Weakness in the Critically Ill Patient

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Weakness in the Critically Ill Patient

• Susan M. Stickevers, MD
• Program Director, Physical Medicine
  Rehabilitation, SUNY Stony Brook

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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
• Diffuse Non-Necrotizing Myopathy
• Thick Filament Myopathy
• Acute Necrotizing Myopathy
• Outcomes

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Introduction

• Severe Muscle Weakness Common in ICU Patients
• 25 - 33 develop clinically overt weakness
• 50 develop electrophysiological abnormality
• Consequences
• Prolonged ventilation ICU stay
• Other complications of ICU stay - pulmonary
  embolism, DVT, decubiti
• Death

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Introduction

• Signs of Critical Illness Neuropathy / myopathy
  may be incorrectly attributed to
• Sedation
• Depression
• Coma
• Deconditioning
• Critical illness Polyneuropathy Myopathy are
  diagnoses of exclusion

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Diagnostic Approach

• Think broadly!
• Long differential diagnosis, depending on the
  clinical context
• Examine the patient - Confirm weakness-
• Suspect critical illness myopathy/neuropathy if
• Unexpected lack of ventilatory weaning
• Accelerated peripheral muscle atrophy ( esp. in
  the upper extremities)
• Inability to hold head/limb off bed
• R/O neuromuscular blockade with
  anticholinesterases

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Diagnostic Clues

• Mental status - not affected in critical illness
  myopathy polyneuropathy
• Pattern of weakness
• Symmetric, with facial sparing
• If cranial nerve weakness is present consider
  alternative diagnoses
• Motor Neuron Disease
• Guillain Barre Syndrome
• Myasthenia Gravis
• Stroke
• DTRs - usually decreased in critical illness
  neuropathy myopathy
• If DTRs are increased, this suggests central
  lesion
• Delayed elevation CPK myoglobin

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Differential Diagnosis

• Spinal Cord Dysfunction
• Guillain Barre Syndrome
• Motor Neuron Disease
• Porphyria
• Pre Existing Neuropathy
• Myasthenia Gravis

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Diagnostic Clues (contd)

• The ICU-specific exam - ventilation!
• Clinical increased respiratory rate, heart
  rate, blood pressure
• 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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Work Up

• MRI Brain (with gadolinium contrast)
• To rule out pontine infarct (locked-in
  syndrome) in severe cases
• EMG - Indications
• Inability to adequately assess peripheral muscle
  strength in the ICU patient
• To rule out potentially treatable condition such
  as myasthenia Guillain Barre Syndrome
• Failure to improve after 3 - 4 weeks
• Muscle biopsy

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Critical Illness Polyneuropathy

• First described in early 1980s
• Also known as neuropathy of critical illness, ICU
  neuropathy
• Occurs in 25 of ICU patients on average -
• Seen in 70-80 of patients with severe sepsis or
  multiple organ system failure
• 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 with multiple organ system
  failure followed 28 days
• 30/43 (70) axonal polyneuropathy on EMG
• 15/43 (35) had clinical muscle dysfunction
• 23 survivors all recovered neuromuscular
  function

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Critical Illness Polyneuropathy - Definition

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

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Critical Illness Polyneuropathy - Pathogenesis

• Etiology - ? Association with
• Systemic Inflammatory Response Syndrome (SIRS)
  multi system organ failure
• Pro- inflammatory cytokines (ie TNF) released
  causing increased microvascular permeability
• Microcirculatory compromise of distal nerves
• Axonal degeneration follows
• Impaired transport of axonal proteins
• Endoneural edema and/or hypoxia

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Association with SIRS .

• Only direct markers
• Increased duration of ICU stay
• Increased serum glucose
• Decreased serum albumin

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Critical Illness Polyneuropathy Clinical
Features

• Delayed weaning from ventilator
• Sensorimotor polyneuropathy
• Generalized muscle atrophy
• Flaccid paralysis
• Decreased / absent DTRs only 1/3 have normal
  DTRs
• Sensory abnormalities (light touch/pain)
• Cranial nerves spared
• Physical exam often nondiagnostic

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Critical Illness Polyneuropathy - Diagnosis

• Work Up
• EMG / NCS Consistent with Sensory Motor
  Axonal Polyneuropathy
• Denervation potentials are widespread in the form
  of fibrillation potentials positive waves
• Nerve conduction velocities are spared
• Decreased CMAP SNAP amplitudes
• Phrenic nerve conduction studies abnormal with
  CMAP amplitude ½ lower limit of normal
• Nerve biopsy or autopsy axonal degeneration
• Primarily distal
• No inflammation or demyelination

