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- •Contents
- •Outcome Evaluation
- •Introduction
- •Clinical Presentation of Muscular Weakness in the Critical Patients
- •Critical Illness Polyneuropathy (CIP) and Critical Illness Myopathy (CIM)
- •Ventilator-Induced Diaphragmatic Dysfunction (VIDD)
- •Dysphagia, Swallowing, and Effective Cough
- •The Pathophysiology of Acute Skeletal Muscle Wasting
- •Risk Factors
- •Short-Term and Long-Term Outcome
- •Conclusions
- •References
- •Introduction
- •The Neuroendocrine Response
- •Pathophysiology of Stress Response
- •The Hypothalamus-Pituitary-Adrenal (HPA) Axis
- •GH Axis
- •Pituitary-Thyroid Axis
- •Pituitary-Adrenal Axis
- •Mitochondrial Dysfunction
- •Metabolic Aspects of Stress Response
- •Conclusion
- •References
- •Introduction
- •Disorders of Fluid Balance
- •Dysionemias
- •Dysnatremias
- •Dyskalemias
- •Other Electrolyte Derangements (Calcium, Magnesium, Phosphorus)
- •Alterations of Acid Base Balance
- •Acid-Base Disturbances
- •Metabolic Acidosis
- •Respiratory Acidosis
- •Metabolic Alkalosis
- •Respiratory Alkalosis
- •Conclusion
- •References
- •Introduction
- •Epidemiology and Risk Factors
- •Diagnosis
- •Differential Diagnosis
- •Treatment
- •Prognosis
- •Future Perspectives
- •References
- •Introduction
- •Gut Microbiome
- •Gut-Organ Axis
- •Gut-Lung Axis
- •ICU Dysbiosis
- •Gut Changes
- •Microbial Therapy in ICU
- •Antimicrobial Stewardship
- •Nutrition as a Key Factor for Gut Microbiome Homeostasis
- •Probiotics, Prebiotics, and Synbiotics
- •Fecal Microbiota Transplantation
- •Conclusion
- •References
- •Introduction
- •Validation Process
- •Screening Tools Overview
- •Discussion
- •Conclusion
- •References
- •Introduction
- •Fight-and-Flight Reaction
- •Calorimetry and Total Energy Expenditure
- •Role of Mitochondria in the Various Stages of Intensive Care Recovery
- •REE in Different Clinical Scenarios
- •Conclusions
- •References
- •Introduction
- •Nutrition in ICU: Evidence from RCTs
- •Inclusion of Too Many Patients Considered at Low Nutritional Risk
- •Unfavorable Energy to Protein Doses
- •Absence of Indirect Calorimetry-Guided Energy Dosing
- •Anabolic Resistance
- •Suppression of Fasting-Induced Recovery Pathways
- •Future Perspectives
- •Development and Validation of Tools to Guide Individualized Nutritional Support
- •Implications for Clinical Practice
- •Conclusion
- •References
- •Introduction
- •Protein Metabolism in Critical Illness
- •Protein Requirements and Current Evidence
- •Timing of Introduction
- •Early mobilization, Exercise, and Adjuvant Therapies
- •Conclusion
- •References
- •Introduction
- •Computed Tomography Scan
- •Bioelectrical Impedance Analysis
- •Musculoskeletal Ultrasound
- •Respiratory Muscle Ultrasound
- •Limb Muscles
- •Conclusions
- •References
- •Functional Principles
- •Hydration Status Evaluations in Critically Ill Patients
- •Body Composition and Nutrition in ICU
- •Limits of BIVA in Critically Ill Patients
- •Conclusions
- •References
- •Introduction
- •Introduction
- •Historical Perspective
- •Enteral Versus Parenteral Nutrition Nowadays
- •Conclusions
- •References
- •Enteral Nutrition
- •Components of Enteral Mixtures
- •Choice of the Enteral Mixture
- •Special Composition Formulas
- •Conclusions
- •References
- •Introduction
- •Complications Related to Enteral Feeding Tubes
- •Aspiration
- •Gastrointestinal Intolerance
- •Diarrhea
- •New Horizons
- •New Technologies to Prevent Enteral Nutrition Complications
- •Advanced Tube Feedings
- •smART Platform
- •Conclusions
- •References
- •Introduction
- •Composition of PN Admixtures
- •Energetic Substrates
- •Carbohydrates
- •Lipid Emulsions
- •Proteins
- •Micronutrients: Electrolytes, Vitamins, and Trace Elements
- •Types of Parenteral Nutrition
- •Compatibility and Stability of the Parenteral Nutrition
- •References
- •Introduction
- •Metabolic Complications
- •Hyperglycemia
- •Hypertriglyceridemia
- •Liver Disease: Steatosis, Cholestatic Disease, and Gallbladder Stones
- •Refeeding Syndrome
- •Mechanical Complications
- •Infectious Complications
- •Conclusions
- •References
- •Introduction
- •Macronutrients
- •Glutamine
- •Arginine
- •Leucine
- •ω-3 Fatty Acids
- •Micronutrients
- •Antioxidant Vitamins
- •Antioxidant Trace Elements
- •Probiotics, Prebiotics or Symbiotics
- •Use of Probiotics in Clinical Practice?
