Neuromuscular blocking agents

Contents

Pharmacology — Neuromuscular Junction

At the neuromuscular junction (NMJ), motor nerve action potentials trigger acetylcholine (ACh) release from presynaptic vesicles. ACh binds nicotinic acetylcholine receptors (nAChR) on the postjunctional motor endplate — ligand-gated ion channels that, when activated, depolarise the muscle membrane and trigger an action potential → muscle contraction.

After binding, ACh is rapidly hydrolysed by acetylcholinesterase (synaptic cleft) and plasma pseudocholinesterase (suxamethonium).

NMBAs produce muscle relaxation by interfering at the nAChR:

  • Depolarising: mimic ACh — sustained receptor activation → depolarisation block
  • Non-depolarising: competitive antagonism at ACh binding sites → prevent receptor activation

Depolarising NMBAs — Suxamethonium

Mechanism

Suxamethonium (succinylcholine) is a bis-cholinester that binds nAChR like ACh but is resistant to acetylcholinesterase. This produces sustained receptor depolarisation:

  • Phase I block (depolarisation block): visible fasciculations then flaccid paralysis; sustained channel opening prevents repolarisation
  • Phase II block (desensitisation block): prolonged exposure → receptor conformational change → resembles non-depolarising block; may occur with repeated doses or infusion

Pharmacokinetics

  • Onset: 30–60 seconds (fastest of all NMBAs)
  • Duration: 8–12 minutes (hydrolysed by plasma pseudocholinesterase — an enzyme encoded by the BCHE gene)
  • Metabolite: succinylmonocholine (10% activity; cleared renally)

Clinical Use

  • Rapid sequence intubation (RSI): fastest onset → shortest laryngoscopy window; dose 1–1.5 mg/kg
  • Useful when rapid recovery of spontaneous ventilation is desirable (anticipated difficult airway, short procedures)

Contraindications and Cautions

Hyperkalaemia risk (from massive K⁺ release via depolarisation of extra-junctional nAChRs):

  • Burns (>48 hours after): upregulation of extra-junctional nAChRs begins after 24–48h
  • Prolonged immobility or ICU-acquired neuromuscular disorders (>1 week)
  • Upper or lower motor neurone lesions (denervation)
  • Crush injuries (>24h)
  • Severe rhabdomyolysis
  • Tetanus (massive depolarisation from fasciculations is particularly hazardous)
  • Note: Safe in the first 24h after burns or crush injury (extra-junctional upregulation has not yet occurred)

Other contraindications:

  • Personal or family history of malignant hyperthermia (MH) — suxamethonium is a potent MH trigger
  • Known pseudocholinesterase deficiency — prolongs block from minutes to hours (clinically manageable if anticipated; neostigmine does not help; sugammadex ineffective; supportive ventilation until recovery)
  • Open eye injury (modest IOP rise from fasciculations — relative contraindication; debated)
  • Myotonias (e.g. myotonic dystrophy) — sustained contraction from fasciculations may occur

Treatment of prolonged suxamethonium block: ventilate and support until recovery; confirm with TOF; fresh frozen plasma may provide pseudocholinesterase (limited evidence).

Non-Depolarising NMBAs

Competitive antagonists at the postjunctional nAChR. Reversed by anticholinesterases or sugammadex.

Classification

Aminosteroids: rocuronium, vecuronium, pancuronium
Benzylisoquinoliniums: cisatracurium, atracurium, mivacurium

Individual Agents

Rocuronium

  • Onset: 60–90 seconds at 0.6 mg/kg; 1.2 mg/kg achieves intubating conditions equivalent to suxamethonium (can be used for RSI)
  • Duration: 30–60 min (0.6 mg/kg); 60–90 min (1.2 mg/kg)
  • Metabolism: hepatic (85%) and renal (15%); prolonged in severe hepatic failure
  • Key advantage: fully reversible with sugammadex even from deep block (zero TOF)
  • First choice for RSI when suxamethonium is contraindicated

Vecuronium

  • Aminosteroid; intermediate duration (25–40 min)
  • Hepatically metabolised; 3-desacetyl metabolite active (may accumulate in renal failure)
  • Rarely used in UK ICU; superseded by rocuronium and cisatracurium

Cisatracurium

  • Benzylisoquinolinium; one isomer of atracurium
  • Hofmann elimination: spontaneous non-enzymatic degradation at physiological pH and temperature → completely independent of organ function
  • Also undergoes ester hydrolysis (non-enzymatic)
  • Metabolite: laudanosine (CNS stimulant) + acrylate — laudanosine levels clinically insignificant with therapeutic doses and adequate clearance
  • Preferred NMBA in ICU, especially in hepatic or renal failure, as metabolism is organ-independent
  • Does NOT release histamine (unlike atracurium)
  • Duration: ~45–75 min

Atracurium

  • Benzylisoquinolinium; similar Hofmann elimination
  • Releases histamine (dose-related) → bronchospasm, hypotension, flushing; administer slowly; avoid large rapid boluses
  • Superseded by cisatracurium in most ICU settings

Pancuronium

  • Aminosteroid; long duration (60–90 min)
  • Tachycardia (vagolytic and sympathomimetic)
  • Largely obsolete; residual block and CV effects are problematic

Train-of-Four Monitoring

Train-of-four (TOF) stimulation delivers four supramaximal ulnar nerve stimuli at 2 Hz (one every 0.5 seconds), observing adductor pollicis twitch response.

