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54 A. Cotoia et al.
Gut-Lung Axis
Resident microbes influence the natural host inflammatory and immune responses in
the gut and respiratory microbiome [5]. Infection and altered immunity have been
linked to altered host-pathogen interactions. Initially, researchers though that the
lung was “sterile” environment, free from bacteria [6]. By enhancing culturing, the
viability of bacteria in healthy lungs has been demonstrated. According to bronchoscopy studies in critical care, the carina represents the densest site of bacterial
DNA along health airways, with a density dropping down as more bifurcations
occur. Micro-aspirations probably cause this [7]. Different from the gut microbiota,
the lung microbiota communicates with mucosal surfaces. The relative balance of
immigration determines the type and load of lung communities through microaspiration and mucosal dispersion and elimination via exhalation [8]. On the other
hand, gut communities are relatively consistent daily due to stable, selective pressure
on resident bacteria. The gut microenvironment is nutrient-rich and characterized by
intense metabolic competition among dense communities. The lung microenvironment is nutrient-poor, and the main competition is between immigrant pharyngeal
microbes and locally tailored alveolar and airway host defences trying to minimize
their outgrowth.
Dysbiosis of the gut microbiome has been identified as a biomarker for late-onset
new sepsis and nosocomial infections, being highly associated with dysbiosis of the
lung microbiome [2].
Other axes have been investigated although gut-liver axis and gut-muscle axis
perfectly show us how changes in the gut balance can affect these organs too.
ICU Dysbiosis
Dysbiosis Definition
It is crucial to note that microbiome composition is not static but rapidly evolves in
life and with the severity of illness. Critically ill patients undergo frequent medical
interventions and therapy changes during their stay in the ICU, which leads to
inflammation and a suppressed immune system. As a result, their gut microbiome
is disrupted, and they end up being in a status called dysbiosis: a loss of healthpromoting commensal microbes and an increase in pathog enic microbes. There is no
definition of a healthy microbiome since it differs among patients and within the
same patient at different times. However, for convenience, we define likely healthy
as a gut microbiome mainly composed of Firmicutes and Bacterioidetes [9].
The mic
side with its human host, but it is constantly evolving and in permanent communication with its host. We can distinguish a commensal mic robiome that is healthpromoting and plays various roles in the maintenance of human wellness, and a
robiome is not simply an innocent bystander, living peacefully side-by-
5 Gut Microbiome in the Critically Ill 55
Mechanical ventilation
Healthy
PPI
Corticosteroids
Antibiotics
ICU specific therapies
Dysbiosis
Firmicutes
Bacterioidetes
Acetate
Propionate
Butyrate
Anti-inflammatory cytokines
IL-10, TGF-ß
Bacterial
diversity
Acetate
Propionate
Butyrate
Tight
junctions
Pro-inflammatory cytokines
IL-6, IL-17, TNF-α
Th-17, Th-1
Enterobacteriaceae
Fig. 5.2 Potential factors influencing microbial disbiosis and typical bacterial composition of
healthy and disbiotic microbiota. PPI proteon pump inhibitors, ICU intensive care unit, IL interleukins, TGF transforming growth factor, TNF tumor necrosis factor, Th T helper cells
pathobiome which is a disease-promoting microbiome typical of multiple disease
states such as sepsis and septic shock and multiorgan dysfunction syndrome
5.2)[7].
(Fig.
Enterotype analysis has recently led to the definitions of “conventional
enterotypes” in
healthy human guts and “ICU-enterotypes” in critically ill patients.
A study of Wanglin Liu at al [10]. identified two ICU-enterotypes:
. ICU-enterotype I (ICU E1) more likely in patients with septic shock → including
Bacteroides and a dominant unclassified genus from Enterobacteriaceae, which
also was correlated with high serum lactate levels.
. ICU-enterotype II (ICU
E2) → predominan
tly Enterococcus.
tudy a
This s
lso stated that the choice of the antibiotic therapy does not determine
the ICU enterotype, which also comes from factors like the infection type, other
medical treatments, and inherited traits.
