REVIEW

CURRENT
OPINION Critical illness myopathy
Nicola Latronico a, Giuliano Tomelleri b, and Massimiliano Filosto c

Purpose of review
To describe the incidence, major risk factors, and the clinical, electrophysiological, and histological
features of critical illness myopathy (CIM). Major pathogenetic mechanisms and long-term consequences of
CIM are also reviewed.
Recent findings
CIM is frequently associated with critical illness polyneuropathy (CIP), and may have a relevant impact on
patients’ outcome. CIM has an earlier onset than CIP, and recovery is faster. Loss of myosin filaments on
muscle biopsy is important to diagnose CIM, and has a good prognosis. Critical illness, use of steroids,
and immobility concur in causing CIM.
Summary
A rationale diagnostic approach to CIM using clinical, electrophysiological, and muscle biopsy
investigations is important to plan adequate therapy and to predict recovery.
Keywords
acute myopathy, chronic disability, mechanical ventilation, muscle weakness, myosin

INTRODUCTION INCIDENCE AND RISK FACTORS

Acute neuromuscular complications are of common
occurrence during critical illness, particularly
among patients with prolonged ICU stay and
mechanical ventilation, and those developing
multiple organ dysfunctions as a consequence of
severe, persistent systemic inflammation [1]. Brain,
lung, heart, and kidney are traditionally described as
the most common failing organs, but no organ is
spared by the devastating ‘autodestructive inflam-
matory response’ [2], and peripheral nerves and
muscles are no exception. Critical illness myopathy
(CIM) is currently proposed as the appropriate term
encompassing all the various subtypes of the acute
myopathy developing during critical illness [1,3–5].
Likewise, the associated polyneuropathy is named
critical illness polyneuropathy (CIP) [1,6].
Critical illness myopathy and CIP are not
irreversible; their onset can be rapid, and resolution
can be complete in a matter of weeks [7]. However,
in some patients CIM and CIP may persist long after
discharge from the acute-care hospital, and can be
responsible for severe chronic disability.
The review describes the incidence, major
risk factors, and the clinical, electrophysiological,
and histological features of CIM. It also describes
the major pathogenetic mechanisms of CIM, and
the long-term consequences associated with CIM
and CIP.
Critical illness myopathy is an acute myopathic
process causing muscle dysfunction and disruption
of the normal muscle fiber structure. CIM is a
primary myopathy that is not secondary to dener-
vation. CIP is a distal axonal degeneration that most
often coexists with CIM and causes muscle dener-
vation [8–11] (Fig. 1e).
Exact incidence of CIM is unknown. The patient
population, the diagnostic criteria used, and the
timing of evaluation are factors influencing the
incidence of CIM. If only the most severe ICU
patients are considered, CIM alone or associated
with CIP is estimated to occur in 33% [7] to 50%
[12] of patients. Incidence up to 100% has been
a
Division of Neuroanesthesia and Neurocritical Care, Department of
Anesthesia, Intensive Care and Perioperative Medicine, University of
Brescia at Spedali Civili, Brescia, bDivision of Clinical Neurology, Depart-
ment of Neurological, Neuropsychological, Morphological and Movement
Sciences, University of Verona, Verona and cDivision of Clinical Neurol-
ogy, Section for Neuromuscular Diseases and Neuropathies, University
of Brescia at Spedali Civili, Brescia, Italy
Correspondence to Professor Nicola Latronico, Department of Anes-
thesia, Intensive Care & Perioperative Medicine, Division of Neuroanes-
thesia and Neurocritical Care, University of Brescia, Spedali Civili,
Piazzale Ospedali Civili, 1, 25123 Brescia, Italy. Tel: +39 030 3995
764/570/841; e-mail: nicola.latronico@med.unibs.it
Curr Opin Rheumatol 2012, 24:616–622
DOI:10.1097/BOR.0b013e3283588d2f

www.co-rheumatology.com Volume 24  Number 6  November 2012

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 Critical illness myopathy Latronico et al.

reported in patients with septic shock [13] or

KEY POINTS
 Critically ill patients may develop a critical illness
myopathy (CIM) characterized by loss of muscle myosin
filaments, muscle fiber necrosis, and atrophy during the
acute stage of disease.
 In some patients CIM may persist for months after
discharge from the acute-care hospital causing severe
muscle weakness and paralysis.
 Critical illness myopathy is often associated with critical
illness polyneuropathy (CIP), an acute axonal
neuropathy. Differential diagnosis between CIM and
CIP is important, because prognosis is more favorable
in CIM than in CIP.
severe sepsis (i.e. sepsis and organ dysfunction)
and coma [8]. Several factors have been identified
as independent risk factors in prospective studies,
including severity of illness and duration of ICU
stay, mechanical ventilation, and multiple organ
failure (MOF).
Among drugs [14], the corticosteroids and neu-
romuscular blocking agents (NMBAs) have received
considerable attention. Myopathy is common after
prolonged use of corticosteroids, which are well
known to induce muscle catabolism, inhibit ana-
bolism, and exacerbate the effects of immobilization
[15,16]. In patients with acute respiratory distress
syndrome, treatment with corticosteroids had the
strongest association with reduced exercise capacity
at 3 months, but at 6 months this negative effect
on functional recovery was no longer evident [17].
Results in patients receiving intensive insulin

