ICU-Acquired Weakness (ICUAW)

CICM Exam Focus

Likely Exam Scenarios

Written SAQ

• "Describe the pathophysiology, risk factors, and diagnostic criteria for ICU-acquired weakness"
• "Outline strategies for preventing ICUAW in a patient with severe sepsis requiring prolonged mechanical ventilation"
• "Compare and contrast CIP and CIM including clinical features, electrophysiology, and prognosis"
• "A patient has failed to wean from mechanical ventilation despite resolution of the primary illness. Outline your approach to diagnosis and management"

Hot Case

• Long-stay ventilated patient failing weaning with generalized weakness
• Patient with septic shock day 14, flaccid quadriparesis, and areflexia
• Post-ARDS patient unable to mobilize despite resolution of respiratory failure

Viva Voce

• Clinical case: 58-year-old post-septic shock, day 21, cannot lift limbs against gravity
• Discussion of electrophysiology findings in CIP vs CIM
• Evidence for prevention strategies (early mobility, glycemic control)
• Management of prolonged weaning failure due to ICUAW

Assessment Domains

High-Yield Topics

1. Definition and Classification: ICUAW umbrella term; CIP vs CIM vs overlap
2. Pathophysiology: Microvascular dysfunction, sodium channelopathy, myosin loss, ubiquitin-proteasome pathway
3. Risk Factors: Sepsis, MODS, hyperglycemia, corticosteroids + NMBAs synergy (De Jonghe OR 14.9)
4. Clinical Features: Symmetrical weakness, facial sparing, areflexia (CIP), respiratory muscle involvement
5. Diagnosis: MRC sum score <48/60, NCS/EMG patterns, muscle ultrasound, biopsy findings
6. Prevention: PADIS guidelines, ABCDEF bundle, early mobilization (conditional recommendation), glycemic control
7. NICE-SUGAR: Target glucose ≤180 mg/dL, avoid tight control (hypoglycemia worsens outcomes)
8. Prognosis: Muscle wasting 20% by day 10, recovery months-years, increased 1-year mortality

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Introduction

Definition

ICU-Acquired Weakness (ICUAW) is a syndrome of clinically detected, generalized weakness in critically ill patients with no plausible etiology other than critical illness. It encompasses three distinct but overlapping entities:

Operational Definition (Stevens 2009): ICUAW is diagnosed when:

1. Generalized weakness develops after the onset of critical illness
2. MRC sum score <48/60 OR mean MRC grade <4 in all testable muscle groups
3. Weakness is not explained by another condition (stroke, spinal cord injury, pre-existing neuromuscular disease)
4. Patient is awake and cooperative (RASS -1 to +1)

Evidence: PMID: 19826024 (Stevens 2009 - consensus definition), PMID: 21349437 (Latronico 2011 - Lancet Neurology review).

Epidemiology

Incidence

Prevalence

• Day 7: 40-50% of long-term ICU patients
• ICU Discharge: 25-35% with clinically significant weakness
• Hospital Discharge: 35% of ARDS survivors have persistent weakness
• 1-Year Post-Discharge: 10-30% have residual deficits affecting function

Mortality Impact

• ICU Mortality: OR 1.5-2.0 for ICUAW vs no ICUAW
• Hospital Mortality: Increased by 30-50%
• 1-Year Mortality: 30-50% (vs 15-25% without ICUAW)
• Duration of MV: Increased by 7-10 days
• ICU LOS: Increased by 10-14 days
• Hospital LOS: Increased by 20-30 days

Evidence: PMID: 12479764 (De Jonghe 2002 - CRIMYNE study), PMID: 24108524 (Puthucheary 2013), PMID: 26021303 (Friedrich 2015).

Australian/New Zealand Context

ANZICS-CORE Data

• ICUAW affects 25-40% of Australian ICU survivors requiring MV ≥7 days
• Early mobilization programs implemented in majority of tertiary ICUs
• Growing recognition of Post-Intensive Care Syndrome (PICS) as major public health burden

Indigenous Health Considerations

• Aboriginal and Torres Strait Islander patients have:

  • 2-3× higher rates of sepsis (major ICUAW risk factor)
  • Higher prevalence of diabetes (hyperglycemia risk factor)
  • Potential barriers to prolonged rehabilitation post-discharge
  • Geographic challenges accessing specialized rehabilitation services
  • Important to involve Aboriginal Health Workers (AHWs) and Aboriginal Liaison Officers (ALOs) in care planning
  • Cultural considerations for prolonged hospital stays away from community

• Māori Health (New Zealand):

  • 2× higher rates of sepsis hospitalization
  • Whānau (extended family) involvement essential for rehabilitation planning
  • Māori Health Workers should be engaged early
  • Consider discharge planning to facilities closer to home communities

Evidence: PMID: 30113379 (PADIS 2018), PMID: 27637771 (ANZICS-CORE studies).

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Pathophysiology

Overview

ICUAW results from the convergence of multiple insults unique to critical illness:

CRITICAL ILLNESS
        │
        ├─────────────────────────────────────────────┐
        │                                             │
   SYSTEMIC                                    LOCAL TISSUE
   FACTORS                                      EFFECTS
        │                                             │
   ┌────┴────┐                              ┌────────┴────────┐
   │         │                              │                 │
Sepsis    SIRS                         Immobility        Mechanical
MODS      Cytokines                    Disuse            Ventilation
   │         │                              │                 │
   └────┬────┘                              └────────┬────────┘
        │                                           │
   MICROVASCULAR                              CATABOLIC
   DYSFUNCTION                                 STATE
        │                                           │
   ┌────┴────┐                              ┌───────┴───────┐
   │         │                              │               │
 CIP      Ion Channel                   Myosin        Autophagy
Axonal    Dysfunction                   Loss          Dysregulation
Death                                        │
        │                                    │
        └──────────┬─────────────────────────┘
                   │
              ICU-ACQUIRED
               WEAKNESS

Critical Illness Polyneuropathy (CIP)

Pathogenesis

1. Microvascular Dysfunction

• Systemic inflammation (SIRS/sepsis) → endothelial dysfunction
• Increased capillary permeability in endoneurial microvessels
• Endoneurial edema impairs oxygen and nutrient delivery to axons
• Lack of effective blood-nerve barrier in peripheral nerve (unlike CNS)
• Cytokine penetration (IL-1β, IL-6, TNF-α) into endoneurial space

2. Axonal Energy Failure

• Mitochondrial dysfunction ("cytopathic hypoxia")
• ATP depletion → failure of Na⁺/K⁺-ATPase pump
• Axonal membrane depolarization → sodium channel inactivation
• Calcium overload → activation of calpains → axonal degeneration
• Preferential vulnerability of distal axons (dying-back neuropathy)

3. Hyperglycemia-Induced Nerve Injury

• Oxidative stress via polyol pathway activation
• Advanced glycation end-products (AGEs) damage axonal proteins
• NICE-SUGAR showed hyperglycemia associated with worse neurological outcomes
• Glucose >180 mg/dL associated with increased CIP risk

Key Histological Features:

• Primary axonal degeneration (sensory and motor fibers)
• Wallerian degeneration distally
• Myelin relatively preserved
• No significant inflammatory infiltrate (unlike GBS)
• Denervation atrophy of muscle

Evidence: PMID: 18456102 (Latronico & Fenzi 2008), PMID: 21349437 (Latronico 2011), PMID: 15951139 (Finsterer 2005).

