Invited Review

Nutrition in Clinical Practice

Volume 34 Number 1
Pathophysiology of Critical Illness and Role of Nutrition February 2019 12–22

C 2018 American Society for

Parenteral and Enteral Nutrition

DOI: 10.1002/ncp.10232
Kavita Sharma, MBBS, MD, CNSC1 ; Kris M. Mogensen, MS, RD-AP, LDN, wileyonlinelibrary.com
CNSC2 ; and Malcolm K. Robinson, MD1

Abstract
Critical illness is a hypercatabolic state. It has been hypothesized that timely and adequate nutrition support may optimize the
host response and thereby minimize nutritionally related complications while improving overall outcome. Any illness in due
course can lead to a malnourished state—critical illness can worsen this state as patients may become immunocompromised and
unable to mount an adequate inflammatory response and therefore susceptible to poor outcomes. Data indicate that prevalence
of malnutrition in the ICU ranges from 38% to 78% and is independently associated with poor outcomes. Hence, exploring the
role of nutrition as a way to mitigate critical illness is important. In this review, the basic pathophysiology of critical illness and
how it alters carbohydrate, protein, and fat metabolism are discussed. This is followed by a discussion of malnutrition and how it
affects patient and hospital outcomes. Finally, a summary of the available evidence regarding nutrition support and its impact on
outcomes are provided. This review is not intended to provide practice-based guidelines; instead, it intends to highlight available
data on the role of nutrition support in critically ill patients. (Nutr Clin Pract. 2019;34:12–22)

Keywords
critical illness; enteral nutrition; intensive care unit; metabolism; nutrition support; parenteral nutrition

Definition of Critical Illness
Broadly speaking, critical illness is any disease state, medical
or surgical, that requires treatment in the intensive care unit
(ICU). Although critical illness is frequently associated with
infection or sepsis, other conditions such as severe trauma,
the postsurgical state, pancreatitis, burn injury, hemorrhage,
and ischemia can produce the same clinical findings as mi-
crobial invasion, even in the absence of an infectious organ-
ism. Hence, these conditions can also fall under the category
of critical illness. Sepsis, as defined by American College
of Chest Physicians, is a life-threatening organ dysfunction
caused by a dysregulated host response to infection.1 This
definition is also used by the Third International Consensus
Definitions for Sepsis and Septic Shock published in JAMA
in 2016.2 The systemic inflammatory response syndrome
(SIRS) describes the complex pathophysiologic response to
an insult such as infection, trauma, burn, pancreatitis, or a
variety of other injuries as defined by the American Col-
lege of Chest Physicians/Society of Critical Care Medicine
(SCCM)–sponsored sepsis definitions consensus conference
held in 1991.1 A patient is diagnosed with SIRS if 2 or more
of severe tissue injury (eg, pancreatitis). The defining
characteristic of critical illness is the body’s inflammatory
response, which incites the catabolic response to injury and
distinguishes it from the adaptive catabolism characteristic
of simple starvation. This series of events is orchestrated by
a coordinated neuroendocrine and cytokine response that
alters energy expenditure and stimulates dramatic protein
catabolism.3
Initial reaction of the host is at the local site of infection
or injury. The reaction begins with cellular activation of
macrophages, monocytes, and neutrophils at the level of
the vascular endothelium. This is followed by activation
of the complement system, leading to vasodilatation and
increased capillary permeability, which results in sequestra-
tion of interstitial fluids and release of chemoattractants
into the local area. Additional macrophages are recruited
in the area, which enhances the inflammatory response by
phagocytic activity.4 This response is also supported by
From the 1 Department of Surgery, Brigham and Women’s Hospital,
Harvard Medical School, Boston, Massachusetts, USA; and the
2 Department of Nutrition, Brigham and Women’s Hospital, Boston,

of the following are present: temperature >38°C or <36°C, Massachusetts, USA.

heart rate >90 beats/min, respiratory rate >20 breaths/min
or PCO2 <32 mm HG, or a white blood cell count
>12,000 mm3 or <4000 mm3 .2
Pathophysiology of Critical Illness
Catabolic critical illness is a life-threatening condition cre-
ated by overwhelming infection, trauma, or other kinds
Financial disclosure: None declared.
Conflicts of interest: None declared.
This article originally appeared online on December 23, 2018.
Corresponding Author:
Malcolm K. Robinson, MD, Department of Surgery, Brigham and
Women’s Hospital, Harvard Medical School, 75 Francis Street,
Boston, MA 02115, USA.
Email: mkrobinson@bwh.harvard.edu
Sharma et al
Table 1. Metabolic Changes After Major Trauma.6
Ebb Phase Flow Phase
Decreased cardiac output Increased cardiac output
Decreased oxygen consumption Increased oxygen
consumption
Increased catecholamines Increased catecholamines
Increased blood glucose level Normal to low blood
glucose level
Increase in free fatty acid level Lipolysis
Increase in acute phase proteins Protein catabolism
Immune activation Immunosuppression
the release of several cytokines including tumor necrosis
factor (TNF), interleukin (IL)-1, IL-2, IL-6, interferons,
and multiple other proinflammatory cytokines.5 Once a high
concentration is achieved, the cytokines are released into
the systemic circulation and cause the signs and symptoms
characteristic of systemic inflammatory response.
The host biologic response to critical illness was initially
described by Cuthbertson6 and expanded upon in subse-
quent studies by Moore in 1959.7 The response is broadly
categorized into the “ebb phase” and “flow phase” of the
postinjury period (Table 1). These phases broadly define the
initial proinflammatory state.
The early ebb phase occurs immediately after insult,
can last from 24 to 48 hours, and is characterized by
hemodynamic instability with decreased cardiac output and
oxygen consumption, low core body temperature, and ele-
vated glucagon, catecholamines, and free fatty acid (FFA)
levels. The duration of this phase may be variable depending
on the type of insult, initiation of resuscitative measures,
and specific treatments to control the primary pathological
process.6-8
The subsequent, more prolonged flow phase is charac-
terized by an increase in total body oxygen consumption,
metabolic rate, cardiac output, and oxidation of fuel sources
(carbohydrates, amino acids, and fats).6,7 The rise in energy
expenditure correlates with the severity of injury. It is
minimal in mild injury and may be doubled in severe burn
injuries. This phase needs aggressive support in the ICU and
management strategies tailored to the etiology of illness.
The increased metabolic demands in critical illness can
lead to breakdown of lean body mass, which may contribute
to malnutrition.9-13 Appropriate nutrition support therapy
at this stage may be important for improving outcomes.3,14
This systemic “ebb-and-flow” proinflammatory response
to infection and tissue damage is the body’s mechanism
to both fight against infection and provide substrates for
healing.3 However, when this proinflammatory response
is severe and overwhelming, it can be harmful to the
host. Hence, there is an anti-inflammatory response that
counterbalances the proinflammatory response. During this
anti-inflammatory response phase, the anti-inflammatory
13
cytokines (IL-4 and IL-10) may predominate rather than
proinflammatory cytokines (TNF-α, IL-2, and interferon-
γ ).15 When the balance shifts disproportionately toward
an anti-inflammatory state, the weakened immune system
is unable to eradicate pathogens and initiate reparative
processes as the host becomes increasingly immunocom-
promised. Thus, there is a delicate balance between proin-
flammatory and anti-inflammatory phases to facilitate host
recovery and have a favorable outcome.