(e) Axonal degeneration

(a) Loss of (thick) myosin filaments

e
a
(d) Inexcitable muscle fiber

d
b
c

(b) Muscle fiber necrosis

(c) Muscle fiber atrophy

FIGURE 1. Major histopathologic features of CIM [1]. (a) Electron microscopy: myofibrils devoid of thick filaments with
preserved Z lines (original magnification 12 000); (b) hematoxylin eosin: necrotic muscle fibers (arrows) (original
magnification 20); (c) ATPase pH 4.6: muscle fiber atrophy (mainly type II) and focal loss of reactivity indicating loss of
myofilaments (arrows) (original magnification 40); (d) schematic representation of inexcitable muscle with preserved
neuromuscular transmission; (e) light microscopic image, toluidine blue stain, sural nerve biopsy: nerve axon degeneration
with decreased density of myelinated fibers, magnification 150. CIM, critical illness myopathy.

1040-8711 ß 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-rheumatology.com 617

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 Myositis and myopathies
treatment are contrasting. In one analysis based
on electrophysiological investigations [18], cortico-
steroids had a protective effect on muscle, possibly
because their beneficial anti-inflammatory effect
was not counteracted by hyperglycemia and insulin
resistance. In another analysis from the same group
&&
based on muscle biopsy findings [19 ], the duration
of corticosteroid treatment was associated with loss
of myofibrillar (mainly myosin) filaments. Taken
together, the available evidence suggests caution
when using high-dose corticosteroids in critically
ill patients. Patients with severe rheumatic diseases
often receive corticosteroids for prolonged periods
of time, and may represent a subgroup with
increased risk of developing CIM in case of ICU
admission. Competitive nondepolarizing NMBAs
can induce prolonged neuromuscular block. Muscle
weakness commonly lasts a few hours. Cases of
several-day durations are probably the consequence
&&
of CIM and CIP [20 ].
Among nondrug-related risk factors, hypergly-
cemia is of common occurrence in critical illness,
and has been recognized as a risk factor for CIP for
a long time [21]. Immobility is another powerful
contributor to muscle atrophy and reduced
muscle strength during critical illness. Patients
may lose half their muscle mass, resulting in severe
physical disability [17,22]. Respiratory muscles
are not spared. Diaphragmatic atrophy, weakness,
and injury develop rapidly during mechanical venti-
&&
lation, a proxy of diaphragm immobility [23 ].
Diaphragmatic weakness can be already evident at
the initiation of mechanical ventilation, indicating
that critical illness and mechanical ventilation are
&&
both contributing factors [23 ]. Prolonged sedation
is a major determinant of patient immobility in the
ICU [24], decreases muscle excitability [25], and
causes hypoactive delirium [26]. Despite this, there
is no evidence that sedation and immobility directly
cause CIM or CIP, as nerve conduction studies remain
normal in patients with muscle wasting [1].
PATHOPHYSIOLOGY
Sepsis, multiple organ failure, drugs, hyperglycemia,
and immobility of limb and diaphragm concur in
causing CIM trough multiple, often inter-related
pathophysiological mechanisms. Increased muscle
proteolysis has a pivotal role in causing muscle wast-
ing [1,3]. Pro-inflammatory cytokines such as tumor
necrosis factor, gamma-interferon, and interleukin-1
promote muscle protein degradation through acti-
vation of calpain and ubiquitine-proteasome [27].
Diaphragmatic immobility during mechanical
ventilation combined with sedation triggers dia-
phragm weakness [28]. Increased expression of
618 www.co-rheumatology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
muscle ring finger-1 (MuRF1) mRNA and protein
in mice model of acute lung injury is a critical
mediator of persisting muscle wasting trough
activation of proteasomal activity [29]. Activation
of the proteases calpain and caspase-3 is essential
for mechanical ventilation-induced diaphragmatic
&&
weakness [23 ,30]. Inhibition of either protease
protects the diaphragm from mechanical venti-
lation-induced dysfunction because of a regulatory
cross-talk between the two proteases [31].
Limb muscle immobility may cause a large loss
of skeletal muscle mass and reduction in muscle
strength within a few days [32]. Increased proteol-
ysis and reduced muscle protein synthesis are key
&&
events [32,33]. In rats [34] but not in patients [19 ]
MuRF1/2 mediates myosin degradation. CIP-related
muscle denervation combined with NMBAs or high-
dose steroids further activates muscle catabolism
[35], and causes selective loss of myosin filaments
in rats [34,36]. However, the same histopathologic
picture has been described in patients with sepsis
not receiving steroids [37], and as a rare idiopathic
form [38]. Immobility increases the production
of pro-inflammatory cytokine and reactive oxygen
species [33], and peripheral insulin resistance.
Insulin resistance with hyperglycemia occurs
frequently during critical illness as a result of
the metabolic and hormonal changes of the stress
response [39]. Insulin has anabolic effects and
exerts several potential beneficial effects on muscle,
including anti-inflammatory effects, endothelial
protection, and improvement of dyslipidemia
[40]. Intensive insulin treatment may prevent
CIM and CIP [18,41], although it remains uncertain
whether this effect is secondary to blood glucose
normalization or to insulin itself [42].
Altered microcirculation is a key factor leading
to organ dysfunction and death during sepsis
[43,44]. In muscle, impaired perfusion results from
a decreased number of perfused capillaries and
an increased number of stopped-flow capillaries
[45], which have been visualized in humans by
orthogonal polarization spectral imaging and side-
stream dark-field imaging [46]. Mechanisms include
activation of coagulation with platelet adhesion
and fibrin deposition in capillaries [47], as well as
stiff leukocytes and red blood cells and endothelial
cell swelling [48].
Mitochondrial muscle dysfunction has been
documented in patients with severe sepsis, particu-
larly in nonsurvivors [49]. Mechanisms include
damage to mitochondria or inhibition of the elec-
tron transport chain enzymes by nitric oxide and
other reactive oxygen species, hormonal influences
that decrease mitochondrial activity, and down-
regulation of mitochondrial protein expression
Volume 24  Number 6  November 2012

