NMB monitoring and complications, train-of-four, agent choice, ACURASYS/ROSE, ICU-acquired weakness

Table of Contents

1. Physiological and Pharmacological Framework
2. Neuromuscular Junction Physiology and NMB Mechanism
3. Drug-Specific Detail: Cisatracurium vs Rocuronium
4. Monitoring: Train-of-Four and Peripheral Nerve Stimulation
5. Reversal Agents: Neostigmine vs Sugammadex
6. Evidence Base: ACURASYS, ROSE, and Beyond
7. ICU-Acquired Weakness: CIM, CIP, and Mixed Syndromes
8. Risk Mitigation Strategies
9. Post-NMB Residual Paralysis
10. Practical ANZ ICU Application
11. Key Numbers Block
12. Viva Points Block

1. Physiological and Pharmacological Framework

• Neuromuscular blocking agents (NMBAs) act at the nicotinic acetylcholine receptor (nAChR) at the neuromuscular junction (NMJ).
• Understanding receptor physiology is essential before interpreting monitoring data or selecting an agent.

The Neuromuscular Junction

The NMJ consists of:

• Presynaptic terminal: motor neuron axon ending, containing vesicles of acetylcholine (ACh), approximately 5,000-10,000 molecules per vesicle
• Synaptic cleft: ~50 nm wide; ACh diffuses across
• Postsynaptic membrane: junctional folds rich in nAChRs (alpha-2-beta-delta-epsilon subunit configuration in adult NMJ)
• On nerve depolarisation, voltage-gated calcium channels open, vesicles fuse, and ACh is released.
• ACh binds two alpha-subunits of the nAChR, opening the ion channel (sodium and potassium flux), causing end-plate potential and subsequent muscle action potential.
• ACh is rapidly hydrolysed by acetylcholinesterase at the NMJ.

Receptor Reserve and Blockade Threshold

• The NMJ has enormous receptor reserve, approximately 75-80% of receptors must be blocked before twitch depression becomes measurable.
• Complete abolition of the twitch requires blockade of ~92-95% of receptors.
• This "margin of safety" is why small amounts of residual receptor occupancy do not automatically impair clinical function, but also why standard clinical observation substantially underestimates residual paralysis.

NMB Mechanism: Competitive (Non-Depolarising) Agents

• Competitive NMBAs, all agents discussed here, bind the alpha-subunits of nAChRs without activating them, preventing ACh binding and channel opening.
• They do not cause membrane depolarisation.

The blockade is:

• Concentration-dependent and reversible
• Modulated by: ACh concentration (more ACh at synapse → competition → reduced block), temperature (hypothermia prolongs), acid-base status (acidosis enhances block with most agents), plasma protein binding, and renal/hepatic clearance

Stimulation of the motor nerve releases ACh quanta normally, but with insufficient receptor occupancy available for response, hence the twitch depression pattern seen on nerve stimulation.

2. Neuromuscular Junction Physiology Applied to Monitoring

Why Peripheral Nerve Stimulation Works

• External electrical stimulation of a peripheral motor nerve at supramaximal current (typically 50-60 mA) depolarises all axons in the nerve, triggering maximal ACh release.
• The muscle twitch response reflects the proportion of nAChRs available (i.e. not blocked).
• This is the physiological basis of all train-of-four (TOF) monitoring.

Fade and Post-Tetanic Potentiation

Two phenomena are fundamental to interpreting nerve stimulation patterns:

• Fade: With repetitive stimulation, presynaptic nAChRs (which regulate ACh mobilisation) become blocked by competitive NMBAs, impairing ACh vesicle mobilisation.
• Successive twitches show progressively reduced amplitude, this is fade, quantified as the TOF ratio (T4/T1).
• Post-tetanic potentiation (PTP): After tetanic stimulation (50 Hz for 5 seconds), a massive release of ACh from presynaptic stores occurs.
• Subsequent single twitches are augmented.
• This is exploited in the post-tetanic count (PTC) to assess deep/profound blockade when TOF twitches are absent.

