Use of electrophysiologic testing

Nicola Latronico, MD; Indrit Shehu, MD†; Bruno Guarneri, MD

Objective: To define the electrophysiologic tests to diagnose critical
illness myopathy and critical illness polyneuropathy in intensive care unit
patients.
Design: Literature review.
Measurements and Main Results: Critical illness myopathy and
neuropathy are common complications in the critically ill patient.
Myopathy and neuropathy are equally common, and often coexist.
Electrophysiological alterations of peripheral nerves and muscle
have an early onset in the first days of intensive care unit stay or
shortly after sepsis, and precede the structural alterations. Con-
ventional electrophysiologic evaluation can be performed easily
on most intensive care unit patients, including patients with
altered consciousness; in conjunction with direct muscle stimu-
lation, it can differentiate myopathy from neuropathy, which
might be important to define the long-term prognosis. However,
electrophysiologic tests are not universally available; their inter-
pretation requires special expertise; and their application is time
consuming. A recently proposed simplified test of peroneal nerve
stimulation could be used as a screening method to select pa-
tients who merit in-depth neurologic evaluation.
Conclusions: Early identification of neuromuscular alterations
by means of electrophysiologic tests may be of value for targeted
treatments and to anticipate the risk of short-term disability.
Complete neurologic and electrophysiological evaluation is im-
portant to define the risk of long-term disability after intensive
care unit discharge. (Crit Care Med 2009; 37[Suppl.]:S316 –S320)
KEY WORDS: neuropathy; myopathy; electroneurography; elec-
tromyography; direct muscle stimulation; bioenergetic failure;
peroneal nerve; axonal excitability; insulin

C lassically, the critical illness
myopathy (CIM) and critical
illness polyneuropathy (CIP)
are suspected in intensive
care unit (ICU) patients who, after a pe-
riod of days or weeks, cannot be weaned
from the ventilator despite the resolution
of lung, cardiac, metabolic, and infec-
tious causes of respiratory failure, or be-
cause of various degrees of limb weakness
or paralysis (1). On attempted weaning,
the voluntary respiration becomes rapid
and weak, and is accompanied by the pa-
tient’s distress. Limb paralysis is flaccid,
and deep tendon reflexes are absent or
reduced.
Failed weaning from the ventilator has
a historical importance, as it was the first
clinically relevant problem prompting
neurologic consultation (2). In the 1980s,
Zochodne, Bolton, and co-workers ana-
From the Neuroanesthesia and Neurointensive
Care (NL), University of Brescia, Spedali Civili of Bres-
cia, Brescia, Italy; Anesthesia and Intensive Care (IS),
S. Orsola Fatebenefratelli Hospital, Brescia, Italy; and
Clinical Neurophysiology (BG), Spedali Civili of Brescia,
Brescia, Italy.
†
Deceased June 21, 2009.
The authors have not disclosed any potential con-
flict of interest.
For information regarding this article, E-mail:
nick.latronico@gmail.com
Copyright © 2009 by the Society of Critical Care
Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/CCM.0b013e3181b6f9f3
lyzed systematically a series of cases, and
were able to define the electrophysiologic
characteristic of the CIP, a syndrome
which they separated from the Guillain-
Barré syndrome, an acute, inflammatory,
demyelinating polyradiculoneuritis (3).
The predominant electrophysiologic find-
ings are a reduction in amplitudes of the
compound and sensory nerve action po-
tential consistent with a primary, axonal,
sensory-motor degeneration of peripheral
nerves.
Substantial changes have occurred
since the initial descriptions of single
case reports or small case series (2, 4 –7)
that suggested the CIM and CIP to be a
rare syndrome. According to a recent sys-
tematic review (8), the prevalence of CIM
and CIP in patients with sepsis, multiple
organ failure, or prolonged ICU stay is
46% (95% confidence interval 53%–
49%). The occurrence is lower, 30.4%
(95% confidence interval 21.9%– 40.4%),
in patients with single organ failure and
normal peripheral nerve and muscle
function on ICU admission (9). Recogni-
tion of this aspect is important when dis-
cussing the diagnostic approach because,
whatever the method proposed, it must
be readily available, easy to use, and rapid
to be applicable in a significant number
of critically ill patients.