[50]. Microcirculatory and mitochondrial mechan-
isms of organ dysfunction are frequently associated –
a condition described as microcirculatory and
mitochondrial distress syndrome [44]. Mitochon-
drial regeneration providing new functional mito-
chondria and restoration of oxidative metabolism
favors survival [51].
Reduced or absent muscle excitability associated
with sodium channel modifications has been dem-
onstrated in models of rat denervation and steroid
administration [52]. Interestingly, similar modifi-
cations have been described in peripheral nerves
suggesting that CIM and CIP might be different
manifestations of an acquired channelopathy [53].
CLINICAL FEATURES
Critical illness myopathy causes generalized muscle
weakness and paralysis, which are indistinguishable
from those caused by CIP. Limb and respiratory
muscles are affected, whereas facial muscles are
usually spared. In some patients facial weakness can
be seen but ophthalmoplegia is exceedingly rare.
Limb muscle weakness is symmetrical, and is most
prominent in the lower extremities. Medical Research
Council (MRC) sumscore is used in the ICU to
manually assess muscle strength [5,54]. If less than
48, it identifies patients with significant weakness, an
independent predictor of morbidity and mortality
[54,55]. Inter-rater reliability of MRC is good in
patients with significant or severe (MRC sumscore
<36) muscle weakness [56], but depends much on
&&
patients’ cooperation [57 ], and may ignore the
less severe forms of muscle weakness. Handgrip dyna-
mometry correlates well with MRC scores and can be
a rapid alternative to comprehensive MRC evaluation
of muscle strength [55]. Difficult weaning of patients
from the ventilator indicating diaphragm weakness
can be a prevailing symptom in the ICU [18,58,59].
The sensory system is intact in CIM.
ELECTROPHYSIOLOGICAL AND MUSCLE
BIOPSY FEATURES
Conventional nerve conduction study demon-
strates low-amplitude compound muscle action
potential (CMAP), fibrillation potentials, and
positive sharp waves. However, these findings are
nonspecific, and can be recorded also in patients
with CIP. Notably, the nerve conduction velocity
remains normal or near normal. Needle electro-
myography (EMG) can distinguish between the
CIM and CIP, provided that the patient is awake,
and able to collaborate and to contract his muscles
voluntarily. In CIM, EMG demonstrates motor unit
potential of low amplitude, short duration, and
polyphasic after minimal voluntary contraction.
1040-8711 ß 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Critical illness myopathy Latronico et al.
Critical illness myopathy can be due to muscle
membrane inexcitability (Fig. 1d). In this case,
direct muscle stimulation combined with con-
ventional nerve conduction study may be helpful
to establish the diagnosis also in noncollaborative
patients. With this technique, both the stimulating
and the recording electrodes are placed in the
muscle distal to the end-plate zone. In CIM the
action potential amplitude will be reduced or absent
after both conventional and direct muscle stimu-
lation. In CIP the action potential amplitude will be
reduced or absent after conventional stimulation
(i.e. through the motor nerve) and normal when
using direct muscle stimulation. CIM is established
if the ratio of the CMAP amplitude after nerve
stimulation versus that obtained after direct muscle
stimulation is less than 0.5, and if the amplitude
of CMAP after direct muscle stimulation is less
than 3 mV. CIM has an earlier onset than CIP,
and recovery is faster [9,60].
Increased duration of the muscle surface-
recorded CMAP associated with the reduction of
CMAP amplitude is a further important electro-
physiological sign of CIM [1]. CMAP duration can
be two to three times longer than in healthy con-
trols, and is most pronounced in lower limb nerves.
Such a change cannot be explained by a neuropathy
because, although demyelinating neuropathies
can increase duration, this increase is greater with
proximal than distal stimulation, and in axonal
neuropathies, as in CIP, the duration is not
increased.
As CIM and CIP are associated in most cases,
signs of both primary myopathy and muscle dener-
vation coexist on muscle biopsy [8]. Aspects of
primary myopathy include selective loss of myosin
filaments (Fig. 1a, c), as well as varying degrees of
fiber necrosis (Fig. 1b) and atrophy (Fig. 1c). Early
fiber IIa atrophy is predominant in patients with
reduced or absent muscle membrane excitability
&&
[61 ], and may coexist with selective loss of myosin
filaments (Fig. 1c). Selective loss of myosin filament
is an important clue to diagnosing CIM in the
appropriate clinical context. In addition to conven-
tional muscle biopsy evaluation, electrophoretic
separation of myofibrillar proteins and measure-
ment of myosin-to-actin ratio on muscle specimens
can be considered to rapidly demonstrate the loss
of myosin [62]. As cited above, CIM can be due
to muscle membrane inexcitability (Fig. 1d), and
is frequently associated with CIP (Fig. 1e).
OUTCOME
Physical impairment is a major contributor to post-
&&
intensive care syndrome [63 ]. Survivors of critical
www.co-rheumatology.com 619
 Myositis and myopathies