The largest
ng fecal, oral, and skin samples from 115 mixed ICU patients across four
collecti
study on the microbiome in ICU (Daniel McDonald et al. [
11
]),
centers in the United States and Canada at two time points, found out that critically
ill patients had rapid depletion of health-promoting organisms and overgrowth of
known pathogens. Specifically, when examining phylum-level taxonomy, the common Gram-positive Firmicutes and Gram-negative Bacteroidetes were both
decreased, as was Faecalibacterium (anti-inflamatory organism). In contrast, potential pathogens such as Enterobacter and Staphylococcus were increased, and
Proteobacteria had a relative increase.
56 A. Cotoia et al.
This analysis of microbiome data from 115 subjects indicates that the microbiome
composition in many ICU patients is derived from unexpected sources and differs
significantly from that of a healthy population. The magnitude of this dysbiosis
appears to increase between time points.
Gut Changes
Dysbiosis leads to several important effects, including changes in gut integrity and in
the production of metabolites such as SCFAs and trimethylamine N-oxide (TMAO).
Colonic mucus changes: the intestinal wall is covered with hydrophobic mucus,
which is continuously produced by the goblet cells of the mucosa. This mucus
protects the enterocytes and colonocytes from digestive enzymes and acts as a barrier
against the passage of bacteria and toxins into the bloodstream. In critically ill
patients with splanchnic hypoperfusion, mucus production and mucus hydrophobicity decrease, leading to enterocytes injury that promotes cell apoptosis and pathogen
translocation. This leads to reduced absorption of nutrients and reduced production
of SCFAs and favors diarrhea.
The intestinal anaerobic microbiota ferments dietary fibers and produces metabolites such as SCFAs, which help to maintain the integrity of the gut barrier and
promote the host’s immune response. SCFAs are the primary source of energy for
the colonic epithelium and contribute to maintaining functional intercellular junctions. Mostly studied in rodent models, they also play a role in intestinal immunity
by controlling the production of T-helper cells, regulatory T cells (Treg), antibodies,
and cytokines with mainly anti-inflammatory effects. SCFAs have also been shown
to induce cytoprotective proteins in epithelial cells that help maintain cell viability
under stress conditions. Critically ill patients exhibit dysbiosis with a reduction in
anaerobic bacteria leading to a decrease in SCFAs concentration, which has been
associated with cellular apoptosis, malabsorption, diarrhea and bacterial
translocation.
TMAO is an important metabolite produced jointly by the intestinal microbiota
and the liver. First, trimethylamine (TMA) is produced by the gut microbiota from
choline, lecithin, and carnitine which are found in food precursors such as meat, fish,
and eggs. Second, TMA is absorbed and translocated to the liver through portal
circulation, where TMAO is converted from TMA directly. As the production of
TMAO depends on the diversity and composition of the gut microbiota, TMAO
levels result to be higher in dysbiosis. A study in humans showed that broadspectrum antibiotics suppressed the production of TMAO, which reappeared after
the discontinuation of the antibiotics, suppor ting the importance of the gut
microbiota in TMAO production. High levels of TMAO have been recognized to
be associated with heart failure, atherosclerosis, and thrombosis formation.
Immune
the immune system and constantly communicates with it. On the one hand, the
microbiota promotes the immune system and adapts it to certain conditions; on the
mucosal changes: The gut microbiota plays a crucial role in developing
5 Gut Microbiome in the Critically Ill 57
other hand, it is tolerated by this adaptive immunity. This occurs through the
involvement and recognition of microbe-associated molecular patterns via the tolllike receptor system and through the release of pro-inflammatory cytokines, mucus
secretion, and the formation of SCFAs that activate Treg. This barrier plays an
important role in preventing colonization by pathogens and appears to be
compromised by antibiotic administration. In order to control its link w
microbiota, the immune system limits the contact between the microbiota and
epithelial cells, thus limiting the possible translocation of bacteria. This “mucosal
firewall” consists of epithelial cells, IgA secretion, antimicrobial peptides, and
immune cells. Alteration of the microbiota can lead to immune system
dysregulation, including a decrease in IgA and T cell levels, favoring bacterial
infection.
