine release, greater cardiovascular stability, and lower laudanosine production. The disadvantage is slightly slower onset due to lower potency (fewer molecules at the NMJ for equivalent effect). Both retain the key advantage of organ-independent metabolism. [53-60]

Pharmacodynamics

Dose-Response Relationships

ED95 (Effective Dose 95%): The dose producing 95% suppression of twitch height at the adductor pollicis muscle is 0.2-0.25 mg/kg. This represents the standard reference dose for non-depolarizing NMBAs.

Intubating Dose: Standard intubating dose is 2× ED95 (0.4-0.5 mg/kg), providing:

• Onset time: 2-3 minutes
• Time to maximum block: 3-5 minutes
• Intubating conditions: Good to excellent at 90 seconds with high-dose opioid technique, 2-3 minutes with standard induction
• Clinical duration: 30-45 minutes

Dose-Response Table:

Higher doses (>0.5 mg/kg) produce faster onset but significantly increase histamine release and are generally not recommended. For rapid sequence induction, rocuronium (1.0-1.2 mg/kg) or succinylcholine are preferred over high-dose atracurium. [61-65]

Maintenance Dosing and Infusion

Intermittent Bolus Dosing:

• Supplemental doses: 0.08-0.10 mg/kg
• Timing: When TOF count returns to 2-3 twitches
• Typical interval: 15-25 minutes

Continuous Infusion:

• Initial rate: 5-10 μg/kg/min (0.3-0.6 mg/kg/hr)
• Maintenance range: 4-12 μg/kg/min
• Titrate to TOF count of 1-2

For operating room use, atracurium infusions provide predictable paralysis with relatively rapid recovery upon discontinuation. For ICU use, the accumulation of laudanosine during prolonged infusions is a consideration, and cisatracurium may be preferred for infusions >24-48 hours, particularly in hepatic impairment. [66-69]

Onset and Duration: Factors Affecting Response

Factors Prolonging Duration:

Factors Shortening Duration or Causing Resistance:

Burns patients represent a particular challenge, with resistance to non-depolarizing NMBAs developing 7-10 days post-injury and persisting for months. The mechanism involves upregulation of extrajunctional acetylcholine receptors and increased receptor density, requiring substantially higher doses (2-5× normal) to achieve adequate paralysis. [70-76]

Cardiovascular Effects: Histamine Release

Mechanism of Histamine Release

Atracurium causes direct (non-immunological, non-IgE mediated) histamine release from mast cells and basophils. This effect is:

• Dose-dependent: Minimal at ≤0.3 mg/kg, clinically significant at ≥0.5 mg/kg
• Rate-dependent: Rapid bolus injection increases release compared to slow injection
• Isomer-dependent: Trans-trans isomers cause more histamine release than cis-cis isomers

The benzylisoquinolinium structure is inherently more prone to histamine release than aminosteroid NMBAs. The mechanism involves direct interaction with mast cell surface proteins, triggering degranulation and release of preformed histamine, prostaglandins, and leukotrienes. [77-80]

Cardiovascular Manifestations

The typical cardiovascular response to intubating doses of atracurium includes:

• Mean arterial pressure decrease: 10-20% (at 0.5 mg/kg)
• Heart rate increase: 10-20% (reflex)
• Effects usually transient (3-5 minutes)

In haemodynamically unstable patients or those with cardiovascular disease, these effects may be clinically significant. Cisatracurium is preferred in such patients due to absence of histamine release. [81-85]

Prevention and Management

Prevention Strategies:

1. Slow injection: Administer over 60-90 seconds (reduces peak plasma concentration)
2. Divided doses: Give in increments rather than single bolus
3. Lower doses: Use 0.3-0.4 mg/kg where acceptable onset time permits
4. Alternative agents: Use cisatracurium or rocuronium in high-risk patients
5. Pretreatment: H1/H2 blockers may attenuate histamine effects (not routinely used)

