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Chapter 1
Acute Skeletal Muscle Wasting During
Critical Illness
Etrusca Brogi, Michele Umbrello, Sergio Lassola, and Francesco Forfori
Introduction
In the last decades, awareness of the huge impact of skeletal muscle wasting on both
short-and long-term disability and outcome in critically ill patients has steadily
grown. In this group of patients, the concept of musculoskeletal monitoring and
health, prevention of locomotor disability, and particular care of the frailty and
vulnerable patients are increasingly becoming an important health-care objective
in the daily routine of ICU. Even more, acute skeletal muscle wasting during critical
illness does not only represent an important impairment of the quality of life but is
also responsible of a considerably increased mortality [1].
The CT scan and ultrasound evaluation of muscle mass (skeletal muscle area at
the third lumbar vertebral level with CT scan, or cross-sectional area and thickness of
the quadriceps muscle with ultrasound) have shown that muscle wasting begins
already in the first week of ICU stay and continues steadily during the hospitalization. It was estimated that critically ill patients lose about 2% of their muscle mass/
day, that almost half of the critically ill patients will develop ICU-Acquired
Supplementary Information The online version contains supplementary material available at
https://doi.org/10.1007/978-3-031-66541-7_1.
E. Brogi · F. Forfori
Department of
e-mail: francesco.forfori@unipi.it
M. Umbrello (
Department of Intensive Care and Anaesthesia, ASST Ovest Milanese, Ospedale Civile
di Legnano, Milan, Italy
e-mail: michele.umbrello@asst-ovestmi.it
S. Lassola
Anestesia e Rianimazione 1, Ospedale S. Chiara, Trento, Italy
e-mail: sergio.lassola@apss.tn.it
© The
A. Cotoia et al. (eds.), Nutrition, Metabolism and Kidney Support,
https://doi.org/10.1007/978-3-031-66541-7_1
Anaesthesia and Intensive Care, University of Pisa, Pisa, Italy
✉)
Author(s), under exclusive license to Springer Nature Switzerland AG 2024
3
4 E. Brogi et al.
weakness [1], and that patients with multi organ failure lose more muscle mass with
consequent functional impairment [2].
Muscle wasting and impaired musc
without neuropathy, and lead to reduced muscle size, structure, muscular tone,
strength, and muscle power with a consequent heterogeneous degree of motor
deficit. In 2014, the American Thoracic Society defined the intensive care acquired
weakness (ICU-AW) as “a syndrome of generalized limb weakness that develops
while the patient is critically ill and for which there is no alternative explanation
other than the critical illness itself” [
also affect respiratory and oropharyngeal muscles, with important consequences on
breathing and swallowing. Under the definition of ICU-AW, three major different
subsets of skeletal muscle disease can be found, namely critical illness
polyneuropathy (CIP), critical illness myopa thy (CIM), and critical illness
polyneuromyopathy (CIPNM) [4].
It is now clear that ICU-AW syndrome includes a complex and heter ogeneous
array of clinical phenotypes with divergent functional outcomes and variable recovery trajectories [5]. Rehabilitation plays a central role in the prevention and treatment
of ICU-AW. In case of low-resource setting, it will be vital to improve early
identification strategies of patients at higher risk of ICU-AW and promote early
rehabilitation allocation.
From a pathophysiological point of view, muscle wasting is the results of muscle
protein breakdown exceeding protein synthesis and of complex metabolic interactions; however, the detailed cellular mechanisms involved in muscle wasting are
only partly understood [6]. Future research should aim to a deeper understanding of
the mechanism implied in muscle wasting in order to potentially individuate novel
therapeutics targets.
In this chapter, we aimed to summarize the current understanding of the pathophysiology of acute skeletal muscle wasting, describe possible clinical manifestations and present long-term outcomes.
le contractility can be observed with or
3]. Noteworthy, skeletal muscle wasting can
Clinical Presentation of Muscular Weakness in the Critical Patients
ICU-AW typically includes the following subgroups: critical illness polyneuropathy
(CIP), critical illness myopathy (CIM), and critical illness polyneuromyopathy
(CIPNM) [ 4 ]. Even more, from a histological point of view, CIM can be further
classified in cachectic myopathy, thick filament myopathy, and necrotizing myopathy. Differential diagnosis between respective subtypes could be challenging and not
always feasible and it requires muscle biopsies and electrophysiological studies
7].
