INVITED REVIEW ABSTRACT: Critical illness, more precisely dened as the systemic inam-

matory response syndrome (SIRS), occurs in 20%50% of patients who

have been on mechanical ventilation for more than 1 week in an intensive
care unit. Critical illness polyneuropathy (CIP) and myopathy (CIM), singly or
in combination, occur commonly in these patients and present as limb
weakness and difculty in weaning from the ventilator. Critical illness my-
opathy can be subdivided into thick-lament (myosin) loss, cachectic myop-
athy, acute rhabdomyolysis, and acute necrotizing myopathy of intensive
care. SIRS is the predominant underlying factor in CIP and is likely a factor
in CIM even though the effects of neuromuscular blocking agents and
steroids predominate in CIM. Identication and characterization of the poly-
neuropathy and myopathy depend upon neurological examination, electro-
physiological studies, measurement of serum creatine kinase, and, if fea-
tures suggest a myopathy, muscle biopsy. The information is valuable in
deciding treatment and prognosis.
Muscle Nerve 32: 140 163, 2005

NEUROMUSCULAR MANIFESTATIONS
OF CRITICAL ILLNESS
CHARLES F. BOLTON, MD

Department of Neurology, Mayo Clinic College of Medicine, 200 First Street SW,
Rochester, Minnesota 55905, USA

Accepted 29 December 2004

Weakness of limb and respiratory muscle is increas-
ingly recognized as a common occurrence in inten-
sive care units (ICU). It occurs in critically ill pa-
tients, with unexplained difculty in weaning from
mechanical ventilation being an early sign. Due to
difculties in accurately assessing the peripheral ner-
vous system in the ICU, electrophysiological studies
and, at times, muscle biopsy, are important methods
of investigating these patients. An accurate diagnosis
is important in deciding the best type of ventilator
support, avoiding when possible neuromuscular
blocking agents and steroids, preventing and treat-
ing sepsis and multiple organ failure, utilizing reha-
bilitation for respiratory and limb weakness, and
guiding future research.
Available for Category 1 CME credit through the AANEM at www.
aanem.org.
Abbreviations: CIM, critical illness myopathy; CIP, critical illness polyneu-
ropathy; CK, creatine kinase; CMAP, compound muscle action potentials;
EMG, electromyogram; ICU, intensive care unit; IVIG, intravenous immuno-
globulins; MRI, magnetic resonance imaging; 31P-NMR, 31P nuclear mag-
netic resonance; SIRS, systematic inammatory response syndrome; SNAP,
sensory nerve action potential; TNF, tumor necrosis factor
Key words: acute quadriplegic myopathy; critical illness myopathy; critical
illness polyneuropathy; sepsis; systemic inammatory response syndrome
Correspondence to: C. F. Bolton; e-mail: CB41@post.queensu.ca
2005 Wiley Periodicals, Inc.
Published online 11 April 2005 in Wiley InterScience (www.interscience.wiley.
com). DOI 10.1002/mus.20304
There remains controversy as to the incidence
alone or in combination of critical illness polyneu-
ropathy and myopathy, the value of electrophysi-
ologic studies and muscle biopsy, mechanisms of
muscle weakness in ICU patients, and the etiologic
role of sepsis, neuromuscular blocking agents, and
steroids.
Of the various neuromuscular conditions compli-
cating critical illness, critical illness polyneuropathy
(CIP) is the best dened. It has been the subject of
numerous review articles, the most recent by Van
Mook and Hulsewe-Evers,170 and Magistris,111 and
theses by Leijten99 and de Letter.47 The primary
disorders of muscle have been a heterogeneous
group,82 but Lacomis et al. have recently proposed
and dened an all-encompassing entity, critical ill-
ness myopathy94 (CIM), recently reviewed by Laco-
mis.90 CIP and CIM may both occur prominently in
the same patients; recent reviews on this subject are
by Bird and Rich14 and Hund,83 and a thesis by de
Letter.47
HISTORICAL REVIEW
Polyneuropathy and myopathy may have always ac-
companied sepsis. However, before the support of
blood pressure and breathing in ICUs, death usually
occurred before the neuromuscular signs were clin-

140 Neuromuscular Features of Critical Illness MUSCLE & NERVE August 2005
ically evident. Nonetheless, Osler126 observed rapid
loss of esh with prolonged sepsis. Erbsloh59 in 1955
observed a polyneuropathy following anoxic coma af-
ter shock or cardiac arrest. In 1961, Mertens118 de-
scribed coma-polyneuropathies in patients who had
circulatory shock associated with acute intoxication
and severe metabolic crises, seemingly due to meta-
bolic and ischemic lesions of the peripheral nervous
system. In 1971, Henderson et al.77 described a poly-
neuropathy in patients with burns. Four septic patients
developed a severe polyneuropathy in 1977, which
Bischoff et al.15 attributed to gentamicin sulfate.
Between 1977 and 1981, we17 observed ve un-
usual patients in critical care units who showed dif-
culty in weaning from the ventilator and had severe
limb weakness. Comprehensive electrophysiologic
and morphologic studies established this condition
as a primary distal, axonal degeneration of motor
and sensory bers.17 The etiology was uncertain, but
nutritional deciency, collagen vascular disease, tox-
icity from antibiotics or heavy metals, and spinal
cord ischemia were discounted. We suggested the
polyneuropathy was due to the toxic effects of
sepsis itself.34 An immediate reaction to our initial
report was that this condition was simply a variant of
GuillainBarre syndrome. However, a comparison of
15 patients with CIP and 16 patients with Guillain
Barre syndrome, all studied in our unit during the
same period, indicated that the two types of polyneu-
ropathies were distinctive in regard to antecedent or
associated illnesses and electrophysiologic and mor-
phologic features.29 GuillainBarre syndrome was of-
ten preceded by a minor infection or inoculation,
with a latent period of days or weeks before its onset;
CIP developed during the course of critical illness.29
During the same period, we also observed ve pa-
tients who had a severe acute axonal polyneuropathy
distinct from the polyneuropathy in our critically ill
patients.62 The polyneuropathy began before critical
illness or injury necessitated admission to the ICU and,
except for its severe axonal nature, was otherwise typ-
ical of GuillainBarre syndrome. This polyneuropathy
was subsequently named acute motor and sensory ax-
onal neuropathy and has since been recognized as one
of the variants of GuillainBarre syndrome.19
Electrophysiologic studies were crucial to identi-
fying these polyneuropathies, hence, they were uti-
lized with increasing frequency in our ICU.22 By
1983, 19 cases of polyneuropathy had been col-
lected. Since the term critical illness was commonly
applied by intensivists to patients who had sepsis and
multiple organ failure, we named the condition crit-
ical illness polyneuropathy.194 During this time, it
became evident that all of these patients had had a
Neuromuscular Features of Critical Illness
septic encephalopathy preceding the development
of the polyneuropathy, and this as-yet poorly recog-
nized entity was to be more clearly dened in subse-
quent prospective investigations.85,184 We181 then
prospectively determined that the frequency of the
polyneuropathy in patients with sepsis and multiple
organ failure was 70% and that antibiotics, neuro-
muscular blocking agents, and nutritional decien-
cies could not be proven to be etiologic factors.
However, features of sepsis and multiple organ dys-
function syndrome (MODS) were, notably, time in
the ICU, a rise in blood glucose, and a decline in
serum albumen with decreasing peripheral nerve
function. Disturbances of the microcirculation to pe-
ripheral nerves, a phenomenon that seems to afict all
organ systems in the sepsis syndrome, were a possible
pathophysiologic mechanism.181,194 From the begin-
ning, it was clear that critical illness polyneuropathy
was an important cause of difculty in weaning from
the ventilator when pulmonary and cardiac causes had
been excluded,17, 28, 191 which was conrmed by Spitzer
et al.158 Finally, electrophysiologic and morphologic
features in some patients strongly suggested that criti-
cal illness also primarily affected muscle in the form of
disturbance of the cytoarchitecture of muscle bers28
and scattered muscle ber necrosis,194 which we
termed the myopathy in critical illness.193
During this time, similar cases of polyneuropathy
were reported from the United States,143 France,9,42
and Holland.109 The more recent literature has been
dominated by reports of paralysis in ICUs that were
presumed complications of neuromuscular blocking
agents and steroids. In 1985, Op de Coul et al.123 in
Holland reported 12 patients with a severe, but re-
versible, axonal motor neuropathy that appeared
due to the use of the competitive neuromuscular
blocking agent pancuronium bromide to facilitate
mechanical ventilation. A number of such pa-
tients have since been reported, including those
patients treated with the shorter-acting vecuro-
nium.10,68,71,89,123,145,159,176 Many patients also re-
ceived corticosteroids; when this neuromuscular
blocking agent and steroids were used to treat acute
asthma, or the posttransplant state, a myosin-de-
cient myopathy resulted.93,110,152 An acute necrotiz-
ing myopathy of intensive care, seemingly triggered
by neuromuscular blocking agents was described in
seven patients by Zochodne et al.195
CRITICAL ILLNESS, SEPSIS, MULTIPLE ORGAN
FAILURE, AND SIRS
In recent years, critical illness, which had been
broadly dened as any life-threatening illness, has
MUSCLE & NERVE August 2005 141
FIGURE 1. The various factors associated with the development of the systemic inammatory response syndrome (SIRS) and its nervous
system complications, septic encephalopathy, critical illness polyneuropathy, and other neuromuscular complications (adapted with
permission from Bolton21).
been more specically dened as a syndrome of
sepsis and multiple organ failure. Sepsis originally
meant putrefaction, a decomposition of organic mat-
ter by bacteria and fungi.2 It has since been associ-
ated increasingly with a severe systemic response to
infection, usually resulting in early death. With im-
provements in medical and surgical care, survival of
many critically ill patients is now prolonged, but the
mortality rate may still be 30%50%, and approxi-
mately 500,000 patients are reported each year with
sepsis in the United States.52,108,140,141,165 Most pa-
tients in an ICU for longer than 1 week will have
SIRS, either as a primary event or as a complication
of invasive procedures such as tracheal intubation or
insertion of intravascular lines. There has been con-
fusion over terminology, gram-negative bactere-
mia, gram-negative sepsis, sepsis syndrome, and
septic shock, being variously applied.37 A consen-
sus conference was convened in 1992 to standardize
denitions.1 Recognizing that a severe systemic re-
sponse can be evoked in the absence of infection
(e.g., by trauma and burns), the panel proposed the
term systemic inammatory response syndrome or
SIRS.1 When SIRS was associated with a documented
infection, the term sepsis could be applied. The
terms severe sepsis and septic shock were re-
served for those patients with organ dysfunction and
hypoperfusion, or hypotension despite adequate
uid replacement.
Thus, bacteria, fungi, viruses, and major trauma
of a mechanical, thermal, or chemical nature will
142 Neuromuscular Features of Critical Illness
induce SIRS (Fig. 1). SIRS includes two or more of
the following clinical manifestations: (1) a body tem-
perature of 38C or 36C; (2) heart rate (HR) of
90 beats/min; (3) tachypnea, as manifested by a
respiratory rate of 20 breaths/min or hyperventi-
lation, as indicated by a PaCO2 of 32torr(4.3
kPa); and (4) an alteration of the white blood cell
count of 12,000 cells/mm3, 4000 cells/mm3, or
the presence of 10% immature neutrophils
(bands).37
In SIRS, cellular and humoral responses are ac-
tivated69,140 to produce changes in the microcircula-
tion throughout the body (Fig. 2). The cellular re-
sponse involves epithelial and endothelial cells,
macrophages, and neutrophils. These induce the
humoral response; pro-inammatory mediators are
activated locally and include interleukins-1, -2, and
-6, tumor necrosis factor (TNF), arachidonic acid,
coagulation factors, free oxygen radicals, and pro-
teases. These cellular and humoral factors interact
with themselves and with adhesion molecules, which
are increased in the blood of septic patients.43 Ad-
hesion molecules adhere to leukocytes, platelets,
and endothelial cells; they also induce rolling neu-
trophils and brin platelet aggregates that obstruct
capillary ow. Endothelial damage increases capil-
lary permeability, which induces local tissue edema.
Levels of protein C are reduced in sepsis.140 Endo-
thelial damage impairs the endothelium-dependent
activation of protein C, thus shifting the balance to
thrombosis.61,149 Activation of nitric oxide, now
MUSCLE & NERVE August 2005
FIGURE 2. Schematic, theoretical presentation of disturbances in the microcirculation to various organs, including brain, peripheral nerve,
and muscle, in SIRS. The result is impaired perfusion due to excessive vasodilatation through overproduction of nitric oxide, and
aggregation of cellular elements through activation of adhesion molecules and deactivation of protein C. Increased capillary permeability
causes edema and the potential for entry of toxic substances (adapted with permission from Bolton21).

