CRITICAL ILLNESS POLYNEUROPATHY AND

MYOPATHY

DR. PIYUSH OJHADM RESIDENT

DEPARTMENT OF NEUROLOGYGOVT MEDICAL COLLEGE, KOTA

• First described by Bolton & colleagues in 1986 (CIP).• ICU-acquired weakness (ICUAW) - “clinically detected

weakness in critically ill patients in whom there is no plausible aetiology other than critical illness”.

• ICUAW further classified into– Critical illness Polyneuropathy (CIP)– Critical illness Myopathy (CIM)• Further subclassified (histologically) into Cachectic

myopathy, thick filament myopathy, and Necrotizing myopathy.

– Critical illness Neuromyopathy(CINM).

• Prevalence of ICUAW ~46% (43-49%) according to a study.

• Prevalence of CIM found to be – ~ 70% in sepsis/SIRS or if ICU stay > 7 days.– ~100% when Sepsis complicated by MODS– ~ 7% after orthotopic liver transplantation– ~36% in Status asthmaticus and severe acute COPD exacerbations.

• CIM risk increases with the duration of neuromuscular block.

• Neither the type of neuromuscular blocking agent nor Corticosteroid are independent risk factors for the development of CIM.

AETIOLOGY

• Exact etiology uncertain.• Multifactorial etiology.• CIM - high incidence in patients receiving large cumulative

doses of steroids and neuromuscular blocking agents, implicating these as risk factors.

• Usually received >10 g of Hydrocortisone over a 1–2 week period and neuromuscular block for 3–5 days.

RISK FACTORS FOR CIP,CIM & CINMPROBABLE POSSIBLE

• Severe sepsis/septic shock • Multiorgan failure • Prolonged mechanical ventilation/bed rest • Increasing duration of SIRS • Increasing duration of multiorgan failure • Hyperglycaemia

• Age• Female gender• Severity of illness on admission• Admission APACHE II score• Hypoalbuminaemia• Hyperosmolality• Parenteral nutrition• Renal replacement therapy• Vasopressors• Corticosteroids• Neuromuscular blocking agents• Aminoglycosides

PATHOPHYSIOLOGYCritical illness Polyneuropathy (CIP) • Leading hypothesis - CIP is the manifestation of peripheral

nervous system organ failure resulting through common systemic inflammation induced pathophysiological processes.

• These include: (i) reduced oxygen and nutrient delivery to the nerve axon through:

(a) macrocirculatory impairment with myocardial depression, vasodilatation, and hypotension

(b) microcirculatory impairment through:1. endothelial dysfunction with increased cellular adhesion, platelet and coagulation system

activation, and resultant luminal obstruction.

2. increased permeability and tissue oedema3. vasodilatation and shunting

(ii) impaired mitochondrial oxygen utilization and ATP generation through increased NO and reactive oxygen species production and inhibition of mitochondrial respiratory chain function.

Other postulated mechanisms include:

• A low molecular weight neurotoxin injuring the nerve axon; possible candidates include lipopolysaccharide and IL2-R.

• Hyperglycaemia induced axonal injury either through direct glucose cellular toxicity or increased oxidative stress.

• A functional component with neuronal membrane inexcitability through increased sodium channel inactivation.

Critical Illness Myopathy (CIM) Main postulated pathophysiological processes include:• Reduced muscle membrane excitability: early in CIM, the

skeletal muscle has reduced membrane excitability through a combination of depolarization of the resting membrane potential and a hyperpolarization shift of inactivation of Na channels.

• Altered sarcoplasmic reticulum function: reduced uptake and release of Ca producing a decrease in muscle contractility.

• Decreased contractile protein function and muscle fibre force generation.

• Mitochondrial dysfunction and bioenergetic failure: due to a reduction in mitochondrial enzyme activity and respiratory chain function -> reduction in oxygen utilization and ATP production. Skeletal muscle mitochondrial content is also reduced.

• Muscle denervation : through either pharmacological (neuromuscular block) or structural (CIP) mechanisms producing an increased expression of corticosteroid

receptors within myocytes -> sensitizing them to the deleterious effects of corticosteroids.

• Muscle atrophy: during critical illness, marked muscle atrophy occurs with approximately a 3–4% decrease in muscle cross-sectional area/day due to increased proteolysis, decreased protein synthesis and increased apoptosis.