[
Indeed, it is still not clear whether CIP and CIM represent two medical entities
or not. In addition, diagnosis of ICU-AW and the corresponding phenotypes could
be challenged by the presence of several confounding factors: lack of patient
1 Acute Skeletal Muscle Wasting During Critical Illness 5
compliance, fluid shifts, unavailability of diagnostic tests and rapid progression of
the primary disease [8]. Eventually, different subtypes may coexist.
Additionally, respiratory function may also be impaired, due to the involvement
of the respiratory muscles. Even more, dysphagia and swallowing issues could
represent an
underestimated presentation of ICU-AW [9].
Critical Illness Polyneuropathy (CIP) and Critical Illness Myopathy (CIM)
In CIP, distal muscles are more commonly affected, whereas in CIM both distal and
proximal muscles may be interested [10–12]. CIP can also show sensory loss of
vibration, pain, and temperature. Reduced or absent deep tendon reflexes and
preservation of cranial nerve function may be observed in both CIP and CIM.
CIP electrophysiology and biopsy studies show:
• Preserved nerve conduction velocity and latency
• Normal compound muscle action potential with reduced amplitude
• Decreased sensory nerve action potential amplitude
• Normal excitability on direct muscle stimulation
• Distal axonal degeneration of sensory nerve fibers in nerve biopsy
• Denervation atrophy of type I and type II at muscle biopsy
CIM electrophysiology and biopsy studies show:
• Normal nerve conduction velocity
• Increased compound muscle action potential duration with reduced amplitude
• Normal sensory nerve action potential amplitude
• Reduced excitability on direct muscle stimulation
• Normal findings on nerve biopsy
• Myofi
ber atrophy, necros
is, fatty degeneration on muscle biopsy
Ventilator-Induced Diaphragmatic Dysfunction (VIDD)
VIDD can be described as a loss of force-generating diaphragmatic capacity with
consequent inspiratory muscle weakness. It represents a serious complication of
mechanical ventilation [13]. VIDD can be the major responsible of difficult to wean
and extubation failure in ICU patients. To make matter worse, contractile dysfunction can affect also additional respiratory muscles (i.e., intercostal muscles) with
severe respiratory consequences [14].
Ultrasound
for the early diagnosis of VIDD. Above all, the measurement of the diaphragmatic
thickening fraction during a respiratory cycle allows the evaluation of muscle
assessment of the diaphragm represents an important diagnostic tool
6 E. Brogi et al.
atrophy and can provide the clinician with an important aid about the probability of
weaning failure [16–18]. Other interesting diagnostic instruments are represented by
the use of oesophageal and gastric balloon catheters for the measurement of
transdiaphragmatic pressures and the invasive analysis of diaphragmatic electrical
activity and phrenic nerve conduction, both during spontaneous or assisted breathing
and under maximal phrenic nerve stimulation.
Dysphagia, Swallowing, and Effective Cough
Muscle weakness may also affect oropharyngeal and abdominal muscles with
consequent dysphagia, swallowing disorders, and difficulties in producing effective
cough [9]. Tracheal/pulmonary aspiration can be a frequent complications with
increased risk of pneumonia and prolong ICU stay [19]. Dysphagia due to atrophy
of swallowing-related muscles is often underestimated; however, it represents a
debilitating condition for the patient.
The Pathophysiology of Acute Skeletal Muscle Wasting
The pathophysiology of acute skeletal muscle wasting is partly understood. Organ
dysfunction, sepsis, burns, prolonged mechanical ventilation, immobility, and
administration of glucocorticoids represent all possible risk factors for bioenergetic
dysfunction, altered protein balance, and consequent muscle wasting [2, 5, 8].
Muscle w
an increased protein degradation. A direct correlation was observed between inflammatory mediator levels (e.g., tumor necrosis factors, C- reactive protein) and muscle
wasting [5]. Histological assessment of muscle specimens of intensive care patients,
in the acute phase, found a decrease in myocyte cross-sectional area with macrophagic infiltrates, cellular atrophy, and necrosis—a destructive myopathic process.
