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Chapter 21
Chapter 21
Mathew Alexander
HISTORY and NMBAs are added, there is oxidative stress. The blood
vessels supplying peripheral nerves lack autoregulation and the
Muscle weakness and atrophy occurring during the course of sepsis
cytokines are responsible for increased capillary permeability,
was described in 1892 by Sir William Osler.1 The first description on
there is endoneurial damage and hypoxia. The glutathione level,
this entity came almost a century later when Charles Bolton described
both total and reduced form, is reduced in the muscle. There is
an axonal polyneuropathy in four patients who had sepsis and coined
mitochondrial dysfunction and oxidative stress, glutamine depletion
the term CIP.2 This has been found to be increasingly associated with
to 15%, impaired reutilization of oxidized glutathione due to reduced
a severe systemic response to infection, resultant multiorgan failure
nicotinamide adenine dinucleotide phosphate (NADPH), with
with resultant motor weakness with mortality as high as 30–50%.3
increased muscle catabolism.
This is now recognized to be a very important etiology for difficulty
Critical illness polyneuropathy (CIP) was described about 30 years
in weaning patients in the intensive care unit (ICU) setting with
ago to be a rare complication of sepsis and multiorgan failure. The
prolonged ICU/hospital stay.
initial reports of cases had only a few cases of associated myopathy,
mainly occurring in conjuncture with prolonged use of NMBAs
EPIDEMIOLOGY and steroids in the required settings.10 There is recent literature on
The prevalence of this disorder varies from 20% to 90%, and now with myopathies occurring in patients who have had no exposure to the
increased awareness, improved sedation protocols, judicious use of implicated agents. Such findings, plus the increased use of extended
neuromuscular blocking agents (NMBAs), good glycemic control, the electrophysiological technique including direct muscle stimulation
incidence of this disorder is coming down. Systemic inflammatory (DMS), along with the profuse use of punch biopsies have revealed
response syndrome (SIRS) occurs in response to severe infection or that the incidence of CIM maybe on par, or if not more than the
trauma of mechanical, thermal or chemical nature. SIRS is associated classical critical illness neuropathy (CIN) form of weakness in the
with the release of several mediators, such as cytokines and free ICU.12 There are some investigators who use of the term “CIW” as the
radicals, with resultant effect on the microcirculation throughout the apt term for this condition, pending the fact that the site of lesion
body including the central nervous system and peripheral nervous in this disorder is speculative. It therefore only seems reasonable to
system. In patients who have been in the ICU4 for a week or longer, use the term CIP or critical illness myopathy (CIM) to describe the
a good number of them would have SIRS, either as a primary event electrophysiological findings in a subset of patients with CIW11.
or as a complication of invasive procedures such as endotracheal Recent studies have revealed that some patients experience
intubation or insertion of central lines. SIRS, when associated with prolonged (from 6 hours to > 7 days) neuromuscular (NM) blockade
documented infection, the term sepsis could be applied.5-7 Severe after termination of vecuronium therapy.13 The prolonged blockade
sepsis and septic shock is reserved for those patients with organ has been associated with metabolic acidosis, elevated magnesium
dysfunction and hypoperfusion/hypotension, despite adequate fluid levels, females, renal failure and high plasma concentrations of
replacement. Although critical illness weakness (CIW) was thought 3-desacetyl vecuronium. There could be dysfunction of voltage and
to be an axonal neuropathy, there has been an increasing incidence ligand-gated sodium, potassium, calcium and other ion channels in
of reports of a concomitant myopathy, which could be mainly related nerve and muscle membranes, microtubule integrity and functional
to high doses of steroids and NMBA.8,9 integrity of fast axonal transport mechanisms, neurotransmitter
This is of great relevance in the developing world setting, where release and reuptake mechanisms, synaptic cleft integrity,
there are limited resources; the development of CIW would prolong transmitter receptor turnover at the neuromuscular junction (NMJ),
the ICU stay with increased morbidity and mortality. There is a T-tubule function, the mechanochemical mechanisms of myofibrillar
paucity of studies looking at the patterns of electrophysiological excitation: contraction coupling and cross-bridge formation.13,14 The
abnormalities and putative predictors for the development of integrity of these structural and molecular mechanisms is vital to
weakness. maintain normal muscle strength. If abnormalities develop in any of
these mechanisms, in various combinations, this could manifest as
Pathogenesis and Microcirculatory Changes weakness.
When there is SIRS with multiorgan dysfunction syndrome, there is Taking into account the various probable sites of involvement,
a disturbed humoral and cellular response, with increased capillary the term “polyneuromyopathy” has been used in recognition of the
permeability and endothelial damage. There is microcirculatory multifactorial nature of this problem. Hence, it might be prudent to
dysfunction with tissue hypoxia.6 In this setting, when corticosteroids use the term “CIW”.