A second important change is the rec-
ognition that CIM is at least as frequent
as or even more frequent than CIP (10 –
13). However, the definition of CIM is not
as straightforward as that of CIP. We have
proposed the term critical illness myop-
athy as a comprehensive term encom-
passing those myopathies with pure func-
tional impairment and normal histology
as well as those with atrophy and necrosis
(14). Clinical, electrophysiologic, and his-
tologic diagnostic criteria are available
(15), but they are not without criticism
(16). Furthermore, myopathy and CIP of-
ten coexist (10, 12), which explain the
adoption of terms such as critical illness
neuromyopathy (17), critical illness my-
opathy and/or neuropathy (9, 10, 12),
ICU-acquired paresis (18), critical illness
neuromuscular abnormalities (19) or
critical illness polyneuropathy/critical
illness myopathy (20). Implications of
these data are that we need to define
whether or not a precise pathologic dis-
tinction between CIM and CIP is re-
quired, and, if so, at what clinical stage.
A third change is the demonstration of
the precociousness of electrophysiologic
muscle-nerve alterations, which precede
structural alterations. In an earlier study
in 24 critically ill neurologic septic pa-
tients (10), electrophysiologic and histo-
logic investigations gave divergent re-
sults: At electrophysiologic testing, all
patients had reduced amplitudes of the
action potential or nerves were inexcit-

S316 Crit Care Med 2009 Vol. 37, No. 10 (Suppl.)

able, indicating an axonal CIP. However,
at nerve biopsy, 14 of 22 examined pa-
tients had a normal nerve and only 8 an
axonal CIP. On the contrary, electro-
physiologic and histologic findings were
congruent at late biopsies, demonstrating
structural axonal damage. We speculated
that, during sepsis, the nerves were try-
ing to maintain their structure and thus
to survive by reducing or abolishing the
function, a phenomenon easily docu-
mented by electrophysiological testing
(10). With persisting sepsis, the energy
supply and/or use is not restored and
histologic alterations ensue (10, 21).
Generation of the action potential at the
terminal nerve ending is a powerful en-
ergy-consuming process; the axons are
devoid of the machinery for biosynthetic
processes, and all axonal components are
synthesized in the cell body, translocated
from the cell body into the axonal pro-
cess, and then transported to their final
destination within the axon (22). This
anterograde transport requires consider-
able energy expenditure because the ma-
terial is moved rapidly; in case of micro-
circulatory alterations and/or cellular
dysoxia, the axonal transport fails and
distal axonopathy ensues.
Recent studies gave support to the
mechanism of bioenergetic failure. In
one study (23), nine patients with sys-
temic inflammatory response syndrome
had their initial electrophysiological in-
vestigations within a median of 5 days
(range ⫽ 2–25 days) after ICU admission,
and all showed a reduction in the ampli-
tude of the compound muscle action po-
tential. In another study (24), nine pa-
tients with moderate-to-severe multiple
organ dysfunction syndrome had their
initial electrophysiological investigations
within 2 to 5 days after ICU admission,
and all had a reduction in the amplitude
of the compound muscle action potential,
indicating it as the earliest electrophysi-
ological sign of CIP. More recently, pa-
tients admitted to the ICU for severe sep-
sis have been shown to have abnormal
electrophysiologic findings within 3 days
of admission (25). In the multicenter Ital-
ian CRIMYNE study, in which only pa-
tients with normal electrophysiology on
ICU admission were enrolled and patients
were followed-up daily, the median time
of onset of electrophysiologic alterations
was 6 days (9). Of note, 276 patients were
excluded because they already had elec-
trophysiologic signs compatible with an
axonal polyneuropathy, an exclusion cri-
Crit Care Med 2009 Vol. 37, No. 10 (Suppl.)
