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mechanically ventilated patients admitted to intensive care unit. Pak J Med Sci. 2019;36:48–53.
https://doi.org/10.12669/pjms.36.2.1321.
31. Williams DGA, Molinger J, Wischmeyer PE. The malnourished surgery patient: a silent epidemic in perioperative outcomes?
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32. Pironi L, Arends J, Bozzetti F, Cuerda C, Gillanders L, Jeppesen PB, et al. ESPEN guidelines on chronic intestinal failure in adults. Clin Nutr. 2016;35:247–307. https://doi.org/10.1016/j.
clnu.2016.01.020.
33. O’Hanrahan T, Irving MH. The role of home parenteral nutrition in the management of intestinal failure – report of 400 cases. Clin Nutr. 1992;11:331–6. https://doi.org/10.1016/
0261-5614(92)90083-3.
34. Dissanaike S, Shelton M, Warner K, OKeefe GE. The risk for bloodstream infections is associated with increased parenteral caloric intake in patients receiving parenteral nutrition. Crit Care. 2007;11:R114. https://doi.org/10.1186/cc6167.
35. Olieman J, Kastelijn W. Nutritional feeding strategies in pediatric intestinal failure. Nutrients. 2020;12:177. https://doi.org/10.3390/nu12010177.
36. Blumberg JB, Cena H, Barr SI, Biesalski HK, Dagach RU, Delaney B, et al. The use of multivitamin/multimineral supplements: a modied Delphi consensus panel report. Clin Ther. 2018;40:640–57. https://doi.org/10.1016/j.clinthera.2018.02.014.
37. Shah S, Hollands JM, Pontiggia L, Bingham AL. Impact of the time to initiation of parenteral nutrition on patient outcomes in critically ill adults. Nutr Metab Insights. 2019;12:
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38. Sartelli M, Abu-Zidan FM, Ansaloni L, Bala M, Beltrán MA, BifWL, et al. The role of the open abdomen procedure in managing severe abdominal sepsis: WSES position paper. World J Emerg Surg. 2015;10:35. https://doi.org/10.1186/s13017-015-0032-7.
39. Hunt L, Frost SA, Hillman K, Newton PJ, Davidson PM. Management of intra-abdominal hypertension and abdominal compartment syndrome: a review. J Trauma Manag Outcomes. 2014;8:2. https://doi.org/10.1186/1752-2897-8-2.
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41. Worhunsky DJ, Magee G, Spain DA. Challenges in the management of the open abdomen. ICU Dir. 2013;4:33–9. https://doi.org/10.1177/1944451612469628.
42. Kirkpatrick AW, Coccolini F, Ansaloni L, Roberts DJ, Tolonen M, McKee JL, et al. Closed or open after source control laparotomy for severe complicated intra-abdominal sepsis (the COOL trial): study protocol for a randomized controlled trial. World J Emerg Surg. 2018;13:26. https://
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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 signicant 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 inammatory responses. These changes, such as hypermetabolism, hypercatabolism, and glucose intolerance, exert a negative impact on patient outcomes [35]. 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 decits
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 SantAntonio 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 signicant loss of lean body mass in the critical care phase. The initiation of nutrition support is essential to meet patientsnutritional 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 uctuate throughout the intensive care unit (ICU) course as various therapies commonly used in neurocritical care inuence 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 rst 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 inuence 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 reection of the patients 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 inammation, and the
18].
likelihood of multiple organ dysfunction [
This intervention is critical in limiting the intensity of the in ammatory 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 ow, which counterbalances alterations in GI blood ow 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 rst 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 uid 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 observeda 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-glycolysisis 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 sparingpathways 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-hydroxybutyrateBHB) 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 (gentlevs tightglycemic 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 [3335]. 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 dened [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, conrming 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 conrm 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 signicantly 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-efcient 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 signicant neuroprotection including attenuation of oxidative stress, improve cerebral blood ow 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 modied 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 modied 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-inammatory 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 insufcient 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 rst-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 neuroinammation 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).

References

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