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1 Acute Skeletal Muscle Wasting During Critical Illness 13
speed, any stop during the walking, oxygen saturation, heart rate, dyspnoea, and
fatigue levels. The 6MWD measures muscle functional capacity and correlates
with health-related quality of life. Even more, the 6MWD can be used to evaluate
possible changes in patient performance over time, with a possible role in followup [
46]. It represents a volitional method; consequently, it requires patient
cooperation.
• Five-times sit to stand test (5xSTS): the test evaluates the time needed for
performing five repetitions of sit to stand with the arms folded across the chest.
5xSTS evaluates the lower limb muscle strength, balance, and fall risk. As for
6MWD, it requires patient cooperation.
• Battery outcome measurement form for the evaluation of health-related quality of
life (especially useful for patients not able to perform the 6MWD/5xSTS). These
evaluation forms represent useful predictive tools for the evaluation of a possible
disability, to evaluate dependence and independence ad for the monitoring of
physical performance status and autonomy. Possible examples of the performance battery include but it is not limited to the following: the scored physical
function in intensive care Test (PFIT), Short performance physical battery
(SPPB), Functional Status Score for the ICU, Chelsea Critical Care Physical
Assessment Tool, Clinical frailty scale (CFS). A deeper description of these
scores is outside the scope of this chapter.
Conclusions
Acute skeletal muscle wasting commonly occurs in critically ill patients after sepsis,
prolonged mechanical ventilation, and immobility; this condition has repeatedly
been shown to have an important impact on long-term outcome and mortality.
Acute skeletal muscle wasting is characterized by muscle protein breakdown
exceeding protein synthesis, due to the activation of the four main proteolytic
systems and consequent metabolic reprogramming. Nutritional support and rehabilitation represent two main strategies for prevention and treatment of ICU-AW, as
well as avoidance of some risk factors. Additionally, a deeper understanding of the
mechanisms implied in muscle wasting would be useful to potentially individuate
novel therapeutic targets.
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Chapter 2
Endocrine Aspects of Acute and Prolonged
Critical Illness
Maria Giuseppina Annetta
Introduction
Critical illness (such as trauma, burns, and major surgery) is characterized by an
evolving series of modifications involving the autonomic nervous system, the
endocrine system, the immune system (both cellular and humor al), the inflammatory
response, and the coagulation pathway. The purpose of this chain of events, also
defined as the “stress response,” is to maintain body homeostasis and promote
survival in the acute phase of critical illness. The magnitude of this response is
proportional to the severity of the acute illness, and it may change during the
evolution of the illness itself. The development of modern treatments in the intensive
care unit—mechanical ventilation, renal repla cement, inotropic and antibiotic
therapies—has certainly improved the chances of survival, leading to a prolonged
or “chronic” phase of critical illness. The exact time of the transition from the acute
to the chronic phase cannot be established, but it is probably around 10 days of
illness. This prolonged phase is characterized by speci fic neuroendocrine alterations,
which are no longer aimed at the survival of the patient.
The alterations in the function of the mitochondrial respiratory chain associated
with hypoxia and hypoperfusion, especially in the acute phase, have been more
recently investigated. Such mitochondrial dysfunction is associated with a sort of
metabolic and bioene rgetic hibernation of the cell, a phenomenon that may also have
an adaptive and protective purpose, with the aim of preventing deterioration and cell
death in the acute phase of critical illness. The fact that mitochondria at this stage are
not capable of utilizing substrate s for energetic purposes could explain why
Supplementary Information The online version contains supplementary material available at
https://doi.org/10.1007/978-3-031-66541-7_2.
M. G. Annetta (
Department of Anesthesia and Intensive Care, Fondazione Universitaria Policlinico Gemelli,
Rome, Italy
© The
A. Cotoia et al. (eds.), Nutrition, Metabolism and Kidney Support,
https://doi.org/10.1007/978-3-031-66541-7_2
✉)
Author(s), under exclusive license to Springer Nature Switzerland AG 2024
17
18 M. G. Annetta
aggressive nutrition in the early hyperacute phase of critical illness may be detrimental, increasing oxidative stress and worsening the clinical outcome.