Importantly, nutrition plays a key role in modulating
the inflammatory responses, maintaining immune func-
tion, slowing skeletal muscle catabolism, promoting tis-
sue repair,16 and maintaining the gastrointestinal and
pulmonary mucosal barrier.17
Pathophysiology in Starvation
In contrast to critical illness, starvation is a hypometabolic
state. During starvation, the body systems adapt to using fat
as the primary energy source. Initially, the body generates
glucose to supply fuel for the nervous system and blood
cells. This is achieved during the first 24 hours of starvation
by mobilizing glycogen stores from the liver and later
glucose produced by hepatic gluconeogenesis from skeletal
muscle amino acids, glycerol, and lactate. Fuel for other
tissues (eg, heart, kidney, muscle) is sustained by mobilizing
fatty acids from adipose tissue.18 This stage of lipolysis
is mainly dependent on a fall in circulating insulin levels,
which appears to be the dominant hormone regulating
homeostasis during starvation. Lipolysis helps preserve the
lean muscle tissue to some extent as the liver converts
FFAs to ketone bodies, which are used by brain tissue for
metabolism, thereby lessening the need for skeletal muscle
amino acids to produce glucose. Central nervous system
adaptation to utilizing ketones (so-called ketoadaptation)
is a very important adaptive response to starvation, as it
spares glucose and muscle protein and helps to preserve
muscle and liver glycogen.18 Other tissues (heart, kidney,
muscle) mainly utilize fatty acids, either directly released
into circulation from adipose tissue or converted to ketone
bodies after partial oxidation in liver. Figure 1 illustrates this
process.
Thus, during prolonged starvation, tissues do not utilize
large quantities of glucose, which helps prevent the de novo
synthesis of glucose (gluconeogenesis) from amino acids
and the need for skeletal muscle breakdown to provide the
amino acid building blocks. Hence, ketoadaptation is an
important mechanism for preserving muscle protein and
thus lean body mass. As a consequence, the debilitation of
the host during starvation is much slower than that ob-
served during critical illness, during which ketoadaptation
is less prominent. During prolonged starvation, the liver
can also produce necessary glucose from other substrates,
primarily lactate, pyruvate, and glycerol. The release of
14
Figure 1. Fasting physiology (adapted with permission from Cahill18 ). CNS, central nervous system; RBC, red blood cell; WBC,
white blood cell.
endogenous catecholamines during fasting is one of the
important factors regulating the mobilization of fatty acids
from adipose tissue. Fasting stimulates the adrenal medulla
and increases the concentration of circulating epinephrine,
which enhances the mobilization of gluconeogenic precur-
sors and FFAs.18,19
These adaptive mechanisms of starvation are in stark
contrast to the fat metabolism during critical illness, during
which there is a relative block in fatty acid utilization, and
both ketogenesis and ketone body oxidation are suppressed.
Hence, tissues depend on carbohydrate and protein as the
primary energy source, leading to more rapid development
of protein-calorie malnutrition during critical illness com-
pared with simple starvation. (See details in fat metabolism
below). The neurohormonal mechanism for this difference
in metabolism between critical illness and starvation is not
clearly understood.
Changes in Macronutrient Metabolism During
Critical Illness
Carbohydrate Metabolism
Hyperglycemia and insulin resistance are common find-
ings in critical illness.20 Proinflammatory cytokines po-
tentiate the release of catabolic hormones (glucagon,
catecholamines, and cortisol). These hormones stimulate
glycogenolysis and gluconeogenesis in the liver to mobilize
glucose for utilization by tissues and cells that require
glucose as their primary energy source.21 This includes the
central nervous system and inflammatory cells. Unfortu-
nately, glycogen stores are depleted within hours, and thus,
endogenous fat and protein become the major source of
oxidative energy substrate.22 Protein can be converted to
glucose via gluconeogenesis. The glycerol moiety of fat (ie,
Nutrition in Clinical Practice 34(1)
triacylglycerol) can be used to form glucose. However, the
triacyl side chains cannot be converted to glucose, because
the human body does not possess the enzymatic machinery
necessary for this conversion. Thus, during critical illness,
there is large-scale protein degradation in the absence of an
exogenous source of glucose. This is necessary to supply fuel
for those tissues that preferentially require glucose for en-
ergy. Hyperglycemia is also caused by increased endogenous
glucose production, decreased glucose uptake, and insulin
resistance.20
Protein Metabolism
Protein is the main source of energy substrate during the
catabolic stress phase of critical illness. The human body
does not have any “reserve protein stores,” as all protein in
the body serves a structural or functional purpose. When
protein is used for fuel or other metabolic processes, it is
derived from the catabolism of “labile” amino acid sources
in skeletal muscle, connective tissue, and the gastrointestinal
tract.23 The protein in skeletal muscle is rapidly metab-
olized in response to increased demands after injury or
acute inflammatory illness. If this phase continues, the net
protein catabolism leads to loss of lean body mass and may
contribute to organ dysfunction and poor outcome.
The degradation of protein for gluconeogenesis results
in increased excretion of nitrogen from the body. One way
to monitor the degree of protein loss is to assess “nitrogen
balance,” which is nitrogen intake in the form of protein
minus the amount of nitrogen excreted. As an approxima-
tion, 6.25 g of protein contains 1 g of nitrogen. During
critical illness, patients are invariably in a net-negative
nitrogen balance, meaning nitrogen excretion exceeds ni-
trogen intake.24 They remain in generalized net-negative
nitrogen balance for variable periods even after the primary
Sharma et al
pathology is resolved.22 This may be several months in some
cases, such as burn patients. The amino acids released by
muscles are directed to the liver, where ureagenesis takes
place and synthesis of creatinine, uric acid, and ammonia
are all increased.25 The increased amino acid efflux from
peripheral sources provides a substrate for enhanced hepatic
gluconeogenesis and positive acute-phase protein synthesis,
including haptoglobin and C-reactive protein.26 There is a
decrease in the production of negative acute-phase proteins
such as serum albumin and prealbumin, which is why these
proteins should not be used as a marker of nutrition status
in critical illness.27 This concept is often known as hepatic
reprioritization.
