Skeletal muscle dysfunction in critical care: Wasting, weakness,

and rehabilitation strategies

Zudin Puthucheary, MRCP; Stephen Harridge, PhD; Nicholas Hart, PhD

Understanding the trajectory of skeletal muscle loss, evaluat-
ing its relationship to the subsequent functional impairment, and
understanding the underlying mechanisms of skeletal muscle
wasting will provide goals for novel treatment strategies in the
intensive care setting. A focused approach on the effect of critical
illness on muscle morphology, muscle protein turnover, and the
associated muscle-signaling pathways during the early and re-
covery stages of critical illness is required. This could potentially
lead to targeted pharmacologic and nonpharmacologic strategies
to treat, or even prevent, peripheral muscle wasting and weak-
ness. (Crit Care Med 2010; 38[Suppl.]:S676 –S682)
KEY WORDS: critical illness; muscle weakness; muscle protein
turnover; muscle-signaling pathways

I
ncreasing numbers of critically ill
patients are admitted to the inten-
sive care unit (ICU). Although ad-
vances in medical practice and
technology have resulted in improved
outcomes, these early survival rates are
poorly predictive of long-term health and
functional status. Following a critical ill-
ness, impaired health status is frequently
protracted. Long-term sequelae need to
be longitudinally evaluated through mea-
surements of self-reported, health-related
quality of life, exercise capacity, and other
detailed validated measurements of pe-
ripheral muscle performance. Experience
with acute respiratory distress syndrome
survivors reveals that exercise capacity,
assessed by using the 6-min walk test,
and health-related quality of life are
markedly reduced 1 yr after hospital dis-
charge (1). Furthermore, in an observa-
tional cohort of ⬎800 patients, more than
From the Lane Fox Respiratory Unit (ZP), Respira-
tory & Critical Care Medicine (NH), Guy’s and St
Thomas’ Foundation Trust and Kings College, London,
UK; Centre of Human & Aerospace Physiological Sci-
ences (SH), School of Biomedical and Health Sciences,
Kings College, London, UK; National Institute of Health
Research Comprehensive Biomedical Research Centre
(NH), London, UK.
Dr. Hart has received speaker’s fees from Phillips-
Respironics and Fisher-Paykel, and unrestricted re-
search grants from Phillips-Respironics, B&D Electro-
medical, Resmed, Fisher-Paykel, and Guy’s and St
Thomas Charity. The remaining authors have not dis-
closed any potential conflicts of interest.
For information regarding this article, E-mail:
nicholas.hart@gstt.nhs.uk
Copyright © 2010 by the Society of Critical Care
Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/CCM.0b013e3181f2458d
half of those discharged required some
form of caregiver assistance at 1 yr (2). A
study following neuromuscular abnormal-
ities in survivors up to 5 yrs after critical
illness showed ongoing disability and a
three-fold increase in mortality over this
period (3). The 114th World Health Orga-
nization executive board focused on human
disability in its broadest terms; so, in 2004,
it prompted its member states 1) to pro-
mote early intervention and identification
of disability and full physical, informa-
tional, and economic accessibility, includ-
ing rehabilitation services, in order to en-
sure full participation and equality of
persons with disabilities; and 2) to facilitate
access to appropriate assistive technologies
for rehabilitation. This is wholly relevant to
patients both during and after critical ill-
ness. Despite the overall paucity of data in
this field, this statement on healthcare plus
other data has highlighted the need for a
concerted effort to understand critical ill-
ness-acquired muscle weakness and how
rehabilitation may be optimized. Indeed,
recent guidelines in this regard have been
published by the United Kingdom National
Institute of Clinical Excellence (4). An up-
to-date PubMed search using the terms
“critical care” and “muscle weakness” re-
vealed only a total of 281 articles in this
area. However, 30% of these were pub-
lished in the last 3 years, highlighting the
limited previous data and an increasing in-
terest among the critical care community.
