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7 Dynamic Metabolic Changes Measured by Indirect Calorimetry 75
In this phase of mitochondrial metabolic and bioenergetic downregulation, an
excessive supply of metabolic substrates may exacerbate cellular damage, as the
mitochondria struggle to use these substrates for energy purposes, resulting in
increased oxidative damage. Var ious factors contribute to the reduced mitochondrial
capacity for oxygen utilization and oxidative phosphorylation, including an excess
of inflammatory mediators, hormonal function alterations, and reduced production
of mitochondrial proteins. This downregulation of mitochondrial function needs
consideration when planning energy support in the diverse metabolic phases of
critical illness [9] (Fig. 7.1).
Metabolic alterations associated with acute disease are proportionate to the
severity of the illness and involve changes in body temperature and heart rate
[7]. Essentially, there is a reduction in metabolism in the very early phase of trauma
(ebb phase), leading to a catabolic response where the body depletes its stores of
glycogen, fat, and muscle in the flow phase. This is followed by a resumption of
protein synthesis and replenishment of lean mass in the anabolic phase once critical
disease is under control (recovery phase).
In the hyperacute phase of critical or post-traumatic illness, the neuroendocrine
response aims to maintain homeostasis, ensuring the survival of the organism.
Metabolically, this response is characterized by decreased oxygen consumption,
decreased body temperature, and increased urinary nitrogen excretion. This phenomenon is hypothesized to be the result of a decrease in mitochondrial function,
acting as an adaptive strategy of metabolic hibernation to prevent cell death due to
energy substrate overload when mitochondria cannot keep up with energy demand.
In patients with sepsis, reduced oxygen utilization by 22–42% was found compared
to healthy volunteers. A higher Resting Energy Expenditure (REE) in severe sepsis
patients has been associated with higher mortality, supporting the notion that
metabolic downregulation might sometimes be adaptive rather than a sign of
malfunction.
An important metabolic characteristic of this phase is the hyperglycemic
response, directly proportional to the severity of the acute critical event in terms of
the extent of the trauma and tissue damage. Early in the ebb phase, liver glycogen
stores are used for a period of about 12–24 h, producing an endogenous share of
energy from glucose itself. Subsequen tly, glucose synthesis is ensured via a flow of
amino acids, lactates, pyruvate, and glycerol, which are utilized for hepatic and renal
gluconeogenesis. About 360 g of endogenous glucose, equal to about 1300 kcal, is
produced in this phase through gluconeogenesis. Hepatic gluconeogenesis is essential for the supply of glucose to non-insulin-dependent cells such as neurons,
erythrocytes, and inflammatory cells present in the wound.
Quant
itatively, i
n this phase, lactates are the most important substrates used for
gluconeogenesis, while in the following catabolic phase, amino acids of muscle
origin are mainly used. Lactates are derived from the anaerobic metabolism of
glucose in peripheral tissues and the liver via the cycle of Cori [7–9].
The hypers
ecretion of glucagon, catecholamines, cortisol, and growth hormone
(GH), along with the inflammatory reaction generated by cytokines, determines
peripheral resistance to insulin, worsening hyperglycemia, and inhibiting anabolism.
76 M. Scarcella et al.
Table 7.1 Factors Influencing Resting Energy Expenditure (REE)
Increase REE Decrease REE
Caucasian ethnicity Female sex
Overfeeding Older age
Physical exercise, agitation Low lean body mass
MV Neuro muscolar blockade
Hypertermia Sedation
Hypertyroidism Paralysis, coma
Metabolic acidosis Low minute volume
HR Hypotermia
Stress (cortisol, glucagon, norepinephrine) Hypotyroidism
Burn injury Metabolic alkalosis
Systemic
Citrate anticoagulation for CRRT
Legend: CRRT continuous renal replacement
inflammation, sepsis Medication: beta- blockers
therapy, HR heart rate, MV mechanical ventilation
The dysfunction of mitochondria in the acute phase of critical illness, during which
the organelles are also reduced in number, could explain why exogenous subst rates
are not used, furthermore increasing mitochondrial oxidative damage.
After several days, Resting Energy Expenditure (REE) increases again, and as
endogenous energy production is simultaneously reduced, the risk of underfeeding
increases. This might be
considered the chronic metabolic phase of critical illness.