Supplementing adequate amino acids may play an
important role during this phase. It does not prevent
catabolism completely but can help the host machinery by
increasing protein synthesis to offset some of the exagger-
ated protein catabolism.28 Studies have shown that patients
who receive adequate amino acid support are more likely to
survive, as discussed in more detail below.14
Fat Metabolism
During the early phase of critical illness, carbohydrate is the
preferred energy substrate over fats.29 Conversion of fat to
ATP requires large amounts of oxygen and fully functioning
mitochondria, both of which are impaired during stress or
injury.30 Stress hormones (epinephrine, norepinephrine, and
glucagon) directly stimulate lipase, leading to hydrolysis of
triglycerides stored in adipose tissue, which are then released
as FFAs and glycerol into the bloodstream.31 However,
the ability of the cells to transport long-chain FFAs from
cytosol to mitochondria is impaired. This can lead to
accumulation of FFAs within cells, which can inhibit the
function of pyruvate dehydrogenase, leading to accumu-
lation of pyruvate, lactate, and consequently intracellular
acidosis. This is a major cause of the decrease in aerobic
respiration and the cell’s ability to use the Krebs’s cycle for
energy production.32,33 In the later phases of critical illness,
the oxidation of FFAs can occur in peripheral tissues,
whereas in the liver, they are converted to ketone bodies or
reesterified to triglycerides and released into bloodstream as
very low-density lipoproteins. Overall metabolism of fats is
increased, but complete oxidation can only happen in tissues
where mitochondria are functional.30
Energy Expenditure
Although hypermetabolism is a typical feature in catabolic
critical illness,34 energy expenditure varies at different stages
of illness and with type of illness.35 Studies have shown
that resting energy expenditure (REE) is high during the
first week and remains elevated for up to 3 weeks, even
when sepsis or other cause of critical illness has been
adequately treated.27 Elevated catecholamine levels influ-
15
ence the metabolic rate and substrate catabolism. Several
metabolic pathways are activated, which consume large
amounts of energy, including gluconeogenesis, the Cori
cycle, and lipolysis.35 Apart from stress and infection, other
factors that increase energy expenditure are fever, pain,
respiratory distress, and agitation. After major surgical pro-
cedures, such as thoracoabdominal operations, REE usually
amounts to 120%–140% of reference values.36 With severe
trauma and complicated medical and surgical infection that
require intensive care management, REE can be in the
120%–150% range.37 The most extensive hypermetabolism
is found in patients with major burns (>40% body surface
area), in whom REE may reach 140%–160%.38
Malnutrition and Critical Illness
Malnutrition is defined as an acute, subacute, or chronic
state of nutrition in which varying degrees of overnutrition
or undernutrition, with or without inflammatory state,
have led to a change in body composition and diminished
function.39 A consensus statement by the Academy of Nu-
trition and Dietetics (AND) and the American Society for
Parenteral and Enteral Nutrition (ASPEN) was published
in 2012, which defined malnutrition as the presence of 2
or more of the following characteristics: insufficient energy
intake, weight loss, loss of muscle mass, loss of subcuta-
neous fat, localized or generalized fluid accumulation, or
decreased functional status.40
Approximately one-third of patients hospitalized in de-
veloped countries have some degree of malnutrition at the
time of admission.41 It is estimated that two-thirds of these
patients may experience a further decline without timely
nutrition intervention.9 This can have negative impact on
their recovery and may increase risk of complications and
readmissions.9-13 Also, approximately one-third of patients
admitted to the hospital without malnutrition will become
malnourished during their hospital stay.42 In critically ill
patients, the range of malnutrition is wide, with prevalence
reported from 38% to 78%.43
Malnutrition worsens outcomes, which is why the high
prevalence of malnourished patients is so concerning. For
example, Schneider showed that malnutrition is an inde-
pendent risk factor for nosocomial infections in hospital-
ized patients.44 Approximately 2 million nosocomial infec-
tions, which are now known as hospital-acquired infections
(HAIs), occur annually in the United States.45 HAIs pose
a heavy burden, as these patients are sicker and at higher
risk for ICU admissions and mortality.46 Hence, identifying
and managing malnutrition during hospital admission may
theoretically help prevent HAIs.
Data from several recent studies show that malnutrition
may also influence hospital readmission rates.47-49 The
largest of these studies, a retrospective observational anal-
ysis of >10,000 consecutive admissions, reported a 30-day
16 Nutrition in Clinical Practice 34(1)

readmission rate of 17%.47 Comorbidities that significantly Table 2. NUTRIC Score Variables.53,54
increased the risk of readmission included weight loss
Variable Range Points
(degree of weight loss not defined) and iron-deficiency
anemia. Weight loss correlated with a 26% increase in risk Age <50 0
of readmission.47 Evidence also shows that preexisting 50–<75 1
malnutrition influences postdischarge outcomes, including >75 2
mortality, readmission rates, and discharge to rehabilitation APACHE II <15 0
facilities rather than to home.12,50,51 Finally, it has been 15–<20 1
demonstrated that early recognition of malnourishment and 20–28 2
>28 3
nutrition intervention in malnourished patients can reduce SOFA <6 0
complications, length of hospital stay, and readmission 6–<10 1
rates, all of which reduce the overall cost of care.9,52 >10 2
Number of comorbidities 0–1 0
>2 1
Malnutrition Screening in the Obese and Days from hospital to ICU admission 0–<1 0
Nonobese >1 1
IL-6 0–<400 0
The high prevalence of malnutrition in hospitalized patients >400 1
and its association with poor outcomes and increased costs
suggest that the prevention and treatment of this condition APACHE, Acute Physiology and Chronic Health Evaluation; ICU,
can have a high impact. The first step in intervening is intensive care unit; IL, interleukin; NUTRIC, Nutrition Risk in
Critically Ill; SOFA, Sequential Organ Failure Assessment.
recognizing that patients are malnourished or at risk of Table 2 reproduced with permission from Critical Care Nutrition: The
becoming malnourished. Toward that end, screening for NUTRIC Score:
nutrition risk in the ICU helps identify high-risk patients https://www.criticalcarenutrition.com/resources/nutric-score
who require aggressive intervention. In the 2016 SCCM- (Accessed: Nov 23, 2018)
ASPEN critical care guidelines, the use of either the
Nutrition Risk in Critically Ill (NUTRIC) Score43,53,54 or Table 3. NUTRIC Scoring System.53,54
the Nutrition Risk Screening 2002 (NRS-2002)55 has been Sum of Points Category Explanation
recommended as an appropriate screening tool for the ICU
setting.56 6–10 (5–9 if IL-6 not High score Associated with worse
The NUTRIC Score (Table 2) is designed to quantify the availablea ) clinical outcomes
risk of critically ill patients developing adverse events that (mortality, ventilation).
may be modified by aggressive nutrition therapy. The score, These patients are the
most likely to benefit
which ranges from 1 to 10, is based on 6 variables defined in
from aggressive
Table 2. The scoring system is shown in Table 3. nutrition therapy.
Although malnutrition screening tools are important, a 0–5 (0–4 if IL-6 not Low score These patients have a low
comprehensive nutrition assessment is essential to deter- available) malnutrition risk.
mine the patient’s degree of malnutrition. Anthropometric
IL, interleukin; NUTRIC, Nutrition Risk in Critically Ill.
measurements and calculation of body mass index (BMI)
Table 3 reproduced with permission from Critical Care Nutrition: The
may provide information about a patient’s nutrition status NUTRIC Score:
and risk of complications. For example, a low BMI has https://www.criticalcarenutrition.com/resources/nutric-score
been correlated with increased mortality in surgical ICU (Accessed: Nov 23, 2018)
a IL-6 data was shown to contribute very little to the overall prediction
patients.57 That being said, it is important to recognize that
of the NUTRIC score, and therefore, it is acceptable to not include it
obese or high-BMI patients can also be malnourished58 in the score calculation when it is not routinely available.54
and that a high BMI does not necessarily mean that an
individual is well nourished. Unfortunately, data are still
lacking about malnutrition in obese patients, and it is not fuel source (ie, fat) and must depend on other fuel sources.19
always recognized, which may result in these patients not These individuals mobilize relatively more protein and less
receiving appropriate nutrition therapy. fat compared with nonobese patients because of a relative
block both in lipolysis and fat oxidation. This leads to an
often-unrecognized degradation of lean body mass with
Obesity and Critical Illness
relative preservation of fat mass. Furthermore, overweight
The metabolic response to stress and critical illness is very patients are prone to insulin resistance.59 This leads to
different in obese patients. Contrary to the general belief, hyperglycemia with increased risk for infection, which in
obese patients cannot effectively use their most abundant turn can cause release of inflammatory mediators that
Sharma et al
further worsen insulin resistance.20,60 Thus, it is particularly
important to avoid both overfeeding in these patients, which
can worsen insulin resistance and hyperglycemia, and undue
underfeeding, which can accelerate degradation of lean
body mass.61
Results from various studies elucidate a very diverse
obesity-mortality association: increased mortality,62,63 no
effect,64,65 and decreased mortality.66,67 When malnutrition
was not addressed in patient groups, studies showed a
protective effect of obesity in critically ill medical and
surgical patients. This protective effect of obesity in the
past was known as the “obesity paradox.”68 Robinson et
al hypothesized that nutrition status of obese patient may
have the biggest influence on mortality outcomes.58 This
reiterates what has been shown in earlier studies—that
malnutrition can independently increase mortality in many
chronic diseases and is true for both the obese and nonobese
populations.12,50 An important take-home message is that
BMI should not be used as an indicator of malnutrition
independent of a comprehensive nutrition assessment, as
many obese patients can still be malnourished and suffer the
consequences of such.69
The 2016 SCCM-ASPEN critical care guidelines recom-
mend hypocaloric feeding with higher protein provision.56
The expert panel recommends that for all classes of obesity,
energy provision should not exceed >65%–70% of the
energy requirements as measured by indirect calorimetry
(IC). Mogensen et al conducted a validation study of these
recommendations with IC and with other well-known pre-
dictive equations56 and found that the guidelines performed
much more reliably when refined based on the degree of
obesity.70 However, further studies are required to deter-
mine if permissive hypocaloric feeding with higher protein
is beneficial for obese patient population and if it should be
the standard of care.