Section 16 Chapter 121 Intensive Care Unit-Acquired Paresis: Spectrum of Neuromyopathies
There could be different components encompassing the spectrum independently of, or in association with, CIP. CIM develops in at
of CIW: least one-third of ICU patients treated for status asthmaticus, in 7%
• Myopathic component of patients after orthotopic liver transplantation and in patients after
• Neuropathic component heart transplant. In one prospective study, all 22 critically ill patients
• Neuromuscular junction component showed clinical, electrophysiological and muscle biopsy evidence of
• Metabolic component a primary myopathy.
• Encephalopathic component. The clinical features overlap with those of CIP and prolonged NMJ
The recognition of these components help in the understanding blockade and include flaccid weakness which tends to be diffuse,
that “CIW” is a continuum and should not be seen in isolation. involving all limb muscles and the neck flexors, and often the facial
muscles and diaphragm. Thus, most patients are difficult to wean
SPECTRUM OF CRITICAL ILLNESS WEAKNESS from mechanical ventilation. The tendon reflexes are often depressed,
but normal reflexes do not exclude CIM. Electrodiagnostic testing
Critical Illness Neuropathy is important in separating these disorders. Stimulation of muscle
Charles Bolton had first described this entity in 1984.2 CIN is an directly and indirectly (by stimulating the nerves to the muscle) is a
acute sensorimotor polyneuropathy and this occurs in about 50– very sensitive aid in this aspect. The myopathy may also be part of a
70% of patients who develop SIRS. SIRS occurs in about 20–50% of generalized reduction in membrane excitability in the setting of sepsis,
patients admitted to ICU’s which makes CIN one of the important resulting in weakness, encephalopathy and transiently low SNAP
causes of acute polyneuropathy.9 This is not identified clinically in amplitudes (which quickly normalize as the myopathy recovers).
most patients, as this is usually preceded by an encephalopathy. During the initial descriptions of the condition, most cases were
On clinical examination, they exhibit features of flaccid weakness associated with prolonged use of corticosteroids or NMBAs, either
of the extremities which is often severe with loss of tendon reflexes. as single agents or in combination. Such reports had prompted these
The neuropathy is a distal axonopathy, of both motor and sensory agents to be implicated as major etiological factors in this condition.
axons, with no inflammation. Electrodiagnostic studies will But of lately there have been reports of several cases that have occurred
demonstrate reduction or absence of both compound muscle and in isolation or absence of clinical use of either steroids or NMBAs. In
sensory nerve action potential (SNAP) and electromyography (EMG) patients who are exposed to vecuronium, repetitive nerve stimulation
shows features of denervation.13 Nerve Conduction Studies would studies have shown transient features of prolonged NMJ blockade,
demonstrate the involvement of the phrenic nerves along with the especially during the week after discontinuation of the paralytic agent,
peripheral neuropathy which would account for the difficulty in and this could mimic or aggravate the weakness in CIM.
weaning.13 This would cause significant burden on the duration of
ventilation, morbidity and ICU mortality. It is important to recognize DIAGNOSTIC CRITERIA FOR CRITICAL
this entity early and differentiate from more commonly occurring ILLNESS MYOPATHY
conditions like Guillain-Barré syndrome (GBS), porphyria, botulism, Given the controversy in differentiating CIM from a putative
myasthenic crisis, prolonged blockade due to NMBAs and CIM. motor variant of CIP, diagnostic criteria for CIM are necessary for
research studies. Moreover, a diagnosis of a “motor” variant of CIP
DIAGNOSTIC CRITERIA FOR CRITICAL should not be made without excluding myopathy with myosin loss
ILLNESS POLYNEUROPATHY histopathologically.16-23
The proposed diagnostic criteria for CIP include: The proposed major diagnostic features for CIM are:
• The patient is critically ill (sepsis and multiple organ failure, SIRS) • Sensory nerve action potential amplitudes more than 80% of the
• Limb weakness or difficulty weaning patient from ventilator after lower limit of normal (LLN) in two or more nerves
non-neuromuscular causes such as heart and lung disease have • Needle EMG with short duration, low amplitude motor unit
been excluded potentials (MUPs) with early or normal full recruitment, with or
• Electrophysiological evidence of axonal motor and sensory without fibrillation potentials
polyneuropathy • Absence of a decremental response on repetitive nerve stimulation
• Absence of decremental response on repetitive nerve stimulation. • Muscle histopathologic findings of myopathy with myosin loss.