• Early decline in muscle strength –predominately due to functional changes (muscle membrane inexcitability, decreased contractile protein function, altered sarcoplasmic reticulum function and mitochondrial dysfunction).

• Long term weakness predominately due to structural changes along with the marked muscle atrophy.

CLINICAL FEATURES• CIP, CIM, and CINM have similar presentations that cannot be

reliably differentiated clinically.

• Present beyond the 1st week of ICU stay in patients having systemic inflammation, multiple organ failure, or those managed with high cumulative dosages of corticosteroids and/or neuromuscular blocking agents.

• Involvement - Lower limbs > upper limbs

The criteria for diagnosing ICUAW are as follows : - 1. Weakness developing after the onset of critical illness.2. The weakness being generalized (both proximal and distal muscles), symmetrical, flaccid, and generally sparing

the cranial nerves (e.g. facial grimace is intact).3. Causes of weakness not related to the underlying critical illness have been excluded. AND4. Muscle power assessed by the Medical Research Council (MRC) sum score of <48 (or a mean score of <4 in all testable muscle groups) noted on >2 occasions separated by >24 hrs. OR5. Dependence on mechanical ventilation

• The earliest sign may be of facial grimacing without limb movement in response to painful stimuli.• Extraocular muscle involvement is rare and if present –

search another aetiology. • Muscle wasting is variable and frequently disguised by oedema. • Accurate sensory examination if possible is normal in CIM,

with predominately a distal sensory loss of pain, temperature, and/or vibration sensation in CIP.

• Autonomic function not affected.• DTRs usually normal or reduced in pure CIM and absent in

CIP.

MRC sum score • Involves the assessment of muscle power from 3

movements of each limb:– Shoulder abduction– Elbow flexion– Wrist extension– Hip flexion– Knee extension and– Ankle dorsiflexion.

• Maximal power graded according to MRC scale.• Total score =60

INVESTIGATIONS• First thing to decide – whether weakness was present at the

onset or developed after a sustained period of critical illness.

• Muscle biopsy, nerve biopsy, or both are only indicated if diagnostic uncertainty and are not indicated specifically for the diagnosis of CIP, CIM, or CINM.

INVESTIGATIONS IN CIP,CIM & CINMINVESTIGATION CIP CIM CINM

CPK Normal or mildly elevated

Elevated in majority

Normal or elevated

CSF Normal cell counts,Normal or slightly elevated protein (<0.8g/L)

Normal Normal or slightly elevated protein (<0.8g/L)

NERVE CONDUCTION

STUDIES

Reduced CMAP amplitudes;Reduced SNAPamplitudes; Normal conduction velocities andLatencies

Reduced CMAP amplitudes;Normal SNAP amplitudes;Normal conduction velocities and latencies

Reduced CMAP amplitudes; ReducedSNAP amplitudes; Normalconduction velocities and latencies

INVESTIGATION CIP CIM CINM

EMG Spontaneous fibrillation potentials and sharp waves;+ long duration, high-amplitude polyphasicMUPs (reinnervation)

Spontaneous fibrillation potentials and sharp waves; short duration, low-amplitude MUPs with early recruitment

Features of both CIP and CIM

DIRECT MUSCLE STIMULATION

Nerve: muscle ratio <0.5; Normal direct muscleCMAP amplitude

Nerve:muscle ratio >0.5; Reduced direct muscle CMAPamplitude

Variable depending on the relativecomponents of CIP and CIM

INVESTIGATION CIP CIM CINM

MUSCLE BIOPSY Features of denervation and reinnervation: smallangulated muscle fibres; target and targetoidfibres; group fibre atrophy; fibre type regrouping

Cachectic myopathy with myofibrillar degeneration; Thick filament myopathy with a selective loss of myosin filaments; Necrotizing myopathy with muscle fibrenecrosis

Both features of CIP and CIM

NERVE BIOPSY Normal, or motor and sensory nerve axonalDegeneration

Normal Normal, or motor and sensory nerveaxonal degeneration

DIAGNOSTIC CRITERIACRITICAL ILLNESS POLYNEUROPATHY (CIP) The diagnosis of CIP is made with the presence of all of thefollowing:(i) Patient meets the criteria for ICUAW(ii) CMAP amplitudes are decreased to <80% of the lower limit of normal in >2 nerves.(iii) SNAP amplitudes are decreased to <80% of the lower limit of normal in >2 nerves.(iv) Normal or near normal nerve conduction velocities(v) The absence of a decremental response on repetitive nerve stimulation.