known to be the endovascular relaxing factor,127
causes arteriolar dilation, which may further slow
capillary ow. Thus, essential nutrients fail to reach
the organ parenchyma. For example, despite ade-
quate oxygenation via mechanical ventilation, there
is a severe oxygen debt at the parenchymal level
contributing to multiple organ dysfunction.69
Considering the profound disturbances of the
microcirculation and the impaired delivery of sub-
strates, especially oxygen and glucose, upon which
the nervous system depends, it is not surprising that
the nervous system is affected. Just how these distur-
bances may affect the peripheral nervous system is
discussed later. The chief manifestations are septic
encephalopathy184 and CIP,21 each occurring in
70% of septic patients.36 Critical illness myopathy
is usually associated with the use of neuromuscular
blocking agents and steroids, in addition to SIRS
(Fig. 1). Because of difculties in clinical assessment
in the ICU, electrophysiologic studies,22 measure-
ment of serum creatine kinase, and muscle biopsy
have been important in diagnosis. Thus, unex-
plained difculty in weaning from the ventilator,
weakness in the limbs, and delayed rehabilitation
can now be detected using these methods. The
knowledge is important in management, rendering a
prognosis and in assessing cost-effectiveness.24
SEPTIC ENCEPHALOPATHY
Septic encephalopathy is an early neurological com-
plication of SIRS.36 However, since it is often a diag-
nosis of exclusion being detected by eliminating se-
dation as a factor and requiring the nding of near-
normal cerebral spinal uid184 and imaging
studies,85,180 and an abnormal electroencephalo-
gram,183 it is rarely reported in association with CIP.
Nonetheless, prospective studies of critically ill pa-
tients181,184 indicate both septic encephalopathy and
CIP occur together in 70%, septic encephalopathy
appearing rst. The severity of polyneuropathy cor-
relates with deterioration in the Glasgow Coma
Scale.180 The relatively normal head scans,184 and
brain in some patients at autopsy,85 despite evidence
of a severe encephalopathy, suggests functional de-
rangement without structural change. Thus, recov-
ery from septic encephalopathy may be relatively
rapid and complete as SIRS is successfully treated,
but difculty in weaning from mechanical ventila-
tion then becomes the rst evidence of CIP.36
GENERAL APPROACH TO LIMB AND RESPIRATORY
WEAKNESS IN THE ICU
Two considerations are important in investigating
neuromuscular conditions in the ICU.33 The rst is
to exclude conditions that began before admission
to the ICU and may not have had SIRS as an under-
lying factor.33 Acute infective, traumatic, or neoplas-
tic spinal cord compression, motor neurone dis-
ease,40 GuillainBarre syndrome,144,187 myasthenia
gravis,112 Lambert-Eaton myasthenic syndrome,122
muscular dystrophy, and so forth, are usually obvious
before the patient is placed on a ventilator. However,

Neuromuscular Features of Critical Illness MUSCLE & NERVE August 2005 143
FIGURE 3. The pattern of nerve conduction abnormalities in critical illness polyneuropathy; reduction of CMAP and SNAP, and the
presence of brillation potentials in muscle. All are most marked in severe polyneuropathy. CMAP amplitudes are more reduced than
SNAP. The speed of impulse conduction is only mildly reduced (not shown). These ndings indicate a primary axonal degeneration of
motor and sensory bers (with permission from Zochodne et al.194).
occasionally, conditions worsen so rapidly that an
early diagnosis is not possible, and investigations
must be undertaken while the patient is in the ICU
(Fig. 3).
The second consideration is patients in the ICU
for a variety of severe, primary illnesses or injury,
who develop SIRS and then, after a period of days or
weeks are observed to have difculty in weaning
from the ventilator. An underlying neuromuscular
condition can be suspected if, after lung or cardiac
causes of respiratory insufciency have been elimi-
nated, on attempted weaning, voluntary respirations
are rapid and weak and are accompanied by an
increasing blood concentration of CO2. Clinical
signs of neuropathy or myopathy in the limbs may
not be present at this stage. The neuromuscular
conditions associated with SIRS and their differenti-
ating features are shown in Table 1.20,25
In both categories, involvement of the high cer-
vical spinal cord, peripheral nerves, neuromuscular
junctions, and muscles should be systematically in-
vestigated. Depending on clinical variables, it may be
necessary to perform one or more of the following
assessments: (a) magnetic resonance imaging of the
cervical spinal cord; (b) motor and sensory nerve
conduction; (c) repetitive nerve stimulation for in-
vestigation of neuromuscular transmission defect;
(d) needle electromyography of muscle; (e) tests of
the respiratory system by phrenic nerve conduc-
tion studies and needle electromyography of the
diaphragm20; (f) measurements of serum creatine
144 Neuromuscular Features of Critical Illness
phosphokinase concentration; and (g) biopsy of
muscle.22,25 Nerve biopsy is rarely indicated. Investi-
gations may reveal a variety of high cervical lesions
causing reduced central drive, or disorders of the
peripheral neuromuscular system. Knowledge of
these underlying causes may aid more effective
weaning procedures, indicate specic treatment
such as immunosuppression for GuillainBarre syn-
drome, or provide information in determining long-
term prognosis.18
CRITICAL ILLNESS POLYNEUROPATHY
Clinical Features. CIP has been reported world-
wide.21,84,100,170,174 Prospective studies indicate that
CIP occurs in 50%70% of patients suffering from
SIRS.102,181 SIRS occurs in 20%50% of patients in
major ICUs.165 Hence, CIP must now be regarded as
a particularly common neuromuscular disorder.27
CIP is often preceded by septic encephalopa-
thy.36 This is followed by difculty in weaning from
the ventilator. Because of difculty in examining the
neuromuscular system in these patients, the poly-
neuropathy may not be identied clinically in half of
the patients.181 As an initial observation, when a
painful stimulus is induced by compressing the nail
beds with a pencil to assess the level of conscious-
ness, there is facial grimacing but reduced or absent
movement of the limbs. Even in moderately severe
polyneuropathies, deep tendon reexes may be pre-
served.35,84,181 Sensory testing is often unreliable, but
MUSCLE & NERVE August 2005
 Table 1. Generalized neuromuscular conditions associated with critical illness*
Clinical Electrophysiologic Serum
Condition Incidence features ndings creatine kinase Muscle biopsy Prognosis