terion, at ICU admission (unpublished
data). Not only was the reduction of the
action potential amplitude early, but it
also occurred rapidly, within 24 hrs of
normal electrophysiology in the majority
of patients (9); this represents a substan-
tial divergence from the traditional ob-
servation that at least 1 wk is needed for
axonal CIP to become apparent. Finally,
the electrophysiologic alterations re-
solved in 10 of 28 patients during the ICU
stay, but persisted in 18 patients for sev-
eral months after ICU discharge. The
pathophysiological mechanism of bioen-
ergetic failure, which is thought to be a
relevant pathophysiological mechanism
of multiple organ dysfunction and failure
(21, 26, 27), can explain the early involve-
ment of long inferior limb nerves, such as
the peroneal nerve, as well as the sudden
onset of electrophysiologic alterations (9,
10, 28, 29).
A fourth change is the demonstration
that intensive insulin treatment with
maintenance of normoglycemia may re-
duce the frequency, duration, and sever-
ity of CIP. This effect has been demon-
strated in two prospectively planned
subgroup analyses (20, 30) of two ran-
domized controlled trials in surgical and
medical ICU patients (31, 32). These re-
sults need to be confirmed, as they derive
from post hoc analyses of single-center
studies, using denervation potentials as
the sole criterion to diagnose the CIP.
Concerns about safety and risk for hypo-
glycemia also need to be carefully ad-
dressed (33).
ELECTROPHYSIOLOGIC
TESTING
Conventional Electrophysiologic
Investigation
In axonal CIP, such as the CIP, the
total number of nerve fibers is reduced;
hence, the nerve action potential ampli-
tude is reduced or the nerve is unexcit-
able. Surviving fibers have normal myelin
sheath; hence, the nerve conduction ve-
locity remains within normal limits.
Other findings are fibrillation potentials
and positive sharp waves at the electro-
myography (EMG).
In demyelinating CIP, such as the
most common subtype of Guillain-Barré
syndrome (the acute inflammatory demy-
elinating polyradiculoneuropathy), the
total number of nerve fibers is normal;
however, the majority of them have lost
their myelin sheath; therefore, the elec-
trophysiologic findings mirror those of
axonal forms with normal amplitude and
reduced velocity (16).
Comprehensive electrophysiologic
studies are important to define precisely
the diagnosis (34), although routine elec-
trophysiologic examination often cannot
discriminate between myopathy and neu-
ropathy in critically ill, sedated, uncoop-
erative, or extremely weak patients (16).
These studies should include motor and
sensory nerve conduction studies as well
as needle EMG in upper and lower limbs.
Phrenic nerve conduction studies and
needle EMG of the respiratory muscles
may establish the CIP as the cause of
failure to wean from the ventilator. Stan-
dard protocols include orthodromic con-
duction studies in motor nerves (more
commonly, ulnar and common peroneal
nerves bilaterally) and antidromic con-
duction studies in sensory nerves (ulnar
and sural nerves bilaterally). Needle EMG
from upper and lower limb muscles (bi-
ceps brachii, abductor digiti minimi of
hand, tibialis anterior and quadriceps
femori muscles) is performed with assess-
ment of spontaneous activity and, if pos-
sible, recruitment and interference pat-
terns. If the patient may collaborate on
the electrophysiologic evaluation and
may volitionally activate the muscle con-
traction, a differential diagnosis between
myopathy and CIP can be sought: motor
unit potentials with a low amplitude and
short duration and early rapid recruit-
ment provide evidence for a CIM (15). If
not, the differential diagnosis remains
elusive, with the exception of rare cases of
isolated sensory nerve action potential am-
plitude reduction that rules out an ongoing
CIM (16). Preserved sensory nerve action
potential amplitude is not a unique feature
of CIM, because pure motor forms of CIP
have been described (10, 35).