Management of Histamine-Mediated Hypotension:

• Usually self-limiting (3-5 minutes)
• IV fluid bolus
• Vasopressor (ephedrine 5-10 mg or phenylephrine 50-100 μg) if significant
• Adrenaline if severe reaction or bronchospasm

It is important to distinguish histamine-mediated reactions (dose-dependent, predictable, usually mild) from true anaphylaxis (IgE-mediated, unpredictable, potentially severe). True anaphylaxis to atracurium is rare (<1:5,000 to 1:20,000) but requires standard anaphylaxis management including adrenaline, fluids, and cessation of the triggering agent. [86-90]

Drug Interactions

Potentiating Interactions (Increased Block)

Magnesium Interaction: The interaction with magnesium is particularly important in obstetric practice, where magnesium sulfate is used for eclampsia prophylaxis/treatment. Patients receiving magnesium may require only 50% of the usual atracurium dose, and recovery may be significantly prolonged. Close neuromuscular monitoring is essential. [91-95]

Antagonising Interactions (Reduced Block)

Reversal: Neostigmine (NOT Sugammadex)

Atracurium is a benzylisoquinolinium NMBA and is NOT reversed by sugammadex. Sugammadex is a modified γ-cyclodextrin that specifically encapsulates aminosteroid NMBAs (rocuronium, vecuronium) by forming a tight inclusion complex with the steroidal ring structure. Benzylisoquinolinium compounds lack this steroidal nucleus and therefore cannot be reversed by sugammadex.

Neostigmine Reversal Protocol:

Neostigmine inhibits acetylcholinesterase, increasing acetylcholine concentration at the neuromuscular junction to competitively overcome the atracurium block. The anticholinergic (glycopyrrolate preferred for stability) prevents muscarinic side effects (bradycardia, salivation, bronchospasm). Recovery to TOF ratio ≥0.9 should be confirmed before extubation. [96-100]

Special Populations

Renal Failure

Atracurium is often described as the "ideal" NMBA for patients with renal failure because:

1. Primary elimination is organ-independent (Hofmann + ester hydrolysis)
2. No accumulation of parent drug with repeated doses or infusion
3. No prolongation of clinical effect (normal onset and duration)

However, laudanosine is renally excreted, and accumulation occurs with repeated dosing or prolonged infusion. In clinical practice, laudanosine levels in renal failure patients receiving atracurium infusions are elevated (2-3× normal) but rarely reach levels associated with CNS toxicity in animal studies. Cisatracurium may be preferred for prolonged ICU infusions in renal failure due to lower laudanosine production. [101-104]

Hepatic Failure

Similarly, hepatic failure does not significantly affect atracurium pharmacokinetics because:

1. Hofmann elimination is independent of hepatic function
2. Ester hydrolysis is performed by non-specific plasma esterases (NOT hepatic)

Laudanosine is metabolised hepatically, so accumulation is greater in hepatic failure. The clinical significance remains uncertain, but cisatracurium may be preferred for prolonged use in severe hepatic impairment. The volume of distribution may be increased due to ascites and oedema, potentially requiring higher loading doses. [105-108]

Elderly Patients

Age-related changes affecting atracurium pharmacology:

• Pharmacokinetic: Modest reduction in clearance (~20-30%)
• Pharmacodynamic: Increased sensitivity (possibly receptor changes)
• Practical effect: Duration may be prolonged by 10-20%; onset is similar

Standard dosing is appropriate, but monitoring and titration to effect are particularly important. Elderly patients are also more susceptible to the cardiovascular effects of histamine release. [109-111]

Burns Patients

Major burns (>20% total body surface area) result in profound resistance to non-depolarizing NMBAs beginning 7-10 days post-injury and persisting for months to years. The mechanisms include:

1. Extrajunctional receptor proliferation: Acetylcholine receptors spread beyond the motor end-plate
2. Increased receptor density: More receptors to block for equivalent effect
3. Altered receptor subtypes: Immature (fetal) receptors with different pharmacology
4. Increased volume of distribution: Fluid resuscitation, oedema
5. Altered protein binding: Hypoalbuminaemia, acute phase proteins