3. Drug-Specific Detail: Cisatracurium vs Rocuronium

• These are the two agents used for infusion NMB in ANZ ICUs.
• Each has a distinct pharmacokinetic profile that dictates suitability in different clinical scenarios.

Pharmacodynamic Comparison

Cisatracurium in Detail

• Mechanism of elimination, Hofmann degradation: This is a spontaneous, temperature- and pH-dependent chemical process occurring in plasma (not enzymatic).
• At physiological temperature and pH 7.4, cisatracurium undergoes non-enzymatic breakdown to laudanosine (a tertiary amine) and a monoquaternary acrylate.

Hofmann degradation is:

• Organ-independent: does not require hepatic or renal function
• Temperature-sensitive: hypothermia slows elimination, so paralysis is prolonged in therapeutic hypothermia
• pH-sensitive: alkalosis accelerates, acidosis slows
• Laudanosine: The primary metabolite of Hofmann degradation.
• In animal models, high laudanosine concentrations cause seizures and CNS excitation.
• In clinical ICU use with normal dosing, laudanosine accumulation does not reach clinically significant concentrations; however, theoretical concern exists in prolonged infusions, hepatic failure (laudanosine is hepatically metabolised), and renal failure (which impairs its excretion).
• Clinical niche: Preferred for patients with multi-organ failure (particularly combined hepatorenal failure), where organ-independent elimination is advantageous.
• It is the agent typically used in ARDS infusion protocols (as in ACURASYS).

Dose: Intubation 0.1-0.2 mg/kg; infusion 0.5-10 mcg/kg/min (typical 1-3 mcg/kg/min for moderate block in ARDS).

Rocuronium in Detail

• Mechanism of elimination: Primarily hepatic with biliary excretion.
• Approximately 10-25% undergoes renal excretion.
• Minimal active metabolites.
• Duration is significantly prolonged in hepatic failure and to a lesser extent in renal failure.
• Volume of distribution is relatively large, contributing to a longer context-sensitive half-time with prolonged infusions.

Sugammadex reversibility: Rocuronium is the only agent in common ANZ ICU use that can be rapidly reversed with sugammadex. This is a crucial advantage in two settings:

1. Failed RSI: rocuronium 1.2 mg/kg (high-dose RSI) reversed with sugammadex 16 mg/kg
2. Post-infusion residual paralysis: rapid reversal possible after prolonged ICU infusions

Clinical niche: Preferred when sugammadex reversal capability is required, when rapid onset is needed (RSI), or when Hofmann-dependent metabolism is not critical.

Dose: RSI 1.0-1.2 mg/kg; infusion 6-12 mcg/kg/min (titrated to TOF target).

Vecuronium and Pancuronium (Historical Context)

• Vecuronium and pancuronium are aminosteroids still occasionally encountered.
• Both accumulate in renal/hepatic failure and are associated with prolonged neuromuscular blockade and ICU-acquired myopathy risk.
• Their use for infusion in the modern ICU is discouraged.
• Pancuronium's vagolytic and sympathomimetic effects (tachycardia, hypertension) are undesirable in the critically ill.

4. Monitoring: Train-of-Four and Peripheral Nerve Stimulation

Train-of-Four (TOF): Physiological Basis

• TOF monitoring delivers four supramaximal electrical stimuli at 2 Hz (i.e. 0.5 seconds apart) to a peripheral motor nerve.
• The ratio of the fourth twitch amplitude to the first, the TOF ratio (TOFR), reflects the degree of NMB.

$$\text{TOFR} = \frac{T4}{T1}$$

• At complete absence of NMBAs: TOFR = 1.0 (no fade).
• As NMB deepens, T4 disappears first, then T3, T2, and finally T1.

