Sharma 2019

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Invited Review
Nutrition in Clinical Practice
Volume 34 Number 1
February 2019 12–22
C© 2018 American Society for
Parenteral and Enteral Nutrition
DOI: 10.1002/ncp.10232
wileyonlinelibrary.com
Pathophysiology of Critical Illness and Role of Nutrition
Kavita Sharma, MBBS, MD, CNSC1; Kris M. Mogensen, MS, RD-AP, LDN,
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 the following are present: temperature >38°C or 90 beats/min, respiratory rate >20 breaths/min
or PCO2 12,000 mm3 oras 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
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14 Nutrition in Clinical Practice 34(1)
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,
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 15
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 totransport 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-
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
increased the risk of readmission included weight loss
(degree of weight loss not defined) and iron-deficiency
anemia. Weight loss correlated with a 26% increase in risk
of readmission.47 Evidence also shows that preexisting
malnutrition influences postdischarge outcomes, including
mortality, readmission rates, and discharge to rehabilitation
facilities rather than to home.12,50,51 Finally, it has been
demonstrated that early recognition of malnourishment and
nutrition intervention in malnourished patients can reduce
complications, length of hospital stay, and readmission
rates, all of which reduce the overall cost of care.9,52
Malnutrition Screening in the Obese and
Nonobese
The high prevalence of malnutrition in hospitalized patients
and its association with poor outcomes and increased costs
suggest that the prevention and treatment of this condition
can have a high impact. The first step in intervening is
recognizing that patients are malnourished or at risk of
becoming malnourished. Toward that end, screening for
nutrition risk in the ICU helps identify high-risk patients
who require aggressive intervention. In the 2016 SCCM-
ASPEN critical care guidelines, the use of either the
Nutrition Risk in Critically Ill (NUTRIC) Score43,53,54 or
the Nutrition Risk Screening 2002 (NRS-2002)55 has been
recommended as an appropriate screening tool for the ICU
setting.56
The NUTRIC Score (Table 2) is designed to quantify the
risk of critically ill patients developing adverse events that
may be modified by aggressive nutrition therapy. The score,
which ranges from 1 to 10, is based on 6 variables defined in
Table 2. The scoring system is shown in Table 3.
Although malnutrition screening tools are important, a
comprehensive nutrition assessment is essential to deter-
mine the patient’s degree of malnutrition. Anthropometric
measurements and calculation of body mass index (BMI)
may provide information about a patient’s nutrition status
and risk of complications. For example, a low BMI has
been correlated with increased mortality in surgical ICU
patients.57 That being said, it is important to recognize that
obese or high-BMI patients can also be malnourished58
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
always recognized, which may result in these patients not
receiving appropriate nutrition therapy.
Obesity and Critical Illness
The metabolic response to stress and critical illness is very
different in obese patients. Contrary to the general belief,
obese patients cannot effectively use their most abundant
Table 2. NUTRIC Score Variables.53,54
Variable Range Points
Age 75 2
APACHE II 28 3
SOFA 10 2
Number of comorbidities 0–1 0
>2 1
Days from hospital to ICU admission 0–1 1
IL-6 0–400 1
APACHE, Acute Physiology and Chronic Health Evaluation; ICU,
intensive care unit; IL, interleukin; NUTRIC, Nutrition Risk in
Critically Ill; SOFA, Sequential Organ Failure Assessment.
Table 2 reproduced with permission from Critical Care Nutrition: The
NUTRIC Score:
https://www.criticalcarenutrition.com/resources/nutric-score
(Accessed: Nov 23, 2018)
Table 3. NUTRIC Scoring System.53,54
Sum of Points Category Explanation
6–10 (5–9 if IL-6 not
availablea)
High score Associated with worse
clinical outcomes
(mortality, ventilation).
These patients are the
most likely to benefit
from aggressive
nutrition therapy.
0–5 (0–4 if IL-6 not
available)
Low score These patients have a low
malnutrition risk.
IL, interleukin; NUTRIC, Nutrition Risk in Critically Ill.
Table 3 reproduced with permission from Critical Care Nutrition: The
NUTRIC Score:
https://www.criticalcarenutrition.com/resources/nutric-score(Accessed: Nov 23, 2018)
aIL-6 data was shown to contribute very little to the overall prediction
of the NUTRIC score, and therefore, it is acceptable to not include it
in the score calculation when it is not routinely available.54
fuel source (ie, fat) and must depend on other fuel sources.19
These individuals mobilize relatively more protein and less
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
relative preservation of fat mass. Furthermore, overweight
patients are prone to insulin resistance.59 This leads to
hyperglycemia with increased risk for infection, which in
turn can cause release of inflammatory mediators that
https://www.criticalcarenutrition.com/resources/nutric-score
https://www.criticalcarenutrition.com/resources/nutric-score
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Sharma et al 17
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 onmortality 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
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
(�25 kcal/kg vs �17 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 Nutrition in Clinical Practice 34(1)
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 (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
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 inmalnourished
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
CompletingEnteralNutrition inAdult Critically Ill Patients
(EPaNIC) trial compared early initiation of PN within
48 hours (European guidelines) with late initiation on day
Sharma et al 19
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 withmalnutrition 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, andM.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.
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