Interpretation

Twitches (TOF count) Approximate receptor occupancy
0 twitches >95%
1 twitch ~90%
2 twitches ~80%
3 twitches ~75%
4 twitches (no fade) ≤70%
4 twitches + fade 70–80% (residual block)

Clinical targets:

  • ICU maintenance paralysis: 1–2 twitches (sufficient block without unnecessary overdose)
  • Intubation/surgery: 0 twitches
  • Safe for extubation / adequate reversal: 4 twitches with TOF ratio ≥0.9 (requires acceleromyography or quantitative TOF monitor)

Post-Tetanic Count (PTC)

Used when TOF count = 0; 50 Hz tetanic stimulus for 5 seconds, then count post-tetanic twitches. PTC 1–2 → profound block; PTC >15 → TOF will recover soon.

Reversal Agents

Anticholinesterases (Neostigmine)

  • Inhibit acetylcholinesterase → ↑ ACh at NMJ → competitively displaces non-depolarising NMBA
  • Only effective when TOF ≥2 twitches (insufficient ACh to displace if block is profound)
  • Must be combined with glycopyrrolate or atropine to block muscarinic effects (bradycardia, excessive secretions, bronchoconstriction)
  • Dose: neostigmine 2.5 mg IV + glycopyrrolate 0.5 mg IV
  • Ineffective against suxamethonium (depolarising block) — may prolong it

Sugammadex

  • Modified γ-cyclodextrin: encapsulates and sequesters rocuronium (primary) and vecuronium in plasma → rapid reduction in free drug concentration → NMBA dissociates from nAChR
  • Does NOT work for benzylisoquinoliniums (cisatracurium, atracurium, suxamethonium)
Clinical scenario Sugammadex dose
Routine reversal (TOF 2–3 twitches) 2 mg/kg
Deep block reversal (TOF 0, PTC ≥2) 4 mg/kg
Immediate reversal post-RSI dose 16 mg/kg

Advantages over neostigmine:

  • Effective at any depth of block
  • Faster reversal
  • Safe in suxamethonium contraindications (no interaction)
  • Can reverse profound block immediately after 1.2 mg/kg rocuronium RSI dose (failed intubation rescue)
  • No muscarinic side effects (no need for anticholinergic)

Cautions: may reduce efficacy of hormonal contraception (theoretical — advise barrier contraception for 7 days); prolongs activated partial thromboplastin time (transient, clinically insignificant); bradycardia reported rarely.

NMBAs in the ICU

Indications

  • Facilitation of mechanical ventilation in severe ARDS (eliminate ventilator dyssynchrony)
  • Treatment of refractory status epilepticus (EEG monitoring essential)
  • Management of elevated ICP (prevent Valsalva from coughing)
  • Control of refractory shivering (therapeutic hypothermia)
  • Tetanus or strychnine poisoning

Preferred Agent

Cisatracurium: organ-independent metabolism; preferred for prolonged ICU use; no histamine release.

Complications of Prolonged NMB in ICU

  • ICU-acquired weakness (ICUAW): critical illness myopathy and/or polyneuropathy; worsened by prolonged NMBA + corticosteroid exposure + sepsis; difficult to extubate; prolonged rehabilitation
  • Inadequate sedation: patients may be aware but unable to communicate or move (pharmacological horror); mandatory to ensure adequate sedation/analgesia before and during NMBA
  • Pressure injuries: reduced spontaneous movement → pressure necrosis
  • DVT: immobility; ensure thromboprophylaxis
  • Corneal injury: loss of blink reflex; tape eyes closed and apply lubricant

Monitoring Requirements

  • TOF every 4h (target 1–2 twitches); adjust infusion accordingly
  • Daily sedation and NMBA review with clear justification for continuation
  • Evaluate for continued need every 24–48h; discontinue as soon as the indication resolves

Key Trials

Trial Year Question Finding
ACURASYS (Papazian, NEJM) 2010 48h cisatracurium vs placebo in moderate-severe ARDS (P:F <150) Improved 90-day survival, reduced barotrauma, reduced ICU-acquired weakness
ROSE (ROSE Network, NEJM) 2019 Cisatracurium + light sedation vs lighter sedation alone in moderate-severe ARDS No 90-day survival benefit; no difference in any clinical outcome

The discrepancy between ACURASYS and ROSE is largely explained by the control arm: ROSE used protocolised lighter sedation in the control group (unlike ACURASYS, which used deeper sedation), suggesting the benefit seen in ACURASYS was from reducing dyssynchrony and oversedation, not from NMBA per se. Current practice: use NMBAs selectively in severe ARDS when lighter sedation fails to control dyssynchrony or when life-threatening hypoxaemia persists.