The degree of muscle atrophy seemed to be related to the disease severity. Additional findings include axonal degeneration and loss of myelinated fibers. In addition, data from biopsies demonstrated that muscle deteriorates not only
quantitatively but also qualitatively with a decrease in type II muscle fibers and
consequent reduction in muscle power [20]. Even more, studies observed an apparent increased loss of myosin in comparison to actin [2, 21, 22].
A huge
synthesis and proteolysis came from biochemical studies with the evaluation of
leucine incorporation, D5 phenylalanine, creatine kinase, and myoglobin levels
[
2]. IGF1-PI3K-Akt/PKB-mTOR pathway is a central signalling network for the
protein synthesis process. This pathway is upregulated by mechanical load, nutrition,
and growth factors. In ICU patients, immobility and altered nutritional support result
in a downregulation of this signalling network with subsequent reduced expression
ast
ing is characterized not only by reduced protein synthesis but also by
impact on the possible understanding of the imbalance between protein
1 Acute Skeletal Muscle Wasting During Critical Illness 7
Table 1.1 Effects of the main proteolytic systems on muscle protein breakdown
Muscle protein breakdown
Proteolytic
system Mechanism Effects
Ubiquitine (Ub)/
Proteasome sys-
tem (UPS)
Autophagy Chaperon mediated autophagy, lyso-
Calpain and
Caspace-3
Inflammatory factors (IL-6, IL-1,
TBF-alfa, ROS) and glucocorticoids
activates and upregulates gene transcription of proteins of the UPS;
E1 ubiquitin activating enzyme activates Ubiquitine;
Ubiquitin conjugating E2 enzyme
binds activated Ubiquitine;
Muscle specific E3 Ubiquitine ligase
attaches Ubiquitine to the muscle;
The protein bind to Ubiquitine is recognized and degraded by 26S
proteasome into peptides.
somal pathway of proteolysis, responsible of the degradation of cytosolic
protein during fasting;
Microautopaghy; non-selective lysosomal degradative process
Macroautophaghy; catabolic process,
cytoplasm is sequestrated in vesicles
(autophagosomes) and transported to
lysosomes for degradation process.
Cysteine proteases;
Activated by Calcium;
Increase during fasting;
Concentrated in the Z-disk;
Caspace-3 degrade endogenous
calpain inhibitor;
Calpain facilitate Caspace-3 activation;
Calpain degrades structural protein
(e.g., nebulin, titin)/Caspace-3
degrade actomyosin! E3 ligases to
Ubiquitine can bind the released actin
and myosin from sarcomeres.
Protein degradation control, release
of amino acids;
Regulates cellular processes (e.g.,
DNA repair, stress response and cell
proliferation);
Degrading defective cellular proteins;
Active ATP-dependent degradation
process within the catalytic core;
Ubiquitin does not cleave large
myofibril ! Calpain and Caspace-3
assists UPS by releasing
myofilaments.
Clearance of damaged proteins/
organelles;
Vacuolization of myofibers and
nuclei;
Accumulation of p62 and
ubiquitinated proteins;
Muscle atrophy;
Proteolysis.
Proteolysis;
Mediate degradation of the myofibrillar apparatus;
Digestion of individual myofibrillar
proteins;
Disassembly of the myofibril;
Myosin cleavage;
Initiation and regulation of cell
death;
Do not degrade α-actin, α-actinin;
Ubiquitin does not cleave large
myofibril ! Calpain and Caspace-3
assists UPS by releasing
myofilaments.
of the mRNA for myosin heavy chains at the translational level [23]. Even more,
inflammatory mediators and hypoxia (with consequent reduced ATP bioavailability)
contribute, through the mTOR pathway, to altered translation processes and reduced
protein synthesis, all leading to an impaired anabolic signalling network.