Burns patients may require 2-5× the normal atracurium dose and more frequent redosing. Neuromuscular monitoring is essential. Interestingly, succinylcholine is contraindicated in burns (>24 hours post-injury) due to life-threatening hyperkalaemia from depolarisation of upregulated receptors, but non-depolarizing agents simply show resistance, not contraindication. [112-116]

Hypothermia

Hofmann elimination is temperature-dependent, with the rate decreasing approximately 4% per 1°C reduction in temperature. During therapeutic hypothermia (32-34°C) or accidental hypothermia, atracurium duration may be significantly prolonged:

• At 34°C: Duration increased ~15-20%
• At 32°C: Duration increased ~30-40%
• At 28°C: Duration may be doubled

Careful monitoring and dose reduction are essential during hypothermic procedures (cardiac surgery with cardiopulmonary bypass, therapeutic hypothermia post-cardiac arrest). Recovery should be assessed at patient's actual temperature, and rewarming may unmask residual block. [117-120]

ICU Infusion Considerations

Atracurium infusions in the ICU setting require consideration of:

1. Laudanosine accumulation: Levels increase with prolonged infusion; consider cisatracurium for >48 hours
2. Drug holidays: Daily interruption of paralysis for neurological assessment and to reduce ICUAW risk
3. Depth of sedation: Adequate sedation must precede paralysis (patient awareness during paralysis is devastating)
4. Monitoring: Continuous or frequent TOF monitoring to titrate to target (typically TOF count 1-2)
5. ROSE trial implications: Routine early paralysis in ARDS does not improve mortality with modern light sedation practices

The ACURASYS trial (2010) suggested mortality benefit with early cisatracurium in severe ARDS (PaO2/FiO2 <150), but the subsequent ROSE trial (2019) with protocolised light sedation showed no benefit for routine NMB use. Current practice favours NMB for specific indications (severe patient-ventilator dyssynchrony, prone positioning, ECMO) rather than routine use. [121-125]

Australian/New Zealand Specific Considerations

TGA-Approved Formulations

Atracurium besylate is TGA-approved in Australia and available as:

• Atracurium Injection (generic): 10 mg/mL solution in 2.5 mL (25 mg) and 5 mL (50 mg) ampoules
• Tracrium® (original brand, Aspen): 10 mg/mL solution

Storage: Refrigerate at 2-8°C. Protect from light. Once removed from refrigeration, single-use vials should be used within 14 days if stored below 25°C.

The solution is preservative-free and should be drawn up immediately before use. It is compatible with common IV fluids (0.9% saline, 5% dextrose, Hartmann's solution) for dilution but should not be mixed with alkaline solutions (accelerates Hofmann degradation). [126-128]

PBS Listing and Cost

Atracurium is listed on the Pharmaceutical Benefits Scheme (PBS) as a Section 100 (Highly Specialised Drugs) item, available through public and private hospitals. It is significantly less expensive than cisatracurium:

• Atracurium: ~AUD $3-5 per 50 mg ampoule
• Cisatracurium: ~AUD $15-25 per 50 mg vial

This cost difference influences formulary decisions. Many Australian hospitals stock atracurium as the "workhorse" benzylisoquinolinium NMBA, reserving cisatracurium for patients in whom histamine release must be avoided (severe asthma, cardiovascular instability, prolonged ICU infusion).