- •References
- •Introduction
- •Pathophysiological Mechanisms, Risk Factors, and Clinical Implications
- •Pathophysiological Mechanisms of ICUAW
- •Risk Factors Associated with Physical and Functional Recovery in Critically Ill Patients
- •Clinical Impact of Poor Physical and Functional Recovery in Critical Illnesses
- •How to Assess Physical and Functional Recovery in Critical Illnesses
- •Management and Therapies
- •Nutritional Therapy
- •Other Supportive Therapies
- •Patient- and Family-centered ICU Environment
- •Conclusions
- •References
- •Bioethics in Clinical Practices
- •Ethical Consideration on Nutrition
- •Conclusion
- •References
- •Introduction
- •Nutrition in ARDS
- •Caloric Goals
- •Diet Composition
- •Immunonutrition
- •Oral Versus Enteral Versus Parenteral Nutrition
- •Nutrition in COVID-19 Respiratory Failure
- •Nutrition in ECMO Support
- •Enteral Nutrition
- •Parenteral Nutrition
- •Nutritional Goals
- •Conclusions
- •References
- •Introduction
- •Timing and Route of Nutritional Support
- •Initial Assessment of the Burn Patient
- •Estimation of Energy Expenditure
- •Macronutrients and Micronutrients
- •Proteins
- •Carbohydrates
- •Immunonutrients
- •Arginine
- •Nucleotides
- •ω3 Fatty Acids
- •Glutamine
- •Monitoring of Nutritional Support
- •Nutritional Support for Trauma Patients
- •Route of Feeding: Digestive Tract (Enteral Nutrition) Versus Intravenous (Parenteral Nutrition)
- •Standard or Immune-Enhancing Enteral Nutrition
- •Estimation or Measurement of Energy Requirements
- •Macronutrients
- •Conclusions
- •References
- •Introduction
- •General Considerations
- •Assessment of Nutritional Needs
- •Metabolic Changes Induced by Sepsis, AKI, and CRRT
- •Protein Metabolism
- •Lipid Metabolism
- •Vitamins and Trace Elements
- •Phosphates
- •Approaches to Nutrition
- •Enteral
- •Parenteral
- •Timing
- •Recommendations
- •Conclusion
- •References
- •Introduction
- •Acute Liver Failure
- •Nutrition in ALF
- •Acute Pancreatitis
- •IAP Management
- •Conclusions
- •References
- •Introduction
- •Nutritional Considerations in Major Surgery
- •Nutritional Requirements During and After Major Surgery
- •Challenges in Meeting Nutritional Needs Post-Surgery
- •Strategies for Enhancing Nutritional Intake and Absorption
- •Intestinal Failure: Nutritional Challenges and Management
- •Impact of Intestinal Failure on Nutritional Status
- •Nutritional Management Strategies for Patients with Intestinal Failure
- •Role of Parenteral Nutrition and Enteral Nutrition in Intestinal Failure Cases
- •Open Abdomen: Nutritional Support and Wound Healing
- •Nutritional Requirements for Patients with Open Abdomen Wounds
- •Challenges in Providing Nutritional Support to Patients with Open Abdomen
- •Clinical Protocols and Guidelines for Nutritional Support
- •Conclusions
- •References
- •Introduction
- •Nutrition Therapy
- •Determination of Energy Expenditure
- •Route and Timing of Enteral Nutrition
- •Intolerance to Enteral Nutrition
- •Brain Energy Metabolism and Energy Dysfunction Following Acute Brain Injury
- •In Vivo Brain Energy and Glucose Monitoring
- •Alternative Energy Substrates
- •Lactate
- •Ketone Bodies
- •Immunonutrition and Micronutrients
- •Conclusions and Future Directions
- •References
- •Introduction
- •AKI and Cardiac Surgery
- •AKI and Vascular Surgery
- •AKI and Sepsis
- •AKI and Surgery
- •Trauma
- •Burn
- •AKI and COVID-19
- •Conclusion
- •References
- •Introduction
- •AKI Etiology
- •Subclinical AKI and AKI Biomarkers
- •Subphenotyping AKI
- •Conclusions
- •References
- •Introduction
- •What Are Biomarkers?