illness have persistent reduction in their ability
to exercise years after discharge from the ICU
&&
[64 ]. Causes are several, including peripheral
nerve, muscle, bone, and joint alterations [65,66],
but the relative role of each condition is currently
unknown. Among patients discharged from the
ICU with a diagnosis of CIM or CIP, nearly one-
third may not recover to their physical condition
before critical illness [67]. In the most severe
cases the patient can have tetraparesis or tetraplegia
and ventilator dependency [67]. CIM may have
a relatively good prognosis compared to CIP [60],
although in organ transplant patients CIM has a
similar prognosis than CIP [68]. In CIP disability
may persist for years [60,69,70].
DIAGNOSIS
In the ICU, difficulty in weaning the patient from
mechanical ventilation is a common presentation
for CIM and CIP, and is often the first sign noted.
Generalized symmetric limb weakness affecting
both proximal and distal muscles is also common,
and can be associated with prominent muscle wast-
ing. Manual muscle strength testing with MRC or
dominant-hand dynamometry in alert patients
will show significant muscle weakness, but milder
degrees of muscle weakness may remain undetected.
Sensory testing, if feasible, gives normal findings
in CIM.
At a later stage, patients may complain of
focal muscle weakness caused by nerve entrapment
neuropathy, but more commonly muscle weakness
is generalized. If severe, diagnosis is usually obvious.
In milder cases, accurate testing of all muscle groups
is needed together with functional assessment of
patients’ motor ability, that is climbing stairs, rising
from the floor or a squat, walking on heels or toes.
Sensory assessment reveals normal perception of
tactile, temperature and pain stimuli, and normal
vibration thresholds. In addition to history (ICU
admission, critical illness) and clinical examination,
electrophysiological investigations and muscle
biopsy can contribute to establishing the diagnosis.
Needle EMG can prove CIM. If the patient cannot
collaborate to the electrophysiological investi-
gation, direct muscle stimulation and analysis of
the duration of CMAP can be useful. Muscle biopsy
should be considered in case of diagnostic un-
certainty. Minimally invasive percutaneous muscle
biopsy using needle or open muscle biopsy may
demonstrate selective loss of myosin filaments that
usually has a good prognosis (Fig. 1a, c). Diagnostic
algorithms can be useful for an ordered approach
to clinical, electrophysiological, and muscle biopsy
investigations [1,5].
620 www.co-rheumatology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
MANAGEMENT
There are no specific treatments for CIM. Tight
control of blood glucose using intensive insulin
treatment during the ICU stay may reduce the
incidence and severity of CIM and CIP. However,
intensive insulin treatment targeting normoglyce-
mia increases mortality [71], and the optimal level
of blood glucose remains unsettled. Among non-
pharmacological treatments, the electrical muscle
stimulation may prevent CIM and CIP [72], but
definitive evidence of efficacy is lacking [1,73].
In a recent randomized controlled trial, ICU
patients receiving early comprehensive rehabilita-
tion in conjunction with a low level of sedation
had increased functional independence compared
with patients receiving standard treatment [74].
However, it remains unknown if this strategy effec-
tively reduced the occurrence of CIM or CIP, because
electrophysiological investigations of peripheral
nerves and muscles were not performed. Interest-
ingly, muscle strength measured with MRC or hand-
grip dynamometry was not different in the two
groups of patients.
Future research targeting specific pathophysio-
logical mechanisms would be helpful to clarify the
relative contribution to muscle weakness of factors
implicated in the interplay between hormonal and
inflammatory changes of critical illness, primary
and secondary (denervation) myopathy, pharmaco-
logic side-effects, and, not least, immobility. Initial
evidence in animal models suggests that continuous
administration of pyridostigmine, an acetylcholin-
esterase inhibitor used to treat patients with myas-
thenia gravis, can improve neuromuscular weakness
in animal models, but mechanisms remain unclear
[75]. Ascorbate and nitric oxide donors attenuate
platelet adhesion in septic capillaries and may
become novel adjuvant therapies to improve muscle
microcirculation during sepsis [47]. Suppression
of MuRF1 prevents muscle fiber atrophy in rat
acute lung injury [29]. Finally, it is promising that
pharmacological inhibition of calpain and inhibition
of caspase-3 protect the diaphragm from mechanical
ventilation-induced proteolysis, atrophy, and con-
tractile dysfunction [31].
CONCLUSION
Critical illness myopathy and CIP are frequent
complications of critical illness and are relevant
causes of persisting muscle weakness. Delayed wean-
ing from mechanical ventilation with increased ICU
and hospital stay and costs, increased mortality, and
protracted disability are common consequences.
Despite their importance, much remains to be
understood about prevalence, causes, pathogenetic
Volume 24  Number 6  November 2012

