Weakness in the Critically Ill Patient

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Weakness in the Critically Ill Patient

• Rheumatology Rounds
• May 25, 2004
• Sachin R. Pendharkar, PGY2

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Objectives

• To define the problem of ICU-associated weakness
• To outline an approach to weakness in critically
  ill patients
• To discuss common causes of this phenomenon

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Outline

• Diagnostic Approach
• Causes of Weakness in the ICU
• Critical illness polyneuropathy
• Critical illness myopathy syndromes
• Diffuse non-necrotizing myopathy
• Thick filament myopathy
• Acute necrotizing myopathy
• Outcomes

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Introduction

• Severe muscle weakness common in ICU
• 25-33 clinically overt weakness
• 50 electrophysiologic abnormality
• Consequences
• Prolonged ventilation/ICU stay
• Other complications of ICU stay (PE, VAP)
• Unnecessary investigations
• Death

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Introduction

• Signs may be attributed to
• Sedation dose reduction
• Depression/indifference inappropriate meds
• Residual lung disease unnecessary tests
• Coma withdrawal of care
• CIP/CIM must be a diagnosis of exclusion

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Diagnostic Approach

• Think broadly!
• Long differential diagnosis, depending on the
  clinical context
• Examine the patient! Confirm weakness!
• Unexpected lack of ventilatory weaning
• Accelerated peripheral muscle atrophy (UE)
• Inability to hold head/limb off bed
• R/O NM blockade with anticholinesterase

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Diagnostic Clues

• Mental status - not affected in CIPN/CIM
• Pattern of weakness
• symmetric, facial sparing
• CN weakness - think GBS, MG, BS stroke
• DTR - usually decreased
• if increased, suggests central lesion
• Delayed elevation CK/myoglobin
• suggests process not related to initial insult

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Diagnostic Clues (contd)

• The ICU-specific exam - ventilation!
• Clinical increased RR, HR, BP
• Laboratory acidosis, hypercapnia, hypoxemia
• Ventilator measurements
• Rapid Shallow Breathing Index (f/Vt gt 105)
• Validated for demand-induced fatigue
• Maximum inspiratory pressure (lt 20 cm H2O)
• Integrated indices (e.g. CROP)
• Demand vs. work of breathing

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Investigations

• MRI (with gadolinium)
• may delineate pontine involvement (locked-in
  syndrome)
• EMG - Indications
• inability to adequately examine peripheral muscle
  strength
• potentially treatable condition (MG, GBS)
• failure to improve after 3-4 weeks
• Muscle biopsy

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Critical Illness Polyneuropathy

• First described in early 1980s
• 25 MICU/SICU patients
• 70-80 in severe sepsis and MOSF
• Usual onset gt 7 days after onset of critical
  illness

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Critical Illness Polyneuropathy

• Witt et al. Chest. 1991
• 43 patients sepsis/MOSF followed 28 days
• 30/43 (70) axonal polyneuropathy on EMG
• 15/43 (35) had clinical muscle dysfunction
• 23 survivors all recovered NM function

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CIPN - Definition

• Acute axonal neuropathy
• Follows course of illness
• Self-limited
• Recovery excellent in mild-mod disease
• Permanent disability in severe forms
• Not-attributable to other neurologic insult

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CIPN - Pathogenesis

• Generally unclear
• Similar to sepsis-induced organ damage
• Cytokines TNF, histamines, complement, AA, CAM,
  free radicals, etc.
• Microcirculatory compromise of distal nerves
• Low MW factor targets motor neurons

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CIPN Clinical Features

• Delayed weaning NYD
• Sensorimotor polyneuropathy
• Generalized muscle atrophy
• Flaccid paralysis
• Decreased/absent DTRs N in 1/3
• Sensory abnormalities (light touch/pain)
• Cranial nerve sparing
• Physical exam often nondiagnostic

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CIPN - Diagnosis

• Investigations
• EMG/NCS motor/sensory axonal neuropathy
• Denervation with fibrillation potentials
• Impulse speed preserved
• Decreased compound motor/sensory AP amplitude
• Nerve biopsy/autopsy axonal degeneration
• Primarily distal
• No inflammation/demyelination

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ICU Myopathy Syndromes

• Similar clinical presentation as CIPN
• Diffuse, non-necrotizing myopathy
• Thick filament myopathy
• Acute Necrotizing myopathy
• Rarer entities
• Pyomyositis seen with pyogenic organisms

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Non-necrotizing myopathy

• Also known as
• Critical illness myopathy
• Cachectic myopathy
• Mild changes on EMG/biopsy
• CK usually N
• Accompany CIPN