The Neuroendocrine Response
Any life-threatening critical event (such as major surgery, trauma, septic shock,
burns, or severe acute respiratory failure) triggers a series of chain reactions aimed at
ensuring the survival of the organism. The concept of “homeostasis” was first
introduced by Cannon (1871–1945), who defined it as an ideal steady state of the
organism, maintained through minimal changes in various physiological components as external conditions change [
The inability to maintain this steady state would be responsible for the disease
state. Cannon himself, at the beginning of the twentieth century, described the fightand-flight reaction as a physiological response to a dangerous situation for the body.
It is characterized by increased blood supply to the brain, heart, lungs, and skeletal
muscles, with a concomitant reduction in blood flow to less essential organs such as
the gastroenteric system [2]. Increased alertness, heightened sweating to lower body
temperature, dilation of the pupillary diameter, and so on were described as essential
parts of the response to a stressful event, preparing the organism for fight or flight.
David Cuthbertson (1900–1989) provided an even more detailed description of
the pathophysiological response to a traumatic event, differentiating two phases: the
“ebb” and the “flow” phase [3]. The ebb (shock) phase begins immediately after the
traumatic event, lasting approximately 24–48 h. It is characterized by hemodynamic
instability and hormonal alterations that yield a reduction in metabolic response.
This results in decreased oxygen consumption, increased plasma glucose concentration, peripheral insulin resistance, sodium retention, and tissue edema due to
increased vascular permeability. These alterations aim to maintain the transport of
energy substrates to vital organs, necessary for the survival of the organism, through
increased endogenous glucose production and reduced energy expenditure.
The n
48 h, lasts about 3–10 days, and is characterized by increased nitrogen catabolism
with muscle proteolysis (mainly at the expense of skeletal muscle). There is also
increased gluconeogenesis from free amino acids and fatty acids to provide the
energy substrates needed for the fight-or-flight response. Additionally, there is
increased synthesis of acute-phase proteins and substrates required for favoring
wound healing and minimizing the risk of bleeding and infection. This “flow”
phase ends with the beginning of the healing process and the progressive restoration
of tissue stores. This signifies the transition into an anabolic phase with the
re-synthesis of lost muscle tissue. In a small percentage of patients, the anabolic
phase never occurs, and the patients remain in a chronic catabolic phase, sometimes
called “chronic critical illness” [4–6].
Currently, it is not possible to precisely identify the time or indicators (either
biochemical or physiological) that may signal the transition from one phase to
hase, referred to as the flow (post-shock) phase, begins after the first
ext p
1].
2 Endocrine Aspects of Acute and Prolonged Critical Illness 19
another. International experts typically refer to the chronic phase as occurring after
the first 10 days of critical illness [7, 8]. Depending on the criteria adopted, 5–30% of
patients admitted to the ICU will enter the chronic phase of illness. The European
Society of Parenteral and Enteral Nutrition (ESPEN 2019) describes these phases as
follows: early acute phase (first 1–2 days after the acute event), late acute phase
(approximately day 3 to day 7 of intensive care), and anabolic recovery phase (after
9]
day 7) [
.
Pathophysiology of Stress Response
The sympathetic nervous system originates in the brain system from nuclei in the
locus coeruleus (LC) and uses norepinephrine as its main neurotransmitter. From the
LC, through the intermedia-lateral columns of the spinal cord, neurons send
pre-ganglionic fibers to the paraspinal ganglia from which post-ganglionic fibers
depart, representing the sympathetic nerve fibers that reach the heart, blood vessels,
lungs, intestines, kidneys, and other organs. These nerves release norepinephrine at
the level of the end organs. Other preganglionic fibers innervate the adrenal medulla
and regulate the release of adrenaline into the bloodstream [10, 11].
Follow
and paraventricular nucleus, resulting in increased secretion of norepinephrine,
5-hydroxytryptamine (serotonin), corticotropin-releasing hormone (CRH), and
dopamine.