Simplified Electrophysiologic
Investigation
Measurement of the nerve action po-
tential amplitude of the peroneal nerve is
a recently proposed simplified electro-
physiologic investigation in critically ill
patients (9). Reduction of the amplitude
⬍2 standard deviations of the normal
value identifies patients with ICU-ac-
quired neuromuscular alterations with
100% sensitivity and 67% specificity (9).
High-sensitivity diagnostic tests have a
high negative predictive value and are
particularly useful when normal. There-
S317
fore, this test can be used as a screening
test before a patient’s discharge from the
ICU or the acute care hospital. The time
needed to measure a peroneal compound
muscle action potential amplitude in one
leg is 5 mins, which is substantially less
than 45 mins to 90 mins needed for a
complete electrophysiological investiga-
tion (9, 36).
The presence of abundant spontaneous
activity on EMG in the form of positive
sharp waves and fibrillation potentials has
been used as an evidence of neuromuscular
alterations in critically ill patients in two
randomized controlled trials on intensive
insulin treatment (31, 32); however, this
test has not been validated.
Direct Muscle Stimulation
Direct muscle stimulation enables the
investigation of electrical (in)excitability
of muscle membrane (37). In direct mus-
cle stimulation, both the stimulating and
the recording electrodes are placed in the
muscle distal to the end-plate zone (16).
A patient with CIP will have a reduced or
absent action potential when using con-
ventional stimulation (i.e., through the
motor nerve), but normal action poten-
tial when using direct muscle stimula-
tion; in the case of CIM, the action po-
tential will be reduced or absent after
both conventional stimulation and direct
muscle stimulation. Using the ratio of
compound muscle action potential am-
plitude evoked by nerve stimulation to
that evoked by direct muscle stimulation,
the CIP is diagnosed if the ratio is ⬍0.5,
whereas CIM is diagnosed if the ratio is
⬎0.5 (11, 13, 37–39). Lefaucheur et al
(13) proposed the serial evaluation of the
amplitude of the muscle action potential
after direct muscle stimulation, the ratio
of nerve/direct muscle stimulation ampli-
tude, and the sensory nerve action poten-
tial amplitude as a method to differenti-
ate the CIM from the CIP.
In this algorithm, 1) the patients with
reduced amplitude of the direct com-
pound muscle action potential always
have a CIM that can be either: 1a) isolated
(ratio increased); 1b) possibly associated
with motor CIP (normal ratio); or 1c)
associated with predominant motor CIP
(ratio reduced); 2) the patients with nor-
mal amplitude of the direct compound
muscle action potential may have ei-
ther: 2a) a mild CIM (ratio increased);
2b) normal electrophysiology (normal
ratio); or 2c) possible pure motor CIP
(ratio reduced); 3) a reduced amplitude
S318
of the sensory nerve action potential (20, 46 – 49), and, in critically ill coma-
adds the evidence of an axonal sensory tose patients, instigate unreasonable pes-
CIP (13). simistic prognoses by obscuring the mo-
Direct muscle stimulation is useful to tor reflex response to pain (10). In these
differentiate CIM from CIP in the ICU settings, it remains uncertain whether
setting, however, despite its apparent clinical or electrophysiological testing is
simplicity, it is technically demanding the best strategy. It is possible that dif-
and requires thorough practice to obtain ferent diagnostic methods identify differ-
reliable results. Furthermore, concor- ent patient groups, and that electrophys-
dance with the results of muscle biopsy is iological and clinical abnormalities have
limited (11). different implications (50). However, the
available evidence suggests that electro-
Axonal Excitability Testing physiological and clinical testing do in-
tercept the disease process at different
In 1971, Cunningham et al demon-
stages according to the sequence: func-
strated a reduction of resting transmem-
tional alterations 3 structural alter-
brane potential difference of skeletal
ations 3 muscle weakness. If this se-
muscle in severely ill patients (⫺66.3 ⫾
9.0 mv) compared with patients with quence is confirmed, electrophysiologic
mild disease (⫺89 ⫾ ⫺2.1 mv) and testing would offer the advantage of a
healthy subjects (⫺88 ⫾ 3.8 mv) (26). timely diagnosis and start of potentially
valuable interventions before structural
They also noted that depression of muscle
muscle-nerve alterations become estab-
resting transmembrane potential differ-
lished. Clinical evaluation is, in general,
ence was severe enough that there should
less sensitive than electrophysiologic
have been depolarization block, yet by
evaluation; clinical signs of polyneurop-
clinical evaluation there was no paralysis
athy or CIM are present in only half of
or neuromuscular defect other than sub-
patients with neuromuscular alterations
jective weakness. Intracellular sodium
(36, 51). The evaluation of muscle
concentrations were uniformly increased
strength, using the Medical Research
in the muscle samples of the severely ill
Council score, has the advantage that can
subjects, suggesting a generalized cellu-
be easily performed by most clinicians
lar abnormality.