- •Novel Biomarkers: How Can They be Implemented?
- •Biomarkers for the Prediction of AKI and Detection of Subclinical Stages
- •Postoperative Biomarker-Guided Prevention of AKI in Patients at High Risk
- •Biomarkers for Other Indications
- •Conclusion
- •References
- •Introduction
- •The Machine Learning Arena
- •The Challenges of Timely Prediction of Acute Kidney Injury
- •Early Machine Learning Models for AKI Prediction
- •New Techniques for AKI Prediction Using Deep Learning ML Models
- •Clinical Decision Support Systems
- •The Translational Research Gap and the Value of Data Sharing: A Plea for Data Sharing
- •Limitations of Machine Learning Models
- •Conclusions
- •References
- •Introduction
- •Doppler Assesses Vascular Congestion
- •Arterial Renal Doppler Ultrasound in AKI
- •Integration of Renal Resistive Index and Intrarenal Venous Flow
- •Contrast-Enhanced Ultrasound for Assessing Renal Perfusion
- •Conclusions
- •References
- •Introduction
- •Renal Perfusion and Goals of Fluids in AKI
- •Clinical Evaluation of a Patient with AKI in ICU
- •Studies Which Investigated the Association of Fluid Therapy and AKI
- •Volume of Fluid
- •Type of Fluid
- •Crystalloids
- •Colloids
- •Starches
- •Gelatins
- •Conclusion
- •References
- •Introduction
- •Pathophysiology of Renal Perfusion
- •Acute Kidney Injury
- •Norepinephrine
- •Epinephrine
- •Dopamine
- •Vasopressin
- •Terlipressin
- •Angiotensin II
- •Conclusions
- •References
- •Introduction
- •Pharmacology of Diuretics
- •Loop Diuretics
- •Other Classes of Diuretics
- •Indications for Diuretics in AKI
- •Control of Fluid Overload
- •AKI Prognostication
- •Situations in Which Diuretics Are Not Indicated
- •AKI Recovery
- •How to Use Diuretics in the ICU
- •Class and Dose Selection
- •Modality of Loop Diuretic Administration
- •Conclusions
- •References
- •Introduction
- •What Is Acute Kidney Disease?
- •Clinical Course of AKD Within the ICU
- •Management of AKD in Critical Care and Beyond
- •Conclusions and Future Directions
- •References
- •Introduction
- •Renal Functional Reserve
- •Renal Functional Reserve and Renal Recovery After Acute Kidney Injury
- •Conclusion
- •References
- •Background
- •Membrane and Filter Characteristics
- •Geometric Characteristics
- •Performance Characteristics
- •Mechanisms of Fluid and Solute Transport
- •Treatment Modalities
- •Treatment Dose
- •Nomenclature of Renal Replacement Therapies
- •Continuous Therapies
- •Intermittent Therapies
- •Hybrid Therapies
- •Conclusion
- •References
- •Introduction
- •Dialysis Catheters: Technical Aspects
- •Selection of the Site for Dialysis
- •Catheter Insertion Technique
- •Dialysis Catheter Complications
- •Dialysis Catheter Maintenance
- •Conclusions
- •References
- •Introduction
- •Non-pharmacological Strategies to Reduce Membrane Fouling
- •Pharmacological Strategies to Reduce Membrane Clotting
- •Unfractionated Heparin (UFH) Systemic Anticoagulation
- •Systemic Anticoagulation with Low Molecular Weight Heparin (LMWH)
- •Regional Citrate Anticoagulation (RCA)
- •Systemic Anticoagulation with Direct Thrombin Antagonists
- •Nafamostat
- •Conclusions
- •References
- •Introduction
- •CRRT Dose/Outcome Studies: Consideration of Solute Kinetics
- •CRRT Dose as a Quality Criterion
- •CRRT Dose in the Context of Therapy Quality
- •Conclusions
- •References
- •Introduction
- •Patient Selection and Indications for Starting RRT
- •Strategies to Identify Need for RRT
- •Rationale for an Early Strategy to Starting RRT
- •Rationale for a Conservative Strategy to Starting RRT
- •RRT Replacement Therapy and Clinical Outcomes
- •Current Clinical Practice Guideline Recommendations
- •Clinical Trial Evidence on Timing of Starting RRT
- •Implications for Practice
- •Existing Knowledge Gaps and Future Research
- •Conclusions
- •References
- •Introduction
- •Early ICU Phase before KRT
- •Nutrition Care
- •Monitoring