Polyneuropathy
Critical illness polyneuropathy Common Flaccid limbs; Axonal degeneration Nearly normal Denervation atrophy Variable
respiratory of motor and
weakness sensory bers
Neuromuscular transmission
defect
Transient neuromuscular Common with Flaccid limbs; Abnormal repetitive Normal Normal Good
blockade neuromuscular respiratory nerve stimulation
blocking agents weakness studies
Critical illness myopathy
Thick-lament myosin loss Common with steroids, Flaccid limbs; Abnormal Mildly elevated Loss of thick Good
neuromuscular respiratory spontaneous (myosin) laments
blocking agents, weakness activity
and sepsis
Rhabdomyolysis Rare Flaccid limbs Near normal Markedly Normal or mild Good
elevated necrosis
(myoglobinuria)
Necrotizing myopathy of Rare Flaccid Severe myopathy Markedly Marked necrosis Poor
intensive care weakness; elevated,
myoglobinuria myoglobinuria
Disuse (cachectic) myopathy Common (?) Muscle Normal Normal Normal or type II Good
wasting ber atrophy
Combined polyneuropathy Common Flaccid limbs; Indicate combined Variable Denervation atrophy Variable
and myopathy respiratory polyneuropathy and myopathy
weakness and myopathy

*Adapted with permission from Bolton.25

evidence of distal loss to pain, temperature, and
vibration may be observed in alert patients.190,194
Difculties in clinical assessment may explain the
variation in the reported incidence and descriptions
of clinical ndings.84,100,190,191
CIP has been reported in children,55,67,132,153,167
but the incidence may be less than in adults due to
the considerably lower incidence of SIRS in pediatric
than adult ICUs.
Electrophysiologic Features. Comprehensive elec-
trophysiologic studies are important.22,33 These stud-
ies should include motor and sensory nerve conduc-
tion studies as well as needle electromyography
(EMG) in upper and lower limbs. Phrenic nerve
conduction studies and needle EMG of the respira-
tory muscles20 will establish CIP as the cause of
failure to wean from the ventilator.113,148,190 The
ndings are consistent with a primary, axonal degen-
eration. Reduction in amplitudes of the compound
muscle action potential (CMAP) and sensory nerve
action potential (SNAP) is the predominant nding
(Fig. 3).
A decline in the CMAP amplitude occurs within 2
weeks of onset of SIRS and predates clinical and
other electrophysiologic signs.163 There may be an
accompanying prolongation of the CMAP duration
indicating an associated myopathy (Fig. 4).23,192
This, plus the inexcitability of the muscle on direct
stimulation,13 indicates involvement of muscle (Fig.
5). Abnormal spontaneous activity on needle elec-
tromyography and a decline in SNAP amplitude oc-
cur later.190 Motor unit potentials on needle electro-
myography may be variably reduced in number,
some having myopathic features.181,194 Stimulation
single-ber EMG studies indicate there is a dysfunc-
tion of terminal motor axons.150 This may explain
the myopathic features in some patients. As with
other acute neuropathies, electrophysiologic nd-
ings depend on the time of examination. Sensory
nerve conduction studies may be normal in the early
stage of CIP, become abnormal later, and return
towards normal during recovery. Hence, serial stud-
ies aid in differentiating neuropathy from myopathy.
Morphologic Features. Nerve biopsy studies and
comprehensive morphologic studies of both the cen-
tral and peripheral nervous system at autopsy in nine
patients were performed28,194 (Fig. 6). The spinal
cord and nerve roots were studied. Multiple samples
were taken of motor and sensory nerves, and muscle,
both proximally and distally. There was ber loss and
primary axonal degeneration, distal nerve segments
being more severely involved. Semithin sections and
teased-ber preparations revealed early and late
changes of primary axonal degeneration and some