mechanisms, prevention, and treatment. Future
studies should define the true incidence and risk
factors for CIM, and the range of therapeutic inter-
ventions to reduce the burden of disease.
Acknowledgements
None.
Conflicts of interest
The authors have no conflicts of interests to declare.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (p. 695).
1. Latronico N, Bolton CF. Critical illness polyneuropathy and myopathy: a major
cause of muscle weakness and paralysis. Lancet Neurol 2011; 10:931–
941.
2. Baue AE. Multiple, progressive, or sequential systems failure: a syndrome of
the 1970s. Arch Surg 1975; 110:779–781.
3. Latronico N, Candiani A. Muscular wasting as a consequence of sepsis.
In Gullo A, editor. Anaesthesia, pain, intensive care and emergency medicine,
APICE. 13th ed. Milan: Springer-Verlag; 1998. pp. 517–522.
4. Lacomis D, Zochodne DW, Bird SJ. Critical illness myopathy. Muscle Nerve
2000; 23:1785–1788.
5. Stevens RD, Marshall SA, Cornblath DR, et al. A framework for diagnosing
and classifying intensive care unit-acquired weakness. Crit Care Med 2009;
37 (Suppl):299–308.
6. Bolton CF. The discovery of critical illness polyneuropathy: a memoir. Can J
Neurol Sci 2010; 37:431–438.
7. Latronico N, Bertolini G, Guarneri B, et al. Simplified electrophysiological
evaluation of peripheral nerves in critically ill patients: the Italian multicentre
CRIMYNE study. Crit Care 2007; 11:R11.
8. Latronico N, Fenzi F, Recupero D, et al. Critical illness myopathy and
neuropathy. Lancet 1996; 347:1579–1582.
9. Koch S, Spuler S, Deja M, et al. Critical illness myopathy is frequent:
accompanying neuropathy protracts ICU discharge. J Neurol Neurosurg
Psychiatry 2011; 82:287–293.
10. Lefaucheur JP, Nordine T, Rodriguez P, Brochard L. Origin of ICU acquired
paresis determined by direct muscle stimulation. J Neurol Neurosurg Psy-
chiatry 2006; 77:500–506.
11. Bednarik J, Lukas Z, Vondracek P. Critical illness polyneuromyopathy:
the electrophysiological components of a complex entity. Intensive Care
Med 2003; 29:1505–1514.
12. Stevens RD, Dowdy DW, Michaels RK, et al. Neuromuscular dysfunction
acquired in critical illness: a systematic review. Intensive Care Med 2007;
33:1876–1891.
13. Tennila A, Salmi T, Pettila V, et al. Early signs of critical illness polyneuropathy
in ICU patients with systemic inflammatory response syndrome or sepsis.
Intensive Care Med 2000; 26:1360–1363.
14. Hermans G, De Jonghe B, Bruyninckx F, Van den Berghe G. Clinical review:
critical illness polyneuropathy and myopathy. Crit Care 2008; 12:238.
15. Schakman O, Gilson H, Thissen JP. Mechanisms of glucocorticoid-induced
myopathy. J Endocrinol 2008; 197:1–10.
16. Fitts RH, Romatowski JG, Peters JR, et al. The deleterious effects of bed rest
on human skeletal muscle fibers are exacerbated by hypercortisolemia and
ameliorated by dietary supplementation. Am J Physiol Cell Physiol 2007;
293:C313–C320.
17. Herridge MS, Cheung AM, Tansey CM, et al. One-year outcomes in survivors
of the acute respiratory distress syndrome. N Engl J Med 2003; 348:683–
693.
18. Hermans G, Wilmer A, Meersseman W, et al. Impact of intensive insulin
therapy on neuromuscular complications and ventilator dependency in the
medical intensive care unit. Am J Respir Crit Care Med 2007; 175:480–489.
19. Derde S, Hermans G, Derese I, et al. Muscle atrophy and preferential loss of
&& myosin in prolonged critically ill patients. Critical Care Med 2012; 40:79–89.
Muscle atrophy was mostly prevalent in 208 limb and abdominal muscle biopsies
from ICU patients compared with 35 controls. ICU patients also had down-
regulation of myofibrillar protein synthesis at the gene expression level (particularly
myosin) and increased muscle proteolysis. Duration of corticosteroid treatment
was an important risk factor for decreased muscle myosin content.
1040-8711 ß 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Critical illness myopathy Latronico et al.
