1. Weakness in the Critically Ill Patient Susan M. Stickevers, MD Program Director, Physical Medicine & Rehabilitation, SUNY Stony Brook

2. 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

3. 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

4. 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

5. Introduction Signs of Critical Illness Neuropathy / myopathy may be incorrectly attributed to: Sedation Depression Coma Deconditioning Critical illness Polyneuropathy & Myopathy are diagnoses of exclusion

6. Diagnostic Approach Think broadly! Long differential diagnosis, depending on the clinical contextdifferential 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

7. 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

8. Differential Diagnosis Spinal Cord Dysfunction Guillain – Barre Syndrome Motor Neuron Disease Porphyria Pre – Existing Neuropathy Myasthenia Gravis

9. Diagnostic Clues (cont’d) 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 > 105) Validated for demand-induced fatigue Maximum inspiratory pressure (< 20 cm H 2 O) Integrated indices (e.g. CROP) Demand vs. work of breathing

10. 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

11. 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 > 7 days after onset of critical illness

12. 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

13. 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

14. 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

15. Association with SIRS &…. Only direct markers: Increased duration of ICU stay Increased serum glucose Decreased serum albumin

16. 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

17. 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

18. Critical Illness Myopathy Synonyms : - Myopathy of Critical Illness - Intensive Care Myopathy - Acute Quadriplegic Myopathy - Acute Necrotizing Myopathy

19. 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

20. Non-Necrotizing Myopathy Mild changes on EMG/biopsy CPK usually normal Seen in association with critical illness polyneuropathy

21. 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

22. 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

23. 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

24. A Rose by Any Other Name… Bednarik et al. Intensive Care Medicine, 2003. 46 patients with >1 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

25. 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

26. 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

27. 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 > 72 hours)

28. Acute Necrotizing Myopathy Less common Pathology – vacuolization/phagocytosis Pathogenesis - ?similar to Thick Filament Myopathy CPK often elevated Risk of rhabdomyolysis in this disorder

29. 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

30. 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

31. 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

32. 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

33. 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

34. Treatment (cont’d) 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

35. 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 >90%, pure myopathy unusual

36. 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

37. Thanks for your attention …