ANZCA Position

The Australian and New Zealand College of Anaesthetists (ANZCA) recommends:

1. Quantitative neuromuscular monitoring whenever NMBAs are administered (PS18)
2. Confirmation of TOF ratio ≥0.9 before extubation
3. Appropriate agent selection based on patient factors and clinical context
4. Awareness of residual neuromuscular blockade as a cause of postoperative respiratory complications

Atracurium remains an appropriate choice for routine use in patients with normal airway reflexes and cardiovascular status, with cisatracurium preferred when histamine release is contraindicated. [129-131]

Indigenous Health Considerations

Aboriginal and Torres Strait Islander Populations

Limited pharmacokinetic data exist specifically for Aboriginal and Torres Strait Islander populations regarding atracurium, but several clinical considerations are relevant:

Renal Disease Prevalence: Aboriginal and Torres Strait Islander Australians have 3-4 times higher rates of chronic kidney disease (CKD) and end-stage renal disease (ESRD) compared to non-Indigenous Australians. While atracurium's organ-independent elimination makes it suitable for renal impairment, laudanosine accumulation remains a consideration for prolonged infusions. In remote communities, baseline renal function may be unknown; point-of-care creatinine testing prior to anaesthesia is valuable where available.

Obesity and Metabolic Disease: Higher rates of type 2 diabetes and obesity in some Indigenous communities may affect dosing considerations. Atracurium dosing should be based on ideal body weight for initial doses, with careful titration to effect using neuromuscular monitoring.

Remote and Rural Access: Many Aboriginal and Torres Strait Islander communities are located in remote areas where access to intensive care and prolonged postoperative monitoring may be limited. Atracurium's predictable recovery profile is advantageous, but adequate neuromuscular monitoring equipment must be available. In remote settings, transfer decisions should account for the potential for residual neuromuscular blockade if monitoring is suboptimal.

Cultural Considerations: Clear explanation of the purpose and effects of muscle relaxants, using culturally appropriate communication and involving Aboriginal Health Workers or interpreters when needed, supports informed consent. Family involvement in perioperative care discussions is important in many Indigenous cultures.

Māori Health Considerations (New Zealand)

Māori patients have higher rates of diabetes, obesity, and chronic kidney disease, which may affect atracurium pharmacokinetics through changes in volume of distribution and laudanosine elimination. Whānau (extended family) involvement in perioperative care decisions aligns with tikanga (cultural protocols) and supports patient-centred care. Explanation of neuromuscular blockade and monitoring should include family members as appropriate.

In rural New Zealand with significant Māori populations, similar considerations regarding access to monitoring and postoperative care apply as in remote Australian settings. [132-135]

ANZCA Primary Exam Focus

Common MCQ Patterns

ANZCA Primary MCQs frequently test the following atracurium concepts:

1. Mechanism of action: Competitive nicotinic receptor antagonism (NOT depolarizing)
2. Stereochemistry: 10 isomers, cisatracurium is the 1R-cis-1'R-cis isomer
3. Elimination pathways: Hofmann elimination AND ester hydrolysis (organ-independent)
4. Hofmann elimination: Non-enzymatic, temperature and pH dependent
5. Laudanosine: CNS-active metabolite, tertiary amine, crosses BBB, hepatic/renal elimination
6. Histamine release: Dose-dependent, distinguishes atracurium from cisatracurium
7. ED95 and dosing: ED95 0.2-0.25 mg/kg, intubating dose 0.4-0.5 mg/kg
8. NOT reversed by sugammadex: Benzylisoquinolinium, requires neostigmine
9. Temperature effects: Hypothermia prolongs duration
10. Special populations: Safe in renal/hepatic failure (organ-independent)

Primary Viva Question Themes

Viva scenarios typically explore:

• Comparison of atracurium with cisatracurium (structure, potency, histamine, laudanosine)
• Choice of NMBA in renal failure, hepatic failure, burns
• Mechanism and clinical significance of histamine release
• Effects of hypothermia, acidosis on atracurium pharmacology
• Management of residual neuromuscular blockade
• Drug interactions (aminoglycosides, magnesium, volatiles)
• Laudanosine toxicity: mechanism, clinical significance, risk factors

Calculation Questions

Candidates should be comfortable calculating:

• Intubating doses based on patient weight and ED95
• Infusion rates (μg/kg/min to mL/hr conversion)
• Dose adjustments for drug interactions (e.g., with magnesium)
• Expected duration changes with temperature

Example Calculation 1: A 70 kg patient requires atracurium intubation. Calculate the dose at 2× ED95.