Post-Tetanic Count (PTC)

When TOF count = 0, the PTC is used to estimate the depth of block and predict time to TOF recovery:

• Deliver tetanic stimulus (50 Hz, 5 sec)
• Wait 3 seconds
• Deliver 15 single twitches at 1 Hz
• Count the number of post-tetanic twitches

A higher PTC (e.g. PTC = 10-15) indicates lighter deep block; lower PTC (1-2) indicates profound block with longer time to TOF recovery.

Target in ARDS Protocols

Based on ACURASYS methodology, the target for ICU NMB infusion in ARDS is:

TOF count 1-2 out of 4 (T1 and T2 present, T3 and T4 absent)

• This represents moderate-to-deep block with approximately 80-90% receptor occupancy.
• It avoids the risk of inadvertent over-paralysis (profound/PTC-only block) while maintaining the clinical goal of synchrony, reduced effort, and lung protection.

Monitoring Sites and Technique

Preferred sites (in decreasing order of reliability):

1. Ulnar nerve at the wrist (adductor pollicis response, thumb adduction); most reproducible and best validated
2. Facial nerve (orbicularis oculi); accessible when upper limb not available, but resistance to NMB is higher, may overestimate depth of paralysis in the limbs; do not use to guide dosing upward
3. Common peroneal nerve (dorsiflexion of great toe); less commonly used
4. Posterior tibial nerve (plantar flexion)

• Electrode placement: Negative electrode (black) distal, positive electrode (red) proximal.
• Ensure good skin contact; dry, clean skin reduces impedance.

Quantitative vs qualitative monitoring:

• Qualitative (subjective): clinician feels or observes twitch; subject to significant inter-observer variability; cannot reliably detect TOFR <0.9
• Quantitative (objective): acceleromyography (AMG), mechanomyography (MMG), kinemyography, or electromyography; AMG devices (e.g. TOF-Watch, TOFScan) are most practical at the bedside and provide numerical TOFR; considered gold standard for detecting residual paralysis

In ANZ ICU practice, qualitative (tactile or visual) is most common but quantitative monitoring should be used whenever available, particularly when titrating infusions and assessing recovery.

Practical Titration

1. Confirm adequate sedation/analgesia before commencing NMB
2. Obtain baseline TOF without NMB to confirm supramaximal stimulation and baseline TOFR = 1.0
3. Commence infusion, recheck TOF every 15-30 min until target achieved
4. Maintenance monitoring: TOF every 1-4 hours; document count and stimulation site
5. If TOF = 0/4, check PTC; if PTC ≥ 1-2, infusion may be acceptable; if PTC = 0, consider reducing or suspending infusion
6. Daily reassessment of indication for continued NMB

5. Reversal Agents: Neostigmine vs Sugammadex

Neostigmine (Anticholinesterase)

• Mechanism: Inhibits acetylcholinesterase at the NMJ, increasing synaptic ACh concentration, thereby competing with and displacing NMBAs.
• Because it raises ACh everywhere, muscarinic side effects (bradycardia, bronchospasm, increased secretions, gut motility) require co-administration of an anticholinergic (glycopyrrolate or atropine).

Limitations:

• Cannot reverse profound block (TOFR <0.2 or TOF count <2); in deep block, insufficient ACh can be generated
• Ceiling effect, once acetylcholinesterase is fully inhibited, further doses worsen outcome (paradoxical weakness from excess ACh)
• Works for benzylisoquinoliniums AND aminosteroids

Dose: 50 mcg/kg IV (max 5 mg), with glycopyrrolate 10 mcg/kg or atropine 20 mcg/kg

Onset: 5-10 minutes

Applicability in ICU: Has a role in reversal after cisatracurium infusion when TOF count is ≥2 and sugammadex is not available or being conserved.

Sugammadex (Selective Relaxant Binding Agent)

• Mechanism: Modified gamma-cyclodextrin molecule that encapsulates aminosteroid NMBAs (rocuronium > vecuronium) within its hydrophobic core, forming a tight, water-soluble complex that is renally excreted.
• Plasma-free drug concentration drops precipitously, creating a gradient that draws drug away from the NMJ into the central compartment and then into the sugammadex complex.
• This is NOT enzyme inhibition, it is direct molecular encapsulation.