In critically ill patients, the proteolytic pathway predominantly involved during
muscle wastin
g is represented by the Ubiquitine (Ub)/proteasome system (UPS) [23]
(as shown in Table 1.1). This pathway is responsible for protein degradation control,
and it regulates cellular processes such as DNA repair, stress response, and cell
8 E. Brogi et al.
proliferation. During acute skeletal muscle wasting, ubiquitine-proteasome (UPP)
activity is increased. As a matter of fact, several proinflammatory stimuli can activate
the proteolytic pathway (e.g., TNF-α, IL-1, IL-6, ROS). Inflammatory cytokines can
increase UPP gene transcription and thus accelerating muscle catabolism. Important
Ub ligases implied in proteolytic process during muscle wasting are FoxO1, FoxO3,
atrogin-1, MuRF1 and 2, FBOX31, SMART, and TR
IM 32. mRNA expression and
protein levels of these ligases as well as proteasome activity is increased during
muscle wasting [
24]. In addition to ubiquitination/UPS, autophagy represents a
physiological process that eliminate unnecessary components through a lysosomedependent regulated mechanism [25]. Autophagy is upregulated by fasting, ROS,
inflammation, growth factors, and infection [
26]. However, regardless of their
central role in the protein degradation, novel therapeutic strategies that aim to inhibit
the proteolytic pathway failed to prevent muscle wasting in the critical ill patients
(e.g., Bortezomib) [
Another important m
27].
echanism implied in ICU-AW is represented by glucose
metabolism. Hyperglycemia is common in intensive care patients due to both
increased gluconeogenesis and peripheral insulin resistance [
6]. Glycogenolysis
and gluconeogenesis represent a physiological response pathw ay essential for glucose homeostasis in response to stress metabolism. These pathways allow a quick
release of glucose and supply glucose to the cells, especially those which depend on
glucose for their metabolism (i.e., the brain). During the catabolic phase of critical
illness, the consequent hyperglycemia due to glycogenolysis and gluconeogenesis
represents an adaptive response which aims to supply the reduced nutrient delivery;
however, increased levels of glucose can represent a hazardous effect on cells.
Insulin resistance represent the consequence of reduced glucose transporters
(GLUT4) expression in muscle cells and altered post-receptors insulin signalling
pathway. Significantly, the heart and the brain metabolism do not depend on these
mechanisms. Hyperglycemia is responsible for the activation of caspase 3, and the
ubiquitin–proteasomal degradation pathway, leading to muscle atrophy [
28]. Conse-
quently, hyperglycemia contributes to the activation of pathways involved in protein
degradation, then again leading to muscle atrophy. High glucose level also results in
increased production of reactive oxygen species, that in turn intensify the activation
of the proteolytic pathways. Hyperglycemia may induce axonal injury not only
through oxidative stress but also due to direct glucose cellular toxicity. In the
nervous system, fructose kinase is not expressed, and the consequent accumulation
of sorbitol and fructose can lead to an intracellular hyperosmotic state with cell
swelling and necrosis. Glucose levels also affect respiratory muscle function. Interestingly, several studies found that insulin therapy and tight glycemic control may
have important impact on respiratory weaning and hospital stay [29, 30].
Altered intracellular Ca
+2
homeostasis and channelopathy represent two other
central mechanisms that contribute to muscle weakness, with important consequences on fiber contractility and neuronal membrane excitability [15]. The consequent excitation-contraction uncoupling events are frequent in acute skeletal wasting
syndrome, with important impact on muscle function. Caspase and calpain are
cysteine protease with a central role in proteolysis and actin and myosin myofibril
1 Acute Skeletal Muscle Wasting During Critical Illness 9
Fasting
Immobility
NMBAs
Burns
Hyperglycemia
Sepsis
Glucocorticoids
Inadequate
Nutritional support
MOF
Sedation
Pancreatitis
UPS
Reduce Glucose transporter
Mitochondrial dysfunction
Altered intracellular Ca+2
Reduced ATP production
Insulin resistance
ROS
Caspain and Caspace -3
Channelopathy
Autophagy
Protein synthesis
Protein degradation
Muscle wasting
Fig. 1.1 Schematic representation of the possible mechanisms involved in the pathophysiology of
Acute Skeletal Muscle Wasting. NMBAs neuromuscular blocking agents, MOF multiple organ
failure, UPS ubiquitine/proteasome system, ATP adenosine triphosphate, ROS reactive oxygen
species
degradation. The disruption of myofilament structure leads to reduced contractility
and force generation. Caspase and calpain are activated by inflammatory cytokines
[31]. Since calpain is a calcium-dependent cysteine protease, the consequent altered
calcium balance can lead to an upregulation of calpain expression and subsequent
increase in proteolysis [32]. Intracellular calcium level is controlled by Ca
transporters, Ca
exchangers, and Ca
+2
channels, Na+ /Ca
+2
binding proteins. Altered receptors and ion channel function
+2
pumps exchangers, Na+ /K+ pumps
+2
voltage
can lead to abnormal calcium release from the cells and consequent activation of
protein degradation system. This mechanism seems particularly important in the
development of ventilator- induced diaphragm wasting [
15]. It was suggested that
the selective blockage of calpain activation can markedly reduce mechanical ventilation induced diaphragmatic atrophy and muscle contraction dysfunction [33]. An
overview of the effects of the main proteolytic systems on muscle protein breakdown
is shown in Fig. 1.1.