ith the
Microbial Therapy in ICU
From the latest studies, our microbiome is known to play a key role in our physiology, including protection against infections, in drug metabolism, vitamin synthesis, nutrition, as well as in respon se to disease. A surprising finding is that disruption
of the homeostasis of the microbiota may be as important as host genetics in the
development of various diseases, such as inflammatory bowel disease, obesity,
diabetes, and cardiovascular disease. This suggests that it may be possible to
monitor, prevent, or even cure human disease by regulating the microbiota. The
first attempt is usually to eradicate the microbial life. At the same time, perhaps, we
should instead consider how to preserve or re-establish a “ health-promoting”
microbiome during and after critical illness through targeted interventions, such as
appropriate nutrition, probiotics, prebiotics, fecal transplantation, and or even synthetic “stool pills” to improve outcome in critically ill patients.
Antimicrobial Stewardship
Much time and effort is spent in eradicating bacteria and other microbial, fungal, and
viral species in the ICU [
hospitalized patients receive an antibiotic during their stay, and in the ICU, this
number increases to 70% of patients. Evidence suggests that as many as 37% of
antibiotic regimens are unnecessary or not compliant with guidelines. This inappropriate antibiotic use leads to the emergence of multidrug resistant bacterial infections. Shall we rethink our strategy against infections in ICU?
Antibiotics do not only kill pathogens but also “health-promoting” microbes,
leading to a loss of commensal gastrointestinal microbiota, which enables overgrowth of unwanted organisms (dysbiosis). This may have significant implications
for organs far outside the gastrointestinal tract as well. The gut has long been
12]. The US Centers for Disease Control reveal 55% of all
58 A. Cotoia et al.
described as the “motor” of systemic inflammatory response syndrome and of organ
failure regardless of the location of the initial infection. In fact, the effect of
alterations in the gut mic robiota and gut barrier homeostasis are thought to be
transmitted to and propagated by downstream organs, such as the spleen and lung
where large immune cell populations are located, leading to inflammation-induced
organ failure in the ICU.
the
At
cellular level, organ
long been attributed to mitochondrial failure. It has long been known that mitochondria trace their evolution from bacteria that produce energy for our cells. Recent
studies reveal that mitochondria are known to be damaged by many of the antibiotics
we commonly administer in the ICU. Thus, antibiotics may be contributing to organ
failure by not only leading to dysbiosis but also by damaging the very core of our
cells’ energy production.
failure that ultimately leads to death in the ICU has
Nutrition as a Key Factor for Gut Microbiome Homeostasis
Nutrition is another key factor for the gut microbiome homeostasis since it primarily
depends on the availability of enteral nutrients for survival. Thus, the nutritional
components (carbohydrates, lipids, and proteins) and the route of administration
(enteral/parenteral) might also alter the health of the microbiome.
Medic
management of critically ill patients and the outcome of disease could be notably
improved by monitoring their metabolic profile and implementing an individualized
nutritional treatment.
Many studies have shown that the lack of enteral nutrition, which is very frequent
in the ICU, may alter the intestina l microbiome composition and weaken the
epithelial barrier function, predisposing it to bacterial translocation, which is also
associated with septic complications. The ESPEN guidelines recommend medical
nutritional therapy for all patients admitted to the ICU, and particularly to those
staying for more than 48 h, including administration of oral nutritional supplements,
enteral nutrition, and parenteral nutrition. Moreover, they encourage the use of oral
nutrition, but when it is not possible, enteral nutrition should be initiated within 48 h.