• ED95 = 0.23 mg/kg
• Dose = 2 × 0.23 × 70 = 32.2 mg ≈ 30-35 mg (or use standard 0.5 mg/kg = 35 mg)

Example Calculation 2: Target rate: 8 μg/kg/min for 70 kg patient using 10 mg/mL solution

• Required dose: 8 × 70 = 560 μg/min = 0.56 mg/min = 33.6 mg/hr
• Infusion rate: 33.6 mg/hr ÷ 10 mg/mL = 3.36 mL/hr

Example Calculation 3: A 60 kg patient receives magnesium sulfate infusion for pre-eclampsia. What atracurium dose adjustment is needed?

• Standard dose: 0.5 mg/kg × 60 kg = 30 mg
• With magnesium: Reduce by 50% → 15 mg initial dose
• Monitor TOF closely; redosing interval may be substantially prolonged

High-Yield Comparison Tables

Benzylisoquinolinium vs Aminosteroid NMBAs:

Comparison of Non-Depolarizing NMBAs:

Adverse Effects and Complications

Common Adverse Effects

Rare but Serious Complications

ICU-Acquired Weakness

Prolonged NMBA use in the ICU is associated with ICU-acquired weakness (ICUAW), a spectrum of critical illness myopathy and polyneuropathy. Risk factors include:

• Duration of NMBA use (>48 hours)
• Concurrent corticosteroid use
• Sepsis and multi-organ failure
• Hyperglycaemia
• Immobility

Prevention strategies:

• Use NMBAs only when clearly indicated
• Daily sedation/paralysis interruption for neurological assessment
• Target lightest effective paralysis (TOF count 1-2)
• Early physiotherapy and mobilisation when paralysis discontinued
• Glycaemic control

The ROSE trial demonstrated no mortality benefit for routine NMB in ARDS with modern sedation practices, reinforcing selective rather than routine use. [136-140]

Assessment Content

SAQ Practice Question (20 marks)

Question:

A 58-year-old, 75 kg woman with end-stage renal disease (ESRD) on haemodialysis presents for urgent laparoscopic cholecystectomy. The surgeon requests deep muscle relaxation for the procedure.

(a) Explain why atracurium is often recommended for patients with renal failure. Include a description of its elimination pathways and the clinical implications of organ-independent metabolism. (8 marks)

(b) Compare atracurium with cisatracurium with respect to potency, cardiovascular effects, and metabolite production. Which would you prefer for this patient and why? (6 marks)

(c) The patient becomes hypothermic (34°C) during surgery. Explain how this affects atracurium pharmacology and describe your management approach. (4 marks)

(d) At the end of surgery, the TOF count is 2. Outline your reversal strategy, including why sugammadex cannot be used. (2 marks)

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Model Answer:

(a) Atracurium in Renal Failure (8 marks)

Elimination pathways (4 marks):

• Atracurium undergoes organ-independent elimination via two pathways:
  • Hofmann elimination (~30-45%): Spontaneous, non-enzymatic chemical degradation at physiological pH (7.4) and temperature (37°C)
  • Ester hydrolysis (~55-70%): Catalysed by non-specific plasma esterases (NOT pseudocholinesterase)
• Neither pathway requires hepatic metabolism or renal excretion
• Plasma clearance (~6 mL/kg/min) exceeds hepatic blood flow, confirming extra-hepatic elimination

Clinical implications in ESRD (4 marks):

• Onset time (2-3 min), duration (30-45 min), and recovery are unchanged in renal failure
• No accumulation of parent drug with repeated doses or infusion
• No need for dose adjustment based on renal function
• Predictable pharmacokinetics allows reliable surgical conditions
• Laudanosine (metabolite) IS renally excreted and accumulates in ESRD, but rarely reaches clinically significant levels with surgical dosing
• For prolonged ICU infusions in ESRD, cisatracurium may be preferred (lower laudanosine)