As a matter of fact, an increase in REE has been demonstrated in both surgical
and medical ICU patients, with a maximum REE found about the ninth or tenth day
after ICU admission. Clinical data on the course of energy expenditure (EE) during
the recovery or convalescence phase of critical illness are scarce and usually derived
from studies with a small sample size. When available, measured REE is still
significantly elevated several weeks after ICU admission, as shown in burns, trauma,
and sepsis patients, including recently in COVID-19. During this phase, Total
Energy Expenditure (TEE) is likely to increase above REE due to increased physical
and mental activity, as the focus of treatment shifts toward rehabilitation. Ideally, the
patient enters a recovery phase with enhanced anabolism, requiring more substrates.
In contrast, the persistent inflammation, immunosuppression, and catabolism syndrome (PICS) may arise in some patients. Metabolically, PICS is characterized by a
persistent catabolic state and hormonal disruption leading to anabolic resistance and
inflammation-induced cachexia [8] (Table 7.1).
However, when the transition into different metabolic phases occurs in individual
patients, it is still unidentifiable in clinical practice. Because of not only the high
variability between patients, but also during the disease in the individual patient,
regular measurements of EE by IC could provide a better target for nutrition therapy
in the subsequent phases of disease and convalescence.
Indirect calor
imetry is the method that allows to evaluate the energy expenditure
through the measurement of the variations of concentration of oxygen and carbon
7 Dynamic Metabolic Changes Measured by Indirect Calorimetry 77
dioxide in the respiratory gases and to calculate the oxidation of the energy substrates (carbohydrates, lipids, proteins).
Calorimetry makes it possible to
measuring oxygen consumption (VO
tion (VCO
), the heat (or energy) produced by the body in the unit of time.
2
evaluate energy expenditure after calculating, by
= volume/min) and carbon dioxide produc-
2
If we assume that all the oxygen consumed is used by the body to oxidize the
energy substrates and that all the carbon dioxide produced is eliminated in the lungs,
it is then possible to calculate the energy expenditure (EE) of the individual.
Energy production is therefore calculated by measuring the exchange of respiratory gases (VO
and VCO2) associated with the oxidation of the four main macro-
2
nutrients: carbohydrates, lipids, proteins, and alcohol. There are two different ways
of performing indirect calorimetry. In the so-called Whole Body indirect procedure,
the subject is in a closed and ventilated chamber with a constant flow, from which air
samples are continuously collected to analyze the concentration of oxygen and
carbon dioxide. The difference between the concentration of the two gases inside
and outside the room allows for the calculation of the subject’s energy expenditure
(EE). An alternative method involves collecting the exhaled gases through a mask, a
mouthpiece, or a “canopy” that surrounds the subject’s head. In the first case, only
the exhaled gases are collected, while in the second case, the exhaled air is diluted
inside the “canopy” and drawn in by a pump with a constant airflow.
and VCO2 are calculated from the subject ’s pulmonary ventilation (VE) and
VO
2
from the concentrations of O
IC m
and FeCO2).
2
easures r
espiratory gas exchange to estimate energy metabolism. On a
air (FeO
and CO2 in ambient air (FiO2 and FiCO2) and expired
2
cellular level, metabolism entails the production of adenosine triphosphate (ATP),
with carbon dioxide (CO
) and water as by-products, by consuming oxygen (O2) and
2
burning substrates such as glucose, free fatty acids, and amino acids. As the energy
produced equals the energy consumed, IC measuring O
consumption and CO
2
production represents real-time energy metabolism. Direct calorimetry, in contrast,
measures heat production and, therefore, energy production directly, but this method
is not feasible in clinical practice, as it requires the patients to be measured inside an
. M
9]
insulated chamber [
oreover, direct calorimetry does not give any meaningful
information as regards the type of substrate used by the body.
IC determin
es REE by measuring oxygen consumption (VO
carbon dioxide production (VCO
, in L/mi n) and subsequently calculates REE
2
, in L/min) and
2
according to the adjusted Weir’s equation, based on the caloric values of the
oxidation of 1L of O
metabolizing a fat and carbohydrate mixture. The original
2
Weir equation includes urinary nitrogen measurement content representing protein
oxidation. However, IC uses an adjusted version of the equation, based on the
Haldane transformation, which assumes that nitrogen is physiologically inert, and
therefore, the volume of inspired nitrogen must equal the volume of expired nitrogen. This adjustment excludes the need for urinary measurem ents, which improves
feasibility and introduces only a small error up to 1– 2% in final the REE calculation.