Other acute axonal polyneuropathies, such as those due to thiamine Supportive features are:
deficiency, porphyria, etc. should be excluded: • Compound muscle action potentials (CMAP) amplitudes less
• Definite diagnosis of CIP in criteria 1–4 are fulfilled than 80% LLN in two or more nerves without conduction block
• Probable diagnosis of CIP if criteria 1, 3 and 4 are fulfilled • Elevated serum creatine kinase (CK) (best assessed in the first
• Diagnosis of ICU: Acquired weakness is established if only criteria week of illness)
1 and 2 are fulfilled.9 • 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
Critical Illness Myopathy
of CIM, patients should have all four major features. For probable
This is an acute myopathy that often affects critically ill patients. While CIM, patients should have any three major features and one or more
acute quadriplegic myopathy has been the commonest designation, supportive feature. For possible CIM, patients should have either—
it has been given a number of descriptive titles that identify its major features 1 and 3 or 2 and 3 and one or more supportive feature.
major features, including CIM, acute quadriplegic myopathy, The typical features of CIM on nerve conduction studies are low
acute (necrotizing) myopathy of intensive care, thick filament amplitude, sometimes broadened or absent CMAPs with relatively
myopathy, acute corticosteroid myopathy, acute hydrocortisone preserved SNAPs.15
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 CRITICAL ILLNESS NEUROMYOPATHY
single description for this disorder therefore seems appropriate. Combined CIP and CIM which could be usually mild but severe
By definition, patients are critically ill and weakness may occur in some cases and this is the most common cause of weakness in
553
Neurology Section 16
the critically ill patient.27 Electrophysiological studies could show determined and studies using intensive insulin treatment to promote
mild drop in CMAP and SNAPs to severe drop in CMAP and SNAP, normoglycemia, have resulted in increased mortality in adult ICU
depending on the severity of affection. Needle EMG could show mild patients.30
changes in milder cases and histopathology could range from mild There has been a change in practice to judiciously use NMBAs,
changes to a necrotic pattern. In the severe form, mortality could be coordinated daily interrupted sedation with wakeup protocols,
high or could have a protracted recovery. interruption of mechanical ventilation with spontaneous breathing
and these measures would reduce the duration of mechanical
Diagnosis ventilation, coma, ICU and hospital stay.31
There is a paucity of studies in the developing world setting. A
The diagnosis needs to be considered when there is difficulty
prospective study done at the author’s institution on 30 patients in 2006
in weaning some patients who are critically ill from mechanical
had shown a high incidence of CIW and 90% had electrophysiological
ventilation (see Diagnostic Criteria for Critical Illness Neuropathy
evidence of dysfunction: axonal motor-sensory polyneuropathy-
and Critical Illness Myopathy) and this cannot be explained by
CIN (33.3%), critical illness motor syndromes (CIMS) (pure motor)
increased respiratory or cardiac load, metabolic disturbances,
(13.3%) and axonal polyneuropathy with concomitant myopathy-
nutritional disorders, anemia or delirium. The setting is that while
CINM (48.1%). CIN group had classical axonal.
withdrawing sedation, the ICU staff identifies patients who are weak
Motor sensory neuropathy with markedly low phrenic nerve
and flaccid. There will be paucity of limb movements in patients
amplitudes; CIMS (pure motor) had markedly reduced motor
whose sensorium is low but would have facial grimacing. The deep
amplitudes with phrenic nerve abnormalities and elevated CK levels
tendon reflexes are usually absent, but could be preserved and a
and CINM had combination of myopathy with axonal motor sensory
reliable sensory examination is not possible. In this setting, CIP/CIM
neuropathy. Patients with CIMS had higher exposure to steroids and
should be considered and appropriate electrophysiological studies
NMBAs while those with CINM had higher exposure to steroids only.
including nerve conduction studies, phrenic nerve conductions and
The overall mortality was 43.4%, but subgroups with CIM (75%) and
EMG should be done and muscle biopsy, if feasible. There would be a
CINM (69.2%) had higher mortality.
need to do follow-up studies and then discern if the patient has CIN,
It is important to identify CIW in the ICU, as this would help in
CIM or critical illness neuromyopathy (CINM).
predicting increased morbidity, prolonged ICU and hospital stay and
higher mortality. This is important in a resource crunch situation, as
Differential Diagnosis along with prolonged hospital stay, the cost of treatment would be
It is important to exclude pre-existent causes and exclude central higher. Hence, it is important to implement measures to reduce the
nervous system causes of weakness, in order to avoid unnecessary incidence of CIW and resultant morbidity and mortality.
diagnosis and giving a pessimistic prognosis. Metabolic disturbances The most crucial advances in ICU care is the concept of introducing
like hypokalemia and hypophosphatemia can cause acute myopathic early rehabilitation, early passive mobilization, electrical muscle
process and hypermagnesemia can impair NM transmission. Sepsis stimulation, daily cycle sessions with a bedside ergometer, these
alone does not impair NM transmission, but NMBAs, cytotoxic drugs, would improve quadriceps muscle force and functional outcome in
statins and antiretroviral drugs can affect NM transmission. patients who leave the ICU. There is scope for further research on this
It is important to rule out an axonal variant of GBS which is very important entity.
amenable to treatment with intravenous immunoglobulin/plasma
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