Neuromuscular Features of Critical Illness MUSCLE & NERVE August 2005 145

FIGURE 4. Measurement of compound thenar muscle action
potentials at the onset of sepsis (A) and 3 weeks later (B). Note
the marked decline in amplitude and increase in duration, without
change in latency, on stimulation of the median nerve at the wrist
and elbow. These changes suggest primary dysfunction of the
muscle ber membrane, in addition to denervation. (Polaroid
pictures of oscilloscope traces from 1987 study,192 with permis-
sion from Bolton.23)
regeneration. Central chromatolysis of anterior horn
cells and moderate loss of dorsal root ganglion cells
reected the peripheral axonal degeneration. There
was no evidence of inammation in the peripheral
nervous system. Muscle showed acute and chronic
denervation and occasional myopathic changes.28,194
Primary axonal degeneration of intercostal and
phrenic nerve and denervation atrophy of respira-
tory muscles explained the respiratory insufcien-
cy.194 However, autopsy studies in 2 patients,109 and
nerve biopsy studies in 14 of 2298 patients and 8 of 8
patients,147 revealed normal nerve pathology, de-
spite clinical and electrophysiologic (and even mus-
cle light microscopy147) evidence of peripheral neu-
ropathy. These ndings in other centers may be
partly explained by a failure to detect early nerve
pathology by utilizing semithin sections and teased-
ber preparations, and by the biopsying of sensory
nerves despite predominant motor involvement.
Since axonal degeneration is predominantly distal,
146 Neuromuscular Features of Critical Illness
polyneuropathy may be missed if only nerve roots
are examined at autopsy. Functional change preced-
ing structural alteration in critically ill patients is
likely a further explanation.23,98
Differential Diagnosis. The diagnostic criteria for CIP
are shown in Table 2, and the differentiating feature of
other neuromuscular disorders in critical illness are
shown in Table 1. The differentiation of an acute ax-
onal pure motor neuropathy from CIP may be dif-
cult.26 A pure motor neuropathy in association with
neuromuscular blocking agents has been report-
ed.10,66,68,70,71,89,124,129,151 However, some patients also
had sensory signs and symptoms and abnormal sensory
nerve conduction. Thus, this neuropathy is probably a
variant of CIP, with sepsis and neuromuscular blocking
agents as underlying factors. The axonal variants of
GuillainBarre syndrome (acute motor and sensory
axonal neuropathy, and acute motor axonal neuropa-
thy) develop before admission to the ICU and are
often associated with Campylobacter jejuni infection.19
Finally, patients with the demyelinating form of Guil-
lainBarre syndrome and who are in ICUs receiving
mechanical ventilation may develop sepsis and multi-
ple organ dysfunction syndrome, complicating the in-
vasive procedures of endotracheal intubation and in-
travascular catheterization. A worsening in their
peripheral neuropathy might be attributed to an exac-
erbation of the GuillainBarre syndrome. However, if
electrophysiologic studies show this worsening is re-
lated to axonal degeneration, CIP is the more likely
cause. Thus, instead of further attempts at immuno-
suppression by plasmapheresis or administration of im-
munoglobulin, management of SIRS should be the
prime consideration.21
Weakness due to transient neuromuscular block-
ade is not uncommon in patients receiving high
doses of neuromuscular blocking agents.151,191 Al-
though the clinical features may be similar to CIP or
CIM, the diagnosis can be easily established by re-
petitive nerve stimulation studies.
There has been a debate as to the incidence and
nature of a myopathy, which may occur independently
or in association with CIP, and the role that electro-
physiologic testing, measurements of serum creatine
kinase, and muscle biopsy may play in differentiating
neuropathy from myopathy.26,44,56,78,87,91,98,124,133 Stim-
ulation of muscle directly and indirectly (by stimulat-
ing the nerves to the muscle) may aid in differentiating
CIP from CIM (Fig. 5).
A variety of mononeuropathies and plexopathies
may occur in isolation or coexist with CIP and CIM.33
These may occur as a result of nerve compression
from prolonged recumbency, direct trauma, isch-
MUSCLE & NERVE August 2005
FIGURE 5. Results of direct and indirect muscle stimulation. Compound muscle action potentials (CMAPs) from the anterior tibial muscles
of a patient with critical illness polyneuropathy (left) and critical illness myopathy (right). Top four traces, obtained with direct muscle
stimulation. Bottom trace, recorded with supramaximal nerve stimulation. Shown at the right of each tracing: stimulation current intensity
(adapted with permission from Bird13).
emia, or hemorrhagic compression.4,33,92,160,177,178
The nerves in critically ill patients may be unusually
susceptible to trauma.160
Treatment. Avoidance of SIRS is important. This is
often not possible before admission to the ICU. After
ICU admission, important considerations are scru-
pulous aseptic techniques, constant surveillance for
infecting organisms, and avoidance whenever possi-
ble of surgical procedures. Since steroids and neu-
romuscular blocking agents may contribute to CIM,
they should be avoided or used in lowest possible
dosage and for as short a time as possible.
Once the diagnosis of CIP is made, management
involves (1) treatment of sepsis and multiple organ
dysfunction syndrome; (2) management of difculty
in weaning from the ventilator; (3) attempts at direct
treatment of CIP (still unproven); and (4) physio-
therapy and rehabilitation.
The main approach to treatment of CIP is to
treat SIRS.12,46,48,98,103,163,181,194 The initial insult
should be identied, appropriate antibiotics admin-
istered, and a septic focus drained surgically. Epi-
sodes of septic shock should be treated vigorously,
the circulation maintained, and airways protected.
This early and progressive treatment may prevent
development of the multiple organ dysfunction syn-
drome, but when it does develop, a variety of treat-
ments are instituted for each organ. For example,
Neuromuscular Features of Critical Illness
dysfunction of the gut may be prevented by early use
of enteral feedings through a tube passed through
the pylorus. In the kidney, uid resuscitation, the
use of inotropics, and diuretic drugs, in various com-
binations, may prevent renal failure. Despite these
measures, the mortality rate in sepsis and multiple
organ failure in the ICU is 30%50%.52,108 Nonethe-
less, with institution of treatment, critical illness poly-
neuropathy improves in a matter of weeks in mild
cases and months in severe cases.103,181,194 Clinical
and electrophysiologic studies indicate a progressive
reinnervation of muscle and restoration of sensory
function.29,190,194
Patients with CIP typically go through a period of
difculty in weaning from the ventilator, usually after
the sepsis and multiple organ failure have come under
control and there is no apparent cardiac or pulmonary
cause for difculty in weaning. CIP is thus often rst
identied at this stage. The information is valuable in
respiratory management. However, diagnosis may be
delayed until discharge from the ICU, when weakness
of the limbs prevent sitting or walking, feeding, or
dressing. In either circumstance, referral to a rehabil-
itation specialist should be arranged. Initially, only
light exercises to promote muscle strength, maintain
joint mobility, and prevent contracture should be in-
stituted. As the patient improves, greater strengthening
exercises should be utilized. The program of rehabili-
MUSCLE & NERVE August 2005 147
 Table 2. Diagnostic criteria for critical illness polyneuropathy*
1. The patient is critically ill (sepsis and multiple organ failure,
SIRS)
2. Difculty weaning patient from ventilator after
nonneuromuscular causes such as heart and lung disease
have been excluded
3. Possible limb weakness
4. Electrophysiologic evidence of axonal motor and sensory
polyneuropathy

*These diagnostic criteria are now well established, but in certain

circumstances other acute axonal polyneuropathies, such as those due to
thiamine deciency, porphyria, etc., should be excluded (with permission
from Bolton27).

tation may be lengthy and require the use of a variety

of assistive devices.51,102,169,189
The role of parenteral and enteral nutrition is
controversial. Some have theorized that these proce-
dures may induce alteration in the metabolism of
fats and glucose, which would have a deleterious
effect on peripheral nerve.114,172 However, stud-
ies31,101,181 have shown no statistical relationship be-
tween the administration of enteral or parenteral
nutrition and the development of CIP.
Treatment of CIP with intravenous immuno-
globulins (IVIG) has been attempted. IVIG has been
widely used as a supplemental treatment of sepsis in
critically ill patients and shows some promise in re-
ducing the morbidity associated with sepsis. In an
open trial in 3 patients, Wijdicks and Fulgham175
failed to show improvement in CIP, but, in a more
extensive study, albeit retrospective, of 33 pa-
tients,121 early treatment of gram-negative sepsis with
IVIG may have prevented the development of CIP.
Specic intervention to interrupt the septic cas-
cade at its early stages have been unsuccessful. Ap-
proaches have included the use of monoclonal and
polyclonal antibodies directed against bacterial en-
dotoxin; monoclonal antibodies to tumor necrosis
factor (TNF) alpha; fusion protein constructs of sol-
uble TNF receptors; interleukin-1 receptor antago-
nists108; the platelet activating factor receptor antag-
onist, BN520253; N-acetylcysteine, a drug that acts as
an oxygen radical scavenger157; and various hemol-
tration techniques and plasma exchange.26,125 De-
toxication plasma ltration, which clears several
cytokines from plasma, has shown some promise in a
small preliminary trial.105

4
FIGURE 6. Pathology of critical illness polyneuropathy. There is
chromatolysis of anterior horn cells (A); severe axonal degener-
ation in this cross-section of supercial peripheral nerve (B) and
longitudinal section of deep peroneal nerve (C); and acute and
chronic denervation of intercostal muscle (D) and iliopsoas mus-
cle (E) (with permission from Zochodne et al.194).