2
78 M. Scarcella et al.
Table 7.2 Caloric yield and
respiratory quotient (R/Q) for
different macronutrients
REE kcal=dayðÞ= 1:44 × VO2 mL= minðÞ× 3:94½]þ VCO2 mL= minðÞ× 1:11½ð
Nutrient Caloric yield kcal/g R/Q
CHO 4.18 1.00
Fat 9.46 0.71
Protein 4.32 0.81
Legend: CHO carbohydrates
]Þ
Furthermore, IC calculates the respiratory quotient (RQ) during the measurement,
i.e., the CO
-production to O2-consumption ratio: RQ = VCO2/VO
2
2
The RQ is an indicator of the composition of substrate use. It indicates which
macronutrients are being metabolized,
specific costs of oxygen and CO
as different energy pathways are used, and
production characterize the single macronutrients.
2
A human RQ of 1.0, 0.8, and 0.7 represents glucose, protein, and fat oxidation,
respectively. The physiological range of the RQ is 0.67–1.3; therefore, it can also be
used as a quality indicator of the measurement adequacy. The approximate respiratory quotient of a mixed oral diet is 0.8 (Table 7.2).
REE in Different Clinical Scenarios
In patients with
REE. In chronic pathologies, both conditions of hypermetabolism and conditions of
hypometabolism have been observed due to metabolic alterations, modifications of
lean body mass, organ function, and the presence of an inflammatory state.
In the postoperative period after uncomplicated surgery, for minor and medium
surgery, an increase in basal metabolic rate of about 7% is expected, as an effect of
the surgery itself, which cannot be predicted by the equations [10]. Non-septic
pancreatitis patients have a 110 ± 11% increase in REE. Sepsis is characterized by
a hyperdynamic cardiovascular response in response to infection with a 55 ± 14%
increase in REE for sepsis, 24 ± 12% for sepsis syndrome, and 24 ± 2% for septic
shock [11]. The oncological pathology influences the metabolism in a variable way
according to the type of tumor, the location, the extension, and the presence of
metastases.
or c
As f
chronic kidney disease conditions, while other similar studies showed instead a
reduction of the metabolism [12]. In diabetes there is a 5–10% increase in the REE
due to an increase in the activity of the sympathetic nervous system which is
antagonized by antidiabetic drugs [13]. In patients with COPD, there is an increase
in energy expenditure related to the severity of the disease due to the increase in
respiratory effort and despite the consequent reduction in physical activity [14]
Alterations
patients have a much higher basal metabolic rate than anorexic patients, who have a
chronic disease, it is more difficult to establish individual changes in
hronic illnesses, some studies reported an increase in REE in patients with
.
of the basal metabolic rate are also found in eating disorders: obese
7 Dynamic Metabolic Changes Measured by Indirect Calorimetry 79
low REE due to adaptation to fasting, due to the loss of fat and fat mass [15]. In
neurological disorders such as Alzheimer’s disease, Parkinson’s disease,
Huntington’s disease, and amyotrophic lateral sclerosis, an increase in basal metabolic rate has been found due to motor, endocrine, and metabolic abnormalities [
16].
Factors that Influence Metabolism
Multiple factors have been found to influence REE: endogenous physiologic
changes such as increased temperature, increased minute volume, and increased
heart rate all can elevate metabolic rate and increase REE. In addition to these
physiological parameters, clinical interventions such as the use of citrate during
renal replacement (CRRT) therapy, caloric intake, vasopressor/inotrope use, and/or
rehabilitation activity will also increase REE. Metabolism can be minorly reduced
(~6.6%) by paralysis and possibly with deep sedation and lower core temperature
(hypothermia) if compensating mechanism like shivering are disabled.
The only tool to assess the effect of these ever-evolving modulators of metabolism and REE is the use of indirect calorimetry (IC) [17].
The continuous changes in physiology and clinical care of the ICU patient also
demand that repeated, longitudinal IC measurements should be performed when any
significant change in clin ical condition (i.e., new infection or surgery) or clinical care
of the patient occurs [5].