The Impact of Nutrition Support
Although the theoretical importance of nutrition support
in the critically ill patient is well established, research
demonstrating the importance of nutrition intervention in
improving outcome is lacking. The little data that do exist
regarding nutrition support therapy in critically ill patients
and clinical outcome are conflicting and often inconclusive.
This is due to several reasons. First, nutrition intervention
studies often have insufficient patient numbers to demon-
strate an effect on mortality or other clinical outcomes. That
is, the studies are not statistically powered (ie, have a large
enough sample size) to demonstrate an effect if one were
to exist. Second, nutrition studies that rely on surrogate
markers such as improvement in serum prealbumin level, ni-
trogen balance, and weight do not necessarily correlate with
or indicate a cause-effect relationship in improvement of
clinical outcome parameters such as infection rates, length
17
of mechanical ventilation, length of hospital or ICU stay, or
mortality. Third, nutrition studies are frequently conducted
in “ICU” patients. However, ICU patient populations tend
to be heterogeneous, and thus, nutrition interventions that
may be demonstrably beneficial in some ICU patients may
be obscured by lack of effect in other ICU patients with
different disease status.
There are other issues that can complicate interpretation
of nutrition studies. Many studies exclude malnourished
patients, as it seems unethical to deprive feeding to these in-
dividuals. However, feeding relatively healthier patients may
show minimal quantifiable benefit in outcomes. Moreover,
nutrition interventions (EN or parenteral nutrition [PN])
are often brief, with patients receiving only 5–10 days of
intervention. This is a very short time to demonstrate a clin-
ical impact on patient outcomes. Finally, a single nutrient
or intervention alone is unlikely to have a major impact
on clinical outcome. These are just some of the facts that
complicate the ability of investigations to accurately discern
the impact of nutrition support therapy on outcomes in the
critically ill. This is not to mention the fact that there is a
synergistic effect of various other modalities in improving
outcomes in critically ill patients in addition to nutrition
therapy, such as timely therapeutic medical interventions,
good nursing care, and supportive physical therapy.71 The
above being said, there are some findings that can inform
nutrition care of the critically ill patients, as discussed below.
Of note, nutrition support therapy is a medical therapy
and, if not properly managed, can have adverse effects. One
must be careful when trying to provide close to estimated
energy and protein needs and keep in mind the risk for
adverse outcome from such interventions. For example, a
study by Braunschweig et al in which aggressive nutrition
intervention was studied in patients with acute lung injury
(ALI) was stopped early because of significantly greater
mortality in the intervention group.72 The authors found
that the major difference between intervention groups was
energy delivery and hypothesized that high energy delivery
(ࣈ25 kcal/kg vs ࣈ17 kcal/kg) was harmful. Energy delivery
from all sources (including intravenous fluids and fat-based
medications such as propofol) should be monitored closely
and the nutrition support regimen adjusted accordingly to
avoid overfeeding energy. In addition, appropriate monitor-
ing is required to assess fluid balance, glucose variations,
insulin requirements, infections, patient tolerance, reflux,
and aspiration episodes.73,74
Protein or Energy Dilemma: Optimization Is
the Key
There appears to be an association between overfeeding
calories and increased mortality, which has been noted in
several studies53,72,75,76 and elaborated on in review articles77
and meta-analysis.78 The precise dividing line between
18
adequate energy provision that improves recovery and ex-
cessive energy delivery that may be harmful is not known.
There may also be situations when underfeeding calories
(eg, in obese individuals) may be beneficial.56,61,70 This
is known as hypocaloric, high-protein feeding, which is
distinct from permissive underfeeding, which is underfeed-
ing of both calories and protein. For example, Dickerson
et al79 demonstrated that hypocaloric (<20 kcal/kg) high-
protein (2 g/kg ideal body weight [IBW]) compared with
eucaloric (ࣙ20 kcal/kg) high-protein feeding (2 g/kg IBW)
enteral nutrition (EN) in critically ill obese patients led to
shorter ICU length of stay, decreased duration of antibiotic
therapy, and a trend toward decreased days of mechanical
ventilation.
IC is the gold standard for energy estimation, since
no single predictive equation accurately estimates energy
expenditure. A metabolic cart is used to assess oxygen
consumption and carbon dioxide production during a spec-
ified time period, which is then used to assess the REE
and daily calorie needs. Unfortunately, metabolic carts
and the personnel trained to use them are not universally
available in various centers and it is also technically difficult
to perform.80 Unlike energy determination, there is no
clinically practical way to measure protein needs in the
critically ill. Protein needs are therefore estimated theo-
retically based on ideal, actual, or adjusted body weight
measurements. It is known that critically ill patients are
often protein deprived,81 but the exact amount of protein
needs is unclear.82
Meta-analysis83 and other reviews84 suggest that high-
calorie, low-protein feeding increases complications in pa-
tients who are not malnourished. This points to the im-
portance of protein supplementation in this group of pa-
tients. Furthermore, data from some observational stud-
ies indicate that adequate protein delivery to critically ill
patients is associated with decreased length of stay and
reduced mortality.14,85 Greater protein delivery can improve
outcomes,86-89 cause fewer infections,90 and decrease ven-
tilator days.91 Thus, an effective strategy for some patient
populations may be hypocaloric feeding while maintaining
ideal protein delivery.
Recent randomized controlled trials (RCTs), including
PERMIT trial92 and EDEN trial,90 that compared permis-
sive underfeeding of calories with target enteral feedings
did not find any statistical difference in mortality. A review
of other RCTs suggested that permissive underfeeding or
trophic EN with slow ramp-up may be more beneficial than
aggressive full feeding in patients with acute respiratory dis-
tress syndrome and ALI.90,93-95 These studies show similar
effects on clinical outcomes and no statistical difference in
mortality rate, length of stay, or duration of mechanical
ventilation. Although we do not have strong data about
improved mortality outcomes, observational studies have
suggested that full enteral feedings are associated with
Nutrition in Clinical Practice 34(1)
improved outcomes in nutritionally high-risk critically ill
patients.53,54,96 This again emphasizes the fact that baseline
nutrition status of patients is a strong predictor for clinical
outcomes in nutrition studies.
Unfortunately, these results cannot be generalized to
all critically ill patients. There are many questions to be
answered, including what is optimal nutrition based on
nutrition risk; how to individualize energy and protein
goals; and what is the appropriate timing, composition,
and advancement of energy and protein delivery during
the early acute phase of critical illness. Many studies have
clearly shown the benefit of high protein delivery during
stress states, and these findings suggest that provision of
hypocaloric, high-protein feeding with slow advancement
may be the optimal strategy in certain patient populations.