Kinetics:

• No ceiling effect
• Reverses any depth of block, including profound (PTC = 0)
• Rapid: ~3 minutes for full reversal of 1.2 mg/kg rocuronium RSI dose
• Not affected by hepatic function; cleared renally (caution in severe CKD, complex may slowly dissociate; recommended to avoid in eGFR <30 mL/min or use with caution)

Dosing by depth of block:

Adverse effects:

• Hypersensitivity/anaphylaxis: rare but reported (~0.01-0.1%); more common than previously appreciated
• Bradycardia (uncommon, transient)
• Recurrence of NMB if insufficient dose given (under-dosing in obesity) or if drug redistributes from peripheral compartment
• Interaction with toremifene and hormonal contraceptives (binds progesterone, patients should use additional contraception for 7 days post-sugammadex)

Re-paralysis after sugammadex: If re-paralysis is required within 24 hours of sugammadex, rocuronium should be avoided (residual sugammadex may limit effectiveness); use cisatracurium instead.

6. Evidence Base: ACURASYS, ROSE, and Beyond

ACURASYS (2010)

Full name: Neuromuscular Blockers in Early Acute Respiratory Distress Syndrome

Design: French multicentre, double-blind, RCT; 340 patients with moderate-severe ARDS (PaO2/FiO2 <150, PEEP ≥5, within 48 hours of onset)

Intervention: Cisatracurium infusion 37.5 mg/hour for 48 hours vs placebo (with equivalent sedation depth in both arms using target RASS -3 to -5)

Key findings:

• Adjusted 90-day mortality: 31.6% (cisatracurium) vs 40.7% (placebo), significantly lower (HR 0.68; 95% CI 0.48-0.98; p=0.04)
• Pneumothorax rate lower in cisatracurium group
• Improved PaO2/FiO2 at 48 and 96 hours
• No significant difference in ICU-acquired weakness at 28 days

Mechanistic hypothesis: NMB reduced patient self-inflicted lung injury (P-SILI) by abolishing spontaneous breathing effort, reduced oxygen consumption, reduced pendelluft, and possibly reduced pulmonary inflammation (lower levels of IL-6, IL-8, TNF-alpha in BAL in cisatracurium group).

Limitations: Unblinded in terms of clinical monitoring; sedation assessment required touching patients (not possible in NMB group), so sedation depth may have differed; relatively small sample.

ROSE (2019)

Full name: Reevaluation Of Systemic Early Neuromuscular Blockade

Design: North American multicentre, unblinded, RCT (PETAL/ARDS Network); 1,006 patients with moderate-severe ARDS (PaO2/FiO2 <150)

Intervention: Cisatracurium infusion for 48 hours (with deep sedation, RASS -5) vs usual care (light sedation with cisatracurium rescue allowed for ventilator dyssynchrony)

Key findings:

• 90-day in-hospital mortality: 42.5% (cisatracurium) vs 42.8% (control), no significant difference (p=0.93)
• Respiratory outcomes (ventilator-free days, organ failure-free days), no difference
• Higher sedation in control group receiving cisatracurium than expected

Why does ROSE contradict ACURASYS?

This remains one of the most analysed questions in critical care. Proposed explanations:

1. ROSE mandated deep sedation in the NMB arm (RASS -5), whereas ACURASYS did not mandate deep sedation in the control arm, meaning the ACURASYS control group may have been undertreated (higher agitation, dyssynchrony, P-SILI)
2. ROSE control arm received more rescue cisatracurium than anticipated (~17% received NMB), blurring the difference
3. Time period: ROSE was performed later; changes in general ICU practice (lung-protective ventilation, liberal prone positioning, higher standard of care) may have reduced the marginal benefit of NMB
4. Mechanism of harm in ACURASYS control: may have been more related to excess sedation given to manage ventilator dyssynchrony rather than absence of NMB per se