Increased metabolism is also associated with the use of vasoactive drugs and
young age. On the other side, iatrogenic factors such as beta-blockers, analgesics,
and sedatives decrease the response and attenuate the hypermetabolism. Other
factors that decrease energy expenditure are immobilization, atrophy, loss of lean
body mass, and mechanical ventilation. Recent trials have shown that the influences
of CRRT and ECMO methods on indirect calorimetry are not significant as these are
closed systems; therefore, it is not necessary to modify the Weir’ s formula to take
their presence into account However, it must be taken into consideration that CRRT
could reduce the value of CO
the following balance:
, varying the concentration of bicarbonates, acting on
2
þ H2O $ H2CO3 $ HCO3 þ H
CO
2
þ
Also, continuous hemodialysis systems using citrate (CVVH) can theoretically
affect Resting Energy Expenditure (REE) in two different ways: CRRT produces
heat loss and immune activation, and the molecules that act as an energy substrate
are exchanged inside the filter, in addition to citrate itself [15, 16]. Indirect calorimetry is, therefore, a tool of fundamental importance, necessary to optimize nutritional
therapy in various critical conditions. The ESPEN guidelines suggest gradually
increasing exogenous nutritional support to respect the endogenous production of
glucose in the early phase of the disease and to avoid overnutrition. Additionally,
80 M. Scarcella et al.
they recommend gradually increasing nutritional support in the late phase to prevent
conditions of undernutrition [5]. Recent techno logical developments allow the use of
calorimetry in a higher number of patients, both in spontaneous breathing and in
mechanical ventilation, effectively improving mortality and morbidity, reducing the
risk of under or overfeeding in critically ill patients [18].
Conclusions
Understanding and managing the EE of critically ill patients is paramount for
providing effective nutritional support throughout various phases of the disease.
The metabolic response to traumatic stress involves distinct phases, such as the ebb
phase characterized by reduced metabolism and the flow phase marked by
hypermetabolism. IC emerges as a crucial tool to accurately measure EE, especially
when considering the poor correlation between measured and predicted EE in
critically ill patients using formulaic approaches. Factors influencing met abolism,
such as physiological changes, clinical interventions, and various pathologies,
further underscore the need for personalized approaches. IC remains indispensable
in assessing the impact of these factors on metabolism. While technological
advancements enhance the feasibility of IC, its role in optimizing nutritional therapy,
preventing overnutrition or undernutrition, and improving patient outcomes cannot
be overstated. In conclusion, a nuanced understanding of the metabolic dynamics in
critical illness, coupled with the precise measurement afforded by indirect calorimetry, is indispensable for tailoring effective nutritional interventions and ultimately
improving the prognosis of critically ill patients.
References
1. Corish CA, Kennedy NP. Protein-energy undernutrition in hospital in-patients. Br J Nutr.
2000;83:575–91.
2. Delsoglio M, Achamrah N, Berger MM, et al. Indirect calorimetry
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3. Casaer MP, Mesotten D, Hermans G, et al. Early versus late parenteral nutrition in critically ill
adults. No Engl J Med. 2011;365:506–17.
4. Moonen HP, Beckers KJ, van Zanten AR. Energy expenditure and indirect calorimetry in
critical illness and convalescence: current evidence and practical considerations. J Intensive
Care. 2021;9:8.
5. Singer P, Reintam Blaser A, Berger MM, et al. ESPEN guideline on clinical nutrition in the
intensive care unit. Clin Nutr. 2019;38(1):48–79.
6. Fraipont V, Preiser JC. Energy estimation and measurement in critically ill patients. J Parent
Enter Nutr. 2013;37:705–13.
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bedside. Indian J Endocrinol Metab. 2017;21:594–9.
R, Ramachandran R, Venkatesan P, et al. Indirect calorimetry: from bench to
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8. Merritt R. Use of indirect calorimetry in critically ill patients. In: ASPEN nutrients support
practice man. 2nd ed. Silver Spring: American Society for Parenteral and Enteral Nutrition;
2005. p. 277–80.
9. Oshima T, Berger MM, De Waele E, et al. Indirect calorimetry in nutritional therapy. A position
paper by the ICALIC study group. Clin Nutr. 2017;36:651–62.
10. Brandi LS, Oleggini M, Lachi S, et al. Energy metabolism of surgical patients in the early
postoperative period: a reappraisal. Crit Care Med. 1988;16:18–22.
11. Kreymann G, Grosser S, Buggisch P, et al. Oxygen consumption and resting metabolic rate in
sepsis, sepsis syndrome, and septic shock. Crit Care Med. 1993;21:1012–9.
12. Avesani CM, Draibe SA, Kamimura MA, et al. Decreased resting energy expenditure in
non-dialysed chronic kidney disease patients. Nephrol Dial Transplant. 2004;19:3091–7.