Viva Questions

1. Explain why suxamethonium can cause hyperkalaemia and in which patients this is dangerous.

Suxamethonium binds and activates nicotinic ACh receptors at the motor endplate, causing sustained depolarisation. This channel activation allows K⁺ to efflux from muscle cells — in healthy individuals, this raises serum potassium by only 0.5–1 mmol/L, which is clinically insignificant. However, in conditions associated with upregulation of extra-junctional acetylcholine receptors (extra-junctional nAChRs spread across the entire muscle membrane rather than being confined to the endplate), the same depolarising stimulus causes a massive increase in membrane area exposed to K⁺ efflux, potentially raising serum K⁺ by 3–5 mmol/L or more — sufficient to cause fatal ventricular arrhythmia. Extra-junctional nAChR upregulation occurs in: burns (begins 24–48h post-injury), prolonged immobility or critical illness neuromuscular disease, upper or lower motor neurone injury, denervation, severe rhabdomyolysis. These conditions are therefore contraindications. The window matters: suxamethonium is safe in the first 24 hours after burns or crush injury (upregulation has not yet occurred) but contraindicated thereafter.

2. What is Hofmann elimination and why is it clinically important for cisatracurium?

Hofmann elimination is a spontaneous, non-enzymatic degradation reaction that occurs at physiological pH (~7.4) and temperature (37°C). Cisatracurium (and atracurium) undergo this reaction, breaking down into laudanosine and a monoacrylate compound regardless of hepatic or renal function. This means cisatracurium metabolism is completely organ-independent — it does not rely on hepatic enzymes, renal excretion, or plasma cholinesterases. This makes it the NMBA of choice in hepatic failure, renal failure, multi-organ dysfunction, and prolonged ICU infusions where accumulation of renally or hepatically cleared drugs would be expected. Laudanosine is a CNS stimulant (convulsions in animal models at very high doses), but levels achieved with therapeutic cisatracurium use in patients with adequate clearance are well below toxic thresholds. An important practical point: cisatracurium does NOT release histamine (unlike atracurium at equivalent doses), making it haemodynamically stable. It is the ideal NMBA for prolonged ICU infusion.

3. Describe the ACURASYS trial, the ROSE trial, and how you reconcile their apparently contradictory findings.

ACURASYS (Papazian 2010) randomised moderate-severe ARDS patients (P:F <150) to 48h of cisatracurium infusion versus placebo and reported improved 90-day survival, reduced barotrauma, and reduced ICU-acquired weakness in the cisatracurium group. ROSE (2019) repeated the question with a larger sample and found no difference in any clinical outcome. The critical methodological difference lies in the control group: ACURASYS used a relatively deeply sedated control arm; ROSE used protocolised lighter sedation in the control. This suggests that the benefit in ACURASYS came from eliminating ventilator dyssynchrony (which causes cyclic lung injury) and avoiding excessive sedation, rather than from muscle relaxation per se. When lighter sedation is already used in the control group and dyssynchrony is minimised, adding NMBA confers no additional benefit. The practical conclusion: optimise sedation and ventilator settings first in severe ARDS; use NMBAs selectively when dyssynchrony persists despite appropriate sedation, or in life-threatening hypoxaemia where all dyssynchrony must be eliminated.

4. A patient undergoing RSI for a difficult airway scenario cannot be intubated or oxygenated after 1.2 mg/kg rocuronium. What do you do?

This is a cannot-intubate-cannot-oxygenate (CICO) emergency. Immediate priorities: (1) Call for help — second anaesthetist, ENT/airway team, theatre; (2) Attempt to oxygenate by all means: bag-mask with 2-person technique, insert oral or nasopharyngeal airway, attempt supraglottic airway device (SAD — second-generation LMA/iGel); (3) Declare a CICO emergency; prepare for front-of-neck airway (FONA) if oxygenation fails: scalpel cricothyroidotomy is the definitive rescue technique (bougie-assisted scalpel technique per DAS guidelines); (4) Give sugammadex 16 mg/kg (immediate reversal dose for 1.2 mg/kg rocuronium) — this is a key advantage of rocuronium over suxamethonium in RSI: full reversal is possible within 3 minutes. Note that sugammadex is an option if oxygenation can be maintained and the decision is to abandon the attempt, wake the patient up, and make alternative arrangements. It does NOT preclude FONA if the patient is truly desaturating and not oxygenatable. The airway takes absolute priority — sugammadex may allow reversal and spontaneous breathing if oxygenation is borderline, but is not a substitute for FONA if the patient is critically hypoxic.