Chapter 121
Intensive Care Unit-Acquired Paresis:
Spectrum of Neuromyopathies
Mathew Alexander
HISTORY
Muscle weakness and atrophy occurring during the course of sepsis
was described in 1892 by Sir William Osler.1 The first description on
this entity came almost a century later when Charles Bolton described
an axonal polyneuropathy in four patients who had sepsis and coined
the term CIP.2 This has been found to be increasingly associated with
a severe systemic response to infection, resultant multiorgan failure
with resultant motor weakness with mortality as high as 30–50%.3
This is now recognized to be a very important etiology for difficulty
in weaning patients in the intensive care unit (ICU) setting with
prolonged ICU/hospital stay.
EPIDEMIOLOGY
The prevalence of this disorder varies from 20% to 90%, and now with
increased awareness, improved sedation protocols, judicious use of
neuromuscular blocking agents (NMBAs), good glycemic control, the
incidence of this disorder is coming down. Systemic inflammatory
response syndrome (SIRS) occurs in response to severe infection or
trauma of mechanical, thermal or chemical nature. SIRS is associated
with the release of several mediators, such as cytokines and free
radicals, with resultant effect on the microcirculation throughout the
body including the central nervous system and peripheral nervous
system. In patients who have been in the ICU4 for a week or longer,
a good number of them would have SIRS, either as a primary event
or as a complication of invasive procedures such as endotracheal
intubation or insertion of central lines. SIRS, when associated with
documented infection, the term sepsis could be applied.5-7 Severe
sepsis and septic shock is reserved for those patients with organ
dysfunction and hypoperfusion/hypotension, despite adequate fluid
replacement. Although critical illness weakness (CIW) was thought
to be an axonal neuropathy, there has been an increasing incidence
of reports of a concomitant myopathy, which could be mainly related
to high doses of steroids and NMBA.8,9
This is of great relevance in the developing world setting, where
there are limited resources; the development of CIW would prolong
the ICU stay with increased morbidity and mortality. There is a
paucity of studies looking at the patterns of electrophysiological
abnormalities and putative predictors for the development of
weakness.
Pathogenesis and Microcirculatory Changes
When there is SIRS with multiorgan dysfunction syndrome, there is
a disturbed humoral and cellular response, with increased capillary
permeability and endothelial damage. There is microcirculatory
dysfunction with tissue hypoxia.6 In this setting, when corticosteroids
and NMBAs are added, there is oxidative stress. The blood
vessels supplying peripheral nerves lack autoregulation and the
cytokines are responsible for increased capillary permeability,
there is endoneurial damage and hypoxia. The glutathione level,
both total and reduced form, is reduced in the muscle. There is
mitochondrial dysfunction and oxidative stress, glutamine depletion
to 15%, impaired reutilization of oxidized glutathione due to reduced
nicotinamide adenine dinucleotide phosphate (NADPH), with
increased muscle catabolism.
Critical illness polyneuropathy (CIP) was described about 30 years
ago to be a rare complication of sepsis and multiorgan failure. The
initial reports of cases had only a few cases of associated myopathy,
mainly occurring in conjuncture with prolonged use of NMBAs
and steroids in the required settings.10 There is recent literature on
myopathies occurring in patients who have had no exposure to the
implicated agents. Such findings, plus the increased use of extended
electrophysiological technique including direct muscle stimulation
(DMS), along with the profuse use of punch biopsies have revealed
that the incidence of CIM maybe on par, or if not more than the
classical critical illness neuropathy (CIN) form of weakness in the
ICU.12 There are some investigators who use of the term “CIW” as the
apt term for this condition, pending the fact that the site of lesion
in this disorder is speculative. It therefore only seems reasonable to
use the term CIP or critical illness myopathy (CIM) to describe the
electrophysiological findings in a subset of patients with CIW11.