Enteral vs Parenteral
Early administration of EN has been shown to reduce
infectious complications and decrease length of ICU stay in
critical care populations when compared with PN.97-101 This
is well documented by various RCTs especially in patients
with trauma,102 burns,103 head injury,104 major surgery,105
and acute pancreatitis.106
That being said, EN may be contraindicated in some
individuals, poorly tolerated in others, and sometimes inad-
equate because of various reasons. Under these conditions,
PN should be considered. There are some misconceptions
about PN-related complications based on data from older
studies94,107-109 in which energy delivery and glucose control
were not optimized. However, more recent studies have not
shown an increase in infectious complications, which can be
attributed to overfeeding avoidance, glucose control, and
appropriate central line insertion and care, all of which were
not common practices during that time period.101,110-113
Another study that compared early EN vs PN within 48
hours in mechanically ventilated medical ICU patients did
not show any difference in ventilator-associated pneumonia,
length of stay, or mortality rates but noted that feeding
goals can more effectively be attained by PN.74 Modern-day
PN management suggests that the benefits of PN outweigh
its risks when EN is not possible for a prolonged period. For
example, Heyland found that the use of PN in malnourished
ICU patients was associated with significantly fewer overall
complications.114 Similarly, optimizing energy needs
by supplementing EN with PN when EN was not well
tolerated showed superior outcomes and fewer nosocomial
infections.115,116
There is a major practice difference in Europe vs the
U.S. and Canada in terms of when PN should be initiated.
To address the controversy, the Early Parenteral Nutrition
Completing Enteral Nutrition in Adult Critically Ill Patients
(EPaNIC) trial compared early initiation of PN within
48 hours (European guidelines) with late initiation on day
Sharma et al
8 (American and Canadian guidelines) in adult patients
receiving inadequate EN.117 They found that the mortality
and survival rates were similar in both groups. However, the
early PN initiation group had a higher infection rate, greater
number of patients who required more days on mechanical
ventilation, and increased cost.118 This suggests that the
early institution of PN may not be beneficial and could be
harmful. The important practice point is that prolonged
starvation should be avoided and that early prophylactic
initiation of PN may be harmful. Timing and indication
of PN initiation should be considered carefully. Presence
of malnutrition and its severity should be considered when
making decisions about the type and timing of nutrition
support.
Conclusion
Critical illness is a hypercatabolic state and, in the ab-
sence of adequate nutrition interventions, can predispose
to malnutrition, leading to poor clinical outcomes. The
risks associated with malnutrition are well recognized. Most
studies agree that effective management of malnutrition
may help with overall recovery. However, it is important to
identify at-risk patients who are already malnourished or
can become malnourished during their critical illness and
initiate early intervention. For low-risk patients, the role
of nutrition intervention is not clear. In addition, there is
a lack of high-quality, well-controlled studies on optimal
energy and protein delivery for cases in which nutrition
intervention is required. Permissive underfeeding of calories
while maintaining full protein delivery may be appropriate
in some clinical cases and perhaps beneficial for many
critically ill patients early in their clinical course. The impact
of malnutrition, timing of initiation of nutrition support
therapy, mode of nutrition support therapy, and appropriate
targets for energy and protein delivery remain major areas
of research in the critically ill population. Understanding
the metabolic alterations in critical illness is an important
part of evaluating this evolving literature as well as essential
to developing and implementing an appropriate nutrition
plan for critically ill patients.
Statement of Authorship
K. Sharma, K. M. Mogensen, and M. K. Robinson equally
contributed to the conception and design of the work;
K. Sharma, K. M. Mogensen, and M. K. Robinson
contributed to the acquisition and analysis of the data; K.
Sharma, K. M. Mogensen, and M. K. Robinson contributed
to the interpretation of the data; and K. Sharma, K. M.
Mogensen, and M. K. Robinson drafted the manuscript.
All authors critically revised the manuscript, agree to be
fully accountable for ensuring the integrity and accuracy of
the work, and read and approved the final manuscript.
19
References
1. Bone RC, Balk RA, Cerra FB et al. Definitions for sepsis and
organ failure and guidelines for the use of innovative therapies in
sepsis. American College of Chest Physicians/Society of Critical Care
Medicine. Chest. 1992;101(6):1644-1655.
2. Singer M, Deutschman CS, Seymour CW, et al. The third consensus
definitions for sepsis and septic shock. JAMA. 2016;315(8):801-810.
3. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis.
N Engl J Med. 2003;348(2):138-150.
4. Cinel I, Opal SM. Molecular biology of inflammation and sepsis: a
primer. Crit Care Med. 2009;37(1):291-304.
5. Matarese G, La Cava A. The intricate interface between immune
system and metabolism. Trends Immunology. 2004;25(4):195-196.
6. Cuthbertson DP. Post-shock metabolic response. Lancet.
1942;239(6189):433-437.
7. Moore FD. Metabolic care of the surgical patient. Philadelphia. WB
Saunders 1959.
8. Balija TM, Lowry SF. Lipopolysaccaride and sepsis-associated my-
ocardial dysfunction. Curr Opin Infect Dis. 2011;24(3):248-253.
9. Barker LA, Gout BS, Crowe TC. Hospital malnutrition: prevalence,
identification and impact on patients and the healthcare system. Int J
Environ Res Public Health. 2011;8(2):514-527.
10. Bistrian BR, Blackburn GL, Hallowell E, Heddle R. Protein status of
general surgical patients. JAMA. 1974;230(6):858-860.
11. Christensen KS, Gstundtner KM. Hospital-wide screening improves
basis for nutrition intervention. J Am Diet Assoc. 1985;85(6):704-
706.
12. Lim SL, Ong KC, Chan YH, Loke WC, Ferguson M, Daniels L.
Malnutrition and its impact on cost of hospitalization, length of stay,
readmission and 3-year mortality. Clin Nutr. 2012;31(3):345-350.
13. Somanchi M, Tao X, Mullin GE. The facilitated early enteral and
dietary management effectiveness trial in hospitalized patients with
malnutrition. JPEN J Parenter Enteral Nutr. 2011;35(2):209-216.
14. Allingstrup MJ, Esmailzadeh N, Wilkens Knudsen A, Espersen K,
Hartvig Jensen T, Wiis J, Perner A, Kondrup J. Provision of protein
and energy in relation to measured requirements in intensive care
patients. Clin Nutr. 2012;31(4):462-468.
15. Zhang JM, An J. Cytokines, inflammation, and pain. Int Anesthesiol
Clin. 2007;45(2):27-37.
16. Demling RH. Nutrition, anabolism, and wound healing process: an
overview. EPlasty. 2009;9:65-94.
17. Martindale RG, Nishikawa R, Siepler JK. The metabolic response
to stress and alterations in nutrient metabolism. In: SA Shikora, RG
Martindale, SD Schwaitzberg (eds.). Nutritional Considerations in the
Intensive Care Unit: Science Rationale and Practice: Dubuque, IA:
Kendall Hunt 2002:11-20.
18. Cahill GF. Starvation in Man. N Engl J Med. 1970;282(12):668-675.
19. Jeevanandam M, Young DH, Schiller WR. Obesity and the metabolic
response to severe multiple trauma. J Clin Invest. 1991;87(1):262-269.
20. McCowen KC, Malhotra A, Bistrian BR. Stress-induced hyper-
glycemia. Crit Care Clin. 2001;17(1):107-124.