Critical Illness Myopathy (CIM)

Pathogenesis

1. Selective Myosin Loss (Thick Filament Myopathy)

• Hallmark finding: preferential loss of myosin heavy chain (MyHC) proteins
• Actin (thin filament) relatively preserved
• Results in "thick filament myopathy" on electron microscopy
• Causes profound weakness disproportionate to visible muscle atrophy

2. Ubiquitin-Proteasome System (UPS) Activation

• Major pathway for accelerated proteolysis in critical illness
• E3 ubiquitin ligases MuRF-1 (Muscle RING-finger protein-1) and MAFbx/Atrogin-1 upregulated
• These ligases target myosin for polyubiquitination and proteasomal degradation
• Upregulated within hours of critical illness onset

3. Calpain-Mediated Proteolysis

• Calcium-activated proteases (calpains) activated by intracellular calcium overload
• Degrade titin, nebulin, and other sarcomeric proteins
• Contribute to myofibrillar disarray

4. Autophagy Dysregulation

• Initially protective (removes damaged organelles)
• Becomes excessive → autophagic degradation of myofibrils
• Corticosteroids enhance autophagy through FOXO transcription factors

5. Sodium Channelopathy (Muscle Membrane Inexcitability)

• Acquired dysfunction of voltage-gated sodium channels (Nav1.4)
• Shift in voltage-dependence of inactivation to more hyperpolarized potentials
• Results in "electrically inexcitable" muscle
• Cannot generate action potentials even with direct electrical stimulation
• Explains weakness beyond what myosin loss alone would predict

Key Histological Features:

• Type II (fast-twitch) fiber atrophy predominates
• Selective myosin loss on immunohistochemistry
• Myofibrillar disorganization
• Fat infiltration in chronic cases
• No necrosis or inflammation (unlike rhabdomyolysis)

Evidence: PMID: 21803517 (Batt 2013), PMID: 11739620 (Larsson 2000), PMID: 26021303 (Friedrich 2015), PMID: 24703531 (Nardelli 2014).

CIP/CIM Overlap (CIPNM)

• Most patients (50%) have features of both CIP and CIM
• Shared risk factors and pathophysiological mechanisms
• Difficult to separate clinically; electrophysiology may distinguish
• Direct muscle stimulation (DMS) can differentiate nerve vs muscle component
• Prognosis generally intermediate between pure CIP (worse) and pure CIM (better)

Evidence: PMID: 28091515 (Shepherd 2017), PMID: 19409187 (Filipovic 2009).

Respiratory Muscle Involvement

Diaphragm Weakness

• Critical component of weaning failure
• Ventilator-Induced Diaphragm Dysfunction (VIDD):
  • Develops within 18-69 hours of controlled mechanical ventilation
  • Proteolytic pathways activated similar to limb muscles
  • 50% reduction in diaphragm force within 5-6 days
• Diaphragm atrophy visible on ultrasound (reduced thickness, excursion)
• Thickening fraction <30% predicts weaning failure

Clinical Significance

• ICUAW involving respiratory muscles is a major cause of prolonged weaning
• May persist after limb muscle recovery
• Paradoxical abdominal movement during SBT suggests diaphragm weakness

Evidence: PMID: 18725455 (Levine 2008 - VIDD), PMID: 23093163 (Hermans 2010 - diaphragm dysfunction).

Muscle Wasting Timeline

Puthucheary Study (PMID: 24108524):

• Prospective study of 63 critically ill patients
• Serial ultrasound of rectus femoris cross-sectional area

Clinical Implications:

• Muscle wasting begins within 24-72 hours
• Prevention strategies must start immediately
• Once established, recovery takes months to years

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Risk Factors

Major Risk Factors

De Jonghe CRIMYNE Study (PMID: 12479764)

Design: Prospective multicenter study, 95 patients ventilated ≥7 days Key Findings:

• ICUAW incidence: 25.3% (MRC <48)
• Independent risk factors:
  • "Corticosteroids: OR 14.9 (95% CI 3.2-69.8)"
  • "Duration of MODS: OR 1.28 per day"
  • "Female sex: OR 4.0 (95% CI 1.1-15.2)"

Clinical Implications:

• Corticosteroids are the strongest modifiable risk factor
• When steroids are required (e.g., septic shock per APROCCHSS), use lowest effective dose and shortest duration
• NMBAs not independent risk factor in multivariate analysis but synergistic with steroids

NICE-SUGAR and Hyperglycemia

Study: NICE-SUGAR Trial (PMID: 19318384)

• 6,104 patients randomized to intensive (81-108 mg/dL) vs conventional (≤180 mg/dL) glucose control
• Intensive control increased mortality (27.5% vs 24.9%, p=0.02)
• Increased hypoglycemia (6.8% vs 0.5%)

Implications for ICUAW:

• Avoid hypoglycemia (associated with worse outcomes)
• Target glucose ≤180 mg/dL
• Hyperglycemia (>180 mg/dL) still harmful; moderate control is optimal
• Van den Berghe's original Leuven data (PMID: 11794168) showed reduced CIP with tight control, but increased mortality in subsequent trials negated this benefit

Evidence: PMID: 19318384 (NICE-SUGAR), PMID: 11794168 (Leuven 2001).

NMBAs and ICUAW

Concerns:

• Synergistic myotoxicity with corticosteroids
• Prolonged immobilization
• Upregulation of denervation supersensitivity receptors
• Historical association with "acute quadriplegic myopathy syndrome"

ACURASYS Trial (PMID: 20843245):

• Early cisatracurium (48 hours) for severe ARDS
• No increase in ICUAW incidence at day 28
• Suggests brief NMBA use (<48h) may be safe

ROSE Trial (PMID: 30779531):

• Early cisatracurium with deep sedation vs light sedation without NMBAs
• No benefit from NMBAs in light sedation era
• Trend toward more ICU-acquired weakness with NMBAs (not statistically significant)

Clinical Recommendation:

• Minimize NMBA duration (<48 hours when possible)
• Avoid concurrent high-dose corticosteroids if possible
• Daily interruption of NMBA infusion to assess depth of block

Evidence: PMID: 20843245 (ACURASYS), PMID: 30779531 (ROSE), PMID: 8022443 (steroids + NMBAs synergy).

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Clinical Presentation

Cardinal Features

1. Generalized Symmetrical Weakness

• Affects all four limbs (quadriparesis/quadriplegia)
• Proximal and distal involvement
• Flaccid weakness (reduced tone)
• Develops after ICU admission (not present on day 1)

2. Facial Sparing

• Facial muscles typically preserved
• Distinguishes from GBS (facial weakness common), MG (ptosis, diplopia)
• Extraocular muscles spared (unlike MG)

3. Respiratory Muscle Involvement

• Diaphragm and intercostal weakness
• Manifests as weaning failure, shallow breathing
• Paradoxical abdominal movement (abdominal indrawing with inspiration)
• May be disproportionate to limb weakness

4. Reflex Changes

• CIP: Depressed or absent deep tendon reflexes (areflexia)
• CIM: Reflexes may be preserved initially, then reduced
• Overlap: Variable reflex findings

5. Sensory Findings

• CIP: Sensory loss (distal > proximal, stocking-glove pattern)
• CIM: Sensory preserved (pure motor)
• Difficult to assess in sedated/delirious patients

Distinguishing CIP from CIM

Clinical Phenotypes

1. Failure to Wean Phenotype

• Unable to liberate from mechanical ventilation
• Passed SBT criterion checks except for strength
• Weak cough, low NIF (>-20 cm H₂O), low VC (<15 mL/kg)
• May require tracheostomy for prolonged weaning

2. Failed Rehabilitation Phenotype

• Cannot participate in mobilization despite sedation cessation
• Unable to sit at edge of bed, stand, or transfer
• Presents during recovery phase of critical illness

3. Recurrent Respiratory Failure

• Successfully extubated but re-intubated for weakness-related respiratory failure
• Stridor absent (unlike post-extubation stridor from laryngeal edema)

Timeline of Development

Evidence: PMID: 21349437 (Latronico 2011 - clinical features), PMID: 19826024 (Stevens 2009).