- •ICU Phase with KRT
- •Gains and Losses During CRRT
- •Electrolyte Loss in CRRT
- •Macronutrient Loss in CRRT
- •Macronutrient Gain in CRRT
- •Micronutrients and Vitamin Loss in CRRT
- •Management of Losses During CRRT
- •Monitoring During CRRT
- •Indirect Calorimetry During CRRT
- •ICU Phase After CRRT
- •EN and PN Product Selection
- •Conclusions
- •References
- •Introduction
- •Nomenclature
- •Continuous Therapies
- •Intermittent Renal Replacement Therapies (IRRTs)
- •Hybrid Therapies
- •Technical Aspects of RRT Techniques
- •Hemodynamic Stability
- •Solute Clearance
- •Fluid Balance
- •Vascular Access
- •Anticoagulation
- •Drug Dosing
- •Patient Mobilization
- •The Process of RRT Prescription and Administration
- •Indications of RRT
- •Timing
- •Prescription Parameters
- •Dosing
- •Membrane Choice
- •Dialysate and Reinfusion Solutions
- •Limitations of RRT in Critical Care
- •Patient Safety During RRT in Critical Care
- •Introduction
- •Steps in RRT Management and Protocol Application

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L. Cattin et al.

Chapter 25
Nutrition in Neurocritical Care
Sandra Magnoni, Marina Munari, Adriano Bernini, and Chiara Robba
Introduction
Acute brain injuries (ABIs) present a significant global health challenge, marked by
a high incidence of overall mortality and the potential for long-term neurological
disabilities. The trajectory of ABI involves primary injury and a cascade of systemic
and local events leading to secondary injury [1, 2]. The brain, a vital regulator of
several metabolic activities, undergoes profou nd metabolic alterations following
ABI, resulting in aberrant cellular metabolism, hormonal shifts, and inflammatory
responses. These changes, such as hypermetabolism, hypercatabolism, and glucose
intolerance, exert a negative impact on patient outcomes [3–5]. Nutritional support
plays a crucial role in managing secondary metabolic disorders arising from ABI.
However, patients with ABI face a risk of substantial protein and energy deficits
Supplementary Information The online version contains supplementary material available at
https://doi.org/10.1007/978-3-031-66541-7_25.
S. Magnoni (
Anesthesiology and Pain Medicine Service, Department of Medicine, Surgery and Pharmacy,
University of Sassari, Sassari, Italy
e-mail: smagnoni@uniss.it
M. Munari
Sant’Antonio Anesthesia and Intensive Care Unit, University-Hospital of Padua, Padua, Italy
e-mail: marina.munari@aopd.veneto.it
A. Bernini
Department of Clinical Neuroscience & NeuroDigital@Neurotech, Lausanne UniversityHospital, Lausanne, Switzerland
C. Robba
Department of Anesthesiology and Intensive Care Medicine; IRCCS Policlinico San Martino,
Genoa, Italy
e-mail: chiara.robba@unige.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_25
✉)
293

294 S. Magnoni et al.
during hospitalization, leading to significant loss of lean body mass in the critical
care phase. The initiation of nutrition support is essential to meet patients’ nutritional
requirements, preventing malnutrition and mitigating the catabolic effects of ABI.
Determining energy expenditure and managing the route, timing, and intolerance to
enteral nutrition present challenges in this population [
6–8]. Additionally, under-
standing cerebral neuroenergetics needs and energy fuel supply is crucial. Recent
guidelines for traumatic brain injury (TBI) recommend by day 5, and no later
than day 7 post-injury to decrease mortality, and utilizing transgastric jejunal feeding
to reduce the risk of ventilator-associated pneumonia [
9]. However, these recom-
mendations lack individualization based on systemic and cerebral physiology, as
well as the course and severity of the injury. This chapter aims to provide an updated
perspective on the nutritional and metabolic management of critically ill patients
with acute brain injuries, incorporating recent evidence on brain metabolism.