21. Simpson IA, Cushman SW. Hormonal regulation of mammalian
glucose transport. Annu Rev Biochem. 1986;55:1059-1089.
22. Plank LD, Hill GL. Sequential metabolic changes following induction
of systemic inflammatory response in patients with severe sepsis or
major blunt trauma. World J Surg. 2000;24(6):630-638.
23. Hoffer LJ. Human protein and amino acid requirements. JPEN J
Parenter Enteral Nutr. 2016;40(4):460-474.
24. Liebau F, Norberg A, Rooyackers O. Does feeding induce maximal
stimulation of protein balance? Curr Opin Clin Nutr Metab Care.
2016;19(2):120-124.
25. Shaw JH, Wildbore M, Wolfe RR. Whole body protein kinetics in
severely septic patients. The response to glucose infusion and total
parenteral nutrition. Ann Surg. 1987;205(3):288-294.
20
26. Gabay C, Kushner I. Acute-phase proteins and other systemic re-
sponses to inflammation. N Engl J Med. 1999;340(6):448-454.
27. Plank LD, Connolly AB, Hill GL. Sequential changes in the metabolic
response in severely septic patients during the first 23 days after the
onset of peritonitis. Ann Surg. 1998;228(2):146-158.
28. Cerra FB. Hypermetabolism, organ failure, and metabolic support.
Surgery. 1987;101(1):1-14.
29. Tappy L, Schwarz JM, Schneiter P, Cayeux C, Revelly JP, Fagerquist
CK, Jequier E, Chiolero R. Effects of isoenergetic glucose-based
or lipid-based parenteral nutrition on glucose metabolism, de novo
lipogenesis, and respiratory gas exchanges in critically ill patients. Crit
Care Med. 1998;26(5):860-867.
30. Preiser JC, Ichai C, Orban JC, Groeneveld ABJ. Metabolic response
to stress of critical illness. Br J Anaesth. 2014;113(6):945-954.
31. Krogh-Madsen R, Plomgaard P, Akerstrom T, Moller K, Schmitz O,
Pedersen BK. Effect of short-term intralipid infusion on the immune
response during low-dose endotoxemia in humans. Am J Physiol
Endocrinol Metab. 2008;294(2):E371-9.
32. Hassemann M, Reimund JM. Lipids in nutritional support of the
critically ill patients. Curr Opin Crit Care. 2004;10(6):449-455.
33. Martinez A, Chiolero R, Bollman M, Revelly JP, Berger M, Cayeux
C, Tappy L. Assessment of adipose tissue metabolism by means
of subcutaneous microdialysis in patients with sepsis or circulatory
failure. Clin Physiol Funct Imaging. 2003;23(5):286-292.
34. Wilmore D, Robinson M. Metabolism and nutritional support. Fisher
J, ed. Surgical Basic Science. St. Louis, MO: Mosby, 1993:125-169.
35. Chiolero R, Revelly J-P, Tappy L. Energy Metabolism in Sepsis and
Injury. Nutrition. 1997;13(9Suppl):45S-51S.
36. Weissman C, Kemper M. Assessing hypermetabolism and hy-
pometabolism in the postoperative critically ill patient. Chest.
1992;102(5):1566-1571.
37. Kreymann G, Grosser S, Buggiseh P, Gottschall C, Matthaei S,
Greten H. Oxygen consumption and resting metabolic rate in sepsis,
sepsis syndrome, and septic shock. Crit Care Med. 1993;21(7):1012-
1019.
38. Cunningham JJ, Hegarty MT, Meara PA, Burke JF. Measured and
predicted calorie requirements of adults during recovery from severe
burn trauma. Am J Clin Nutr. 1989;49(3):404-408.
39. Soeters PB, Schols AM. Advances in understanding and assessing
malnutrition. Curr Opin Clin Nutr Metab Care. 2009;12(5):487-494.
40. White JV, Guenter P, Jensen G, Malone A, Schofield M. Consensus
statement: Academy of Nutrition and Dietetics and American Society
for Parenteral and Enteral Nutrition: characteristics recommended for
the identification and documentation of adult malnutrition (undernu-
trition). JPEN J Parenter Enteral Nutr. 2012;36(3):275-283.
41. Bistrian BR, Blackburn GL, Vitale J, Cochran D, Naylor J.
Prevalence of malnutrition in general medical patients. JAMA.
1976;235(15):1567-1570.
42. Braunschweig C, Gomez S, Sheehan PM. Impact of declines in
nutritional status on outcomes in adult patients hospitalized for more
than 7 days. J Am Diet Assoc. 2000;100(11):1316-1322; quiz: 1323–
1324.
43. Lew CCH, Yandell R, Fraser RJL, Chua AP, Chong MFF, Miller
M. Association between malnutrition and clinical outcomes in the
intensive care unit: a systematic review. JPEN J Parenter Enteral Nutr.
2017;41(5):744-758.
44. Schneider SM, Veyres P, Pivot X, Soummer AM, Jambou P, Filippi
J, van Obberghen E, Hebuterne X. Malnutrition is an indepen-
dent factor associated with nosocomial infections. Brit J Nutrition.
2004;92(1):105-111.
45. Jarvis WR. Selected aspects of the socioeconomic impact of noso-
comial infections: morbidity, mortality, cost, and prevention. Infect
Control Hosp Epidemiol. 1996;17(8):552-557.
Nutrition in Clinical Practice 34(1)
46. Kirkland KB, Briggs JP, Trivette SL, Wilkinson WE, Sexton DJ. The
impact of surgical-site infections in the 1990s: attributable mortality,
excess length of hospitalization, and extra costs. Infect Control Hosp
Epidemiol. 1999;20(11):725–730.
47. Allaudeen N, Vidyarthi A, Maselli J, Auerbach A. Redefining read-
mission risk factors for general medicine patients. J Hosp Med.
2011;6(2):54-60.
48. Kassin MT, Owen RM, Perez SD, Leeds I, Cox JC, Schnier K, Sadiraj
V, Sweeny JF. Risk factors for 30-day hospital readmission among
general surgery patients. J Am Coll Surg. 2012;215(3):322-330.
49. Mudge AM, Kasper K, Clair A, Redfern H, Bell JJ, Barras MA,
Dip G, Pachana NA. Recurrent readmissions in medical patients: a
prospective study. J Hosp Med. 2011;6(2):61-67.
50. Mogensen KM, Horkan CM, Purtle SW, Moromizato T, Rawn
JD, Robinson MK, Christopher KB. Malnutrition, critical illness
survivors, and post-discharge outcomes: a cohort study. JPEN J
Parenter Enteral Nutr. 2018;42(3):557-565.
51. Yeh DD, Fuentes E, Quraishi SA, et al. Adequate nutrition may
get you home: effect of caloric/protein deficits on the discharge
destination of critically ill surgical patients. JPEN J Parenter Enteral
Nutr. 2016;40(1):37-44.
52. Tappenden KA; Quatrara B, Parkhurst ML, Malone AM, Fanjiang
G, Ziegler TR. Critical role of nutrition in improving quality of
care: an interdisciplinary call to action to address adult hospi-
tal malnutrition. JPEN J Parenter Enteral Nutr. 2013;37(4):482-
497.
53. Heyland DK, Dhaliwal R, Jiang X, Day AG. Identifying critically ill
patients who benefit the most from nutrition therapy: the development
and initial validation of a novel risk assessment tool. Crit Care.
2011;15(6):R268
54. Rahman A, Hasan RM, Agarwala R, Martin C, Day AG, Heyland
DK. Identifying critically-ill patients who will benefit most from
nutritional therapy: further validation of the “modified NUTRIC”
nutritional risk assessment tool. Clin Nutr. 2016;35(1):158-162.