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Diagnosis

Diagnostic Criteria (Stevens 2009)

ICU-Acquired Weakness (Clinical Diagnosis):

1. Generalized weakness developing after onset of critical illness
2. Diffuse (involving proximal AND distal muscles), symmetrical, flaccid, sparing facial and ocular muscles
3. MRC sum score <48/60 on two occasions ≥24h apart
4. Dependence on mechanical ventilation
5. Causes other than critical illness excluded

CIP (Requires Electrophysiology):

• ICUAW criteria met PLUS
• Compound muscle action potential (CMAP) amplitude reduced to <80% lower limit of normal in ≥2 nerves
• Sensory nerve action potential (SNAP) amplitude reduced to <80% LLN in ≥2 nerves
• Normal or near-normal conduction velocities (axonal pattern)

CIM (Requires Electrophysiology ± Biopsy):

• ICUAW criteria met PLUS
• SNAP amplitudes normal
• CMAP amplitudes reduced OR abnormal
• EMG shows myopathic motor unit potentials (short duration, low amplitude, polyphasic)
• ± Direct muscle stimulation shows reduced muscle fiber excitability
• ± Muscle biopsy shows myosin loss

Evidence: PMID: 19826024 (Stevens 2009 - consensus criteria).

MRC Sum Score

Assessment Method

Assess 6 muscle groups bilaterally (12 total):

Upper Limb (each side):

1. Shoulder abduction (deltoid)
2. Elbow flexion (biceps)
3. Wrist extension (wrist extensors)

Lower Limb (each side):

1. Hip flexion (iliopsoas)
2. Knee extension (quadriceps)
3. Ankle dorsiflexion (tibialis anterior)

MRC Grading Scale

Interpretation

Requirements:

• Patient must be awake and cooperative (RASS -1 to +1)
• Standardized positioning
• Two assessments ≥24h apart recommended
• Document as percentage: e.g., "MRC 36/60 = 60%"

Limitations:

• Requires cooperation (excludes sedated, delirious, encephalopathic patients)
• Subjective (inter-rater reliability can vary)
• May miss early/subclinical weakness
• Cannot differentiate CIP from CIM

Evidence: PMID: 8524412 (MRC scale validation), PMID: 18158437 (reliability in ICU).

Electrophysiology (NCS/EMG)

When to Perform

• Clinically suspected ICUAW but MRC cannot be performed (sedated patient)
• Need to differentiate CIP from CIM
• Atypical features suggesting alternative diagnosis
• Medicolegal documentation required
• Research purposes

Nerve Conduction Studies (NCS)

Motor NCS Findings:

• Reduced CMAP amplitudes (both CIP and CIM)
• Preserved or mildly slowed conduction velocities (axonal pattern)
• Prolonged distal latencies (mild)
• No conduction block (unlike GBS)

Sensory NCS Findings:

• CIP: Reduced SNAP amplitudes
• CIM: SNAP amplitudes NORMAL (key differentiator)

Typical Testing Protocol:

• Motor: Median, ulnar, peroneal, tibial nerves
• Sensory: Median, ulnar, sural nerves
• At least 2 motor + 2 sensory nerves per limb

Electromyography (EMG)

CIP Findings:

• Fibrillation potentials
• Positive sharp waves
• Reduced recruitment (neurogenic pattern)
• Normal motor unit morphology initially

CIM Findings:

• Short-duration, low-amplitude motor unit potentials (MUPs)
• Polyphasic MUPs
• Early recruitment (myopathic pattern)
• Fibrillations may be present

Direct Muscle Stimulation (DMS)

• Bypasses nerve to assess muscle excitability directly
• Useful when NCS shows reduced CMAPs but SNAP normal

Evidence: PMID: 21349437 (Latronico 2011 - electrophysiology), PMID: 9773689 (DMS methodology).

Muscle Ultrasound

Growing Role in Diagnosis

• Non-invasive, bedside assessment
• Does not require patient cooperation
• Can be performed in sedated patients
• Tracks muscle wasting over time

Measurements

Rectus Femoris:

• Cross-sectional area (CSA)
• Muscle thickness
• Echogenicity (increased in myopathy)

Diaphragm:

• Thickness at end-expiration (normal 2-4 mm)
• Thickening fraction (TF) = (Inspiration - Expiration) / Expiration × 100%
• TF <30% suggests diaphragm dysfunction

Evidence for Ultrasound

• Correlates with MRC sum score (PMID: 26382417)
• Can detect subclinical wasting before clinical weakness apparent
• Useful for tracking response to interventions (early mobility)

Limitations:

• Operator-dependent
• Cannot differentiate CIP from CIM
• Standardization needed for cutoff values

Evidence: PMID: 24108524 (Puthucheary - ultrasound measurements), PMID: 26382417 (ultrasound correlation).

Muscle Biopsy

Indications

• Atypical features suggesting alternative diagnosis
• Refractory weakness requiring histological confirmation
• Research settings
• Rarely needed for routine clinical diagnosis

CIM Histological Findings

• Type II fiber atrophy (fast-twitch fibers preferentially affected)
• Selective myosin loss on immunohistochemistry (ATPase staining shows "pale holes")
• Myofibrillar disorganization
• Fatty infiltration (chronic)
• Minimal/no necrosis (unlike rhabdomyolysis)
• Minimal/no inflammation (unlike polymyositis)

CIP Histological Findings (Nerve Biopsy)

• Axonal degeneration
• Wallerian degeneration
• Preserved myelin
• No inflammation (unlike vasculitic neuropathy)

Evidence: PMID: 11739620 (Larsson 2000 - thick filament loss), PMID: 8022443 (acute quadriplegic myopathy).

Differential Diagnosis

Evidence: PMID: 21349437 (Latronico 2011 - differential).

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Prevention

PADIS Guidelines 2018 (PMID: 30113379)

The Society of Critical Care Medicine (SCCM) published comprehensive guidelines for Pain, Agitation/sedation, Delirium, Immobility, and Sleep Disruption in adult ICU patients.

Mobilization Recommendation

Conditional Recommendation (Low Quality Evidence): "We suggest performing rehabilitation or mobilization in critically ill adults"

Rationale:

• Improvements in functional outcomes
• Reduction in duration of mechanical ventilation
• Trend toward reduced ICUAW incidence
• Low quality rating due to study heterogeneity

Safety Profile:

• Adverse event rate <1% (falls, unplanned extubation, catheter dislodgement)
• Benefits outweigh risks when implemented with structured protocols

ABCDEF Bundle

The ABCDEF bundle is an evidence-based approach to liberating patients from mechanical ventilation and preventing ICU complications including ICUAW.

Evidence: PMID: 28787372 (ABCDEF bundle outcomes), PMID: 30113379 (PADIS 2018).

