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Chapter 4
Critical Illness Polyneuropathy
and Myopathy
Nicola Nasuelli, Isabella Caterina Campini, Laura Godi,
and Davide Colombo
Introduction
Intensive care unit– acquired weakness (ICU-AW) is suspected in critically ill
patients who develop flaccid muscle weakness and cannot be weaned from the
ventilator despite the absence of pulmonary or cardiac causes of respiratory failure
[1]. It is the most common neuromuscular impairment occurring in the critical setting
affects the clinical course and outcomes of ICU patients [2]. The first cases were
and
extensively described in the early 1980s [3]. The classification of ICU-AW includes
severa
l conditions: Critical Illness Myopa thy (CIM), Critical Illness Polyneuropathy
(CIP), a combination of the two, or diaphragmatic weakness [2, 3]. CIM typically
manifests as symmetrical weakness affecting predominantly proximal limb muscles
and respiratory muscles, whereas cranial muscles are mostly spared. In CIP, there is
a loss of sensory function and deep tendon hyporeflexia. Diaphragmatic weakness is
suspected when weaning from ventilation fails, and it may be demonstrated by
esophageal pressure measurement or electrical activity of the diaphragm (EAdi).
Thorough clinical examination may detect ICU-AW, but often it is not possible in
an ICU setting due to a lack of cooperation by the patient and other confounding
factors such as limb edema (Fig. 4.1).
Supplementary Information The online version contains supplementary material available at
https://doi.org/10.1007/978-3-031-66541-7_4.
N. Nasuelli · I. C. Campini · L. Godi
Neurological Department, SS Trinità Hospital – ASL Novara, Borgomanero, Italy
e-mail: nicolaalessandro.nasuelli@asl.novara.it; isabellacaterina.campini@asl.novara.it;
laura.godi@asl.novara.it
D. Colombo (
Anesthesia and Intensive Care Department, SS Trinità Hospital – ASL Novara, Borgomanero,
Italy
e-mail: davide.colombo@med.uniupo.it
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
A.
Cotoia et al. (eds.), Nutrition, Metabolism and Kidney Support,
https://doi.org/10.1007/978-3-031-66541-7_4
✉)
43
44 N. Nasuelli et
Fig. 4.1 It reports a severe
ICU-AW secondary to
COVID infection. CIP and
CIM were both represented
as well as diaphragmatic
weakness leading to prolong
ventilation
al.
Epidemiology and Risk Factors
The main risk factors for ICU-AW include high severity of illness upon admission,
sepsis and its duration, multiple organ failure, prolonged immobilization, hyperglycemia, thyrotoxicosis, older age, and systemic inflammatory response syndrome
(SIRS) [4, 5]. The association of glucocorticoid exposure with ICU-AW is controversial. While it has been linked to ICU-AW in patients with sepsis, a protective
effect has been suggested in those with hyperglycemia [
cular blocking agents have been implicated in ICU-AW, but the evidence is primarily based on observational studies with high heterogeneity [6, 7]. ICU-AW is a
common finding in critical patients, with a prevalence of approximately 25% among
those undergoing prolonged mechanical ventilation [2, 8]. It has been also reported
after severe asthma, COPD, and liver transplant. Several clinical reports describe
ICU-AW in critical COVID-19 patients, where a precipitating role was postulated
9].
for cytokine storm and prone positioning [
ICU-AW due to COVID-19 appears to
have similar characteristics to ICU-AW caused by other factors, although early
evidence suggests a higher prevalence of Critical Illness Polyneuropathy (CIP) in
COVID-19 patients [6, 10]. An Italian prospective, multi-center study—the
“CRYMINE” study—provided insight into the epidemiology and risk factors of
ICU-AW. It involved 92 critical patients who underwent serial neurophysiological
examinations. A loss of 25% peroneal Compoun d Muscle Action Potential (CMAP)
amplitude was identified as the best predictor of weakness. The median interval from
ICU admission to ICU-AW was 6 days [
1].
6].