Recent studies have revealed that some patients experience
prolonged (from 6 hours to > 7 days) neuromuscular (NM) blockade
after termination of vecuronium therapy.13 The prolonged blockade
has been associated with metabolic acidosis, elevated magnesium
levels, females, renal failure and high plasma concentrations of
3-desacetyl vecuronium. There could be dysfunction of voltage and
ligand-gated sodium, potassium, calcium and other ion channels in
nerve and muscle membranes, microtubule integrity and functional
integrity of fast axonal transport mechanisms, neurotransmitter
release and reuptake mechanisms, synaptic cleft integrity,
transmitter receptor turnover at the neuromuscular junction (NMJ),
T-tubule function, the mechanochemical mechanisms of myofibrillar
excitation: contraction coupling and cross-bridge formation.13,14 The
integrity of these structural and molecular mechanisms is vital to
maintain normal muscle strength. If abnormalities develop in any of
these mechanisms, in various combinations, this could manifest as
weakness.
Taking into account the various probable sites of involvement,
the term “polyneuromyopathy” has been used in recognition of the
multifactorial nature of this problem. Hence, it might be prudent to
use the term “CIW”.
 Section 16 Chapter 121  Intensive Care Unit-Acquired Paresis: Spectrum of Neuromyopathies
There could be different components encompassing the spectrum
of CIW:
• Myopathic component
• Neuropathic component
• Neuromuscular junction component
• Metabolic component
• Encephalopathic component.
The recognition of these components help in the understanding
that “CIW” is a continuum and should not be seen in isolation.
SPECTRUM OF CRITICAL ILLNESS WEAKNESS
Critical Illness Neuropathy
Charles Bolton had first described this entity in 1984.2 CIN is an
acute sensorimotor polyneuropathy and this occurs in about 50–
70% of patients who develop SIRS. SIRS occurs in about 20–50% of
patients admitted to ICU’s which makes CIN one of the important
causes of acute polyneuropathy.9 This is not identified clinically in
most patients, as this is usually preceded by an encephalopathy.
On clinical examination, they exhibit features of flaccid weakness
of the extremities which is often severe with loss of tendon reflexes.
The neuropathy is a distal axonopathy, of both motor and sensory
axons, with no inflammation. Electrodiagnostic studies will
demonstrate reduction or absence of both compound muscle and
sensory nerve action potential (SNAP) and electromyography (EMG)
shows features of denervation.13 Nerve Conduction Studies would
demonstrate the involvement of the phrenic nerves along with the
peripheral neuropathy which would account for the difficulty in
weaning.13 This would cause significant burden on the duration of
ventilation, morbidity and ICU mortality. It is important to recognize
this entity early and differentiate from more commonly occurring
conditions like Guillain-Barré syndrome (GBS), porphyria, botulism,
myasthenic crisis, prolonged blockade due to NMBAs and CIM.
DIAGNOSTIC CRITERIA FOR CRITICAL
ILLNESS POLYNEUROPATHY
The proposed diagnostic criteria for CIP include:
• The patient is critically ill (sepsis and multiple organ failure, SIRS)
• Limb weakness or difficulty weaning patient from ventilator after
non-neuromuscular causes such as heart and lung disease have
been excluded
• Electrophysiological evidence of axonal motor and sensory
polyneuropathy
• Absence of decremental response on repetitive nerve stimulation.
Other acute axonal polyneuropathies, such as those due to thiamine
deficiency, porphyria, etc. should be excluded:
• Definite diagnosis of CIP in criteria 1–4 are fulfilled
• Probable diagnosis of CIP if criteria 1, 3 and 4 are fulfilled
• Diagnosis of ICU: Acquired weakness is established if only criteria
1 and 2 are fulfilled.9
Critical Illness Myopathy
This is an acute myopathy that often affects critically ill patients. While
acute quadriplegic myopathy has been the commonest designation,
it has been given a number of descriptive titles that identify its
major features, including CIM, acute quadriplegic myopathy,
acute (necrotizing) myopathy of intensive care, thick filament
myopathy, acute corticosteroid myopathy, acute hydrocortisone
myopathy, acute myopathy in severe asthma, acute corticosteroid
and pancuronium-associated myopathy and critical care myopathy.
All of these designations refer to a common syndrome, and a
single description for this disorder therefore seems appropriate.
By definition, patients are critically ill and weakness may occur
independently of, or in association with, CIP. CIM develops in at
least one-third of ICU patients treated for status asthmaticus, in 7%
of patients after orthotopic liver transplantation and in patients after
heart transplant. In one prospective study, all 22 critically ill patients
showed clinical, electrophysiological and muscle biopsy evidence of
a primary myopathy.
