Weakness in the Critically Ill Patient

Susan M. Stickevers, MD

Program Director, Physical Medicine & Rehabilitation, SUNY Stony Brook

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

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

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

Introduction

Signs of Critical Illness Neuropathy / myopathy may be incorrectly attributed to: Sedation Depression Coma Deconditioning

Critical illness Polyneuropathy & Myopathy are diagnoses of exclusion

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

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

Differential Diagnosis

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

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 H2O) Integrated indices (e.g. CROP)

Demand vs. work of breathing

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

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

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

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

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

Association with SIRS &….

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

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

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

Critical Illness Myopathy

Synonyms :

- Myopathy of Critical Illness

- Intensive Care Myopathy

- Acute Quadriplegic Myopathy

- Acute Necrotizing Myopathy

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

Non-Necrotizing Myopathy

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

polyneuropathy

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

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

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

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

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

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

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)

Acute Necrotizing Myopathy

Less common Pathology – vacuolization/phagocytosis Pathogenesis - ?similar to Thick Filament

Myopathy CPK often elevated Risk of rhabdomyolysis in this disorder

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

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

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

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

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

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

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

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

Thanks for your attention …