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Critical illness polyneuropathy and myopathy

Created: 22/5/2007

Critical Ilness Polyneuropathy

Dr John Griffiths DICM MRCP FRCA MA
CriticalCareUK Editor

Focus on critical illness polyneuropathy

Critical illness polyneuropathy (CIP) and critical illness myopathy (CIM) are acquired during the course of critical illness, and cause weakness and paralysis. The incidence of these neuromuscular diseases in ICU patients with sepsis or multi-organ dysfunction is estimated at 70 to 80%. Risk factors for CIP and CIM include sepsis and multi-organ dysfunction, prolonged duration of stay on the ICU and hyperglycaemia. Weakness associated with CIP and CIM may be exacerbated by muscle wasting secondary to catabolism and immobility. It is proposed that CIP and CIM are caused primarily by the use of glucocorticoids or neuromuscular blocking agents or by nutritional deficiencies. However, conclusive evidence regarding the true aetiology of CIP and CIM is currently lacking and the exact pathophysiological mechanisms remain to be determined. Cytokines such as interleukin-1 and tumour necrosis factor, which are released during sepsis, have been identified as mediators of skeletal muscle proteolysis in animal models and may therefore play a pivotal aetiological role. CIP and CIM are important disorders because they might prolong the duration of mechanical ventilation and both ICU and hospital length of stay. The need for intensive physiotherapy and extended rehabilitation add considerably to the cost of care. Although muscle strength generally seems to recover well, some patients report weakness for a prolonged period of time, sometimes even up to 4 years after ICU discharge. In one study of survivors of at least 28 days of ICU treatment, nearly all patients displayed electrophysiological evidence of chronic partial denervation (indicative of either a previous CIP or pure motor neuropathy) 5 years after ICU discharge.

Focus on histopathological features of CIP and CIM

CIP is a primary axonal degeneration of motor and sensory fibres. It is commonly accompanied by myopathic changes with scattered atrophic and occasional necrotic muscle fibres, but no evidence of inflammation. Acute motor neuropathy is a variant of CIP in which the axonal degeneration affects primarily motor fibres.

Critical illness myopathy (CIM) is usually a mild myopathy. Features seen on biopsy include fibre atrophy and angulated fibres, fatty degeneration and fibrosis with minimal necrosis. It may be present simultaneously with CIP. Plasma creatinine kinase levels are mostly normal.

A different type of myopathy has been described in patients who have received high-dose corticosteroids for acute severe asthma, in recipients of organ transplantation and in patients with myasthenia gravis. A thick filament myopathy has been described, characterised by selective loss of myosin filaments. There are usually no neuropathic changes. However, plasma creatinine kinase levels are often elevated, and progression to diffuse myonecrosis (rhabdomyolysis) is possible. Experimentally, thick filament myopathy can be produced by surgical denervation of muscle followed by exposure of the muscle to corticosteroids. This causes an upregulation in the number of steroid receptors and a resultant steroid hypersensitivity. It follows that denervation of neuromuscular transmission by either pharmacological (e.g. neuromuscular blocking agents) or immunological (e.g. myasthenia gravis) means could render muscle susceptible to the myopathic effects of corticosteroids. However, the fact that thick filament myopathy has been described in patients who have not received muscle relaxants or steroids suggests that other factors are involved in its aetiology.

In acute necrotising ICU myopathy, myonecrosis with vacuolisation and phagocytosis of muscle fibres is prominent. Plasma creatinine kinase levels are frequently raised, and in a minority of patients frank rhabdomyolysis may ensue. Necrotising myopathy has also been described in patients admitted to ICU with status asthmaticus. These patients were generally non-septic and received high-dose corticosteroids, either alone or in combination with muscle relaxants. Myonecrosis has also been reported in other critically ill patients, some of which had received very high doses of neuromuscular blocking agents alone.

Focus on the diagnosis of CIP and CIM

The diagnosis of CIP and CIM is based on the triad of clinical examination, electrophysiological studies and muscle biopsy. However, in order to make a confident diagnosis of CIP and CIM, it is important to exclude any existing conditions associated with neuromuscular weakness. These conditions include spinal cord disorders, Guillain-Barré syndrome and chronic inflammatory demyelinating neuropathy, diabetic polyneuropathy, myasthenia gravis and Lambert-Eaton syndrome, and muscular dystrophy. Low electrolyte states (hypokalaemia, hyponatraemia, hypophosphataemia) are recognised causes of muscle weakness and rhabdomyolysis and need to be excluded. Other recognised causes of myonecrosis and rhabdomyolysis are trauma, prolonged immobility with muscle compression, status epilepticus, toxins and drugs, hypothermia and heat stroke.

Electrophysiological studies and muscle biopsy
Electroneurography (ENG) and needle electromyography (EMG) show reduced amplitude of nerve action potentials but normal conduction velocities in >90% of patients with either CIP or CIM, or both. However, ENG and EMG seem to be of little use to distinguish between CIP and CIM. This requires muscle biopsy. Myopathy appears to be more common than neuropathy. In one series of ICU patients with generalised weakness, myopathy was diagnosed on biopsy in 23 out of 24 patients, whereas only eight out 24 had histological evidence of axonal degeneration. Five patients had mixed changes.

Focus on the prevention of CIP and CIM

Prevention of both CIP and CIM involves the prompt and effective treatment of sepsis and multi-organ dysfunction. It is prudent to use neuromuscular blocking agents and corticosteroids as cautiously as possible. The need for neuromuscular blocking agents should be reviewed frequently and overdosing should be avoided by the use of a peripheral nerve stimulator. Patients that are prescribed neuromuscular blocking agents and/or steroids should be monitored for the development of neuropathy and myopathy, including serial serum creatinine kinase measurements and repeated electrophysiological testing. Recent evidence suggests that tight glycaemic control reduces the incidence of CIP and CIM. In one study, tight glycaemic control lowered the incidence of CIP from 52% to 29%.

Key learning points

• CIP and CIM are a source of considerable ICU-related morbidity
• CIP and CIM can result in weakness that persists beyond ICU and hospital discharge, ultimately to affect a patient’s quality of life
• Any patient who develops a CIP or CIM needs adequate long-term follow-up to ensure adequate recovery and rehabilitation
• The exact aetiology of CIP and CIM remains to be determined
• Prevention of CIP and CIM involves early and effective treatment of sepsis, tight glycaemic control and cautious use of muscle relaxants and corticosteroids on the ICU

Key references

Hund E. Myopathy in critically ill patients.
Crit Care Med 1999; 27: 2544-2547.  

Fletcher SN, Kennedy DD, Ghosh IR et al.
Persistent neuromuscular and neurophysiological abnormalities in long-term survivors of prolonged critical illness.
Crit Care Med 2003; 31: 1012-1016

Latronico N, Fenzi F, Recupero D et al.
Critical illness myopathy and neuropathy. 
Curr Opin Crit Care 2005; 11(2):126-32 

Van Den Berghe G, Wouters P, Weekers F et al.
Intensive insulin therapy in critically ill patients.
N Engl J Med 2001; 345: 1359-1367.

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