20. Puthucheary Z, Rawal J, Ratnayake G, et al. Neuromuscular blockade and
&& skeletal muscle weakness in critically ill patients: time to rethink the evidence?
Am J Respir Crit Care Med 2012; 185:911–917.
Mice with acute lung injury developed severe muscle weakness and atrophy with
reduction of type II fibers and preferential loss of myofibrillar proteins associated
with marked up-regulation of muscle ring finger-1 mRNA (MuRF1) and protein
expression. Muscle atrophy, but not muscle weakness, was suppressed in MuRF1-
deficient animals.
21. Witt NJ, Zochodne DW, Bolton CF, et al. Peripheral nerve function in sepsis
and multiple organ failure. Chest 1991; 99:176–184.
22. Lightfoot A, McArdle A, Griffiths RD. Muscle in defense. Crit Care Med 2009;
37:S384–S390.
23. Jaber S, Petrof BJ, Jung B, et al. Rapidly progressive diaphragmatic weakness
&& and injury during mechanical ventilation in humans. Am J Respir Crit Care Med
2011; 183:364–371.
In humans, the longer the duration of controlled mechanical ventilation, the worse
the diaphragmatic function assessed by measuring changes in endotracheal tube
pressure induced by bilateral magnetic twitch stimulation of the phrenic nerves
during airway occlusion (TwPtr). Moreover, the longer the duration of mechanical
ventilation, the higher the magnitude of diaphragmatic muscle injury and atrophy.
Serial measurements revealed a rapid decline in TwPtr values 5–6 days after
the onset of mechanical ventilation. Baseline TwPtr values were also reduced
suggesting that critical illness and mechanical ventilation concur in adversely
affecting diaphragmatic function.
24. Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of sedative
infusions in critically ill patients undergoing mechanical ventilation. N Engl J
Med 2000; 342:1471–1477.
25. Vasilevskis EE, Ely EW, Speroff T, et al. Reducing iatrogenic risks: ICU-
acquired delirium and weakness–crossing the quality chasm. Chest 2010;
138:1224–1233.
26. Pandharipande P, Cotton BA, Shintani A, et al. Motoric subtypes of delirium in
mechanically ventilated surgical and trauma intensive care unit patients.
Intensive Care Med 2007; 33:1726–1731.
27. Friedrich O. Critical illness myopathy: what is happening? Curr Opin Clin Nutr
Metab Care 2006; 9:403–409.
28. Ochala J, Renaud G, Llano Diez M, et al. Diaphragm muscle weakness in an
experimental porcine intensive care unit model. PLoS One 2011; 6:e20558.
29. Files DC, D’Alessio FR, Johnston LF, et al. A critical role for muscle ring finger-
1 in acute lung injury-associated skeletal muscle wasting. Am J Respir Crit
Care Med 2012; 185:825–834.
30. McClung JM, Kavazis AN, DeRuisseau KC, et al. Caspase-3 regulation
of diaphragm myonuclear domain during mechanical ventilation-induced
atrophy. Am J Respir Crit Care Med 2007; 175:150–159.
31. Nelson WB, Smuder AJ, Hudson MB, et al. Cross-talk between the calpain
and caspase-3 proteolytic systems in the diaphragm during prolonged
mechanical ventilation. Crit Care Med 2012; 40:1857–1863.
32. Kortebein P, Ferrando A, Lombeida J, et al. Effect of 10 days of bed rest on
skeletal muscle in healthy older adults. J Am Med Assoc 2007; 297:1772–
1774.
33. Truong AD, Fan E, Brower RG, Needham DM. Bench-to-bedside review:
mobilizing patients in the intensive care unit–from pathophysiology to clinical
trials. Crit Care 2009; 13:216.
34. Ochala J, Gustafson AM, Diez ML, et al. Preferential skeletal muscle myosin
loss in response to mechanical silencing in a novel rat intensive care unit
model: underlying mechanisms. J Physiol 2011; 589:2007–2026.
35. Horinouchi H, Kumamoto T, Kimura N, et al. Myosin loss in denervated rat
soleus muscle after dexamethasone treatment. Pathobiology 2005; 72:108–
116.
36. Massa R, Carpenter S, Holland P, Karpati G. Loss and renewal of thick
myofilaments in glucocorticoid-treated rat soleus after denervation and