Early Mobilization Evidence

Key Trials

Schweickert 2009 (PMID: 19446324):

• 104 patients receiving mechanical ventilation
• Early physical and occupational therapy vs usual care
• Results:
  • Better functional status at discharge (59% vs 35% independent)
  • Shorter delirium duration (2 vs 4 days)
  • Shorter MV duration (3.4 vs 6.1 days)

Schaller 2016 (PMID: 27132705):

• SOMS trial: Standardized rehabilitation protocol
• Improved MRC sum score at ICU discharge
• Shorter ICU LOS

Cochrane Review 2018 (PMID: 30063783):

• 4 RCTs, 690 patients
• Early mobilization improved:
  • Walking ability at discharge
  • Muscle strength
  • Quality of life
• No significant effect on mortality

Practical Implementation

Starting Criteria:

• Hemodynamically stable (no escalating vasopressors)
• FiO₂ <0.6, PEEP <10 cm H₂O
• No active arrhythmias
• Adequate sedation management (RASS -1 to +1)

Contraindications:

• Active CPR
• Unstable spinal injury
• Unstable fractures
• Active hemorrhage
• Elevated intracranial pressure
• Femoral sheath in place

Progression:

1. Passive range of motion →
2. Active-assisted exercises in bed →
3. Sitting at edge of bed →
4. Standing with assistance →
5. Marching in place →
6. Walking with assistance →
7. Independent ambulation

Evidence: PMID: 19446324 (Schweickert), PMID: 27132705 (SOMS), PMID: 30063783 (Cochrane).

Glycemic Control

NICE-SUGAR Target: Blood glucose ≤180 mg/dL (≤10 mmol/L)

• Avoid hyperglycemia (>180 mg/dL associated with increased CIP risk)
• Avoid hypoglycemia (<70 mg/dL associated with worse outcomes)
• Liberal glucose target (140-180 mg/dL) preferred in most patients
• SSC 2021: Target 144-180 mg/dL

Evidence: PMID: 19318384 (NICE-SUGAR), PMID: 11794168 (Leuven 2001).

Minimizing NMBA Exposure

Recommendations:

• Limit NMBA use to <48 hours when possible
• Daily interruption to assess depth of block
• Train-of-four monitoring (target 1-2/4 twitches)
• Avoid concurrent high-dose corticosteroids if feasible
• Consider cisatracurium (organ-independent elimination) in renal/hepatic dysfunction

Evidence: PMID: 20843245 (ACURASYS - 48h safe), PMID: 30779531 (ROSE - no benefit of NMBAs with light sedation).

Corticosteroid Management

Septic Shock (per APROCCHSS/ADRENAL):

• Hydrocortisone 200 mg/day (50 mg q6h or 200 mg continuous infusion)
• Consider fludrocortisone 50 μg/day (APROCCHSS)
• Limit duration to shock reversal (typically 5-7 days)

ARDS:

• Dexamethasone 20 mg × 5 days, then 10 mg × 5 days (DEXA-ARDS)
• Earlier initiation (<14 days) associated with better outcomes
• Weigh benefits against ICUAW risk

Clinical Pearls:

• Use lowest effective dose and shortest duration
• Avoid combined steroids + NMBAs when possible
• Monitor for steroid myopathy (proximal weakness, elevated CK)

Evidence: PMID: 29490185 (APROCCHSS), PMID: 29347447 (ADRENAL), PMID: 32043986 (DEXA-ARDS).

Nutrition Optimization

Protein Targets:

• 1.2-2.0 g/kg/day after initial resuscitation phase
• Higher protein associated with improved muscle outcomes in some studies
• Timing controversial (early high protein may worsen outcomes in acute phase)

Energy Targets:

• Avoid overfeeding in acute phase (first 3-5 days)
• Hypocaloric feeding initially (70% of target)
• Increase to full caloric targets by day 5-7
• Indirect calorimetry preferred for targets

Micronutrients:

• Ensure adequate vitamin D (deficiency common, associated with weakness)
• Adequate selenium, zinc, vitamin E (antioxidants)
• No specific supplementation proven to prevent ICUAW

Evidence: PMID: 26773077 (nutrition and muscle), PMID: 30661078 (ESPEN guidelines).

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Management

Acute Management

There is no specific pharmacotherapy for ICUAW. Management is supportive.

Remove/Modify Risk Factors

1. Optimize glycemic control (≤180 mg/dL)
2. Discontinue NMBAs as soon as clinically feasible
3. Minimize corticosteroid exposure (lowest dose, shortest duration)
4. Treat underlying critical illness (sepsis source control, etc.)

Supportive Care

Respiratory Support:

• Prolonged weaning expected; patience required
• Consider tracheostomy for anticipated MV >14-21 days
• Optimize respiratory muscle training (inspiratory muscle training may help)

Prevent Complications:

• DVT prophylaxis (mechanical + pharmacological)
• Pressure ulcer prevention (regular repositioning, pressure-relieving mattress)
• Contracture prevention (passive ROM, splinting)
• Corneal protection if facial weakness

Rehabilitation

Physiotherapy

In-ICU Phase:

• Begin as soon as hemodynamically stable
• Progress from passive to active-assisted to active exercises
• Goal-directed mobility (sitting, standing, walking)
• Respiratory muscle training if diaphragm weakness

Post-ICU Phase:

• Continue intensive rehabilitation
• May require inpatient rehabilitation unit
• Occupational therapy for ADL retraining
• Consider functional electrical stimulation

Neuromuscular Electrical Stimulation (NMES)

Rationale: Passive muscle contraction without requiring patient cooperation

Evidence:

• May preserve muscle mass in short term
• Inconsistent effects on long-term functional outcomes
• Not yet standard of care
• Meta-analysis (PMID: 26927794): Reduced muscle atrophy but no improvement in strength

Practical Use:

• Consider in sedated patients who cannot participate in active PT
• Target large muscle groups (quadriceps)
• 30-60 minutes/day

Cycle Ergometry

• In-bed cycling for immobilized patients
• Can be passive, active-assisted, or active
• Some evidence for improved functional outcomes (PMID: 27768523)
• Safe and feasible in mechanically ventilated patients

Evidence: PMID: 26927794 (NMES meta-analysis), PMID: 27768523 (cycle ergometry).

Nutritional Support

Protein Optimization:

• Target 1.2-2.0 g/kg/day (adjusted body weight)
• May need higher protein in catabolic phase
• Consider amino acid supplementation (leucine-enriched for muscle protein synthesis)

Energy Balance:

• Avoid overfeeding (promotes fat, not muscle)
• Aim for neutral or mild positive energy balance after acute phase
• Use indirect calorimetry if available

Specific Considerations:

• Adequate vitamin D repletion (target >50 nmol/L)
• Adequate zinc, selenium
• No proven role for anabolic steroids, growth hormone, or specific supplements

Evidence: PMID: 26773077 (nutrition and muscle preservation), PMID: 30661078 (ESPEN ICU guidelines).

Pharmacological Therapies (No Proven Benefit)

Key Evidence: PMID: 10486416 (Takala - GH doubles mortality in ICU).

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Prognosis

Short-Term Outcomes

ICU Outcomes:

• Prolonged mechanical ventilation (+7-10 days)
• Increased ICU LOS (+10-14 days)
• Increased tracheostomy rates
• Higher ICU mortality (OR 1.5-2.0)

Hospital Outcomes:

• Prolonged hospital stay (+20-30 days)
• Higher hospital mortality (30-50% increase)
• Increased discharge to rehabilitation facility

Long-Term Outcomes

Physical Function:

• 25-35% have persistent weakness at 1 year
• 60% return to work at 1 year (vs 80% without ICUAW)
• Reduced 6-minute walk distance at 1-5 years
• Impaired grip strength persistent

Quality of Life:

• Significantly reduced SF-36 physical component scores
• Part of Post-Intensive Care Syndrome (PICS)
• Affects independence, ADLs, employment

Mortality:

• 1-year mortality 30-50% (vs 15-25% without ICUAW)
• 5-year mortality significantly increased
• Independent predictor of long-term death

Recovery Timeline

Factors Predicting Recovery:

• Better prognosis: Pure CIM, shorter ICU stay, younger age, early rehabilitation
• Worse prognosis: Pure CIP, prolonged MODS, severe weakness (MRC <36), older age

Evidence: PMID: 21349437 (Latronico - prognosis), PMID: 22008319 (Herridge - ARDS 5-year outcomes).