Additionally, neuromus-
4 Critical Illness Polyneuropathy and Myopathy 45
Diagnosis
A good and reliable diagnostic tool for ICU-AW in the awake patient is handgrip
dynamometry of the dominant hand, with a cut-off of less than 11 kg for males and
less than 7 kg for females [2]. Clinically, the segmental muscular strength is
evaluated with a Medical Research score—each movement is assigned with a
score from 0—complete lack of strength—to 5—normal strength. A composite
MRC score to define global strength can be employed, some authors suggest even
a score threshold [
patients cannot grant enough collaboration for these tests. Hence, electrophysiological studies (Edx) are often needed for diagnosis. Edx comprehends nervous conduction studies (NCS), which allow registration of nervous conduction velocity and
compound action potential in selected motors, sensitive or mixed nerves. The study
of action potentials (CMAP from motor nerves, SNAP from sensory nerves) needs to
measure their amplitude, morphology, and duration. Very slow conduction velocity
indicates myelin damage, while low-amplitude potentials are linked to axonal
damage. Another important part of Edx is elect romyography (EMG), in which
needle registration of selected muscles can give information about their activity at
rest or during increasing effort, and about potential spontaneous pathological activity. Peculiar patterns due to myopathy, acute or chronic denervation can also be
identified. Various combinations of Edx patterns can thus discriminate between
different conditions:
11]. Deep tendon hypo- or areflexia suggests CIP. However, most
• Sensitive vs. motor neuropathy
• Axonal vs. demyelinizing neuropathy
• Radiculopathy
• Myopathy
CIP is a
affected, indeed NCS shows normal velocity and normal latency. This feature is an
important factor in differentiating between CIP and Guillain–Barré syndrome
[
2, 11]. The first Edx sign is a reduction in amplitude of CMAP or SNAP or both
with preserved conduction velocity, which can occur within 2–5 days after the onset .
The reduction in amplitudes often precedes spontaneous activity such as fibrillation
potentials and positive sharp waves on EMGs, that may not occur until the second or
third week [12]
on behalf of the finding that unilateral peroneal CMAP reduction below two standard
deviations of the normal value accurately identified patie nts with CIP/CIM, to be
referred to more extensive assessment. The peroneal nerve test showed 100%
sensitivity and 80–90% specificity [1].
Differential
conditions can show low-amplitude CMAPs and abnormal spontaneous activity. A
low-amplitude SNAP should be absent in CIM, but its measure may be difficult due
to local edema in critically ill patients.
n axonal sensorimotor polyneuropathy. Myelin sheath is typically not
implified screening test (peroneal nerve test) has been proposed
. A s
diagnosis between pure CIP and CIM is difficult because both
46 N. Nasuelli et al.
Neuroimaging studies are usually requested if there is a need to rule out central
nervous system lesions that may result in quadriplegia or contribute to it. There are
several imaging methods for muscle and nerve study, currently mostly used for
research purposes. Shoulder girdle RM and measurement of muscle area at third
lumbar vertebra via CT scan can be reliably used to measure muscle hypotrophy [
Exploratory ultrasound studies found hypoechoic nerves in clinically relevant
ICU-AW [13]. With ultrasonographic criteria, it is also possible to diagnose diaphragmatic weakness, in which parameters like diaphragm excursion and diaphragm
thickening fraction are reduced [
muscle thickness and pathological increased echogenicity has been used in association to Edx studies, resulting in a good screening test for probable CIM [15].
Nerve and muscle biopsies could provide essential and precise information of
muscle conditions but are invasive, expensive, and require specialized techniques, so
they are used exclusively in research or if there is consistent clinical suspicion of
inflammatory myopathy [6].
2, 14]. Ultrasound of rectus femoris measuring
6].
Differential Diagnosis
Other neuromuscular conditions can lead to ICU admission, rather than occurring de
novo during the ICU stay. Of these, the acute motor axonal neuropathy form of
Guillain Barré syndrome (GBS) could mimic CIP. It is comparatively rare in western
countries and is usually preceded by an infection in the previous weeks. The
cerebrospinal fluid usually shows elevation of proteins with a normal cell count.