Emphasis is placed on the pivotal role of nutrition as a therapeutic strategy to
maintain an adequate substrate deli
very to the injured brain.
Nutrition Therapy
Determination of Energy Expenditure
Critically ill patients with acute brain injuries (ABIs) are prone to malnutrition
[6]. Early nutritional support is crucial in this population due to known
hypermetabolism, primarily mediated by glucocorticoids, catecholamines, and glucagon [5]. However, metabolic requirements may fluctuate throughout the intensive
care unit (ICU) course as various therapies commonly used in neurocritical care
influence metabolic demands, including sedation and temperature management
strategies [10].
The optimal caloric goal in neurocritically ill patients remains controversial
11, 12]. In acute stroke patients, energy requirements vary widely depending on
[
stroke type. More than 40% of patients with ischemic stroke may experience a
negative nitrogen balance, indicating catabolism and malnutrition. In the first
2–4 weeks following brain trauma, resting energy expenditure (REE) has been
found to be as high as 200% of usual needs in two-thirds of patients, depending
on the severity of the neurotrauma and level of recovery [ 7 ]
rhage can induce a catabolic state similar to traumatic brain injury (TBI), with a
potential association between cerebral vasospasm and increased catabolic state [13].
Indirect calor
imetry (IC) is the gold standard method for determining energy
requirements when available. However, variables such as sedation, fever, air leakages in the respiratory circuit, high positive end-expiratory pressure (PEEP >10),
and fraction of inspired oxygen (FiO
) >80% can affect the accuracy of the
2
measurement. IC systems estimate respiratory gas exchange as a surrogate for substrates consumed and produced during metabolism, providing a measurement of
REE extrapolated over a 24-h period. IC determines REE by measuring oxygen
consumption (VO
, in L/min) and carbon dioxide production (VCO2, in L/min).
2
. S
ubarachnoid hemor-

25 Nutrition in Neurocritical Care 295
IC measurements are snapshots of continuously changing metabolic states,
requiring a steady state during the procedure to avoid undue influence on REE
interpretation [14]. Calibration of the IC systems, minimal ventilator circuit or
endotracheal tube leaks, FiO
< 80%, and inspired tidal volumes larger than the
2
lower limit set by the manufacturer should be ensured before measurement. The
patient should be at rest, with the last endotracheal tube suction performed at least
20 min before the measurement, no ventilat ory changes, and minimal changes in
medications administered in the previous 60 min. Continuous enteral and parenteral
nutrition should not be discontinued. While IC is noninvasive, it is costly and
requires specially trained clinicians. Factors in the acute phase of brain injury,
including body temperature, sedative use, mechanical ventilation, and injury severity, can modify REE, making it challenging to predict individual nutritional requirements. Additionally, IC use may be limited by the need for high positive pressure
and oxygen settings in mechanically ventilated patients, including those requiring
noninvasive mechanical ventilation. IC should be routinely repeated as conditions
change to ensure accurate reflection of the patient’s metabolic state and prevent
under or overfeeding. In the absence of IC, weight-adapted formulas may be used
when applicable.
Route and Timing of Enteral Nutrition
Early enteral nutrition (EN) is suggested as a best practice and has been shown to
lead to improved clinical outcomes, yet only a limited numbe r of studies have
investigated nutritional care in critically ill patients with acute brain injuries (ABIs).
Clinical pract
15], Clinical Canadian Practice [16], and European Society of Intensive Care
[
ice guidelines from the Society of Critical Care Medicine (SCCM)
Medicine [17] all recommend initiating early EN within 24–48 h of admission for
critically ill adult patients. For neurological patients at high nutritional risk, early EN
should be initiated with the same timing as indicated in most international critical
care guidelines. The primary purpose of nutritional therapy in neurocritical patients
is to identify, prevent, and treat malnutrition and its complications, such as bacterial
translocation, an increased risk for systemic infection and inflammation, and the
18].
likelihood of multiple organ dysfunction [
This intervention is critical in limiting
the intensity of the in flammatory response to brain injury. Early EN supports the
functional integrity of endothelial cells and junctions within the gut and stimulates
gastrointestinal (GI) post-prandial hyperemia, enhancing mucosal blood flow, which
counterbalances alterations in GI blood flow due to situations of increased intrathoracic pressure and during vasopressor use. Nutrition therapy should be initiated
early, aiming to reach 80% of estimated or measured energy expenditure over the
next 7 days: 20–25 kcal/kg of actual body weight per day during the acute phase and
reaching 25–30 kcal/kg body weight per day in the stable phase [
19].