Current consensus interpretation: Routine early NMB in moderate-severe ARDS is NOT mandated by evidence. However, cisatracurium NMB remains appropriate for:

• Refractory dyssynchrony despite optimised analgosedation
• Refractory hypoxaemia (as rescue)
• Prone positioning facilitation
• Life-threatening bronchospasm or severe ICP elevation

ACURASYS vs ROSE: Key Comparison Table

Other Relevant Trials

• ARMA (2000): Established 6 mL/kg IBW tidal volume as standard in ARDS.
• NMB use was permitted.
• This underpins why lung-protective ventilation is the non-negotiable background against which NMB is layered.
• PROSEVA (2013): Prone positioning reduces 28-day mortality in severe ARDS.
• NMB was used in >90% of PROSEVA patients in the prone group.
• While not an NMB trial, it supports that NMB and proning are complementary strategies in severe ARDS.
• SPICE-III (2019): Tested early goal-directed dexmedetomidine vs usual sedation in mechanically ventilated patients.
• Not primarily an NMB trial but informs sedation strategy: dexmedetomidine-based sedation did not reduce 90-day mortality, and lighter sedation targets are now standard, making the need for NMB less frequent when adequate analgosedation is achieved.
• AID-ICU (2022): Assessed haloperidol for ICU delirium.
• Not directly NMB-related but contextually relevant, NMB prevents any assessment of delirium or agitation during infusion, representing a clinical trade-off.

7. ICU-Acquired Weakness: CIM, CIP, and Mixed Syndromes

ICU-acquired weakness (ICUAW) is a clinically significant complication of critical illness and its treatments, with NMBAs as one of several contributing factors.

Definition

ICUAW is diagnosed clinically:

• Medical Research Council (MRC) Sum Score <48 out of 60 (testing 6 muscle groups bilaterally)
• Or grip strength <11 kg (male) / <7 kg (female)
• Must be attributable to critical illness itself (not pre-existing)

Prevalence: Approximately 25-60% of patients requiring mechanical ventilation >5-7 days.

Critical Illness Myopathy (CIM)

Pathophysiology:

• Loss of thick (myosin) filaments, selective myosin filament loss is the histological hallmark
• Downregulation of muscle-specific protein synthesis
• Increased muscle protein catabolism (ubiquitin-proteasome pathway activation)
• Mitochondrial dysfunction, oxidative stress
• Reduced sodium channel excitability (inexcitable muscle membrane)
• NMBA use (especially combined with corticosteroids) is a risk factor, exact mechanism unclear but may involve reduced muscle activity causing atrophy and reduced anabolic drive

Electrophysiology: Low amplitude CMAPs with normal conduction velocities; early fibrillation potentials on EMG

Histology: Selective myosin heavy chain loss; myofilament disorganisation; necrosis in severe cases

Risk factors for CIM: Corticosteroids (strong association), NMBAs (moderate association, particularly when combined with steroids), sepsis, hyperglycaemia, female sex, immobility

Critical Illness Polyneuropathy (CIP)

Pathophysiology:

• Primarily axonal degeneration of both motor and sensory axons
• Thought to be driven by microvascular dysfunction of the vasa nervorum in the context of sepsis-associated inflammatory mediator excess
• Impaired axonal energy metabolism (sodium channel dysfunction)
• Distinct from Guillain-Barré syndrome (no demyelination; no albuminocytological dissociation)

Electrophysiology: Reduced CMAP and SNAP amplitudes with preserved conduction velocities; denervation potentials on EMG

Risk factors for CIP: Sepsis (strongest), multi-organ failure, prolonged ICU stay, hyperglycaemia, aminoglycosides

NMBAs: NMBAs do not directly cause CIP but contribute to the clinical severity by preventing mobilisation and adding to muscle deconditioning.