(18). Handgrip dynamometry provides a
Multiple measures of axonal excitabil-
rapid alternative to comprehensive Med-
ity aiming at investigating the electrical
ical Research Council examination (50).
properties of the nerve membrane (mem-
Both, however, require an awake and col-
brane potential) in vivo have been pro-
laborative patient able to activate voli-
posed, representing one of the most ex-
tional muscle groups, which would ex-
citing innovations in the field of
clude critically ill neurologic patients as
electrophysiologic investigations (40 –
well as nonneurologic patients with en-
44). By using dedicated computer pro-
cephalopathy (52, 53) from proper evalu-
grams to measure excitability indices
ation. Supporters of clinical evaluation as
within recording sessions of 10 mins to
the preferred diagnostic method indicate
15 mins, axons have been found to be
the start of weaning from mechanical
depolarized in patients with CIP to a sim-
ventilation as the optimal timing for eval-
ilar degree as was previously reported in
uation (54); however, this would delay
patients with chronic renal failure (42,
evaluation by several days to weeks, thus
43). Raised extracellular potassium and
making potential therapeutic interven-
hypoperfusion seem to be causally related
tion less effective.
to membrane depolarization (42, 43).
These results have not been confirmed by
Novak et al (45), who found no relation-
After ICU Discharge
ship with electrolyte abnormalities, and a
hyperpolarized shift in the voltage depen-
Severe disability with tetraparesis, tet-
dence of sodium channel inactivation,
raplegia, or paraplegia is reported in one
causing increased sodium inactivation
third of patients discharged from the
and reduced axonal excitability.
acute care hospital with a diagnosis of
CIM or CIP (55). Milder disabilities in-
THE WHEN AND WHAT
cluding reduced or absent deep tendon
reflexes, stocking and glove sensory loss,
In the ICU
muscle atrophy, painful hyperesthesia,
CIM and/or CIP can significantly delay and footdrop are common, as are limita-
weaning from mechanical ventilation tions in daily life activities (55). Patients
Crit Care Med 2009 Vol. 37, No. 10 (Suppl.)
with CIM might have a better long-term
prognosis than patients with CIP (56);
therefore, an accurate pathologic diagno-
sis based on complete neurologic evalua-
tion and conventional nerve conduction
velocity and EMG is relevant to plan
proper rehabilitation.
Future studies should address
whether clinical testing of muscle
strength in awake and collaborative pa-
tients or simplified peroneal nerve elec-
trophysiological testing in patients with
altered consciousness could be used ef-
fectively to rapidly screen those patients
who deserve complete neurologic and
electrophysiological evaluation.
ACKNOWLEDGMENT
We dedicate this paper to the memory
of Dr. Indrit Shehu, a friend and a great
doctor and researcher.
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