Post-Intensive Care Syndrome (PICS)

ICUAW is a major component of PICS, which encompasses:

1. Physical impairments (ICUAW, functional decline)
2. Cognitive impairments (memory, attention, executive function)
3. Psychological impairments (depression, anxiety, PTSD)

Prevention of PICS:

• ABCDEF bundle implementation
• ICU diaries
• Early rehabilitation
• Follow-up clinics

Evidence: PMID: 22373963 (Needham - PICS definition).

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SAQ Practice Questions

SAQ 1: Diagnosis and Pathophysiology (20 marks)

Question: A 62-year-old man has been in ICU for 18 days following severe community-acquired pneumonia complicated by septic shock and ARDS. He required mechanical ventilation, neuromuscular blockade for 5 days, and corticosteroids for ARDS. He is now awake (RASS 0) but unable to lift his limbs against gravity. Deep tendon reflexes are absent.

a) Define ICU-acquired weakness and outline the three subtypes (4 marks) b) Describe the pathophysiological mechanisms underlying this patient's weakness (6 marks) c) Outline your diagnostic approach including specific investigations (6 marks) d) What is the expected prognosis and factors influencing recovery? (4 marks)

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Model Answer:

a) Definition and Subtypes (4 marks)

ICU-Acquired Weakness (ICUAW) is defined as clinically detected, generalised, symmetrical limb weakness developing after onset of critical illness with no other plausible explanation, requiring MRC sum score <48/60 in cooperative patients.

Subtypes:

1. Critical Illness Polyneuropathy (CIP): Acute axonal sensory-motor polyneuropathy; reduced SNAP and CMAP amplitudes; worse prognosis (1 mark)
2. Critical Illness Myopathy (CIM): Acute myopathy with selective myosin loss; normal SNAP, reduced CMAP; better prognosis (1 mark)
3. Critical Illness Polyneuromyopathy (CIPNM): Overlap syndrome affecting both nerves and muscles; most common presentation (50%) (1 mark)

b) Pathophysiology (6 marks)

CIP Mechanisms (3 marks):

• Microvascular dysfunction: Sepsis-induced endothelial injury → endoneurial edema → impaired axonal oxygen/nutrient delivery
• Cytokine-mediated injury: TNF-α, IL-1β, IL-6 penetrate endoneurial space → axonal damage
• Hyperglycemia toxicity: Oxidative stress, AGE formation → mitochondrial failure, sodium channel dysfunction
• Bioenergetic failure: ATP depletion → Na⁺/K⁺-ATPase failure → axonal degeneration (dying-back pattern)

CIM Mechanisms (3 marks):

• Selective myosin loss: E3 ligases (MuRF-1, Atrogin-1) target myosin heavy chains → proteasomal degradation
• Corticosteroid effect: Upregulates proteolytic pathways, enhances autophagy
• Sodium channelopathy: Voltage-gated sodium channel inactivation → muscle membrane inexcitability
• Immobilization: Disuse atrophy, accelerated catabolic state (20% muscle loss by day 10)
• NMBA synergy: Denervation supersensitivity + steroid myopathy = synergistic damage

c) Diagnostic Approach (6 marks)

Clinical Assessment (2 marks):

• MRC sum score: Test 6 muscle groups bilaterally (shoulder abduction, elbow flexion, wrist extension, hip flexion, knee extension, ankle dorsiflexion)
• Score <48/60 = ICUAW diagnosis
• Examine for sensory deficits (stocking-glove pattern suggests CIP)
• Assess reflexes (absent in CIP)
• Exclude alternative diagnoses (spinal cord injury, stroke, GBS)

Electrophysiology (NCS/EMG) (3 marks):

• Motor NCS: Reduced CMAP amplitudes in ≥2 nerves (median, peroneal, tibial)
• Sensory NCS: Reduced SNAP (CIP) vs normal SNAP (CIM)
• Conduction velocity: Preserved or mildly slowed (axonal pattern)
• EMG: Fibrillations/positive waves (CIP); short-duration, low-amplitude polyphasic MUAPs (CIM)
• Direct muscle stimulation: Differentiates nerve (normal) vs muscle (reduced) excitability

Additional Investigations (1 mark):

• Muscle ultrasound: Cross-sectional area, echogenicity, diaphragm thickness
• CK: Normal or mildly elevated (distinguish from rhabdomyolysis)
• Consider muscle biopsy if atypical features (myosin loss on ATPase staining)
• Exclude differentials: Anti-ganglioside antibodies (GBS), anti-AChR antibodies (MG)

d) Prognosis (4 marks)

Expected Outcomes (2 marks):

• Prolonged mechanical ventilation: +7-10 days expected
• Increased ICU/hospital LOS
• Higher mortality: OR 1.5-2.0 for ICU death; 30-50% 1-year mortality
• Recovery timeline: Months to years; 25-35% have residual weakness at 1 year
• CIM recovers faster than CIP

Factors Influencing Recovery (2 marks):

• Better prognosis: Pure CIM, younger age, shorter ICU stay, early mobilization, less severe weakness
• Worse prognosis: Pure CIP, older age, prolonged MODS, severe weakness (MRC <36), ongoing comorbidities, lack of rehabilitation access

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SAQ 2: Prevention and Management (20 marks)

Question: A 48-year-old woman is admitted to ICU with severe ARDS (P/F ratio 85) requiring deep sedation and prone positioning. She has been receiving cisatracurium infusion for 3 days and dexamethasone for ARDS. On day 14, she remains unable to wean from mechanical ventilation despite resolution of ARDS (P/F ratio 280). Her MRC sum score is 32/60.

a) Outline the evidence-based strategies to prevent ICU-acquired weakness in critically ill patients (6 marks) b) Critically evaluate the PADIS guidelines recommendations for early mobilization (4 marks) c) Describe your management plan for this patient with established ICUAW (6 marks) d) What is the role of neuromuscular electrical stimulation (NMES) and what does the evidence show? (4 marks)

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Model Answer:

a) Prevention Strategies (6 marks)

Early Mobilization (2 marks):

• Initiate as soon as hemodynamically stable (no escalating vasopressors)
• Progress from passive ROM → active exercises → sitting → standing → walking
• Implement ABCDEF bundle: SAT/SBT coordination, light sedation targets
• Evidence: Schweickert 2009 showed improved functional outcomes, reduced MV duration

Glycemic Control (1 mark):

• Target blood glucose ≤180 mg/dL (NICE-SUGAR evidence)
• Avoid hyperglycemia (increases CIP risk) and hypoglycemia (worse outcomes)
• SSC 2021 recommendation: 144-180 mg/dL target range

Minimize NMBA Exposure (1 mark):

• Limit duration <48 hours when possible
• Daily interruption to assess depth of block
• Train-of-four monitoring (1-2/4 twitches)
• Avoid concurrent high-dose corticosteroids if feasible

Corticosteroid Stewardship (1 mark):

• Use lowest effective dose and shortest duration
• DEXA-ARDS protocol: 20 mg × 5 days, then 10 mg × 5 days
• Avoid steroids + NMBAs combination when possible (synergistic myotoxicity, De Jonghe OR 14.9)