(b) Atracurium vs Cisatracurium Comparison (6 marks)

Preference for this patient (2 marks):

• Either agent is appropriate given organ-independent elimination
• For a single surgical case, atracurium is acceptable and cost-effective
• Cisatracurium would be preferred if: cardiovascular instability, asthma, or prolonged ICU course anticipated
• In ESRD, both have predictable pharmacokinetics; cisatracurium produces less laudanosine

(c) Hypothermia Effects (4 marks)

Mechanism (2 marks):

• Hofmann elimination is temperature-dependent (~4% rate change per 1°C)
• At 34°C, Hofmann degradation is slowed by ~15-20%
• This prolongs duration of atracurium block

Management (2 marks):

• Expect longer duration of action (may be 20-30% prolonged at 34°C)
• Reduce maintenance dosing or increase redosing interval
• Continue neuromuscular monitoring throughout
• Assess recovery at actual patient temperature
• Ensure adequate warmth before extubation; rewarming may unmask residual block

(d) Reversal Strategy (2 marks)

Why not sugammadex:

• Sugammadex encapsulates aminosteroid NMBAs (rocuronium, vecuronium) by binding the steroidal ring
• Atracurium is a benzylisoquinolinium without a steroidal structure—no binding occurs
• Sugammadex is INEFFECTIVE for atracurium reversal

Reversal protocol:

• Neostigmine 50-70 μg/kg (max 5 mg) with glycopyrrolate 10-15 μg/kg
• Wait for TOF count ≥2 (ideally ≥3) before reversal
• Confirm TOF ratio ≥0.9 before extubation (10-15 minutes)

Total: 20 marks

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Primary Viva Scenario (15 marks)

Scenario:

You are the anaesthetist for a 35-year-old woman (65 kg) with severe asthma presenting for emergency appendicectomy. She reports multiple allergies and had "a reaction to something" during a previous general anaesthetic, though details are unclear from her records.

Examiner: What are your considerations regarding neuromuscular blockade for this patient?

Candidate:

Initial assessment (3 marks):

"This patient has two concerning features relevant to NMBA selection: severe asthma and a history of a previous anaesthetic reaction of unclear nature.

For severe asthma, I would avoid agents with significant histamine-releasing potential. Atracurium causes dose-dependent histamine release, which can trigger bronchospasm in susceptible patients. Cisatracurium, the isolated isomer of atracurium, does not cause histamine release at clinical doses and would be preferred.

Regarding the previous reaction, I would need to investigate further. If this was an anaphylactic reaction to a neuromuscular blocking agent, cross-reactivity between different NMBAs is common (60-80%). I would review any available documentation, allergy clinic letters, or skin prick testing results."

Examiner: Assume the previous reaction was cutaneous flushing only. How would this change your approach?

Candidate (3 marks):

"Cutaneous flushing alone, without cardiovascular collapse or bronchospasm, is more consistent with histamine release than true anaphylaxis. Histamine release from benzylisoquinolinium agents is dose-dependent and non-IgE mediated.

If the previous agent was atracurium, switching to cisatracurium (no histamine release) would be appropriate. If it was rocuronium (minimal histamine release), the reaction may have had another cause.

For this asthmatic patient with previous flushing, I would:

1. Choose cisatracurium for its absence of histamine release
2. Have bronchodilators immediately available
3. Consider pretreatment with salbutamol nebuliser
4. Ensure deep anaesthesia before instrumentation of the airway"

Examiner: Describe the key pharmacological differences between atracurium and cisatracurium that explain the difference in histamine release.