The clinical features overlap with those of CIP and prolonged NMJ
blockade and include flaccid weakness which tends to be diffuse,
involving all limb muscles and the neck flexors, and often the facial
muscles and diaphragm. Thus, most patients are difficult to wean
from mechanical ventilation. The tendon reflexes are often depressed,
but normal reflexes do not exclude CIM. Electrodiagnostic testing
is important in separating these disorders. Stimulation of muscle
directly and indirectly (by stimulating the nerves to the muscle) is a
very sensitive aid in this aspect. The myopathy may also be part of a
generalized reduction in membrane excitability in the setting of sepsis,
resulting in weakness, encephalopathy and transiently low SNAP
amplitudes (which quickly normalize as the myopathy recovers).
During the initial descriptions of the condition, most cases were
associated with prolonged use of corticosteroids or NMBAs, either
as single agents or in combination. Such reports had prompted these
agents to be implicated as major etiological factors in this condition.
But of lately there have been reports of several cases that have occurred
in isolation or absence of clinical use of either steroids or NMBAs. In
patients who are exposed to vecuronium, repetitive nerve stimulation
studies have shown transient features of prolonged NMJ blockade,
especially during the week after discontinuation of the paralytic agent,
and this could mimic or aggravate the weakness in CIM.
DIAGNOSTIC CRITERIA FOR CRITICAL
ILLNESS MYOPATHY
Given the controversy in differentiating CIM from a putative
motor variant of CIP, diagnostic criteria for CIM are necessary for
research studies. Moreover, a diagnosis of a “motor” variant of CIP
should not be made without excluding myopathy with myosin loss
histopathologically.16-23
The proposed major diagnostic features for CIM are:
• Sensory nerve action potential amplitudes more than 80% of the
lower limit of normal (LLN) in two or more nerves
• Needle EMG with short duration, low amplitude motor unit
potentials (MUPs) with early or normal full recruitment, with or
without fibrillation potentials
• Absence of a decremental response on repetitive nerve stimulation
• Muscle histopathologic findings of myopathy with myosin loss.
Supportive features are:
• Compound muscle action potentials (CMAP) amplitudes less
than 80% LLN in two or more nerves without conduction block
• Elevated serum creatine kinase (CK) (best assessed in the first
week of illness)
• Demonstration of muscle excitability.
By definition, patients should be critically ill and weakness should
have started after the onset of critical illness. For a definite diagnosis
of CIM, patients should have all four major features. For probable
CIM, patients should have any three major features and one or more
supportive feature. For possible CIM, patients should have either—
major features 1 and 3 or 2 and 3 and one or more supportive feature.
The typical features of CIM on nerve conduction studies are low
amplitude, sometimes broadened or absent CMAPs with relatively
preserved SNAPs.15
CRITICAL ILLNESS NEUROMYOPATHY
Combined CIP and CIM which could be usually mild but severe
in some cases and this is the most common cause of weakness in
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 Neurology
the critically ill patient.27 Electrophysiological studies could show
mild drop in CMAP and SNAPs to severe drop in CMAP and SNAP,
depending on the severity of affection. Needle EMG could show mild
changes in milder cases and histopathology could range from mild
changes to a necrotic pattern. In the severe form, mortality could be
high or could have a protracted recovery.
Diagnosis
The diagnosis needs to be considered when there is difficulty
in weaning some patients who are critically ill from mechanical
ventilation (see Diagnostic Criteria for Critical Illness Neuropathy
and Critical Illness Myopathy) and this cannot be explained by
increased respiratory or cardiac load, metabolic disturbances,
nutritional disorders, anemia or delirium. The setting is that while
withdrawing sedation, the ICU staff identifies patients who are weak
and flaccid. There will be paucity of limb movements in patients
whose sensorium is low but would have facial grimacing. The deep
tendon reflexes are usually absent, but could be preserved and a
reliable sensory examination is not possible. In this setting, CIP/CIM
should be considered and appropriate electrophysiological studies
including nerve conduction studies, phrenic nerve conductions and
EMG should be done and muscle biopsy, if feasible. There would be a
need to do follow-up studies and then discern if the patient has CIN,
CIM or critical illness neuromyopathy (CINM).