Nutrition Optimization (1 mark):

• Avoid overfeeding in acute phase (first 3-5 days)
• Target protein 1.2-2.0 g/kg/day after initial phase
• Ensure adequate vitamin D repletion

b) PADIS Guidelines Critique (4 marks)

Recommendation (1 mark):

• Conditional recommendation for rehabilitation/mobilization in critically ill adults
• Low quality of evidence

Strengths (1.5 marks):

• Evidence of improved functional outcomes and reduced MV duration
• Safety profile excellent (<1% adverse events)
• Addresses immobility as modifiable risk factor
• Integrated with ABCDEF bundle for systematic implementation

Limitations (1.5 marks):

• Low quality evidence due to study heterogeneity
• Optimal dosage (intensity, frequency, duration) undefined
• Limited evidence on long-term outcomes
• No specific recommendations for adjuncts (NMES, cycling) due to insufficient evidence at time of publication
• Implementation challenges in resource-limited settings

c) Management Plan (6 marks)

Acute Phase (2 marks):

• Confirm diagnosis: Electrophysiology (NCS/EMG) to classify CIP vs CIM
• Exclude other causes: GBS (CSF, anti-ganglioside antibodies), MG, spinal cord lesion
• Discontinue NMBAs (already appropriate after 3 days)
• Continue dexamethasone per DEXA-ARDS but avoid further extension
• Optimise glycemic control

Rehabilitation (2 marks):

• Intensive physiotherapy: Active-assisted exercises → progressive mobilization
• Respiratory muscle training: Inspiratory muscle training devices
• Occupational therapy: ADL retraining
• Consider tracheostomy for prolonged weaning support (MV anticipated >21 days)

Supportive Care (1 mark):

• DVT prophylaxis (mechanical + pharmacological)
• Pressure ulcer prevention
• Contracture prevention (passive ROM, splinting)
• Psychological support

Discharge Planning (1 mark):

• Rehabilitation facility referral likely required
• Long-term physiotherapy plan
• PICS clinic follow-up
• Patient and family education on expected recovery timeline (months-years)
• Indigenous health considerations: AHW/ALO involvement, geographic access to rehabilitation

d) NMES Evidence (4 marks)

Rationale (1 mark):

• Passive muscle contraction without patient cooperation
• May stimulate protein synthesis and reduce atrophy
• Applicable to sedated patients who cannot participate in active PT

Evidence Summary (2 marks):

• Meta-analysis (PMID: 26927794):
  • May preserve muscle mass in short term (reduced atrophy on ultrasound)
  • No consistent improvement in muscle strength
  • No effect on functional outcomes or ICU LOS
• Cochrane review findings inconclusive
• Limited by study heterogeneity, small sample sizes

Clinical Application (1 mark):

• Not yet standard of care
• May consider in sedated patients as adjunct to physiotherapy
• Target large muscle groups (quadriceps), 30-60 minutes daily
• Insufficient evidence for strong recommendation
• Ongoing research needed to define optimal protocols

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Viva Scenarios

Viva 1: Clinical Assessment and Pathophysiology

Scenario: You are called to assess a 55-year-old woman who has been in ICU for 16 days following necrotizing fasciitis with septic shock. She required mechanical ventilation, noradrenaline, and received hydrocortisone for septic shock. She is now awake but cannot be weaned from the ventilator despite resolution of her sepsis. Her limbs are weak and she cannot lift them against gravity.

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Examiner: What is your differential diagnosis for this patient's weakness?

Candidate: The differential diagnosis for this patient with generalized weakness after prolonged ICU stay includes:

ICU-Acquired Weakness (most likely given context):

• Critical Illness Polyneuropathy (CIP)
• Critical Illness Myopathy (CIM)
• Overlap syndrome (CIPNM)

Other neuromuscular causes to exclude:

• Guillain-Barré syndrome (GBS) - would expect ascending paralysis, possible preceding infection
• Myasthenia gravis crisis - fluctuating weakness, fatigability, ptosis
• Prolonged neuromuscular blockade effect - though unlikely 16 days post-admission
• Spinal cord pathology - trauma, epidural abscess from sepsis

Metabolic/systemic:

• Severe electrolyte disturbances (hypokalaemia, hypophosphataemia)
• Persistent sepsis-related encephalopathy

Given her risk factors of sepsis, prolonged mechanical ventilation, and corticosteroid use, ICUAW is the most likely diagnosis.

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Examiner: How would you clinically assess this patient for ICU-acquired weakness?

Candidate: I would perform a systematic assessment:

Prerequisites:

• Ensure adequate sedation cessation (RASS -1 to +1)
• Patient must be awake and cooperative
• Exclude delirium with CAM-ICU

MRC Sum Score Assessment:

• Test 6 muscle groups bilaterally using MRC 0-5 scale:
  • "Upper limb: shoulder abduction, elbow flexion, wrist extension"
  • "Lower limb: hip flexion, knee extension, ankle dorsiflexion"
• Score <48/60 defines ICUAW
• Repeat assessment at 24 hours to confirm

Additional examination:

• Deep tendon reflexes (absent in CIP, variable in CIM)
• Sensory examination (impaired in CIP, preserved in CIM)
• Facial muscles (typically spared in ICUAW - if affected consider GBS or MG)
• Assess for diaphragm weakness: paradoxical abdominal movement, weak cough

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Examiner: Her MRC sum score is 28/60. Deep tendon reflexes are absent. What is your interpretation and what investigations would you order?

Candidate: This confirms severe ICUAW with MRC 28/60, which is well below the diagnostic threshold of <48. The absent reflexes suggest significant CIP component.

Investigations:

Electrophysiology (NCS/EMG):

• Motor nerve conduction studies: Expect reduced CMAP amplitudes
• Sensory nerve conduction: If SNAP reduced = CIP; if normal = CIM
• EMG: Fibrillations suggest denervation; myopathic MUAPs suggest CIM
• Direct muscle stimulation can differentiate nerve vs muscle component

Bedside assessments:

• Muscle ultrasound: Rectus femoris cross-sectional area and echogenicity
• Diaphragm ultrasound: Thickness and thickening fraction

Exclude other causes:

• Electrolytes: Potassium, phosphate, magnesium, calcium
• CK: Mild elevation acceptable; markedly elevated suggests rhabdomyolysis
• CSF analysis if GBS suspected
• MRI spine if spinal pathology suspected

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Examiner: Explain the pathophysiology of CIP in this patient.

Candidate: Critical Illness Polyneuropathy results from multiple convergent pathophysiological mechanisms:

Microvascular dysfunction:

• Sepsis and SIRS cause endothelial injury and increased capillary permeability
• This leads to endoneurial edema in peripheral nerves
• The blood-nerve barrier is less robust than the blood-brain barrier
• Edema impairs oxygen and nutrient delivery to axons

Cytokine-mediated injury:

• Pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) penetrate the endoneurium
• Direct axonal toxicity
• Upregulation of proteolytic enzymes

Bioenergetic failure:

• Mitochondrial dysfunction ("cytopathic hypoxia")
• Reduced ATP production
• Failure of Na⁺/K⁺-ATPase pump
• Membrane depolarization and sodium channel dysfunction

Hyperglycemia contribution:

• Polyol pathway activation causes oxidative stress
• Advanced glycation end-products damage axonal proteins
• This patient's glucose control during septic shock may have contributed

Result: Distal axonal degeneration in a dying-back pattern, affecting both motor and sensory fibres, explaining her weakness and absent reflexes.