ICU-acquired weakness
Increasingly recognized, skeletal mus-
cle weakness can be commonplace in the
intensive care setting. ICU-acquired
weakness (ICU-AW) is defined as bilateral
symmetrical limb weakness and has been
reported, at the time of wakening, in 50%
of patients mechanically ventilated for
⬎7 days, and in 25% of patients 7 days
later (5). This acquired muscle weakness
may be due to an axonal polyneuropathy
(critical illness polyneuropathy), myop-
athy (critical illness myopathy), or, more
frequently, a combination of both (criti-
cal illness neuromyopathy) (6 – 8). Disuse
atrophy occurs in the limb muscles of
many ICU survivors, and it is not surpris-
ing that muscle wasting and weakness are
frequent complaints (9) with evidence of
critical illness polyneuropathy, critical
illness myopathy, and critical illness neu-
romyopathy persisting months to years
after hospitalization (10 –13). Depending
on whether clinical, electrophysiologic,
or histologic diagnostic criteria are met,
the prevalence of critical illness neuro-
myopathy ranges from 25% to 100% (6 –
8). As regards to clinical outcome,
ICU-AW and reduction in limb muscle
strength are associated with respiratory
muscle weakness and delayed weaning
from mechanical ventilation (14). The
main risk factors for developing ICU-AW
are severity and duration of systemic in-
flammatory response, length of ICU stay,
and duration of mechanical ventilation.
Other factors implicated are hyperglyce-
mia, hypoalbuminemia, parenteral nutri-
tion, corticosteroid administration, and
neuromuscular-blocking agents. Inter-
estingly, renal replacement therapy ap-
pears to be protective (5, 15). As expected,
in addition to the impact of muscle weak-
ness on weaning, and ICU, hospital stay,

S676 Crit Care Med 2010 Vol. 38, No. 10 (Suppl.)

and healthcare costs (14, 16, 17), recent
studies have confirmed that both the
presence and severity of ICU-AW are in-
dependent risk factors for death (15, 18).
Identification and stratification
Immobilization, as occurs in all pa-
tients with critical illness, has been
shown to alter skeletal muscle morphol-
ogy (19), the proportion of slow and fast
muscle twitch fibers (20), contractility
(21–23), aerobic capacity (24), muscle
protein synthesis (23, 25), subsequent
physical activity (24), and the electrome-
chanical relationship of the nerve-muscle
interface (26). All of these factors contrib-
ute to decreased muscle strength, power,
and fatigue resistance. However, in addi-
tion to immobilization, other frequently
encountered factors such as systemic
inflammation in critically ill patients
compound this loss of muscle mass and
function (5, 15). Identification and strat-
ification of the patients at risk of devel-
oping ICU-AW, with significant associ-
ated long-term functional impairment,
must be a priority of critical care physi-
cians. Patients who may benefit from
critical care rehabilitation and other po-
tential management strategies must be
identified, particularly as combined seda-
tion holds and whole-body rehabilitation
have been demonstrated to be safe and
efficacious in the early stages of critical
illness (27). This is important because the
patient population has marked heteroge-
neity. Resources need to be focused on
these at-risk patients, identified at the
earliest possible stage. However, patients
are often immobile, especially during the
early part of their admission, due to their
life-threatening illness and the sedatives
and opiates administered. This hinders
the volitional assessment of their periph-
eral muscles as such patients are unable
to cooperate with the physical examina-
tion. Fortunately, there are a number of
nonvolitional neurophysiologic and mus-
cle strength assessments that can be un-
dertaken by using such techniques as
electrical (10, 12) and magnetic (28 –30)
stimulation of peripheral nerves. These
have provided detailed physiologic data
demonstrating reductions in peripheral
and respiratory muscle strength (30 –33).