13. Huggett RJ, Scott EM, Gilbey SG, et al. Impact of type 2 diabetes mellitus on sympathetic
neural mechanisms in hypertension. Circulation. 2003;108:3097– 101.
14. Farooqi N, Carlsson M, Håglin L, et al. Energy expenditure in women and men with COPD.
Clin Nutr ESPEN. 2018;28:171–8.
15. Cuerda C, Ruiz A, Velasco C, et al. How accurate are predictive formulas calculating energy
expenditure in adolescent patients with anorexia nervosa? Clin Nutr. 2007;26:100–6.
16. Çekici H, Acar TN. Determining energy requirement and evaluating energy expenditure in
neurological diseases. Nutr Neurosci. 2020;23:543–53.
17. Faisy C, Gurot E, Diehl JL, et al. Assessment of resting energy expenditure in mechanically
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18. de Koning
MLY, van Zanten ARH. Association of PROtein and CAloric intake and clinical
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Chapter 8
The Energy Intake: How Much, and at
What Time?
Caroline Lauwers, Michael P. Casaer, and Jan Gunst
Introduction
Critically ill patients are usually unable to receive oral feeding. Hence, artificial
nutrition consisting of macronutrients (carbohydrates, lipids, and protein), electrolytes, and micronutrients (vitamins and trace elements) needs to be initiated if one
wants to avoid prolonged starvation. When discussing energy intake in this chapter,
we will focus on non-protein macronutrient intake, since proteins are generally
administered to be used as amino acid sources for the synthesis of muscular and
other proteins, and not to be used as energy substrates. However, randomized
controlled trials (RCTs) have often studied the impact of a combined increase
in energy and protein intake in intensive care unit (ICU) patients. We will review
recent RCT evidence, pathophysiological mechanisms affected by fasting and feeding, as well as future research perspectives.
Nutrition in ICU: Evidence from RCTs
Numerous observational studies have associated a cumulative energy deficit through
prolonged underfeeding with impaired outcomes of critically ill patients [1, 2]. However,
the clinical implications of such observations remained obscure, since these
associations are heavily confounded by illness severity. Indeed, sicker pati ents with
a higher intrinsic risk of mortality also tend to tolerate feeding less. In the last decade,
several large high-quality RCTs have shown that, in contrast to the expectations,
early full feeding did not benefit ICU patients and even induced dose-dependent
C. Lauwers · M. P. Casaer · J. Gunst (✉)
Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and
Molecular Medicine, KU Leuven, Leuven, Belgium
e-mail: caroline.lauwers@kuleuven.be; michael.casaer@uzleuven.be; jan.gunst@kuleuven.be
© 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_8
83
84 C. Lauwers et al.
harm [3, 4]. Indeed, in the adult EPaNIC (N = 4640) and pediatric PEPaNIC
(N = 1440) RCTs, withholding parenteral nutrition until 1 week after ICU admission
decreased dependency on intensive care as compared with early supplementation of
insufficient enteral nutrition with parenteral nutrition [
3–5]. Withholding early
parenteral nutrition, and hence accepting low macronutrient intake in the first
week, reduced the duration of vital organ support and the incidence of new infections
3, 4]. I
[
n critically ill children, the intervention also improved neurodevelopmental
outcomes after 2 and 4 years [6, 7]. Theoretically, harm by early parenteral nutrition
could be related to the increased feeding dose or to the parenteral route being
harmful. In this regard, results from other RCTs suggest that harm is dose-related
[5, 8–10]. Indeed, the Nutrirea-3 RCT (N = 3044) showed that early full feeding
provided through either enteral or parenteral nutrition and targeting 25 kcal/kg/d was
harmful as compared with low-dose feeding in the first week in ICU (6 kcal/kg/d)
5]. As in the EPaNIC and PEPaNIC RCTs, early full feeding in the Nutrirea-3 RCT
[
increased dependency on intensive care, with a prolonged need for mechanical
ventilation, more liver dysfunction, and a trend toward more infections [5]. Also,
the EDEN (N = 1000), PermiT (N = 894), and TARGET (N = 3957) RCTs did not
show benefit of higher-dose enteral nutrition in critically ill patients as compared
with lower doses of enteral nutrition, and some of these RCTs suggested harm on
secondary endpoints [
8–10]. Conversely, the CALORIES (N = 2400) and Nutrirea-
2(N = 2410) RCTs, which compared the enteral versus parenteral feeding route for
1 week, with similar feeding doses provided in both arms, did not show clinical harm
by the parenteral feeding route [11, 12]. In the Nutrirea-2 RCT, early parenteral
nutrition even prevented rare, but potentially life-threatening bowel ischemia in
patients with shock as compared with isocaloric enteral nutrition [
12]. Altogether,
recent RCT evidence suggests that providing early full nutritional support is harmful
to critically ill patients, regardless of the feeding route. In line with this, a higher
nutritional dose through either enteral or parenteral nutrition in the acute phase
was associated with progressively more harm in secondary analyses of the EPaNIC
and PEPaNIC RCTs [13, 14].