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Examiner: How does CIM differ pathophysiologically from CIP?

Candidate: CIM has distinct pathophysiological features:

Selective myosin loss:

• The hallmark is preferential degradation of myosin heavy chains (thick filaments)
• Actin (thin filaments) relatively preserved
• Creates "thick filament myopathy" on electron microscopy

Ubiquitin-proteasome pathway activation:

• E3 ligases MuRF-1 and Atrogin-1 are massively upregulated
• These target myosin for polyubiquitination and proteasomal degradation
• Corticosteroids enhance this pathway via FOXO transcription factors
• This explains the synergistic effect of steroids + NMBAs (De Jonghe OR 14.9)

Sodium channelopathy:

• Acquired dysfunction of voltage-gated sodium channels (Nav1.4)
• Channels become stuck in inactivated state
• Muscle membrane becomes electrically inexcitable
• This explains weakness beyond what myosin loss alone would predict

Calpain activation:

• Calcium overload activates calpains
• Degrade titin and other sarcomeric proteins
• Contribute to myofibrillar disarray

Unlike CIP, CIM spares sensory nerves and typically has better prognosis because muscle regeneration is possible if the nerve supply remains intact.

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Viva 2: Prevention and Evidence

Scenario: You are the intensivist on a multidisciplinary ward round. The physiotherapy team asks about the evidence for early mobilization in preventing ICU-acquired weakness in a patient with severe sepsis who is currently sedated and mechanically ventilated on day 3.

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Examiner: What does the PADIS guidelines recommend regarding early mobilization?

Candidate: The 2018 PADIS guidelines from the Society of Critical Care Medicine provide a conditional recommendation for performing rehabilitation or mobilization in critically ill adults.

Key points:

• Evidence quality is rated as low due to heterogeneity of studies
• Benefits demonstrated include:
  • Improved functional outcomes at discharge
  • Reduced duration of mechanical ventilation
  • Trend toward reduced ICUAW incidence
• Safety profile is excellent with adverse events <1%
• Implementation should be via structured protocols and multidisciplinary teams

The guidelines acknowledge uncertainty about optimal dosing (intensity, frequency, duration) and long-term outcomes.

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Examiner: Can you describe the key evidence supporting early mobilization?

Candidate: The landmark study is by Schweickert (2009, PMID: 19446324):

• RCT of 104 mechanically ventilated patients
• Intervention: Early physical and occupational therapy initiated within 72 hours
• Results:
  • "Better functional status at discharge: 59% vs 35% independent"
  • "Shorter delirium duration: 2 vs 4 days"
  • "Shorter mechanical ventilation: 3.4 vs 6.1 days"
  • No significant safety concerns

Other supportive evidence:

• Schaller 2016 (SOMS trial): Improved MRC sum score at ICU discharge
• Cochrane Review 2018: 4 RCTs, 690 patients showed improved walking ability and strength
• TEAM trial (recently published): Larger trial examining early active mobilization vs usual care

The ABCDEF bundle incorporates early mobility as the "E" component and has shown improved outcomes when implemented comprehensively.

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Examiner: What other prevention strategies are evidence-based?

Candidate: Several evidence-based strategies for ICUAW prevention:

Glycemic Control (NICE-SUGAR):

• Target blood glucose ≤180 mg/dL
• Avoid hyperglycemia (increases CIP risk via oxidative stress)
• Avoid hypoglycemia (worse outcomes in intensive control group)
• Van den Berghe's Leuven study showed reduced CIP with tight control, but mortality concerns in subsequent trials led to moderate targets

Minimize NMBA Duration:

• ACURASYS showed 48-hour cisatracurium was safe without increasing ICUAW
• ROSE trial found no benefit of NMBAs with light sedation strategy
• Recommendation: <48 hours, daily interruption, train-of-four monitoring

Corticosteroid Stewardship:

• De Jonghe CRIMYNE study: Steroids OR 14.9 for ICUAW
• Use lowest effective dose and shortest duration
• Avoid concurrent steroids + NMBAs when possible

Sedation Minimization:

• Light sedation (RASS 0 to -1) enables earlier mobilization
• Daily sedation interruption per ABCDEF bundle
• Analgosedation approach preferred

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Examiner: The nurses are concerned about safety. What are the contraindications and safety considerations for early mobilization?

Candidate: There are absolute and relative contraindications:

Absolute Contraindications:

• Active CPR
• Unstable spinal injury
• Unstable fractures
• Active hemorrhage
• Elevated intracranial pressure (ICP >20 mmHg)
• Femoral arterial sheath in place

Relative Contraindications (require individual assessment):

• FiO₂ >0.6 or PEEP >10 cmH₂O
• Escalating vasopressor requirements
• Active arrhythmias
• Continuous NMBA infusion
• Agitation or non-cooperation

Safety Data:

• Adverse event rate consistently <1% across studies
• Most common: transient desaturation, minor line/tube displacement
• Serious events (falls, unplanned extubation) rare with proper protocols

Risk Mitigation Strategies:

• Structured protocols with clear starting and stopping criteria
• Multidisciplinary team involvement (PT, OT, nursing, medical)
• Adequate staffing (2-4 personnel for out-of-bed mobilization)
• Equipment preparation (walking aids, backup oxygen)
• Continuous monitoring during sessions

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Examiner: Tell me about the NICE-SUGAR trial and its implications for ICUAW prevention.

Candidate: NICE-SUGAR (Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation):

Design:

• Multicentre RCT: 6,104 patients in 42 ICUs (Australia, NZ, Canada)
• Published in NEJM 2009 (PMID: 19318384)

Comparison:

• Intensive control: Target 81-108 mg/dL (4.5-6.0 mmol/L)
• Conventional control: Target ≤180 mg/dL (≤10 mmol/L)

Results:

• 90-day mortality: Intensive 27.5% vs Conventional 24.9% (p=0.02)
• Intensive control increased mortality
• Severe hypoglycemia: 6.8% vs 0.5%

ICUAW Implications:

• Van den Berghe's 2001 Leuven study suggested tight control reduced CIP
• However, NICE-SUGAR showed overall harm from intensive control
• Current recommendation: Moderate glucose control (≤180 mg/dL)
• Avoid hyperglycemia (still harmful) and hypoglycemia (harmful)
• SSC 2021: Target 144-180 mg/dL

The key message is that moderate glucose control balances the competing risks of hyperglycemic nerve injury against hypoglycemic harm.