It should be appreciated that these are
primarily research tools and probably
have limited widespread clinical utility,
in part due to the need for experienced
staff and expensive equipment to perform
these tests; clinical outcome data are
Crit Care Med 2010 Vol. 38, No. 10 (Suppl.)
therefore limited (12). Other measure-
ments have been proposed, such as man-
ual muscle testing and hand grip
strength, which are easier to perform, but
such volitional tests are difficult to inter-
pret, especially if a borderline result is
obtained, as this could indicate weakness,
poor motivation, or inability to complete
the task (5, 18). These limitations make
manual muscle strength testing either
unreliable or impractical, in particular,
during the early stages of critical illness
or in patients with an impaired cognitive
state.
As strength measurements are not al-
ways feasible for assessing the severity of
muscle weakness, attention has more re-
cently focused on muscle wasting. This is
a valid, rational approach, as a linear re-
lationship is present between quadriceps
muscle strength and rectus femoris
cross-sectional area (34, 35) and fat-free
mass, which is an indicator of whole-body
muscle mass (36). Furthermore, ultra-
sound measurements of the rectus femo-
ris muscle are sensitive enough to track Figure 1. a, Ultrasound measurement of rectus
changes in muscle layer thickness (37, femoris cross-sectional area. b, Mean ⫾ SEM rec-
tus femoris cross-sectional area (solid line) vs.
38) and cross-sectional area, indicative of thigh circumference (dashed line) as percentage
muscle wasting during immobilization of baseline (day 1) value. (Adapted from reference
(39 – 43), despite the presence of fluid re- 34.) #Significant (p ⬍ .05) change from day 1.
tention and edema observed in critically RFCSA, rectus femoris cross-sectional area; ICU,
ill patients (36, 44). We are therefore cur- intensive care unit.
rently investigating this relatively novel
application of ultrasound (34, 45), which
is simple, portable, and now widely avail- flammation as likely causative factors
able in the ICU, to measure the quadri- (47). While these are rational explana-
ceps rectus femoris cross-sectional area tions, our current knowledge of fiber-
(34) (Fig. 1). Whereas this has the poten- type morphology, changes in fiber-type
tial to be a clinically useful tool, the abil- morphology (Figs. 2 and 3), muscle atro-
ity of ultrasound to sequentially measure phy– hypertrophy-signaling pathways,
cross-sectional area to quantify muscle and muscle protein synthesis and prote-
loss and predict functional outcome re- olysis pathways are mainly based on data
mains as yet unproven. Nevertheless, if from healthy humans and animals. It is
validated, the early identification of those important to highlight differences be-
patients with low muscle mass and those tween animal models and humans and, in
with significant loss of muscle mass early particular, that the rate of protein turn-
in their critical illness will allow the over in small mammals, such as rats, is
stratification of patients to target thera- 2.5-fold greater than in humans (48). In
pies to those most likely to benefit. addition, human data have shown a dis-
sociation between actual protein turn-
Mechanisms contributing to over and alterations in signaling path-
ICU-AW ways purported to control protein
synthesis and breakdown (25, 49, 50).
Although important, muscle inexcit- Furthermore, the loss of muscle mass
ability as a cause of a loss of muscle and the fall in protein synthesis observed
performance in critically ill patients will with immobilization are not accompa-
not be addressed; data addressing this nied by an increase in proteolytic enzyme
issue can be found elsewhere (46). In gene expression (51). Although there are
critically ill patients, observational data data in healthy subjects with limb immo-
identify risk factors associated with mus- bilization to show that the balance be-
cle weakness with immobility, disuse- tween muscle protein breakdown (MPB)
related muscle atrophy, and systemic in- and muscle protein synthesis (MPS) is
S677

Figure 2. Twenty-four-year-old woman with
septic shock and multiorgan failure. Hematoxy-
lin-and-eosin stains of serial vastus lateralis bi-
opsy samples. Day 1 demonstrated normal mus-
cle morphology, with day 7 showing fiber
atrophy, muscle necrosis, and inflammatory cel-
lular infiltrate. (Used with permission from the
Musculoskeletal Ultrasound Study in Critical
Care: Longitudinal Evaluation [MUSCLE] study.)
Figure 3. Twenty-four-year-old man with poly-
trauma. Adenosine triphosphatase stain at pH 9.4
showing type 1 (light) and type 2 (dark) fibers.