Risk Factors
Organ dysfunction, sepsis, systemic inflammatory response syndrome, altered neuroendocrine responses, prolonged mechanical ventilation, immobility, and malnutrition are all potentially responsible for the negative protein balance state with
consequent muscle wasting [8]. Even more, a growing body of evidence suggests
10 E. Brogi et al.
Minimizing administration
of neuromuscular blocking
agents
Avoiding early parenteral
nutrition
Rehabilitation
Prevent and treat
hyperosmolality
Fig. 1.2 Possible intervention strategies for the prevention and treatment of ICU-AW
Neuromuscular electrical
stimulation
Prevention and treatment of
ICU- AW
Glycemic control –
avoiding hyperglycemia
Minimizing administration of
corticosteroids
Minimizing sedation
Prevent and treat
electrolytes imbalance
Prevent and treat
Hypoalbuminaemia
Early mobilization
that patients that survive severe acute respiratory syndrome Coronavirus 2 (SARSCoV-2) are at increased risk of sarcopenia and acute muscle wasting [34, 35]. In
addition, several not modifiable risk factors are associated with increased risk of
muscle atrophy, such as female gender and older age. Contrarily, obesity seems to
represent an independent protective factor. Possible intervention strategies for the
prevention and treatment of ICU-AW are shown in Fig.
Comm
on
risk
factors:
1.2.
• Immobi
patient during the first week of ICU stay [
lity:
a
reduction
in force generating capacity is already evident in septic
36]. Mechanical load represents an
important positive regulator of protein synthesis. Unloading and muscle disuse
lead to a switch from type I to type II fibers and a reduction in the actine:myosin
ratio. Immobility is also associated with altered microcirculation and increased
vascular permeability. Rehabilitation and neuromuscular electrical stimulation
are increasingly being considered as potential therapeutic strategies in order to
reduce ICU-AW short- and long-term complications.
• Dose and duration of neuromuscular blocking agents (NMBAs) administration:
NMBAs could represent an imp ortant risk factor for ICU-AW through two main
mechanisms [37]. Longer exposition to NMBAs is responsible for prolonged
immobility and muscle disuse. Furthermore, the chronic exposure to NMBAs
upregulates ac etylcholine receptor expression at the neuromuscular junction with
increased absolute number of receptors. However, these receptors present a
different structure composition, which has been termed “juvenile receptors.”
Even more, SIRS can increase the sensitivity to the effects of NMBA. However,
a 2016 systematic review and meta-analysis found an only modest association
between NMBAs administration and acute musc le wasting in critically ill
patients [
38].
1 Acute Skeletal Muscle Wasting During Critical Illness 11
• Glucocorticoids are associated to skeletal muscles wasting via three main mechanisms. Corticosteroids can inactivate sodium channels with consequent altered
electrical muscle excitability. Furthermore, steroids may exert a direct catabolic
effect on skeletal muscle with consequent reduced protein synthesis, loss of
myosin filaments, and type II muscle fiber alterations. Eventually, corticosteroids
exert a direct effect on the synaptic muscle junction. The importance of reducing
the dosage and the duration of steroid therapy in critically ill patients is currently
widely recognized [30].
• Inadequate nutritional support: malnutrition is still very common in critically ill
patients, with a consequent, important impact on protein synthesis, muscle
atrophy, and loss of muscle mass [39]. Fasting increases protein breakdown.