148 Neuromuscular Features of Critical Illness MUSCLE & NERVE August 2005
 An international conference has recently recom-
mended a wide variety of approaches using evidence-
based principles.52 Newer research approaches are
being explored.141 Two have shown convincing ben-
et. Van den Berghe et al.168 reported that intensive
insulin therapy in critically ill patients, possibly
through stimulating peripheral glucose uptake and
restoring abnormal lip proles,119 reduces the mor-
bidity and mortality, including a 44% reduction in
the incidence of CIP. (In an earlier study, Witt et
al.181 showed a correlation between rising blood glu-
cose and deteriorating peripheral nerve function in
septic patients and speculated on a direct toxic effect
of glucose.) Reduced levels of activated protein C in
sepsis, which promotes intravascular thrombosis, was
increased by the administration of recombinant hu-
man activated protein C with signicant reduction of
morbidity and mortality,141 but whether this treat-
ment affected CIP was not investigated in this large
multicenter trial.
Prognosis. In CIP, with distal axonal degeneration,
recovery depends on the distance over which regen-
eration occurs; the distance may be longer in severe
cases, and recovery time is then longer28,194 and may
be incomplete.169,181,189 Clinical and neurophysio-
logic evidence of neuropathy may remain for up to 5
years after ICU discharge.64 Patients with very severe
CIP may remain quadriplegic.181
OTHER POLYNEUROPATHIES POSSIBLY RELATED TO
SEPSIS
Critical illness polyneuropathy may occur in settings
other than the ICU.21 Patients in end-stage renal
failure may develop an especially severe and rapidly
developing axonal, predominantly motor, polyneu-
ropathy should they experience trauma or sep-
sis.32,162 Such a polyneuropathy was particularly com-
mon during the early years of chronic hemodialysis
when recurring attacks of sepsis complicated the use
of Scribner shunts. With the switch to Cimino-Bres-
cia stulas, recurring attacks of sepsis and polyneu-
ropathy were less frequent. However, I have ob-
served the occasional patient in end-stage renal
failure whose mild uremic polyneuropathy was wors-
ened by SIRS.21 Similarly, whereas chronic liver dis-
ease induces a mild, predominantly demyelinating
motor and sensory polyneuropathy,8 SIRS occurring
in this setting may rarely induce a critical illness
polyneuropathy.21
Critical illness polyneuropathy may occur as an
unusually early complication of severe respiratory
insufciency, later requiring ventilator support.72
Neuromuscular Features of Critical Illness
There is a tendency to recurring infections because
of immunosuppression after organ transplantation.
CIM is more common than CIP in this setting be-
cause of the use of neuromuscular blocking agents
and steroids. However, Amato et al.7 reported four
patients who, after organ transplantation, developed
a severe, generalized, demyelinating polyneuropathy
as a presumed complication of graft-versus-host dis-
ease. This polyneuropathy, unlike CIP, improved af-
ter treatment with immunosuppression or with res-
olution of the underlying disease.
Burns or chemicals are traumatic causes of SIRS.
Henderson and colleagues77 reported polyneurop-
athy as a complication of burns and anticipated
present theories by speculating on metabolic or
toxic causes. In further studies,76,115 the frequency
varied from 3% to 50%. De Saint-Victor et al.50 de-
scribed two patients with severe burns who had typ-
ical CIP. Wilmshurst et al.179 reported two patients
who developed CIP in association with high fever.
Teitelbaum et al.161 reported a polyneuropathy as a
toxic effect of the ingestion of domoic acid through
eating mussels. The severe chemical insult may have
induced SIRS with complicating septic encephalop-
athy and CIP.101
A variety of polyneuropathies may be associated
with acquired immune deciency syndrome
(AIDS).95 Because of immunosuppression, these pa-
tients are susceptible to recurring infections. How-
ever, the axonal polyneuropathy that occurs is pre-
dominantly sensory in its manifestation, unlike
CIP.21
NEUROMUSCULAR BLOCKING AGENTS,
NEUROPATHY, AND MYOPATHY
Sepsis itself does not cause a neuromuscular trans-
mission defect.28,194 However, neuromuscular block-
ing agents, used to facilitate mechanical ventilation,
may cause a transient neuromuscular blockade. Neu-
romuscular blocking agents are metabolized by the
liver and cleared by the kidney. Hence, with failure
of these organs, the effect of the neuromuscular
blocking agent may be prolonged for a number of
days after use of the drug has been discontinued.151
Repetitive stimulation studies will correctly identify
the defect in neuromuscular transmission.
Both myasthenia gravis112 and LambertEaton
myasthenic syndrome122 may present undiagnosed
with acute respiratory failure requiring admission to
the ICU and mechanical ventilation. Electrophysio-
logical studies may be diagnostic.73 Patients with my-
asthenia gravis whose acetylcholine receptor anti-
bodies are negative are especially prone to isolated
MUSCLE & NERVE August 2005 149
respiratory muscle weakness,112 and electrodiagnos-
tic studies may be equivocal or similar to those seen
with competitive neuromuscular blocking agents.
Measurement of anti-MuSK (muscle-specic recep-
tor tyrosine kinase) antibodies81 may establish the
diagnosis.
In many reports,10,44,56,60,68,71,75,78,85,89,91,124,145,151,159
it was concluded that neuromuscular blocking agents,
such as pancuronium bromide or the shorter acting
vecuronium, and steroids, singly or in combination,
induced either a pure axonal motor neuropathy or a
primary myopathy. These agents will generally have
been used for longer than 24 h, occasionally for days or
weeks. When they are discontinued, difculty in wean-
ing from the ventilator and limb paralysis are noted.
The serum creatine kinase concentration is mildly or
moderately elevated. Nerve conduction and needle
EMG studies indicate a severe, primary axonal degen-
eration predominantly of motor bers. Needle EMG
may show myopathic-appearing motor unit poten-
tials. Muscle biopsy shows varying degrees of denerva-
tion atrophy, muscle necrosis, and thick lament my-
osin loss (a distinctive myopathy in this group44). The
combination of functional denervation due to neuro-
muscular blocking agents and the subsequent direct
effects of steroids on muscle are presumed mecha-
nisms. However, some patients with this type of myop-
athy have had neither neuromuscular blocking agents
nor steroids but were septic79,134,154; and, in patients
who received these drugs, sepsis may have been a pre-
dominant underlying factor. Thus, in prospective stud-
ies of CIP12,100 and of CIP and myopathy,98 there was
no correlation between neuromuscular disease and the
use of steroids and neuromuscular blocking agents.
However, both of these drugs likely have an additional
toxic effect on nerve and muscle, and their use should
be avoided if possible.12,98,102,181
CRITICAL ILLNESS MYOPATHY
An acute myopathy often affects critically ill patients.
While acute quadriplegic myopathy78 has been the
commonest designation, others include critical care
myopathy, acute necrotizing myopathy of intensive
care, thick lament myopathy, critical illness myop-
athy, acute corticosteroid myopathy, acute hydrocor-
tisone myopathy, acute myopathy in severe asthma,
and acute corticosteroid and pancuronium-associ-
ated myopathy. The term critical illness myopathy
(CIM) is now considered the most appropriate de-
scription for this syndrome.94 By denition, patients
are or were critically ill, and weakness should have
started after the onset of critical illness. Diagnostic
criteria have been proposed94 (Table 3).
150 Neuromuscular Features of Critical Illness
CIM may occur independently of, or in associa-
tion with, CIP. De Letter et al.48 showed a relation-
ship between the early onset and severity of CIP and
CIM and Apache III scores, which measure the se-
verity of critical illness and sepsis. CIM develops in at
least one-third of ICU patients treated for status
asthmaticus,56 in 7% of patients after orthoptic liver
transplantation,39and in patients after heart trans-
plant.131 In a prospective study by Trojaborg et al.,166
all 22 critically ill patients showed clinical, electro-
physiological, and muscle biopsy evidence of a pri-
mary myopathy.
The major feature is accid weakness, which
tends to be diffuse, involving all limb muscles and
the neck exors, and often the facial muscles and
diaphragm. Thus, most patients are difcult to wean
from mechanical ventilation. Ophthalmoplegia may
be present.156 Tendon reexes are often depressed,
but normal reexes do not exclude CIM. Myalgias
are uncommon. Although the myopathy develops
acutely, the time of onset is usually difcult to deter-
mine because of the commonly associated encepha-
lopathy and administration of neuromuscular block-
ing agents.
Nerve conduction studies reveal low-amplitude
CMAPs, some of which may be of long duration (Fig.
4). The SNAPS should be normal but may be re-
duced in amplitude due to tissue edema. Near-nerve
recordings overcome this difculty.29 Examination
of motor unit potentials may be impaired by the
attendant septic encephalopathy and sedation. This
difculty may be partially overcome by recording
from the tibialis anterior muscle and activating mo-
tor units by plantar stimulation. Fibrillation poten-
tials and positive sharp waves will be present in both
CIM and CIP. In CIM, motor unit potentials are of
low amplitude and short duration, with high-fre-
quency components. Quantitative studies of motor
unit potentials conrm that their duration is de-
Table 3. Diagnostic criteria of critical illness myopathy*
1. SNAP amplitudes 80% of the lower limit of normal;
2. Needle EMG with short-duration, low-amplitude MUPs with
early or normal full recruitment, with or without brillation
potentials;
3. Absence of a decremental response on repetitive nerve
stimulation; and
4. Muscle histopathologic ndings of myopathy with myosin loss.
5. CMAP amplitudes 80% of the lower limit of normal in two or
more nerves without conduction block;
6. Elevated serum creatine kinase (CK); and
7. Demonstration of muscle inexcitability.
*For a denite diagnosis of critical illness myopathy, patients should have all
of the rst ve features.
MUSCLE & NERVE August 2005
creased in CIM.166 However, such units are also seen
in CIP with predominantly distal motor axonopathy,
as demonstrated in single-ber studies.150 Electrical
inexcitability of the muscle membrane can be dem-
onstrated by direct needle stimulation of the mus-
cle134 in patients with severe CIM who have markedly
reduced or absent CMAPs.139 In CIP, there is a re-
sponse to direct muscle stimulation, but not to stim-
ulation of the nerve supplying the muscle. Direct
muscle stimulation may therefore be helpful in the
differentiation of CIM and CIP14 (Fig. 5). However,
the results of direct muscle stimulation are only
semiquantitative, and this, coupled with the coexist-
ence of CIP and CIM, may make interpretation dif-
cult. Determination of serum creatine kinase (CK)
may be helpful in differential diagnosis. Markedly
elevated levels suggest a necrotizing myopathy,133,195
whereas in other types of CIM, serum CK elevations
are not as severe and may be delayed for 10 days or
more after administration of steroids.74 By contrast,
serum CK levels in CIP are normal or only mildly
elevated.181
Phrenic nerve conduction studies and needle
EMG of the diaphragm and chest wall muscles are
valuable in assessing patients with suspected CIM.18
Phrenic nerve conduction studies typically show nor-
mal latencies but diaphragm CMAP amplitudes may FIGURE 7. Muscle histopathology in a critically ill patient with
be reduced, with a return toward normal as recovery thick lament myosin loss. (A) In this trichrome-stained section,
occurs. Needle EMG may reveal positive sharp waves note abnormal variation in ber size and dark atrophic bers
and brillation potentials in respiratory muscles. (original magnication, 160) (with permission from Showalter
and Engel154). (B) In this toluidine blue ATPase reaction, note
Motor unit potentials may be difcult to interpret in focal loss of ATPase reactivity in type 1 bers (original magni-
the diaphragm, because they normally have a myo- cation, 100) (courtesy of Dr. Andrew Engel).
pathic appearance.
The changes on muscle biopsy have been re-
viewed by Showalter and Engel154; atrophy of only
type 2 bers, only type 1 bers (less often reported), patients revealed a necrotizing myopathy in the tib-
or of bers of all histochemical types has been re- ialis anterior muscle in 15 patients.75
ported. Features of the histopathology in thick la- Identication of the subtypes of CIM, as de-
ment myosin loss, including variation in myober scribed below, may aid in prognostication.26
size and focal loss of ATPase reactivity in type 1
bers, are shown in Figure 7. Necrosis and vacuolar Thick Filament Myosin Loss. This syndrome, fre-
changes are less commonly seen. Electron micros- quently termed acute quadriplegic myopathy, occurs
copy reveals selective loss of thick (myosin) laments in the setting of sudden, severe asthma requiring
(Fig. 8). This pattern of abnormalities has been ob- tracheal intubation and placement on a ventilator in
served in subsequent comprehensive studies.60,91,147 combination with high-dose corticosteroids and neu-
It conforms to what has most often been termed romuscular blocking agents. It may also be seen in
acute quadriplegic myopathy78 but, perhaps more posttransplant patients who have received these
precisely, myopathy with thick lament (myosin) medications while in the ICU. Serum CK levels may
loss.44 However, other pathologic features may be be elevated only mildly. Muscle biopsy shows destruc-
found in critically ill patients rendered acutely quad- tion of the thick myosin laments, often seen on
riplegicwidespread necrosis occurs in the entity of light microscopy but found more denitely on elec-
acute necrotizing myopathy of intensive care41,195 tron microscopy. The typical histopathologic fea-
and much milder necrosis in acute rhabdomyoly- tures154 are shown in Figures 7 and 8. Recovery may
sis.13 Percutaneous muscle biopsies in 31 critically ill occur more rapidly then in CIP. There is no specic

