By Dr Piyush Ojha , DM Resident, GMC Kota under guidance of Prof. Dr Vijay Sardana (HOD,Neurology)

1. CRITICAL ILLNESS
POLYNEUROPATHY AND
MYOPATHY
DR. PIYUSH OJHA
DM RESIDENT
DEPARTMENT OF NEUROLOGY
GOVT MEDICAL COLLEGE, KOTA

2. • 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).

3. • 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.

4. • 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.

5. 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.

6. RISK FACTORS FOR CIP,CIM & CINM
PROBABLE 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

7. PATHOPHYSIOLOGY
Critical 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

8. (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 oedema
3. 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.

9. 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.

10. 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.

11. • 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.

12. • 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.

13. • 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.

14. 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

15. 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.
AND
4. 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. OR
5. Dependence on mechanical ventilation

16. • 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.

17. 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

18. 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.

19. INVESTIGATIONS IN CIP,CIM & CINM
INVESTIGATION 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 SNAP
amplitudes;
Normal conduction
velocities and
Latencies
Reduced CMAP
amplitudes;
Normal SNAP
amplitudes;
Normal conduction
velocities and
latencies
Reduced CMAP
amplitudes;
Reduced
SNAP amplitudes;
Normal
conduction
velocities and
latencies

20. INVESTIGATION CIP CIM CINM
EMG Spontaneous
fibrillation potentials
and sharp waves;
+ long duration, high-
amplitude polyphasic
MUPs (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 muscle
CMAP amplitude
Nerve:muscle ratio
>0.5;
Reduced direct
muscle CMAP
amplitude
Variable
depending on the
relative
components of
CIP and CIM

21. INVESTIGATION CIP CIM CINM
MUSCLE BIOPSY Features of
denervation and
reinnervation: small
angulated muscle
fibres; target and
targetoid
fibres; 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 fibre
necrosis
Both features of CIP
and CIM
NERVE BIOPSY Normal, or motor
and sensory nerve
axonal
Degeneration
Normal Normal, or motor
and sensory nerve
axonal degeneration

22. DIAGNOSTIC CRITERIA
CRITICAL ILLNESS POLYNEUROPATHY (CIP)
The diagnosis of CIP is made with the presence of all of the
following:
(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.

23. 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 ICUAW
2. 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.

24. 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.

25. 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

26. 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.

27. 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

28. • 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

29. 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.

30. • 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

31. 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%.

32. • 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.

33. 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