55. Kondrup J, Allison SP, Elia M, Vellas B, Plauth M; Educational
and Clinical Practice Committee, European Society of Parenteral
and Enteral Nutrition (ESPEN). ESPEN Guidelines for Nutrition
Screening 2002. Clin Nutr. 2003;22(4):415-421.
56. McClave SA, Taylor BE, Martindale RG, et al. Guidelines for the
provision and assessment of nutrition support therapy in the adult
critically ill patient. Society of Critical Care Medicine (SCCM) and
American Society of Parenteral and Enteral Nutrition (A.S.P.E.N.).
JPEN J Parenter Enteral Nutr. 2016;40(8):159-211.
57. Gupta R, Knobel D, Gunabushanam V, Agaba E, Ritter G, Marini C,
Barrera R. The effect of low body mass index on outcome in critically
ill surgical patients. Nutr Clin Pract. 2011;26(5):593-597.
58. Robinson MK, Mogensen KM, Casey JD, McKane CK, Moromizato
T, Rawn JD, Christopher KB. The relationship among obesity,
nutritional status, and mortality in the critically ill. Crit Care Med.
2015;43(1):87-98.
59. Reaven GM. Insulin resistance: the link between obesity and cardio-
vascular disease. Med Clin North Am. 2011;95(5):875-892.
60. Saberi F, Heyland D, Lam M, Rapson D, Jeejeebhoy K. Prevalence,
incidence, and clinical resolution of insulin resistance in critically
ill patients: an observational study. JPEN J Parenter Enteral Nutr.
2008;32(3):227-235.
61. Choban PS, Burge JC, Scales D, Flancbaum L. Hypoenergetic
nutrition support in hospitalized obese patients: a simplified method
for clinical application. Am J Clin Nutr. 1997;66(3):546-50.
62. Bercault N, Boulain T, Kuteifan K, Wolf M, Runge I, Fleury JC.
Obesity-related excess mortality rate in an adult intensive care unit:
a risk-adjusted matched cohort study. Crit Care Med. 2004;32(4):998-
1003.
Sharma et al
63. Bochicchio GV, Joshi M, Bochicchio K, Nehman S, Tracy SK,
Scalea TM. Impact of obesity in the critically ill trauma patient: A
prospective study. J Am Coll Surg. 2006;203(4):533-538.
64. Alban RF, Lyass S, Marguiles DR, Shabot MM. Obesity does not
affect mortality after trauma. Am Surg. 2006;72(10):966-969.
65. Tremblay A, Bandi V. Impact of body mass index on outcomes
following critical care. Chest. 2003;123(4):1202-1207.
66. Peake SL, Moran JL, Ghelani DR, Lloyd AJ, Walker MJ. The effect
of obesity on 12 month survival following admission to intensive care:
A prospective study. Crit Care Med. 2006;34(12):2929-2939.
67. Marik P, Doyle H, Varon J. Is obesity protective during critical
illness? An analysis of a national ICU database. Crit Care Shock.
2003;6(3):156-162.
68. Fonarow GC, Srikanthan P, Costanzo MR, Cintron GB, Lopatin
M; ADHERE Scientific Advisory Committee and Investigators. An
obesity paradox in acute heart failure: analysis of body mass index and
inhospital mortality for 108,927 patients in the Acute Decompensated
Heart Failure National Registry. Am Heart J. 2007;153(1):74-81.
69. Jensen GL, and Hsiao PY. Obesity in older adults: Relation-
ship to functional limitation. Curr Opin Clinc Nutr Metab Care.
2010;13(1):46-51.
70. Mogensen KM, Andrew BY, Corona JC, Robinson MK. Validation
of the Society of Critical Care Medicine and American Society
for Parenteral and Enteral Nutrition Recommendations for Caloric
Provision to Critically Ill Obese Patients: A Pilot Study. JPEN J
Parenter Enteral Nutr. 2016;40(5):713-21.
71. Heyland DK, Rooyakers O, Mourtzakis M, Stapleton RD. Proceed-
ings of the 2016 Clinical Nutrition Week Research Workshop: the
optimal dose of protein provided to critically ill patients. JPEN J
Parenter Enteral Nutr. 2017;41(2):208-216.
72. Braunschweig CA, Sheean PM, Peterson SJ, Gomez Perez S, Freels
S, Lateef O, Gurka D, Fantuzzi G. Intensive nutrition in acute
lung injury: a clinical trial (INTACT). JPEN J Parent Enteral Nutr.
2015;39(1):13-20.
73. Peter JV, Morgan JL, Phillips-Hughes J. A meta-analysis of treatment
outcomes of early enteral vs early parenteral nutrition in hospitalized
patients. Crit Care Med. 2005;33:213-220.
74. Altintas ND, Aydin K, Turkoglu MA, Abbasoglu O, Topeli A. Effect
of enteral versus parenteral nutrition on outcome of medical patients
requiring mechanical ventilation. Nutr Clin Pract. 2011;26(3):322-329.
75. Krishnan JA, Parce PB, Martinez A, Diette GB, Brower RG. Caloric
intake in medical ICU patients: consistency of care with guidelines
and relationship to clinical outcomes. Chest 2003;124(1):297-305.
76. Crosara IC, Melot C, Preiser JC. J-shaped relationship between
caloric intake and survival in critically ill patients. Ann Intensive Care.
2015;5(1):37.
77. Rice TW. Gluttony in the intensive care unit: time to push back from
the consensus table. Am J Respir Crit Care Med. 2013;187(3):223-224.
78. Arabi YM, Haddad SH, Tamim HM, Rishu AH, Sakkijha MH,
Kahoul SH, Britts RJ. Near-target caloric intake in critically ill
medical-surgical patients is associated with adverse outcomes. JPEN
J Parenter Enteral Nutr. 2010;34(3):280-288.
79. Dickerson RN, Boschert KJ, Kudsk KA, Brown RO. Hypocaloric
enteral tube feeding in critically ill obese patients. Nutrition.
2002;18(3):241-246.
80. Frankenfield DC, Ashcraft CM. Estimating energy needs in nutrition
support patients. JPEN J Parenter Enteral Nutr. 2011;35(5):563-570.
81. Hoffer LJ, Bistrian BR. Why critically ill patients are protein deprived.
JPEN J Parenter Enteral Nutr. 2013;37(3):300-309.
82. Hoffer LJ, Bistrian BR. Appropriate protein provision in criti-
cal illness: a systematic and narrative review. Am J Clin Nutr.
2012;96(3):591-600.
83. Tian F, Wang X, Gao X, Wan X, Wu C, Zhang L, Li N, Li J. Effect
of initial calorie intake via enteral nutrition in critical illness: a meta-
analysis of randomised controlled trials. Crit Care. 2015;19:180.
21
84. Hoffer LJ, Bistrian BR. Nutrition in critical illness: a current conun-
drum. F1000Research. 2016(5):2531-2533.
85. Nicolo M, Heyland DK, Chittams J, Sammarco T, Compher C. Clin-
ical outcomes related to protein delivery in a critically ill population: a
multicenter, multinational observation study. JPEN J Parenter Enteral
Nutr. 2016;40(1):45-51.
86. Fetterplace K, Deane AM, Tierney A et al. Targeted full energy and
protein delivery in critically ill patients: a pilot randomized controlled
trial (FEED Trial). JPEN J Parenter Enteral Nutr. 2018;42(8):1252-
1262.