reinnervation. Muscle Nerve 1992; 15:1290–1298.
37. Helliwell TR, Wilkinson A, Griffiths RD, et al. Muscle fibre atrophy in critically ill
patients is associated with the loss of myosin filaments and the presence of
lysosomal enzymes and ubiquitin. Neuropathol Appl Neurobiol 1998;
24:507–517.
38. Vattemi G, Tonin P, Filosto M, et al. Reversible upper limb muscle weakness
with selective loss of thick filaments. Neurology 2003; 61:863–864.
39. Singer M, De Santis V, Vitale D, Jeffcoate W. Multiorgan failure is an adaptive,
endocrine-mediated, metabolic response to overwhelming systemic inflam-
mation. Lancet 2004; 364:545–548.
40. Vanhorebeek I, Langouche L, Van den Berghe G. Glycemic and nonglycemic
effects of insulin: how do they contribute to a better outcome of critical
illness? Curr Opin Crit Care 2005; 11:304–311.
41. Van den Berghe G, Schoonheydt K, Becx P, et al. Insulin therapy protects the
central and peripheral nervous system of intensive care patients. Neurology
2005; 64:1348–1353.
42. Bertolini G, Latronico N, Brazzi L, Radrizzani D. Insulin dose or glycemic
control for the critically ill? Crit Care Med 2003; 31:2565–2566; author reply
6.
43. Sakr Y, Dubois MJ, De Backer D, et al. Persistent microcirculatory alterations
are associated with organ failure and death in patients with septic shock.
Crit Care Med 2004; 32:1825–1831.
44. Ince C. The microcirculation is the motor of sepsis. Crit Care 2005; 9 (Suppl 4):
S13–S19.
www.co-rheumatology.com 621
 Myositis and myopathies
45. Lam C, Tyml K, Martin C, Sibbald W. Microvascular perfusion is impaired
in a rat model of normotensive sepsis. J Clin Investig 1994; 94:2077–
2083.
46. De Backer D, Ospina-Tascon G, Salgado D, et al. Monitoring the micro-
circulation in the critically ill patient: current methods and future approaches.
Intensive Care Med 2010; 36:1813–1825.
47. Secor D, Li F, Ellis CG, et al. Impaired microvascular perfusion in sepsis
requires activated coagulation and P-selectin-mediated platelet adhesion in
capillaries. Intensive Care Med 2010; 36:1928–1934.
48. Balestra GM, Legrand M, Ince C. Microcirculation and mitochondria in
sepsis: getting out of breath. Curr Opin Anaesthesiol 2009; 22:184–
190.
49. Brealey D, Brand M, Hargreaves I, et al. Association between mitochondrial
dysfunction and severity and outcome of septic shock. Lancet 2002;
360:219–223.
50. Azevedo LC. Mitochondrial dysfunction during sepsis. Endocrine Metab
Immune Disord Drug Targets 2010; 10:214–223.
51. Haden DW, Suliman HB, Carraway MS, et al. Mitochondrial biogenesis
restores oxidative metabolism during Staphylococcus aureus sepsis. Am J
Respir Crit Care Med 2007; 176:768–777.
52. Rich MM, Pinter MJ, Kraner SD, Barchi RL. Loss of electrical excitability in an
animal model of acute quadriplegic myopathy. Ann Neurol 1998; 43:171–
179.
53. Khan J, Harrison TB, Rich MM. Mechanisms of neuromuscular dysfunction in
critical illness. Crit Care Clin 2008; 24:165–177.
54. De Jonghe B, Sharshar T, Lefaucheur JP, et al. Paresis acquired in the
intensive care unit: a prospective multicenter study. J Am Med Assoc
2002; 288:2859–2867.
55. Ali NA, O’Brien JM Jr, Hoffmann SP, et al. Acquired weakness, handgrip
strength, and mortality in critically ill patients. Am J Respir Crit Care Med
2008; 178:261–268.
56. Hermans G, Clerckx B, Vanhullebusch T, et al. Interobserver agreement of
Medical Research Council sum-score and handgrip strength in the intensive
care unit. Muscle Nerve 2012; 45:18–25.
57. Hough CL, Lieu BK, Caldwell ES. Manual muscle strength testing of
&& critically ill patients: feasibility and interobserver agreement. Crit Care
2011; 15:R43.
In the everyday ICU practice, manual muscle strength testing was feasible in only a
small fraction of patients. Coma, delirium, or limb injury precluded careful
examination in many patients.
58. De Jonghe B, Bastuji-Garin S, Sharshar T, et al. Does ICU-acquired paresis