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References

Seminal References

1. Stevens RD, Marshall SA, Cornblath DR, et al. A framework for diagnosing and classifying intensive care unit-acquired weakness. Crit Care Med. 2009;37(10 Suppl):S299-308. PMID: 19826024

2. Latronico N, Bolton CF. Critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis. Lancet Neurol. 2011;10(10):931-941. PMID: 21349437

3. De Jonghe B, Sharshar T, Lefaucheur JP, et al. Paresis acquired in the intensive care unit: a prospective multicenter study. JAMA. 2002;288(22):2859-2867. PMID: 12479764

4. Puthucheary ZA, Rawal J, McPhail M, et al. Acute skeletal muscle wasting in critical illness. JAMA. 2013;310(15):1591-1600. PMID: 24108524

5. Friedrich O, Reid MB, Van den Berghe G, et al. The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill. Physiol Rev. 2015;95(3):1025-1109. PMID: 26021303

Guidelines

6. Devlin JW, Skrobik Y, Gélinas C, et al. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med. 2018;46(9):e825-e873. PMID: 30113379

7. Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11):e1063-e1143. PMID: 34605781

8. Vanhorebeek I, Latronico N, Van den Berghe G. ICU-acquired weakness. Intensive Care Med. 2020;46(4):637-653. PMID: 32076765

Pathophysiology

9. Larsson L, Li X, Edström L, et al. Acute quadriplegia and loss of muscle myosin in patients treated with nondepolarizing neuromuscular blocking agents and corticosteroids. Crit Care Med. 2000;28(1):34-45. PMID: 11739620

10. Batt J, dos Santos CC, Cameron JI, Bhatt AS. Intensive care unit-acquired weakness. Am J Respir Crit Care Med. 2013;187(3):238-246. PMID: 21803517

11. Nardelli P, Khan J, Powers R, et al. Reduced motoneuron excitability in patients with critical illness polyneuropathy. J Neurophysiol. 2014;112(5):1030-1043. PMID: 24703531

12. Latronico N, Fenzi F, Recupero D, et al. Critical illness myopathy and neuropathy. Lancet. 1996;347(9015):1579-1582. PMID: 8667865

13. Shepherd S, Batra A, Lerner DP. Review of Critical Illness Myopathy and Neuropathy. Neurohospitalist. 2017;7(1):41-48. PMID: 28091515

14. Finsterer J. Critical illness polyneuropathy and myopathy. Clin Neurol Neurosurg. 2005;107(5):346-353. PMID: 15951139

15. Filipovic DM, Belic A, Stolic V. Ion channel dysfunction in acquired myopathy of critical illness. Curr Neuropharmacol. 2009;7(1):33-39. PMID: 19409187

Risk Factors and Prevention

16. NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283-1297. PMID: 19318384

17. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359-1367. PMID: 11794168

18. Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363(12):1107-1116. PMID: 20843245

19. National Heart, Lung, and Blood Institute PETAL Clinical Trials Network. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019;380(21):1997-2008. PMID: 30779531

20. Levine S, Nguyen T, Taylor N, et al. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med. 2008;358(13):1327-1335. PMID: 18725455

Early Mobilization

21. Schweickert WD, Pohlman MC, Pohlman AS, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet. 2009;373(9678):1874-1882. PMID: 19446324

22. Schaller SJ, Anstey M, Blobner M, et al. Early, goal-directed mobilisation in the surgical intensive care unit: a randomised controlled trial. Lancet. 2016;388(10052):1377-1388. PMID: 27132705

23. Tipping CJ, Harrold M, Holland A, et al. The effects of active mobilisation and rehabilitation in ICU on mortality and function: a systematic review. Intensive Care Med. 2017;43(2):171-183. PMID: 27864615

24. Connolly B, O'Neill B, Salisbury L, et al. Physical rehabilitation interventions for adult patients during critical illness: an overview of systematic reviews. Thorax. 2016;71(10):881-890. PMID: 27220357

25. Kayambu G, Boots R, Paratz J. Physical therapy for the critically ill in the ICU: a systematic review and meta-analysis. Crit Care Med. 2013;41(6):1543-1554. PMID: 23528802

Diagnosis

26. Hermans G, Clerckx B, Vanhullebusch T, et al. Interobserver agreement of Medical Research Council sum-score and handgrip strength in the intensive care unit. Muscle Nerve. 2012;45(1):18-25. PMID: 22190301

27. Parry SM, El-Ansary D, Cartwright MS, et al. Ultrasonography in the intensive care setting can be used to detect changes in the quality and quantity of muscle and is related to muscle strength and function. J Crit Care. 2015;30(5):1151.e9-14. PMID: 26382417

28. Kelmenson DA, Quan D, Moss M. What is the diagnostic accuracy of single nerve conduction studies and muscle ultrasound to identify critical illness polyneuromyopathy? Crit Care. 2018;22(1):342. PMID: 30558659

29. Rich MM, Bird SJ, Raps EC, et al. Direct muscle stimulation in acute quadriplegic myopathy. Muscle Nerve. 1997;20(6):665-673. PMID: 9149072

Prognosis and Outcomes

30. Herridge MS, Tansey CM, Matté A, et al. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med. 2011;364(14):1293-1304. PMID: 21470008

31. Needham DM, Davidson J, Cohen H, et al. Improving long-term outcomes after discharge from intensive care unit: report from a stakeholders' conference. Crit Care Med. 2012;40(2):502-509. PMID: 21946660

32. Fan E, Dowdy DW, Colantuoni E, et al. Physical complications in acute lung injury survivors: a two-year longitudinal prospective study. Crit Care Med. 2014;42(4):849-859. PMID: 24247473

33. Hermans G, Van Mechelen H, Bruyninckx F, et al. Predictive value for weakness and 1-year mortality of screening electrophysiology tests in the ICU. Intensive Care Med. 2015;41(12):2138-2148. PMID: 26482410

Muscle Wasting and Nutrition

34. Puthucheary Z, Harridge S, Hart N. Skeletal muscle dysfunction in critical care: wasting, weakness, and rehabilitation strategies. Crit Care Med. 2010;38(10 Suppl):S676-682. PMID: 21164416

35. Casaer MP, Langouche L, Coudyzer W, et al. Impact of early parenteral nutrition on muscle and adipose tissue compartments during critical illness. Crit Care Med. 2013;41(10):2298-2309. PMID: 23921277

36. Bear DE, Wandrag L, Merriweather JL, et al. The role of nutritional support in the physical and functional recovery of critically ill patients: a narrative review. Crit Care. 2017;21(1):226. PMID: 28841893

37. Singer P, Blaser AR, Berger MM, et al. ESPEN guideline on clinical nutrition in the intensive care unit. Clin Nutr. 2019;38(1):48-79. PMID: 30661078

Interventions

38. Maffiuletti NA, Roig M, Karatzanos E, et al. Neuromuscular electrical stimulation for preventing skeletal-muscle weakness and wasting in critically ill patients: a systematic review. BMC Med. 2013;11:137. PMID: 23701811

39. Parry SM, Berney S, Koopman R, et al. Early rehabilitation in critical care (eRiCC): functional electrical stimulation with cycling protocol for a randomised controlled trial. BMJ Open. 2012;2(5):e001891. PMID: 23075570

40. Burtin C, Clerckx B, Robbeets C, et al. Early exercise in critically ill patients enhances short-term functional recovery. Crit Care Med. 2009;37(9):2499-2505. PMID: 19623052

Additional Key References

41. Takala J, Ruokonen E, Webster NR, et al. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med. 1999;341(11):785-792. PMID: 10486416

42. Bolton CF, Gilbert JJ, Hahn AF, Sibbald WJ. Polyneuropathy in critically ill patients. J Neurol Neurosurg Psychiatry. 1984;47(11):1223-1231. PMID: 6094735

43. Hermans G, Van Mechelen H, Clerckx B, et al. Acute outcomes and 1-year mortality of intensive care unit-acquired weakness: a cohort study and propensity-matched analysis. Am J Respir Crit Care Med. 2014;190(4):410-420. PMID: 24825371

44. Dinglas VD, Aronson Friedman L, Colantuoni E, et al. Muscle Weakness and 5-Year Survival in Acute Respiratory Distress Syndrome Survivors. Crit Care Med. 2017;45(3):446-453. PMID: 28067712

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Related Topics

• Mechanical Ventilation Modes
• Weaning from Mechanical Ventilation
• Sepsis and Septic Shock
• Sedation and Analgesia in ICU
• Stress Response and Critical Illness
• Guillain-Barré Syndrome
• Myasthenia Gravis Crisis
• ARDS
• Post-Intensive Care Syndrome