Differential Diagnosis
It is important to exclude pre-existent causes and exclude central
nervous system causes of weakness, in order to avoid unnecessary
diagnosis and giving a pessimistic prognosis. Metabolic disturbances
like hypokalemia and hypophosphatemia can cause acute myopathic
process and hypermagnesemia can impair NM transmission. Sepsis
alone does not impair NM transmission, but NMBAs, cytotoxic drugs,
statins and antiretroviral drugs can affect NM transmission.
It is important to rule out an axonal variant of GBS which is
amenable to treatment with intravenous immunoglobulin/plasma
exchange. They usually have an antecedent diarrheal illness due
to Campylobacter jejuni. The presence of bifacial weakness, a high
cerebrospinal fluid (CSF) protein, dysautonomia, if present, testing
for antibodies to gangliosides and serial conductions would help in
differentiating the disorders.
Predictors for Outcome
Critical illness polyneuropathy and myopathy can cause severe
disability after critical illness. The patients with CIW cause limb and
diaphragmatic weakness that could persist for months or years after
resolution. Leitjen had studied 50 patients undergoing mechanical
ventilation for more than 7 days, 29/50 had developed peripheral
neuropathy, and they spent more days on the ventilator and had an
ICU mortality of 48 versus 19% (without CIP) and this was found to
be statistically significant.24 De Jonghe et al. have found ICU-acquired
paresis to be an independent predictor for prolonged weaning and
Zifko has shown 11/13 CIP survivors to have clinical evidence of
peripheral neuropathy 1–2 years later with impaired quality of life.25,26
Preventive Strategies
No specific treatment has reduced the incidence and severity of CIP
and CIM. The various agents that have been tried are nutritional,
antioxidants, hormonal therapy and intravenous immunoglobulin.27
Intensive insulin therapy to maintain normal blood glucose
concentrations (4.4–6.1 mmol/L) reduces the incidence of
electrophysiologically diagnosed CIP and the need for prolonged
mechanical ventilation in both surgical and medical patients in the
ICU.28,29 However, the optimum blood glucose target is not well
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Section 16
determined and studies using intensive insulin treatment to promote
normoglycemia, have resulted in increased mortality in adult ICU
patients.30
There has been a change in practice to judiciously use NMBAs,
coordinated daily interrupted sedation with wakeup protocols,
interruption of mechanical ventilation with spontaneous breathing
and these measures would reduce the duration of mechanical
ventilation, coma, ICU and hospital stay.31
There is a paucity of studies in the developing world setting. A
prospective study done at the author’s institution on 30 patients in 2006
had shown a high incidence of CIW and 90% had electrophysiological
evidence of dysfunction: axonal motor-sensory polyneuropathy-
CIN (33.3%), critical illness motor syndromes (CIMS) (pure motor)
(13.3%) and axonal polyneuropathy with concomitant myopathy-
CINM (48.1%). CIN group had classical axonal.
Motor sensory neuropathy with markedly low phrenic nerve
amplitudes; CIMS (pure motor) had markedly reduced motor
amplitudes with phrenic nerve abnormalities and elevated CK levels
and CINM had combination of myopathy with axonal motor sensory
neuropathy. Patients with CIMS had higher exposure to steroids and
NMBAs while those with CINM had higher exposure to steroids only.
The overall mortality was 43.4%, but subgroups with CIM (75%) and
CINM (69.2%) had higher mortality.
It is important to identify CIW in the ICU, as this would help in
predicting increased morbidity, prolonged ICU and hospital stay and
higher mortality. This is important in a resource crunch situation, as
along with prolonged hospital stay, the cost of treatment would be
higher. Hence, it is important to implement measures to reduce the
incidence of CIW and resultant morbidity and mortality.
The most crucial advances in ICU care is the concept of introducing
early rehabilitation, early passive mobilization, electrical muscle
stimulation, daily cycle sessions with a bedside ergometer, these
would improve quadriceps muscle force and functional outcome in
patients who leave the ICU. There is scope for further research on this
very important entity.
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