Candidate (4 marks):

"Atracurium is a racemic mixture of 10 stereoisomers with varying properties:

• Cis-cis isomers (~52%): Most potent, includes cisatracurium
• Cis-trans isomers (~36%): Intermediate potency
• Trans-trans isomers (~12%): Least potent, highest histamine release

Cisatracurium is the purified 1R-cis-1'R-cis isomer, representing about 15% of the racemic mixture. It is 3-4 times more potent than the mixture.

The histamine-releasing property of atracurium is primarily attributed to the trans-trans isomers, which are absent in cisatracurium. Additionally, because cisatracurium is more potent, lower total doses are administered (ED95 0.05 mg/kg vs 0.2-0.25 mg/kg), further reducing any potential for histamine release.

This explains why cisatracurium produces essentially no cardiovascular effects at clinical doses, while atracurium can cause hypotension and tachycardia, particularly at doses ≥0.5 mg/kg."

Examiner: At the end of the case, you want to reverse the cisatracurium. Can you use sugammadex?

Candidate (3 marks):

"No, sugammadex cannot reverse cisatracurium (or atracurium).

Sugammadex is a modified γ-cyclodextrin specifically designed to encapsulate aminosteroid NMBAs. Its hydrophobic cavity accommodates the steroidal ring structure of rocuronium and vecuronium, forming a tight 1:1 inclusion complex.

Cisatracurium and atracurium are benzylisoquinolinium compounds without a steroidal nucleus. They cannot fit into the sugammadex cavity and are therefore not reversed by it.

For reversal of cisatracurium, I would use neostigmine 50-70 μg/kg with glycopyrrolate once TOF count is ≥2, and confirm TOF ratio ≥0.9 before extubation."

Examiner: What would you do if the patient developed bronchospasm during induction?

Candidate (2 marks):

"I would:

1. Increase FiO2 to 100%
2. Deepen anaesthesia (propofol, volatiles reduce bronchospasm)
3. Administer salbutamol via ETT (8-10 puffs via spacer)
4. IV hydrocortisone 200 mg
5. Consider IV salbutamol (5-10 μg boluses or 5-20 μg/min infusion)
6. If severe or associated with hypotension/cardiovascular collapse, consider anaphylaxis and give adrenaline (50-100 μg IV boluses)
7. Exclude mechanical causes (ETT malposition, secretions, light anaesthesia)"

Total: 15 marks

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Primary Viva Scenario 2: Hofmann Elimination and Temperature Effects (15 marks)

Scenario:

A 52-year-old man (80 kg) is undergoing coronary artery bypass grafting with cardiopulmonary bypass. The perfusionist reports the patient's core temperature is 28°C during the cooling phase. You had administered atracurium 40 mg at induction 45 minutes ago.

Examiner: What effect does this degree of hypothermia have on atracurium pharmacology?

Candidate:

Understanding the mechanism (4 marks):

"Atracurium is eliminated primarily through Hofmann elimination and ester hydrolysis, both of which are temperature-dependent processes.

Hofmann elimination is a non-enzymatic chemical reaction that follows Arrhenius kinetics—the rate approximately decreases by 4% for each 1°C reduction in temperature. At 28°C (a 9°C reduction from 37°C), Hofmann degradation would be slowed by approximately 35-40%.

Ester hydrolysis by plasma esterases is also temperature-dependent, with enzyme activity reduced at lower temperatures.

The net effect is that at 28°C, the elimination of atracurium is substantially slowed, and the duration of neuromuscular block will be significantly prolonged—potentially doubled or more compared to normothermia."

Examiner: How would you manage neuromuscular blockade during this hypothermic period?

Candidate (4 marks):

"My approach would include:

1. Reduce or withhold additional atracurium doses: The drug already administered will have a much longer effect during hypothermia. I would not give routine supplemental doses unless specifically needed.

2. Neuromuscular monitoring: I would use train-of-four monitoring throughout, recognising that:

   • At 28°C, the twitch response itself may be diminished due to direct muscle effects
   • Lack of response does not necessarily indicate deep block—temperature must be considered
   • Standard monitoring sites (adductor pollicis) may be less reliable if the hand is cold

3. Anticipate prolonged recovery: When rewarming begins, I would expect residual block to persist. The drug will begin to clear more rapidly as temperature rises, but complete recovery will be delayed.