The recent literature seems to suggest that avoiding early parenteral nutrition and
promoting early full feeding via the enteral route represents a cornerstone in
preventing ICU-AW. Even more, it is important to avoid aggressive early caloric
intake strategies, and to administer proteins with a stepwise approach so that the
nutritional targets are reached after the early, acute phase while providing a
balanced administration of vitamins and micronutrients ever since the first days
of ICU stay.
• Hyperglycemia is common during critical illness, and it results from both
increased hepatic glucose liberation and reduced peripheral muscular glucose
uptake (i.e., insulin resistance) [40]. As described above, hyperglycemia contributes to the activation of pathways involved in protein degradation. Even more,
glucose can have a direct cellular toxicity effect. Consequently, a strict maintenance of euglycemia and higher insulin levels likely have protective effects on
muscle mass and function [
• Other: hyperthyroidism, administration of aminoglycosides, electrolytes imbalance, hyperosmotic pressure, burns, dose and duration of sedation, dose and
duration of vasoactive drug administration, high lactate levels [41].
41].
Short-Term and Long-Term Outcome
Acute skeletal muscle wasting is characterized by a generalized bilateral weakness of
the lower limbs. Muscle weakness can also impair respiratory muscles with difficult
to wean from mechanical ventilation and higher extubation failure rates. Even more,
oropharyngeal, and abdominal muscles can also be affected, with important consequences on swallowing. Consequently, acute skeletal muscle wasting is associated
with higher risk of in-ICU mortality [1].
In addit
ion to ICU-AW, a condition called post-intensive care syndrome (PICS) is
indeed very common in critically ill patients after discharge. PICS involves both the
physical, the mental and the emotional aspects of patients, which persist after ICU
discharge. Neuromuscular weakness represents an aspect of this syndrome as well,
with sequelae that may include persistent general ized weakness, joint contractures,
poor mobility, falls, and disabilities in activities of daily living [
42, 43].
It is then
12 E. Brogi et al.
vital to individuate patients at major risk of developing PICS, in order to provide
adequate, post-discharge support services and refer patients to specific health-care
professionals (i.e., occupational therapist, physiatrist, physical therapist, psychologist, speech therapists).
Outcome Evaluation
It is important to distinguish between muscle strength
and muscle power. Muscle
strength represents the ability to generate a maximal force after one single contraction (force output), whereas muscle power refers to the force production generated
over a period of time. Muscle strength is important because it represents the ability to
exert force in order to overcome resistance and it is vital for the accomplishment of
several daily activities such as lifting weights, climbing stairs, and cycling. Muscle
power is related to strength and speed (work/time). The rate of force development
(explosive contraction) in the shortest period of time is essential to overcome
gravity, such as when standing up from a seated position (e.g., chair, toilet). In the
elderly and post-intensive care pati ents, muscle power declines earlier in comparison
to strength and it is related to a selective decrease in type II muscle fibers.
Possible tolls for muscle strength evaluation:
• Medical Research Council Sum Score (MRC-SS) for muscle strength is a scale
used for measuring global peripheral muscle strength and it represents the
standard of care for the diagnosis ICU-AW [44]. This scale ranges from
0 to 60, where 0 corresponds to complete paralysis and 60 to normal strength.
A score less than 48 implies a diagnosis of ICU-AW, while a score below
36 denotes a severe muscle weakness. This grading system at ICU discharge is
directly related with 5-year mortality [42].
• Dynamometry for hand grip and quadriceps strength measurement: this technique
provides a quantitative evaluation of muscle strength. Dynamometry allows the
evaluation of isometric muscle strength and of the rate of force development [45].
Possible tolls for muscle power evaluation:
• Potentiometer: it allows the evaluation of muscle power through the analysis of
the velocity and peak velocity (work/time) generated by a leg press during a
physical exercise. It represents a volitional method to assess muscle power,
requiring patient cooperation, as subjects have to perform three flexion using a
leg press.
Possible tolls for muscle function evaluation:
• Six-min walking distance test (6MWD): developed by the American Thoracic
Society, this test measures the aerobic muscle capacity and endurance. Initially
introduced to test cardiopulmonary disease, 6MWD can allow the evaluation of
several conditions such as fibromyalgia, arthritis, spinal cord injury, and muscle
disorders. Patients are asked to walk for 6 min, and the operator’s record walking