However, many critically ill patients cannot receive enteral nutrition: in these
patients, parenteral nutrition has been a life-saving supportive treatment. Current
guidelines recom mend the implementation of parenteral nutrition, in the case of oral
and enteral nutrition contraindications, within 3–7 days.
utritional therapy in critically ill patients is a challenge [13, 14]. The
al n
5 Gut Microbiome in the Critically Ill 59
Probiotics, Prebiotics, and Synbiotics
Different studies have shown that restoration of commensal “healthy microbes”
following illness via interventions such as probiotics may exert their beneficial
effects via multiple pathways. This topic will be discussed in Chap. 17.
Fecal Microbiota Transplantation
Restoration of a healthy gut microbiome may be important for improving outcomes
in critically ill patients. The depletion of Firmicutes and increase of Proteobacteria
could be ameliorated by fecal transplantation, followed by rapid recovery of the
patient [15]. However, this treatment is still under investigation and poorly applied
in clinical practice, thus implementation is needed.
Conclusion
In the intricate landscape of critical illness, the dynamic interplay between the human
microbiota and the host’s physiological systems emerges as a pivotal factor influencing health and disease outcomes. The journey through this chapter has unraveled the
profound impact of microbiota on critical care scenarios, shedding light on its
diverse roles in the gut, brain, lungs, liver, and beyond. As we navigate the
complexities of the microbiome, it becomes evident that the microbiota is not a
passive bystander but an active participant, orchestrating intricate communication
networks with various organs.
References
1. Ursell LK, Metcalf JL, Parfrey LW, Knight R. Defining the human microbiome. Nutr Rev.
2012;70(Suppl 1):S38–44.
2. Otani S, Chihade DB, Coopersmith CM. Critical illness and the role of the microbiome. Acute
Med Surg. 2019;6:91–4.
3. Battaglini D, Pelosi P, Robba C. The emerging role of the microbiota in neurocritical care. In:
Annual update in intensive care and emergency medicine book series; March 2022.
4. Battaglini D, Pimentel-Coelho PM, Robba C, Dos Santos CC, Cruz FF, Pelosi P, Rocco PRM.
Gut microbiota in acute ischemic stroke: from pathophysiology to therapeutic implications.
Front Neurol. 2020;11:598.
Martin-Loeches I,
5.
Bozza F, Vincent JL, Murthy S, Bauer M, Marshall J, Cilloniz C, Bos LD. The importance of
airway and lung microbiome in the critically ill. Crit Care. 2020;24(1):537.
Dickson R, Torres A, Hanberger H, Lipman J, Antonelli M, de Pascale G,
60 A. Cotoia et al.
6. Cotran RS, Kumar V, Collins T, Robbins SL. Robbins pathologic basis of disease, vol.
xv. Philadelphia: Saunders; 1999. p. 1425.
7. Venkataraman A, Bassis CM, Beck JM, Young VB, Curtis JL, Huffnagle GB, et al. Application
of a neutral community model to assess structuring of the human lung microbiome. MBio.
2015;6:e02284.
8. Dickson RP, Erb-Downward JR, Freeman CM, McCloskey L, Falkowski NR, Huffnagle GB,
et al. Bacterial topography of the healthy human lower respiratory tract. MBio. 2017;8:8.
9. Magne F, Gotteland M, Gauthier L, Zazueta A, Pesoa S, Navarrete P, Balamurugan R. The
firmicutes/bacteroidetes ratio: a relevant marker of gut dysbiosis in obese patients? Nutrients.
2020;12(5):1474.
10. Liu W, Cheng M, Li J, Zhang P, Fan H, Hu Q, Han M, Su L, He H, Tong Y, Ning K, Long
Y. Classification of the gut microbiota of patients in intensive care units during development of
sepsis and septic shock. Genomics Proteomics Bioinformatics. 2020;18(6):696–707.
11. McDonald D, Ackermann G, Khailova L, et al. Extreme dysbiosis of the microbiome in critical
illness. mSphere. 2016;1:e00199–16.
12. Wischmeyer PE, McDonald D, Knight R. Role of the microbiome, probiotics, and ‘dysbiosis
therapy’ in critical illness. Curr Opin Crit Care. 2016;22(4):347–53.