Importantly, the
beneficial effects of nutrient restriction in acute critical illness
have been solely studied for macronutrient restriction. Prolonged micronutrient
restriction may lead to deficiencies of essential vitamins, electrolytes, and trace
elements, which may go unnoticed, since most micronutrients are not routinely
measured, and symptoms of deficiencies
are unspecifi
c [15]. Moreover, even if
asymptomatic in a fasted state, low micronutrient stores increase the risk of potentially lethal refeeding syndrome. Indeed, after prolonged starvation, enhanced metabolic needs and elevated insulin concentrations may unmask previously
undiagnosed deficiencies in potassium, phosphate, and thiamine, among others
16].
[
There are no established clinical or laboratory criteria for the resultant refeeding
syndrome. In the absence of such criteria, recent studies have assessed refeeding
complications by the occurrence of refeeding hypophosphatemia, as defined by a
phosphate drop of at least 0.16 mmol/L (0.50 mg/dL) to blood concentrations below
0.65 mmol/L (2.01 mg/dL) within 72 h after the start of artificial nutrition [17–20]. In
patients developing refeeding hypophosphatemia, it seems prudent to temporarily
8 The Energy Intake: How Much, and at What Time? 85
decrease or withhold artificial nutrition while correcting hypophosphatemia and
micronutrient deficiencies, since continuing and progressing macronutrient intake
in such condition was associated with increased mortality in the Refeeding RCT
(N = 339) [
not be predicted by baseline risk factors, including markers of nutritional risk
[18]. Since refeeding hypophosphatemia may identify patients who are harmed by
increased nutritional support, it may be indicated to closely monitor phosphate
concentrations in all patients when artificial nutrition is initiated, and to start
phosphate supplementation when necessary. At current, however, routine phosphate
monitoring is not standard practice in a considerable number of centers [
tantly, in the EPaNIC and PEPaNIC RCTs, phosphate was routinely monitored, and
intravenous micronutrients wer e administered early in both randomization groups to
avoid refeeding syndrome [3, 21].
17]. Interestingly, the occurrence of refeeding hypophosphatemia could
16]. Impor-
Mechanisms Potentially Explaining the Lack of Benefit
of Early Full Feeding in RCTs
Experts have attributed the lack of benefit of early nutritional support to inclusion of
too many patients considered at low nutritional risk, a too high energy-to-protein
dose, and absence of indirect calorimetry to guide the energy target [22–25]. However, as outlined below, these assumptions are not supported by RCT evidence.
Moreover, recent evidence suggests that the lack of benefit by full feeding is rather
explained by anabolic resistance, as well as suppression of recovery-enhancing
processes including autophagy and ketogenesis (Table
8.1)[26].
Inclusion of Too Many Patients Considered at Low Nutritional Risk
Large recent feeding RCTs showing no benefit and even harm by early full nutritional support have been criticized for including too many patients deemed at low
nutritional risk, which may have obscured a potential benefit in hypothesized highrisk patients [23, 24]. However, subgroup analyses from large RCTs do not support
such heterogeneity of treatment, at least not with the studied biomarkers or classifications [3, 4, 10, 27, 28]. Indeed, in the EPaNIC and PEPaNIC RCTs, harm by
early parenteral nutrition was present in all studied subgroups, including patients
with a high nutritional risk score, patients with high or low body-mass index,
patients with sepsis upon admission, critically ill neonates, and patients with a
surgical contraindication to enteral nutrition [
(N = 517), in which the intervention corresponded to early total parenteral nutrition
versus 1 week of relative starvation, the effect size appeared even larger than in the
Moreover, in the latter subgroup
3, 4].