CRITICAL ILLNESS MYOPATHY (CIM) The diagnostic criteria for CIM are separated into probable CIM (1, 2, 4 or 5; or 1 and 3) and definite CIM (1, 2, 3, 4 or 5):1. Patient meets the criteria for ICUAW2. SNAP amplitudes on nerve conduction studies are >80% of

the lower limit of normal in >2 nerves.3. EMG in >2 muscle groups demonstrating short-duration,

low-amplitude MUPs with early or normal full recruitment with or without fibrillation potentials.

4. Direct muscle stimulation demonstrating reduced excitability (nerve:muscle ratio >0.5 in >2 muscle groups)5. Muscle histology consistent with myopathy.

CRITICAL ILLNESS NEUROMYOPATHY (CINM)

CINM is diagnosed when all of the following are met: (i) Patient meets criteria for ICUAW (ii) Patient meets criteria for CIP (iii) Patient meets criteria for probable or definite CIM.

MANAGEMENT• No intervention shown to improve the outcome from ICUAW

in prospective studies.

• So Aim in all ICU patients should be :– To prevent the development of ICUAW and – optimize the rehabilitation for those patients in whom

the condition develops

PREVENTION OF ICUAW• Mainstay is minimization of risk factors.• Intensive insulin therapy (target Blood sugar= 80-110mg/dl)

earlier showed in several studies to reduce the prevalence of CIP/CIM.

• Recent NICE-SUGAR study doesnot support it and supports the use of Conventional Insulin Therapy (Aim is RBS <215 mg/dl) in ICU patients.

• More recently, in a single small study, electrical muscle stimulation(EMS) to lower limb muscles - shown to reduce the prevalence of ICUAW.

Working Group Grades of Evidence :-

HIGH QUALITY : further research is very unlikely to change our confidence in the estimate of effect.

MODERATE QUALITY : further research is very likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

LOW QUALITY : further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

VERY LOW QUALITY : we are very uncertain about the estimate.

COCHRANE REVIEW 2014 CONCLUSIONS

• Moderate quality evidence from 2 large trials (n=825) - intensive insulin therapy(IIT) reduces CIP/CIM, and high quality evidence that It reduces duration of mechanical ventilation, ICU stay and 180-day mortality, at the expense of hypoglycaemia.

• Moderate quality evidence (n=180) suggesting no effect of corticosteroids on CIP/ CIM and high quality evidence that steroids do not affect secondary outcomes, except for fewer new shock episodes.

COCHRANE REVIEW 2014 CONCLUSIONS

COCHRANE REVIEW 2014 CONCLUSIONS

• Moderate quality (n=104 ) suggesting a potential benefit of early rehabilitation on CIP/CIM which is accompanied by a shorter duration of mechanical ventilation but without an effect on ICU stay.

• Very low quality evidence (n=52) suggesting no effect of EMS, although data are prone to bias.

• Strict diagnostic criteria for CIP/CIM urgently needed for research purposes.

• Large RCTs need to be conducted to further explore the role of early rehabilitation and EMS and to develop new preventive strategies.

COCHRANE REVIEW 2014 CONCLUSIONS

PROGNOSIS• ICUAW – an independent risk factor for :

– increased duration of mechanical ventilation– increased weaning duration.– increased duration of ICU and length of hospital stay and– increased hospital mortality.

• Approximately 45% of patients diagnosed with ICUAW die within their hospital admission with a further 20%

mortality within the first year after ICU discharge.• ICUAW associated with acute severe asthma - lower

hospital mortality ~11%.

• Those patients who do survive, almost all patients demonstrate improvement in both electrophysiological and clinical findings over time.

• Complete functional recovery = occurs only in ~68% patients.

• Persistent severe disability in ~28%.• No prognostic difference between CIP, CIMand CINM. • However, CIP is identified more frequently on follow up electrophysiological testing and is associated with a more protracted and less complete recovery than CIM.

REFERENCES• Bradley’s textbook of neurology 6th edition• Clinical review: Critical illness polyneuropathy

and myopathy, Critical Care 2008• Intensive care unit acquired weakness :

Continuing Education in Anaesthesia, Critical Care & Pain , January 6, 2012

• Uptodate.com