13. Moron R, Galvez J, Colmenero M, Anderson P, Cabeza J, Rodriguez-Cabezas ME. The
importance of the microbiome in critically ill patients: role of nutrition. Nutrients. 2019;11:
3002.
14. Cotoia A, Paradiso R, Ferrara G, Borriello G, Santoro F, Spina I, Mirabella L, Mariano K,
Fusco G, Cinnella G, Singer P. Modifications of lung microbiota structure in traumatic brain
injury ventilated patients according to time and enteral feeding formulas: a prospective randomized study. Crit Care. 2023;27(1):244.
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Szychowiak P, Villageois-Tran K, Patrier J, Timsit J-F, Ruppé É. The role of the microbiota in
the management of intensive care patients. Ann Intensive Care. 2022;12:3.
Chapter 6
Nutrition Risk Screening Tools
Giorgio Fullin
Introduction
Patients in critical condition are at a high risk of malnutrition due to the severity of
their illness and injuries. Several factors contribute to malnutrition in critical care,
including difficult-to-estimate nutrient requirements, hypermetabolism, gastrointestinal intolerance, limited oral intake, and obstacles to reaching the set targets
[1]. Malnutrition can have significant negative consequences on patient outcomes,
ing impaired wound healing, higher infection rates, longer hospital stays, a
includ
prolonged need for mechanical ventilation, and even higher mortality [2]. Therefore,
early identification of patients at risk of malnutrition is crucial to enable timely
nutritional intervention and support.
Subjective parameters, such as appetite assessment and dietary intake, are chal-
lengin
g to evaluate in critical patients who are often sedated, intubated, or neurologically impaired. Changes in weight can be influenced by fluid status, given the
large volumes necessary to maintain hemodynamic stability, and consequently, the
evaluation of muscle and fat wasting becomes more difficult. Other objective
measures, like arm muscle circumference, air plethysmography, biochemical indicators, ultrasonography, computerized tomography, and magnetic resonance, may
be useful and are discussed later in the book.
Nutritional risk screening tools have been published, and their prognostic capa-
bility
has been tested on the population of critical patients, yielding non-uniform
results. Some of these tools are relatively simple and effective; therefore, evaluation
with these tools is feasible and recommended according to ASPEN guidelines.
Supplementary Information The online version contains supplementary material available at
https://doi.org/10.1007/978-3-031-66541-7_6.
G. Fullin (
Department of Anesthesia and Intensive Care, Ca’ Foncello Hospital, Anesthesia and Intensive
Care, Treviso, Italy
© The
A. Cotoia et al. (eds.), Nutrition, Metabolism and Kidney Support,
https://doi.org/10.1007/978-3-031-66541-7_6
✉)
Author(s), under exclusive license to Springer Nature Switzerland AG 2024
61
62 G. Fullin
However, European societies encourage a more pragmatic approach, suggesting
considering at-risk any patient expected to remain in the ICU for more than 48 h.
For identifying patients in a state of
care unit, nutritional risk screening should be conducted close to admission in critical
care. Nutritional risk scores often need interpretation based on individual patient
factors such as usual body weight, pre-illness dietary habits, and pre-existing
nutritional deficiencies or obesity. Clinical judgment is required to determine if a
patient is truly at nutritional risk or would benefit from nutritional support. Nutritional risk scores have limitations in predicting clinical outcomes and should not be
used as the sole determinant of nutrition therapy. Furthermore, patients may transition between levels of risk during thei r ICU stay due to changes in clinical status,
nutrient intake, and metabolic demands. Nutrition plans need to be adapted
accordingly.
Beyond screening tools addressing potential malnutrition risk, the Global Leadership Initiative on Malnutrition has developed a tool for diagnosing the actual
nutritional status, which will be discussed at the chapter’s conclusion.
malnutrition before admission to the intensive
Validation Process
Validating a nutrition risk screening tool involves several steps and is not easy. The
first step is to identify a reference standard; this is a gold standard used to determine
whether the tool accurately identifies patients who are at risk of malnutrition. The
reference standard can be a subjective assessment by a clinician, a laboratory test, or
a combination of both. Determining sensitivity and specificity is also crucial:
sensitivity is the ability of the tool to correctly identify patients at risk of malnutrition, while specificity is the ability to correctly identify patients not at risk of
malnutrition. These values can be calculated by comparing the tool’s results to the
reference standard.