Neuromuscular Features of Critical Illness MUSCLE & NERVE August 2005 151

FIGURE 8. Electron microscopy of muscle in CIM. Imaged ber
region shows a loss of thick laments from all sarcomeres. The
sarcomeres are collapsed. The myobrils are disorganized, and
the membranous organelles are dislocated (original magnica-
tion, 44,000) (courtesy of Dr. Andrew Engel).
treatment. The best approach is to avoid neuromus-
cular blocking agents, and especially steroids, or to
use these medications as sparingly as possible.
FIGURE 9. Pathology of necrotizing myopathy of intensive care. The rectus femoris muscle shows a widespread, panfascicular
destructive process affecting many of the muscle bers, associated with myophagocytosis and numerous, small, regenerating muscle
bers that contain groups of vesicular nuclei with prominent nucleoli. Haleys xative; HPS, original magnication, 414. Bar, 50 m (with
permission from Ramsay et al.133).
152 Neuromuscular Features of Critical Illness
Rhabdomyolysis. Rhabdomyolysis occurs in the
setting of critical illness and the use of neuromus-
cular blocking agents and corticosteroids.13 Rhab-
domyolysis may be due to a variety of caus-
es 13,45,130,155,185 and presents with weakness,
myalgia, and swelling in the affected muscles. Mas-
sive muscle necrosis results in the release of potas-
sium and initially sequesters calcium. The result-
ant hyperkalemia and hypocalcemia may produce
life-threatening cardiac arrhythmias and renal fail-
ure. Serum CK level is elevated, often to greater
than 10,000 IU/L. Myoglobinuria occurs fre-
quently. The electrophysiologic ndings are those
of an acute myopathy. Motor and sensory nerve
conduction studies are usually normal. On needle
electromyography, brillation potentials are usu-
ally sparse and transient and motor unit potentials
are often normal.5 Muscle biopsy may be normal
or show varying degrees of myober necrosis with-
out inammation, myosin loss, or other specic
features. Thus, despite considerable weakness and
elevated serum levels of CK, EMG and muscle
biopsy are unimpressive, consistent with rapid and
complete recovery.
During bacteremia, microabscesses may be de-
posited throughout skeletal muscle and portray the
MUSCLE & NERVE August 2005
clinical picture of acute rhabdomyolysis.96 Blood cul-
ture will identify the offending organism, and mus-
cle biopsy will identify the microabscesses. This is a
variant of pyomyositis typically seen in tropical coun-
tries or in children.
Acute Necrotizing Myopathy. Acute necrotizing my-
opathy of intensive care133,195 may be simply an ex-
tension of acute rhabdomyolysis and is induced by
the same wide variety of infective, chemical, and
other insults. Serum CK levels are markedly elevated,
myoglobulinuria is present, electrophysiologic exam-
inations suggest a severe myopathy, and pathologic
studies show widespread necrosis of muscle bers
(Fig. 9). Recovery of muscle strength may not occur
in severe cases.195
Cachectic Myopathy. Muscle weakness and wasting
commonly occur in starvation and malnutrition, as
in anorexia nervosa or following gastric bypass sur-
gery for morbid obesity,80,117 and is termed cachectic
myopathy or disuse atrophy. It is likely a common
complication of critical illness and accounts for sig-
nicant wasting and weakness of muscle. Electro-
physiologic ndings and serum CK levels are nor-
mal. Muscle biopsy is normal or reveals type 2 ber
atrophy. The diagnosis of cachectic myopathy is
made by exclusion of other neuromuscular compli-
cations of critical illness.
Management of Critical Illness Myopathy. Whether a
clinician should routinely pursue a muscle biopsy in
order to distinguish critical illness myopathy from
other myopathies or from critical illness polyneurop-
athy is questionable. Muscle biopsy should be con-
sidered if another myopathic processes, such as an
inammatory myopathy, is suspected or if the histo-
logic ndings may affect management. For example,
a rm diagnosis of CIM may lead to avoidance of
intravenous corticosteroids or neuromuscular block-
ing agents. As indicated in Table 1, the various types
of CIM can be distinguished by clinical, electrophysi-
ologic, and histologic features.26 This is important
for prognosis. Severe CIP181 and necrotizing myop-
athy of intensive care133 may have a poor prognosis
for recovery of strength, but the prognosis is much
better for rhabdomyolysis, cachectic myopathy, and
thick lament myosin loss.
CRITICAL ILLNESS POLYNEUROPATHY AND
MYOPATHY
In early studies of CIP, morphologic studies of mus-
cle, in addition to showing evidence of acute and
Neuromuscular Features of Critical Illness
chronic denervation,28,194 also showed evidence of
cytoarchitectural disorganization,28 muscle ber ne-
crosis,194 and other myopathic features suggesting an
associated primary muscle change. Motor nerve con-
duction studies in addition revealed a marked de-
cline in CMAP amplitude and a prolongation of
CMAP duration, without abnormal change of latency
on proximal and distal stimulation, strongly suggest-
ing primary involvement of the muscle ber mem-
brane.35 Subsequent 31P-nuclear magnetic reso-
nance (31P-NMR) spectroscopy studies of muscle
were performed. Patients who had only denervation
of forearm muscles, but were not septic, showed a
marked depletion of bioenergetic reserves196 sec-
ondary to denervation. Weak limbs of nonseptic pa-
tients with disuse atrophy showed no signicant re-
duction in bioenergetic reserves.196 By contrast, two
patients with evidence of CIP and associated CIM
had a reduction in bioenergetic reserves that was
severe and more marked than that due to denerva-
tion of muscle alone.35 This supported the theory
that depletion of bioenergetic reserves was an impor-
tant factor in the induction of both CIP and CIM.
Early investigations by Op de Coul et al.123 sug-
gested in 11 patients that weakness developing in the
ICU related to administration of pancuronium bro-
mide, a neuromuscular-blocking agent. However, in
later studies,124 these authors concluded that multi-
conditional causes were likely and raised the possi-
bility of involvement of a tumor necrosis factor, a key
mediator in sepsis. Since their studies also suggested
associated involvement of muscle, they proposed the
term critical illness neuromyopathy. In a prospec-
tive study49 of patients with combined CIP and CIM,
muscle biopsy revealed neuropathic changes in 37%,
myopathic changes in 40%, and both in 23%. In
another prospective study,98 24 patients with severe
quadriplegia following coma had neurophysiological
studies and muscle and nerve biopsy. All patients
showed evidence of involvement of muscle, and 8 of
22 patients had evidence on nerve biopsy of an
axonal neuropathy. However, patients undergoing
nerve biopsy early in the course of sepsis had normal
histologic ndings despite the fact that sensory nerve
conduction studies were abnormal. This suggested
that dysfunction preceded structural change in pe-
ripheral nerve. Further evidence for combined in-
volvement of nerve and muscle has come from the
recent report by DeJonghe et al.46 Twenty-two pa-
tients who had electrophysiological studies all
showed an axonal sensory-motor polyneuropathy,
and 10 of these patients who underwent muscle
biopsy all had evidence of combined denervation atro-
phy and primary myopathic changes. Finally, de Letter
MUSCLE & NERVE August 2005 153
et al.,48 in a well-designed prospective study, recorded
evidence of both a critical illness polyneuropathy and
myopathy. Assessment of the Apache III score, a quan-
titative index of disease severity, and the presence of
SIRS showed that both predicted the later develop-
ment of these neuromuscular complications.
The predominance of either CIP or CIM in an
individual patient probably varies depending on the
use of neuromuscular blocking agents and steroids.
Thus, in an ICU where these medications were used
in posttransplant patients, the incidence of CIM was
high92 whereas, in another ICU where there were no
posttransplant patients, and neuromuscular block-
ing agents and steroids were rarely used, the inci-
dence of myopathy was low.190
The range of severity of combined CIP and CIM
may be quite marked. Despite severe respiratory and
limb weakness with electrophysiologic evidence of
predominant involvement of muscle and marked
elevations of serum CK, if the muscle biopsy is nor-
mal,30 the patient may make a relatively rapid recov-
ery.30 Conversely, a patient with clinical and electro-
physiologic evidence of severe involvement of both
nerve and muscle, high elevations of serum CK, and
myoglobin in the urine, and necrosis of muscle on
morphologic study may not recover.30
DIFFICULTY IN WEANING FROM
MECHANICAL VENTILATION
Difculty in weaning from mechanical ventilation88
may occur in up to 30% of patients in the ICU.104
Patients are deemed as having failed to wean when, on
discontinuation of ventilatory support, the respiratory
rate becomes unacceptably high (35 per min), tidal
volumes become unacceptably low (5 ml/kg), and
respiratory acidosis develops. Weaning is considered
successful if breathing is spontaneous without mechan-
ical ventilatory support for more than 6 to 24 h. Mea-
surements such as rapid shallow breathing index, vital
capacity, respiratory rate divided by the vital capacity,
peak negative inspiratory pressure, maximum volun-
tary ventilation, or occlusion pressure may give further
valuable information as to whether weaning will be
successful. Cardiac, pulmonary, and chest wall causes
of failure to wean are excluded rst, since these are
relatively common. After that, neurologic cause may be
suspected. Based on bedside clinical assessment, a cen-
tral cause (coma or stroke) was found in 26% and a
peripheral cause in 17%.104 However, when electro-
physiologic studies are utilized, the incidence of pe-
ripheral (neuromuscular) disease is higher.158 In one
study of 40 patients who failed to wean, all but 1 had a
neuromuscular cause.113 Polyneuropathy, usually CIP,
154 Neuromuscular Features of Critical Illness
was the commonest cause. However, unilateral phrenic
neuropathy, often traumatic; defects in neuromuscular
transmission, either drug-induced or due to myasthe-
nia gravis; and myopathy, were other causes. In 38%,
there was a combination of causes.113 Autopsy studies
of phrenic and intercostal nerves, chest wall muscles,
and diaphragm have provided a morphologic basis for
respiratory insufciency in CIP.194
In the ICU, neurophysiologic studies for respira-
tory disorders of unclear etiology should be started
with measurements of motor and sensory nerve con-
duction velocities in the limbs. Often these will
establish the presence of neuropathy and its underly-
ing pathophysiologic basis (axonal or demyelinating).
Phrenic nerve conduction can easily be performed in
the ICU. Rarely, subclavian vein catheters or open
chest injuries may pose a problem. If phrenic nerve
conduction is noncontributory or an abnormality of
neuromuscular transmission is suspected clinically, re-
petitive nerve stimulation at 3 Hz and 30 or 40 Hz
should be added. The selection of nerve to be stimu-
lated depends on the clinical ndings. If isolated dia-
phragmatic involvement is suspected, the phrenic
nerve is appropriate. Rarely single-ber EMG, prefera-
bly stimulated, will be needed. Neurophysiologic stud-
ies should also include EMG of proximal and distal
limb-muscles. Intercostal and diaphragmatic EMGs
provide important information on the type and extent
of respiratory muscle involvement (Fig. 10). Auto-
nomic involvement can be tested by recording sympa-
thetic skin responses and heart rate variability.16
If the patient has a CIP, muscle strengthening ex-
ercises are unlikely to be helpful until there has been
signicant reinnervation of the respiratory muscles. By
contrast, if there is little evidence of CIP and the cause
of the respiratory weakness is disuse atrophy of the
diaphragm, muscle-strengthening exercises will be of
great value. Finally, if the patient is thought to have the
phenomenon of diaphragmatic fatigue,3 which in clin-
ical situations is almost impossible to prove, then the
best method of management may be continued venti-
latory support, rest of the diaphragm, and more grad-
ual attempts at weaning, without the use of vigorous
muscle training exercises.
In cases of severe CIP, prolonged stay on the ven-
tilator may be anticipated. The fact that a neuromus-
cular cause has been identied aids attending physi-
cians in determining the most appropriate methods of
ventilation, other treatments, and long-term prognosis.
PATHOPHYSIOLOGY
Many factors107 have been incriminated in the patho-
genesis of CIP: types of primary illness or injury,28,194
MUSCLE & NERVE August 2005