Care must be
taken to optimize nutrient delivery and prevent overfeeding. The use of repeated IC
measures or simplistic predictive equations is recommended when determining

296 S. Magnoni et al.
needs and feeding goals, as previously reported. Researchers generally agree that
early enteral feeding improves outcomes, though there is debate regarding dose
adequacy and advancement goals concerning how much and how quickly to advance
calorie delivery in critically ill patients.
If EN is contraindicated, in s
(PN) should be implemented progressively within 3–7 days rather than providing no
nutrition, although it is associated with a higher risk of complications and mortality [20].
everely malnourished patients, parenteral nutrition
Intolerance to Enteral Nutrition
There are numerous reasons for intolerance to enteral nutrition (EN) in patients with
acute brain injuries (ABIs). Neurotrauma increases intracranial pressure and damages the autonomic nervous system [
is one of the major factors causing feeding intolerance, exhibited in 45–50% of
traumatic brain injury (TBI) patients [19]. Gastrointestinal hypokinesia typically
persists during the first 1– 2 weeks after injury, and the delay in emptying may
continue depending on the severity of the brain injury and if elevated intracranial
pressure persists. Sedatives, such as opioid agents, may delay gastric emptying,
consequently increasing gastric residual volume and the risk of vomiting. Delayed
gastric emptying may be assumed when there is feeding tube intolerance with a large
gastric residual volume. Ileus may be present, but it appears more commonly when
brain injury is accompanied by spinal cord injury.
Additionally, several aspects of patient care can interrupt EN, such as surgery,
extubation or intubation, or radiological exams. Gastric residual volume (GRV) is
the volume of gastric fluid removed by aspirating stomach contents with a syringe
attached to a gastric tube. GRV measurement, as in the general population, must not
be systematically monitored [19]. Current guidelines recommend against using GRV
due to a lack of correlation with the incidence of pneumonia, regurgitation, or
aspiration [
the only FDA-approved promotility agent. The ESPEN guidelines recommend that
post-pyloric feeding should be considered in critically ill patients whose gastric
feeding intolerance has not been resolved with prokinetic agents or in patients whose
risk for aspiration is high [20].
15]. Gastric intolerance must be treated using metoclopramide, currently
21]. Gastroparesis, or delayed gastric emptying,
Brain Energy Metabolism and Energy Dysfunction Following Acute Brain Injury
The human brain, although representing only about 2% of the body weight, is a
highly demanding organ that consumes approximately 20% of the total body energy.
Consequently, it is highly vulnerable to periods of reduced substrate provision

25 Nutrition in Neurocritical Care 297
[22]. Glucose is the principal substrate for the brain and is also crucial for several
pathways that are essential for brain cell survival [23]. Continuous glucose delivery
to the brain is facilitated by transporters (GLUT 1), which are mostly independent of
insulin action and depend on a constant and adequate glucose supply from the blood.
In traumatic brain injury (TBI), a reduction in cerebral glucose metabolism is
observed post-injury and appears to be independent of ischemia [
increase in
brain glucose utilization is observed—a form of hypermetabolic period,
24]. Initially, an
leading to increased cerebral glycolysis, lactate, and pyruvate, causing an elevation
of the lactate/pyruvate (LP) ratio. This short-lived adaptive response aims to supply
energy to restore or maintain ionic balance and membrane function during injury.
Due to the limited brain capacity to store glycogen, “hyper-glycolysis” is rapidly
n, r
followed by tissue exhaustio
“hypom
etabolism
” as repeatedly shown by post-TBI reduction in the cerebral
,
educed glucose utilization, secondary
metabolic rate of glucose and suppressed cerebral glucose uptake. Importantly,
glucose transport mechanisms to the injured brain may also be impaired, further
exacerbating brain glucose depletion [
25, 26].
When brain glucose supply is diminished (e.g., during starvation or sustained
energy demand, as in acute brain injury), the brain can switch to adaptive alternative
energy metabolic and “glucose sparing” pathways and substrates, aiming to preserve
its function [
27]. Well-known alternative substrates include lactate and ketone
bodies (KBs) (i.e., acetone, acetoacetate (AcAc), and β-hydroxybutyrate—BHB)
produced in the liver from the mobilization of free fatty acids (FFAs) in adipose
tissue (Fig. 25.1). Additional substrates include energy precursor amino acids such
as ketogenic amino acids (KAAs), glucogenic amino acids, branched-chain amino
acids, and medium-chain triglycerides [
28].