Activation
onds after the acute stressful event and is mediated by the release of catecholamines
by sympathetic nerves and the adrenal medulla, enhanced by the inhibition of
parasympathetic system activity. The immediate activation of the medullary
sympathetic-adrenergic system results in the so-cal led fight-and-flight reaction,
with its characteristic psychological and behavioral reactions and typical pathophysiological alterations (tachycardia, increased arterial pressure, tachypnea, fear,
increased vigilance, motor activation with tremor, hair erection). The effector hormones of such alterations are mainly the catecholamines released from the adrenal
medulla, which act on specific cell receptors widely distributed throughout the body
[
12, 13],
flow to “noble” organs such as the brain, with simultaneous reduction of blood flow
to less essential organs such as the intestines. This sympathetic-adrenergic response
is extremely rapid and intersects with the activation of other systems involved in the
stress reaction, such as the hormonal and cytokine systems.
n acute stressful event, there is central activation at the level of the LC
ing a
of the sympathetic-adrenergic nervous system occurs within millisec-
inducing glycolysis, activating the immune system, and increasing blood
20 M. G. Annetta
The Hypothalamus-Pituitary-Adrenal (HPA) Axis
The hypothalamus-pituitary axis plays a central role in the endocrine regulation of
metabolic homeostasis. Critical illness is characterized by significant alterations in
the neuroendocrine system, leading to the release of several pituitary hormones—
adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), growth
hormone (GH), follicle-stimulating hormone (FSH), and luteinizing hormone
(LH)—along with the loss of the feedback-type control mechanism that characterizes the system under normal conditions. These alterations follow a predominantly
biphasic course, with a different neuroendocrine response in the various stages of
critical illness [14].
GH Axis
Within a few hours of the onset of critical illness, GH hormone secretion increases
markedly, leading to high peaks in blood concentrations— accompanied by high
levels between peaks—and an increased frequency of such peaks. Simu ltaneously,
the systemic inflammatory response, releasing pro-inflammatory cytokines, promotes the development of peripheral GH resistance. This results in the loss of
functional tissue GH receptors, low blood levels of transport proteins (GH binding
protein), low levels of the peripheral effector, insulin-like growth factor-1 (IGF-1),
and the respective transport proteins insulin-like growth factor binding protein-3
(IGFBP-3) and acid-labile subunit (ALS). Increased clearance of IGF-1 further
reduces its blood levels. Reduced cellular receptor expression and low blood levels
of IGF-1 contribute to the increase in blood levels of GH.
From a metabolic point of view, the lipolytic and insulin-antagonist effect of GH
results in the release of endogenous fatty acids and glucose, while the anabolic
effects of IGF-1 are inhibited. Increased circulating levels of free fatty acids, amino
acids, and glucose promote gluconeogenesis, while anabolism, a phenomenon
requiring high energy consumption, is absent in the acute phase of critical illness
[13–19].
chronic phase of critical illness , secretion of GH is blunted, and IGF-1,
In the
IGFBP-3, and ALS levels remain low. The hallmark of this phase is reduced
anabolism, with ongoing catabolism and a wasting syndrome. The reduced hypothalamic drive seems to be responsible for the endocrine alteration in the chronic
phase [7].
2 Endocrine Aspects of Acute and Prolonged Critical Illness 21
Pituitary-Thyroid Axis
The initial response of the thyroid axis involves an immediate and rapid decline in
circulating levels of the activ e effector hormone triiodothyronine (T3) and an
increase in levels of the inactive hormone reverse T3 (rT3). The reduction of active
thyroid hormone levels is fundamentally related to a failure of the conversion of
thyroxine (T4) to active T3 hormone due to reduced type 1 deiodinase (D1) activity.
The concomitant increase in type 3 deiodinase (D3) activity results in the conversion
of thyroxine (T4) to rT3 rather than T3. Thyroid Stimulating Hormone (TSH) and T4
are temporarily elevated but quickly return to normal values [20, 21]. The presence
of reduced T3 levels with normal TSH is often referred to as “low T3 syndrome” or
“non-thyroidal illness.” The severity of such a syndrome correlates with the severity
of critical illness, as the lowest T3 levels occur in the most severe patients with the
poorest prognosis [21].