The typical demyelinating form of GBS also has neurophysiologic typical features of
a demyelinating polyneuropathy, especially prolongation of F-wave latencies and
sometimes conduction block, in contrast to CIP. Neuromuscular junction disorders
may worsen in the ICU due to the stress of illness and the use of magnesium or
antibiotics [16].
Treatment
The management of ICU-AW necessitates addressing the underlying conditions as a
primary step. While there is some evidence associating ICU-AW with exposure to
steroids and neuromuscular blocking agents, albeit controversial, it is advisable to
minimize or avoid these therapies as much as possible [16, 17]. Despite previous
evidence suggesting that intensive insulin therapy reduces the incidence of critical
illness polyneuropathy/myopathy [5], it is now preferred to maintain a blood glucose
target of 180 mg/dl and avoid hypoglycemia due to its higher mortality rate [18]. The
cornerstone of therapy is mobilization and physical rehabilitati on. Although there
are no randomized controlled trials (RCTs) on the effects of physical rehabilitation
therapies, exercises such as marching in place and walking away from the bedside,
4 Critical Illness Polyneuropathy and Myopathy 47
initiated in the ICU and continued through an outpatient program, are safe and
feasible for survivors of critical illness [19]. Studies indicate that early mobilization
may offer protection against the development of ICU-AW compared to physical
therapy started after 72 h or more [19, 20]. Currently, there is no pharmacological
treatment supported by sufficient evidence. Several approaches have been anecdotally reported, including the use of anabolic steroid oxandrolone and growth hormone
(to increase muscle mass), propranolol (to decrease muscle loss), immunoglobulin
(to control inflammation), and glutamine therapy (to improve nutritional status)
6]. The role of nutrition requires clarification, as randomized controlled trials
[
focusing on clinical outcomes such as muscle mass and/or motor function have
failed to provide conclusive results. Recommendations for the initial phase of ICU
stay (1–4 days) include progressively delivering calories and proteins, while from
day five onward, a full caloric supplementation is recommended [21].
Prognosis
Most ICU-AW patients experience good recovery, with approximately 70% achieving full recovery in less than 12 months, and up to 88% in longer follow-ups. Limited
data suggests that Critical Illness Polyneuropathy (CIP) is associated with a worse
prognosis compared to Critical Illness Myopathy (CIM). Patients with CIM typically
recover within 6 months, whereas those with CIP alone or in combination with CIM
tend to have a more delayed recovery, with over 50% experiencing persistent deficits
at the 1-year follow-up [22, 23].
period compared to a non-COVID reference population [24, 25].
COV
ID-19 patients often face an extended recovery
Future Perspectives
Therapeutic possibilities for ICU-AW require further exploration, particularly
regarding rehabilitation interventions and their impact on functional outcomes and
quality of life. Dedicated investigations are needed to address these aspects comprehensively. In terms of pharmacologic therapies, there is emerging evidence
suggesting a potential role for modulating the renin-angiotensin-aldosterone axis
in reducing skeletal muscle hypotrophy. Established agents or novel vasoactive
peptides such as angiotensin-(1–7) represent potential treatments for ICU-AW
[6]. Neuromuscular electrical stimulation treatments hold promises for reducing
skeletal muscle atrophy and decreasing the duration of mechanical ventilation.
However, experimental trials have yet to demonstrate efficacy, and evidence remains
limited due to heterogeneity in protocols. As a result, this therapy is not currently
recommended nor widely utilized [26]. It is essential to clarify precise prognostic
factors and the timing of functional recovery through targeted investigations with
methodological consistency. Additionally, distinguishing between different types of
48 N. Nasuelli et al.
ICU-AW and considering the co-occurrence of ICU-AW and central nervous system
damage are crucial aspects to be addressed in clinical trials [22].
References
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3. van Mook WNKA, Hulsewé-Evers RPMG. Critical illness polyneuropathy. Curr Opin Crit
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5. Hermans G, Wilmer A, Meersseman W, Milants I, Wouters PJ, Bobbaers H, Bruyninckx F, Van
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7. Bellaver P, Schaeffer AF, Leitao CB, Rech TH, Nedel WL. Association between neuromuscular
blocking agents and the development of intensive care unit-acquired weakness (ICU-AW): a
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2023;42:101202.