87. Weijs PJ, Looijaard WG, Beishuizen A, Girbes AR, Oudemans-van
Straten HM. Early high protein intake is associated with low mortality
and energy overfeeding with high mortality in non-septic mechanically
ventilated critically ill patients. Crit Care. 2014;18(6):701.
88. Zusman O, Theilla M, Cohen J, Kagan I, Bendavid I, Singer P.
Resting energy expenditure, calorie and protein consumption in crit-
ically ill patients: a retrospective cohort study. Crit Care. 2016;20(1):
367.
89. Rugeles S, Villarraga-Angulo LG, Ariza-Gutierrez A, Chaverra-
Kornerup S, Lasalvia P, Rosselli D. High-protein hypocaloric vs
normocaloric enteral nutrition in critically ill patients: a randomized
clinical trial. J Crit Care. 2016;35:110-114.
90. National Heart, Lung, and Blood Institute Acute Respiratory Dis-
tress Syndrome (ARDS) Clinical Trials Network, Rice TW, Wheeler
AP, Thompson BT, et al. Initial trophic vs full enteral feeding in
patients with acute lung injury: the EDEN randomized trial. JAMA.
2012;307(8):795-803.
91. Heyland DK, Stephens KE, Day AG, McClave SA. The success of
enteral nutrition and ICU-acquired infections: a multicenter observa-
tional study. Clin Nutr. 2011;30(2):148-155.
92. Arabi YM, Tamim HM, Dhar GS, et al. Permissive underfeeding
and intensive insulin therapy in critically ill patients: a randomized
controlled trial. Am J Clin Nutr. 2011;93(3):569-577.
93. Rice TW, Mogan S, Hays MA, Bernard GR, Jensen GL, Wheeler AP.
Randomized trial of initial trophic versus full-energy enteral nutrition
in mechanically ventilated patients with acute respiratory failure. Crit
Care Med. 2011;39(5):967-974.
94. Patel JJ, Martindale RG, and McClave SA. Controversies surrounding
critical care nutrition: an appraisal of permissive underfeeding, pro-
tein, and outcomes. JPEN J Parent Enteral Nutr. 2018;42(3):508-515.
95. Casaer MP, van den Berghe G. Nutrition in the acute phase of critical
illness. N Engl J Med. 2014;370(13):1227-1236.
96. Lee ZY, Noor Airini I, Barakatun-Nisak MY. Relationship of
energy and protein adequacy with 60-day mortality in mechanically
ventilated critically ill patients: a prospective observational study. Clin
Nutr. 2018;37(4):1264-1270.
97. Gramlich L, Kichian K, Pinilla J, Rodych NJ, Dhaliwal R, Heyland
DK. Does enteral nutrition compared to parenteral nutrition result in
better outcomes in critically ill adult patients? A systematic review of
the literature. Nutrition. 2004;20(10):843-848.
98. Marik PE, Zaloga GP. Early enteral nutrition in acutely ill patients a
systemic review. Crit Care Med. 2001;29(12):2264-2270.
99. Heyland DK, Dhaliwal R. Early enteral nutrition vs. early parenteral
nutrition: an irrelevant question for the critically ill? Crit Care Med.
2005;33(1):260-261.
100. Elke G, Wang M, Weiler N, Day AG, Heyland DK. Close to
recommended caloric and protein intake by enteral nutrition is
associated with better clinical outcome of critically ill septic patients:
secondary analysis of a large international nutrition database. Crit
Care. 2014;18(1):R29.
101. Heyland DK, Dhaliwal R, Drover JW, Gramlich L, Dodek P; Cana-
dian Critical Care Clinical Practice Guidelines Committee. Canadian
clinical practice guidelines for nutrition support in mechanically
ventilated, critically ill adult patients. JPEN J Parenter Enteral Nutr.
2003;27(5):355-373.
22
102. Kudsk KA, Minard G, Croce MA, Brown RO, Lowrey TS, Pritchard
FE, Dickerson RN, Fabian TC. A randomized trial of isonitrogenous
enteral diets after severe trauma. An immune-enhancing diet reduces
septic complications. Ann Surg. 1996;224(4):531-540.
103. Jenkins ME, Gottschlich MM, Warden GD. Enteral feeding dur-
ing operative procedures in thermal injuries. J Burn Care Rehabil.
1994;15(2):199-205.
104. Chourdakis M, Kraus MM, Tzellos T, Sardeli C, Peftoulidou M,
Vassilakos D, Kouvelas D. Effect of early compared with delayed
enteral nutrition on endocrine function in patients with traumatic
brain injury: an open-labeled randomized trial. JPEN J Parenter
Enteral Nutr. 2012;36(1):108-116.
105. Adams S, Dellinger EP, Wertz MJ, Oreskovich MR, Simonowitz D,
Johansen K. Enteral versus parenteral nutrition support following
laparotomy for trauma: a randomized prospective trial. J Trauma.
1986;26(10):882-891.
106. Windsor AC, Kanwar S, Li AG et al. Compared with parenteral
nutrition, enteral feeding attenuates the acute phase response and
improves disease severity in acute pancreatitis. Gut. 1998;42(3):431-
435.
107. Jeejeebhoy KN. Parenteral nutrition in the intensive care unit. Nutr
Rev. 2012;70(11):623-630.
108. Elke G, van Zanten AR, Lemieux M, et al. Enteral versus par-
enteral nutrition in critically ill patients: an updated systematic
review and meta-analysis of randomized controlled trials. Crit Care.
2016;20(1):117.
109. Braunschweig CL, Levy P, Sheean PM, Wang X. Enteral com-
pared with parenteral nutrition: a meta-analysis. Am J Clin Nutr.
2001;74(4):534-542.
Nutrition in Clinical Practice 34(1)
110. Worthington P, Balint J, Bechtold M, et al. When is parenteral
nutrition appropriate? JPEN J Parenter Enteral Nutr. 2017;41(3):324-
377.
111. Koretz RL, Lipman TO, Klein S; American Gastroenterological
Association. AGA technical review on parenteral nutrition. Gastroen-
terology. 2001;121(4):970-1001.
112. Cahill NE, Murch L, Jeejeebhoy K, McClave SA, Day AG, Wang M,
Heylan DK. When early enteral feeding is not possible in critically ill
patients: results of a multicenter observational study. JPEN J Parenter
Enteral Nutr. 2011;35(2):160-168.
113. Harvey SE, Parrott F, Harrison DA, et al. CALORIES Trial Inves-
tigators. Trial of the route of early nutritional support in critically ill
adults. N Engl J Med. 2014;371(18):1673-1684.
114. Heyland DK, MacDonald S, Keefe L, Drover JW. Total par-
enteral nutrition in the critically ill patient: a meta-analysis. JAMA.
1998;280(23):2013-2019.
115. Heidegger CP, Berger MM, Graf S, et al. Optimisation of energy pro-
vision with supplemental parenteral nutrition in critically ill patients:
a randomised controlled clinical trial. Lancet. 2013;381(9864):385-
393.
116. Heidegger CP, Berger MM, Thibault R, Zingg W, and Pichard C.
Supplemental parenteral nutrition in critically ill patients-author’s
reply. Lancet. 2013;381(9878):1716-1717.
117. Casaer MP, Mesotten D, Hermans G, et al. Early versus late par-
enteral nutrition in critically ill adults. N Engl J Med. 2011;365(6):506-
517.
118. Vanderheyden S, Casaer MP, Kesteloot K, et al. Early versus late
parenteral nutrition in ICU patients: cost analysis of the EPaNIC
trial. Crit Care. 2012;16(3):R96.