FIGURE 10. Phrenic nerve conduction and needle EMG of the
diaphragm in a patient with failure to wean from mechanical
ventilation due to severe critical illness polyneuropathy. The dia-
phragm compound muscle action potential amplitude was ab-
sent. (The potential of short latency and initial positive deection
was from chest wall muscles activated by inadvertent brachial
plexus stimulation.) Needle electromyography of the diaphragm
revealed no motor unit potentials with attempted inspiration, only
denervation potentials. The ndings were consistent with severe
axonal degeneration of phrenic nerve bers and total denervation
of the diaphragm (with permission from Bolton et al.18).
immune mediation, GuillainBarre syndrome,29
malnutrition and critical illness,28 antibiotics,181
neuromuscular blocking agents,71 nerve frailty due
to premorbid conditions,9 hypoxia,58 hypotension,142
hyperpyrexia,179 iatrogenic mechanisms,29,36,124,151,181,182
endotoxin,9,182 tumor necrosis factor,124 and hyper-
osmolality and hyperglycemia.168,171
We speculated that sepsis itself is the cause.181,194
Subsequent studies have shown a strong association
between CIP and sepsis, multiple organ failure, and
Neuromuscular Features of Critical Illness
SIRS.12,46,48,98,103,163,190,195 The severity of the poly-
neuropathy can be quantied from electrophysi-
ologic data.181 It is more severe with length of stay in
the ICU and with increasing serum glucose and de-
creasing serum albumin concentrations.181 All three
are recognized manifestations of sepsis and multiple
organ failure syndrome. Elevated serum glucose may
impair the microcirculation to peripheral nerve and
induce hypoxia,106 which may explain the improve-
ment in CIP that occurs with lowering of blood
glucose in critically ill patients.168
As indicated earlier, the microcirculation to organs
throughout the body is disturbed in sepsis (Fig. 2).
Such disturbances may explain dysfunction of nerve
and muscle in sepsis. Blood vessels supplying the pe-
ripheral nerves lack autoregulation,107 rendering these
vessels especially susceptible to such disturbances. Cy-
tokines that are secreted in sepsis have histamine-like
properties that increase microvascular permeability.194
Endoneural edema promoted by hyperglycemia and
hypoalbuminemia could induce hypoxia by an in-
crease in intercapillary distance and other mecha-
nisms.181,194 Despite administration of oxygen by me-
chanical ventilation, there is a severe oxygen debt at
the parenchymal level.69 Biochemical studies of muscle
biopsies in critically ill septic patients reveal mitochon-
drial dysfunction.38 31P-NMR spectroscopic studies of
human muscle in patients with critical illness polyneu-
ropathy and myopathy have shown bioenergetic fail-
ure.35 The resulting bioenergetic (energy stored as
ATP) failure would induce a primary axonal degener-
ation, most likely distally, if highly energy-dependent
systems involving axonal transport of structural pro-
teins are involved. The predominantly distal involve-
ment may explain why recovery in some patients can
be surprisingly short, conforming to the short length of
nerve through which axonal regeneration takes place.
Bioenergetic failure may also explain the reduced am-
plitude and increased duration of the CMAP (Fig. 4), a
phenomenon that is observed in muscle fatigue in
healthy persons.120
Standard histologic studies of nerve and muscle
in critically ill patients have failed to reveal abnormal
cellular inltration, but special studies have pro-
vided some support for the above concepts (Fig. 11).
Fenzi et al.63 in immunohistochemical studies ob-
served enhanced expression of E-selectin in the vas-
cular endothelium of peripheral nerve, this adhe-
sion molecule perhaps mediating disturbances of
the microcirculation. De Letter et al.49 have shown
in similar studies of muscle biopsies of patients with
critical illness polyneuropathy and myopathy evi-
dence of activated leukocytes producing pro- and
anti-inammatory cytokines (Fig. 12).
MUSCLE & NERVE August 2005 155
FIGURE 11. Immunohistochemistry of supercial peroneal nerve biopsy specimens from critically ill and control patients; parafn sections,
hematoxylin counterstain. (a, b) E-selectin localization in epineurial and endoneurial blood vessels from a critically ill patient. (a) Strong
immunostaining of the endothelial cell surface in epineurial vessel. An adjacent arteriole shows very weak labeling of the endothelium, 280.
(b) Some reactive vessels in the endoneurium of a fascicle, 150. (Inset) Magnication of an endoneurial microvessel showing intense
immunoreactivity on the whole endothelium, 1,000. (c) VCAM-1immunostained endoneurial vessels are visible also in control patients,
300. (d) ICAM-1 is strongly expressed by several microvessels in the endoneurium of a critically ill patient, 750. (e, f) Expression of TNF-
from a control patient (e). Mild immunoreactivity is diffusely detected within the endoneurium of a fascicle, 150. (f) Intense positivity is seen
in two endothelial cells of a venule in the epineurium, 780 (with permission from Fenzi et al.63).