8. Fan E, Cheek F, Chlan L, et al. An official American Thoracic Society Clinical Practice
guideline: the diagnosis of intensive care unit-acquired weakness in adults. Am J Respir Crit
Care Med. 2014;190:1437–46.
9. Nasuelli NA, De Marchi F, Cecchin M, De Paoli I, Onorato S, Pettinaroli R, Savoini G, Godi
L. A case of acute demyelinating polyradiculoneuropathy with bilateral facial palsy after
ChAdOx1 nCoV-19 vaccine. Neurol Sci. 2021;42:4747–9.
10. Bocci T, Campiglio L, Zardoni M, Botta S, Coppola S, Groppo E, Chiumello D, Priori
A. Critical illness neuropathy in severe COVID-19: a case series. Neurol Sci. 2021;42:4893–8.
11. Attwell C, Sauterel L, Jöhr J, Piquilloud L, Kuntzer T, Diserens K. Early detection of
ICU-acquired weakness in septic shock patients ventilated longer than 72 h. BMC Pulm Med.
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12. Bednarik J, Lukas Z, Vondracek P. Critical illness polyneuromyopathy: the electrophysiological components of a complex entity. Intensive Care Med. 2003;29:1505–14.
13. Fisse AL, May C, Motte J, Pedreiturria X, Breuer TGK, Schneider-Gold C, Marcus K, Gold R,
Yoon M-S, Pitarokoili K. New approaches to critical illness polyneuromyopathy: highresolution neuromuscular ultrasound characteristics and cytokine profiling. Neurocrit Care.
2021;35:139–52.
14. Cammarota G, Sguazzotti I, Zanoni M, et al. Diaphragmatic ultrasound assessment in subjects
with acute hypercapnic respiratory failure admitted to the emergency department. Respir Care.
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Kelmenson DA,
15.
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Quan D, Moss M. What is the diagnostic accuracy of single nerve conduction
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4 Critical Illness Polyneuropathy and Myopathy 49
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Eur J Phys Rehabil Med. 2015;51:655–61.
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24. Gamberini L, Mazzoli CA, Sintonen H, et al. Quality of life of COVID-19 critically ill survivors
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Chapter 5
Gut Microbiome in the Critically Ill
Antonella Cotoia, Tecla Giuseppina Zimotti, and Denise Battaglini
Introduction
The human microbiota was firstly recognized in late 1970s. Since then, researchers
have tried to understand its characteristics and potential impact on healthy and
disease The term “microbiota,” meaning the microbial taxa of humans, was coined
by Joshua Lederberg in 2001 [1]. The term “microbiome” represents the
microbio
ronment. Despite clear differences, these terms have been used interchangeably. The
diversity among the microbiome of individuals is immense compared with genomic
variation: individuals are about 99.9% identical to one another in terms of their
human genome but can be 80–90% different from one another in terms of the
microbiome. Each organ and system presents a specific microbial composition.
Notably, the microbiota differs between subjects and among organs within the
same subject.
critical
theless, the literature concerning microbiota in critical care is still very poor and need
further implementation. This chapter aims to characterize and describe the advances
ta’s collective genomes and gene products residing within a host or envi-
Over the last few years, researchers have focused on studying microbiota in
illnesses as a potential target for therapies and improving outcomes. Never-
Supplementary Information The online version contains supplementary material available at
https://doi.org/10.1007/978-3-031-66541-7_5.
A. Cotoia (
Department of Anesthesia and Intensive Care, University of Foggia, Azienda OspedalieroUniversitaria Ospedali Riuniti, Foggia, Italy
e-mail: antonella.cotoia@unifg.it
D. Battaglini
Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and
Neuroscience, Genoa, Italy
© The
A. Cotoia et al. (eds.), Nutrition, Metabolism and Kidney Support,
https://doi.org/10.1007/978-3-031-66541-7_5
✉) · T. G. Zimotti
Author(s), under exclusive license to Springer Nature Switzerland AG 2024
51
52 A. Cotoia et al.
in microbiota in critical illnesses as potential therapeutic targets to improve
outcomes.