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Critical Illness Myopathy

• Pathology
• Muscle fibre size variability/atrophy
• Fatty degeneration
• Fibrosis/necrosis
• Inflammatory changes absent
• Helliwell et al. J Pathol. 1991.
• 12/31 muscle biopsies showed atrophy
• 15/31 showed necrosis
• 5/12 serial biopsies progressive necrosis

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CIM Pathogenesis

• Mechanisms of injury related to sepsis
• Direct microorganism toxin
• Inflammatory mediators causing SIRS
• IL-1, TNF, glucocorticoids proteolysis
• Intracellular myofibrillar protein degradation
• Intramuscular immune activation

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CIM or CIPN?

• Different entities found in similar patients
• Postulated reasons
• Simultaneous injury from same stressors
• Sequential injury time of biopsy key
• Coakley et al. Intensive Care Med. 1993.
• 23 patients evaluated with muscle biopsy/EMG
• Multiple abnormalities in 22/23
• Distal axonal degeneration, necrotizing myopathy

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A rose by any other name

• Bednarik et al. Intensive Care Med. 2003.
• 46 patients with gt1 organ failure
• EMG in all patients
• Muscle biopsy in 11
• Sural nerve biopsy in 5
• Overlapping findings in most patients
• Suggest polyneuromyopathy as more appropriate
  descriptor - CIPNM

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Thick Filament Myopathy

• First described in association with high-dose
  steroids
• Asthmatics, transplant recipients
• Often in combination with NMBA
• Selective thick (myosin) filament loss
• ?decreased myosin transcription
• Neurogenic component absent
• CK may be elevated, /- myoglobinuria

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TFM - Pathogenesis

• Mechanisms poorly understood
• Corticosteroid hypersensitivity in denervated
  muscle
• Neuromuscular blocking agents
• Potentiated by CIPN
• ?Sepsis mediated proteolysis
• Disuse vulnerability
• Membrane inexcitability TNF

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Thick Filament Myopathy

• Leatherman et al. Am J Respir Crit Care Med.
  1996.
• 107 pts ventilated for asthma
• All received steroid, 69 also had NMBA
• Weakness only in patients given both drugs
• Seen with all NMBAs
• Duration of paralysis important (85 weakness if
  gt 72 hrs NMBA)

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Acute Necrotizing Myopathy

• Less common
• Pathology vacuolization/phagocytosis
• Pathogenesis - ?similar to TFM
• CK often elevated
• Risk of rhabdomyolysis

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Diagnosis of Myopathy

• Physical, serum tests, EMG insensitive
• Normal CK often seen
• EMG usually captures few motor units
• True neuropathy vs. functional denervation from
  end-plate myonecrosis
• Evoked compound muscle AP

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Muscle Biopsy

• Modality of choice
• Invasive, time sensitive
• Findings
• Atrophy
• Selective thick (myosin) filament loss (EM)
• ?role of myosin/actin ratio
• Stibler et al. Intensive Care Med. 2003.
• Necrosis/phagocytosis/vacuolization

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When to biopsy?

• Any patient with paresis NYD without EMG/NCS c/w
  pure CIPN
• N sensory neurography
• Low motor amplitudes
• Little spontaneous EMG activity

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Management of ICU Weakness

• No specific measures, but overall
• Do not attempt early weaning
• Early mobilization not helpful
• Judicious use of GCS, NMBA
• Special attention to myonecrosis if using GCS and
  NMBA
• Watch drug metabolism/elimination factors

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Treatment (contd)

• Prevention no specific measures
• de Letter et al. Crit Care Med. 2001
• APACHE III and SIRS were only true risk factors
• van den Burghe et al. N Engl J Med. 2001
• Intensive insulin therapy reduced ICU LOS
• Fewer patients screened for CIPN
• Lower incidence of CIPN
• More rapid resolution

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Prognosis

• High overall ICU mortality in patients with
  neuropathy/myopathy
• Recovery over weeks/months in mild/mod disease
• Slower/incomplete recovery if severe
• Slow conduction assoc with worse prognosis
• Fletcher et al. Crit Care Med 2003
• Median follow-up 43 months after protracted ICU
  stay
• Partial denervation gt90, pure myopathy unusual

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Conclusion

• ICU-associated weakness is a real entity
• Neurogenic and myopathic components
• Diagnosis of exclusion
• Difficult to differentiate from each other
• EMG/biopsies may be helpful
• No specific treatment
• Careful monitoring of use of NMBA/GCS
• Complete recovery in most