Fig. 25.1 Brain energy metabolism in traumatic brain injury patients General overview of all
the adaptive mechanisms that take place following TBI in adult patient. Picture adapted from (Eiden
M. et al., [29]), courtesy of M. Oddo

298 S. Magnoni et al.
In Vivo Brain Energy and Glucose Monitoring
In vivo exploration of the injured human brain can be achieved through the intracerebral microdialysis (CMD) technique, enabling repeated sampling and direct measurement of the brain interstitial tissue concentrations of main cerebral energy
metabolites, including glucose, lactate, and pyruvate. While it provides a regional
assessment of brain metabolism—in contrast to neuroimaging techniques (magnetic
resonance spectroscopy—MRS; positron emission tomography—PET) or jugular
bulb venous catheterization, which offer measurement of global brain metabolic
function—a major advantage of the CMD technique is its ability to enable an online
semicontinuous (every 1–2 h) measurement of energy metabolites at the patient’s
bedside. Furthermore, CMD provides immediate insights into dynamic variations of
cerebral metabolic function and a timely response to therapy aiming at restoring
energy metabolism function. The CMD, through the monitoring of the LP ratio
(normal brain values 20 ± 3, as opposed to 10 ± 3 systemically)—the main
biomarker of cerebral oxidative metabolism—and glucose, the main energy substrate (normal brain values 1–2 mmol/L), has thus evolved to become a trigger and
target of therapeutic intervention and a robust predictor of patient outcome [30, 31].
Cerebral metabolic dysfunction detected with CMD has been investigated as a
potential therapeutic target by the individualized use of insulin therapy (“gentle” vs
“tight” glycemic control) [32]. Along the same lines, CMD has been used with very
promising results as a tool to guide nutrition therapy with standard formula or with
lactate and KBs as alternative substrates in patients with TBI [33–35]. To maintain
the targeted levels of 8–11 mmol/L of plasma glucose in patients with acute brain
injury, ideally in combination with monitoring of brain glucose to ensure values of
1–2 mmol/L, frequent glucose monitoring is fundamental [36]. However, the optimal frequency or duration for blood glucose monitoring remains poorly defined
[37]. Continuous glucose monitoring (i.e., through subcutaneous devices) represents
a potentially better alternative to the standard point-of-care intermittent methods for
glucose monitoring (i.e., on arterial blood) [38].
Alternative Energy Substrates
Lactate
Lactate can be mobilized after TBI and acts as substrate. The body will attempt to
support the increased energy needs of the injured brain in mobilizing the extracerebral glycogen reserves. In TBI patients, high rates of systemic lactate production
(up to 70% compared to healthy volunteers) from hepatic gluconeogenesis have
been measured, confirming lactate as energy alternative in this setting
[39, 40]. These clinical data are in line with the astrocyte-neuron lactate shuttle
concept, i.e., the capaci ty of astrocytes to transport lactate to neurons to be used as

25 Nutrition in Neurocritical Care 299
energy substrate, and confirm the large body of experimental data demonstrating that
lactate can indeed be used as immediate extra fuel by brain cells [41].
In TBI patients, recent studies p
roved that brain lactate uptake is significantly
increased after the injury and the administration of hypertonic lactate solutions can
contribute to oxidative cerebral metabolism (via tricarboxylic acid cycle) to overcome the increased energy demand, thus sparing glucose and being at the same time
neuroprotective [42]. This proves that alternative substrates can be utilized by the
injured brain when facing glucose shortage and open to therapies aiming at
supplementing the injured brain with alternative non-glucose substrates to compensate for decreased cerebral metabolic rate for glucose consumption. However, the
use of hypertonic lactate to improve brain energy metabolism remains investigational, though it may be considered safe and effective as hypertonic solutions [43].
Ketone Bodies
KBs (including principally AcAc and BHB) are key energy substrates that play
supportive roles in the setting of energy (glucose) shortage [44]. KBs are endogenously produced by the liver upon mobilization of FFAs from adipose tissue and
KAAs. Naturally, endogenous blood KB levels are about 0.1–0.2 mmol/L, up to
1–2 mmol/L after prolonged (2–3 days) fasting [45].
atie
In p
nts with TBI and other neurological diseases, KBs have the potential to
satisfy brain energy demand in conditions of reduced glucose availability, thus
preserving limited glucose reserve. KBs reach the brain through mono-carboxylate
transporters. The main advantage of KBs is that they are more energy-efficient than
glucose because they do not require entering the glycolytic pathways and they
consume fewer NAD molecules during acetyl-CoA synthesis (4 NAD
per glucose molecule, no NAD
+
for AcAc, and one NAD+ to convert BHB to AcAc),
thereby leading to an increased NAD availability and concomitantly reducing L/P
ratio. Apart from being a supportive energy substrate, KBs confer significant
neuroprotection including attenuation of oxidative stress, improve cerebral blood
flow and mitochondrial and adenosine trisphosphate production, and reduce apoptotic cell death and microglial activation [
45].