From day 1 to day 7, there was a 43% mean
reduction in type 1 fiber cross-sectional area and
a 5% mean reduction in type 2 fiber cross-
sectional area. (Used with permission from the
Musculoskeletal Ultrasound Study in Critical
Care: Longitudinal Evaluation [MUSCLE] study.)
S678
altered mainly by a fall in MPS (23, 52),
there are no data in critically ill patients
to define muscle loss as a consequence of
either impaired MPS, accelerated MPB, or
both. MPS blunting has been reported to
occur and been termed anabolic resis-
tance (48, 52–54). The mechanisms dem-
onstrated to promote these processes are
many of the factors encountered in crit-
ically ill patients. In particular, these in-
clude loss of muscle mass with immobi-
lization (23, 25), reduced MPS response
to excess dietary amino acid loading (55,
56), and insulin inhibition of MPB with
no effect on MPS (56). Indeed, this may in
part add validity to the observation that
intensive insulin therapy to control hy-
perglycemia has an association with a re-
duction in critical illness-related neuro-
muscular complications (57). It can be
postulated that this may be an effect of
increased insulin levels facilitating inhi-
bition of MPB, which is already blunted
in the elderly, rather than any effect me-
diated by controlling serum glucose lev-
els, although this needs to be studied
further. In addition to the paucity of data
defining the relative roles of MPS and
MPB in critical illness, the time course of
normalization during recovery and reha-
bilitation is unknown. However, there are
data to suggest that, following acute ill-
ness, there is a preference to increase fat
mass rather than fat-free muscle mass (1,
58, 59). This would suggest that there is a
fundamental modification in body com-
position after critical illness that stimu-
lates MPB and/or inhibits MPS. It is clear
from the data generated from non-
critically ill patients and from healthy
subjects that aging, exercise, immobiliza-
Figure 4. Muscle atrophy– hypertrophy-signaling pathways downstream of insulin-like growth fac-
tor-1 (IGF-1). PI3K, phosphoinositide 3-kinase; mTOR, mammalian target of rapamycin; foxO, fork-
head transcription factors; PGC-1␣, peroxisome proliferator-activated receptor-␦ coactivator 1␣.
tion, response to dietary amino acids, and
insulin play important roles in muscle
protein turnover, with stress and inflam-
mation increasing MPB (60). However,
we need more data from critically ill pa-
tients.
In addition to the balance between
MPS and MPB, we must also consider the
atrophy– hypertrophy-signaling path-
ways, which should have an association
with muscle protein turnover although,
as mentioned previously, this is a contro-
versial area (49, 50). In health, the atro-
phic signals are balanced by hypertrophic
signals, but the relative roles of each of
these processes in critical illness are
poorly understood (49, 50). MPB in both
systemic disease and disuse is regulated
by muscle-specific ubiquitin ligases or
atrogenes (61, 62), with accelerated ca-
tabolism observed in patients with sys-
temic inflammation and immobilization
(63– 67). The main atrogenes (Fig. 4),
atrogin-1, also known as muscle atrophy
F-box protein (MAFbx) and muscle ring-
finger-1 (MuRF-1), are dependent on the
activity of forkhead (FoxO) transcription
factors (68, 69). These atrogenes are ren-
dered inactive by phosphorylation of
AKT, a downstream target of insulin-like
growth factor 1 (IGF-1) and insulin,
which inhibits the dephosphorylation of
forkhead (Fig. 3). Thus, IGF-1 can block
transcriptional up-regulation of atro-
genes. A further requirement for the re-
habilitation of muscle is fatigue resis-
tance, which is linked to a muscle
oxidative activity. PGC-1␣ (peroxisome
proliferator-activated receptor-␦ coacti-
vator 1␣) is the master regulator of mi-
tochondrial biogenesis (68), which is in-
Crit Care Med 2010 Vol. 38, No. 10 (Suppl.)