Gut Microbiome
The number of microbes living within the intestinal lumen is similar to the number of
all cells of human origin in the host [2]. Approximately 40 trillion microorganisms
reside inside our intestines. Figure 5.1 shows taxa identified in phyla and genera in a
healthy microbiome.
The intestinal microbiome has many funct ions: (1) anaerobic bacteria degrade
food polysaccharides, that are fermented into various metabolites including shortchain fatty acids (SCFAs) such as butyrate, acetate, and propionate, which are
necessary substrates for enterocyte function, (2) role in the defense against infections
of the digestive tract by a competitive effect between commensal and pathogenic
bacteria and in building the local immune defense, and (3) gut microbiota is closely
linked to all our organs and contributes to their normal functioning (gut–organ axis).
Gut microbiota can be examined using various methods, the two most commonly
used in clinical practice are the 16S ribosomal ribonucleic acid (RNA) (rRNA)
profiling (metataxonomics) and the unbiased sequencing of all deoxyribonucleic
acid (DNA) (shotgun metagenomics). The first technique is simple, fast, and
low-cost and provides a taxonomic overview of the bacteria present in a sample
and gives information on microbial richness and diversity. The shotgun
metagenomics allows the identification of bacteria up to species level and provides
information on microbial richness, diversity, and gene functions. This one is a higher
resolution approach but more expensive. For 16S amplicon sequencing, lower
taxonomic ranks like family, genus, or species are preferred to study the relationship
between the microbiome and metabolome.
Fig. 5.1 Taxonomic classification of most abundant microbiota taxa identified in phyla and genus
5 Gut Microbiome in the Critically Ill 53
Gut-Organ Axis
There is increasing evidence that gut microbiota and its alteration interact with other
organs, highlighting the concept of the gut–organ axis. The gut microbiota constantly communicates with key organs of our organism and strongly influences them
(heart, lung, liver etc.). According to the latest evidence, gut microbiota could be
considered as an organ and its failure, manifested by dysbiosis, as an organ failure,
which is possibly associated with poor clinical outcomes. The exact roles and
contributions of the gut microbiota and its interactions with the various organs are
an intense and challenging area of research, and much remains to be discovered.
Another aspect that should not be neglected is that the compo sition of the gut
microbiota is influenced by genetic and non-genetic factors such as lifestyle, diet,
but also by diseases and their treatments. Further research on the gut microbiota is
needed to understand these processes better and offer new disease prevention,
management, and therapy opportunities, especially in critical care where multiorgan failure is often the focus.
Gut–Brain Axis
Gut–brain axis is an important, constant bidirectional communication system, taking
place via immunological, endocrine, neural, and metabolic pathways. Immune
signalling is mediated by cytokines and interleukins (IL)-1 and IL-6, produced in
the gut, travel through the bloodstream and cross the blood–brain barrier. These
cytokines then influence one of the most powerful activators of the stress system, the
hypothalamic–pituitary–adrenal axis.
The gut
ters and the vagus nerve. The neurotransmitters produced and consumed by the gut
include dopamine, norepinephrine, gamma-aminobutyric acid (GABA), and serotonin. Some bacteria have been shown to express more neurotransmitters (such as
Lactobacillus rhamnosus, which is associated with neurological GABA secretion)
[
3]. Interestingly, the vagus nerve appears to recognize metabolites of the gut
microbiota and responds through a cholinergic pathway that appears to reduce
intestinal inflammation and intestinal permeability, thus modulating the gut
microbiota. Recent studies also suggested that alterations of these neurotransmitters
by the microbiota have an impact on the onset and development of neurological
diseases such as ischemic stroke or neuroimmune diseases [
seems to be activated by SCFAs. Metabolic components also serve as communication pathways between the brain and the gut microbiota. The gut–brain interaction
has been demonstrated in neurocritical ill patients. Indeed, their gut microbiota
appears different from that of healthy subjects and dysbiosis seems to increase
with ICU length of stay.
microbiota has been shown to interact with the brain via neurotransmit-
The vagus nerve also
4].