4. Document temperature at key assessment points: Any neuromuscular assessment must be interpreted in context of patient temperature."

Examiner: The patient is now rewarmed to 37°C and the TOF count is 2. Describe your reversal strategy.

Candidate (4 marks):

"With TOF count of 2 at normothermia, the patient has moderate neuromuscular block suitable for reversal with neostigmine.

Reversal protocol:

• Neostigmine 50-70 μg/kg (in an 80 kg patient: 4-5.6 mg; I would give 5 mg)
• Glycopyrrolate 10-15 μg/kg (0.8-1.2 mg; I would give 1 mg)
• Administer anticholinergic first or simultaneously to prevent bradycardia

Monitoring:

• Continue TOF monitoring and wait for TOF ratio ≥0.9
• Expected recovery time: 10-15 minutes from TOF count 2-3
• Do not extubate until quantitative monitoring confirms adequate recovery

Important considerations for cardiac surgery:

• Glycopyrrolate preferred over atropine (more predictable, less tachycardia)
• Avoid anticholinesterase-induced bradycardia in patient with potential cardiac irritability post-bypass
• Some centres delay reversal until patient fully warmed and stable"

Examiner: Could you use sugammadex instead?

Candidate (3 marks):

"No, sugammadex cannot be used to reverse atracurium.

Sugammadex is a modified γ-cyclodextrin that works by encapsulating aminosteroid neuromuscular blocking agents—specifically rocuronium and vecuronium. The hydrophobic cyclodextrin cavity binds the steroidal ring structure of these drugs.

Atracurium is a benzylisoquinolinium compound without a steroidal structure. It lacks the molecular features required for sugammadex binding, so no encapsulation occurs and there is no reversal effect.

If sugammadex reversal capability were desired for cardiac surgery, rocuronium would need to be used as the primary NMBA instead of atracurium. However, rocuronium has predominantly hepatic elimination, and its pharmacokinetics may be less predictable in the context of cardiopulmonary bypass affecting hepatic blood flow."

Total: 15 marks

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Clinical Pearls: Key Exam Points

Essential Facts to Memorise

1. Structure: Benzylisoquinolinium bis-quaternary diester (10 stereoisomers)
2. ED95: 0.2-0.25 mg/kg
3. Intubating dose: 0.4-0.5 mg/kg (2× ED95)
4. Onset: 2-3 minutes
5. Duration: 30-45 minutes (intermediate-acting)
6. Elimination: Hofmann elimination (30-45%) + ester hydrolysis (55-70%)
7. Hofmann temperature coefficient: ~4% rate change per °C
8. Principal metabolite: Laudanosine (tertiary amine, crosses BBB)
9. Cisatracurium: 1R-cis-1'R-cis isomer, 3-4× more potent, NO histamine release
10. Reversal: Neostigmine ONLY (NOT sugammadex)

Common Exam Mistakes to Avoid

1. ❌ Stating Hofmann elimination is the "major" pathway (it's ~30-45%, ester hydrolysis is actually more)
2. ❌ Confusing pseudocholinesterase (succinylcholine, mivacurium) with the non-specific esterases that hydrolyse atracurium
3. ❌ Saying sugammadex can reverse atracurium
4. ❌ Forgetting that laudanosine is hepatically/renally eliminated (unlike parent drug)
5. ❌ Not recognising that hypothermia prolongs atracurium more than most NMBAs
6. ❌ Stating cisatracurium is "safer" without specifying why (no histamine, less laudanosine)
7. ❌ Giving neostigmine when TOF count is 0 (ceiling effect—cannot overcome deep block)

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This content is designed for ANZCA Primary Examination preparation. Always verify current guidelines and local protocols.