The infla
of thyroid hormone transport proteins (thyroid-binding proteins), as well as the
inhibition of thyroid hormone binding, transport, and metabolism by free fatty
acids and bilirubin, all contribute to the low T3 syndrome. From a metabolic point
of view, in the acute phase of critical illness, the low T3 syndrome may have the
adaptive function of reducing energy expenditure to promote the survival of the
organism, also optimizing bactericidal activity through the increase of D3 activity in
the immune cells [7, 20–23]. In this phase, treatment with T3 is not indicated and
might even be dangerous. In the chronic phase of illness, TSH and T4 levels decline
while T3 levels remain low. Currently, it is not clear if treatment with T3 in this
phase could be beneficial. No randomized controlled trials (RCTs) are available on
this topic. Treatment with high doses of T4 and T3 might restore the serum levels of
these hormones but might further suppress TSH release [7].
mmatory respon
se with pro-inflammatory cytokine release, the reduction
Pituitary-Adrenal Axis
In response to an acute critical event or trauma, blood levels of cortisol increase,
likely stimulated by corticotrophin-releasing hormone (CRH) released by the hypothalamus and adrenocorticotropic hormone (ACTH, Corticotrophin) released by the
pituitary gland [24]. Inflammatory cytokines can also directly stimulate the production of cortisol, the number of cellular receptors for cortisol, as well as their affinity
for circulating cortisol [25]. A reduced concentration of albumin and corticosteroidbinding globulin results in an increase in the free plasma fraction of cortisol. The
increase in the plasma concentration of free cortisol is also secondary to the
suppression of hepatic metabolism of cortisol [26–2
The diurnal
of acute illness or immediately after trauma. From a teleological point of view, this
state of post-traumatic hypercorticosurrenalism is critical for the survival of the
variations in cortisol secretion also disappear during the acute phase
9].
22 M. G. Annetta
PROLONGED CRITICAL ILLNESS
ACTH
CORTISOL
and other
Hormones
Hypotalamus
CRH
Pituitary gland
Adrenal gland
Tar get C ell s
Negative
Feedback
1. Increase in abundance and affinity of
glucocorticoids receptors inhibits CRH and
ACTH release
2. Suppression of pulsatile ACTH secretion
3. Adrenal Atrophy
4. Lower cortisol levels
Fig. 2.1 Pituitary-adrenal axis. The regulation of the stress response is performed by the
hypothalamic-pituitary-adrenal (HPA) axis, which induces hormone cascades and feedback loops.
Along this axis, stress leads to the secretion of cortisol from the adrenal cortex. Cortisol activates
different metabolic pathways, including gluconeogenesis (the synthesis of glucose in the liver),
proteolysis (protein disassembly), and lipid metabolism. At the same time, cortisol weakens the
activity of the immune system. However, in the case of prolonged critical illness, the increase in the
abundance and affinity of glucocorticoid receptors inhibits the release of corticotropin-releasing
hormone (CRH) and adrenocorticotropic hormone (ACTH). This causes a suppression of pulsatile
ACTH secretion, adrenal atrophy, and lower cortisol levels
organism since it improves the hemodynamic state through a process of water
retention and enhanced sensitivity to vasopressors, provides energy through the
stimulation of gluconeogenesis, and protects against the effects of excessive inflammation [25–30]. In the prolonged phase of illness (more than 1 month after the initial
injury), cortisol levels decrease to normal, while ACTH remains low. It is still not
known if in this phase treatment with exogenous corticosteroids or CRH or ACTH
2.1)
might be beneficial (Fig.
.
Mitochondrial Dysfunction
Mitochondria are recognized as the powerhouse of the cell due to their role in energy
production, releasing adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS) of macronutrients (Krebs cycle).
During critical
be significantly impaired, leading to a reduced ability to utilize macronutrients for
energy. This results in decreas ed ATP synthesis and an increased generation of
reactive oxygen species (ROS) [31, 32].
illness, particularly in the acute phase, mitochondrial function may