The predictive value of a nutrition risk screening tool is its ability to predict
outcomes such as length of hospital stay, readmission rates, and mortality. This can
be assessed by comparing the tool’s results to these outcomes. However, finding
appropriate outcomes is complex, as factors beyond nutrition can determine a
patient’s history, especially in the critically ill subgroup.
Inter-rater reliability is the degree of agreement among multiple raters using the
tool, assessed by having independent raters use the tool and comparing thei r results.
Test-retest reliability is the consistency of the tool over time, assessed by administering it to the same patient at different times and comparing the results. Validity is
the extent to which the tool measures what it is intended to measure, obtained by
comparing its results to other measures of malnutrition or related outcomes.
Many nutritional screening assessment tools have been studied, with most incorporating inflammatory system biomarkers and severity scores, as these are closely
related to the pathophysiology of malnutrition in critical ly ill patients. Presently, no
single screening tool is considered the gold standard for critical care patients.
6 Nutrition Risk Screening Tools 63
Screening Tools Overview
Here is an overview of the main nutritional screening tools used in critical care and
their main differences (see summary—Table 6.1):
• Subjective Global Assessment (SGA): This tool, made by the Canadian Malnu-
trition Task Force, was initially developed for post-gastrointestinal surgery
patients, and later studied in critically ill patients [3]. The SGA scale includes
parameters to assess muscle wasting, subcutaneous fat, fluid retention, weight
change, recent food intake, gastrointestinal symptoms, functional capacity, and
the disease’s effect on nutritional requirements. The main limitations of SGA are
that the severity of illness is not included, assessing weight and food history in
critically ill patients is chall enging, and it relies more on clinical judgment and
less on objective measures, making it potentially less useful in ICU settings where
it also has limited validation. Despite this, some institutions, like the Indian
Society of Critical Care Medicine, recommend its use in critically ill patients.
• Mini Nutritional Assessment (MNA—Table 6.2): Originally developed for
elderly patients [4], the current MNA consists of six questions, streamlining the
screening process [5]. It includes parameters related to diet, anthropometry,
mobility, psychological, and lifestyle factors. While it has limited validation in
critically ill patients, it is comprehensive and easy to perform. Malnutrition
Universal Screening Tool (MUST—Tables 6.3 and 6.4): Commonly used in
ICUs, this tool was developed by the Malnutrition Advisory Group, a standing
committee of the British Association for Parenteral and Enteral Nutrition
[6]. Although commonly used for hospitalized patients, it has shown limited
performance in critically ill patients. However, in the Netherlands, the MUST
score has been used for years as a hospital quality indicator to benchmark
hospitals. To date, there are no other usable tools to assess nutritional risk in
ICU patients; hence, the MUST score has been frequently used in critical patients
[7]. Some studies found that the MUST may overestimate the risk of malnutrition
in obese ICU patients. Furthermore, as it is not validated in the ICU population,
the MUST score cannot be recommended for nutritional risk assessment in the
Table 6.1 Comparative summary
Score Pros Cons
SGA Comprehensive and very
MNA Comprehensive and easy
MUST Easy and quick to perform Limitation evidence in ICU, may overestimate the
NRS
2002
NUTRIC Developed f
detailed
perform
Validate for ICU population,
suggest by ASPEN
or I
tion, suggest by ASPEN
CU popula-
Not validate for ICU, complex to calculate, severity
of illness is not
to
Developed for elderly patient and not validate for
ICU
risk of malnutrition
May overestimate the risk of APACHE II is above
10
Complex to
consider APACHE II, SOFA and IL-6
included
calculate and time consuming, need to