lengthen weaning from mechanical ventilation? Intensive Care Med 2004;
30:1117–1121.
59. Garnacho-Montero J, Amaya-Villar R, Garcia-Garmendia JL, et al. Effect of
critical illness polyneuropathy on the withdrawal from mechanical ventilation
and the length of stay in septic patients. Crit Care Med 2005; 33:349–
354.
60. Guarneri B, Bertolini G, Latronico N. Long-term outcome in patients with
critical illness myopathy or neuropathy: the Italian multicentre CRIMYNE
study. J Neurol Neurosurg Psychiatry 2008; 79:838–841.
622 www.co-rheumatology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
61. Bierbrauer J, Koch S, Olbricht C, et al. Early type II fiber atrophy in intensive
&& care unit patients with nonexcitable muscle membrane. Critical care medicine
2012; 40:647–650.
Conventional nerve conduction study together with direct muscle stimulation and
muscle biopsy at an early ICU stage revealed that reduced or absent electrical
muscle excitability is frequently associated with type II fiber atrophy, but not
selective myosin depletion.
62. Stibler H, Edstrom L, Ahlbeck K, et al. Electrophoretic determination of the
myosin/actin ratio in the diagnosis of critical illness myopathy. Intensive Care
Med 2003; 29:1515–1527.
63. Needham DM, Davidson J, Cohen H, et al. Improving long-term outcomes
&& after discharge from intensive care unit: report from a stakeholders’ con-
ference. Critical Care Med 2012; 40:502–509.
The term postintensive care syndrome is proposed to describe new or worsening
impairments in physical, cognitive, or mental health status arising after critical
illness and persisting beyond acute care hospitalization either in survivors of critical
illness or family members.
64. Herridge MS, Tansey CM, Matte A, et al. Functional disability 5 years after
&& acute respiratory distress syndrome. N Engl J Med 2011; 364:1293–1304.
Survivors of acute respiratory distress syndrome may suffer from severe physical
limitation years after ICU discharge despite resolution of lung injury.
65. Angel MJ, Bril V, Shannon P, Herridge MS. Neuromuscular function in
survivors of the acute respiratory distress syndrome. Can J Neurol Sci
2007; 34:427–432.
66. Orford NR, Saunders K, Merriman E, et al. Skeletal morbidity among survivors
of critical illness. Crit Care Med 2011; 39:1295–1300.
67. Latronico N, Shehu I, Seghelini E. Neuromuscular sequelae of critical illness.
Curr Opin Crit Care 2005; 11:381–390.
68. Lacomis D, Petrella JT, Giuliani MJ. Causes of neuromuscular weakness in
the intensive care unit: a study of ninety-two patients. Muscle Nerve 1998;
21:610–617.
69. Intiso D, Amoruso L, Zarrelli M, et al. Long-term functional outcome and health
status of patients with critical illness polyneuromyopathy. Acta Neurol Scand
2011; 123:211–219.
70. Fletcher SN, Kennedy DD, Ghosh IR, et al. Persistent neuromuscular and
neurophysiologic abnormalities in long-term survivors of prolonged critical
illness. Crit Care Med 2003; 31:1012–1016.
71. Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional glucose
control in critically ill patients. N Engl J Med 2009; 360:1283–1297.
72. Routsi C, Gerovasili V, Vasileiadis I, et al. Electrical muscle stimulation
prevents critical illness polyneuromyopathy: a randomized parallel intervention
trial. Crit Care 2010; 14:R74.
73. Poulsen JB, Moller K, Jensen CV, et al. Effect of transcutaneous electrical
muscle stimulation on muscle volume in patients with septic shock. Crit Care
Med 2011; 39:456–461.
74. Schweickert WD, Pohlman MC, Pohlman AS, et al. Early physical and
occupational therapy in mechanically ventilated, critically ill patients: a ran-
domised controlled trial. Lancet 2009; 373:1874–1882.
75. Frick CG, Helming M, Martyn JA, et al. Continuous administration of
pyridostigmine improves immobilization-induced neuromuscular weakness.
Crit Care Med 2010; 38:922–927.
Volume 24  Number 6  November 2012