Disturbances of the microcirculation to nerve
and muscle (Fig. 13) may also explain the effects of
neuromuscular blocking agents and corticosteroids.
Neuromuscular blocking agents may cause func-
tional denervation through their prolonged neuro-
muscular blocking action,173 and thus denervation
atrophy of muscle.
Through increased capillary permeability induced
by sepsis, neuromuscular blocking agents, notably ve-
curonium or its metabolite, 3 desacetyl-vecuronium,151
could have a direct toxic effect on peripheral nerve
axons. Antibiotics, particularly aminoglycosides with
their known neural toxicity, might also gain access to
the peripheral nerve as a result of increased capillary
permeability. (However, there has been no statistical
proof that antibiotics cause peripheral nerve dysfunc-
tion in sepsis.181) Finally, a low molecular weight toxin
identied in the serum of CIP patients57 may act
through a similar mechanism.
This schema (Fig. 13) also explains the acute
myopathy that develops when asthmatic patients or
those in the post-organ transplant state are treated
with neuromuscular blocking agents and corticoste-
roids. Many of these patients may suffer from SIRS,
since infection is often a precipitating event in acute,
severe asthma and is a common occurrence in the
posttransplant state. Animal experiments by Karpati
et al.87,116,146 have shown that if the muscle is rst
denervated by nerve transection and then corticoste-
roids are given, a myosin-decient myopathy can be

156 Neuromuscular Features of Critical Illness MUSCLE & NERVE August 2005
FIGURE 12. Immunohistochemical staining of muscle biopsies in patients with critical illness polyneuropathy and myopathy. Positive
staining red, except for IL-10 orange-brown. (a) Macrophages (CD68) near a necrotic muscle ber. (b) HLA-DR staining on the
vascular endothelium. (c) VCAM is present on the endothelium of a blood vessel. (d) Membrane attack complex (C5b-9) staining in a
necrotic muscle ber. (e) TNFR75 is present on the endothelium of a blood vessel in the perimysium. (f) The arrows point at IFN-
staining juxtanuclear in the cytoplasm of a muscle ber. The juxtanuclear production of this cytokine makes it look like a nuclear staining.
(g) IL-10 is present on the vascular endothelium. (h) IL-12 staining is positive in the cytoplasm of a cell with a horseshoe-like nucleus
containing a basophilic spot. Histomorphologic characteristics of a monocyte (with permission from De Letter et al.49).

induced. Thus, in the human condition, CIP and the
additional effects of neuromuscular blocking agents
would denervate muscle, and steroids would then
induce the typical myopathic changes. The rapidly
evolving myopathy reported by Al-Lozi et al.,6 char-
acterized by destruction of myosin laments
throughout the muscle bers, and the acute, necro-
tizing myopathy of intensive care,133,195 may simply
represent further stages of this process.
Rich et al. have shown that individual muscle bers
that are steroid treated and denervated (SD) become
electrically inexcitable.138 Depolarization of the resting

Neuromuscular Features of Critical Illness MUSCLE & NERVE August 2005 157
FIGURE 13. A simplied depiction of theoretical mechanisms of dysfunction in critical illness polyneuropathy and myopathy. Sepsis with
disturbance of microcirculation (Fig. 2) is a common underlying factor, neuromuscular (N-M) blocking agents enhance denervation, and
steroids subsequently induce a myopathy with thick lament myosin loss. Varying pathologic changes in muscle may result. In the early
stages of sepsis, there may be a purely functional loss, with no structural change in nerve or muscle (adapted with permission from
Bolton25).

potential, decreased specic membrane resistance,
number of sodium channels, and a change in the
voltage dependence of inactivation of sodium channels
all contribute to decreased muscle excitability.137,138
Depolarization of the resting membrane potential and
a shift in the voltage dependence of sodium channel
fast inactivation towards more negative potentials ap-
pear to be the dominant factors.14
Voltage dependence of sodium channel inactiva-
tion might be altered through changes in gene expres-
sion and posttranslational modication.11,86,128,135,186
Larsson et al.97 studied the mechanism of myosin de-
pletion in patients with CIM and found a decrease in
myosin mRNA that correlated with the reduction in
myosin protein levels. This nding suggest that abnor-
malities of gene transcription may play a critical role in
the development of weakness.14 Di Giovanni et al.,54
utilizing a genomewide microarray analysis of human
skeletal muscle in CIM, showed that neurogenic atro-
phy and myogenic atrophy shared the same ubiquitin
ligase pathway, but only acute quadriplegic myopathy
activated the TGF-/MAPK pathway (tumor growth
factor/mitogen associated protein kinase). The nd-
ing suggests possible therapeutic targets.54 Showalter
and Engel154 found evidence of enhanced expression
of calpain, a calcium-activated protease, in atrophic
myobers. Such ndings suggest that altered cellular
calcium homeostasis may play a role in the loss of
myosin, and perhaps other proteins as well. A further
effect may occur through the cytokine TNF, which
decreases the resting transmembrane potential of skel-
etal muscle bers in vitro164 and induces muscle pro-
teolysis in animals.65
Tissues other than brain, peripheral nerve, and
muscle may be involved. In 80% of critically ill patients
with septic shock, there is a signicant decrease in QRS
amplitude of the electrocardiogram during sepsis, sug-
gesting dysfunction of cardiac muscle.136 No such re-
duction in QRS amplitude occurred in a control group
of ICU patients. The changes were reversible following
recovery from sepsis. In a preliminary study, we16 ob-
served abnormalities of cardiac R-R interval and the
sympathetic skin response in the majority of critically ill
patients suggesting dysfunction of both the parasympa-
thetic and sympathetic nervous systems.
FUTURE DIRECTIONS
The septic syndrome has an early and widespread
effect on neural membranes including those of the
peripheral nervous system. De Letter et al.48 have
shown that neurologic and electrophysiologic mea-
surements act as predictors for the development of
critical illness polyneuropathy and myopathy. Elec-
trophysiologic methods provide early and quantita-
tive measurements of dysfunction of the peripheral
nervous system. Such methods were also utilized by
Van den Berghe et al.168 in determining the effec-
tiveness of better control of blood glucose levels in
septic patients to reduce the morbidity, including
CIP, and mortality. An early electrophysiologic sign
is a fall in the amplitude and an increase in the
duration of the CMAP. Thus, the simple noninvasive
technique of motor and sensory nerve conduction of
one nerve, such as the median nerve, could be uti-
lized to detect dysfunction at its earliest stages. A

158 Neuromuscular Features of Critical Illness MUSCLE & NERVE August 2005
variety of experimental interventions could be tried
and their effect monitored by this method.170
Difculty in weaning from mechanical ventila-
tion is an early sign of neuromuscular dysfunction in
septic patients and its precise cause is often in doubt.
Phrenic nerve conduction and needle EMG of the
diaphragm will more precisely identify the cause and
aid in deciding various treatment strategies. Mea-
surements of the electrical frequency of the dia-
phragm would determine whether diaphragmatic fa-
tigue was present as indicated by a fall in frequency.
Such changes could be correlated with ventilatory
measurements of the strength of respiratory muscle
contractions. Magnetic resonance imaging (MRI)
could determine the development of atrophy of the
diaphragm muscle.
Continued basic research is needed to determine
whether various medications used in the intensive
care unit (neuromuscular blocking agents, steroids,
and antibiotics, especially aminoglycosides) may
cause neuromuscular dysfunction. Finally, molecular
biology, such as abnormalities of gene transcrip-
tion,14,135 may give further insights not only into the
mechanism of nerve and muscle dysfunction in sep-
tic patients but also into therapeutic targets.54
I thank Ms. Raquel J. S. Nelson for manuscript preparation, Dr.
Douglas W. Zochodne and Dr. Michael J. Murray for reviewing the
manuscript, and the Departments of Clinical Neurological Sci-
ences and Medicine, University of Western Ontario, London,
Ontario, Canada.
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