Figure 5. Muscle atrophy F-box in samples from
day 1 and day 7. Data are normalized to ␣-tubulin
protein expression. (Used with permission from
the Musculoskeletal Ultrasound Study in Critical
Care: Longitudinal Evaluation [MUSCLE] study.)
duced by exercise. This also has an
inhibitory effect on forkhead dephosphor-
ylation and highlights the complex inter-
action between different signaling path-
ways. The extent to which this complex
regulation of signaling pathways is al-
tered in the muscles of critically ill pa-
tients remains to be determined (50, 66,
70). Preliminary data are becoming avail-
able; Figure 5 shows the down-regulation
of muscle atrophy F-box protein in the
quadriceps muscle in a patient following
a 7-day stay in an ICU.
Strategies to treat and prevent
muscle loss
Pharmacologic Strategies. Progress in
the understanding of the muscle-signal-
ing pathways that mediate skeletal mus-
cle hypertrophy and atrophy allows scien-
tists to generate hypotheses to facilitate
drug design and discovery. A rational ap-
proach would be to develop drugs that
either inhibit MPB pathways during skel-
etal muscle atrophy, or stimulate MPS
pathways during hypertrophy, to develop
antiatrophy or prohypertrophy drugs
(Fig. 4). A simple approach for an antiat-
rophy drug would be to inhibit the ubiq-
uitin proteosome pathways by using pro-
teosome inhibitors, which would reduce
the rate of proteolysis and atrophy in
skeletal muscle (71). However, blocking
these pathways could have a systemic ef-
fect on other tissues. This has led to an
approach to inhibit the enzymatic activity
Crit Care Med 2010 Vol. 38, No. 10 (Suppl.)
of muscle-specific MURF-1 and atrogin-1.
These ubiquitin ligases, which are the
proteins that bind and mediate ubiquiti-
nation, promote skeletal muscle atrophy
and therefore are potential targets for
drug therapy. An alternative approach
would be to develop a prohypertrophy
drug, such as IGF-1. IGF-1 infused di-
rectly into the tibialis anterior muscles of
mice produced muscle hypertrophy (72).
However, in contrast to increased local
IGF-1 expression resulting from muscle
overload (73), increasing circulating
IGF-1, through growth hormone admin-
istration, has not resulted in increased
MPS (74, 75). Finally, the IGF-1 receptor
is ubiquitous and could result in a sys-
temic effect rather than being limited to
skeletal muscle; therefore, targeting it for
drug therapy may not provide any bene-
fits to muscle protein turnover and mus-
cle mass. IGF-1 acts through the phos-
phoinositide 3-kinase (PI3K)/Akt/
mammalian target of rapamycin (mTOR)
pathway (76), a pathway that can be acti-
vated independent of IGF-1 (77). In ani-
mal studies, activation of phosphoinosi-
tide 3-kinase not only results in skeletal
muscle hypertrophy but also defends
against denervation-induced atrophy
(78), whereas an absence of Akt reduces
muscle mass and results in insulin resis-
tance (79), depending on which of the
three identifiable forms are lacking. How-
ever, human data show that resistance
training reduces Akt (80). In animal stud-
ies, activation of Akt and subsequent ac-
tivation of mammalian target of rapamy-
cin increases hypertrophy (77, 81),
whereas rapamycin inhibition of mTOR
inhibited hypertrophy (77). Although
these data provide understanding of the
signaling pathways in animal studies and
selected patient groups, they must be
confirmed in critically ill patients before
any clinical intervention trials that target
specific pathways are undertaken. It
would be reasonable to focus attention in
the first instance on the activity of
MURF-1 and atrogin-1 in the muscle of
critically ill patients, because these mus-
cle-specific ubiquitin ligases are essential
for muscle atrophy and are potentially
the best targets for an antiatrophy drug.