Mixed CIM + CIP

• The majority (~50%) of patients with ICUAW have features of both.
• Clinically and electrophysiologically, separation can be difficult.
• Nerve conduction studies (NCS) and EMG are the diagnostic gold standard but require specialised input.

Comparative Summary

NMB-Specific Contribution to ICUAW

The relationship between NMBAs and ICUAW is modulated by:

1. Duration of NMB: Risk increases substantially beyond 48-72 hours; 48-hour protocols (as in ACURASYS/ROSE) have not shown significantly increased ICUAW at 28 days
2. Agent: Aminosteroids (pancuronium, vecuronium) carry higher risk than cisatracurium, likely due to accumulation and prolonged blockade rather than intrinsic toxicity
3. Concurrent corticosteroids: The combination of high-dose steroids + NMBAs dramatically increases CIM risk
4. Immobility: NMB prevents any voluntary muscle activity, worsening disuse atrophy

8. Risk Mitigation Strategies

For ICU-Acquired Weakness

For Residual Paralysis

• Implement quantitative TOF monitoring on cessation of NMB
• Use sugammadex for rocuronium-based infusions where reversal is required
• Do not extubate until TOFR ≥ 0.9 confirmed by quantitative monitoring
• Maintain awareness of factors prolonging NMB (hypothermia, acidosis, renal/hepatic failure, drug interactions)

Drug Interactions Prolonging NMB

9. Post-NMB Residual Paralysis

Definition and Significance

Residual neuromuscular blockade (RNMB) is defined as TOFR <0.9 after intended clinical recovery. In the perioperative setting, RNMB significantly increases risk of:

• Aspiration (pharyngeal muscle weakness)
• Upper airway obstruction and hypoxia
• Atelectasis and pneumonia
• ICU re-admission

In the ICU context, RNMB after prolonged infusion carries additional risks of:

• Delayed weaning from mechanical ventilation
• Failure to recognise return of awareness
• Inability to assess neurological status

Why TOFR 0.9 is the Target

• At TOFR of 0.7: patients have obvious clinical weakness, inability to sustain head lift, impaired swallowing.
• At TOFR 0.8: subtle weakness but upper airway reflexes remain impaired.
• At TOFR ≥0.9: pharyngeal muscle coordination normalises and clinical adequacy of recovery is established.
• However, some evidence suggests TOFR ≥0.95 for complete recovery of hypoxic ventilatory response.

Assessing Recovery After ICU NMB Infusion

1. Cease infusion and allow washout (context-sensitive, depends on agent used, duration, renal/hepatic function, temperature)
2. Monitor TOF every 30 minutes until count recovers
3. Confirm TOF count 4/4, then use quantitative monitoring to confirm TOFR ≥0.9
4. Clinical tests: sustained 5-second head lift, sustained hand grip, adequate tidal volumes with pressure support
5. Consider sugammadex for rocuronium infusions where active reversal is clinically indicated

Context-Sensitive Half-Time and Prolonged Infusions

• With prolonged ICU infusions, the apparent duration of action extends substantially as peripheral compartments (muscle, fat) become saturated and continue to release drug after the infusion ceases.
• This is particularly relevant for rocuronium in renal failure and for cisatracurium in hepatic failure (impaired laudanosine clearance).
• Sugammadex can reverse even profound rocuronium block rapidly regardless of infusion duration, which is one of its key advantages in the ICU.

Awareness During NMB

Patients paralysed without adequate sedation are at risk of awareness with recall, a deeply distressing and potentially traumatic experience. Institutional protocols must mandate:

• Assessment and documentation of sedation before commencing NMB
• Continued sedation monitoring (indirect surrogates: haemodynamic parameters, pupillary response, lacrimation, electroencephalography-based monitors such as BIS where available, noting BIS has limitations in the ICU)
• Prompt response to signs suggesting inadequate sedation during NMB (tachycardia, hypertension, diaphoresis, tearing)

10. Practical ANZ ICU Application

When to Commence NMB Infusion