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Critical Illness Myopathy

• Synonyms
• - Myopathy of Critical Illness
• - Intensive Care Myopathy
• - Acute Quadriplegic Myopathy
• - Acute Necrotizing Myopathy

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ICU Myopathy Syndromes

• Similar clinical presentation to critical illness
  polyneuropathy
• Diffuse Non - Necrotizing Myopathy
• Thick Filament Myopathy
• Acute Necrotizing Myopathy
• Rarer entities
• Pyomyositis seen with pyogenic organisms

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Non-Necrotizing Myopathy

• Mild changes on EMG/biopsy
• CPK usually normal
• Seen in association with critical illness
  polyneuropathy

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Critical Illness Myopathy

• Pathology
• Muscle fiber size variability atrophy
• Fatty degeneration
• Fibrosis necrosis
• Inflammatory changes absent
• Helliwell et al. Journal of Pathology, 1991.
  studied muscle biopsies of CIM patients
• 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 effect of toxins secreted by
  microorganisms
• Inflammatory mediators involved in pathogenesis
• 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 Medicine, 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 Medicine, 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
• Well described in asthmatics transplant
  recipients
• Often seen in patients on steroids in combination
  with neuromuscular blocking agents
• Selective thick (myosin) filament loss
• ? decreased myosin transcription
• Neurogenic component absent
• CPK may be elevated, with or without myoglobinuria

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Thick Filament Myopathy - Pathogenesis

• Mechanisms poorly understood
• Corticosteroid hypersensitivity in denervated
  muscle
• Neuromuscular blocking agents
• Potentiated by critical illness polyneuropathy
• ?Sepsis mediated proteolysis
• Disuse vulnerability
• Membrane inexcitability secondary to TNF

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Thick Filament Myopathy

• Leatherman et al. Am J Respiratory Critical Care
  Medicine, 1996.
• 107 pts ventilated for asthma
• All received steroids, 69 also had neuromuscular
  blocking agents
• Weakness only in patients given both drugs
• Seen with all neuromuscular blocking agents
• Duration of paralysis important (85 of pts.
  developed weakness if on NMBA gt 72 hours)

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Acute Necrotizing Myopathy

• Less common
• Pathology vacuolization/phagocytosis
• Pathogenesis - ?similar to Thick Filament
  Myopathy
• CPK often elevated
• Risk of rhabdomyolysis in this disorder

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Diagnosis of Myopathy

• Physical, serum tests, EMG often negative
• Normal CPK often seen
• EMG usually captures few motor units
• True neuropathy vs. functional denervation from
  end-plate myonecrosis
• Low or Normal Compound Motor Action Potentials
• Sensory Nerve Action Potentials are normal

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Muscle Biopsy

• Modality of choice
• Invasive, time sensitive
• Findings
• Atrophy
• Selective thick (myosin) filament loss on
  electron microscopy
• ?Role of myosin / actin ratio
• Stibler et al. Intensive Care Medicine, 2003.
• Necrosis / phagocytosis/ vacuolization

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Indications to Biopsy for Suspected CIM

• Any patient with paresis without EMG evidence
  consistent with pure critical illness
  polyneuropathy and
• Normal sensory nerve studies
• Low or Normal CMAP amplitudes
• Little spontaneous EMG activity

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Management of Critical Illness Weakness Syndromes

• Supportive Care
• Do not attempt early weaning from ventilator
• Early mobilization to prevent contractures,
  decubiti, deconditioning
• Judicious use of steroids neuromuscular
  blocking agents
• Special attention to myonecrosis if using
  steroids neuromuscular blocking agents
• Watch drug metabolism / elimination factors

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Work Up May Also Include

• MRI C spine, LS spine
• Repetitive Stimulation to rule out myasthenia
  gravis
• Phrenic Nerve studies, especially in those who
  are difficult to wean from ventilator

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Treatment (contd)

• Prevention no specific measures
• de Letter et al. Critical Care Medicine, 2001
• APACHE III score septic inflammatory response
  syndrome were only true risk factors
• van den Burghe et al. N Engl J Med. 2001
• Intensive insulin therapy reduced ICU length of
  stay
• 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 / moderate
  disease
• Slower / incomplete recovery if severe
• Slow conduction velocities associated with poor
  prognosis
• Fletcher et al. Critical Care Medicine, 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 myopathic components
• Diagnosis of exclusion
• CIM CIPN - Difficult to differentiate from each
  other
• EMG/biopsies may be helpful
• No specific treatment other than supportive care
  and therapy
• Careful monitoring of use of neuromuscular
  blocking agents steroids
• Complete recovery in most

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Thanks for your attention