Another target for consideration is testos-
terone, used by athletes to improve mus-
cle size and performance. Clinical trials
have shown its efficacy in promoting
muscle mass (82), but its use as a thera-
peutic agent needs to be carefully evalu-
ated as it has both a prothrombotic and
carcinogenic effect. Similarly, although
growth hormone had been proposed as an
agent to modify the catabolic effects of
critical illness by modifying protein turn-
over and nitrogen balance, in a multina-
tional, randomized controlled trial it was
shown to increase mortality (83). Myosta-
tin, or growth factor differentiation factor
8, in contrast to IGF-1 and testosterone,
is a negative regulator of muscle mass
(84). Myostatin knockout animal models
exhibit a markedly hypertrophied pheno-
type; natural inhibitors of myostatin may
have therapeutic value (85). However, the
efficacy of such a treatment needs further
evaluation; although the animal data
have shown an increase in muscle size,
this hypertrophied muscle generates a
lower force per unit area, which is an
obvious weakness in any strategy to im-
prove long-term function.
Nonpharmacologic Strategies. As we
have described, there is compelling evi-
dence that ICU-AW exists, with strong
supporting evidence that aging, immobi-
lization, and altered response to dietary
amino acids, and insulin have significant
deleterious effects on skeletal muscle. In
an attempt to counteract critical illness
immobility, there has been a recent and
substantial focus on critical care rehabil-
itation, both during and following ICU
admission, and assessment of rehabilita-
tion in terms of functional outcomes in-
cluding health-related quality of life and
exercise capacity after ICU discharge (47,
86 –90). A multicenter randomized con-
trolled study has demonstrated the effi-
cacy of combined sedation holds and re-
habilitation in the early stages of critical
illness with improved functional outcome
at hospital discharge (27). More data are
emerging with a number of ongoing tri-
als; however, to date, there has been little
focus on the premorbid condition of the
patient that may exacerbate neuromuscu-
lar complications of critical illness. This
approach to ICU-AW has been driven, in
part, by the anabolic effects induced by
physical training and the enhanced exer-
cise performance observed in patients
with chronic respiratory and cardiac dis-
ease who have undergone rehabilitation
exercise programs (91, 92). However, the
common goal of rehabilitation is whole-
body exercise which, even with the ad-
vances in technology to allow ICU pa-
tients to mobilize while receiving
ventilator support (93, 94), is difficult to
deliver to all patients due to the resources
required. An alternative modality, using
neuromuscular electrical stimulation,
could be a useful additional peripheral
S679
muscle training and rehabilitation tool.
Neuromuscular electrical stimulation has
previously been demonstrated to amelio-
rate the fall in MPS in immobilized mus-
cle (95). This supports the finding from a
recent randomized controlled trial that
neuromuscular electrical stimulation at-
tenuates the decline in quadriceps mus-
cle mass in critically ill patients (96).
Furthermore, neuromuscular electrical
stimulation does not require active pa-
tient cooperation and has been shown to
have functional benefits with an increase
in exercise performance, skeletal muscle
performance, and health-related quality
of life (97–99) in patients with chronic
obstructive pulmonary disease. These
outcomes need to be evaluated in criti-
cally ill patients.
CONCLUSION
We consider the next challenge to be
the development of simple tools to iden-
tify patients early in the course of their
critical illness. A direct focus on the
pathophysiologic processes occurring
within the muscle, in particular muscle
morphology, protein turnover, and its re-
lationship to the muscle-signaling path-
ways, is required. With this approach, we
will be able not only to potentially target
particular pathways with antiatrophy or
prohypertrophy drugs but also to use
techniques such as neuromuscular stim-
ulation to train the quadriceps muscle in
both the early and recovery stages of crit-
ical illness. All of these interventions, in-
cluding studies of the effects of rehabili-
tation in patients with skeletal muscle
weakness during and after critical illness,
will need to be correlated with short- and
long-term functional and health-related
quality of life outcomes.
ACKNOWLEDGMENTS
We acknowledge Professor Michael
Rennie (University of Nottingham) for his
expert advice and guidance in this work,
Dr. Anthea Rowlerson for assistance in
processing the samples shown in Figures
2 and 3, and Chibeza Agley for the West-
ern blot data shown in Figure 5.
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