Ketone supplementation is achieved either by endogenous nutritional ketosis
(using modified ketogenic dietetic formulations, with medium-chain fatty acids—
KDs) or by exogenous enteral ketosis (using ketone esters (KE) or ketone salts
(KS)). Notably, the ketoge nic diet has long been used to control seizures, and
prospective controlled studies have shown its effectiveness against medically intractable epilepsy mainly in children. Commercial ketogenic formulation can be safety
administered enterally to TBI patients with no clinically relevant changes in the acid
base status (i.e., metabolic acidosis) or other adverse effects [
46]. The advantage of
newly available KE and KS is the rapid achievement of effective therapeutic blood
KB levels (approx. 2–4 mmol/L), contrary to modified KDs which only reach
approx. 0.5–1 mmol/L KBs in the blood and in a relatively slower time [47].
+
molecules

300 S. Magnoni et al.
Immunonutrition and Micronutrients
Immunonutrition with amino acid-containing and/or omega-3 fatty acid
(docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) formulation may
exert anti-inflammatory properties and stimulate protein synthesis in patients with
ABI [48]. However, further additional research with high quality studies and larger
sample size is needed, to determine whether immunonutrition translates into better
clinical outcomes. Nonetheless, the use of immune-enhancing enteral formula
containing arginine, glutamine, and omega-3 fatty acid may be recommended,
based on expert opinion, paying attention to overdosage as excessive dose or
supplementation (i.e., with glutamine) may cause harm in critically ill patients.
Micronutrients, such as vitamins, minerals, and trace elements (mainly magnesium, zinc, copper, manganese, chromium, and selenium), are included in the
nutritional formulations for critically ill patients, in concentrations respecting their
daily requirements. There is insufficient evidence for an enhanced metabolic consumption of these elements in the acute phase of ABI and to recommend its routine
supplementation.
Several human and animal studies evaluated the neuroprotective effects of magnesium in the acute phase of TBI and in subarachnoid hemorrhage to prevent
vasospasm. Low serum magnesium levels on admission are frequently found in
TBI patients, and hypomagnesemia appears to be an independent factor related to
poor outcome [49]. Despite the absence of strong evidence, maintaining magnesium
levels in the normal range may be recommended in ABI patients.
Conclusions and Future Directions
Because of the hypermetabolic state in patients after ABI, in the absence of contraindications, it is fundamental that nutritional supplementation begins within 24–48 h
from injury and that full nutritional requirements be achieved within 7 days.
s m
EN i
should be considered as first-line nutrition support therapy. If EN is contraindicated,
PN can be started, although it is associated with a higher risk of complications and
mortality. When starting nutrition in ABI patients, physicians should pay attention to
the pathophysiological mechanisms which can lead to altered glycemic control, loss
of body mass, and especially cerebral metabolic dysfunction, which can impact
outcomes. In this context, multimodal monitoring with CMD can be used as
integrated approach to optimize immune system and organ function and to ensure
an adequate delivery of substrate to the brain.
Research is
nisms and on a more individualized treatment of patients. The use of biomarkers, for
instance, is gaining particular interest as easy methods to assess cerebra l damage
progression. Recently, a combination of immuno-modulating nutrient
ore cost-effective and physiologically appropriate, and therefore, it
currently moving towards a better understanding of these mecha-

25 Nutrition in Neurocritical Care 301
supplementation has been suggested, with the aim to modulate the
neuroinflammation cascade leading to free radical generation, oxidative stress, and
excitatory toxicity [48].
Ketogenic formulas are also promising nutritional therapies to meet the needs of
the brain during the energy crisis in ABI.
Finally, to better understand the physiological needs
of acute brain injured
patients, the use of measured REE through indirect calorimetry is highly
recommended, to target nutritional requirements or monitor nutritional support
with the aim to understand the real metabolic needs of the patients.
Key points are illustrated in the Supplementary Material (slide 1–3).
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